Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation.

Higher-order chromosomal organization for transcription regulation is poorly understood in eukaryotes. Using genome-wide Chromatin Interaction Analysis with Paired-End-Tag sequencing (ChIA-PET), we mapped long-range chromatin interactions associated with RNA polymerase II in human cells and uncovered widespread promoter-centered intragenic, extragenic, and intergenic interactions. These interactions further aggregated into higher-order clusters, wherein proximal and distal genes were engaged through promoter-promoter interactions. Most genes with promoter-promoter interactions were active and transcribed cooperatively, and some interacting promoters could influence each other implying combinatorial complexity of transcriptional controls. Comparative analyses of different cell lines showed that cell-specific chromatin interactions could provide structural frameworks for cell-specific transcription, and suggested significant enrichment of enhancer-promoter interactions for cell-specific functions. Furthermore, genetically-identified disease-associated noncoding elements were found to be spatially engaged with corresponding genes through long-range interactions. Overall, our study provides insights into transcription regulation by three-dimensional chromatin interactions for both housekeeping and cell-specific genes in human cells.

Non-additive expression genes play a critical role in leaf vein ratio heterosis in Nicotiana tabacum L.

Heterosis, recognized for improving crop performance, especially in the first filial (F1) generation, remains an area of significant study in the tobacco industry. The low utilization of leaf veins in tobacco contributes to economic inefficiency and resource waste. Despite the positive impacts of heterosis on crop genetics, investigations into leaf-vein ratio heterosis in tobacco have been lacking. Understanding the mechanisms underlying negative heterosis in leaf vein ratio at the molecular level is crucial for advancing low vein ratio leaf breeding research. This study involved 12 hybrid combinations and their parental lines to explore heterosis associated with leaf vein ratios. The hybrids displayed diverse patterns of positive or negative leaf vein ratio heterosis across different developmental stages. Notably, the F1 hybrid (G70 × Qinggeng) consistently exhibited substantial negative heterosis, reaching a maximum of -19.79% 80 days after transplanting. A comparative transcriptome analysis revealed that a significant proportion of differentially expressed genes (DEGs), approximately 39.04% and 23.73%, exhibited dominant and over-dominant expression patterns, respectively. These findings highlight the critical role of non-additive gene expression, particularly the dominance pattern, in governing leaf vein ratio heterosis. The non-additive genes, largely associated with various GO terms such as response to abiotic stimuli, galactose metabolic process, plant-type cell wall organization, auxin-activated signaling pathway, hydrolase activity, and UDP-glycosyltransferase activity, were identified. Furthermore, KEGG enrichment analysis unveiled their involvement in phenylpropanoid biosynthesis, galactose metabolism, plant hormone signal transduction, glutathione metabolism, MAPK signaling pathway, starch, and sucrose metabolism. Among the non-additive genes, we identified some genes related to leaf development, leaf size, leaf senescence, and cell wall extensibility that showed significantly lower expression in F1 than in its parents. These results indicate that the non-additive expression of genes plays a key role in the heterosis of the leaf vein ratio in tobacco. This study marks the first exploration into the molecular mechanisms governing leaf vein ratio heterosis at the transcriptome level. These findings significantly contribute to understanding leaf vein ratios in tobacco breeding strategies.

