Age-related bone diseases: Role of inflammaging.

Bone aging is characterized by an imbalance in the physiological and pathological processes of osteogenesis, osteoclastogenesis, adipogenesis, and chondrogenesis, resulting in exacerbated bone loss and the development of age-related bone diseases, including osteoporosis, osteoarthritis, rheumatoid arthritis, and periodontitis. Inflammaging, a novel concept in the field of aging research, pertains to the persistent and gradual escalation of pro-inflammatory reactions during the aging process. This phenomenon is distinguished by its low intensity, systemic nature, absence of symptoms, and potential for management. The mechanisms by which inflammaging contribute to age-related chronic diseases, particularly in the context of age-related bone diseases, remain unclear. The precise manner in which systemic inflammation induces bone aging and consequently contributes to the development of age-related bone diseases has yet to be fully elucidated. This article primarily examines the mechanisms underlying inflammaging and its association with age-related bone diseases, to elucidate the potential mechanisms of inflammaging in age-related bone diseases and offer insights for developing preventive and therapeutic strategies for such conditions.

Urinary exosomal microRNA-145-5p and microRNA-27a-3p act as noninvasive diagnostic biomarkers for diabetic kidney disease.

BACKGROUND: Diabetic kidney disease (DKD), characterized by increased urinary microalbumin levels and decreased renal function, is the primary cause of end-stage renal disease. Its pathological mechanisms are complicated and multifactorial; Therefore, sensitive and specific biomarkers are needed. Urinary exosome originate from diverse renal cells in nephron segments and partially mirror the pathological changes in the kidney. The microRNAs (miRNAs) in urinary exosome are remarkably stable and highly tissue-specific for the kidney. AIM: To determine if urinary exosomal miRNAs from diabetic patients can serve as noninvasive biomarkers for early DKD diagnosis. METHODS: Type 2 diabetic mellitus (T2DM) patients were recruited from the Second Hospital of Hebei Medical University and were divided into two groups: DM, diabetic patients without albuminuria [urinary albumin to creatinine ratio (UACR) < 30 mg/g] and DKD, diabetic patients with albuminuria (UACR ≥ 30 mg/g). Healthy subjects were the normal control (NC) group. Urinary exosomal miR-145-5p, miR-27a-3p, and miR-29c-3p, were detected using real-time quantitative polymerase chain reaction. The correlation between exosomal miRNAs and the clinical indexes was evaluated. The diagnostic values of exosomal miR-145-5p and miR-27a-3p in DKD were determined using receiver operating characteristic (ROC) analysis. Biological functions of miR-145-5p were investigated by performing Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment. RESULTS: Urinary exosomal expression of miR-145-5p and miR-27a-3p was more upregulated in the DKD group than in the DM group (miR-145-5p: 4.54 ± 1.45 vs 1.95 ± 0.93, P < 0.001; miR-27a-3p: 2.33 ± 0.79 vs 1.71 ± 0.76, P < 0.05) and the NC group (miR-145-5p: 4.54 ± 1.45 vs 1.55 ± 0.83, P < 0.001; miR-27a-3p: 2.33 ± 0.79 vs 1.10 ± 0.51, P < 0.001). The exosomal miR-145-5p and miR-27a-3p positively correlated with albuminuria and serum creatinine and negatively correlated with the estimated glomerular filtration rate. miR-27a-3p was also closely related to blood glucose, glycosylated hemoglobin A1c, and low-density lipoprotein cholesterol. ROC analysis revealed that miR-145-5p had a better area under the curve of 0.88 [95% confidence interval (CI): 0.784-0.985, P < 0.0001] in diagnosing DKD than miR-27a-3p with 0.71 (95%CI: 0.547-0.871, P = 0.0239). Bioinformatics analysis revealed that the target genes of miR-145-5p were located in the actin filament, cytoskeleton, and extracellular exosome and were involved in the pathological processes of DKD, including apoptosis, inflammation, and fibrosis. CONCLUSION: Urinary exosomal miR-145-5p and miR-27a-3p may serve as novel noninvasive diagnostic biomarkers or promising therapeutic targets for DKD.

Clinical Efficacy of Polyethylene Glycol Loxenatide in the Treatment of Obese or Overweight Patients with Type 2 Diabetes Mellitus.

