GLP1R rs3765467 Polymorphism Is Associated with the Risk of Early Onset Type 2 Diabetes.

Objective: To investigate the relationship between glucagon-like peptide-1 receptor gene polymorphisms and susceptibility to early onset type 2 diabetes. Methods: Samples from 316 type 2 diabetes patients with early onset type 2 diabetes (n = 137) and late-onset type 2 diabetes (n = 179) and 145 nondiabetic individuals were analyzed. Multiplex PCR combined with resequencing Hi-Reseq technology was used to detect single nucleotide polymorphisms of the glucagon-like peptide-1 receptor gene, and the allele frequency, genotype distribution, and clinical parameters were analyzed between each diabetes subgroup and the control group. Results: Sixteen single nucleotide polymorphisms were identified in the exonic region of the glucagon-like peptide-1 receptor gene according to the minor allele frequency (MAF > 0.05) in the participants. Among these, the glucagon-like peptide-1 receptor rs3765467 (G⟶A) mutation was statistically associated with early onset type 2 diabetes. Compared with that of the GG carriers, carriers of genotype AA at rs3765467 had a decreased risk of early onset type 2 diabetes after adjusting for sex and body mass index. In the dominant model, the frequencies of the rs3765467 AA + GA genotype were significantly decreased in the early onset type 2 diabetes group, and carriers of genotype AA + GA at rs3765467 had a decreased risk of early onset type 2 diabetes after adjusting for sex and body mass index. Moreover, fasting C peptide levels were significantly higher in GA + AA genotype carriers than those in GG genotype carriers. Conclusion: The glucagon-like peptide 1 receptor rs3765467 polymorphism was significantly associated with age at type 2 diabetes diagnosis and thus may be used as a marker to screen and detect individuals at risk of developing early onset type 2 diabetes.

Huangkui capsule attenuates diabetic kidney disease through the induction of mitophagy mediated by STING1/PINK1 signaling in tubular cells.

BACKGROUND: Mitochondria is critic to tubulopathy, especially in diabetic kidney disease (DKD). Huangkui capsule (HKC; a new ethanol extract from the dried corolla of Abelmoschus manihot) has significant clinical effect on DKD. Previous studies have shown that HKC protects kidney by regulating mitochondrial function, but its mechanism is still unclear. The latest research found that the stimulator of interferon genes (STING1) signal pathway is closely related to mitophagy. However, whether HKC induces mitophagy through targeting STING1/PTEN-Induced putative kinase (PINK1) in renal tubular remains elusive. OBJECTIVE: This study aims to clarify the therapeutic effect of HKC on renal tubular mitophagy in DKD and its potential mechanism in vivo and in vitro. METHODS: Forty male C57BL/6 mice were randomly divided into 5 groups: CON group, DKD group, HKC-L (1.0 g/kg/day, by gavage), HKC-H (2.0 g/kg/day), and LST group. Diabetes model was induced by high-fat diet (HFD) combined with intraperitoneal injection of Streptozotocin (STZ). LST (losartan) is used as a positive control drug. Then, the glomeruli, renal tubular lesions, mitochondrial morphology and function of renal tubular cells and mitophagy levels were detected in mice. In addition, a high glucose injury model was established using HK2 human renal tubular cells. Pretreate HK2 cells with HKC or LST and detect mitochondrial function, mitophagy level, and autophagic flux. In addition, small interfering RNAs (siRNAs) of STING1 and PINK1 and overexpressing pcDNA3.1 plasmids were transfected into HK-2 cells to validate the mitophagy mechanism regulated by STING1/PINK1 signaling. RESULTS: The ratio of urinary albumin to creatinine (ACR), fasting blood glucose, body weight in the early DKD mice model was increased, with damage to the glomerulus and renal tubules, mitochondrial structure and dysfunction in the renal tubules, and inhibition of STING1/PINK1 mediated mitophagy. Although the fasting blood glucose, body weight and serum creatinine levels were hardly ameliated, high dose HKC (2.0 g/kg/day) treatment significantly reduced ACR in the DKD mice to some extent, improved renal tubular injury, accurately upregulated STING1/PINK1 signaling mediated mitophagy levels, improved autophagic flux, and restored healthy mitochondrial pools. In vitro, an increase in mitochondrial fragments, fusion to fission, ROS and apoptosis, and a decrease in respiratory function, mtDNA, and membrane potential were observed in HK2 cells exposed to high glucose. HKC treatment significantly protected mitochondrial dynamics and function, which is consistent with in vivo results. Further research has shown that HKC can increase the level of mitophagy mediated by STING1/PINK1 in HK2 cells. CONCLUSIONS: Our results suggest that HKC ameliorates renal tubulopathy in DKD and induces mitophagy partly through the up-regulation of the STING1/PINK1 pathway. These findings may provide an innovative therapeutic basis for DKD treatment.

