Physiological genomics最新文献

Although the intratumoral microbiota has been discovered to have a close connection with tumor immunity, the specific role played by intratumoral microbiota in regulating the tumor immune microenvironment (TIME) of lung cancer remains largely unexplored. Here, we comprehensively investigated the association between intratumoral microbiota and the TIME in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). First, we found that intratumoral microbiota and host transcriptome profile significantly differed between LUAD and LUSC. Moreover, there were strong associations between the abundance of intratumoral microbes and the expression of host genes in both LUAD and LUSC. Furthermore, we found an association between intratumoral Lachnoclostridium and chemokine expression, suggesting a role for these species of microbiota in modulating tumor immunity. In addition, we found that tumors harbor distinct relative abundance of Lachnoclostridium presented variation in response to immunotherapy and sensitivity to potential drug candidates. Our study provided important insights into the regulation of intratumoral microbiota on the TIME in LUAD and LUSC, which may serve as a precursor for a hypothesis-driven study to better understand the causational relationship of intratumoral microbiota in lung cancer.NEW & NOTEWORTHY LUAD and LUSC exhibited significant differences in intratumoral microbiome and the TIME profile. The relative abundance of intratumoral Lachnoclostridium correlated with the tumor immune infiltration in both LUSC and LUAD. Intratumoral Lachnoclostridium impacted the patients' sensitivity to potential targeted drugs, especially in LUSC.

Ischemia-reperfusion (I/R) injury is an important initiating cause of chronic kidney disease and renal failure. Changes in proximal tubule (PT) morphology, including brush border loss, occur rapidly in response to ischemic stress and I/R injury. Vacuole membrane protein 1 (VMP1) is a compelling target for ischemia-associated renal damage because it is a necessary regulator of autophagy, and the genomic location of hypoxia-responsive microRNA miR-21 lies within an intronic region of the Vmp1 gene. Autophagy is reported to have protective and pathological effects on I/R injury. In this study, we find that VMP1 is rapidly upregulated in renal cortex tissue in response to 15 and 30 min of ischemia. Intravenous delivery of Vmp1-targeting GameR or a scrambled GapmeR was performed on adult male Sprague-Dawley rats for 2 days before either 30 min of renal ischemia, 30 min of ischemia followed by 24 h of reperfusion (I/R), or corresponding control procedures. Autophagy markers and PT morphology were assessed in the renal cortex. Suppression of ischemia-induced upregulation of VMP1 attenuated PT brush border loss following 30 min of ischemia and 24 h post-I/R. Our study reveals a novel and mechanistically important dissociation between VMP1 expression, miR-21-5p expression, autophagy markers, and I/R tubular injury in the renal cortex.NEW & NOTEWORTHY The impact of autophagy on renal ischemia/reperfusion injury (IRI) remains unclear. VMP1 promotes autophagy through interaction with beclin-1 and subsequent localization to the endoplasmic reticulum. In this study, GapmeR-mediated suppression of VMP1 in rats and attenuated proximal tubule damage following 30 min of ischemia or following 24 h of reperfusion, without altering autophagy markers following reperfusion. This new insight suggests that increased VMP1 did not afford autophagy-mediated protection from IRI in proximal tubules.

Decades of artificial selection have markedly enhanced egg production efficiency, yet the epigenetic underpinnings, notably DNA methylation dynamics in the gut, remain largely unexplored. Here, we investigate how breeds and developmental stages influence DNA methylation profiles in laying hens, and their potential relationship to laying performance and gut health. We compared two highly selected laying hen strains, Lohmann Brown-Classic (LB) and Lohmann Selected Leghorn-Classic (LSL), which exhibited similar egg production but divergent physiological, metabolic, and immunological characteristics. Our sampling encompassed key developmental stages: the pullet stage (10 and 16 wk old), peak production (24 and 30 wk old), and later stage (60 wk old) (n = 99; 10 per group), allowing us to elucidate the temporal dynamics of epigenetic regulation. Our findings highlight a crucial window of epigenetic modulation during the prelaying period, characterized by stage-specific methylation alterations and the involvement of predicted transcription factor motifs within methylated regions. This observation was consistent with the expression patterns of DNA methyltransferases (DNMTs), including DNMT1, DNMT3A, and DNMT3B. In addition, a higher methylation level was observed in specific loci or regions in the LSL compared with the LB strain. Notably, we uncover strain-specific differences in methylation levels, particularly pronounced in genomic regions associated with intestinal integrity, inflammation, and energy homeostasis. Our research contributes to the multidisciplinary framework of epigenetics and egg-laying performance, offering valuable implications for poultry production and welfare.NEW & NOTEWORTHY Our study reveals key methylation changes in the jejunum mucosa of laying hens across developmental stages and between strains, with implications for gut health, immune function, and egg production. These findings highlight a crucial role of epigenetic regulation in optimizing performance.

