Central administration of Dapagliflozin alleviates a hypothalamic neuroinflammatory signature and changing tubular lipid metabolism in type 2 diabetic nephropathy by upregulating MCPIP1.

BACKGROUND: Hypothalamic neuroinflammation is associated with disorders of lipid metabolism. Considering the anti-neuroinflammation effects of sodium-glucose cotransporter 2(SGLT2) inhibitors, a central administration of Dapagliflozin is postulated to provide hypothalamic protection and change lipid metabolism in kidney against diabetic kidney disease (DKD). METHODS: Blood samples of DKD patients were collected. Male Sprague-Dawley (SD) rats with 30 mg/kg streptozotocin and a high-fat diet, db/db mice and palmitic acid (PA)-stimulated BV2 microglia were used for study models. 0.28 mg/3ul dapagliflozin was injected into the lateral ventricle in db/db mice. Genes and protein expression levels were determined by qPCR, western blotting, immunofluorescence, and immunohistochemistry staining. Secreted IL-1ß and IL-6 were quantified by ELISA. Oil red O staining, lipidomic, and non-targeted metabolomics were performed to evaluate abnormal lipid metabolism in kidney. RESULTS: The decrease of serum MCPIP1 was an independent risk factor for renal progression in DKD patients (OR=1.22, 95 %CI: 1.02-1.45, P = 0.033). Higher microglia marker IBA1 and lower MCPIP1 in the hypothalamus, as well as lipid droplet deposition increasing in the kidney were observed in DKD rats. Central dapagliflozin could reduce the blood sugar, hypothalamic inflammatory cytokines, lipid droplet deposition in renal tubular. Lipidomics and metabolomics results showed that dapagliflozin changed 37 lipids and 19 metabolites considered on promoting lipolysis. These lipid metabolism changes were attributed to dapagliflozin by upregulating MCPIP1, and inhibiting cytokines in the microglia induced by PA. CONCLUSIONS: Central administrated Dapagliflozin elicits an anti-inflammatory effect by upregulating MCPIP1 levels in microglia and changes lipid metabolism in kidney of DKD.

The association of left ventricular fraction shortening with cardiovascular events in peritoneal dialysis patients.

BACKGROUND: Peritoneal dialysis (PD) patients have a high incidence of cardiovascular events (CVEs). Left ventricular fraction shortening (LVFS), one of the echocardiographic parameters, is an independent risk factor for mortality in previous studies. The aim of this study was to evaluate associations between LVFS and CVEs in PD patients. METHODS: This was a single-center observational cohort study. Seven hundred and eighty-four PD patients were enrolled from 1 January 2012 to 1 June 2021 and followed until 1 June 2022. The primary outcome was the incidence of CVEs. PD patients were categorized into three groups according to the tertiles of LVFS levels (tertile 1-tertile 3). Kaplan-Meier method, Cox proportional hazard models and competing risk regression models were used for survival analysis. The areas under the curve (AUC) of receiver-operating characteristic analysis was used to determine the predictive values of LVFS for CVEs. A preplanned subgroup analysis was assessed according to age, gender, and the presence of hypertension and dyslipidemia, etc. RESULTS: During a median follow-up period of 42.3 months (interquartile range 24.0-79.0 months), 259 CVEs occurred. Compared to the other two groups respectively, patients in tertile 3 group had the lowest incidence of CVEs (24.5% vs 31.6% vs 43.0%, respectively, p < 0.05). After multiple adjustments, the tertile 3 group was associated with the 45.1% decrease in the CVEs hazard compared to that of the tertile1 group (SHR = 0.549, 95%CI: 0.395-0.762, p < 0.001). Subgroup analysis demonstrated that tertile 1 group as the reference, the association between LVFS and CVEs in tertile 3 group was robust among female patients (HR = 0.506, 95%CI: 0.309-0.829, p = 0.007), aged < 45 years (HR = 0.496, 95%CI: 0.331-0.744, p = 0.001), history of hypertension (HR = 0.586, 95%CI: 0.349-0.872, p = 0.008) and combined with dyslipidemia (HR = 0.464, 95%CI: 0.269-0.799, p = 0.006). CONCLUSIONS: This study suggests that LVFS is independently associated with the increased risk of CVEs in PD patients, especially those with aged < 45 years, female, with hypertension and dyslipidemia.

