CsiR-mediated signal transduction pathway in response to low iron conditions promotes Escherichia coli K1 invasion and penetration of the blood-brain barrier.

Escherichia coli K1 is the leading cause of neonatal Gram-negative bacterial meningitis, but the pathogenesis of E. coli K1 meningitis remains unclear. Blood-brain barrier (BBB) penetration is a crucial step in E. coli meningitis development. Here, we uncovered the crucial role of CsiR, a GntR family regulator, in E. coli K1 virulence. During infection, csiR expression was induced due to the derepression by Fur in the blood and human brain microvascular endothelial cells (HBMECs). CsiR positively regulated ilvB expression, which is associated with branched chain amino acid synthesis. Furthermore, we revealed that IlvB activated the FAK/PI3 K pathway of HBMECs to induce actin cytoskeleton rearrangements, thereby promoting the bacterial invasion and penetration of the BBB. Overall, this study reveals a CsiR-mediated virulence regulation pathway in E. coli K1, which may provide a useful target for the prevention or therapy of E. coli meningitis.

Altered effective connectivity among face-processing systems in major depressive disorder.

BACKGROUND: Neuroimaging studies have revealed abnormal functional interaction during the processing of emotional faces in patients with major depressive disorder (MDD), thereby enhancing our comprehension of the pathophysiology of MDD. However, it is unclear whether there is abnormal directional interaction among face-processing systems in patients with MDD. METHODS: A group of patients with MDD and a healthy control group underwent a face-matching task during functional magnetic resonance imaging. Dynamic causal modelling (DCM) analysis was used to investigate effective connectivity between 7 regions in the face-processing systems. We used a Parametric Empirical Bayes model to compare effective connectivity between patients with MDD and controls. RESULTS: We included 48 patients and 44 healthy controls in our analyses. Both groups showed higher accuracy and faster reaction time in the shape-matching condition than in the face-matching condition. However, no significant behavioural or brain activation differences were found between the groups. Using DCM, we found that, compared with controls, patients with MDD showed decreased self-connection in the right dorsolateral prefrontal cortex (DLPFC), amygdala, and fusiform face area (FFA) across task conditions; increased intrinsic connectivity from the right amygdala to the bilateral DLPFC, right FFA, and left amygdala, suggesting an increased intrinsic connectivity centred in the amygdala in the right side of the face-processing systems; both increased and decreased positive intrinsic connectivity in the left side of the face-processing systems; and comparable task modulation effect on connectivity. LIMITATIONS: Our study did not include longitudinal neuroimaging data, and there was limited region of interest selection in the DCM analysis. CONCLUSION: Our findings provide evidence for a complex pattern of alterations in the face-processing systems in patients with MDD, potentially involving the right amygdala to a greater extent. The results confirm some previous findings and highlight the crucial role of the regions on both sides of face-processing systems in the pathophysiology of MDD.

Diquat causes mouse testis injury through inducing heme oxygenase-1-mediated ferroptosis in spermatogonia.

Diquat dibromide (DQ) is a globally used herbicide in agriculture, and its overuse poses an important public health issue, including male reproductive toxicity in mammals. However, the effects and molecular mechanisms of DQ on testes are limited. In vivo experiments, mice were intraperitoneally injected with 8 or 10 mg/kg/ day of DQ for 28 days. It has been found that heme oxygenase-1 (HO-1) mediates DQ-induced ferroptosis in mouse spermatogonia, thereby damaging testicular development and spermatogenesis. Histopathologically, we found that DQ exposure caused seminiferous tubule disorders, reduced germ cells, and increased sperm malformation, in mice. Reactive oxygen species (ROS) staining of frozen section and transmission electron microscopy (TEM) displayed DQ promoted ROS generation and mitochondrial morphology alterations in mouse testes, suggesting that DQ treatment induced testicular oxidative stress. Subsequent RNA-sequencing further showed that DQ treatment might trigger ferroptosis pathway, attributed to disturbed glutathione metabolism and iron homeostasis in spermatogonia cells in vitro. Consistently, results of western blotting, measurements of MDA and ferrous iron, and ROS staining confirmed that DQ increased oxidative stress and lipid peroxidation, and accelerated ferrous iron accumulation both in vitro and in vivo. Moreover, inhibition of ferroptosis by deferoxamine (DFO) markedly ameliorated DQ-induced cell death and dysfunction. By RNA-sequencing, we found that the expression of HO-1 was significantly upregulated in DQ-treated spermatogonia, while ZnPP (a specific inhibitor of HO-1) blocked spermatogonia ferroptosis by balancing intracellular iron homeostasis. In mice, administration of the ferroptosis inhibitor ferrostatin-1 effectively restored the increase of HO-1 levels in the spermatogonia, prevented spermatogonia death, and alleviated the spermatogenesis disorders induced by DQ. Overall, these findings suggest that HO-1 mediates DQ-induced spermatogonia ferroptosis in mouse testes, and targeting HO-1 may be an effective protective strategy against male reproductive disorders induced by pesticides in agriculture.

