REVIEW   Open Access    

The versatility of Penicillium species to degrade organic pollutants and its use for wastewater treatment

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  • The removal of xenobiotics from industrial wastewater is of great interest to avoid environmental contamination. Penicillium species have been shown to be able to adapt its metabolism to many different circumstances and these fungi can use different xenobiotics as a carbon source. In this review, the ability of Penicillium to degrade different xenobiotic compounds is discussed. This review describes not only the biodegradation processes but also addresses the toxicity of the degradation products as well as the potential application of these processes in wastewater treatment. Penicillium strains have proven to be versatile and capable of being used for the biodegradation of different organic pollutants (phenols, azo dyes, hydrocarbons, pharmaceutical compounds, etc.) and show high potential to be used for wastewater treatment. From this review, it is concluded that beyond the degradation and optimization processes; pilot scale studies and toxicity must be carried out.
  • Atractylodes macrocephala Koidz. (common names 'Baizhu' in Chinese and 'Byakujutsu' in Japanese) is a diploid (2n = 2x = 24) and out-crossing perennial herb in the Compositae family, and has a long history of cultivation in temperate and subtropical areas of East Asia as it is widely used in traditional herbal remedies with multiple pharmacological activities[13]. The 'Pharmacopoeia of the People's Republic of China' states that 'Baizhu' is the dry rhizome of A. macrocephala Koidz. (Atractylodis Macrocephalae Rhizoma, AMR). However, in Japanese traditional medicine 'Baizhu' can be referred to both: A. japonica or A. macrocephala[4].

    A. macrocephala is naturally endemic to China and cultivated in more than 200 towns in China, belonging to Zhejiang, Hunan, Jiangxi, Anhui, Fujian, Sichuan, Hubei, Hebei, Henan, Jiangsu, Guizhou, Shanxi, and Shaanxi Provinces[3]. A. macrocephala grows to a height of 20–60 cm (Fig. 1). The leaves are green, papery, hairless, and generally foliole with 3–5 laminae with cylindric glabrous stems and branches. The flowers grow and aggregate into a capitulum at the apex of the stem. The corollas are purplish-red, and the florets are 1.7 cm long. The achenes, densely covered with white, straight hairs, are obconic and measure 7.5 mm long. The rhizomes used for medicinal purposes are irregular masses or irregularly curving cylinders about 3–13 cm long and 1.5–7 cm in diameter with an outwardly pale greyish yellow to pale yellowish color or a sparse greyish brown color. The periderm-covered rhizomes are externally greyish brown, often with nodose protuberances and coarse wrinkles. The cross-sections are white with fine dots of light yellowish-brown to brown secretion. Rhizomes are collected from plants that are > 2 years old during the spring. The fibrils are removed, dried, and used for medicinal purposes[5, 6].

    Figure 1.  Plant morphology of A. macrocephala.

    The medicinal properties of AMRs are used for spleen deficiency, phlegm drinking, dizziness, palpitation, edema, spontaneous sweating, benefit Qi, and fetal restlessness[7]. The AMR contains various functional components, among which high polysaccharide content, with a yield close to 30%[8]. Therefore, the polysaccharides of A. macrocephala Koidz. rhizome (AMRP) are essential in assessing the quality control and bioactivity of A. macrocephala. Volatile oil accounts for about 1.4% of AMR, with atractylon and atractylodin as the main components[9]. Atractylon can be converted to atractylenolide I (AT-I), atractylenolide II (AT-II), and atractylenolide III (AT-III) under ambient conditions. AT-III can be dehydrated to AT-II under heating conditions[10, 11]. AMRs, including esters, sesqui-, and triterpenes, have a wide range of biological activities, such as improving immune activity, intestinal digestion, neuroprotective activity, immune anti-inflammatory, and anti-tumor.

    In recent years, research on the pharmacological aspects of AMR has continued to increase. Still, the discovery of the main active components in AMR is in its infancy. The PAO-ZHI processing of AMR is a critical step for AMR to exert its functional effects, but also, in this case, further work is required. Studies on the biosynthesis of bioactive compounds and different types of transcriptomes advanced current knowledge of A. macrocephala, but, as mentioned, required more systematic work. Ulteriorly, an outlook on the future research directions of A. macrocephala was provided based on the advanced technologies currently applied in A. macrocephala (Fig. 2).

    Figure 2.  Current progress of A. macrocephala.

    A. macrocephala is distributed among mountainous regions more than 800 m above sea level along the middle and lower reaches of the Yangtze River (China)[5]. Due to over-exploitation and habitat destruction, natural populations are rare, threatened, and extinct in many locations[1,12]. In contrast to its native range, A. macrocephala is widely cultivated throughout China, in a total area of 2,000–2,500 ha, with a yield of 7,000 t of rhizomes annually[13]. A. macrocephala is mainly produced in Zhejiang, Anhui, and Hebei (China)[14]. Since ancient times, Zhejiang has been the famous producing area and was later introduced to Jiangxi, Hunan, Hebei, and other places[15]. Wild A. macrocephala is currently present in at least 14 provinces in China. It is mainly distributed over three mountain ranges, including the Tianmu and Dapan mountains in Zhejiang Province and the Mufu mountains along the border of Hunan and Jiangxi Provinces. A. macrocephala grows in a forest, or grassy areas on mountain or hill slopes and valleys at an altitude of 600–2,800 m. A. macrocephala grows rapidly at a temperature of 22–28 °C, and favors conditions with total precipitation of 300–400 mm evenly distributed among the growing season[16]. Chen et al. first used alternating trilinear decomposition (ATLD) to characterize the three-dimensional fluorescence spectrum of A. macrocephala[17]. Then they combined the three-dimensional fluorescence spectrum with partial least squares discriminant analysis (PLS-DA) and k-nearest neighbor method (kNN) to trace the origin of Atractylodes samples. The results showed that the classification models established by PLS-DA and kNN could effectively distinguish the samples from three major Atractylodes producing areas (Anhui, Hunan, and Zhejiang), and the classification accuracy rate (CCR) of Zhejiang atractylodes was up to 80%, and 90%, respectively[17]. Zhang et al. compared the characteristics, volatile oil content, and chemical components of attested materials from six producing areas of Zhejiang, Anhui, Hubei, Hunan, Hebei, and Henan. Differences in the shape, size, and surface characteristics were reported, with the content of volatile oil ranging from 0.58% to 1.22%, from high to low, Hunan (1.22%) > Zhejiang (1.20%) > Anhui (1.02%) > Hubei (0.94%) > Henan (0.86%) > Hebei (0.58%)[18]. This study showed that the volatile oil content of A. macrocephala in Hunan, Anhui, and Hubei is not much different from that of Zhejiang, which is around 1%. A. macrocephala is a local herb in Zhejiang, with standardized cultivation techniques, with production used to reach 80%–90% of the country. However, in recent years, the rapid development of Zhejiang's real estate economy has reduced the area planted with Zhejiang A. macrocephala, resulting in a sudden decrease in production. Therefore, neighboring regions, such as Anhui and Hunan, vigorously cultivate A. macrocephala, and the yield and quality of A. macrocephala can be comparable to those of Zhejiang. The results were consistent with the data reports[18]. Guo et al. analyzed the differentially expressed genes of Atractylodes transcripts from different regions by the Illumina HiSeq sequencing platform. It was found that 2,333, 1,846, and 1,239 DEGs were screened from Hubei and Hebei, Anhui and Hubei, and Anhui and Hebei Atrexia, respectively, among which 1,424, 1,091, and 731 DEGs were annotated in the GO database. There were 432, 321, and 208 DEGs annotated in the KEGG database. These DEGs were mainly related to metabolic processes and metabolic pathways of secondary metabolites. The highest expression levels of these genes were found in Hubei, indicating higher terpenoid production in Hubei[19]. Other compounds were differentially accumulated in Atractylodes. Chlorogenic acid from Hebei was 0.22%, significantly higher than that from Zhejiang and Anhui[20]. Moreover, the content of neochlorogenic acid and chlorogenic acid decreased after processing, with the highest effect reported in Zhejiang, with the average transfer rate of neochlorogenic acid and chlorogenic acid reaching 55.68% and 55.05%[20]. All these changes would bring great help in distinguishing the origins of A. macrocephala.

    Medicinal AMR can be divided into raw AMR and cooked AMR. The processing method is PAO-ZHI; the most traditional method is wheat bran frying. The literature compared two different treatment methods, crude A. macrocephala (CA) and bran-processed A. macrocephala, and found that the pharmacological effects of AMR changed after frying with wheat bran, mainly in the anti-tumor, antiviral and anti-inflammatory effects[21]. The anti-inflammatory effect was enhanced, while the anti-tumor and antiviral effects were somewhat weakened, which may be related to the composition changes of the compounds after frying. The study of the content of AT-I, II, and III, and atractyloside A, in rat serum provided helpful information on the mechanism of wheat bran processing[22]. In addition to frying wheat bran, Sun et al. used sulfur fumigation to treat AMR[23]. They found that the concentration of different compounds changed, producing up to 15 kinds of terpenoids. Changes in pharmacological effects were related to treatment and the type of illumination[24,25]. Also, artificial light can improve the various biological functions. A. macrocephala grew better under microwave electrodeless light, with a chlorophyll content of 57.07 ± 0.65 soil and plant analyzer develotrnent (SPAD)[24]. The antioxidant activity of AMR extract treated with light-emitting diode (LED)-red light was the highest (95.3 ± 1.1%) compared with other treatments[24]. The total phenol and flavonoid contents of AMR extract treated with LED-green light were the highest at 24.93 ± 0.3 mg gallic acid equivalents (GAE)/g and 11.2 ± 0.3 mg quercetin equivalents (QE)/g compared with other treatments[24, 25]. Polysaccharides from Chrysanthemun indicum L.[26] and Sclerotium rolfsiisacc[27] can improve AMR's biomass and bioactive substances by stimulating plant defense and thus affect their efficacy. In summary, there are compositional differences between A. macrocephala from different origins. Besides, different treatments, including processing mode, light irradiation, and immune induction factors, which can affect AMR's biological activity, provide some reference for the cultivation and processing of A. macrocephala (Fig. 3).

    Figure 3.  Origin, distribution and processing of A. macrocephala.

    The AMR has been reported to be rich in polysaccharides, sesquiterpenoids (atractylenolides), volatile compounds, and polyacetylenes[3]. These compounds have contributed to various biological activities in AMR, including immunomodulatory effects, improving gastrointestinal function, anti-tumor activity, neuroprotective activity, and anti-inflammatory.

    AMRP has received increasing attention as the main active component in AMR because of its rich and diverse biological activities. In the last five years, nine AMRP have been isolated from AMR. RAMP2 had been isolated from AMR, with a molecular weight of 4.354 × 103 Da. It was composed of mannose, galacturonic acid, glucose, galactose, and arabinose, with the main linkages of →3-β-glcp-(1→, →3,6-β-glcp-(1→, →6-β-glcp-(1→, T-β-glcp-(1→, →4-α-galpA-(1→, →4-α-galpA-6-OMe-(1→, →5-α-araf-(1→, →4,6-β-manp-(1→ and →4-β-galp-(1→[28]. Three water-soluble polysaccharides AMAP-1, AMAP-2, and AMAP-3 were isolated with a molecular weight of 13.8 × 104 Da, 16.2 × 104 Da, and 8.5 × 104 Da, respectively. Three polysaccharides were deduced to be natural pectin-type polysaccharides, where the homogalacturonan (HG) region consists of α-(1→4)-linked GalpA residues and the ramified region consists of alternating α-(1→4)-linked GalpA residues and α-(1→2)-linked Rhap residues. Besides, three polysaccharides were composed of different ratios of HG and rhamnogalacturonan type I (RG-I) regions[29]. Furthermore, RAMPtp has been extracted from AMR with a molecular weight of 1.867 × 103 Da. It consists of glucose, mannose, rhamnose, arabinose, and galactose with 60.67%, 14.99%, 10.61%, 8.83%, and 4.90%, connected by 1,3-linked β-D Galp and 1,6-linked β-D Galp residues[30]. Additionally, PAMK was characterized by a molecular weight of 4.1 kDa, consisting of galactose, arabinose, and glucose in a molar ratio of 1:1.5:5, with an alpha structure and containing 96.47% polysaccharide and small amounts of protein, nucleic acid, and uric acid[31]. Another PAMK extracted from AMR had a molecular weight of 2.816 × 103 Da and consisted of glucose and mannose in molar ratios of 0.582 to 0.418[32]. Guo et al. isolated PAMK with a molecular weight of 4.748 × 103 g/mol from AMR, consisting of glucose, galactose, arabinose, fructose, and mannose in proportions of 67.01%, 12.32%, 9.89%, 1.18%, and 0.91%, respectively[33]. In addition, AMP1-1 is a neutral polysaccharide fragment with a molecular weight of 1.433 kDa isolated from AMR. It consists of glucose and fructose, and the structure was identified as inulin-type fructose α-D-Glcp-1→(2-β-D-Fruf-1)7[34]. These reports indicated that, in general, polysaccharides are extracted by water decoction, ultrasonic-assisted extraction, enzyme hydrolysis method, and microwave-assisted extraction. The separation and purification are column chromatography, stepwise ethanol precipitation, and ultrafiltration. Their physicochemical properties and structural characterization are generally achieved by determining the molecular weight, determining the monosaccharide composition, analyzing the secondary structure, and glycosidic bond configuration of polysaccharides with Fourier transform infrared (FT-IR) and nuclear magnetic resonance (NMR). The advanced structures of polysaccharides can be identified by high-performance size exclusion chromatography-multiangle laser light scattering (HPSEC-MALLS), transmission electron microscopy (TEM), and scanning electron microscopy (SEM) techniques (Table 1). AMRP has various physiological functions, including immunomodulatory effects, improving gastrointestinal function, and anti-tumor activity. The related biological activities, animal models, monitoring indicators, and results are summarized in Table 1.

