Ganoderma lucidum dry extract supplementation modulates T lymphocyte function in older women.

Ganoderma lucidum (a mushroom used in traditional Chinese medicine) compounds may attenuate ageing-related physiological changes and restore normal immunity. However, studies on the physiological effects of Ganoderma lucidum dry extract food supplements are few. Therefore, here, we aimed to investigate the effects of Ganoderma lucidum dry extract food supplement on the lymphocyte function of older women. This was a double-blind clinical trial (n 60) with a final 39 older volunteers, divided into two groups Ganoderma lucidum (n 23) and placebo (n 16). The Ganoderma lucidum group received 2000 mg/d of Ganoderma lucidum dry extract for 8 weeks. We used flow cytometry to determine the lymphocyte profile. CD4+ lymphocyte gene expression was evaluated by real-time polymerase chain reaction. We observed that in the Ganoderma lucidum group, concanavalin A stimulation increased lymphocyte proliferation. Further, we observed an increase in expression of Forkhead box P3, transforming growth factor-beta, IL-10, IL-6, retinoic acid receptor-related orphan receptor gamma, GATA-binding protein 3 and interferon gamma genes in the Ganoderma lucidum group. Furthermore, in the Ganoderma lucidum group, ionomycin and phorbol 12-myristate 13-acetate stimulation led to decrease in Th17+ cells and increase in Th2+ cells. Thus, in older women, Ganoderma lucidum regulates T lymphocyte function leading to a predominant anti-inflammatory action but does not induce T lymphocyte proliferation through CD28 signalling pathway.

The Anti-Inflammatory Effect of Lactococcus lactis-Ling-Zhi 8 on Ameliorating Atherosclerosis and Nonalcoholic Fatty Liver in High-Fat Diet Rabbits.

Inflammation plays a crucial role in atherosclerosis and nonalcoholic fatty liver disease (NAFLD). We previously engineered a recombinant Lactococcus lactis strain expressing the Ling-Zhi immunomodulatory protein (L. lactis-LZ8). This study investigated the anti-atherosclerotic effects of L. lactis-LZ8 in rabbits fed a high-fat diet (HFD). Changes in body weight, serum lipid profiles, and liver function were monitored. The aorta and liver tissues were analyzed for gross pathology and histopathology. Eight-week administration of L. lactis-LZ8 with HFD ameliorated atherosclerosis by downregulating protein and gene expression associated with lipid metabolism and inflammation in the aortas. The rabbits receiving L. lactis-LZ8 exhibited a significant dose-dependent reduction in hepatic fat accumulation. RNA sequencing of the livers revealed that inflammatory genes in the L. lactis-LZ8 groups were downregulated compared to the HFD group. Disease ontology enrichment analysis indicated that these genes were involved in atherosclerosis. Gene set enrichment analysis plots revealed significant enrichment in the gene sets related to cholesterol homeostasis. CIBERSORT immune cell fraction analysis indicated significant infiltration by regulatory T cells, CD8+ T cells, activated dendritic cells, and natural killer cells in the L. lactis-LZ8 group. Our studies underscore LZ8's role in precision nutrition, providing a potential solution to the current challenges in modifying atherosclerosis and NAFLD.

Classification, Biological Characteristics and Cultivations of Ganoderma.

Species of Ganoderma (Ling-zhi) have been widely researched and cultivated due to their highly prized medicinal value, which is famous as a traditional Chinese medicine. The aims of this chapter are to (1) review the historical taxonomy of the family Ganodermataceae, (2) provide an account of the genera and species of Ganoderma together with the distributions and habitats, (3) evaluate morphological features and phylogenetic methods to define the genera and species and (4) present two commonly used cultivated methods (wood-log cultivation and substitute cultivation) for Ganoderma.

Induction of Cbl-dependent epidermal growth factor receptor degradation in Ling Zhi-8 suppressed lung cancer.