OBJECTIVE: To determine the clinical efficacy of Polyethylene Glycol Loxenatide in the treatment of obese or overweight Type 2 Diabetes mellitus (T2DM) patients. STUDY DESIGN: A randomised-controlled trial. Place and Duration of the Study: Department of Endocrinology, Baoding No. 1 Central Hospital, Hebei, China, from January 2020 to January 2022. METHODOLOGY: One hundred overweight and obese patients who were diagnosed with T2DM were prospectively included. They were randomly divided into two groups, with 50 cases in each group. The control group was given oral metformin + subcutaneous insulin injection. The combined treatment group was also given Polyethylene Glycol Loxenatide in addition to the control treatment. The duration of treatment was 6 months for both groups. The clinical efficacy of the two group treatments was compared. The height, body mass, weight index (body mass index (BMI)), total cholesterol (TC), 2-h postprandial blood glucose (2hPBG), high-density lipoprotein cholesterol, fasting insulin (FINS), lipids (triglycerides (TG), low-density lipoprotein cholesterol, homeostasis model assessment of insulin resistance (HOMA-IR) levels, fasting blood glucose (FPG), and glycosylated haemoglobin (HbAlc) were evaluated before and 6 months after the treatment. In addition, any adverse reactions in the two groups were observed. RESULTS: The overall effective rate of clinical therapy was 92% (46/50) in the combined treatment group, which was higher than that of the control group (76%, 38/50, p = 0.029). The weight and BMI levels of the combined treatment group became considerably lower than those of the control group (weight p = 0.004; BMI p <0.001), and the levels of FPG, 2hPBG, FINS, HbAlc and HOMA-IR (all p = <0.001), and the TG and TC values decreased in both groups (TG p = 0.001; TC p = 0.016). CONCLUSION: PEG Loxenatide considerably affects obese and overweight T2DM patients. With no noticeable adverse reactions, this drug is highly recommended for application and clinical promotion. KEY WORDS: Polyethylene Glycol Loxenatide, Type 2 Diabetes mellitus, Obesity, Overweight, Clinical efficacy.

Changes of Serum Bone Metabolism Indexes and Ultrasonic Bone Mineral Density in Patients with Diabetic Nephropathy at Different Stages and their effects on Diabetic Renal Microvascular Complications.

Objective: To determine the changes in serum bone metabolism indexes and ultrasonic bone mineral density (BMD) in patients with diabetic nephropathy at different stages, and their effects on diabetic renal microvascular complications. Methods: This is a clinical comparative study. One hundred twenty two diabetic patients admitted to the Baoding No.1 Central Hospital from January 2020 to March 2022 were selected as subjects and divided into three groups according to their actual condition: the simple diabetes (Group-A, 40 cases), diabetic nephropathy with micro urinary protein (Group-B, 40 cases) and diabetic nephropathy with massive proteinuria (Group-C, 42 cases). Another 36 healthy subjects were selected as the control group. Differences in serum bone metabolism indexes and ultrasound BMD levels were compared. Results: Twenty five hydroxy-vitamin D, BGP, T-PINP and ultrasound BMD levels in the control group were > Group-A > Group-B > Group-C, PTH and ß-CTX in the control group were < Group-A < Group-B < Group-C, statistically significant differences (p<0.05). The urinary albumin to urinary creatinine ratio (ACR) value in Group-B was significantly lower than Group-C (p<0.05). Logistic regression analysis showed that 25-hydroxy-vitamin D, PTH, BGP, ß-CTX, T-PINP and ultrasound BMD were the influencing factors of diabetic renal microvascular complications (p<0.05). Conclusion: Bone metabolism indexes and ultrasound bone mineral density are abnormally expressed in patients with diabetic nephropathy at different stages, which are closely related to the urine protein of patients. They have important clinical value in the diagnosis of early diabetic nephropathy.

Embelin protects against apoptosis and inflammation by regulating PI3K/Akt signaling in IL-1ß-stimulated human nucleus pulposus cells.

