Research advances on CaMKs-mediated neurodevelopmental injury.

Calcium/calmodulin-dependent protein kinases (CaMKs) are important proteins in the calcium signaling cascade response pathway, which can broadly regulate biological functions in vivo. Multifunctional CaMKs play key roles in neural development, including neuronal circuit building, synaptic plasticity establishment, and neurotrophic factor secretion. Currently, four familial proteins, calcium/calmodulin-dependent protein kinase I (CaMKI), calcium/calmodulin-dependent protein kinase II (CaMKII), eukaryotic elongation factor 2 kinase (eEF2K, popularly known as CaMKIII) and calcium/calmodulin-dependent protein kinase IV (CaMKIV), are thought to have been the most extensively studied during neurodevelopment. Although their spatial structures are extremely similar, as well as the initial starting point of activation, both require the activation of calcium and calmodulin (CaM) complexes to be involved in the process, and the phosphorylation sites and modes of each member are different. Furthermore, due to the high structural similarity of CaMKs, their members may play synergistic roles in the regulation of neural development, but different CaMKs also have their own means of regulating neural development. In this review, we first describe the visualized protein structural forms of CaMKI, CaMKII, eEF2K and CaMKIV, and then describe the functions of each kinase in neurodevelopment. After that, we focus on four main mechanisms of neurodevelopmental damage caused by CaMKs: CaMKI/ERK/CREB pathway inhibition leading to dendritic spine structural damage; Ca2+/CaM/CaMKII through induction of mitochondrial kinetic disorders leading to neurodevelopmental damage; CaMKIII/eEF2 hyperphosphorylation affects the establishment of synaptic plasticity; and CaMKIV/JNK/NF-κB through induction of an inflammatory response leading to neurodevelopmental damage. In conclusion, we briefly discuss the pathophysiological significance of aberrant CaMK family expression in neurodevelopmental disorders, as well as the protective effects of conventional CaMKII and CaMKIII antagonists against neurodevelopmental injury.

Development and application of a cycleave dual-probe fluorescence quantitative PCR method for simultaneous detection of Mycoplasma gallisepticum ts-11 vaccine strain and non-ts-11 strains.

An attenuated vaccine against the Mycoplasma gallisepticum ts-11 strain has become an effective prevention and control method against MG infection. However, the ts-11 strain is usually difficult to distinguish from the non-ts-11 strain (including field isolates and other vaccine strains (F and 6/85)). Therefore, it is critical to establish a rapid and effective method to distinguish ts-11 strains from non-ts-11 strains. The gene sequences of the ts-11 strain (CP044225.1) and the non-ts-11 strain (including the wild-type (CP006916.3), 6/85 (CP044224.1), and F strains (NC_017503.1) were used to construct a conserved region containing a single point mutation in the potC gene in the ts-11 strain, after which a primer-probe combination method was designed. The primer-probe method was able to accurately and efficiently identify the ts-11 and non-ts-11 strains with minimum detection limits of 2.43 copies/µL and 1.65 copies/µL, respectively. Moreover, it could simultaneously distinguish the ts-11 strain from a non-ts-11 strain, and amplifications of avian influenza virus, infectious bronchitis virus, Newcastle disease virus, fowl adenovirus, infectious laryngotracheitis virus, infectious bursal disease virus, chicken anemia virus, Marek's disease virus, Mycoplasma synoviae, and Ornithobacter rhinotracheale were negative. The detection of clinical samples revealed that the established dual-probe fluorescence quantitative PCR method could be used to screen for mixed and single infections of the ts-11 strain and non-ts-11 strains effectively, with lower variation coefficients for intra- and interbatch repetition. The established cycleave dual-probe fluorescence quantitative PCR method showed good specificity, sensitivity, and repeatability and provides powerful technical support for the rapid and efficient differential diagnosis of the MG ts-11 strain from non-ts-11 strains.

Vesicle-associated membrane protein 8 knockdown exerts anti-proliferative, pro-apoptotic, anti-autophagic, and pro-ferroptotic effects on colorectal cancer cells by inhibition of the JAK/STAT3 pathway.

