Discovery and Optimization of Novel SaFabI Inhibitors as Specific Therapeutic Agents for MRSA Infection.

As the rate-limiting enzyme in fatty acid biosynthesis, Staphylococcus aureus enoyl-acyl carrier protein reductase (SaFabI) emerges as a compelling target for combating methicillin-resistant S. aureus (MRSA) infections. Herein, compound 1, featuring a 4-(1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one scaffold, was identified as a potent SaFabI inhibitor (IC50 = 976.8 nM) from an in-house library. Subsequent optimization yielded compound n31, with improved inhibitory efficacy on enzymatic activity (IC50 = 174.2 nM) and selective potency against S. aureus (MIC = 1-2 µg/mL). Mechanistically, n31 directly inhibited SaFabI in cellular contexts. Moreover, n31 exhibited favorable safety and pharmacokinetic profiles, and dose-dependently treated MRSA-induced skin infections, outperforming the approved drug, linezolid. The chiral separation of n31 resulted in (S)-n31, with superior activities (IC50 = 94.0 nM, MIC = 0.25-1 µg/mL) and in vivo therapeutic efficacy. In brief, our research proposes (S)-n31 as a promising candidate for SaFabI-targeted therapy, offering specific anti-S. aureus efficacy and potential for further development.

Can pre-exercise photobiomodulation improve muscle endurance and promote recovery from muscle strength and injuries in people with different activity levels? A meta-analysis of randomized controlled trials.

Photobiomodulation therapy (PBMT) was introduced as an ergogenic aid for sport performance in healthy individuals is still controversial. The main aim of this study is to assess the potential enhancements in muscle endurance and recovery from muscle strength and injuries mediated by PBMT among individuals exhibiting diverse activity levels. Randomized controlled trials (RCT) of PBMT interventions for healthy people (both trained and untrained individuals) exercising were searched (up to January 16, 2024) in four electronic databases: Web of Science, PubMed, Scopus and Embase. Primary outcome measures included muscle endurance, muscle strength and creatine kinase (CK) levels; secondary outcome measure included Lactate dehydrogenase (LDH) levels. Subgroup analyses based on physical activity levels were conducted for each outcome measure. Thirty-four RCTs were included based on the article inclusion and exclusion criteria. Statistical results showed that PBMT significantly improved muscle endurance (standardized mean difference [SMD] = 0.31, 95%CI 0.11, 0.51, p < 0.01), indicating a moderate effect size. It also facilitated the recovery of muscle strength (SMD = 0.24, 95%CI 0.10, 0.39, p < 0.01) and CK (mean difference [MD] = -77.56, 95%CI -112.67, -42.44, p < 0.01), indicating moderate and large effect sizes, respectively. Furthermore, pre-application of PBMT significantly improved muscle endurance, recovery of muscle strength and injuries in physically inactive individuals and athletes (p < 0.05), while there was no significant benefit for physically active individuals. Pre-application of PBMT improves muscle endurance and promotes recovery from muscle strength and injury (includes CK and LDH) in athletes and sedentary populations, indicating moderate to large effect sizes, but is ineffective in physically active populations. This may be due to the fact that physically active people engage in more resistance training, which leads to a decrease in the proportion of red muscle fibres, thus affecting photobiomodulation.

Discovery of 2,8-dihydroxyadenine in HUA patients with uroliths and biomarkers for its associated nephropathy.

Currently, it is acknowledged that gout is caused by uric acid (UA). However, some studies have revealed no correlation between gout and UA levels, and growing evidence suggests that 2,8-dihydroxyadenine (2,8-DHA), whose structural formula is similar to UA but is less soluble, may induce gout. Hence, we hypothesized that uroliths from hyperuricemia (HUA) patients, which is closely associated with gout, may contain 2,8-DHA. In this study, 2,8-DHA in uroliths and serum of HUA patients were determined using HPLC. Moreover, bioinformatics was used to investigate the pathogenic mechanisms of 2,8-DHA nephropathy. Subsequently, a mouse model of 2,8-DHA nephropathy established by the gavage administration of adenine, as well as a model of injured HK-2 cells induced by 2,8-DHA were used to explore the pathogenesis of 2,8-DHA nephropathy. Interestingly, 2,8-DHA could readily deposit in the cortex of the renal tubules, and was found in the majority of these HUA patients. Additionally, the differentially expressed genes between 2,8-DHA nephropathy mice and control mice were found to be involved in inflammatory reactions. Importantly, CCL2 and IL-1ß genes had the maximum degree, closeness, and betweenness centrality scores. The expressions of CCL2 and IL-1ß genes were significantly increased in the serum of 24 HUA patients with uroliths, indicating that they may be significant factors for 2,8-DHA nephropathy. Further analysis illustrated that oxidative damage and inflammation were the crucial processes of 2,8-DHA renal injury, and CCL2 and IL-1ß genes were verified to be essential biomarkers for 2,8-DHA nephropathy. These findings revealed further insights into 2,8-DHA nephropathy, and provided new ideas for its diagnosis and treatment.

