Recent evidence has suggested that synovial inflammation and macrophage polarization were involved in the pathogenesis of osteoarthritis (OA). Additionally, high-molecular-weight hyaluronic acid (HMW-HA) was often used clinically to treat OA. GRP78, an endoplasmic reticulum (ER) stress chaperone, was suggested to contribute to the hyperplasia of synovial cells in OA. However, it was still unclear whether HMW-HA affected macrophage polarization through GRP78. Therefore, we aimed to identify the effect of HMW-HA in primary synovial cells and macrophage polarization and to investigate the role of GRP78 signaling. We used IL-1β to treat primary synoviocytes to mimic OA, and then treated them with HMW-HA. We also collected conditioned medium (CM) to culture THP-1 macrophages and examine the changes in the phenotype. IL-1β increased the expression of GRP78, NF-κB (p65 phosphorylation), IL-6, and PGE2 in primary synoviocytes, accompanied by an increased macrophage M1/M2 polarization. GRP78 knockdown significantly reversed the expression of IL-1β-induced GRP78-related downstream molecules and macrophage polarization. HMW-HA with GRP78 knockdown had additive effects in an IL-1β culture. Finally, the synovial fluid from OA patients revealed significantly decreased IL-6 and PGE2 levels after the HMW-HA treatment. Our study elucidated a new form of signal transduction for HMW-HA-mediated protection against synovial inflammation and macrophage polarization and highlighted the involvement of the GRP78-NF-κB signaling pathway.

Increasing evidence suggests that high glucose (HG) causes abnormalities in endothelial and vascular smooth muscle cell function (VSMC) and contributes to atherosclerosis. Receptor for advanced glycation end-products (RAGE) has been linked to the pathogenesis of both the macrovascular and microvascular complications of diabetes. Cilostazol is used to treat diabetic vasculopathy by ameliorating HG-induced vascular dysfunction. In this study, we investigated whether the cilostazol suppression of HG-induced VSMC dysfunction is through RAGE signaling and its possible regulation mechanism. We investigated the effect of HG and cilostazol on RAGE signaling in A7r5 rat VSMCs. Aortic tissues of streptozotocin (STZ) diabetic mice were also collected. Aortic tissue samples from the diabetic mice exhibited a significantly decreased RAGE expression after cilostazol treatment. HG increased RAGE, focal adhesion kinase (FAK), matrix metalloproteinase-2 (MMP-2), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expressions, and was accompanied with increased reactive oxygen species (ROS), cell proliferation, adhesion and migration. Cilostazol significantly reversed HG-induced RAGE, ROS, downstream gene expressions and cell functions. RAGE knockdown significantly reversed the expressions of HG-induced vasculopathy related gene expressions and cell functions. Cilostazol with RAGE knockdown had additive effects on downstream ERK/NF-κB signaling pathways, gene expressions and cell functions of A7r5 rat VSMCs in HG culture. Both in vitro and in vivo experimental diabetes models showed novel signal transduction of cilostazol-mediated protection against HG-related VSMC dysfunction, and highlighted the involvement of RAGE signaling and downstream pathways.

Background: Patients with diabetes have a relatively high risk of fracture due to osteoporosis. However, the risk of osteoporosis associated with the use of oral hypoglycemic drugs and dipeptidyl peptidase-4 inhibitor (DPP-4i) by patients with diabetes is unclear. This study aimed to explore the effect of DPP-4i on the risk of osteoporosis in Taiwanese patients with type 2 diabetes mellitus (T2DM). Methods: This study enrolled 6339 patients on DPP-4i (DPP-4i group) and 25 356 patients without DPP-4i (non-DPP-4i group). They were matched by 1:4 propensity score matching, using confounding variables including sex, age, comorbidities, medication, and index year. Cox proportional hazards analysis was used to compare hospitalization and mortality during an average follow-up period of 7 years. Results: The mean age of patients in the two groups was 66 years. Men were slightly higher in number (51.79%) than women. At the end of the follow-up period, 113 (0.36%) patients had osteoporosis, of which 15 (0.24%) were in the case group and 98 (0.39%) in the control group. The risk of all-cause osteoporosis was significantly lower in the DPP-4i group than in the non-DPP-4i group (adjusted hazard ratio [HR] 0.616; 95% confidence interval [CI] 0.358–0.961; p = 0.011). Kaplan–Meier analysis showed that the preventive effect on osteoporosis was positively correlated with the cumulative dose of DPP-4i (log-rank, p = 0.039) with the class effect. Conclusion: Compared with not using DPP-4i, the use of DPP-4i in Taiwanese T2DM patients was associated with a lower risk of osteoporosis due to the class effect, and the preventive effect was dose-dependent. However, larger prospective studies are needed to validate this finding and to explore the possible mechanism of the preventive effect of DPP-4i.

Cardiovascular events such as myocarditis following mRNA COVID-19 vaccination are increasing. We present a 67-year-old postmenopausal woman with Takotsubo Syndrome and Graves’ disease after mRNA COVID-19 vaccination. She developed chest pain and shortness of breath one week after vaccination. An electrocardiogram revealed ST elevation in the precordial leads. Coronary angiography revealed the absence of obstructive coronary artery disease, and the left ventriculography showed a typical feature with apical ballooning. Laboratory workup showed the elevation of free T4 and thyrotropin receptor antibodies. It was presumed that Takotsubo Syndrome and Graves’ disease were probably related to the COVID-19 mRNA vaccination. The patient was treated with low-dose bisoprolol, diuretics, carbimazole, and steroid and discharged uneventfully. The mRNA COVID-19 vaccination is still safe and effective to defend against COVID-19 pandemic. However, clinicians should be aware of the possible cardiovascular adverse events other than myocarditis following vaccination.

Type 2 diabetes mellitus (T2DM) is an independent risk factor of knee osteoarthritis (KOA). This study was mainly based on data from the Taiwan National Health Insurance Database. Using big data analysis, we showed that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment is helpful for patients with T2DM who have a lower risk of KOA or total knee replacement (TKR). A total of 35,762 patients with T2DM were included in this study. We divided these patients into 988 patients with T2DM without KOA and 372 patients with T2DM with KOA who received GLP-1RA treatment and those who did not receive GLP-1RA treatment. The patients were matched for sex, age, and inclusion date by 1:1 propensity score, which was included in the control group. Cox proportional hazards analyses were performed to compare KOA risk and TKR rate during a maximum follow-up period of 5 years. There were 1976/744 patients with T2DM without/with KOA who received and did not receive GLP-1RA treatment, including 1052/322 men (53.24/43.28%) and 924/422 women (46.76/56.72%). At the end of follow-up, there were 46/39 (4.66/10.48%) patients with T2DM without/with KOA who received GLP-1RA treatment and underwent KOA/TKR were lower than those without GLP-1RA treatment 87/70 (8.81/18.82%). Cox proportional hazard regression analysis showed a lower rate of KOA/TKR among patients with GLP-1RA treatment (adjusted hazard ratio [HR] = .852; 95% confidence interval [CI] = .784–.930, P < .001/ adjusted HR = .913; 95% CI = .885–.977, P = .015, respectively). Kaplan–Meier analysis showed that the cumulative risk of KOA/TKR in patient with/without GLP-1RA was significantly different (log-rank test, P < .001/P < .001, respectively). This study aimed to provide clinicians with the option of GLP-1RA as a treatment for patients with T2DM with or without KOA to reduce the risk of KOA or TKR among such patients.