Vesicle-associated membrane protein 8 (VAMP8), a soluble n-ethylmaleimide-sensitive factor receptor protein, acts as an oncogenic gene in the progression of several malignancies. Nevertheless, the roles and mechanisms of VAMP8 in colorectal cancer (CRC) progression remain unknown. The expression and prognostic significance of VAMP8 in CRC samples were analyzed through bioinformatics analyses. Cell proliferation was detected using CCK-8 and EdU incorporation assays and apoptosis was evaluated via flow cytometry. Western blot analysis was conducted to examine the protein expression. Ferroptosis was evaluated by measurement of iron metabolism, lipid peroxidation, and glutathione (GSH) content. VAMP8 was increased in CRC samples relative to normal samples on the basis of GEPIA and HPA databases. CRC patients with high level of VAMP8 had a worse overall survival. VAMP8 depletion led to a suppression of proliferation and promotion of apoptosis in CRC cells. Additionally, VAMP8 knockdown suppressed beclin1 expression and LC3-II/LC3-I ratio, elevated p62 expression, increased Fe2+, labile iron pool, lipid reactive oxygen species, and malondialdehyde levels, and repressed GSH content and glutathione peroxidase activity. Moreover, VAMP8 knockdown inhibited the activation of janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway in CRC cells. Mechanistically, activation of the JAK/STAT3 pathway by JAK1 or JAK2 overexpression attenuated VAMP8 silencing-mediated anti-proliferative, pro-apoptotic, anti-autophagic, and pro-ferroptotic effects on CRC cells. In conclusion, VAMP8 knockdown affects the proliferation, apoptosis, autophagy, and ferroptosis by the JAK/STAT3 pathway in CRC cells.

Molecular mechanisms of artificial light at night affecting circadian rhythm disturbance.

Artificial light at night (ALAN) pollution has been regarded as a global environmental concern. More than 80% of the global population is exposed to light pollution. Exacerbating this issue, artificially lit outdoor areas are growing by 2.2% per year, while continuously lit areas have brightened by 2.2% each year due to rapid population growth and expanding urbanization. Furthermore, the increasing prevalence of night shift work and smart device usage contributes to the inescapable influence of ALAN. Studies have shown that ALAN can disrupt endogenous biological clocks, resulting in a disturbance of the circadian rhythm, which ultimately affects various physiological functions. Up until now, scholars have studied various disease mechanisms caused by ALAN that may be related to the response of the circadian system to light. This review outlines the molecular mechanisms by which ALAN causes circadian rhythm abnormalities in sleep disorders, endocrine diseases, cardiovascular disease, cancer, immune impairment, depression, anxiety and cognitive impairments.

Study of ATF4/CHOP axis-mediated mitochondrial unfolded protein response in neuronal apoptosis induced by methylmercury.

Methylmercury (MeHg) is a widely distributed environmental pollutant that can easily cross the blood-brain barrier and accumulate in the brain, thereby damaging the central nervous system. Studies have shown that MeHg-induced mitochondrial damage and apoptosis play a crucial role in its neurotoxic effects. Mitochondrial unfolded protein response (UPRmt) is indispensable to maintain mitochondrial protein homeostasis and ensure mitochondrial function, and the ATF4/CHOP axis is one of the signaling pathways to activate UPRmt. In this study, the role of the ATF4/CHOP axis-mediated UPRmt in the neurotoxicity of MeHg has been investigated by C57BL/6 mice and the HT22 cell line. We discovered that mice exposed to MeHg had abnormal neurobehavioral patterns. The pathological section showed a significant decrease in the number of neurons. MeHg also resulted in a reduction in mtDNA copy number and mitochondrial membrane potential (MMP). Additionally, the ATF4/CHOP axis and UPRmt were found to be significantly activated. Subsequently, we used siRNA to knock down ATF4 or CHOP and observed that the expression of UPRmt-related proteins and the apoptosis rate were significantly reduced. Our research showed that exposure to MeHg can over-activate the UPRmt through the ATF4/CHOP axis, leading to mitochondrial damage and ultimately inducing neuronal apoptosis.

Mendelian-randomization study reveals causal relationships between nitrogen dioxide and gut microbiota.

