Adipose-derived stem cell exosomes loaded with icariin attenuated M1 polarization of macrophages via inhibiting the TLR4/Myd88/NF-κB signaling pathway.

Abnormal macrophage polarization is one of the common pathological bases of various inflammatory diseases. The current research focus involves targeting macrophages to remodel their phenotype as a treatment approach for inflammatory diseases. Notably, exosomes can be delivered to specific types of cells or tissues or inflammatory area to realize targeted drug delivery. Although icariin (ICA) exhibits regulatory potential in macrophage polarization, the practical application of ICA is impeded by its water insolubility, poor permeability, and low bioavailability. Exploiting the inherent advantages of exosomes as natural drug carriers, we introduce a novel drug delivery system-adipose-derived stem cells-exosomes (ADSCs-EXO)-ICA. High-performance liquid chromatography analysis confirmed a loading rate of 92.7 ± 0.01 % for ADSCs-EXO-ICA, indicating the successful incorporation of ICA. As demonstrated by cell counting kit-8 assays, ADSCs-EXO exerted a significantly higher promotion effect on macrophage proliferation. The subsequent experimental results revealed the superior anti-inflammatory effect of ADSCs-EXO-ICA compared to individual treatments with EXO or ICA in the lipopolysaccharide + interferon-gamma-induced M1 inflammation model. Additionally, results from enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, and western blot analyses revealed that ADSCs-EXO-ICA effectively inhibited macrophage polarization toward the M1-type and concurrently promoted polarization toward the M2-type. The underlying mechanism involved the modulation of macrophage polarization through inhibition of the Toll-like receptor 4/myeloid differentiation factor 88/nuclear transcription factor-kappa B signaling pathway, thereby mitigating inflammation. These findings underscore the potential therapeutic value of ADSCs-EXO-ICA as a novel intervention for inflammatory diseases.

Developmental Toxicity of Fine Particulate Matter: Multifaceted Exploration from Epidemiological and Laboratory Perspectives.

Particulate matter of size ≤ 2.5 µm (PM2.5) is a critical environmental threat that considerably contributes to the global disease burden. However, accompanied by the rapid research progress in this field, the existing research on developmental toxicity is still constrained by limited data sources, varying quality, and insufficient in-depth mechanistic analysis. This review includes the currently available epidemiological and laboratory evidence and comprehensively characterizes the adverse effects of PM2.5 on developing individuals in different regions and various pollution sources. In addition, this review explores the effect of PM2.5 exposure to individuals of different ethnicities, genders, and socioeconomic levels on adverse birth outcomes and cardiopulmonary and neurological development. Furthermore, the molecular mechanisms involved in the adverse health effects of PM2.5 primarily encompass transcriptional and translational regulation, oxidative stress, inflammatory response, and epigenetic modulation. The primary findings and novel perspectives regarding the association between public health and PM2.5 were examined, highlighting the need for future studies to explore its sources, composition, and sex-specific effects. Additionally, further research is required to delve deeper into the more intricate underlying mechanisms to effectively prevent or mitigate the harmful effects of air pollution on human health.

Identifying the genetic association between systemic lupus erythematosus and the risk of autoimmune liver diseases.

BACKGROUND: Previous studies on the relationship between systemic lupus erythematosus (SLE) and autoimmune liver diseases (AILDs) are inconclusive. Therefore, we employed Mendelian randomization (MR) to explore the causal associations between SLE and AILDs. METHODS: A two-sample MR analysis was performed using summary-level statistics sourced from genome-wide association study (GWAS) datasets. Inverse-variance weighting (IVW), MR‒Egger, and weighted median (WM) were further supported by several sensitivity analyses. RESULTS: We detected causal genetic associations between SLE and primary biliary cholangitis (PBC) (odds ratio (OR) = 1.31, 95% CI = 1.15-1.51, P < 0.01; adjusted OR = 1.63, 95% CI = 1.39-1.90, P < 0.01) and between SLE and primary sclerosing cholangitis (PSC) (OR = 1.09, 95% CI = 1.01-1.08, P = 0.03; adjusted OR = 1.10, 95% CI = 1.00-1.21, P = 0.04). No causal association was found between SLE and autoimmune hepatitis. CONCLUSIONS: We are the first to use MR analysis to explore the causal relationships between SLE and various AILDs, revealing an increased risk of PBC and PSC in individuals with SLE.

