Background Early-life lead (Pb) exposure has been confirmed to cause long-term cognitive impairment, but the mechanisms of its programmed cell death remain incompletely elucidated. This study aims to investigate the key role of Nrf2-mediated ferroptosis in early-life Pb exposure-induced cognitive impairment in mice. Methods By employing both in vivo and in vitro approaches, we explored the involvement of Keap1/Nrf2-mediated ferroptosis in early-life Pb exposure-induced cognitive impairment. Results Our findings showed that early-life Pb exposure induced ferroptosis by upregulating hippocampal Keap1 expression and inhibiting the Nrf2 pathway and its downstream antioxidant proteins (GPX4, SLC7A11, and SLC3A2), and altering the expression of iron metabolism-related proteins (downregulating FTH1/FTL and upregulating DMT1). This process led to ferroptosis, as evidenced by elevated levels of the lipid peroxidation product MDA and reduced glutathione peroxidase activity. Furthermore, this process was accompanied by upregulation of the neurodegeneration-related protein APP in hippocampal tissues, which ultimately resulted in neurodegenerative lesions. Conclusion This study reveals the mechanism of Keap1/Nrf2-mediated ferroptosis in cognitive dysfunction induced by early-life Pb exposure, providing a potential therapeutic strategy targeting this pathway to alleviate Pb exposure-associated neurodegenerative lesions.

Peanut oil is prone to contamination with aflatoxin B1 (AFB1). Traditional ultraviolet (UV) irradiation methods demonstrate limited effectiveness in detoxification and may compromise the oil quality. To address this, this study developed a novel UV LED cold light source temperature control system, offering a new solution for AFB1 detoxification in peanut oil production. On the basis of this system, peanut oil samples spiked with varying concentrations of AFB1 were prepared and treated under different operational conditions. Then, the AFB1 content, acid value, and peroxide value of the decontaminated oils were quantitatively determined to identify the optimal UV wavelength, exposure duration, and intensity for AFB1 degradation. The system's efficacy was also evaluated using oil pressed from mold-contaminated peanuts. In this study, the 365 nm UV LED cold light showed a higher degradation efficiency than its 254 nm. AFB1 concentrations in peanut oil progressively decreased with increasing irradiation duration and intensity, achieving over 30% enhancement. Similar effects were observed using peanut oil pressed from mold contaminated peanuts sourced from actual situation. Following UV LED cold light treatment, no significant alterations were noted in the oil's acid value, peroxide value, indicating that the degradation process does not compromise lipid quality. In conclusion, the UV LED cold light system presents a superior, low-cost, and low-heat-loss solution for AFB1 detoxification in peanut oil, effectively overcoming the drawbacks of conventional thermal UV methods.

Emerging evidence suggests a potential association between high selenium (Se) exposure and the development of type 2 diabetes mellitus (T2DM), a condition often associated with chronic low-grade inflammation. Pyroptosis, a form of programmed cell death characterized by the cleavage and activation of GSDMD by Caspases, has been implicated in T2DM. As an interferon regulatory factor, IRF2 plays a key role in regulating Caspase-GSDMD-mediated pyroptosis. However, the role of IRF2 in Se-induced islet cell pyroptosis and its contribution to T2DM development remain unclear. This study investigates the relationship between Se exposure and T2DM, focusing on the molecular mechanisms through which IRF2 mediates pyroptosis. Our findings show that Se accumulates in the serum of diabetic mice, exacerbating hyperglycemia, reducing serum insulin levels, and triggering pancreatic tissue atrophy and inflammation. Additionally, Se exposure leads to its accumulation in INS-1 cells, decreasing cell viability and impairing insulin secretion. Treatment with the pyroptosis inhibitor disulfiram (DSF) effectively suppressed Se-induced GSDMD expression, GSDMD-N cleavage, and the production of apoptosis-associated speck-like protein (ASC) and interleukins (IL)-18, confirming that Se exposure triggers pyroptosis in pancreatic islet cells. Both in vivo and in vitro experiments consistently demonstrate that Se exposure induces pyroptosis through activation of the IRF2/Caspase-4/GSDMD signaling pathway. Notably, lentivirus-mediated silencing of IRF2 significantly suppressed Se-induced pyroptosis. In conclusion, our study suggests that accumulated Se exposure promotes the progression of T2DM via the IRF2/Caspase-4/GSDMD-mediated pyroptosis pathway. Moreover, targeting IRF2 expression may effectively alleviate Se-induced pancreatic β-cell damage, providing a promising therapeutic target for the prevention and treatment of T2DM.