Exposure to nitrogen dioxide might potentially change the makeup and operation of gut microbes. Nitrogen dioxide data was procured from the IEU Open GWAS (N = 456 380). Subsequently, a two-sample Mendelian randomization study was executed, utilizing summary statistics of gut microbiota sourced from the most expansive available genome-wide association study meta-analysis, conducted by the MiBioGen consortium (N = 13 266). The causal relationship between nitrogen dioxide and gut microbiota was determined using inverse variance weighted, maximum likelihood, MR-Egger, Weighted Median, Weighted Model, Mendelian randomization pleiotropy residual sum and outlier, and constrained maximum likelihood and model averaging and Bayesian information criterion. The level of heterogeneity of instrumental variables was quantified by utilizing Cochran's Q statistic. The colocalization analysis was used to examine whether nitrogen dioxide and the identified gut microbiota shared casual variants. Inverse variance weighted estimate suggested that nitrogen dioxide was causally associated with Akkermansia (ß = -1.088, 95% CI: -1.909 to -0.267, P = 0.009). In addition, nitrogen dioxide presented a potential association with Bacteroides (ß = -0.938, 95% CI: -1.592 to -0.284, P = 0.005), Barnesiella (ß = -0.797, 95% CI: -1.538 to -0.055, P = 0.035), Coprococcus 3 (ß = 1.108, 95% CI: 0.048-2.167, P = 0.040), Eubacterium hallii group (E. hallii) (ß = 0.776, 95% CI: 0.090-1.463, P = 0.027), Holdemania (ß = -1.354, 95% CI: -2.336 to -0.372, P = 0.007), Howardella (ß = 1.698, 95% CI: 0.257-3.139, P = 0.021), Olsenella (ß = 1.599, 95% CI: 0.151-3.048, P = 0.030) and Sellimonas (ß = -1.647, 95% CI: -3.209 to -0.086, P = 0.039). No significant heterogeneity of instrumental variables or horizontal pleiotropy was found. The associations of nitrogen dioxide with Akkermansia (PH4 = 0.836) and E. hallii (PH4 = 0.816) were supported by colocalization analysis. This two-sample Mendelian randomization study found that increased exposure to nitrogen dioxide had the potential to impact the human gut microbiota.

Dual roles of UPRer and UPRmt in neurodegenerative diseases.

The unfolded protein response (UPR) is a cellular stress response mechanism induced by the accumulation of unfolded or misfolded proteins. Within the endoplasmic reticulum and mitochondria, a dynamic balance exists between protein folding mechanisms and unfolded protein levels under normal conditions. Disruption of this balance or an accumulation of unfolded proteins in these organelles can result in stress responses and UPR. The UPR restores organelle homeostasis and promotes cell survival by increasing the expression of chaperone proteins, regulating protein quality control systems, and enhancing the protein degradation pathway. However, prolonged or abnormal UPR can also have negative effects, including cell death. Therefore, many diseases, especially neurodegenerative diseases, are associated with UPR dysfunction. Neurodegenerative diseases are characterized by misfolded proteins accumulating and aggregating, and neuronal cells are particularly sensitive to misfolded proteins and are prone to degeneration. Many studies have shown that the UPR plays an important role in the pathogenesis of neurodegenerative diseases. Here, we will discuss the possible contributions of the endoplasmic reticulum unfolded protein response (UPRer) and the mitochondrial unfolded protein response (UPRmt) in the development of several neurodegenerative diseases.

Hepatitis C virus infection is associated with high risk of breast cancer: a pooled analysis of 68,014 participants.

Introduction: Breast cancer is the most common malignancy among women. Previous studies had shown that hepatitis C virus (HCV) infection might serve as a risk factor for breast cancer, while some studies failed to find such an association. Methods: In this study, we presented a first attempt to capture and clarify this clinical debate via a cumulative analysis (registration ID: CRD42023445888). Results: After systematically searching and excluding the irrelevant publications, five case-control or cohort studies were finally included. The synthetic effect from the eligible studies showed that patients with HCV infection had a significantly higher prevalence of breast cancer than non-HCV infected general population (combined HR= 1.382, 95%CI: 1.129 to 1.692, P=0.002). There was no evidence of statistical heterogeneity during this pooled analysis (I2 = 13.2%, P=0.33). The sensitivity analyses confirmed the above findings. No significant publication bias was observed among the included studies. The underlying pathophysiological mechanisms for this relationship might be associated with persistent infection/inflammation, host immune response, and the modulation of HCV-associated gene expression. Discussion: Though the causal association between HCV infection and breast cancer did not seem quite as strong, screening for HCV might enable the early detection of breast cancer and help to prevent the progression of the disease. Since the topic of this study remains a matter of clinical debate, further studies are still warranted to validate this potential association. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023445888.

