Mitochondria-associated endoplasmic reticulum membranes tethering protein VAPB-PTPIP51 protects against ischemic stroke through inhibiting the activation of autophagy.

AIMS: Mitochondria-associated endoplasmic reticulum membranes (MAMs) serve as a crucial bridge connecting the endoplasmic reticulum (ER) and mitochondria within cells. Vesicle-associated membrane protein-associated protein B (VAPB) and protein tyrosine phosphatase interacting protein 51 (PTPIP51) are responsible for the formation and stability of MAMs, which have been implicated in the pathogenesis of various diseases. However, the role of MAMs in ischemic stroke (IS) remains unclear. We aimed to investigate the role of MAMs tethering protein VAPB-PTPIP51 in experimental cerebral ischemia. METHODS: We simulated cerebral ischemia-reperfusion injury (CIRI) by using a mouse middle cerebral artery occlusion (MCAO) model. RESULTS: We observed a decrease in VAPB-PTPIP51 expression in the brain tissue. Our findings suggested compromised MAMs after MCAO, as a decreased mitochondria-ER contact (MERC) coverage and an increased distance were observed through the transmission electron microscope (TEM). Upon VAPB or PTPIP51 knockdown, the damage to MAMs was exacerbated, accompanied by excessive autophagy activation and increased reactive oxygen species (ROS) production, resulting in an enlarged infarct area and exacerbated neurological deficits. Notably, we observed that this damage was concomitant with the inhibition of the PI3K/AKT/mTOR pathway and was successfully mitigated by the treatment with the PI3K activator. CONCLUSIONS: Our findings suggest that the downregulation of VAPB-PTPIP51 expression after IS mediates structural damage to MAMs. This may exacerbate CIRI by inhibiting the PI3K pathway and activating autophagy, thus providing new therapeutic targets for IS.

Incidence and risk factors of stress urinary incontinence after laparoscopic hysterectomy.

OBJECTIVE: To observe the long-term effects of total hysterectomy on urinary function, evaluate the effects of preoperative nutritional status, urinary occult infection, and surgical factors on the induction of postoperative stress urinary incontinence (SUI), and explore the incidence and risk factors of SUI. STUDY DESIGN: From January 2017 to December 2017, 164 patients with benign non-prolapsing diseases who underwent a laparoscopic total hysterectomy in the First People's Hospital of Taicang were selected as the analysis objects. The International Incontinence Standard Questionnaire for Female Lower Urinary Tract Symptoms (ICIQ-FLUTS) and Pelvic Floor Impact Questionnaire-short version 20 (PFDI-20) were used for telephone follow-up to subjectively assess the urinary function of patients, collect their medical records, and statistically analyze the number of postoperative SUI cases. Logistic multivariate analysis was used to analyze the influencing factors of postoperative female SUI, presented as adjusted odds ratios with 95% confidence intervals. RESULTS: Only 97 out of 164 patients completed the ICIQ-FLUTS and PFDI-20 questionnaires. Among these participants, 28 patients (28.86%) were diagnosed with SUI (study group), while 69 patients (71.13%) were classified as women without SUI (control group). The age, menopause, parity ≥ 2 times, Body mass index (BMI) ≥ 28 kg/m2, neonatal weight ≥ 4000 g, history of chronic cough, preoperative hemoglobin ≤ 100 g/L, preoperative urine bacteria ≥ 100u/L, preoperative uterine volume ≥ 90 cm3, intraoperative blood loss, and operation time of the study group were compared with those of the control group. The differences were statistically significant (P < 0.05). Further Logistic multivariate analysis showed that menopause, preoperative hemoglobin ≤ 100 g/L, preoperative urine bacteria ≥ 100u/L, uterine volume ≥ 90 cm3, history of chronic cough, BMI ≥ 28 kg/m2 were risk factors for postoperative SUI in patients undergoing hysterectomy (P < 0.05). CONCLUSIONS: Hysterectomy for benign non-prolapse diseases has a long-term potential impact on the urinary system of patients, and the risk of postoperative SUI increases. The main risk factors of SUI are parity, menopausal status, obesity, preoperative nutritional status, and occult infection of the urinary system.