Aspirin (ASA) is a proven chemoprotective agent for colorectal cancer (CRC), though interindividual responses and cellular mechanisms are not well characterized. Human organoids are ideal to study treatment responses across individuals. Here, colonic organoids from African-Americans (AA) and European-Americans (EA) were used to profile genomic and cellular ASA responses. Colonic organoids from 67 participants, 33 AA and 34 EA, were treated with 3 mM ASA or vehicle control for 24 h. Gene expression was assessed by RNA-seq, and differentially responsive genes were analyzed by condition, population, and for gene set enrichment. Top differentially responsive genes were assessed by time and ASA doses in independent organoids. Expression quantitative trait loci (eQTL) mapping was performed to identify variants associated with condition-specific responses. Apoptosis and necrosis assays were performed, and apoptosis gene expression was measured in organoids. Overall, 8,343 genes were differentially responsive to ASA with differences between AA and EA. Significant enrichment for fatty acid oxidation (FAO) and peroxisome proliferator-activated receptor (PPAR) signaling was found. Significant treatment eQTLs were identified for relevant genes involved in FAO, apoptosis, and prostaglandin metabolism. ASA-induced apoptosis and secondary necrosis were confirmed with the identification of significant differential responses of apoptotic genes to ASA. Results demonstrate large transcriptional responses to ASA treatment with differences in responses between individuals. Genomic and cellular results suggest that ASA effects on the mitochondria are key mechanisms of action that could underlie clinical effects. These results could be used to assess clinical treatment responses for chemoprevention in the future.NEW & NOTEWORTHY Aspirin treatment in colonic organoids from diverse individuals revealed significant transcriptome-wide responses, especially for genes in lipid and apoptosis signaling pathways. In normal organoids, apoptosis was induced by aspirin, providing one possible mechanism of colorectal cancer chemoprevention. Our results are a first step toward implementation of personalized medicine for aspirin in colorectal cancer prevention.

"Jiedu Tongluo Tiaoying Formula" (JDTLTYF) is a kind of traditional Chinese medicine (TCM) prescription for treating hyperthyroidism, which can effectively improve the condition of patients. The main active ingredients of JDTLTYF were collected from the traditional Chinese medicine systems pharmacology (TCMSP) database, and the target was predicted. Genes related to hyperthyroidism were identified using DisGeNET, GeneCards, and Online Mendelian Inheritance in Man (OMIM) databases. Protein-protein interaction (PPI) network and interaction network of "formula-herb-active ingredient-target genes" was constructed. Mass spectrometry was used to identify the components. The binding of key components to the target was verified by molecular docking and molecular dynamics (MD) simulations. A hyperthyroidism mouse model was established by using levothyroxine sodium tablets, and the hormone and expression levels of inflammatory factors were examined by ELISA and Western blot. The key genes of JDTLTYF in the treatment of hyperthyroidism were TNF and AKT1. The results of mass spectrometry also showed that quercetin was one of the main components. The results of molecular docking and MD simulation showed that the binding-free energy between AKT1 and quercetin was the lowest, and the binding was stable. In vivo experimental results showed that gastric lavage with JDTLTYF could target AKT1 and TNF-α, effectively alleviate the pathological features of hyperthyroidism in mice, and reduce inflammation response. This study elucidated the key small molecule compounds and their action targets of JDTLTYF in the treatment of hyperthyroidism. It provides a direction for the development of new drugs for clinical hyperthyroidism.NEW & NOTEWORTHY Based on the network pharmacology and molecular dynamics (MD) simulation, this study elucidated the key small molecule compounds and their action targets of JDTLTYF Chinese herbal prescription (debark peony root, common selfheal fruit-spike, figwort root, thunberg fritillary bulb, and oyster shell) in the treatment of hyperthyroidism, preliminarily analyzed its molecular mechanism, and provided a reference direction for subsequent cell experiments.

