Mer activation ameliorates nerve injury-induced neuropathic pain by regulating microglial polarization and neuroinflammation via SOCS3 in male rats.

Accumulating evidence has demonstrated that M1 microglial polarization and neuroinflammation worsen the development of neuropathic pain. However, the mechanisms underlying microglial activation during neuropathic pain remain incompletely understood. Myeloid-epithelial-reproductive tyrosine kinase (Mer), which is a member of the Tyro-Axl-Mer (TAM) family of receptor tyrosine kinases, plays a crucial role in the regulation of microglial polarization. However, the effect of Mer on microglial polarization during neuropathic pain has not been determined. In this study, western blotting, immunofluorescence analysis, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay (ELISA) were used to examine the role of Mer in pain hypersensitivity and microglial polarization in rats with chronic constriction injury (CCI) of the sciatic nerve. The results indicated that Mer expression in microglia was prominently increased in the spinal cords of rats subjected to CCI. Furthermore, treatment with recombinant protein S (PS, an activator of Mer) alleviated mechanical allodynia and thermal hyperalgesia, promoted the switch in microglia from the M1 phenotype to the M2 phenotype, and ameliorated neuroinflammation in rats subjected to CCI. However, the use of suppressor of cytokine signalling 3 (SOCS3) siRNA abolished these changes. These results indicated that Mer regulated M1/M2 microglial polarization and neuroinflammation and may be a potential target for treating neuropathic pain.

Contrasting the relationship of serum uric acid/albumin ratio on quantitative flow ratio with other multiple composite parameters in patients with suspected coronary artery disease.

OBJECTIVE: The aim of this study was to investigate the association between quantitative coronary flow reserve (CFR) and the blood uric acid/albumin ratio, as well as multiple clinical parameters, in order to assess the severity of coronary artery functional stenosis. METHODS: This retrospective cross-sectional study included 257 suspected coronary artery disease patients who underwent coronary angiography (CAG) and quantitative flow ratio (QFR) examinations in the Department of Cardiovascular Medicine at the First Affiliated Hospital of Yangtze University in Jingzhou City, China, between September 2022 and March 2023. The study subjects were divided into two groups based on their QFR values: QFR ≤ 0.80 group and QFR > 0.80 group. Correlation of uric acid-to-albumin ratio (UAR), high-density lipoprotein ratio (MHR), systemic immune-inflammation index (SII), Systemic Inflammation Response Index (SIRI), and Aggregate Index of Systemic Inflammation (AISI) with coronary artery QFR was analyzed using univariate and multivariate logistic regression models, considering them as both continuous and binary variables. RESULTS: The QFR ≤ 0.80 group consisted of 83 patients, while the QFR > 0.80 group included 174 patients. Significant differences were observed between the QFR ≤ 0.80 and QFR > 0.80 groups in the following parameters: UAR (9.19 ± 2.47 vs 7.61 ± 1.91; p < 0.001), MHR (0.46 ± 0.19 vs 0.37 ± 0.16, p < 0.001), SII (674.98 ± 332.30 vs 571.43 ± 255.82; p = 0.006), SIRI (1.53 ± 0.83 vs 1.29 ± 1.10; p = 0.047), and AISI (340.22 ± 242.10 vs 243.97 ± 151.97; p < 0.001). ROC curve analysis revealed an area under the curve of 0.701 (CI: 0.633-0.770; p < 0.001) for UAR. In the univariate analysis, when treated as binary variables, high levels of UAR, MHR, SII, SIRI, and AISI were found to be significantly associated with the risk of QFR ≤ 0.80 (all P < 0.05). However, in the multivariate regression analysis, only high levels of UAR and AISI remained significantly associated with QFR ≤ 0.80 (all P < 0.05). When treated as continuous variables, the univariate analysis indicated that UAR (OR: 1.412, CI: 1.231-1.620, p < 0.001), e^MHR (OR: 1.394, CI: 1.151-1.687, p < 0.001), lnSII (OR: 1.001, CI: 1.000-1.002, p = 0.008), and lnAISI (OR: 2.695, CI: 1.539-4.719, p = 0.001) were significantly associated with QFR ≤ 0.80. In the multivariate analysis, UAR (OR: 1.373, CI: 1.187-1.587, p < 0.001) and AISI (OR: 2.217, CI: 1.309-3.757, p < 0.001) remained significantly associated with QFR ≤ 0.80. CONCLUSIONS: The results of this study indicate a significant association between UAR and AISI with QFR ≤ 0.80, suggesting its potential role in predicting the extent of functional coronary artery stenosis in patients with CAD. Additionally, AIRI, identified as an inflammatory marker in the complete blood count, was found to exert influence on the severity of coronary artery physiology.

