Sarm1 Controls the MYD88-Mediated Inflammatory Responses in Inflammatory Bowel Disease via the Regulation of TRAF3 Recruitment.

BACKGROUND: Sterile alpha and TIR motif-containing 1 (Sarm1) is known as a negative regulator of inflammatory responses. However, its role in inflammatory bowel disease (IBD) is still unclear. OBJECTIVE: This study aimed to explore the function of Sarm1 in IBD and its underlying mechanisms. Sarm1 and tumor necrosis factor (TNF) receptor associated factor 3 (TRAF3) knockout (KO) micewere established. METHODS: The colitis was induced using dextran sulfate sodium (DSS). Bone marrow-derived macrophages (BMDMs) were isolated and stimulated with lipopolysaccharides (LPS) or cytidine phosphate guanosine(CpG). Inflammatory cytokines were measured viaELISA. qPCR and Western blotting were used to determine the levels of the mRNA and protein expression, respectively. RESULTS: It was demonstrated that reduced expression of Sarm1 was correlated with the severity of IBD in ulcerative colitis patients, and also with the reduction of pro-inflammatory cytokines in the mouse model induced by DSS. It was further observed that Sarm1 KO enhanced the induction of pro-inflammatory cytokines in both animal and in vitro cell models. Sarm1 deficiency in macrophages increased the severity of colitis in the mouse model induced by DSS. Moreover, Sarm1 regulatedTRAF3 recruitment to myeloid differentiation primary response protein 88 (MyD88), which in turn controlled the MYD88-mediated inflammatory responses. CONCLUSIONS: In summary, our data suggest that Sarm1 controls the MYD88-mediated inflammatory responses in IBD via its regulation of TRAF3 recruitment.

1. Sarm1 KO enhances the induction of pro-inflammatory cytokines in both animal and in vitro cell models.2. Sarm1 deficiency in macrophages increases the severity of colitis in the mouse model.3. Sarm1 regulates TRAF3 recruitment to MyD88.

Osteoclast Cancer Cell Metabolic Cross-talk Confers PARP Inhibitor Resistance in Bone Metastatic Breast Cancer.

The majority of patients with late-stage breast cancer develop distal bone metastases. The bone microenvironment can affect response to therapy, and uncovering the underlying mechanisms could help identify improved strategies for treating bone metastatic breast cancer. Here, we observed that osteoclasts reduced the sensitivity of breast cancer cells to DNA damaging agents, including cisplatin and the PARP inhibitor (PARPi) olaparib. Metabolic profiling identified elevated glutamine production by osteoclasts. Glutamine supplementation enhanced the survival of breast cancer cells treated with DNA damaging agents, while blocking glutamine uptake increased sensitivity and suppressed bone metastasis. GPX4, the critical enzyme responsible for glutathione oxidation, was upregulated in cancer cells following PARPi treatment through stress-induced ATF4-dependent transcriptional programming. Increased glutamine uptake and GPX4 upregulation concertedly enhanced glutathione metabolism in cancer cells to help neutralize oxidative stress and generate PARPi resistance. Analysis of paired patient samples of primary breast tumors and bone metastases revealed significant induction of GPX4 in bone metastases. Combination therapy utilizing PARPi and zoledronate, which blocks osteoclast activity and thereby reduces the microenvironmental glutamine supply, generated a synergistic effect in reducing bone metastasis. These results identify a role for glutamine production by bone-resident cells in supporting metastatic cancer cells to overcome oxidative stress and develop resistance to DNA-damaging therapies. SIGNIFICANCE: Metabolic interaction between osteoclasts and tumor cells contributes to resistance to DNA-damaging agents, which can be blocked by combination treatment with PARP and osteoclast inhibitors to reduce bone metastatic burden.

Influence of Community Health Management on Self-management Ability and Pulmonary Function in Patients With Stable Chronic Obstructive Pulmonary Disease.

Context: Chronic obstructive pulmonary disease (COPD) is a common chronic airway condition. Community health service centers can have significant value for improving the prognosis of older adults with chronic diseases. Objective: The study intended to analyze the influence of community health management on the pulmonary function (PF) and self-management ability of patients with stable COPD, aiming to provide a reliable reference for future clinical applications. Design: The research team performed a prospective controlled case study. Setting: The study took place at a community health service center in Xining, China. Participants: Participants were 116 stable COPD patients who received treatment at the center. Intervention: The research team divided participants into two groups: (1) the intervention group who took part in community health management and (2) the control group who received usual care. Outcome Measures: At baseline and postintervention, the research team: (1) measured participants' pulmonary function (PF)-forced vital capacity (FVC) and forced expiratory volume in 1s (FEV1)-and calculated the FEV1/FVC ratio; (2) assessed participants' symptoms using the modified British Medical Research Council (mMRC) scale and COPD Assessment Test (CAT); (3) tested participants' mobility using the six-minute walking test (6MWT) and the Barthel index (BI); (4) evaluated participants' quality of life using the Generic Quality of Life Inventory-74 (GQOL-74); (5) counted the rates of drug abuse, smoking control, and smoking cessation for both groups; and (6) created a COPD knowledge questionnaire survey on COPD awareness and used it to test participants' awareness. Results: The research group had significantly higher FVC, FEV1, and FEV1/FVC levels and 6MWT, BI, and GQOL-74 scores (all P < .001) and significantly lower mMRC and CAT scores than those of the control group (both P < .001). No significant difference existed between the groups in the drug-abuse rate (P = .511), but the intervention group's percentage of participants who had controlled or quit smoking was significantly higher than that of the control group (P = .033). The intervention group's COPD awareness score was also significantly higher than that of the control group (P < .001). Conclusions: Community health management can improve the rehabilitation and self-management of PF for stable COPD patients and can improve the quality of care, enhance patients' health level and quality of life, reduce medical investment, and lower the burden on patients and society.