This research explored the effect of a high-fiber diet based on gut microbiota on patients with chronic heart failure (HF). Patients with chronic HF, who had undergone a dietary survey indicating a daily dietary fiber intake of less than 15 g/day, were divided into the control and study groups (n = 50). In addition to conventional heart failure treatment, the study group received dietary guidance, while the control group did not receive any dietary guidance and maintained their usual low-fiber dietary habits. After 1 yr intervention, the daily dietary fiber intake, abundance of gut microbiota, plasma trimethylamine N-oxide (TMAO), albumin (ALB), prealbumin (PA), transferrin (TF), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), left ventricular ejection fraction (LVEF), left ventricular end-diastolic index (LVEDVI), and left ventricular end-systolic volume index (LVESVI), Barthel index (BI), and 6 min walking distance (6 MWD) were compared. After the intervention, in both groups, the daily dietary fiber intake increased and the abundance of Firmicutes, Proteobacteria, Actinobacteria, and Fusobacteria decreased and that of Bacteroides increased; the plasma TMAO decreased; serum ALB, PA, and TF levels increased; serum CRP, TNF-α, IL-6, and IL-8 levels decreased, and the change was greater in the study group; LVEF elevated, LVEDVI and LVESVI reduced, and the differences between both groups were not significant; BI and 6 MWD elevated, and the study group was higher than the control group. High-fiber diet positively regulates the composition of gut microbiota, nutritional status, and microinflammatory level in patients with chronic HF, thereby improving patients' quality of life.NEW & NOTEWORTHY Traditional heart failure (HF) treatment primarily focuses on medications and surgery, whereas this study explores the improvement effects of a diet high in dietary fiber on patients with chronic HF from the perspective of gut microbiota, providing a new perspective for HF treatment.

This study aimed to examine the protective effect of celastrol on testicular dysfunction in diabetic rats and the potential underlying mechanisms. All rats included in the study were divided into four groups: a control group treated with sodium citrate buffer and vehicle), a celastrol-treated control group, a streptozotocin (STZ)-induced diabetic group following insulin resistance, and a celastrol-treated diabetic group. Serum glucose, triglyceride, total cholesterol, high-density lipoprotein cholesterol, interleukin (IL)-1β, tumor necrosis factor-α, and testosterone levels were measured. In addition, the levels of testicular homogenate superoxide dismutase and malondialdehyde were assessed. Furthermore, testicular tissue relative toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), and myeloid differentiation factor 88 (MYD88) expressions were quantitatively measured using polymerase chain reaction. Histopathological and immunohistochemical studies were also conducted. The results revealed that treatment with celastrol significantly reduced TLR4, MyD88, and NF-κB expressions, and the levels of inflammatory mediators such as tumor necrosis factor-α and IL-1β in the testicular tissue of treated rats. These findings suggest that celastrol has the potential to be effective in the treatment of diabetes-induced testicular injury by inhibiting testicular inflammation, apoptosis, and oxidative stress.NEW & NOTEWORTHY Celastrol inhibits the production of proinflammatory cytokines in the testicular tissue by specifically targeting the TLR4/MyD88/NF-κB signaling cascade pathways. This indicates that celastrol may serve as a promising new therapeutic target for treating diabetic reproductive dysfunction.