Fructus Ligustri Lucidi inhibits ferroptosis in ovariectomy­induced osteoporosis in rats via the Nrf2/HO­1 signaling pathway.

Postmenopausal osteoporosis (PMOP) has increased in prevalence in recent years, thus researchers have evaluated alternative medicine therapies. Fructus Ligustri Lucidi (FLL) can inhibit bone loss, and ferroptosis serves an important role in osteoporosis. Therefore, the present study assessed the presence of ferroptosis in PMOP and whether FLL could inhibit ferroptosis to improve bone microstructure in ovariectomized rats. Ovariectomized rats were treated with FLL (1.56 g/kg/day) for 12 weeks. Micro-CT was performed to evaluate the bone microstructure and bone mineral density. Western blotting and reverse transcription-quantitative PCR were performed to assess the relative expression levels of proteins and mRNA. Subsequently, malondialdehyde (MDA) and Fe2+ assay kits were used to quantify the MDA and Fe2+ content, respectively. The results demonstrated that ovariectomy (OVX) resulted in iron overload and the accumulation of lipid peroxide. Furthermore, the expression of key factors that inhibited ferroptosis, glutathione peroxidase 4 and solute carrier family 7 member 11 was significantly downregulated in ovariectomized rats, which was significantly reversed by FLL treatment. Furthermore, bone formation was assessed using the expression of osteogenesis-related genes, runt-related transcription factor 2 and osterix, which revealed significantly higher levels in FLL-treated rats compared with ovariectomized rats. The levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were also significantly recovered following FLL treatment. In the present study, OVX of postmenopausal osteoporotic rats was found to induce ferroptosis by enhancing lipid peroxidation and Fe2+ levels. FLL significantly suppressed ferroptosis, protected the osteogenic ability of ovariectomized rats and promoted the Nrf2/HO-1 signaling pathway.

Copper-Catalyzed Asymmetric Allylation of N-Aryl Aldimines.

The copper-catalyzed enantioselective allylation reaction of N-aryl aldimines has been developed using a combination of Cu(OAc)2 and SPINOL-based phosphonamidite. This protocol significantly broadens the substrate scope, such that imines bearing various ortho-substituents on the N-aryl were converted smoothly into homoallylic amines in up to 99% yield and 98% ee. Taking advantage of the diversity of the N-aryl motif, three kinds of N-heterocyclic compounds were constructed, respectively, from the corresponding homoallylic amines in merely one step.

JANet: A joint attention network for balancing accuracy and speed in left ventricular ultrasound video segmentation.

Multiple cardiac diseases are closely associated with functional parameters of the left ventricle, but functional parameter quantification still requires manual involvement, a time-consuming and less reproducible task. We develop a joint attention network (JANet) and expand it into two versions (V1 and V2) that can be used to segment the left ventricular region in echocardiograms to assist physicians in diagnosis. V1 is a smaller model with a size of 56.3 MB, and V2 has a higher accuracy. The proposed JANet V1 and V2 achieve a mean dice score (DSC) of 93.59/93.69(V1/V2), respectively, outperforming the state-of-the-art models. We grade 1264 patients with 87.24/87.50 (V1/V2) accuracy when using the 2-level classification criteria and 83.62/84.18 (V1/V2) when using the 5-level classification criteria. The results of the consistency analysis show that the proposed method is comparable to that of clinicians.

A Predictive Model of New-Onset Atrial Fibrillation After Percutaneous Coronary Intervention in Acute Myocardial Infarction Based on the Lymphocyte to C-Reactive Protein Ratio.