The skin tears knowledge among geriatric ward nurses and associated factors: A cross-sectional study.

AIM: To determine the level of knowledge about skin tears among geriatric ward nurses and identify associated factors. METHODS: In this cross-sectional study in Southwest China, 1172 geriatric ward nurses from 10 hospitals participated. Data were collected using Sojump, a Chinese web-based platform, and the Skin Tear Knowledge Assessment Instrument was used to assess their knowledge. The analysis involved descriptive statistics, correlation analysis, and multiple linear regression. RESULTS: The study involved participants with an average age of 36.73 (SD = 6.54) years. More than half of the participants had less than 10 years of experience in geriatric wards. 27 % specialized in wound care, and 68.1 % lacked specific training in skin tear (ST) knowledge. Additionally, 82.7 % of geriatric nurses had never been exposed to guidelines on ST prevention and management. In the geriatric ward, 36.6 % of nurses received training in ST prevention. The average knowledge score about Skin Tears (STs) was 9.52 (SD = 2.39) out of 18. 'Treatment' had the lowest mean score, while 'Specific patient groups' had the highest. The multiple linear regression analysis found that nurses' knowledge of STs was influenced by sex(ß = 0.096, P < 0.001), educational level(ß = 0.062, P < 0.001), participation in ST (ß = -0.193, P < 0.001 and wound care training(ß = -0.120, P = 0.004), and specialization as a wound care nurse(ß = -0.350, P = 0.001). These factors explained 61.3 % of the variance in knowledge about STs among the participants. CONCLUSION: The geriatric ward had limited knowledge of STs. To improve their skills in dealing with STs, managers should provide tailored training to nurses and establish a standardized, evidence-based nursing process.

Characteristics of soil organic carbon fractions in four vegetation communities of an inland salt marsh.

BACKGROUND: The study of soil organic carbon characteristics and its relationship with soil environment and vegetation types is of great significance to the evaluation of soil carbon sink provided by inland salt marshes. This paper reports the characteristics of soil organic carbon fractions in 0-50 cm soil layers at four vegetation communities of the Qinwangchuan salt marsh. RESULTS: (1) The soil organic carbon content of Phragmites australis community (9.60 ± 0.32 g/kg) was found to be higher than that of Salicornia europae (7.75 ± 0.18 g/kg) and Tamarix ramosissima (4.96 ± 0.18 g/kg) and Suaeda corniculata community (4.55 ± 0.11 g/kg). (2) The soil dissolved organic carbon, particulate organic carbon and soil microbial biomass carbon in 0-50 cm soil layer of Phragmites australis community were higher, which were 0.46 ± 0.01 g/kg, 2.81 ± 0.06 g/kg and 0.31 ± 0.01 g/kg, respectively. (3) Soil organic carbon was positively correlated with dissolved organic carbon, particulate organic carbon, and microbial biomass carbon, and negatively correlated with easily oxidized organic carbon. (4) Above-ground biomass has a strong direct positive effect on soil organic carbon, total nitrogen and pH have a strong direct positive effect on microbial biomass carbon content, pH and average density have a strong direct negative effect on easily oxidized organic carbon, and particulate organic carbon. CONCLUSIONS: The interaction between plant community characteristics and soil factors is an important driving factor for soil organic carbon accumulation in inland salt marshes.

Adenine's impact on mice's gut and kidney varies with the dosage administered and relates to intestinal microorganisms and enzyme activities.

