Prokaryotic Expression and Functional Verification of Antimicrobial Peptide LRGG.

The antimicrobial peptide LRGG (LLRLLRRGGRRLLRLL-NH2) was designed and chemically synthesized in a study conducted by Jia et al. Gram-negative bacteria were found to be sensitive to LRGG and exhibited a high therapeutic index. Genetic engineering methods were used to create the prokaryotic fusion expression vector pQE-GFP-LRGG, and the resulting corresponding fusion protein GFP-LRGG was subsequently expressed and purified. The precursor GFP was then removed by TEV proteolysis, and pure LRGG was obtained after another round of purification and endotoxin removal. The prokaryotic-expressed antimicrobial peptide LRGG displays a broad-spectrum antibacterial effect on Gram-negative bacteria, and its minimum inhibitory activity (MIC) against Escherichia coli can reach 2 µg/mL. Compared to the chemically synthesized LRGG, the prokaryotic-expressed LRGG exhibits similar temperature, pH, salt ion, serum stability, and cell selectivity. Furthermore, prokaryotic-expressed LRGG showed excellent therapeutic effects in both the infection model of cell selectivity and no embryotoxicity in a Galleria mellonella infection model. The mechanism by which LRGG causes bacterial death was found to be the disruption of the Gram-negative cell membrane.

Unveiling the causal link between metabolic factors and ovarian cancer risk using Mendelian randomization analysis.

Background: Metabolic abnormalities are closely tied to the development of ovarian cancer (OC), yet the relationship between anthropometric indicators as risk indicators for metabolic abnormalities and OC lacks consistency. Method: The Mendelian randomization (MR) approach is a widely used methodology for determining causal relationships. Our study employed summary statistics from the genome-wide association studies (GWAS), and we used inverse variance weighting (IVW) together with MR-Egger and weighted median (WM) supplementary analyses to assess causal relationships between exposure and outcome. Furthermore, additional sensitivity studies, such as leave-one-out analyses and MR-PRESSO were used to assess the stability of the associations. Result: The IVW findings demonstrated a causal associations between 10 metabolic factors and an increased risk of OC. Including "Basal metabolic rate" (OR= 1.24, P= 6.86×10-4); "Body fat percentage" (OR= 1.22, P= 8.20×10-3); "Hip circumference" (OR= 1.20, P= 5.92×10-4); "Trunk fat mass" (OR= 1.15, P= 1.03×10-2); "Trunk fat percentage" (OR= 1.25, P= 8.55×10-4); "Waist circumference" (OR= 1.23, P= 3.28×10-3); "Weight" (OR= 1.21, P= 9.82×10-4); "Whole body fat mass" (OR= 1.21, P= 4.90×10-4); "Whole body fat-free mass" (OR= 1.19, P= 4.11×10-3) and "Whole body water mass" (OR= 1.21, P= 1.85×10-3). Conclusion: Several metabolic markers linked to altered fat accumulation and distribution are significantly associated with an increased risk of OC.

Assessing causal associations of bile acids with obesity indicators: A Mendelian randomization study.

Maintaining a balanced bile acids (BAs) metabolism is essential for lipid and cholesterol metabolism, as well as fat intake and absorption. The development of obesity may be intricately linked to BAs and their conjugated compounds. Our study aims to assess how BAs influence the obesity indicators by Mendelian randomization (MR) analysis. Instrumental variables of 5 BAs were obtained from public genome-wide association study databases, and 8 genome-wide association studies related to obesity indicators were used as outcomes. Causal inference analysis utilized inverse-variance weighted (IVW), weighted median, and MR-Egger methods. Sensitivity analysis involved MR-PRESSO and leave-one-out techniques to detect pleiotropy and outliers. Horizontal pleiotropy and heterogeneity were assessed using the MR-Egger intercept and Cochran Q statistic, respectively. The IVW analysis revealed an odds ratio of 0.94 (95% confidence interval: 0.88, 1.00; P = .05) for the association between glycolithocholate (GLCA) and obesity, indicating a marginal negative causal association. Consistent direction of the estimates obtained from the weighted median and MR-Egger methods was observed in the analysis of the association between GLCA and obesity. Furthermore, the IVW analysis demonstrated a suggestive association between GLCA and trunk fat percentage, with a beta value of -0.014 (95% confidence interval: -0.027, -0.0004; P = .04). Our findings suggest a potential negative causal relationship between GLCA and both obesity and trunk fat percentage, although no association survived corrections for multiple comparisons. These results indicate a trend towards a possible association between BAs and obesity, emphasizing the need for future studies.

