生物学最新文献

The crosstalk between the tumour immune microenvironment (TIME) and tumour cells promote immune evasion and resistance to immunotherapy in gastrointestinal (GI) tumours. Post-transcriptional regulation of genes is pivotal to GI tumours progression, and RNA-binding proteins (RBPs) serve as key regulators via their RNA-binding domains. RBPs may exhibit either anti-tumour or pro-tumour functions by influencing the TIME through the modulation of mRNAs and non-coding RNAs expression, as well as post-transcriptional modifications, primarily N6-methyladenosine (m⁶A). Aberrant regulation of RBPs, such as HuR and YBX1, typically enhances tumour immune escape and impacts prognosis of GI tumour patients. Further, while targeting RBPs offers a promising strategy for improving immunotherapy in GI cancers, the mechanisms by which RBPs regulate the TIME in these tumours remain poorly understood, and the therapeutic application is still in its early stages. This review summarizes current advances in exploring the roles of RBPs in regulating genes expression and their effect on the TIME of GI tumours, then providing theoretical insights for RBP-targeted cancer therapies.

The objective of this study was to identify key secretory protein-encoding differentially expressed genes (SP-DEGs) in adipose tissue in female metabolic syndrome, thus detecting potential targets in treatment. We examined gene expression profiles in 8 women with metabolic syndrome and 7 healthy, normal body weight women. A total of 143 SP-DEGs were screened, including 83 upregulated genes and 60 downregulated genes. GO analyses of these SP-DEGs included proteolysis, angiogenesis, positive regulation of endothelial cell proliferation, immune response, protein processing, positive regulation of neuroblast proliferation, cell adhesion and ER to Golgi vesicle-mediated transport. KEGG pathway analysis of the SP-DEGs were involved in the TGF-beta signalling pathway, cytokine‒cytokine receptor interactions, the hippo signalling pathway, Malaria. Two modules were identified from the PPI network, namely, Module 1 (DNMT1, KDM1A, NCoR1, and E2F1) and Module 2 (IL-7 R, IL-12A, and CSF3). The gene DNMT1 was shared between the network modules and the WGCNA brown module. According to the single-gene GSEA results, DNMT1 was significantly positively correlated with histidine metabolism and phenylalanine metabolism. This study identified 7 key SP-DEGs in adipose tissue. DNMT1 was selected as the central gene in the development of metabolic syndrome and might be a potential therapeutic target.

Vulvovaginal candidiasis (VVC) is one of the most common infections caused by Candida albicans. VVC is characterized by an inadequate hyperinflammatory response and clinical symptoms associated with Candida colonization of the vaginal mucosa. Compared to other host niches in which C. albicans can cause infection, the vaginal environment is extremely rich in lactic acid that is produced by the vaginal microbiota. We examined how lactic acid abundance in the vaginal niche impacts the interaction between C. albicans and the human immune system using an in vitro culture in vaginal simulative medium (VSM). The presence of lactic acid in VSM (VSM+LA) increased C. albicans proliferation, hyphal length, and its ability to cause damage during subsequent infection of vaginal epithelial cells. The cell wall of C. albicans cells grown in VSM+LA displayed a robust mannan fibrillar structure, β-glucan exposure, and low chitin content. These cell wall changes were associated with altered immune responses and an increased ability of the fungus to induce trained immunity. Neutrophils were compromised in clearing C. albicans grown in VSM+LA conditions, despite mounting stronger oxidative responses. Collectively, we found that fungal adaptation to lactic acid in a vaginal simulative context increases its immunogenicity favouring a pro-inflammatory state. This potentially contributes to the immune response dysregulation and neutrophil recruitment observed during recurrent VVC.

Multiple porcine reproductive and respiratory syndrome virus (PRRSV) subtypes coinfect numerous pig farms in China, and commercial PRRSV vaccines offer limited cross-protection against heterologous strains. Our previous research confirmed that a PRRSV lineage 1 branch attenuated live vaccine (SD-R) provides cross-protection against HP-PRRSV, NADC30-like PRRSV and NADC34-like PRRSV. HP-PRRSV has undergone significant genetic variation following nearly two decades of evolution and has transformed into a subtype referred to as HP-like PRRSV, which also exhibits high pathogenicity. The effectiveness of immunising piglets with the SD-R strain to provide protection against infection with HP-like PRRSV remains uncertain. In the present study, we evaluated the protective effects of SD-R vaccine strains on DLF-challenged piglets. The results revealed that piglets challenged with DLF presented clinical symptoms such as continuous high fever and an obvious decrease in daily weight gain. Importantly, the piglets immunised with SD-R exhibited notable reductions in pathological damage, especially of decreases in DLF-induced thymic atrophy. Moreover, the serum of SD-R-immunised piglets strongly neutralised DLF, and the number of SD-R-vaccinated piglets demonstrating viraemia was greatly reduced. These results suggest that the PRRSV lineage 1 branch live vaccine candidate provides broad cross-protection against HP-like PRRSV in piglets.

