SGLT2 inhibitors: a novel therapy for cognitive impairment via multifaceted effects on the nervous system.

The rising prevalence of diabetes mellitus has casted a spotlight on one of its significant sequelae: cognitive impairment. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for diabetes management, are increasingly studied for their cognitive benefits. These benefits may include reduction of oxidative stress and neuroinflammation, decrease of amyloid burdens, enhancement of neuronal plasticity, and improved cerebral glucose utilization. The multifaceted effects and the relatively favorable side-effect profile of SGLT2 inhibitors render them a promising therapeutic candidate for cognitive disorders. Nonetheless, the application of SGLT2 inhibitors for cognitive impairment is not without its limitations, necessitating more comprehensive research to fully determine their therapeutic potential for cognitive treatment. In this review, we discuss the role of SGLT2 in neural function, elucidate the diabetes-cognition nexus, and synthesize current knowledge on the cognitive effects of SGLT2 inhibitors based on animal studies and clinical evidence. Research gaps are proposed to spur further investigation.

Wearable monitoring device based on an internet management platform improves metabolic parameters in type 2 diabetes patients: a prospective pilot study.

OBJECTIVES: This pilot study aimed to prospectively investigate the effects of a wearable monitoring device, based on an Internet management platform, on the comprehensive management of type 2 diabetes mellitus (T2DM) patients. METHODS: A total of 120 hospitalized patients with T2DM were enrolled and randomly divided into the control group and the intervention group. Patients in the control group only received conventional diabetes treatments, while patients in the intervention group were provided with a wearable monitoring device in addition to conventional diabetes treatments. Moreover, the wearable device could connect to an Internet platform for diabetes management and upload self-monitoring data. All patients were followed for 3 months. The changes in parameters representing glucose metabolism, blood lipids, renal function, and patient satisfaction were compared between the two groups. All results were analyzed on an intention-to-treat basis. RESULTS: One hundred twenty subjects met all criteria and agreed to participate in this study. During the follow-up period, 5 and 4 subjects were lost to follow-up in the intervention and control groups, respectively. Compared with the control group, the blood glucose of the intervention group decreased significantly after 3 months (p < 0.05). Subgroup analysis found that females, those younger than 60 years, with baseline glycated hemoglobin A1c (HbA1c) levels of 8% or greater, and patients with good adherence showed significant improvements in HbA1c (p < 0.05). However, there was no significant difference in blood lipid and renal function. The intervention group showed a better adherence rate to blood glucose, comprehensive adherence rate, and diabetes treatment satisfaction (p < 0.05). One subject in the intervention group and two subjects in the control group reported mild hypoglycemia. No other adverse events such as infections and skin allergies occurred in the two groups. CONCLUSION: The intervention of a wearable monitoring device based on an Internet management platform significantly improved blood glucose control in T2DM patients, as well as the overall adherence rate and patient satisfaction with treatment. CLINICAL TRIAL REGISTRATION: NCT04973644.

Screening parameters for diagnosing primary aldosteronism in patients with moderate to severe obstructive sleep apnea hypopnea syndrome and resistant hypertension.

Background: Patients with obstructive sleep apnea hypopnea syndrome (OSAHS) combined with resistant hypertension (RH) have a high risk of developing primary aldosteronism (PA). This study investigated the aldosterone-renin ratio (ARR), plasma aldosterone concentration (PAC), and plasma renin activity (PRA) to determine the optimal cutoff values for PA diagnosis in patients with OSAHS combined with RH. Methods: Patients diagnosed with moderate and severe OSAHS combined with RH were recruited from the inpatient clinic of the Department of Endocrinology at Ji'an Central Hospital between October 2020 and April 2023. The included patients were divided into PA and no-PA groups. Diagnostic accuracy measures were calculated for each group, and receiver operating characteristic (ROC) curves were generated. Results: A total of 241 patients were included, of which 103 had positive ARR screening results in the diagnostic accuracy analysis and 66 were diagnosed with PA. PAC and ARR showed moderate predictive capacity for PA, with area under the curve (AUC) values of 0.66 [95% confidence interval (CI): 0.55-0.77] and 0.72 (95% CI: 0.63-0.82), respectively, while PRA exhibited a limited predictive capacity (AUC = 0.51, 95% CI: 0.40-0.63). Using 45 as the optimal cutoff value for ARR, the sensitivity was 86% and the specificity was 52%. The optimal cutoff value for PAC was 17, with a sensitivity of 78% and a specificity of 55%. Notably, in patients with severe OSAHS, ARR at screening demonstrated significant predictive value for PA, with an AUC of 0.84 (95% CI: 0.72-0.96), a sensitivity of 85%, and a specificity of 76%. Conversely, in patients with moderate OSAHS, only ARR demonstrated significant predictive value for PA diagnosis, while PAC did not demonstrate notable diagnostic value. Conclusion: ARR and PAC are initial screening tools for PA, facilitating early detection, particularly in low-resource settings. In patients with OSAHS and RH, the ARR and PAC thresholds for PA diagnosis may require more stringent adjustment.