The action mechanism by which C1q/tumor necrosis factor-related protein-6 alleviates cerebral ischemia/reperfusion injury in diabetic mice.

JOURNAL/nrgr/04.03/01300535-202409000-00034/figure1/v/2024-01-16T170235Z/r/image-tiff Studies have shown that C1q/tumor necrosis factor-related protein-6 (CTRP6) can alleviate renal ischemia/reperfusion injury in mice. However, its role in the brain remains poorly understood. To investigate the role of CTRP6 in cerebral ischemia/reperfusion injury associated with diabetes mellitus, a diabetes mellitus mouse model of cerebral ischemia/reperfusion injury was established by occlusion of the middle cerebral artery. To overexpress CTRP6 in the brain, an adeno-associated virus carrying CTRP6 was injected into the lateral ventricle. The result was that oxygen injury and inflammation in brain tissue were clearly attenuated, and the number of neurons was greatly reduced. In vitro experiments showed that CTRP6 knockout exacerbated oxidative damage, inflammatory reaction, and apoptosis in cerebral cortical neurons in high glucose hypoxia-simulated diabetic cerebral ischemia/reperfusion injury. CTRP6 overexpression enhanced the sirtuin-1 signaling pathway in diabetic brains after ischemia/reperfusion injury. To investigate the mechanism underlying these effects, we examined mice with depletion of brain tissue-specific sirtuin-1. CTRP6-like protection was achieved by activating the sirtuin-1 signaling pathway. Taken together, these results indicate that CTRP6 likely attenuates cerebral ischemia/reperfusion injury through activation of the sirtuin-1 signaling pathway.

Cuproptosis facilitates immune activation but promotes immune escape, and a machine learning-based cuproptosis-related signature is identified for predicting prognosis and immunotherapy response of gliomas.

AIMS: Cell death, except for cuproptosis, in gliomas has been extensively studied, providing novel targets for immunotherapy by reshaping the tumor immune microenvironment through multiple mechanisms. This study aimed to explore the effect of cuproptosis on the immune microenvironment and its predictive power in prognosis and immunotherapy response. METHODS: Eight glioma cohorts were included in this study. We employed the unsupervised clustering algorithm to identify novel cuproptosis clusters and described their immune microenvironmental characteristics, mutation landscape, and altered signaling pathways. We verified the correlation among FDX1, SLC31A1, and macrophage infiltration in 56 glioma tissues. Next, based on multicenter cohorts and 10 machine learning algorithms, we constructed an artificial intelligence-driven cuproptosis-related signature named CuproScore. RESULTS: Our findings suggested that glioma patients with high levels of cuproptosis had a worse prognosis owing to immunosuppression caused by unique immune escape mechanisms. Meanwhile, we experimentally validated the positive association between cuproptosis and macrophages and its tumor-promoting mechanism in vitro. Furthermore, our CuproScore exhibited powerful and robust prognostic predictive ability. It was also capable of predicting response to immunotherapy and chemotherapy drug sensitivity. CONCLUSIONS: Cuproptosis facilitates immune activation but promotes immune escape. The CuproScore could predict prognosis and immunotherapy response in gliomas.

Neutral polysaccharide from Gastrodia elata alleviates cerebral ischemia-reperfusion injury by inhibiting ferroptosis-mediated neuroinflammation via the NRF2/HO-1 signaling pathway.