Umbilical artery thrombosis risk factors and perinatal outcomes.

PURPOSE: The purpose of this study was to investigate the risk factors for umbilical artery thrombosis (UAT) and the relationship between umbilical artery thrombosis and perinatal outcomes. METHODS: This was a retrospective study that enrolled singleton pregnant women who were diagnosed with umbilical artery thrombosis. The control group recruited pregnant woman with three umbilical vessels or those with isolated single umbilical artery (iSUA) who were matched with umbilical artery thrombosis group. The risk factors and perinatal outcomes were compared between the groups. RESULTS: Preconception BMI (OR [95%CI]: 1.212 [1.038-1.416]), abnormal umbilical cord insertion (OR [95%CI]: 16.695 [1.333-209.177]) and thrombophilia (OR [95%CI]: 15.840 [1.112-223.699]) were statistically significant risk factors for umbilical artery thrombosis. An elongated prothrombin time (OR [95%CI]: 2.069[1.091-3.924]) was strongly associated with the occurrence of UAT. The risks of cesarean delivery, preterm birth, fetal growth restriction, neonatal asphyxia, and intraamniotic infection were higher in pregnancies with UAT than in pregnancies with three umbilical vessels or isolated single umbilical artery (P<0.05). Additionally, the incidence of thrombophilia was higher in pregnant women with umbilical artery thrombosis than those with isolated single umbilical artery (P = 0.032). Abnormal umbilical cord insertion was also found to be associated with an elevated risk of iSUA (OR [95%CI]: 15.043[1.750-129.334]). CONCLUSIONS: Abnormal umbilical cord insertion was the risk factor for both umbilical artery thrombosis and isolated single umbilical artery. The pregnancies with umbilical artery thrombosis had a higher risk of the adverse perinatal outcomes.

Analysis of mandibular asymmetry in adolescent and adult patients with unilateral posterior crossbite on cone-beam computed tomography.

INTRODUCTION: This study aimed to evaluate mandibular asymmetry in unilateral posterior crossbite (UPXB) patients and compare the asymmetry between adolescents and adults with UPXB. METHODS: This study included and analyzed cone-beam computed tomography scans of 125 subjects. The subjects were divided into a UPXB group and a control group according to the presence or absence of UPXB, and each group included adolescent patients (aged 10-15 years) and adult patients (aged 20-40 years). Linear, angular, and volumetric measurements were obtained to evaluate the asymmetries of the mandibles. RESULTS: Both adolescent and adult patients in the UPXB group presented asymmetries in condylar unit length, ramal height, body length, and mediolateral ramal inclination (P <0.05). Adult patients with UPXB showed greater asymmetries than adolescents. Differences with condylar unit length, condylar unit width, ramal height, condylar unit volume, and hemimandibular volume were significantly greater in adult UPXB patients than adolescent UPXB patients (P <0.05). CONCLUSIONS: The worsening of mandibular asymmetries in UPXB adults suggests that asymmetry in UPXB patients may progress over time; therefore, early treatment should be considered for UPXB adolescent patients. Further studies are still needed to evaluate the effectiveness of early treatment.

Gastroesophageal Reflux Disease and Rhinosinusitis: A Bidirectional Mendelian Randomization Study.