Activating mutation of epidermal growth factor receptor (EGFR) is correlated with malignant lung tumor. In our study, we demonstrated that recombinant LZ-8 (rLZ-8), a medicinal mushroom Ganoderma lucidum protein, induced cell cycle arrest and apoptosis by downregulating the expression of wild-type and mutated EGFR and inhibiting EGFR downstream effectors, AKT and ERK1/2 in lung cancer cells. We showed that rLZ-8 effectively inhibited lung cancer progression and suppressed EGFR expression of lung tumor lesions in mouse model. Functional studies revealed that rLZ-8 reduced the amount of EGFR in cell membranes by altering EGFR localization to enhance the EGF-induced degradation of EGFR. Mechanistically, we demonstrated that rLZ-8 bound to EGFR to induce EGFR autophosphorylation at tyrosine1045 and trigger ubiquitination by inducing the formation of EGFR/Cbl complexes, resulting in the degradation of EGFR; however, Cbl-shRNA abolished rLZ-8-induced EGFR degradation. We provide the first evidence showing that rLZ-8 inhibits growth and induces apoptosis of lung cancer cells by promoting EGFR degradation. The current findings therefore suggest a novel anti-cancer function of rLZ-8 that targeting EGFR overexpression or mutation as well as EGFR-dependent processes in cancer cells.

Ling Zhi-8, a fungal immunomodulatory protein in Ganoderma lucidum, alleviates CPT-11-induced intestinal injury via restoring claudin-1 expression.

CPT-11 (Irinotecan) remains an important chemotherapeutic agent against various solid tumors nowadays. Potential adverse effects, especially gastrointestinal toxicities, are the main limiting factor for its clinical utility. Ling Zhi-8 (LZ-8), a fungal immunomodulatory protein in Ganoderma lucidum mycelia, has potential for drug development due to its multiple bioactivities and functions. This study aimed to explore the influence of LZ-8 on CPT-11-treated IEC-6 cells in vitro and on mice with CPT-11-induced intestinal injury in vivo. The mechanism through which LZ-8 exerted its protective effects was also investigated. In the in vitro study, the viability and claudin-1 expression of IEC-6 cells decreased gradually with increasing concentrations of CPT-11, but LZ-8 treatment had no obvious influence on their viability, morphology, and claudin-1 expression. Pretreatment of LZ-8 significantly improved CPT-11-decreased cell viability and claudin-1 expression in IEC-6 cells. In mice with CPT-11-induced intestinal injury, LZ-8 treatment could ameliorate symptoms and mitigate intestinal damage. Meanwhile, LZ-8 restored claudin-1 expression in the intestinal membranes in CPT-11-treated mice. Collectively, our results demonstrated the protective effects of LZ-8 against CPT-11 damage in both IEC-6 cells and mice. LZ-8 can restore claudin-1 expression in intestinal cells following CPT-11 treatment, suggesting the role of claudin-1 in the scenario.

Involvement of N-glycan in Multiple Receptor Tyrosine Kinases Targeted by Ling-Zhi-8 for Suppressing HCC413 Tumor Progression.

The poor prognosis of hepatocellular carcinoma (HCC) is resulted from tumor metastasis. Signaling pathways triggered by deregulated receptor tyrosine kinases (RTKs) were the promising therapeutic targets for prevention of HCC progression. However, RTK-based target therapy using conventional kinase-based inhibitors was often hampered by resistances due to compensatory RTKs signaling. Herein, we report that Ling-Zhi-8 (LZ-8), a medicinal peptide from Ganoderma lucidium, was effective in suppressing cell migration of HCC413, by decreasing the amount and activity of various RTKs. These led to the suppression of downstream signaling including phosphorylated JNK, ERK involved in HCC progression. The capability of LZ-8 in targeting multiple RTKs was ascribed to its simultaneous binding to these RTKs. LZ-8 may bind on the N-linked glycan motif of RTKs that is required for their maturation and function. Notably, pretreatment of the N-glycan trimming enzyme PNGase or inhibitors of the mannosidase (N-glycosylation processing enzyme), kifunensine (KIF) and swainsonine (SWN), prevented LZ-8 binding on the aforementioned RTKs and rescued the downstream signaling and cell migration suppressed by LZ-8. Moreover, pretreatment of KIF prevented LZ-8 triggered suppression of tumor growth of HCC413. Our study suggested that a specific type of N-glycan is the potential target for LZ-8 to bind on multiple RTKs for suppressing HCC progression.

Development of Ling-zhi industry in China - emanated from the artificial cultivation in the Institute of Microbiology, Chinese Academy of Sciences (IMCAS).

