[Spatiotemporal Characterization and Driving Factors of Fine Particulate Matter and Its Chemical Components in the Huaihe River Basin].

According to the data sets of fine particulate matter （PM2.5） and its components in 35 cities in the Huaihe River Basin from 2015 to 2021, the temporal and spatial distribution patterns of pollutants were analyzed. The influence of meteorological factors on PM2.5 concentrations was examined using a random forest model. The original series of PM2.5, sulfate （SO42-）, nitrate （NO3-）, ammonium salt （NH4+）, organic matter （OM）, and black carbon （BC） were rebuilt using KZ （Kolmogorov-Zurbenko） filtering and multiple linear regression （MLR） to quantify the effects of meteorological conditions. The results demonstrated that from 2015 to 2021, the declining rates of PM2.5, SO42-, NO3-, NH4+, OM, and BC in the Huaihe River Basin were 4.71, 0.99, 1.05, 0.77, 1.01, and 0.19 µg·ï¼ˆm3·a）-1, respectively. The high mass concentrations of PM2.5 and its components were concentrated in the central and western regions of the HRB, whereas those in coastal and southern cities were lower. The variance contributions of the short-term, seasonal, and long-term components of PM2.5 to the original PM2.5 sequences in 35 cities were 51.6%, 35.9%, and 7.0%, respectively. The PM2.5 in coastal cities were more affected by the short-term components. The meteorological conditions were unfavorable for PM2.5 reduction in the HRB from 2015 to 2018, whereas the meteorological conditions supported the PM2.5 decrease from 2019 to 2021. From 2015 to 2021, the contribution rates of meteorological conditions to the long-term component reductions of PM2.5, SO42-, NO3-, NH4+, OM, and BC were 28.3%, 29.1%, 31.0%, 29.3%, 27.8%, and 28.6%, respectively. The contribution rates of meteorological conditions to the long-term PM2.5 reduction were 43.4%, 25.6%, 25.5%, and 20.6% in the HRB cities in Anhui, Shandong, Jiangsu, and Henan Provinces, respectively. With the decrease in PM2.5 concentration in the HRB, the sulfur oxidation rate （SOR） increased significantly, while the nitrogen oxide oxidation rate （NOR） changed little.

Dietary supplementary with ellagic acid improves the intestinal barrier function and flora structure of broiler chicken challenged with E. coli K88.

Ellagic acid (EA) contributes to the immunity and anti-oxidant function of body, whereas there are few reports about its effect on the intestinal health and growth performance of broiler chickens. Hence, the present study was arranged to investigate the effect of dietary supplementary with EA on the intestinal barrier function and flora structure of broiler chickens challenged with Escherichia coli K88 (E. coli K88). A total of 216 healthy 1-day-old, Ross 308 broilers with uniform weight were randomly assigned into three treatment groups, six replicates in each group and twelve birds in each replicate. Broilers in the control (CTR) group and E. coli K88 infected group (ETEC) were fed with the basic diet, and 200 mg/kg EA was supplemented into the diet of the E. coli K88 infected group treated with EA (EAETEC). The animal trial had lasted for 42 days, and the outcomes showed that the ADG and ADFI during the animal trial, the jejunal villi height (VH) and the ratio of VH to crypt depth (CD) tended to be decreased with E. coli K88 treated (P< 0.05). Additionally, the level of serum diamine oxidase (DAO) and intestinal malondialdehyde (MDA) were elevated, the activity of intestinal total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px), the mRNA levels in jejunal claudin-1 and occludin were down-regulated with E. coli K88 treated as well as the transcription levels of ileal Mucin-2, aquaporin-3 (AQP-3) and Na+/H+ exchanger proteins-3 (NHE-3) (P< 0.05). In addition, E. coli K88 down-regulated the α-diversity index of cecal flora, the ratio of Bacteroidota to Firmicutes and the relative abundance of Barnesiella were up-regulated and it of Alistipes was descended with E. coli K88 treated (P< 0.05). Beyond that, the content of propionic acid in the cecal chyme was decreased and the amino acid metabolic pathways were inhibited with E. coli K88 challenged (P< 0.05). Additionally, there was a significant positive correlation between the relative abundance of Alistipes and the levels of butyric acid in the caecal chyme and the activity of GSH-Px in the intestine (P< 0.05). Interestingly, dietary supplementary with EA could reshape the intestinal flora structure and alleviate the above negative effects of E. coli K88 on broiler chickens. In conclusion, dietary supplementary with ellagic acid improved the intestinal barrier function and flora structure of broiler chickens challenged with E. coli K88.

