Molecular biomedicine最新文献

The intestinal microbiota is considered to be a forgotten organ in human health and disease. It maintains intestinal homeostasis through various complex mechanisms. A significant body of research has demonstrated notable differences in the gut microbiota of patients with gastrointestinal tumours compared to healthy individuals. Furthermore, the dysregulation of gut microbiota, metabolites produced by gut bacteria, and related signal pathways can partially explain the mechanisms underlying the occurrence and development of gastrointestinal tumours. Therefore, this article summarizes the latest research progress on the gut microbiota and gastrointestinal tumours. Firstly, we provide an overview of the composition and function of the intestinal microbiota and discuss the mechanisms by which the intestinal flora directly or indirectly affects the occurrence and development of gastrointestinal tumours by regulating the immune system, producing bacterial toxins, secreting metabolites. Secondly, we present a detailed analysis of the differences of intestinal microbiota and its pathogenic mechanisms in colorectal cancer, gastric cancer, hepatocellular carcinoma, etc. Lastly, in terms of treatment strategies, we discuss the effects of the intestinal microbiota on the efficacy and toxic side effects of chemotherapy and immunotherapy and address the role of probiotics, prebiotics, FMT and antibiotic in the treatment of gastrointestinal tumours. In summary, this article provides a comprehensive review of the pathogenic mechanisms of and treatment strategies pertaining to the intestinal microbiota in patients with gastrointestinal tumours. And provide a more comprehensive and precise scientific basis for the development of microbiota-based treatments for gastrointestinal tumours and the prevention of such tumours.

In this study, we examined the combined impact of osteopontin (OPN) and treadmill training on mice with spinal cord injury (SCI). OPN was overexpressed by injecting AAV9-SPP1-GFP into the sensorimotor cortex, followed by a left incomplete C5 crush injury two weeks later. Mice (Ex or Ex + OPN group) were trained at 50% maximum running speed for 8 weeks. To analyze the effects, we used biotinylated dextran amine (BDA) for tracing the corticospinal tract (CST) and performed Western blotting and immunohistochemical methods to assess the activation of the mammalian target of rapamycin (mTOR). We also examined axonal regeneration and conducted behavioral tests to measure functional recovery. The results demonstrated that treadmill training promoted the expression of neurotrophic factors such as brain-derived neurotrophic factor (BNDF) and insulin-like growth factor I (IGF-1) and activated mTOR signaling. OPN amplified the effect of treadmill training on activating mTOR signaling indicated by upregulated phosphorylation of ribosomal protein S6 kinase (S6). The combination of OPN and exercise further promoted functional recovery and facilitated limited CST axonal regeneration which did not occur with treadmill training and OPN treatment alone. These findings indicate that OPN enhances the effects of treadmill training in the treatment of SCI and offer new therapeutic insights for spinal cord injury.

Mesenchymal stem cells (MSCs) have been applied in transplantation to treat intracerebral hemorrhage (ICH) but with limited efficacy. Accumulated evidence has shown that glial cell-derived neurotrophic factor (GDNF) plays a crucial part in neuronal protection and functional recovery of the brain after ICH; however, GDNF has difficulty crossing the blood-brain barrier, which limits its application. In this study, we investigated the influences of MSCs overexpressing GDNF (MSCs/GDNF) on the brain structure as well as gait of rats after ICH and explored the possible mechanisms. We found that cell transplantation could reverse the neurological dysfunction and brain damage caused by ICH to a certain extent, and MSCs/GDNF transplantation was superior to MSCs transplantation. Moreover, Transplantation of MSCs overexpressing GDNF effectively reduced the volume of bleeding foci and increased the level of glucose uptake in rats with ICH, which could be related to improving mitochondrial quality. Furthermore, GDNF produced by transplanted MSCs/GDNF further inhibited neuroinflammation, improved mitochondrial quality and function, promoted angiogenesis and the survival of neurons and oligodendrocytes, and enhanced synaptic plasticity in ICH rats when compared with simple MSC transplantation. Overall, our data indicate that GDNF overexpression heightens the curative effect of MSC implantation in treating rats following ICH.

Glioblastoma (GBM) is an aggressive intracranial tumour, and current chemotherapy regimens have limited efficacy. Aloperine (ALO), a natural alkaline compound, has shown potential as an antitumor agent. However, the effect of ALO against GBM remains unclear. This study aimed to investigate the function of ALO in treating GBM. U87, A172, and GL261 cell lines were used for in vitro experiments, and GL261 was also used to establish in vivo models. The results showed that ALO inhibited the proliferation of GBM cells by cell cycle arrest and apoptosis. Furthermore, autophagy was found to play a critical role, suggested by observation of autophagosomes under the transmission electron microscopy. It was discovered for the first time that ALO targeted lysosomes directly in glioma cells, tested by fluo-rescence-labelled ALO and organelle-localizing probes. In addition, ALO inhibited late autophagy and induced paraptosis in GBM, verified by classical gene expression changes in qPCR and western blotting. Also, ALO inhibited tumour growth and acted synergistically with temozolomide in intracranial glioma mice models in vivo. Our findings suggest that ALO targets lysosomes to inhibit late autophagy in GBM, inducing cell cycle arrest, paraptosis, and apoptosis. ALO may therefore be a promising therapeutic agent for the treatment of GBM.

