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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.

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.

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.

In traditional Chinese medicine theory, aging is hypothesized to arise from severe deficiency of kidney essence, which is posited to induce “emptiness of the sea of marrow”. Ganoderma has been documented to possess properties that nourish kidney qi and enrich essence and blood. It has been demonstrated that ganoderma triterpenoids are capable of mitigating age-related cerebral atrophy and retarding the aging process in murine models. Ganoderic acid A (GAA) has been characterized as the principal bioactive metabolite of these triterpenoids. Leveraging thermal proteomics profiling, CASTOR1 was identified as a target protein exhibiting significant disparities in melting curves. Through functional annotation via GO terms and pathway analysis using KEGG, it has been indicated that GAA may modulate metabolic regulatory pathways through interaction with specific molecular targets. A pronounced association between GAA and the GATOR2 complex, a downstream effector of CASTOR1, has been revealed by GO enrichment analysis, suggesting a potential mechanistic link. Thus, it is inferred that one potential target of GAA in neuronal cells is presumably CASTOR1 protein. It is hypothesized that ganoderic acid A exerts its pharmacological effects likely through regulation mediated by the potential target protein CASTOR1, which in turn modulates the mTOR signaling pathway.

Although platinum-based chemotherapeutics such as cisplatin are the cornerstone of treatment for ovarian cancer, their clinical application is profoundly limited due to chemoresistance and severe adverse effects. Sporoderm-broken spores of Ganoderma lucidum (SBSGL) have been reported to possess antitumor effects. However, the function and mechanism of SBSGL and its essential composition, ganoderic acid D (GAD), in the cisplatin therapy on ovarian cancer have yet to be investigated. Here, we investigated the combined effect of SBSGL and cisplatin in an ovarian tumor xenograft model. The results showed that combining SBSGL with cisplatin reduced tumor growth and ameliorated cisplatin-induced intestinal injury and myelosuppression. We also confirmed that GAD could enhance the therapeutic effect of cisplatin in SKOV3 and cisplatin-resistant SKOV3/DDP cells by increasing the intracellular reactive oxygen species (ROS). Mechanistically, we proved that ROS-mediated ERK signaling inhibition played an important role in the chemo-sensitization effect of GAD on cisplatin in ovarian cancer. Taken together, combining SBSGL with cisplatin provides a novel therapeutic strategy against ovarian cancer.

Ganoderic acid A (GAA), a major bioactive triterpenoid from Ganoderma lucidum, is known for its anti-inflammatory effects; however, its precise molecular targets in sepsis-related liver injury (SRLI) remain unclear. Integrating network pharmacology and transcriptomic analysis, we identified Tumor Necrosis Factor-alpha (TNFα) as a primary candidate target. Subsequent biophysical validation using surface plasmon resonance (SPR) and molecular dynamics (MD) simulations confirmed that GAA directly binds to TNFα. Functionally, this interaction inhibits the TNFα/NF-κB signaling axis, thereby suppressing macrophage M1 polarization and ameliorating liver injury in vitro and in vivo . This study identifies TNFα as a primary candidate target of GAA, providing a mechanistic basis for its hepatoprotective effects and therapeutic potential.

Alzheimer’s disease (AD) is a neurodegenerative disorder that occurs with aging. Ganoderma lucidum (Curtis.) P. Karst. (G. lucidum) is a traditional medicinal fungus believed to nourish the brain and anti-aging. Ganoderic acid A (GAA), a triterpenoid from G. lucidum, has demonstrated natural neuroprotective effects. This study aims to explore the therapeutic effect and molecular mechanism of GAA on AD. Systematic network pharmacology identified 95 targets, 8 biological functions, and multiple pathways. The results highlighted MAPK family members as core genes, with MAPK1 (ERK2) showing the highest binding affinity to GAA in molecular docking. In vitro experiments revealed that GAA dose-dependently increased the viability of Aβ25-35-injured HT22 cells and inhibited MAPK pathway-related protein expression. Similar to FR180204, 100 µM GAA significantly reversed ERK protein expression, oxidative stress markers, and mitochondrial damage in AD cell model. GAA also downregulated cleaved caspase-3 protein levels, apoptosis rates, Aβ and p-Tau expression by inhibiting the ERK signaling pathway. The therapeutic effect of GAA on AD was predicted and validated through network pharmacology and in vitro experiments. The ability of GAA to inhibit apoptosis via the ERK/MAPK signaling pathway positions it as a promising candidate for AD treatment.HighlightsThe potential targets and mechanisms of GAA treatment for AD were predicted.GAA protected HT22 cells from Aβ25−35-induced damage.GAA inhibited apoptosis and MAPK signaling pathways in the AD cell model.GAA exerted anti-AD effects by suppressing the ERK/MAPK cascade.GAA can inhibit the expression of the MAPK signaling pathway. Among them, GAA can inhibit the ERK/MAPK pathway to alleviate oxidative stress and mitochondrial damage, reduce cell apoptosis, and ultimately protect HT22 cells from AD pathological damage.

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.

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).

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.