Progressive sarcopenia and myosteatosis predict prognosis of advanced HCC patients treated with immune checkpoint inhibitors.

Background: Immunotherapy stands as a pivotal modality in the therapeutic landscape for the treatment of advanced hepatocellular carcinoma, yet responses vary among patients. This study delves into the potential impact of sarcopenia, myosteatosis and adiposity indicators, as well as their changes during immunotherapy, on treatment response and prognosis in patients with advanced hepatocellular carcinoma treated with immune checkpoint inhibitors. Methods: In this retrospective analysis, 116 patients with advanced hepatocellular carcinoma receiving immune checkpoint inhibitors were recruited. Skeletal muscle, intramuscular, subcutaneous, and visceral adipose tissue were assessed by computed tomography at the level of the third lumbar vertebrae before and after 3 months of treatment. Sarcopenia and myosteatosis were evaluated by skeletal muscle index and mean muscle density using predefined threshold values. Patients were stratified based on specific baseline values or median values, along with alterations observed during the treatment course. Overall survival (OS) and progression-free survival (PFS) were compared using the log-rank test and a multifactorial Cox proportional risk model. Results: A total of 116 patients were recruited and divided into two cohorts, 81 patients for the training set and 35 patients for the validating set. In the overall cohort, progressive sarcopenia (P=0.021) and progressive myosteatosis (P=0.001) were associated with objective response rates, whereas progressive myosteatosis (P<0.001) was associated with disease control rates. In the training set, baseline sarcopenia, myosteatosis, and subcutaneous and visceral adipose tissue were not significantly associated with PFS and OS. In multivariate analysis adjusting for sex, age, and other factors, progressive sarcopenia(P=0.002) and myosteatosis (P=0.018) remained independent predictors of PFS. Progressive sarcopenia (P=0.005), performance status (P=0.006) and visceral adipose tissue index (P=0.001) were all independent predictors of OS. The predictive models developed in the training set also had good feasibility in the validating set. Conclusion: Progressive sarcopenia and myosteatosis are predictors of poor clinical outcomes in patients with advanced hepatocellular carcinoma receiving immune checkpoint inhibitors, and high baseline visceral adiposity is associated with a poorer survival.

Tenascin C activates the toll­like receptor 4/NF­κB signaling pathway to promote the development of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a globally prevalent gynecological disorder among women of childbearing age. The present study aimed to investigate the role of tenascin C (TNC) in PCOS and its potential mechanisms. Fasting blood glucose and serum insulin, the homeostasis model assessment of insulin resistance and the serum hormone levels were determined in PCOS rats. In addition, H&E staining was used for assessing pathology. In addition, the effects of TNC on oxidative stress and inflammation response in PCOS rat and cell models was assessed. Furthermore, the roles of TNC on KGN cell proliferation and apoptosis were determined employing EdU assay and flow cytometry. TLR4/NF­κB pathway­related proteins were measured using western blotting, immunofluorescence and immunohistochemistry. It was found that the mRNA and protein expression was upregulated in PCOS rats and in KGN cells induced by dihydrotestosterone (DHT). Knockdown of TNC relieved the pathological characteristics and the endocrine abnormalities of PCOS rats. Knockdown of TNC inhibited ovarian cell apoptosis, oxidative stress and inflammation in PCOS rats. Knockdown of TNC reversed the DHT­induced reduction in cell proliferation and increase in apoptosis in KGN cells. Furthermore, knockdown of TNC alleviated oxidative stress and inflammatory responses induced by DHT in KGN cells. Additionally, knockdown of TNC inhibited the toll­like receptor 4 (TLR4)/NF­κB signaling pathway in PCOS rats and DHT­treated KGN cells. In conclusion, knockdown of TNC could ameliorate PCOS in both rats and a cell model by inhibiting cell apoptosis, oxidative stress and inflammation via the suppression of the TLR4/NF­κB signaling pathway.

Association Between rs2278426 Polymorphism of the ANGPTL8 Gene and Polycystic Ovary Syndrome.