AIMS: The crosstalk between ferroptosis and neuroinflammation considerably impacts the pathogenesis of cerebral ischemia-reperfusion injury (CIRI). Neutral polysaccharide from Gastrodia elata (NPGE) has shown significant effects against oxidative stress and inflammation. This study investigated the potential effects of NPGE on CIRI neuropathology. METHODS: The effects of NPGE were studied in a mouse model of ischemic stroke (IS) and in oxygen-glucose deprivation/reperfusion (OGD/R)-induced HT22 cells. RESULTS: NPGE treatment decreased neurological deficits, reduced infarct volume, and alleviated cerebral edema in IS mice, and promoted the survival of OGD/R-induced HT22 cells. Mechanistically, NPGE treatment alleviated neuronal ferroptosis by upregulating GPX4 levels, lowering reactive oxygen species (ROS), malondialdehyde (MDA), and Fe2+ excessive hoarding, and meliorating GSH levels and SOD activity. Additionally, it inhibited neuroinflammation by down-regulating the level of IL-1ß, IL-6, TNF-α, NLRP3, and HMGB1. Meanwhile, NPGE treatment alleviated ferroptosis and inflammation in erastin-stimulated HT22 cells. Furthermore, NPGE up-regulated the expression of NRF2 and HO-1 and promoted the translocation of NRF2 into the nucleus. Using the NRF2 inhibitor brusatol, we verified that NRF2/HO-1 signaling mediated the anti-ferroptotic and anti-inflammatory properties of NPGE. CONCLUSION: Collectively, our results demonstrate the protective effects of NPGE and highlight its therapeutic potential as a drug component for CIRI treatment.

Targeting Microglia/Macrophages Notch1 Protects Neurons from Pyroptosis in Ischemic Stroke.

BACKGROUND AND AIMS: The immune-inflammatory cascade and pyroptosis play an important role in the pathogenesis of cerebral ischemia-reperfusion injury (CIRI). The maintenance of immune homeostasis is inextricably linked to the Notch signaling pathway, but whether myeloid Notch1 affects microglia polarization as well as neuronal pyroptosis in CIRI is not fully understood. This study was designed to clarify the role of myeloid Notch1 in CIRI, providing new therapeutic strategies for ischemic stroke. METHODS AND RESULTS: Myeloid-specific Notch1 knockout (Notch1M-KO) mice and the floxed Notch1 (Notch1FL/FL) mice were subjected to middle cerebral artery occlusion (MCAO). After 3 days of CIRI, we evaluated the neurological deficit score and cerebral infarction volume. Immunofluorescence staining was used to detect the expression of Notch1 and microglial subtype markers. Cerebral infiltrating macrophages were detected by flow cytometry. RT-qPCR was used to detect pro-inflammatory cytokines. Western blot was used to detect the expression of pyroptosis related proteins. The Notch1-siRNA transfected BV2 cells were co-cultured with HT22 cells to investigate the potential mechanisms by which microglial Notch1 affects neuronal pyroptosis induced by anoxia/reoxygenation in vitro. We found that Notch1 was activated in cerebral microglia/macrophages after CIRI. Myeloid Notch1 deficiency decreased the cerebral infarct volume (24.17 ± 3.29 vs. 36.17 ± 2.27, p < 0.001), neurological function scores (2.33 ± 0.47 vs. 3.17 ± 0.37, p < 0.001) and the infiltration of peripheral monocytes/macrophages (3.26 ± 0.53 vs. 5.67 ± 0.57, p < 0.01). Strikingly, myeloid-specific Notch1 knockout alleviated pyroptosis. Compared with microglia M1, increased microglia M2 were detected in the ischemic penumbra. In parallel in vitro co-culture experiments, we found that Notch1 knockdown in microglial BV2 cells inhibited anoxia/reoxygenation-induced JAK2/STAT3 activation and pyroptosis in hippocampal neuron HT22 cells. CONCLUSIONS: Our findings elucidate the underlying mechanism of the myeloid Notch1 signaling pathway in regulating neuronal pyroptosis in CIRI, suggesting that targeting myeloid-specific Notch1 is an effective strategy for the treatment of ischemic stroke.

CAR-T treatment for cancer: prospects and challenges.