Role of liver FGF21-KLB signaling in ketogenic diet-induced amelioration of hepatic steatosis.

BACKGROUND: The effectiveness of ketogenic diet (KD) in ameliorating fatty liver has been established, although its mechanism is under investigation. Fibroblast growth factor 21 (FGF21) positively regulates obesity-associated metabolic disorders and is elevated by KD. FGF21 conventionally initiates its intracellular signaling via receptor ß-klotho (KLB). However, the mechanistic role of FGF21-KLB signaling for KD-ameliorated fatty liver remains unknown. This study aimed to delineate the critical role of FGF21 signaling in the ameliorative effects of KD on hepatic steatosis. METHODS: Eight-week-old C57BL/6 J mice were fed a chow diet (CD), a high-fat diet (HFD), or a KD for 16 weeks. Adeno-associated virus-mediated liver-specific KLB knockdown mice and control mice were fed a KD for 16 weeks. Phenotypic assessments were conducted during and after the intervention. We investigated the mechanism underlying KD-alleviated hepatic steatosis using multi-omics and validated the expression of key genes. RESULTS: KD improved hepatic steatosis by upregulating fatty acid oxidation and downregulating lipogenesis. Transcriptional analysis revealed that KD dramatically activated FGF21 pathway, including KLB and fibroblast growth factor receptor 1 (FGFR1). Impairing liver FGF21 signaling via KLB knockdown diminished the beneficial effects of KD on ameliorating fatty liver, insulin resistance, and regulating lipid metabolism. CONCLUSION: KD demonstrates beneficial effects on diet-induced metabolic disorders, particularly on hepatic steatosis. Liver FGF21-KLB signaling plays a critical role in the KD-induced amelioration of hepatic steatosis.

Pioglitazone ameliorates ischemia/reperfusion-induced acute kidney injury via oxidative stress attenuation and NLRP3 inflammasome.

Acute kidney injury (AKI) induced by renal ischemia/reperfusion injury (IRI) is a severe clinical condition. ROS accumulation, antioxidant pathways deficiency, and inflammation are involved in IRI. Pioglitazone (Pio) exerts anti-inflammatory and antioxidant effects. The aim of this study was to explore the protective effects of pioglitazone against IRI-induced AKI. Pathogen-free Sprague-Dawley (SD) rats were arbitrarily divided into four groups: Sham operation group Control (CON) group, CON + Pio group, I/R + Saline group, and I/R + Pio group. In addition, HK-2 cells were subjected to hypoxia and reoxygenation to develop an H/R model for investigation of the protective mechanism of Pio. Pretreatment with pioglitazone in the model rats reduced urea nitrogen and creatinine levels, histopathological scores, and cytotoxicity after IRI. Pioglitazone treatment significantly attenuated renal cell apoptosis, decreased cytotoxicity, increased Bcl-2 expression, and downregulated Bax expression. Besides, the levels of ROS and inflammatory factors, including NLRP3, ASC, pro-IL-1ß, pro-caspase-1, cleaved-caspase-1, TNF-α, IL-6, and IL-1ß, in I/R rats and H/R cells were normalized by the pioglitazone treatment. Pioglitazone improved IRI-induced AKI by attenuating oxidative stress and NLRP3 inflammasome activation. Therefore, pioglitazone has the potential to serve as a novel agent for renal IRI treatment and prevention.

Glucagon-Like Peptide-1 Receptor Agonist and Risk of Diabetic Retinopathy in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis of Randomized Placebo-Controlled Trials.