Purpose: Lymphocyte to C-reactive protein ratio (LCR) is a recognized systemic inflammatory marker and novel prognostic indicator for several cancers. This study investigated the relationship between preoperative LCR and new-onset atrial fibrillation (NOAF) in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI). Patients and Methods: Patients with AMI (n=662) with no history of atrial fibrillation (AF) were enrolled and classified into NOAF and non-NOAF groups based on the occurrence of postoperative NOAF during hospitalization. Logistic regression models were used to analyze NOAF risk factors and to assess the association between preoperative LCR and NOAF incidence. We constructed a new nomogram from the selected NOAF risk factors, and tested its predictive performance, degree of calibration, and clinical utility using receiver operating characteristic and calibration curves, decision curve analysis, and clinical impact curves. Results: Overall, 84 (12.7%) patients developed NOAF during hospitalization. The LCR was significantly lower in the NOAF group. Preoperative LCR accurately predicted NOAF after AMI and was correlated with increased NOAF risk. Age, body mass index, diabetes, serum albumin levels, uric acid levels, left atrium (LA) diameter, left ventricular ejection fraction, left circumflex artery stenosis > 50%, and Killip class II status were independent predictors of NOAF after AMI. In addition, a new nomogram combined with LCR was constructed to stratify the risk of NOAF in patients with AMI. The performance of the new nomogram was satisfactory, as shown by the receiver operating characteristic curve, calibration curve, decision curve analysis and clinical impact curve. Conclusion: Preoperative LCR was an independent predictor of NOAF in patients with AMI after PCI. The novel nomogram combined with LCR could rapidly and individually identify and treat patients at a high risk of NOAF.

Elevated triglyceride-glucose index predisposes to the initial episode of peritonitis in chronic peritoneal dialysis patients.

OBJECTIVE: The serum triglyceride-glucose (TyG) index is a marker of inflammation. However, the relationship between TyG index and peritoneal dialysis-related peritonitis (PDRP) is unclear. This study aimed to investigate the potential relationship between the baseline TyG index and the initial episode of PDRP. METHODS: A total of 208 peritoneal dialysis (PD) patients were enrolled from January 1, 2012, to December 31, 2019 and followed up until December 31, 2022. They were divided into 2 groups according to the median TyG. The primary outcome was the occurrence of the initial episode of PDRP while on PD therapy. Kaplan-Meier curves and Cox regression analyses were used to examine the association between them. RESULTS: Eighty-five initial episodes of PDRP were identified. The risk of PDRP was higher in the high-TyG index group (p = 0.030). Multivariate Cox regression analysis showed a higher risk of PDRP in patients with a high TyG index (HR = 1.800, 95% CI 1.511-2.815, p = 0.010). CONCLUSION: The baseline serum TyG index was an independent risk factor for the initial episode of PDRP in chronic PD patients.

Nomogram to predict the incidence of new-onset heart failure after acute coronary syndrome among women.

Background: Although great progress has been made in caring for patients with acute coronary syndrome (ACS), the incidence of heart failure (HF) after discharge remains high after ACS. Aims: We aimed to investigate the risk predictors for new-onset HF and build a simple nomogram to optimize the clinical management of female patients. Methods: The clinical data of 319 female patients with ACS between January 1, 2021 and January 1, 2022, were obtained from the Zhejiang Provincial People's Hospital. Multivariate logistic regression analysis was carried out to build the prediction model among all participants and then verified by 10-fold cross-validation. The discrimination, calibration, and clinical usefulness of the prediction model were assessed using receiver operating characteristic curve, calibration curve, and decision curve analyses. Results: This study analyzed 15 potential independent risk predictors of new-onset HF in 319 female patients with ACS. The incidence of HF onset was 23.2%. The following 5 independent risk predictors were filtered out as most relevant for predicting 12-month HF onset: left ventricular ejection fraction ≤ 60.5%, high-density lipoprotein ≤ 1.055 mmol/L, human epididymal protein 4 > 69.6 pmol/L, creatinine > 71.95 µmol/L, and diagnosis of myocardial infarction (MI). Conclusion: Our nomogram, which used five easily obtained clinical variables, could be a useful tool to help identify female individuals with ACS who are at high risk of developing HF after discharge and facilitate communication between female patients and physicians.

Electroacupuncture Alleviates Pain Responses and Inflammation in Collagen-Induced Arthritis Rats via Suppressing the TLR2/4-MyD88-NF-κB Signaling Pathway.

Results: EA intervention and OxPAPC injection could relieve mechanical allodynia and thermal hyperalgesia caused by CIA. Paw edema and pathological damage of synovium were significantly ameliorated after EA intervention and OxPAPC injection. Furthermore, EA intervention and OxPAPC injection markedly reduced the contents of serum TNF-α, IL-1ß, and IL-6, as well as the protein expression levels of synovial TLR2, TLR4, MyD88, and NF-κB p-p65. In particular, the expression of TLR2 and TLR4 on synovial fibroblasts and macrophages in synovium was significantly reduced by EA intervention. Conclusions: Repeated EA stimulation at ST36 and SP6 can effectively relieve joint pain and synovial inflammation caused by RA in CIA rats. The analgesic and anti-inflammatory effect of EA may be closely related to the inhibition of innate immune responses driven by the TLR2/4-MyD88-NF-κB signaling pathway in the synovium.