The increasing incidence of infections attributed to hypervirulent carbapenem-resistant Klebsiella pneumoniae (Hv-CRKp) is of considerable concern. Bacteriophages, also known as phages, are viruses that specifically infect bacteria; thus, phage-based therapies offer promising alternatives to antibiotic treatments targeting Hv-CRKp infections. In this study, two isolated bacteriophages, Kpph1 and Kpph9, were characterized for their specificity against the Hv-CRKp K. pneumoniae NUHL30457 strain that possesses a K2 capsule serotype. Both phages exhibit remarkable environmental tolerance, displaying stability over a range of pH values (4-11) and temperatures (up to 50°C). The phages demonstrate potent antibacterial and antibiofilm efficacy, as indicated by their capacity to inhibit biofilm formation and to disrupt established biofilms of Hv-CRKp. Through phylogenetic analysis, it has been revealed that Kpph1 belongs to the new species of Webervirus genus, and Kpph9 to the Drulisvirus genus. Comparative genomic analysis suggests that the tail fiber protein region exhibits the greatest diversity in the genomes of phages within the same genus, which implies distinct co-evolution histories between phages and their corresponding hosts. Interestingly, both phages have been found to contain two tail fiber proteins that may exhibit potential depolymerase activities. However, the exact role of depolymerase in the interaction between phages and their hosts warrants further investigation. In summary, our findings emphasize the therapeutic promise of phages Kpph1 and Kpph9, as well as their encoded proteins, in the context of research on phage therapy targeting hypervirulent carbapenem-resistant Klebsiella pneumoniae.

The effects of chronically stressing male mice can be transmitted across generations by stress-specific changes in their sperm miRNA content, which induce stress-specific phenotypes in their offspring. However, how each stress paradigm alters the levels of distinct sets of sperm miRNAs is not known. We showed previously that exposure of male mice to chronic social instability (CSI) stress results in elevated anxiety and reduced sociability specifically in their female offspring across multiple generations because it reduces miR-34c levels in sperm of stressed males and their unstressed male offspring. Here, we describe evidence that astrocyte-derived exosomes (A-Exos) carrying miR-34c mediate how CSI stress has this transgenerational effect on sperm. We found that CSI stress decreases miR-34c carried by A-Exos in the prefrontal cortex and amygdala, as well as in the blood of males. Importantly, miR-34c A-Exos levels are also reduced in these tissues in their F1 male offspring, who despite not being exposed to stress, exhibit reduced sperm miR-34c levels and transmit the same stress-associated traits to their male and female offspring. Furthermore, restoring A-Exos miR-34c content in the blood of CSI-stressed males by intravenous injection of miR-34c-containing A-Exos restores miR-34c levels in their sperm. These findings reveal an unexpected role for A-Exos in maintaining sperm miR-34c levels by a process that when suppressed by CSI stress mediates this example of transgenerational epigenetic inheritance.

Polyhydroxyalkanoates (PHA) are bioplastics produced by few bacteria as intracellular lipid inclusions under excess carbon source and nutrient-deprived conditions. These polymers are biodegradable and resemble petroleum-based plastics. The rising environmental concerns have increased the demand for PHA, but the low yield in wild-type bacterial strains limits large-scale production. An improvement in the PHA production can be achieved by genetically engineering the wild-type bacterial strains by removing competitive pathways that divert the metabolites away from PHA biosynthesis, cloning strong promotors to overexpress the genes involved in PHA biosynthesis and constructing non-native metabolic pathways that feed the metabolites for PHA production. The desired monomers in the PHA polymers were obtained by elimination of genes involved in PHA biosynthetic pathway. The chain length degradation specific-gene deletion of β-oxidation pathway resulted in the accumulation of PHA monomers having high carbon chain length. A controlled accumulation of monomers in the PHA polymer was achieved by constructing novel pathways in the bacteria and deleting native genes of competitive pathways from the genome of non-PHA producers. The present review attempts to showcase the novel genetic modification approaches conducted so far to enhance the PHA production with a special focus on metabolic pathway gene deletion in various bacteria.