Dissecting the associations of KCNH2 genetic polymorphisms with various types of cardiac arrhythmias.

BACKGROUND: Cardiac arrhythmia, a common cardiovascular disease, is closely related to genetic polymorphisms. However, the associations between polymorphisms in KCNH2 and various arrhythmias remain inadequately explored. METHODS: Guided by the assumption that KCNH2 genetic polymorphisms significantly contribute to the development of arrhythmias, we thoroughly explored the associations between 85 KCNH2 genetic variations and 16 cardiac arrhythmias in a sample obtained from the UK Biobank (UKBB, N = 307,473). The illnesses documented in the electronic medical records of the sample were mapped to a phecode system for a more accurate representation of distinct phenotypes. Survival analysis was used to test the effect of KCNH2 variants on arrhythmia incidence, and a phenotype-wide association study (PheWAS) was performed to investigate the effect of KCNH2 polymorphisms on 102 traits, including physical measurements, biomarkers, and hematological indicators. RESULTS: Novel associations of variants rs2269001 and rs7789585 in KCNH2 with paroxysmal tachycardia (PT) and atrial fibrillation/flutter (AF/AFL), respectively, were identified. Moreover, with an increase in the number of minor alleles of these two variants, the incidence rates of PT and AF/AFL decreased. In addition, the PheWAS results suggested that these two single nucleotide polymorphisms were associated with multiple parameters in physical measurements and neutrophil percentage. CONCLUSION: The multiple novel associations observed in this study illustrate the importance of KCNH2 genetic variations in the pathogenesis of arrhythmia.

Dissecting causal associations of type 2 diabetes with 111 types of ocular conditions: a Mendelian randomization study.

Background: Despite the well-established findings of a higher incidence of retina-related eye diseases in patients with diabetes, there is less investigation into the causal relationship between diabetes and non-retinal eye conditions, such as age-related cataracts and glaucoma. Methods: We performed Mendelian randomization (MR) analysis to examine the causal relationship between type 2 diabetes mellitus (T2DM) and 111 ocular diseases. We employed a set of 184 single nucleotide polymorphisms (SNPs) that reached genome-wide significance as instrumental variables (IVs). The primary analysis utilized the inverse variance-weighted (IVW) method, with MR-Egger and weighted median (WM) methods serving as supplementary analyses. Results: The results revealed suggestive positive causal relationships between T2DM and various ocular conditions, including "Senile cataract" (OR= 1.07; 95% CI: 1.03, 1.11; P=7.77×10-4), "Glaucoma" (OR= 1.08; 95% CI: 1.02, 1.13; P=4.81×10-3), and "Disorders of optic nerve and visual pathways" (OR= 1.10; 95% CI: 0.99, 1.23; P=7.01×10-2). Conclusion: Our evidence supports a causal relationship between T2DM and specific ocular disorders. This provides a basis for further research on the importance of T2DM management and prevention strategies in maintaining ocular health.

Assessing causal associations of hyperparathyroidism with blood counts and biochemical indicators: a Mendelian randomization study.

