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Stem cell senescence is an important cause of aging. Delaying senescence may present a novel way to combat aging and age‐associated diseases. This study provided a mechanistic insight into the protective effect of ganoderic acid D (GA‐D) against human amniotic mesenchymal stem cell (hAMSCs) senescence. GA‐D, a Ganoderma lucidum‐derived triterpenoid, markedly prevented hAMSCs senescence via activating the Ca2+ calmodulin (CaM)/CaM‐dependent protein kinase II (CaMKII)/nuclear erythroid 2‐related factor 2 (Nrf2) axis, and 14‐3‐3ε was identified as a target of GA‐D. 14‐3‐3ε‐encoding gene (YWHAE) knockdown in hAMSCs reversed the activation of the CaM/CaMKII/Nrf2 signals to attenuate the GA‐D anti‐aging effect and increase senescence‐associated β‐galactosidase (SA‐β‐gal), p16 and p21 expression levels, including reactive oxygen species (ROS) production, thereby promoting cell cycle arrest and decreasing differentiation potential. YWHAE overexpression maintained or slightly enhanced the GA‐D anti‐aging effect. GA‐D prevented d‐galactose‐caused aging in mice by significantly increasing the total antioxidant capacity, as well as superoxide dismutase and glutathione peroxidase activity, and reducing the formation of malondialdehyde, advanced glycation end products, and receptor of advanced glycation end products. Consistent with the protective mechanism of GA‐D against hAMSCs senescence, GA‐D delayed the senescence of bone‐marrow mesenchymal stem cells in this aging model in vivo, reduced SA‐β‐gal and ROS production, alleviated cell cycle arrest, and enhanced cell viability and differentiation via regulating 14‐3‐3ε and CaM/CaMKII/Nrf2 axis. Therefore, GA‐D retards hAMSCs senescence by targeting 14‐3‐3ε to activate the CaM/CaMKII/Nrf2 signaling pathway. Furthermore, the in vivo GA‐D anti‐aging effect may involve the regulation of stem cell senescence via the same signal axis. GA‐D prevents MSC senescence via regulating 14‐3‐3e to activate the CaM/CaMKII/Nrf2 pathway; GA‐D prevents d‐gal‐caused aging in mice by enhancing antioxidative defense and retards the BMSCs senescence in d‐gal‐caused aging mice; GA‐D may be a potential anti‐aging agent.

Neuroinflammation plays an important role in the onset and progression of neurodegenerative diseases. Microglia-mediated neuroinflammation have been proved to be the main reason for causing the neurodegenerative diseases. Ganoderic acid A (GAA), isolated from Ganoderma lucidum, showed anti-inflammatory effect in metabolism diseases. However, little research has been focused on the effect of GAA in neuroinflammation and the related mechanism. In the present study, lipopolysaccharide(LPS)-stimulated BV2 microglial cells were used to evaluate the anti-inflammatory capacity of GAA. Our data showed that GAA significantly suppressed LPS-induced BV2 microglial cells proliferation and activation in vitro. More strikingly, GAA promoted the conversion of BV2 microglial cells from M1 status induced by LPS to M2 status. Furthermore, GAA inhibited the pro-inflammatory cytokines release and promoted neurotrophic factor BDNF expression in LPS-induced BV2 microglial cells. Finally, we found that the expression of farnesoid-X-receptor (FXR) was prominently downregulated in LPS-stimulated BV2 microglial cells, antagonism of FXR with z-gugglesterone and FXR siRNA can reverse the effect of GAA in LPS-induced BV2 microglial cells. Taking together, our findings demonstrate that GAA can significantly inhibit LPS-induced neuroinflammation in BV2 microglial cells via activating FXR receptor.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common life-threatening monogenetic diseases characterized by progressive enlargement of fluid-filled renal cysts. Our previous study has shown that Ganoderma triterpenes (GT) retards PKD renal cyst development. In the present study we identified the effective ingredient of GT in suppression of kidney cyst development. Using an in vitro MDCK cystogenesis model, we identified ganoderic acid A (GA-A) as the most promising candidate among the 12 ganoderic acid (GA) monomers. We further showed that GA-A (6.25−100 μM) significantly inhibited cyst growth in MDCK cyst model and embryonic kidney cyst model in vitro, and the inhibitory effect was reversible. In kidney-specific Pkd1 knockout (kPKD) mice displaying severe cystic kidney disease, administration of GA-A (50 mg· kg −1  ·d −1 , sc) significantly attenuated renal cyst development. In both MDCK cells and kidney of kPKD mice, we revealed that GA-A dose-dependently downregulated the Ras/MAPK signaling pathway. The expression of proliferating cell nuclear antigen (PCNA) was also suppressed, suggesting a possible effect of GA-A on cell proliferation. These experimental data suggest that GA-A may be the main ingredient of GT as a potential therapeutic reagent for treating ADPKD.