    Table 1.  Components and bioactivity of polysaccharides from Atractylodes macrocephala Koidz. Rhizome.
    Pharmacological activitiesDetailed functionPolysaccharides informationModelDoseTest indexResultsRef.
    Immunomodulatory effectsRestore immune
    function
    /Chicken models
    (HS-induced)
    200 mg/kgOxidative index;
    Activities of mitochondrial complexes and ATPases;
    Ultrastructure in chicken spleens;
    Expression levels of cytokines, Mitochondrial dynamics- and apoptosis-related genes
    Alleviated
    the expression of
    IL-1 ↑,TNF-α ↑, IL-2 ↓, IFN- γ ↓; mitochondrial dynamics- and anti-apoptosis-related genes ↓; pro-apoptosis-related genes ↑;
    the activities of mitochondrial complexes and ATPases ↓ caused by HS
    [35]
    Regulate the immune function/Chicken models
    (HS-induced)
    200 mg/kgiNOS–NO activities;
    ER stress-related genes;
    Apoptosis-related genes;
    Apoptosis levels
    Alleviated NO content ↑; activity of iNOS ↑ in the chicken spleen; GRP78, GRP94, ATF4, ATF6, IRE ↑; caspase3 ↑; Bcl-2 ↓ caused by HS[36]
    Relieve immunosuppressionCommercial AMR powder (purity 70%)Geese models
    (CTX-induced)
    400 mg/kgSpleen development;
    Percentages of leukocytes in peripheral blood
    Alleviated the spleen damage;
    T and B cell proliferation ↓; imbalance of leukocytes; disturbances of humoral; cellular immunity caused by CTX
    [37]
    Active the lymphocytesCommercial AMR powder (purity 95%)Geese models
    (CTX-induced)
    400 mg/kgThymus morphology;
    The level of serum GMC-SF, IL-1b, IL-3, IL-5;
    mRNA expression of CD25, novel_mir2, CTLA4 and CD28 signal pathway
    Maintain normal cell morphology of thymus;
    Alleviated GMC-SF ↓, IL-1b ↓, IL-5↓, IL-6↓, TGF-b↓; IL-4 ↑, IL-10 ↑; novel_mir2 ↓, CD25↓, CD28↓ in thymus and lymphocytes caused by CTX
    [38]
    Alleviate immunosuppressionCommercial AMR powder (purity 70%)Geese models
    (CTX-induced)
    400 mg/kgThymus development;
    T cell proliferation rate;
    The level of CD28, CD96, MHC-II;
    IL-2 levels in serum;
    differentially expressed miRNAs
    Alleviated thymus damage;
    T lymphocyte proliferation rate ↓; T cell activation ↓; IL-2 levels ↓ caused by CTX;
    Promoted novel_mir2 ↑; CTLA4 ↓; TCR-NFAT signaling pathway
    [39]
    Alleviates T cell activation declineCommercial AMR powder (purity 95%)BALB/c female mice (CTX-induced)200 mg/kgSpleen index;
    Morphology, death, cytokine concentration of splenocytes;
    Th1/Th2 ratio, activating factors of lymphocytes;
    T cell activating factors;
    mRNA expression level in CD28 signal pathway
    Improved the spleen index;
    Alleviated abnormal splenocytes morphology and death; Balance Th1/Th2 ratio; IL-2 ↑, IL-6 ↑, TNF-α ↑, IFN-γ ↑; mRNA levels of CD28, PLCγ-1, IP3R, NFAT, AP-1 ↑
    [40]
    Immunoregulation and ImmunopotentiationCommercial AMR powder (purity 80%)BMDCs (LPS-induced);
    Female BALB/c mice (ovalbumin as a model antigen)
    /Surface molecule expression of BMDCs;
    Cytokines secreted by dendritic cell supernatants;
    OVA-specific antibodies in serum;
    Cytokines in serum;
    Lymphocyte immunophenotype
    Expression of CD80 and CD86 ↑; IL-1β ↑, IL-12 ↑, TNF-α↑ and IFN-γ ↑; OVA-specific antibodies in serum ↑; Secretion of cytokines ↑; Proliferation rate of spleen lymphocytes ↑; Activation of CD3+CD4+ and CD3+CD8+ lymphocytes[46]
    Increase immune-response capacity of the spleen in miceCommercial AMR powder (purity 70%)BALB/c female mice100, 200, 400 mg/kgSpleen index;
    Concentrations of cytokines;
    mRNA and protein expression levels in TLR4 signaling
    In the medium-PAMK group:
    IL-2, IL-4, IFN-c, TNF-a ↑; mRNA and protein expression of TLR4, MyD88, TRAF6, TRAF3, NF-κB in the spleen ↑
    [41]
    Immunological activityCommercial AMR powder (purity 80%)Murine splenic lymphocytes (LPS or PHA-induced)13, 26, 52, 104, 208 μg/mLT lymphocyte surface markersLymphocyte proliferation ↑;
    Ratio of CD4+/CD8+ T cells ↑
    [47]
    Immunomodulatory activityTotal carbohydrates content 95.66 %Mouse splenocytes
    (Con A or LPS-induced)
    25, 50, 100 μg/mLSplenocyte proliferation;
    NK cytotoxicity;
    Productions of NO and cytokines;
    Transcription factor activity;
    Signal pathways and receptor
    Promoted splenocyte proliferation; Cells enter S and G2/M phases; Ratios of T/B cells ↑; NK cytotoxicity ↑; Transcriptional activities of NFAT ↑; NF-κB, AP-1 ↑; NO, IgG, IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-6, IL-10, IL-12p40, IL-12p70, IL-13, IFN-γ, TNF-α, G-CSF, GM-CSF, KC, MIP-1α, MIP-1β, RANTES, Eotaxin ↑[42]
    Promote the proliferation of thymic epithelial cellsContents of fucrhaara, galactose, glucose, fructose,
    and xylitol: 0.98%, 0.40%, 88.67%, 4.47%, and 5.47%
    MTEC1 cells50 μg/mLCell viability and proliferation;
    lncRNAs, miRNAs, and mRNAs expression profiles in MTEC1 cells
    The differential genes were 225 lncRNAs, 29 miRNAs, and 800 mRNAs; Genes enriched in cell cycle, cell division, NF-κB signaling, apoptotic process, and MAPK signaling pathway[44]
    Immunomodulatory activityMW: 4.354 × 103 Da;
    Composed of mannose, galacturonic acid, glucose, galactose and arabinose;
    The main linkages are →3-β-glcp-(1→, →3,6-β-glcp-(1→, →6-β-glcp-(1→, T-β-glcp-(1→,
    →4-α-galpA-(1→, →4-α-galpA-6-OMe-(1→, →5-α-araf-(1→, →4,6-β-manp-(1→ and →4-β-galp-(1→
    CD4+ T cell50, 100, 200 μg/mLMolecular weight;
    Monosaccharide composition;
    Secondary structure;
    Surface topography;
    Effect on Treg cells
    Treg cells percentage ↑; mRNA expressions of Foxp3, IL-10 and IL-2 ↑; STAT5 phosphorylation levels ↑; IL-2/STAT5 pathway[28]
    Immunostimulatory activityMW of AMAP-1, AMAP-2, and AMAP-3 were 13.8×104 Da, 16.2×104 Da and 8.5×104 Da;
    HG region consists of α-(1→4)-linked GalpA residues
    RAW264.7 cells (LPS-induced)80, 40, 200 μg/mLMolecular weight;
    Total carbohydrate;
    Uronic acid contents;
    Secondary structure;
    Monosaccharide composition;
    Immunostimulatory activity
    RG-I-rich AMAP-1 and AMAP-2 improved the release of NO[29]
    Immunomodulatory effectMW: 1.867×103 Da;
    Contents of glucose, mannose, rhamnose,
    arabinose and galactose: 60.67%, 14.99%, 10.61%, 8.83% and 4.90%
    SMLN lymphocytes25
    μg/ml
    Molecular weight;
    Monosaccharide composition;
    Ultrastructure;
    Intracellular Ca2+concentration;
    Target genes;
    Cell cycle distribution
    [Ca2+]i ↑; More cells in S and G2/M phases; IFN-γ ↑, IL-17A ↑; mRNA expressions of IL-4 ↓[30]
    Macrophage activationTotal carbohydrates content 95.66 %RAW264.7 macrophages (LPS-induced)25, 50, 100 μg/mLPinocytic activity;
    Phagocytic uptake;
    Phenotypic characterization;
    Cytokine production;
    Bioinformatics analysis;
    Transcription factor inhibition
    IL-6, IL-10 and TNF-α ↑; CCL2 and CCL5 ↑; Pinocytic and phagocytic activity ↑; CD40, CD80, CD86, MHC-I, MHC-II ↑; NF-κB and Jak-STAT pathway[43]
    Immunomodulatory effectTotal carbohydrates content 95.66 %SMLN lymphocytes25, 50, 100 μg/mLCytokine production;
    CD4+ and CD8+ lymphocytes;
    Target genes;
    Bioinformatics analysis;
    T and B lymphocyte proliferation;
    Receptor binding and blocking
    IFN-γ, IL-1α, IL-21, IFN-α, CCL4, CXCL9, CXCL10 ↑; CD4+ and CD8+subpopulations proportions ↑;
    c-JUN, NFAT4, STAT1, STAT3 ↑;
    67 differentially expressed miRNAs (55 ↑ and
    12 ↓), associated with immune system pathways; Affect T and B lymphocytes
    [45]
    Improving gastrointestinal functionRelieve enteritis and improve intestinal
    flora disorder
    Commercial AMR powder (purity 70%);
    Contents of fucrhaara, galactose, glucose, xylitol, and fructose: 0.98%, 0.40%, 88.67%, 4.47%, and 5.47%
    Goslings (LPS-induced)400 mg/kgSerum CRP, IL-1β, IL-6, and TNF-α levels;
    Positive rate of IgA;
    TLR4, occludin, ZO-1, cytokines, and immunoglobulin mRNA expression;
    Intestinal flora of gosling excrement
    Relieved IL-1β, IL-6, TNF-α levels in serum ↑; the number of IgA-secreting cells ↑; TLR4 ↑; tight junction occludin and ZO-1 ↓; IL-1β mRNA expression in the small intestine ↑; Romboutsia ↓ caused by LPS[48]
    Ameliorate ulcerative colitisMW: 2.391 × 104 Da;
    Composed of mannose, glucuronic acid, glucose and arabinose in a molar ratio of 12.05:6.02:72.29:9.64
    Male C57BL/6J mice (DDS-induced)10, 20, 40 mg/kg bwHistopathological evaluation;
    Inflammatory mediator;
    Composition of gut microbiota;
    Feces and plasma for global metabolites profiling
    Butyricicoccus, Lactobacillus ↑;
    Actinobacteria, Akkermansia, Anaeroplasma, Bifidobacterium, Erysipelatoclostridium, Faecalibaculum, Parasutterella,
    Parvibacter, Tenericutes, Verrucomicrobia ↓;
    Changed 23 metabolites in fecal content; 21 metabolites in plasma content
    [49]
    Attenuate ulcerative colitis/Male SD rats (TNBS-induced);
    Co-culture BMSCs and IEC-6 cells
    540 mg/kg
    (for rats);
    400 μg/mL (for cell)
    Histopathological analysis;
    Cell migration;
    Levels of cytokines
    Potentiated BMSCs’ effect on preventing colitis and homing the injured tissue, regulated cytokines;
    BMSCs and AMP promoted the migration of IEC
    [52]
    Against intestinal mucosal injuryMW: 3.714 × 103 Da;
    Composed of glucose, arabinose, galactose, galacturonic acid, rhamnose
    and mannose with molar ratios of 59.09:23.22:9.32:4.70:2.07:1.59
    Male C57BL/6 mice (DDS-induced)100 mg/kgIntestinal morphology;
    IL-6, TNF-α and IL-1β in serum;
    mRNA expression;
    Intestinal microbiota
    Alleviated body weight ↓; colon length ↓; colonic damage caused by DSS;
    Over-expression of TNF-α, IL-1β, IL-6 ↓; Infiltration of neutrophils in colon ↓; Mucin 2 ↑;
    Tight junction protein Claudin-1 ↑;
    Harmful bacteria content ↓;
    Beneficial bacteria content ↑
    [50]
    Against intestinal injuryTotal carbohydrates 95.66 %IECs (DDS-induced)5, 25, 50 μg/mLCell proliferation and apoptosis;
    Expression levels of intercellular TJ proteins;
    lncRNA screening
    Proliferation and survival of IECs ↑;
    Novel lncRNA ITSN1-OT1 ↑;
    Blocked the nuclear import of phosphorylated STAT2
    [51]
    Anti-tumor activityInduce apoptosis in transplanted H22 cells in miceMW: 4.1× 103 Da;
    Neutral heteropolysaccharide composed of galactose, arabinose, and glucose with α-configuration (molar ratio, 1:1.5:5)
    Female Kunming mice100 and 200 mg/kg (for rats)Secondary structure;
    Molecular weight;
    Molecular weight;
    Thymus index and Spleen index;
    Lymphocyte Subpopulation in peripheral blood;
    Cell cycle distribution
    In tumor-bearing mice CD3+, CD4+, CD8+ ↓;
    B cells ↑
    [31]
    Regulate the innate immunity of colorectal cancer cellsCommercial AMR powder (purity 70%)C57BL/6J mice (MC38 cells xenograft model)500 mg/kgExpression of pro-inflammatory cytokines and secretionIL-6, IFN-λ, TNF-α, NO ↑ through MyD88/TLR4-dependent signaling pathway;
    Survival duration of mice with tumors ↑;
    Prevent tumorigenesis in mice
    [54]
    Induce apoptosis of Eca-109 cellsMW: 2.1× 103 Da;
    Neutral hetero polysaccharide composed
    of arabinose and glucose (molar ratio, 1:4.57) with pyranose rings and α-type and β-type glycosidic linkages
    Eca-109 cells0.25, 0.5, 1, 1.5, 2.00 mg/mLCell morphology;
    Cell cycle arrest;
    Induction of apoptosis
    Accelerate the apoptosis of Eca109 cells[53]
    '/' denotes no useful information found in the study.
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    To study the immunomodulatory activity of AMRP, the biological models generally adopted are chicken, goose, mouse, and human cell lines. Experiments based on the chicken model have generally applied 200 mg/kg doses. It was reported that AMRP protected the chicken spleen against heat stress (HS) by alleviating the chicken spleen immune dysfunction caused by HS, reducing oxidative stress, enhancing mitochondrial function, and inhibiting cell apoptosis[35]. Selenium and AMRP could improve the abnormal oxidation and apoptosis levels and endoplasmic reticulum damage caused by HS, and could act synergistically in the chicken spleen to regulate biomarker levels[36]. It indicated that AMRP and the combination of selenium and AMRP could be applied as chicken feed supplementation to alleviate the damage of HS and improve chicken immunity.