Background:Adverse reproductive outcomes (AROs) in women can lead to the occurrence of a variety of diseases later in life. However, research on AROs and dementia risk in women has not been reported. Objective:This study explored the effects of miscarriage and stillbirth on future dementia risk in women. Methods:The Cox proportional hazards model was used to clarify the association between miscarriage, stillbirth, and dementia risk. In this cohort, only women with a history of miscarriage and stillbirth were selected. A genetic risk score for dementia was constructed, and the combined effect of miscarriage, stillbirth, and the genetic risk score for dementia on the future risk of incident dementia was determined. Results:For each increase in the number of miscarriages and stillbirths, the risk of dementia increased by 5% and 22%, respectively. Compared to women who had a low genetic risk score, no miscarriages and at least one live-born infant, women with more than 3 miscarriages and a high genetic risk score had a significantly increased risk of dementia. Conclusions:Our results indicate that miscarriage and stillbirth are associated with an increased risk of dementia, especially in women with a high genetic risk score.

OBJECTIVE:The purpose of this work was to investigate whether resveratrol affects lead-induced oxidative damage in HT-22 cells, characterizing mechanisms and strategies for preventing and treating lead-induced neurotoxicity. METHODS:Various lead and resveratrol concentrations were applied to HT-22 cells over different time periods. First, we established the lead treatment (12.5, 50 and 200 μmol/L) and resveratrol (40 μmol/L) intervention model for the study. MTT was used to analyze HT-22 cell survival rate. The rates of cell death, mitochondrial membrane potential, lipid peroxidation, and reactive oxygen species (ROS) generation were all measured by flow cytometry. Cellular oxidant (MDA) and antioxidant (SOD, GSH-Px) levels were measured with test kits. Western blotting was used to assess the expression of proteins related to autophagy and apoptosis. RESULTS:Lead reduced HT-22 cell viability in a concentration/time-dependent manner. In addition, lead (200 μmol/L) decreased the protein expression of BCL2, while increasing PARP and BAX expression and apoptotic rate. Moreover, the lead-exposed group had significantly higher levels of ROS, lipid-ROS, and MDA than the control group. This was accompanied by increased MDA levels and decreased SOD, GSH-Px, and MMP levels in the lead-exposed cells. Furthermore, lead lowered SIRT1 protein expression, while increasing the levels of autophagy-related proteins, including P62, ATG5, Beclin-1 and LC3 Ⅱ/Ⅰ. Resveratrol (40 μmol/L), an agonist of SIRT1, restored the effects of lead (200 μmol/L) to levelsindistinguishable from controls. CONCLUSION:Resveratrol inhibited mitochondrial damage and restored the lead-induced block of autophagic flux and oxidative stress by activating SIRT1, thereby alleviating lead-induced damage in HT-22 cells.

