Mechanism of action of cordycepin in the treatment of hepatocellular carcinoma via regulation of the Hippo signaling pathway

Hepatocellular carcinoma(HCC)is one of the common most malignant tumors.This study aimed to determine the in vitro and in vivo anticancer activity of cordycepin and elucidate its mechanism of action.The results of in vitro and in vivo studies revealed that cordycepin inhibited proliferation and migration in HepG-2 cells and inhibited the growth of HepG-2 xenograft-bearing nude mice by inducing apoptosis.Transcriptome sequencing analysis revealed a total of 403 differential genes,which revealed that cordycepin may play an anti-HCC role by regulating Hippo signaling pathway.The regulatory effects of cordycepin on the Hippo signaling pathway was further investigated using a YAP1 inhibitor.The results demonstrated that cordycepin upregulated the expression of MST1 and LAST1,and subsequently inhibited YAP1,which activated the Hippo signaling pathway.This in turn downregulated the expression of GBP3 and ETV5,and subsequently inhibited cell proliferation and migration.Additionally,YAP1 regulated the expression of Bax and Bcl-2,regulated the mitochondrial apoptotic pathway,and induced apoptosis by upregulating the expression of the caspase-3 protein.In summary,this study reveals that cordycepin exerts its anti-hepatocarcinoma effect through regulating Hippo signaling pathway,and GBP3 and ETV5 may be potential therapeutic targets for hepatocarcinoma.

Fermented Lentinus edodes extract containingα-glucan ameliorates concanavalin A-induced autoimmune hepatitis in mice

Autoimmune hepatitis(AIH)is a chronic inflammatory liver disease that threatens human health worldwide.The aim of this study was to detect the protective effect of a fermented Lentinus edodes extract containingα-glucan(FLA),in a concanavalin A(Con A)-induced AIH mouse model and to determine the underlying liver-protective mechanism.The results showed that compared with the model group,the level of proinflammatory cytokines in serum of FLA pretreated mice was significantly decreased,and the degree of inflammatory cell infiltration in liver,thymus and spleen was significantly reduced.Quantitative polymerase chain reaction,immunohistochemistry,and Western blotting showed that FLA pre-treatment inhibited the Con A-induced apoptosis of hepatocytes by down-regulating the expression of BAX and up-regulating the expression of BCL-2.Further research found that FLA may improve liver injury in mice by activating NRF2 signaling pathway and inhibiting TRAF6/NF-κB signaling pathway.Thus,FLA may improve liver injury in mice by shifting gut microbial composition to reduce the release of inflammatory cytokines in the serum and prevent the necrosis of hepatocytes.Up-regulation of NRF2 signaling pathway,down-regulation of TRAF6/NF-κB signaling pathway,and an increase in the relative abundance of Lactobacillus_johnsonii and Ligilactobacillus_murinus play a protective role in liver.

Involvement of Dectin-2 in the Innate Inflammatory Response Triggered by Influenza Virus Hemagglutinin

C-type lectin receptors (CLRs) are representative pattern recognition receptors that recognize microbial polysaccharides expressed on antigen-presenting cells. In the present study, we carried out further detailed analysis on the involvement of Dectin-2, a CLR that senses high mannose polysaccharide, in innate immune responses induced by influenza virus hemagglutinin (HA). Treatment of HA with periodate or PNGase F induced lower interleukin (IL)-12p40 secretion by conventional dendritic cells (DCs) compared with the untreated group. In contrast, treatment with O-glycosidase did not affect cytokine production. Green fluorescent protein expression in canonical Dectin-2-transducing cells was approximately 3% - 12% following HA stimulation, except with the A/H1N1pdm09 subtype HA. This expression was markedly reduced in cells possessing mutated amino acids in the carbohydrate recognition domain of Dectin-2, especially following stimulation with HA derived from the A/H3N2 subtype. Interferon (IFN)-α production from CD11c+Siglec-H+PDCA-1+ plasmacytoid DCs was significantly increased in Dectin-2 knockout mice compared with wild-type mice upon stimulation with HA except for the B/Yamagata lineage HA. These results suggested that Dectin-2 is involved in initiating inflammatory responses via mannose polysaccharide on HA. However, other mechanisms may function in the antiviral response, including the type I IFN axis.