This study aimed to investigate the effects of different dosages of adenine on intestinal microorganisms and enzyme activities, laying the experimental groundwork for subsequent exploration of the microbial mechanisms underlying diarrhea with kidney yang deficiency syndrome. Twenty-four mice were assigned to the following four groups: the control (NC) group, low-dosage adenine (NML) group, middle-dosage adenine (NMM) group, and high-dosage adenine (NMH) group. Mice in the NML, NMM, and NMH groups received 25 mg/(kg·d), 50 mg/(kg·d), and 100 mg/(kg·d) of adenine, respectively, 0.4 mL/each, once a day for 14 days. The NC group received 0.4 mL sterile water. Parameters including body weight, rectal temperature, intestinal microorganisms, enzyme activities, and microbial activity were measured. Results indicated that mice in the experimental group displayed signs of a poor mental state, curled up with their backs arched, and felt sleepy and lazy, with sparse fur that was easily shed, and damp bedding. Some mice showed fecal adhesion contamination in the perianal and tail areas. Dosage-dependent effects were observed, with decreased food intake, body weight, rectal temperature, and microbial activity and increased water intake and fecal water content. Enzyme activity analyses revealed significantly higher activities of protease, sucrase, amylase, and cellulase in intestinal contents and lactase, sucrase, amylase, and cellulase in the mucosa of the NMM group compared to those of other groups. Ultimately, the higher adenine dosage was associated with more pronounced symptoms of kidney yang deficiency syndrome, with 50 mg/kg adenine exhibiting the most substantial impact on the number of intestinal microbial colonies and enzyme activities.

Sishen Pill inhibits intestinal inflammation in diarrhea mice via regulating kidney-intestinal bacteria-metabolic pathway.

Background: Sishen Pill (SSP) has good efficacy in diarrhea with deficiency kidney-yang syndrome (DKYS), but the mechanism of efficacy involving intestinal microecology has not been elucidated. Objective: This study investigated the mechanism of SSP in regulating intestinal microecology in diarrhea with DKYS. Methods: Adenine combined with Folium sennae was used to construct a mouse model of diarrhea with DKYS and administered with SSP. The behavioral changes and characteristics of gut content microbiota and short-chain fatty acids (SCFAs) of mice were analyzed to explore the potential association between the characteristic bacteria, SCFAs, intestinal inflammatory and kidney function-related indicators. Results: After SSP intervention, the body weight and anal temperature of diarrhea with DKYS gradually recovered and approached the normal level. Lactobacillus johnsonii was significantly enriched, and propionic, butyric, isobutyric and isovaleric acids were elevated. Serum creatinine (Cr), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) levels of the mice were reduced, while serum blood urea nitrogen (BUN) and secretory immunoglobulin A (sIgA) in the colonic tissues were increased. Moreover, there were correlations between L. johnsonii, SCFAs, intestinal inflammatory, and kidney function. Conclusion: SSP might suppress the intestinal inflammation by regulating the "L. johnsonii-propionic acid" pathway, thus achieving the effect of treating diarrhea with DKYS.

Young TSPC-Derived Exosomal circPVT1 Ameliorates Aging-Impaired Cell Function via SIRT1/NF-κB.

Tendon stem/progenitor cell (TSPC) senescence is often associated with age-dependent tendon diseases and greatly reduces the capacities for tendon repair and replacement. Exosomes contain bioactive molecules and have been increasingly used in regenerative medicine. In the present study, we demonstrated the antiaging effects of young exosomes from circPVT1-overexpressing TSPCs at early passages (circPVT1-exo). These exosomes attenuated the phenotypes of aged TSPCs at late passages (L-TSPCs) by enhancing self-renewal and proliferation abilities, suppressing cell senescence, maintaining their tenogenic capacity, and weakening their osteogenic differentiation. Mechanistically, circPVT1-exo inhibited the NF-κB pathway and increased SIRT1 expression in L-TSPCs. Knockdown of SIRT1 reversed these effects as evidenced by increased senescence, decreased proliferation, and tenogenic differentiation. These results suggest that circPVT1-exo may ameliorate aging-impaired TSPC function by modulating the SIRT1/NF-κB pathway, suggesting that circPVT1-exo has therapeutic potential for age-related diseases.