Association between age and incidence of deep vein thrombosis in patients with spinal cord injury: an observational cross-sectional study.

STUDY DESIGN: Cross-sectional study. OBJECTIVE: To elucidate the association between age and incidence of deep vein thrombosis (DVT) in patients with spinal cord injury (SCI). SETTING: Rehabilitation Medicine Department of the First Affiliated Hospital of China University of Science and Technology. METHODS: Patients from August 2018 to December 2020 with SCI (N = 260) were tertiles divided the age into three groups to analyze the association between age and incidence of DVT. RESULTS: American Spinal Cord Injury Association impairment scale (AIS), urinary tract infection (UTI), pulmonary infection (PI), and anticoagulation therapy (AT) were confounders for the association between age and incidence of DVT. The incidence of DVT increased by 1.07-fold (Non-adjusted model, OR = 1.07, P < 0.001), 1.05-fold (Minimally-adjusted model: adjusted for confounders, OR = 1.05, P = 0.010) and 1.06-fold [Fully-adjusted model: adjusted for confounders and unbalanced probable variables: AIS, UTI, PI, AT, Sex, D-dimer(new), Fibrinogen (new), Modes of injury and Level of injury, OR = 1.06, P = 0.012] when age increased by 1 year. The incidence of DVT had an increasing trend with age in different age tertile in the three models (P for trend <0.05). Age had a linearly association with incidence of DVT (OR = 1.07, P = 0.065) and stable in different subgroups, for lower age, the association was also linearly (OR = 4.40, P = 1.000), for middle (fold point = 46.46, P < 0.001) and higher age (fold point = 66, P = 0.017), the association was curvilinear. CONCLUSION: Age had a linearly association with incidence of DVT. Quitting smoking, preventing/treating UTI and AT should be adopted in advance for patients with SCI for all age, especially for older.

Association of age-adjusted D-dimer with deep vein thrombosis risk in patients with spinal cord injury: a cross-sectional study.

STUDY DESIGN: Article. OBJECTIVE: To elucidate the association of age-adjusted D-dimer (AAD) with deep vein thrombosis (DVT) risk to lower limbs in patients with spinal cord injury (SCI). SETTING: Rehabilitation Medicine Department of the First Affiliated Hospital of China University of Science and Technology. METHODS: Retrospective analysis of 250 patients with SCI in the rehabilitation department from August 2018 to December 2021. Quartiles divided the D-dimer level into four groups to analyze the association between AAD level and DVT risk. RESULTS: Age was identified as a covariate of D-dimer and DVT risk. For non-adjusted model, when D-dimer increased by 1 mg/L, DVT risk increased 0.23-fold (P < 0.05); for minimally-adjusted model (adjusted for age), the risk increased 0.22-fold (P < 0.05); and for fully-adjusted model (adjusted for age, sex, pulmonary infection, degree, grades, and career), it increased 0.19-fold (P < 0.05). AAD had a curvilinear association with DVT risk, and the fold point was 1.9 mg/L (P < 0.05). When serum AAD level was <1.9 mg/L (K < 1.9), the estimated change in DVT risk was 3.34 (P < 0.05), and when serum AAD level was >1.9 mg/L (K > 1.9), the estimated change was 1.14 (P < 0.05). Urinary tract infection (UTI) and fibrinogen(tertile) had a interaction association with D-dimer level and DVT risk (P interaction < 0.05). CONCLUSION: Patients with SCI who receive rehabilitation treatment with AAD level >1.9 mg/L need to be paid close attention to, especially those with UTI and high levels of fibrinogen.