Factors associated with prolonged duration of ultrasound-guided brachial plexus block for the upper limb fracture surgery: a cross-sectional study.

Background: Previous studies of factors associated with prolonged duration of ultrasound-guided brachial plexus block have included multiple surgical procedures or multiple anesthetic approaches, all of which are important confounders, and there is no study based on a single method of anesthesia exploring the factors affecting the resolution of brachial plexus block during upper limb surgery, especially in Asians. This study aimed to identify the risk factors affecting the prolonged duration of US-guided brachial plexus block in American Society of Anesthesiologists (ASA) I-II grade patients to improve postoperative analgesia. Methods: This study enrolled patients scheduled to undergo surgery for upper limb fracture in Anting Hospital, Shanghai from May 2021 to September 2021. Inclusion criteria: (I) patients aged 18 years and above; (II) ASA I-II grade patients; (III) success of US-guided brachial plexus block. Based on the median duration of brachial plexus block, patients were divided into a <5-hour group and a ≥5-hour group. The factors were selected base on previous studies conclution and clinical demographic characteristics of patients. Multivariable logistic regression was used to estimate relevant influencing factors. Results: A total of 129 patients (51.2% males; 51.01±16.54 years old) were analyzed. The duration of brachial plexus block was 2-12 hours, with a median duration of 5.09 hours. Multivariable analysis suggested that age 40-49 years [odds ratio (OR): 4.841; 95% confidence interval (CI): 1.033 to 22.695; P=0.045], 50-59 years (OR: 4.730, 95% CI: 1.149 to 19.474; P=0.031), 60 years (OR: 8.540; 95% CI: 1.605 to 45.449; P=0.012), gender (OR: 3.314; 95% CI: 1.330 to 8.257; P=0.010), alanine aminotransferase (ALT; OR: 5.817, 95% CI: 1.509 to 22.472; P=0.011), and glomerular filtration rate (GFR) <60 (OR: 22.700; 95% CI: 1.994 to 198.386; P=0.012) were the risk factors for the duration of brachial plexus block. Conclusions: It is advisable to use the lowest effective dose for the shortest possible time when using ropivacaine in upper limb fracture surgery patients with elevated ALT (≥40 U/L) and lower GFR (<60 mL/min) in male patients aged ≥60 years.

Electrolysis of Bacteria Based on Microfluidic Technology.

Cell lysis is a key step for studying the structure and function of proteins in cells and an important intermediate step in drug screening, cancer diagnosis, and genome analysis. The current cell lysis methods still suffer from limitations, such as the need for large instruments, a long and time-consuming process, a large sample volume, chemical reagent contamination, and their unsuitability for the small amount of bacteria lysis required for point-of-care testing (POCT) devices. Therefore, a fast, chemical-free, portable, and non-invasive device needs to be developed. In the present study, we designed an integrated microfluidic chip to achieve E. coli lysis by applying an alternating current (AC) electric field and investigated the effects of voltage, frequency, and flow rate on the lysis. The results showed that the lysis efficiency of the bacteria was increased with a higher voltage, lower frequency, and lower flow rate. When the voltage was at 10 Vp-p, the lysis efficiency was close to 100%. The study provided a simple, rapid, reagent-free, and high-efficiency cleavage method for biology and biomedical applications involving bacteria lysis.

Evaluation of Carotid Artery Atherosclerosis and Arterial Stiffness in Cardiovascular Disease Risk: An Ongoing Prospective Study From the Kailuan Cohort.

