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Purines and their derivatives, most notably adenosine and ATP, are the key molecules controlling intracellular energy homoeostasis and nucleotide synthesis. Besides, these purines support, as chemical messengers, purinergic transmission throughout tissues and species. Purines act as endogenous ligands that bind to and activate plasmalemmal purinoceptors, which mediate extracellular communication referred to as “purinergic signalling”. Purinergic signalling is cross-linked with other transmitter networks to coordinate numerous aspects of cell behaviour such as proliferation, differentiation, migration, apoptosis and other physiological processes critical for the proper function of organisms. Pathological deregulation of purinergic signalling contributes to various diseases including neurodegeneration, rheumatic immune diseases, inflammation, and cancer. Particularly, gout is one of the most prevalent purine-related disease caused by purine metabolism disorder and consequent hyperuricemia. Compelling evidence indicates that purinoceptors are potential therapeutic targets, with specific purinergic agonists and antagonists demonstrating prominent therapeutic potential. Furthermore, dietary and herbal interventions help to restore and balance purine metabolism, thus addressing the importance of a healthy lifestyle in the prevention and relief of human disorders. Profound understanding of molecular mechanisms of purinergic signalling provides new and exciting insights into the treatment of human diseases.

N-methyl-D-aspartate receptors (NMDARs) are a major class of glutamate receptors crucial for neural development and function. Here, we report that NMDARs expressed on neurons regulate brain vascular development via neurovascular communication. Dysfunction of neuronal NMDARs impairs the formation of the zebrafish brain vasculature and abrogates the neural activity-induced enhancement of the brain vascular development. These defects are attributed to the reduced growth of vascular endothelial tip cells (ETCs) situating at the leading edge of brain angiogenic sprouts. At the molecular level, NMDAR dysfunction down-regulates neuronal expression of vascular endothelial growth factor and subsequent global Ca 2+ activities of ETCs, thereby impairing ETC growth. Thus, our study uncovers an important role of NMDARs in brain vascular development, expanding the functional repertoire of NMDARs and the mechanistic understanding of the interplay between nervous and vascular systems during development. Neurovascular interaction is critical for normal brain vascular development. Here, the authors show that neuronal NMDARs regulate brain vascular development via VEGF-induced global Ca2+ activities of endothelial tip cells.

Osteoarthritis (OA) is a degenerative disease with a high prevalence in the elderly population, but our understanding of its mechanisms remains incomplete. Analysis of serum exosomal small RNA sequencing data from clinical patients and gene expression data from OA patient serum and cartilage obtained from the GEO database revealed a common dysregulated miRNA, miR-199b-5p. In vitro cell experiments demonstrated that miR-199b-5p inhibits chondrocyte vitality and promotes extracellular matrix degradation. Conversely, inhibition of miR-199b-5p under inflammatory conditions exhibited protective effects against damage. Local viral injection of miR-199b-5p into mice induced a decrease in pain threshold and OA-like changes. In an OA model, inhibition of miR-199b-5p alleviated the pathological progression of OA. Furthermore, bioinformatics analysis and experimental validation identified Gcnt2 and Fzd6 as potential target genes of MiR-199b-5p . Thus, these results indicated that MiR-199b-5p / Gcnt2 and Fzd6 axis might be a novel therapeutic target for the treatment of OA.

We aimed to use transcriptomics, bioinformatics analysis, and core gene validation to identify the core gene and potential mechanisms for electroacupuncture (EA) treatment of ulcerative colitis (UC). EA was performed in mice after induction of UC dextran sodium sulfate. Body weight, disease activity index (DAI), colon length, and hematoxylin-eosin of the colon tissue were used to evaluate the effects of EA. Mice transcriptome samples were analyzed to identify the core genes, and further verified with human transcriptome database; the ImmuCellAI database was used to analyze the relationship between the core gene and immune infiltrating cells (IICs); and immunofluorescence was used to verify the results. EA could reduce DAI and histological colitis scores, increase bodyweight and colon length, and improve the expression of local and systemic proinflammatory factors in the serum and colon of UC mice. Eighteen co-differentially expressed genes were identified by joint bioinformatics analyses of mouse and human transcriptional data; was the core gene. EA affected IICs by inhibiting expression and regulated the polarization of macrophages by affecting the Th1 cytokine IFN-γ, inhibiting the expression of CXCL1. CXCL1 is the target of EA, which is associated with the underlying immune mechanism related to Th1 cytokine IFN-γ.