Inhibition of SIRT1 promotes ultraviolet B induced cataract via downregulation of the KEAP1/NFE2L2 signaling pathway.

Due to continuous exposure to ultraviolet B(UVB) radiation, eye lenses are constantly subjected to oxidative stress that induces lens epithelial cell (LEC) apoptosis, which has been associated with the inactivation of Sirtuin1 (SIRT1). It is well-established that NFE2L2 has a major protective effect on UVB-induced oxidative stress and damage. However, whether UVB radiation affects oxidative/antioxidative imbalance and damages LECs by inactivating the protective NFE2L2-mediated antioxidative stress pathway through inhibition of SIRT1 is unknown. In our research, we established in vivo and in vitro UVB exposure models in Sprague Dawley rats and SRA01/04 cells, respectively, to investigate the effect of UVB radiation on the NFE2L2/ KEAP1 pathway and the role of SIRT1 in this process. The in vivo findings revealed that UVB radiation exposure decreased Sirt1 and Nfe2l2 levels, upregulated Keap1 expression, led to an oxidative/antioxidative imbalance and increased LEC apoptosis in the eye lens. Sirt1 downregulated Keap1 expression levels, but activated Nfe2l2 and its downstream target proteins. The in vitro findings showed that UVB inhibited the deacetylation of SIRT1 target proteins and increased the acetylation levels of KEAP1 and NFE2L2. We also found that UVB radiation exposure led to a significant decrease in both co-localization levels and protein interaction between SIRT1 and KEAP1. In addition, the inhibition of SIRT1 increased KEAP1 levels, inhibited the activity of NFE2L2 and decreased co- localization levels and protein interactions between NFE2L2 and KEAP1. These results suggested that UVB radiation decreased SIRT1 levels and inhibited the KEAP1/NFE2L2 pathway, thereby reducing its antioxidant effect, which might be an important mechanism of UVB-induced cataract.

Ferroptosis and Neurodegenerative Diseases: Insights into the Regulatory Roles of SLC7A11.

Programed cell death plays a key role in promoting human development and maintaining homeostasis. Ferroptosis is a recently identified pattern of programmed cell death that is closely associated with the onset and progression of neurodegenerative diseases. Ferroptosis is mainly caused by the intracellular accumulation of iron-dependent lipid peroxides. The cysteine/glutamate antibody Solute carrier family 7 member 11 (SLC7A11, also known as xCT) functions to import cysteine for glutathione biosynthesis and antioxidant defense. SLC7A11 has a significant impact on ferroptosis, and inhibition of SLC7A11 expression promotes ferroptosis. Moreover, SLC7A11 is also closely associated with neurodegenerative diseases. In this paper, we summarize the relationship between ferroptosis and neurodegenerative diseases and the role of SLC7A11 during this process. The various regulatory mechanisms of SLC7A11 are also discussed. In conclusion, we are looking forward to a theoretical basis for further understanding the occurrence and development of ferroptosis in SLC7A11 and neurodegenerative diseases, and to seek new clues for the treatment of neurodegenerative diseases.

Methylmercury promotes oxidative stress and autophagy in rat cerebral cortex: Involvement of PI3K/AKT/mTOR or AMPK/TSC2/mTOR pathways and attenuation by N-acetyl-L-cysteine.