Unraveling the role of HIF and epigenetic regulation in pulmonary arterial hypertension: implications for clinical research and its therapeutic approach.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling with high pulmonary pressure, which ultimately leads to right heart failure and premature death. Emerging evidence suggests that both hypoxia and epigenetics play a pivotal role in the pathogenesis of PAH development. In this review article, we summarize the current developments in regulation of hypoxia inducible factor (HIF) isoforms in PAH vascular remodeling and the development of suitable animal models for discovery and testing of HIF pathway-targeting PAH therapeutics. In addition, we also discuss the epigenetic regulation of HIF-dependent isoforms in PAH and its therapeutic potential from a new perspective which highlights the importance of HIF isoform-specific targeting as a novel salutary strategy for PAH treatment.

Genetically predicted 486 blood metabolites in relation to risk of esophageal cancer: a Mendelian randomization study.

Background and Objective: Enhancing therapy choices for varying stages of esophageal cancer and improving patient survival depend on timely and precise diagnosis. Blood metabolites may play a role in either causing or preventing esophageal cancer, but further research is needed to determine whether blood metabolites constitute a genetic risk factor for the disease. In order to tackle these problems, we evaluated the causal association between esophageal cancer and 486 blood metabolites that functioned as genetic proxies using a two-sample Mendelian randomization (MR) study. Methods: We utilized two-sample MR analyses to evaluate the causal links between blood metabolites and esophageal cancer. For the exposure, we used a genome-wide association study (GWAS) of 486 metabolites, and a GWAS study on esophageal cancer from Sakaue et al. was used for preliminary analyses. Causal analyses employed randomized inverse variance weighted (IVW) as the main method, supplemented by MR-Egger and weighted median (WM) analyses. Sensitivity analyses included the MR-Egger intercept test, Cochran Q test, MR-PRESSO, and leave-one-out analysis. Additionally, independent esophageal cancer GWAS data were utilized for replication and meta-analysis. FDR correction was applied to discern features with causal relationships. For conclusive metabolite identification, we conducted Steiger tests, linkage disequilibrium score regression, and colocalization analyses. Moreover, we utilized the program MetaboAnalyst 5.0 to analyze metabolic pathways. Results: This study found an important association between esophageal cancer and three metabolites: 1-linoleoylglycerophosphoethanolamine* [odds ratio (OR) = 3.21, 95% confidence interval (CI): 1.42-7.26, p < 0.01], pyroglutamine* (OR = 1.92, 95% CI: 1.17-3.17, p < 0.01), and laurate (12:0) (OR = 3.06, 95% CI: 1.38-6.78, p < 0.01). Conclusion: This study establishes a causal link between three defined blood metabolites and esophageal cancer, offering fresh insights into its pathogenesis.

Dual trigger or hCG alone: A retrospective analysis on patients with diminished ovarian reserve under in vitro fertilization and embryo transfer (IVF-ET) treatment.

