PubMed
Study on the underlying mechanism of Huachansu Capsule induced cardiotoxicity of normal rat by integrating transcriptomics, metabolomics and Network toxicology
J Ethnopharmacol. 2024 Aug 28:118751. doi: 10.1016/j.jep.2024.118751. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Huachansu Capsule (HCSc) is a simple enteric-coated capsule refined from the skin of the dried toad, a traditional medicinal herb. It has been used clinically for many years to treat a variety of malignant tumors with remarkable efficacy. To date, a number of main components of HCSc have been reported to be cardiotoxic, but the specific mechanism of cardiotoxicity is still unknown.AIM OF THE STUDY: The aim of this study is to elucidate the adverse effects of HCSc in clinical application, clarify the main toxic components of HCSc and the mechanism of cardiotoxicity caused by HCSc.MATERIALS AND METHODS: UPLC-Q-Exactive Orbitrap MS and network toxicology were used to identify and predict the potential toxic components, related signaling pathways. Then, we used acute and subacute toxicity experiments to reveal the apparent phenomenon of HCSc-induced cardiotoxicity. Finally, we combined transcriptomics and metabolomics to elucidate the potential mechanism of action, and verified the putative mechanism by molecular docking, RT-qPCR, and Western blot.RESULTS: We found 8 toad bufadienolides components may be induced cardiac toxicity HCSc main toxic components. Through toxicity experiments, we found that high dose of HCSc could increase a variety of blood routine indexes, five cardiac enzymes, heart failure indexes (BNP), troponin (cTnI and cTnT), heart rate and the degree of heart tissue damage. In addition, by molecular docking, found that 8 kinds of main toxic components and cAMP, AMPK, IL1β, mTOR all can be a very good combination, especially in the cAMP. Meanwhile, RT-qPCR and Western blot results showed that HCSc could induce cardiotoxicity by regulating a variety of heart-related differential genes and activating the cAMP signaling pathway.CONCLUSIONS: In this study, network toxicology, transcriptomics and metabolomics were used to elucidate the complex mechanism of high-dose HCSc-induced cardiotoxicity. Animal experiments, molecular docking, Western blot and RT-qPCR experiments were also used to verify the above mechanism. These findings will inform further mechanistic studies and provide theoretical support for its safe clinical application.PMID:39214192 | DOI:10.1016/j.jep.2024.118751
Bacteroides ovatus alleviates dysbiotic microbiota-induced graft-versus-host disease
Cell Host Microbe. 2024 Aug 22:S1931-3128(24)00291-9. doi: 10.1016/j.chom.2024.08.004. Online ahead of print.ABSTRACTAcute lower gastrointestinal GVHD (aLGI-GVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation. Although the intestinal microbiota is associated with the incidence of aLGI-GVHD, how the intestinal microbiota impacts treatment responses in aLGI-GVHD has not been thoroughly studied. In a cohort of patients with aLGI-GVHD (n = 37), we found that non-response to standard therapy with corticosteroids was associated with prior treatment with carbapenem antibiotics and a disrupted fecal microbiome characterized by reduced abundances of Bacteroides ovatus. In a murine GVHD model aggravated by carbapenem antibiotics, introducing B. ovatus reduced GVHD severity and improved survival. These beneficial effects of Bacteroides ovatus were linked to its ability to metabolize dietary polysaccharides into monosaccharides, which suppressed the mucus-degrading capabilities of colonic mucus degraders such as Bacteroides thetaiotaomicron and Akkermansia muciniphila, thus reducing GVHD-related mortality. Collectively, these findings reveal the importance of microbiota in aLGI-GVHD and therapeutic potential of B. ovatus.PMID:39214085 | DOI:10.1016/j.chom.2024.08.004
Microbiota but not immune modulation by a pro- and postbiotic was associated with the diet-additive interaction in broilers