BACKGROUND: Glucagon-like peptide 1 receptor agonists (GLP-1RAs) exhibit glucose-lowering, weight-reducing, and blood pressure-lowering effects. Nevertheless, a debate exists concerning the association between GLP-1RA treatment and the risk of diabetic retinopathy (DR) in patients diagnosed with type 2 diabetes mellitus (T2DM). OBJECTIVE: To ascertain the risk of DR in patients with T2DM undergoing GLP-1RA treatment, we conducted a meta-analysis utilizing data derived from randomized placebo-controlled studies (RCTs). METHODS: A comprehensive literature search was conducted using PubMed, Cochrane Library, Web of Science, and EMBASE. We focused on RCTs involving the use of GLP-1RAs in patients with T2DM. Utilizing R software, we compared the risk of DR among T2DM patients undergoing GLP-1RA treatment. The Cochrane risk of bias method was employed to assess the research quality. RESULTS: The meta-analysis incorporated data from 20 RCTs, encompassing a total of 24,832 T2DM patients. Across all included trials, randomization to GLP-1 RA treatment did not demonstrate an increased risk of DR (odds ratio = 1.17; 95% CI 0.98-1.39). Furthermore, no significant heterogeneity or publication bias was detected in the analysis. CONCLUSION: The results of this systematic review and meta-analysis indicate that the administration of GLP-1 RA is not associated with an increased risk of DR. PROSPERO REGISTRATION IDENTIFIER: CRD42023413199.

Mechanism of the Change in the Intestinal Microbiota of C-Strain Spodoptera frugiperda (Lepidoptera: Noctuidae) after an Interspecific Transference between Rice and Corn.

Spodoptera frugiperda (J.E.Smith) (Lepidoptera: Noctuidae) was first found in 2019 in Yunnan, China, and it was characterized as a corn strain; it was also found on rice strains there, and it damages rice in China, but little is known about the effect of host plant transfer on the intestinal microbiota and the activities of detoxification enzymes in the C-strain (corn strain) S. frugiperda. The intestinal microbiota and the protective enzyme activity of S. frugiperda that were transferred from rice plants were assessed, and the fourth generation of insects transferred from corn were studied; the gene types of S. frugiperda that were transferred from rice plants were tested using mitochondrial Tpi gene sequences. The results showed that the intestinal microbiota in the C-strain S. frugiperda were changed after the host transference, and the diversity and richness of the intestinal bacterial communities of the S. frugiperda feeding on rice were significantly reduced after the transfer of the host from corn. The predominant species of intestinal bacteria of the S. frugiperda on rice transferred from corn were Enterococcus and Enterobacter, with relative abundances of 28.7% and 66.68%; the predominant species of intestinal bacteria of the S. frugiperda that were transferred from rice and feeding on corn were Enterococcus (22.35%) and Erysipelatoclostridium (73.92%); and the predominant species of intestinal bacteria of S. frugiperda feeding on corn was Enterococcus, with a relative abundance of 61.26%. The CAT (catalase) activity of the S. frugiperda transferred from corn onto rice from corn was reduced, the POD (peroxidase) activity was significantly increased after the transfer from corn, and no significant variations were found for the SOD (superoxide dismutase), CarE (carboxylesterase), and GST (glutathione S-transferase) activities of S. frugiperda after the host plant transfer. The results showed that after feeding on rice, the activities of CAT and POD in the in S. frugiperda body changed in order to resist plant secondary metabolites from corn or rice, but there was no significant change in the detoxification enzymes in the body. In summary, switching the host plant between corn and rice induced variations in the intestinal microbiota in C-strain S. frugiperda owing to the strain difference between the C-strain and the R-strain (rice strain), and this was consistent with the results of the activities of detoxification enzymes. The results indicat that changes in intestinal microbiota and physiological enzymes may be important reasons for the adaptive capacity of C-strain S. frugiperda to rice.

The triglyceride-glucose index is a predictor for cardiovascular and all-cause mortality in CVD patients with diabetes or pre-diabetes: evidence from NHANES 2001-2018.