Period circadian regulator 2-mediated steroid hormone synthesis by regulating transcription of steroidogenic acute regulatory protein in porcine granulosa cells.

Steroidogenesis is associated with circadian clock genes. However, the regulation of steroid hormone production in sow granulosal cells by Per2, a crucial circadian regulator, remains unexplored. In this study, we have identified the presence of Per2 in ovarian granulosa cells and have observed its circadian expression pattern. Employing siRNA to interfere with Per2 expression, our investigation revealed that Per2 knockdown notably elevated progesterone (P4) levels along with increasing the expression of StAR but interference of Per2 did not alter the rhythm of clock-related gene (Bmal1, Clock, Per1, and Cry1) in granulosa cells. Subsequent mechanistic analysis showed that Per2 formed complexes with PPARγ and interference with Per2 promoted the formation of the PPARγ:RXRα heterodimer. Importantly, we uncovered that PPARγ:RXRα heterodimer could control the expression of StAR via direct peroxisome proliferator response element binding to its promoter to regulate its activity, and knockdown of Per2 promoted the transcription of StAR via increasing the binding of PPARγ:RXRα ligands. Altogether, these findings indicated a noncanonical role of Per2 in controlling PPARγ:RXRα binding to regulate transcription of StAR and progesterone synthesis, thus revealing potential avenues of pharmacological and therapeutic intervention.

The circadian clock can regulate ovarian function, and disruption of the circadian clock caused by environmental factors can seriously affect the reproductive capacity of female animals, leading to ovarian diseases. Therefore, it is necessary to investigate the relationship between clock genes and ovarian function. In this study, Per2, a key gene for the circadian clock, was expressed in ovarian granulosa cells according to a rhythmic pattern, but knocking out Per2 did not alter the circadian rhythm in granulosa cells. Interference of Per2 notably elevated progesterone (P4) levels along with increasing the expression of StAR (a key gene for P4 synthesis) in granulosa cells. Subsequent mechanistic analysis showed that knockdown of Per2 enhanced transcription of StAR by promoting the formation of the PPARγ:RXRα heterodimer. These results indicated a noncanonical role of Per2 in regulating PPARγ:RXRα binding to control transcription of StAR and P4 production.

A red-emitting mitochondria targetable fluorescent probe for detecting viscosity in HeLa, zebrafish, and mice.

Viscosity, an essential parameter of the cellular microenvironment, has the ability to indicate the condition of living cells. It is closely linked to numerous diseases like Alzheimer's disease, diabetes, and cardiovascular disorders. Therefore, it is necessary to design tools to effectively monitor viscosity changes, which could provide promising avenues for therapeutic interventions in these diseases. Herein, we report a novel mitochondria-targeting fluorescent probe GX-VS which was suitable for the detection of viscosity changes in vivo and in vitro. The probe GX-VS had many advantages such as long emission wavelength (650 nm), large Stokes shift (105 nm), significant fluorescence enhancement (59-fold), high sensitivity, good biocompatibility and so on. Biological experiments showed that the probe could target mitochondria and detect viscosity alterations in HeLa cells. Moreover, it has been successfully utilized to monitor viscosity changes induced by lipopolysaccharides (LPS) in inflammatory zebrafishes and living mice, which further underscored the capacity of GX-VS to explore fluctuations in viscosity within living organisms.

Highly efficient Mn2+, Mg2+, and NH4+ recovery from electrolytic manganese residue via leaching, solvent extraction, coprecipitation, and atmospheric oxidation.

