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Inducible nitric oxide synthase (iNOS) and vascular endothelial dysfunction have been implicated in the development and progression of atherosclerosis. This study aimed to elucidate the role of iNOS in vascular endothelial dysfunction. Ultrahigh performance liquid chromatography-quadrupole time-of-flight mass spectrometry combined with multivariate data analysis was used to characterize the metabolic changes in human umbilical vein endothelial cells (HUVECs) in response to different treatment conditions. In addition, molecular biology techniques were employed to explain the molecular mechanisms underlying the role of iNOS in vascular endothelial dysfunction. Tumor necrosis factor-α (TNF-α) enhances the expression of iNOS, TXNIP, and the level of reactive oxygen species (ROS) facilitates the entry of nuclear factor-κB (NF-κB) into the nucleus and promotes injury in HUVECs. iNOS deficiency reversed the TNF-α-mediated pathological changes in HUVECs. Moreover, TNF-α increased the expression of tumor necrosis factor receptor-2 (TNFR-2) and the levels of p-IκBα and IL-6 proteins and CD31, ICAM-1, and VCAM-1 protein expression, which was significantly reduced in HUVECs with iNOS deficiency. In addition, treating HUVECs in the absence or presence of TNF-α or iNOS, respectively, enabled the identification of putative endogenous biomarkers associated with endothelial dysfunction. These biomarkers were involved in critical metabolic pathways, including glycosylphosphatidylinositol-anchor biosynthesis, amino acid metabolism, sphingolipid metabolism, and fatty acid metabolism. iNOS deficiency during vascular endothelial dysfunction may affect the expression of TNFR-2, vascular adhesion factors, and the level of ROS via cellular metabolic changes, thereby attenuating vascular endothelial dysfunction.NEW & NOTEWORTHY Inducible nitric oxide synthase (iNOS) deficiency during vascular endothelial dysfunction may affect the expression of tumor necrosis factor receptor-2 and vascular adhesion factors via cellular metabolic changes, thereby attenuating vascular endothelial dysfunction.
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NF-kappa B , Fator de Necrose Tumoral alfa , Humanos , Fator de Necrose Tumoral alfa/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Espécies Reativas de Oxigênio/metabolismo , NF-kappa B/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Óxido Nítrico/metabolismoRESUMO
PURPOSE: The renewal and iteration of chemotherapy drugs have resulted in more frequent long-term remissions for patients with multiple myeloma (MM). MM has transformed into a chronic illness for many patients, but the cancer-related fatigue (CRF) of many MM convalescent patients experience is frequently overlooked. We investigated whether the accompanying treatment of family members would affect MM patients' CRF and explore their serum metabolomics, so as to provide clinicians with new ideas for identifying and treating CRF of MM patients. METHODS: This was a single-center study, and a total of 30 MM patients were included in the study. Patients were divided into two groups based on whether they have close family members accompanying them through the whole hospitalization treatment. These patients received regular chemotherapy by hematology specialists, and long-term follow-up was done by general practitioners. Patients' CRF assessment for several factors used the Chinese version of the Brief Fatigue Inventory (BFI-C). Face-to-face questionnaires were administered at a time jointly determined by the patient and the investigator. All questionnaires were conducted by a general practitioner. The LC-MS-based metabolomics analysis determined whether the patients' serum metabolites were related to their fatigue severity. A correlation analysis investigated the relationship between serum metabolites and clinical laboratory indicators. RESULTS: The fatigue severity of MM patients whose family members participated in the treatment process (group A) was significantly lower than patients whose family members did not participate in the treatment process (group B). There was a statistically significant difference (fatigue severity composite score: t = - 2.729, p = 0.011; fatigue interference composite score: t = - 3.595, p = 0.001). There were no differences between the two groups of patients' gender, age, regarding clinical staging, tumor burden, blood routine, biochemical, or coagulation indexes. There were 11 metabolites, including guanidine acetic acid (GAA), 1-(Methylthio)-1-hexanethiol, isoeucyl-asparagine, L-agaritine, tryptophyl-tyrosine, and betaine, which significantly distinguished the two groups of MM patients. GAA had the strongest correlation with patient fatigue, and the difference was statistically significant (fatigue severity composite score: r = 0.505, p = 0.0044; fatigue interference composite score: r = 0.576, p = 0.0009). The results showed that GAA negatively correlated with albumin (r = - 0.4151, p = 0.0226) and GGT (r = - 0.3766, p = 0.0402). Meanwhile, GAA positively correlated with PT (r = 0.385, p = 0.0473), and the difference was statistically significant. CONCLUSION: The study is the first to report that family presence throughout the whole hospitalization may alleviate CRF in MM patients. Moreover, the study evaluated serum metabolites linked to CRF in MM patients and found that CRF has a significant positive correlation with GAA. GAA may be a more sensitive biomarker than liver enzymes, PT, and serum albumin in predicting patient fatigue. While our sample may not represent all MM patients, it proposes a new entry point to help clinicians better identify and treat CRF in MM patients.