INTRODUCTION: Comorbidities, such as gastroesophageal reflux disease (GERD), are common in patients with rhinosinusitis (RS). However, the link between RS and GERD has not been fully understood. This study aimed to investigate the causal relationship between GERD and acute (ARS) or chronic RS (CRS), providing references for the pathogenesis and management of RS. METHODS: The data were obtained from the Integrative Epidemiology Unit Open GWAS project and FinnGen. A total of 972,838 individuals were included. The inverse variance-weighted (IVW) method was applied to obtain the primary results of the study. Weighted median, MR-Egger, and mode-based methods were used to determine the robustness of the results. Cochran's Q statistic and MR-Egger method were applied to detect heterogeneity and pleiotrophy in instrumental variables (IVs). Other sensitivity analyses included MR-PRESSO and leave-one-out analysis. RESULTS: The MR study showed that GERD was associated with an increased risk of CRS (OR: 1.36, 95% CI: 1.18-1.57, p < 0.001). The results of other analysis methods were broadly consistent with the IVW estimate. No heterogeneity was detected by Cochran's Q test (p = 0.061) and MR-PRESSO (p = 0.074). No horizontal pleiotropy was shown in IVs (p = 0.700). GERD was also associated with an increased risk of ARS (OR: 1.31, 95% CI: 1.17-1.48, p < 0.001). Some analytical results were inconsistent with the IVW estimate. No heterogeneity and pleiotropy were observed. There was no sufficient evidence for a reverse causal effect of RS on GERD. CONCLUSION: Our study supported that GERD promoted the risk of CRS and may be a potential risk factor for ARS. This provides additional support for further investigation into the mechanisms of GERD on RS.

Machine Learning Approach to Analyze the Heavy Quark Diffusion Coefficient in Relativistic Heavy Ion Collisions.

The diffusion coefficient of heavy quarks in a deconfined medium is examined in this research using a deep convolutional neural network (CNN) that is trained with data from relativistic heavy ion collisions involving heavy flavor hadrons. The CNN is trained using observables such as the nuclear modification factor RAA and the elliptic flow v2 of non-prompt J/ψ from the B-hadron decay in different centralities, where B meson evolutions are calculated using the Langevin equation and the instantaneous coalescence model. The CNN outputs the parameters, thereby characterizing the temperature and momentum dependence of the heavy quark diffusion coefficient. By inputting the experimental data of the non-prompt J/ψ(RAA,v2) from various collision centralities into multiple channels of a well-trained network, we derive the values of the diffusion coefficient parameters. Additionally, we evaluate the uncertainty in determining the diffusion coefficient by taking into account the uncertainties present in the experimental data (RAA,v2), which serve as inputs to the deep neural network.

The relationship between gut microbiota, short-chain fatty acids, and glucolipid metabolism in pregnant women with large for gestational age infants.

AIM: To elucidate the association between gut microbiota, short-chain fatty acids (SCFAs), and glucolipid metabolism in women with large for gestational age (LGA) infants. METHODS AND RESULTS: A single-center, observational prospective cohort study was performed at a tertiary hospital in Wenzhou, China. Normal pregnant women were divided into LGA group and appropriate for gestational age (AGA) group according to the neonatal birth weight. Fecal samples were collected from each subject before delivery for the analysis of gut microbiota composition (GMC) and SCFAs. Blood samples were obtained at 24-28 weeks of gestation age to measure fasting blood glucose and fasting insulin levels, as well as just before delivery to assess serum triglycerides, total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein. The GMC exhibited differences at various taxonomic levels. Within the Firmicutes phylum, genus Lactobacillus, genus Clostridium, species Lactobacillus agil, and species Lactobacillus salivarius were enriched in the LGA group. Microbispora at genus level, Microbispora rosea at species level belonging to the Actinobacteria phylum, Neisseriales at order level, Bartonellaceae at family level, Paracoccus aminovorans, and Methylobacterium at genus level from the Proteobacteria phylum were more abundant in the LGA group. In contrast, within the Bacteroidetes phylum, Prevotella at genus level and Parabacteroides distasonis at species level were enriched in the AGA group. Although there were few differences observed in SCFA levels and most glucolipid metabolism indicators between the two groups, the serum HDL level was significantly lower in the LGA group compared to the AGA group. No significant relevance among GMC, SCFAs, and glucolipid metabolism indicators was found in the LGA group or in the AGA group. CONCLUSIONS: Multiple different taxa, especially phylum Firmicutes, genus Prevotella, and genus Clostridium, might play an important role in excessive fetal growth, and LGA might be associated with the lower serum HDL level.

Associations between the size and duration of asymptomatic subchorionic hematoma and pregnancy outcomes in women with singleton pregnancies.

