Molecular mechanism of islet ß-cell functional alternations during type 2 diabetes.

In recent years, the incidence rate of type 2 diabetes (T2D) has risen rapidly and has become a global health crisis. Recent experimental and clinical studies have shown that islet ß-cell dysfunction is an important cause of T2D and its related complications. ß-cells undergo dynamic compensation and decompensation in the course of T2D. In this process, metabolic stress responses, such as ER stress, oxidative stress and inflammation, are key regulators of ß-cell functional alternations. In this review, we summarize the research progress on the ß-cell functional dynamics in the course of T2D, in order to deepen the understanding of the molecular mechanism of T2D, and provide reference for its precise diagnosis and clinical intervention.

Dietary intervention preserves ß cell function in mice through CTCF-mediated transcriptional reprogramming.

Pancreatic ß cell plasticity is the primary determinant of disease progression and remission of type 2 diabetes (T2D). However, the dynamic nature of ß cell adaptation remains elusive. Here, we establish a mouse model exhibiting the compensation-to-decompensation adaptation of ß cell function in response to increasing duration of high-fat diet (HFD) feeding. Comprehensive islet functional and transcriptome analyses reveal a dynamic orchestration of transcriptional networks featuring temporal alteration of chromatin remodeling. Interestingly, prediabetic dietary intervention completely rescues ß cell dysfunction, accompanied by a remarkable reversal of HFD-induced reprogramming of islet chromatin accessibility and transcriptome. Mechanistically, ATAC-based motif analysis identifies CTCF as the top candidate driving dietary intervention-induced preservation of ß cell function. CTCF expression is markedly decreased in ß cells from obese and diabetic mice and humans. Both dietary intervention and AAV-mediated restoration of CTCF expression ameliorate ß cell dysfunction ex vivo and in vivo, through transducing the lipid toxicity and inflammatory signals to transcriptional reprogramming of genes critical for ß cell glucose metabolism and stress response.

A risk score based on procalcitonin for predicting acute kidney injury in COVID-19 patients.

BACKGROUND: Acute kidney injury (AKI) has been reported developing commonly in coronavirus disease 2019 (COVID-19) patients and could increase the risk of poor outcomes in these patients. We design this study to explore the value of serum procalcitonin (PCT) on predicting AKI and construct risk score for predicting AKI in COVID-19 patients. METHODS: Patients diagnosed with COVID-19 and hospitalized in Renmin Hospital of Wuhan University between January 30 and February 24, 2020, were included. The least absolute shrinkage and selection operator (LASSO) regression was performed to identify the strongest predictors of AKI. Multivariate logistic regression analysis was conducted to find independent risk factors for AKI and construct risk score using odds ratio (OR) value of those risk factors. Receiver operating characteristics (ROC) curves were plotted, and area under the ROC curve (AUC) value was calculated to evaluate the predictive value of single PCT level and the constructed risk score. RESULTS: Among 389 included COVID-19 patients, 28 (7.2%) patients developed AKI. LASSO regression showed hypertension, saturation of arterial oxygen (SaO2 ), PCT, and blood urea nitrogen (BUN) were the strongest predictors for AKI. After multivariate logistic regression analysis, only SaO2 (<0.001), PCT (p = 0.004), and BUN (p = 0.005) were independently associated with development of AKI in COVID-19 patients. The AUC of single PCT and constructed risk score was 0. 881 and 0.928, respectively. CONCLUSION: PCT level is correlated with AKI in COVID-19 patients. The efficient risk score consisted of SaO2 , PCT, and BUN is readily accessible for physicians to evaluate the possibility of AKI in COVID-19 patients.

A nomogram based on serum cystatin C for predicting acute kidney injury in patients with traumatic brain injury.

BACKGROUND: Acute kidney injury (AKI) is a common complication in traumatic brain injury (TBI) patients and is associated with unfavorable outcome of these patients. We designed this study to explore the value of serum cystatin C, an indicator of renal function, on predicting AKI after suffering TBI. METHODS: Patients confirmed with TBI and hospitalized in the West China Hospital of Sichuan University between January 2015 and December 2019 were included. Patients were divided into two groups according to occurrence of AKI. Univariate and multivariate logistic regression analyses were sequentially utilized to find risk factors of AKI in included TBI patients. Nomogram composed of discovered risk factors for predicting AKI was constructed. Receiver operating characteristics (ROC) curves were drawn and area under the ROC curve (AUC) were calculated to evaluate the predictive value of cystatin C alone and the constructed nomogram. RESULTS: Among 234 included TBI patients, 55 were divided into AKI group. AKI group had shorter length of stay (p < 0.001) and higher in-hospital mortality (p < 0.001). Multivariate logistic regression analysis showed absolute lymphocyte count (p = 0.034), serum creatinine (p < 0.001), serum cystatin C (p = 0.017) and transfusion of red blood cell (p = 0.005) were independently associated with development of AKI after TBI. While hypertonic saline use was not associated with the development of AKI (p = 0.067). The AUC of single cystatin C and predictive nomogram were 0.804 and 0.925, respectively. CONCLUSION: Higher serum cystatin C is associated with development of AKI in TBI patients. Predictive nomogram incorporating cystatin C is beneficial for physicians to evaluate possibilities of AKI and consequently adjust treatment strategies to avoid occurrence of AKI.

The Predictive Value of Serum Uric Acid on Acute Kidney Injury following Traumatic Brain Injury.

