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.

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.

Background: Pulmonary metastases in osteosarcoma (OS) are associated with a poor prognosis. Rotenone has shown anti-cancer activity. However, its effects on metastasis and the underlying mechanisms remain unknown. This study investigated the potential use of Rotenone for OS treatment.

Methods: The effect of Rotenone and ROS/Ca²⁺/AMPK/ZO-2 pathway on metastasis and EMT was evaluated by Western blot, Transwell and Wound healing. Flow cytometer was employed to measure the intracellular Ros and Ca²⁺ levels. The subcellular location of ZO-2 was detected by IF, interaction between AMPK and ZO-2 were examined by Co-IP. Then, subcutaneous tumor and metastasis models were used to evaluate the function of Rotenone in OS metastasis.

Results: Rotenone-induced ROS led to increased intracellular Ca²⁺, which promoted the EMT of OS cells through activation of AMPK and ZO-2 nuclear translocation. Inhibition of ROS production decreased intracellular Ca²⁺, restraining AMPK activity. Knock-down of ZO-2 significantly suppressed the anti-metastasis effects of Rotenone in OS cells. Moreover, Rotenone elevated p-AMPK and ZO-2 expression but inhibited EMT and lung metastasis in vivo.Conclusion These results provide evidence supporting an anti-metastatic effect of Rotenone. These findings support the use of Rotenone in the prevention of OS metastasis.

One of the most common hospital-acquired infections is caused by toxigenic Clostridioides difficile. Although C. difficile ST37 only produces a functional toxin B, it causes disease as severe as that caused by hypervirulent ST1. We aim to compare the differences in virulence and drug resistance between ST37 and ST1 isolates. We conducted whole-genome sequencing on ST37 and ST1 isolates, analyzing their type-specific genes, and the distribution and mutation of genes related to virulence and antibiotic resistance. We compared the in vitro virulence-related phenotypes of ST37 and ST1 isolates, including: TcdB concentration, number of spores formed, aggregation rate, biofilm formation, swimming diameter in semi-solid medium, motility diameter on the surface of solid medium, and their resistance to 14 CDI-related antibiotics. We detected 4 ST37-specific genes related to adherence, including lytC, cbpA, CD3246, and srtB. We detected 97 virulence-related genes in ST37 isolates that exhibit genomic differences compared to ST1. ST37 isolates showed increased aggregation, biofilm formation, and surface motility compared to ST1 in vitro. Chloramphenicol resistance gene catQ and tetracycline resistance gene tetM are present in ST37 but absent in ST1 strains. The resistance rates of ST37 to chloramphenicol and tetracycline were 45.4% and 81.8%, respectively, whereas ST1 isolates were sensitive to both antibiotics. ST1 was more resistant to rifaximin than ST37. ST37 isolates showed stronger aggregation, biofilm formation and surface motility, and had higher resistance rates to chloramphenicol and tetracycline. ST1 isolates showed stronger ability to produce toxin and sporulation, and was highly resistant to rifaximin.

The long-term resistance to desiccation on abiotic surfaces is a key determinant of the adaptive success of Acinetobacter baumannii as a healthcare-associated bacterial pathogen. Here, the cellular and molecular mechanisms enabling A. baumannii to resist desiccation and persist on abiotic surfaces were investigated. Experiments were set up to mimic the A. baumannii response to air-drying that would occur when bacterial cells contaminate fomites in hospitals. Resistance to desiccation and transition to the "viable but nonculturable" (VBNC) state were determined in the laboratory-adapted strain ATCC 19606^T and the epidemic strain ACICU. Culturability, membrane integrity, metabolic activity, virulence, and gene expression profile were compared between the two strains at different stages of desiccation. Upon desiccation, ATCC 19606^T and ACICU cells lose culturability and membrane integrity, lower their metabolism, and enter the VBNC state. However, desiccated A. baumannii cells fully recover culturability and virulence in an insect infection model following rehydration in physiological buffers or human biological fluids. Transcriptome and chemical analyses of A. baumannii cells during desiccation unveiled the production of protective metabolites (L-cysteine and L-glutamate) and decreased energetic metabolism consequent to activation of the glyoxylate shunt (GS) pathway, as confirmed by reduced resuscitation efficiency of aceA mutants, lacking the key enzyme of the GS pathway. VBNC cell formation and extensive metabolic reprogramming provide a biological basis for the response of A. baumannii to desiccation, with implications on environmental control measures aimed at preventing the transmission of A. baumannii infection in hospitals.