BACKGROUND: The purpose of this study was to investigate the relationship between the size and duration of asymptomatic subchorionic hematoma and pregnancy outcomes in women with singleton pregnancies. METHODS: This was a retrospective study that enrolled 701 singleton pregnant women who were diagnosed with asymptomatic subchorionic hematoma by ultrasound at 5-10 gestational weeks. The control group recruited 640 normal pregnant women without subchorionic hematoma who were matched with subchorionic hematoma group on baseline characteristics. The pregnancy outcomes were compared between the two groups, and the associations of the size and duration of subchorionic hematoma with pregnancy outcomes were analyzed by logistic regression model. RESULTS: Compared with the normal pregnancy group, the incidence of, gestational diabetes mellitus, gestational thrombocytopenia, placenta adhesion, fetal growth restriction, macrosomia in subchorionic hematoma group were higher (all P < 0.05). After adjusting for confounding factors, the hematoma size was positively associated with the occurrence of gestational hypothyroidism (adjusted OR[95%CI]: 1.029[1.004-1.054]), intrahepatic cholestasis of pregnancy (adjusted OR[95%CI]: 1.095[1.047-1.146]), term premature rupture of membranes (adjusted OR[95%CI]: 1.044[1.005-1.085]), hypertensive disorders of pregnancy (adjusted OR[95%CI]: 1.030[1.0004-1.060]), gestational thrombocytopenia (adjusted OR[95%CI]: 1.078 [1.045-1.113]), placenta adhesion (adjusted OR[95%CI]: 1.054 [1.027-1.082]), and the duration of hematoma was positively associated with the incidence of term premature rupture of membranes (adjusted OR[95%CI]: 1.070[1.027-1.115]), gestational diabetes mellitus (adjusted OR[95%CI]: 1.938 [1.886-1.993]) and fetal growth restriction (adjusted OR[95%CI]: 1.194 [1.124-1.268]). CONCLUSIONS: The presence, size and duration of a first-trimester asymptomatic subchorionic hematoma may be associated with adverse pregnancy outcomes at later gestations such as term premature rupture of membranes and fetal growth restriction.

Tanshinone IIA changed the amniotic fluid volume and regulated expression of AQP1 and AQP3 in amniotic epithelium cells: a promising drug treating abnormal amniotic fluid volume.

BACKGROUND: Many studies have confirmed the association of aquaporins (AQPs) with abnormal amniotic fluid volume (AFV). In our previous experiments, we found that Tanshinone IIA was able to regulate the expression of AQP1 and AQP3. However, the exact mechanism by which Tanshinone IIA regulates AQPs protein expression and its effect on AFV remains unclear. The purpose of this study was to investigate the effects of Tanshinone IIA on AFV and the possible molecular mechanism of regulation of AQP1 and AQP3. METHODS: The expression of AQPs protein in the amniotic membranes was compared between pregnant women with normal pregnancy and those with isolated oligohydramnios. The AQP1 knockout (AQP1-KO) mice and wild-type (WT) mice were treated with saline or Tanshinone IIA (10 mg/kg) at 13.5GD and 16.5GD. Human amniotic epithelium cells (hAECs) from pregnant women with normal AFV and isolated oligohydramnios were incubated with 35 µmmol/L Tanshinone IIA or 25 mmol/L LiCl [inhibitor of glycogen synthetic kinase 3ß (GSK-3ß)]. The protein expressions of AQPs, GSK-3ß, phospho-GSK-3ß (Ser9) in fetal membranes of mice and human amniotic epithelium cells were detected by western blotting. RESULTS: The expression of AQP1 protein in the amniotic membrane of isolated oligohydramnios was increased compared with normal pregnancy. The AFV in AQP1-KO mice is higher than that in WT mice. In wild-type mice, AFV in Tanshinone IIA group was significantly higher than that in control group, and AQP1 protein expression was significantly lower than that in control group, but in AQP1 knockout mice, Tanshinone IIA reduced amniotic fluid volume and AQP3 protein expression at 16.5GD. Tanshinone IIA reduced AQP1, AQP3 and p-GSK-3ß (Ser9) protein expression in normal hAECs, and this effect was inhibited by LiCl. In hAECs with oligohydramnios, the down-regulation of AQP1 and up-regulation of AQP3 by Tanshinone IIA was independent of GSK-3ß signaling pathway. CONCLUSIONS: Tanshinone IIA may increase AFV in normal pregnancy by downregulating AQP1 protein expression in the fetal membranes, which may be associated with p-GSK-3ß signaling pathway. But a larger AFV in AQP1-KO mice was significantly attenuated by Tanshinone IIA, which may be related to AQP3. Tanshinone IIA is a promising drug for the treatment of amniotic fluid abnormality.