BACKGROUND: The association between the triglyceride-glucose (TyG) index and mortality in cardiovascular disease (CVD) patients with diabetes or pre-diabetes remains unclear. This study aimed to investigate the relationship between baseline TyG index and all-cause and cardiovascular (CV) mortality in CVD patients with diabetes or pre-diabetes among American adults. . METHODS: This study enrolled 1072 CVD patients with diabetes or pre-diabetes from the National Health and Nutrition Examination Survey (2001-2018). Mortality outcomes were determined by linking to National Death Index (NDI) records up to December 31, 2019. Multivariate Cox proportional hazards models were constructed to analyze explore the associations between baseline TyG index and mortality. Non-linear correlations were explored using restricted cubic splines, and a two-piecewise Cox proportional hazards model for both sides of the inflection point was constructed. RESULTS: During 7541 person-years of follow-up, a total of 461 all-cause deaths and 154 CVD-related deaths were recorded. The restricted cubic splines revealed a U-shaped association between the baseline TyG index with all-cause and CVD mortality in CVD patients with diabetes or pre-diabetes. Specifically, baseline TyG index lower than the threshold values (TyG index < 9.05 in all-cause mortality and < 8.84 in CVD mortality) was negatively associated with mortality (HR 0.47, 95% CI = 0.27-0.81 for all-cause mortality and HR 0.25, 95% CI = 0.07-0.89 for CVD mortality). In contrast, baseline TyG index higher than the threshold values (TyG index > 9.05 in all-cause mortality and > 8.84 in CVD mortality) was positively associated with mortality (HR 1.42, 95% CI = 1.02-1.99 for all-cause mortality and HR 1.77, 95% CI = 1.08-2.91 for CVD mortality). CONCLUSIONS: A U-shaped association was observed between the baseline TyG index with CVD and all-cause mortality in CVD patients with diabetes or pre-diabetes in a American population. The thresholds of 8.84 and 9.05 for CVD and all-cause mortality, respectively.

Pioglitazone-Enhanced Brown Fat Whitening Contributes to Weight Gain in Diet-Induced Obese Mice.

INTRODUCTION: Pioglitazone is an insulin sensitizer used for the treatment of type 2 diabetes mellitus (T2DM) by activating peroxisome proliferator-activated receptor gamma. This study aimed to investigate the effects of pioglitazone on white adipose tissue (WAT) and brown adipose tissue (BAT) in diet-induced obese (DIO) mice. METHODS: C57BL/6 mice were treated with pioglitazone (30 mg/kg/day) for 4 weeks after a 16-week high-fat diet (HFD) challenge. Body weight gain, body fat mass, energy intake, and glucose homeostasis were measured during or after the treatment. Histopathology was observed by hematoxylin and eosin, oil red O, immunohistochemistry, and immunofluorescence staining. Expression of thermogenic and mitochondrial biogenesis-related genes was detected by quantitative real-time PCR and western blotting. RESULTS: After 4-week pioglitazone treatment, the fasting blood glucose levels, glucose tolerance, and insulin sensitivity were significantly improved, but the body weight gain and fat mass were increased in DIO mice. Compared with the HFD group, pioglitazone did not significantly affect the weights of liver and WAT in both subcutaneous and epididymal regions. Unexpectedly, the weight of BAT was increased after pioglitazone treatment. Histological staining revealed that pioglitazone ameliorated hepatic steatosis, reduced the adipocyte size in WAT, but increased the adipocyte size in BAT. CONCLUSION: Though pioglitazone can promote lipolysis, thermogenesis, and mitochondrial function in WAT, it leads to impaired thermogenesis, and mitochondrial dysfunction in BAT. In conclusion, pioglitazone could promote the browning of WAT but led to the whitening of BAT; the latter might be a new potential mechanism of pioglitazone-induced weight gain during T2DM treatment.

Cross-talk between gut microbiota and liver steatosis: Complications and therapeutic target.

Liver steatosis is the most widespread chronic liver condition. Its global incidence is rising swiftly and is currently estimated to be 24%. Liver steatosis is strongly related with numerous metabolic syndrome characteristics, like obesity, insulin resistance, hyperlipidemia, and hypertension. The gastrointestinal tract contains about 100 trillion commensal organisms and more than 7,000 distinct bacterial strains. Fat deposition in the liver without secondary causes is known as liver steatosis. Dysregulation of the gut flora is one of the factors connected to the onset of fatty liver disease. Dietary choices may alter constitution of the microbiome and cause gut microbiome dysbiosis, particularly due to the intake of food high in fructose sugars, animal products, and saturated fats. Various gut bacteria cause nutrient metabolism in multiple ways, setting off different inflammatory cascades that encourage liver disease and pathways that help fat build up in the liver. Due to their relatively stable nature, genetic factors may not be responsible for the constant increase in liver steatosis incidence. Genetic factors set the stage for liver steatosis pathogenesis. This review will offer an overview of our present knowledge of the roles played by gut microbiota in regulating the development of liver steatosis, potential side effects, and potential treatment targets.