Electrolytic manganese residue (EMR), a solid waste generated during electrolytic manganese production, exhibits substantial leaching toxicity owing to its elevated levels of soluble Mn2+ and NH4+. The leaching and recovery of valuable metal ions and NH4+ from EMR are key to the hazard-free treatment and resource utilization of EMR. In this study, two-stage countercurrent leaching with water was used to leach Mn2+, Mg2+, and NH4+ from EMR. Subsequently, two-stage countercurrent extraction was conducted using α-hydroxy-2-ethylhexyl phosphinic acid (α-H-2-EHA) as an extractant to enrich Mn2+, and Mg2+, and NH4+ were recovered via coprecipitation. Based on the calculations for a single leaching-extraction process, the recoveries of Mn2+, Mg2+, and NH4+ ions exceeded 80%, 99%, and 90%, respectively. In addition, high-purity Mn3O4 with an Mn content of 71.61% and struvite were produced. This process represents a win-win strategy that facilitates the hazard-free treatment of EMR while simultaneously recovering valuable Mn2+, Mg2+, and NH4+ resources from waste. Thus, this study provides a novel approach to the hazard-free and resourceful management of solid waste. ENVIRONMENTAL IMPLICATION: Electrolytic manganese residue (EMR), a solid waste generated during electrolytic manganese production, poses significant environmental risks due to its soluble heavy metals and ammonia nitrogen content. Efforts have been made to address this issue, but there has been no mature industrial application due to cost or processing capacity constraints. In this work, solvent extraction was first used to enrich Mn2+ from EMR leachate, and a novel α­hydroxy­2­ethylhexyl phosphinic acid was used as extractant. High purity Mn3O4 and struvite was synthesized through this process. The win­win strategy offers a novel approach for the hazard­free and resourceful utilization of solid waste.

Geniposide for treating atherosclerotic cardiovascular disease: a systematic review on its biological characteristics, pharmacology, pharmacokinetics, and toxicology.

In recent years, the prevalence and fatality rates of atherosclerotic cardiovascular disease have not only shown a consistent rise that cannot be ignored, but have also become a pressing social health problem that requires urgent attention. While interventional surgery and drug therapy offer significant therapeutic results, they often come with common side effects. Geniposide, an active component extracted from the Chinese medicine Gardenia jasminoides Ellis, shows promise in the management of cardiac conditions. This review comprehensively outlines the underlying pharmacological mechanisms by which geniposide exerts its effects on atherosclerosis. Geniposide exhibits a range of beneficial effects including alleviating inflammation, inhibiting the development of macrophage foam cells, improving lipid metabolism, and preventing platelet aggregation and thrombosis. It also demonstrates mitochondrial preservation, anti-apoptotic effects, and modulation of autophagy. Moreover, geniposide shows potential in improving oxidative stress and endoplasmic reticulum stress by maintaining the body's antioxidant and oxidative balance. Additionally, this review comprehensively details the biological properties of geniposide, including methods of extraction and purification, as well as its pharmacokinetics and toxicological characteristics. It further discusses the clinical applications of related biopharmaceuticals, emphasizing the potential of geniposide in the prevention and treatment of atherosclerotic cardiovascular diseases. Furthermore, it highlights the limitations of current research, aiming to provide insights for future studies.

The association of initial and changes in serum A-FABP level with the development and improvement of pre-sarcopenia.

CONTEXT: Several cross-sectional studies have reported the association between serum adipocyte fatty acid binding protein (A-FABP) level and pre-sarcopenia. However, data on the impacts of serum A-FABP level and its changes over time on the development and improvement of pre-sarcopenia are scarce. METHODS: This longitudinal cohort study included 1496 adults (41.2% men; median age, 58 [53-63] years) in 2013-2014 and was followed up to 2015-2016. Participants underwent serum A-FABP level measurements at baseline and follow-up visit. Visceral fat area (VFA) was measured using magnetic resonance imaging. Skeletal muscle mass (SMM) was estimated by bioelectrical impedance analysis and converted to skeletal muscle index (SMI). Pre-sarcopenia was defined as SMI < 1 standard deviation of the sex-specific mean for the young reference group. RESULTS: During an average follow-up period of 2.1 years, baseline serum A-FABP level was positively associated with the incidence of pre-sarcopenia (standardized by weight: risk ratio [RR] 3.22, 95% confidence interval [CI] 1.96-5.38; standardized by VFA: RR 2.11, 95%CI 1.29-3.51) and negatively associated with the improvement of pre-sarcopenia (standardized by weight: RR 0.66, 95%CI 0.45-0.97; standardized by VFA: RR 0.71, 95%CI 0.54-0.94), regardless of whether SMM was standardized by weight or VFA. Moreover, changes in serum A-FABP level provided additional information on the incidence and improvement of pre-sarcopenia, independent of baseline serum A-FABP level (all P < 0.05). CONCLUSIONS: Baseline serum A-FABP level and its changes were positively associated with the incidence, and negatively associated with the improvement of pre-sarcopenia.