Background Peripheral immune cells may accelerate the progression of Alzheimer's disease (AD), and blood metabolites provide potential biomarkers for AD, but it remains to be explored whether the effect of the immune cells is mediated by blood metabolites. The study aims to explore the pathogenic role of immune cells in AD and explore whether this role is mediated by blood metabolites using Mendelian randomization analysis. Methods This study employed a two-sample, two-way MR design to investigate the causal relationships between immune cells, blood metabolites, and AD. Data sources included genome-wide association studies (GWAS) datasets for AD, immune cell traits, and blood metabolites. Instrumental variables (IVs) were screened according to strict criteria and Mendelian randomization analyses were performed using various statistical methods. Results MR analyses determined the protective effects of 7 immune cell traits on AD and 10 traits that increase the risk of developing AD. In addition, 17 blood metabolite indicators were suggestively associated with AD. Of note, X-13723 and Androstenediol (3beta,17beta) monosulfate (2) acetate respectively exert neuroprotective effects in the myeloid inhibitory cell-AD and CD33 + monocyte-AD pathways, while X-25828 has the unique bidirectional regulatory characteristics of immune cell subsets. Conclusion The study highlights the interplay relationship between immune cells, blood metabolites, and AD, shedding light on potential mechanisms underlying AD pathogenesis. Further research is needed to explore additional mediators and validate these findings in diverse populations. The study's findings contribute to the understanding of AD etiology and offer new avenues for clinical interventions.

The SMC-5/6 complex safeguards genome stability through the coordinated action of its core SMC proteins and associated NSE subunits. NSE-1 is a key component of the complex and is essential for DNA repair, yet it remains poorly characterized in Caenorhabditis elegans. To further elucidate the functional mechanisms of NSE-1, we performed an EMS-based forward genetic screen in an nse-1::gfp(wsh1) reporter strain to identify mutants with defective NSE-1 expression or nuclear localization. We isolated three mutants; smc-5(wsh31), smc-5(wsh32), and smc-5(wsh33), that display impaired NSE-1::GFP nuclear localization. SNP mapping and whole-genome sequencing revealed three novel smc-5 alleles: two truncations, alleles smc-5(wsh31) (C587*) and smc-5(wsh32) (Q655*), and one missense variant, smc-5(wsh33) (Y975D), each altering a highly conserved residue in the SMC domain. All three mutants exhibited significantly reduced brood size, progeny viability, and slightly elevated male percentages. Phenotypic characterization revealed that the truncations completely abrogate NSE-1::GFP nuclear localization, whereas the missense allele causes stage-dependent, partial mislocalization. Functional assays further demonstrated allele-specific and developmental stage-dependent hypersensitivities to DNA-damaging agents (MMS, HU, and cisplatin). These separation-of-function smc-5 alleles underscore the importance of domains and conserved residues in complex integrity and genome maintenance, and provide powerful genetic tools to dissect SMC-5/6 functions in vivo.

BACKGROUND:This study aimed to investigate the effects of environmental benzene exposure and its interaction with genetic susceptibility on inflammatory bowel disease (IBD), with a specific focus on ulcerative colitis (UC) and Crohn's disease (CD). METHODS:A total of 432,727 participants from the UK Biobank who were free of IBD at baseline were included in the analysis. The annual average benzene concentrations during the follow-up period were evaluated by air dispersion models. The study assessed the incidence of IBD in relation to ambient benzene exposure using Cox proportional hazard models and estimated the exposureresponse relationships using restricted cubic spline models. Additive interactions included relative excess risk due to interaction (RERI) and the attributable proportion (AP) to evaluate the interaction between ambient benzene exposure and genetic predisposition. RESULTS:A significant association was identified between ambient benzene exposure and the incidence of IBD, with hazard ratios (95 % confidence intervals) of 1.06 (1.03, 1.09) for IBD, 1.08 (1.04, 1.12) for UC, and 1.03 (0.98, 1.09) for CD per 0.1 μg/m3 increase. Furthermore, genetic predispositions were found to significantly modify the relationship between ambient benzene exposure and IBD risk. Individuals with the highest genetic risk and benzene exposure had the highest risk of UC. CONCLUSION:This study provides compelling evidence of the interaction between environmental factors and genetic susceptibility in the pathogenesis of UC. These findings underscore the importance of considering both genetic and environmental influences in future prevention and intervention strategies for IBD.

