ObjectiveTo observe the pharmacodynamic efficacy of phlorizin in improving hepatic glycolipid metabolism disorders in type 2 diabetic mellitus （T2DM） rats and to explore its mechanism of action based on the insulin receptor substrate-1 （IRS-1）/phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway. MethodsA high-fat diet and streptozotocin （STZ） were used to establish T2DM rat models. The rats were randomly assigned into six groups： the blank control group， model group， metformin group （300 mg·kg^-1）， and phlorizin high-dose （100 mg·kg^-1） and low-dose groups （25 mg·kg^-1）. The rats were given intragastric administration for 6 weeks. The changes in body weight and fasting blood glucose （FBG） were observed， and the oral glucose tolerance test （OGTT） was carried out. The levels of total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein cholesterol （LDL-C）， high-density lipoprotein cholesterol （HDL-C）， glycated serum protein （GSP）， aspartate aminotransferase （AST）， and alanine aminotransferase （ALT） in serum were detected by an automatic biochemical analyzer. The levels of fasting insulin （FINS）， interleukin （IL）-1β， IL-6， and tumour necrosis factor （TNF）-α were detected by enzyme-linked immunosorbent assay （ELISA）. The levels of superoxide dismutase （SOD） and malondialdehyde （MDA） were detected by the biochemical assays. The pancreas index， liver index， and insulin resistance index were calculated. Hematoxylin-eosin （HE） staining was used to evaluate the pathological changes in liver and pancreatic tissues. The immunofluorescence method was used to detect the changes in insulin and glucagon in pancreatic tissue. Western blot was used to detect the expression of related proteins in the IRS-1/PI3K/Akt pathway of liver tissue and its downstream glycogen synthase kinase-3β （GSK-3β） and forkhead box transcription factor O1 （FoxO1） proteins. ResultsCompared with the blank control group， the body weight of rats in the model group continued to decrease， while the FBG level increased significantly. The area under the OGTT blood glucose curve （AUC）， GSP， TC， TG， LDL-C， IL-1β， IL-6， TNF-α， MDA， pancreatic index and liver index increased significantly， while the levels of HDL-C， SOD， and FINS decreased significantly （P0.05， P0.01）. Histological results showed that the pancreatic islets of rats in the model group exhibited atrophy and severe structural abnormalities. The insulin-positive β-cells decreased significantly （P0.01）， while the glucagon-positive α-cells increased significantly （P0.01）. Inflammatory cell infiltration and partial necrosis were observed in the liver tissues of the model group rats. The expressions of p-IRS-1/IRS-1， p-GSK-3β/GSK-3β， and p-FoxO1/FoxO1 proteins in the liver of the model group increased significantly （P0.01）， while the expressions of p-PI3K/PI3K and p-Akt/Akt proteins decreased significantly （P0.01）. Compared with the model group， the diabetic symptoms of rats in all administration groups were improved. The changes in body weight and FBG were close to those of the blank control group. The levels of OGTT-AUC， GSP， TC， TG， LDL-C， MDA， IL-1β， IL-6， TNF-α and the pancreatic index， liver index were obviously reduced （P0.05， P0.01）， while the levels of HDL-C， SOD， and FINS obviously increased （P0.05， P0.01）. The pathological changes of the pancreas and liver in rats in all treatment groups were effectively improved. The insulin-positive β-cells in the pancreas increased significantly （P0.01）， while the glucagon-positive α-cells decreased significantly （P0.01）. The protein expressions of p-IRS-1/IRS-1， p-GSK-3β/GSK-3β， and p-FoxO1/FoxO1 in the liver were significantly reduced （P0.01）， while the protein expressions of p-PI3K/PI3K and p-Akt/Akt significantly increased （P0.01）. ConclusionPhlorizin reversed the weight loss and abnormal increase of FBG in T2DM rats， improved blood lipid profiles， oxidative stress， and inflammatory levels， alleviated insulin resistance， and had certain protective effects on the liver and pancreas. The hypoglycemic mechanism may involve regulating the IRS-1/PI3K/Akt signaling pathway to inhibit the activities of GSK-3β and FoxO1， thereby promoting liver glycogen synthesis and suppressing hepatic gluconeogenesis， ultimately improving glycolipid metabolism disorders.