Embelin is a natural benzoquinone compound that displays a beneficial effect in various inflammatory-related diseases. However, the effect of embelin on degeneration of intervertebral disc (IDD), a chronic inflammatory disorder, has not been reported. This study was attempted to explore the therapeutic action of embelin on IDD in vitro. Network pharmacology analysis was performed for evaluating the link between embelin and IDD. The human nucleus pulposus cells (NPCs) were stimulated with IL-1ß to induce inflammation. Cell viability of NPCs was assessed by CCK-8 assay. Western blotting was conducted to detect the expression levels of PI3K, p-PI3K, Akt, p-Akt, cleaved caspase-3, caspase-3, Bax, Bcl-2, p65 and p-p65. Apoptotic deaths of NPCs were examined by TUNEL assay. The production of COX-2, IL-6, IL-8, and TNF-α was examined by ELISA. It can be seen that 16 overlapping genes were selected from 109 possible targets of embelin and 342 possible targets of IDD. KEGG pathway enrichment analysis showed that the PI3K/Akt signaling pathway was a close link between embelin and IDD. We found that embelin dose-dependently improved the cell viability in IL-1ß-stimulated NPCs. Embelin elevated the relative levels of p-PI3K/PI3K and p-Akt/Akt in IL-1ß-stimulated NPCs. IL-1ß induced a significant increase in apoptotic deaths of NPCs, which was attenuated by embelin treatment. IL-1ß-induced alternations in expression levels of apoptotic-related proteins including cleaved caspase-3, Bax and Bcl-2 were prevented by embelin treatment. Pretreatment with LY294002 (an inhibitor of PI3K) reversed the inhibitory effect of embelin on IL-1ß-induced apoptosis in NPCs. Embelin treatment caused inhibitory effects on the IL-1ß-stimulated production of COX-2, IL-6, IL-8, and TNF-α, which were abolished by LY294002 treatment. Furthermore, embelin treatment prevented IL-1ß-induced phosphorylation of p65 in NPCs, while LY294002 elevated the embelin-caused decrease in p-p65/p65 level. Overall, embelin protected human NPCs against IL-1ß-stimulated apoptosis and inflammation by regulating the PI3K/Akt signaling pathway. These findings provided new ideas for the clinical usage of embelin in the prevention and treatment of IDD.

Baicalin suppresses interleukin-1ß-induced apoptosis, inflammatory response, oxidative stress, and extracellular matrix degradation in human nucleus pulposus cells.

OBJECTIVE: To explore the effect of baicalin on human nucleus pulposus cells (NPCs) in response to interleukin (IL)-1ß stimulation. METHODS: Viability of NPCs was measured by cell counting kit-8 (CCK-8) assay. TUNEL staining assay and flow cytometry were performed to detect apoptotic cell death of NPCs. Western blot analysis was conducted to detect the expression levels of proteins. Enzyme-linked immunosorbent assay (ELISA) was applied for the determination of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor alpha (TNF-α), and IL-6. Oxidative stress indicators including reactive oxygen species (ROS) production, malondialdehyde (MDA) level, and superoxide dismutase (SOD) activity were measured. RESULTS: Baicalin attenuated IL-1ß-caused cell viability reduction and apoptosis in NPCs. IL-1ß-induced increase in Bax expression and decrease in Bcl-2 expression were attenuated by baicalin treatment. IL-1ß-induced production of iNOS, COX-2, IL-6, and TNF-α in NPCs was inhibited by baicalin treatment. Baicalin treatment reversed IL-1ß-induced increase in ROS production and MDA level, as well as decrease in SOD activity. Furthermore, baicalin treatment elevated the expression levels of Col II and Aggrecan and downregulated the expression levels of MMP3, MMP13, and ADAMTS5 in IL-1ß-induced NPCs. A total of 402 related targets of baicalin and 134 related targets of intervertebral disk degeneration were found, and nine intersection targets were screened out. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that mitogen-activated protein kinase (MAPK) pathway was found to be involved in the effects of baicalin. CONCLUSIONS: Baicalin exhibited protective effects on IL-1ß-caused cell viability reduction, apoptosis, oxidative stress, inflammation, and extracellular matrix degradation in NPCs. In addition, we found c-Jun N-terminal kinase (JNK) and p38 MAPK pathways as targets of baicalin through bioinformatic analysis.

The efficacy and safety of quantitative flow ratio-guided complete revascularization in patients with ST-segment elevation myocardial infarction and multivessel disease: A pilot randomized controlled trial.

BACKGROUND: In patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease (MVD), the treatment strategy for non-infarct-related artery (non-IRA) remains controversial. Quantitative flow ratio (QFR) is a new angiography-based physiological assessment index. However, there is little evidence on the practical clinical application of QFR. METHODS: Two hundred and twenty-nine patients with STEMI and MVD were recruited for this study. Patients were randomly assigned to either receive QFR-guided complete revascularization (QFR-G-CR) of non-IRA or receive no further invasive treatment. The primary (1°) endpoint analyzed included death due to all causes, non-fatal myocardial infarction (MI), and ischemia-induced revascularization at 12 months post-surgery. Secondary (2°) endpoints included cardiovascular death, unstable angina, stent thrombosis, New York Heart Association (NYHA) class IV heart failure, and stroke at 1 year post surgery. Massive bleeding and contrast-associated acute kidney injury (CAKI) were used as safety endpoints. RESULTS: Around the 12 month follow up, the 1o outcome was recorded in 11/115 patients (9.6%) in the QFR-G-CR population, relative to 23/114 patients (20.1%) in the IRA-only PCI population (hazard ratio [HR]: 0.45; 95% confidence interval [CI]: 0.22-0.92; p = 0.025). Unstable angina in 6 (5.2%) and 16 (14.0%) patients (HR: 0.36; 95% CI: 0.14-0.92; p = 0.026), respectively. No marked alterations were found in the massive bleeding and CAKI categories. CONCLUSIONS: In conclusion, STEMI and MVD patients can benefit from QFR-G-CR of non-IRA lesions in the initial stages of acute MI. This can help reduce incidences of major adverse cardiovascular events and unstable angina, relative to IRA treatment only. Chinese Clinical Trial Registration number: ChiCTR2100044120.