Aim Given that electroacupuncture (EA) pretreatment inhibits lactate production and lactate‐derived lysine lactation (Kla) aggravates ischemic brain injury, we aimed to investigate whether the formation of Kla protein is involved in EA pretreatment to alleviate ischemic brain injury. Methods EA was performed on the Baihui acupoint (GV20) of male C57BL/6J mice before receiving the permanent middle cerebral artery occlusion (pMCAO) surgery. Western blot and immunofluorescent staining were used to observe neuronal survival, astrocyte activation, and protein Kla levels, and the lactate levels in ischemic brains were assayed with a commercial kit. TTC staining and neurological function scores are performed to evaluate the brain damage in mice. Results We found that the increased lactate content and protein Kla levels were significantly decreased in ischemic brain tissue of mice after receiving EA pretreatment, and accompanied by the reduction of astrocyte activation and neuronal injury and death. Meantime, we found that EA pretreatment was effective in reversing the worsening of ischemic brain injury caused by lactate supplementation. However, EA pretreatment did not further reduce the lactate content and protein Kla levels and ameliorate brain injury in ischemic stroke mice after inhibition of glycolysis. Conclusion Our study reveals that EA pretreatment reduced ischemic brain damage by inhibiting lactate production and its derived protein Kla formation in mice with ischemic stroke. Electroacupuncture pretreatment can inhibit the glycolysis process in astrocytes after ischemia, reduce the activation of astrocytes, and reduce the lactate‐derived lysine lactation level, thereby reducing neuronal damage and improving ischemia‐induced brain injury.

A sustained imbalance between excitatory and inhibitory mechanisms within the glutamatergic and GABAergic systems of the cerebral cortex, induced by noxious stimuli, is a fundamental characteristic in the development and maintenance of chronic pain. This review provides a comprehensive summary of the roles and interaction of glutamatergic and GABAergic systems in the processing of chronic pain signals. Specifically, we present a systematic summary of the processing patterns of the cerebral cortex in the cross-modular integration and output of chronic pain information, according to four aspects, molecular, cellular, neural network and behavioral cognition. These patterns consist of neuronal responses in individual cortical regions, neuron-astrocyte interactions, sharing and cascading of inter-cortical signals, and downward cortical modulation. Furthermore, a number of potential therapeutic approaches to the chronic pain are discussed from the pain management perspective.

Background: Probiotic and low fermentable oligosaccharide, disaccharide, monosaccharide, and polyol (FODMAP) diet are two commonly used management approaches for patients with irritable bowel syndrome (IBS). We aimed to evaluate the most effective combinations and components among different probiotics or low FODMAP diet through component network meta-analysis (NMA). Methods: We searched Embase, Ovid Medline, and Web of Science from inception to 21 January 2021. Randomized controlled trials (RCTs) examining the efficacy of probiotics and low FODMAP diet for IBS were included, with placebo, sham diet, or conventional treatments as controls. Binary outcomes were compared among treatments using the relative ratio (RR). A minimally contextualized framework recommended by the GRADE group was used to evaluate the certainty of evidence. The primary efficacy outcome was the relief of global IBS symptoms, and the secondary efficacy outcome was the reduction in IBS symptom scores or abdominal pain scores. Key Results: We included 76 RCTs (n = 8058) after screening 1940 articles. Eight RCTs were classified as low risk of bias. Standard network meta-analysis (NMA) showed that Lactobacillus (RR 1.74, 95% CI 1.22–2.48) and Bifidobacterium (RR 1.76, 95% CI 1.01–3.07) were the most effective for the primary efficacy outcome (high certainty evidence); component NMA showed that Bacillus (RR 5.67, 95% CI 1.88 to 17.08, p = 0.002) and Lactobacillus (RR 1.42, 95% CI 1.07 to 1.91, p = 0.017) were among the most effective components. The results of standard NMA and CNMA analysis of the improvement of overall IBS symptom scores or abdominal pain scores were consistent with this finding. Conclusion: Lactobacillus was the most effective component for the relief of IBS symptoms; Bifidobacterium and Bacillus were possibly effective and need further verification. Systematic Review Registration: website, identifier registration number.

