Our previous study revealed that microRNA-125a-5p plays a crucial role in regulating hepatic glycolipid metabolism by targeting STAT3 in type 2 diabetes mellitus (T2DM). Dioscin, a major active ...ingredient in Dioscoreae nipponicae rhizomes, displays various pharmacological activities, but its role in T2DM has not been reported.
The aim of this study was to investigate the effect of dioscin on T2DM and elucidate its potential mechanism.
The effect of dioscin on glycolipid metabolic disorder in insulin-induced HepG2 cells, palmitic acid-induced AML12 cells, high-fat diet- and streptozotocin- induced T2DM rats, and spontaneous T2DM KK-Ay mice were evaluated. Then, the possible mechanisms of dioscin were comprehensively evaluated.
Dioscin markedly alleviated the dysregulation of glycolipid metabolism in T2DM by reducing hyperglycemia and hyperlipidemia, improving insulin resistance, increasing hepatic glycogen content, and attenuating lipid accumulation. When the mechanism was investigated, dioscin was found to markedly elevate miR-125a-5p level and decrease STAT3 expression. Consequently, dioscin increased phosphorylation levels of STAT3, PI3K, AKT, GSK-3β, and FoxO1 and decreased gene levels of PEPCK, G6Pase, SREBP-1c, FAS, ACC, and SCD1, leading to an increase in glycogen synthesis and a decrease in gluconeogenesis and lipogenesis. The effects of dioscin on regulating miR-125a-5p/STAT3 pathway were verified by miR-125a-5p overexpression and STAT3 overexpression.
Dioscin showed potent anti-T2DM activity by improving the inhibitory effect of miR-125a-5p on STAT3 signaling to alleviate glycolipid metabolic disorder of T2DM.
Objectives
To investigate the clinical efficacy of integrated multidomain intervention among community-living older adults with multimorbidity and physio-cognitive decline syndrome (PCDS).
Design, ...Setting and Participants
This is the secondary analysis from a randomized controlled trial that data of 340 participants with Montreal Cognitive Assessment (MoCA) scores≥18 were excerpted for analysis.
Intervention
Sixteen 2-hour sessions per year were provided for participants, including physical exercise, cognitive training, dietician education and individualized integrated care for multimorbidity.
Measurements
Handgrip strength, 6-m walking speed, MoCA (total score and sub-domains), Cardiovascular Health Study (CHS) frailty score, quality of life, and serum biochemistry biomarkers.
Results
Overall, 96/340 (28.2%) of all participants have PCDS, and the integrated multidomain intervention significantly improved global cognitive performance (overall difference 1.1, 95% CI 0.4–1.8, p=0.003), and domains of concentration (overall difference 0.3, 95%CI 0.1–0.5, p=0.011), language (overall difference 0.2, 95%CI 0.1–0.3, p=0.006), abstract thinking (overall difference 0.1, 95%CI 0.0–0.3, p=0.027), and orientation(overall difference 0.2, 95%CI 0.0–0.4, p=0.013) across all timepoints among those with PCDS. Besides, interventions also significantly reduced frailty score among those with cognitive impairment no dementia (overall difference −0.3, 95%CI −0.5 − −0.1, p=0.011) and mobility impairment no disability (overall difference −0.3, 95%CI −0.4 − −0.1, p=0.004). and improved quality of life at domain of physical role limitation among those with PCDS (overall difference 5.3, 95%CI 0.3–10.4, p=0.038).
Conclusions
The integrated multidomain lifestyle intervention plus multimorbidity management significantly improved cognitive function, and enhanced quality of life among older adults with multimorbidity and PCDS in the communities.
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MiR-23a-5p is involved in the occurrence and development of some serious diseases, but its effects on intestinal ischemia–reperfusion (II/R) injury is unclear. In this research, the ...hypoxia/reoxygenation (H/R) model on IEC-6 cells and II/R model in mice were used. The data showed that the ROS level in model group was significantly increased compared with control group. The level of intestinal MPO was increased and serum SOD was decreased in mice compared with sham group. Moreover, the expression levels of miR-23a-5p in model groups were obviously increased in vitro and in vivo, while the expression levels of PPARα, FOXO3α, PGC-1α, Nrf2, CAT, NQO1, HO-1 and SOD2 were significantly decreased. The double luciferase reporter gene assay showed that there was binding site between miR-23a-5p and PPARα. When miR-23a-5p was inhibited or PPARα gene was overexpressed, H/R-caused cell damage was alleviated and ROS level was decreased compared with NC group. PPARα expression level was increased, accompanied by the increased levels of FOXO3α, PGC-1α, Nrf2, CAT, NQO1, HO-1 and SOD2. After enhancing miR-23a-5p expression or silencing PPARα gene, H/R-caused cell damage was further aggravated compared with NC group, and ROS level was increased associated with the decreased levels of FOXO3α, PGC-1α, Nrf2, CAT, NQO1, HO-1 and SOD2. Our study demonstrated that miR-23a-5p exacerbated II/R injury by promoting oxidative stress via targeting PPARα, which should be considered as one new drug target to treat II/R injury.