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Mieloma Múltiplo , Humanos , Mieloma Múltiplo/complicações , Mieloma Múltiplo/tratamento farmacológico , Fadiga/etiologia , Fadiga/terapia , Inquéritos e QuestionáriosRESUMO
Among digestive system cancers, the extremely poor prognosis of pancreatic cancer (PC) is a pressing concern. Nonoperative treatments such as targeted and immunotherapy, have improved the current situation, however, the accompanying side effects of these chemicals should not be ignored. Here, we discovered a novel hydroxycinnamic acid named sinapic acid (SA) derived from fruits, vegetables, cereals, and oil crops as an effective anti-PC molecule. Both the in vitro and in vivo models we designed showed that SA exhibited anticancer activities but not apoptosis induction. Research on the underlying mechanisms illustrated that AKT phosphorylation was blocked by SA, and the downstream Gsk-3ß was downregulated subsequently. Our study revealed the inhibitory activity and underlying mechanisms of SA, providing evidence that SA is a potential strategy for cancer research and can be a promising option of PC chemotherapy.
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Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas c-akt , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Ácidos Cumáricos/farmacologia , Regulação para Baixo , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Neoplasias PancreáticasRESUMO
BACKGROUND: Growing evidence indicates that systemic immune inflammation index (SII) can predict the prognosis of various solid tumors. The objective of this study aimed to investigate the efficacy of SII in predicting the prognosis of gallbladder carcinoma (GBC) patients after radical surgery. METHODS: A consecutive series of 93 patients with GBC who underwent radical resection were enrolled in the retrospective study. The cutoff value for the SII was calculated using the time-dependent receiver operating characteristic (ROC) curve analysis by overall survival (OS) prediction. The associations between the SII and the clinicopathologic characteristics were analyzed using Pearson's χ2 test and Fisher's exact test. Survival curves were calculated using the Kaplan-Meier method. Univariate analysis was performed to evaluate the prognostic relevance of preoperative parameters. The multivariate Cox regression proportional hazard model was used to assess variables significant on univariate analysis. RESULTS: The Kaplan-Meier survival analysis and the multivariate analysis of patients with GBC who received radical resection showed SII independently predicted OS. The univariate analysis showed that the TNM stage, SII, CA19-9, ALP, prealbumin, NLR, MLR, lymph node metastasis, and histopathological type were all associated with overall survival. In time-dependent ROC analysis, the area of the SII-CA19-9 under the ROC curve (AUC) was higher than that of the preoperative SII or CA19-9 levels for the prediction of OS. CONCLUSION: Our results demonstrate that high SII was a predictor of poor long-term outcomes among patients with GBC undergoing curative surgery. SII-CA19-9 classification may be more effective in predicting the postoperative prognosis of GBC patients.