Methylmercury (MeHg) is a potent neurotoxicant that could induce oxidative stress and autophagy. However, the underlying mechanisms through which MeHg affects the central nervous system have not been fully elucidated, and little has been known of the interaction between oxidative stress and autophagy. Therefore, rats were administrated with different MeHg concentrations to evaluate the neurotoxic effects and autophagy in cerebral cortex. Moreover, we have investigated the neuroprotective role of N-acetyl-L-cysteine (NAC) against MeHg-induced neurotoxicity in order to estimate the regulation effects of oxidative stress on autophagy. A total of 64 rats, 40 of which were randomly divided into control and MeHg-treated (4, 8 and 12 µ mol/kg) groups. The remaining 24 rats were divided into control, NAC control (1 mmol/kg), 12 µ mol/kg MeHg, and NAC pretreatment. Administration of 12 µ mol/kg MeHg significantly increased behavioral and pathological abnormalities, and autophagy levels. In addition, the oxidative stress levels increased, together with abnormal expression of autophagy-related molecules. Pretreatment with NAC significantly prevented MeHg-induced oxidative stress and PI3K/AKT/mTOR or AMPK/TSC2/mTOR-mediated autophagy. In conclusion, the present study suggested that oxidative stress can regulate autophagy through PI3K/AKT/mTOR or AMPK/TSC2/mTOR pathways. This study provides a theoretical basis for the study and treatment of MeHg-induced neurotoxicity.

The Beneficial Role of Sirtuin 1 in Preventive or Therapeutic Options of Neurodegenerative Diseases.

Sirtuin 1 (SIRT1) is an NAD+ dependent deacetylase that modify the gene expression through histone deacetylation. SIRT1 plays a crucial role in regulating a wide range of physiological processes by adjustment multiple mechanisms through the deacetylation of multiple substrates. Neurodegenerative diseases are a series of chronic diseases characterized by dysfunction and loss of neurons. Its basic pathogenesis is filamentous tangles and amyloid deposits, such as Amyloid-ß (Aß), tau protein, α-synuclein, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). This summarizes introduces the structure and function of SIRT1, and then analyzes the protective effects of SIRT1 on neurological diseases by regulating circadian rhythm, aging, oxidative stress, mitochondrial dysfunction and neuroinflammation related pathways.

Exploring the molecular mechanisms underlie the endoplasmic reticulum stress-mediated methylmercury-induced neuronal developmental damage.

Methylmercury (MeHg) is a ubiquitous environmental pollutant, which can cross the placenta and blood brain barrier, thus affecting fetal growth and development. Although previous studies have demonstrated that MeHg induces endoplasmic reticulum (ER) stress in rat cerebral cortex and primary neurons, the role of ER stress in MeHg-induced neurodevelopmental toxicity remains unclear. Here, we used ICR pregnant mice and hippocampal neurons cells (HT22 cells) to investigate the molecular mechanism by which MeHg exposure during pregnancy affects neurodevelopment. We found that prenatal MeHg exposure caused developmental delay in offspring, accompanied with ER stress, cell apoptosis, cell cycle arrest and abnormal DNA methylation. Then, we used ER stress specific inhibitor 4-PBA and CHOP siRNA to investigate the role of ER stress on HT22 cells damage caused by MeHg. The results showed that 4-PBA pretreatment restored MeHg-induced axonal shortening and alleviated apoptosis, cell cycle arrest and DNA methylation. At the same time, the activation of CHOP/c-Jun/GADD45A signaling pathway was inhibited, and the interaction between CHOP and c-Jun was weakened. In addition, CHOP siRNA reduced the expression of c-Jun and GADD45A, and relieved DNA methylation levels to some extent. In summary, our study suggested that ER stress induced by MeHg mediated cell apoptosis and cell cycle arrest, and may affect DNA methylation through activation of CHOP/c-Jun/GADD45A signaling pathway, thus leading to neuronal damage.

Unbalanced ER-mitochondrial calcium homeostasis promotes mitochondrial dysfunction and associated apoptotic pathways activation in methylmercury exposed rat cortical neurons.