In this era of unprecedented longevity, healthy aging is an important public health priority. Avoiding or shortening the period of disability or dementia before death is critical to achieving the ...defining objectives of healthy aging, namely to develop and maintain functional capabilities that enable wellbeing in older age. The first step is to identify people who are at risk and then to implement effective primary interventions. Geriatricians have identified a distinct clinical phenotype of concurrent physical frailty and cognitive impairment, which predicts high risk of incident dementia and disability and is potentially reversible. Differing operational definitions for this phenotype include “cognitive frailty”, “motoric cognitive risk syndrome” and the recently proposed “physiocognitive decline syndrome (PCDS)”. PCDS is defined as concurrent mobility impairment no disability (MIND: slow gait or/and weak handgrip) and cognitive impairment no dementia (CIND: ≥1.5 SD below the mean for age-, sex-, and education-matched norms in any cognitive domain but without dementia). By these criteria, PCDS has a prevalence of 10–15% among community-dwelling older persons without dementia or disability, who are at increased risk for incident disability (HR 3.9, 95% CI 3.0–5.1), incident dementia (HR 3.4, 95% CI 2.4–5.0) and all-cause mortality (HR 6.7, 95% CI 1.8–26.1). Moreover, PCDS is associated with characteristic neuroanatomic changes in the cerebellum and hippocampus, and their neurocircuitry, which are distinct from neuroimaging features in normal aging and common dementia syndromes. Basic research and longitudinal clinical studies also implicate a hypothetical muscle-brain axis in the pathoetiology of PCDS. Most important, community-dwelling elders with PCDS who participated in a multidomain intervention had significant improvements in global cognitive function, and especially in the subdomains of naming and concentration. Our proposed operational definition of PCDS successfully identifies an appreciable population of at-risk older people, establishes a distinct phenotype with an apparently unique pathoetiology, and is potentially reversible. We now need further studies to elucidate the pathophysiology of PCDS, to validate neuroimaging features and muscle-secreted microRNA biomarkers, and to evaluate the effectiveness of sustained multidomain interventions.
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•RI/R injury significantly increased the expression level of miR-27a-3p.•miR-27a-3p aggravated RI/R injury by promoting oxidative stress.•miR-27a-3p directly targeted Grb2.•Grb2siRNA ...further enhanced RI/R-caused renal injury.
Renal ischemia-reperfusion (RI/R) injury with high morbidity and mortality is one common clinical disease. Development of drug targets to treat the disorder is critical important. MiR-27a-3p plays important roles in regulating oxidative stress. However, its effects on RI/R injury have not been reported. In this paper, hypoxia/reoxygenation (H/R) models on NRK-52E and HK-2 cells, and RI/R model in C57BL/6 mice were established. The results showed that H/R in vitro decreased cell viability and increased ROS levels in cells, and RI/R caused renal injury and oxidative damage in mice. The expression levels of miR-27a-3p were up-regulated based on real-time PCR and FISH assays in model groups compared with control groups, which directly targeted Grb2 based on dual luciferase reporter assay and co-transfaction test. In addition, miR-27a- 3p markedly reduced Grb2 expression to down-regulate the expression levels of p-PI3K, p-AKT, Nrf2, HO-1, and up-regulate Keap1 expression in model groups. MiR-27a-3p mimics in vitro enhanced H/R-caused oxidative stress via increasing ROS levels and decreasing Grb2 expression to down-regulate PI3K-AKT signal. In contrary, miR-27a-3p inhibitor in vitro significantly reduced H/R-caused oxidative damage via decreasing ROS levels and increasing Grb2 expression to up-regulate PI3K-AKT signal. In vivo, miR-27a- 3p agomir exacerbated RI/R-caused renal damage by decreasing SOD level and increasing Cr, BUN, MDA levels via suppressing Grb2 expression to down-regulate PI3K- AKT signal. However, miR-27a -3p antagomir alleviated RI/R-caused oxidative damage via increasing Grb2 expression to up-regulate PI3k-AKT signal. Grb2siRNA in mice further enhanced RI/R-caused renal injury by increasing Cr, BUN, MDA levels and decreasing SOD level via inhibiting the expression levels of Grb2, Nrf2, HO-1, and increasing Keap1 expression. Our data showed that miR-27a-3p aggravated RI/R injury by promoting oxidative stress via targeting Grb2, which should be considered as one new drug target to treat RI/R injury.
Objective
How implementing diagnostic-related grouping (DRG) payment affected the use of opioids and psychotropics by hip fracture patients following hospitalization remained unknown.
Design
A ...retrospective, pre-post design, cohort study of data excerpted from Taiwan’s National Health Insurance Research database (NHIRD).