Serum lipidome reveals lipid metabolic dysregulation in severe fever with thrombocytopenia syndrome.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is a rapidly progressing infectious disease with a high fatality rate caused by a novel bunyavirus (SFTSV). The role of lipids in viral infections is well-documented; however, the specific alterations in lipid metabolism during SFTSV infection remain elusive. This study aims to elucidate the lipid metabolic dysregulations in the early stages of SFTS patients. METHODS: This study prospectively collected peripheral blood sera from 11 critical SFTS patients, 37 mild SFTS patients, and 23 healthy controls during the early stages of infection for lipidomics analysis. A systematic bioinformatics analysis was conducted from three aspects integrating lipid differential expressions, lipid differential correlations, and lipid-clinical indices correlations to reveal the serum lipid metabolic dysregulation in SFTSV-infected individuals. RESULTS: Our findings reveal significant lipid metabolic dysregulation in SFTS patients. Specifically, compared to healthy controls, SFTS patients exhibited three distinct modes of lipid differential expression: increased levels of lipids including phosphatidylserine (PS), hexosylceramide (HexCer), and triglycerides (TG); decreased levels of lipids including lysophosphatidylcholine (LPC), acylcarnitine (AcCa), and cholesterol esters (ChE); and lipids showing "dual changes" including phosphatidylcholine (PC) and phosphatidylethanolamine (PE). Finally, based on lipid metabolic pathways and literature analysis, we systematically elucidated the potential mechanisms underlying lipid metabolic dysregulation in the early stage of SFTSV infection. CONCLUSIONS: Our study presents the first global serum lipidome profile and reveals the lipid metabolic dysregulation patterns in the early stage of SFTSV infection. These findings provide a new basis for the diagnosis, treatment, and further investigation of the disease.

Decoding molecular features of bovine oocyte fate during antral follicle growth via single-cell multi-omics analysis†.

Antral follicle size is a useful predictive marker of the competency of enclosed oocytes for yielding an embryo following in vitro maturation and fertilization. However, the molecular mechanisms underpinning oocyte developmental potential during bovine antral follicle growth are still unclear. Here, we used a modified single-cell multi-omics approach to analyze the transcriptome, DNA methylome, and chromatin accessibility in parallel for oocytes and cumulus cells collected from bovine antral follicles of different sizes. Transcriptome profiling identified three types of oocytes (small, medium, and large) that underwent different developmental trajectories, with large oocytes exhibiting the largest average follicle size and characteristics resembling metaphase-II oocytes. Differential expression analysis and real-time polymerase chain reaction assay showed that most replication-dependent histone genes were highly expressed in large oocytes. The joint analysis of multi-omics data revealed that the transcription of 20 differentially expressed genes in large oocytes was associated with both DNA methylation and chromatin accessibility. In addition, oocyte-cumulus interaction analysis showed that inflammation, DNA damage, and p53 signaling pathways were active in small oocytes, which had the smallest average follicle sizes. We further confirmed that p53 pathway inhibition in the in vitro maturation experiments using oocytes obtained from small antral follicles could improve the quality of oocytes and increased the blastocyte rate after in vitro fertilization and culture. Our work provides new insights into the intricate orchestration of bovine oocyte fate determination during antral folliculogenesis, which is instrumental for optimizing in vitro maturation techniques to optimize oocyte quality.

Association between sarcopenia and new-onset chronic kidney disease among middle-aged and elder adults: findings from the China Health and Retirement Longitudinal Study.

BACKGROUND: Sarcopenia is a senile syndrome of age-related muscle loss. It is thought to affect the development of chronic kidney disease and has a serious impact on the quality of life of the elder adults. Little is known about the association between sarcopenia and new-onset chronic kidney disease in middle-aged and elder adults. Using nationally representative data from the China Health and Retirement Longitudinal Study (CHARLS), we conducted a longitudinal analysis to investigate the association between sarcopenia status and new-onset chronic kidney disease in middle-aged and elder adults in China. METHODS: The study population consisted of 3676 participants aged 45 or older selected from 2011 CHARLS database who had no history of chronic kidney disease at the baseline and completed the follow-up in 2015. A multivariate cox regression model was employed to examine the association between sarcopenia and the incidence of new-onset chronic kidney disease. RESULTS: Followed up for 4 years, a total of 873 (22.5%) new cases of chronic kidney disease occurred. Among them, participants diagnosed with sarcopenia (HR1.45; 95% CI 1.15-1.83) were more likely to develop new-onset chronic kidney disease than those without sarcopenia. Similarly, patients with sarcopenia were more likely to develop new-onset chronic kidney disease than those with possible sarcopenia (HR 1.27; 95%CI 1.00-1.60). Subgroup analysis revealed that elder adults aged between 60 and 75 years old (HR 1.666; 95%CI 1.20-22.28), with hypertension (HR 1.57; 95%CI 1.02-2.40), people with sarcopenia had a significantly higher risk of developing new-onset chronic kidney disease than those without sarcopenia (all P < 0.05). CONCLUSION: Middle-aged and elder adults diagnosed with sarcopenia have a higher risk of developing new-onset chronic kidney disease.