Nutritional Status as a Risk Factor for New-Onset Atrial Fibrillation in Acute Myocardial Infarction.

Purpose: Our study aimed to identify new-onset atrial fibrillation (NOAF) risk factors in acute myocardial infarction (AMI) patients after treatment with percutaneous coronary intervention (PCI) and investigate whether their nutritional status can be a predicting factor of NOAF. Patients and Methods: We analyzed 662 AMI patients after PCI for NOAF occurrence during follow-up hospitalization and divided them into an NOAF and non-NOAF group. The patients' nutritional status was assessed using the controlling nutritional status (CONUT) score and geriatric nutritional risk index (GNRI). The Kaplan‒Meier analysis was used to assess NOAF-free survival in varying degrees of malnutrition. Cox proportional hazards models were used to identify the risk factors for NOAF. Results: Eighty-four (12.7%) patients developed NOAF during hospitalization. There was a statistically significant difference in the occurrence of NOAF among different categories of nutritional status. The CONUT score and GNRI classifications were independent predictors of NOAF. NOAF occurrence was associated with older age, higher uric acid levels, higher N-terminal pro-B-type natriuretic peptide levels, greater left atrial size, and worse Killip class upon admission. Conclusion: The nutritional status can affect NOAF occurrence in AMI patients after PCI. The CONUT score and GNRI are ideal tools for evaluating the nutritional status of AMI patients, with an excellent predictive effect on NOAF.

Serum Human Epididymis Protein 4 as a Prognostic Predictor of New-Onset Heart Failure among Women after Acute Coronary Syndrome: A Single-Center Retrospective Study.

INTRODUCTION: Little is known about the prognostic factors among women with acute coronary syndrome (ACS), partly due to the small number of women included in heart failure (HF) clinical trials. Human epididymis protein 4 (HE4) has been proven to be a new biomarker for acute and chronic HF over the years. We hypothesize that HE4 could be a promising predictor. METHODS: This retrospective study analyzed data from Zhejiang Provincial People's Hospital. This study included 302 female patients with ACS between January 1, 2021, and December 1, 2021. The primary outcome was new-onset HF after ACS during the 12-month follow-up period. We used a logistic regression model to evaluate the association between serum HE4 levels and the incidence of HF. Serum HE4 levels were measured at baseline (within 24 h after admission). RESULTS: Of the 302 female patients, 70 (23.2%) developed new-onset HF within 12 months. Serum HE4 levels in patients with adverse events were significantly higher than those in patients without events (8.9 [7.3-11.5] pmol/dL versus 5.9 [5.0-6.8] pmol/dL, p < 0.001). The levels of HE4, troponin I peak, left ventricular ejection fraction (LVEF), and estimated glomerular filtration rate (eGFR) were validated as independent predictors, with HE4 being the best laboratory predictor (area under the curve, 0.863; 95% confidence interval, 0.817-0.909). Serum HE4 concentrations of >6.93 pmol/dL distinguished patients at risk of HF with 82.9% sensitivity and 78.0% specificity (maximum Youden index J, 0.609). Moreover, HE4 levels were associated with an increased risk of HF. DISCUSSION: We found a strong relationship between HE4 and the occurrence of HF after ACS among women, which might help identify patients at high risk of HF for whom close or intense management should be mandatory.

Association of Hemoglobin to Red Blood Cell Distribution Width-Standard Deviation (RDW-SD) Ratio and 3-Month Readmission in Elderly Chinese Patients with Heart Failure: A Retrospective Cohort Study.

