Oxidative Phosphorylation Pathway Research Articles

Gestational Diabetes Mellitus-Induced Milk Fat Globule Membrane Protein Changes of Human Mature Milk Based on TMT Proteomic Analysis

Breastfeeding by mothers with gestational diabetes mellitus (GDM) has been shown to reduce maternal insulin demands and diminish the risks of diabetes in infants, leading to improved long-term health outcomes. Milk fat globule membrane (MFGM) proteins play a crucial role in influencing the immunity and cognitive development of infants. Understanding the alterations in MFGM proteins in breastmilk from mothers with GDM is essential for enhancing their self-efficacy and increase breastfeeding rates. The objective of this study is to investigate and compare MFGM proteins in milk from mothers with GDM and without based on tandem mass tag (TMT) labeling and liquid chromatography tandem mass spectrometry (LC-MS) techniques. A total of 5402 proteins were identified, including 4 upregulated proteins and 24 downregulated proteins. These significantly altered proteins were found to be associated with human diseases, cellular processes, and metabolism pathways. Additionally, the oxidative phosphorylation pathway emerged as the predominant pathway through Gene Set Enrichment Analysis (GSEA) involving all genes.

Promoting Glutathione Synthesis: A Possibility for Treating Cardiomyopathy Induced by a Maternal Western Diet.

The adverse effects of a Western diet on obesity and diabetes among reproductive-aged women pose a significant threat to the cardiovascular health of their offspring. Given the crucial role of glutathione metabolism and glutathione-related antioxidant defense systems in cardiovascular diseases through scavenging ROS and maintaining redox homeostasis, further exploration of their specific influence is imperative to develop therapeutic strategies for cardiomyopathy induced by a maternal Western diet. We developed a prenatal maternal Western diet exposure model in C57/B6 mice to investigate cardiac morphology and function through histological analysis and echocardiography. RNA sequencing and analysis were utilized to elucidate the mechanisms underlying the impact of a maternal Western diet and N-acetylcysteine treatment on cardiomyopathy. Additionally, ELISAs, transmission electron microscopy, and flow cytometry were employed to assess the antioxidant defense system and mitochondrial ROS levels in progenitor cardiomyocytes. N-acetylcysteine significantly mitigated cardiomyocyte hypertrophy, myocardial interstitial fibrosis, collagen type I accumulation, and left ventricular remodeling induced by a maternal Western diet, particularly in male offspring. Furthermore, N-acetylcysteine reversed the increase in apoptosis and the increase in the β/α-MyHC ratio in the myocardium of offspring that results from a maternal Western diet. RNA sequencing and GSEA revealed that the beneficial effects of N-acetylcysteine were linked to its ability to modulate oxidative phosphorylation pathways. Additionally, N-acetylcysteine treatment during pregnancy can markedly elevate glutathione levels, augment glutathione peroxidase (GPx) activity, and mitigate the accumulation of mitochondrial ROS caused by a maternal Western diet. N-acetylcysteine mitigated cardiomyopathy induced by a maternal Western diet by bolstering glutathione synthesis and enhancing GPx activity, thereby scavenging mitochondrial ROS and modulating oxidative phosphorylation pathways.

The Combined Analysis of GC-IMS and GC-MS Reveals the Differences in Volatile Flavor Compounds between Yak and Cattle-Yak Meat.

In order to investigate the composition and differences in volatile organic compounds (VOCs) in yak and cattle-yak meat and determine the key metabolites and metabolic pathways related to flavor formation. In this study, the VOCs and non-volatile metabolites in Longissimus dorsi muscle of two groups of samples were detected and analyzed by gas chromatography-ion migration spectrometry (GC-IMS) and gas chromatography-mass spectrometry (GC-MS). The results showed that 31 VOCs were identified by GC-IMS, including 5 alcohols, 5 ketones, 5 esters, 3 aldehydes, 2 furans, 2 hydrocarbons, 1 amine, 1 acid, 1 thiazole, 1 pyrazine, and 5 others. Most of them were alcohols, ketones, esters, and aldehydes. A total of 75 non-volatile metabolites with significant differences were obtained by GC-MS screening, among which amino acid contents such as serine, glycine, phenylalanine, and aspartic acid were significantly up-regulated in cattle-yak, and glutamic acid and tyrosine were significantly up-regulated in yak. The non-volatile differential metabolites in the two groups were significantly enriched in the metabolic pathways of arginine biosynthesis and oxidative phosphorylation. By combining GC-IMS and GC-MS, this study comprehensively and intuitively reflected the differences in VOCs between yak and cattle-yak meat, and clarified the metabolomic reasons for the differences in VOCs, so as to provide a theoretical basis for meat quality improvement.