Poult Sci. 2024 Aug 14;103(11):104184. doi: 10.1016/j.psj.2024.104184. Online ahead of print.ABSTRACTThis study investigated the diet-additive interactions of a Lactobacilli-based probiotic (Pro) and postbiotic (Post) on immune parameters and cecal microbiota composition, with subsequent effects on the metabolome in broilers. A completely randomized block design was employed with 2 diets [standard (SD), and challenge (CD)] and 3 additive conditions (Control, Pro, Post) involving 1,368 one-day-old male Ross 308 broilers equally distributed among 36 pens in a 42 d study. Diets were formulated to contain identical nutrient levels, with CD higher than SD in non-starch polysaccharide content by including rye and barley. Total non-specific serum Ig A, M and G concentrations were determined weekly from d14 to 35. Following vaccination, titres of specific antibodies binding Newcastle disease virus (NDV) and infectious bursal disease virus (IBDV) were measured. Microbiota composition was analyzed by 16S rRNA gene sequencing at d14 and 35, and α- and β-diversity indexes (Observed, Chao1, Bray, Jaccard) were calculated. Cecal short-chain fatty acids and the semi-polar metabolome were determined in the Control SD and all CD groups at d35. At d35, a diet-additive interaction was observed on cecal microbiota composition. Within SD, Pro and Post did not affect operational taxonomic units (OTU) abundance (adjusted-P > 0.05) and diversity indexes (P > 0.05). Within CD, Pro and Post affected the relative abundances of 37 and 44 OTUs, respectively (adjusted-P < 0.05), with Post but not Pro affecting β-diversity indexes (P = 0.041 and 0.064 for Bray and Jaccard, respectively). Within CD, Post increased cecal acetate (21%; P = 0.007) and butyrate (41%; P = 0.002) concentration and affected the concentration of 2 metabolites (adjusted-P < 0.05), while Pro affected 240 metabolites (adjusted-P < 0.05). No diet-additive interactions were observed on serum Ig (P > 0.05), except for IgM at d14 (P = 0.004). Diet composition, but not the additives, affected immune status parameters. The Pro and Post affected cecal microbiota composition only under dietary challenging conditions as previously reported for growth.PMID:39214057 | DOI:10.1016/j.psj.2024.104184
Acidity induces durable enhancement of T<sub>reg</sub> cell suppressive functions for tumor immune evasion
Mol Immunol. 2024 Aug 29;174:57-68. doi: 10.1016/j.molimm.2024.08.004. Online ahead of print.ABSTRACTThe microenvironment within solid tumors often becomes acidic due to various factors associated with abnormal metabolism and cellular activities, including increased lactate production as a result of dysregulated tumor glycolysis. Recently, we have identified multiple tumor microenvironment (TME) factors that potentiate regulatory T (Treg) cell function in evading anti-tumor immunosurveillance. Despite the strong correlation between lactate and acidity, the potential roles of acidity in intratumoral Treg cell adaptation and underlying molecular mechanisms have gone largely unstudied. In this study, we demonstrate that acidity significantly enhances immunosuppressive functions of nTreg cells, but not iTreg cells, without altering the expression of either FoxP3 or the cell surface receptors CD25, CTLA4, or GITR in these cells. Surprisingly, the addition of lactate, often considered a major contributor to increased acidity of the TME, completely abolished the acidity-induced enhancement of nTreg suppressive functions. Consistently, metabolic flux analyses showed elevated basal mitochondrial respiratory capacity and ATP-coupled respiration in acidity-treated nTreg cells without altering glycolytic capacity. Genome-wide transcriptome and metabolomics analyses revealed alterations in multiple metabolic pathways, particularly the one-carbon folate metabolism pathway, with reduced SAM, folate, and glutathione, in nTreg cells exposed to low pH conditions. Addition of a one-carbon metabolic contributor, formate, diminished the acidity-induced enhancement in nTreg cell suppressive functions, but neither SAM nor glutathione could reverse the phenotype. Remarkably, in vitro transient treatment of nTreg cells resulted in sustained enhancement of their functions, as evidenced by more vigorous tumor growth observed in mice adoptively receiving acidity-treated nTreg cells. Further analysis of intratumoral infiltrated T cells confirmed a significant reduction in CD8+ T cell frequency and their granzyme B production. In summary, our study elucidates how acidity-mediated metabolic reprogramming leads to sustained Treg-mediated tumor immune evasion.PMID:39213947 | DOI:10.1016/j.molimm.2024.08.004
Ecophysiological, transcriptomic and metabolomic analyses shed light on the response mechanism of Bruguiera gymnorhiza to upwelling stress