Purpose: Hemoglobin (Hb) and red blood cell distribution width-standard deviation (RDW-SD) have clinical significance in the prognosis of heart failure (HF). Little is known regarding the prognostic value of the Hb/RDW-SD ratio in patients with HF. This study sought to investigate the association between Hb/RDW-SD ratio and HF 3-month readmission in Chinese elderly patients. Patients and Methods: The present study was a retrospective cohort study. A total of 1816 HF patients were extracted from the Chinese HF database. A generalized linear model was used to explore the association between Hb/RDW-SD and 3-month readmission in HF. The generalized additive model was used to explore the nonlinear relationship, and a two-piecewise linear regression model was used to find the inflection point. Subgroup analysis explored interactions and whether each subgroup was consistent with the primary outcome direction. Results: Result showed Hb/RDW-SD was negatively associated with HF 3-month readmission (OR = 0.70, 95% CI: 0.55 to 0.89, P = 0.0031). A non-linear relationship was detected between Hb/RDW-SD and HF 3-month readmission with two inflection points (1.78 and 2.17). Both Hb/RDW-SD < 1.78 and Hb/RDW-SD > 2.17 showed a significant correlation between them, with corresponding effect values of (OR = 0.38, 95% CI: 0.17 to 0.87, P = 0.0209) and (OR = 0.44, 95% CI: 0.27 to 0.71, P = 0.0007), respectively. Conclusion: Hb/RDW-SD is negatively associated with HF 3-month readmission. The relationship between Hb/RDW-SD and HF 3-month readmission is also non-linear. Both Hb/RDW-SD < 1.78 and Hb/RDW-SD > 2.17 were strong negatively associated with HF 3-month readmission.

Guizhi longgu muli decoction ameliorates pathological changes in heart and bone in ovariectomized rats.

The aim of this study is to investigate the pathological changes in cardiac function, blood pressure, blood lipids and bone metabolism in ovariectomized (OVX) rats, as well as the intervention effect of Guizhi Longgu Muli decoction (GZLM). Bilateral oophorectomy was used to establish an OVX menopausal model. Four groups of rats were randomly selected: Sham surgery group, OVX group, estradiol (0.018g/L) and GZLM group (20g/kg). Cardiac function was assessed using ultrasound, blood pressure was measured using the tail cuff method. The oxidase method was used to determine the total cholesterol (TC) and triglycerides in serum. Direct measurement of high-density lipoprotein and low-density lipoprotein levels (LDL-C). Hematoxylin eosin staining and electron microscopy examination of myocardial structure. Microscopic CT was used to determine the bone microstructure. GZLM improved pathological cardiac changes and reduced the LVIDs, LVVols and LVVold. There was a decrease in systolic pressure, diastolic pressure and mean blood pressure in GZLM group. A decrease in serum TC and LDL-C levels was observed in the GZLM group. The BMD, BV/TV, Tb.Th, Tb.N of GZLM group raised, while Tb.SP and SMI significantly decreased or decreased. GZLM may have the effect of improving abnormal cardiac structure and function, promoting bone metabolism in OVX rats.

The B-type response regulator GmRR11d mediates systemic inhibition of symbiotic nodulation.

Key to the success of legumes is the ability to form and maintain optimal symbiotic nodules that enable them to balance the trade-off between symbiosis and plant growth. Cytokinin is essential for homeostatic regulation of nodulation, but the mechanism remains incompletely understood. Here, we show that a B-type response regulator GmRR11d mediates systemic inhibition of nodulation. GmRR11d is induced by rhizobia and low level cytokinin, and GmRR11d can suppress the transcriptional activity of GmNSP1 on GmNIN1a to inhibit soybean nodulation. GmRR11d positively regulates cytokinin response and its binding on the GmNIN1a promoter is enhanced by cytokinin. Intriguingly, rhizobial induction of GmRR11d and its function are dependent upon GmNARK that is a CLV1-like receptor kinase and inhibits nodule number in shoots. Thus, GmRR11d governs a transcriptional program associated with nodulation attenuation and cytokinin response activation essential for systemic regulation of nodulation.

Serum lipid profile in relation to free thyroxine and the effect of levothyroxine treatment on lipids in patients with isolated hypothyroxinemia during pregnancy: a single-center retrospective study.