    The general application dose in the goose model is also 200 mg/kg, and the main injury inducer is cyclophosphamide (CTX). AMRP alleviated CTX-induced immune damage in geese and provided stable humoral immune protection[37]. Little is known about the role of AMRP in enhancing immunity in geese through the miRNA pathway. It was reported that AMRP alleviated CTX-induced decrease in T lymphocyte activation levels through the novel _mir2/CTLA4/CD28/AP-1 signaling pathway[38]. It was also reported that AMRP might be achieved by upregulating the TCR-NFAT pathway through novel_mir2 targeting of CTLA4, thereby attenuating the immune damage induced by CTX[39]. This indicated that AMRP could also be used as goose feed supplementation to improve the goose's autoimmunity.

    The typical injury inducer for mouse models is CTX, and the effects on mouse spleen tissue are mainly observed. BALB/c female mice were CTX-induced damage. However, AMRP increased cytokine levels and attenuated the CTX-induced decrease in lymphocyte activation levels through the CD28/IP3R/PLCγ-1/AP-1/NFAT signaling pathway[40]. It has also been shown that AMRP may enhance the immune response in the mouse spleen through the TLR4-MyD88-NF-κB signaling pathway[41].

    Various cellular models have been used to study the immune activity of AMRP, and most of these studies have explored the immune activity with mouse splenocytes and lymphocytes. Besides, the commonly used damage-inducing agents are LPS, phytohemagglutinin (PHA), and concanavalin A (Con A).

    In one study, the immunoreactivity of AMRP was studied in cultured mouse splenocytes. LPS and Con A served as controls. Specific inhibitors against mitogen-activated protein kinases (MAPKs) and NF-κB significantly inhibited AMRP-induced IL-6 production. The results suggested that AMRP-induced splenocyte activation may be achieved through TLR4-independent MAPKs and NF-κB signaling pathways[42]. Besides, AMRP isolated from AMR acting on LPS-induced RAW264.7 macrophages revealed that NF-κB and Jak-STAT signaling pathways play a crucial role in regulating immune response and immune function[43]. RAMP2 increased the phosphorylation level of STAT5 in Treg cells, indicating that RAMP2 could increase the number of Treg cells through the IL-2/STAT5 signaling pathway[28]. Furthermore, the relationship between structure and immune activity was investigated. Polysaccharides rich in RG-I structure and high molecular weight improved NO release from RAW264.7 cells. Conversly, polysaccharides rich in HG structure and low molecular weight did not have this ability, indicating that the immunoreactivity of the polysaccharide may be related to the side chain of RG-I region[29]. Moreover, the effect of AMRP on the expression profile of lncRNAs, miRNAs, and mRNAs in MTEC1 cells has also been investigated. The differentially expressed genes include lncRNAs, Neat1, and Limd1. The involved signaling pathways include cell cycle, mitosis, apoptotic process, and MAPK[44].

    Xu et al. found that AMRP affects supramammary lymph node (SMLN) lymphocytes prepared from healthy Holstein cows. Sixty-seven differentially expressed miRNAs were identified based on microRNA sequencing and were associated with immune system pathways such as PI3K-Akt, MAPKs, Jak-STAT, and calcium signaling pathways. AMRP exerted immunostimulatory effects on T and B lymphocytes by binding to T cell receptor (TCR) and membrane Ig alone, thereby mobilizing immune regulatory mechanisms within the bovine mammary gland[45].

    AMRP can also be made into nanostructured lipid carriers (NLC). Nanoparticles as drug carriers can improve the action of drugs in vivo. NLC, as a nanoparticle, has the advantages of low toxicity and good targeting[46]. The optimization of the AMRP-NLC preparation process has been reported. The optimum technologic parameters were: the mass ratio of stearic acid to caprylic/capric triglyceride was 2:1. The mass ratio of poloxamer 188 to soy lecithin was 2:1. The sonication time was 12 min. The final encapsulation rate could reach 76.85%[47]. Furthermore, AMRP-NLC interfered with the maturation and differentiation of bone marrow-derived dendritic cells (BMDCs). Besides, AMRP-NLC, as an adjuvant of ovalbumin (OVA), could affect ova-immunized mice with enhanced immune effects[46].

    AMRP also has the effect of alleviating intestinal damage. They are summarized in Table 1. The common damage-inducing agents are lipopolysaccharide (LPS), dextran sulfate sodium (DDS), and trinitrobenzene sulfonic acid (TNBS). A model of LPS-induced enteritis in goslings was constructed to observe the effect of AMRP on alleviating small intestinal damage. Gosling excrement was analyzed by 16S rDNA sequencing to illuminate the impact of AMRP on the intestinal flora. Results indicated that AMRP could maintain the relative stability of cytokine levels and immunoglobulin content and improve intestinal flora disorder[48]. Feng et al. used DDS-induced ulcerative colitis (UC) in mice and explored the alleviating effects of AMRP on UC with 16S rDNA sequencing technology and plasma metabolomics. The results showed that AMRP restored the DDS-induced disruption of intestinal flora composition, regulated the production of metabolites such as short-chain fatty acids and cadaveric amines, and regulated the metabolism of amino acids and bile acids by the host and intestinal flora[49]. A similar study has reported that AMRP has a protective effect on the damage of the intestinal mucosal barrier in mice caused by DSS. It was found that AMRP increased the expression of Mucin 2 and the tight junction protein Claudin-1. In addition, AMRP decreased the proportion of harmful bacteria and increased the potentially beneficial bacteria content in the intestine[50]. The protective effect of AMRP on DSS-induced damage to intestinal epithelial cells (IECs) has also been investigated. The results showed that AMRP promoted the proliferation and survival of IECs.

    In addition, AMRP induced a novel lncRNA ITSN1-OT1, which blocked the nuclear import of phosphorylated STAT2 and inhibited the DSS-induced reduced expression and structural disruption of tight junction proteins[51]. AMRP can also act in combination with cells to protect the intestinal tract. The ulcerative colitis model in Male Sprague-Dawley (SD) rats was established using TNBS, and BMSCs were isolated. IEC-6 and BMSCs were co-cultured and treated by AMRP. The results showed that AMRP enhanced the prevention of TNBS-induced colitis in BMSCs, promoted the migration of IEC, and affected the expression of various cytokines[52]. These reports indicated that the 16S rDNA sequencing technique could become a standard method to examine the improvement of gastrointestinal function by AMRP.

    AMRP has anti-tumor activity and other biological activities. AMRP can induce apoptosis in Hepatoma-22 (H22) and Eca-109 cells and modulate the innate immunity of MC38 cells. For instance, the anti-tumor effects of AMRP were investigated by constructing a tumor-bearing mouse model of H22 tumor cells. AMRP blocked the S-phase of H22 tumor cells and induced an immune response, inhibiting cell proliferation[31]. In addition, AMRP can inhibit cell proliferation through the mitochondrial pathway and by blocking the S-phase of Eca-109 tumor cells[53]. AMRP affects MC38 tumor cells, and the anti-tumor effect of AMRP was investigated with Toll-like receptor 4 (TLR4) KO C57BL/6 mice and the construction of the MC38 tumor cell xenograft model. AMRP significantly inhibited the development of MC38 cells in mice and prolonged the survival of tumor-bearing mice. AMRP activity was diminished in TLR4 KO mice. Combined with the immunoblotting assay results, it was shown that TLR4 regulated the MyD88-dependent signaling pathway, which has a critical effect on the anti-tumor effect of AMRP[54].

    AMR contains a large number of bioactive compounds. Among them, small molecule compounds include esters, sesquiterpenes, and other compounds. These small molecule compounds have significant pharmacological activities, including anti-tumor, neuroprotective, immunomodulatory, and anti-inflammatory. In the last five years, small molecule compounds have been increasingly identified (Fig. 4), with atractylenolides as the main component of AMR extracts[11]. Atractylenolides are a small group of sesquiterpenoids. Atractylenolides include AT-I, AT-II, and AT-III, lactones isolated from AMR.

    Figure 4.  Structure of small molecule compounds with bioactivities from AMR. Atractylenolide I (1); Atractylenolide II (2); Atractylenolide III (3); 3β-acetoxyl atractylenolide I (4); 4R,5R,8S,9S-diepoxylatractylenolide II (5); 8S,9S-epoxyla-tractylenolide II (6); Atractylmacrols A (7); Atractylmacrols B (8); Atractylmacrols C (9); Atractylmacrols D (10); Atractylmacrols E (11); 2-[(2E)-3,7-dimethyl-2,6-octadienyl]-6-methyl-2,5-cyclohexadiene-1,4-dione (12); 8-epiasterolid (13); (3S,4E,6E,12E)-1-acetoxy-tetradeca-4,6,12-triene-8,10-diyne-3,14-diol (14); (4E,6E,12E)-tetradeca-4,6,12-triene-8,10-diyne-13,14-triol (15); 1-acetoxy-tetradeca-6E,12E-diene-8, 10-diyne-3-ol (16); 1,3-diacetoxy-tetradeca-6E, 12E-diene-8,10-diyne (17); Biatractylenolide II (18); Biepiasterolid (19); Biatractylolide (20).

    The anti-tumor activity was mainly manifested by AT-I and AT-II, especially AT-I (Table 2). Anti-tumor activity has been studied primarily in vivo and in vitro. However, there is a lack of research on the anti-tumor activity of atractylenolide in human clinical trials. The concentration of atractylenolide applied on cell lines was < 400 μM, or < 200 mg/kg on tumor-bearing mice.

    Table 2.  Anti-tumor activity of atractylenolides.
    TypesSubstancesModelIndexDoseSignal pathwayResultsRef.
    Human colorectal cancerAT-IIIHCT-116 cell;
    HCT-116 tumor xenografts bearing in nude mice
    Cell viability;
    Cell apoptotic;
    mRNAs and protein
    expressions of Bax, Bcl-2, caspase-9 and caspase-3
    25, 50, 100, 200 μM (for cell);
    50, 100,
    200 mg/kg (for rats)
    Bax/Bcl-2 signaling pathwayPromoting the expression of proapoptotic related gene/proteins; Inhibiting the expression of antiapoptotic related gene/protein; Bax↑; Caspase-3↓; p53↓; Bcl-2↓[55]
    Human gastric carcinomaAT-IIHGC-27 and AGS cell
    Cell viability;
    Morphological changes;
    Flow cytometry;
    Wound healing;
    Cell proliferation, apoptosis, and motility
    50, 100, 200, 400 μMAkt/ERK signaling pathwayCell proliferation, motility↓; Cell apoptosis↑; Bax↑;
    Bcl-2↓; p-Akt↓; p-ERK↓
    [56]
    Mammary
    tumorigenesis
    AT-IIMCF 10A cell;
    Female SD rats (NMU-induced)
    Nrf2 expression and nuclear accumulation;
    Cytoprotective effects;
    Tumor progression;
    mRNA and protein levels of Nrf2;
    Downstream detoxifying enzymes
    20, 50, 100 μM (for cell);
    100 and 200 mg/kg (for rats)
    JNK/ERK-Nrf2-ARE signaling pathway;
    Nrf2-ARE signaling pathway
    Nrf2 expressing↑; Nuclear translocation↑; Downstream detoxifying enzymes↓; 17β-Estradiol↓; Induced malignant transformation[57]
    Human colon adenocarcinomaAT-IHT-29 cellCell viability;
    TUNEL and Annexin V-FITC/PI double stain;
    Detection of initiator and
    executioner caspases level
    10, 20, 40, 80, 100 μMMitochondria-dependent pathwayPro-survival Bcl-2↓; Bax↑; Bak↑; Bad↑; Bim↑; Bid↑; Puma↑[58]
    Sensitize triple-negative
    TNBC cells to paclitaxel
    AT-IMDA-MB-231 cell;
    HS578T cell;
    Balb/c mice (MDA-MB-231 cells-implanted)
    Cell viability
    Transwell migration
    CTGF expression
    25, 50, 100 μM (for cell);
    50 mg/kg (for rats)
    /Expression and secretion of CTGF↓; CAF markers↓; Blocking CTGF expression and fibroblast activation[59]
    Human ovarian cancerAT-IA2780 cellCell cycle;
    Cell apoptosis;
    Cyclin B1 and CDK1 level
    12.5, 25, 50, 100 and 200 μMPI3K/Akt/mTOR
    signaling pathway
    Cyclin B1, CDK1↓; Bax↑;
    Caspase-9↓; Cleaved caspase-3↓; Cytochrome c↑; AIF↑; Bcl-2↓; Phosphorylation level of PI3K, Akt, mTOR↓
    [60]
    Impaired metastatic properties transfer of CSCsAT-ILoVo-CSCs; HT29-CSCsCell migration
    and invasion;
    miR-200c expression;
    Cell apoptosis
    200 μMPI3K/Akt/mTOR signaling pathwaySuppressing miR-200c activity; Disrupting EV uptake by non-CSCs[61]
    Colorectal cancerAT-IHCT116 cell;
    SW480 cell;
    male BALB/c nude mice (HCT116-implanted)
    Cell viability;
    Cell apoptosis;
    Glucose uptake;
    Lactate Production;
    STAT3 expression;
    Immunohistological analysis
    25, 50, 100, 150, 200 μM (for cell);
    50 mg/kg (for rats)
    JAK2/STAT3 signalingCaspase-3↑; PARP-1↓;
    Bax↑; Bcl-2↓; Rate-limiting glycolytic
    enzyme HK2↓; STAT3 phosphorylation↓
    [62]
    Human lung cancerAT-INSCLC cells (A549 and H1299);
    female nude mice (A549-Luc cells- implanted)
    Cell viability;
    Cell cycle;
    Phosphorylation and protein expression of
    ERK1/2, Stat3,
    PDK1, transcription factor SP1;
    mRNA levels of PDK1 gene
    12.5, 25, 50, 100, 150 μM (for cell);
    25 and 75 mg/kg (for rats)
    /ERK1/2↑; Stat3↓; SP1↓;
    PDK1↓
    [63]
    '/' denotes no useful information found in the study.
     | Show Table
    DownLoad: CSV