Lacking Communication Would Increase General Symptom Index Scores of Medical Team Members During COVID-19 Pandemic in China: A Retrospective Cohort Study.

There are few studies on the psychological status of medical staff during the COVID-19 outbreak. Our study addresses whether lack of communication affects the psychological status of medical team members supporting Wuhan during the COVID-19 pandemic in China. We used general symptom index (GSI) scores of the Symptom Checklist-90 (SCL-90) to evaluate participants' psychological status. We adopted a stratified sampling method and selected the fourth team, with a total of 137 members, as participants. In total 76.6% and 69.7% of female and male participants, respectively, had bachelor's degrees; 41.6% and 21.2% of female and male participants, respectively, were unmarried. Regarding communication, 14.29% and 6.06% of female and male participants, respectively, reported a lack of communication with the team (LCWT). Additionally, 13.0% and 6.1% of female and male participants, respectively, experienced fear of being infected (FoBI). LCWT and FoBI were positively correlated with GSI score (estimated change = 0.2, 95% CI [0.1-0.3]). When adjusted for gender, age, and FoBI, LCWT was positively correlated with GSI score (P < .05). Increasing communication among medical team members can reduce GSI scores.

The 14-3-3 protein YWHAB inhibits glucagon-induced hepatic gluconeogenesis through interacting with the glucagon receptor and FOXO1.

Glucagon antagonism has been reported as a new therapeutic approach to hyperglycaemia. As the 14-3-3 protein YWHAB has been identified as a regulator of the glucagon receptor (GCGR) by affinity purification and mass spectrometry, we examined the role of YWHAB in vivo. Ywhab knockout mice display impaired blood glucose homeostasis only under pyruvate stimulation. Deletion of Ywhab in mouse primary hepatocytes (MPHs) increases hepatocyte glucose production by magnifying the effect of glucagon. Mechanistic analysis indicates that YWHAB forms a phosphorylation-dependent complex with GCGR and directly interacts with forkhead box O1 (FOXO1). Together, these results reveal the inhibitory role of YWHAB in glucagon-mediated hepatic glucose production, which may be a potential target for the control of gluconeogenesis and associated metabolic diseases.

Liraglutide Alleviates Hepatic Steatosis by Activating the TFEB-Regulated Autophagy-Lysosomal Pathway.

Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has been demonstrated to alleviate non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism has not been fully elucidated. Increasing evidence suggests that autophagy is involved in the pathogenesis of hepatic steatosis. In this study, we examined whether liraglutide could alleviate hepatic steatosis through autophagy-dependent lipid degradation and investigated the underlying mechanisms. Herein, the effects of liraglutide on NAFLD were evaluated in a high-fat diet (HFD)-induced mouse model of NAFLD as well as in mouse primary and HepG2 hepatocytes exposed to palmitic acid (PA). The expression of the GLP-1 receptor (GLP-1R) was measured in vivo and in vitro. Oil red O staining was performed to detect lipid accumulation in hepatocytes. Electron microscopy was used to observe the morphology of autophagic vesicles and autolysosomes. Autophagic flux activity was measured by infecting HepG2 cells with mRFP-GFP-LC3 adenovirus. The roles of GLP-1R and transcription factor EB (TFEB) in autophagy-lysosomal activation were explored using small interfering RNA. Liraglutide treatment alleviated hepatic steatosis in vivo and in vitro. In models of hepatic steatosis, microtubule-associated protein 1B light chain-3-II (LC3-II) and SQSTM1/P62 levels were elevated in parallel to blockade of autophagic flux. Liraglutide treatment restored autophagic activity by improving lysosomal function. Furthermore, treatment with autophagy inhibitor chloroquine weakened liraglutide-induced autophagy activation and lipid degradation. TFEB has been identified as a key regulator of lysosome biogenesis and autophagy. The protein levels of nuclear TFEB and its downstream targets CTSB and LAMP1 were decreased in hepatocytes treated with PA, and these decreases were reversed by liraglutide treatment. Knockdown of TFEB expression compromised the effects of liraglutide on lysosome biogenesis and hepatic lipid accumulation. Mechanistically, GLP-1R expression was decreased in HFD mouse livers as well as PA-stimulated hepatocytes, and liraglutide treatment reversed the downregulation of GLP-1R expression in vivo and in vitro. Moreover, GLP-1R inhibition could mimic the effect of the TFEB downregulation-mediated decrease in lysosome biogenesis. Thus, our findings suggest that liraglutide attenuated hepatic steatosis via restoring autophagic flux, specifically the GLP-1R-TFEB-mediated autophagy-lysosomal pathway.