Factors affecting the simple febrile seizures in COVID-19 children: a case-control study from China.

Objective: The over-age phenomenon of simple febrile seizures (SFS) was found during the epidemic in COVID-19, but there was no clear explanation, especially in China. This study aimed to analyze the clinical and auxiliary examination features of SFS in children infected with the coronavirus disease 2019 (COVID-19). Methods: In total, 78 patients with SFS in the Department of Pediatric and Neurology of Qujing First People's Hospital were enrolled and divided into the COVID-19-positive group (case group) and the COVID-19-negative group (control group). The clinical characteristics, auxiliary examinations, and risk factors were analyzed. Results: There were significant differences in age stratification between the two groups. The proportion of children aged over 5 years old in the case group (47.4%) was higher than that of the control group (5%) (p < 0.0001). In terms of sex distribution, the proportion of males in the case group was higher than that in the control group (71.1% vs. 50%), but the difference was not statistically significant (p = 0.0678). For blood cell analysis, the values of white blood cells (WBC), lymphocytes (LY), and monocytes (MN) in the case group were significantly lower than those in the control group (p < 0.01). Serum electrolyte analysis showed the greatest difference in blood sodium. The proportion of hyponatremia in the case group was higher than that in the control group (36.8% vs. 17.5%), but the difference did not reach statistical significance (p = 0.0745). A multivariate logistic regression analysis showed that the history of FS was a independent protective factors for SFS in children with COVID-19 (OR = 0.115, p = 0.009), and age was an independent risk factor for SFS in children with COVID-19 (OR = 1.042, p = 0.001). Conclusion: Age distribution, sex a previous history of FS and hyponatremia were different between children with and without COVID-19 in SFS. The history of FS was an independent protective factors for SFS in children with COVID-19.

POEMS syndrome: A rare cause of ascites and pelvic effusion.

POEMS syndrome is a rare clonal plasma cell disease associated with multisystem involvement. We reported a case of 48-year-old woman with large volume of exudative ascites with an increased level of λ-light chain and hepatosplenomegaly. The patient was treated with thalidomide and dexamethasone and showed a good clinical response.

ASB13 inhibits breast cancer metastasis through promoting SNAI2 degradation and relieving its transcriptional repression of YAP.

Transcription factor SNAI2 plays key roles during development and has also been known to promote metastasis by inducing invasive phenotype and tumor-initiating activity of cancer cells. However, the post-translational regulation of SNAI2 is less well studied. We performed a dual-luciferase-based, genome-wide E3 ligase siRNA library screen and identified ASB13 as an E3 ubiquitin ligase that targets SNAI2 for ubiquitination and degradation. ASB13 knockout in breast cancer cells promoted cell migration and decreased F-actin polymerization, while overexpression of ASB13 suppressed lung metastasis. Furthermore, ASB13 knockout decreased YAP expression, and such regulation is dependent on an increased protein level of SNAI2, which in turn represses YAP transcription. YAP suppresses tumor progression in breast cancer, as YAP knockout increases tumorsphere formation, anchorage-independent colony formation, cell migration in vitro, and lung metastasis in vivo. Clinical data analysis reveals that ASB13 expression is positively correlated with improved overall survival in breast cancer patients. These findings establish ASB13 as a suppressor of breast cancer metastasis by promoting degradation of SNAI2 and relieving its transcriptional repression of YAP.

Risk analysis of systemic levels of estrogen and adipokines as well as estrogen receptors from PBMCs in childbearing and perimenopausal women with obesity.

PURPOSE: We aimed to evaluate the clinical value of systemic levels of estrogen and adipokines as well as estrogen receptors from peripheral blood mononuclear cells (PBMCs) in childbearing and perimenopausal women with obesity. SUBJECTS AND METHODS: We observed 292 women, including 160 perimenopausal women (80 with obesity and 80 without obesity) and 132 women of childbearing age (67 with obesity and 65 without obesity). Body parameters, such as body mass index and waist circumference, were measured. Fat distribution was evaluated using a computerized tomography scanner. The levels of serum estrogen, leptin, visfatin, and adiponectin were measured using an enzyme-linked immunosorbent assay. The expression of circulating ERs was evaluated by Western blot analysis. RESULTS: Perimenopausal women and childbearing women with obesity exhibited lower levels of estrogen and adiponectin, in addition to a distribution of visceral fat with higher levels of leptin and visfatin. These findings reflect the current data of menopausal women, which confirms the reliability of this experimental system. However, the expression of ERα in peripheral blood was significantly enhanced in women with obesity of both childbearing and perimenopausal age. This result is contrary to the common understanding of adipose tissue, namely that ERα is protective. The expression of ERß in the women without obesity of both childbearing and perimenopausal age was higher than in women with obesity, which coincides with the results of a previous study on adipose tissue. CONCLUSION: Our data fundamentally contradicts the utility of circulating ERα and ERα/ERß evaluations in obesity studies. Because estrogen exerts pleiotropic effects on multiple tissues in the body through differential regulation of ERs, although the expression of ERß coincides with the results of a previous study on adipose tissue, the expression levels of ERs in blood cannot be used as a diagnostic of informative tool for obesity in women.