Purpose: To study the relationship between the single nucleotide polymorphism (SNP) rs2278426 in the angiopoietin-like protein 8 gene (ANGPTL8) and polycystic ovary syndrome (PCOS). Patients and methods: A total of 122 patients with PCOS and 108 controls were recruited for comparison of glucose, lipid, insulin, sex hormone, and ANGPTL8 levels. Polymerase chain reaction (PCR) and gene sequencing were performed for comparison of the frequency of the CC, CT, and TT rs2278426 genotypes and the rs2278426 allele distributions between the PCOS and control groups and between the obese and non-obese subgroups of the PCOS and control groups. Results: The frequency of the T allele was significantly higher in the PCOS group than that in the controls (P = 0.037). In the dominant genetic model, the proportion of the CT+TT genotype in the PCOS group was significantly higher than that in the controls (P = 0.047). Subgroup analysis demonstrated that the T allele proportion was significantly higher in obese PCOS group than obese control group (P = 0.027). PCOS with the CT+TT genotype had significantly higher body mass index (BMI; P = 0.001), triglyceride (TG; P = 0.005), homeostasis model assessment of insulin resistance (HOMA-IR; P = 0.035), testosterone (P = 0.041), and ANGPTL8 (P = 0.037) levels and significantly lower high-density lipoprotein (HDL) levels (P = 0.025) than PCOS with the CC genotype. Obese PCOS group with the CT+TT genotype had significantly higher TG (P = 0.015), luteinizing hormone (LH; P = 0.030), fasting insulin (FINS; P = 0.039), HOMA-IR (P = 0.018), and ANGPTL8 (P = 0.049) levels than obese PCOS group with the CC genotype. Conclusion: Polymorphisms of rs2278426 may induce glycolipid metabolic disorders by affecting ANGPTL8 levels and functions in Han Chinese females with obesity from the Shandong region, increasing the risk of PCOS in this population.

Immunotherapy and drug sensitivity predictive roles of a novel prognostic model in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most significant causes of cancer-related deaths in the worldwide. Currently, predicting the survival of patients with HCC and developing treatment drugs still remain a significant challenge. In this study, we employed prognosis-related genes to develop and externally validate a predictive risk model. Furthermore, the correlation between signaling pathways, immune cell infiltration, immunotherapy response, drug sensitivity, and risk score was investigated using different algorithm platforms in HCC. Our results showed that 11 differentially expressed genes including UBE2C, PTTG1, TOP2A, SPP1, FCN3, SLC22A1, ADH4, CYP2C8, SLC10A1, F9, and FBP1 were identified as being related to prognosis, which were integrated to construct a prediction model. Our model could accurately predict patients' overall survival using both internal and external datasets. Moreover, a strong correlation was revealed between the signaling pathway, immune cell infiltration, immunotherapy response, and risk score. Importantly, a novel potential drug candidate for HCC treatment was discovered based on the risk score and also validated through ex vivo experiments. Our finds offer a novel perspective on prognosis prediction and drug exploration for cancer patients.

Sex-specific grey matter abnormalities in individuals with chronic insomnia.

Previous studies have reported sex differences in altered brain function in patients with chronic insomnia (CI). However, sex-related alterations in brain morphology have rarely been investigated. This study aimed to investigate sex-specific grey matter (GM) alterations in patients with CI and to examine the relationship between GM alterations and neuropsychological assessments. Ninety-three (65 females and 28 males) patients and 78 healthy (50 females and 28 males) controls were recruited. Structural magnetic resonance imaging data were analysed using voxel-based morphometry to test for interactions between sex and diagnosis. Spearman's correlation was used to assess the associations among structure, disease duration, and sleep-, mood-, and cognition-related assessments. Males with CI showed reduced GM volume in the left inferior parietal lobe, left middle cingulate cortex, and right supramarginal gyrus. Females with CI showed increased GM volume in the right Rolandic operculum. Moreover, mood-related assessments were negatively correlated with GM volumes in the right supramarginal gyrus and left inferior parietal lobe in the male patients, and cognitive-related assessments were positively correlated with GM volumes in the Rolandic operculum in the female patients. Our findings indicate sex-specific alterations in brain morphology in CI, thereby broadening our understanding of sex differences in CI and potentially providing complementary evidence for the development of more effective therapies and individual treatments.