RNA binding proteins (RBPs) are crucial for cell function, tissue growth, and disease development in disease or normal physiological processes. RNA binding motif protein 47 (RBM47) has been proven to have anti-tumor effects on many cancers, but its effect is not yet clear in renal cancer. Here, we demonstrated the expression and the prognostic role of RBM47 in public databases and clinical samples of clear cell renal carcinoma (ccRCC) with bioinformatics analysis. The possible mechanism of RBM47 in renal cancer was verified by gene function prediction and in vitro experiments. The results showed that RBM47 was downregulated in renal cancers when compared with control groups. Low RBM47 expression indicated poor prognosis in ccRCC. RBM47 expression in renal cancer cell lines was reduced significantly when compared to normal renal tubular epithelial cells. Epithelial-mesenchymal transition (EMT) and transforming growth factor-β signaling pathway was associated with RBM47 in ccRCC by Gene set enrichment analysis. RBM47 expression had a positive correlation with e-cadherin, but a negative correlation with snail and vimentin. RBM47 overexpression could repress the migration, invasion activity, and proliferation capacity of renal cancer cells, while RBM47 inhibition could promote the development of the malignant features through EMT signaling by RNA stability modification. Therefore, our results suggest that RBM47, as a new molecular biomarker, may play a key role in the cancer development of ccRCC.

The Janus kinase-signal transducer and transcription activator pathway (JAK-STAT) serves as a cornerstone in cellular signaling, regulating physiological and pathological processes such as inflammation and stress. Dysregulation in this pathway can lead to severe immunodeficiencies and malignancies, and its role extends to neurotransduction and pro-inflammatory signaling mechanisms. Although JAK inhibitors (Jakinibs) have successfully treated immunological and inflammatory disorders, their application has generally been limited to diseases with similar pathogenic features. Despite the modest expression of JAK-STAT in the CNS, it is crucial for functions in the cortex, hippocampus, and cerebellum, making it relevant in conditions like Parkinson's disease and other neuroinflammatory disorders. Furthermore, the influence of the pathway on serotonin receptors and phospholipase C has implications for stress and mood disorders. This review expands the understanding of JAK-STAT, moving beyond traditional immunological contexts to explore its role in stress-related disorders and CNS function. Recent findings, such as the effectiveness of Jakinibs in chronic conditions such as rheumatoid arthritis, expand their therapeutic applicability. Advances in isoform-specific inhibitors, including filgotinib and upadacitinib, promise greater specificity with fewer off-target effects. Combination therapies, involving Jakinibs and monoclonal antibodies, aiming to enhance therapeutic specificity and efficacy also give great hope. Overall, this review bridges the gap between basic science and clinical application, elucidating the complex influence of the JAK-STAT pathway on human health and guiding future interventions.

Recent studies challenge the dogma that a 21-mer phosphopeptide P140 protects against direct cell damage in the phase-III clinical trial (NCT02504645) for lupus, involving reactive oxygen species (ROS)-dependent release of citrullinated histone H3 (H3cit)-linked neutrophil extracellular traps. An open question is the cellular location of ROS production and H3cit formation in lupus. In this study, we examined the effects of P140 peptides on ROS production and H3cit location in lupus with in vivo and situ fluorescence imaging with subcellular resolution. We developed a mouse model of the B6 strain harbouring a bioluminescent reporter under the control of the Lysozyme M promoter. Based on the imiquimod-induced disease model of B6 mice, we used bioluminescent imaging, flow cytometry analysis, and immunohistology staining to study the effects of P140 peptides in lupus. We found a profound accumulation of CX3CR1-positive macrophages in the lungs of lupus mice after the application of P140, accompanied by lung fibrosis formation. The defined P140-mediated macrophage responses were associated with an increase of H3cit in the cytosol, interleukin-1 receptor type 1 on the extracellular membrane, and intracellular production of ROS. Of interest, the disease of imiquimod-induced lupus was prevented with an antioxidant drug apocynin. This study shows that P140 peptides play a role in aggravated murine lupus in a manner dependent on ROS production and H3cit upregulation through pulmonary macrophages.

Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive system, and represents a severe threat to the life and health of individuals. Increasing evidence supports the role of small nucleolar RNAs (snoRNAs) as critical regulatory gene in cancer development. Small Cajal body-specific RNAs (scaRNAs), a subtype of snoRNAs, are named for their subcellular localization within Cajal bodies. SCARNA12, which located at the intronic region of PHB2 in chromosome 12p13.31 with 270 nucleotides (nt) in length. It has been reported function as a diagnostic marker for cervical cancer. However, its biological functions and molecular mechanisms in CRC have yet to be elucidated. In this study, bioinformatics analysis revealed that SCARNA12 was highly expressed in CRC and positively correlated with poor prognosis in CRC patients. Additionally, SCARNA12 showed upregulated expression in CRC cell lines and clinical CRC tissue samples. Moreover, SCARNA12 overexpression in SW620 cells accelerated cell proliferation, suppressed the apoptosis rate, and enhanced tumorigenesis in vivo. The knockdown of SCARNA12 expression in HCT116 and HT29 cells resulted in contrasting effects. The functioning of SCARNA12 is mechanically independent of its host gene PHB2. Notably, the overexpression of SCARNA12 activated PI3K/AKT pathway in SW620 cells, and the malignancy degree of CRC cells was attenuated after treatment with MK2206 (a specific AKT inhibitor). Our findings demonstrated that SCARNA12 plays an oncogenic role in CRC progression and can be used as a potential diagnostic biomarker for CRC.