An extra honey polyphenols-rich diet ameliorates the high-fat diet induced chronic kidney disease via modulating gut microbiota in C57BL/6 mice.

Honey is not equivalent to sugar and possess a worldwide health promoting effects such as antioxidant, antibacterial, anti-inflammatory, and hepatoprotective activities. Nevertheless, the potential impacts of honey on high-fat diet induced chronic kidney disease (CKD) and gut microbiota remain to be explored. Herein a high-fat diet was used to induce a mouse CKD model, and analysis was conducted on liver, kidney, spleen indices, tissue morphology, biochemical parameters, CKD related genes, and gut microbial diversity. The results indicated that significant inhibitory effects on renal damage caused by a high-fat diet in mice and improvement in disease symptoms were observed upon honey treatment. Significant changes were also found in serum TC, TG, UA, and BUN as well as the inflammation-related protein TNF-α and IL-6 levels in renal tissues. Gene expression analysis revealed that honey intake closely relates to gut microbiota diversity, which can regulate the composition of gut microbiota, increase microbial diversity, especially Bifidobacteriales and S24_7 and promote the synthesis of short chain fatty acids (SCFAs). In summary, this study suggests that honey has both preventive and therapeutic effects on CKD, which may be associated with its ability to improve microbial composition, increase microbial diversity, and regulate SCFAs levels.

Lignite-steel slag constructed wetland with multi-functionality and effluent reuse.

Constructed wetlands (CWs) are widely used to treat wastewater, while innovative studies are needed to support resource conservation, enhance multi-functionality, and improve the effectiveness of effluent usage. This study assessed the potential of CW's multiple functions by combining low-rank coal (lignite) and industrial waste (steel slag) in different configurations as CW substrates. The results of scanning electron microscope (SEM), energy dispersive spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), and metagenomic sequencing showed that the experimental treatment with lignite and steel slag mixtures had the highest multi-functionality, including efficient nutrient removal and carbon sequestration, as well as hydroponic crop production. Lignite and steel slag were mixed to form lignite-steel slag particle clusters, where Ca2+ dissolved on the surface of steel slag was combined with PO43- in wastewater to form Ca3(PO4)2 precipitation for phosphorus removal. A biofilm grew on the surface of lignite in this cluster, and OH- released from steel slag promoted lignite to release fulvic acid, which provided a carbon source for heterotrophic microorganisms and promoted denitrification. Moreover, fulvic acid enhanced carbon sequestration in CWs by increasing the biomass of Phragmites australis. The effluent from lignite-steel slag CW increased cherry tomato yield and quality while saving N and P applications. These results provide new ideas for the "green" and economic development of CW technology.

Dissecting the molecular features of bovine-arrested eight-cell embryos using single-cell multi-omics sequencing†.

The regulation of mammalian early-embryonic development is a complex, coordinated process that involves widespread transcriptomic and epigenetic remodeling. The main cause of developmental failure in preimplantation embryos after in vitro fertilization is the irreversible arrested-at-cleavage stage. To deepen our understanding of this embryonic block, we profiled a single-cell multi-omics map of copy number variations (CNVs), the transcriptome, the DNA methylome, and the chromatin state of bovine eight-cell embryos with a two-cell fate that either arrested or developed into blastocysts. To do this, we sequenced a biopsied blastomere and tracked the developmental potential of the remaining cells. Aneuploid embryos inferred by CNVs from DNA- and RNA-library data tended to lose their developmental potency. Analysis of distinct genomic regions of DNA methylation and chromatin accessibility revealed that enrichment of gene function and signaling pathways, such as the MAPK signaling pathway, was altered in arrested euploid eight-cell embryos compared with blastocyst-developed euploid eight-cell embryos. Moreover, the RNA expression and chromatin accessibility of embryonic genome activation-associated genes were lower in arrested euploid embryos than in blastocyst-developed embryos. Taken together, our results indicate that the developmental block of eight-cell embryos can be caused by multiple molecular layers, including CNVs, abnormality of DNA methylation and chromatin accessibility, and insufficient expression of embryonic genome activation-associated genes. Our integrated and comprehensive data set provides a valuable resource to further dissect the exact mechanisms underlying the arrest of bovine eight-cell embryos in vitro.