BACKGROUND:Lead (Pb) exposure is recognized for its contribution to the development of neurodegenerative diseases. However, the precise mechanisms underlying Pb-induced neurological dysfunction remain elusive. This study aimed to investigate the role of oxidative stress and the autophagy-related P62/kelch like ECH-associated protein 1 (Keap1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in neuronal impairment caused by Pb. METHODS:By employing both in vivo and in vitro approaches, we explored the involvement of the P62/Nrf2/Keap1 pathway in Pb-induced neurotoxicity. RESULTS:Our findings demonstrated that Pb exposure triggers excessive production of reactive oxygen species (ROS), upregulates Keap1 protein expressions, promotes Nrf2 degradation, and inhibits expression of antioxidant proteins such as heme Oxygenase-1 (HO-1) and glutathione peroxidase (GPx), resulting in oxidative damage in neurons. Furthermore, we observed that the autophagy protein P62 disrupts the normal autophagy process by interacting with the Nrf2/Keap1 axis, leading to an accumulation of Tau, a protein associated with Alzheimer's disease (AD), ultimately resulting in neurodegeneration. However, treatment with the antioxidant N-acetylcysteine, Nrf2 activator Artemisitene, and autophagy activator Rapamycin attenuated these detrimental changes. CONCLUSION:The P62/Nrf2/Keap1 pathway mediates Pb-induced neuronal dysfunction and highlights its potential as a therapeutic target for mitigating the neurodegenerative effects associated with Pb exposure.

Sodium para-aminosalicylic acid (PAS-Na) treatment for manganese (Mn) intoxication has shown efficacy in experimental and clinical studies, giving rise to additional studies on its efficacy for lead (Pb) neurotoxicity and its associated mechanisms of neuroprotection. The difference between PAS-Na and other metal complexing agents, such as edetate calcium sodium (CaNa2-EDTA), is firstly that PAS-Na can readily pass through the blood-brain barrier (BBB), and complex and facilitate the excretion of manganese and lead. Secondly, PAS-Na has anti-inflammatory effects. Recent studies have broadened the understanding on the mechanisms associated with efficacy of PAS-Na. The latter has been shown to modulate multifarious manganese- and lead- induced neurotoxicity, via its anti-apoptotic and anti-inflammatory effects, as well as its ability to inhibit pyroptosis, and regulate abnormal autophagic processes. These observations provide novel scientific bases and new concepts for the treatment of lead, mercury, copper, thallium, as well as other toxic encephalopathies, and implicate PAS-Na as a compound with greater prospects for clinical medical application.

Aging and age-related diseases are intricately associated with oxidative stress and inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown their promise in mitigating age-related conditions and potentially extending lifespan in various model organisms. However, the efficacy of NSAIDs in older individuals may be influenced by age-related changes in drug metabolism and tolerance, which could result in age-dependent toxicities. This study aimed to evaluate the potential risks of toxicities associated with commonly used NSAIDs (aspirin, ibuprofen, acetaminophen, and indomethacin) on lifespan, healthspan, and oxidative stress levels in both young and old Caenorhabditis elegans. The results revealed that aspirin and ibuprofen were able to extend lifespan in both young and old worms by suppressing ROS generation and enhancing the expression of antioxidant SOD genes. In contrast, acetaminophen and indomeacin accelerated aging process in old worms, leading to oxidative stress damage and reduced resistance to heat stress through the pmk-1/skn-1 pathway. Notably, the harmful effects of acetaminophen and indomeacin were mitigated when pmk-1 was knocked out in the pmk-1(km25) strain. These results underscore the potential lack of benefit from acetaminophen and indomeacin in elderly individuals due to their increased susceptibility to toxicity. Further research is essential to elucidate the underlying mechanisms driving these age-dependent responses and to evaluate the potential risks associated with NSAID use in the elderly population.