Transplantation of neural stem cells, Schwann cells and olfactory ensheathing cells for spinal cord injury:A Web of Science-based literature analysis

OBJECTIVE： To identify global research trends in transplantation of neural stem cells, Schwann cells and olfactory ensheathing cells for spinal cord injury. DATA RETRIEVAL： We performed a bibliometric analysis of studies on transplantation of neural stem cells, Schwann cells and olfactory ensheathing cells for spinal cord injury published from 2002 to 2011 and retrieved from the Web of Science, using the key words spinal cord injury along with either neural stem cell, Schwann cell or olfactory ensheathing cell. SELECTION CRITERIA： Inclusion criteria： （a） peer-reviewed published articles on neural stem cells, Schwann cells or olfactory ensheathing cells for spinal cord injury indexed in the Web of Science; （b） original research articles, reviews, meeting abstracts, proceedings papers, book chapters, editorial materials and news items; and （c） published between 2002 and 2011. Exclusion criteria： （a） articles that required manual searching or telephone access; （b） documents that were not published in the public domain; and （c） corrected papers. MAIN OUTCOME MEASURES： （1）Annual publication output, distribution by journal, distribution by institution and top-cited articles on neural stem cells; （2） annual publication output, distribution by journal, distribution by institution and top-cited articles on Schwann cells; （3） annual publication output, distribution by journal, distribution by institution and top-cited articles on olfactory ensheathing cells. RESULTS： This analysis, based on articles indexed in the Web of Science, identified several research trends among studies published over the past 10 years in transplantation of neural stem cells, Schwann cells and olfactory ensheathing cells for spinal cord injury. The number of publications increased over the 10-year period examined. Most papers appeared in journals with a focus on neurology, such as Journal of Neurotrauma, Experimental Neurology and Gila. Research institutes publishing on the use of neural stem cells to repair spinal cord injury were mostly in the USA and Canada. Those publishing on the use of Schwann cells were mostly in the USA and Canada as well. Those publishing on the use of olfactory ensheathing cells were mostly in the UK, the USA and Canada. CONCLUSION： On the basis of the large number of studies around the world, cell transplantation has proven to be the most promising therapeutic approach for spinal cord injury.

Therapeutic effect of natural melanin from edible fungus Auricularia auricula on alcohol-induced liver damage in vitro and in vivo

This study explored the therapeutic effects of Auricularia auricula melanin(AAM)on alcoholic liver damage in vitro and in vivo.Human normal liver L02 cells were pre-treated with ethanol and then treated with AAM to explore the therapeutic effect of AAM on ethanol-induced hepatocyte injury.The results show that AAM signifi cantly elevated the cell viability,ameliorated the cell morphology,reduced the ROS and increased the GSH/GSSG of ethanol-pretreated L02 cells.Then,mice were administered with ethanol to induce acute alcoholic liver damage,and administered with AAM to further study the therapeutic effect of AAM on alcoholic liver damage in mice.As a result,AAM reduced the levels of ALT,AST,TG,and MDA,increased the levels of ADH,SOD,and CAT in liver damage mice.The therapeutic effect of AAM may be related to inhibition of CYP2E1 expression and activation of Nrf2 and its downstream antioxidase.The research enriched the bioactivity of AAM and provided some ideas for the development of melanin-related health foods.

Mating System of Tricholoma giganteum

Microscopical examination demonstrated that Tricholoma giganteum basidia bear 4 basidiospores. Mating tests revealed that T. giganteum has a tetra-polar, heterothallic mating system. New types of factor B (Br) occurred as a result of recombination within the B-type mating factor.

