Inactivation of a non-canonical gp130 signaling arm attenuates chronic systemic inflammation and multimorbidity induced by a high-fat diet.

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.

Association between previous surgical termination of pregnancy and pregnancy outcomes in frozen-thawed embryo transfer cycles of IVF/ICSI: a retrospective cohort study.

This study aimed to evaluate the effect of previous surgical termination of pregnancy (STP) on pregnancy outcomes in women undergoing FET cycles of IVF/ICSI. Retrospective cohort study. Reproductive Center of Maternal and Child Health Care Hospital in Lianyungang city. Data were selected from all IVF/ICSI FET cycles performed between January 2014 and December 2020. A total of 761 cycles met the criteria were included in this study. The primary outcome measures were clinical pregnancy and live birth rates. Secondary outcome measures were biochemical pregnancy rate, spontaneous abortion rate, and preterm birth rate. After adjustments for a series of potential confounding factors, the previous STP was an influential factor in reducing FET cycle clinical pregnancy rate compared with women who had not previously undergone STP (OR = 0.614, 95% CI 0.413-0.911, P = 0.016). The effect of the previous STP on the live birth rate was not statistically significant. (OR = 0.745, 95% CI 0.495-1.122, P = 0.159). Also, an increase in the number of previous STPs relative to only 1-time abortion was an independent risk factor in reducing clinical pregnancy rate and live birth rate (OR = 0.399,95% CI 0.162-0.982, p = 0.046; OR = 0.32,95% CI 0.119-0.857, p = 0.023). Previous STP was an independent factor contributing to the decline in FET cycle clinical pregnancy rates.

Sex-specific associations between nine metal mixtures in urine and urine flow rate in US adults: NHANES 2009-2018.

Background: The urinary system serves as a crucial pathway for eliminating metallic substances from the body, making it susceptible to the effects of metal exposure. However, limited research has explored the association between metal mixtures and bladder function. This study aims to investigate the relationship between urinary metal mixtures (specifically barium, cadmium, cobalt, cesium, molybdenum, lead, antimony, thallium, and tungsten) and urine flow rate (UFR) in the general population, utilizing multiple mixture analysis models. Methods: This study utilizes data obtained from the National Health and Nutrition Examination Survey. After adjusting for relevant covariates, we assessed the correlations between metal mixtures and UFR using three distinct analysis models: weighted quantile sum (WQS), quantile g-computation (qgcomp), and Bayesian kernel machine regression (BKMR). Additionally, a gender-stratified analysis was conducted. Finally, we also performed sensitivity analyses. Results: A total of 7,733 subjects were included in this study, with 49% being male. The WQS regression model, when fitted in the positive direction, did not yield any significant correlations in the overall population or in the male and female subgroups. However, when analyzed in the negative direction, the WQS index exhibited a negative correlation with UFR in the overall group (ß = -0.078; 95% CI: -0.111, -0.045). Additionally, a significant negative correlation between the WQS index and UFR was observed in the female group (ß = -0.108; 95% CI: -0.158, -0.059), while no significant correlation was found in the male group. The results obtained from the qgcomp regression model were consistent with those of the WQS regression model. Similarly, the BKMR regression model revealed a significant negative correlation trend between metal mixtures and UFR, with cadmium and antimony potentially playing key roles. Conclusion: Our study revealed a significant negative correlation between urinary metal mixture exposure and mean UFR in US adults, with notable gender differences. Specifically, higher urinary levels of cadmium and antimony were identified as potential key factors contributing to the decrease in mean UFR. These findings significantly contribute to the existing knowledge on the impact of metal mixtures on bladder function and provide valuable insights for safeguarding bladder health and preventing impaired bladder function.

STAT3 promotes a youthful epigenetic state in articular chondrocytes.

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.

Impact of prolonged one or more natural menstrual cycles on the outcomes of ovulation induction intrauterine artificial insemination pregnancy: a single-centre, retrospective study in China.