ObjectiveTo observe the pharmacodynamic efficacy of phlorizin in improving hepatic glycolipid metabolism disorders in type 2 diabetic mellitus （T2DM） rats and to explore its mechanism of action based on the insulin receptor substrate-1 （IRS-1）/phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway. MethodsA high-fat diet and streptozotocin （STZ） were used to establish T2DM rat models. The rats were randomly assigned into six groups： the blank control group， model group， metformin group （300 mg·kg^-1）， and phlorizin high-dose （100 mg·kg^-1） and low-dose groups （25 mg·kg^-1）. The rats were given intragastric administration for 6 weeks. The changes in body weight and fasting blood glucose （FBG） were observed， and the oral glucose tolerance test （OGTT） was carried out. The levels of total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein cholesterol （LDL-C）， high-density lipoprotein cholesterol （HDL-C）， glycated serum protein （GSP）， aspartate aminotransferase （AST）， and alanine aminotransferase （ALT） in serum were detected by an automatic biochemical analyzer. The levels of fasting insulin （FINS）， interleukin （IL）-1β， IL-6， and tumour necrosis factor （TNF）-α were detected by enzyme-linked immunosorbent assay （ELISA）. The levels of superoxide dismutase （SOD） and malondialdehyde （MDA） were detected by the biochemical assays. The pancreas index， liver index， and insulin resistance index were calculated. Hematoxylin-eosin （HE） staining was used to evaluate the pathological changes in liver and pancreatic tissues. The immunofluorescence method was used to detect the changes in insulin and glucagon in pancreatic tissue. Western blot was used to detect the expression of related proteins in the IRS-1/PI3K/Akt pathway of liver tissue and its downstream glycogen synthase kinase-3β （GSK-3β） and forkhead box transcription factor O1 （FoxO1） proteins. ResultsCompared with the blank control group， the body weight of rats in the model group continued to decrease， while the FBG level increased significantly. The area under the OGTT blood glucose curve （AUC）， GSP， TC， TG， LDL-C， IL-1β， IL-6， TNF-α， MDA， pancreatic index and liver index increased significantly， while the levels of HDL-C， SOD， and FINS decreased significantly （P0.05， P0.01）. Histological results showed that the pancreatic islets of rats in the model group exhibited atrophy and severe structural abnormalities. The insulin-positive β-cells decreased significantly （P0.01）， while the glucagon-positive α-cells increased significantly （P0.01）. Inflammatory cell infiltration and partial necrosis were observed in the liver tissues of the model group rats. The expressions of p-IRS-1/IRS-1， p-GSK-3β/GSK-3β， and p-FoxO1/FoxO1 proteins in the liver of the model group increased significantly （P0.01）， while the expressions of p-PI3K/PI3K and p-Akt/Akt proteins decreased significantly （P0.01）. Compared with the model group， the diabetic symptoms of rats in all administration groups were improved. The changes in body weight and FBG were close to those of the blank control group. The levels of OGTT-AUC， GSP， TC， TG， LDL-C， MDA， IL-1β， IL-6， TNF-α and the pancreatic index， liver index were obviously reduced （P0.05， P0.01）， while the levels of HDL-C， SOD， and FINS obviously increased （P0.05， P0.01）. The pathological changes of the pancreas and liver in rats in all treatment groups were effectively improved. The insulin-positive β-cells in the pancreas increased significantly （P0.01）， while the glucagon-positive α-cells decreased significantly （P0.01）. The protein expressions of p-IRS-1/IRS-1， p-GSK-3β/GSK-3β， and p-FoxO1/FoxO1 in the liver were significantly reduced （P0.01）， while the protein expressions of p-PI3K/PI3K and p-Akt/Akt significantly increased （P0.01）. ConclusionPhlorizin reversed the weight loss and abnormal increase of FBG in T2DM rats， improved blood lipid profiles， oxidative stress， and inflammatory levels， alleviated insulin resistance， and had certain protective effects on the liver and pancreas. The hypoglycemic mechanism may involve regulating the IRS-1/PI3K/Akt signaling pathway to inhibit the activities of GSK-3β and FoxO1， thereby promoting liver glycogen synthesis and suppressing hepatic gluconeogenesis， ultimately improving glycolipid metabolism disorders.

