Microglial Pdcd4 deficiency mitigates neuroinflammation-associated depression via facilitating Daxx mediated PPARγ/IL-10 signaling.

The dysregulation of pro- and anti-inflammatory processes in the brain has been linked to the pathogenesis of major depressive disorder (MDD), although the precise mechanisms remain unclear. In this study, we discovered that microglial conditional knockout of Pdcd4 conferred protection against LPS-induced hyperactivation of microglia and depressive-like behavior in mice. Mechanically, microglial Pdcd4 plays a role in promoting neuroinflammatory responses triggered by LPS by inhibiting Daxx-mediated PPARγ nucleus translocation, leading to the suppression of anti-inflammatory cytokine IL-10 expression. Finally, the antidepressant effect of microglial Pdcd4 knockout under LPS-challenged conditions was abolished by intracerebroventricular injection of the IL-10 neutralizing antibody IL-10Rα. Our study elucidates the distinct involvement of microglial Pdcd4 in neuroinflammation, suggesting its potential as a therapeutic target for neuroinflammation-related depression.

Association of physical activity with socio-economic status and chronic disease in older adults in China: cross-sectional findings from the survey of CLASS 2020 after the outbreak of COVID-19.

BACKGROUND: In 2021, China had a population of 264·01 million individuals over the age of 60, indicating a high prevalence of chronic diseases. Among older adults, physical inactivity (PI) is a significant risk factor for chronic diseases. However, few studies have been conducted on the correlation of physical activity (PA) with the economic status, geography and chronic disease risks in Chinese elderly. The objectives of this study were to better understand the distribution of PA among older adults in China and its relationship with economic status, geography, and chronic disease risks. METHODS: This study utilized data from the China Longitudinal Aging Social Survey (CLASS) in 2020, post-COVID-19. The study employed a stratified, multistage, probabilistic sampling approach and included 11,396 adults over the age of 59 from 28 provinces in China. Data on demographics, the duration and intensity of PA, history of diseases and personalized factors influencing PA were collected via structured interviews by researchers. In this study, we conducted a comprehensive analysis, employing a range of statistical methods including descriptive analysis, Wilcoxon rank-sum tests, Bayesian networks, and chi-square tests. RESULTS: The prevalence of PI among older adults over 59 in China is 28·82%. Significant regional differences were observed in the duration of PA at different intensities. Older adults residing in more economically developed areas were more likely to engage in moderate-to-vigorous physical activity (MVPA) and exhibited longer sedentary behavior. Economic status and urban-rural disparities consistently emerged as direct influential factors across all intensity types. Chronic disease risks were significantly lower in active older adults compared to inactive ones. Lack of social guidance, family support, and personal inclination towards sedentary behavior were the main personalized factors affecting PA among older adults, and these factors could be relatively easily modified. CONCLUSIONS: Economic status, geography, and living areas (urban and rural) significantly influenced the distribution of physical activities in China. Particularly, economic status and living areas acted as direct factors. Older adults reaching the recommended standards for PA had significantly lower chronic disease risks, highlighting the importance of improving personalized factors which are crucial for promoting PA.

Medial Protrusio Technique Versus Structural Autologous Bone-Grafting Technique in Total Hip Arthroplasty for Crowe Type II to III Hip Dysplasia.

BACKGROUND: It is unclear whether acetabular reconstruction techniques have any impact on clinical outcomes. This study aimed to determine (1) whether acetabular reconstruction techniques influenced the position of the acetabular cup and (2) whether clinical outcomes based on the acetabular reconstruction techniques differ in patients undergoing total hip arthroplasty (THA) with Crowe II to III developmental dysplasia of the hip. METHODS: This was a retrospective analysis of prospectively collected data from 69 patients (74 hips) who were treated with cementless THA using medial protrusio technique (MPT) or structural autologous bone-grafting technique (SABT). There were 39 patients (41 hips) included in the MPT group and 30 patients (33 hips) in the SABT group. Clinical and radiographic outcomes were evaluated. RESULTS: All patients were followed up for at least 3 years. There were similar results between the 2 groups in terms of blood loss, Harris hip score, leg length discrepancy, cup inclination, cup anteversion, and proportion of cup coverage (P > .05). The operative time was significantly longer in the SABT group compared with the MPT group (P < .001). The postoperative vertical center of rotation was significantly higher in the MPT group compared with the SABT group (P = .001), and postoperative horizontal center of rotation was significantly shallower in the SABT group compared with the MPT group (P < .001). CONCLUSION: The MPT and SABT provide similar clinical and radiographic outcomes in the management of Crowe II to III developmental dysplasia of the hip by cementless THA. However, the MPT has the advantage of a shorter operative time, whereas the SABT is more conducive to placing the acetabular cup in an anatomic position. LEVEL OF EVIDENCE: Level III, Therapeutic, Case-Control Study.