Lead (Pb), a dense, soft, blue-gray metal, is widely used in metallurgy, cables, storage batteries, pigments, and other industrial applications. Pb has been shown to cause hippocampal neurodegeneration. Necroptosis, a newly described cell death modality, is closely associated with neurodegenerative diseases. Whether Pb can cause programmed neuronal cell death and its mechanisms has yet to be characterized. Here, we explored the role of the TNF-R1-RIPK1/RIPK3 signaling pathway in necroptosis induced by Pb. Our results showed that Pb exposure elevated lead levels in murine whole blood and hippocampal tissue in a dose-response relationship. Protein expression levels of PARP, c-PARP, RIPK1, p-RIPK1, RIPK3, MLKL, and p-MLKL in the hippocampal tissues were elevated, while the protein expression of caspase-8 was decreased. Furthermore, Pb exposure reduced the survival rates in HT-22 cells and primary mouse hippocampal neurons, while increasing the protein expressions of RIPK1 and p-MLKL. Collectively, these novel findings suggest that the TNF-R1/RIPK1/RIPK3 signaling pathway mediates Pb-induced necroptosis in hippocampal neurons in mice.

Chronic lead (Pb) exposure causes neurodysfunction and contributes to the development of neurodegenerative disease. However, the mechanism of Pb-induced neurological dysfunction have yet to be fully elucidated. This study determined the role pyroptosis plays in Pb-induced neurodysfunction in neurons. We used both in vitro and in vivo approaches to explore whether Pb exposure induces caspase-1-mediated pyroptosis in neurons and its relationship to Pb-induced neurological disorders. Our findings showed that caspase-1-mediated pyroptosis in Pb-exposed neurons activated glycogen synthase kinase 3 protease activity by disrupting Ca2+/calmodulin-dependent protein kinase II /cAMP-response element binding protein pathway, leading to neurological disorders. Moreover, the caspase-1 inhibition VX-765 or the non-steroidal anti-inflammatory drug sodium para-aminosalicylic acid (PAS-Na) attenuated the Pb-induced neurological disorders by alleviating caspase-1 mediated neuronal pyroptosis. Our novel studies suggest that caspase-1-mediated pyroptosis in neurons represents a potential mechanism for Pb-induced neurodysfunction, identifying a putative target for attenuating the neurodegenerative effects induced by this metal.

Lead (Pb), a dense, soft, blue-gray metal, is widely used in metallurgy, cables, storage batteries, pigments, and other industrial applications. Pb has been shown to cause degenerative changes in the nervous system. Necroptosis, a form of non-apoptotic programmed cell death modality, is closely associated with neurodegenerative diseases. Whether the TNF-R1-RIPK1/RIPK3 pathway is involved in the neurodegeneration induced by Pb has yet to be determined. Here, we explored the role of the TNF-R1-RIPK1/RIPK3 signaling pathway in the Pb-induced necroptosis by using HT-22 cells, primary mouse hippocampal neurons, and C57BL/6 mice models, demonstrating that Pb exposure elevated lead levels in murine whole blood and hippocampal tissue in a dose-response relationship. Protein expression levels of PARP, c-PARP, RIPK1, p-RIPK1, RIPK3, MLKL, and p-MLKL in the hippocampal tissues were elevated, while the protein expression of caspase-8 was decreased. Furthermore, Pb exposure reduced the survival rates in HT-22 cells and primary mouse hippocampal neurons, while increasing the protein expressions of RIPK1 and p-MLKL. Collectively, these novel findings suggest that the TNF-R1/RIPK1/RIPK3 signaling pathway is associated with Pb-induced neurotoxicity in hippocampal neurons in mice.