Objective: To assess whether carotid artery ultrasonography and brachial-ankle pulse wave velocity (baPWV) measurement can accurately predict cardiovascular and cerebrovascular events, and all-cause mortality in patients with cardiovascular diseases (CVD). Methods: Patients from the Kailuan Study Stroke Cohort (Tangshan, China) who underwent carotid artery ultrasonography and baPWV measurement between June 2010 and June 2011 were included in this study. The effects of carotid plaque, baPWV, and their combination on cardiovascular events, including myocardial infarction (MI), cerebral ischemic stroke, cerebrovascular events, and all-cause mortality, were evaluated using Kaplan-Meier analysis and Cox proportional hazards regression. Results: A total of 4,899 participants (59.7% males; 54.18 ± 11.52 years old) were analyzed. During a mean follow-up of 5.68 ± 0.66 years, the incidence of cardiovascular events and all-cause mortality were 4.94‰ person-years and 7.02‰ person-years, respectively; 32.8% of participants had both carotid artery atherosclerosis and increased arterial stiffness. A high baPWV alone was associated with an increased risk of CVD events [hazard ratio (HR): 2.68; 95% confidence interval (95% CI): 1.20-6.00; P = 0.007] and cerebral infarction (HR: 5.92; 95% CI: 1.76-19.93; P = 0.004), but not with MI or all-cause death. The presence of both carotid plaque and high baPWV was highly associated with an increased risk of CVD events (HR: 4.65; 95% CI: 2.06-10.45; P < 0.001) and cerebral infarction (HR: 9.21; 95% CI: 2.71-31.19; P < 0.001), but not with MI or all-cause death. Similar results were obtained by the Kaplan-Meier analyses. Conclusion: The presence of carotid plaque and high baPWV were associated with a high risk of CVD events and ischemic stroke. Moreover, the combination of carotid artery ultrasonography and baPWV measurement could predict the risk for CVD ability more accurately than a single measurement alone.

2D/1D MXene/MWCNT Hybrid Membrane-Based Evaporator for Solar Desalination.

Solar vapor generation through evaporation using photothermal materials is a promising candidate for seawater desalination. The Ti3C2 MXene membrane has exhibited photothermal behavior in solar water evaporation. However, dense packed two-dimensional (2D) MXene membrane with high reflection loss and insufficient vapor escape channels limited its solar evaporation performance. In this work, one-dimensional (1D) multi-walled carbon nanotubes (MWCNT) were added into 2D Ti3C2 nanosheets as the holder to form a 2D/1D hybrid photothermal membrane. Owing to the 2D/1D hybrid structure, more effective broadband solar absorption, water transportation and vapor escape were achieved.

[Prediction of the epitopes of SARS-CoV-2 by immunoinformatics].

Objective To predict the epitopes of B cells, cytotoxic T lymphocytes (CTL), and T helper (Th) cells of SARS-CoV-2 by immunoinformatics. Methods The SARS-CoV-2 protein sequences were retrieved from NCBI database and screened, and the sequences with antigenicity ≥0.5 and amino acid number ≥100 were used for epitopes prediction. The Phyre2 server was used to predict the three-dimensional (3D) structure, the GalaxyRefine system to optimize the 3D structure, and the SWISS-MODEL system to evaluate the accuracy of the optimized structure. The CTL, Th cells, and sequential B-cell antigen peptide prediction was based on the sequences of proteins, and the structural B-cell antigen peptide prediction on the 3D structures of proteins. The cytotoxic T lymphocyte (CTL) and Th cell epitopes of SARS-CoV-2 were predicted by the IEDB database. The sequential B-cell antigen peptide prediction and the structural B-cell antigen peptide prediction were performed by BepiPred-2.0: Sequential B-Cell Epitope Predictor and ElliPro-a structure-based tool for the prediction of epitopes, respectively. Results Twenty seven SARS-CoV-2 protein sequences were obtained from the NCBI database. After removing the proteins with antigenicity <0.5 and amino acid number <100, nine proteins were selected for antigen peptide prediction. Finally, 24 epitopes from CTLs, 20 epitopes from Th cells, and 12 sequential epitopes and 16 structural epitopes from B cells were obtained. Conclusion The epitopes obtained can be used for developing multi-epitope SARS-CoV-2 vaccines. Compared with epitopes that only target a single protein, multi-target epitopes have stronger immunogenicity. These epitopes have certain reference value for the development of SARS-CoV-2 vaccine.