Genes that escape from X-chromosome inactivation and sexual dimorphism of systemic lupus erythematosus.

X chromosome inactivation can balance the effects of the two X chromosomes in females, and emerging evidence indicates that numerous genes on the inactivated X chromosome have the potential to evade inactivation. The mechanisms of escape include modification of DNA, RNA, histone, epitope, and various regulatory proteins, as well as the spatial structure of chromatin. The study of X chromosome inactivation escape has paved the way for investigating sex dimorphism in human diseases, particularly autoimmune diseases. It has been demonstrated that the presence of TLR7, CD40L, IRAK-1, CXCR3, and CXorf21 significantly contributes to the prevalence of SLE (systemic lupus erythematosus) in females. This article mainly reviews the molecular mechanisms underlying these genes that escape from X-chromosome inactivation and sexual dimorphism of systemic lupus erythematosus. Therefore, elucidating the molecular mechanisms underlying sexual dimorphism in SLE is not only crucial for diagnosing and treating the disease, but also holds theoretical significance in comprehensively understanding the development and regulatory mechanisms of the human immune system.

IL-33 in the basolateral amygdala integrates neuroinflammation into anxiogenic circuits via modulating BDNF expression.

Hyper-inflammatory reaction plays a crucial role in the pathophysiology of depression and anxiety disorders. However, the mechanisms underlying inflammation-induced anxiety changes remain poorly understood. Here, we showed that in the lipopolysaccharide (LPS)-induced anxiety model, Interleukin (IL)-33, a member of the IL-1 family, was up-regulated in the basolateral amygdala, and IL-33 deficiency prevent anxiety-like behavior. Overexpression of IL-33 in amygdalar astrocytes led to anxiety-like response via repressing brain-derived neurotrophic factor (BDNF) expression. Mechanically, IL-33 suppressed BDNF expression through NF-κB pathway to impair GABAergic transmission in the amygdala and NF-κB inhibitor abolished the effect of IL-33 on anxiety. Administration of an inverse GABAA receptor agonist increased the anxiety of IL-33- deficient mice. These results reveal that inflammatory response can activate anxiogenic circuits by suppressing BDNF and GABAergic neurons transmission, suggesting that IL-33 in basolateral amygdalar is a linker between inflammation and anxiety.

Serum-derived exosomes from SD rats induce inflammation in macrophages through the mTOR pathway.

Inhalation of beryllium and its compounds can cause lung injuries, resulting from inflammation and oxidative stress. Multivesicular bodies (MVB), such as exosomes, are membrane vesicles produced by early and late endosomes that mediate intercellular communications. However, the role of exosomes in beryllium toxicity has not been elucidated. This current study aimed to investigate the functional role of exosomes in lung injury resulting from beryllium sulfate (BeSO4 ). Here, Sprague-Dawley (SD) rats were exposed to 4, 8, and 12 mg/kg BeSO4 by nonexposed intratracheal instillation. Murine macrophage (RAW 264.7) cells were pretreated with 50 nmol/L rapamycin (an mTOR signaling pathway inhibitor) for 30 min and then cultured for 24 h with 100 µg/mL exosomes, which had been previously isolated from the serum of 12 mg/kg BeSO4 -treated SD rats. Compared with those of the controls, exposure to BeSO4 in vivo increased LDH activity, elevated levels of inflammatory cytokines (IL-10, TNF-α, and IFN-γ) alongside inflammation-related proteins expression (COX-2 and iNOS), and enhanced secretion of exosomes from the SD rat's serum. Moreover, the BeSO4 -Exos-induced upregulation of LDH activity and inflammatory responses in RAW 264.7 cells can be alleviated following pretreatment with rapamycin. Collectively, these results suggest that serum exosomes play an important role in pulmonary inflammation induced by BeSO4 in RAW 264.7 cells via the mTOR pathway.

Hydrogen sulfide alleviates apoptosis and autophagy induced by beryllium sulfate in 16HBE cells.