Biomechanical analysis of titanium-alloy and biodegradable implants in dual plate osteosynthesis for AO/ASIF type 33-C2 fractures.

Background and objective: Treating geriatric osteoporotic distal femur fractures has always presented challenges, but developing biodegradable materials has brought new opportunities for therapeutic intervention. Despite this progress, there currently needs to be more evidence-based biomechanical guidelines for using dual plate fixation and biodegradable materials in treating osteoporotic comminuted distal femoral fractures.In this study, finite element analysis was conducted to evaluate the mechanical effectiveness of different implant materials (titanium alloys, biodegradable materials, and combinations of both) in the fixation of physiological and osteoporotic distal femoral fractures. Methods: We constructed finite element models of 33-C2 fractures and three types of plates: the Lateral Less Invasive Stabilization System (LISS) plate, the titanium-alloy medial plate (TAP), and the biodegradable plate (BP). To evaluate the biomechanical advantages in both physiological femur (PF) and osteoporotic femur (OF) conditions, three scenarios were developed: LISS + TAP, LISS + BP, and double biodegradable plates (DBPs). Five loading conditions were applied to measure structural stiffness, fracture micromotion, and implant stress: medio-lateral four-point bending, antero-posterior four-point bending, axial loading, torsional loading, and sideways falling. Several parameters were examined, including peak Von Mises Stress (VMS) of the femur and lateral plate, maximum displacement, bending angle, torsional angle of fracture, and risk of fracture. Results: In four-point bending tests, the lateral plate of the DBPs group exhibited a slightly lower peak VMS compared to the LISS + TAP and LISS + BP groups. When subjected to axial loading, the stiffness values of the LISS + TAP (OF) were 1.42 times and 1.86 times higher than LISS + BP (OF) and DBPs (OF) groups, and the peak VMS of lateral plate of DBPs (OF) construct was approximately 2% and 16% lower than that of the LISS + TAP (OF) and LISS + BP (OF) constructs. Under torsional loading, DBPs (OF) demonstrated rotational stiffness that was respectively 2% and 52% greater than that of LISS + TAP (OF) and LISS + BP (OF). Regarding the peak VMS of femur, the values of DBPs (OF) were almost 8% and 15% lower than those of LISS + TAP (OF) and LISS + BP (OF). Conclusions: The use of DBPs at 11.33 GPa facilitated early mobilization of load-bearing joints but exhibited limited ability to support full weight-bearing activities. Though LISS + TAP met practical strength requirements, one should consider the potential biological irritation and stress shielding. Thus, employing a combination of biodegradable and metal internal fixation is a valid approach to effectively treat weight-bearing joint fractures in clinical practice.

Mendelian randomization and Bayesian model averaging of autoimmune diseases and Long COVID.

Background: Following COVID-19, reports suggest Long COVID and autoimmune diseases (AIDs) in infected individuals. However, bidirectional causal effects between Long COVID and AIDs, which may help to prevent diseases, have not been fully investigated. Methods: Summary-level data from genome-wide association studies (GWAS) of Long COVID (N = 52615) and AIDs including inflammatory bowel disease (IBD) (N = 377277), Crohn's disease (CD) (N = 361508), ulcerative colitis (UC) (N = 376564), etc. were employed. Bidirectional causal effects were gauged between AIDs and Long COVID by exploiting Mendelian randomization (MR) and Bayesian model averaging (BMA). Results: The evidence of causal effects of IBD (OR = 1.06, 95% CI = 1.00-1.11, p = 3.13E-02), CD (OR = 1.10, 95% CI = 1.01-1.19, p = 2.21E-02) and UC (OR = 1.08, 95% CI = 1.03-1.13, p = 2.35E-03) on Long COVID was found. In MR-BMA, UC was estimated as the highest-ranked causal factor (MIP = 0.488, MACE = 0.035), followed by IBD and CD. Conclusion: This MR study found that IBD, CD and UC had causal effects on Long COVID, which suggests a necessity to screen high-risk populations.

Adipocyte-Specific Hnrnpa1 Knockout Aggravates Obesity-Induced Metabolic Dysfunction via Upregulation of CCL2.

Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) is involved in lipid and glucose metabolism via mRNA processing. However, whether and how HNRNPA1 alters adipocyte function in obesity remain obscure. Here, we found that the obese state downregulated HNRNPA1 expression in white adipose tissue (WAT). The depletion of adipocyte HNRNPA1 promoted markedly increased macrophage infiltration and expression of proinflammatory and fibrosis genes in WAT of obese mice, eventually leading to exacerbated insulin sensitivity, glucose tolerance, and hepatic steatosis. Mechanistically, HNRNPA1 interacted with Ccl2 and regulated its mRNA stability. Intraperitoneal injection of CCL2-CCR2 signaling antagonist improved adipose tissue inflammation and systemic glucose homeostasis. Furthermore, HNRNPA1 expression in human WAT was negatively correlated with BMI, fat percentage, and subcutaneous fat area. Among individuals with 1-year metabolic surgery follow-up, HNRNPA1 expression was positively related to percentage of total weight loss. These findings identify adipocyte HNRNPA1 as a link between adipose tissue inflammation and systemic metabolic homeostasis, which might be a promising therapeutic target for obesity-related disorders.

Triglyceride-glucose index's link to cardiovascular outcomes post-percutaneous coronary intervention in China: a meta-analysis.

Percutaneous coronary intervention (PCI) addresses myocardial ischaemia, but a significant subset of patients encounter major adverse cardiovascular events (MACE) post-treatment. This meta-analysis investigated the relationship between the post-PCI triglyceride-glucose (TyG) index and MACE. Comprehensive searches of the Embase, PubMed, Cochrane Library, and Web of Science databases were conducted up to 3 March 2023, using relevant keywords. The effect size was determined based on I2 statistic using random-effects models. Cluster-robust standard errors crafted the dose-response curve, and the GRADE Evaluation Scale was employed to rate the quality of evidence. The group with the highest TyG index had significantly higher post-PCI MACE rates than the lowest index group, with hazard ratios (HRs) of 2.04 (95% CI 1.65-2.52; I2 = 77%). Each unit increase in TyG index corresponded to HRs of 1.82 for MACE (95% CI 1.34-2.46; I2 = 92%), 2.57 for non-fatal MI (95% CI 1.49-4.41; I2 = 63%), and 2.06 for revascularization (95% CI 1.23-3.50; I2 = 90%). A linear relationship between TyG index and MACE risk was established (R2 = 0.6114). For all-cause mortality, the HR was 1.93 (95% CI 1.35-2.75; I2 = 50%), indicating a higher mortality risk with elevated TyG index. The GRADE assessment yielded high certainty for non-fatal MI but low certainty for all-cause mortality, revascularization, and MACE. The TyG index may predict risks of post-PCI MACE, all-cause mortality, non-fatal MI, and revascularization, with varied levels of certainty. A potential linear association between the TyG index and MACE post-PCI was identified. Future research should validate these findings.

Effect of add-on transcranial alternating current stimulation (tACS) in major depressive disorder: A randomized controlled trial.