Dynamic regulation of HIF-1 signaling in the rhesus monkey heart after ischemic injury.

BACKGROUND: Hypoxia inducible factor-1 (HIF-1) plays a key role in modulating post-infarct healing after myocardial ischemic injury through transcriptional regulation of hundreds of genes involved in diverse cardiac remodeling processes. However, the dynamic changes in HIF-1 target gene expression in the ischemic heart after myocardial infarction (MI) have not been well characterized. METHODS: We employed a rhesus monkey model of MI induced by left anterior descending artery ligation and examined the expression pattern of HIF-1 target genes in the ischemic heart at 1, 7, and 28 days after injury by bulk RNA-sequencing analysis. RESULTS: Myocardial transcriptomic analysis demonstrated a temporal-specific regulation of genes associated with the inflammatory response, cell proliferation, fibrosis and mitochondrial metabolism during the pathological progression of MI. HIF-1 target genes involved in processes related to glycolysis, angiogenesis, and extracellular matrix (ECM) remodeling also exhibited distinct expression patterns during MI progression. Copper concentrations were gradually decreased in the heart after ischemic injury, which was positively correlated with the expression of HIF-1-mediated angiogenic and glycolytic genes but negatively correlated with the expression of HIF-1-mediated ECM remodeling genes. Moreover, genes related to intracellular copper trafficking and storage were suppressed along with the loss of myocardial copper in the ischemic heart. CONCLUSIONS: This study demonstrated a dynamic, functional-specific regulation of HIF-1 target gene expression during the progression of MI. The fine-tuning of HIF-1 signaling in the ischemic heart may be relate to the alteration in myocardial copper homeostasis. These findings provide transcriptomic insights into the distinct roles of HIF-1 signaling in the heart after ischemic injury, which will help determine the beneficial cutoff point for HIF-1 targeted therapy in ischemic heart diseases.

Construction and validation of an early warning model for predicting the acute kidney injury in elderly patients with sepsis.

BACKGROUND: Sepsis-induced acute kidney injury (S-AKI) is a significant complication and is associated with an increased risk of mortality, especially in elderly patients with sepsis. However, there are no reliable and robust predictive models to identify high-risk patients likely to develop S-AKI. We aimed to develop a nomogram to predict S-AKI in elderly sepsis patients and help physicians make personalized management within 24 h of admission. METHODS: A total of 849 elderly sepsis patients from the First Affiliated Hospital of Xi'an Jiaotong University were identified and randomly divided into a training set (75%, n = 637) and a validation set (25%, n = 212). Univariate and multivariate logistic regression analyses were performed to identify the independent predictors of S-AKI. The corresponding nomogram was constructed based on those predictors. The calibration curve, receiver operating characteristics (ROC)curve, and decision curve analysis were performed to evaluate the nomogram. The secondary outcome was 30-day mortality and major adverse kidney events within 30 days (MAKE30). MAKE30 were a composite of death, new renal replacement therapy (RRT), or persistent renal dysfunction (PRD). RESULTS: The independent predictors for nomogram construction were mean arterial pressure (MAP), serum procalcitonin (PCT), and platelet (PLT), prothrombin time activity (PTA), albumin globulin ratio (AGR), and creatinine (Cr). The predictive model had satisfactory discrimination with an area under the curve (AUC) of 0.852-0.858 in the training and validation cohorts, respectively. The nomogram showed good calibration and clinical application according to the calibration curve and decision curve analysis. Furthermore, the prediction model had perfect predictive power for predicting 30-day mortality (AUC = 0.813) and MAKE30 (AUC = 0.823) in elderly sepsis patients. CONCLUSION: The proposed nomogram can quickly and effectively predict S-AKI risk in elderly sepsis patients within 24 h after admission, providing information for clinicians to make personalized interventions.