Asiaticoside attenuates oxygen-glucose deprivation/reoxygenation-caused injury of cardiomyocytes by inhibiting autophagy.

Asiaticoside is a natural triterpene compound derived from Centella asiatica, possessing confirmed cardioprotective property. However, the roles of asiaticoside in regulating oxygen-glucose deprivation/reoxygenation (OGD/R)-caused cardiomyocyte dysfunction remain largely obscure. Human cardiomyocyte AC16 cells were stimulated with OGD/R to mimic myocardial ischemia/reperfusion injury and treated with asiaticoside. Cytotoxicity was investigated by CCK-8 assay and lactate dehydrogenase (LDH) release analysis. Autophagy- and Wnt/ß-catenin signaling-related protein levels were measured via western blotting. Asiaticoside (0-20 µM) did not induce cardiomyocyte cytotoxicity. Asiaticoside (20 µM) mitigated OGD/R-induced autophagy, cytotoxicity, oxidative stress, and myocardial injury. Rapamycin, an autophagy inductor, reversed the influences of asiaticoside on autophagy, cytotoxicity, oxidative stress, and myocardial injury, whereas 3-methyadanine, an autophagy inhibitor, played an opposite effect. Asiaticoside (20 µM) attenuated OGD/R-induced Wnt/ß-catenin signaling inactivation, which was reversed after transfection with si-ß-catenin. Transfection with si-ß-catenin attenuated the influences of asiaticoside on autophagy, cytotoxicity, oxidative stress, and myocardial injury. In conclusion, asiaticoside protected against OGD/R-induced cardiomyocyte cytotoxicity, oxidative stress, and myocardial injury via blunting autophagy through activating the Wnt/ß-catenin signaling, indicating the therapeutic potential of asiaticoside in myocardial ischemia/reperfusion injury.

The abnormal level and prognostic potency of multiple inflammatory cytokines in PCI-treated STEMI patients.

OBJECTIVE: Inflammatory cytokines modulate atherogenesis and plaque rupture to involve in ST-segment elevation myocardial infarction (STEMI) progression. The present study determined eight inflammatory cytokine levels in 212 percutaneous coronary intervention (PCI)-treated STEMI patients, aiming to comprehensively investigate their potency in estimating major adverse cardiac event (MACE) risk. METHODS: Serum tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-17A, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) of 212 PCI-treated STEMI patients and 30 angina pectoris patients were determined using enzyme-linked immunosorbent assay. RESULTS: TNF-α (52.5 (43.9-62.6) pg/ml versus 46.4 (39.0-59.1) pg/ml, p = 0.031), IL-8 (61.6 (49.6-81.7) pg/ml versus 46.7 (32.5-63.1) pg/ml, p = 0.001), IL-17A (57.4 (45.7-77.3) pg/ml versus 43.2 (34.2-64.6) pg/ml, p = 0.001), and VCAM-1 (593.6 (503.4-811.4) ng/ml versus 493.8 (390.3-653.7) ng/ml, p = 0.004) levels were elevated in STEMI patients compared to angina pectoris patients, while IL-1ß (p = 0.069), IL-6 (p = 0.110), IL-10 (p = 0.052), and ICAM-1 (p = 0.069) were of no difference. Moreover, both IL-17A high (vs. low) (p = 0.026) and VCAM-1 high (vs. low) (p = 0.012) were linked with increased cumulative MACE rate. The multivariable Cox's analysis exhibited that IL-17A high (vs. low) (p = 0.034) and VCAM-1 high (vs. low) (p = 0.014) were independently associated with increased cumulative MACE risk. Additionally, age, diabetes mellitus, C-reactive protein, multivessel disease, stent length, and stent type were also independent factors for cumulative MACE risk. CONCLUSION: IL-17A and VCAM-1 high level independently correlate with elevated MACE risk in STEMI patients, implying its potency in identifying patients with poor prognoses.

Effects of Rhythmic Gymnastics on Joint Attention and Emotional Problems of Autistic Children: A Preliminary Investigation.