The frequency of autoimmune diseases such as rheumatoid arthritis is increasing annually. Current treatments for these diseases cause new problems due to their side effects. In this study, we investigated the impact of Ganoderic Acid A (GAA), a potent anti-inflammatory herbal molecule, to evaluate the potential efficacy of GAA in alleviating Rheumatoid arthritis (RA)-associated clinical and histopathological manifestations. 40 Balb/c male mice were randomly divided into five groups (n = mice number per each group) as control (C), acetic acid (AA), rheumatoid arthritis (RA), low dose GAA (LGA) and high dose GAA (HGA) groups. Collagen emulsion was applied intra-articularly (ia), and complete Freund’s adjuvant (CFA) was applied subcutaneously (sc) to the RA and GA groups to induce an experimental model of rheumatoid arthritis. Other groups were given physiologic saline (PS) or AA at the same dose and in the same way. The procedures were repeated on the 22nd day; however, incomplete Freund’s adjuvant was applied to the RA and GA groups instead of CFA. PS was given to groups C, AA and RA for 9 days starting from the 22nd day; GAA was applied to the LGA (20 mg/kg) and HGA (40 mg/kg) groups by gavage. We evaluated body weight, arthritis score, knee temperature, knee circumference, behavioural assessment of pain, gait, tail-flick test, hot plate test, locomotor activity test, lower extremity index, spectrophotometric and histopathological evaluation methods, respectively. Compared to the RA group, the clinical arthritis score was reduced in the HGA group (p < 0.05). GAA significantly reduced knee temperatures and knee circumference, with changes in hot plate scores and tail flip test response. In the GAA groups, serum concentrations of AST, IL-6, TNF-α, NFkB were reduced, and joint damage and arthritis scores were also reduced histologically (p < 0.05). The results of this study suggest that the arthritis regressed with GAA treatment. Edema and inflammation were found to be reduced in the GAA groups compared with the RA group. GAA treatment resulted in significant improvements in behavioural activity, reduced inflammation and the damage to cartilage and bone structure and had an antinociceptive effect.