The ISR downstream target ATF4 represses long-term memory in a cell type–specific manner

The integrated stress response (ISR), a pivotal protein homeostasis network, plays a critical role in the formation of long-term memory (LTM). The precise mechanism by which the ISR controls LTM is not well understood. Here, we report insights into how the ISR modulates the mnemonic process by using targeted deletion of the activating transcription factor 4 (ATF4), a key downstream effector of the ISR, in various neuronal and non-neuronal cell types. We found that the removal of ATF4 from forebrain excitatory neurons (but not from inhibitory neurons, cholinergic neurons, or astrocytes) enhances LTM formation. Furthermore, the deletion of ATF4 in excitatory neurons lowers the threshold for the induction of long-term potentiation, a cellular model for LTM. Transcriptomic and proteomic analyses revealed that ATF4 deletion in excitatory neurons leads to upregulation of components of oxidative phosphorylation pathways, which are critical for ATP production. Thus, we conclude that ATF4 functions as a memory repressor selectively within excitatory neurons.

Saikosaponin-d mediates FOXG1 to reverse docetaxel resistance in prostate cancer through oxidative phosphorylation

BackgroundProstate cancer (PCa), a prevalent malignancy worldwide, is frequently identified in advanced stages due to the absence of distinctive early symptoms, thereby culminating in the development of chemotherapy-induced drug resistance. Exploring novel resistance mechanisms and identifying new therapeutic agents can facilitate the advancement of more efficacious strategies for PCa treatment. MethodsBioinformatics analysis was employed to investigate the expression of FOXG1 in PCa tissues. Subsequently, qRT-PCR was utilized to validate FOXG1 mRNA expression levels in corresponding PCa cell lines. FOXG1 knockdown was performed, and cell proliferation was assessed using CCK-8 assays, while cell migration and invasion capabilities were evaluated through wound healing and Transwell assays. Western blot and Seahorse analyzer were used to measure oxidative phosphorylation (OXPHOS) levels. Additionally, to explore potential approaches to alleviate PCa drug resistance, this study assessed the impact of biologically active saikosaponin-d (SSd) on PCa malignant progression and resistance by regulating FOXG1 expression. ResultsFOXG1 exhibited high expression in PCa tissues and cell lines. Knockdown of FOXG1 inhibited the proliferation, migration, and invasion of PCa cells, while FOXG1 overexpression had the opposite effect and promoted OXPHOS levels. The addition of an OXPHOS inhibitor prevented this outcome. Finally, SSd was shown to suppress FOXG1 expression and reverse docetaxel resistance in PCa cells through the OXPHOS pathway. ConclusionThis work demonstrated that SSd mediated FOXG1 to reverse malignant progression and docetaxel resistance in PCa through OXPHOS.

Integrative multi-omics analysis reveals the underlying toxicological mechanisms of enrofloxacin on the growth of wheat seedling roots

The continuous release of antibiotics into agroecosystems has raised concerns about the potential negative effects of antibiotic residues on crops. In this study, the toxicological effects of enrofloxacin (ENR) on wheat seedlings were analyzed using a combination of morpho-physiological, transcriptomic, proteomic, and metabolomic approaches. ENR inhibited the growth of wheat (Triticum aestivum L.) roots and induced oxidative stress. In particular, ENR downregulated the oxidative phosphorylation pathway, while it enhanced glycolysis and the tricarboxylic acid cycle, thereby regulating the balance of intracellular energy metabolism. In addition, sustained exposure to excessive reactive oxygen species (ROS) resulted in an increase in reduced glutathione (GSH), a slight decrease in ascorbic acid (AsA), and a significant decrease in the ratio of GSH to oxidized glutathione (GSSG), which imbalanced the AsA-GSH cycle. In addition, the resulting increase in abnormal proteins triggered ubiquitin-independent proteasomal degradation pathways. Further, an increase in abscisic acid (ABA) and a decrease in jasmonic acid (JA) and its derivatives alleviated the inhibitory effect of ENR on the growth of wheat roots. In conclusion, direct damage and signaling by ROS, hormonal regulation, a decrease in the GSH to GSSG ratio, and insufficient energy supply were identified as key factors for the significant inhibition of wheat root growth under ENR stress.