Chimeric antigen receptor (CAR-T) cell therapy has been widely used in hematological malignancies and has achieved remarkable results, but its long-term efficacy in solid tumors is greatly limited by factors such as the tumor microenvironment (TME). In this paper, we discuss the latest research and future views on CAR-T cell cancer immunotherapy, compare the different characteristics of traditional immunotherapy and CAR-T cell therapy, introduce the latest progress in CAR-T cell immunotherapy, and analyze the obstacles that hinder the efficacy of CAR-T cell therapy, including immunosuppressive factors, metabolic energy deficiency, and physical barriers. We then further discuss the latest therapeutic strategies to overcome these barriers, as well as management decisions regarding the possible safety issues of CAR-T cell therapy, to facilitate solutions to the limited use of CAR-T immunotherapy.

Inhibition of CCR1 attenuates neuroinflammation via the JAK2/STAT3 signaling pathway after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Neuroinflammation is an important mechanism underlying brain injury caused by subarachnoid hemorrhage (SAH). C-C chemokine receptor type 1 (CCR1)-mediated inflammation is involved in the pathology of many central nervous system diseases. Herein, we investigated whether inhibition of CCR1 alleviated neuroinflammation after experimental SAH and aimed to elucidate the mechanisms of its potential protective effects. METHODS: To analyze SAH transcriptome data R studio was used, and a mouse model of SAH was established using endovascular perforations. In this model, the selective CCR1 antagonist Met-RANTES (Met-R) and the CCR1 agonist recombinant CCL5 (rCCL5) were administered 1 h after SAH induction. To investigate the possible downstream mechanisms of CCR1, the JAK2 inhibitor AG490 and the JAK2 activator coumermycin A1 (C-A1) were administered 1 h after SAH induction. Furthermore, post-SAH evaluation, including SAH grading, neurological function tests, Western blot, the terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and Fluoro-Jade B and fluorescent immunohistochemical staining were performed. Cerebrospinal fluid (CSF) samples were detected by ELISA. RESULTS: CCL5 and CCR1 expression levels increased significantly following SAH. Met-R significantly improved neurological deficits in mice, decreased apoptosis and degeneration of ipsilateral cerebral cortex neurons, reduced infiltrating neutrophils, and promoted microglial activation after SAH induction. Furthermore, Met-R inhibited the expression of p-JAK2, p-STAT3, interleukin-1ß, and tumor necrosis factor-α. However, the protective effects of Met-R were abolished by C-A1 treatment. Furthermore, rCCL5 injection aggravated neurological dysfunction and increased the expression of p-JAK2, p-STAT3, interleukin-1ß, and tumor necrosis factor-α in SAH mice, all of which were reversed by the administration of AG490. Finally, the levels of CCL5 and CCR1 were elevate in the CSF of SAH patient and high level of CCL5 and CCR1 levels were associated with poor outcome. CONCLUSION: The present results suggested that inhibition of CCR1 attenuates neuroinflammation after SAH via the JAK2/STAT3 signaling pathway, which may provide a new target for the treatment of SAH.

Bibliometric and visualization analysis of matrix metalloproteinases in ischemic stroke from 1992 to 2022.

Background: Matrix metalloproteinases (MMPs) are important players in the complex pathophysiology of ischemic stroke (IS). Recent studies have shown that tremendous progress has been made in the research of MMPs in IS. However, a comprehensive bibliometric analysis is lacking in this research field. This study aimed to introduce the research status as well as hotspots and explore the field of MMPs in IS from a bibliometric perspective. Methods: This study collected 1,441 records related to MMPs in IS from 1979 to 2022 in the web of science core collection (WoSCC) database, among them the first paper was published in 1992. CiteSpace, VOSviewer, and R package "bibliometrix" software were used to analyze the publication type, author, institution, country, keywords, and other relevant data in detail, and made descriptive statistics to provide new ideas for future clinical and scientific research. Results: The change in the number of publications related to MMPs in IS can be divided into three stages: the first stage was from 1992 to 2012, when the number of publications increased steadily; the second stage was from 2013 to 2017, when the number of publications was relatively stable; the third stage was from 2018 to 2022, when the number of publications began to decline. The United States and China, contributing more than 64% of publications, were the main drivers for research in this field. Universities in the United States were the most active institutions and contributed the most publications. STROKE is the most popular journal in this field with the largest publications as well as the most co-cited journal. Rosenberg GA was the most prolific writer and has the most citations. "Clinical," "Medical," "Neurology," "Immunology" and "Biochemistry molecular biology" were the main research areas of MMPs in IS. "Molecular regulation," "Metalloproteinase-9 concentration," "Clinical translation" and "Cerebral ischemia-reperfusion" are the primary keywords clusters in this field. Conclusion: This is the first bibliometric study that comprehensively mapped out the knowledge structure and development trends in the research field of MMPs in IS in recent 30 years, which will provide a reference for scholars studying this field.

