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The Chinese name “Lingzhi” refers to Ganoderma genus, which are increasingly used in the food and medical industries. Ganoderma species are often used interchangeably since the differences in their composition are not known. To find compositional metabolite differences among Ganoderma species, we conducted a widely targeted metabolomics analysis of four commonly used edible and medicinal Ganoderma species based on ultra performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Through pairwise comparisons, we identified 575–764 significant differential metabolites among the species, most of which exhibited large fold differences. We screened and analyzed the composition and functionality of the advantageous metabolites in each species. Ganoderma lingzhi advantageous metabolites were mostly related to amino acids and derivatives, as well as terpenes, G. sinense to terpenes, and G. leucocontextum and G. tsugae to nucleotides and derivatives, alkaloids, and lipids. Network pharmacological analysis showed that SRC, GAPDH, TNF, and AKT1 were the key targets of high-degree advantage metabolites among the four Ganoderma species. Analysis of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes demonstrated that the advantage metabolites in the four Ganoderma species may regulate and participate in signaling pathways associated with diverse cancers, Alzheimer’s disease, and diabetes. Our findings contribute to more targeted development of Ganoderma products in the food and medical industries.

Artificial cultivation of Morchella sextelata and other morels is expanding in China, but continuous cropping reduces Morchella for unknown reasons. Here, we investigated soil that had been used or not used for M. sextelata cultivation for 0, 1, and 2 years. We found that the continuous cropping of M. sextelata substantially reduced the pH and the nutrient content of the hyphosphere soil and increased sclerotia formation by M. sextelata. Changes in the structure of bacterial and fungal communities were associated with levels of available nitrogen (N) and phosphorus in the soil. With continuous cropping, the richness and diversity of fungal and bacterial communities increased, but the abundance of Bacillus and Lactobacillus decreased and the abundance of pathogenic fungi increased. FAPROTAX analysis indicated that N cycle functions were enriched more with than without continuous cultivation, and that enrichment of N cycle and sulfate respiration functions was higher in the second than in the first year of cultivation. FunGuild analysis indicated that the functions related to pathotrophs and wood saprotrophs were enriched by M. sextelata cultivation. Overall, the results suggest that continuous cropping may reduce M. sextelata production by acidifying the soil and increasing the abundance of pathogenic fungi. Additional research is needed to determine whether increases in the abundance of pathogenic fungi and changes in soil chemistry result in the declines in production that occur with continuous M. sextelata cultivation.

Major depressive disorder is a devastating psychiatric disease that afflicts up to 17% of the world's population. Postmortem brain analyses and imaging studies of patients with depression have implicated basal lateral amygdala (BLA) dysfunction in the pathophysiology of depression. However, the circuit and molecular mechanisms through which BLA neurons modulate depressive behavior are largely uncharacterized. Here, in mice, we identified that BLA cholecystokinin (CCK) glutamatergic neurons mediated negative reinforcement via D2 medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and that chronic social defeat selectively potentiated excitatory transmission of the CCK.sup.BLA-D2.sup.NAc circuit in susceptible mice via reduction of presynaptic cannabinoid type-1 receptor (CB.sub.1R). Knockdown of CB.sub.1R in the CCK.sup.BLA-D2.sup.NAc circuit elevated synaptic activity and promoted stress susceptibility. Notably, selective inhibition of the CCK.sup.BLA-D2.sup.NAc circuit or administration of synthetic cannabinoids in the NAc was sufficient to produce antidepressant-like effects. Overall, our studies reveal the circuit and molecular mechanisms of depression. Activating cannabinoid receptors in a newly identified neural circuit ameliorates depressive-like behaviors in mice., Author(s): Chen-Jie Shen [sup.1] , Di Zheng [sup.1] , Ke-Xin Li [sup.1] , Jian-Ming Yang [sup.1] , Hao-Qi Pan [sup.1] , Xiao-Dan Yu [sup.1] , Jia-Yu Fu [sup.1] , Yi [...]

This review provides a brief overview of the basic principles of epigenetic gene regulation and then focuses on recent development of epigenetic drugs for cancer treatment and prevention with an emphasis on the molecular mechanisms of action. The approved epigenetic drugs are either inhibitors of DNA methyltransferases or histone deacetylases (HDACs). Future epigenetic drugs could include inhibitors for histone methyltransferases and histone demethylases and other epigenetic enzymes. Epigenetic drugs often function in two separate yet interrelated ways. First, as epigenetic drugs per se, they modulate the epigenomes of premalignant and malignant cells to reverse deregulated epigenetic mechanisms, leading to an effective therapeutic strategy (epigenetic therapy). Second, HDACs and other epigenetic enzymes also target non-histone proteins that have regulatory roles in cell proliferation, migration and cell death. Through these processes, these drugs induce cancer cell growth arrest, cell differentiation, inhibition of tumor angiogenesis, or cell death via apoptosis, necrosis, autophagy or mitotic catastrophe (chemotherapy). As they modulate genes which lead to enhanced chemosensitivity, immunogenicity or dampened innate antiviral response of cancer cells, epigenetic drugs often show better efficacy when combined with chemotherapy, immunotherapy or oncolytic virotherapy. In chemoprevention, dietary phytochemicals such as epigallocatechin-3-gallate and sulforaphane act as epigenetic agents and show efficacy by targeting both cancer cells and the tumor microenvironment. Further understanding of how epigenetic mechanisms function in carcinogenesis and cancer progression as well as in normal physiology will enable us to establish a new paradigm for intelligent drug design in the treatment and prevention of cancer.