    AT-III affects human colorectal cancer. AT-II affects human gastric carcinoma and mammary tumorigenesis. AT-I affects human colon adenocarcinoma, human ovarian cancer, metastatic properties transfer of Cancer stem cells (CSCs), colorectal cancer, and human lung cancer, and enhances the sensitivity of triple-negative breast cancer cells to paclitaxel. Current techniques have made it possible to study the effects of atractylenolide on tumors at the signaling pathway level (Table 2). For instance, AT-III significantly inhibited the growth of HCT-116 cells and induced apoptosis by regulating the Bax/Bcl-2 apoptotic signaling pathway. In the HCT116 xenograft mice model, AT-III could inhibit tumor growth and regulate the expression of related proteins or genes. It indicated that AT-III could potentially treat human colorectal cancer[55]. AT-II significantly inhibited the proliferation and motility of HGC-27 and AGS cells and induced apoptosis by regulating the Akt/ERK signaling pathway. It suggested that AT-II can potentially treat gastric cancer[56]. However, in this study, the anti-tumor effects of AT-II in vivo were not examined. AT-II regulated intracellular-related enzyme expression in MCF 10A cells through the JNK/ERK-Nrf2-ARE signaling pathway. AT-II reduced inflammation and oxidative stress in rat mammary tissue through the Nrf2-ARE signaling pathway. AT-II inhibited tumor growth in the N-Nitroso-N-methyl urea (NMU)-induced mammary tumor mice model, indicating that AT-II can potentially prevent breast cancer[57]. AT-I induced apoptosis in HT-29 cells by activating anti-survival Bcl-2 family proteins and participating in a mitochondria-dependent pathway[58]. It indicated that AT-I is a potential drug effective against HT-29 cells. However, the study was only conducted in vitro; additional in vivo experimental data are needed. AT-I can enhance the sensitivity of triple-negative breast cancer (TNBC) cells to paclitaxel. MDA-MB-231 and HS578T cell co-culture systems were constructed, respectively. AT-I was found to impede TNBC cell migration. It also enhanced the sensitivity of TNBC cells to paclitaxel by inhibiting the conversion of fibroblasts into cancer-associated fibroblasts (CAFs) by breast cancer cells. In the MDA-MB-231 xenograft mice model, AT-I was found to enhance the effect of paclitaxel on tumors and inhibit the metastasis of tumors to the lung and liver[59]. AT-I inhibited the growth of A2780 cells through PI3K/Akt/mTOR signaling pathway, promoting apoptosis and blocking the cell cycle at G2/M phase change, suggesting a potential therapeutic agent for ovarian cancer[60]. However, related studies require in vivo validation trials. CSCs are an important factor in tumorigenesis. CSCs isolated from colorectal cancer (CRC) cells can metastasize to non-CSCs via miR-200c encapsulated in extracellular vesicles (EVs).

    In contrast, AT-I could inhibit the activity and transfer of miR-200c. Meanwhile, interfere with the uptake of EVs by non-CSCs. This finding contributes to developing new microRNA-based natural compounds against cancer[61]. AT-I has the function of treating colorectal cancer. HCT116 and SW480 cells were selected for in vitro experiments, and AT-I was found to regulate STAT3 phosphorylation negatively. The HCT116 xenograft mice model was constructed, and AT-I was found to inhibit the growth of HCT116. AT-I induced apoptosis in CRC cells, inhibited glycolysis, and blocked the JAK2/STAT3 signaling pathway, thus exerting anti-tumor activity[62]. The in vitro experiments were performed with A549 and H1299 cell lines. The in vivo experiments were performed to construct the A549-Luc xenograft mice model. The results showed that AT-I inhibited lung cancer cell growth by activating ERK1/2. AT-I inhibited SP1 protein expression and phosphorylation of Stat3, decreasing PDK1 gene expression. The study showed that AT-I could inhibit lung cancer cell growth and targeting PDK1 is a new direction for lung cancer treatment[63]. The research on the anti-tumor of atractylenolide is relatively complete, and there are various signaling pathways related to its anti-tumor activity. Based on the above information, the anti-tumor mechanism of atractylenolide in the past five years was schemed (Fig. 5).

    Figure 5.  Schematic diagram for the anti-tumor mechanism of atractylenolides.

    In recent years, few studies have been conducted on the neuroprotective activity of esters or sesquiterpenoids from AMR. The neuroprotective effects of AT-III have been studied systematically. Biatractylolide has also been considered to have a better neuroprotective effect. New compounds continue to be identified, and their potential neuroprotective effects should be further explored. The related biological activities, animal models, monitoring indicators, and results are summarized in Table 3. Neuroprotective effects include the prevention and treatment of various diseases, such as Parkinson's, Alzheimer's, anti-depressant anxiety, cerebral ischemic injury, neuroinflammation, and hippocampal neuronal damage. In vivo and in vitro will shed light on the potential effect of sesquiterpenoids from AMR and other medicinal plants.

    Table 3.  Neuroprotective effects of esters and sesquiterpenoids.
    ActivitiesSubstancesModelIndexDoseSignal pathwayResultsRef.
    Establish a PD modelAT-II; AT-I;
    Biepiasterolid;
    Isoatractylenolide I;
    AT-III; 3β-acetoxyl atractylenolide I;
    (4E,6E,12E)- tetradeca-4,6,12-triene-8,10-diyne-13,14-triol;
    (3S,4E,6E,12E)-1-acetoxy-tetradeca-4,6,12-triene-8,10-diyne-3,14-diol
    SH-SY5Y cell (MPP+-induced)Cell viability10, 1, 0.1 μM/All compounds have inhibitory activity on MPP+-
    induced SH-SY5Y cell
    [64]
    /4R,5R,8S,9S-diepoxylatractylenolide II;
    8S,9S-epoxyla-tractylenolide II
    BV-2 microglia cells (LPS-induced)Cell viability;
    NO synthase
    inhibitor;
    IL-6 levels
    6.25, 12.5, 25, 50, 100 μMNF-κB signaling
    pathway
    NO inhibition with IC50 values
    of 15.8, and 17.8 μМ, respectively;
    IL-6 ↓
    [65]
    Protecting Alzheimer’s diseaseBiatractylolidePC12 cell (Aβ25-35-induced);
    Healthy male Wistar rats (Aβ25-35-induced)
    Cell viability;
    Morris water maze model;
    TNF-α, IL-6, and IL-1β
    20, 40, 80 μM (for cells);
    0.1, 0.3, 0.9 mg/kg (for rats)
    NF-κB signaling
    pathway
    Reduce apoptosis; Prevent cognitive decline; Reduce the activation of NF-κB signal pathway[66]
    /BiatractylolidePC12 and SH-SY5Y cell (glutamate-induced)Cell viability;
    Cell apoptosis;
    LDA;
    Protein expression
    10, 15, 20 μMPI3K-Akt-GSK3β-Dependent
    Pathways
    GSK3β protein expression ↓;
    p-Akt protein expression ↑
    [67]
    Parkinson's DiseaseAT-IBV-2 cells (LPS-induced);
    Male C57BL6/J mice (MPTP-intoxicated)
    mRNA and protein levels;
    Immunocytochemistry; Immunohistochemistry;
    25, 50, 100 μM (for cells);
    3, 10, 30 mg/kg/mL (for rats)
    /NF-κB ↓; HO-1 ↑; MnSOD ↑; TH-immunoreactive neurons ↑; Microglial activation ↓[68]
    Anti depressant like effectAT-IMale ICR mice (CUMS induced depressive like behaviors)Hippocampal neurotransmitter levels;
    Hippocampal pro inflammatory cytokine levels;
    NLRP3 inflammasome in the hippocampi
    5, 10, 20 mg/kg/Serotonin ↓;
    Norepinephrine ↓; NLRP3 inflammasome ↓; (IL)-1β ↓
    [69]
    Alzheimer's diseaseBiatractylenolide II/AChE inhibitory activities;
    Molecular docking
    //Biatractylenolide II can interact with PAS and CAS of AChE[70]
    Cerebral ischemic injury and
    neuroinflammation
    AT-IIIMale C57BL/6J mice (MCAO- induced);
    Primary microglia (OGDR
    stimulation)
    Brain infarct size;
    Cerebral blood flow;
    Brain edema;
    Neurological deficits;
    Protein expressions of proinflammatory;
    Anti-inflammatory
    cytokines
    0.01, 0.1, 1, 10, 100 μM (for cells);
    0.1–10 mg/kg
    (for rats)
    JAK2/STAT3/Drp1-dependent mitochondrial fissionBrain infarct size ↓;
    Restored CBF;
    ameliorated brain edema; Improved neurological deficits;
    IL-1β ↓; TNF-α ↓; IL-6 ↓;
    Drp1 phosphorylation ↓
    [71]
    Reduces depressive- and anxiogenic-like behaviorsAT-IIIMale SD rats (LPS-induced and CUMS rat model)Forced swimming test;
    Open field test;
    Sucrose preference test;
    Novelty-suppressed feeding test;
    Proinflammatory cytokines levels
    3, 10, 30 mg/kg/30 mg/kg AT-III produced an anxiolytic-like effect; Prevented depressive- and anxiety-like behaviors; Proinflammatory cytokines levels ↓[72]
    Alleviates
    injury in rat
    hippocampal neurons
    AT-IIIMale SD rats (isoflurane-induced)Apoptosis and autophagy in the hippocampal neurons;
    Inflammatory factors;
    Levels of p-PI3K,
    p-Akt, p-mTOR
    1.2, 2.4, 4.8 mg/kgPI3K/Akt/mTOR signaling pathwayTNF-α ↓; IL-1β ↓; IL-6 ↓; p-PI3K ↑; p-Akt ↑; p-mTOR ↑[73]
    ''/' denotes no useful information found in the study.
     | Show Table
    DownLoad: CSV

    Zhang et al. identified eight compounds from AMR, two newly identified, including 3β-acetoxyl atractylenolide I and (3S,4E,6E,12E)-1-acetoxy-tetradecane-4,6,12-triene-8,10-diyne-3,14-diol. 1-Methyl-4-phenylpyridinium (MPP+) could be used to construct a model of Parkinson's disease. A model of MPP+-induced damage in SH-SY5Y cells was constructed. All eight compounds showed inhibitory effects on MPP+-induced damage[64]. Si et al. newly identified eight additional sesquiterpenoids from AMR. A model of LPS-induced BV-2 cell injury was constructed. 4R, 5R, 8S, 9S-diepoxylatractylenolide II and 8S, 9S-epoxylatractylenolide II had significant anti-neuroinflammatory effects. Besides, the anti-inflammatory effect of 4R, 5R, 8S, 9S-diepoxylatractylenolide II might be related to the NF-κB signaling pathway[65]. Biatractylolide has a preventive effect against Alzheimer's disease. In vitro experiments were conducted by constructing an Aβ25-35-induced PC12 cell injury model. In vivo experiments were conducted by constructing an Aβ25-35-induced mice injury model to examine rats' spatial learning and memory abilities. Biatractylolide reduced hippocampal apoptosis, alleviated Aβ25-35-induced neurological injury, and reduced the activation of the NF-κB signaling pathway. Thus, it can potentially treat Aβ-related lesions in the central nervous system[66]. It has also been shown that biatractylolide has neuroprotective effects via the PI3K-Akt-GSK3β-dependent pathway to alleviate glutamate-induced damage in PC12 and SH-SY5Y cells[67]. The attenuating inflammatory effects of AT-I were examined by constructing in vivo and in vitro Parkinson's disease models. Furthermore, AT-I alleviated LPS-induced BV-2 cell injury by reducing the nuclear translocation of NF-κB. AT-I restored 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral impairment in C57BL6/J mice, protecting dopaminergic neurons[68]. AT-I also has anti-depressant effects. Chronic unpredictable mild stress (CUMS) induced depressive behavior in institute of cancer research (ICR) mice, and AT-I achieved anti-depressant function by inhibiting the activation of NLRP3 inflammatory vesicles, thereby reducing IL-1β content levels[69]. Biatractylenolide II is a newly identified sesquiterpene compound with the potential for treating Alzheimer's disease. The AChE inhibitory activity of biatractylenolide II was measured, and molecular simulations were also performed. It was found to interact with the peripheral anion site and active catalytic site of AChE[70]. AT-III has a broader neuroprotective function. The middle cerebral artery (MCAO) mouse model and oxygen-glucose deprivation-reoxygenation (OGDR) microglia model were constructed. AT-III was found to ameliorate brain edema and neurological deficits in MCAO mice. In addition, AT-III suppressed neuroinflammation and reduced ischemia-related complications through JAK2/ STAT3-dependent mitochondrial fission in microglia[71]. In order to investigate the anti-depressant and anti-anxiolytic effects of AT-III, the LPS-induced depression model and CUMS model were constructed. Combined with the sucrose preference test (SPT), novelty-suppressed feeding test (NSFT), and forced swimming test (FST) to demonstrate that AT-III has anti-depressant and anti-anxiolytic functions by inhibiting hippocampal neuronal inflammation[72]. In addition, AT-III also has the effect of attenuating hippocampal neuronal injury in rats. An isoflurane-induced SD rats injury model was constructed. AT-III alleviated apoptosis, autophagy, and inflammation in hippocampal neurons suggesting that AT-III can play a role in anesthesia-induced neurological injury[73]. However, AT-III attenuates anesthetic-induced neurotoxicity is not known.