The adaptive rhythmic gymnastics (ARG) course has been specially designed for children with autism spectrum disorders (ASD). The purpose of this study is to discover the influence of the course on the joint attention and emotional problems of ASD children. This study adopted A-B-A cross-subject multibaseline design in a single case research design. The joint attention behaviour of two 6-year-old ASD children was examined. The experiment process was recorded and coded, and the results were analysed. The results illustrated the following: (1) ARG is effective in promoting the development of joint attention in ASD children, but it has a better effect on increasing responding joint attention, and (2) to a certain extent, ARG can boost the classroom participation of ASD children and improve their emotional problems.

Effects of Antidiabetic Drugs on Endothelial Function in Patients With Type 2 Diabetes Mellitus: A Bayesian Network Meta-Analysis.

Background: The changes of endothelial function in type 2 diabetes mellitus (T2DM) patients are closely associated with the development of cardiovascular disease (CVD). However, it is still unclear whether commonly used antidiabetic drugs can improve endothelial function. Flow-mediated dilation (FMD) is a noninvasive tool for evaluating endothelial function, which typically examines changes in the brachial artery diameter in response to ischemia using ultrasound. We performed a network meta-analysis (NMA) to explore the associations between changes in endothelial function and antidiabetic drugs by evaluating FMD in T2DM patients. Methods: We systematically searched several electronic databases for randomized controlled trials (RCTs) published from inception until January 25, 2022 with no language restriction. The primary outcome was FMD change in all studies, and we performed subgroup analysis in T2DM patients without CVD. NMA was performed to calculate the mean differences (MDs) with 95% confidence intervals (CIs). Results: From the 1,987 candidate articles identified in the initial search, 30 RCTs were eventually included in the analysis. In all studies, glucagon-like peptide-1 receptor (GLP-1R) agonists [MD = 3.70 (1.39-5.97)], TZD [MD = 1.96 (0.006-3.89)] produced improvement of FMD change compared to lifestyle intervention. GLP-1R agonists [MD = 3.33 (1.36-5.34) and MD = 3.30 (1.21-5.43)] showed significantly greater improvements in FMD change in pairwise comparisons with sulfonylureas and placebo. SGLT-2i also showed efficacy compared to sulfonylureas (MD = 1.89, 95% CI, 0.10, 3.75). In studies of T2DM patients without CVD, GLP-1R agonists [MD = 3.53 (1.24-5.76)], and TZD [MD = 2.30 (0.27-3.24)] produced improvements in FMD change compared to lifestyle treatment. GLP-1R agonists [MD = 3.25 (1.13-5.40), and MD = 3.85 (1.68-6.13)] showed significantly greater improvements in pairwise comparisons with sulfonylureas, and placebo. Conclusion: In T2DM patients, both GLP-1R agonists, SGLT-2i and TZD have favorable effects to improve endothelial function in T2DM patients. In T2DM patients without CVD, GLP-1R agonists had a greater effect to improve endothelial function than sulfonylureas. These suggested that GLP-1R agonists are associated with significantly improved endothelial function in T2DM patients.

Cyanidin-3-glucoside protects against high glucose-induced injury in human nucleus pulposus cells by regulating the Nrf2/HO-1 signaling.

Cyanidin-3-glucoside (C3G) is a well-known natural anthocyanin with antioxidant and anti-inflammatory properties. In this study, we explored the role and action mechanism of C3G in high glucose (HG)-induced damage of human nucleus pulposus cells (HNPCs). Cell viability was assessed by CCK-8 assay. TUNEL assay was performed for detecting apoptotic rate. Western blot was performed to determine the expression levels of cl-caspase-3, caspase-3, Bax, Bim, collagen II, aggrecan, MMP-3, MMP-13, and ADAMTS5. Reactive oxygen species (ROS) generation was analyzed using DCFH-DA staining. The Nrf2 was knocked down or overexpressed in HNPCs through transfection with si-Nrf2 or pcDNA3.0-Nrf2. C3G treatment (12.5, 25, and 50 µM) improved cell viability of HNPCs under HG condition. HG-induced cell apoptosis of HNPCs was attenuated by C3G with decreased apoptotic rate and relative levels of cl-caspase-3/caspase-3, Bax, and Bim. C3G treatment caused significant increase in expression levels of collagen II and aggrecan and decrease in the relative levels of MMP-3, MMP-13, and ADAMTS5. After treatment with C3G, ROS generation in HNPCs was markedly reduced. Treatment with N-acetylcysteine (NAC) reversed HG-induced cell apoptosis and extracellular matrix (ECM) degradation. C3G treatment induced the expression of Nrf2 and HO-1 in HG-induced HNPCs. Moreover, knockdown of Nrf2 reversed the inhibitory effect of C3G on ROS production. Summarily, C3G exerted a protective effect on ROS-mediated cellular damage in HNPCs under HG condition, which was attributed to the induction of the Nrf2/HO-1 signaling pathway.