Plant Physiol Biochem. 2024 Aug 27;215:109074. doi: 10.1016/j.plaphy.2024.109074. Online ahead of print.ABSTRACTMangroves, due to their unique habitats, endure dual stressors from land to ocean and ocean to land directions. While extensive researches have been conducted on land-ocean stressors, studies on ocean-land stressors like upwelling are considerably scarce. In this study, ecophysiological, transcriptome, and metabolome analyses were conducted to determine the responses of mangrove plant (Bruguiera gymnorhiza, B. gymnorhiza) to upwelling stress. The results suggested that upwelling stress in B. gymnorhiza induces oxidative stress and membrane damage, which are mitigated by the synergistic actions of antioxidant enzymes and osmoprotectants. Transcriptomic and metabolomic analyses revealed that upregulated genes related to oxidation-reduction and carbohydrate metabolism, along with accumulated metabolites such as amino acids, lipids, phenols, and organic acids, contribute to enhancing antioxidant capacity and maintaining osmotic balance. Further analysis identified key KEGG pathways involved in the response to upwelling stress, including amino acid metabolism, carbohydrate and energy metabolism, flavonoid biosynthesis, and plant hormone signal transduction. These findings provide vital information into the multi-level response mechanisms of mangrove plants to upwelling stress.PMID:39213943 | DOI:10.1016/j.plaphy.2024.109074
Multi-omics analysis identified extracellular vesicles as biomarkers for cardiovascular diseases
Talanta. 2024 Aug 16;280:126710. doi: 10.1016/j.talanta.2024.126710. Online ahead of print.ABSTRACTCell-derived extracellular vesicles (EVs) have emerged as a promising non-invasive liquid biopsy technique due to their accessibility and their ability to encapsulate and transport diverse biomolecules. EVs have garnered substantial research interest, notably in cardiovascular diseases (CVDs), where their roles in pathophysiology and as diagnostic and prognostic biomarkers are increasingly recognized. This review provides a comprehensive overview of EVs, starting with their origins, followed by the techniques used for their isolation and characterization. We explore the diverse cargo of EVs, including nucleic acids, proteins, lipids, and metabolites, highlighting their roles in intercellular communication and as potential biomarkers. We then delve into the application of genomics, transcriptomics, proteomics, and metabolomics in the analysis of EVs, particularly within the context of CVDs. Finally, we discuss how integrated multi-omics approaches are unveiling novel biomarkers, offering fresh insights into the diagnosis and prognosis of CVDs. This review underscores the growing importance of EVs in clinical diagnostics and the potential of multi-omics to propel future advancements in CVD biomarker discovery.PMID:39213888 | DOI:10.1016/j.talanta.2024.126710
Regulation of host metabolism and defense strategies to survive neonatal infection
Biochim Biophys Acta Mol Basis Dis. 2024 Aug 29;1870(8):167482. doi: 10.1016/j.bbadis.2024.167482. Online ahead of print.ABSTRACTTwo distinct defense strategies, disease resistance (DR) and disease tolerance (DT), enable a host to survive infectious diseases. Newborns, constrained by limited energy reserves, predominantly rely on DT to cope with infection. However, this approach may fail when pathogen levels surpass a critical threshold, prompting a shift to DR that can lead to dysregulated immune responses and sepsis. The mechanisms governing the interplay between DR and DT in newborns remain poorly understood. Here, we compare metabolic traits and defense strategies between survivors and non-survivors in Staphylococcus epidermidis (S. epidermidis)-infected preterm piglets, mimicking infection in preterm infants. Compared to non-survivors, survivors displayed elevated DR during the initial phase of infection, followed by stronger DT in later stages. In contrast, non-survivors showed clear signs of respiratory and metabolic acidosis and hyperglycemia, together with exaggerated inflammation and organ dysfunctions. Hepatic transcriptomics revealed a strong association between the DT phenotype and heightened oxidative phosphorylation in survivors, coupled with suppressed glycolysis and immune signaling. Plasma metabolomics confirmed the findings of metabolic regulations associated with DT phenotype in survivors. Our study suggests a significant association between the initial DR and subsequent DT, which collectively contributes to improved infection survival. The regulation of metabolic processes that optimize the timing and balance between DR and DT holds significant potential for developing novel therapeutic strategies for neonatal infection.PMID:39213794 | DOI:10.1016/j.bbadis.2024.167482
Multi-omics profiling combined with molecular docking reveals immune-inflammatory proteins as potential drug targets in colorectal cancer