Berberine attenuates uric acid-induced cell injury by inhibiting NLRP3 signaling pathway in HK-2 cells.

Hyperuricemia (HUA) is a common chronic metabolic disease that can cause renal failure and even death in severe cases. Berberine (BBR) is an isoquinoline alkaloid derived from Phellodendri Cortex with strong antioxidant, anti-inflammatory, and anti-apoptotic properties. The purpose of this study was to investigate the protective effects of berberine (BBR) against uric acid (UA)-induced HK-2 cells and unravel their regulatory potential mechanisms. The CCK8 assay was carried out to detect cell viability. The expression levels of inflammatory factors interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) and Lactate dehydrogenase (LDH) were measured using Enzyme-linked immunosorbent assays (ELISA). The expression of the apoptosis-related protein (cleaved-Caspase3, cleaved-Caspase9, BAX, BCL-2) was detected by western blot. The effects of BBR on the activities of the NOD-like receptor family pyrin domain containing 3 (NLRP3) and the expression of the downstream genes were determined by RT-PCR and western blot in HK-2 cells. From the data, BBR significantly reversed the up-regulation of inflammatory factors (IL-1ß, IL-18) and LDH. Furthermore, BBR down-regulated protein expression of pro-apoptotic proteins BAX, cleaved caspase3 (cl-Caspase3), cleaved caspase9 (cl-Caspase9), and enhanced the expression of antiapoptotic protein BCL-2. Simultaneously, BBR inhibited the activated NLPR3 and reduced the mRNA levels of NLRP3, Caspase1, IL-18, and IL-1ß. Also, BBR attenuated the expression of NLRP3 pathway-related proteins (NLRP3, ASC, Caspase1, cleaved-Caspase1, IL-18, IL-1ß, and GSDMD). Furthermore, specific NLRP3-siRNA efficiently blocked UA-induced the level of inflammatory factors (IL-1ß, IL-18) and LDH and further inhibited activated NLRP3 pathway. Collectively, our results suggested that BBR can alleviate cell injury induced by UA. The underlying unctionary mechanism may be through the NLRP3 signaling pathway.

Brucea javanica oil alleviates intestinal mucosal injury induced by chemotherapeutic agent 5-fluorouracil in mice.

Background: Brucea javanica (L.) Merr, has a long history to be an anti-dysentery medicine for thousand of years, which is commonly called "Ya-Dan-Zi" in Chinese. The common liquid preparation of its seed, B. javanica oil (BJO) exerts anti-inflammatory action in gastrointestinal diseases and is popularly used as an antitumor adjuvant in Asia. However, there is no report that BJO has the potential to treat 5-Fluorouracil (5-FU)-induced chemotherapeutic intestinal mucosal injury (CIM). Aim of the study: To test the hypothesis that BJO has potential intestinal protection on intestinal mucosal injury caused by 5-FU in mice and to explore the mechanisms. Materials and methods: Kunming mice (half male and female), were randomly divided into six groups: normal group, 5-FU group (5-FU, 60 mg/kg), LO group (loperamide, 4.0 mg/kg), BJO group (0.125, 0.25, 0.50 g/kg). CIM was induced by intraperitoneal injection of 5-FU at a dose of 60 mg/kg/day for 5 days (from day 1 to day 5). BJO and LO were given orally 30 min prior to 5-FU administration for 7 days (from day 1 to day 7). The ameliorative effects of BJO were assessed by body weight, diarrhea assessment, and H&E staining of the intestine. Furthermore, the changes in oxidative stress level, inflammatory level, intestinal epithelial cell apoptosis, and proliferation, as well as the amount of intestinal tight junction proteins were evaluated. Finally, the involvements of the Nrf2/HO-1 pathway were tested by western blot. Results: BJO effectively alleviated 5-FU-induced CIM, as represented by the improvement of body weight, diarrhea syndrome, and histopathological changes in the ileum. BJO not only attenuated oxidative stress by upregulating SOD and downregulating MDA in the serum, but also reduced the intestinal level of COX-2 and inflammatory cytokines, and repressed CXCL1/2 and NLRP3 inflammasome activation. Moreover, BJO ameliorated 5-FU-induced epithelial apoptosis as evidenced by the downregulation of Bax and caspase-3 and the upregulation of Bcl-2, but enhanced mucosal epithelial cell proliferation as implied by the increase of crypt-localized proliferating cell nuclear antigen (PCNA) level. Furthermore, BJO contributed to the mucosal barrier by raising the level of tight junction proteins (ZO-1, occludin, and claudin-1). Mechanistically, these anti-intestinal mucositis pharmacological effects of BJO were relevant for the activation of Nrf2/HO-1 in the intestinal tissues. Conclusion: The present study provides new insights into the protective effects of BJO against CIM and suggests that BJO deserves to be applied as a potential therapeutic agent for the prevention of CIM.

