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Improvement of triterpenoid production in mycelia of Antrodia camphorata through mutagenesis breeding and amelioration of CCl₄-induced liver injury in mice.

ABSTRACT: Due to the scarcity of wild fruiting bodies, submerged fermentation of the medicinal fungus Antrodia camphorata is attracting much attention, but the production of bioactive triterpenoids is low. Therefore, there is an urgent need to improve the triterpenoid yield of submerged fermentation. Here, the A. camphorata mutant E3-64 was generated from strain AC16101 through random mutagenesis breeding, producing 172.8 mg triterpenoid per gram of dry mycelia. Further optimization of culture parameters resulted in a yield of 255.5 mg/g dry mycelia (i.e., an additional >1.4-fold increase), which is the highest reported yield thus far. Notably, mutant E3-64 produced 94% and 178% more of the triterpenoid components antcin A and antcamphin A, respectively, while it produced 52% and 15% less antcin B and G, respectively. Mutant E3-64 showed increased expression of key genes involved in triterpenoid biosynthesis, as well as different genome-wide single-nucleotide polymorphisms as compared with AC16101. Triterpenoids of the E3-64 mycelia exhibited remarkably protective activity against acute CCl₄-induced liver injury in mice. This study shows the potential of A. camphorata for scientific research and commercial application.

SUBMITTER: Wang HJ

PROVIDER: S-EPMC10558866 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Improvement of triterpenoid production in mycelia of Antrodia camphorata through mutagenesis breeding and amelioration of CCl4-induced liver injury in mice.

Wang Huan-Ju HJ Cui Ce C Gong Xiao-Mei XM Wang Shuo S Li Cheng-Xi CX Guo Hao H Wang Ya-Ling YL Huang Yu-Dan YD Jiang Jian-Lin JL Luo Xue-Mei XM Miao Jian-Hua JH Liu Tian-Qi TQ Zhao Shuai S Feng Jia-Xun JX

Heliyon 20230830 9

Due to the scarcity of wild fruiting bodies, submerged fermentation of the medicinal fungus Antrodia camphorata is attracting much attention, but the production of bioactive triterpenoids is low. Therefore, there is an urgent need to improve the triterpenoid yield of submerged fermentation. Here, the A. camphorata mutant E3-64 was generated from strain AC16101 through random mutagenesis breeding, producing 172.8 mg triterpenoid per gram of dry mycelia. Further optimization of cultu ...[more]

PMID: 37809917

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Project description:The present study was designed to evaluate the protective effect of sulphurenic acid (SA), a pure compound from Antrodia camphorata, on diabetes and hyperlipidemia in an animal model study and to clarify the underlying molecular mechanism. Diabetes was induced by daily 55 mg/kg intraperitoneal injections of streptozotocin (STZ) solution over five days. Diabetic mice were randomly divided into six groups and orally gavaged with SA (at three dosages) or glibenclamide (Glib), fenofibrate (Feno) or vehicle for 3 weeks. Our findings showed that STZ-induced diabetic mice had significantly increased fasting blood glucose, glycated hemoglobin (HbA1C), plasma triglyceride (TG), and total cholesterol (TC) levels (p < 0.001, p < 0.001, p < 0.001, and p < 0.05, respectively) but decreased blood insulin, adiponectin, and leptin levels compared to those of the control group (p < 0.001, p < 0.001, and p < 0.001, respectively). Administration of SA to STZ-induced diabetic mice may lower blood glucose but it increased the insulin levels with restoration of the size of the islets of Langerhans cells, implying that SA protected against STZ-induced diabetic states within the pancreas. At the molecular level, SA treatment exerts an increase in skeletal muscle expression levels of membrane glucose transporter 4 (GLUT4) and phospho-Akt to increase the membrane glucose uptake, but the mRNA levels of PEPCK and G6Pase are decreased to inhibit hepatic glucose production, thus leading to its hypoglycemic effect. Moreover, SA may cause hypolipidemic effects not only by enhancing hepatic expression levels of peroxisome proliferator-activated receptor α (PPARα) with increased fatty acid oxidation but also by reducing lipogenic fatty acid synthase (FAS) as well as reducing mRNA levels of sterol regulatory element binding protein (SREBP)1C and SREBP2 to lower blood TG and TC levels. Our findings demonstrated that SA displayed a protective effect against type 1 diabetes and a hyperlipidemic state in STZ-induced diabetic mice.