OBJECTIVE: With remarkable deficiency in both oocyte stock and competence, the prognosis of IVF-ET in diminished ovarian reserve (DOR) is obstinately poor, underscoring warranted optimization to current procedures. We compared the efficacy of dual-trigger (hCG plus GnRH-a) and hCG alone on the outcomes for DOR patients. STUDY DESIGN: A total of 381 couples and 857 controlled ovarian stimulation (COS) cycles, and 222 couples and 366 frozen embryo transfer (FET) ones were included. The intermediate outcomes during oocyte retrieval and in vitro culture were compared based on COS dataset, while outcomes after embryo transfer analyzed based on FET dataset. The marginal effect of all study factors and covariates were evaluated with a cluster-weighted GEE model. RESULTS AND CONCLUSION: Neither the intermediate nor implantation outcomes were improved by dual-trigger. The OR values were 1.08 (95 % CI: 0.41-2.78) for retrieval cancellation, 1.33 (95 % CI: 0.89-2.00) for oocyte harvest, 1.04(95 %CI: 0.94-1.15) for viable embryo and 1.03(95 %CI: 0.88-1.19) for top-quality embryo. Similarly, the ORs were 0.90 (95 %CI: 0.62-1.30) for implantation and 0.97 (95 %CI: 0.56-1.69) for clinical pregnancy. This equivalence remained unchanged after adjusting for the covariates such as age, BMI, controlled ovarian stimulation protocols, etc. Thus, dual-trigger cannot provide significant advantage over hCG in related to immediate or clinical outcomes of IVF-ET treatments in DOR patients.

Screening and analysis of GULP1 downstream target genes based on transcriptomic sequencing.

GULP1 is an engulfment adaptor protein containing a phosphotyrosine-binding (PTB) domain, and existing studies have shown that it can promote glucose uptake in 3T3-L1 adipocytes. To further explore key metabolically related differential genes downstream of GULP1, this study conducted transcriptome analysis on adipocytes and skeletal muscle cells overexpressing GULP1. Subsequently, abnormally expressed genes were subjected to bioinformatic analysis, and real-time fluorescent quantitative PCR (qRT-PCR) was used for mutual validation with transcriptome sequencing. The results indicated that, with a threshold of P < 0.05 and |Log2FoldChange| ≥ 1 for screening differentially expressed genes, compared with control cells, there were 278 upregulated and 263 downregulated genes in adipocytes overexpressing GULP1. Metabolism-related GO (Gene Ontology) terms included cholesterol biosynthetic process, cholesterol metabolic process, response to lipopolysaccharide, lipid metabolic process, etc. A total of 52 metabolically related differentially expressed genes were enriched in 10 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, with lipid metabolism being highly enriched. In skeletal muscle cells overexpressing GULP1, there were 280 upregulated and 302 downregulated genes, with metabolism-related GO terms including hormone metabolic process, response to lipopolysaccharide, one-carbon metabolic process, etc. A total of 86 metabolically related differentially expressed genes were enriched in 10 KEGG pathways, with amino acid metabolism, lipid metabolism, and carbohydrate metabolism being highly enriched. GULP1's biological functions are extensive, including lipid metabolism and oncology. This study, through transcriptomics and bioinformatic analysis, identified key metabolically related differential genes downstream of GULP1, obtained metabolically related differential genes and signaling pathways after GULP1 overexpression, providing important theoretical basis for future research on GULP1 downstream target genes.

Dietary supplementation with N-acetylcysteine confers a protective effect on muscle and liver in lipopolysaccharide-challenged piglets.