Behavioral Interpretation of Willingness to Use Wearable Health Devices in Community Residents: A Cross-Sectional Study.

Wearable health devices (WHDs) have become increasingly advantageous in long-term health monitoring and patient management. However, most people have not yet benefited from such innovative technologies, and the willingness to accept WHDs and their influencing factors are still unclear. Based on two behavioral theories: the theory of planned behavior (TPB) and the diffusion of innovation (DOI), this study aims to explore the influencing factors of willingness to use WHDs in community residents from the perspective of both internal and external factors. A convenience sample of 407 community residents were recruited from three randomly selected Community Health Service Centers (CHSCs) in Nanjing, China, and were investigated with a self-developed questionnaires. The mean score of willingness to use WHDs was 17.00 (range 5-25). In the dimensions of TPB, perceived behavioral control (ß = 1.979, p < 0.001) was the strongest influencing factor. Subjective norms (ß = 1.457, p < 0.001) and attitudes (ß = 0.651, p = 0.016) were also positively associated with willingness. In innovation characteristics of DOI, compatibility (ß = 0.889, p < 0.001) and observability (ß = 0.576, p = 0.003) had positive association with the willingness to wear a WHD. This study supports the applicability of the two behavioral theories to interpret the willingness to use WHDs in Chinese community residents. Compared with the innovative features of WHDs, individual cognitive factors were more critical predictors of willingness to use.

Objective sleep characteristics and continuous glucose monitoring profiles of type 2 diabetes patients in real-life settings.

AIM: To investigate the association between objective sleep parameters and glycaemic variability determined by continous glucose monitoring (CGM) among patients with type 2 diabetes, given the significant role of sleep in glycaemic control. METHODS: In this study, CGM was carried out in 28 patients with T2D (aged 62.3 ± 4.8 years, 57% women). Sleep characteristics were assessed by actigraphy within the CGM period. CGM-derived outcomes included glucose level, and percentages of time in range (TIR) and time above range (TAR) during the monitoring period. Associations between intraindividual night-to-night variations in sleep characteristics and overall CGM outcomes were analysed using linear regression. Associations between sleep characteristics during each night and time-matched CGM outcomes were analysed using linear mixed models. RESULTS: A total of 249 person-days of CGM, coupled with 221 nights of sleep characteristics, were documented. Greater standard deviation (SD) of objective sleep duration (minutes) between measurement nights was associated with higher glucose level (coefficient 0.018 mmol/L [95% confidence interval {CI} 0.004, 0.033], P = 0.017), smaller proportion of TIR (% in observation period; coefficient -0.20% [95% CI -0.36, -0.03], P = 0.023), and greater proportion of TAR (coefficient 0.22% [95% CI 0.06, 0.39], P = 0.011). Later sleep midpoint (minutes from midnight) was associated with greater SD of glucose during the same sleep period (coefficient 0.002 minutes [95% CI 0.0001, 0.003], P = 0.037), longer nocturnal sleep duration was associated with smaller coefficient of variation of glucose level in the upcoming day (-0.015% [95% CI -0.03, -0.001], P = 0.041). CONCLUSION: Objectively determined sleep duration and sleep midpoint, as well as their daily variability, are associated with CGM-derived glucose profiles in T2D patients.

Activation of Swell1 in microglia suppresses neuroinflammation and reduces brain damage in ischemic stroke.