BACKGROUNDS: Acute kidney injury (AKI) is a prevalent nonneurological complication in patients with traumatic brain injury (TBI). We designed this study to explore the association between serum uric acid (SUA) level and the occurrence of AKI following TBI. METHODS: This is a retrospective single-center study. A total of 479 patients admitted with TBI were included in this study. We utilized SUA and other risk factors for AKI to construct a predictive model by performing multivariate logistic regression. 374 patients and 105 patients were, respectively, divided into a training set and validation set. The predictive value of the single SUA and constructed model was evaluated by drawing a receiver operating characteristic (ROC) curve. AKI was diagnosed according to the KIDGO criteria. RESULTS: 79 (21.12%) patients were diagnosed with AKI in the training cohort. The patients in the AKI group are older than those in the non-AKI group (p = 0.01). And the Glasgow Coma Scale (GCS) of the AKI group was lower than that of the non-AKI group (p < 0.001). In a multivariate logistic regression analysis, we found that heart rate (p = 0.041), shock (p = 0.018), serum creatinine (p < 0.001), and serum uric acid (SUA) (p < 0.001) were significant risk factors for AKI. Bivariate correlation analyses showed that serum creatinine was moderately positively correlated with SUA (r = 0.523, p < 0.001). Finally, the area under the receiver operating characteristic curve (AUC) of SUA for predicting AKI in the training set and validation set was 0.850 (0.805-0.895) and 0.869 (0.801-0.938), respectively. CONCLUSIONS: SUA is an effective risk factor for AKI following TBI. Combining SUA with serum creatinine could more accurately identify TBI patients with high risk of developing AKI.

The predictive value of RDW in AKI and mortality in patients with traumatic brain injury.

BACKGROUND: Red blood cell distribution width (RDW) has been validated valuable in predicting outcome and acute kidney injury (AKI) in several clinical settings. The aim of this study was to explore whether RDW is associated with outcome and AKI in patients with traumatic brain injury (TBI). METHODS: Patients admitted to our hospital for TBI from January 2015 to August 2018 were included in this study. Multivariate logistic regression analysis was performed to identify risk factors of AKI and outcome in patients with TBI. The value of RDW in predicting AKI and outcome was evaluated by receiver operating characteristic (ROC) curve. RESULTS: Three hundred and eighteen patients were included in this study. The median of RDW was 14.25%. We divided subjects into two groups based on the median and compared difference of variables between two groups. The incidence of AKI and mortality was higher in high RDW (RDW > 14.25) group (31.45% vs 9.43%, P < .001; 69.81% vs 29.56%, P < .001). Spearman's method showed RDW was moderately associated with 90-day Glasgow Outcome Scale (GOS) (P < .001). In multivariate logistic regression analysis, RDW, lymphocyte, chlorine, and serum creatinine were risk factors of AKI. And Glasgow Coma Scale (GCS), glucose, chlorine, AKI, and RDW were risk factors of mortality. The area under the ROC curve (AUC) of RDW for predicting AKI and mortality was 0.724 (0.662-0.786) and 0.754 (0.701-0.807), respectively. Patients with higher RDW were likely to have shorter median survival time (58 vs 70, P < .001). CONCLUSIONS: Red blood cell distribution width is an independent risk factor of AKI and mortality in patients with TBI.

The SWI/SNF chromatin-remodeling factors BAF60a, b, and c in nutrient signaling and metabolic control.

Metabolic syndrome has become a global epidemic that adversely affects human health. Both genetic and environmental factors contribute to the pathogenesis of metabolic disorders; however, the mechanisms that integrate these cues to regulate metabolic physiology and the development of metabolic disorders remain incompletely defined. Emerging evidence suggests that SWI/SNF chromatin-remodeling complexes are critical for directing metabolic reprogramming and adaptation in response to nutritional and other physiological signals. The ATP-dependent SWI/SNF chromatin-remodeling complexes comprise up to 11 subunits, among which the BAF60 subunit serves as a key link between the core complexes and specific transcriptional factors. The BAF60 subunit has three members, BAF60a, b, and c. The distinct tissue distribution patterns and regulatory mechanisms of BAF60 proteins confer each isoform with specialized functions in different metabolic cell types. In this review, we summarize the emerging roles and mechanisms of BAF60 proteins in the regulation of nutrient sensing and energy metabolism under physiological and disease conditions.

Different Forms of Selenoprotein M Differentially Affect Aß Aggregation and ROS Generation.

Selenoprotein M (SelM), one of the executants of selenium in vivo, is highly expressed in human brain and most probably involved in antioxidation, neuroprotection, and intracellular calcium regulation, which are the key factors for preventing the onset and progression of Alzheimer's disease (AD). In this paper, human SelM was successfully overexpressed in human embryonic kidney cells HEK293T. Sodium selenite (Na(2)SeO(3) 0.5 µmol/L) increased the expression of full-length SelM and inhibited the expression of truncated SelM. The full-length SelM exhibited higher antioxidant activity than its selenocysteine-to-cysteine mutation form SelM', whereas the truncated SelM had an adverse effect that increased the oxidative stress level of cells. When ß-amyloid (Aß(42), an AD relevant peptide) was cotransfected with the empty expression vector, SelM, or SelM' under the induction of 0.5 µmol/L Na(2)SeO(3), the intracellular Aß(42) aggregation rates were detected to be 57.9% ± 5.5%, or 22.3% ± 2.6%, or 26.3% ± 2.1%, respectively, showing the inhibitory effects on Aß aggregation by the full-length SelM and SelM'. Meanwhile, the intumescentia of mitochondria caused by Aß(42) transfection was significantly mitigated by the cotransfection of SelM or SelM' with Aß(42) under the induction of 0.5 µmol/L Na(2)SeO(3). On the contrary, cotransfection of SelM and Aß(42) without the induction of Na(2)SeO(3) increased Aß(42) aggregation rate to 65.1% ± 3.2%, and it could not inhibit the Aß-induced intumescent mitochondria. In conclusion, full-length SelM and SelM¢ might prevent Aß aggregation by resisting oxidative stress generated during the formation of Aß oligomers in cells.