OBJECTIVES: We determined if the time interval between two ovulation induction intrauterine artificial insemination (IUI) treatment cycles should be extended by one or more natural menstrual cycles in patients undergoing successive cycles of ovulation stimulation, and whether this affects clinical pregnancy rate (CPR). DESIGN: This study was conducted on infertility patients treated under the ovulation induction programme IUI in a large reproductive centre in China. Study participants were assigned into continuous and discontinuous groups. Differences in baseline clinical pregnancy and abortion rates were compared between the groups. A multivariate logistic model was used to evaluate the effects of time interval on clinical pregnancy outcomes. SETTING: Reproductive Centre of Maternal and Child Health Hospital of Lianyungang city. INTERVENTIONS: None. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was CPR, the secondary outcome measure was the abortion rate. RESULTS: A total of 550 IUI treatment cycles involving 275 couples were included in this study. Differences in CPR and abortion rate between the groups were not significant (20.5% vs 21.9% and 27.8% vs 22.0%, p≥0.05). Stratified analyses based on infertility factors did not reveal any significant differences in pregnancy and abortion rates between the groups (p≥0.05). Multivariate analysis showed that increased endometrial thickness correlates with CPR (OR 1.205, 95% CI 1.05 to 1.384, p=0.008). Compared with primary infertility, secondary infertility significantly correlated with improved CPR (OR 2.637, 95% CI 1.313 to 5.298, p=0.006). The effects of time interval between the first two ovulation induction IUI treatment cycles on clinical pregnancy were not significant (OR 1.007, 95% CI 0.513 to 1.974, p=0.985). CONCLUSIONS: Longer time intervals between the first two ovulation induction IUI treatment cycles did not significantly improve CPR. Therefore, in the absence of clear clinical indications, it may not be necessary to deliberately prolong the interval between two ovulation induction IUI treatment cycles.

Increased expression of Suppressor of cytokine signaling 2 (BmSOCS2) is correlated with suppression of Bombyx mori nucleopolyhedrovirus replication in silkworm larval tissues and cells.

The resistance of silkworm to infection by Bombyx mori nuclear polyhedrosis virus (BmNPV) is a main focus of sericultural research. Previously, a BmNPV-resistant strain, NB, was identified among a collection of Chinese silkworm strains in our lab. To better understand the molecular mechanism of NB strain resistance, the patterns of host immune response gene transcription in resistant (NB) and susceptible (306) strains were examined. Quantative real-time PCR (qRT-PCR) revealed that multiple insect innate immune signaling pathways (Toll, Imd and JAK/STAT) were strongly activated upon infection with BmNPV. Notably, Suppressor of cytokine signaling 2 (BmSOCS2) mRNA expression was significantly up-regulated in midgut tissues of the resistant NB strain, suggesting that the BmSOCS2 gene product may be involved in host immune defense against BmNPV infection. A significant inhibition of BmNPV replication was also observed in BmN cells transfected with a vector encoding BmSOCS2. The results suggest that BmSOCS2 is a key gene involved in the resistance of the NB silkworm strain to BmNPV infection.

Synthesis and Structure-Activity Relationship of Pyxinol Derivatives as Novel Anti-Inflammatory Agents.

Pyxinol, the main metabolite of 20S-protopanaxadiol in human liver, was chosen as a novel skeleton for the development of anti-inflammatory agents. Pyxinol derivatives modified at C-3, C-12, or C-25 and selected stereoisomers were designed, prepared, and investigated for in vitro anti-inflammatory activities. Structure-activity relationship (SAR), focused on skeleton, was analyzed based on their ability to inhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) synthesis. The preliminary SAR results signified that the biological activity of the pyxinol derivatives is largely dependent on the R/S stereochemistry of pyxinol skeleton and the hydroxy at C-3 is a modifiable position. Among the tested compounds, the 3-oximinopyxinol (4a) exhibited the most potent NO-inhibitory activity and was even comparable to the steroid drug. Furthermore, compound 4a also significantly decreased LPS-induced TNF-α and IL-6 synthesis and iNOS and COX-2 expressions via the NF-κB pathway. This study proves that pyxinol is an interesting skeleton for anti-inflammatory drug discovery.

Design, synthesis, and discovery of ocotillol-type amide derivatives as orally available modulators of P-glycoprotein-mediated multidrug resistance.

Multidrug resistance (MDR) is a major cause of failure in cancer treatment, in which the overexpression of P-glycoprotein (Pgp) plays a crucial role. Herein, a novel class of ocotillol-type amide derivatives has been designed, synthesized, and evaluated for their ability to reverse MDR. The structure-activity relationship of the reversal activity was analyzed. Ten compounds showed promising chemo-reversal ability, among which the 24R-ocotillol-type amide derivative 6c with an N-Boc-hexanoyl unit exhibited the most potency in reversing paclitaxel resistance in KBV cells. Compound 6c could inhibit Pgp-mediated rhodamine123 efflux function via stimulating Pgp-ATPase activity and exhibited high binding affinity with Pgp in molecular docking studies. Importantly, compound 6c enhanced the efficacy of paclitaxel against KBV cancer cell-derived xenograft tumors in nude mice after oral administration. These results indicate that ocotillol-type amide derivatives are promising lead compounds for overcoming MDR in cancer.