Does social capital aid in leveling the income gradient in child mental health? A structural analysis of the left-behind and not-left-behind Chinese children.

BACKGROUND: Few prior studies have investigated the income gradient in child mental health from a socio-environmental perspective. In an age when child mental health problems in a rapidly changing social environment have become a worldwide issue, an understanding of the socio-environmental mechanisms of the income disparities in child mental health outcomes is imperative and cost-effective. METHODS: By conducting structural equation analyses with Chinese nationally representative survey data, this study explored the family income gradient in child depression and its potential socio-environmental pathways at the neighborhood, family and school levels, differentiating left-behind and not-left-behind children. RESULTS: We found a robust family income gradient in depressive symptoms. Neighborhood cohesion mitigated the income gradient in depressive symptoms by playing a suppression role. School social capital acted as a mediator. Neighborhood trust, neighborhood safety and family social capital played no significant impact. The mitigating and mediating roles of social capital components were significant among only the not-left-behind children. CONCLUSIONS: To reduce income-related inequalities in child mental health in the long run, integrating policies that directly reduce poverty with policies that improve distal socio-environments is necessary.

Gene Targets of CAR-T Cell Therapy for Glioblastoma.

Glioblastoma (GBM) is an aggressive primary brain tumor with a poor prognosis following conventional therapeutic interventions. Moreover, the blood-brain barrier (BBB) severely impedes the permeation of chemotherapy drugs, thereby reducing their efficacy. Consequently, it is essential to develop novel GBM treatment methods. A novel kind of pericyte immunotherapy known as chimeric antigen receptor T (CAR-T) cell treatment uses CAR-T cells to target and destroy tumor cells without the aid of the antigen with great specificity and in a manner that is not major histocompatibility complex (MHC)-restricted. It has emerged as one of the most promising therapy techniques with positive clinical outcomes in hematological cancers, particularly leukemia. Due to its efficacy in hematologic cancers, CAR-T cell therapy could potentially treat solid tumors, including GBM. On the other hand, CAR-T cell treatment has not been as therapeutically effective in treating GBM as it has in treating other hematologic malignancies. CAR-T cell treatments for GBM have several challenges. This paper reviewed the use of CAR-T cell therapy in hematologic tumors and the selection of targets, difficulties, and challenges in GBM.

Neuroinflammatory Biomarkers in the Brain, Cerebrospinal Fluid, and Blood After Ischemic Stroke.

The most frequent type of stroke, known as ischemic stroke (IS), is a significant global public health issue. The pathological process of IS and post-IS episodes has not yet been fully explored, but neuroinflammation has been identified as one of the key processes. Biomarkers are objective indicators used to assess normal or pathological processes, evaluate responses to treatment, and predict outcomes, and some biomarkers can also be used as therapeutic targets. After IS, various molecules are produced by different cell types, such as microglia, astrocytes, infiltrating leukocytes, endothelial cells, and damaged neurons, that participate in the neuroinflammatory response within the ischemic brain region. These molecules may either promote or inhibit neuroinflammation and may be released into extracellular spaces, including cerebrospinal fluid (CSF) and blood, due to reasons such as BBB damage. These neuroinflammatory molecules should be valued as biomarkers to monitor whether their expression levels in the blood, CSF, and brain correlate with the diagnosis and prognosis of IS patients or whether they have potential as therapeutic targets. In addition, although some molecules do not directly participate in the process of neuroinflammation, they have been reported to have potential diagnostic or therapeutic value against post-IS neuroinflammation, and these molecules will also be listed. In this review, we summarize the neuroinflammatory biomarkers in the brain, CSF, and blood after an IS episode and the potential value of these biomarkers for the diagnosis, treatment, and prognosis of IS patients.