Abstract: Integrated stress response is an adaptive response produced by eukaryotic cells after intracellular and extracellular stimulation. The activation of integrated stress response inhibits the translation of most proteins, yet it can promote the translation of certain proteins to cope with complex cellular microenvironment changes. A large number of studies have found that in a variety of nervous system diseases, the integrated stress response can be activated by stress signals of disease-related cells and participates in the occurrence and progression of diseases through processes such as learning and memory consolidation, myelin regeneration and synaptic plasticity. This article summarizes the role, mechanism and possible drug targets of integrated stress response in central nervous system diseases and discusses the potential of pharmacological methods to regulate integrated stress response in the treatment of central nervous system diseases, in order to provide reference for pathological research on and drug development for central nervous system diseases.

Objective:To explore the risk factors of severe acute kidney injury (AKI) in septic patients, and to establish an hour-specific prediction model.Methods:Based on the information of septic patients in the Medical Information Mart for Intensive Care-Ⅳ (MIMIC-Ⅳ) database, general information, comorbidities, vital signs, severity scoring system, laboratory indicators, invasive operations and medication use were recorded. The enrolled patients were randomized into a training set and a validation set according to a ratio of 7∶3. AKI was diagnosed according to the guidelines of Kidney Disease: Improving Global Outcome (KDIGO). Based on Lasso regression and Cox regression, the risk factors of severe AKI (AKI stage 2 and stage 3) in septic patients were analyzed and hour-specific prediction model were established. Consistency index (C-index), area under the receiver operator characteristic curve (AUC) and calibration curve were used to assess the predictive efficacy of the model.Results:A total of 20 551 septic patients were enrolled, including 14 385 patients in the training set and 6 166 patients in the validation set. Multivariate Cox regression analysis showed that atrial fibrillation [hazard ratio ( HR) = 1.266, 95% confidence interval (95% CI) was 1.150-1.393], heart failure ( HR = 1.348, 95% CI was 1.217-1.493), respiratory failure ( HR = 1.565, 95% CI was 1.428-1.715), heart rate ( HR = 1.004, 95% CI was 1.002-1.007), mean arterial pressure ( HR = 1.245, 95% CI was 1.126-1.377), lactic acid ( HR = 1.051, 95% CI was 1.025-1.077), simplified acute physiology score Ⅱ (SAPSⅡ, HR = 1.019, 95% CI was 1.016-1.023), serum creatinine ( HR = 1.171, 95% CI was 1.127-1.216), anion gap ( HR = 1.024, 95% CI was 1.010-1.038), serum potassium ( HR = 1.155, 95% CI was 1.079-1.236), white blood cell count ( HR = 1.006, 95% CI was 1.003-1.009) and furosemide use ( HR = 0.414, 95% CI was 0.368-0.467) were independently associated with severe AKI in septic patients (all P < 0.01). The above predictors were applied to construct an hour-specific prediction model for the occurrence of severe AKI in septic patients. The C-index of the prediction model was 0.723 and 0.735 in the training and validation sets, respectively. The AUC for the occurrence of severe AKI at 12, 24, and 48 hours were 0.795 (95% CI was 0.782-0.808), 0.792 (95% CI was 0.780-0.805), and 0.775 (95% CI was 0.762-0.788) in the training set, and the AUC were 0.803 (95% CI was 0.784-0.823), 0.791 (95% CI was 0.772-0.810), and 0.773 (95% CI was 0.752-0.793) in the validation set, respectively. The calibration curves of the two cohorts were in good agreement. Conclusion:The hour-specific prediction model effectively identifies high-risk septic patients for developing severe AKI within 48 hours, aiding clinicians in stratifying patients for early therapeutic interventions to improve outcomes.

