Ganoderma is a significant source of natural fungal medicines and has been used for the treatment of various diseases for many years. However, the use of Ganoderma in cancer immunotherapy is poorly elucidated. In this study, we have analyzed 2,398 English-language papers and 6,968 Chinese-language papers published between 1987 and 2017 by using bibliometrics. A steady growth in the number of publications was observed before 2004, followed by an exponential increase between 2004 and 2017. The most common category for publications about Ganoderma was "Pharmacology & Pharmacy," in which immunomodulation (25.60%) and cancer treatment (21.40%) were the most popular subcategories. Moreover, we have provided an overview of the bioactive components and combinatorial immunomodulatory effects for the use of Ganoderma in the treatment of cancer, including the major pathways of immune cells. Immunomodulatory protein and polysaccharides are the key bioactive factors responsible for cancer immunotherapy, and the NF-κB and MAPK pathways are the most comprehensively investigated major pathways. Our results indicate that Ganoderma has a broad-spectrum application for the treatment of cancer through the regulation of the immune system. This review provides guidance for future research into the role of Ganoderma in cancer immunotherapy.

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Ganoderma: A Cancer Immunotherapy Review.

Bioactive metabolites in Codonopsis pilosula are of particular interest as an immunostimulant. Methyl jasmonate (MeJA) plays an important role in the elicitation of metabolite biosynthesis. Here, we explored the response of metabolites to MeJA elicitation in C. pilosula adventitious roots and multiple shoots. The results showed that the biomass, polysaccharide, and lobetyolin content of adventitious roots exhibited the highest increases with 100 µmol·L-1 MeJA at the 16th day of subculture, whereas the atractylenolide III (a terpenoid) content increased extremely with 50 µmol·L-1 MeJA treatment at the 7th day of subculture. In addition, the biomass and lobetyolin content significantly increased at the 4th day after treatment. Similarly, the polysaccharide and lobetyolin content increased in multiple shoots. Further identification of different metabolites responding to MeJA by ¹H-NMR showed an extremely significant increase of the lobetyolinin level, which coincided with lobetyolin. Accordingly, the precursor, fatty acids, showed a highly significant decrease in their levels. Furthermore, a significant increase in β-d-fructose-butanol glycoside was detected, which was accompanied by a decrease in the sucrose level. Accordingly, the enzyme genes responsible for terpenoid and carbohydrate biosynthesis, CpUGPase, and CpPMK, were up regulated. In conclusion, MeJA promoted culture growth and accelerated bioactive metabolite accumulation by regulating the expression of the metabolite biosynthesis related genes, CpUGPase and CpPMK in C. pilosula.

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Response of Bioactive Metabolite and Biosynthesis Related Genes to Methyl Jasmonate Elicitation in Codonopsis pilosula

Nitrogen metabolism repression (NMR) has been well studied in filamentous fungi, but the molecular mechanism of its effects on fungal secondary metabolism has been generally unexplored. Ganoderic acid (GA) biosynthesis in Ganoderma lucidum differs between ammonia and nitrate nitrogen sources. To explain the functions of NMR in secondary metabolism, AreA, which is a core transcription factor of NMR, was characterized in G. lucidum. The transcription level of AreA was dramatically increased (approximately 4.5-folds), with the nitrate as the sole nitrogen source, compared with that with ammonia as the source. In addition, the expression of related genes involved in NMR was changed (upregulated of MeaB and downregulated of Nmr and GlnA) when AreA was knockdown. Yeast one-hybrid and electrophoretic mobility shift assay results showed that AreA could directly bind to the promoter of fps (encoding farnesyl-diphosphate synthase) to activate its expression. However, GA biosynthesis was increased (27% in the ammonia source and 77% in the nitrate source) in AreAi mutant strains versus that in control strains. These results showed that another important factor must participate in regulating GA biosynthesis other than the direct activation of AreA. Furthermore, we found that the content of nitric oxide (NO) was increased approximately 2.7-folds in the nitrate source compared with that in the ammonia. By adding the NO donor (SNP) or scavenger (cPTIO) and using NR-silenced or NR-overexpressed strains, we found that there was a negative correlation between the NO contents and GA biosynthesis. NO generated by nitrate reductase (NR) during the nitrogen utilization burst and could negatively influence GA biosynthesis. As a global transcription factor, AreA could also regulate the expression of NR. Our studies provide novel insight into the dual functions of AreA in GA biosynthesis during nitrogen assimilation.

