Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in humans with type 2 diabetes (T2D); however, the underlying mechanism remains unclear. Activation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome and subsequent interleukin (IL)-1β release induces atherosclerosis and heart failure. Here we show the effect of SGLT2 inhibitor empagliflozin on NLRP3 inflammasome activity. Patients with T2D and high cardiovascular risk receive SGLT2 inhibitor or sulfonylurea for 30 days, with NLRP3 inflammasome activation analyzed in macrophages. While the SGLT2 inhibitor’s glucose-lowering capacity is similar to sulfonylurea, it shows a greater reduction in IL-1β secretion compared to sulfonylurea accompanied by increased serum β-hydroxybutyrate (BHB) and decreased serum insulin. Ex vivo experiments with macrophages verify the inhibitory effects of high BHB and low insulin levels on NLRP3 inflammasome activation. In conclusion, SGLT2 inhibitor attenuates NLRP3 inflammasome activation, which might help to explain its cardioprotective effects.

Betatrophin/angiopoietin-like protein 8 (ANGPTL8) is a liver-secreted protein recently identified as a potent stimulator of beta cell proliferation in mice. However, it is unclear how betatrophin is regulated in humans with non-alcoholic fatty liver disease (NAFLD). We investigated the role of betatrophin in mice and in humans with and without NAFLD. Serum betatrophin levels were examined by ELISA in 164 subjects, including 96 patients with NAFLD. Levels were significantly elevated in subjects with NAFLD compared with controls (1.301 ± 0.617 vs. 0.900 ± 0.574 μg/L, P < 0.001), even after stratification by diabetic or obesity status. Circulating betatrophin positively correlated with obesity or glycemic indices, liver enzyme profiles, and NAFLD status, and was confirmed by multivariate regression analyses (β = 0.195, P = 0.040). However, when including insulin resistance index in the model, the significant association between betatrophin level and NAFLD was diminished due to a mediation effect of insulin resistance on this relationship. Palmitate or tunicamycin increased betatrophin expression in HepG2 cells, while a chemical chaperone blocked its induction. Hepatic expression of betatrophin was elevated in mice with NAFLD including db/db or ob/ob mice and mice with a high-fat or methionine-choline deficient diet. In conclusion, circulating betatrophin was increased in mice and humans with NAFLD and its expression was induced by endoplasmic reticulum stress in hepatocytes (Clinical trial no. NCT02285218).

Background: High mobility group box-1 (HMGB1) is a newly recognized factor regulating cancer cell tumorigenesis, expansion and invasion. We investigated the correlation between the serum HMGB1 levels and the clinical and pathologic features of gastric cancer and evaluated the validity of HMGB1 as a potential biomarker for the early diagnosis of gastric cancer. Methods: A total of 227 subjects were classified into 5 disease groups according to the 'gastritis-dysplasia-carcinoma' sequence of gastric carcinogenesis and their serum levels of HMGB1 were analyzed by an enzyme-linked immunosorbent assay (ELISA) method. Clinical parameters, International Union Against Cancer (UICC) TNM stage, cancer size, differentiation or lymphatic invasion, vascular or perineural invasion and prognosis were used as analysis variables. Results: The serum HMGB1 levels were significantly different among disease groups (ANOVA, p < 0.05) and HMGB1 levels tended to increase according to the progression of gastric carcinogenesis. Serum HMGB1 levels were significantly associated with depth of invasion, lymph node metastasis, tumor size, and poor prognosis (p < 0.05). However, HMGB1 levels were not associated with patient gender or age, differentiation of tumor cells, or lymphatic, vascular and perineural invasion, or the existence of distant metastasis in advanced cancer (p > 0.05). The sensitivity and specificity of serum HMGB1 was 71% and 67% (cut-off value of 5 ng/ml) for the diagnosis of early gastric cancer, and 70% and 64% (cut-off value of 4 ng/ml) for the diagnosis of high-risk lesions, respectively. These values were greater than those for carcinoembryonic antigen (CEA) (30–40% of sensitivity). Conclusion: HMGB1 appears to be a useful serological biomarker for early diagnosis as well as evaluating the tumorigenesis, stage, and prognosis of gastric cancer.

To examine mutations within the penA, mtrR, porB, ponA and pilQ genes of Neisseria gonorrhoeae to determine their contribution to cephalosporin resistance. A total of 46 N. gonorrhoeae isolates with reduced susceptibility to cefixime or ceftriaxone (MICs ≥ 0.12 mg/L) and two susceptible isolates were selected. The full sequence of penA and partial sequences previously reported as hot mutation sites of the other genes were analysed. Genotyping by N. gonorrhoeae multiantigen sequence typing (NG-MAST) was also performed. A mosaic penicillin-binding protein 2 (PBP 2) was found in a single isolate that exhibited the highest cefixime MIC (0.5 mg/L). The majority of the isolates with reduced susceptibility to cephalosporins contained non-mosaic PBP 2 sequences, of which PBP 2 pattern XIII was most common (28/46). All isolates with reduced susceptibility to cephalosporins also had mtrR and porB mutations. Two susceptible isolates had the PBP 2 pattern XIV and an incomplete MtrR protein, which was a new mutation. Isolates with identical PBP 2 patterns comprised multiple NG-MAST sequence types. Reduced susceptibility of N. gonorrhoeae to ceftriaxone and cefixime was associated with diverse penA mutations, particularly PBP 2 pattern XIII containing an Ala-501→Val substitution, together with mtrR and porB mutations. The existence of only one strain having the mosaic penA sequence indicated that ceftriaxone and cefixime resistance in Korea is mostly not associated with a mosaic penA sequence. Highly heterogeneous NG-MAST sequence types excluded the clonal expansion of a particular subtype.

Although tuberculosis (TB) is a severe health problem worldwide, the current diagnostic methods are far from optimal. Metabolomics is increasingly being used in the study of infectious diseases. We performed metabolome profiling to identify potential biomarkers in patients with active TB. Serum samples from 21 patients with active pulmonary TB, 20 subjects with latent TB infection (LTBI), and 28 healthy controls were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) followed by multivariate and univariate analyses. Metabolic profiles indicated higher serum levels of glutamate, sulfoxy methionine, and aspartate and lower serum levels of glutamine, methionine, and asparagine in active TB patients than in LTBI subjects or healthy controls. The ratios between metabolically related partners (glutamate/glutamine, sulfoxy methionine/methionine, and aspartate/asparagine) were also elevated in the active TB group. There was no significant difference in the serum concentration of these metabolites according to the disease extent or risk of relapse in active TB patients. Novel serum biomarkers such as glutamate, sulfoxy methionine, aspartate, glutamine, methionine, and asparagine are potentially useful for adjunctive, rapid, and noninvasive pulmonary TB diagnosis.