Biochem Biophys Res Commun. 2024 Aug 23;739:150598. doi: 10.1016/j.bbrc.2024.150598. Online ahead of print.ABSTRACTColorectal cancer is globally ranked as the third most common malignant tumor. Its development involves a complex biological process driven by various genetic and epigenetic alterations. To elucidate the biological significance of the extensive omics data, we conducted comparative multi-omics studies on colorectal cancer patients at different clinical stages. Bioinformatics methods were applied to analyze multi-omics datasets and explore the molecular landscape. Drug prediction and molecular docking also were conducted to assess potential therapeutic interventions. In vitro experiments were used to validate the inhibitory effect on the migration and proliferation of cell lines. The results indicate up-regulated proteins involved in immune-inflammatory related pathways, while biomarkers related to muscular contraction and cell adhesion are significantly down-regulated. Drug prediction, coupled with in vitro experiments, suggests that AZ-628 may act as a potential drug to inhibit the proliferation and migration of CRC cell lines HCT-116 and HT-29 by regulating the aforementioned key biological pathways or proteins. Complementing these findings, metabolomics analysis unveiled a down-regulation of key carbon metabolism pathways, alongside an up-regulation in amino acid metabolism, particularly proline metabolism. This metabolic shift may reflect an adaptive response in cancer cells, favoring specific amino acids to support their growth. Together, these integrated results provide valuable insights into the intricate landscape of tumor development, highlighting the crossroads of immune regulation, cellular structure, and metabolic reprogramming in the tumorigenic process and providing valuable insights into cancer pathology.PMID:39213754 | DOI:10.1016/j.bbrc.2024.150598
Unique intestinal microflora and metabolic profile in different stages of hypertension reveal potential biomarkers for early diagnosis and prognosis
J Med Microbiol. 2024 Aug;73(8). doi: 10.1099/jmm.0.001839.ABSTRACTIntroduction. Hypertension is the most prevalent chronic disease and a major risk factor for cardiovascular and cerebrovascular diseases.Gap statement. However, there has been no substantial breakthrough in aetiology, new drug targets, and drug development of hypertension in recent 50 years.Research aim. Therefore, this study was to screen unique intestinal microbiome and serum metabolic biomarkers which can early diagnose and track the prognosis of hypertension patients in different periods, and analyse its underlying mechanisms and functions.Methods. Four groups of stool and serum samples, including healthy controls (HCs), prehypertension (PHT), hypertension (HT), and hypertension-related complications (HTC), were collected. Microbial diversity assessed using 16S rRNA sequencing. The metabolites in serum samples were detected through LC-MS/MS analysis.Results. The composition of gut microbiota in patients exhibited dissimilarities compared to that in healthy subjects, which was distinguished by Prevotella, Slackia, Enterococcus, Bifidobacterium, and Lactobacillales may be potential markers for tracking the progression of hypertension, and Bifidobacterium, Butyricimonas, Adlercreutzia, Faecalibacterium, Lactobacillus, Ruminococcus, Clostridium, and Acidaminococcus demonstrated diagnostic value. Meanwhile, tracking the dynamic changes of deoxycholic acid, 4-oxododecanedioic acid, and l-arginine can serve as biomarkers for early diagnosis, and investigation into the mechanism by which the intestinal microbiome influences the onset and progression of hypertension. In terms of pathogenesis, the findings revealed that Bifidobacterium may caused the changes of AST, indirect bilirubin, ALT, triglyceride and uric acid by affecting metabolites cis-7-hexadecenoic acid methyl ester and N1-acetylspermidine. Additionally, Coprococcus may cause changes in albumin through the influence of androsterone enanthate.Conclusions. These findings highlight that the unique intestinal microbiome and serum metabolic profile in different periods of hypertension will provide valuable insight for timely diagnosis and prognosis tracking in hypertension patients with promising clinical applications.PMID:39213028 | DOI:10.1099/jmm.0.001839
Modeling "Two-Hit" Severe Pneumonia in Mice: Pathological Characteristics and Mechanistic Studies