Effects of different enantiomers of amlodipine on lipid profiles and vasomotor factors in atherosclerotic rabbits.

This research aimed to describe the functions of vascular endothelial cells (VECs) in protecting target organs and the anti-atherosclerotic effects of different enantiomers of amlodipine on a rabbit model of atherosclerosis. Thirty male New Zealand white rabbits were randomly allocated to four groups (nA = 9, nB = 7, nC = 7, and nD = 7 rabbits): rabbits in group-A (control group) were fed a high-fat diet, group-B rabbits were fed a high-fat diet plus 2.5 mg/kg/day S-amlodipine, group-C rabbits were fed a high-fat diet plus 2.5 mg/kg/day R-amlodipine, and group-D rabbits were fed a high-fat diet plus 5 mg/kg/day racemic amlodipine. Different enantiomers of amlodipine did not influence lipid profiles and serum level of eNOS in the rabbit atherosclerosis model but decreased ET-1 expression to some extent. The serum NO and iNOS levels in the drug intervention groups were significantly reduced. No significant differences in the rabbits' body weights were observed. At the 4th and 8th weeks, the serum lipid profiles significantly increased in high cholesterol diet groups. The serum ET-1 level was significantly increased in each group of rabbits at the 8th week. Both S-amlodipine and R-amlodipine may protect the endothelium by reducing the serum ET-1 level, downregulating iNOS expression.

Liraglutide Protects Nucleus Pulposus Cells Against High-Glucose Induced Apoptosis by Activating PI3K/Akt/ mTOR/Caspase-3 and PI3K/Akt/GSK3ß/Caspase-3 Signaling Pathways.

Background and Objective: Diabetes mellitus (DM) is reportedly a significant risk factor for intervertebral disc degeneration (IDD). Incretin system and particularly glucagon-like peptide 1 (GLP-1) because of its glucose-lowering effects has become an important target in therapeutic strategies of type 2 diabetes (T2D). Liraglutide is a GLP-1 receptor (GLP-1R) agonist with glucoregulatory and insulinotropic functions as well as regulatory functions on cell proliferation, differentiation, and apoptosis. However, little is known on the roles and signaling pathways of apoptosis protecting effects of liraglutide in IDD. This study aimed to investigate the potential protective effects of liraglutide against high glucose-induced apoptosis of nucleus pulposus cells (NPCs) and the possible involved signaling pathways. Methods: The human NPCs were incubated with 100 nM liraglutide alone or in combination with LY294002 (PI3K inhibitor), rapamycin (mTOR inhibitor), and SB216763 (GSK3ß inhibitor) in a high glucose culture for 48 h. The four groups were assessed further for apoptosis and genes expressions. The apoptotic effect was evaluated by flow cytometry and further confirmed by cell death detection enzyme-linked immunoassay plus (ELISAPLUS). The gene and protein expression levels were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting techniques. The results were comparatively assessed between the four groups. Results: The results confirmed the presence of GLP-1R in the NPCs indicating that liraglutide inhibited the high glucose-induced apoptosis, which was blocked by silencing GLP-1R with siRNA. Moreover, liraglutide stimulated the phosphorylation of Akt, mTOR and GSK3ß. Treatment with LY294002 significantly increased the apoptosis of NPCs and reduced the levels of their downstream substrates (p-AKT, p-mTOR, and p-GSK3ß). Further assessments revealed that activation of mTOR and GSK3ß was almost completely inhibited by rapamycin and SB216763, respectively, which significantly increased the caspase-3 levels. Conclusion: Liraglutide could protect NPCs against high glucose-induced apoptosis by activating the PI3K/AKT/mTOR/caspase-3 and PI3K/AKT/GSK3ß/caspase-3 signaling pathways.

The Relationship Between Earlier Onset of Natural Menopause and Elevated Urinary Albumin-Creatinine Ratio in Postmenopausal Chinese Women.