Aflatoxin M1 Contamination of Milk and Its Products in Bomet County, Kenya

Aflatoxin M1 (AFM1) is a major carcinogenic compound that may be found in milk and dairy products resulting from ingestion of aflatoxin B1 by dairy animals. The study aimed at determining the level of aflatoxin M1 in milk and milk products from Bomet County. A total of 185 samples (150 raw milk and 35 processed milk and milk products) were randomly collected from milk collection sites and randomly selected milk kiosks respectively. The AFM1 was analyzed using a commercial ELISA kit (Ridascreen, aflatoxin M1 R-Biopharm, Product code, R5812, Darmstadt, Germany). Out of 185 samples investigated, 156 samples were positive for AFM1, an overall contamination rate of 84.32%. The samples with levels higher than the tolerance limit of 0.05 μg/l recommended by Food and Agriculture Organization (FAO) and World Health Organization (WHO) limits were 43.8% mainly contributed by the raw milk compared to processed milk (52.0% versus 8.6%). Processed milk had insignificant level of contamination with aflatoxin M1 (Median 0.00 (IQR: 0.00, 0.00 μg/l) with a minimum of 0.00 μg/l and a maximum of 0.69 μg/l. Raw milk showed significant contamination, median 0.09 (IQR: 0.00, 0.50) μg/l with a minimum of 0.00 μg/l and a maximum of 2.93 μg/l. Although there was no significant differences in AFM1 levels with study sites (P = 0.217);the median levels of aflatoxin M1 was high in sites 1, 3, and 7. The sites that had median aflatoxin M1 levels below the WHO/FAO acceptable limits of 0.05 μg/l were sites 2, 4 and 6. Due to high incidence of AFM1 contamination of milk and milk samples in Bomet County, there is need for regular monitoring and regulation of AFM1 contamination in milk and its products in the County.

Identification of Trichosporon spp. Strains by Sequencing D1/D2 Region and Sub-typing by Sequencing Ribosomal Intergenic Spacer Region of Ribosomal DNA

To re-identify and further group 25 isolates of Trichosporon spp. identified morphologically previously, sequences of D1/D2 region of large subunit （LSU） of ribosomal DNA （rDNA） of 25 tested strains for identification and those of ribosomal intergenic space 1 （IGS1） region of 11 strains for subgrouping were detected. The identifications of tested strains were changed except 6 strains. According to the alignment of the IGS1 region, 6 T. asahii isolates tested fell into 4 groups and 5 T. faecale isolates into 3 groups. Polymorphism of 2 T. japonicum isolates was found in 10 positions. With the alignments obtained in this research compared with the relative GenBank entries, it was found that T. asahii, T. faecale and T. japonicum species were divided into 7, 3 and 2 subtypes respectively. Morphological and biophysical methods are not sufficient for Trichosporon spp. identification. Sequencing becomes necessary for Trichosporon diagnosis. There is obvious diversity within a species.

Single-cell analysis for identification of T-cell clonotypes associated with IgG4 production of autoimmune pancreatitis

Introduction Autoimmune pancreatitis(AIP)is one of the recently established immunoglobulin G4-related diseases(IgG4-RD)[1].The detailed pathogenic mechanisms have been an intensive research area for prophylactic and therapeutic purposes because aberrant immune activation and tissue fibrosis in AIP are the major factors that worsen the disease outcomes in these patients.