    Immunomodulatory and anti-inflammatory activities are studied in vivo and in vitro. The construction of an inflammatory cell model in vitro generally uses RAW 264.7 macrophages. Different cells, such as BV2 microglia, MG6 cells, and IEC-6 cells, can also be used. Active compounds' immune and anti-inflammatory activity is generally examined using LPS-induced cell and mouse models. For enteritis, injury induction is performed using TNBS and DSS. Several studies have shown that AT-III has immunomodulatory and anti-inflammatory activities. Other sesquiterpene compounds also exhibit certain activities. The related biological activities, animal models, monitoring indicators, and results are summarized in Table 4. For example, five new sesquiterpene compounds, atractylmacrols A-E, were isolated from AMR. The anti-inflammatory effect of the compounds was examined with LPS-induced RAW264.7 macrophage damage, and atractylmacrols A-E were found to inhibit NO production[74]. Three compounds, 2-[(2E)-3,7-dimethyl-2,6-octadienyl]-6-methyl-2, 5-cyclohexadiene-1, 4-dione (1); 1-acetoxy-tetradeca-6E,12E-diene-8, 10-diyne-3-ol (2); 1,3-diacetoxy-tetradeca-6E, 12E-diene-8,10-diyne (3) were isolated from AMR. All three compounds could inhibit the transcriptional activity and nuclear translocation of NF-κB. The most active compound was compound 1, which reduced pro-inflammatory cytokines and inhibited MAPK phosphorylation[75]. Twenty-two compounds were identified from AMR. LPS-induced RAW 264.7 macrophages and BV2 cell injury models were constructed, respectively. Among them, three compounds, AT-I, AT-II, and 8-epiasterolid showed significant damage protection in both cell models and inhibited LPS-induced cell injury by inactivating the NF-κB signaling pathway[76]. To construct a TNBS-induced mouse colitis model, AT-III regulated oxidative stress through FPR1 and Nrf2 signaling pathways, alleviated the upregulation of FPR1 and Nrf2 proteins, and reduced the abundance of Lactobacilli in injured mice[77]. AT-III also has anti-inflammatory effects in peripheral organs. A model of LPS-injured MG6 cells was constructed. AT-III alleviated LPS injury by significantly reducing the mRNA expression of TLR4 and inhibiting the p38 MAPK and JNK pathways[78]. It indicated that AT-III has the potential as a therapeutic agent for encephalitis. The neuroprotective and anti-inflammatory effects of AT-III were investigated in a model of LPS-induced BV2 cell injury and a spinal cord injury (SCI) mouse model. AT-III alleviated the injury in SCI rats, promoted the conversion of M1 to M2, and attenuated the activation of microglia/macrophages, probably through NF-κB, JNK MAPK, p38 MAPK, and Akt signaling pathways[79]. AT-III has a protective effect against UC. DSS-induced mouse model and LPS-induced IEC-6 cell injury model were constructed. AT-III alleviated DSS and LPS-induced mitochondrial dysfunction by activating the AMPK/SIRT1/PGC-1α signaling pathway[80].

    Table 4.  Immunomodulatory and anti-inflammatory activities of esters and sesquiterpenoids.
    ActivitiesSubstanceModelIndexDoseSignal pathwayResultRef.
    Against LPS-induced NO productionAtractylmacrols A-ERAW264.7 macrophages (LPS-induced)Isolation;
    Structural identification;
    Inhibition activity of
    NO production
    25 μM/Have effects on LPS-induced NO production[74]
    Anti-inflammatory2-[(2E)-3,7-dimethyl-2,6-octadienyl]-6-methyl-2,5-cyclohexadiene-1,
    4-dione;
    1-acetoxy-tetradeca-6E,12E-diene-8, 10-diyne-3-ol;
    1,3-diacetoxy-tetradeca-6E, 12E-diene-8,
    10-diyne
    RAW 264.7
    macrophages (LPS-induced)
    Level of NO and PGE2;
    Level of iNOS, COX-2;
    Levels of pro-inflammatory cytokines;
    Phosphorylation of MAPK(p38, JNK, and ERK1/2)
    2 and 10 μMNF-κB signaling pathwayIL-1β ↓; IL-6 ↓; TNF-α ↓;
    p38 ↓; JNK ↓; ERK1/2 ↓
    [75]
    Anti-inflammatoryAT-I; AT-II;
    8-epiasterolid
    RAW264.7 macrophages;
    BV2 microglial cells (LPS-
    induced)
    Structure identification;
    NO, PGE2 production;
    Protein expression of iNOS, COX-2, and cytokines
    40 and 80 μMNF-κB signaling pathway.NO ↓; PGE2 ↓; iNOS ↓;
    COX-2 ↓; IL-1β ↓; IL-6 ↓; TNF-α ↓
    [76]
    Intestinal inflammationAT-IIIMale C57BL/6 mice (TNBS-induced)Levels of myeloperoxidase;
    Inflammatory factors;
    Levels of the prooxidant markers, reactive oxygen species, and malondialdehyde;
    Antioxidant-related enzymes;
    Intestinal flora
    5, 10, 20 mg/kgFPR1 and Nrf2 pathwaysDisease activity index score ↓; Myeloperoxidase ↓; Inflammatory factors interleukin-1β ↓; Tumor necrosis factor-α ↓; Antioxidant enzymes catalase ↓; Superoxide dismutase ↓; Glutathione peroxidase ↓; FPR1 and Nrf2 ↑; Lactobacilli ↓[77]
    Anti-inflammatoryAT-IIIMG6 cells (LPS-
    induced)
    mRNA and protein levels of TLR4,
    TNF-α, IL-1β, IL-6, iNOS, COX-2;
    Phosphorylation of p38 MAPK and JNK
    100 μMp38 MAPK and JNK signaling pathwaysTNF-α ↓; IL-1β ↓; IL-6 ↓;
    iNOS ↓; COX-2 ↓
    [78]
    Ameliorates spinal cord injuryAT-IIIBV2 microglial (LPS-
    induced);
    Female SD rats (Infinite Horizon impactor)
    Spinal cord lesion area;
    Myelin integrity;
    Surviving neurons;
    Locomotor function;
    Microglia/macrophages;
    Inflammatory factors
    1, 10, 100 μM (for cell);
    5 mg/kg (for rats)
    NF-κB,
    JNK MAPK, p38 MAPK, and Akt pathways
    Active microglia/macrophages;
    Inflammatory mediators ↓
    [79]
    Ulcerative colitisAT-IIIIEC-6 (LPS-induced);
    C57BL/6J male mice (DSS-induced)
    MDA,GSH content;
    SOD activity;
    Intestinal permeability;
    Mitochondrial membrane potential;
    Complex I and complex IV activity
    40 and 80 μM (for cell);
    5 and 10 mg/kg (for rats)
    AMPK/
    SIRT1/PGC-1α signaling pathway
    Disease activity index ↓;
    p-AMPK ↑; SIRT1 ↑;
    PGC-1α ↑;
    Acetylated PGC-1α ↑
    [80]
    '/' denotes no useful information found in the study.
     | Show Table
    DownLoad: CSV

    The biosynthetic pathways for bioactive compounds of A. macrocephala are shown in Fig. 6. The biosynthetic pathways of all terpenes include the mevalonate (MVA) pathway in the cytosol and the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway in the plastid[81]. The cytosolic MVA pathway is started with the primary metabolite acetyl-CoA and supplies isopentenyl (IPP), and dimethylallyl diphosphate (DMAPP) catalyzed by six enzymatic steps, including acetoacetyl-CoA thiolase (AACT), hydroxymethylglutaryl-CoA synthase (HMGS), hydroxymethylglutaryl-CoA reductase (HMGR), mevalonate kinase (MVK), phosphomevalonate kinase (PMK) and mevalonate 5-phosphate decarboxylase (MVD)[82]. IPP and DMAPP can be reversibly isomerized by isopentenyl diphosphate isomerase (IDI)[83]. In the MEP pathway, D-glyceraldehyde-3-phosphate (GAP) and pyruvate are transformed into IPP and DMAPP over seven enzymatic steps, including 1-deoxy-d-xylulose 5-phosphate synthase (DXS), 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), 2C-methyl-d-erythritol 4-phosphate cytidyltransferase (MECT), 4-(cytidine 5′-diphospho)-2C-methyl-d-erythritol kinase (CMK), 2C-methyl-d-erythritol-2,4-cyclodiphosphate synthase (MECP), 4-hydroxy-3-methylbut-2-enyl diphosphate synthase (HDS) and 4-hydroxy-3-methylbut-2-enyl diphosphate reductase (HDR) were involved in the whole process[84]. The common precursor of sesquiterpenes is farnesyl diphosphate (FPP) synthesized from IPP and DMAPP under the catalysis of farnesyl diphosphate synthase (FPPS)[85]. Various sesquiterpene synthases, such as β-farnesene synthase (β-FS), germacrene A synthase (GAS), β-caryophyllene synthase (QHS), convert the universal precursor FPP into more than 300 different sesquiterpene skeletons in different species[8689]. Unfortunately, in A. macrocephala, only the functions of AmFPPS in the sesquiterpenoid biosynthetic pathway have been validated in vitro[90]. Identifying sesquiterpene biosynthesis in A. macrocephala is difficult due to the lack of: isotope-labeled biosynthetic pathways, constructed genetic transformation system, and high-quality genome.

    Figure 6.  Biosynthetic pathways for bioactive compounds of A. macrocephala.

    With the gradual application of transcriptome sequencing technology in the study of some non-model plants, the study of A. macrocephala has entered the stage of advanced genetics and genomics. Yang et al. determined the sesquiterpene content in the volatile oil of AMR by gas chromatography and mass spectrometry (GC-MS) in A. macrocephala. Mixed samples of leaves, stems, rhizomes, and flowers of A. macrocephala were sequenced by Illumina high throughput sequencing technology[91]. Similarly, compounds' relative content in five A. macrocephala tissue was quantitatively detected by ultra-performance liquid chromatography-tandem mass spectrometry. Sesquiterpenoids accumulations in rhizomes and roots were reported[90]. Seventy-three terpenoid skeleton synthetases and 14 transcription factors highly expressed in rhizomes were identified by transcriptome analysis. At the same time, the function of AmFPPS related to the terpenoid synthesis pathway in A. macrocephala was verified in vitro[90]. In addition to the study of the different tissue parts of A. macrocephala, the different origin of A. macrocephala is also worthy of attention. The AMR from different producing areas was sequenced by transcriptome. Seasonal effects in A. macrocephala were also studied. Interestingly, compared with one-year growth AMR, the decrease of terpenes and polyketone metabolites in three-year growth AMR was correlated with the decreased expression of terpene synthesis genes[92]. Infestation of Sclerotium rolfsii sacc (S. rolfsii) is one of the main threats encountered in producing A. macrocephala[93]. To explore the expression changes of A. macrocephala-related genes after chrysanthemum indicum polysaccharide (CIP) induction, especially those related to defense, the samples before and after treatment were sequenced. The expression levels of defense-related genes, such as polyphenol oxidase (PPO) and phenylalanine ammonia-lyase (PAL) genes, were upregulated in A. macrocephala after CIP treatment[94].

    Traditional Chinese Medicine (TCM), specifically herbal medicine, possesses intricate chemical compositions due to both primary and secondary metabolites that exhibit a broad spectrum of properties, such as acidity-base, polarity, molecular mass, and content. The diverse nature of these components poses significant challenges when conducting quality investigations of TCM[95]. Recent advancements in analytical technologies have contributed significantly to the profiling and characterizing of various natural compounds present in TCM and its compound formulae. Novel separation and identification techniques have gained prominence in this regard. The aerial part of A. macrocephala (APA) has been studied for its anti-inflammatory and antioxidant properties. The active constituents have been analyzed using high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS). The results indicated that APA extracts and all sub-fractions contain a rich source of phenolics and flavonoids. The APA extracts and sub-fractions (particularly ACE 10-containing constituents) exhibited significant anti-inflammatory and antioxidant activity[96]. In another study, a four-dimensional separation approach was employed using offline two-dimensional liquid chromatography ion mobility time-of-flight mass spectrometry (2D-LC/IM-TOF-MS) in combination with database-driven computational peak annotation. A total of 251 components were identified or tentatively characterized from A. macrocephala, including 115 sesquiterpenoids, 90 polyacetylenes, 11 flavonoids, nine benzoquinones, 12 coumarins, and 14 other compounds. This methodology significantly improved in identifying minor plant components compared to conventional LC/MS approaches[97]. Activity-guided separation was employed to identify antioxidant response element (ARE)-inducing constituents from the rhizomes of dried A. macrocephala. The combination of centrifugal partition chromatography (CPC) and an ARE luciferase reporter assay performed the separation. The study's results indicate that CPC is a potent tool for bioactivity-guided purification from natural products[98]. In addition, 1H NMR-based metabolic profiling and genetic assessment help identify members of the Atractylodes genus[99]. Moreover, there were many volatile chemical compositions in A. macrocephala. The fatty acyl composition of seeds from A. macrocephala was determined by GC-MS of fatty acid methyl esters and 3-pyridylcarbinol esters[100]. Fifteen compounds were identified in the essential oil extracted from the wild rhizome of Qimen A. macrocephala. The major components identified through gas chromatography-mass spectrometry (GC-MS) analysis were atractylone (39.22%) and β-eudesmol (27.70%). Moreover, gas purge microsolvent extraction (GP-MSE) combined with GC-MS can effectively characterize three species belonging to the Atractylodes family (A. macrocephala, A. japonica, and A. lancea)[101].