PURPOSE: There is a close correlation between menopausal age and cardiovascular disease (CVD) risk. Some research suggests that this risk is attributable to an elevated urinary albumin-creatinine ratio (UACR), but further work is needed to explore the link between UACR and age at time of menopause. PATIENTS AND METHODS: Data analyzed in the present study were derived from seven regional centers participating in the REACTION study. A total of 21,672 postmenopausal women met with our study inclusion and exclusion criteria, and were split into three groups based upon their age at onset of natural menopause. A UACR ≥ 30 mg/g was the primary outcome measure for this study. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with a logistic regression approach. RESULTS: Relative to women who were 46-50 years old at time of natural menopause, those with an earlier onset of menopause (≤45 years) exhibited an increased risk of UACR elevation following adjustment for confounding variables (OR: 1.18, 95% CI: 1.04-1.33), whereas the opposite was true for women with a later age of menopause onset (>50 years) (OR: 0.86, 95% CI: 0.78-0.94). For every 1-year delay in the onset of menopause, UACR risk fell by 3% (OR: 0.97, 95% CI: 0.96-0.98). CONCLUSION: In summary, early menopause (≤45 years old) was linked to a higher risk of UACR elevation in postmenopausal women. However, further work will be needed to understand the mechanistic basis for these findings.

Improving Physical Fitness of Children with Intellectual and Developmental Disabilities through an Adapted Rhythmic Gymnastics Program in China.

BACKGROUND: Health-related physical fitness is vital for children with intellectual and developmental disabilities (IDD) to gain healthier lives. The adapted rhythmic gymnastics (ARG) program was designed for children with IDD and is aimed at testing the effects of the exercise program on children's physical fitness. METHODS: Participants were recruited from two special needs schools in Beijing of China. Twenty-two children with IDD were assigned to an ARG experimental group or a traditional control group. The experimental group took part in a 16-week ARG program consisting of three 50 min sessions each week. And children's body composition, aerobic capacity, and musculoskeletal functioning were measured by the Brockport Physical Fitness Test (BPFT) before and after the program. RESULTS: The between-group analysis revealed great improvements for the experimental group in abdominal strength (curl-up test: p = 0.025 < 0.05) and upper limb strength (dumbbell press test: p = 0.038 < 0.05). Compared to the pretest, most of the physical fitness parameters improved significantly in the experimental group except BMI, and flexibility of the experimental group children showed a substantial increase. CONCLUSIONS: Most of the physical fitness parameters of children with IDD in the experimental group improved significantly, especially on abdominal strength and upper limb muscle strength when comparing to the control group.

Marein protects human nucleus pulposus cells against high glucose-induced injury and extracellular matrix degradation at least partly by inhibition of ROS/NF-κB pathway.

Intervertebral disc degeneration (IDD), a major cause of discogenic low back pain, is a musculoskeletal disorder involving the apoptosis of nucleus pulposus cells (NPCs) and extracellular matrix (ECM) degradation. Marein is a major active flavonoid ingredient extracted from the hypoglycemic plant Coreopsis tinctoria with several beneficial biological activities including anti-diabetic effects. Nevertheless, there are no reports concerning the effects of marein on IDD. Our study aimed to evaluate the effects of marein on high glucose (HG)-induced injury and ECM degradation in human NPCs (HNPCs). CCK-8 assay was applied to evaluate cell viability. Flow cytometry analysis, a cell death detection ELISA, and caspase-3 activity assay were used to assess apoptosis. The mRNA expression of ECM-related proteins matrix metalloproteinase (MMP)-3, MMP-13, Collagen II, and aggrecan were determined by qRT-PCR. The changes of the nuclear factor-kappa B (NF-κB) pathway were examined by western blot. Stimulation with HG significantly reduced cell viability and induced apoptosis in HNPCs. Moreover, HG exposure increased MMP-3 and MMP-13 expression and decreased Collagen II and aggrecan expression in HNPCs. Notably, marein effectively alleviated HG-induced viability reduction, apoptosis and ECM degradation in HNPCs. We also found that marein inhibited HG-induced ROS generation and NF-κB activation in HNPCs. Inhibition of NF-κB pathway reinforced HG-induced injury and ECM degradation in HNPCs. In summary, marein protected HNPCs against HG-induced injury and ECM degradation at least partly by inhibiting the ROS/NF-κB pathway.

Use of flash glucose-sensing technology in patients with type 2 diabetes treated with liraglutide combined with CSII: a pilot study