BACKGROUND: Thyroid function is widely considered a lipid metabolism regulator. However, studies on lipid metabolism in pregnant women with low free thyroxine (FT4) levels are limited and inconclusive. Furthermore, the association between maternal FT4 deficiency and adverse lipid metabolic parameters is unknown. Therefore, we aimed to investigate this association and the effects of levothyroxine (L-T4) treatment on these metabolic indicators. METHODS: This retrospective study included 164 patients with isolated hypothyroidism (IH) (FT4 levels below the 5th percentile with normal thyroid stimulating hormone levels according to the gestational-specific reference range) and 407 euthyroidism patients (control group who had regular antenatal examinations at Zhejiang Provincial People's Hospital, Hangzhou, China) between January 1, 2019, and December 31, 2020. Patients with IH were divided into levothyroxine (L-treatment group, n = 77) and dietary iodine supplement treatment groups (dietary treatment group, n=87) according to the hospital's treatment policy and clinical experience. The intervention lasted for at least 8 weeks. Metabolic indicators, including thyroid function and lipid parameters, were collected at least twice before and after the intervention. Other data collected included maternal age, history of abortion, prepregnancy BMI, and gestational weight gain (Fig. 1). RESULTS: Compared with the control group, Patients with IH had a higher degree of dyslipidemia, reflected in elevated total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B) levels. In IH patients, an inverse correlation was found between FT4 and TG levels, which remained after adjusting for prepregnancy BMI. The L-treatment group demonstrated a significantly slower rate of hypercholesterolemia progression during pregnancy than the dietary treatment group. In addition, there was a relationship between the therapeutic effect and the degree of disease, with the main factors being FT4, TSH and TG levels prior to starting treatment. CONCLUSIONS: Low FT4 levels were associated with elevated blood lipid levels. Serum FT4 and lipid levels in patients could be improved by medical intervention.

A simple APACHE IV risk dynamic nomogram that incorporates early admitted lactate for the initial assessment of 28-day mortality in critically ill patients with acute myocardial infarction.

BACKGROUND: Early risk stratification is important for patients with acute myocardial infarction (AMI). We aimed to develop a simple APACHE IV dynamic nomogram, combined with easily available clinical parameters within 24 h of admission, thus improving its predictive power to assess the risk of mortality at 28 days. METHODS: Clinical information on AMI patients was extracted from the eICU database v2.0. A preliminary XGBoost examination of the degree of association between all variables in the database and 28-day mortality was conducted. Univariate and multivariate logistic regression analysis were used to perform screening of variables. Based on the multifactorial analysis, a dynamic nomogram predicting 28-day mortality in these patients was developed. To cope with missing data in records with missing variables, we applied the multiple imputation method. Predictive models are evaluated in three main areas, namely discrimination, calibration, and clinical validity. The discrimination is mainly represented by the area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Calibration is represented by the calibration plot. Clinical validity is represented by the decision curve analysis (DCA) curve. RESULTS: A total of 504 people were included in the study. All 504 people were used to build the predictive model, and the internal validation model used a 500-bootstrap method. Multivariate analysis showed that four variables, APACHE IV, the first sample of admission lactate, prior atrial fibrillation (AF), and gender, were included in the nomogram as independent predictors of 28-day mortality in AMI. The prediction model had an AUC of 0.819 (95%CI 0.770-0.868) whereas the internal validation model had an AUC of 0.814 (95%CI 0.765-0.860). Calibration and DCA curves indicated that the dynamic nomogram in this study were reflective of real-world conditions and could be applied clinically. The predictive model composed of these four variables outperformed a single APACHE IV in terms of NRI and IDI. The NRI was 16.4% (95% CI: 6.1-26.8%; p = 0.0019) and the IDI was 16.4% (95% CI: 6.0-26.8%; p = 0.0020). Lactate accounted for nearly half of the total NRI, which showed that lactate was the most important of the other three variables. CONCLUSION: The prediction model constructed by APACHE IV in combination with the first sample of admission lactate, prior AF, and gender outperformed the APACHE IV scoring system alone in predicting 28-day mortality in AMI. The prediction dynamic nomogram model was published via a website app, allowing clinicians to improve the predictive efficacy of the APACHE IV score by 16.4% in less than 1 min.

Recognizing the role of the vagus nerve in depression from microbiota-gut brain axis.

Depression is a worldwide disease causing severe disability, morbidity, and mortality. Despite abundant studies, the precise mechanisms underlying the pathophysiology of depression remain elusive. Recently, cumulate research suggests that a disturbance of microbiota-gut-brain axis may play a vital role in the etiology of depression while correcting this disturbance could alleviate depression symptoms. The vagus nerve, linking brain and gut through its afferent and efferent branches, is a critical route in the bidirectional communication of this axis. Directly or indirectly, the vagus afferent fibers can sense and relay gut microbiota signals to the brain and induce brain disorders including depression. Also, brain changes in response to stress may result in gut hyperpermeability and inflammation mediating by the vagal efferents, which may be detrimental to depression. Notably, vagus nerve stimulation owns an anti-inflammatory effect and was proved for depression treatment. Nevertheless, depression was accompanied by a low vagal tone, which may derive from response to stress and contribute to pathogenesis of depression. In this review, we aim to explore the role of the vagus nerve in depression from the perspective of the microbiota-gut-brain axis, highlighting the relationship among the vagal tone, the gut hyperpermeability, inflammation, and depression.