Gut microbiota impacts host homeostasis and diseases. Chronic plus binge ethanol consumption has been linked to increased injuries than chronic or binge ethanol intake alone. We hypothesized that distinct shapes in gut microbiota composition are induced by chronic, binge, and the association of these treatments, thereby affecting host functions and contributing to sex-based differences in alcohol use disorders. Male and female C57BL/6J mice were submitted to chronic, binge, or chronic plus binge ethanol feeding. DNA was extracted from fecal microbiota, followed by analysis of the V3-V4 region of the 16S rRNA gene and sequencing on an Illumina platform. Gut microbiome analysis was performed using QIIME v2022.2.0. Functional profiling of the gut microbiome was performed using PICRUSt2. Ethanol differentially affected the gut microbiota of female and male mice. Decreased α diversity was observed in male and female mice from the chronic plus binge and chronic groups, respectively. The genera Faecalibaculum, Lachnospiraceae, and Alistipes were identified as major potential biomarkers for gut dysbiosis induced by ethanol consumption. In addition, ethanol-induced gut dysbiosis altered several metabolic pathways. Ethanol consumption modifies the mouse gut microbiome in a drinking pattern- and sex-dependent manner, potentially leading to different susceptibility to ethanol-related diseases. Chronic plus binge ethanol intake induces a more pronounced gut dysbiosis in male mice. Conversely, chronic ethanol is linked to a greater degree of gut dysbiosis in female mice. The changed gut microbiome may be potentially targeted to prevent, mitigate, or treat alcohol use disorders.NEW & NOTEWORTHY Ethanol alters the mouse gut microbiome in a drinking pattern- and sex-dependent manner. Chronic plus binge ethanol intake induces a more severe gut dysbiosis in male mice, whereas chronic ethanol consumption appears to be a more potent inductor of gut dysbiosis in female mice. Ethanol-induced gut dysbiosis alters several pathways linked to metabolism, genetic and environmental information processing, cellular processes, organism systems, and neurological human diseases.

Preeclampsia (PE) is a life-threatening hypertensive disorder of pregnancy with an incidence rate of up to 8% worldwide. However, the complete pathogenesis is still unknown. Obesity increases the risk of developing PE threefold. To better understand the relationship of maternal risk factors, the BPH/5 mouse was described as a model of superimposed PE. Previous research demonstrated that adult BPH/5 female mice have an adverse cardiometabolic phenotype characterized by hypertension, obesity with increased white adipose tissue, and dyslipidemia, exaggerated by pregnancy. We hypothesize that BPH/5 mice have gut dysbiosis characterized by changes in alpha and beta diversity of bacterial community structure as well as perturbed short-chain fatty acids (SCFAs) compared with controls in pregnancy. Fecal samples were used for Illumina sequencing of 16S v4 rRNA amplicons. Microbial community composition of the pregnant BPH/5 mice compared with C57 controls was different using permutational multivariate analysis of variance (PERMANOVA) with Bray-Curtis dissimilarity. Alpha diversity was increased in pregnant BPH/5 dams compared with controls. Alistipes and Helicobacter were increased, whereas Bacteroides, Lactobacillus, Parasutterella, and Parabacteroides were decreased compared with controls. Fecal SCFAs were not different between groups, but BPH/5 serum acetic and butyric acids were decreased, whereas isobutyric and isovaleric acids were increased specifically in pregnancy. BPH/5 pregnant colons had decreased expression of free fatty acid receptor, GPR41. In conclusion, the BPH/5 maternal fecal microbiome demonstrates microbial dysbiosis characterized by community structure and diversity changes before and after the onset of pregnancy. Gut dysbiosis may be a key mechanism linking SCFA signaling and obesity to the BPH/5 PE-like phenotype.NEW & NOTEWORTHY This is the first time the pregnant fecal microbiome has been identified in the BPH/5 spontaneous mouse model of superimposed PE. Community composition changed with the onset of pregnancy in this model. BPH/5 showed an altered colonic signaling with decreased GPR41 expression, suggesting that gut dysbiosis may link SCFA signaling to the PE phenotype. This data highlights the importance of the maternal obesogenic gut microbiome in pregnancy.