ABSTRACT Lipid metabolism disorders (LMDs) can cause many metabolic diseases and seriously threaten human health. It is necessary to develop safe drugs for long‐term use in LMDs patients. Ganoderma lucidum (G. lucidum), as an edible and traditional medicinal mushroom, has been widely used for its health benefits in Asian countries. Ganoderic acid A (GA), an important bioactive product from G. lucidum, has multiple pharmacological activities. Farnesoid X receptor (FXR) is a ligand‐activated nuclear receptor involved in regulate lipid absorption and metabolism. Recently, FXR has emerged as a promising therapeutic target for LMD. The purpose of this study was to determine whether GA can alleviate LMDs and to elucidate its mechanism in a high‐fat diet‐induced LMD mouse model. GA administration attenuated the weight gain, hyperlipidemia, and hepatic lipid accumulation in LMD model mice. Metabolomic analysis revealed that GA inhibited intestinal lipid absorption. The intestinal expressions of FXR target genes, including Ibabp, Fgf15, and Shp, was significantly decreased by GA (20 mg/kg), indicating that GA inhibits intestinal FXR activity. Oral lipid tolerance test disclosed that the inhibitory effect of GA on intestinal FXR significantly reduced lipid absorption. Surface plasmon resonance and thermal drift experiments revealed that GA bound FXR and competitively inhibited its activity. These data suggest that GA reduces lipid accumulation and hyperlipemia by inhibiting intestinal FXR. Ganoderic acid A (GA) improved lipid metabolism disorders by inhibiting intestinal FXR. GA markedly suppressed the ileal intestinal FXR activity. Then, GA changed bile acid composition and upregulated hepatic Cyp7a1 mRNA through decreasing FXR target genes encoded protein levels. Noteworthily, the decreased bile acid reabsorption level inhibited lipid absorption. Meanwhile, the enhanced hepatic Cyp7a1 could promote the conversion of hepatic cholesterol into BAs, relieving liver lipid accumulation. In conclusion, GA acted in part through an intestinal FXR‐BAs‐hepatic CYP7A1 axis to improve LMD, then prevent obesity, fatty liver, hyperlipidemia, and other related metabolic diseases. Chenodeoxycholic acid (CDCA); glycochenodeoxycholic acid (GCDCA).

Post-stroke depression (PSD) is a common complication after stroke. Ganoderic acid A (GAA), one of the main bioactive Ganoderma triterpenoids, exerts preventive and therapeutic effects in many diseases. However, the function of GAA in PSD has not been well studied. PSD model was established via stimulating rats with chronic unpredictable mild stress stimulations (CUMS) after middle cerebral artery occlusion (MCAO). Rats were treated with GAA before CUMS. Depressive-like behaviors were investigated by body weight alteration, open field test (OFT), and sucrose preference test (SPT). Neuronal damage was evaluated by hematoxylin and eosin (HE) staining and Western blotting. Inflammation was detected by enzyme-linked immunosorbent assay (ELISA) and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Microglial polarization was analyzed via qRT-PCR and Western blotting. The extracellular signal-regulated kinase (ERK)/cAMP-response element-binding protein (CREB) pathway was analyzed by Western blotting, and inactivated by the inhibitor PD98059 (PD). GAA attenuated PSD-induced depressive-like behaviors in rats. GAA mitigated PSD-induced neuronal damage and reduced BDNF and NGF levels in the cerebral hippocampus. GAA weakened PSD-induced inflammatory response in the cerebral hippocampus. GAA prevented pro-inflammatory (M1) polarization and promoted anti-inflammatory (M2) polarization, as indicated by decreased iNOS and CD86 levels and increased Arg-1 and CD206 levels. GAA restored the PSD-induced inactivation of the ERK/CREB pathway. GAA regulated M1/M2 microglial polarization by activating the ERK/CREB pathway. GAA alleviated the depressive-like behaviors and brain inflammation in PSD rats, indicating its potential for PSD therapy.

Microglia mediated neuronal inflammation has been widely reported to be responsible for neurodegenerative disease. Deacetyl ganoderic acid F (DeGA F) is a triterpenoid isolated from Ganoderma lucidum, which is a famous edible and medicinal mushroom used for treatment of dizziness and insomnia in traditional medicine for a long time. In this study the inhibitory effects and mechanisms of DeGA F against lipopolysaccharide (LPS)-induced inflammation both in vitro and in vivo were investigated. On murine microglial cell line BV-2 cells, DeGA F treatment inhibited LPS-triggered NO production and iNOS expression and affected the secretion and mRNA levels of relative inflammatory cytokines. DeGA F inhibited LPS-induced activation of the NF-κB pathway, as evidenced by decreased phosphorylation of IKK and IκB and the nuclear translocation of P65. In vivo, DeGA F treatment effectively inhibited NO production in zebrafish embryos. Moreover, DeGA F suppressed the serum levels of pro-inflammatory cytokines, including TNF-α and IL-6 in LPS-stimulated mice model. DeGA F reduced inflammatory response by suppressing microglia and astrocytes activation and also suppressed LPS-induced NF-κB activation in mice brains. Taken together, DeGA F exhibited remarkable anti-inflammatory effects and promising therapeutic potential for neural inflammation associated diseases.