MTA1 promotes tumorigenesis and development of esophageal squamous cell carcinoma via activating the MEK/ERK/p90RSK signaling pathway.

Metastasis-associated protein 1 (MTA1) is upregulated in multiple malignancies and promotes cancer proliferation and metastasis, but whether and how MTA1 promotes esophageal squamous cell carcinoma (ESCC) tumorigenesis remain unanswered. Here, we established an ESCC model in MTA1 transgenic mice induced by the chemical carcinogen 4-nitroquinoline 1-oxide (4-NQO) and found that MTA1 promotes ESCC tumorigenesis in mice. MTA1 overexpression was observed in ESCC cells and clinical ESCC samples. Overexpressed MTA1 increased colony formation and the invasiveness and migration of ESCC cells, whereas knock down of MTA1 in ESCC cells significantly decreased colony formation, invasion and migration in vitro and inhibited the growth of xenograft tumors in vivo. RNA sequencing (RNA-seq) analysis combined with western blot assays revealed that MTA1 promotes carcinogenesis by enhancing MEK/ERK/p90RSK signaling. The phosphorylation of MEK, ERK and their downstream target p90RSK was significantly decreased after MTA1 knockdown in ESCC cells and was increased in MTA1-overexpressing cells. Moreover, colony formation, invasion and migration potential were dramatically suppressed when cells overexpressing MTA1 were treated with MEK (PD0325901) or ERK (SCH772948) inhibitors. In conclusion, MTA1 plays a pivotal oncogenic role in ESCC tumorigenesis and development through activating the MEK/ERK/p90RSK pathway.

Methane attenuates lung ischemia-reperfusion injury via regulating PI3K-AKT-NFκB signaling pathway.

Objective: This study aims to investigate the protective effects and possible mechanism of methane-rich saline (MS) on lung ischemia-reperfusion injury (LIRI) in rats.Methods: MS (2 ml/kg and 20 ml/kg) was injected intraperitoneally in rats after LIRI. Lung injury was assayed by Hematoxylin-eosin (HE) staining and wet-to-dry weight (W/D). The cells in the bronchoalveolar lavage fluid (BALF) and blood were counted. Oxidative stress was examined by the level of malondialdehyde (MDA) and superoxide dismutase (SOD). Inflammatory factors including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-10 (IL-10) were determined by ELISA. Lung tissue apoptosis was detected by TUNEL staining and western blotting of Bcl-2, Bax, and caspase-3. The expressions of IкBα, p38, PI3K, AKT, and NF-κB were analyzed with Western blotting.Results: MS effectively decreased the lung W/D ratio as well as the lung pathological damage and reduced the localized infiltration of inflammatory cells. Methane suppressed the expression of the PI3K-AKT-NFκB signaling pathway during the lung IR injury, which inhibited the activation of NF-kB and decreased the level of inflammatory cytokines, such as TNF-α, IL-1ß, and IL-10. Moreover, we found that MS treatment relieved reactive oxygen species (ROS) damage by downregulating MDA and upregulating SOD. MS treatment also regulated apoptosis-related proteins, such as Bcl-2, Bax, and caspase-3.Conclusions: MS could repair LIRI and reduce the release of oxidative stress, inflammatory cytokines, and cell apoptosis via the PI3K-AKT-NFκB signaling pathway, which may provide a novel and promising strategy for the treatment of LIRI.