Molecular mechanisms regulating NLRP3 inflammasome activation

Inflammasomes are multi-protein signaling complexes that trigger the activation of inflammatory caspases and the maturation of interleukin-1β. Among various inflammasome complexes, the NLRP3 inflammasome is best characterized and has been linked with various human autoinflammatory and autoimmune diseases. Thus, the NLRP3 inflammasome may be a promising target for anti-inflammatory therapies. In this review, we summarize the current understanding of the mechanisms by which the NLRP3 inflammasome is activated in the cytosol. We also describe the binding partners of NLRP3 inftammasome complexes activating or inhibiting the inflammasome assembly. Our knowledge of the mechanisms regulating NLRP3 inflammasome signaling and how these influence inflammatory responses offers further insight into potential therapeutic strategies to treat inflammatory diseases associated with dysregulation of the NLRP3 inflammasome,

Regulation of RIG-I-like receptor-mediated signaling:interaction between host and viral factors

Retinoic acid-inducible gene I(RIG-l)-like receptors(RLRs)are RNA sensor molecules that play essential roles in innate antiviral immunity.Among the three RLRs encoded by the human genome,RIG-1 and melanoma differentiation-associated gene 5,which contain N-terminal caspase recruitment domains,are activated upon the detection of viral RNAs in the cytoplasm of virus-infected cells.Activated RLRs induce downstream signaling via their interactions with mitochondrial antiviral signaling proteins and activate the production of type Ⅰ and Ⅲ interferons and inflammatory cytokines.Recent studies have shown that RLR-mediated signaling is regulated by interactions with endogenous RNAs and host proteins,such as those involved in stress responses and posttranslational modifications.Since RLR-mediated cytokine production is also involved in the regulation of acquired immunity,the deregulation of RLR-mediated signaling is associated with autoimmune and autoinflammatory disorders.Moreover,RLRmediated signaling might be involved in the aberrant cytokine production observed in coronavirus disease 2019.Since the discovery of RLRs in 2004,significant progress has been made in understanding the mechanisms underlying the activation and regulation of RLR-mediated signaling pathways.Here,we review the recent advances in the understanding of regulated RNA recognition and signal activation by RLRs,focusing on the interactions between various host and viral factors.

Comparison on effect of hydrophobicity on the antibacterial and antifungal activities of α-helical antimicrobial peptides

HPRP-A1, a 15-mer α-helical cationic peptide, was derived from N-terminus of ribosomal protein L1 (RpL1) of Helicobacter pylori. In this study, HPRP-A1 was used as a framework to obtain a series of peptide analogs with different hydrophobicity by single amino acid substitutions in the center of nonpolar face of the amphipathic helix in order to systematically study the effect of hydrophobicity on biological activities of -helical antimicrobial peptides. Hydrophobicity and net charge of peptides played key roles in the biological activities of these peptide analogs; HPRP-A1 and peptide analogs with relative higher hydrophobicity exerted broad spectrum antimicrobial activity against Gram-negative bacteria, Gram-positive bacteria and pathogenic fungi, but also showed stronger hemolytic activity; the change of hydrophobicity and net charge of peptides had similar effects with close trend and extent on antibacterial activities and antifungal activities. This indicated that there were certain correlations between the antibacterial mode of action and the antifungal mode of action of these peptides in this study. The peptides exhibited antimicrobial specificity for bacteria and fungi, which provided potentials to develop new antimicrobial drugs for clinical practices.

White-opaque Switching in Different Mating Type-like Locus Gene Types of Clinical Candida albicans Isolates

Background：Candida albicans （C.albicans） can become a pathogen causing superficial as well as life-threatening systemic infections,especially in immunocompromised patients.Many phenotypic attributes contribute to its capacity to colonize human organs.In our study,93 C.albicans isolates from patients of various candidiasis in a hospital of China were surveyed.We aimed to investigate the white-opaque （WO） switching competence,drug sensitivity,and virulence of mating type-like （MTL） a/α isolates.Methods：Internal transcribed spacer （ITS） gene and the MTL configuration were detected in all the isolates by reverse transcription-polymerase chain reaction.White/opaque phenotype and doubling time of cell growth were determined.The minimum inhibitory concentrations of antifungal agent were measured using broth microdilution method.Results：Sixty-four isolates （69.6%） were classified to serotype A,19 （20.6%） to serotype B,and 9 （9.8%） to serotype C.Moreover,phylogenetic analysis showed that these isolates were divided into four different subgroups of ITS genotypes.Most of our clinical isolates were MTLa/α type,while 6.8% remained MTLa or MTLα type.The frequency of opaque phenotype was 71.0% （66 isolates）.Following the guidelines of Clinical and Laboratory Standards Institute M27-A3,all isolates were susceptible to caspofungin and a few （0.6-3.2%） of them showed resistance against amphotericin B,flucytosine,fluconazole,itraconazole,and voriconazole.Conclusions：From these analyses,there were comparatively more C.albicans strains classified into serotype B,and the frequency of opaque phase strains was significant in the clinical isolates from China.Genetic,phenotypic,or drug susceptibility patterns were not significantly different from previous studies.MTLa/α isolates could also undergo WO switching which facilitates their survival.