Adipose Kiss1 controls aerobic exercise-related adaptive responses in adipose tissue energy homeostasis.

Kisspeptin signaling regulates energy homeostasis. Adiposity is the principal source and receiver of peripheral Kisspeptin, and adipose Kiss1 metastasis suppressor (Kiss1) gene expression is stimulated by exercise. However, whether the adipose Kiss1 gene regulates energy homeostasis and plays a role in adaptive alterations during prolonged exercise remains unknown. Here, we investigated the role of Kiss1 role in mice and adipose tissues and the adaptive changes it induces after exercise, using adipose-specific Kiss1 knockout (Kiss1adipoq-/-) and adeno-associated virus-induced adipose tissue Kiss1-overexpressing (Kiss1adipoq over) mice. We found that adipose-derived kisspeptin signal regulates lipid and glucose homeostasis to maintain systemic energy homeostasis, but in a sex-dependent manner, with more pronounced metabolic changes in female mice. Kiss1 regulated adaptive alterations of genes and proteins in tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OxPhos) pathways in female gWAT following prolonged aerobic exercise. We could further show that adipose Kiss1 deficiency leads to reduced peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α) protein content of soleus muscle and maximum oxygen uptake (VO2 max) of female mice after prolonged exercise. Therefore, adipose Kisspeptin may be a novel adipokine that increases organ sensitivity to glucose, lipids, and oxygen following exercise.

HES6 Mediates Oxidative Phosphorylation Pathway to Promote Immune Infiltration of CD8 + T Cells in Lung Adenocarcinoma.

Tumor immunotherapy has recently gained popularity as a cancer treatment strategy. The molecular mechanism controlling immune infiltration in lung adenocarcinoma (LUAD) cells, however, is not well characterized. Investigating the immune infiltration modulation mechanism in LUAD is crucial. LUAD patient samples were collected, and HES6 expression and immune infiltration level of CD8 + T cells in patient tissues were analyzed. Bioinformatics was utilized to identify binding relationship between E2F1 and HES6, and enrichment pathway of HES6. The binding of E2F1 to HES6 was verified using dual-luciferase and ChIP experiments. HES6 and E2F1 expression in LUAD cells was detected. LUAD cells were co-cultured with CD8 + T cells, and the CD8 + T cell killing level, IFN-γ secretion, and CD8 + T-cell chemotaxis level were measured. Expression of key genes involved in oxidative phosphorylation was detected, and the oxygen consumption rate of LUAD cells was assessed. A mouse model was constructed to assay Ki67 expression and apoptosis in tumor tissue. High expression of HES6 promoted CD8 + T-cell infiltration and enhanced T-cell killing ability through oxidative phosphorylation. Further bioinformatics analysis, molecular experiments, and cell experiments verified that E2F1 negatively regulated HES6 by oxidative phosphorylation, which suppressed CD8 + T-cell immune infiltration. In addition, in vivo assays illustrated that silencing HES6 repressed tumor cell immune evasion. E2F1 inhibited HES6 transcription, thereby mediating oxidative phosphorylation to suppress immune infiltration of CD8 + T cells in LUAD. The biological functions and signaling pathways of these genes were analyzed, which may help to understand the possible mechanisms regulating immune infiltration in LUAD.

Genomic and proteomic analyses reveal the reduction mechanism of hexavalent chromium by the culturing supernatant of strain Pediococcus acidilactici 13-7

This study used lactic acid bacteria with high antioxidative properties to screen for strains capable of reducing hexavalent chromium [Cr (VI)] in their culturing supernatants. The strain Pediococcus acidilactici 13–7 exhibited potent Cr (VI)-reducing capability and remarkable resistance to Cr (VI) even at concentration as high as 24 mM. Comparative genomics analysis revealed a unique gene, ChrR, associated with Cr (VI) reduction in this strain, distinguishing it from four reference strains of P. acidilactici. The proteomic investigation identified proteins linked to the ChrR gene, such as nqo1, frdA, and gshR, indicating significant enrichment in redox-related functions and oxidative phosphorylation pathways. These findings suggest that P. acidilactici 13–7 possesses superior electron transfer capacity compared to other strains, making it more adaptable under highly oxidative conditions by modulating the external environment to mitigate oxidative stress. Collectively, the results demonstrated the potential application of this lactic acid bacterial strain for bioremediation of heavy metals by its ability to reduce Cr (VI), and shed light on the molecular mechanisms underlying Cr (VI) reduction of the strain P. acidilactici 13–7.