Beryllium and its compounds are systemic toxicants that are widely applied in many industries. Hydrogen sulfide has been found to protect cells. The present study aimed to determine the protective mechanisms involved in hydrogen sulfide treatment of 16HBE cells following beryllium sulfate-induced injury. 16HBE cells were treated with beryllium sulfate doses ranging between 0 and 300 µM BeSO4 . Additionally, 16HBE cells were subjected to pretreatment with either a 300 µM dose of sodium hydrosulfide (a hydrogen sulfide donor) or 10 mM DL-propargylglycine (a cystathionine-γ-lyase inhibitor) for 6 hr before then being treated with 150 µM beryllium sulfate for 48 hr. This study illustrates that beryllium sulfate induces a reduction in cell viability, increases lactate dehydrogenase (LDH) release, and increases cellular apoptosis and autophagy in 16HBE cells. Interestingly, pretreating 16HBE cells with sodium hydrosulfide significantly reduced the beryllium sulfate-induced apoptosis and autophagy. Moreover, it increased the mitochondrial membrane potential and alleviated the G2/M-phase cell cycle arrest. However, pretreatment with 10 mM DL-propargylglycine promoted the opposite effects. PI3K/Akt/mTOR and Nrf2/ARE signaling pathways are also activated following pretreatment with sodium hydrosulfide. These results indicate the protection provided by hydrogen sulfide in 16HBE cells against beryllium sulfate-induced injury is associated with the inhibition of apoptosis and autophagy through the activation of the PI3K/Akt/mTOR and Nrf2/ARE signaling pathways. Therefore, hydrogen sulfide has the potential to be a promising candidate in the treatment against beryllium disease.

Persistence of Antibody and Cellular Immune Responses in Coronavirus Disease 2019 Patients Over Nine Months After Infection.

BACKGROUND: The duration of humoral and T and B cell response after the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. METHODS: We performed a cross-sectional study to assess the virus-specific antibody and memory T and B cell responses in coronavirus disease 2019 (COVID-19) patients up to 343 days after infection. Neutralizing antibodies and antibodies against the receptor-binding domain, spike, and nucleoprotein of SARS-CoV-2 were measured. Virus-specific memory T and B cell responses were analyzed. RESULTS: We enrolled 59 patients with COVID-19, including 38 moderate, 16 mild, and 5 asymptomatic patients; 31 (52.5%) were men and 28 (47.5%) were women. The median age was 41 years (interquartile range, 30-55). The median day from symptom onset to enrollment was 317 days (range 257 to 343 days). We found that approximately 90% of patients still have detectable immunoglobulin (Ig)G antibodies against spike and nucleocapsid proteins and neutralizing antibodies against pseudovirus, whereas ~60% of patients had detectable IgG antibodies against receptor-binding domain and surrogate virus-neutralizing antibodies. The SARS-CoV-2-specific IgG+ memory B cell and interferon-γ-secreting T cell responses were detectable in more than 70% of patients. CONCLUSIONS: Severe acute respiratory syndrome coronavirus 2-specific immune memory response persists in most patients approximately 1 year after infection, which provides a promising sign for prevention from reinfection and vaccination strategy.

Identification of an Immune-Related LncRNA Prognostic Signature in Uterine Corpus Endometrial Carcinoma Patients.

BACKGROUND: Uterine corpus endometrial carcinoma (UCEC) is the third most prevalent female reproductive system malignant tumor with poor prognosis, particularly at advanced stage. On the other hand, recent studies have reported the prognostic role of long non-coding RNAs (lncRNAs) in UCEC. The aim of this study was to determine the immune-related lncRNA signature for predicting overall survival (OS) in UCEC patients. METHODS: The genomic data and clinical information of UCEC patients were extracted from the Cancer Genome Atlas. Pearson's correlation analysis was carried out to identify the immune-related lncRNAs. Univariate and multivariate Cox regression analyses were conducted to obtain the prognostic lncRNAs from the immune-related lncRNAs for the construction of the prognostic signature. Afterwards, the UCEC patients were divided into high-risk and low-risk groups. The prognostic value of the signature was assessed by survival, receiver operating characteristic (ROC), and nomogram analyses. Finally, the immune status for high-risk and low-risk groups was evaluated by the ESTIMATE algorithm. RESULTS: A total of 13 immune-related lncRNAs (AC108860.2, AC015849.5, AL592494.3, LINC01234, U91319.1, AC092969.1, AL356133.2, AC103563.2, AL138962.1, AC138965.1, LINC01687, AC091987.1, and MIR7-3HG) were finally identified for the construction of the prognostic signature. Patients in the high-risk group had worse prognosis than those in the low-risk group. The prognostic signature was confirmed as an independent prognostic factor through the multivariate Cox regression analysis. The nomogram based on the prognostic signature and clinicopathologic features was constructed with a superior overall predictive power to evaluate the survival outcomes in UCEC patients. Finally, according to the ESTIMATE algorithm results, we discovered different immune statuses in the low-risk and high-risk groups. CONCLUSIONS: The immune-related lncRNA signature for the assessment of the OS of UCEC patients had a good practical value.