MG53 ameliorates nerve injury induced neuropathic pain through the regulation of Nrf2/HO-1 signaling in rats.

Neuropathic pain is one of the most common types of chronic pain, and it arises as a direct consequence of a lesion or disease that affects the somatosensory system. Mitsugumin53 (MG53), which is a member of the TRIM family of proteins and is known as TRIM72, exerts protective effects on muscle, lung, kidney, brain, and other cells or tissues. Recently, increasing evidence has indicated that MG53 plays a vital role in regulating neuroinflammation and oxidative stress. However, the relationship between MG53 and neuropathic pain is unclear. In this study, we aimed to explore the role of MG3 in neuropathic pain after chronic constriction injury (CCI) to the sciatic nerve in rats. To explore the mechanism of MG53 regulating the development of neuropathic pain, the rats was injected (intrathecal injection) of recombinant human MG53 (rhMG53) protein and/or nuclear factor erythroid 2-related factor 2 (Nrf2) siRNA after CCI. Mechanical allodynia or thermal hyperalgesia was assessed by the 50% paw withdrawal threshold (PWT) or the paw withdrawal latency (PWL). The target molecules was detected using western blotting (WB), immunofluorescence (IF), quantitative real-time polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), biochemical evaluations, and Dihydroethidium (DHE) staining. The results indicated that the expression level of MG53 in the spinal cord was increased after CCI in rats. Moreover, intrathecal injection with rhMG53 protein notably alleviated CCI-induced mechanical allodynia, thermal hyperalgesia, neuroinflammation，oxidative stress and the increased level of reactive oxygen species (ROS) via activation of the Nrf2/heme oxygenase-1 (HO-1) signaling pathway. However, administration of Nrf2 siRNA abrogated the analgesic, anti-inflammatory and antioxidant effects of rhMG53 in CCI model rats. Our study demonstrated that MG53 improved neuropathic pain, neuroinflammation, and oxidative stress via activation of the Nrf2/HO-1 signaling pathway in the spinal cord of CCI model rats, which suggested that MG53 may serve as a new target for the treatment of neuropathic pain.

Fusobacterium nucleatum aggravates ulcerative colitis through promoting gut microbiota dysbiosis and dysmetabolism.

BACKGROUND: The correlation between periodontitis and ulcerative colitis (UC) has drawn widespread attention recently. Fusobacterium nucleatum (F. nucleatum) as a periodontal pathogen also has reservoirs in gut and may play a role in intestinal diseases. However, its role in the pathogenesis of UC is unclear. METHODS: Mice were orally given dextran sulphate sodium (DSS) solution and F. nucleatum to construct experimental models. The survival rate, weight, and disease activity index (DAI) of mice were monitored. Alveolar bone loss, abundance of F. nucleatum in colon, colon length, histopathological assessment, and inflammatory cytokines were detected. Apoptosis of intestinal epithelial cells (IECs) were evaluated by TUNEL assay and pro-apoptotic gene Bax. The epithelial barrier function was assessed by tight junction proteins. By 16S rRNA gene sequencing and LC-MS-based methods, the composition of the intestinal microbiota and metabolites in mice were analyzed. RESULTS: F. nucleatum facilitated alveolar bone loss and colonized only in infected colon tissue. Mice fed with DSS showed destruction of gut structure, increased expressions of interleukin one-beta (IL-1ß) and tumor necrosis factor alpha (TNF-α), decreased expression of IL-10, higher apoptosis of IECs, microbiota dysbiosis and bile acid dysmetabolism compared to healthy ones. F. nucleatum further aggravated intestinal inflammation and epithelial barrier damage. Probiotics such as Bifidobacterium and Faecalibacterium decreased, opportunistic pathogens Escherichia-Shigella increased and the differential microorganisms highly associated with inflammatory parameters and metabolites. Meanwhile, level of uric acid involving in the purine metabolism significantly elevated compared to UC mice. CONCLUSIONS: F. nucleatum promotes gut inflammation, epithelial barrier dysfunction, microbiota dysbiosis and dysmetabolism to aggravate UC.

The Correlation between Periodontal Parameters and Cell-Free DNA in the Gingival Crevicular Fluid, Saliva, and Plasma in Chinese Patients: A Cross-Sectional Study.