Background: The existing literature on the relationship of hyperparathyroidism with both blood counts and biochemical indicators primarily comprises observational studies, which have produced inconsistent findings. This study aimed to evaluate the causal relationship between hyperparathyroidism and blood counts and biochemical indicators. Methods: Mendelian randomization (MR) analyses were conducted to investigate the associations between hyperparathyroidism and the identified 55 blood counts and biochemical indicators. The genome-wide association study (GWAS) for hyperparathyroidism data was obtained from FinnGen, while the GWASs for the blood counts and biochemical indicators were sourced from the UK Biobank (UKBB). Results: The MR analysis using the inverse-variance weighted (IVW) method revealed potential causality between genetically predicted hyperparathyroidism and seven out of 55 blood counts and biochemical indicators. These markers include "Platelet count" (Beta = -0.041; 95% CI: -0.066, -0.016; p = 0.001), "Platelet distribution width (PDW)" (Beta = 0.031; 95% CI: 0.006, 0.056; p = 0.016), "Mean platelet volume (MPV)" (Beta = 0.043; 95% CI: 0.010, 0.076; p = 0.011), "Vitamin D" (Beta = -0.038; 95% CI: -0.063, -0.013; p = 0.003), "Calcium (Ca2+)" (Beta = 0.266; 95% CI: 0.022, 0.509; p = 0.033), "Phosphate" (Beta = -0.114; 95% CI: -0.214, -0.014; p = 0.025), and "Alkaline phosphatase (ALP)" (Beta = 0.030; 95% CI: 0.010, 0.049; p = 0.003). Conclusion: The findings of our study revealed a suggestive causal relationship between hyperparathyroidism and blood cell count as well as biochemical markers. This presents a novel perspective for further investigating the etiology and pathological mechanisms underlying hyperparathyroidism.

Dissecting the mediating and moderating effects of depression on the associations between traits and coronary artery disease: A two-step Mendelian randomization and phenome-wide interaction study

Background: Depression is often present concurrently with coronary artery disease (CAD), a disease with which it shares many risk factors. However, the manner in which depression mediates and moderates the association between traits (including biomarkers, anthropometric indicators, lifestyle behaviors, etc.) and CAD is largely unknown. Methods: In our causal mediation analyses using two-step Mendelian randomization (MR), univariable MR was first used to investigate the causal effects of 108 traits on liability to depression and CAD. The traits with significant causal effects on both depression and CAD, but not causally modulated by depression, were selected for the second-step analyses. Multivariable MR was used to estimate the direct effects (independent of liability to depression) of these traits on CAD, and the indirect effects (mediated via liability to depression) were calculated. To investigate the moderating effect of depression on the association between 364 traits and CAD, a cross-sectional phenome-wide interaction study (PheWIS) was conducted in a study population from UK Biobank (UKBB) (N=275,257). Additionally, if the relationship between traits and CAD was moderated by both phenotypic and genetically predicted depression at a suggestive level of significance (Pinteraction≤0.05) in the PheWIS, the results were further verified by a cohort study using Cox proportional hazards regression. Results: Univariable MR indicated that 10 of 108 traits under investigation were significantly associated with both depression and CAD, which showed a similar direct effect compared to the total effect for most traits. However, the traits “drive faster than speed limit” and “past tobacco smoking” were both exceptions, with the proportions mediated by depression at 24.6% and 7.2%, respectively. (AU)

Dissecting the mediating and moderating effects of depression on the associations between traits and coronary artery disease: A two-step Mendelian randomization and phenome-wide interaction study.

