BcSDR1 is involved in regulation of glucose transport and cAMP and MAPK signaling pathways in Botrytis cinerea

Botrytis cinerea is a typical necrotrophic pathogenic fungus that causes severe diseases in a wide range of plant species, leading to significant economic losses. Our previous study showed that BcSDR1 positively regulates growth,development, and pathogenicity of B. cinerea. However, the regulation mechanism of BcSDR1 and the relationship between BcSDR1 and cAMP and MAPK signaling pathways are not well understood. In this study, transcriptome data showed that BcSDR1 is involved in glucose transmembrane transport, signal transduction, secondary metabolism, and other biological processes. BcSDR1 mutant(BCt41) showed remarkably weak sensitivity to cAMP and MAPK signaling pathways specific inhibitors, SQ22536 and U0126, and significantly decreased cAMP content. The key genes of cAMP and MAPK signaling pathways, BcGB1, BcBTP1, BcBOS1, BcRAS1, and BcBMP3 were significantly upregulated,whereas BcPLC1, BcBCG1, BcCDC4, BcSAK1, BcATF1, and BcBAP1 were significantly downregulated(P<0.05).BcSDR1 was obviously upregulated in BcBCG2, BcBCG3, BcPKA1, and BcPKAR RNA interference(RNAi) mutants, but significantly downregulated in BcPKA2, BcBMP1, and BcBMP3 RNAi mutants. Thus, BcBCG2, BcBCG3, BcPKA1, and BcPKAR negatively regulate BcSDR1 expression, whereas BcPKA2, BcBMP1, and BcBMP3 positively regulate BcSDR1expression.

Effect of Down-regulation of MMP-2 by Quercetin on the Migration and Invasion of Uterine Fibroids Cells through the cAMP Signaling Pathway

Objective:To investigate the effect of down-regulation of matrix metalloproteinase-2(MMP-2)by down-regulating the cyclic adenosine monophosphate(cAMP)signaling pathway on the migration and invasion of uterine fibroids cells.Methods:A total of 65 female SD rats were randomly divided into five groups after being adaptively fed for 7 d.Except for the blank group,the remaining four groups of rats were injected with 0.05 mg/(100 g·d)estradiol benzoate and 0.5 mg/(100g·d)progesterone into the muscle to establish a uterine fibroids rat model.After successful modeling,the blank group and model group were given 200 mg/(kg·d)physiological saline by gavage,the low-dose group was given 100 mg/(kg·d)mifepristone by gavage,the medium-dose group was given 200 mg/(kg·d)mifepristone by gavage,and the high-dose group was given 300 mg/(kg·d)mifepristone by gavage.After continuous gavage treatment for 21 d,serum and uterine tissues were collected from rats to observe and compare the expression levels of MMP-2 mRNA,TIMP-2 mRNA,estradiol(E2),cAMP signaling pathway related proteins,and the migration and invasive ability of uterine fibroids cells in the five groups of rats.Results:The expression levels of MMP-2 mRNA and E2in the high-dose group were lower than those in the low-dose group and the medium-dose group,and the expression level of TIMP-2 mRNA was higher than that in the low-dose group and the medium-dose group(P<0.05).The number of cell migration in a single visual field of rats in the high-dose group was lower than that in the low-dose group and the medium-dose group(P<0.05).The number of cell invasion in a single visual field of rats in the high-dose group was lower than that in the low-dose group and the medium-dose group(P<0.05).The mRNA expression levels of cAMP,PDE and PK in the high-dose group were higher than those in the low-dose group,and the mRNA expression levels of AC in the high-dose group were lower than those in the low-dose group(P<0.05).The mRNA expression levels of cAMP and PDE in the high-dose group were higher than those in the mediumdose group(P<0.05).Conclusion:Letrozole may down-regulate the expression level of MMP-2 through the cAMP signaling pathway to inhibit the migration and invasion of uterine fibroids cells.With increasing doses of letrozole,its inhibitory effect on the migration and invasion of uterine fibroids cells will be enhanced.However,the optimal dosage of letrozole for inhibiting the migration and invasion of uterine fibroids cells is yet to be determined.