Methylmercury (MeHg) is a cumulative environmental pollutant that can easily cross the blood-brain barrier and cause damage to the brain, mainly targeting the central nervous system. The purpose of this study is to investigate the role of calcium ion (Ca2+ ) homeostasis between the endoplasmic reticulum (ER) and mitochondria in MeHg-induced neurotoxicity. Rat primary cortical neurons exposed to MeHg (0.25-1 µm) underwent dose-dependent cell damage, accompanied by increased Ca2+ release from the ER and elevated levels of free Ca2+ in cytoplasm and mitochondria. MeHg also increased the protein and messenger RNA expressions of the inositol 1,4,5-triphosphate receptor, ryanodine receptor 2, and mitochondrial calcium uniporter. Ca2+ channel inhibitors 2-aminoethyl diphenylborinate and procaine reduced the release of Ca2+ from ER, while RR and 4,4'-diisothiocyanatostilbene-2,2'-disulfonate inhibited Ca2+ uptake from mitochondria. In addition, pretreatment with Ca2+ chelator BAPTA-AM effectively restored mitochondrial membrane potential levels, inhibited over opening of mitochondrial permeability transition pore, and maintained mitochondrial function stability. Meanwhile, the expression of mitochondrial apoptosis-related proteins recovered to some extent, along with the reduction of the early apoptosis ratio. These results suggest that Ca2+ homeostasis plays an essential role in mitochondrial damage and apoptosis induced by MeHg, which may be one of the important mechanisms of MeHg-induced neurotoxicity.

Shedding new light on methylmercury-induced neurotoxicity through the crosstalk between autophagy and apoptosis.

Methylmercury (MeHg) is a bio-accumulative global environmental contaminant present in fish and seafood. MeHg accumulates in the aquatic environment and eventually reaches the human system via the food chain by bio-magnification. The central nervous system is the primary target of toxicity and is particularly vulnerable during development. It is well documented that developmental MeHg exposure can lead to neurological alterations, including cognitive and motor dysfunction. Apoptosis is a primary characteristic of MeHg-induced neurotoxicity, and may be regulated by autophagic activity. However, mechanisms mediating the interaction between apoptosis and autophagy remains to be explored. Autophagy is an adaptive response under stressful conditions, and the basal level of autophagy ensures the physiological turnover of old and damaged organelles. Autophagy can regulate cell fate through different crosstalk signaling pathways. A complex interplay between autophagy and apoptosis determines the degree of apoptosis and the progression of MeHg-induced neurotoxicity as demonstrated by pre-clinical models and clinical trials. This review summarizes recent advances in the roles of autophagy and apoptosis in MeHg neurotoxicity and thoroughly explores the relationship between them. The autophagic pathway may be a potential therapeutic target in MeHg neurotoxicity through modulation of apoptosis.

Advances on the Influence of Methylmercury Exposure during Neurodevelopment.

Mercury (Hg) is a toxic heavy-metal element, which can be enriched in fauna and flora and transformed into methylmercury (MeHg). MeHg is a widely distributed environmental pollutant that may be harmful to fish-eating populations through enrichment of aquatic food chains. The central nervous system is a primary target of MeHg. Embryos and infants are more sensitive to MeHg, and exposure to MeHg during gestational feeding can significantly impair the homeostasis of offspring, leading to long-term neurodevelopmental defects. At present, MeHg-induced neurodevelopmental toxicity has become a hotspot in the field of neurotoxicology, but its mechanisms are not fully understood. Some evidence point to oxidative damage, excitotoxicity, calcium ion imbalance, mitochondrial dysfunction, epigenetic changes, and other molecular mechanisms that play important roles in MeHg-induced neurodevelopmental toxicity. In this review, advances in the study of neurodevelopmental toxicity of MeHg exposure during pregnancy and the molecular mechanisms of related pathways are summarized, in order to provide more scientific basis for the study of neurodevelopmental toxicity of MeHg.

The effects of mTOR or Vps34-mediated autophagy on methylmercury-induced neuronal apoptosis in rat cerebral cortex.