BACKGROUND: The effect of transcranial alternating current stimulation (tACS) on major depressive disorder (MDD) was not confirmed. OBJECTIVE: To evaluate the feasibility, safety, and efficacy of tACS as an add-on treatment for the symptoms of depression and to understand how tACS affects brain activity. METHODS: The 4-week, double-blind, randomized, sham-controlled trial was performed from January 29, 2023 to December 22, 2023. Sixty-six participants were recruited and randomly assigned to receive 20 40-min sessions of either active (77.5Hz, 15 mA) or sham stimulation, with one electrode on the forehead and two on the mastoid, each day (n = 33 for each group) for four weeks (till Week 4). The participants were followed for 4 more weeks (till Week 8) without stimulation for efficacy/safety assessment. During the 4-week trial, all participants were required to take 10-20 mg of escitalopram daily. The primary efficacy endpoint was the change in HAMD-17 scores from baseline to Week 4 (with 20 treatment sessions completed). Resting-state electroencephalography (EEG) was collected with a 64-channel EEG system (Brain Products, Germany) at baseline and the Week 4 follow-up. The chi-square test, Fisher's exact test, independent-sample t-test, or Wilcoxon rank-sum test were used, as appropriate, to compare the differences in variables between groups. The effect of the intervention on the HAMD-17 score was also evaluated with linear mixed modeling (LMM) as sensitivity analysis. The correlation between the mean reduction in EEG and the mean reduction in the HAMD-17 total score was evaluated using Spearman correlation analysis. RESULTS: A total of 66 patients (mean [SD] age, 28.4 [8.18] years; 52 [78.8 %] female) were randomized, and 57 patients completed the study. Significant differences were found in the reductions in the HAMD-17 scores at Week 4 (t = 3.44, P = 0.001). Response rates at Week 4 were significantly higher in the active tACS group than in the sham tACS group (22 out of 33 patients [66.7 %] versus 11 out of 33 [33.3 %], P = 0.007). In the active tACS group, a correlation between the mean change in alpha power and HAMD-17 scores at Week 4 was found (r = 2.38, P = 0.024), and the mean change in alpha power was significantly bigger for responders (Z = 2.46, P = 0.014). No serious adverse events were observed in this trial. CONCLUSION: The additional antidepressant effect of tACS is significant, and the combination of tACS with antidepressants is a feasible and effective approach for the treatment of MDD. The antidepressant mechanism of tACS may be the reduction in alpha power in the left frontal lobe. Future research directions may include exploring more appropriate treatment parameters of tACS.

Isorhamnetin Improves Oocyte Maturation by Activating the Pi3k/Akt Signaling Pathway.

SCOPE: Isorhamnetin is a natural flavonoid with various pharmacological activities, which can be widely and continuously ingested by humans and animals through their daily diet. The aim of this study is to explore the benefits and molecular mechanisms of isorhamnetin on oocyte maturation. METHODS AND RESULTS: Oocytes are incubated with isorhamnetin (5, 10, 20, and 30 µM) for 44 h. Isorhamnetin (10 µM) increases the polar body extrusion rate of oocytes. Furthermore, isorhamnetin alleviates oxidative stress by inhibiting reactive oxygen species levels and stimulating SOD2 protein expression. The changes in intracellular mitochondrial autophagy and apoptosis-related proteins (Bcl-2, Bax/Bcl-2, and C-Casp3) indicate that isorhamnetin inhibits oocyte apoptosis. Isorhamnetin inhibits endoplasmic reticulum stress by reducing the protein expression of CHOP and GRP78 and improving the normal distribution rate of endoplasmic reticulum. Mechanistic studies show that isorhamnetin activates the PI3K/Akt signaling pathway. CONCLUSION: Isorhamnetin promotes oocyte maturation by inhibiting oxidative stress, mitochondrial dysregulation, apoptosis, and endoplasmic reticulum stress, which have important potential for improving oocyte quality and treating female infertility.

Durable protective efficiency provide by mRNA vaccines require robust immune memory to antigens and weak immune memory to lipid nanoparticles.

The Pegylated lipids in lipid nanoparticle (LNPs) vaccines have been found to cause acute hypersensitivity reactions in recipients, and generate anti-LNPs immunity after repeated administration, thereby reducing vaccine effectiveness. To overcome these challenges, we developed a new type of LNPs vaccine (SAPC-LNPs) which was co-modified with sialic acid (SA) - lipid derivative and cleavable PEG - lipid derivative. This kind of mRNA vaccine can target dendritic cells (DCs) and rapidly escape from early endosomes (EE) and lysosomes with a total endosomal escape rate up to 98 %. Additionally, the PEG component in SAPC-LNPs was designed to detach from the LNPs under the catalysis of carboxylesterase in vivo, which reduced the probability of PEG being attached to LNPs entering antigen-presenting cells. Compared with commercially formulated vaccines (1.5PD-LNPs), mice treated with SAPC-LNPs generated a more robust immune memory to tumor antigens and a weaker immune memory response to LNPs, and showed lower side effects and long-lasting protective efficiency. We also discovered that the anti-tumor immune memory formed by SAPC-LNPs mRNA vaccine was directly involved in the immune cycle to rattack tumor. This immune memory continued to strengthen with multiple cycles, supporting that the immune memory should be incorporated into the theory of tumor immune cycle.