Mitochondrial complex I inhibition by homoharringtonine: A novel strategy for suppression of chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a hematologic malignancy predominantly driven by the BCR-ABL fusion gene. One of the significant challenges in treating CML lies in the emergence of resistance to tyrosine kinase inhibitors (TKIs), especially those associated with the T315I mutation. Homoharringtonine (HHT) is an FDA-approved, naturally-derived drug with known anti-leukemic properties, but its precise mechanisms of action remain incompletely understood. In this study, we rigorously evaluated the anti-CML activity of HHT through both in vitro and in vivo assays, observing substantial anti-CML effects. To elucidate the molecular mechanisms underpinning these effects, we performed proteomic analysis on BCR-ABL T315I mutation-bearing cells treated with HHT. Comprehensive pathway enrichment analysis identified oxidative phosphorylation (OXPHOS) as the most significantly disrupted, suggesting a key role in the mechanism of action of HHT. Further bioinformatics exploration revealed a substantial downregulation of proteins localized within mitochondrial complex I (MCI), a critical OXPHOS component. These results were validated through Western blot analysis and were supplemented by marked reductions in MCI activity, ATP level, and oxygen consumption rate (OCR) upon HHT exposure. Collectively, our results shed light on the potent anti-CML properties of HHT, particularly its effectiveness against T315I mutant cells through MCI inhibition. Our study underscores a novel therapeutic strategy to overcome BCR-ABL T315I mutation resistance, illuminating a previously uncharted mechanism of action for HHT.

Aberrant single-subject morphological cerebellar connectome in chronic insomnia.

BACKGROUND: To systematically investigate the topological organisation of morphological networks of the cerebellum using structural MRI and examine their clinical relevance in chronic insomnia (CI). METHODS: One hundred and one patients with CI and 102 healthy controls (HCs) were recruited in this study. Individual morphological networks of the cerebellum were constructed based on regional grey matter volume, and topologically characterised using weighted graph theory-based network approaches. Between-group comparisons were performed using permutation tests, and Spearman's correlation was used to examine the relationships between topological alterations and clinical variables. RESULTS: Compared with HCs, patients with CI exhibited a lower normalised clustering coefficient. Locally, CI patients exhibited lower nodal efficiency in the cerebellar lobule VIIb and vermis regions, but higher nodal efficiency in the right cerebellar lobule VIIIa regions. No correlations were observed between network alterations and clinical variables. CONCLUSIONS: Individual morphological network analysis provides a new strategy for investigating cerebellar morphometric changes in CI, and our findings may have important implications in establishing diagnostic and categorical biomarkers.

Combined exposure to lead and high-fat diet induced neuronal deficits in rats: Anti-neuroinflammatory role of SIRT1.

INTRODUCTION: Lead (Pb) exposure and high-fat diet (HFD) trigger neurotoxicity, which may involve neuroinflammation. However, the mechanism by which combined Pb and HFD exposure induces nucleotide oligomerization domain-like receptor family pyrin domain 3 (NLRP3) inflammasome activation has not been fully elucidated. MATERIAL AND METHODS: The Sprague-Dawley (SD) rat model of exposure to Pb and HFD was established to reveal the influence of co-exposure on cognition and identify signaling clues that mediate neuroinflammation and synaptic dysregulation. PC12 cells was treated with Pb and PA in vitro. Silent information regulator 1 (SIRT1) agonist (SRT 1720) was employed as intervention agent. RESULTS: Our results showed that Pb and HFD exposure induced cognitive impairment and lead to neurological damage in rats. Meanwhile, Pb and HFD could stimulate the NLRP3 inflammasome assembly and activate caspase 1, releasing proinflammatory cytokines interleukin-1ß (IL-1ß) and interleukin-18 (IL-18), further promoting neuronal cell activation and amplifying neuroinflammatory responses. Additionally, our findings suggest that SIRT1 plays a role in Pb and HFD induced neuroinflammation. However, the use of SRT 1720 agonists showed some potential in alleviating these impairments. CONCLUSION: Pb exposure and HFD intake could induce neuronal damage through activation of the NLRP3 inflammasome pathway and synaptic dysregulation, while the NLRP3 inflammasome pathway may be rescued via activating SIRT1.