Methylmercury (MeHg) is a environmental contaminant, which can induce neurotoxic effects. So far, the exact molecular mechanisms of autophagy and its effect on apoptosis in MeHg-induced neurotoxicity have not been elucidated. Here, rats were exposed to MeHg (4, 8, or 12 µmol/kg) for 4 weeks to evaluate the dose-effect relationship between MeHg and apoptosis, or autophagy in cerebral cortex. On this basis, rapamycin (Rapa) or 3-methyladenine (3-MA) was administrated to further explore the regulatory mechanisms of autophagy on MeHg-induced neuronal apoptosis. The pathological changes, autophagy or apoptosis levels, expression of autophagic or apoptotic-associated factors such as mTOR, S6K1, 4EBP1, Vps34, Beclin1, p62, LC3, Bcl-2/Bax, caspase, or MAPKs were investigated. Results showed that MeHg dose-dependently induced pathological changes in cerebral cortex, and the levels of autophagy and apoptosis were increased. Furthermore, Rapa pretreatment antagonized MeHg-induced apoptosis, whereas 3-MA further aggravated apoptosis, which were supported by findings that Rapa activated mTOR-mediated autophagy while 3-MA inhibited Vps34-related autophagy, further affect neuronal apoptosis through regulation of apoptotic factors mentioned above. In conclusion, the findings indicated that MeHg dose-dependently induced autophagy or apoptosis, and mTOR or Vps34 may play important roles in mediating autophagy, which further regulated apoptosis through MAPKs or mitochondrial apoptosis pathways.

The Roles of Oxidative Stress in Regulating Autophagy in Methylmercury-induced Neurotoxicity.

Methylmercury (MeHg) is a potential neurotoxin that is highly toxic to the human central nervous system. Although MeHg neurotoxicity has been widely studied, the mechanism of MeHg neurotoxicity has not yet been fully elucidated. Some research evidence suggests that oxidative stress and autophagy are important molecular mechanisms of MeHg-induced neurotoxicity. Researchers have widely accepted that oxidative stress regulates the autophagy pathway. The current study reviews the activation of Nuclear factor-erythroid-2-related factor (Nrf2)-related oxidative stress pathways and autophagy signaling pathways in the case of MeHg neurotoxicity. In addition, autophagy mainly plays a role in the neurotoxicity of MeHg through mTOR-dependent and mTOR-independent autophagy signaling pathways. Finally, the regulation of autophagy by reactive oxygen species (ROS) and Nrf2 in MeHg neurotoxicity was explored in this review, providing a new concept for the study of the neurotoxicity mechanism of MeHg.

Cooking with biomass fuels increased the risk for cognitive impairment and cognitive decline among the oldest-old Chinese adults (2011-2018): A prospective cohort study.

BACKGROUNDS: While the pernicious effects of outdoor air pollution on cognitive ability have been previously examined, evidence regarding household air pollution is scarce. METHODS: Using data from the Chinese Longitudinal Healthy Longevity Survey, we explored the relationship between cooking with biomass fuel and cognitive impairment and cognitive decline using a Cox proportional hazards model. We further assessed the correlation of biomass fuels and cognitive score using a generalized estimating equation. Cognitive ability was measured based on the Chinese version of the Mini-Mental State Examination (MMSE) and cognitive impairment was defined as MMSE < 24 points and cognitive decline was defined as a reduction of MMSE ≥ 3 points. On follow-up, we investigated the effect of switch-cooking combustibles on cognitive ability. RESULTS: The mean (SD) age of 4161 participants was 81.7 (10.0) years old. The reported cooking with biomass fuels was correlated with an elevated risk of cognitive impairment (hazard ratio (HR): 1.19, 95% confidence interval (CI): 1.04, 1.37) and cognitive decline (HR: 1.18, 95% CI: 1.04, 1.33). Besides, cooking with biomass fuels was related to a decrease in cognitive score (ß: -0.43, 95% CI: -0.73, -0.14). In comparison to persistent biomass fuel users, participants who reported changing their primary cooking fuels from biomass to clean fuels exhibited a reduced risk of cognitive impairment (HR: 0.68, 95% CI: 0.57, 0.82) and cognitive decline (HR: 0.66, 95% CI: 0.56, 0.76) and a higher cognitive score (ß: 0.72, 95% CI: 0.17, 1.26). Cooking without ventilated cookstoves was associated with a higher risk of cognitive impairment (HR: 1.31, 95% CI: 1.10, 1.58) and cognitive decline (HR: 1.18, 95% CI: 1.02, 1.38), regardless of types of cooking fuels. Interaction and stratified analyses showed relatively poor cognitive ability in participants who engaged in irregular exercise or were not living with family members. CONCLUSIONS: Cooking with biomass fuels was correlated with a higher risk of cognitive impairment and cognitive decline. Among the oldest-old population, this risk may, however, be lower for those changing their primary cooking fuels from biomass to clean fuels.