Romiplostim in primary immune thrombocytopenia that is persistent or chronic: phase III multicenter, randomized, placebo-controlled clinical trial in China.

Background: Multiple trials have confirmed that romiplostim could increase platelet count in individuals with primary immune thrombocytopenia (ITP), but no related study has assessed Chinese patients. Objectives: To assess the effectiveness of romiplostim as a second-line treatment of persistent or chronic ITP in Chinese adults. Methods: This phase III multicenter, randomized, placebo-controlled, double-blind, then open-label clinical trial (NCT02868099, CTR20150395) was conducted at 28 investigational sites in China. The patients were randomly assigned (3:1) to romiplostim (starting and maximum doses of 1 and 10 µg/kg, respectively) or placebo for 9 weeks (double-blind period), followed by the open-label period (both groups administered romiplostim) to week 22. The primary endpoint was the time (in weeks) during which platelet counts were ≥50 × 109/L in the double-blind period. Results: In this study, 202 patients (romiplostim, n = 151; placebo, n = 51) started the treatment. The median (range) numbers of weeks with platelet response after 6 weeks of treatment were 2 (0-6) and 0 (0-2) in patients administered romiplostim and placebo, respectively (P < .001). During the double-blind period, the proportions of patients with treatment-emergent adverse events were comparable between the romiplostim and placebo groups (82.8% vs 82.4%). The treatment-emergent adverse event with ≥10% difference in incidence between these 2 groups was injection site bleeding (1.3% vs 11.8%). Conclusion: Romiplostim significantly increased the time with maintained platelet response in patients with persistent or chronic ITP in comparison with placebo. No new safety signal was observed. Trial registration: ClinicalTrials.gov, NCT02868099. www.chinadrugtrials.org.cn/clinicaltrials.searchlist.dhtml, CTR20150395.

SGLT2 inhibitor empagliflozin downregulates miRNA-34a-5p and targets GREM2 to inactivate hepatic stellate cells and ameliorate non-alcoholic fatty liver disease-associated fibrosis.

BACKGROUND AND RATIONALE: Activation of hepatic stellate cells (HSCs), the central event of fibrosis, indicates the severe stage of non-alcoholic fatty liver disease (NAFLD). MicroRNAs (miRNAs) participate in this process. Treatment with a sodium-glucose cotransporter 2 inhibitor (SGLT2i) alleviates liver fibrosis in patients with type 2 diabetes and NAFLD; however, the role of SGLT2i in ameliorating liver fibrosis in NAFLD by regulating miRNAs remains unclear. APPROACH AND RESULTS: We monitored the expression of NAFLD-associated miRNAs in the livers of two NAFLD models and observed high expression of miR-34a-5p. miR-34a-5p was highly expressed in mouse primary liver non-parenchymal cells and LX-2 HSCs, and this miRNA was positively correlated with alanine transaminase levels in NAFLD models. Overexpression of miR-34a-5p enhanced LX-2 activation, whereas its inhibition prevented HSCs activation by regulating the TGFß signaling pathway. The SGLT2i empagliflozin significantly downregulated miR-34a-5p, inhibited the TGFß signaling pathway, and ameliorated hepatic fibrosis in NAFLD models. Subsequently, GREM2 was identified as a direct target of miR-34a-5p through database prediction and a dual-luciferase reporter assay. In LX-2 HSCs, the miR-34a-5p mimic and inhibitor directly downregulated and upregulated GREM2, respectively. Overexpressing GREM2 inactivated the TGFß pathway whereas GREM2 knockdown activated it. Additionally, empagliflozin upregulated Grem2 expression in NAFLD models. In methionine- and choline-deficient diet-fed ob/ob mice, a fibrosis model, empagliflozin downregulated miR-34a-5p and upregulated Grem2 to improve liver fibrosis. CONCLUSIONS: Empagliflozin ameliorates NAFLD-associated fibrosis by downregulating miR-34a-5p and targeting GREM2 to inhibit the TGFß pathway in HSCs.