Aging, a complex biological process influenced by genetic, environmental, and pharmacological factors, presents a significant challenge in understanding its underlying mechanisms. In this study, we explored the divergent impacts of metformin treatment on the lifespan and healthspan of young and old C. elegans, demonstrating a intriguing “elixir in youth, poison in elder” phenomenon. By scrutinizing the gene expression changes in response to metformin in young (day 1 of adulthood) and old (days 8) groups, we identified nhr-57 and C46G7.1 as potential modulators of age-specific responses. Notably, nhr-57 and C46G7.1 exhibit contrasting regulation patterns, being up-regulated in young worms but down-regulated in old counterparts following metformin treatment. Functional studies employing knockdown approaches targeting nhr-57, a gene under the control of hif-1 with a documented protective function against pore-forming toxins in C. elegans, and C46G7.1, unveiled their critical roles in modulating lifespan and healthspan, as well as in mediating the biphasic effects of metformin. Furthermore, deletion of hif-1 retarded the influence of metformin, implicating the involvement of hif-1/nhr-57 in age-specific drug responses. These findings underscored the necessity of deciphering the mechanisms governing age-related susceptibility to pharmacological agents to tailor interventions for promoting successful aging.

Abstract Excessive exposure to manganese (Mn) may lead to neurotoxicity, referred to as manganism. In several studies, sodium para-aminosalicylic acid (PAS-Na) has shown efficacy against Mn-induced neurodegeneration by attenuating the neuroinflammatory response. The present study investigated the effect of Mn on inflammation and apoptosis in the rat thalamus, as well as the underlying mechanism of the PAS-Na protective effect. The study consisted of sub-acute (Mn treatment for 4 weeks) and sub-chronic (Mn and PAS-Na treatment for 8 weeks) experiments. In the sub-chronic experiments, pro-inflammatory cytokines, namely tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and cyclooxygenase 2 (COX-2) were significantly increased in the Mn-exposed group compared to the control II. PAS-Na treatment led to a significant reduction in the Mn-induced neuroinflammation by inhibiting IL-1β and COX-2 mRNA expression and reducing IL-1β secretion and JNK/p38 MAPK pathway activity. Furthermore, immunohistochemical analysis showed that the expression of caspase-3 was significantly increased in both the sub-acute and sub-chronic experimental paradigms concomitant with a significant decrease in B-cell lymphoma 2 (Bcl-2) in the thalamus of Mn-treated rats. PAS-Na also decreased the expression levels of several apoptotic markers downstream of the MAPK pathway, including Bcl-2/Bax and caspase-3, while up-regulating anti-apoptotic Bcl-2 proteins. In conclusion, Mn exposure led to inflammation in the rat thalamus concomitant with apoptosis, which was mediated via the MAPK signaling pathway. PAS-Na treatment antagonized effectively Mn-induced neurotoxicity by inhibiting the MAPK activity in the same brain region.

Manganese (Mn) is a heavy metal that occurs widely in nature and has a vital physiological role in growth and development. However, excessive exposure to Mn can cause neurological damage, especially cognitive dysfunction, such as learning disability and memory loss. Numerous studies on the mechanisms of Mn-induced nervous system damage found that this metal targets a variety of metabolic pathways, for example, endoplasmic reticulum stress, apoptosis, neuroinflammation, cellular signaling pathway changes, and neurotransmitter metabolism interference. This article reviews the latest research progress on multiple signaling pathways related to Mn-induced neurological dysfunction.

为提高教学水平与研究生科研能力提供科学依据,文章采用问卷软件经微信移动客户端对广西医科大学选修医学科研入门的2021级医学硕士/博士生进行问卷调查,比较分析不同类型研究生对医学科研入门的教学满意度、教学内容喜好.结果显示,研究生对医学科研入门教学满意度较高,提示医学科研入门教学可满足研究生的医学科研方法学习要求,并可为培养研究生科研工作能力提供较好的理论支撑.

公共卫生专业硕士(MPH)是我国高层次应用型公共卫生人才的重要组成部分,其培养质量直接影响着服务国家关键领域的能力与水平.本文分析了MPH人才培养中的若干重点问题,并以广西医科大学为例,创新并实践了以提升MPH岗位胜任能力为重点的人才培养模式.