A Five-Gene Signature for Recurrence Prediction of Hepatocellular Carcinoma Patients.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies with poor prognosis. There are many selectable treatments with good prognosis in Barcelona Clinic Liver Cancer- (BCLC-) 0, A, and B HCC patients, but the most crucial factor affecting survival is the high recurrence rate after treatments. Therefore, it is of great significance to predict the recurrence of BCLC-0, BCLC-A, and BCLC-B HCC patients. AIM: To develop a gene signature to enhance the prediction of recurrence among HCC patients. MATERIALS AND METHODS: The RNA expression data and clinical data of HCC patients were obtained from the Gene Expression Omnibus (GEO) database. Univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) regression analysis were conducted to screen primarily prognostic biomarkers in GSE14520. Multivariate Cox regression analysis was introduced to verify the prognostic role of these genes. Ultimately, 5 genes were demonstrated to be related with the recurrence of HCC patients and a gene signature was established. GSE76427 was adopted to further verify the accuracy of gene signature. Subsequently, a nomogram based on gene signature was performed to predict recurrence. Gene functional enrichment analysis was conducted to investigate the potential biological processes and pathways. RESULTS: We identified a five-gene signature which performs a powerful predictive ability in HCC patients. In the training set of GSE14520, area under the curve (AUC) for the five-gene predictive signature of 1, 2, and 3 years were 0.813, 0.786, and 0.766. Then, the relative operating characteristic (ROC) curves of five-gene predictive signature were verified in the GSE14520 validation set, the whole GSE14520, and GSE76427, showed good performance. A nomogram comprising the five-gene signature was built so as to show a good accuracy for predicting recurrence-free survival of HCC patients. CONCLUSION: The novel five-gene signature showed potential feasibility of recurrence prediction for early-stage HCC.

Combined effects of carotid plaques and hypertension on the risk of cardiovascular disease and all-cause mortality.

BACKGROUND: Both hypertension and atherosclerotic plaques are risk factors for cardiovascular disease (CVD). HYPOTHESIS: This study aimed to investigate whether the combined effects of carotid plaques and hypertension increase the risks of CVD and all-cause mortality. METHODS: Patients from the stroke and elderly cohorts of the Kailuan study in China who completed a carotid sonography examination were included in the study. Participants in both cohorts underwent physical examinations between 2010 and 2011 and were divided into four groups: no carotid plaques with normal blood pressure (n = 2227), hypertension only (n = 1290), carotid plaques only (n = 1128), and hypertension with carotid plaques (n = 1862). The outcomes included the first occurrence of CVD and all-cause mortality. RESULTS: Among the 6507 participants (mean age, 58.1 ± 11.8 years, 61% males), 157 cardiovascular events, and 210 deaths occurred after average follow-ups of 4.5 and 4.9 years, respectively. After adjusting for covariates, carotid plaques only and hypertension with carotid plaques were associated with excess risk (hazard ratio [HR]; confidence interval [CI]) for the first occurrence of CVD (HR = 1.85; 95% CI, 1.01-3.44; and HR = 2.97; 95% CI, 1.66-5.29, respectively), cerebral infarction (HR = 2.66; 95% CI, 1.16-6.15; and HR = 4.15; 95% CI, 1.87-9.19, respectively), and all-cause mortality (HR = 1.96; 95% CI, 1.16-3.31; and HR = 1.85; 95% CI, 1.09-3.13, respectively). CONCLUSIONS: The combination of hypertension and atherosclerotic plaques may increase the risk of CVD events and all-cause mortality, especially cerebral infarction, compared with participants without those factors.

Nonalcoholic Fatty Liver Disease and Risk of Diabetes: A Prospective Study in China.