    So far, the research on A. macrocephala has focused on pharmacological aspects, with less scientific attention to biogeography, PAO-ZHI processing, biosynthesis pathways for bioactive compounds, and technology application. The different origins lead to specific differences in appearance, volatile oil content, volatile oil composition, and relative percentage content of A. macrocephala. However, A. macrocephala resources lack a systematic monitoring system regarding origin traceability and quality control, and there is no standardized process for origin differentiation. Besides, the PAO-ZHI processing of A. macrocephala is designed to reduce toxicity and increase effectiveness. The active components will have different changes before and after processing. But current research has not been able to decipher the mechanism by which the processing produces its effects. Adaptation of in vivo and in vitro can facilitate understanding the biological activity. The choice of the models and doses is particularly important. The recent studies that identified AMR bioactivities provided new evidence but are somewhat scattered. For example, in different studies, the same biological activity corresponds to different signaling pathways, but the relationship between the signaling pathways has not been determined. Therefore, a more systematic study of the various activities of AMR is one of the directions for future pharmacological activity research of A. macrocephala. In addition, whether there are synergistic effects among the active components in AMR also deserves further study, but they are also more exhaustive. As for the biosynthesis of bioactive compounds in A. macrocephala, the lack of isotopic markers, mature genetic transformation systems, and high-quality genomic prediction of biosynthetic pathways challenge the progress in sesquiterpene characterization. In recent years, the transcriptomes of different types of A. macrocephala have provided a theoretical basis and research foundation for further exploration of functional genes and molecular regulatory mechanisms but still lack systematicity. Ulteriorly, applying new technologies will gradually unlock the mystery of A. macrocephala.

    This work was supported by the Key Scientific and Technological Grant of Zhejiang for Breeding New Agricultural Varieties (2021C02074), National Young Qihuang Scholars Training Program, National 'Ten-thousand Talents Program' for Leading Talents of Science and Technology Innovation in China, National Natural Science Foundation of China (81522049), Zhejiang Provincial Program for the Cultivation of High level Innovative Health Talents, Zhejiang Provincial Ten Thousands Program for Leading Talents of Science and Technology Innovation (2018R52050), Research Projects of Zhejiang Chinese Medical University (2021JKZDZC06, 2022JKZKTS18). We appreciate the great help/technical support/experimental support from the Public Platform of Pharmaceutical/Medical Research Center, Academy of Chinese Medical Science, Zhejiang Chinese Medical University.

  • The authors declare that they have no conflict of interest.

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  • Cite this article

    Wolski EA. 2023. The versatility of Penicillium species to degrade organic pollutants and its use for wastewater treatment. Studies in Fungi 8:2 doi: 10.48130/SIF-2023-0002
    Wolski EA. 2023. The versatility of Penicillium species to degrade organic pollutants and its use for wastewater treatment. Studies in Fungi 8:2 doi: 10.48130/SIF-2023-0002

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The versatility of Penicillium species to degrade organic pollutants and its use for wastewater treatment

Studies in Fungi  8 Article number: 2  (2023)  |  Cite this article

Abstract: The removal of xenobiotics from industrial wastewater is of great interest to avoid environmental contamination. Penicillium species have been shown to be able to adapt its metabolism to many different circumstances and these fungi can use different xenobiotics as a carbon source. In this review, the ability of Penicillium to degrade different xenobiotic compounds is discussed. This review describes not only the biodegradation processes but also addresses the toxicity of the degradation products as well as the potential application of these processes in wastewater treatment. Penicillium strains have proven to be versatile and capable of being used for the biodegradation of different organic pollutants (phenols, azo dyes, hydrocarbons, pharmaceutical compounds, etc.) and show high potential to be used for wastewater treatment. From this review, it is concluded that beyond the degradation and optimization processes; pilot scale studies and toxicity must be carried out.

    • Wastewater generated by chemical, petrochemical, textile, resins, paper, leather, and glue, pharmaceutical and steel industries frequently contain high concentrations of xenobiotic compounds that represent a serious ecological problem due to their toxicity and widespread occurrence in the environment.

      A xenobiotic compound is a chemical substance whose structure is rare or non-existent in nature as they are synthesized by humans in the laboratory. Xenobiotic compounds are also defined as substances that are present in concentrations much higher than usual and that would not be expected to be present within organisms. The discharge of wastewater containing different kinds of xenobiotics, into receiving water bodies endanger aquatic life, even at relatively low contaminant concentrations. Therefore, the removal of these xenobiotics from industrial wastewater is of great practical significance for environmental protection.

      Several physicochemical and biological methods have been adapted for the treatment of different kinds of xenobiotics. In recent years, biological processes for xenobiotic degradation and wastewater reutilization have been developed including aerobic and anaerobic bacteria as well as fungi. There are many reports about the potential of filamentous fungi for sludge treatment which have been well described and reviewed by More et al.[1]. Aspergillus niger showed biodegradation and bioflocculation activities, arsenic bioremediation and bioconversion of olive mill waste. Phanerochaete chrysosporium showed biodegradation and bioflocculation activities, bioremediation of lignin, PCB's, PCP's and azo dyes. Penicillium (in particular P. chrysogenum) and Paecilomyces species showed pathogen removal, bioflocculation and biodegradation activities, and the removal of arsenic compounds and insecticides, among others.

      In general, filamentous fungi have shown to be more tolerant to high concentrations of pollutants and they are less sensitive than bacteria and yeast to changes in their environment[1, 2]. Some fungi tolerate extreme environmental conditions (temperatures of –5 to +60 °C; pH of 1 to 9) and grow at a water activity of only 0.65, or with 0.2% oxygen[3]. They are able to grow on low nitrogen medium, at low pH and low temperature[1]. In addition, they are easy to grow in fermenters and be separated by mechanical methods, due to their filamentous structure[2, 4]. All these characteristics make them a promising alternative among various wastewater treatment technologies.

      Among fungi, the most widely studied are the ligninolytic fungi or white rot basidiomycota fungi. However, these types of fungi often have two major limiting factors that hinder their applicability in industry: 1) they have high nutritional requirements (lignocellulosic substrate), and 2) many species have slow growth kinetics[5]. This encourages the study of other types of fungi[46]. Many non-basidiomycota fungi are also able to degrade aromatic compounds and other complex structures[2, 612]. A good example of this kind of non-basidiomycota fungi is Penicillium sp., which belongs to the phylum Ascomycota.

      Penicillium species are able to adapt their metabolism to many different environments, and are considered ubiquitous in nature, commonly found in food, indoor air and soil. In addition, they are among the most common fungi that spoil food and contaminate indoor environments[2, 13, 14]. Diversity and adaptable metabolism of Penicillium species allows them to survive in some of the most extreme environments on earth including deep-sea sediments[15], polar regions[16, 17] to the Himalayas[18], regions of extreme acidic pH[19] and in extreme temperatures[20]. Although, primarily categorized as decomposers, Penicillium are good hydrocarbon assimilators with low co-substrate requirements, and they can synthesize a of wide variety of biomolecules[2, 13, 14]. The use of various carbon sources demonstrates their capability to adapt to changing nutritional environments and their potential to decompose diverse materials.

      There are many reports showing the ability of Penicillium to degrade various materials, including food waste, cellulose- and lignin-containing residues, and hydrocarbons[9, 11, 21, 22] and to transform xenobiotic compounds into less mutagenic substances[68, 23, 24]. The occurrence of Penicillium spp. in sewage sludge has been reported[25]. In addition, Penicillium corylophilum was more efficient compared to Aspergillus niger for biodegradation of the domestic activated sludge, enhancing the sludge degradation rate by decreasing chemical oxygen demand (COD).

      Filamentous fungi can grow on different matrices. In submerged culture, fungi can either grow in dispersed form or as spherical pellets consisting of aggregated hypha structures. Pellet morphology, process control and productivity are highly interlinked. The control process in a bioreactor usually requires compact and small pellets due to rheological issues[26]. For example, within P. chrysogenum pellets, problems with internal transport of substrates and products may occur, depending on size and compactness of pellets[27]. Cronenberg et al.[28], reported the formation of pellets with a diameter of less than 400 μm by P. chrysogenum, where the mass transfer resistance will be very low in these pellets, being an advantage for the wastewater treatment process. Moreover, the immobilization of P. chrysogenum on loofah showed a significant increase of azo dye degradation rate, with respect to the free cells[4]. Both, the immobilization and the pellet formation, leads to the possibility of biomass reuse and simplifies the operation for downstream processes.

      All the features mentioned above make Penicillium particularly suitable to be used in wastewater treatment and degradation of organic pollutants. In this review, a summary of the capabilities of some species of Penicillium to degrade different toxic compounds are described and the analysis of its potential use for wastewater treatment is discussed.

    • Phenol and its derivatives are widely distributed as environmental pollutants due to their presence in the effluents of many industrial processes like chemical, petrochemical, steel, pulp and paper mill industries[2]. These effluents frequently contain high concentrations of phenolics compounds that represents a serious ecological problem due to their widespread use, toxicity and occurrence throughout the environment. Many phenolic compounds are hazardous, toxic, endocrine disrupting, mutagenic, teratogenic, and/or carcinogenic[29]. Therefore, the removal of phenol and its derivatives from industrial wastewater is of great practical significance for environmental protection. Moreover, chlorophenols have been introduced into the environment through their use as biocides, for example penta chlorophenol (PCP), trichlorophenol (TCP) and tectrachloro phenol (TeCP) were used historically as fungicides in wood-preservative formulations[30, 31].

      The biodegradation of phenols and chlorophenols by Penicillium species has been reported since the 90's and several works have continued studys in this regard (Table 1). In 1993, Hofrichter et al.[32] reported a Penicillium strain (Bi 7/2) able to grow on phenol (1,000 mg·l−1) as sole source of carbon and energy, and metabolized the phenol by the ortho-pathway. This strain also metabolizes 4-, 3- and 2-chlorophenol (50 mg·l−1) and 4-, 3- and 2-nitrophenol (50 mg·l−1), with phenol or glucose as co-substrate. The fact that an external carbon source, such as glucose, is needed implies an additional cost for the process. However, many Penicillium species can use phenol as a carbon source. This facilitates the development of a treatment process, since most of the effluents that contain chlorophenols, for example effluents from pulp and paper mill industries, contains phenol that can be utilized as a carbon source. Later, Marr et al.[33] found a Penicllium simplicissimum SK9117 strain able to degrade 3-chlorophenol, 4-chlorophenol, 4-bromophenol, 3-fluorophenol and 4-fluorophenol. However, monobromophenols and monochlorophenols were transformed to other intermediates (chlorohydroquinone, 4-chlorocatechol, 4-chloro-1,2,3-trihydroxybenzene, and 5-chloro-1,2,3-trihydroxybenzene) and could not support the fungus growth as the sole carbon and energy source, while monofluorophenols were mineralized completely without a co-substrate. In addition, difluorophenols were transformed by P. frequentans strain Bi 7/2, using phenol as a sole source of carbon and energy[35]. From the 90’s onwards, even up to 2021, more species of Penicillium were described with the ability to degrade phenol and chlorophenols (Table 1).

      Table 1.  Degradation of phenol and its derivatives by Penicillium spp.

      Chemical compoundExternal
      carbon source
      Penicillium spp.Reference
      PhenolNoneP. frequentans Bi 7/2[32]
      P. chrysogenum var. halophenolicum[23]
      P. chrysogenum ERK1[8, 37]
      P. notatum[41]
      ResorcinolNoneP. chrysogenum var. halophenolicum[24, 36]
      Catechol,
      Hydroquinone
      NoneP. chrysogenum var. halophenolicum[36]
      2-chlorophenolPhenolP. frequentans Bi 7/2[32]
      AcetateP. camemberti[39]
      3-chlorophenolPhenolP. frequentans Bi 7/2[32]
      P. simplicissimum[33]
      4-chlorophenolPhenolP. frequentans Bi 7/2[32]
      P. simplicissimum[33]
      2-nitrophenolPhenolP. frequentans Bi 7/2[32]
      3-nitrophenolPhenolP. frequentans Bi 7/2[32]
      4-nitrophenolPhenolP. frequentans Bi 7/2[32]
      4-bromophenolPhenolP. simplicissimum[33]
      3-fluorophenolNoneP. simplicissimum[33]
      4-fluorophenolNoneP. simplicissimum[33]
      2,3- difluorophenolPhenolP. frequentans Bi 7/2[35]
      2,4- difluorophenolPhenolP. frequentans Bi 7/2[35]
      2,5- difluorophenolPhenolP. frequentans Bi 7/2[35]
      3,4- difluorophenolPhenolP. frequentans Bi 7/2[35]
      2,4,6-trichlorophenolAcetateP. chrysogenum ERK1[7]
      PentachlorophenolAcetateP. camemberti[39]
      3,5-dimethyl-2,4-dichlorophenolNonePenicillium spp[40]

      A case worth mentioning is that described by Leitão et al.[23], where a Penicillium chrysogenum var. halophenolicum was able to mineralize phenol completely at 5.8% NaCl, since this fungus was found to be halotolerant. This condition increases the chances to use this strain in biological treatments of phenol-containing wastewater, since some of them contain high concentrations of salts. The same strain degraded up to 250 mg·l−1 of resorcinol, as the sole carbon source in batch experiments in the presence of 58.5 g·l−1 of sodium chloride[24]. In addition, the authors showed the decrease of the acute toxicity of phenol and resorcinol, on Artemia franciscana larvae, after the bioremediation process with P. chrysogenum var. halophenolicum. Ferreira-Guedes & Leitão[36], described the removal efficiency of hydroquinone, catechol and resorcinol in binary substrate systems under saline conditions by the same P. chrysogenum var. halophenolicum strain. Catechol, resorcinol and hydroquinone are dihydroxybenzene isomers. The simultaneous presence of two or three isomers in a mixture will be defined as binary or ternary mixtures. The results of Ferreira-Guedes & Leitão[36] showed that the efficiency to remove dihydroxybenzene in binary substrate systems was higher than in mono substrate systems, except for hydroquinone. In the binary substrate systems, dihydroxybenzenes were removed not only simultaneously, but also preferentially. At high dihydroxybenzene concentration, fungal strain preferentially degraded hydroquinone followed by catechol and resorcinol.

      Most of the results reported in Table 1, were obtained in batch culture in shaking conditions between 80 to 160 rpm. However, some studies showed that Penicillium frequentans Bi 7/2 and Penicillium chrysogeunm ERK1 could degrade dichlorophenols and phenol, respectively in resting mycelium conditions[35,37]. This may be convenient in terms of reducing the costs of wastewater treatment processes.