Objective:To explore the status of coronavirus disease 2019 (COVID-19) vaccines, safety and the influencing factors of adverse reactions in maintenance hemodialysis (MHD) patients.Methods:The study was a retrospective study. The MHD patients vaccinated with COVID-19 vaccines in Tianjin city from January 2020 to July 2022 were enrolled in the study. The data of general information, vaccination situation, adverse reactions, and laboratory tests before and after vaccination were collected. Logistic regression analysis was used to analyze the risk factors of adverse reactions after vaccination.Results:A total of 7 375 patients were registered to receive hemodialysis treatment in Tianjin city, of whom 1 036 patients (14.05%) vaccinated with COVID-19 vaccines were enrolled from 53 hemodialysis centers in the study, with age of (54.00±13.27) years old (17-88 years old), and 676 males (65.25%). There were 171 patients (16.51%) receiving the first dose of vaccines only, 464 patients (44.79%) receiving two doses of vaccines, 401 patients (38.71%) receiving three doses of vaccines, and 67 patients (6.47%) had adverse reactions. No serious adverse reaction occurred. The number of neutrophils after vaccination was lower than that before vaccination ( P < 0.05), while the number of lymphocytes, alanine aminotransferase, glutamic oxaloacetic aminotransferase, and serum albumin after vaccination were higher than those before vaccination (all P < 0.05). Logistic regression analysis showed that age ( OR=0.967, 95% CI 0.946-0.990, P=0.005), previous allergic history ( OR=0.013, 95% CI 0.001-0.151, P < 0.001), serum uric acid ( OR=1.004, 95% CI 1.001-1.008, P=0.020), numbers of vaccinations administered ( OR=0.505, 95% CI 0.330-0.774, P=0.002), leukocytes ( OR=0.766, 95% CI 0.628-0.935, P=0.009) and lymphocytes ( OR=0.082, 95% CI 0.045-0.148, P < 0.001) were independently correlated with the incidence of adverse reactions. Conclusions:The proportion of MHD patients vaccinated with COVID-19 vaccines is 14.05%. The incidence of adverse reactions is 6.47%, and there is no serious adverse reaction. Age, previous allergic history, serum uric acid, and numbers of vaccinations administered, leukocytes and lymphocytes are independently correlated with the incidence of adverse reactions in MHD patients.

Objective:To study the effect of shear stress on the expression of KLF2 and eNOS in venous endothelial cells under physiological and uremic conditions, and to explore the mechanism leading to dysfunction of venous endothelial cells.Methods:Under physiological conditions and uremia conditions, different shear stresses were simulated in the parallel plate flow cavity, and the shear stresses were applied to the venous endothelial cells of each group for 4, 12, and 24 hours. The expression of KLF2 and eNOS was detected by immunohistochemical fluorescent staining technique and real-time fluorescent quantitative PCR technique.Results:Under physiological conditions, KLF2 is obviously regulated by shear stresses. High-intensity shear stresses and physiological shear stresses will up-regulate the expression of KLF2, while low-intensity shear stresses and oscillating shear stresses will down-regulate the expression of KLF2. As the duration of action increases, the expression of KLF2 will also increase. In the state of uremia, the expression of KLF2 is significantly inhibited. Even if high shear stresses is applied, the level of KLF2 is not high-expressed as the physiological state. And under the action of low shear stresses and oscillating shear stresses, KLF2 expression is more significantly inhibited. KLF2 is mainly expressed in the nucleus. With the action of shear stresses, KLF2 is also expressed in the cytoplasm, while eNOS is mainly expressed in granular form in the cytoplasm and nucleus.Conclusions:After arteriovenous fistula operation, the expression of KLF2 and eNOS is inhibited under the action of multiple factors of uremia environment and oscillating shear stresses, which may be the main cause of the occurrence and development of venous endothelial cell dysfunction, intimal hyperplasia, and AVF failure.