Setting and participants
Adults aged ≥ 65 years first admitted for hip fracture surgery from 2007 to 2012 were identified and divided into two 1:1 propensity-score matched groups: pre-DRG (2007–2009); DRG (2010–2012).
Measurements
The outcome measures were use of opioid and/or psychotropic drugs within 30 days, 90 days, 180 days, and 365 days after discharge.
Results
Data of 16,522 subjects were excerpted, and 8,261 propensity-score matched subjects each classified into the pre-DRG and DRG groups. After adjustment, the DRG group was significantly more likely than the pre-DRG group to have used antipsychotics after discharge from hip fracture surgery (≤30 days, ≤90 days, ≤180 days and ≤365 days). The DRG group also had significantly higher prescription rates of benzodiazepines and antipsychotics during the observation period. Moreover, the DRG group was less likely to use non-steroidal anti-inflammatory drugs (≤30 days, ≤90 days, ≤180 days and ≤365 days) and more likely to use acetaminophen (≤30 days, ≤180 days, and ≤365 days).
Conclusions
In conclusion, DRG implementation in Taiwan substantially increased post-acute prescription of antipsychotic and psychotropic agents for hip fracture patients, and changed use of analgesics, which may result in suboptimal quality and safety for these patients. Further research is needed to evaluate the long-term outcomes of DRG implementation, and the potential benefits of appropriate post-acute care bundled with DRG payment.
Objectives
To investigate the effect of body weight, waist circumference and their changes on all-cause and cardiovascular mortality.
Design
A nationwide population-based cohort study
Participants
...627 community-dwelling older adults.
Measurements
Participants were interviewed for demographic and anthropometric data collected. Blood were drawn for testing biochemistry data. Central obesity was defined as waist circumference is greater than 80 cm for women and 90 cm for men. Obesity, overweight, normal and underweight were defined as BMI ≥27 kg/m2, ≥24 kg/m2,18.5-24 kg/m2 and <18.5 kg/m2. Cox proportion hazard model was used to explore the impact of body weight and its change on mortality.
Results
The distribution of weight changes and mortality was right skewed, but U-shape of waist change for all-cause mortality was observed. Compared to normal BMI at baseline, the association between underweight (HR: 1.7, 95% CI: 0.7-4.0), overweight (HR:0.7, 95% CI:0.4-1.2) and obesity (HR:1.3,95% CI:0.8-2.3) showed insignificantly associated with all-cause mortality. The HR of those weight loss >5% (HR: 1.7, 95% CI: 1.1-2.8) and waist decrease >5% (HR: 1.7, 95% CI: 1.0-2.8) were higher than those of stable weight/waist +/- 5% over a 6-year period. Compared to those stable weight/waist, the mortality risk was similar in those of weight gain or waist increase (HR 0.7,95%CI: 0.4-1.5 and HR:0.9, 95%CI:0.4-1.6).
Conclusion
Weight loss and waist decrease were significantly associated with long-term mortality risk, a life-course approach for body weight management is needed to pursuit the most optimal health benefits for the middle-aged and older adults.
Aims
To compare the efficacy and safety of combination of vildagliptin and metformin therapy with metformin uptitration in Chinese patients with type 2 diabetes (T2DM) inadequately controlled with ...low‐dose metformin.
Methods
In this 24‐week prospective, randomized, multicentre, open‐label study, patients with T2DM inadequately controlled with metformin ≤1000 mg daily were divided 1 : 1 : 1 : 1 into four prespecified subgroups based on age and body mass index (BMI). Patients in each subgroup were randomized 5 : 1 to receive either vildagliptin (50 mg twice daily) plus metformin 500 mg twice daily; vildagliptin and low‐dose metformin (VLDM) group or metformin uptitration 1000 mg twice daily; high‐dose metformin (HDM) group. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline at week 24. The key secondary endpoints included percentage of patients achieving target HbA1c without adverse gastrointestinal (GI) events and mean change in fasting plasma glucose (FPG) from baseline to week 24.
Results
A total of 3084 patients were randomized. HbA1c reduction of 0.54% at week 24 in the VLDM group was non‐inferior and statistically superior compared with 0.40% in the HDM group (P < 0.0001). VLDM's non‐inferiority to HDM was confirmed in the four subgroups and its superiority was shown for all subgroups (p < 0.05) except for the subgroup of patients aged <60 years with a BMI of ≥24 kg/m2. Compared with HDM, VLDM significantly increased the percentage of patients achieving HbA1c ≤6.5% and HbA1c ≤6.5% without GI events. FPG levels in the VLDM group were lower at week 24 numerically than in the HDM group. The two treatment arms had similar safety profiles.
Conclusions
VLDM was non‐inferior and statistically superior to HDM in glycaemic control in Chinese patients with T2DM inadequately controlled with low‐dose metformin.