Dual functions of AreA, a GATA transcription factor, on influencing ganoderic acid biosynthesis in Ganoderma lucidum

Performance of mycelial biomass and exopolysaccharide from Malaysian Ganoderma lucidum for the fungivore red hybrid Tilapia (Oreochromis sp.) in Zebrafish embryo

This study first systematically analyzed the constituents of an albino mutant strain of Auricularia cornea (AU). After 8 weeks of continuous treatment with metformin (Met) (0.1 g/kg) and AU (0.1 and 0.4 g/kg), db/db mice showed hypoglycemic functioning, indicated by reduced bodyweight, food intake, plasma glucose, serum levels of glycated hemoglobin A1c and glucagon, hepatic levels of phosphoenolpyruvate carboxykinase and lucose-6-phosphatasem, and increased serum levels of insulin. The effect of hypolipidemic functions were indicated by suppressed levels of total cholesterol and triglyceride, and enhanced levels of hepatic glycogen and high-density lipoprotein cholesterol. The renal protective effect of AU was confirmed by the protection in renal structures and the regulation of potential indicators of nephropathy. The anti-oxidative and anti-inflammatory effects of AU were verified by a cytokine array combined with an enzyme-linked immunosorbent assay. AU decreased the expression of protein kinase C α and β2 and phosphor-nuclear factor-κB, and enhanced the expression of catalase, nuclear respiratory factor 2 (Nrf2), manganese superoxide dismutase 2, heme oxygenase-1 and-2, heat shock protein 27 (HSP27), HSP60, and HSP70 in the kidneys of db/db mice. The results confirmed that AU's anti-diabetic and anti-nephritic effects are related to its modulation on oxidative stress.

The Antidiabetic and Antinephritic Activities of Auricularia cornea (An Albino Mutant Strain) via Modulation of Oxidative Stress in the db/db Mice.

Ganoderma lucidum is a medicinal mushroom that has been widely used in East Asia for the treatment of various diseases. The pharmacological activity of this fungus is primarily attributable to the polysaccharides and triterpenoids. In this study, to obtain the fruit bodies with improved content of active constituents, we examined the effect of salicylic acid (SA) and calcium ion on the biosynthesis of polysaccharides and triterpenoids by spraying the chemicals during the fruiting. To explore the underlying mechanisms for the variation, the transcripts of related genes involved in the polysaccharide and triterpenoid biosynthesis were measured. Results showed that Ca2+ had no effect on production of polysaccharides and triterpenoids, whereas SA increased triterpenoid content by 23.32%, compared to the control, but it had little influence on polysaccharide production. Interestingly, the combined induction increased polysaccharide and triterpenoid content by 9.02% and 13.61%, respectively, compared to the control. Under Ca2+ induction, the transcript of ugp gene in the polysaccharide biosynthetic pathway up-regulated in all three stages (mycelium, primordium, and fruit body), while pgm and gls gave no response in the mycelium and primordium stages, and up-regulated in the fruit body stage. Differently, six key triterpenoid biosynthetic genes including hmgr, hmgs, mvd, fps, sqs, and ls did not respond to the induction. In the case of SA and combined induction, pgm and ugp were up-regulated in all three stages, while gls showed an increased expression in the primordium stage and no response in other stages. The six triterpenoid biosynthetic genes were up-regulated in all three stages. The present study provides a useful approach to producing G. lucidum fruit bodies with high polysaccharide and triterpenoid content. This is important to the G. lucidum industry.

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Enhanced production of polysaccharides and triterpenoids in Ganoderma lucidum fruit bodies on induction with signal transduction during the fruiting stage.

Isolation and varietal characterization of Ganoderma resinaceum from areas of Ganoderma lucidum production in China

The invention discloses a processing method for improving sporocarp yield and polysaccharide and triterpene contents of ganoderma lucidum, which comprises the steps of strain culture, calcium ion and salicylic acid induction and harvesting. According to the method, the sporocarp yield and the polysaccharide and triterpene contents of the ganoderma lucidum are remarkably improved through spraying calcium ion and salicylic acid for induction during a germinating period of the ganoderma lucidum, wherein the yield of the ganoderma lucidum is 9.09g/bag, and is improved by 33.09% compared with that by conventional cultivation; the polysaccharide content is 5.64mg/g, which is two times of that by conventional cultivation; the triterpene content reaches 8.52mg/g and is improved by 24.74% compared with that by conventional cultivation; that is to say, the method can be used to efficiently improve the quality of the ganoderma lucidum; furthermore, the operation method is simple, and the cost is low.