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Biomarcadores Tumorais/análise , Plaquetas/patologia , Colecistectomia/mortalidade , Neoplasias da Vesícula Biliar/mortalidade , Mediadores da Inflamação/análise , Linfócitos/patologia , Neutrófilos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Neoplasias da Vesícula Biliar/imunologia , Neoplasias da Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Bisphenol A (BPA) is widely distributed in the environment and human surroundings and is closely related to the occurrence of many chronic diseases including female infertility. Although BPA-induced granulosa cell apoptosis has been widely reported, the underlying mechanisms remain unknown. In this study, we evaluated the induction effect of BPA exposure on apoptosis and mechanisms of regulation in KGN cells (a human granulosa-like tumor cell line). Our results indicated that BPA induced apoptosis of KGN cells in a dose- and time-dependent manner. BPA exposure significantly promoted the expression of pro-apoptotic proteins and decreased mitochondrial membrane potential. We also observed that high concentrations of BPA significantly promoted the generation of reactive oxygen species (ROS) and calcium ion (Ca2+) accumulation. The involvement of ROS and Ca2+ in BPA-induced KGN cell apoptosis was confirmed by pretreatment with NAC (an antioxidant) and BAPTA-AM (a calcium chelator). After inhibitors pretreatment to block the corresponding signaling pathways, it was found that BPA-induced phosphorylation of JNK and ASK1 proteins and apoptosis of KGN cells were significantly inhibited. We pretreated with G15 (a GPER inhibitor) and found that BPA-induced ROS generation and Ca2+ accumulation and apoptosis were significantly inhibited. These results suggest that BPA exposure induces KGN cell apoptosis through GPER-dependent activation of the ROS/Ca2+-ASK1-JNK signaling pathway. Our study provides mechanisms by which BPA induced apoptosis of granulosa cells and ovarian dysfunction.
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Compostos Benzidrílicos/toxicidade , Poluentes Ambientais/toxicidade , Fenóis/toxicidade , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose , Linhagem Celular Tumoral , Feminino , Células da Granulosa/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Aspirin eugenol ester (AEE) possesses anti-thrombotic, anti-atherosclerotic and anti-oxidative effects. The study aims to clarify the mechanism underlying the anti-atherosclerotic effects of AEE on vascular endothelial dysfunction. Both the high-fat diet (HFD)-induced atherosclerotic rat model and the H2O2-induced human umbilical vein endothelial cells (HUVECs) model were used to investigate the effects of AEE on vascular endothelial dysfunction. UPLC/QTOF-MS coupled with a multivariate data analysis method were used to profile the variations in the metabolites of HUVECs in response to different treatments. Pretreatment of HUVECs with AEE significantly ameliorated H2O2-induced apoptosis, the overexpression of E-selectin and VCAM-1, and the adhesion of THP-1 cells. Putative endogenous biomarkers associated with the inhibition of endothelial dysfunction were identified in HUVECs pretreated with AEE in the absence or presence of H2O2, and these biomarkers were involved in important metabolic pathways, including amino acid metabolism, carbohydrate metabolism, and glutathione metabolism. Moreover, in vivo, AEE also significantly reduced vascular endothelial dysfunction and decreased the overexpression of VCAM-1 and E-selectin. Based on our findings, the mechanism underlying the anti-atherosclerotic effects of AEE might be related to a reduction in vascular endothelial dysfunction mediated by ameliorating alterations in metabolism, inhibiting oxidative stress, and decreasing the expression of adhesion molecules.
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Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/análogos & derivados , Endotélio Vascular/efeitos dos fármacos , Eugenol/análogos & derivados , Placa Aterosclerótica/tratamento farmacológico , Inibidores da Agregação Plaquetária/farmacologia , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Apoptose , Aspirina/farmacologia , Aspirina/uso terapêutico , Linhagem Celular , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Selectina E/metabolismo , Endotélio Vascular/metabolismo , Eugenol/farmacologia , Eugenol/uso terapêutico , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Metaboloma , Inibidores da Agregação Plaquetária/uso terapêutico , Ratos , Ratos Sprague-Dawley , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Oxidative balance plays a pivotal role in physiological homeostasis, and many diseases, particularly age-related conditions, are closely associated with oxidative imbalance. While the strategic role of oxidative regulation in various diseases is well-established, the specific involvement of oxidative stress in atherosclerosis remains elusive. Atherosclerosis is a chronic inflammatory disorder characterized by plaque formation within the arteries. Alterations in the oxidative status of vascular tissues are linked to the onset, progression, and outcome of atherosclerosis. This review examines the role of redox signaling in atherosclerosis, including its impact on risk factors such as dyslipidemia, hyperglycemia, inflammation, and unhealthy lifestyle, along with dysregulation, vascular homeostasis, immune system interaction, and therapeutic considerations. Understanding redox signal transduction and the regulation of redox signaling will offer valuable insights into the pathogenesis of atherosclerosis and guide the development of novel therapeutic strategies.