The Reasonableness and Spatial Differences of the Food Consumption Structure of Urban and Rural Residents in China, 2015-2021.

Based on residents' food consumption data from 31 provinces in China from 2015-2021, this study analyzes the deviation in food consumption from nutrition targets and the spatial distribution characteristics of urban and rural residents in China from 2015-2021, and finds that there are irrationalities in the structure of food consumption of Chinese residents as well as regional differences in consumption. The food consumption of Chinese residents deviates from the recommended values of the Chinese Food Guide Pagoda to a certain extent, with large differences between urban and rural areas and provinces. Therefore, a new concept of food security with nutrition as the target should be established to guide residents' food consumption scientifically and rationally, and to adopt focused attention and targeted measures for regions with serious imbalances in food consumption.

The Involvement of Immune Cells Between Ischemic Stroke and Gut Microbiota.

Ischemic stroke, a disease with high mortality and disability rate worldwide, currently has no effective treatment. The systemic inflammation response to the ischemic stroke, followed by immunosuppression in focal neurologic deficits and other inflammatory damage, reduces the circulating immune cell counts and multiorgan infectious complications such as intestinal and gut dysfunction dysbiosis. Evidence showed that microbiota dysbiosis plays a role in neuroinflammation and peripheral immune response after stroke, changing the lymphocyte populations. Multiple immune cells, including lymphocytes, engage in complex and dynamic immune responses in all stages of stroke and may be a pivotal moderator in the bidirectional immunomodulation between ischemic stroke and gut microbiota. This review discusses the role of lymphocytes and other immune cells, the immunological processes in the bidirectional immunomodulation between gut microbiota and ischemic stroke, and its potential as a therapeutic strategy for ischemic stroke.

The spatial-temporal pattern of Japanese encephalitis and its influencing factors in Guangxi, China.

Japanese encephalitis (JE) is a major global public health threat. Using Japanese encephalitis incidence data from 2004 to 2010 in Guangxi Province, China, this study comprehensively explored the driving forces and the interactive effects between environmental and social factors of Japanese encephalitis using the Geo-detector method. The results indicated that the incidence of Japanese encephalitis showed a fluctuating downward trend from 2004 to 2010. The onset of JE was seasonal, mainly concentrated in June-July, and highly aggregated in northwestern Guangxi. Among the factors associated with Japanese encephalitis, days with temperatures >30 °C, accumulated temperatures >25 °C, slope, the normalized difference vegetation index, the gross domestic product of tertiary industries, the gross domestic product of primary industries and the number of pigs slaughtered showed higher contributions to Japanese encephalitis incidence. An enhanced interactive effect was found between environmental and social factors, and the interaction between days with humidity levels >80% and the gross domestic product of tertiary industries had the greatest combined effect on JE. These findings enhanced the understanding of the combined effect of social and environmental factors on the incidence of Japanese encephalitis and could help improve Japanese encephalitis transmission control and prevention strategies.

Trends in NLRP3 inflammasome research in ischemic stroke from 2011 to 2022: A bibliometric analysis.