N-acetylcysteine (NAC) is a well-established antioxidant that offers exciting opportunities for intestinal health in weaned piglets, while the effects of NAC on muscle and liver has not been fully characterized. Therefore, the present study was performed to investigate the effects of dietary supplementation with NAC on muscle and liver in weaned piglets challenged with lipopolysaccharide (LPS). Twenty-four piglets (24-day-old) were randomly assigned to three treatment groups, the piglets in the control (CTR) and LPS- challenged (LPS) groups were fed the basal diet and those in the LPS+ NAC group was fed the basal diet supplemented with 500 mg/kg NAC. The animal trial lasted for 21 days. At the end of the trial, piglets in the LPS and LPS+ NAC groups were injected intraperitoneally with LPS (100 µg/kg body weight) and piglets in the CTR group were administrated with an equal volume of normal saline. 3 h later, the blood was collected and tissue samples were obtained after 6 h of LPS or normal saline treatment. The results showed that the level of IL-1ß, and the mRNA levels of C-X-C motif chemokine receptor 3 (CXCR3) and interferon-γ (IFN-γ) in the liver were up-regulated, and the mRNA levels of insulin-like growth factor 1 (IGF-1), total glutathione (T-GSH), and the ratio of total protein to DNA in the liver were decreased under LPS challenge (P < 0.05). At the same time, LPS increased the level of H2O2 and decreased the content of T-GSH and DNA in the longissimus dorsi and gastrocnemius muscles (P < 0.05). In addition, the percentage of monocytes and the level of epidermal growth factor (EGF) were down-regulated in the LPS treatment (P < 0.05). Interestingly, dietary NAC supplementation reversed the above changes induced by LPS (P < 0.05). Furthermore, NAC might alleviate the muscle and liver injury in LPS-challenged piglets by regulating the expression of genes related to the type I interferon signaling pathway, as well as hypoxia inducible factor 1 (HIF1) and nuclear factor erythroid-2 related factor 2 (Nrf-2). Our findings suggested that dietary supplementation with NAC could benefit the health of muscle and liver in LPS-challenged weaned piglets.

Poultry Nutrition: Achievement, Challenge, and Strategy.

Poultry, a vital economic animal, provide a high-quality protein source for human nutrition. Over the past decade, the poultry industry has witnessed substantial achievements in breeding, precision feeding, and welfare farming. However, there are still many challenges restricting the sustainable development of the poultry industry. First, overly focused breeding strategies on production performance have been shown to induce metabolic diseases in poultry. Second, a lack of robust methods for assessing the nutritional requirements poses a challenge to the practical implementation of precision feeding. Third, antibiotic alternatives and feed safety management remain pressing concerns within the poultry industry. Lastly, environmental pollution and inadequate welfare management in farming have a negative effect on poultry health. Despite numerous proposed strategies and innovative approaches, each faces its own set of strengths and limitations. In this review, we aim to provide a comprehensive understanding of the poultry industry over the past decade, by examining its achievements, challenges, and strategies, to guide its future direction.

Long-Term Administration of Nicotinamide Mononucleotide Mitigates High-Fat-Diet-Induced Physiological Decline in Aging Mice.

BACKGROUND: Nicotinamide adenine dinucleotide (NAD+) concentrations decline with age, and boosting it can improve multi-organ functions and lifespan. OBJECTIVES: Nicotinamide mononucleotide (NMN) is a natural NAD+ precursor with the ability to enhance NAD+ biosynthesis. Numerous studies have shown that a high-fat diet (HFD) can accelerate the process of aging and many diseases. We hypothesized that long-term administration of NMN could exert protective effects on adipose, muscle, and kidney tissues in mice on an HFD act by affecting the autophagic pathway. METHODS: Mice at 14 mo of age were fed an HFD, and NMN was added to their drinking water at a dose of 400 mg/kg for 7 mo. The locomotor ability of the mice was assessed by behavioral experiments such as grip test, wire hang test, rotarod, and beam-walking test. At the end of the behavioral experiments, the pathological changes of each peripheral organ and the expression of autophagy-related proteins, as well as the markers of the senescence and inflammaging were analyzed by pathological staining, immunohistochemical staining, and western blotting, respectively. RESULTS: We found that NMN supplementation increased NAD+ concentrations and ultimately attenuated age- and diet-related physiological decline in mice. NMN inhibited HFD-induced obesity, promoted physical activity, improved glucose and lipid metabolism, improved skeletal muscle function and renal damage, as well as mitigated the senescence and inflammaging as demonstrated by p16, interleukin 1ß, and tumor necrosis factor α concentrations. In addition, the present study further emphasizes the potential mechanisms underlying the bidirectional relationship between NAD+ and autophagy. We detected changes in autophagy concentrations in various tissue organs, and NMN may play a protective role by inhibiting excessive autophagy induced by HFD. CONCLUSIONS: Our findings demonstrated that NMN administration attenuated HFD-induced metabolic disorders and physiological decline in aging mice.