Iodine status and its association with prevalence of thyroid diseases in adults from Jiangxi Province, China.

BACKGROUND: Iodine is an essential element for the biosynthesis of thyroid-stimulating hormone (TSH). Both excessive and deficient iodine are major risk factors for thyroid diseases, including thyroid dysfunction, thyroid nodules, and thyroid autoimmunity (TAI). This study aimed to elucidate the relationship between iodine status and the prevalence of thyroid diseases through a national cross-sectional epidemiological survey in Jiangxi province (China). METHODS: This population-based, cross-sectional study enrolled 2636 Chinese local inhabitants who aged over 18 years old from April to August in 2015. Physical examination was performed and biochemical indices, urinary iodine concentration (UIC), and TSH level were measured. The Chi-square test, nonparametric test, and 4 multivariate logistic regression models adjusted for risk factors were applied to analysis. Spearman correlation coefficients were calculated to investigate the relationship between iodine intake level and the prevalence of thyroid diseases. RESULTS: The median UIC was 176.4 µg/L, and a significant difference was found in median UIC between men (182.45 µg/L) and women (169.25 µg/L) (P = 0.03). Among these study subjects, 14.4%, 44.5%, 26.1%, and 15.0% had deficient, adequate, more than adequate, and excessive iodine concentrations, respectively. The prevalence rates of hyperthyroidism, subclinical hyperthyroidism, hypothyroidism, subclinical hypothyroidism, thyroid nodules, and TAI were 0.91%, 0.57%, 0.34% and 7.89%, 9.45%, and 12.7%, respectively. Significant differences were found in iodine status, waist circumstance, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), TSH, thyroid nodules, and TAI between men and women (P < 0.05). Compared with those with adequate UIC, subjects with excessive UIC had higher prevalence rates of thyroid dysfunction (odds ratio (OR) = 1.74, 95% confidence interval (CI): 1.40-2.54) and thyroid nodules (OR = 3.33, 95%CI 1.32-8.42). In addition, subjects with deficient and excessive UIC were at the higher risk of TAI compared with those with adequate UIC (OR = 1.68, 95%CI: 1.19-2.60; OR = 1.52, 95%CI: 1.04-2.96, respectively). UIC was positively correlated with the prevalence rates of thyroid nodules (r = -0.44, P < 0.01) and TAI (r = -0.055, P < 0.01). On the contrary, UIC was negatively correlated with the risk of thyroid dysfunction (r = -0.24, P > 0.05). CONCLUSION: Adult inhabitants from Jiangxi province in the TIDE study were in the adequate iodine status. Excessive iodine status was noted as a risk factor for thyroid dysfunction and thyroid nodules. In addition, both iodine deficiency and excessive iodine were risk factors for TAI.

Plasma exosome miRNA-26b-3p derived from idiopathic short stature impairs longitudinal bone growth via the AKAP2/ERK1/2 axis.

BACKGROUND: Currently, the etiology of idiopathic short stature (ISS) is still unclear. The poor understanding of the molecular mechanisms of ISS has largely restricted this strategy towards safe and effective clinical therapies. METHODS: The plasma exosomes of ISS children were co-cultured with normal human chondrocytes. The differential expression of exosome miRNA between ISS and normal children was identified via high-throughput microRNA sequencing and bioinformatics analysis. Immunohistochemistry, In situ hybridization, RT-qPCR, western blotting, luciferase expression, and gene overexpression and knockdown were performed to reveal the key signaling pathways that exosome miRNA of aberrant expression in ISS children impairs longitudinal bone growth. RESULTS: Chondrocytes proliferation and endochondral ossification were suppressed after coculture of ISS plasma exosomes with human normal chondrocytes. High-throughput microRNA sequencing and RT-qPCR confirmed that plasma exosome miR-26b-3p was upregulated in ISS children. Meanwhile, exosome miRNA-26b-3p showed a high specificity and sensitivity in discriminating ISS from normal children. The rescue experiment showed that downregulation of miR-26b-3p obviously improved the repression of chondrocyte proliferation and endochondral ossification caused by ISS exosomes. Subsequently, miR-26b-3p overexpression inhibited chondrocyte proliferation and endochondral ossification once again. In situ hybridization confirmed the colocalization of miR-26b-3p with AKAP2 in chondrocytes. In vitro and in vivo assay revealed exosome miRNA-26b-3p impairs longitudinal bone growth via the AKAP2 /ERK1/2 axis. CONCLUSIONS: This study is the first to confirm that miR-26b-3p overexpression in ISS plasma exosomes leads to disorders in proliferation and endochondral ossification of growth plate cartilage via inhibition of AKAP2/ERK1/2 axis, thereby inducing ISS. This study provides a new research direction for the etiology and pathology of ISS and a new idea for the biological treatment of ISS.