The aim of this study is to investigate the effects of ganoderic acid A (GAA) on OVA-induced asthma in mice. Mouse asthma model was established by ovalbumin (OVA) in vitro. Diff-Quik staining was used to observe the total numbers of cells and the number of classification cells in each group, and HE staining was used to observe lung inflammation in lung tissue sections. ELISA was used to detect the effect of GAA on the levels of interleukin-4 (IL-4), IL-5, and IL-13 in serum and lung tissue. The expression levels of TLR/NF-κB were detected by Western blot. Immunohistochemistry was used to observe the expression changes of TLR4 and P-P65. Compared with the normal group, the inflammatory cell count, IL-4, IL-5, and IL-13 expression in the model group increased, and TLR/NF-kB signal protein expression increased. Compared with the model group, in GAA group, the number of inflammatory cells, the expression of IL-4, IL-5, and IL-13 decreased, and the expression of TLR/NF-kB signaling protein decreased. GAA regulated lung inflammation in asthmatic mice by inhibiting TLR/NF-kB signaling pathway.

AbstractIntervertebral disc (IVD) degeneration is a major cause of low back pain associated with several pathological changes in the IVD, including dysfunction of nucleus pulposus (NP) cells. Ganoderic Acid A (GAA), one of triterpenoid extracts of Ganoderma lucidum (G. lucidum), has been reported to possess anti-inflammatory effect. In the current study, we aimed to evaluate the effect of Ganoderic Acid A (GAA) on the interleukin-1β (IL-1β)-induced inflammation in human NP cells. Our results showed that the IL-1β-stimulated production of inflammatory mediators including nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 were suppressed by GAA. In addition, treatment of NP cells with GAA significantly inhibited the production of inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in IL-1β-stimulated human NP cells. GAA improved the reduced expression levels of extracellular matrix (ECM) proteins, collagen II and aggrecan in IL-1β-stimulated human NP cells. GAA also alleviated IL-1β-induced the levels of matrix metalloproteinase (MMP)-3 and MMP-13. Furthermore, GAA inhibited the IL-1β-induced upregulation of the phosphorylation of p65 and downregulation of IκBα. Taken together, these findings indicated that GAA alleviated IL-1β-induced inflammation and ECM degradation in NP cells through regulating NF-κB pathway.

Excessive nitric oxide (NO) causes extensive damage to the nervous system, and the adrenergic system is disordered in many neuropsychiatric diseases. However, the role of the adrenergic system in protection of the nervous system against sodium nitroprusside (SNP) injury remains unclear. In this study, we investigated the effect of ganoderic acid A (GA A) against SNP injury in neural cells and the role of adrenergic receptors in GA A neuroprotection. We found that SNP (0.125−2 mM) dose-dependently decreased the viability of both SH-SY5Y and PC12 cells and markedly increased NO contents. Pretreatment with GA A (10 μM) significantly attenuated SNP-induced cytotoxicity and NO increase in SH-SY5Y cells, but not in PC12 cells. Furthermore, pretreatment with GA A caused significantly higher adrenaline content in SH-SY5Y cells than in PC12 cells. In order to elucidate the mechanism of GA A-protecting SH-SY5Y cells, we added adrenaline, phentolamine, metoprolol, or ICI 118551 1 h before GA A was added to the culture medium. We found that addition of adrenaline (10 μM) significantly improved GA A protection in PC12 cells. The addition of β1-adrenergic receptor antagonist metoprolol (10 μM) or β2-adrenergic receptor antagonist ICI 118551 (0.1 μM) blocked the protective effect of GA A, whereas the addition of α-adrenergic receptor antagonist phentolamine (0.1 μM) did not affect GA A protection in SH-SY5Y cells. These results suggest that β-adrenergic receptors play an important role in the protection of GA A in SH-SY5Y cells against SNP injuries, and excessive adrenaline system activation caused great damage to the nervous system.