Inflammation. 2024 Aug 30. doi: 10.1007/s10753-024-02136-w. Online ahead of print.ABSTRACTSevere pneumonia is one of the most common critical diseases in clinical practice. Existing models for severe pneumonia have limitations, leading to limited clinical translation. In this study, a two-hit severe pneumonia mouse model was established by inducing primary pneumonia through intratracheal instillation of 800 μg lipopolysaccharide (LPS), followed by intraperitoneal injection of 10 mg/kg LPS. The effectiveness of various inflammatory indicators and the lung tissue damage during the time course of this model were confirmed and evaluated. At 3 h post two-hit, the IL-6, TNF-α levels in peripheral blood and bronchoalveolar lavage fluid (BALF), and the white blood cells, neutrophils, and lymphocytes in BALF notably exhibited the most pronounced elevation. At 12 h post two-hit, the white blood cells and neutrophils in peripheral blood significantly increased, accompanied by notable alterations in splenic immune cells and worsened pulmonary histopathological damage. Transcriptomics of lung tissue, microbiota analysis of lung and gut, as well as plasma metabolomics analyses further indicated changes in transcriptional profiles, microbial composition, and metabolites due to the two-hit modeling. These results validate that the two-hit model mimics the clinical presentation of severe pneumonia and serves as a robust experimental tool for studying the pathogenesis of severe pneumonia and developing and assessing treatment strategies.PMID:39212889 | DOI:10.1007/s10753-024-02136-w
Metabolomics Reveals Disturbed Amino Acid Metabolism During Different Stages of RA in Collagen-Induced Arthritis Mice
Inflammation. 2024 Aug 30. doi: 10.1007/s10753-024-02123-1. Online ahead of print.ABSTRACTRheumatoid arthritis (RA) is an autoimmune disease featured by chronic synovitis and progressive joint damage. Early treatment before the onset of clinical symptoms (also known as the pre-RA stage) may slow or stop the progression of the disease. We sought to discover the dynamic metabolic changes during the evolution of collagen-induced arthritis (CIA) to better characterize the disease stages. Untargeted metabolomics analysis using gas chromatography-mass spectrometry revealed that the metabolic profiles of CIA mice gradually differed from that of the control group with the progression of the disease. During the induction phase, the CIA group showed some metabolic alterations in galactose metabolism, arginine biosynthesis, tricarboxylic acid cycle (TCA cycle), pyruvate metabolism, and starch/sucrose metabolism. During the early inflammatory phase, no joint swelling was observed in CIA mice, and metabolites changed mainly involving amino acid metabolism (arginine biosynthesis, arginine/proline metabolism, phenylalanine/tyrosine/tryptophan biosynthesis), and glutathione metabolism. During the peak inflammatory phase, severe arthritis symptoms were observed in CIA mice, and there were more extensive metabolic alterations in valine/leucine/isoleucine biosynthesis, phenylalanine/tyrosine/tryptophan biosynthesis, TCA cycle, galactose metabolism, and arginine biosynthesis. Moreover, the reduction of specific amino acids, such as glycine, serine, and proline, during the early stages may result in an imbalance in macrophage polarization and enhance the inflammatory response in CIA mice. Our study confirmed that specific perturbations in amino acid metabolism have occurred in CIA mice prior to the onset of joint symptoms, which may be related to autoimmune disorders. The findings could provide insights into the metabolic mechanism and the diagnosis of pre-RA.PMID:39212888 | DOI:10.1007/s10753-024-02123-1
Effect of weight loss interventions on metabolomic signatures in obese children with insulin resistance
Amino Acids. 2024 Aug 30;56(1):54. doi: 10.1007/s00726-024-03409-2.ABSTRACTThe obesity epidemic among children has become a major public health issue, and the presence of childhood insulin resistance (IR) has been demonstrated prior to the onset of type 2 diabetes mellitus. However, it is unclear whether the metabolomic signature is associated with weight loss interventions in obese children with IR. Thirty-six obese children with IR were selected from the weight loss camp (Shenzhen Sunshine Xing Yada health Technology Co., LTD). Clinical parameters were collected before and after weight loss intervention. Targeted metabolomics of plasma samples was performed by ultra-performance liquid chromatography coupled to the tandem mass spectrometry, and principal component analysis, variable importance in projection, and orthogonal partial least squares discriminant analysis were used to obtain the differentially expressed metabolites. Pathway analysis was conducted with the Homo sapiens (HSA) sets in the Kyoto Encyclopedia of Genes and Genomes. We used machine learning algorithms to obtain the potential biomarkers and Spearman correlation analysis to clarify the association between potential biomarkers and clinical parameters. We found that clinical parameters and metabolite clusters were significantly changed in obese children with IR before and after weight loss intervention. Mechanistically, weight loss intervention significantly changed 61 metabolites in obese children with IR. Furthermore, 12 pathways were significantly changed. Moreover, the machine learning algorithm found 6 important potential biomarkers. In addition, these potential biomarkers were strongly associated with major clinical parameters. These data indicate different metabolomic profiles in obese children with IR after weight loss intervention, providing insights into the clinical parameters and metabolite mechanisms involved in weight loss programs.PMID:39212734 | DOI:10.1007/s00726-024-03409-2