Impact of DEHP on mitochondria-associated endoplasmic reticulum membranes and reproductive toxicity in ovary

Di(2-ethylhexyl) phthalate (DEHP) is a widely recognized environmental endocrine disruptor that potentially impacts female reproductive function, although the specific mechanisms leading to such impairment remain unclear. A growing body of research has revealed that the endoplasmic reticulum and mitochondrial function significantly influence oocyte quality. The structure of mitochondria-associated endoplasmic reticulum membranes (MAMs) is crucial for facilitating the exchange of Ca2+, lipids, and metabolites. This study aimed to investigate the alterations in the composition and function of MAMs after DEHP exposure and to elucidate the underlying mechanisms of ovarian toxicity. The female mice were exposed to DEHP at doses of 5 and 500 mg/kg/day for one month. The results revealed that DEHP exposure led to reduced serum anti-Müllerian hormone levels and increased atretic follicles in mice. DEHP induced endoplasmic reticulum stress and disrupted calcium homeostasis in oocytes. Furthermore, DEHP impaired the mitochondrial function of oocytes and reduced their membrane potential, and promoting apoptosis. Similar results were observed in human granulosa cells after exposure to mono-(2-ethylhexyl) phthalate (MEHP, metabolites of DEHP) in vitro. Proteomic analysis and transmission electron microscopy revealed modifications in the functional proteins and structure of the MAMs, and the suppression of oxidative phosphorylation pathways. The findings of this investigation provide a new perspective on the mechanism underlying the reproductive toxicity of DEHP in females.

Aflatoxin B1 as a complicit in intestinal damage caused by Eimeria ovinoidalis in lambs: Novel insights to reveal parasite-gut battle

Mycotoxins, unavoidable contaminants in feed and feed ingredients, have the potential to influence the incidence and severity of various diseases upon ingestion. Sheep coccidiosis is an enteric disease caused by protozoa of Eimeria spp. However, the extent to which the presence of aflatoxin b1 (AFB1) synergistically exacerbates damage to intestinal health in lambs with Eimeria remains unclear. 50-day-old female lambs were randomly assigned to a 2 × 2 factorial arrangement of treatments for 15 days to assess the impact of AFB1 exposure on lambs with or without Eimeria (E.) ovinoidalis infection. Our findings reveal that AFB1 synergistically intensifies damage to intestinal health in lambs challenged by E. ovinoidalis. This is evidenced by disruptions to the intestinal microbiota and reductions in the production of short-chain fatty acids. AFB1 further aggravates damage to the cecal mechanical barrier. Additionally, AFB1 contributes to the entry of lipopolysaccharide into the bloodstream, activating the inflammatory response. Interestingly, AFB1 exposure history results in an early peak of oocyst excretion and a decreased number of oocyst excretion in E. ovinoidalis infected lambs. This may be closely linked to the destruction of the intestinal epithelial cell structure and its apoptosis, as indicated by a decreased ratio of Bcl-2 to Bax and increased caspase-3 levels. Mechanistically, proteomics analysis identified mitochondrial dysfunction (inhibition of the oxidative phosphorylation pathway) as the primary factor intensifying intestinal epithelial cell destruction caused by coccidia, exacerbated by AFB1 through the inhibiting the conversion of NADH to NAD+ in the cecum of lambs via down-regulation of the PGC-1α/NRF1/TFAM pathway. Overall, these results offer novel insights into the AFB1 complicity in accelerating intestinal damage caused by E. ovinoidalis in lambs. Targeting the mitochondrial oxidative phosphorylation pathway of the intestine may represent a new therapeutic strategy against the detrimental effects of mycotoxin and coccidia.