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SCOPE: While probiotics-based therapies have exhibited potential in alleviating alcohol-associated liver disease (ALD), the specific role of postbiotics derived from Lactobacillus reuteri (L. reuteri) in ALD remains elusive. This study aims to investigate the impact of postbiotics on ameliorating alcohol-induced hepatic steatosis and the underlying mechanisms. METHODS AND RESULTS: Using network pharmacology, the study elucidates the targets and pathways impacted by postbiotics from L. reuteri, identifying the farnesoid X receptor (FXR) as a promising target for postbiotics against ALD, and lipid metabolism and alcoholism act as crucial pathways associated with postbiotics-targeting ALD. Furthermore, the study conducts histological and biochemical analyses coupled with LC/MS to evaluate the protective effects and mechanisms of postbiotics against ALD. Postbiotics may modulate bile acid metabolism in vivo by regulating FXR signaling, activating the FXR/FGF15 pathway, and influencing the enterohepatic circulation of bile acids (BAs). Subsequently, postbiotics regulate hepatic FXR activated by BAs and modulate the expression of FXR-mediated protein, including short regulatory partner (SHP) and sterol regulatory element binding protein-1c (SREBP-1c), thereby ameliorating hepatic steatosis in mice with ALD. CONCLUSION: Postbiotics effectively alleviate ethanol-induced hepatic steatosis by regulating the FXR/SHP/SREBP-1c axis, as rigorously validated in both in vivo and in vitro.
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Ácidos e Sais Biliares , Etanol , Limosilactobacillus reuteri , Camundongos Endogâmicos C57BL , Receptores Citoplasmáticos e Nucleares , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 1 , Limosilactobacillus reuteri/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Animais , Receptores Citoplasmáticos e Nucleares/metabolismo , Masculino , Transdução de Sinais/efeitos dos fármacos , Ácidos e Sais Biliares/metabolismo , Camundongos , Hepatopatias Alcoólicas/prevenção & controle , Probióticos/farmacologia , Fatores de Crescimento de Fibroblastos/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , HumanosRESUMO
Species are facing strong selection pressures to adapt to inhospitable high-altitude environments. Yaks are a valuable species and an iconic symbol of the Qinghai-Tibet Plateau. Extensive studies of high-altitude adaptation have been conducted, but few have focused on metabolism. In the present study, we determined the differences in the serum metabolomics between yaks and the closely related species of low-altitude yellow cattle and dairy cows. We generated high-quality metabolite profiling data for 36 samples derived from the three species, and a clear separation trend was obtained between yaks and the other animals from principal component analysis. In addition, we identified a total of 63 differentially expressed metabolites among the three species. Functional analysis revealed that differentially expressed metabolites were related to the innate immune activation, oxidative stress-related metabolism, and energy metabolism in yaks, which indicates the important roles of metabolites in high-altitude adaptation in yaks. The results provide new insights into the mechanism of adaptation or acclimatization to high-altitude environments in yaks and hypoxia-related diseases in humans.
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The complex etiopathology of retained placenta (RP) and hazards associated with it has made it crucial for researchers and clinical veterinarians to study pathogenesis, early-warning diagnosis, and treatment. This study aimed to screen the potential prognostic markers of RP in dairy cows using plasma metabolomics coupled with clinical laboratory indicators. Blood samples were collected from 260 dairy cows at 21, 14, 7, and 0 days before parturition and 7, 14, and 21 days after parturition. Consequently, 10 healthy cows and 10 cows with RP with similar parity, body condition score, and age were included in the study. The changes in clinical laboratory indicators of the enrolled cows from 21 before parturition to 21 days after parturition were assessed. After initial overview of the multivariate statistical data using PCA analysis, the data were subjected to orthogonal partial least-squares discriminant analysis. Compared with cows with RP at 7 days before parturition, the levels of endothelin and 6-keto-prostaglandin F1α were increased in healthy cows, while the level of estradiol and progesterone decreased. Adenine dinucleotide phosphate, hypoxanthine, guanine dinucleotide phosphate, inosine monophosphate, and L-arginine were revealed as potential prognostic markers of cows with RP at 7 days before parturition involved in the regulation of taste transduction, purine and glutathione metabolism, and autophagy. The best period for the early-warning diagnosis of RP in dairy cows is 7 days before parturition, and purine metabolism and autophagy may play a vital role in the occurrence and development of RP in dairy cows.