Cervical cancer, the fourth most common cancer globally and the second most prevalent cancer among women in India, is primarily caused by Human Papilloma Virus (HPV). The association of diet with cancer etiology and prevention has been well established and nutrition has been shown to regulate cancer through modulation of epigenetic markers. Dietary fatty acids, especially omega-3, reduce the risk of cancer by preventing or reversing the progression through a variety of cellular targets, including epigenetic regulation. In this work, we have evaluated the potential of ALA (α linolenic acid), an ω-3 fatty acid, to regulate cervical cancer through epigenetic mechanisms. The effect of ALA was evaluated on the regulation of histone deacetylases1, DNA methyltransferases 1, and 3b, and global DNA methylation by ELISA. RT-PCR was utilized to assess the expression of tumor regulatory genes (hTERT, DAPK, RARβ, and CDH1) and their promoter methylation in HeLa (HPV18-positive), SiHa (HPV16-positive) and C33a (HPV-negative) cervical cancer cell lines. ALA increased DNA demethylase, HMTs, and HATs while decreasing global DNA methylation, DNMT, HDMs, and HDACs mRNA expression/activity in all cervical cancer cell lines. ALA downregulated hTERT oncogene while upregulating the mRNA expression of TSGs (Tumor Suppressor Genes) CDH1, RARβ, and DAPK in all the cell lines. ALA reduced methylation in the 5' CpG island of CDH1, RARβ, and DAPK1 promoters and reduced global DNA methylation in cervical cancer cell lines. These results suggest that ALA regulates the growth of cervical cancer cells by targeting epigenetic markers, shedding light on its potential therapeutic role in cervical cancer management.

Obesity is characterized by macrophage infiltration into adipose tissue. White adipose tissue remodelling under inflammatory conditions involves both hypertrophy and adipogenesis and is regulated by transcription factors, which are influenced by bone morphogenetic protein (BMP) signalling. MicroRNAs (miRNAs) regulate gene expression and are involved in obesity-related processes such as adipogenesis. Therefore, we identified differentially expressed miRNAs in the epididymal white adipose tissue (eWAT) of mice fed a normal diet (ND) and those fed a high-fat diet (HFD). The expression of miR-6402 was significantly suppressed in the inflamed eWAT of HFD-fed mice than in ND-fed mice. Furthermore, Bmpr2, the receptor for BMP4, was identified as a target gene of miR-6402. Consistently, miR-6402 was downregulated in the inflamed eWAT of HFD-fed mice and in 3T3-L1 cells (preadipocytes) and differentiated 3T3-L1 cells (mature adipocytes) , and BMPR2 expression in these cells was upregulated. Adipogenesis was induced in WAT by BMP4 injection (in vivo) and in 3T3-L1 cells by BMP4 stimulation (in vitro), both of which were inhibited by miR-6402 transfection. Inflamed eWAT showed higher expression of BMPR2 and the adipogenesis markers C/EBPβ and PPARγ, which was suppressed by miR-6402 transfection. Our findings suggest that miR-6402 is a novel anti-adipogenic miRNA that combats obesity by inhibiting the BMP4/BMPR2 signalling pathway and subsequently reducing adipose tissue expansion.

Cirrhosis is a form of end-stage liver disease characterized by extensive hepatic fibrosis and loss of liver parenchyma. It is most commonly the result of long-term alcohol abuse in the United States. Large animal models of cirrhosis, as well as of one of its common long-term sequelae, HCC, are needed to study novel and emerging therapeutic interventions. In the present study, liver fibrosis was induced in the Oncopig cancer model, a large animal HCC model, via intrahepatic, intra-arterial ethanol infusion. Liver sections from five fibrosis induced and five age-matched controls were harvested for RNA-seq (mRNA and lncRNA), small RNA-seq (miRNA), and reduced representation bisulfite sequencing (RRBS; DNA methylation). Single- and multi-omic analysis was performed to investigate the transcriptomic and epigenomic mechanisms associated with fibrosis deposition in this model. A total of 3,439 genes, 70 miRNAs, 452 lncRNAs, and 7,715 methylation regions were found to be differentially regulated through individual single-omic analysis. Pathway analysis indicated differentially expressed genes were associated with collagen synthesis and turnover, hepatic metabolic functions such as ethanol and lipid metabolism, and proliferative and anti-proliferative pathways including PI3K and BAX/BCL signaling pathways. Multi-omic latent variable analysis demonstrated significant concordance with the single-omic analysis. lncRNA's associated with UHRF1BP1L and S1PR1 genes were found to reliably discriminate the two arms of the study. These genes were previously implicated in human cancer development and vasculogenesis, respectively. These findings support the validity and translatability of this model as a useful preclinical tool in the study of alcoholic liver disease and its treatment.