Correlation analysis of risk factors and GSI score of a medical team assisting Wuhan city during the epidemic of COVID-19 in China -A cohort study

ImportanceThere are few studies on the psychological status of medical staff during the COVID-19 outbreak. This study is the first in the world about the psychological status of the medical team during the COVID-19 outbreak. ObjectiveTo study the correlation between risk factors and general symptom index (GSI) score of medical team members who support Wuhan against COVID-19. DesignCohort study. SettingPopulation-based. ParticipantsAnhui Province sent a total of eight medical teams, including 1382 members, to support Hubei Province. We adopted a stratified sampling method and selected the fourth team sent by Anhui Provincial Hospital, with a total of 137 members as our subjects. ExposuresFour main exposures were collected, including basic information, preparations before going to Wuhan, life issues and working issues after going to Wuhan. Main Outcomes and MeasuresThe GSI score of SCL-90 scale was used to reflect the frequency and intensity of psychological symptoms. We made the hypothesis of this study before data collection. Results110(80.29%) members completed the questionnaire, of which, 77(70.00%) female and 33(30.00%) male. When adjusted age, gender and covariates, DC, LCWT had a positive correlations with GSI score({beta} was10.17, 95%CI was 3.30 to 17.04 for DC, P=0.00<0.05; {beta} was 11.55, 95%CI was 0.40 to 22.71 for LCWT, P =0.04<0.05;respectively), RBT had a negative positive correlation with GSI score ({beta} was -28.09, 95%CI was -45.79 to -10.40, P=0.00<0.05), AoBI did not had a correlation with GSI score ({beta} was 11.55, 95%CI was 0.40 to 22.71, P=0.16>0.05). When adjusted covariates, DC had a positive and RBT had a negative correlation with GSI score of female ({beta} was 13.20, 95%CI was 4.55 to 21.85, P=0.00<0.05; {beta} was -57.85, 95%CI was -94.52 to -21.18, P=0.00<0.05; respectively), but for male was not (P=0.59>0.05, P=0.08>0.05, respectively), LCWT and AoBI didnt had correlation with GSI score between genders (P>0.05). Conclusions and RelevanceImproving DC, RBT and decreasing LCWT can reduce the GSI score. AoBI didnt affect the psychological status; male members have a more stable mood than female. Whether other countries medical team has the same result still needs further research. Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the correlation between risk factors and general symptom index (GSI) score of medical team members who support Wuhan against COVID-19? FindingsDietary conditions (DC) had a positive and relationship between team (RBT) had a negative correlation with GSI score of female, but for male was not (P=0.59>0.05, P=0.08>0.05, respectively), lacking communication with teams (LCWT) and afraid of being infected (AoBI) didnt had correlation with GSI score between genders, a significant difference. MeaningImproving DC, RBT and decreasing LCWT between team members can reduce the GSI score. Whether they are AoBI, didnt affect the psychological status, male members have a more stable mood than female.

Autophagy and hippocampal neuronal injury.

BACKGROUND: Autophagy is a specific universal biological phenomenon in eukaryotic cells, which is characterized by cytoplasmic vacuoles in the process of degrading cellular contents in lysosomes. The hippocampus plays an important role in higher nervous activities such as emotional integration, cognition, and memory. As an area closely related to learning and memory functions of the brain, the hippocampus is particularly sensitive to injuries caused by various reasons. PURPOSE: Autophagy has certain links with a variety of causes of hippocampal neuronal injury. This short review discusses and summarizes this correlation with a focus on the possible role of autophagy and mechanisms in it. CONCLUSION: The current correlation between autophagy and hippocampal neuronal injury has not been completely determined by the general public alike. Further studies are needed to determine special effects of autophagy on hippocampal neuronal injury, which might accelerate the development of therapeutic interventions in hippocampal neuronal injury in many neurological disorders.