Rbm8a regulates neurogenesis and reduces Alzheimer's disease-associated pathology in the dentate gyrus of 5×FAD mice

Alzheimer’s disease is a prevalent and debilitating neurodegenerative condition that profoundly affects a patient’s daily functioning with progressive cognitive decline,which can be partly attributed to impaired hippocampal neurogenesis.Neurogenesis in the hippocampal dentate gyrus is likely to persist throughout life but declines with aging,especially in Alzheimer’s disease.Recent evidence indicated that RNA-binding protein 8A(Rbm8a)promotes the proliferation of neural progenitor cells,with lower expression levels observed in Alzheimer’s disease patients compared with healthy people.This study investigated the hypothesis that Rbm8a overexpression may enhance neurogenesis by promoting the proliferation of neural progenitor cells to improve memory impairment in Alzheimer’s disease.Therefore,Rbm8a overexpression was induced in the dentate gyrus of 5×FAD mice to validate this hypothesis.Elevated Rbm8a levels in the dentate gyrus triggered neurogenesis and abated pathological phenotypes(such as plaque formation,gliosis reaction,and dystrophic neurites),leading to ameliorated memory performance in 5×FAD mice.RNA sequencing data further substantiated these findings,showing the enrichment of differentially expressed genes involved in biological processes including neurogenesis,cell proliferation,and amyloid protein formation.In conclusion,overexpressing Rbm8a in the dentate gyrus of 5×FAD mouse brains improved cognitive function by ameliorating amyloid-beta-associated pathological phenotypes and enhancing neurogenesis.

Dynamic localization of hepatocellular transporters in health and disease

Vesicle-based traffi cking of hepatocellular transporters involves delivery of the newly-synthesized carriers from the rough endoplasmic reticulum to either the plasma membrane domain or to an endosomal,submembrane compartment,followed by exocytic targeting to the plasma membrane. Once delivered to the plasma membrane,the transporters usually undergo recycling between the plasma membrane and the endosomal compartment,which usually serves as a reservoir of pre-existing transporters available on demand. The balance between exocytic targeting and endocytic internalization from/to this recycling compartment is therefore a chief determinant of the overall capability of the liver epithelium to secrete bile and to detoxify endo and xenobiotics. Hence,it is a highly regulated process. Impaired regulation of this balance may lead to abnormal localization of these transporters,which results in bile secretory failure due to endocytic internalization of key transporters involved in bile formation. This occurs in several experimental models of hepatocellular cholestasis,and in most human cholestatic liver diseases. This review describes the molecular bases involved in the biology of the dynamic localization of hepatocellular transporters and its regulation,with a focus on the involvement of signaling pathways in this process. Their alterations in different experimental models of cholestasis and in human cholestatic liver disease are reviewed. In addition,the causes explaining the pathological condition (e.g. disorganization of actin or actin-transporter linkers) and the mediators involved (e.g. activation of cholestatic signaling transduction pathways) are also discussed. Finally,several experimental therapeutic approaches based upon the administration of compounds known to stimulate exocytic insertion of canalicular transporters (e.g. cAMP,tauroursodeoxycholate) are described.

Protective effects of VMY-2-95 on corticosterone-induced injuries in mice and cellular models

Nicotinicα4β2 receptor antagonists have drawn increasing attention in the development of new antidepressants.In this study,we aimed to investigate the protective effect of VMY-2-95,the new selective antagonist ofα4β2 nicotinic acetylcholine receptor(nAChR)on corticosterone(CORT)injured mice and cellular models.Fluoxetine was applied as a positive control,and the effects of VMY-2-95 were investigated with three different doses or concentrations(1,3,10 mg/kg in mice,and 0.003,0.03,0.1μmol/L in cells).As a result,VMY-2-95 showed significant antidepressant-like effects in the CORT injured mice by improving neuromorphic function,promoting hippocampal nerve proliferation,and regulating the contents of monoamine transmitters.Meanwhile,VMY-2-95 exhibited protective effects on cell viability,cell oxidant,cell apoptosis,and mitochondrial energy metabolism on corticosterone-impaired SH-SY5 Y cells.Also,the PKA-CREB-BDNF signaling pathway was up-regulated by VMY-2-95 both in vitro and in vivo,and pathway blockers were also combined with VMY-2-95 to verify the effects furtherly.Therefore,we preliminarily proved that VMY-2-95 had protective effects in depressed mice and SH-SY5 Y cells against injuries induced by corticosterone.This work indicated that the application of VMY-2-95 is a potential pharmacological solution for depression.This study also supported the development ofα4β2 nAChR antagonists towards neuropsychiatric dysfunctions.