Anti-diabetic drug canagliflozin hinders skeletal muscle regeneration in mice.

Canagliflozin is an antidiabetic medicine that inhibits sodium-glucose cotransporter 2 (SGLT2) in proximal tubules. Recently, it was reported to have several noncanonical effects other than SGLT2 inhibiting. However, the effects of canagliflozin on skeletal muscle regeneration remain largely unexplored. Thus, in vivo muscle contractile properties recovery in mice ischemic lower limbs following gliflozins treatment was evaluated. The C2C12 myoblast differentiation after gliflozins treatment was also assessed in vitro. As a result, both in vivo and in vitro data indicate that canagliflozin impairs intrinsic myogenic regeneration, thus hindering ischemic limb muscle contractile properties, fatigue resistance recovery, and tissue regeneration. Mitochondrial structure and activity are both disrupted by canagliflozin in myoblasts. Single-cell RNA sequencing of ischemic tibialis anterior reveals a decrease in leucyl-tRNA synthetase 2 (LARS2) in muscle stem cells attributable to canagliflozin. Further investigation explicates the noncanonical function of LARS2, which plays pivotal roles in regulating myoblast differentiation and muscle regeneration by affecting mitochondrial structure and activity. Enhanced expression of LARS2 restores the differentiation of canagliflozin-treated myoblasts, and accelerates ischemic skeletal muscle regeneration in canagliflozin-treated mice. Our data suggest that canagliflozin directly impairs ischemic skeletal muscle recovery in mice by downregulating LARS2 expression in muscle stem cells, and that LARS2 may be a promising therapeutic target for injured skeletal muscle regeneration.

Ox-LDL induces dysfunction of endothelial progenitor cells via activation of NF-κB.

Dyslipidemia increases the risks for atherosclerosis in part by impairing endothelial integrity. Endothelial progenitor cells (EPCs) are thought to contribute to endothelial recovery after arterial injury. Oxidized low-density lipoprotein (ox-LDL) can induce EPC dysfunction, but the underlying mechanism is not well understood. Human EPCs were cultured in endothelial growth medium supplemented with VEGF (10 ng/mL) and bFGF (10 ng/mL). The cells were treated with ox-LDL (50 µg/mL). EPC proliferation was assayed by using CCK8 kits. Expression and translocation of nuclear factor-kabba B (NF-κB) were evaluated. The level of reactive oxygen species (ROS) in cells was measured using H2DCF-DA as a fluorescence probe. The activity of NADPH oxidase activity was determined by colorimetric assay. Ox-LDL significantly decreased the proliferation, migration, and adhesion capacity of EPCs, while significantly increased ROS production and NADPH oxidase expression. Ox-LDL induced NF-κB P65 mRNA expression and translocation in EPCs. Thus ox-LDL can induce EPC dysfunction at least by increasing expression and translocation of NF-κB P65 and NADPH oxidase activity, which represents a new mechanism of lipidemia-induced vascular injury.

Factors associated with decision time for patients with ST-segment elevation acute myocardial infarction.

Increased delay in visiting a hospital for patients with ST-segment elevation myocardial infarction (STEMI) is often associated with poor outcomes. The factors associated with the decision time were analyzed by comparing the characteristics of patients with delays longer or shorter than the median of 60 min. Pre-hospital delay tended to be longer for patients living in suburban areas compared to those in urban areas (P=0.015). Shorter decision time was more likely among older patients. Being married, medical insurance coverage, and the level of educational qualification did not affect decision time. More efforts should be paid to educate the patients with high risk in suburban areas in order to effectively reduce pre-hospital delays.

Danshen protects endothelial progenitor cells from oxidized low-density lipoprotein induced impairment.

In this study, we examined the protective effects of Danshen both on endothelial progenitor cells (EPCs) in patients with hypercholesterolemia and on in-vitro EPCs of healthy volunteers. In the clinical study, we randomly divided 24 subjects with hypercholesterolemia into two groups (the control group and the Danshen-treated group). At the end of two weeks of treatment, the EPC cellular functions of both groups were tested. The results indicated that, compared to the control group, EPCs in the Danshen-treated group showed significantly better cellular functions, which was manifested in the cloning number, the proliferation capacity, the number of EPC adhesions, and cell migration. In the subsequent in-vitro experiments, EPCs were treated with vehicle, oxidized low-density lipoprotein (Ox-LDL, 100 microg/ml), or Ox-LDL (100 microg/ml) plus different concentrations of Danshen (Danshensu 2, 10, or 50 microg/ml, respectively) for 24 h. The results showed that Danshen treatments can prevent the detrimental effects of Ox-LDL on EPC cellular functions measured by proliferation capacity (0.24+/-0.08, 0.37+/-0.11, 0.30+/-0.04 vs. 0.13+/-0.02, P<0.05, P<0.01, and P<0.01, respectively), and adhesion ability (63.00+/-11.60, 70.00+/-10.80, 85.50+/-11.41 vs. 40.50+/-6.85, all P<0.01). Compared to the group treated with Ox-LDL alone, Danshen treatment significantly decreased the lipid peroxidation end product malondialdehyde (MDA) [(4.34+/-0.54), (3.98+/-0.47), (3.46+/-0.31) vs. (5.57+/-0.64) nmol/ml, all P<0.01], increased the production of superoxide dismutase (SOD) [(29.74+/-0.71), (31.09+/-0.83), (30.41+/-0.65) vs. (14.76+/-3.99) U/ml, all P<0.01], and lowered the expression of interleukin-6 (IL-6) [(24.62+/-7.69), (27.04+/-3.14), (33.38+/-18.86) vs. (230.67+/-33.53) pg/ml, all P<0.01] and tumor necrosis factor-alpha (TNF-alpha) [(41.72+/-6.10), (17.02+/-6.82), (3.73+/-2.26) vs. (228.71+/-41.53) pg/ml, all P<0.01] in Ox-LDL treated EPCs. These results suggest that Danshen may exert a protective effect through its antioxidant and anti-inflammatory features.