Digit ratio (2D:4D) in Chinese women with gastric cancer.

OBJECTIVES: Digit ratio, especially the second-to-fourth digit ratio (2D:4D), is a proxy indicator for prenatal exposure and sensitivity to sexual hormones which may influence the susceptibility to certain cancers. The aim of the present study was to investigate whether there is a possible association between 2D:4D and gastric cancer (GCA) in north Chinese women. METHODS: Photographs of the left and right hands of 167 women (controls: 113; patients: 54) were collected. Left hand, right hand, and right minus left hand (Dr-l) 2D:4D were analyzed and compared. RESULTS: The GCA group presented significantly lower 2D:4D than controls (left: P < .01; right: P < .05). No significant difference was observed in Dr-l between the two groups. In patients, there were no correlations between 2D:4D and age at GCA or tumor staging. CONCLUSIONS: Decreased 2D:4D (especially of the left hand) may suggest a higher prenatal testosterone (lower prenatal estrogen) exposure in north Chinese women with GCA.

Digit ratio (2D:4D) in Chinese women with breast cancer.

OBJECTIVES: Digit ratio, especially second-to-fourth digit ratio (2D:4D) is established in utero and is positively correlated with oestrogen in men and women. It is a putative biomarker for prenatal hormone exposure and may represent an individual predisposition to certain diseases (e.g., breast cancer). The aim of the present study is to investigate whether there is a link between digit ratio (2D:4D) and breast cancer in Chinese populations. METHODS: The controls we chose were healthy subjects-age and -sex matched to the patients diagnosed with breast cancer. Photocopies of the two hands of 218 women (controls: 109; patients: 109) were collected. Left hand, right hand, mean hand, and right minus left 2D:4D (Dr-l ) were analyzed. RESULTS: The patients with breast cancer presented significantly higher 2D:4D than controls (left: P < 0.01; right: P < 0.05; mean: P < 0.05). The mean values of 2D:4D on the left hand were significantly higher than those on the right hand in the two groups, respectively (controls: P < 0.05; patients: P ≤ 0.01). In patients, there was a significantly negative correlation between 2D:4D (left hand: P < 0.01; right hand, mean: P < 0.05) and the presented age with breast cancer, but no association between Dr-l and age of presented disease. CONCLUSIONS: Digit ratio (2D:4D) may correlate with the increased risk of breast cancer.

Preoperative Clinical and Ultrasonographic Predictors for Aggressive Behaviors in Sporadic Medullary Thyroid Carcinomas.

Objective: To explore the clinical and ultrasonographic predictors for aggressive behaviors preoperatively in sporadic medullary thyroid carcinomas (MTCs). Materials and Methods: The preoperative clinical and ultrasonographic characteristics of patients diagnosed with MTCs between January 2009 and May 2022 were retrospectively reviewed. MTCs were described and categorized according to the American College of Radiology (ACR) thyroid imaging reporting and data system classification by 2 radiologists. Interobserver agreement was evaluated by kappa test. Univariate and multivariate analyses were performed to identify predictors of aggressive behaviors in MTCs. The log-rank test was utilized to compare differences in Kaplan-Meier (K-M) curves for postoperative disease-free survival (PDFS). Results: A total of 120 patients were enrolled in the final study. Male sex was significant risk factor for metastasis, perithyroidal invasion, and lateral cervical lymph node (LCLN) metastasis [odds ratio (OR): 3.109, P = .019; OR: 5.316, P = .018; OR: 5.154 P = .012, respectively]. The kappa values for all ultrasonic characteristics were high (ranged from 0.811 to 0.941). Size, focality, and margin of the nodule were independent risk factors for metastasis, as well as for LCLN metastasis. Whereas margin (P < .001) and a subcapsular location (P = .021) were risk factors for perithyroidal invasion. According to K-M analysis, PDFS of patients differed significantly between groups with/without metastasis (P < .001), groups with/without perithyroidal extension (P < .001) and groups with/without LCLN metastasis (P < .001). Conclusions: Male sex is an independent risk factor for metastasis, perithyroidal invasion, and LCLN metastasis. The large size (≥2.55 cm for metastasis, ≥2.15 cm for LCLN metastasis, respectively), multifocality, and irregular margin of nodules were independent risk factors for both metastasis and LCLN metastasis. Extrathyroidal extension and a subcapsular location were risk factors for perithyroidal invasion. Moreover, patients with metastasis/perithyroidal extension/LCLN metastasis exhibited worse PDFS.