Cl- movement and Cl--sensitive signal pathways contributes to the survival and switch of inflammatory phenotype of microglia and are believed to play a key role in the inflammatory brain injury after ischemic stroke. Here, we demonstrated an important role of Cl- transmembrane transporter Swell1, in the survival and M2-like polarization of microglia in ischemic stroke. Knockdown or overexpression of Swell1 in cultured microglia inhibited or increased hypotonic-activated Cl- currents, respectively, and these changes were completely blocked by the volume-regulated anion channels (VRACs) inhibitor DCPIB. Swell1 conditional knock-in mice promoted microglia survival in ischemic brain region and resulted in significant reductions in neural cell death, infarction volume and neurological deficits following transient middle cerebral artery occlusion (tMCAO). Using gene manipulating technique and pharmacological inhibitors, we further revealed that Swell1 opening led to SGK1 (a Cl--sensitive kinase)-mediated activation of FOXO3a/CREB as well as WNK1 (another Cl--sensitive kinase)-mediated SPAK/OSR1-CCCs activation, which promoted microglia survival and M2-like polarization, thereby attenuating neuroinflammation and ischemic brain injury. Taken together, our results demonstrated that Swell1 is an essential component of microglia VRACs and its activation protects against ischemic brain injury through promoting microglia survival and M2-like polarization.

Metabolic and Transcriptomic Profiling Reveals Etiolated Mechanism in Huangyu Tea (Camellia sinensis) Leaves.

Leaf color is one of the key factors involved in determining the processing suitability of tea. It relates to differential accumulation of flavor compounds due to the different metabolic mechanisms. In recent years, photosensitive etiolation or albefaction is an interesting direction in tea research field. However, the molecular mechanism of color formation remains unclear since albino or etiolated mutants have different genetic backgrounds. In this study, wide-target metabolomic and transcriptomic analyses were used to reveal the biological mechanism of leaf etiolation for 'Huangyu', a bud mutant of 'Yinghong 9'. The results indicated that the reduction in the content of chlorophyll and the ratio of chlorophyll to carotenoids might be the biochemical reasons for the etiolation of 'Huangyu' tea leaves, while the content of zeaxanthin was significantly higher. The differentially expressed genes (DEGs) involved in chlorophyll and chloroplast biogenesis were the biomolecular reasons for the formation of green or yellow color in tea leaves. In addition, our results also revealed that the changes of DEGs involved in light-induced proteins and circadian rhythm promoted the adaptation of etiolated tea leaves to light stress. Variant colors of tea leaves indicated different directions in metabolic flux and accumulation of flavor compounds.

A Comprehensive Review on Beneficial Effects of Catechins on Secondary Mitochondrial Diseases.

Mitochondria are the main sites for oxidative phosphorylation and synthesis of adenosine triphosphate in cells, and are known as cellular power factories. The phrase "secondary mitochondrial diseases" essentially refers to any abnormal mitochondrial function other than primary mitochondrial diseases, i.e., the process caused by the genes encoding the electron transport chain (ETC) proteins directly or impacting the production of the machinery needed for ETC. Mitochondrial diseases can cause adenosine triphosphate (ATP) synthesis disorder, an increase in oxygen free radicals, and intracellular redox imbalance. It can also induce apoptosis and, eventually, multi-system damage, which leads to neurodegenerative disease. The catechin compounds rich in tea have attracted much attention due to their effective antioxidant activity. Catechins, especially acetylated catechins such as epicatechin gallate (ECG) and epigallocatechin gallate (EGCG), are able to protect mitochondria from reactive oxygen species. This review focuses on the role of catechins in regulating cell homeostasis, in which catechins act as a free radical scavenger and metal ion chelator, their protective mechanism on mitochondria, and the protective effect of catechins on mitochondrial deoxyribonucleic acid (DNA). This review highlights catechins and their effects on mitochondrial functional metabolic networks: regulating mitochondrial function and biogenesis, improving insulin resistance, regulating intracellular calcium homeostasis, and regulating epigenetic processes. Finally, the indirect beneficial effects of catechins on mitochondrial diseases are also illustrated by the warburg and the apoptosis effect. Some possible mechanisms are shown graphically. In addition, the bioavailability of catechins and peracetylated-catechins, free radical scavenging activity, mitochondrial activation ability of the high-molecular-weight polyphenol, and the mitochondrial activation factor were also discussed.