Behavioral impairments and disrupted mitochondrial energy metabolism induced by polypropylene microplastics in zebrafish larvae

Polypropylene microplastics (PP-MPs) are emerging pollutant commonly detected in various environmental matrices and organisms, while their adverse effects and mechanisms are not well known. Here, zebrafish embryos were exposed to environmentally relevant concentrations of PP-MPs (0.08–50 mg/L) from 2 h post-fertilization (hpf) until 120 hpf. The results showed that the body weight was increased at 2 mg/L, heart rate was reduced at 0.08 and 10 mg/L, and behaviors were impaired at 0.4, 10 or 50 mg/L. Subsequently, transcriptomic analysis in the 0.4 and 50 mg/L PP-MPs treatment groups indicated potential inhibition on the glycolysis/gluconeogenesis and oxidative phosphorylation pathways. These findings were validated through alterations in multiple biomarkers related to glucose metabolism. Moreover, abnormal mitochondrial ultrastructures were observed in the intestine and liver in 0.4 and 50 mg/L PP-MPs treatment groups, accompanied by significant decreases in the activities of four mitochondrial electron transport chain complexes and ATP contents. Oxidative stress was also induced, as indicated by significantly increased ROS levels and significant reduced activities of CAT and SOD and GSH contents. All the results suggested that environmentally relevant concentrations of PP-MPs could induce disrupted mitochondrial energy metabolism in zebrafish, which may be associated with the observed behavioral impairments. This study will provide novel insights into PP-MPs-induced adverse effects and highlight need for further research.

Different effects of bariatric surgery on epigenetic plasticity in skeletal muscle of individuals with and without type 2 diabetes

AimBariatric surgery is highly effective for the treatment of obesity in individuals without (OB11OB: individuals with obesity.) and in those with type 2 diabetes (T2D22T2D: individuals with obesity and type 2 diabetes.). However, whether bariatric surgery triggers similar or distinct molecular changes in OB and T2D remains unknown. Given that individuals with type 2 diabetes often exhibit more severe metabolic deterioration, we hypothesized that bariatric surgery induces distinct molecular adaptations in skeletal muscle, the major site of glucose uptake, of OB and T2D after surgery-induced weight loss. MethodsAll participants (OB, n = 13; T2D, n = 13) underwent detailed anthropometry before and one year after the surgery. Skeletal muscle biopsies were isolated at both time points and subjected to transcriptome and methylome analyses using a comprehensive bioinformatic pipeline. ResultsBefore surgery, T2D had higher fasting glucose and insulin levels but lower whole-body insulin sensitivity, only glycemia remained higher in T2D than in OB after surgery. Surgery-mediated weight loss affected different subsets of genes with 2,013 differentially expressed in OB and 959 in T2D. In OB differentially expressed genes were involved in insulin, PPAR signaling and oxidative phosphorylation pathways, whereas ribosome and splicesome in T2D. LASSO regression analysis revealed distinct candidate genes correlated with improvement of phenotypic traits in OB and T2D. Compared to OB, DNA methylation was less affected in T2D in response to bariatric surgery. This may be due to increased global hydroxymethylation accompanied by decreased expression of one of the type 2 diabetes risk gene, TET2, encoding a demethylation enzyme in T2D. ConclusionOB and T2D exhibit differential skeletal muscle transcriptome responses to bariatric surgery, presumably resulting from perturbed epigenetic flexibility.

Current Trends and Challenges in Targeting Tumor Mitochondrial Glycolysis and Oxidative Phosphorylation Pathways for Cancer Therapy.

Current Trends and Challenges in Targeting Tumor Mitochondrial Glycolysis and Oxidative Phosphorylation Pathways for Cancer Therapy.

Fuzheng Huayu recipe inhibits bleomycin-induced pulmonary fibrosis in rats by inhibiting M2 polarization of macrophages via the oxidative phosphorylation pathway

Fuzheng Huayu recipe (FZHYR) is a Chinese patent medicine for the treatment of fibrosis. The effects of FZHYR on pulmonary fibrosis and macrophage polarization were investigated in vitro. FZHYR inhibited pulmonary inflammation and fibrosis and M2 polarization of macrophages in bleomycin-induced pulmonary fibrosis (BPF) of rat model. Differentially expressed genes were screened by high-throughput mRNA sequencing and GSEA showed that oxidative phosphorylation (OXPHOS) was correlated with BPF. FZHYR inhibited expressions of Ndufa2 and Ndufa6 in lung tissues of BPF rats. These findings suggest that OXPHOS pathway serves as a possible target for pulmonary fibrosis therapy by FZHYR.