Ling-zhi is a medicinal herb that generally refers to a fungus in the genus Ganoderma. It has been used as a medicinal mushroom in traditional Chinese medicine for more than 2000 years. Mycologists at the Institute of Microbiology, Chinese Academy of Sciences (IMCAS) first artificially cultivated the Ling-zhi fruiting body in the late 1960s (X.J. Liu's team). In IMCAS, different research teams have extensively studied Ling-zhi in the aspects of national resource surveys, systematic taxonomy, chemical analysis, and processing for medicinal and health applications. The research results from IMCAS have provided essential support and prompted the development of the Ling-zhi industry in China to some extent. This review aims to summarize the history of research on Ling-zhi in IMCAS and its role in the development of the Ling-zhi economy.

Ling Zhi-8 reduces lung cancer mobility and metastasis through disruption of focal adhesion and induction of MDM2-mediated Slug degradation.

We recently reported that recombinant Ling Zhi-8 (rLZ-8), a medicinal mushroom Ganoderma lucidum recombinant protein, effectively prevents lung cancer cells proliferation in vivo mice model. In our current study, we demonstrated that rLZ-8 suppressed tumor metastasis and increased the survival rate in Lewis lung carcinoma cell-bearing mice. The epithelial to mesenchymal transition (EMT) process is regarded as the critical event in tumor metastasis. Herein, we showed that rLZ-8 effectively induced changes in EMT by interfering with cell adhesion and focal adhesion kinase (FAK) functions in lung cancer cells. Slug, a transcription factor, represses E-cadherin transcription and is regarded as a critical event in EMT and tumor metastasis. Functional studies revealed that downregulation of Slug as a result of rLZ-8-induced FAK inactivation enhanced E-cadherin expression and repressed cancer cell mobility. Moreover, we found that rLZ-8 enhanced the ubiquitination proteasome pathway (UPP)-mediated degradation of Slug in CL1-5 cells. Mechanistically, we demonstrated that rLZ-8 promoted the interaction between MDM2 and Slug, resulting in Slug degradation; however, MDM2-shRNA abolished rLZ-8-enhanced Slug degradation. This study is the first to determine anti-metastatic activity of rLZ-8 and its potential mechanism, with how the regulation of EMT and cell mobility is via the negative modulation of FAK, and thereby leading to the ubiquitination and degradation of Slug. Our findings suggest that the targets of FAK play a key role in metastasis. Moreover, rLZ-8 may be useful as a chemotherapeutic agent for treating lung cancer.

Distinguishing commercially grown Ganoderma lucidum from Ganoderma lingzhi from Europe and East Asia on the basis of morphology, molecular phylogeny, and triterpenic acid profiles.

In China and other countries of East Asia, so-called Ling-zhi or Reishi mushrooms are used in traditional medicine since several centuries. Although the common practice to apply the originally European name 'Ganoderma lucidum' to these fungi has been questioned by several taxonomists, this is still generally done in recent publications and with commercially cultivated strains. In the present study, two commercially sold strains of 'G. lucidum', M9720 and M9724 from the company Mycelia bvba (Belgium), are compared for their fruiting body (basidiocarp) morphology combined with molecular phylogenetic analyses, and for their secondary metabolite profile employing an ultra-performance liquid chromatography-electrospray ionization mass spectrometry (UPLC-ESIMS) in combination with a high resolution electrospray ionization mass spectrometry (HR-ESI-MS). According to basidiocarp morphology, the strain M9720 was identified as G. lucidum s.str. whereas M9724 was determined as Ganoderma lingzhi. In molecular phylogenetic analyses, the M9720 ITS and beta-tubulin sequences grouped with sequences of G. lucidum s.str. from Europe whereas those from M9724 clustered with sequences of G. lingzhi from East Asia. We show that an ethanol extract of ground basidiocarps from G. lucidum (M9720) contains much less triterpenic acids than found in the extract of G. lingzhi (M9724). The high amount of triterpenic acids accounts for the bitter taste of the basidiocarps of G. lingzhi (M9724) and of its ethanol extract. Apparently, triterpenic acids of G. lucidum s.str. are analyzed here for the first time. These results demonstrate the importance of taxonomy for commercial use of fungi.