Pin1: Advances in pancreatic cancer therapeutic potential and inhibitors research.

The peptidyl-prolyl cis/trans isomerase NIMA-interaction 1 (Pin1) catalyzes the transition of the proline ring from the cis to trans conformation, resulting in conformational and functional changes in proteins that are regulated by proline-guided serine/threonine phosphorylation. In recent years, Pin1 has emerged as a novel molecular target for the diagnosis and treatment of various malignant tumors. Notably, it has been found that Pin1 is highly expressed in pancreatic cancer. This article focuses on the mechanisms by which Pin1 orchestrates multiple oncogenic functions in the development of pancreatic cancer. By exploring the intricate interactions between Pin1 and the pancreatic tumor microenvironment, we provide an overview of Pin1's role in modifying glycolytic metabolism, redox balance, and the hypoxic microenvironment of pancreatic cancer. Furthermore, we summarize the potential anticancer effects of Pin1 inhibitors, aiming to elucidate Pin1's promise as a potential anticancer agent, particularly in the context of pancreatic cancer.

Unveiling senescence-associated secretory phenotype in epidermal aging: insights from reversibly immortalized keratinocytes.

Aging of epidermal keratinocytes profoundly impacts skin health, contributing to changes in appearance, barrier function, and susceptibility to diseases. Despite its significance, the molecular mechanisms underlying epidermal aging remain elusive. In this study, a reversible immortalized cell line was established by expressing SV40T in keratinocytes using the Tet-Off lentiviral system. Inducing a senescent phenotype by terminating SV40T expression revealed a significant reduction in mitotic ability, as well as characteristics of cellular aging. RNA sequencing analysis revealed alterations in gene expression and signaling pathways including DNA repair dysfunction, notably senescence-associated secretory phenotype (SASP)-related genes, such as MMP1, SERPINB2 and VEGFA. Our study provides insights into the molecular mechanisms of epidermal aging, offering potential therapeutic targets and highlighting the role of SASP in the aging process.

A p21 Reporter iPSC Line for Evaluating CRISPR-Cas9 and Vector-Induced Stress Responses.

CRISPR-Cas9 editing triggers activation of the TP53-p21 pathway, but the impacts of different editing components and delivery methods have not been fully explored. In this study, we introduce a p21-mNeonGreen reporter iPSC line to monitor TP53-p21 pathway activation. This reporter enables dynamic tracking of p21 expression via flow cytometry, revealing a strong correlation between p21 expression and indel frequencies, and highlighting its utility in guide RNA screening. Our findings show that p21 activation is significantly more pronounced with double-stranded oligodeoxynucleotides (ODNs) or adeno-associated viral vectors (AAVs) compared to their single-stranded counterparts. Lentiviral vectors (LVs) and integrase-defective lentiviral vectors (IDLVs) induce notably lower p21 expression than AAVs, suggesting their suitability for gene therapy in sensitive cells such as hematopoietic stem cells or immune cells. Additionally, specific viral promoters like SFFV significantly amplify p21 activation, emphasizing the critical role of promoter selection in vector development. Thus, the p21-mNeonGreen reporter iPSC line is a valuable tool for assessing the potential adverse effects of gene editing methodologies and vectors.

A convenient research strategy for functional verification of epigenetic regulators during spermatogenesis.

Spermatogenesis is a fundamental process that requires a tightly controlled epigenetic event in spermatogonial stem cells (SSCs). The mechanisms underlying the transition from SSCs to sperm are largely unknown. Most studies utilize gene knockout mice to explain the mechanisms. However, the production of genetically engineered mice is costly and time-consuming. In this study, we presented a convenient research strategy using an RNA interference (RNAi) and testicular transplantation approach. Histone H3 lysine 9 (H3K9) methylation was dynamically regulated during spermatogenesis. As Jumonji domain-containing protein 1A (JMJD1A) and Jumonji domain-containing protein 2C (JMJD2C) demethylases catalyze histone H3 lysine 9 dimethylation (H3K9me2), we firstly analyzed the expression profile of the two demethylases and then investigated their function. Using the convenient research strategy, we showed that normal spermatogenesis is disrupted due to the downregulated expression of both demethylases. These results suggest that this strategy might be a simple and alternative approach for analyzing spermatogenesis relative to the gene knockout mice strategy.