The Clinical Impact of Time-restricted Eating on Cancer: A Systematic Review
Nutr Rev. 2024 Aug 30:nuae105. doi: 10.1093/nutrit/nuae105. Online ahead of print.ABSTRACTCONTEXT: In the face of the growing global burden of cancer, there is increasing interest in dietary interventions to mitigate its impacts. Pre-clinical evidence suggests that time-restricted eating (TRE), a type of intermittent fasting, induces metabolic effects and alterations in the gut microbiome that may impede carcinogenesis. Research on TRE in cancer has progressed to human studies, but the evidence has yet to be synthesized.OBJECTIVE: The objective of this study was to systematically evaluate the clinical and/or metabolomic effects of TRE compared with ad libitum eating or alternative diets in people with cancer.DATA SOURCES: Ovid MEDLINE, Ovid Embase, CINAHL, Ovid Cochrane Central Register of Control Trials (CENTRAL), Web of Science Core Collection (ESCI, CPCI-SSH, CPCI-S), and SCOPUS were searched up to January 4, 2023, using the core concepts of "intermittent fasting" and "cancer." Original study designs, protocols, and clinical trial registries were included.DATA EXTRACTION: After evaluating 13 900 results, 24 entries were included, consisting of 8 full articles, 2 abstracts, 1 published protocol and 13 trial registries. All data were extracted, compared, and critically analyzed.DATA ANALYSIS: There was heterogeneity in the patient population (eg, in tumor sites), TRE regimens (eg, degree of restriction, duration), and clinical end points. A high rate (67-98%) of TRE adherence was observed, alongside improvements in quality of life. Four articles assessed cancer markers and found a reduction in tumor marker carcinoembryonic antigen, reduced rates of recurrence, and a sustained major molecular response, following TRE. Five articles demonstrated modified cancer risk factors, including beneficial effects on body mass index, adiposity, glucoregulation, and inflammation in as short a period as 8 weeks. None of the completed studies assessed the effect of TRE on the microbiome, but analysis of the microbiome is a planned outcome in 2 clinical trials.CONCLUSIONS: Preliminary findings suggest that TRE is feasible and acceptable by people with cancer, may have oncological benefits, and improves quality of life.REGISTRATION: PROSPERO registration No. CRD42023386885.PMID:39212676 | DOI:10.1093/nutrit/nuae105
The role of gut microbiome and its metabolites in pancreatitis
mSystems. 2024 Aug 30:e0066524. doi: 10.1128/msystems.00665-24. Online ahead of print.ABSTRACTGut microbiome plays a vital role in the intestinal ecosystem and has close association with metabolites. Due to the development of metabolomics and microbiomics, recent studies have observed that alteration of either the gut microbiome or metabolites may have effects on the progression of pancreatitis. Several new treatments based on the gut microbiome or metabolites have been studied extensively in recent years. Gut microbes, such as Bifidobacterium, Akkermansia, and Lactobacillus, and metabolites, such as short-chain fatty acids, bile acids, vitamin, hydrogen sulfide, and alcohol, have different effects on pancreatitis. Some preliminary studies about new intervention measures were based on the gut microbiome and metabolites such as diet, prebiotic, herbal medicine, and fecal microbiota transplantation. This review aims to summarize the recent advances about the gut microbiome, metabolites, and pancreatitis in order to determine the potential beneficial role of the gut microbiome and metabolites in pancreatitis.PMID:39212377 | DOI:10.1128/msystems.00665-24
Action mechanisms of Qianlie Jindan Tablets on chronic nonbcterial prostatitis in rats: An exploration based on non-targeted urine metabolomics