NLR we there yet? Nucleocytoplasmic coordination of NLR-mediated immunity.

Plant intracellular nucleotide-binding leucine-rich repeat immune receptors (NLRs) perceive the activity of pathogen-secreted effector molecules that, when undetected, promote colonisation of hosts. Signalling from activated NLRs converges with and potentiates downstream responses from activated pattern recognition receptors (PRRs) that sense microbial signatures at the cell surface. Efficient signalling of both receptor branches relies on the host cell nucleus as an integration point for transcriptional reprogramming, and on the macromolecular transport processes that mediate the communication between cytoplasm and nucleoplasm. Studies on nuclear pore complexes (NPCs), the nucleoporin proteins (NUPs) that compose NPCs, and nuclear transport machinery constituents that control nucleocytoplasmic transport, have revealed that they play important roles in regulating plant immune responses. Here, we discuss the contributions of nucleoporins and nuclear transport receptor (NTR)-mediated signal transduction in plant immunity with an emphasis on NLR immune signalling across the nuclear compartment boundary and within the nucleus. We also highlight and discuss cytoplasmic and nuclear functions of NLRs and their signalling partners and further consider the potential implications of NLR activation and resistosome formation in both cellular compartments for mediating plant pathogen resistance and programmed host cell death.

[Effects of transcutaneous auricular vagus nerve stimulation on bone and cartilage destruction in rats with rheumatoid arthritis].

OBJECTIVE: To observe the alleviating effect of transcutaneous auricular vagus nerve stimulation (taVNS) on articular cartilage and bone destruction in rats with collagen-induced arthritis (CIA), and explore the cellular and molecular mechanisms of taVNS against rheumatoid arthritis (RA). METHODS: The male SD rats were randomly divided into normal control group (n=12), model group (n=12), and taVNS group (n=12). The CIA rat model was established by multi-point injection of emulsion prepared from type Ⅱ bovine collagen and Freund's incomplete adjuvant into the root of rat tail. The rats in the taVNS group were treated with taVNS at bilateral auricular conchae, 30 min per time, once a day, for consecutive 28 d. The cartilage destruction of the ankle joint was observed by safranin O-fast green staining, the production of osteoclasts in the joint tissue by tartrate-resistant acid phosphatase (TRAP) staining, and the bone erosion by X-ray and Micro-CT imaging. The protein expression levels of matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, receptor activator of nuclear factor-κB ligand (RANKL), and osteoprotegerin (OPG) in the synovial tissues were detected by Western blot. RESULTS: Compared with the normal control group, the CIA rats presented with typical RA symptoms and elevated arthritis index (AI,P<0.05). After intervention with taVNS, the AI remarkably declined in comparison with that in the model group (P<0.05). Compared with the control group, the model group displayed loss of cartilage matrix in the ankle joint, thinned cartilage layer, obvious cartilage damage, and increased number of osteo-clasts in the joint (P<0.01); the imaging results showed bone loss and three-dimensional structural destruction of ankle joint and aggravated bone erosion (P<0.01); the expression levels of MMP-1, MMP-3 and MMP-13, and RANKL/OPG ratio were significantly elevated in the synovial tissue of ankle joint (P<0.01, P<0.05), while the expression level of OPG was decreased (P<0.05). Compared with the model group, taVNS resulted in relatively intact cartilage layer of ankle joint, alleviated cartilage destruction, decreased number of osteoclasts (P<0.01), improved bone erosion, loss, and three-dimensional structural destruction (P<0.01), and diminished MMP-1, MMP-3, and MMP-13 expression and RANKL/OPG ratio in the synovial tissue of ankle joint (P<0.05, P<0.01), while the expression level of OPG was increased (P<0.05). CONCLUSION: taVNS effectively relieves bone and cartilage destruction in CIA rats, which might be related to its efficacy in reducing the production of osteoclasts in joint tissues and down-regulating the expression levels of MMP-1, MMP-3 and MMP-13, and RANKL/OPG ratio.