Processing method for improving sporocarp yield and polysaccharide and triterpene contents of ganoderma lucidum

Budgerigar fledgling disease virus (BFDV) is the causative polyomavirus of budgerigar fledgling disease, an important avian immunosuppressive disease in budgerigars (Melopsittacus undulatus). In the current study, we explored the etiological role and molecular characteristics of BFDV. We identified a novel BFDV strain, designated as SC-YB19, belonging to a unique cluster with three other domestic strains (WF-GM01, SD18, and APV-P) and closely related to Polish isolates based on complete sequences. Sequence analysis showed that SC-YB19 had an 18-nucleotide (nt) deletion in the enhancer region, corresponding to the sequence position 164–181 nt, which differed significantly from all other BFDV strains. Based on sequence alignment, three unique nucleotide substitutions were found in VP4 (position 821), VP1 (position 2,383), and T-antigen (position 3,517) of SC-YB19, compared with SD18, WF-GM01, QDJM01, HBYM02, APV7, and BFDV1. Phylogenetic analyses based on complete sequences suggested that SC-YB19, along with the domestic WF-GM01, SD18, and APV-P strains, formed a single branch and were closely related to Polish, Japanese, and American isolates. These results demonstrate that BFDV genotype variations are co-circulating in China, thus providing important insight into BFDV evolution.

Molecular Characterization of a Novel Budgerigar Fledgling Disease Virus Strain From Budgerigars in China

Gut and oral microbes form complex communities and play key roles in co-evolution with their hosts. However, little is understood about the bacterial community in lizards.In this study, we investigated the gut and oral bacterial communities in Japalura sensu lato from Sichuan Province, China, using 16S rRNA gene sequencing. Results showed that Bacteroidota (36.5%) and Firmicutes (32.8%) were the main phyla in the gut, while Proteobacteria, Bacteroidota, Firmicutes, and Actinobacteriota were the dominant phyla in the oral cavity. 16 S rRNA sequencing analysis of fecal samples showed that: (1) Bacteroidota was the most abundant in Japalura sensu lato, which was different from the bacterial community of insectivorous animals; (2) Bacteroidota, Firmicutes, Actinobacteriota, Fusobacteriota, and Cyanobacteria were the most abundant phylum in Japalura sensu lato. (3) Proteobacteria was the dominant phylum in Japalura sensu lato and other domestic insectivorous lizards (Shinisaurus crocodilurus, Phrynocephalus vlangalii, and Takydromus septentrionalis); (4) Comparing with the bacterial community of Shinisaurus crocodilurus, Phrynocephalus vlangalii, Takydromus septentrionalis, Liolaemus parvus, L. ruibali, and Phymaturus williamsi, Desulfobacterota was uniquely present in the gut of Japalura sensu lato. 16 S rRNA sequencing of oral samples showed that Chloroflexi and Deinococcota phyla were enriched in the oral cavity, which may have a significant influence on living in extreme environments.Thus, based on 16 S rRNA sequencing analysis of the community composition of the gut and oral microbiomes, this study firstly represents a foundation for understanding the gut and oral microbial ecology of Japalura sensu lato, and constitutes a detail account of the diversity of the microbiota inhabiting the gut and oral cavity of Japalura sensu lato. Further researches will continue to reveal how gut and oral microbial communities may be impacting the ecology and evolution of lizards. 

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Lili Zhao

Papers

Enhanced production of polysaccharides and triterpenoids in Ganoderma lucidum fruit bodies on induction with signal transduction during the fruiting stage.

Isolation and varietal characterization of Ganoderma resinaceum from areas of Ganoderma lucidum production in China

Processing method for improving sporocarp yield and polysaccharide and triterpene contents of ganoderma lucidum

Molecular Characterization of a Novel Budgerigar Fledgling Disease Virus Strain From Budgerigars in China

Characterization of the bacterial microbiota in different gut and oral compartments of splendid japalure (Japalura sensu lato)