Exposure to greenspaces sourced soils improves mice gut microbiota.

Greenspaces are important components of our living environment and have been linked to various human health. However, the mechanisms underlying the linkages remain unclear. Enriching microbiota has emerged as a novel mechanism, but the corresponding evidence is still limited. We collected soil samples from forest land, grassland, and barren land in Zunyi City, southwestern China and prepared soil solutions. A total of 40 BALB/c mice were evenly divided into normal control group, model control group, forest soil group, grassland soil group, and barren land soil group. After establishing the pseudo germ-free mouse model, different soil solutions were administered through gavage, lasting for seven weeks. Fecal samples were collected and a 16S rRNA high-throughput sequencing analysis was performed. Then, alpha- and beta-diversity were calculated and employed to estimate the effects of soil exposures on mice gut microbial diversity and composition. Further, Linear Discriminant Analysis Effect Size (LEfSe) analysis was carried out to evaluate the effects of soil exposures on gut microbiota specific genera abundances and functional pathways. Compared to mice exposed to barren land soils, those exposed to soils sourced from forest land showed an increase of 0.43 and 70.63 units in the Shannon index and the Observed ASVs, respectively. In addition, exposure to soils sourced from forest land and grassland resulted in healthier changes (i.e., more short-chain fatty acids (SCFAs)-producing bacteria) in gut microbiota than those from barren land. Furthermore, mice exposed to forest soil and grassland soil showed enrichment in 5 and 3 pathways (e.g., butanoate metabolism) compared to those exposed to barren land soil, respectively. In conclusion, exposure to various greenspaces soils may modify the gut microbial communities of mice, potentially fostering a more beneficial microbiota profile. Further better-designed studies are needed to validate the current findings and to explore the effects of greenspace related gut microbiota on human health.

Diversity and Activity of Soil N2O-Reducing Bacteria Shaped by Urbanization.

Nitrous oxide (N2O) is a potent greenhouse gas with various production pathways. N2O reductase (N2OR) is the primary N2O sink, but the distribution of its gene clades, typically nosZI and atypically nosZII, along urbanization gradients remains poorly understood. Here we sampled soils from forests, parks, and farmland across eight provinces in eastern China, using high-throughput sequencing to distinguish between two N2O-reducing bacteria clades. A deterministic process mainly determined assemblies of the nosZI communities. Homogeneous selection drove nosZI deterministic processes, and both homogeneous and heterogeneous selection influenced nosZII. This suggests nosZII is more sensitive to environmental changes than nosZI, with significant changes in community structure over time or space. Ecosystems with stronger anthropogenic disturbance, such as urban areas, provide diverse ecological niches for N2O-reducing bacteria (especially nosZII) to adapt to environmental fluctuations. Structural equation modeling (SEM) and correlation analyses revealed that pH significantly influences the community composition of both N2O-reducing bacteria clades. This study underscores urbanization's impact on N2O-reducing bacteria in urban soils, highlighting the importance of nosZII and survival strategies. It offers novel insights into the role of atypical denitrifiers among N2O-reducing bacteria, underscoring their potential ecological importance in mitigating N2O emissions from urban soils.

A New Orthonairovirus Associated with Human Febrile Illness.