      Furthermore, Aranciaga et al.[7] studied the biodegradation of 2,4,6-trichlorophenol, demonstrating that Penicillium chrysogenum ERK1 was able to degrade 85% of TCP in batch cultures in the presence of sodium acetate. In their study, hydroquinone and benzo quinone were identified as degradation intermediates, and although the complete mineralization of the TCP did not occur, a reduction on the phytotoxicity (50% approximately) was observed. The extent of degradation depends on the structure of the compound, the number of chlorine substituents, and the position of chlorine in the compound[38]. This directly influences the toxicity of the compound, which generally increases as the chlorinated substituents number increases. That is why it is equally important to reduce the toxicity of the effluent, even when the compound cannot be completely mineralized.

      In the case of pentachlorophenol (PCP), Taseli & Gokcay[39] showed that Penicillium camemberti was able to remove 56% of PCP in batch experiments with acetate as a carbon source. In other experiments, without acetate but in the presence of Tween 80, P. camemberti removed 86% of the PCP. Moreover, an up-flow column reactor was operated with this fungus in the laboratory[39] and 77% of PCP removal was achieved in 4 d of contact without aeration and with minimum amount of carbon supplement. The percentages of PCP removal continued decreasing to 18.8% until the 18th day. These results agree with the results mentioned above, and show almost ideal conditions with respect to operating costs, without aeration and a reduced concentration of external carbon source.

      In another study, Yan et al.[40] studied the performance of a Penicillium sp. strain to remove a 3,5-dimethyl-2,4-dichlorophenol (DCMX) from saline industrial wastewater. The results of batch experiments showed that biodegradation of DCMX was affected by pH value, salinity and DCMX concentration. The maximum DCMX removal efficiency was obtained at salinity 2.6%, temperature 32 °C and pH 5.87.

    • The term colorant, which includes dyes and pigments, refers to substances capable of colouring a substrate. Colorants are used in industries like clothing, paints, plastics, photographs, prints and ceramics. They are used alone or in combination with other ingredients, which impart or alter the colour of the product[42]. Most dyes used in these processes are synthetic and are classified based on chromophore structures (namely acidic, basic, disperse, reactive, azo dyes and anthraquinone).

      Dye wastewater treatment, mainly from textile industries, is really important in order to control its negative impact on the environment. Some dye precursors or its degradation byproducts were reported as toxic, carcinogenic and mutagenic[43,44], like aromatic amines which damage the DNA in cells and this leads to a risk of cancer[42].

      The mycoremediation of dyes has shown to be a possible option to the conventional physico-chemical treatment technologies. The most widely used fungi in decolorization and degradation of dyes are the lignolytic fungi of class Basidiomycetes. However, non basidiomycotas fungi such as Aspergillus niger and A. terreus[45], Rhizopus oryzae[46] and some species of Penicillium[39,4749] can also decolorize and/or biosorb diverse dyes[50,51].

      For example, Shedbalkar et al.[47] showed that Penicillium ochrochloron decolorized cotton blue (50 mg·l−1), a triphenylmethane dye (Table 2). In this case, the dye was degraded to sulphonamide and triphenylmethane, as final products, by a battery of enzymes (lignin peroxidase, tyrosinase and aminopyrine N-demethylase) and the analysis of the phytotoxicity and microbial toxicity of extracted metabolites, suggested a decrease in their toxicity. The same P. ochrochloron has been shown to detoxify malachite green into p-benzyl-N,N-dimethylaniline and N,N-dimethyl-aniline hydrochloride. These metabolites were nontoxic when tested on Triticum aestivum and Ervum lens Linn (Table 2)[48]. The reaction was mediated by lignin peroxidase and the fungal culture was also found to have detoxified the textile effluent, reducing the values of total dissolved solids (TDS), total suspended solids (TSS), biochemical oxygen demand (BOD), and chemical oxygen demand (COD). In both works, it was demonstrated that P. ochrochloron was able to degrade and reduce the toxicity of two different dyes. However, it would be interesting to study the degradation and the analysis of the toxicity of the mixture of both dyes.

      Table 2.  Dye decolorization and degradation by Penicillium spp.

      Penicillium sppChemical groupDye nameConcentration
      (mg·l−1)
      Toxicity analysisWastewater testedReference
      P. chrysogenumAzo
      Direct Black 22,
      Direct Yellow 86,
      Direct Blue 200
      200T. aestivumDiluted effluent[4, 6]
      P. ochrochloronTriphenylmethane
      Cotton blue50T. aestivum
      E. lens
      A. vinelandii

      No[47]
      Malachite green50T. aestivum
      E. lens
      Diluted effluent[48]
      P. simplicissimum

      Azo

      Reactive Red 198 Reactive Blue 214200
      D. pulexNo[52]
      PhthalocyanineReactive Blue 21200D. pulexNo[52]
      TriphenylmethaneMethyl Violet, Crystal Violet, Malachite Green
      Cotton Blue
      50−100

      V. radiate
      B. cereus
      S. aureus
      No[53, 54]
      P. oxalicumAzoAcid Red 183, Direct Blue 15 Direct Red 75100−300NoNo[5]
      P. pinophilumTriphenylmethaneMalachite Green10NoNo[55]

      Moreover, Penicillium simplicissimum INCQS 40211 decolorized the textile dyes: Reactive Red 198 (RR198), Reactive Blue 214 (RB214), Reactive Blue 21 (RB21) and their mixture[52]. In this case, it was suggested that dye decolorization involved dye adsorption by the biomass first, followed by degradation. In addition, P. simplicissimum reduced the toxicity of RB21 from moderately acutely toxic to minor acutely toxic and it also reduced the toxicity of RB214 and the mixture of the three dyes, which remained minor acutely toxic. It is also worth noticing that the fungus increased the toxicity of RR198. These results showed that more studies regarding dye degradation and toxicity reduction by P. simplicissimum INCQS 40211 are necessary. Later, Chen & Ting[53] and Chen et al.[54] described the biosorption and biodegradation activities of the same Penicillium species towards triphenylmethane dyes. Crystal Violet (CV), Methyl Violet (MV), Malachite Green (MG), and Cotton Blue (CB) were decolorized by P. simplicissimum with 98.7%, 97.5%, 97.1%, and 96.1 % of decolorization efficiency, respectively, within 2 h of incubation (50 mg·l−1, pH 5.0, 25 ± 2 °C) (Table 2). In this work, only UV–visible spectral analysis of dyes was conducted before and after treatment with P. simplicissimum, indicating the occurrence of biodegradation, however the intermediate products of the degradation or complete mineralization could not be confirmed. Some enzymatic activities were detected as manganese peroxidase, tyrosinase, triphenylmethane reductase activities, suggesting their involvement in the degradation pathway. In addition, reduction of phytotoxicity and microbial toxicity were observed only for MG.

      Other Penicillium species that have been reported to have decolorization/degradation abilities are: Penicillium oxalicum[5], Penicillium pinophilum[55], Penicillium purpurogenum[56] and a Penicillium strain not characterized at the species level[57].

      In all the cases mentioned above, degradation occurs with the addition of some external carbon source. In general, dyes are evaluated in culture media and only in a few cases mixtures of dyes and real effluents are studied.

      Another strain, which is worth mentioning, is Penicillium chrysogenum. This fungus showed great potential to decolorize and degrade three azo dyes (at 200 mg·l−1) independently or a mixture of them, even in a complex wastewater matrix as it was real textile wastewater[6] (Table 2). The degradation process was carried out in the presence of glucose as a carbon source and showed that decolorization rates differed depending on the azo dye structure (number of azo bonds, terminal or substituent groups, steric hindrance, etc.). Moreover, a kinetic model for degradation was developed, which allowed prediction of the degradation kinetics of the mixture of the three azo dyes and the real textile wastewater[6]. Later, the immobilization on loofah of the same strain of P. chrysogenum significantly increased the degradation rate of DB22 in a laboratory scale as well as at bench scale reactor, with respect to the non-immobilized treatment[4]. The degradation rate of immobilized cells increased twice as compared to free-cells control and at day 5 the decolorization was almost complete, while without loofah, the total decolorization took more than 10 d. The results of these studies show an improvement in the azo dye degradation process, however, using glucose as a carbon source is still costly. Therefore, more studies should be carried out using alternative carbon sources such as waste from food industries, for example starch, beer bagasse, etc. to minimize effluent treatment costs.

      Erdal & Taskin[58], also showed the potential of a strain of P. chrysogenum MT-6 to decolorize the textile dye Reactive Black-5. However, degradation was not confirmed in this case.

      Lately, Fouda et al.[59] biosynthesized maghemite nanoparticles (γ-Fe2O3-NPs) using Penicillium expansum with the purpose of treating wastewater. Decolorization and degradation analyses, indicated that γ-Fe2O3-NPs was an effective biocatalyst for dye degradation under dose- and time-dependent manner. The highest decolorization (89%–90%) occurred after 6.0–8.0 h of incubation. The contaminant load of the textile wastewater was improved, as indicated by the reduction in COD, TDS, and TSS. Although, GC-MS results showed the complete disappearance of peaks in treated textile wastewater in comparison with the untreated samples, no toxicity analysis was carried out.

    • In recent years, the increase in the use and production of pharmaceutical compounds represent a potential environmental risk, since it could lead to antibiotic resistance, toxicity and can also cause endocrine disruption[10, 12, 60, 61]. For this reason, a proper disposal and treatment or degradation of these compounds is necessary.

      In this area, additional examples of biodegradation with Penicillium isolates can be found[10, 12]. For example, the non-steroidal anti-inflammatory drug [2-(2,6-dichloroanilino) phenyl] acetic acid (Diclofenac; DFC) is used for the treatment of pain and inflammation, and it is one of the most widely used drugs around the world. It is considered as an emerging contaminant, being the number one persistent pharmaceutical substance in water bodies in 50 countries of the EU, Africa and America[62]. Olicón-Hernández et al.[10], were the first to describe the use of a Penicillium isolate able to transform DFC. They studied DFC degradation by Penicillium oxalicum in flask and bench scale bioreactors, both with free and immobilized biomass. Pellets of P. oxalicum degraded 100 μM of DFC within 24 h, and the activity of CYP450 enzymes was the key for the drug elimination. The use of P. oxalicum reduced the acute toxicity of the medium supplemented with DFC, and the free biomass system exhibited the highest rate of DFC degradation in comparison with immobilized cells in the batch bioreactor. In addition, the same Penicillium isolate was able to reduce the concentration of other pharmaceutical active compounds, such as ketoprofen, naproxen and paracetamol in batch bench scale bioreactor in 24 h[61]. In general, the industrial effluents are not sterile and they usually have microorganisms, which can inhibit the growth and/or the degradation of toxic compounds by the degrading microorganisms that are of interest for wastewater treatment. For this reasons, the results obtained by Olicón-Hernández et al.[61] are of great importance since they showed that P. oxalicum inhibited the native fungal populations, present in the non-sterile real hospital wastewater, along with opportunistic human pathogens.

      As it can be seen, in the case of DFC degradation, the immobilized cells did not improve the process, contrary to what was observed for the degradation of azo dyes with P. chrysogenum. For this reason, the treatment process of each effluent must be analysed independently to achieve optimal operating conditions.

      Additionally, Li et al.[12], recently reported a Penicillium oxalicum strain that could efficiently degrade lincomycin (88.2% by day 6) from the antibiotic wastewater treatment plant and the fungal mycelium could be reused for at least ten batches with similar biodegradation efficiency. Besides, an endophytic strain of the same species could effectively degrade triclosan, which is an antibacterial and antifungal agent, into low toxic products[63].

      These studies showed that P. oxalicum was able to reduce the concentration of pharmaceutical compounds in batch bench scale bioreactor, also it was not inhibited by the native fungal populations present in the effluent and the mycelium could be reused with good biodegradation efficiency. These characteristics strongly suggest that P. oxalicum has a high potential for the treatment of pharmaceutical compounds.

    • Polycyclic aromatic hydrocarbons (PAHs) are poorly soluble, hydrophobic organic compounds which are among the most widely distributed organic contaminants[2]. They are released/transposed due to incomplete combustion of organic matter in petrochemical industries and proven to be highly genotoxic, mutagenic, carcinogenic as well as teratogenic to humans[64]. The PAHs are considered important environmental pollutants since they are the most frequently found in soil pollutants[65].

      As described by Leitão[2] and Rabha & Jha[14], there are several reports regarding biodegradation of PAHs by Penicillium species[34, 6672] (Table 3). The effect of oxygen, ciclodextrins, surfactants, carbon and nitrogen sources, and other factors on PAHs biodegradation were studied in these reports. In addition, the presence of pyrene for example was described to influence the size and shape of the fungal pellets as well as the density of mycelium and hyphal length[71]. These studies, showed the degradation of different PAHs separately. In 2014, Vanishree et al.[73] isolated a Penicillium sp. strain from petrol bunks soils and automobile workshops which can tolerate, grow and degrade different petrol concentrations.

      Table 3.  Hydrocarbon degradation by Penicillium spp.

      Chemical compoundPenicillium sppReference
      AcenaphthenePenicillium sp. CHY-2[74]
      AnthraceneP. oxalicum[75]
      P. ilerdanum[76]
      P. oxalicum SYJ-1[77]
      Benzo[a]pyrenePenicillium sp. CHY-2[74]
      P. janthinellum[66, 67]
      Benz[a]antraceneP. janthinellum[67]
      ButylbenzenePenicillium sp. CHY-2[74]
      ChryseneP. janthinellum[67]
      EthylbenzenePenicillium sp. CHY-2[74]
      Dibenz[a,h]anthraceneP. janthinellum[67]
      DibenzothiopheneP. oxalicum[75]
      DibenzofuranP. oxalicum[75]
      FluoreneP. italicum[69]
      P chrysogenum[68]
      FluorantheneP. ilerdanum[76]
      NaphthaleneP. ilerdanum[76]
      Penicillium sp. CHY-2[74]
      PhenanthreneP. frequentans[72]
      P. ilerdanum[76]
      P. oxalicum[75]
      P. oxalicum SYJ-1[77]
      PyreneP. simplicissimum,
      P. funiculosum,
      P. harzianum,
      P. terrestre
      [70]
      P. janthinellum,[66,67,70]
      P. ochrochloron[71]
      P. glabrum[34]
      P. ilerdanum[76]
      Penicillium oxalicum SYJ-1[77]
      PetrolPenicillium sp[73]
      DecanePenicillium sp. CHY-2[74]
      DodecanePenicillium sp. CHY-2[74]
      OctanePenicillium sp. CHY-2[74]

      Penicillium oxalicum was also reported to be able to completely remove anthracene and dibenzothiophene within 4 d, as well as phenanthrene and dibenzofuran, although at slower rates[75]. Most Penicillium strains which degrade PAHs carried out the degradation through the cytochrome P450 monooxygenase enzyme pathway. However, cytochrome P450 monooxygenase plays a role in the first steps of transformation of PAHs, while induction of oxygenase activity was detected in the subcellular fraction of the fungal mycelium exposed to these aromatic compounds.