HbA1c is a predictive factor of severe coronary stenosis and major adverse cardiovascular events in patients with both type 2 diabetes and coronary heart disease.

BACKGROUND: Coronary heart disease (CHD) is not only a macrovascular complication of type 2 diabetes mellitus (T2DM). Cardiovascular disease (CVD) is one of the leading causes of mortality among individuals with T2DM. Reducing the risk of adverse cardiovascular events (MACE) is crucial for the management of patients with CHD. This study aimed to investigate the effect of glycemic control on CHD severity and 3-point MACE (3p-MACE) risk in patients with T2DM and CHD. METHODS: 681 patients with both T2DM and CHD throughout October 2017 and October 2021 who were hospitalized in the second affiliated hospital of Nanchang university were included. A total of 300 patients were eventually enrolled in this retrospective cohort research. The severity of CHD in these patients was assessed, and the primary outcome during follow-up was recorded, with the primary result being the 3-point major adverse cardiovascular event (3p-MACE). The correlation between baseline glycated hemoglobin A1c (b-HbA1c) and the severity of CHD was evaluated by logistic regression analysis. The effect of b-HbA1c and follow-up HbA1c (f-HbA1c) levels on the risk of 3p-MACE were investigated by cox regression analysis. RESULTS: b-HbA1c was positively correlated with the severity of CHD (r = 0.207, p = 0.001), and patients with b-HbA1c > 9% were more likely to have severe CHD. The HRs for b-HbA1c and f-HbA1c on the risk of 3p-MACE were 1.24 (95% CI 0.94-1.64, p = 0.123) and 1.32 (95% CI 1.02-1.72, p = 0.036), respectively. Patients with f-HbA1c ≥8.6% had a higher risk of 3p-MACE than f-HbA1c < 8.6% (HR = 1.79, 95% CI 1.16-2.79, p = 0.009). CONCLUSION: In patients with both T2DM and CHD, b-HbA1c was an independent predictive factor of severe CHD. f-HbA1c was an independent predictive factor of 3p-MACE. Having the f-HbA1c below 8.6% significantly reduced the risk of 3p-MACE.

Effectiveness of Wearable Activity Monitors on Metabolic Outcomes in Patients With Type 2 Diabetes: A Systematic Review and Meta-Analysis.

OBJECTIVE: Wearable activity monitors are promising tools for improving metabolic outcomes in patients with type 2 diabetes mellitus (T2DM); however, no uniform conclusive evidence is available. This study aimed to evaluate the effects of the intervention using wearable activity monitors on blood glucose, blood pressure, blood lipid, weight, waist circumference, and body mass index (BMI) in individuals with T2DM. METHODS: Two independent reviewers searched 4 online databases (PubMed, Cochrane Library, Web of Science, and Embase) to identify relevant studies published from January 2000 to October 2022. The primary outcome indicator was hemoglobin A1c (HbA1c), and the secondary outcome indicators included physical activity (steps per day), fasting blood glucose, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, systolic blood pressure, diastolic blood pressure, BMI, waist circumference, and weight. RESULTS: A total of 25 studies were included. The HbA1c level (standardized mean difference [SMD], -0.14; 95% confidence interval [CI], -0.27 to -0.02; P = .02; I2 = 48%), BMI (SMD, -0.16; 95% CI, -0.26 to -0.05; P = .002; I2 = 0), waist circumference (SMD, -0.21; 95% CI, -0.34 to -0.09; P < .001; I2 = 0), and steps/day (SMD, 0.55; 95% CI, 0.36-0.94; P < .001; I2 = 77%) significantly improved. CONCLUSION: Wearable activity monitor-based interventions could facilitate the improvement of the HbA1c level, BMI, and waist circumference and increase in physical activity in individuals with T2DM. Wearable technology appeared to be an effective tool for the self-management of T2DM; however, there is insufficient evidence about its long-term effect.