BACKGROUND: Ischemic stroke is a leading cause of permanent disability and death globally. The nucleotide-biding oligomaerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a multi-protein complex that plays a role in ischemic stroke. Recently, research on the role of NLRP3 in ischemic stroke has developed rapidly worldwide. However, there is no bibliometric analysis of NLRP3 in ischemic stroke to date. AIM: Through bibliometric analysis, the aim of this study was to assess the current state of research on NLRP3 in the field of ischemic stroke research worldwide over the past 12 years and to identify important results, major research areas, and emerging trends. METHODS: Publications related to NLRP3 in ischemic stroke from January 1, 2011 to December 31, 2022 were obtained from the Web of Science Core Collection (WoSCC). We used HistCite, VOSviewer, CiteSpace, and Bibliometrix for bibliometric analysis and visualization. The Total Global Citation Score (TGCS) was employed to assess the impact of publications. RESULTS: We found that research of NLRP3 in ischemic stroke developed rapidly starting in 2011. 601 relevant studies have been published in 245 journals over the past 12 years. Journal of Neuroinflammation and International Immunopharmacology were the most productive journals and Journal of Neuroinflammation was the most cited journal. Additionally, Stroke and Journal of Cerebral Blood Flow & Metabolism were the most co-cited journal. The most productive country was China (records = 430) and the most productive university was the Zhejiang University (records = 24). Arumugam TV (TGCS = 949) was the most cited author in this field. NLRP3 inflammasome activation, nf-κb, oxidative stress, and inflammation were the knowledge bases for the research in this field. CONCLUSION: This study is a scientometric study utilizing quantitative and qualitative methods to comprehensively review the publications on NLRP3 in ischemic stroke. This information provides a reference for scholars to further study NLRP3 in ischemic stroke.

Selenium and Zinc Intakes of Staple Grains and Their Correlation with Urine Selenium and Zinc in the Tibetan Rural Residents along the Yarlung Zangbo River.

Grains account for a large proportion of the diet of rural residents in Tibet. The lack of selenium (Se) and zinc (Zn) threatens the population's nutrition and health. However, the intakes of selenium and zinc in grains remains unclear. To clarify the nutritional status of selenium and zinc consumed from staple grains of residents along the Yarlung Zangbo River in Tibet, 341 grain samples and 242 urine samples were collected, and 244 food frequency questionnaires were completed along the Yarlung Zangbo River in 2020-2021. The results showed that the selenium concentrations of 88.5% of self-produced tsampa and 80.8% of self-produced flour were lower than the grain selenium threshold (<25 µg·kg-1). The intake of selenium and zinc from staple grains (tsampa, flour, and rice) contributed 15.0% and 43.5% to the recommended nutrient intake (RNI) on average, respectively. A geographical detector model analyzed factors affecting urinary selenium and zinc levels. Selenium and zinc intakes in rice and flour, and dietary diversity score (DDS) were the main factors affecting urinary selenium and zinc (p < 0.01). Their interaction effects on urinary selenium and zinc were greater than those of a single factor. The staple grains of rural residents along the Yarlung Zangbo River were in a state of selenium deficiency. The zinc content of the staple grain purchased was lower than that of the main grain produced by rural residents. Changing the grain consumption pattern and adjusting the proportion of exogenous grains can improve selenium and zinc nutrition in residents.

Does Neighborhood Social Capital Longitudinally Affect the Nutritional Status of School-Aged Children? Evidence from China.

Previous research linking social capital to child nutritional status primarily constitutes cross-sectional studies. To investigate whether a longitudinal relationship exists, by conducting fixed-effects analyses with 16,977 repeatedly measured observations of 6193 children from the 2012, 2014, 2016, and 2018 China Family Panel Studies, this study explored the longitudinal effects of neighborhood participation, bonding trust, and bridging trust on the BMI-for-age z-score (BAZ) and BMI categories of school-aged children, differentiating between urban and rural residence. We found an increasing average BAZ, a decreasing prevalence of underweight, an increasing prevalence of overweight/obesity, and a reducing urban/rural gap in nutritional status. The levels of social capital components descended faster in the urban area. Bonding trust was predictive of a lower BAZ, a higher likelihood of being underweight, and a lower likelihood of being overweight/obese. Bridging trust was predictive of a higher BAZ. The longitudinal effects of bonding trust were significant among only the rural children. Our findings indicate that neighborhood social capital may impose causal impacts on the nutritional status of children. To effectively improve child nutritional status, a more empathetic governmental approach that promotes a more supportive distal social environment is needed.

NLRP3 inflammasome deficiency attenuates cerebral ischemia-reperfusion injury by inhibiting ferroptosis.