Methane Alleviates Inflammation and Apoptosis of Dextran Sulfate Sodium-Induced Inflammatory Bowel Diseases by Inhibiting Toll-Like Receptor 4 (TLR4)/Myeloid Differentiation Factor 88 (MyD88)/Nuclear Translocation of Nuclear Factor-κB (NF-κB) and Endoplasmic Reticulum Stress Pathways in Mice.

BACKGROUND Inflammatory bowel diseases (IBDs) are chronic idiopathic diseases with increased occurrence and recurrence rates. The aim of this study was to explore whether methane-rich saline (MRS) would be beneficial to IBD. MATERIAL AND METHODS Dextran sulfate sodium (DSS) was utilized to establish an IBD model. Male C57BL/6J mice were randomly grouped as follows: the control group, the DSS+NS group, the DSS+5-ASA group, the DSS+MRS (1) and DSS+MRS (10) groups. Seven days after model induction, blood and colon tissues were collected to assess the treatment effects. RESULTS The DSS+MRS (10) group showed obviously reduced weight loss, disease activity index, and spleen index. The isolated colon samples had a notably longer length, less thickness and weight, and better macroscopic score with MRS treatment compared with the DSS+NS group. Additionally, assessment of morphological impairment revealed a milder and lower microscopic score in the DSS+MRS (10) group, consistent with the myeloperoxidase (MPO) results. The inflammation-related molecules levels were dramatically reduced by MRS. MRS also significantly reduced oxidative stress related proteins. In addition, apoptotic cells were visually decreased in the DSS+MRS (10) group, in which the pro-apoptotic molecules Bax and cleaved caspase-3 were reduced, whereas the level of Bcl-2 was increased. Furthermore, MRS markedly decreased the TLR4, MyD88, p-NF-kappaB p65, p-IKKalphaß, and p-IkappaBalpha, and increased IL-10, p-JAK1, and p-STAT3 expression levels. Proteins involved in endoplasmic reticulum stress (ERS) were also notably reduced under MRS treatment. CONCLUSIONS MRS exerts protective effects on DSS-induced IBD via inhibiting inflammatory reaction, promoting anti-inflammatory capacity, suppressing oxidative stress, and ameliorating apoptosis.

HHQ-4, a quinoline derivate, preferentially inhibits proliferation of glucose-deprived breast cancer cells as a GRP78 down-regulator.

As a central regulator for endoplasmic reticulum (ER) stress, glucose-regulated protein 78 (GRP78), controls the activation of ER-transmembrane signaling mechanisms by inducing unfolded protein response (UPR) in response to ER stress. Although limited glucose availability often occurs in poorly vascularized solid cancers, cancer cells often initiate the UPR to support cellular homeostasis and survival under stress conditions. Therefore, targeting GRP78 expression and UPR pathway activation may provide a new strategy for anticancer therapy. Based on this premise, we investigated the molecular mechanisms of a synthetic quinolone derivative, 2-hexyl-3-methyl-4(1H)-quinolinone (HHQ-4), in regulating the GRP78 expression and UPR transcriptional program under glucose deprivation or 2-deoxy-d-glucose (2-DG)-stressed conditions. We found that HHQ-4 suppressed the transcriptional and translational expression of GRP78 gene in glucose-deprived breast cancer cells. HHQ-4 also showed selective antiproliferative activity against glucose-deprived breast cancer cells. Constitutive expression of GRP78 completely prevented breast cancer cells from HHQ-4-mediated proliferation inhibition during glucose starvation, stressing the important role of suppression of the GRP78 in HHQ-4-mediated cell proliferation inhibition. HHQ-4 was also found to exert inhibitory activity against breast cancer cell proliferation by suppressing three survival arms of the UPR, including PERK/eIF2α/ATF4, IRE1/XBP1, and ATF6, which orchestrate an intricate signaling network to modulate GRP78 gene transcription under glucose-deprived stress. Furthermore, HHQ-4 combined with 2-DG synergistically inhibited breast cancer cell proliferation. Our findings show HHQ-4 could be a promising candidate, alone or in combination with 2-DG, for selectively inhibiting breast cancer cell proliferation by down-regulating the transcription and expression of GRP78 under stressful microenvironments.