Zhonghua Nan Ke Xue. 2024 Jun;30(6):531-539.ABSTRACTOBJECTIVE: To explore the mechanisms of Qianlie Jindan Tablets (QLJD) acting on chronic nonbacterial prostatitis (CNP) in rats based on non-targeted urine metabolomics.METHODS: According to the body mass index, we equally randomized 30 eight-week-old male SD rats into a blank control, a CNP model control and a QLJD medication group. We established the CNP model in the latter groups and, from the 4th day of modeling, treated the rats in the blank and model control groups intragastrically with normal saline and those in the QLJD medication group with QLJD suspension, qd, for 30 successive days. Then we detected the changes in the metabolites of the rats by ultra-high-performance liquid chromatography-tandem mass spectrometry, and identified the differential metabolites in different groups by multivariate statistical analysis, followed by functional annotation of the differential metabolites.RESULTS: Eight common metabolites were identified by metabolomics analysis, of which 5 were decreased in the CNP model controls and increased in the QLJD medication group, while the other 3 increased in the former and decreased in the latter group. Creatinine and genistein were important differential metabolites, and the arginine and proline metabolic pathways and isoflavone biosynthesis pathways were the main ones for QLJD acting on CNP. Compared with the blank controls, the model controls showed up-regulated arginine and proline metabolic pathways, increased production of creatinine, down-regulated isoflavone biosynthetic pathway and decreased production of genistein. The above changes in the model controls were all reversed in the QLJD medication group.CONCLUSION: QLJD acts effectively on CNP in male rats by regulating L-arginine and proline metabolic pathways, as well as the isoflavone biosynthesis pathway and naringenin metabolism.PMID:39212363
A surge in endogenous spermidine is essential for rapamycin-induced autophagy and longevity
Autophagy. 2024 Aug 30. doi: 10.1080/15548627.2024.2396793. Online ahead of print.ABSTRACTAcute nutrient deprivation (fasting) causes an immediate increase in spermidine biosynthesis in yeast, flies, mice and humans, as corroborated in four independent clinical studies. This fasting-induced surge in spermidine constitutes the critical first step of a phylogenetically conserved biochemical cascade that leads to spermidine-dependent hypusination of EIF5A (eukaryotic translation initiation factor 5A), which favors the translation of the pro-macroautophagic/autophagic TFEB (transcription factor EB), and hence an increase in autophagic flux. We observed that genetic or pharmacological inhibition of the spermidine increase by inhibition of ODC1 (ornithine decarboxylase 1) prevents the pro-autophagic and antiaging effects of fasting in yeast, nematodes, flies and mice. Moreover, knockout or knockdown of the enzymes required for EIF5A hypusination abolish fasting-mediated autophagy enhancement and longevity extension in these organisms. Of note, autophagy and longevity induced by rapamycin obey the same rule, meaning that they are tied to an increase in spermidine synthesis. These findings indicate that spermidine is not only a "caloric restriction mimetic" in the sense that its supplementation mimics the beneficial effects of nutrient deprivation on organismal health but that it is also an obligatory downstream effector of the antiaging effects of fasting and rapamycin.PMID:39212197 | DOI:10.1080/15548627.2024.2396793
Metabolomics and Lipidomics for Studying Metabolic Syndrome: Insights into Cardiovascular Diseases, Type 1 & 2 Diabetes, and Metabolic Dysfunction-Associated Steatotic Liver Disease
Physiol Res. 2024 Aug 30;73(S1):S165-S183.ABSTRACTMetabolomics and lipidomics have emerged as tools in understanding the connections of metabolic syndrome (MetS) with cardiovascular diseases (CVD), type 1 and type 2 diabetes (T1D, T2D), and metabolic dysfunction-associated steatotic liver disease (MASLD). This review highlights the applications of these omics approaches in large-scale cohort studies, emphasizing their role in biomarker discovery and disease prediction. Integrating metabolomics and lipidomics has significantly advanced our understanding of MetS pathology by identifying unique metabolic signatures associated with disease progression. However, challenges such as standardizing analytical workflows, data interpretation, and biomarker validation remain critical for translating research findings into clinical practice. Future research should focus on optimizing these methodologies to enhance their clinical utility and address the global burden of MetS-related diseases.PMID:39212142
A mixed animal and plant protein source replacing fishmeal affects bile acid metabolism and apoptosis in largemouth bass (Micropterus salmoides)