IL-37d suppresses Rheb-mTORC1 axis independently of TCS2 to alleviate alcoholic liver disease.

Tuberous sclerosis complex 2 (TSC2) crucially suppresses Rheb activity to prevent mTORC1 activation. However, mutations in TSC genes lead to mTORC1 overactivation, thereby causing various developmental disorders and cancer. Therefore, the discovery of novel Rheb inhibitors is vital to prevent mTOR overactivation. Here, we reveals that the anti-inflammatory cytokine IL-37d can bind to lysosomal Rheb and suppress its activity independent of TSC2, thereby preventing mTORC1 activation. The binding of IL-37d to Rheb switch-II subregion destabilizes the Rheb-mTOR and mTOR-S6K interactions, further halting mTORC1 signaling. Unlike TSC2, IL-37d is reduced under ethanol stimulation, which results in mitigating the suppression of lysosomal Rheb-mTORC1 activity. Consequently, the recombinant human IL-37d protein (rh-IL-37d) with a TAT peptide greatly improves alcohol-induced liver disorders by hindering Rheb-mTORC1 axis overactivation in a TSC2- independent manner. Together, IL-37d emerges as a novel Rheb suppressor independent of TSC2 to terminate mTORC1 activation and improve abnormal lipid metabolism in the liver.

ACSS2 controls PPARγ activity homeostasis to potentiate adipose-tissue plasticity.

The appropriate transcriptional activity of PPARγ is indispensable for controlling inflammation, tumor and obesity. Therefore, the identification of key switch that couples PPARγ activation with degradation to sustain its activity homeostasis is extremely important. Unexpectedly, we here show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) critically controls PPARγ activity homeostasis via SIRT1 to enhance adipose plasticity via promoting white adipose tissues beiging and brown adipose tissues thermogenesis. Mechanistically, ACSS2 binds directly acetylated PPARγ in the presence of ligand and recruits SIRT1 and PRDM16 to activate UCP1 expression. In turn, SIRT1 triggers ACSS2 translocation from deacetylated PPARγ to P300 and thereafter induces PPARγ polyubiquitination and degradation. Interestingly, D-mannose rapidly activates ACSS2-PPARγ-UCP1 axis to resist high fat diet induced obesity in mice. We thus reveal a novel ACSS2 function in coupling PPARγ activation with degradation via SIRT1 and suggest D-mannose as a novel adipose plasticity regulator via ACSS2 to prevent obesity.

Community composition of nirS-type denitrifier in a shallow eutrophic lake.

Denitrification is a major biological process to reduce nitrate to molecular nitrogen (N2). In shallow eutrophic lakes, this process can remove the largest portion of fixed nitrogen and plays an important role in self-purification of this ecosystem. To understand the structure of denitrifying communities in a shallow eutrophic lake, denitrifier communities in four sub-lakes of East Lake in Wuhan, China, were explored by restriction fragment length polymorphisms (RFLP) analysis and sequencing of nirS gene clone libraries. nirS is a functional marker gene for denitrification encoding cytochrome cd 1-containing nitrite reductase, which catalyzes the reduction of nitrite to nitric oxide. Both RFLP fingerprints clustering analysis and phylogeny analysis based on the amino acid sequences of NirS revealed that NirS-type communities in East Lake sediment could be roughly divided into three clusters. Cluster I accounted for 74-82 % of clones from the moderately eutrophic sub-lakes Tuan, Tang Ling, and Guo Zheng. Cluster II accounted for 76 % of the communities in hypertrophic sub-lake Miao Lake and cluster III as a minor group (7 % of the total), mainly presented in Miao Lake. Phylogenetic analysis revealed that cluster I was related to the reference clones from a broad range of ecological environments, and clusters II and III were more phylogenetically related to the reference clones from entrophic environments. Canonical correspondence analysis indicated that total nitrogen, total phosphate, total organic carbon, and NH4-N and NO2-N were important environmental factors affecting the dispersion of NirS-type denitrifier in the sediments. Cluster I showed a weak relationship with the nutrient content, while cluster II and III were positively related with the nutrient content. Principal coordinates analysis indicated that NirS-type communities from Tuan Lake, Tang Ling Lake, and Guo Zheng Lake sediments were divergent from those found in river, estuary sediment, and forest soil but similar to communities in constructed wetland sediment despite large geographic distances. The communities from the hypertrophic sub-lake Miao Lake deviated from other sub-lakes and the reference communities and clustered independently. Our results support the argument that environmental factors regulate the composition and distribution of the functional bacterial groups.