Adaptive Data Acquisition with Energy Efficiency and Critical-Sensing Guarantee for Wireless Sensor Networks.

Due to the limited energy budget, great efforts have been made to improve energy efficiency for wireless sensor networks. The advantage of compressed sensing is that it saves energy because of its sparse sampling; however, it suffers inherent shortcomings in relation to timely data acquisition. In contrast, prediction-based approaches are able to offer timely data acquisition, but the overhead of frequent model synchronization and data sampling weakens the gain in the data reduction. The integration of compressed sensing and prediction-based approaches is one promising data acquisition scheme for the suppression of data transmission, as well as timely collection of critical data, but it is challenging to adaptively and effectively conduct appropriate switching between the two aforementioned data gathering modes. Taking into account the characteristics of data gathering modes and monitored data, this research focuses on several key issues, such as integration framework, adaptive deviation tolerance, and adaptive switching mechanism of data gathering modes. In particular, the adaptive deviation tolerance is proposed for improving the flexibility of data acquisition scheme. The adaptive switching mechanism aims at overcoming the drawbacks in the traditional method that fails to effectively react to the phenomena change unless the sampling frequency is sufficiently high. Through experiments, it is demonstrated that the proposed scheme has good flexibility and scalability, and is capable of simultaneously achieving good energy efficiency and high-quality sensing of critical events.

Serotonin Exhibits Accelerated Bleomycin-Induced Pulmonary Fibrosis through TPH1 Knockout Mouse Experiments.

BACKGROUND: Pulmonary fibrosis is a chronic progressive fibrosis interstitial lung disease that is characterized by inflammatory infiltration and fibrotic changes. 5-Hydroxytryptamine (5-HT) is an important regulatory factor in inflammation, immunomodulation, and fibrosis. The aim of this study was to investigate the role of 5-HT in bleomycin- (BLM-) induced pulmonary fibrosis through wild-type C57BL/6 (WT) and TPH1 knockout (KO) mouse experiments. METHODS: The mice were grouped as follows: WT control group, KO control group, WT BLM group, and KO BLM group. Mice were administrated bleomycin hydrochloride through intratracheal instillation to induce pulmonary fibrosis. Mice were sacrificed 0, 7, 14, and 21 days after modeling, and bronchoalveolar lavage fluid (BALF) and lung tissues were collected to determine the severity of fibrotic changes. RESULTS: The results showed that the weight loss of mice in the WT BLM group was more severe than that in the KO BLM group. H&E and Sirius Red staining revealed that 5-HT markedly aggravated histological damage and fibrotic changes in the lung. Significantly lower levels of hydroxyproline, Ashcroft fibrosis score, total BALF protein and cells, BALF tumor necrosis factor- (TNF-) α and interleukin- (IL-) 6, TNF-α and IL-6 mRNA, malondialdehyde (MDA), and myeloperoxidase- (MPO-) positive cells in the lung tissues, and fibrosis-associated proteins were discovered in the mice from the KO BLM group compared with the WT BLM group. CONCLUSION: 5-HT aggravated pulmonary fibrosis mainly by promoting the inflammation, exudation of proteins and cells, oxidative stress, and upregulation of fibrosis-associated genes in the lung tissues.

Dihydromyricetin Attenuates Myocardial Hypertrophy Induced by Transverse Aortic Constriction via Oxidative Stress Inhibition and SIRT3 Pathway Enhancement.