Interaction of Intestinal Microbiota with Medications.

INTRODUCTION: It is well known that the response to and metabolism of the drugs entering the human body varies widely across individuals. One of the reasons is that such interpersonal differences may be related to gut microbes. On one hand, drugs or xenobiotics entering the human body may affect the composition of the gut microbiome; on the other hand, the gut microbiota may alter the absorption, distribution, metabolism and excretion (abbreviated as ADME) process of drugs or xenobiotics vice versa. However, the majority of studies focused on the interaction of general population cohorts with the gut microbiota, which is incompatible with the real clinic. For example, the gut microbiota is closely associated with the progression and treatment of irritable bowel syndrome, a common functional disorder of the gastrointestinal tract. Under the disease status, the composition of the gut microbiota is altered affecting the pharmacokinetics, efficacy and toxicity of xenobiotics. Concerning irritable bowel syndrome, a few studies reported that the xenobiotics administration process was gut microbial-mediated, while it also affected drug efficacy and toxicity. Thus, the correlation between gut microbiota and xenobiotics administration, especially the drugs administered, should be elucidated. METHOD: This review paper links differences between the gut microbiome and drug metabolism, which play a significant role in the implications for medical therapy and drug development in irritable bowel syndrome indications. RESULT: The human intestinal microbiota permeates the ADME process of orally administered drugs and has the potential to further modify the efficacy and toxicity of agents through the mediation of various enzymes, while at the same time, medications could also alter the composition and function of the human intestinal microbiota.

Preparation of a Bi6O5(OH)3(NO3)5·2H2O/AgBr composite and its long-lasting antibacterial efficacy.

A novel Bi6O5(OH)3(NO3)5·2H2O/AgBr (6535BBN/AgBr) composite with long-lasting antibacterial efficacy was prepared. The microstructure of the composite was characterized. AgBr nanoparticles (NPs) were sandwiched in 6535BBN nanosheets (NSs) or loaded on their surfaces. The utilization of 6535BBN as carriers contributed to the long-term lasting antibacterial activity of the composite after storage in water or 0.9% NaCl. The antibacterial activity was evaluated by inhibition zones against E. coli. The inhibition zone diameters of 6535BBN/AgBr stored in water for 0 h, 8 h, 16 h, and 48 h were measured as 22.50, 21.71, 20.43, and 20.29 mm, respectively. The activity of the composite after storage in water for 48 h remained 90.2% of that in the beginning. After storing in 0.9% NaCl for 16 h, the activity was determined to be 90.1% of that in the beginning. In comparison with the rapid decrease in the antibacterial activity of pure AgBr, the slow reduction of 6535BBN/AgBr after storage indicates long-lasting efficacy. The excellent dispersion states of 6535BBN/AgBr powders after storage in solutions were revealed, and the positive relationship between the dispersion state and its long-lasting antibacterial activity was suggested. Based on the unique load-on-carrier (LOC) structure, the long-lasting antibacterial performance was promoted by the synergy of the sharp-edge-cutting effect of 6535BBN NSs, prolonged ROS antibacterial effect, and restrained sterilization effects of silver ions caused by their slow release.

Altered Cerebral Blood Flow in the Progression of Chronic Kidney Disease.