Background: Depression is often present concurrently with coronary artery disease (CAD), a disease with which it shares many risk factors. However, the manner in which depression mediates and moderates the association between traits (including biomarkers, anthropometric indicators, lifestyle behaviors, etc.) and CAD is largely unknown. Methods: In our causal mediation analyses using two-step Mendelian randomization (MR), univariable MR was first used to investigate the causal effects of 108 traits on liability to depression and CAD. The traits with significant causal effects on both depression and CAD, but not causally modulated by depression, were selected for the second-step analyses. Multivariable MR was used to estimate the direct effects (independent of liability to depression) of these traits on CAD, and the indirect effects (mediated via liability to depression) were calculated. To investigate the moderating effect of depression on the association between 364 traits and CAD, a cross-sectional phenome-wide interaction study (PheWIS) was conducted in a study population from UK Biobank (UKBB) (N=275,257). Additionally, if the relationship between traits and CAD was moderated by both phenotypic and genetically predicted depression at a suggestive level of significance (Pinteraction≤0.05) in the PheWIS, the results were further verified by a cohort study using Cox proportional hazards regression. Results: Univariable MR indicated that 10 of 108 traits under investigation were significantly associated with both depression and CAD, which showed a similar direct effect compared to the total effect for most traits. However, the traits "drive faster than speed limit" and "past tobacco smoking" were both exceptions, with the proportions mediated by depression at 24.6% and 7.2%, respectively. In the moderation analyses, suggestive evidence of several traits was found for moderating effects of phenotypic depression or susceptibility to depression, as estimated by polygenic risk score, including chest pain when hurrying, reason of smoking quitting and weight change. Consistent results were observed in survival analyses and Cox regression. Conclusion: The independent role of traits in CAD pathogenesis regardless of depression was highlighted in our mediation analyses, and the moderating effects of depression observed in our study may be helpful for CAD risk stratification and optimized allocation of scarce medical resources.

Effect of gender on the association between cumulative cardiovascular risk factors and depression: results from the US National Health and Nutrition Examination Survey.

Background: The comorbidity of cardiovascular disease (CVD) and depression has been well established, as depression usually presents simultaneously with CVD risk factors. However, the potential association between cumulative exposure to CVD risk and depression remains unclear, so we conducted the current investigation. To our knowledge, this is the first study that employs the cumulative risk model to examine the effect of CVD risk factors on depression using nationally representative population and gender, age and CVD status-stratified subpopulations. Aims: To systematically study the possible individual and cumulative effect of 18 CVD risk factors on depression. Methods: A cross-sectional, secondary analysis investigated associations between 18 CVD risk factors and depression. The interaction effect between CVD risk factors and age, gender and CVD status was also examined. Enrolment included 20 816 participants from the US National Health and Nutrition Examination Survey 2005-2016. Participants with Patient Health Questionnaire-9 scores over 15 or who were using an antidepressant were considered depressive; 18 known cardiovascular risk factors were incorporated in the present study. Results: At the individual risk factor level, smoking, drinking, living alone, sleep quality, body mass index, waist circumference and diabetes status had differential associations with depression risk according to the gender, age or CVD status of the participants. Most importantly, gender-stratified cumulative risk analysis indicated that similar depression risk was found in both genders with a small number of CVD risk factors (odds ratio (OR)adjusted=1.32; 95% confidence interval (CI): 0.87 to 1.99), but females had a significantly higher depression risk compared with males under high cumulative risk exposure (ORadjusted=2.86; 95% CI: 1.79 to 4.59). Conclusions: Clarifying the association of numerous CVD risk factors with depression according to gender, age and overall CVD status may be beneficial for risk stratification and the prevention of depression in clinical practice. Moreover, the observed novel evidence of high cumulative risk exposure-mediated gender disparities in depression risk may shed light on the underlying mechanism of females' greater vulnerability to depression.

Icy core-shell composite nanofibers with cooling, antibacterial and healing properties for outdoor burns.

Burns are usually difficult to treat because their susceptibe to bacterial infections. When burns is accompanied by hyperthermia, the heat accumulated on the skin will causes extensive tissue damage. Most dressings focus on the treatment process, while ignoring the first-aid treatment to remove hyperthermia. To make matters worse, when outdoors, it is hard to find clean water to wash and cool the burned area. A dressing which can simultaneously realize first-time cooling and repairing treatment of the burned area can shorten treatment time, and is especially beneficial for outdoor use. In this study, a handheld coaxial electrospinning device is developed for preparing platelet-rich plasma @Polycaprolactone-epsilon polylysine (PRP@PCL/ε-PL) core-shell nanofibers. The nanofibers can be synchronously transformed into ice fibers during the spinning process, and directly deposited on the skin. The whole process is convenient to use outdoor. Via dual cooling mechanisms, first aid can take away the excessive heat in the burn area by nanofibers. These core-shell nanofibers also show its excellent antimicrobial and tissue regeneration-promoting properties. Therefore, it achieves first-time cooling and repair treatment of the burned area at the same time. Moreover, due to direct in-situ deposition of this handheld coaxial electrospinning, better antimicrobial properties, and faster healing performance are achieved. By using this integrated strategy that combines cooling, antibacterial and healing promotion, the burn recovery time is shortened from 21 days to 14 days.

