ß-cell dynamics in type 2 diabetes and in dietary and exercise interventions.

Pancreatic ß-cell dysfunction and insulin resistance are two of the major causes of type 2 diabetes (T2D). Recent clinical and experimental studies have suggested that the functional capacity of ß-cells, particularly in the first phase of insulin secretion, is a primary contributor to the progression of T2D and its associated complications. Pancreatic ß-cells undergo dynamic compensation and decompensation processes during the development of T2D, in which metabolic stresses such as endoplasmic reticulum stress, oxidative stress, and inflammatory signals are key regulators of ß-cell dynamics. Dietary and exercise interventions have been shown to be effective approaches for the treatment of obesity and T2D, especially in the early stages. Whilst the targeted tissues and underlying mechanisms of dietary and exercise interventions remain somewhat vague, accumulating evidence has implicated the improvement of ß-cell functional capacity. In this review, we summarize recent advances in the understanding of the dynamic adaptations of ß-cell function in T2D progression and clarify the effects and mechanisms of dietary and exercise interventions on ß-cell dysfunction in T2D. This review provides molecular insights into the therapeutic effects of dietary and exercise interventions on T2D, and more importantly, it paves the way for future research on the related underlying mechanisms for developing precision prevention and treatment of T2D.

BAF60a Deficiency in Macrophage Promotes Diet-Induced Obesity and Metabolic Inflammation.

Adipose tissue macrophage (ATM) has been shown to play a key role in the pathogenesis of obesity-associated adipose tissue inflammation and metabolic diseases. However, the upstream factors that integrate the environmental signals to control ATM activation and adipose inflammation in obesity remain elusive. Here, we identify BAF60a, a subunit of the switch/sucrose-nonfermentable (SWI/SNF) chromatin remodeling complexes, as the central checkpoint regulator of obesity-induced ATM activation, adipose tissue inflammation, and systemic metabolic impairment. BAF60a expression was robustly downregulated in the adipose tissue stromal vascular fractions in type 2 diabetic mice. Myeloid-specific BAF60a knockout (BaMKO) promotes ATM proinflammatory activation, exacerbating diet-induced obesity, insulin resistance, and metabolic dysfunction. Conversely, myeloid-specific overexpression of BAF60a in mice attenuates macrophage proinflammatory activation. Mechanistically, transcriptome and chromatin landscape analyses demonstrate that BAF60a inactivation triggers the expression of proinflammatory gene program through chromatin remodeling. Moreover, motif analysis of ATAC-Seq and CUT&Tag-Seq data identifies the transcription factor Atf3 that physically interacts with BAF60a to suppress the proinflammatory gene expression, thereby controlling ATM activation and metabolic inflammation in obesity. Consistently, myeloid-specific Atf3 deficiency also promotes the proinflammatory activation of macrophage. This work uncovers BAF60a/Atf3 axis as the key regulator in obesity-associated ATM activation, adipose tissue inflammation, and metabolic diseases.

Genome-wide analysis of hippocampal transfer RNA-derived small RNAs identifies new potential therapeutic targets of Bushen Tiansui formula against Alzheimer's disease.

OBJECTIVE: Bushen Tiansui formula (BSTSF), a traditional Chinese medicine prescription, has been widely used to treat Alzheimer's disease (AD). However, the mechanisms underlying its effects remain largely unknown. In this study, a rat AD model was used to study the effects of BSTSF on cognitive performance and expression of transfer RNA-derived small RNAs (tsRNAs) in the hippocampus, to determine whether treatment of AD with BSTSF could regulate the expression of tsRNAs, a novel small non-coding RNA. METHODS: To generate a validated AD model, oligomeric amyloid-ß1-42 (Aß1-42) was injected intracerebroventricularly into rats. The Morris water maze (MWM) test was used to evaluate rat cognitive performance, and tsRNA-sequencing was conducted to examine tsRNA expression in the rat hippocampus. Potential targets were validated by quantitative real-time polymerase chain reaction (qRT-PCR). Bioinformatic analyses were conducted to investigate the biological function of candidate tsRNAs. RESULTS: The learning and memory deficits of Aß1-42-induced AD rats, assessed by MWM tests, were clearly ameliorated by BSTSF treatment. A total of 387 tsRNAs were detected in the rat hippocampus. Among them, 13 were significantly dysregulated in AD rats compared with sham control rats, while 57 were markedly altered by BSTSF treatment, relative to untreated AD rats (fold change ≥ 2 and P < 0.05). Moreover, six BSTSF treatment-related tsRNAs were identified and validated by qRT-PCR. Bioinformatic analyses indicated that the six treatment-related tsRNAs had potential therapeutic roles, via multiple signaling pathways and Gene Ontology biological functions, including cyclic adenosine monophosphate and retrograde endocannabinoid signaling. CONCLUSION: This study identified a previously uncharacterized mechanism underlying the effects of BSTSF in alleviating the learning and memory deficits in Aß1-42-induced AD rats, demonstrating that tsRNAs are potential therapeutic targets of BSTSF in the treatment of AD.

Erratum: A Network Pharmacology-Based Strategy for Predicting Active Ingredients and Potential Targets of LiuWei DiHuang Pill in Treating Type 2 Diabetes Mellitus [Corrigendum].

[This corrects the article DOI: 10.2147/DDDT.S216644.].

A Network Pharmacology-Based Strategy For Predicting Active Ingredients And Potential Targets Of LiuWei DiHuang Pill In Treating Type 2 Diabetes Mellitus.