Objective:To systematically evaluate the predictive value of neutrophil-lymphocyte ratio (NLR) in acute kidney injury (AKI).Methods:All studies about the predictive effect of NLR on AKI were searched in the National Medical Library of the United States PubMed Database, the Embase database in the Netherlands, the Chinese Biology Medicine disc (CBMdisc) and the Chinese Evidence Based Medicine Cochrane Centre Database (CEBM/CCD). The data updated by October 2020, and regardless of language, region or whether blind method was used. Two authors independently extracted data and evaluated the quality of the studies. Data extracted from the studies were analyzed with RevMan 5.3 to assess the predictive value of NLR on AKI. A subgroup Meta-analysis was conducted to assess the predictive value of NLR on AKI according to different countries, different disease types (cardiovascular surgery, infectious diseases, other diseases including burns, cirrhosis, and emergency), and different sample sizes (≤ 300 cases and > 300 cases). The publication bias of included studies about the predictive effect of NLR on AKI were assessed by funnel plots.Results:A total of 11 studies were included in this Meta-analysis, including 4 997 patients, 1 308 patients in AKI group, and 3 689 patients in non-AKI group. The Meta-analysis results showed that: increased NLR had predictive value for the occurrence of AKI [mean difference ( MD) = 2.73, 95% confidence interval (95% CI) was 1.78-3.68, P < 0.000 01]. Subgroup analysis showed that increased NLR had predictive value for the occurrence of AKI in patients from Southeast Asia ( MD = 4.04, 95% CI was 1.09-6.99, P = 0.007) and Eurasia ( MD = 2.51, 95% CI was 1.12-3.90, P = 0.000 4). Increased NLR had predictive value for the occurrence of AKI in patients undergoing cardiovascular surgery ( MD = 0.77, 95% CI was 0.34-1.20, P = 0.000 4), infectious diseases ( MD = 4.74, 95% CI was 1.51-7.96, P = 0.004) and other diseases ( MD = 8.53, 95% CI was 6.26-10.80, P<0.000 01). Increased NLR had predictive value for the occurrence of AKI in studies with a sample size of ≤ 300 cases ( MD = 6.02, 95% CI was 4.90-7.14, P <0.000 01) and > 300 cases ( MD = 1.32, 95% CI was 0.61-2.03, P = 0.000 3). There was no significant publication bias in the included studies assessed by funnel plots. Conclusion:NLR is an important predictive tool for AKI.

Objective To evaluate the relationship between low vitamin D level and metabolic syndrome (MS) in maintenance hemodialysis (MHD) patients.Methods A total of 143 patients who had received MHD from Jan 2016 to Jan 2017 in the dialysis center of our hospital were enrolled.Their clinical and laboratory data were collected.The serum 25(OH)D3 levels were measured by chemiluminescence instrument.According to the levels of 25(OH)D3,patients were divided into three groups:sufficient group (＞ 30 μg/L),insufficient group (15-30 μg/L) and deficient group (＜ 15 μg/L) to explore how the 25(OH)D3 were associated with MS and abnormal metabolic parameters,including central obesity,raised triglycerides (TG),reduced high-density lipoprotein cholesterol (HDL-C),raised systolic blood pressure (SBP),raised diastolic blood pressure (DBP) and increased fasting blood glucose (FBG).The risk factors of MS and abnormal metabolic factors were analyzed by multivariate logistic regression model.Results Among the 143 MHD patients,the median of serum 25(OH)D3 was 24.30(12.90,29.50) μg/L and the prevalence of MS was 45.45％(65 cases).Among 3 groups the prevalence of MS,the abdominal circumference and the serum TG showed statistical differences,and they increased with the severity of 25(OH)D3 deficiency (all P ＜ 0.05).The body mass indexes of patients in the insufficient and deficient groups were elevated compared with that in the sufficient group (all P ＜ 0.05).SBP,TG and FBG in deficient group were significantly higher but HDL-C was lower than those in the other two groups (all P ＜ 0.05).The more abnormal metabolism existed,the lower 25(OH)D3 levels patients had (H=61.316,P＜0.001).Multivariate logistic regression analysis showed that in MHD patients low 25(OH)D3 negatively correlated with MS (OR=0.889,95％CI 0.846-0.934,P ＜ 0.001) and abnormal metabolic factors central obesity (OR=0.913,95％CI 0.874-0.953,P ＜ 0.001),raised TG (OR=0.932,95％ CI 0.894-0.971,P=0.001),reduced HDL-C (OR=0.901,95％ CI 0.845-0.959,P=0.001),raised SBP (OR=0.898,95％CI 0.847-0.953,P＜ 0.001) and raised FBG (OR=0.956,95％CI 0.920-0.994,P=0.024).Conclusions The prevalence of MS is high in MHD patients and low levels of 25(OH)D3 may be an independent risk factor for MS and abnormal metabolic factors.