Endocrine and metabolic factors and the risk of idiopathic pulmonary fibrosis: a Mendelian randomization study.

Background: Previous observational studies have investigated the association between endocrine and metabolic factors and idiopathic pulmonary fibrosis (IPF), yet have produced inconsistent results. Therefore, it is imperative to employ the Mendelian randomization (MR) analysis method to conduct a more comprehensive investigation into the impact of endocrine and metabolic factors on IPF. Methods: The instrumental variables (IVs) for 53 endocrine and metabolic factors were sourced from publicly accessible genome-wide association study (GWAS) databases, with GWAS summary statistics pertaining to IPF employed as the dependent variables. Causal inference analysis encompassed the utilization of three methods: inverse-variance weighted (IVW), weighted median (WM), and MR-Egger. Sensitivity analysis incorporated the implementation of MR-PRESSO and leave-one-out techniques to identify potential pleiotropy and outliers. The presence of horizontal pleiotropy and heterogeneity was evaluated through the MR-Egger intercept and Cochran's Q statistic, respectively. Results: The IVW method results reveal correlations between 11 traits and IPF. After correcting for multiple comparisons, seven traits remain statistically significant. These factors include: "Weight" (OR= 1.44; 95% CI: 1.16, 1.78; P=8.71×10-4), "Body mass index (BMI)" (OR= 1.35; 95% CI: 1.13, 1.62; P=1×10-3), "Whole body fat mass" (OR= 1.40; 95% CI: 1.14, 1.74; P=1.72×10-3), "Waist circumference (WC)" (OR= 1.54; 95% CI: 1.16, 2.05; P=3.08×10-3), "Trunk fat mass (TFM)" (OR=1.35; 95% CI: 1.10,1.65; P=3.45×10-3), "Body fat percentage (BFP)" (OR= 1.55; 95% CI: 1.15,2.08; P=3.86×10-3), "Apoliprotein B (ApoB)" (OR= 0.78; 95% CI: 0.65,0.93; P=5.47×10-3). Additionally, the sensitivity analysis results confirmed the reliability of the MR results. Conclusion: The present study identified causal relationships between seven traits and IPF. Specifically, ApoB exhibited a negative impact on IPF, while the remaining six factors demonstrated a positive impact. These findings offer novel insights into the underlying etiopathological mechanisms associated with IPF.

Assessment of potential risk factors associated with gestational diabetes mellitus: evidence from a Mendelian randomization study.

Background: Previous research on the association between risk factors and gestational diabetes mellitus (GDM) primarily comprises observational studies with inconclusive results. The objective of this study is to investigate the causal relationship between 108 traits and GDM by employing a two-sample Mendelian randomization (MR) analysis to identify potential risk factors of GDM. Methods: We conducted MR analyses to explore the relationships between traits and GDM. The genome-wide association studies (GWAS) for traits were primarily based on data from the UK Biobank (UKBB), while the GWAS for GDM utilized data from FinnGen. We employed a false discovery rate (FDR) of 5% to account for multiple comparisons. Results: The inverse-variance weighted (IVW) method indicated that the genetically predicted 24 risk factors were significantly associated with GDM, such as "Forced expiratory volume in 1-second (FEV1)" (OR=0.76; 95% CI: 0.63, 0.92), "Forced vital capacity (FVC)" (OR=0.74; 95% CI: 0.64, 0.87), "Usual walking pace" (OR=0.19; 95% CI: 0.09, 0.39), "Sex hormone-binding globulin (SHBG)" (OR=0.86; 95% CI: 0.78, 0.94). The sensitivity analyses with MR-Egger and weighted median methods indicated consistent results for most of the trats. Conclusion: Our study has uncovered a significant causal relationship between 24 risk factors and GDM. These results offer a new theoretical foundation for preventing or mitigating the risks associated with GDM.