The role of cuproptosis-related genes in pan-cancer and the development of cuproptosis-related risk model in colon adenocarcinoma

Cancer is widely regarded as a leading cause of death in humans, with colon adenocarcinoma (COAD) ranking among the most prevalent types. Cuproptosis is a novel form of cell death mediated by protein lipoylation. Cuproptosis-related genes (CRGs) participate in tumourigenesis and development. Their role in pan-cancer and COAD require further investigation. This study comprehensively evaluated the relationship among CRGs, pan-cancer, and COAD. Our research revealed the differential expression of CRGs and the cuproptosis potential index (CPI) between normal and tumour tissues, and further explored the correlation of CRGs or CPI with prognosis, immune infiltration, tumor mutant burden(TMB), microsatellite instability (MSI), and drug sensitivity in pan-cancer. Gene set enrichment analysis (GSEA) revealed that oxidative phosphorylation and fatty acid metabolism pathways were significantly enriched in the high CPI group of most tumours. FDX1 and CDKN2A were chosen for further exploration, and we found an independent association between FDX1 and CDKN2A and prognosis, immune infiltration, TMB, and MSI in pan-cancer. Furthermore, a prognostic risk model based on the association between CRGs and COAD was built, and the correlations between the risk score and prognosis, immune-related characteristics, and drug sensitivity were analysed. COAD was then divided into three subtypes using cluster analysis, and the differences among the subtypes in prognosis, CPI, immune-related characteristics, and drug sensitivity were determined. Due to the level of LIPT1 was notably positive related with the risk score, the cytological identification was carried out to identify the association of LIPT1 with proliferation and migration of colon cancer cells. In summary, CRGs can be used as potential prognostic biomarkers to predict immune infiltration levels in patients with pan-cancer. In addition, the risk model could more accurately predict the prognosis and immune infiltration levels of COAD and better guide the direction of clinical medication. Thus, FDX1, CDKN2A, and LIPT1 may serve as prospective new targets for cancer therapy.

Transcriptome Analysis on the ALAN-Induced Zebrafish Ovary: Desynchronization of Life Processes and Initiation of Diseases

Objective: The effect of artificial light at night (ALAN) on “transcriptome” is prominent owing to its capacity for “desynchronization” of organismal physiology. Light influences the circadian rhythm. This study aims to explore the ALAN-induced ovarian transcriptome of zebrafish for desynchronization of life processes. Methods: Four experimental conditions were set up for female zebrafish: one normal 12-hour light and 12-hour dark (LD) cycle, and three continuous exposures to ALAN for one week (LLW), one month (LLM), and one year (LLY). The whole transcriptome data analysis of the ALAN-exposed samples was then compared with the normal sample using RNA-Seq, followed by exploratory analyses. Results: The analysis revealed two different patterns of expression of genes where LLW and LLM differ with LLY samples in comparison to LD. Compared to LD, downregulation of the predicted hub genes was observed in all treatments; ribosome and oxidative phosphorylation pathways were enriched. LLY vs. LD contrast depicts the enrichment of three more pathways—RNA polymerase, adhesion junction, and signaling. The gene ontology (GO) enrichment portrays more prevalent biological processes in LLW vs. LD and LLM vs. LD than in LLY vs. LD. Contrast-wise disease annotation represents neoplasms as the most prevalent; disease enrichment denotes the major class of neoplasm, carcinoma, coupled with intellectual disability, global developmental delay, and seizures. Conclusion: Our study displayed desynchronization of various genes and pathways leading to the initiation of diseases, for the first time in zebrafish. Even though, this data shows that ALAN is a serious threat, further research is needed to determine the intensity and the duration of ALAN which might cause potential repercussions.