Glycemic variability (GV) may be linked to the development of diabetic complications by inducing inflammation, oxidative stress, and endothelial dysfunction. Flash glucose monitoring (FGM) provides a novel method of continuously monitoring interstitial glucose levels for up to 14 days. This study randomly assigned poorly controlled type 2 diabetes mellitus patients treated with metformin and multiple daily injections of insulin (n=60) to either continuous subcutaneous insulin infusion (CSII) treatment or CSII in combination with liraglutide (CSII+Lira) treatment for 14 days during hospitalization. GV was assessed using a FGM system; weight and cardiometabolic biomarkers were also evaluated. The coefficient of variation was significantly reduced in the CSII+Lira group (P<0.001), while no significant change was observed in the CSII group. The changes differed significantly between the two groups in mean amplitude of glycemic excursions (P=0.004), standard deviation (P=0.006), and the percentage of time in the target range (4-10 mmol/L, P=0.005 and >10 mmol/L, P=0.028). The changes in mean of daily differences, interquartile range, and percentage of time in hypoglycemia (<3.3 mmol/L) and hyperglycemia (>13.9 mmol/L) identified by FGM showed no difference. Treatment with liraglutide increased serum adiponectin [33.5 (3.5, 47.7) pg/mL, P=0.003] and heme oxygenase-1 levels [0.4 (-0.0, 1.8) ng/mL, P=0.001] and reduced serum leptin levels [-2.8 (3.9) pg/mL, P<0.001]. Adding the glucagon-like peptide-1 analog liraglutide improved GV, weight, and some cardiometabolic risk markers. The FGM system is, therefore, shown to be a novel and useful method for glucose monitoring.

Use of flash glucose-sensing technology in patients with type 2 diabetes treated with liraglutide combined with CSII: a pilot study.

Glycemic variability (GV) may be linked to the development of diabetic complications by inducing inflammation, oxidative stress, and endothelial dysfunction. Flash glucose monitoring (FGM) provides a novel method of continuously monitoring interstitial glucose levels for up to 14 days. This study randomly assigned poorly controlled type 2 diabetes mellitus patients treated with metformin and multiple daily injections of insulin (n=60) to either continuous subcutaneous insulin infusion (CSII) treatment or CSII in combination with liraglutide (CSII+Lira) treatment for 14 days during hospitalization. GV was assessed using a FGM system; weight and cardiometabolic biomarkers were also evaluated. The coefficient of variation was significantly reduced in the CSII+Lira group (P<0.001), while no significant change was observed in the CSII group. The changes differed significantly between the two groups in mean amplitude of glycemic excursions (P=0.004), standard deviation (P=0.006), and the percentage of time in the target range (4-10 mmol/L, P=0.005 and >10 mmol/L, P=0.028). The changes in mean of daily differences, interquartile range, and percentage of time in hypoglycemia (<3.3 mmol/L) and hyperglycemia (>13.9 mmol/L) identified by FGM showed no difference. Treatment with liraglutide increased serum adiponectin [33.5 (3.5, 47.7) pg/mL, P=0.003] and heme oxygenase-1 levels [0.4 (-0.0, 1.8) ng/mL, P=0.001] and reduced serum leptin levels [-2.8 (3.9) pg/mL, P<0.001]. Adding the glucagon-like peptide-1 analog liraglutide improved GV, weight, and some cardiometabolic risk markers. The FGM system is, therefore, shown to be a novel and useful method for glucose monitoring.

Hexokinase II Upregulation Contributes to Asiaticoside-Induced Protection of H9c2 Cardioblasts During Oxygen-Glucose Deprivation/Reoxygenation.

Asiaticoside (AS), one of the main functional components of Centella asiatica, has been reported to protect neurons from ischemia-hypoxia-induced injury. However, the role of AS in myocardial oxygen-glucose deprivation/reoxygenation (OGD/R) injury has not been investigated. The aim of this study was to investigate the role of AS in OGD/R-treated H9c2 cardiomyocytes and the underlying mechanism involved. Cell viability was detected using MTT assay. Cell apoptosis was measured using flow cytometry. The oxidative stress was assessed by detecting the malonaldehyde (MDA) content and activities of superoxide dismutase, glutathione peroxidase, and catalase (CAT). The glucose consumption and lactate production were determined to reflect glycolysis rate. The expression levels of hexokinase II (HK2) were detected using reverse transcription quantitative polymerase chain reaction and Western blot. H9c2 cells were transfected with small interfering RNA targeting HK2 (si-HK2) to knockdown HK2. Results showed that AS improved cell viability and inhibited apoptosis in OGD/R-injured H9c2 cells. AS pretreatment prevented OGD/R-induced oxidative stress, as evidenced by the decreased MDA content, and increased activities of superoxide dismutase, glutathione peroxidase, and CAT. The decreased glucose consumption and lactate production in OGD/R-injured H9c2 cells were reversed after AS treatment. Mechanically, AS induced the expression of HK2 in OGD/R-injured H9c2 cells. Knockdown of HK2 abolished the protective effects of AS on OGD/R-injured H9c2 cells. In conclusion, the protective effects of AS on cardiomyocytes from OGD/R-induced injury were mediated at least partly by upregulating HK2.