Staphylococcus aureus (S. aureus) infection can lead to the occurrence of hypoxia, however, the underlying mechanisms have not been fully elucidated. β-hemolysin (Hlb) induced hemolysis of red blood cells (RBCs) requires a temperature transition from "hot" to "cold," a phenomenon not observed under physiological conditions. In this study, we discovered that RBCs treated with Hlb exhibited a high level of intracellular Ca²⁺ and underwent a shape transformation from biconcave discoid to spherical, which was contingent upon the degradation of sphingomyelin of the cell membrane and led to impaired oxygen transport. The increase in intracellular Ca²⁺ levels induced by Hlb was dependent on the activation of the ion channel N-methyl-D-aspartate receptor. Furthermore, we found that Hlb-induced Ca²⁺ influx increased the cytoplasmic pH and subsequently attenuated the oxygen release from RBCs, which were also observed in both hlb transgenic mice and a murine model with S. aureus challenge. Our findings reveal a novel role for Hlb as sphingomyelinase in impairing RBC function under non-lytic conditions, shedding light on the mechanism behind hypoxia associated with S. aureus infection.

The endemic status of goose parvovirus (GPV) continues to devastate the poultry industry in China. Novel GPV (NGPV) and Mutated GPV (MGPV) represent the predominant lineages. However, the comparative pathogenicity between these viruses remains poorly understood. Herein, we selected representative NGPV and MGPV strains as model viruses to assess their pathogenic potential both in vitro and in vivo. In vitro cellular and embryo assays demonstrated that both NGPV and MGPV were capable of replicating in DEF and GEF cells, leading to pronounced cytopathic effects. However, these viruses exhibited distinct levels of intra-embryonic replication capabilities. Furthermore, we conducted in vivo infection experiments and systematically evaluated the pathogenic differences between NGPV and MGPV by examining various indicators, including growth, clinical signs, gross pathology, skeletal development, viral load, and humoral response in the infected animals. The results showed that both NGPV and MGPV inhibited weight gain in goslings and ducklings, with NGPV exerting a more significant suppressive impact. MGPV induced classical gosling plague pathology in goslings, while NGPV led to short beak and dwarfism syndrome in ducklings, notably disrupting skeletal development. Moreover, MGPV and NGPV exhibited diverse host tropisms, with MGPV being more pathogenic to goslings and NGPV to ducklings. Both viruses elicited specific antibody responses, with MGPV being more effective in goslings and NGPV in ducklings. Additionally, MGPV exhibited stronger humoral response compared to NGPV. These findings enhance our understanding of the pathogenicity of prevalent GPV strains in waterfowl, offering a critical theoretical foundation for devising strategies to prevent GPV infections.

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.

Background: Mesenchymal stem cells (MSCs) are a potential therapy for acute respiratory distress syndrome (ARDS), but their mechanisms in repairing mitochondrial damage in ARDS endothelial cells remain unclear.

Methods: We first examined MSCs' mitochondrial transfer ability and mechanisms to mouse pulmonary microvascular endothelial cells (MPMECs) in ARDS. Then, we investigated how MSC-mediated mitochondrial transfer affects the repair of endothelial damage. Finally, we elucidated the mechanisms by which MSC-mediated mitochondrial transfer promotes vascular regeneration.

Results: Compared to mitochondrial-damaged MSCs, normal MSCs showed a significantly higher mitochondrial transfer rate to MPMECs, with increases of 41.68% in vitro (P < 0.0001) and 10.50% in vivo (P = 0.0005). Furthermore, MSC-mediated mitochondrial transfer significantly reduced reactive oxygen species (P < 0.05) and promoted proliferation (P < 0.0001) in MPMECs. Finally, MSC-mediated mitochondrial transfer significantly increased the activity of the tricarboxylic acid (TCA) cycle (MD of CS mRNA: 23.76, P = 0.032), and further enhanced fatty acid synthesis (MD of FAS mRNA: 6.67, P = 0.0001), leading to a 6.7-fold increase in vascular endothelial growth factor release from MPMECs and promoted vascular regeneration in ARDS.

Conclusion: MSC-mediated mitochondrial transfer to MPMECs activates the TCA cycle and fatty acid synthesis, promoting endothelial proliferation and pro-angiogenic factor release, thereby enhancing vascular regeneration in ARDS.