RNA-binding proteins in metabolic-associated fatty liver disease (MAFLD): From mechanism to therapy.

Metabolic-associated fatty liver disease (MAFLD) is the most common chronic liver disease globally and seriously increases the public health burden, affecting approximately one quarter of the world population. Recently, RNA binding proteins (RBPs)-related pathogenesis of MAFLD has received increasing attention. RBPs, vividly called the gate keepers of MAFLD, play an important role in the development of MAFLD through transcription regulation, alternative splicing, alternative polyadenylation, stability and subcellular localization. In this review, we describe the mechanisms of different RBPs in the occurrence and development of MAFLD, as well as list some drugs that can improve MAFLD by targeting RBPs. Considering the important role of RBPs in the development of MAFLD, elucidating the RNA regulatory networks involved in RBPs will facilitate the design of new drugs and biomarkers discovery.

Renal venous sampling assisted the diagnosis of juxtaglomerular cell tumor: a case report and literature review.

Juxtaglomerular cell tumor (JCT) is an endocrine tumor marked by elevated renin levels and high blood pressure. This case report presents the clinical findings of a 47-year-old woman with a history of recurrent hypokalemia, headaches, hypertension, and increased plasma renin activity (PRA). Dynamic enhanced magnetic resonance imaging (MRI) revealed a small nodule on the upper part of the right kidney. Selective renal venous sampling indicated a higher PRA only in the right upper pole renal vein. The patient underwent surgical removal of the right kidney mass, and the pathology results confirmed the diagnosis of JCT. This case underscores the importance of conducting selective renal venous sampling for accurate JCT diagnosis.

Non-steroidal anti-inflammatory drugs and clinical outcomes in patients with COVID-19.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with coronavirus disease 2019 (COVID-19) has raised great concerns. The effect of NSAIDs on the clinical status of COVID-19 remains in question. Therefore, we performed a post-hoc analysis from the ORCHID trial. Patients with COVID-19 from the ORCHID trial were categorized into two groups according to NSAID use. The 28-day mortality, hospitalized discharge, and safety outcomes with NSAIDs for patients with COVID-19 were analyzed. A total of 476 hospitalized patients with COVID-19 were included; 412 patients (86.5%) did not receive NSAIDs, while 64 patients (13.5%) took NSAIDs as regular home medication. Patients who took NSAIDs did not have a significant increase in the risk of 28-day mortality (fully adjusted: hazard ratio [HR]: 1.12, 95% CI: 0.52-2.42) in the Cox multivariate analysis. Moreover, NSAIDs did not decrease hospital discharge through 28 days (fully adjusted: HR: 1.02, 95% CI: 0.75-1.37). The results of a meta-analysis including 14 studies involving 48,788 patients with COVID-19 showed that the use of NSAIDs had a survival benefit (summary risk ratio [RR]: 0.70, 95% CI: 0.54-0.91) and decreased the risk of severe COVID-19 (summary: RR: 0.79, 95% CI: 0.71-0.88). In conclusion, the use of NSAIDs is not associated with worse clinical outcomes, including 28-day mortality or hospital discharge in American adult hospitalized patients with COVID-19. Based on current evidence, the use of NSAIDs is safe and should not be cautioned against during the COVID-19 pandemic. Ongoing trials should further assess in-hospital treatment with NSAIDs for patients with COVID-19.

O-GlycNacylation Remission Retards the Progression of Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease spectrum associated with insulin resistance (IR), from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). O-GlcNAcylation is a posttranslational modification, regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Abnormal O-GlcNAcylation plays a key role in IR, fat deposition, inflammatory injury, fibrosis, and tumorigenesis. However, the specific mechanisms and clinical treatments of O-GlcNAcylation and NAFLD are yet to be elucidated. The modification contributes to understanding the pathogenesis and development of NAFLD, thus clarifying the protective effect of O-GlcNAcylation inhibition on liver injury. In this review, the crucial role of O-GlcNAcylation in NAFLD (from NAFL to HCC) is discussed, and the effect of therapeutics on O-GlcNAcylation and its potential mechanisms on NAFLD have been highlighted. These inferences present novel insights into the pathogenesis and treatments of NAFLD.