BACKGROUND: The role of ferroptosis in ischemic stroke has been hotly debated recently, but the mechanism is not clearly clarified. It has been reported that the NLRP3 inflammasome is essential for the progression of ischemic stroke. Whether the ferroptosis after ischemic stroke mediated by the activation of NLRP3 inflammasome is still not reported. In this study, we investigated the effect of NLRP3 deficiency on ferroptosis following cerebral ischemia-reperfusion injury (CIRI) in vivo and in vitro. MATERIALS: In vivo, we used C57BL/6J mice and NLRP3-/- mice to establish a model of middle cerebral artery occlusion (MCAO). After 3 days of reperfusion, we assessed neurological function and then performed TTC staining to measure the infarct volume. Besides, we measured the expression of NLRP3 inflammasome-related proteins and the ferroptosis-inhibiting protein glutathione peroxidase 4 (GPX4) by western blotting (WB) and immunofluorescence (IF). Moreover, we evaluated the levels of ferroptosis-related factors (Fe2+, MDA and GSH) in the infarct area by using appropriate kits. Furthermore, we used WB to measure the expression of Kelch-like epichlorohydrin-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2), which participate in the progression of ischemic stroke. In vitro, we knocked down NLRP3 with small interfering RNAs (siRNAs) and established an oxygen glucose deprivation/Reperfusion (OGD/R) model in BV2 cells to simulate ischemic conditions. Next, we assessed the viability of BV2 cells by the Cell Counting Kit (CCK)-8 cytotoxicity assay. Moreover, we used WB to measure the expression of NLRP3, IL-1ß, GPX4, Keap1 and Nrf2 proteins which are involved in CIRI. RESULTS: Three days after MCAO, the NLRP3-/- mice exhibited smaller cerebral infarct volumes and lower neurological deficit scores. The expression of NLRP3 inflammasome-associated proteins (IL-18 and IL-1ß) and Keap1/Nrf2 signaling pathway moleculars (Keap1 and Nrf2) in mice brain tissue and BV2 cells were inhibited by NLRP3 knockout/knockdown, while the expression of GPX4, one of the ferroptosis-related factors was increased. Furthermore, the contents of Fe2+ and MDA in the brain tissues of NLRP3-/- mice were decreased, while the content of GSH were increased significantly. CONCLUSION: Inhibition of the NLRP3 inflammasome alleviates CIRI by inhibiting ferroptosis and inflammation, possibly through a mechanism of the Keap1-Nrf2 pathway.

ATG5 Knockdown Attenuates Ischemia‒Reperfusion Injury by Reducing Excessive Autophagy-Induced Ferroptosis.

Autophagy has been described to be both protective and pathogenic in cerebral ischemia/reperfusion (I/R) injury. The underlying association between autophagy and ferroptosis in ischemic stroke has not yet been clearly investigated. The purpose of this study was to explore the role of autophagy-related gene 5 (ATG5) in experimental ischemic stroke. After injection of ATG5 shRNA lentivirus, mice underwent surgery for transient middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia. The infarct volume, neurological function, apoptosis, reactive oxygen species (ROS), autophagy, and ferroptosis levels were evaluated. After MCAO, ATG5-knockdown mice had a smaller infarct size and fewer neurological deficits than wild-type mice. The levels of apoptosis and ROS in ischemic mouse brains were alleviated through ATG5 knockdown. The expression of LC3 I/II was reduced through ATG5 knockdown after MCAO. Additionally, the expression of beclin1 and LC3 II was increased after I/R, but the increase was counteracted by preconditioning with ATG5 knockdown. After ischemic stroke, the levels of Fe2+ and malondialdehyde (MDA) were increased, but they were reduced by ATG5 knockdown. Similarly, the expression of glutathione peroxidase 4 (GPX4) and glutathione (GSH) was decreased by I/R but elevated by ATG5 knockdown. The present study shows that ATG5 knockdown attenuates autophagy-induced ferroptosis, which may offer a novel potential approach for ischemic stroke treatment.