Antimycotic efficacy of Iranian medicinal plants towards dermatophytes obtained from patients with dermatophytosis

从 Artemisia sieberi， Cuminum cyminum， Foeniculum vulgare， Heracleum persicum， Menta spicata， Nigella sativa， Rosmarinus officinalis， Zataria multiflora 和 Ziziphora 瞄准九植物香精油(曙光女神) ，包括那些 clinopodioides，为他们的 anti-dermatophytic 性质被评估。测试皮藓菌包括了 Trichophyton mentagrophytes (号码 32 ) 的方法， T。rubrum (号码 29 ) ， Epidermophyton floccosum (号码 19 ) ， Microsporum gypseum (号码 11 ) 和 M。canis (号码 42 ) 。植物油的危险性测试被由临床的实验室标准协会描述了的肉汤 microdilution 技术以最小的禁止的集中(MIC ) 和最小的杀菌剂集中(MFC ) 执行。所有曙光女神学习了的结果对皮藓菌是活跃的。MIC 为测试的植物油记录了从 0.25 ～ 4 mg ‰ ? 娠潨杮潺杮?? € 楑 ???????????? 丠??? ? ㈠吗？？

New species in Aspergillus section Fumigati from reclamation sites in Wyoming (U.S.A.) and revision of A. viridinutans complex

The Aspergillus viridinutans complex includes morphologically similar,soil-inhabiting species.Although its species boundaries have not been fully defined,many isolates from the complex have been isolated as opportunistic human and animal pathogens.In the present study,these species were dominant in spoil sites subjected to various types of reclamation management after coal mining.These species were characterised using two different PCR-fingerprinting methods,sequence data from the β-tubulin(benA)and calmodulin(caM)genes,macro-and micromorphology(optical and scanning electron microscopy),maximum growth temperatures and mating experiments.In addition,RNA polymerase II gene(RPB2),actin(act1)and ITS sequences were deposited for the ex-type isolates of newly described species.The mating experiment results,phylogenetic analyses and ascospore morphology suggested the presence of five species in the A.viridinutans complex.Aspergillus aureolus(syn.Neosartorya aureola)was the only homothallic species.Three species,A.felis,A.udagawae(syn.N.udagawae)and A.wyomingensis sp.nov.,were heterothallic and their morphologically distinguishable teleomorph was induced by systematic mating experiments.Aspergillus viridinutans s.str.seems to be a very rare species and was represented only by the ex-type isolate in which the MAT1-1 locus was amplified.Aspegillus viridinutans and A.aureolus were typified in accordance with the rules of the new botanical code.Other species outside the A.viridinutans complex isolated from the reclamation sites were A.fumigatiaffinis and A.lentulus as well as two new sister species,A.brevistipitatus sp.nov.and A.conversis sp.nov.which were closely related each to other and to N.papuensis.Both new species are phylogenetically distant from all anamorphic species and resemble A.brevipes,A.duricaulis and A.unilateralis in micromorphology and are distinguishable from each other by the slower growth of A.conversis on all tested media.Interestingly,no isolate from the reclamation sites represented A.fumigatus s.str.which is usually reported as the dominant species from the section Fumigati in soil.