Abstract Background Multiple myeloma (MM) is a B-cell malignancy that is largely incurable and is characterized by the accumulation of malignant plasma cells in the bone marrow. Apigenin, a common flavonoid, has been reported to suppress proliferation in a wide variety of solid tumors and hematological cancers; however its mechanism is not well understood and its effect on MM cells has not been determined. Results In this study, we investigated the effects of apigenin on MM cell lines and on primary MM cells. Cell viability assays demonstrated that apigenin exhibited cytotoxicity against both MM cell lines and primary MM cells but not against normal peripheral blood mononuclear cells. Together, kinase assays, immunoprecipitation and western blot analysis showed that apigenin inhibited CK2 kinase activity, decreased phosphorylation of Cdc37, disassociated the Hsp90/Cdc37/client complex and induced the degradation of multiple kinase clients, including RIP1, Src, Raf-1, Cdk4 and AKT. By depleting these kinases, apigenin suppressed both constitutive and inducible activation of STAT3, ERK, AKT and NF-κB. The treatment also downregulated the expression of the antiapoptotic proteins Mcl-1, Bcl-2, Bcl-xL, XIAP and Survivin, which ultimately induced apoptosis in MM cells. In addition, apigenin had a greater effects in depleting Hsp90 clients when used in combination with the Hsp90 inhibitor geldanamycin and the histone deacetylase inhibitor vorinostat. Conclusions Our results suggest that the primary mechanisms by which apigenin kill MM cells is by targeting the trinity of CK2-Cdc37-Hsp90, and this observation reveals the therapeutic potential of apigenin in treating multiple myeloma.

Abstract Background Cladribine or 2-chlorodeoxyadenosine (2-CDA) is a well-known purine nucleoside analog with particular activity against lymphoproliferative disorders, such as hairy cell leukemia (HCL). Its benefits in multiple myeloma (MM) remain unclear. Here we report the inhibitory effects of cladribine on MM cell lines (U266, RPMI8226, MM1.S), and its therapeutic potential in combination with a specific inhibitor of the signal transducer and activator of transcription 3 (STAT3). Methods MTS-based proliferation assays were used to determine cell viability in response to cladribine. Cell cycle progression was examined by flow cytometry analysis. Cells undergoing apoptosis were evaluated with Annexin V staining and a specific ELISA to quantitatively measure cytoplasmic histone-associated DNA fragments. Western blot analyses were performed to determine the protein expression levels and activation. Results Cladribine inhibited cell proliferation of MM cells in a dose-dependent manner, although the three MM cell lines exhibited a remarkably different responsiveness to cladribine. The IC50 of cladribine for U266, RPMI8226, or MM1.S cells was approximately 2.43, 0.75, or 0.18 μmol/L, respectively. Treatment with cladribine resulted in a significant G1 arrest in U266 and RPMI8226 cells, but only a minor increase in the G1 phase for MM1.S cells. Apoptosis assays with Annexin V-FITC/PI double staining indicated that cladribine induced apoptosis of U266 cells in a dose-dependent manner. Similar results were obtained with an apoptotic-ELISA showing that cladribine dramatically promoted MM1.S and RPMA8226 cells undergoing apoptosis. On the molecular level, cladribine induced PARP cleavage and activation of caspase-8 and caspase-3. Meanwhile, treatment with cladribine led to a remarkable reduction of the phosphorylated STAT3 (P-STAT3), but had little effect on STAT3 protein levels. The combinations of cladribine and a specific STAT3 inhibitor as compared to either agent alone significantly induced apoptosis in all three MM cell lines. Conclusions Cladribine exhibited inhibitory effects on MM cells in vitro. MM1.S is the only cell line showing significant response to the clinically achievable concentrations of cladribine-induced apoptosis and inactivation of STAT3. Our data suggest that MM patients with the features of MM1.S cells may particularly benefit from cladribine monotherapy, whereas cladribine in combination with STAT3 inhibitor exerts a broader therapeutic potential against MM.