Project description:Hepatocellular carcinoma (HCC), the major form of primary liver cancer, is a common cause of cancer-related death worldwide. Signal transducer and activator of transcription 3 (STAT3) signaling is constantly activated in HCC and has been proposed as a chemotherapeutic target for HCC. Antrodia camphorata (AC), a medicinal mushroom unique to Taiwan, is traditionally used for treating HCC. Whereas natural AC is scarce, cultured AC mycelia are becoming alternatives. In this study, we investigated the anti-HCC effects of the ethyl acetate fraction of an ethanolic extract of AC mycelia (EEAC), particularly exploring the involvement of STAT3 signaling in these effects. We found that EEAC reduced cell viability, induced apoptosis, and retarded migration and invasion in cultured HepG2 and SMMC-7721 cells. Immunoblotting results showed that EEAC downregulated protein levels of phosphorylated and total STAT3 and JAK2 (an upstream kinase of STAT3) in HCC cells. Real-time PCR analyses showed that STAT3, but not JAK2, mRNA levels were decreased by EEAC. EEAC also lowered the protein level of nuclear STAT3, decreased the transcriptional activity of STAT3, and downregulated protein levels of STAT3-targeted molecules, including anti-apoptotic proteins Bcl-xL and Bcl-2, and invasion-related proteins MMP-2 and MMP-9. Over-activation of STAT3 in HCC cells diminished the cytotoxic effects of EEAC. In SMMC-7721 cell-bearing mice, EEAC (100 mg/kg, i.g. for 18 days) significantly inhibited tumor growth. Consistent with our in vitro data, EEAC induced apoptosis and suppressed JAK2/STAT3 activation/phosphorylation in the tumors. Taken together, EEAC exerts anti-HCC effects both in vitro and in vivo; and inhibition of STAT3 signaling is, at least in part, responsible for these effects. We did not observe significant toxicity of EEAC in normal human liver-derived cells, nude mice and rats. Our results provide a pharmacological basis for developing EEAC as a safe and effective agent for HCC management.

Project description:This study was designed to investigate the antidiabetic and antihyperlipidemic effects and mechanisms of eburicoic acid (TRR); one component of Antrodia camphorata in vitro and in an animal model for 14 weeks. Expression levels of membrane glucose transporter type 4 (GLUT4); phospho-5'-adenosine monophosphate-activated protein kinase (AMPK)/total AMPK; and phospho-Akt/total-Akt in insulin-resistant C2C12 myotube cells were significantly decreased by palmitate; and such decrease was prevented and restored by TRR at different concentrations. A group of control (CON) was on low-fat diet over a period of 14 weeks. Diabetic mice; after high-fat-diet (HFD) induction for 10 weeks; were randomly divided into six groups and were given once a day oral gavage doses of either TRR (at three dosage levels); fenofibrate (Feno) (at 0.25 g/kg body weight); metformin (Metf) (at 0.3 g/kg body weight); or vehicle (distilled water) (HF group) over a period of 4 weeks and still on HFD. Levels of glucose; triglyceride; free fatty acid (FFA); insulin; and leptin in blood were increased in 14-week HFD-fed mice as compared to the CON group; and the increases were prevented by TRR, Feno, or Metf as compared to the HF group. Moreover, HFD-induction displayed a decrease in circulating adiponectin levels, and the decrease was prevented by TRR, Feno, or Metf treatment. The overall effect of TRR is to decrease glucose and triglyceride levels and improved peripheral insulin sensitivity. Eburicoic acid, Feno, and Metf displayed both enhanced expression levels of phospho-AMPK and membrane expression levels of GLUT4 in the skeletal muscle of HFD-fed mice to facilitate glucose uptake with consequent enhanced hepatic expression levels of phospho-AMPK in the liver and phosphorylation of the transcription factor forkhead box protein O1 (FOXO1) but decreased messenger RNA (mRNA) of phosphenolpyruvate carboxykinase (PEPCK) to inhibit hepatic glucose production; resulting in lowered blood glucose levels. Moreover; TRR treatment increased hepatic expression levels of the peroxisome proliferator-activated receptor α (PPARα) to enhance fatty acid oxidation; but displayed a reduction in expressions of hepatic fatty acid synthase (FAS) but an increase in fatty acid oxidation PPARα coincident with a decrease in hepatic mRNA levels of sterol response element binding protein-1c (SREBP-1c); resulting in a decrease in blood triglycerides and amelioration of hepatic ballooning degeneration. Eburicoic acid-treated mice reduced adipose expression levels of lipogenic FAS and peroxisome proliferator-activated receptor γ (PPARγ) and led to decreased adipose lipid accumulation. The present findings demonstrated that TRR exhibits a beneficial therapeutic potential in the treatment of type 2 diabetes and hyperlipidemia.