Background: In chronic kidney disease (CKD), cognitive impairment is a definite complication. However, the mechanisms of how CKD leads to cognitive impairment are not clearly known. Methods: Cerebral blood flow (CBF) information was collected from 37 patients with CKD (18 in stage 3; 19 in stage 4) and 31 healthy controls (HCs). For CKD patients, we also obtained laboratory results as well as neuropsychological tests. We conducted brain perfusion imaging studies using arterial spin labeling and calculated the relationship between regional CBF changes and various clinical indicators and neuropsychological tests. We also generated receiver operator characteristic (ROC) curves to explore whether CBF value changes in certain brain regions can be used to identify CKD. Results: Compared with HCs, CBF decreased in the right insula and increased in the left hippocampus in the CKD4 group; through partial correlation analysis, we found that CBF in the right insula was negatively correlated with the number connection test A (NCT-A) (r = −0.544, p = 0.024); CBF in the left hippocampus was positively correlated with blood urea nitrogen (r = 0.649, p = 0.005) and negatively correlated with serum calcium level (r = −0.646, p = 0.005). By comparing the ROC curve area, it demonstrated that altered CBF values in the right insula (AUC = 0.861, p < 0.01) and left hippocampus (AUC = 0.862, p < 0.01) have a good ability to identify CKD. Conclusions: Our study found that CBF alterations in the left hippocampus and the right insula brain of adult patients with stage 4 CKD were correlated with disease severity or laboratory indicators. These findings provide further insight into the relationship between altered cerebral perfusion and cognitive impairment in patients with non-end-stage CKD as well as, additional information the underlying neuropathophysiological mechanisms.

Lead-induced neurodevelopmental lesion and epigenetic landscape: Implication in neurological disorders.

Lead (Pb) was implicated in multiple genotoxic, neuroepigenotoxic, and chromosomal-toxic mechanisms and interacted with varying synaptic plasticity pathways, likely underpinning previous reports of links between Pb and cognitive impairment. Epigenetic changes have emerged as a promising biomarker for neurological disorders, including cognitive disorders, Alzheimer's disease (AD), and Parkinson's disease (PD). In the present review, special attention is paid to neural epigenetic features and mechanisms that can alter gene expression patterns upon environmental Pb exposure in rodents, primates, and zebrafish. Epigenetic modifications have also been discussed in population studies and cell experiment. Further, we explore growing evidence of potential linkage between Pb-induced disruption of regulatory pathway and neurodevelopmental and neurological disorders both in vivo and in vitro. These findings uncover how epigenome in neurons facilitates the development and function of the brain in response to Pb insult.

Caspase-11 contributes to pain hypersensitivity in the later phase of CFA-induced pain of mice.

Chronic pain is a common disease that severely disrupts the quality of life. Persistent neuroinflammation and central sensitization play important roles in its pathogenesis. Caspase-11 is a critical modulator of inflammation of central nervous system. However, its role in chronic pain remains elusive. In this study, chronic pain and acute pain were induced via injecting complete Freund's adjuvant (CFA) and 5 % formalin into the plantar of the right hind paw of wild-type (WT) and Caspase-11 deficient (Caspase-11-/-) mice, respectively. In WT mice, CFA injection significantly decreased the hind paw mechanical pain threshold in Von Frey test on 1-7 days after injection and increased the caspase-11 level of ipsilateral dorsal horn of spinal cord on day 2 and day 5 after injection. Compared to the WT mice, Caspase-11-/- mice showed significantly higher mechanical pain threshold in the later phase of CFA-induced pain, but not in the early phase, and had no significant difference in 5 % formalin induced licking and flinching behavior. In addition, the microglial activation, and the mRNA levels of caspase-1 and IL-18 in the spinal cord of Caspase-11-/- mice restored to baseline on the day 5 after CFA injection, but not in WT mice. Our data indicated that Caspase-11 contributed to persistent inflammation in ipsilateral dorsal horn of spinal cord, and consequently pain hypersensitivity in the later phase of CFA-induced pain.

Visual Analysis of Neural Architecture Spaces for Summarizing Design Principles.