BACKGROUND: In June 2019, a patient presented with persistent fever and multiple organ dysfunction after a tick bite at a wetland park in Inner Mongolia. Next-generation sequencing in this patient revealed an infection with a previously unknown orthonairovirus, which we designated Wetland virus (WELV). METHODS: We conducted active hospital-based surveillance to determine the prevalence of WELV infection among febrile patients with a history of tick bites. Epidemiologic investigation was performed. The virus was isolated, and its infectivity and pathogenicity were investigated in animal models. RESULTS: WELV is a member of the orthonairovirus genus in the Nairoviridae family and is most closely related to the tickborne Hazara orthonairovirus genogroup. Acute WELV infection was identified in 17 patients from Inner Mongolia, Heilongjiang, Jilin, and Liaoning, China, by means of reverse-transcriptase-polymerase-chain-reaction assay. These patients presented with nonspecific symptoms, including fever, dizziness, headache, malaise, myalgia, arthritis, and back pain and less frequently with petechiae and localized lymphadenopathy. One patient had neurologic symptoms. Common laboratory findings were leukopenia, thrombocytopenia, and elevated d-dimer and lactate dehydrogenase levels. Serologic assessment of convalescent-stage samples obtained from 8 patients showed WELV-specific antibody titers that were 4 times as high as those in acute-phase samples. WELV RNA was detected in five tick species and in sheep, horses, pigs, and Transbaikal zokors (Myospalax psilurus) sampled in northeastern China. The virus that was isolated from the index patient and ticks showed cytopathic effects in human umbilical-vein endothelial cells. Intraperitoneal injection of the virus resulted in lethal infections in BALB/c, C57BL/6, and Kunming mice. The Haemaphysalis concinna tick is a possible vector that can transovarially transmit WELV. CONCLUSIONS: A newly discovered orthonairovirus was identified and shown to be associated with human febrile illnesses in northeastern China. (Funded by the National Natural Science Foundation of China and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences.).

Mechanisms Underlying the Therapeutic Effects of Nicotinamide Mononucleotide in Treating High-fat Diet-induced Hypertrophic Cardiomyopathy based on GEO Datasets, Network Pharmacology, and Molecular Docking.

BACKGROUND: The beneficial effects of nicotinamide mononucleotide (NMN) on heart disease have been reported, but the effects of NMN on high-fat diet-induced hypertrophic cardiomyopathy (HCM) and its mechanisms of action are unclear. In this study, we systematically explored the effects and mechanism of action of NMN in HCM using network pharmacology and molecular docking. METHODS: Active targets of NMN were obtained from SWISS, CNKI, PubMed, DrugBank, BingingDB, and ZINC databases. HCM-related targets were retrieved from GEO datasets combined with GeneCards, OMIM, PharmGKB, and DisGeNET databases. A Protein-protein Interaction (PPI) network was built to screen the core targets. DAVID was used for GO and KEGG pathway enrichment analyses. The tissue and organ distribution of targets was evaluated. Interactions between potential targets and active compounds were assessed by molecular docking. A molecular dynamics simulation was conducted for the optimal core protein-compound complexes obtained by molecular docking. RESULTS: In total, 265 active targets of NMN and 3918 potential targets of HCM were identified. A topological analysis of the PPI network revealed 10 core targets. GO and KEGG pathway enrichment analyses indicated that the effects of NMN were mediated by genes related to inflammation, apoptosis, and oxidative stress, as well as the FOXO and PI3K-Akt signaling pathways. Molecular docking and molecular dynamics simulations revealed good binding ability between the active compounds and screened targets. CONCLUSION: The possible targets and pathways of NMN in the treatment of HCM have been successfully predicted by this investigation. It provides a novel approach for further investigation into the molecular processes of NMN in HCM treatment.

Depressive symptom mediates the association between the number of chronic diseases and cognitive impairment: a multi-center cross-sectional study based on community older adults.