Project description:Liver disease is a serious health problem affecting people worldwide at an alarming rate. The present study aimed to investigate the protective effects of Ganoderma lucidum against CCl4-induced liver toxicity in rats. The experimental Long Evans rats were divided into five groups, of which four groups were treated with carbon tetrachloride (CCl4). Among the CCl4 treated groups, one of the groups was treated with silymarin and two of them with ethanolic extract of G. lucidum at 100 and 200 mg/Kg body weight. The oxidative stress parameters and endogenous antioxidant enzyme concentrations were assessed by biochemical tests. Liver enzymes ALT, AST, and ALP were determined spectrophotometrically. Histopathological examinations were carried out to assess hepatic tissue damage and fibrosis. Reverse transcription PCR (RT-PCR) was performed to determine the expression of IL-1β, IL-6, IL-10, TNF-α, and TGF-β genes. Gas Chromatography-Mass Spectroscopy (GC-MS) analysis revealed that G. lucidum is rich in several phytochemicals including 6-Octadecanoic acid (55.81%), l-( +)-Ascorbic acid 2,6-dihexadecanoate (18.72%), Cis-11-Eicosenamide (5.76%), and Octadecanoic acid (5.26%). Treatment with the G. lucidum extract reduced the elevated ALT, AST, ALP levels, and cellular oxidative stress markers and increased the endogenous antioxidant levels. Histopathology observations revealed that the inflammation, infiltration of immune cells, and aberration of collagen fibers in the hepatocytes were altered by the G. lucidum treatment. The increased expression of inflammatory cytokines TNF-α, TGF-β, IL-1 β, and IL-6 were markedly suppressed by G. lucidum extract treatment. G. lucidum also prevented the suppression of protective IL-10 expression by CCl4. This study strongly suggests that G. lucidum extract possesses significant hepatoprotective activity as evidenced by reduced oxidative stress and inflammation mediated by suppression in inflammatory cytokine expression and increased protective IL-10 cytokine expression.

Project description:The study is designed to examine the potential effects and underlying mechanisms of eburicoic acid (TRR), a compound from Antrodia camphorata, in streptozotocin (STZ)-induced diabetic mice. Diabetic mice were randomly divided into six groups and given TRR orally by gavage (at three dosage rates) or fenofibrate (Feno) (250 mg kg-1 body weight) or metformin (Metf) (300 mg kg-1 body weight) or vehicle for 2 weeks. STZ-induced diabetic mice were found to have increased blood glucose, HbA1C, plasma triglyceride (TG) and total cholesterol (TC) levels, but reduced blood insulin, adiponectin, and leptin levels as compared with the CON group. TRR was found to lower blood glucose and HbA1C, but increase insulin levels. Plasma TG and TC levels were significantly lowered in TRR, Feno, or Metf-treated STZ-induced diabetic mice as compared with the vehicle-treated STZ group, indicating that TRR, Feno, and Metf ameliorated hyperlipidemia. The islet cells of STZ-induced diabetic mice exhibited a marked reduction from their classic round-shape as compared to the CON mice. The TRR-treated STZ mice revealed restoration of the size of Langerhans islet cells with β-cell repair as compared with the vehicle-treated STZ mice, implying that TRR ameliorated STZ-induced diabetic states within the pancreas. STZ-induction was found to decrease the expressions of membrane glucose transporter 4 (GLUT4), and phosphorylation of Akt in skeletal muscles, and administration of TRR reversed all the decreases. Moreover, administration of TRR increased blood insulin levels and enhanced hepatic expression levels of phospho-Akt and phospho-FoxO1 but decreased the mRNA levels of glucose-6-phosphatase (G6 Pase) and phosphoenolpyruvate carboxykinase (PEPCK) to suppress hepatic glucose production, thus leading to TRR's antidiabetic activity. Additionally, TRR caused an increase in the expression levels of fatty acid oxidation gene peroxisome proliferator-activated receptor α (PPARα), but a decrease in lipogenic fatty acid synthase (FAS) and PPARγ expressions in the liver. TRR treatment suppressed hepatic mRNA levels of sterol regulatory element binding protein (SREBP) 1c and SREBP2, leading to decreased plasma triglyceride and total cholesterol levels. These findings indicate that TRR may effectively enhance therapeutic potential in the treatment of type 1 diabetes mellitus and/or hyperlipidemia.

Dataset Information

Improvement of triterpenoid production in mycelia of Antrodia camphorata through mutagenesis breeding and amelioration of CCl₄-induced liver injury in mice.

Publications

Improvement of triterpenoid production in mycelia of <i>Antrodia camphorata</i> through mutagenesis breeding and amelioration of CCl<sub>4</sub>-induced liver injury in mice.

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