Recent advances in artificial intelligence largely benefit from better neural network architectures. These architectures are a product of a costly process of trial-and-error. To ease this process, we develop ArchExplorer, a visual analysis method for understanding a neural architecture space and summarizing design principles. The key idea behind our method is to make the architecture space explainable by exploiting structural distances between architectures. We formulate the pairwise distance calculation as solving an all-pairs shortest path problem. To improve efficiency, we decompose this problem into a set of single-source shortest path problems. The time complexity is reduced from O(kn2N) to O(knN). Architectures are hierarchically clustered according to the distances between them. A circle-packing-based architecture visualization has been developed to convey both the global relationships between clusters and local neighborhoods of the architectures in each cluster. Two case studies and a post-analysis are presented to demonstrate the effectiveness of ArchExplorer in summarizing design principles and selecting better-performing architectures.

Knowledge mapping of copper-induced cell death: A bibliometric study from 2012 to 2022.

BACKGROUND: The recent article Copper induces cell death by targeting lipoylated TCA cycle proteins has attracted much attention. Although copper-induced cell death has only recently been formally proposed, it has been studied much earlier. This study aims to undertake a bibliometric analysis of the literature on copper-induced cell death to understand the development of copper-induced cell death better and identify potential new research directions. METHODS: With the help of Cite Space software, visual analysis is carried out on the annual number of published papers, countries/regions and institutions, journals co-citation, literature co-citation and reference burst, keywords co-occurrence, clustering, and burst. RESULTS: A search of 770 articles published in English over the last ten years showed a fluctuating trend of increasing numbers of articles. China had the highest number of articles (190% or 24.68%), followed by the USA and India. Inflammation, biological evaluation, nanoparticle, and cu(ii) have been popular research themes in the last 4 years. The keyword clusters are summarized in 8 categories, including exposure, complexe, er stress, cleavage, paraptosis, cancer, glutamate, reactive oxygen species (ROS), expression. The hot topics are mainly focused on the exploration of mechanisms and related diseases, including induced apoptosis, aggregation, autophagy, endoplasmic reticulum stress, induced oxidative stress, and inflammation. Parkinson's disease and cancer are 2 diseases that are closely related to copper-induced cell death. CONCLUSION: This study provides a visual analysis of copper-induced cell death trends and provides some hidden potentially useful information for future research directions.

A Study on Doping and Compound of Zinc Oxide Photocatalysts.

As an excellent semiconductor photocatalyst, zinc oxide is widely used in the field of photocatalysis and is regarded as one of the most reliable materials to solve environmental problems. However, because its band gap energy limits the absorption of visible light and reduces the efficiency of catalytic degradation, it needs to be doped with other substances or compounded with other substances and precious metal. This paper summarizes the research on this aspect at home and abroad in recent years, introduces the doping of transition metal ions by zinc oxide, the compounding of zinc oxide with precious metals or other semiconductors, and the prospect of further improving the catalytic efficiency of zno photocatalyst is also put forward.

Macrophage polarization as a potential therapeutic target for atherosclerosis: a dynamic stochastic modelling study.

We proposed a dynamic stochastic mathematical model to evaluate the role of macrophage polarization in plaque development. The dynamic process of macrophages from proliferation to death was simulated under different lipid microenvironments. The probability of macrophage phenotypic switching was described using a Bernoulli distribution where the stochastic variable was determined by the local lipid level. Moreover, the interactions between macrophages and microenvironmental factors vary with macrophage phenotype. We investigated the distribution of key microenvironmental factors, the dynamics of macrophage polarization and its influence on foam cell formation. M1 macrophages were found to predominate in advanced plaque corresponding to the exacerbated inflammation observed in mice experiments. The imbalance between the deposition of oxidized low-density lipoprotein and phagocytic effects of macrophages governed the formation of foam cells. Furthermore, we simulated targeted therapies by either directly inhibiting the polarization probability to M1 macrophages or indirectly regulating macrophage polarization due to high-density lipoprotein levels. Comparison of simulation results with experimental findings in both therapies indicated that the intervention and regulation of macrophage polarization could influence plaque microenvironment and subsequently induce plaque regression, especially in the early stage. The proposed modelling system can facilitate the evaluation of novel therapies targeting macrophage polarization.