Association between Air Pollution and Physical Activity and Sedentary Behavior among Adults Aged 60 Years or Older in China: A Cross-Sectional Study.

BACKGROUND: Exposure to air pollution is associated with an increased risk of all-cause mortality in older adults. Promoting physical activity (PA) and avoiding sedentary behavior (SB) serve as key strategies to maintain and improve human health. However, ambient air pollution can adversely affect PA and SB, increasing the risks of health problems. This study aimed to visualize national spatial patterns of average AQI concentration, PA, and SB distributions and to examine the associations between air pollution and PA and SB in a national sample of Chinese older adults aged 60 years or older. METHODS: We analyzed the data of the China Longitudinal Aging Social Survey 2020 (CLASS 2020), which sampled 11,399 older men and women from 30 cities in China. Moderate, vigorous, and light PA and SB were measured using the Chinese version of the International Physical Activity Questionnaire-Short Form (IPAQ-C). The environmental measures included the average hourly air quality index (AQI), PM2.5, PM10, and NO2 (µg/m3). The data were analyzed using multivariable linear regression. RESULTS: Increases in the standard deviations (±SD) of AQI, PM2.5, PM10, and NO2 concentrations were associated with decreases in MVPA per week of -2.34 (95%CI = -3.36, -1.32), -2.58 (95%CI = -3.61, -1.55), -1.96 (95%CI = -3.05, -0.08), and -1.19 (95%CI = -2.06, -0.31) and decreases in LPA per week of -6.06 (95%CI = -7.15, -4.97), -4.86 (95%CI = -5.88, -3.85), -4.78 (95%CI = -5.89, -3.68), and -4.59 (95%CI = -5.57, -3.61) h/week, respectively. Increases in one SD of AQI, PM2.5, PM10, and NO2 were associated with increases in SB per week of 1.32 (95%CI = 0.77, 1.88), 0.62 (95%CI = 0.09, 1.14), 1.03 (95%CI = 0.48, 1.59), and 0.98 (95%CI = 0.46, 1.49) h/week, respectively. CONCLUSIONS: The spatial distributions of the average AQI concentration, MVPA, LPA, and SB are useful and allow environmental and health policymakers to identify the areas with the highest priority air pollution environmental equality concerns. AQI was positively associated with MVPA and LPA, and it was negatively associated with SB among older adults. AQI, PM2.5, PM10, and NO2 were hardly associated with women's average time spent engaged in MVPA. Region-specific and multi-level health policy options are needed to reduce ambient air pollution by taking different types of pollutants into account in order to avoid changes in PA and SB in this population, especially in locations with high air pollution concentrations.

(±)-Sarcanan A, a pair of new enantiomeric dihydrobenzofuran neolignans from the aerial parts of Sarcandra glabra.

(+)-Sarcanan A (1a) and (-)-Sarcanan A (1b), a pair of new dihydrobenzofuran neolignan enantiomers, together with six known compounds (2-7), were isolated from the aerial parts of Sarcandra glabra. Their structures were elucidated by spectroscopic analysis, and the absolute configurations of 1a and 1b were determined by analyses of the electronic circular dichroism (ECD) data. All compounds were evaluated for their inhibitory effects on the nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 cells, and compounds 2-4 exhibited moderate inhibition against NO production.

D-mannose is a rapid inducer of ACSS2 to trigger rapid and long-lasting antidepressant responses through augmenting BDNF and TPH2 levels.