Generation and [2,3]-Sigmatropic Rearrangement of Ammonium Ylides from Cyclopropyl Ketones for Chiral Indolizidines with Bridgehead Quaternary Stereocenters.

A sequence of nucleophilic ring opening of cyclopropyl ketones, N-quaternization, deprotonation, and [2,3]-sigmatropic rearrangement of ammonium ylides has been developed. This method enables efficient synthesis of bicyclic indolizidines bearing bridgehead aza-quaternary stereocenters from easily available chiral cyclopropyl ketones. The reactions proceeded with an excellent level of chirality transfer and tolerated various functional groups, providing a diverse array of allenyl- or allyl-substituted indolizidines with high enantiomeric purities (up to >99% ee).

Labor characteristics and intrapartum interventions in women with vaginal birth after cesarean section.

BACKGROUND: With the development of China's two-child-policy, vaginal birth after cesarean section (VBAC) has aroused public concern. It is important to understand the labour characteristics and intrapartum management of women attempting VBAC to enhance the rates of successful VBAC. The purpose of our research was to investigate the differences in the characteristics of labor, intervention measures and perinatal outcomes between women who had a VBAC and primiparas or multiparas not undergoing VBAC, providing clinical references of intrapartum management for women who are planning a VBAC. MATERIAL AND METHODS: This observational retrospective study enrolled all women who laboured spontaneously and who had a VBAC (n = 139) at the Second Affiliated Hospital of Wenzhou Medical University in China between 2016 and 2019. They were allocated into VBAC group A (the previous cesarean section was performed before dilation of the cervix) and VBAC group B (the previous cesarean section was performed after dilation of the cervix). The primipara control group included 149 primiparae, and the multipara control group included 155 multiparae with second vaginal birth. Durations of labor, intervention measures and perinatal outcomes were compared among the groups. RESULTS: The durations of labor, intrapartum interventions and maternal and neonatal outcomes in VBAC group A were similar to those of the VBAC group B. However, all women who had a VBAC and those in VBAC group A had shorter first, second and the total stages of labor than primiparae. All women with VBAC and those in VBAC group B had longer second stage of labor, but shorter third stage of labor than multiparae. Oxytocin, labor analgesia and artificial rupture of membranes were administered less often in women with VBAC than in primiparae, while phloroglucinol was administered more often in women with VBAC than in multiparae. Women who had a VBAC were more likely to receive episiotomy and had higher incidences of postpartum hemorrhage than primipara and multipara women. CONCLUSIONS: Labor characteristics, intrapartum interventions and perinatal outcomes in women who had a VBAC with cervical dilation were similar to those in women who had a VBAC without cervical dilation before the previous cesarean section, but differed significantly from those of multiparae and primiparae who did not undergo VBAC.

Andrographolide sodium bisulfite ameliorates dextran sulfate sodium-induced colitis and liver injury in mice via inhibiting macrophage proinflammatory polarization from the gut-liver axis.

Ulcerative colitis (UC), an inflammatory disease, is widely thought to be associated with colonic barrier damage and inflammatory response. With the destruction of the colonic barrier, lipopolysaccharide (LPS) enters the liver through the portal vein and causes liver injury. Liver injury in turn exacerbates UC to form a vicious cycle, so the treatment of liver injury cannot be ignored. Andrographolide (Andro) has a protective effect against colitis and liver injury, but with low bioavailability. Andrographolide sodium bisulfite (ASB), a water-soluble sulfonate of Andro, has better bioavailability, whether it has a better curative effect against UC and liver injury is rarely reported. Hence, we investigated the protective effect and potential mechanism of ASB against dextran sulfate sodium (DSS)-induced UC and liver injury in mice. The results showed that treatment with ASB significantly relieved the clinical symptoms of UC and liver injury by reducing disease activity index, inhibiting gut-derived LPS leakage, and improving colonic and hepatic injury, and its curative effect was better than Andro. Moreover, ASB effectively decreased the YAP-mediated colonic inflammation and TLR4/MyD88/NF-κB-mediated pro-inflammatory factor release in the liver. Both colonic and hepatic inflammation were associated with macrophage proinflammatory polarization, but they were significantly inhibited by ASB. ASB showed good safety in the treatment of UC and liver injury and has no nephrotoxicity as previously described. In conclusion, ASB has an effective protective effect on DSS-induced UC and liver injury, mainly by suppressing macrophage proinflammatory polarization from the gut-liver axis.