BACKGROUND: Traditional Chinese medicine (TCM) formulations have proven to be advantageous in clinical treatment and prevention of disease. LiuWei DiHuang Pill (LWDH Pill) is a TCM that was employed to treat type 2 diabetes mellitus (T2DM). However, a holistic network pharmacology approach to understanding the active ingredients and the therapeutic mechanisms underlying T2DM has not been pursued. METHODS: A network pharmacology approach including drug-likeness evaluation, oral bioavailability prediction, virtual docking, and network analysis has been used to predict the active ingredients and potential targets of LWDH Pill in the treatment of type 2 diabetes. RESULTS: The comprehensive network pharmacology approach was successfully to identify 45 active ingredients in LWDH Pill. 45 active ingredients hit by 163 potential targets related to T2DM. Ten of the more highly predictive components (such as :quercetin, Kaempferol, Stigmasterol, beta-sitosterol, Kadsurenone, Diosgenin, hancinone C, Hederagenin, Garcinone B, Isofucosterol) are involved in anti-inflammatory, anti-oxidative stress, and the reduction of beta cell damage. LWDH Pill may play a role in the treatment of T2DM and its complications (atherosclerosis and nephropathy) through the AGE-RAGE signaling pathway, TNF signaling pathway, and NF-kappa B signaling pathway. CONCLUSION: Based on a systematic network pharmacology approach, our works successfully predict the active ingredients and potential targets of LWDH Pill for application to T2DM and helps to illustrate mechanism of action on a comprehensive level. This study provides identify key genes and pathway associated with the prognosis and pathogenesis of T2DM from new insights, which also demonstrates a feasible method for the research of chemical basis and pharmacology in LWDH Pill.

Guideline-Based Critical Care Pathway Improves Long-Term Clinical Outcomes in Patients with Acute Coronary Syndrome.

Implementation of a critical care pathway (CCP) for acute coronary syndrome (ACS) has been shown to improve early compliance to guideline-directed therapies and reduce early mortality. Nevertheless its long-term impact on the compliance with medications or clinical outcomes remains unknown. Between 2004 and 2015, 2023 consecutive patients were admitted to our coronary care unit with ACS. We retrospectively compared the outcomes of 628 versus 1059 patients (mean age 66.1 ± 13.3 years, 74% male) managed before and after full implementation of a CCP. Compared with standard care, implementation of the CCP significantly increased coronary revascularization and long-term compliance with guideline-directed medical therapy (both P < 0.01). After a mean follow-up of 66.5 ± 44.0 months, 46.7% and 22.2% patients admitted before and after implementation of the CCP, respectively, died. Kaplan-Meier analyses showed that patients managed by CCP had better overall survival (P = 0.03) than those managed with standard care. After adjustment for clinical covariates and coronary anatomy, CCP remained independently predictive of better survival from all-cause mortality [hazard ratio (HR): 0.75, 95%confidence intervals (CI): 0.62-0.92, P < 0.01]. Stepwise multivariate cox regression model showed that both revascularization (HR: 0.55, 95%CI: 0.45-0.68, P < 0.01) and compliance to statin (HR: 0.70, 95%CI: 0.58-0.85, P < 0.01) were accountable for the improved outcome.

Prognostic implications of early monomorphic and non-monomorphic tachyarrhythmias in patients discharged with acute coronary syndrome.

BACKGROUND: The prognostic implication of early ventricular tachyarrhythmias (VTs) after acute coronary syndrome (ACS) remains unclear. OBJECTIVE: We sought to investigate the clinical outcomes of early monomorphic and non-monomorphic VTs that occur within 48 hours in patients after ACS. METHODS: We retrospectively reviewed the clinical outcomes of 2033 [mean age 67.0 ± 13.4 years; 1486 (73.1%) men] consecutive patients who presented with ACS from 2004 to 2015. RESULTS: A total of 67 (3.3%) and 90 (4.4%) patients developed early monomorphic or non-monomorphic VT, respectively. Killip class IV (odds ratio [OR] 3.05; 95% confidence interval [CI] 1.47-6.36; P < .01), creatine kinase level (OR 1.01; 95% CI 1.00-1.02 per 100 IU/L; P = .01), and left ventricular ejection fraction (OR 0.96; 95% CI 0.94-0.99; P < .01) were independently associated with early monomorphic VT, whereas age (OR 0.98; 95% CI 0.97-0.99; P = .04), ST elevated myocardial infarction (OR 3.53; 95% CI 1.71-7.27; P < .01), Killip class IV (OR 4.91; 95% CI 2.76-8.74; P < .01), diabetes mellitus (OR 0.48; 95% CI 0.28-0.81; P < .01), and left ventricular ejection fraction (OR 0.97; 95% CI 0.95-0.99; P < .01) were independently associated with early non-monomorphic VT. More patients with early monomorphic VT (n = 22 [32.8%]) died in hospital than those with non-monomorphic VT (n = 16 [17.8%]) or without early VT (n = 133 [7.1%]; P < .01). After a mean follow-up of 67.8 ± 43.2 months, 21 patients with early monomorphic VT (46.7%), 22 patients with early non-monomorphic VT (29.7%), and 552 patients without early VT (31.7%) died. Both early monomorphic and non-monomorphic VTs were associated with a long-term increase in sudden arrhythmic deaths and recurrent VTs. Nevertheless, only early monomorphic VT was shown to independently predict overall survival (hazard ratio 1.62; 95% CI 1.03-2.55; P = .04). CONCLUSION: Early monomorphic VT, but not early non-monomorphic VT, independently predicted all-cause mortality in patients with ACS who survived to hospital discharge.

Antimony-dependent expansion for the Keggin heteropolyniobate family.

Nine new Sb-bicapped α-Keggin-type heteropolyoxoniobates (HPNb) were synthesized under hydrothermal conditions. Among them, the As-centered HPNb was never reported before, and the two dimer compounds are the biggest isolated HPNbs at present.