It is unclear how Toll-like receptor (TLR) 4 signaling affects protein succinylation in the brain after intracerebral hemorrhage (ICH). Here, we constructed a mouse ICH model to investigate the changes in ICH-associated brain protein succinylation, following a treatment with a TLR4 antagonist, TAK242, using a high-resolution mass spectrometry-based, quantitative succinyllysine proteomics approach. We characterized the prevalence of approximately 6700 succinylation events and quantified approximately 3500 sites, highlighting 139 succinyllysine site changes in 40 pathways. Further analysis showed that TAK242 treatment induced an increase of 29 succinyllysine sites on 28 succinylated proteins and a reduction of 24 succinyllysine sites on 23 succinylated proteins in the ICH brains. TAK242 treatment induced both protein hypersuccinylations and hyposuccinylations, which were mainly located in the mitochondria and cytoplasm. GO analysis showed that TAK242 treatment-induced changes in the ICH-associated succinylated proteins were mostly located in synapses, membranes and vesicles, and enriched in many cellular functions/compartments, such as metabolism, synapse, and myelin. KEGG analysis showed that TAK242-induced hyposuccinylation was mainly linked to fatty acid metabolism, including elongation and degradation. Moreover, a combined analysis of the succinylproteomic data with previously published transcriptome data revealed that most of the differentially succinylated proteins induced by TAK242 treatment were mainly distributed throughout neurons, astrocytes, and endothelial cells, and the mRNAs of seven and three succinylated proteins were highly expressed in neurons and astrocytes, respectively. In conclusion, we revealed that several TLR4 signaling pathways affect the succinylation processes and pathways in mouse ICH brains, providing new insights on the ICH pathophysiological processes. Data are available via ProteomeXchange with identifier PXD025622.

Background Acupuncture at Neiguan (PC6) has long been used for treating cardiovascular diseases, but its antiarrhythmic effect and the underlying mechanisms have not yet been well investigated, especially regarding premature ventricular complexes (PVCs) that occur post-myocardial infarction (MI). The purpose of this study was to study the antiarrhythmic effect of manual acupuncture applied to PC6 for a relatively long period (28 days) and to elucidate the mechanism in mice . Methods An MI mouse model was generated by ligating the left anterior descending coronary artery in male C57/BL6 mice (n = 31). Manual acupuncture at PC6 was applied seven times weekly for 4 weeks. The state of myocardial injury was characterized by electrocardiography (ECG) and echocardiography. Inflammation was detected by ELISA and immunohistochemical stanning. Fibrosis was evaluated by Masson’s trichrome staining. RNA sequencing was used to explore the differentially expressed genes (DEGs) among the different groups after treatment. Results Acupuncture at PC6 lowered the incidence of spontaneous PVCs after MI injury (1/9, 11%) compared to that in mice without acupuncture treatment (6/9, 67%) and improved the ejection fraction from 31.77% in the MI mice to 44.18% in the MI + PC6 mice. Fibrosis was reduced after PC6 treatment. RNA-seq showed many DEGs involved in the immune system and inflammatory response pathway. Further studies confirmed that inflammation at the circulation level and cardiac tissue was inhibited in MI + PC6 mice, accompanied by suppressed sympathetic activation. Conclusions In conclusion, 28-day treatment of acupuncture at PC6 reduced spontaneous PVCs and improved systolic function, possibly by suppressing inflammatory response-mediated fibrosis and sympathetic hyperactivity.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent joint inflammation and progressive bone destruction. However, its complex pathogenesis remains poorly understood, and effective therapeutic targets are still lacking. Objective: This study aimed to identify key genes associated with RA and elucidate their biological significance by integrating bioinformatic analysis with experimental validation. Methods: Whole-transcriptome data from the anterior cingulate cortex (ACC) of Complete Freund’s Adjuvant (CFA)-induced inflammatory pain and control mice (GSE147216 dataset, GEO database) were collected from NCBI (National Center for Biotechnology Information). Differentially expressed genes (DEGs) were first identified. Subsequent analyses included Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, construction of a protein–protein interaction (PPI) network, and identification of hub genes using a Random Forest machine learning algorithm. Quantitative PCR (qPCR) was performed to validate gene expression levels. Results: A total of 76 DEGs were identified, including 64 upregulated and 12 downregulated genes. Among them, Fn1 (fibronectin 1), Bgn (biglycan), and Lum (lumican) were identified as hub genes. Functional enrichment analysis revealed inflammatory responses, extracellular matrix (ECM) remodeling, and the TGF-β signaling pathway. qPCR validation confirmed significant upregulation of Fn1, Bgn, and Lum mRNA in the CFA group. Conclusions: This study highlights the potential roles of Fn1, Bgn, and Lum in the central sensitization associated with inflammatory pain, offering insights relevant to RA.