Transient receptor potential ankyrin 1 (trpa1) mediates il-1β-induced apoptosis in rat chondrocytes via calcium overload and mitochondrial dysfunction

Abstract Background Chondrocyte apoptosis is a central feature in the progression of osteoarthritis (OA), and would be triggered by sustained elevation of intracellular calcium ion (Ca2+), also known as a cellular second messenger. Transient receptor potential ankyrin 1 (TRPA1) is a membrane-associated cation channel, and the activation of which causes an influx of cation ions, in particularly Ca2+, into the activated cells. Therefore, we investigate the potential role of TRPA1 in mediating Ca2+ influx to promote chondrocyte apoptosis in OA. Methods The expression of TRPA1 in interleukin (IL)-1β-treated rat chondrocytes was assessed by Polymerase chain reaction (PCR) and Western blot (WB), and the functionality of TRPA1 channel by Ca2+ influx measurements. Meanwhile, the chondrocyte apoptosis in IL-1β-treated cells was measured by TUNEL assay and flow cytometry. The measurement of mitochondrial membrane potential and apoptosis-associated proteins after inhibition of TRPA1 were also performed in IL-1β-treated rat chondrocytes. Results After being induced by IL-1β, the gene and protein expression of TRPA1 was increased in the dose-dependent manner. Meanwhile, Ca2+ influx mediated by TRPA1 in rat chondrocytes was also enhanced. Pharmacological inhibition of TRPA1 downregulated the apoptotic rate in IL-1β-treated rat chondrocytes. In addition, the membrane potential depolarization was improved and significantly increased expression of apoptosis-associated proteins also reduced by the TRPA1 antagonist. Conclusions We found the IL-1β caused the increased functional expression of TRPA1, the activation of which involved IL-1β-induced apoptosis in rat chondrocytes. The potential mechanism may be linked to the intracellular calcium overload mediated by TRPA1 and attendant mitochondrial dysfunction

The associations of self-rated health with cardiovascular risk proteins : A proteomics approach

Background: Though subjective, poor self-rated health (SRH) has consistently been shown to predict cardiovascular disease (CVD). The underlying mechanism is unclear. This study evaluates the associations of SRH with biomarkers for CVD, aiming to explore potential pathways between poor SRH and CVD. Methods: Based on the Malmö Diet and Cancer Cardiovascular Cohort study, a targeted proteomics approach was used to assess the associations of SRH with 88 cardiovascular risk proteins, measured in plasma from 4521 participants without CVD. The false discovery rate (FDR) was controlled using the Benjamini and Hochberg method. Covariates taken into consideration were age, sex, traditional CVD risk factors (low-density lipoprotein cholesterol, systolic blood pressure, anti-hypertensive medication, diabetes, body mass index, smoking), comorbidity, life-style and psycho-social factors (education level, living alone, alcohol consumption, low physical activity, psychiatric medication, sleep duration, and unemployment). Results: Age and sex-adjusted associations with SRH was found for 34 plasma proteins. Nine of them remained significant after adjustments for traditional CVD risk factors. After further adjustment for comorbidity, life-style and psycho-social factors, only leptin (β = - 0.035, corrected p = 0.016) and C-C motif chemokine 20 (CCL20; β = - 0.054, corrected p = 0.016) were significantly associated with SRH. Conclusions: Poor SRH was associated with raised concentrations of many plasma proteins. However, the relationships were largely attenuated by adjustments for CVD risk factors, comorbidity and psycho-social factors. Leptin and CCL20 were associated with poor SRH in the present study and could potentially be involved in the SRH-CVD link

Proteomic Profiles of Body Mass Index and Waist-to-Hip Ratio and Their Role in Incidence of Diabetes

Context: It is unclear to what extent the plasma proteome of abdominal fat distribution differs from that of body mass index, and whether the differences have clinical implications. Objective: To evaluate the difference between the plasma proteomic profiles of body mass index (BMI) and waist-to-hip ratio (WHR), and then examine the identified BMI- or WHR-specific proteins in relation to incidence of diabetes. Methods: Data were obtained from the Malmö Diet and Cancer-Cardiovascular Cohort study in the general community. Participants (n = 4203) with no previous diabetes (aged 57.2 ± 6.0 years, 37.8% men) were included. Plasma proteins (n = 136) were measured by the Proseek proximity extension method. BMI- and WHR-specific proteins were identified at baseline using a 2-step iterative resampling approach to optimize internal replicability followed by β coefficient comparisons. The identified proteins were considered internally replicated and were then studied in relation to incident diabetes by Cox proportional hazards regression analysis. The main outcome measure was incident diabetes over a mean follow-up of 20.3 ± 5.9 years. Results: After excluding 21 overlapping proteins and proteins that did not show significantly different associations with BMI vs WHR, 10 internally replicated proteins were found to be specific to BMI, and 22 were found to be specific to WHR (false discovery rate-adjusted P < .05). Of the WHR-specific proteins, 18 remained associated with diabetes risk after multivariate adjustments, whereas none of the BMI-specific proteins showed associations with diabetes risk. Conclusion: Abdominal fat distribution was associated with some unique characteristics of the plasma proteome that potentially could be related to its additional risk of diabetes beyond general obesity

Increased HIF-1α in Knee Osteoarthritis Aggravate Synovial Fibrosis via Fibroblast-Like Synoviocyte Pyroptosis

Fibroblast-like synoviocytes (FLSs) are the main effector cells of knee osteoarthritis (KOA) synovial fibrosis. Our last report showed that NLRP1 and NLRP3 inflammasomes may mediate LPS/ATP-induced FLSs pyroptosis in KOA. In the present study, we found an elevated hypoxia-inducible factor-1α (HIF-1α) level in the synovial tissue of KOA model rats, and inhibiting the increase of HIF-1α could improve synovial fibrosis in rats. Subsequently, we established LPS/ATP-induced model in FLSs mimicking the inflammatory environment of KOA. FLSs transfected with siRNA HIF-1α showed a reduced cell death; meanwhile, the relative expression of pyroptosis-related proteins was also downregulated. Additionally, FLSs transfected with or without siRNA GSDMD were exposed to hypoxia. GSDMD silencing can significantly reduce both gene and protein levels of fibrogenic markers transforming growth factor-β (TGF-β), procollagen-lysine, 2-oxoglutarate 5-dioxygenase2 (PLOD2), collagen type I α1 chain (COL1A1), and tissue inhibitor of metalloproteinases 1 (TIMP1). Taken together, our findings indicate that increased HIF-1α is highly involved in the KOA synovial fibrosis. Moreover, elevated HIF-1α may aggravate synovial fibrosis via FLS pyroptosis