The potentiation of synaptic plasticity and serotonin generation by brain-derived neurotrophic factor (BDNF) and tryptophan hydroxylase 2 (TPH2) is well characterized to facilitate rapid and long-lasting antidepressant actions. Therefore, the identification of the key protein that simultaneously controls both BDNF and TPH2 is important for the treatment of depression. We show here that a lack of acetyl-CoA synthetase short-chain family member 2 (ACSS2) causes impairments in BDNF-dependent synaptic plasticity and tryptophan hydroxylase 2 (TPH2)-mediated serotonin generation, thereby contributing to spontaneous and chronic restraint stress (CRS)-induced depressive-like behavior in mice. Conversely, D-mannose is identified as a rapid ACSS2 inducer and thus mediates rapid and long-lasting antidepressant-like effects. Mechanistically, acute and chronic D-mannose administration inhibits the phosphorylation of EF2 to increase BDNF levels and reverse the reduction of TPH2 histone acetylation and transcription. We reveal that ACSS2 promotes TPH2 histone acetylation and transcription with the requirement of AMPK activation. To elevate nuclear ACSS2 levels, D-mannose can rapidly and persistently activate AMPK via Ca2+-CAMKK2 and the lysosomal AXIN-LKB1 pathway to facilitate its fast-acting and persistent antidepressant responses. Taken together, the results presented here reveal that ACSS2 functions as a novel target to link rapid and persistent antidepressant actions and further suggest that D-mannose is a potential therapeutic agent to resist depression through its augmentation of the ACSS2 dependent BDNF and TPH2 pathways.

Associations between maternal stressful life events experiences and risk of neural tube defects in offspring: a systematic review and meta-analysis.

OBJECTIVES: Multiple factors associated with neural tube defects (NTDs) risk have been identified, yet there is little evidence on the possible effects of maternal stressful life events. In this study, we aimed to investigate the association between stressful life events during the periconceptional period and risk of NTDs in offspring. METHODS: Relevant literature was searched in PubMed, Springer Link, ScienceDirect, and Cochrane Library up to July 2023. The pooled odds ratio (OR) and 95% confidence interval (CI) of NTDs risk with maternal stressful life events were estimated using a random effects model. Publication bias was assessed using Egger's regression asymmetry test and Begg's rank correlation test with Begg's funnel plot. RESULTS: Analysis results showed that mothers who experienced stressful life events during the periconceptional period were at greater risk of having NTDs offspring (OR: 1.37, 95% CI: 1.08-1.73) than those who did not. In subgroup analysis, the pooled OR was 1.37 (1.13-1.67) and 1.73 (0.36-8.32) for with and without adjusting for folic acid supplementation in each included study, while was 1.37 (1.13-1.67) and 1.64 (0.39-6.88) for exposure time of three months preconception until three months post conception and one year preconception until three months post conception, respectively. CONCLUSIONS: This study suggests that maternal stressful life events during the periconceptional period are significantly associated with higher NTDs risk in offspring. Tailored approaches for evaluating the risk and policy of NTDs among women of childbearing age should emphasize individual stressful experiences before and during early pregnancy.

D-mannose acts as a V-ATPase inhibitor to suppress inflammatory cytokines generation and bacterial killing in macrophage.

Vacuolar-type H+-ATPase (V-ATPase) critically controls phagosome acidification to promote pathogen digestion and clearance in macrophage. However, the specific subunits of V-ATPase have been evidenced to play contradictory functions in inflammatory cytokines generation and secretion exposure to external bacterial or LPS stimulation. Therefore, identifying the unique function of the separate subunit of V-ATPase is extremely important to regulate macrophage function. Here, we found that D-mannose, a C-2 epimer of glucose, suppressed ATP6V1B2 lysosomal translocation to inhibit V-ATPase activity in macrophages, thereby causing the scaffold protein axis inhibitor protein (AXIN) recruitment to lysosomal membrane and AMPK activation. Correspondingly, LPS-stimulated macrophage M1 polarization was significantly suppressed by D-mannose via down-regulating NF-κB signaling pathway in response to AMPK activation, while IL-4 induced macrophage M2 polarization were not affected. Furthermore, the failure of lysosomal localization of ATP6V1B2 caused by D-mannose also led to the acidification defects of lysosome. Therefore, D-mannose displayed a remarkable function in inhibiting macrophage phagocytosis and bacterial killing. Taken together, D-mannose acts a novel V-ATPase suppressor to attenuate macrophage inflammatory production but simultaneously prevent macrophage phagocytosis and bacterial killing.