Objective: The purpose of this study was to understand the relationship between the multiple chronic conditions (MCC), mental health and cognitive function of older adults in the community, and to propose a hypothesis that depressive symptom mediate the number of chronic diseases and cognitive impairment in older adults. Method: Participants aged 65 years and older from 35 communities in 14 cities in Guangxi, China were recruited. The residents' depressive symptom (PHQ-9) and cognitive status (AD-8) were evaluated, Chi-square test was used to explore the effects of different socio-demographic characteristics on depressive symptom and cognitive impairment. Pearson correlation analysis and the process model 4 were used to explore the relationship between the number of chronic diseases, depressive symptom and cognitive impairment. Result: A total of 11,582 older adults were included in our analysis. The rate of MCC reaching 26.53%. Hypertension combined with diabetes accounts for the highest proportion of two chronic diseases (13.2%). Among the combination of three chronic diseases, the highest incidence of coexisting hypertension combined with cervical/lumbar spondylosis, and rheumatoid arthritis (7.1%). In this study, depression symptoms accounted for 12.9% of older adults aged 65 and above, and cognitive impairment accounted for 27.4%. Female, older age, reside in urban areas, lower educational levels, no spouse, live alone, and MCC were risk factors for depressive symptom and cognitive impairment in older adults (P<0.05). Depressive symptom had a mediating effect in the number of chronic diseases and cognitive impairment, and the mediating effect (1.109) accounted for 44.13% of the total effect (0.247). Conclusion: The mental health of the older adult needs to be taken seriously, and improving depressive symptom can reduce the occurrence of cognitive impairment in older patients with MCC to a certain extent.

Intestinal microbiota by angiotensin receptor blocker therapy exerts protective effects against hypertensive damages.

Dysbiosis of the gut microbiota has been implicated in hypertension, and drug-host-microbiome interactions have drawn considerable attention. However, the influence of angiotensin receptor blocker (ARB)-shaped gut microbiota on the host is not fully understood. In this work, we assessed the alterations of blood pressure (BP), vasculatures, and intestines following ARB-modified gut microbiome treatment and evaluated the changes in the intestinal transcriptome and serum metabolome in hypertensive rats. Hypertensive patients with well-controlled BP under ARB therapy were recruited as human donors, spontaneously hypertensive rats (SHRs) receiving normal saline or valsartan were considered animal donors, and SHRs were regarded as recipients. Histological and immunofluorescence staining was used to assess the aorta and small intestine, and 16S rRNA amplicon sequencing was performed to examine gut bacteria. Transcriptome and metabonomic analyses were conducted to determine the intestinal transcriptome and serum metabolome, respectively. Notably, ARB-modified fecal microbiota transplantation (FMT), results in marked decreases in systolic BP levels, collagen deposition and reactive oxygen species accumulation in the vasculature, and alleviated intestinal structure impairments in SHRs. These changes were linked with the reconstruction of the gut microbiota in SHR recipients post-FMT, especially with a decreased abundance of Lactobacillus, Aggregatibacter, and Desulfovibrio. Moreover, ARB-treated microbes contributed to increased intestinal Ciart, Per1, Per2, Per3, and Cipc gene levels and decreased Nfil3 and Arntl expression were detected in response to ARB-treated microbes. More importantly, circulating metabolites were dramatically reduced in ARB-FMT rats, including 6beta-Hydroxytestosterone and Thromboxane B2. In conclusion, ARB-modified gut microbiota exerts protective roles in vascular remodeling and injury, metabolic abnormality and intestinal dysfunctions, suggesting a pivotal role in mitigating hypertension and providing insights into the cross-talk between antihypertensive medicines and the gut microbiome.

Vagus nerve stimulation (VNS) preventing postoperative cognitive dysfunction (POCD): two potential mechanisms in cognitive function.

Postoperative cognitive dysfunction (POCD) impacts a significant number of patients annually, frequently impairing their cognitive abilities and resulting in unfavorable clinical outcomes. Aimed at addressing cognitive impairment, vagus nerve stimulation (VNS) is a therapeutic approach, which was used in many mental disordered diseases, through the modulation of vagus nerve activity. In POCD model, the enhancement of cognition function provided by VNS was shown, demonstrating VNS effect on cognition in POCD. In the present study, we primarily concentrates on elucidating the role of the VNS improving the cognitive function in POCD, via two potential mechanisms: the inflammatory microenvironment and epigenetics. This study provided a theoretical support for the feasibility that VNS can be a potential method to enhance cognition function in POCD.