Sodium intake and the risk of various types of cardiovascular diseases: a Mendelian randomization study.

Background: The existing literature on the link between sodium intake and cardiovascular disease (CVD) largely consists of observational studies that have yielded inconsistent conclusions. In this study, our objective is to assess the causal relationship between sodium intake and 50 CVDs using two-sample Mendelian randomization (MR) analysis. Methods: MR analyses were performed to investigate the associations between urinary sodium/creatinine ratio (UNa/UCr), an indicator of sodium intake, and 50 CVDs. The genome-wide association study (GWAS) for UNa/UCr was from the UK Biobank (UKBB), and the GWASs for CVDs were from FinnGen. A false discovery rate (FDR) threshold of 5% was applied for multiple comparison correction. Results: The inverse-variance weighted method indicated that the genetically predicted UNa/UCr was significantly associated with 7 of 50 CVDs, including "Coronary atherosclerosis" (OR = 2.01; 95% CI: 1.37, 2.95), "Diseases of arteries, arterioles and capillaries" (OR = 1.88; 95% CI: 1.20, 2.94), "Hard cardiovascular diseases" (OR = 1.71; 95% CI: 1.24, 2.35), "Ischemic heart diseases" (OR = 2.06; 95% CI: 1.46, 2.93), "Major coronary heart disease event" (OR = 1.99; 95% CI: 1.36, 2.91), "Myocardial infarction" (OR = 2.03; 95% CI: 1.29, 3.19), and "Peripheral artery disease" (OR = 2.50; 95% CI: 1.35, 4.63). Similar results were obtained with the MR-Egger and weighted median methods. No significant heterogeneity or horizontal pleiotropy was found in this analysis. Conclusion: Our study has uncovered a significant positive causal relationship between UNa/UCr and various CVDs. These results offer a new theoretical foundation for advocating the restriction of sodium intake as a preventive measure against CVD.

Cool and hot chitosan/platelet-derived growth factor nanofibers for outdoors burns.

Burns and scalds are thermal injuries caused by a large amount of heat accumulation in local tissues. The first cooling emergency is a key step. However, it is hard that in outdoors to find clean water to cool the scald tissue sites. Moreover, most dressings are concentrated on the treatment process today, neglecting the emergency treatment of temperature reduction. In this study, we imported refrigeration in the electrospinning process while using dirty water, rainwater and even urine of outdoors, so that the cooled sterile fibers were directly deposited on the burn and scald wounds, and the cooling emergency was achieved through the dual cooling mechanism. Since this fiber which is made up of cheap fish gelatin contains CuS adopting the green method, it can generate heat and effectively kill bacteria under the irradiation of an illumination lamp at the front end of a spinning device. As a result of the direct deposition, there is an excellent fit between the fibrous membrane and the skin, which reduces the air gap to achieve a better and quick cooling and heating effects. On the same Chitosan/Platelet-derived Growth Factor fiber membrane, this method of cooling first and heating second can shorten the recovery time from 30 days to 21 days. Thus, this treatment strategy has a great potential application prospect in the field of outdoor burn treatment.

Environmental Regulation Competition and Carbon Emissions.