      Aranda et al.[75] demonstrated that glucose was required for anthracene degradation by P. oxalicum using a defined growth medium with low carbon content for stable isotope tracer experiments with 13C 6-anthracene. Therefore, anthracene mineralization could not be confirmed, but 13C-labelled oxy and hydroxy-derivatives were identified by nuclear magnetic resonance (NMR) as major metabolites. Although P. oxalicum was found to be the fungus with the highest and fastest PAHs degradation capability, the toxicity of these major metabolites should be evaluated, for a safe application in biotechnological pollutant removal processes.

      Antarctic soil has also been a source of hydrocarbon degrading microorganisms[78,79] including Penicillium. A Penicillium sp. CHY-2 isolated from Antarctic soil was able to degrade not only aromatic hydrocarbons but also aliphatic hydrocarbons[74]. The highest level of degradation was for decane (49.0%), followed by butylbenzene (42.0%) and dodecane (33.0%), and lower levels of degradation were found for naphthalene (15.0%), acenaphthene (10.0%), octane (8.0%), ethylbenzene (4.0%), and benzo[a]pyrene (2.0%) at 20 °C. Later, the authors studied decane degradation in depth and showed that the addition of carbon sources such as glucose (5 g·l1) and Tween-80 (5 g·l1) enhanced decane degradation by about 1.8-fold and 1.61-fold respectively at 20 °C. 1,6-hexanediol was identified as one of the metabolites produced during the degradation of decane and a manganese peroxidase (MnP) enzyme was isolated from the fungi.

      Over the years, more and more studies with new isolates able to degrade hydrocarbons have appeared, for example in 2021 a Penicillium ilerdanum NPDF1239-K3-F21, isolated from Arabian sea sediments, showed > 75% ability to degrade naphthalene, phenanthrene, pyrene, fluoranthene and anthracene[76]. However, beyond the degradation processes, further optimization, pilot scale and toxicity studies must be carried out before applying these processes to wastewater or bioremediation treatments.

      Recently, Zhou et al.[77] showed a novel self-assembled PAH-degrading fungal mycelium Penicillium oxalicum SYJ-1-carbon nanotube (CNT) composites for pyrene removal. Their study is a good example of the combination of biodegradation and nanotechnology to increase the total PAH removal efficiency. Anthracene, phenanthrene and pyrene could be removed by 65%–92% within 72 h, while no naphthalene removal was observed by Penicillium oxalicum SYJ-1. Due to pyrene moderate degradation, this was selected as a model substrate to evaluate the possible positive effect of CNTs. The addition of it did not affect the growth of strain SYJ-1 and the complete removal of pyrene (20 mg·l1) was achieved within 48 h, while the sole fungus and CNTs alone could only remove 72% and 80% of pyrene at 72 h, respectively. Besides, the authors carried out a transcriptomic analysis, and a cytochrome P450 inhibition experiment and identified some degradation products, which allowed them to suggest that an intracellular PAH transformation pathway was employed by strain SYJ-1.

      Further, the versatility of the assembly approach was also confirmed by adding different nanomaterials (TiO2, δ-MnO2 and α-MnO2) and using them to remove phenanthrene, which was successful.

      Most of the studies carried out on hydrocarbon degradation by Penicillium spp. showed that pilot scale and toxicity studies on the metabolites are scarce, being an important point for the design of a suitable wastewater treatment.

    • Fats and oils are the major wastes generated by food processing industries, dairy industries, kitchen activities, bakeries and beverages industries, etc.[21]. In most countries, waste grease has been dumped in the litter site or sewage without any pretreatment leading to severe environmental issues[22]. Grease waste in effluents can cause serious problems such as a reduction in the cell-aqueous phase transfer rates (as well as gas-liquid), reduced sedimentation, and formation of floating sludge, clogging and the emergence of unpleasant odours[80]. For these reasons and due to the high pollutant content of these effluents, it is essential to apply an efficient treatment to release it into the environment. A good option for the treatment of fat-rich wastewater is enzymatic hydrolysis with lipases (Triacylglycerol acylhydrolases, E.C. 3.1.1.3)[21, 22, 81]. These enzymes catalyze esterification, inter-esterification, acidolysis, alcoholysis and aminolysis in addition to the hydrolytic activity on triglycerides[82] and are largely produced by filamentous fungi like Penicillium chrysogenum, Penicillium cyclopium, Penicillium simplicissiimum, Penicillium expansum, Candida rugosa, Aspergillus, Trichoderma etc.[8385]. For example, Kumar et al.[21] demonstrated the production of a novel lipase by Penicillium chrysogenum when it was growing in solid media containing waste grease. This enzyme was isolated, purified, characterized and it was applied on cooking oil waste showing high acid value (26.92 mg·g–1), indicating the presence of free fatty acids.

      Later, Kumari et al.[22], reported an effective way to bio-remediate grease waste with the combination of lipase pre-treatment (commercial lipases from different fungi) and P. chrysogenum fermentation. First, the authors pre-treated the grease waste using various lipases and then, this pre-treated grease was used as a substrate by P. chrysogenum. The resulting fermented media was analysed and the production of fatty acids was detected, showing high amounts of palmitic acid (2.8 g of palmitic acid recovered from 1.0 kg grease waste). In this case not only bioremediation was successful, but also fatty acid, a value-added product, was obtained from the waste.

      Moreover, the treatment of dairy wastewater has been described, using sequential and simultaneous treatment processes, where enzymatic hydrolysis was carried out by an isolate of Penicillium citrinum, followed by anaerobic digestion[81]. Free and immobilized whole cells were used as catalysts for the treatment of dairy wastewater. Free whole cells achieved a 1.3-fold higher percent hydrolysis (92.5%) than immobilized whole cells. The biodegradability tests were conducted using crude wastewater, wastewater prehydrolyzed by whole cells, and wastewater simultaneously submitted to whole-cell hydrolysis and biodigestion. The organic matter removal reaches about 43% in all tests. However, the use of whole cells reduced the lag phase time of methanogenic archaea, which accelerated anaerobic digestion, with a higher methane production rate. These results, demonstrated the advantages of using enzymatic hydrolysis combined with anaerobic digestion, whether sequentially or simultaneously.

    • So far we have reviewed large groups of organic pollutants, of which there are many references as we can see above, dyes, phenols, hydrocarbons, and others. Penicillium species have demonstrated their ability to degrade other xenobiotic compounds (Table 4).

      Table 4.  Degradation of other organic pollutants by Penicillium spp.

      CompoundPenicillium sppReference
      FormaldehydeP. chrysogenum DY-F2[86]
      DiethylketonePenicillium spp.[87]
      Polychlorinated biphenylsP. chrysogenum,
      P. citreosulfuratum,
      P. canescens.
      [88]
      Sodium dodecylbenzene sulfonateP. chrysogenum[11]
      Poly ɛ-caprolactone and Polyester vylon 200P. fellutanum (Lipases)
      [89, 90]

      In 2014, Luo et al.[86] reported a formaldehyde-degrading Penicillium chrysogenum DY-F2 strain, which was isolated from deep sea sediment. This characteristic is interesting, as this makes this fungus useful to be used for the bioremediation of polluted marine environment or wastewater with high salt content. In most studies reported previously, the fungi were isolated from contaminated soils, river sediments or from wastewater treatment plants. P. chrysogenum DY-F2 showed high formaldehyde resistance and was able to grow in the presence of formaldehyde up to 3,000 mg·l–1. In addition, it was able to degrade formaldehyde as the sole source of carbon and energy with the formation of formic acid as the intermediate. This study by Luo et al.[86] was the first to report degradation of formaldehyde by marine fungi.

      Some Penicillium species, like P. citreonigrum, P. oxalicum, P. chrysogenum, P. spinulosum, P. verruculosum and P. variabile can efficiently degrade diethyl ketone[87], sodium dodecyl benzene sulfonate[11] and grow well in agar media containing paraffin, chitin, cellulose, leather, pectin, skim milk, sunflower oil, and starch[9] (Table 4). However, the disappearance of the substrates was not measured, and therefore it cannot be confirmed that there was degradation or mineralization of these compounds.

      Polychlorinated biphenyls (PCBs) were widely used in electrical equipment and in heat transfer fluids. These pollutants are widespread, persistent, deleterious to the environment and very dangerous for humans. Germain et al.[88] recently described the isolation of four native fungal strains with a remarkable biodegradation capacity, greater than 70%. Three of the four isolates belong to the genus Penicillium: P. chrysogenum, P. citreosulfuratum and P. canescens. The last one was the only one that reduced the toxicity related to PCBs and their metabolites, significantly.

      Lately, Amin et al.[89, 90] described the degradation of poly ɛ-caprolactone (PCL), a biodegradable aliphatic polyester, and of polyester vylon 200 (PV-200), a synthetic non-biodegradable plastic, by lipases from Penicillium fellutanum. These lipases exhibited stability over a broad pH spectrum and by incubation with various industrially relevant organic solvents (benzene, hexanol, ether, and acetone). Under optimal operating conditions, lipase catalyzed the degradation of PCL film leading to 66% weight loss and 81% weight loss for PV-200. These results showed that P. fellutanum lipase would be a prospective green and ecofriendly biocatalytic system for efficient degradation and depolymerization of polyester for environmental safety.

    • The removal of xenobiotics from industrial wastewater is of great interest to avoid environmental contamination. Even though biodegradation and bioremediation with fungi have been well studied, they have not yet been successfully implemented.

      Penicillium species showed their ability to adapt their metabolism to many different circumstances and these fungi can use different xenobiotics as a carbon source. In this review, many different capabilities to degrade xenobiotic compounds by Penicillium species were summarized. This revision detailed some areas where there are few studies (pilot scale, toxicity, immobilization and consortia studies) and others where there is enough information (fungi isolation and degradation studies); however, in both cases the research should be addressed to obtain new tools for the treatment of wastewater that contain xenobiotic compounds.

      For the degradation of phenols and their chlorinated derivatives, most of the Penicillium species mentioned in this review were able to use phenol as a sole carbon source (with or without shaking) and degrade chlorophenols in the presence of an auxiliary carbon source, like phenol, glucose, acetate, etc. Most of the studies were carried out with P. simplicissimum and P. chrysogenum and in batch reactors, while only in one work an up-flow column reactor was operated.

      In the search for efficient treatments for the degradation of textile effluents, many studies on dye degradation by Penicillium have been carried out. Most of these are in batch culture, testing a few dyes in simulated wastewater and did not test the final toxicity of the degradation products, which is of great importance taking into account the production of toxic aromatic amines. Besides, in the case of azo dyes, the addition of a carbon source is necessary. It is worth mentioning the case of P. chrysogenum and P. ochrochloron which were tested on real textile wastewater and showed good results.

      At the time of this report, Penicillium oxalicum was the only species reported for the degradation of pharmaceutical compounds. This subject area has gained importance as in the last few years, antibiotic pollution has increased considerably. For this reason, more studies on this issue have to be carried out.

      There are several reports about the biodegradation of PAHs by Penicillium species. These studies range from degradation of aromatic hydrocarbons to aliphatic hydrocarbons. Most of the studies showed an increase in degradation by the addition of an external carbon source or surfactants and were carried out in batch cultures with the PAHs tested independently. Therefore, more studies have to be carried out on mixtures of PAHs and crude oil.

      Degradation of fats and oils using enzymatic hydrolysis with lipases from Penicillium species and the fungi have been successful and also allowed the recovery of fatty acids as a value-added product. In general, Penicillium showed good characteristics to be applied in fats and oils treatment, since it could form pellets and can be immobilized on loofa to increase the adsorption and degradation of fats.

      In all the studies, no toxicity assays were carried out or only were done on plants and bacteria. The analysis of the toxicity on different species (more than one toxicity test) is very important to understand the efficiency of the biodegradation treatment and select the final destination of the effluent more appropriately, that is, to determine if it can be dumped into the sea or re-used for irrigation, etc. In addition, there is a lack of studies on pilot and full-scale operation processes to solve large-scale problems. The same happens with consortia studies, since taking into account the great ability of different strains of Penicillium, one could think of using a consortium made up of several Penicillium species with different degrading capacities.

      Finally, Penicillium strains have proven to be versatile and capable of being used for the biodegradation of different pollutants in wastewater. These fungi can be found in abundance naturally in the environment and it would be a reasonably cheap solution. However, for all the cases mentioned and summarized in this review, it is clear that beyond the degradation and optimization processes; pilot scale studies and toxicity studies must be carried out to be able to apply these processes for wastewater or bioremediation treatments.

    • The author would like to thank National Scientific and Technical Research Council (CONICET) and National University of Mar del Plata for supporting this work. Thank you very much to Inés Lanfranconi and Jorge Froilán González for the critical reading of the manuscript and her helpful suggestions.

      • The author declares that there is no conflict of interest.

      • Copyright: © 2023 by the author(s). Published by Maximum Academic Press, Fayetteville, GA. This article is an open access article distributed under Creative Commons Attribution License (CC BY 4.0), visit https://creativecommons.org/licenses/by/4.0/.
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    Wolski EA. 2023. The versatility of Penicillium species to degrade organic pollutants and its use for wastewater treatment. Studies in Fungi 8:2 doi: 10.48130/SIF-2023-0002
    Wolski EA. 2023. The versatility of Penicillium species to degrade organic pollutants and its use for wastewater treatment. Studies in Fungi 8:2 doi: 10.48130/SIF-2023-0002

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