Objective To investigate the possible risk factors for the progression of abdominal aortic calcification (AAC) in MHD patients.Methods Total of 170 patients on MHD between June 2014 and October 2014 in the dialysis center of the Second Hospital of Tianjin Medical University were included prospectively.Lateral lumbar radiography were applied to evaluate patients' AAC score (AACs) at baseline and after two-years of follow-up respectively.According to the change of AACs,the patients were divided into rapid AAC progression group and non-rapid AAC progression group.Multivariable Logistic regression models were used to determine the risk factors for the progression of AAC in MHD patients.Results At baseline,the presence of AAC (AACs≥1) was 43.5％(74/170).The mean follow-up duration was 27.6(24.7,28.0) months.AACs were available in 111 patients,and the presence of AAC was 78.4％(87/111).During the follow up,36 patients developed new AAC;rapid AAC progression was seen in 54 patients,and non-rapid AAC progression was seen in 57 patients.Multivariate Logistic regression analysis demonstrated that hyperphosphatemia (OR=4.373,95％ CI 1.562-7.246,P=0.005) and high density lipoprotein (HDL) (OR=0.031,95％CI 0.003-0.338,P=0.004) were independent risk factors for AAC progression in MHD patients.Conclusions Hyperphosphatemia and low HDL may promote the progression of AAC.Well-controlled serum phosphate and lipid metabolism may slow the progression of vascular calcification,reducing cardiovascular morbidity and mortality.

Objective To investigate the relationship between abdominal aortic calcification (AAC) and outcomes in maintenance hemodialysis (MHD) patients. Methods One hundred and seventy MHD patients in the dialysis center of the Second Hospital of Tianjin Medical University from June 2014 and October 2014 were enrolled prospectively. Abdominal aortic calcification (AAC) was measured using AAC score (AACS) by abdominal lateral plain radiography. According to the AACS, the patients were divided into mild AAC (AACS<5) group and severe AAC (AACS≥5) group for comparison, and Kaplan?Meier analysis was used to compare their survival rates. Multivariable COX regression models were used to determine the risk factors of all?cause mortality and cardiovascular disease mortality in MHD patients. Results Severe AAC (AACS≥5) was present in 28.2%(48/170) patients. The median follow?up duration was 25.6 (22.0, 26.0) months. During the follow?up, 6 patients (4.9%) in AACS<5 group and 14 patients (29.2%) in AACS≥5 group died. Kaplan?Meier analysis showed that patients in AACS≥5 group had higher all?cause mortality rate and cardiovascular disease mortality rate as compared with patients in AACS<5 group (χ2=9.746 ,P=0.002; χ2=9.697 ,P=0.002). Multivariate COX regression analysis demonstrated that high AACS (HR=4.373, 95%CI 1.562?7.246, P=0.005) and hypoproteinemia (HR=0.886, 95%CI 0.797?0.985, P=0.025) were independent risk factors for all?cause mortality, while hypoproteinemia (HR=0.829, 95%CI 0.718?0.956, P=0.010) and low 1,25(OH)D3 (HR=0.769, 95% CI 0.627 ? 0.944, P=0.012) were independent risk factors for cardiovascular disease mortality. Conclusions AAC is significantly associated with overall survival in MHD patients. To further evaluate the relationship between AAC and outcomes in MHD patients, multi?center and long term follow up studies of large sample size are necessary.