J Anim Sci. 2024 Aug 30:skae249. doi: 10.1093/jas/skae249. Online ahead of print.ABSTRACTChicken meal, shrimp meal, blood meal, and soybean protein concentrate (SPC) are common alternatives to fishmeal. This study used them to prepare three diets with different levels of fishmeal (FM48, FM40, FM32) for largemouth bass (Micropterus salmoides). The results found no significant difference in the growth performance of largemouth bass fed different diets. Mixed protein increased the total cholesterol (T-CHO) content in plasma, and reduced the total superoxide dismutase (T-SOD) activity in plasma and liver. Targeted metabolomics analysis found that the low fishmeal diets affected the cholesterol and bile acid metabolism of largemouth bass. Mixed protein inhibited cyp7a1 and enhanced hmgcr and pparγ mRNA levels, as well as enhanced the expression levels of FXR in the liver. The fish fed FM32 diet showed inhibited fxr, rxrα and cyp7a1 mRNA levels in the intestine. The results of TUNEL fluorescence staining showed that mixed protein induced apoptosis in largemouth bass. The caspase 3 and caspase 9 mRNA levels in the fish fed FM40 and FM32 diet significantly increased, as well as the expression levels of CASPASE 3. The experiment also found that it could induce oxidative stress and endoplasmic reticulum stress. In conclusion, replacement of fishmeal with mixed animal and plant protein diets did not affect the growth performance, but the health and bile acid metabolism of largemouth bass was affected when the fishmeal level was reduced to 32 %.PMID:39212095 | DOI:10.1093/jas/skae249
Hypertriglyceridemia as a Key Contributor to Abdominal Aortic Aneurysm Development and Rupture: Insights from Genetic and Experimental Models
medRxiv [Preprint]. 2024 Aug 12:2024.08.07.24311621. doi: 10.1101/2024.08.07.24311621.ABSTRACTAbdominal aortic aneurysm (AAA) is a life-threatening vascular disease without effective medications. This study integrated genetic, proteomic, and metabolomic data to identify causation between increased triglyceride (TG)-rich lipoproteins and AAA risk. Three hypertriglyceridemia mouse models were employed to test the hypothesis that increased plasma TG concentrations accelerate AAA development and rupture. In the angiotensin II-infusion AAA model, most Lpl -deficient mice with severely high plasma TG concentrations died of aortic rupture. Consistently, Apoa5 -deficient mice with moderately increased TG concentrations had accelerated AAA development, while human APOC3 transgenic mice with dramatically increased TG concentrations exhibited aortic dissection and rupture. Increased TG concentrations and palmitate inhibited lysyl oxidase maturation. Administration of antisense oligonucleotide targeting Angptl3 profoundly inhibited AAA progression in human APOC3 transgenic mice and Apoe -deficient mice. These results indicate that hypertriglyceridemia is a key contributor to AAA pathogenesis, highlighting the importance of triglyceride-rich lipoprotein management in treating AAA.PMID:39211871 | PMC:PMC11361217 | DOI:10.1101/2024.08.07.24311621
Exploring blood transcriptomic signatures in patients with herpes zoster and postherpetic neuralgia
Front Cell Infect Microbiol. 2024 Aug 15;14:1425393. doi: 10.3389/fcimb.2024.1425393. eCollection 2024.ABSTRACTPostherpetic neuralgia (PHN) is a common, severe, and hard-to-treat chronic pain condition in clinics. Although PHN is developed from herpes zoster (HZ), the developing mechanism is unknown. A previous study investigated blood metabolomic and proteomic profiling in patients with PHN and HZ. The current study aims to explore the blood transcriptomic signature of PHN compared to HZ patients. Whole blood from eight PHN and 15 HZ patients was used for RNA-Seq analysis. There were 82 and 1,788 genes detected specifically in the PHN and HZ groups, respectively. PHN-specific genes are involved in viral infection, lipid and carbohydrate metabolism, and immune response. For genes coexpressed in PHN and HZ patients, there were 407 differential expression genes (DEGs), including 205 upregulated (UP DEGs) and 202 downregulated (DOWN DEGs) in PHN compared to HZ groups. DEGs are involved in viral infection, type I interferon (IFN), and hemoglobin and oxygen carrier activity. UP DEGs are associated with regulatory T cells (Tregs), activated NK cells, and neutrophils, while DOWN DEGs are associated with Tregs, resting NK cells, and monocytes. The results suggest that the metabolism of lipid, glycan, and nucleotides, type I IFN signaling, and altered neutrophil activation are associated with and might contribute to the development of PHN in HZ. It is also suggested that persistent or altered activation of nonspecific immunity may contribute to the development of PHN from HZ.PMID:39211798 | PMC:PMC11358128 | DOI:10.3389/fcimb.2024.1425393