Dihydromyricetin (DMY), one of the flavonoids in vine tea, exerts several pharmacological actions. However, it is not clear whether DMY has a protective effect on pressure overload-induced myocardial hypertrophy. In the present study, male C57BL/6 mice aging 8⁻10 weeks were subjected to transverse aortic constriction (TAC) surgery after 2 weeks of DMY (250 mg/kg/day) intragastric administration. DMY was given for another 2 weeks after surgery. Blood pressure, myocardial structure, cardiomyocyte cross-sectional area, cardiac function, and cardiac index were observed. The level of oxidative stress in the myocardium was assessed with dihydroethidium staining. Our results showed that DMY had no significant effect on the blood pressure. DMY decreased inter ventricular septum and left ventricular posterior wall thickness, relative wall thickness, cardiomyocyte cross-sectional areas, as well as cardiac index after TAC. DMY pretreatment also significantly reduced arterial natriuretic peptide (ANP), brain natriuretic peptide (BNP) mRNA and protein expressions, decreased reactive oxygen species production and malondialdehyde (MDA) level, while increased total antioxidant capacity (T-AOC), activity of superoxide dismutase (SOD), expression of sirtuin 3 (SIRT3), forkhead-box-protein 3a (FOXO3a) and SOD2, and SIRT3 activity in the myocardium of mice after TAC. Taken together, DMY ameliorated TAC induced myocardial hypertrophy in mice related to oxidative stress inhibition and SIRT3 pathway enhancement.

Remote ischemic conditioning protects against acetaminophen-induced acute liver injury in mice.

AIM: Acetaminophen (APAP) overdose is a major cause of drug-induced acute liver failure. Studies have shown that remote ischemic pre- and post-conditioning (R-IPC and R-IPOST) can protect the liver against ischemia-reperfusion (I/R) and lipopolysaccharide-induced injuries. The aim of this study was to investigate the effect of R-IPC and R-IPOST on APAP-induced hepatotoxicity in mice. METHODS: Mice were randomized (n = 6 per group) to seven major groups: (i) normal control; (ii) sham operated; (iii) APAP; (iv) R-IPC + APAP; (v) R-IPC + APAP + zinc protoporphyrin (ZnPP); (vi) R-IPOST + APAP; and (vii) R-IPOST + APAP + ZnPP. Sixteen hours after APAP treatment, mouse liver and serum were collected to determine the severity of liver injury. RESULTS: The results showed that R-IPC and R-IPOST significantly decreased APAP-induced serum levels of alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor-α, interleukin-6, and hepatic malondialdehyde, as well as nitrotyrosine formation. Both R-IPC and R-IPOST could improve the hepatic superoxide dismutase, glutathione, and glutathione peroxidase activities and depress the expressions of pro-inflammatory associated proteins, such as inducible nitric oxide synthetase and nuclear factor-κB. They could also increase heme oxygenase-1 expression; however, ZnPP could counteract this protective effect. CONCLUSION: Remote ischemic conditioning has significant therapeutic potential in APAP-induced hepatotoxicity by inhibiting oxidative stress and inflammation and promoting heme oxygenase-1 expression.

5-HT Drives Mortality in Sepsis Induced by Cecal Ligation and Puncture in Mice.

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection with a high mortality. 5-Hydroxytryptamine (5-HT) is an important regulatory factor in inflammation. The aim of this study is to investigate the role of 5-HT on cecal ligation and puncture- (CLP-) induced sepsis in the mouse model. CLP was performed on C57B/6 wild-type (WT) mice and tryptophan hydroxylase 1 (TPH1) knockout (KO) mice. The results showed that the 5-HT-sufficient group mice had a significantly lower survival rate than the 5-HT-deficient group in CLP-induced sepsis and septic shock. The KO-CLP sepsis group received a lower clinical score than the WT-CLP sepsis group. Meanwhile, the body temperature of mice in the KO-CLP sepsis group was higher than that in the WT-CLP sepsis group and was much closer to the normal body temperature 24 hours after CLP. The tissue histopathology analysis revealed that 5-HT markedly exacerbated histological damages in the peritoneum, lung, liver, kidney, intestinal tissue, and heart in sepsis. Moreover, significant lower levels of TNF-α, IL-6, bacterial loads, MPO, and ROS were discovered in the KO-CLP sepsis group in contrast to the WT-CLP sepsis group. In conclusion, 5-HT drives mortality and exacerbates organ dysfunction by promoting serum cytokines and bacterial loads as well as facilitating oxidative stress in the process of sepsis.