To clarify the relationship between environmental regulatory competition and carbon emissions and provide a theoretical basis for carbon emission reduction governance, this paper explores the strategic interaction behavior of environmental regulatory competition by constructing a three-way evolutionary game model based on the perspective of the fusion of environmental federalism and local government competition theory. On this basis, the specific forms of carbon emission reduction competition are tested using the spatial Durbin model, and the mechanism of the effect of environmental regulation competition on carbon emissions is analyzed. The evolutionary game model shows that local governments make strategic choices based on the costs and benefits of environmental regulation, and there are strategic equilibria of "race to the bottom", "race to the top", and "differentiation of competition". The empirical results show that the competition for environmental regulations as a whole after the 18th National Congress of the Communist Party of China is a "race to the top", and the increase in the intensity of environmental regulations has an inhibitory effect on carbon emissions, which remains valid after a series of robustness tests. There is heterogeneity in environmental regulatory competition, and the effect of emissions reduction is most obvious in the central region. Mechanism analysis shows that environmental regulatory competition affects carbon emissions mainly through the effect of political performance assessment, the effect of industrial structure optimization, and the effect of low-carbon technology capability improvement. Therefore, the central government should follow the local government interest function and balance the interests of all parties, appropriately increase the proportion of environmental performance assessment and optimize the performance assessment system, and consider regional development differences to find the right carbon emissions reduction path.

Characterization of the complete chloroplast genome of Salvia leucantha (Lamiaceae).

Salvia leucantha (Lamiaceae) is an important horticultural plant with great ornamental and economic value. Here, we report the complete chloroplast genome of this species. The chloroplast genome was determined to be 151021 bp and the GC contents was 38.0%. The sequence includes a large single copy (LSC) region of 82,262 bp, a small single copy (SSC) region of 17,537 bp, and two separated inverted regions of 25,611 bp each. It contains 130 unique genes, including 85 protein-coding genes, 37 tRNA genes, and 8 rRNA genes. Based on the chloroplast genomes data of 26 species in Salvia, our result indicated that S. leucantha, S. tiliifolia, S. hispanica, and S. splendens formed one clade with Bootstrap = 100%. The four species belong to Salvia subgenus Calosphace, and S. leucantha was closely related to Salvia tiliifolia and Salvia hispanica. This result will facilitate population, genetic diversity and phylogenetic studies of S. leucantha.

Naringenin alleviates myocardial ischemia/reperfusion injury by regulating the nuclear factor-erythroid factor 2-related factor 2 (Nrf2) /System xc-/ glutathione peroxidase 4 (GPX4) axis to inhibit ferroptosis.

Ferroptosis is an important form of myocardial cell death in myocardial ischemia-reperfusion injury (MIRI). Naringenin (NAR), as a flavonoid, has a significant advantage in improving MIRI. But the regulatory effect and mechanism of NAR on ferroptosis in MIRI have not been reported. After the rats were given NAR and induced to form myocardial ischemia-reperfusion (MI/R) injury, Tetrazolium chloride (TTC) staining was used to detect the myocardial infarction area of rats, and Hematoxylin-eosin (H&E) staining was used to detect myocardial injury. The markers of tissue inflammation were detected by ELISA. Serum creatine kinase Serum creatin kinase (CPK), Lactate dehydrogenase (LDH), and lipid peroxide (LPO) and oxidative stress related levels were measured. In addition, iron detection kits were used to detect total iron and Fe2+ levels in cardiac tissues, and western blot was used to detect the expression of ferroptosis-related proteins and the expression of nuclear factor-erythroid factor 2-related factor 2 (Nrf2) and glutathione peroxidase 4 (GPX4). At the cellular level, H9C2 cardiomyocytes were induced by hypoxia/reoxygenation (H/R), and ferroptosis inducer Erastin was administered to detect cell viability, ferroptosis-related indicators, oxidative stress related indicators, and expressions of Nrf2 and GPX4, to explore the mechanisms involved. NAR alleviated MI/R-induced pathological damage, inflammation and lipid peroxidation in myocardial tissue of rats. NAR adjusted the NRF2 /System xc - /GPX4 axis and improved ferroptosis. At the cellular level, ferroptosis inducer Erastin reversed the protective effect of NAR on H/R-induced H9C2 cardiomyocytes. In conclusion, NAR can alleviate MIRI by regulating the Nrf2/System xc-/GPX4 axis to inhibit ferroptosis.

Synergistic antibacterial polyacrylonitrile/gelatin nanofibers coated with metal-organic frameworks for accelerating wound repair.