OBJECTIVE: We aimed to investigate whether liver steatosis severity affects the risk of developing diabetes in a large cohort study. METHODS: We prospectively examined the association in 41,650 Chinese adults with negative hepatitis-B surface antigen who were free of alcohol consumption, diabetes, and liver cirrhosis at baseline. Cox proportional models were used to estimate the risk of diabetes after a mean of 3.6 years of follow-up. Nonalcoholic fatty liver disease (NAFLD) was assessed with hepatic ultrasonography. Elevated alanine transaminase (ALT) was defined as ALT concentrations >19 and >30 U/L in females and males, respectively. Diabetes was defined as a fasting glucose 37.0 mmol/L or treatment with hypoglycemic medication. RESULTS: Liver steatosis severity was significantly associated with higher risks of developing diabetes (adjusted hazard ratio [HR] for severe vs. without NAFLD = 2.66, 95% confidence interval [CI]: 2.17-3.25, P-trend<.001) and impaired fasting glucose (fasting glucose between 5.6 and 6.9 mmol/L, adjusted HR = 1.36, 95% CI: 1.16-1.59, P-trend<.001), as well as a faster increase rate of fasting glucose concentrations ( P-trend<.001), during 3.6 years of follow-up. Elevated ALT was also associated with incident diabetes (HR = 1.12, 95% CI: 1.02-1.22), adjusting for NAFLD and other covariates. CONCLUSION: We observed a dose-response relationship between liver steatosis severity and increased diabetes risk, and ALT may predict incident diabetes independently of NAFLD. ABBREVIATIONS: ALT = alanine transaminase; BP = blood pressure; CI = confidence interval; HCV = hepatitis C virus; HR = hazard ratio; IFG = impaired fasting glucose; NAFLD = nonalcoholic fatty liver disease; ULN = upper limit of normal.

Helicobacter pylori modulates cyclooxygenase-2 and 15-hydroxy prostaglandin dehydrogenase in gastric cancer.

Persistent infection with Helicobacter pylori may contribute to the carcinogenesis of gastric cancer through modulating local prostaglandin E2 (PGE2) levels. Cyclooxygenase-2 (COX-2) and 15-hydroxy prostaglandin dehydrogenase (15-PGDH) are two key enzymes that regulate PGE2 synthesis and inactivation, respectively. The present study was designed to investigate the expression of COX-2 and 15-PGDH in gastric cancer specimens (n=66) in comparison to that of control specimens (n=70) and, furthermore, to semi-quantitatively assess the level of COX-2 and 15-PGDH mRNA and protein in tissues with or without H. pylori infection by reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. It was revealed that COX-2 was expressed in almost all gastric cancer specimens infected with H. pylori (32 out of 33 specimens), but it was also expressed in 2/3 gastric cancers without H. pylori infection (22 out of 33 specimens). By contrast, COX-2 was expressed in <1/6 control subjects regardless of H. pylori infection. Furthermore, 15-PGDH was expressed in control samples but significantly downregulated in gastric cancer specimens. H. pylori infection resulted in slight inhibition of 15-PGDH in control subjects, but significant inhibition of 15-PGDH mRNA expression and protein synthesis in the gastric cancer specimens. These findings indicated that COX-2 and 15-PGDH, the two enzymes that regulate PGE2 levels, were significantly altered in gastric cancer, and that H. pylori may contribute to gastric carcinogenesis through modulating COX-2 and 15-PGDH mRNA expression and protein synthesis.

Stem cell-like circulating tumor cells indicate poor prognosis in gastric cancer.

Circulating tumor cells (CTCs), which have stem cell-like characteristics, might play a crucial role in cancer metastasis. CD44 has been identified as gastric cancer (GC) stem cell (CSC) marker. Here, the prognostic significance of CD44-positive CTCs in GC patients was investigated. CTCs were detected in 27 of 45 GC patients. The presence of CTCs was significantly associated with lymph node metastasis, distant metastasis, and recurrence (P = 0.007, P = 0.035, and P = 0.035, resp.). Nineteen of the 27 CTC-positive patients had CD44-positive CTCs. These patients were more likely to develop metastasis and recurrence than patients with CD44-negative CTCs. CD44-positive CTC counts were higher in recurrent patients than in the nonrecurrent ones (means 4.8 and 1.9, resp.; P = 0.010). Furthermore, 13 of 19 patients with CD44-positive CTCs developed recurrent disease, and the mean time to recurrence was shorter than that in patients with CD44-negative CTCs (10.54 ± 5.55 and 19.13 ± 9.72 months, resp.; P = 0.04). COX proportional hazards model indicated that the presence of CD44-positive CTCs and TNM stage were independent predictors of recurrence for GC (P = 0.030 and 0.008). So identifying the stem cell-like CTC subset may provide more clinically useful prognostic information than only detecting CTCs.