Chronic exposure to environmental concentrations of benzo[a]pyrene causes multifaceted toxic effects of developmental compromise, redox imbalance, and modulated transcriptional profiles in the early life stages of marine medaka (Oryzias melastigma)

Polycyclic aromatic hydrocarbons (PAHs) accumulate and integrate into aquatic environments, raising concerns about the well-being and safety of aquatic ecosystems. Benzo[a]pyrene (BaP), a persistent PAH commonly detected in the environment, has been extensively studied. However, the broader multifaceted toxicity potential of BaP on the early life stages of marine fish during chronic exposure to environmentally relevant concentrations needs further exploration. To fill these knowledge gaps, this study assessed the in vivo biotoxicity of BaP (1, 4, and 8 μg/L) in marine medaka (Oryzias melastigma) during early development over a 30-day exposure period. The investigation included morphological, biochemical, and molecular-level analyses to capture the broader potential of BaP toxicity. Morphological analyses showed that exposure to BaP resulted in skeletal curvatures, heart anomalies, growth retardation, elevated mortality, delayed and reduced hatching rates. Biochemical analyses revealed that BaP exposure not only created oxidative stress but also disrupted the activities of antioxidant enzymes. This disturbance in redox balance was further explored by molecular level investigation. The transcriptional profiles revealed impaired oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle pathways, which potentially inhibited the oxidative respiratory chain in fish following exposure to BaP, and reduced the production of adenosine triphosphate (ATP) and succinate dehydrogenase (SDH). Furthermore, this investigation indicated a potential connection to apoptosis, as demonstrated by fluorescence microscopy and histological analyses, and supported by an increase in the expression levels of related genes via real-time quantitative PCR. This study enhances our understanding of the molecular-level impacts of BaP's multifaceted toxicity in the early life stages of marine medaka, and the associated risks.

Single-cell RNA sequencing and multiple bioinformatics methods to identify the biomarkers of ischemic stroke to alzheimer’s disease

Ranked as the world’s second leading cause of mortality, ischemic stroke (IS) imposes a significant global burden, marked by its substantial incidence and economic impact across nations and regions, chiefly attributed to its elevated disability rates. Alzheimer’s disease (AD) is linked to a heightened susceptibility to IS. However, few studies have been reported to explain the potential correlation between IS and AD. We investigated the relationship and relevant mechanisms between IS and AD using single-cell RNA sequencing and multiple bioinformatics approaches. By intersecting differentially expressed genes and WGCNA critical module genes, we obtained 15 IS related AD genes. According to the KEGG pathway analysis, the IS related AD disease genes were significantly enriched in the parkinson disease pathway, oxidative phosphorylation pathway, thermogenesis pathway, alzheimer disease pathway and neurodegeneration pathway. Finally, five genes associated with immunity (TXN, HINT1, TOMM7, COX7C, RPL17) were identified in IS related AD. Significantly, it was found that all hub genes were mainly highly expressed in epithelial cells, endothelial cells, monocytes and oligodendrocytes by single cell RNA sequencing. We believe these hub genes may regulate the immune pathway which may contribute to the development of IS related AD. In addition, these genes may be potential targets for the treatment of IS related AD.

The immunoreactive signature of monocyte-derived dendritic cells from patients with Down syndrome.

The clinical spectrum of Down syndrome (DS) ranges from congenital malformations to premature aging and early-onset senescence. Excessive immunoreactivity and oxidative stress are thought to accelerate the pace of aging in DS patients; however, the immunological profile remains elusive. We investigated whether peripheral blood monocyte-derived dendritic cells (MoDCs) in DS patients respond to lipopolysaccharide (LPS) distinctly from non-DS control MoDCs. Eighteen DS patients (age 2-47 years, 12 males) and 22 controls (age 4-40 years, 15 males) were enrolled. CD14-positive monocytes were immunopurified and cultured for 7 days in the presence of granulocyte-macrophage colony-stimulating factor and IL-4, yielding MoDCs in vitro. After the LPS-stimulation for 48 hours from days 7 to 9, culture supernatant cytokines were measured by multiplex cytokine bead assays, and bulk-prepared RNA from the cells was used for transcriptomic analyses. MoDCs from DS patients produced cytokines/chemokines (IL-6, IL-8, TNF-α, MCP-1, and IP-10) at significantly higher levels than those from controls in response to LPS. RNA sequencing revealed that DS-derived MoDCs differentially expressed 137 genes (74 upregulated and 63 downregulated) compared with controls. A gene enrichment analysis identified 5 genes associated with Toll-like receptor signaling (KEGG: hsa04620, P = 0.00731) and oxidative phosphorylation (hsa00190, P = 0.0173) pathways. MoDCs obtained from DS patients showed higher cytokine or chemokine responses to LPS than did control MoDCs. Gene expression profiles suggest that hyperactive Toll-like receptor and mitochondrial oxidative phosphorylation pathways configure the immunoreactive signature of MoDCs in DS patients.