Purpose: To investigate the correlation between periodontal parameters and cell-free DNA (cfDNA) concentrations in gingival crevicular fluid (GCF), saliva, and plasma. Methods: Full mouth periodontal parameters, including probing depth (PD), bleeding on probing (BOP), and plaque index (PI) were recorded from 25 healthy volunteers, 31 patients with untreated gingivitis, and 25 patients with untreated periodontitis. GCF, saliva, and plasma samples were collected from all subjects. Extraction and quantification assays were undertaken to determine cfDNA concentrations of each sample. Results: GCF and salivary cfDNA levels were increased with aggravation of periodontal inflammation (GCF p < 0.0001; saliva p < 0.001). Plasma cfDNA concentrations in patients with periodontitis were significantly higher than those in healthy volunteers and patients with gingivitis. GCF and salivary cfDNA were positively correlated with mean PD, max PD, BOP, and mean PI (p < 0.0001), whereas plasma cfDNA was not correlated with BOP (p = 0.099). Conclusion: GCF, saliva, and plasma concentrations of cfDNA were significantly elevated in patients with periodontal disease. There were also positive correlations between cfDNA levels in GCF and saliva and periodontal parameters.

PAMPs and DAMPs as the Bridge Between Periodontitis and Atherosclerosis: The Potential Therapeutic Targets.

Atherosclerosis is a chronic artery disease characterized by plaque formation and vascular inflammation, eventually leading to myocardial infarction and stroke. Innate immunity plays an irreplaceable role in the vascular inflammatory response triggered by chronic infection. Periodontitis is a common chronic disorder that involves oral microbe-related inflammatory bone loss and local destruction of the periodontal ligament and is a risk factor for atherosclerosis. Periodontal pathogens contain numerous pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide, CpG DNA, and Peptidoglycan, that initiate the inflammatory response of the innate immunity depending on the recognition of pattern-recognition receptors (PRRs) of host cells. The immune-inflammatory response and destruction of the periodontal tissue will produce a large number of damage-associated molecular patterns (DAMPs) such as neutrophil extracellular traps (NETs), high mobility group box 1 (HMGB1), alarmins (S100 protein), and which can further affect the progression of atherosclerosis. Molecular patterns have recently become the therapeutic targets for inflammatory disease, including blocking the interaction between molecular patterns and PRRs and controlling the related signal transduction pathway. This review summarized the research progress of some representative PAMPs and DAMPs as the molecular pathological mechanism bridging periodontitis and atherosclerosis. We also discussed possible ways to prevent serious cardiovascular events in patients with periodontitis and atherosclerosis by targeting molecular patterns.

Research progress on the relationship between osteocytes and periodontitis / 口腔疾病防治

@#Osteocytes, which develop from osteoblasts, are recognized as the main cells embedded in mature bone tissue. The traditional notion is that osteocytes exclusively play a structural role, however, with the development of related research in recent years, the role of osteocytes in bone metabolism has been explored. Periodontitis is a chronic inflammatory disease initiated by plaque biofilm, and is the main cause of adult tooth loss. Clinically, periodontitis primarily manifests as attachment loss, bleeding on probing and other symptoms. Alveolar bone resorption is the most characteristic pathological change. Current research demonstrated that osteocytes sense mechanical stress, participate in bone remodeling, regulate mineral balance, and participate in endocrine function. Thus, these cells play an important role in bone homeostasis and systemic metabolic balance. Osteocytes are actively involved in the development of periodontitis through the high expression of receptor activator of nuclear factor kappa B ligand (RANKL), secretion of sclerostin, and effect on apoptosis, senescence and autophagy. In the future, the detection of bone cell metabolism-related products will have certain application prospects for the clinical evaluation of periodontitis prevention and treatment. Therefore, this paper reviewed the role of osteocytes in bone homeostasis and the relationship between osteocytes and periodontitis, to provide new ideas for the prevention and treatment of periodontitis.

In vitro antimicrobial activity of honokiol against Staphylococcus aureus in biofilm mode.

Staphylococcus aureus (S. aureus) can attach to food, host tissues and the surfaces of medical implants and form a biofilm, which makes it difficult to eliminate. The purpose of this study was to evaluate the effect of honokiol on biofilm-grown S. aureus. In this report, honokiol showed effective antibacterial activity against S. aureus in biofilms. S. aureus isolates are capable of producing distinct types of biofilms mediated by polysaccharide intercellular adhesion (PIA) or extracellular DNA (eDNA). The biofilms' susceptibility to honokiol was evaluated using confocal laser scanning microscopy (CLSM) analysis. The transcript levels of the biofilm-related genes, the expression of PIA, and the amount of eDNA of biofilm-grown S. aureus exposed to honokiol were also investigated. The results of this study show that honokiol can detach existing biofilms, kill bacteria in biofilms, and simultaneously inhibit the transcript levels of sarA, cidA and icaA, eDNA release, and the expression of PIA.