Prepubertal exposure to Pb alters autophagy in the brain of aging mice: A time-series based model.

As a ubiquitous toxic heavy metal, lead (Pb) exposure is known to be implicated in the onset and development of neurodegenerative diseases which may cause more serious health hazards with age and the accumulation of Pb in the body. Autophagy is the main degradation route for abnormal aggregated proteins and damaged cell organelles. Here, we aimed to study the effects of adolescent Pb exposure on autophagy at different life nodes. In this study, we developed a time-series model of Pb exposure in mice and randomly divided 4-week-old male C57BL/6 mice into six groups (4 C, 13 C, 16 C, 4Pb, 13Pb and 16Pb). Mice in Pb groups was consumed deionized water containing 0.2 % Pb(Ac)2 for 3 months and then reared to anticipated life nodes, while the control group consumed deionized water. Western blot and Real-time qPCR were used to assess the effects of developmental Pb exposure on individual components of the autophagy machinery and modulation of microtubule-associated protein 1 light chain 3 (LC3) at each age stage. Our results showed that Pb exposure during adolescence reduced the p-mTOR/mTOR ratios with enhanced expression of Beclin-1, Atg12 and Atg7in both the hippocampus (HPC) and prefrontal cortex (PFC) of senescent mice while upregulation of LC3II/LC3I ratios and p62 suggested that autophagy mediates degradation was interrupted. Overall, we confirm that Pb exposure during adolescence promotes autophagic processes in the aged mice brain and that autophagic degradation is hindered, ultimately leading to a failure of autophagic degradation.

Advances in COVID-19 Vaccines and New Coronavirus Variants.

With the successful development of the Corona Virus Disease 2019 (COVID-19) vaccines and increased vaccination coverage, great progress in global outbreak control has been made in several countries. However, new coronavirus variants emerge and their rapid spread, causing a new wave of economic and social upheaval worldwide. The spread of new coronavirus variants poses a new and enormous challenge to vaccination and pandemic control, so further studies to explore and develop vaccines for the prevention and control virus infection are warranted. In this review, we provide an overview of the most prevalent variants including Omicron, and explore the effectiveness of COVID-19 vaccines against related variants to better understand existing vaccines and to facilitate improved research into new vaccines. In addition, this review discusses existing strategies to increase vaccine efficacy and introduces novel vaccines by the non-injection route.

SIRT1 modifies DNA methylation linked to synaptic deficits induced by Pb in vitro and in vivo.

To investigate the mechanism of Silent information regulator 1 (SIRT1) regulation of DNA methylation and thus the expression of synaptic plasticity-related genes induced by lead (Pb) exposure, the early-life Sprague-Dawley rats and PC12 cells were used to establish Pb exposure models and treated with SIRT1 agonists (resveratrol and SRT1720). In vivo results demonstrated that Pb exposure increased the expression of DNMTs, MeCP2, PP1 and cleaved caspase3, decreased the expression of SIRT1, BDNF and RELIN and altered DNA methylation levels of synaptic plasticity genes. Moreover, we observed marked pathological damage in the hippocampal CA1 region of the 0.2 % Pb-exposure group. After treatment with resveratrol, the effects of Pb exposure on the expression of the above molecules and pathological features were significantly ameliorated in the hippocampus of rats. In vitro results showed that after the treatment with SRT1720, the expression of SIRT1 was activated and thus reversed the effect on DNMTs, MeCP2, apoptosis and synaptic plasticity-related genes and their DNA methylation levels induced by Pb exposure. In conclusion, we validated the important protective role of SIRT1 in neurotoxicity induced by Pb exposure through in vivo and in vitro experiments, providing potential therapeutic targets for the treatment and prevention of brain damage.