Depression after exposure to stressful events: lessons learned from the severe acute respiratory syndrome epidemic.

AIM: The aim of the study was to examine, among hospital employees exposed to an outbreak of severe acute respiratory syndrome (SARS), post-outbreak levels of depressive symptoms and the relationship between those depressive symptom levels and the types of outbreak event exposures experienced. METHODS: In 2006, randomly selected employees (N = 549) of a hospital in Beijing were surveyed concerning their exposures to the city's 2003 SARS outbreak and the ways in which the outbreak had affected their mental health. Subjects were assessed on sociodemographic factors, on types of exposure to the outbreak, and on symptoms of posttraumatic stress disorder and depression. RESULTS: The results of multinomial regression analyses showed that, with other relevant factors controlled for, being single, having been quarantined during the outbreak, having been exposed to other traumatic events before SARS, and perceived SARS-related risk level during the outbreak were found to increase the odds of having a high level of depressive symptoms 3 years later. Altruistic acceptance of risk during the outbreak was found to decrease the odds of high post-outbreak depressive symptom levels. CONCLUSIONS: Policy makers and mental health professionals working to prepare for potential disease outbreaks should be aware that the experience of being quarantined can, in some cases, lead to long-term adverse mental health consequences.

The psychological impact of the SARS epidemic on hospital employees in China: exposure, risk perception, and altruistic acceptance of risk.

OBJECTIVE: We examined the psychological impact of the 2003 outbreak of severe acute respiratory syndrome (SARS) on hospital employees in Beijing, China. METHODS: In 2006, randomly selected employees (n = 549) of a hospital in Beijing were surveyed concerning their exposure to the 2003 SARS outbreak, and the ways in which the outbreak had affected their mental health. RESULTS: About 10% of the respondents had experienced high levels of posttraumatic stress (PTS) symptoms since the SARS outbreak. Respondents who had been quarantined, or worked in high-risk locations such as SARS wards, or had friends or close relatives who contracted SARS, were 2 to 3 times more likely to have high PTS symptom levels, than those without these exposures. Respondents' perceptions of SARS-related risks were significantly positively associated with PTS symptom levels and partially mediated the effects of exposure. Altruistic acceptance of work-related risks was negatively related to PTS levels. CONCLUSIONS: The psychological impact of stressful events related to an infectious disease outbreak may be mediated by peoples' perceptions of those events; altruism may help to protect some health care workers against these negative impacts.

Alcohol abuse/dependence symptoms among hospital employees exposed to a SARS outbreak.

AIMS: The aim of this study was to examine alcohol abuse/dependence symptoms among hospital employees exposed to a severe acute respiratory syndrome (SARS) outbreak, and the relationship between types of exposure to the SARS outbreak and subsequent alcohol abuse/dependence symptoms. METHODS: A survey was conducted among 549 randomly selected hospital employees in Beijing, China, concerning the psychological impact of the 2003 SARS outbreak. Subjects were assessed on sociodemographic factors and types of exposure to the outbreak, and on symptoms of post-traumatic stress (PTS), alcohol abuse/dependence and depression. RESULTS: Current alcohol abuse/dependence symptom counts 3 years after the outbreak were positively associated with having been quarantined, or worked in high-risk locations such as SARS wards, during the outbreak. However, having had family members or friends contract, SARS was not related to alcohol abuse/dependence symptom count. Symptoms of PTS and of depression, and having used drinking as a coping method, were also significantly associated with increased alcohol abuse/dependence symptoms. The relationship between outbreak exposure and alcohol abuse/dependence symptom count remained significant even when sociodemographic and other factors were controlled for. When the intrusion, avoidance and hyperarousal PTS symptom clusters were entered into the model, hyperarousal was found to be significantly associated with alcohol abuse/dependence symptoms. CONCLUSIONS: Exposure to an outbreak of a severe infectious disease can, like other disaster exposures, lead not only to PTSD but also to other psychiatric conditions, such as alcohol abuse/dependence. The findings will help policy makers and health professionals to better prepare for potential outbreaks of diseases such as SARS or avian flu.