Bacterial infections prolong the wound healing time and increase the suffering of patients, thus it is important to develop wound dressing that can inhibit bacterial infection. Herein, we use two methods including "doping method" and "secondary growth method" to prepare ZIF-8@gentamicin embedded in and coated on polyacrylonitrile/gelatin (PG) nanofibers, separately. Composite nanofibers prepared by the secondary growth method achieve higher drug loading than that of the doping method, and the release rate can be adjusted by pH. Simultaneously increasing drug loading and regulating its release rate are achieved in the secondary growth method, which cannot be achieved by the doping method. Furthermore, synergistic antibacterial property occurs in the composite nanofibers prepared by the secondary growth method, and gentamicin loaded on ZIF-8 promotes the antibacterial effect, which shows better antibacterial effect than the doping method. As a result, during the wound infection of mouse, composite nanofibers prepared by the secondary growth method exhibit a faster recovery effect than the doping method, which effectively shortened the wound healing time from 21 days to 16 days.

Effect of aspirin in takotsubo syndrome: protocol of a systematic review and meta-analysis.

INTRODUCTION: Takotsubo syndrome (TTS) is a sudden reversible weakening of the left ventricle function induced by severe stress and resembles many features as acute coronary syndrome. Even though many guidelines had been published about TTS, there is no consensus regarding the long-term treatment. Aspirin is one of the most common prescribed medicines at discharge for patients with the intention to reduce thrombus events and improve the overall prognosis. However, existing studies yielded conflicting results concerning its effects. This study aims to evaluate the impact of long-term maintenance treatment of aspirin in TTS and provides insights in clinical management. METHODS AND ANALYSIS: After searching through electronic databases (PubMed, Embase, Cochrane Library, Web of Science, National Library of Medicine Gateway, CNKI, Wanfang and VIP), grey literatures, conference abstract and trial registries for clinical studies investigating the impact of aspirin on patients with TTS, a systemic review and meta-analysis will be conducted. The search will be limited from inception of each database to 1 August 2020. The outcomes including all-cause death, TTS recurrence, stroke, transient ischaemic attack or myocardial infarction at 30-day and 5-year follow-up will be examined. Risk of bias will be assessed by Newcastle-Ottawa quality assessment scale for observational studies and Cochrane Effective Practice and Organization of Care evaluation tool for interventional studies. Grading of Recommendations Assessment, Development and Evaluations method will be applied to assess the quality of evidence. If available, the effects of aspirin on the above outcomes for patients with TTS will be evaluated using random-effect modelling with relative risk at 95% CIs. Subgroup analysis and sensitivity analysis will also be performed when possible. ETHICS AND DISSEMINATION: Ethics approval was not required due to the retrospective nature of the study. Results of the review will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42020212729.

Genetic Variability of the SARS-CoV-2 Pocketome.

In the absence of effective treatment, COVID-19 is likely to remain a global disease burden. Compounding this threat is the near certainty that novel coronaviruses with pandemic potential will emerge in years to come. Pan-coronavirus drugs-agents active against both SARS-CoV-2 and other coronaviruses-would address both threats. A strategy to develop such broad-spectrum inhibitors is to pharmacologically target binding sites on SARS-CoV-2 proteins that are highly conserved in other known coronaviruses, the assumption being that any selective pressure to keep a site conserved across past viruses will apply to future ones. Here we systematically mapped druggable binding pockets on the experimental structure of 15 SARS-CoV-2 proteins and analyzed their variation across 27 α- and ß-coronaviruses and across thousands of SARS-CoV-2 samples from COVID-19 patients. We find that the two most conserved druggable sites are a pocket overlapping the RNA binding site of the helicase nsp13 and the catalytic site of the RNA-dependent RNA polymerase nsp12, both components of the viral replication-transcription complex. We present the data on a public web portal (https://www.thesgc.org/SARSCoV2_pocketome/), where users can interactively navigate individual protein structures and view the genetic variability of drug-binding pockets in 3D.