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Interleukin-6 (IL-6) is a major pro-inflammatory cytokine for which the levels in plasma demonstrate a robust correlation with age and body mass index (BMI) as part of the senescence-associated secretory phenotype. IL-6 cytokines also play a crucial role in metabolic homeostasis and regenerative processes, primarily via the canonical STAT3 pathway. Thus, selective modulation of IL-6 signaling may offer a unique opportunity for therapeutic interventions. Recently, we discovered that a non-canonical signaling pathway downstream of tyrosine (Y) 814 within the intracellular domain of gp130, the IL-6 co-receptor, is responsible for the recruitment and activation of SRC family of kinases (SFK). Mice with constitutive genetic inactivation of gp130 Y814 (F814 mice) show accelerated resolution of inflammatory response and superior regenerative outcomes in skin wound healing and posttraumatic models of osteoarthritis. The current study was designed to explore if selective genetic or pharmacological inhibition of the non-canonical gp130-Y814/SFK signaling reduces systemic chronic inflammation and multimorbidity in a high-fat diet (HFD)-induced model of accelerated aging. F814 mice showed significantly reduced inflammatory response to HFD in adipose and liver tissue, with significantly reduced levels of systemic inflammation compared to wild type mice. F814 mice were also protected from HFD-induced bone loss and cartilage degeneration. Pharmacological inhibition of gp130-Y814/SFK in mice on HFD mirrored the effects observed in F814 mice on HFD; furthermore, this pharmacological treatment also demonstrated a marked increase in physical activity levels and protective effects against inflammation-associated suppression of neurogenesis in the brain tissue compared to the control group. These findings suggest that selective inhibition of SFK signaling downstream of gp130 receptor represents a promising strategy to alleviate systemic chronic inflammation. Increased degenerative changes and tissue senescence are inevitable in obese and aged organisms, but we demonstrated that the systemic response and inflammation-associated multi-morbidity can be therapeutically mitigated.
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Epigenetic mechanisms guiding articular cartilage regeneration and age-related disease such as osteoarthritis (OA) are poorly understood. STAT3 is a critical age-patterned transcription factor highly active in fetal and OA chondrocytes, but the context-specific role of STAT3 in regulating the epigenome of cartilage cells remain elusive. In this study, DNA methylation profiling was performed across human chondrocyte ontogeny to build an epigenetic clock and establish an association between CpG methylation and human chondrocyte age. Exposure of adult chondrocytes to a small molecule STAT3 agonist decreased DNA methylation, while genetic ablation of STAT3 in fetal chondrocytes induced global hypermethylation. CUT&RUN assay and subsequent transcriptional validation revealed DNA methyltransferase 3 beta (DNMT3B) as one of the putative STAT3 targets in chondrocyte development and OA. Functional assessment of human OA chondrocytes showed the acquisition of progenitor-like immature phenotype by a significant subset of cells. Finally, conditional deletion of Stat3 in cartilage cells increased DNMT3B expression in articular chondrocytes in the knee joint in vivo and resulted in a more prominent OA progression in a post-traumatic OA (PTOA) mouse model induced by destabilization of the medial meniscus (DMM). Taken together these data reveal a novel role for STAT3 in regulating DNA methylation in cartilage development and disease. Our findings also suggest that elevated levels of active STAT3 in OA chondrocytes may indicate an intrinsic attempt of the tissue to regenerate by promoting a progenitor-like phenotype. However, it is likely that chronic activation of this pathway, induced by IL-6 cytokines, is detrimental and leads to tissue degeneration.
Assuntos
Cartilagem Articular , Osteoartrite , Camundongos , Animais , Humanos , Condrócitos/metabolismo , Células Cultivadas , Osteoartrite/genética , Osteoartrite/metabolismo , Cartilagem Articular/metabolismo , Epigênese Genética , Metilação de DNA/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismoRESUMO
CONTEXT: The 2021 consensus report on the definition and interpretation of remission of type 2 diabetes (T2D) has been released. Although intermittent fasting diets (IF) are becoming very popular, no studies have investigated their benefit in diabetes remission. OBJECTIVE: The present study examined the effectiveness of IF in diabetes remission and potential remission durability. METHODS: Participants between ages 38 and 72 years with a duration of T2D of 1 to 11 years, a body mass index (BMI) of 19.1 to 30.4, 66.7% male, and antidiabetic agent use and/or insulin injection were randomly allocated at a ratio of 1:1 to the Chinese Medical Nutrition Therapy (CMNT) or control group. The primary outcome was diabetes remission, defined as a stable glycated hemoglobin A1c (HbA1c) level of less than 48 mmol/mol (< 6.5%) for at least 3 months after discontinuing all antidiabetic medications. The secondary outcomes included HbA1c level, fasting blood glucose level, blood pressure, weight, quality of life, and medication costs. We conducted a 12-month follow-up to assess the continuation of remission. RESULTS: On completing the 3-month intervention plus 3-month follow-up, 47.2% (17/36) of participants achieved diabetes remission in the CMNT group, whereas only 2.8% (1/36) of individuals achieved remission in the control group (odds ratio 31.32; 95% CI, 2.39-121.07; P < 0.0001). The mean body weight of participants in the CMNT group was reduced by 5.93 kg (SD 2.47) compared to 0.27 kg (1.43) in the control group. After the 12-month follow-up, 44.4% (16/36) of the participants achieved sustained remission, with an HbA1c level of 6.33% (SD 0.87). The medication costs of the CMNT group were 77.22% lower than those of the control group (60.4/month vs 265.1/month). CONCLUSION: This study demonstrated the clinical efficacy of CMNT in achieving diabetes remission for at least 1 year.
Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Masculino , Feminino , Hemoglobinas Glicadas , Glicemia , Qualidade de Vida , Hipoglicemiantes/uso terapêutico , DietaRESUMO
Complex injury and open reconstructive surgeries of the knee often lead to joint dysfunction that may alter the normal biomechanics of the joint. Two major complications that often arise are excessive deposition of fibrotic tissue and acquired heterotopic endochondral ossification. Knee arthrofibrosis is a fibrotic joint disorder where aberrant buildup of scar tissue and adhesions develop around the joint. Heterotopic ossification is ectopic bone formation around the periarticular tissues. Even though arthrofibrosis and heterotopic ossification pose an immense clinical problem, limited studies focus on their cellular and molecular mechanisms. Effective cell-targeted therapeutics are needed, but the cellular origin of both knee disorders remains elusive. Moreover, all the current animal models of knee arthrofibrosis and stiffness are developed in rats and rabbits, limiting genetic experiments that would allow us to explore the contribution of specific cellular targets to these knee pathologies. Here, we present a novel mouse model where surgically induced injury and hyperextension of the knee lead to excessive deposition of disorganized collagen in the meniscus, synovium, and joint capsule in addition to formation of extra-skeletal bone in muscle and soft tissues within the joint capsule. As a functional outcome, arthrofibrosis and acquired heterotopic endochondral ossification coupled with a significant increase in total joint stiffness were observed. By employing this injury model and genetic lineage tracing, we also demonstrate that Gli1+ mesenchymal progenitors proliferate after joint injury and contribute to the pool of fibrotic cells in the synovium and ectopic osteoblasts within the joint capsule. These findings demonstrate that Gli1+ cells are a major cellular contributor to knee arthrofibrosis and acquired heterotopic ossification that manifest after knee injury. Our data demonstrate that genetic manipulation of Gli1+ cells in mice may offer a platform for identification of novel therapeutic targets to prevent knee joint dysfunction after chronic injury.
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ETHNOPHARMACOLOGICAL RELEVANCE: Scutellaria baicalensis Georgi (SBG) is a traditional Chinese medicine with a remarkable remedial effect on diabetes mellitus. However, the precise mechanism involved has not been fully elucidated yet. Here, we aimed to explore the anti-diabetes effects of its traditional decoction in vitro and elucidate the autophagy-related mechanism. AIM OF THE STUDY: This study was designed to investigate the effects of the water extract of SBG (WSB) on the ß cell viability, insulin secretion and the mechanism related to autophagy. MATERIALS AND METHODS: Detection of insulin secretion using an enzyme immunoassay method, and analysis of apoptosis rate in MIN-6 cells by the flow cytometry with PI and Annexin V-FITC staining. In addition, the autophagy levels and pathways were evaluated from the number of autophagosomes and the expression of autophagy-related proteins. 3-Methyladenine (3-MA) was used as the autophagy inhibitor. Autophagosomes were observed using a confocal microscopy, and autophagy-related proteins (LC3-II/I, p62, S6k, p-AMPK/AMPK, p-mTOR/mTOR) were measured by Western blot. RESULTS: Here we detected a significant increase in insulin release from MIN-6 cells after treated with WSB. It is about 1.6 times as much as that of the control group with 2.8 mM glucose and 2.2 times more than the 16.8 mM glucose group. At the same time, WSB increased the number of autophagosomes and the ratio of LC3 â ¡/LC3 â , indicating that autophagy were activated in MIN-6 cells. When inhibiting autophagy, there was no significant difference in insulin release between the two groups. The apoptotic rate of the high glucose group was as high as 33.23%. After pretreatment with WSB, the apoptotic rate decreased to 14.95%, and increased to 22.57% when treated with 3-MA and WSB. At the same time, WSB treatment enhanced the phosphorylation of AMPK, but had no significant effect on the expression of mTOR and S6K. CONCLUSION: Our data suggested that WSB increased insulin secretion and reduced apoptosis under high glucose by inducing autophagy through the AMPK pathway, which elucidated the mechanism of WSB in the treatment of diabetes.