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Doenças dos Bovinos , Placenta Retida , Gravidez , Feminino , Bovinos , Animais , Placenta Retida/diagnóstico , Placenta Retida/veterinária , Placenta Retida/epidemiologia , Período Pós-Parto , Laboratórios Clínicos , Prognóstico , Doenças dos Bovinos/epidemiologia , Metabolômica , Purinas , Fosfatos , LactaçãoRESUMO
BACKGROUND: Rhododendron nivale Hook. f (R.n), one of the four Manna Stash used in Tibetan medicine to delay aging, possesses anti-aging pharmacological activity. However, which R.n ingredients contain anti-aging properties and the underlying mechanisms involved are unclear. HYPOTHESIS/PURPOSE: Based on interactions between gut microbiota and natural medicines and the important role of gut microbiota in anti-aging, the study investigated the hypothesis that R.n possesses anti-aging properties and the interaction of gut microbiota with R.n is responsible for its anti-aging effects. STUDY DESIGN: The primary active ingredients of R.n and their target function and pathway enrichment were explored. An aging mouse model was used to clarify the underlying anti-aging mechanisms of R.n. METHODS: Chromatography, spectroscopy, nuclear magnetic technology, and pharmacology were used to reveal the major active ingredients of ethanol extract residues of R.n (RNEA). The target function and pathway enrichment of these active ingredients were explored. Plasma metabolomics coupled with intestinal flora evaluation and bioinformatics analysis was used to clarify the underlying anti-aging mechanisms of RNEA. RESULTS: Myricetin-3-ß-D-xylopyranoside, hyperin, goospetin-8-methyl ether 3-ß-D-galactoside, and diplomorphanin B were separated and identified from RNEA. The network pharmacology study revealed that the active ingredients' target function and pathway enrichment focused mainly on the glutathione antioxidant system. In a D-galactose-induced mouse model of aging, RNEA was shown to possess suitable anti-aging pharmacological activity, as indicated by the amelioration of memory loss and weakened superoxide dismutase and glutathione peroxidase activities. Plasma metabolomics coupled with intestinal flora examination and bioinformatics analysis revealed that RNEA could regulate the expression of glutathione-related enzymes and ameliorate D-galactose-induced imbalances in methionine, glycine, and serine, and betaine and galactose metabolism. The results showed that RNEA reshaped the disordered intestinal flora and mitigated the D-galactose-mediated decline in glutathione oxidase expression, further confirming that the anti-aging effect of RNEA was closely related to regulation of the glutathione antioxidant system. CONCLUSION: RNEA, consisting of myricetin-3-ß-D-xylopyranoside, hyperin, goospetin-8-methyl ether 3-ß-D-galactoside, and diplomorphanin B, possesses anti-aging activity. The anti-aging effect of RNEA might be due to reshaping intestinal flora homeostasis, increasing the expression of glutathione peroxidase 4 in the intestines and liver, enhancing glutathione peroxidase activity, and reinforcing the glutathione antioxidant system.
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Microbioma Gastrointestinal , Éteres Metílicos , Rhododendron , Envelhecimento , Animais , Antioxidantes/farmacologia , Modelos Animais de Doenças , Flavonoides/farmacologia , Galactose/farmacologia , Galactosídeos/farmacologia , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Éteres Metílicos/farmacologia , Camundongos , Estresse Oxidativo , Rhododendron/metabolismoRESUMO
Metabolic abnormality has been considered to be the seventh characteristic in cancer cells. The potential prospect of using serum biomarkers metabolites to differentiate ALL from AML remains unclear. The purpose of our study is to probe whether the differences in metabolomics are related to clinical laboratory-related indicators. We used LC-MS-based metabolomics analysis to study 50 peripheral blood samples of leukemia patients from a single center. Then Chi-square test and T test were used to analyze the clinical characteristics, laboratory indicators and cytokines of 50 patients with leukemia. Correlation analysis was used to explore the relationship between them and the differential metabolites of different types of leukemia. Our study shows that it is feasible to better identify serum metabolic differences in different types and states of leukemia by metabolomic analysis on existing clinical diagnostic techniques. The metabolism of choline and betaine may also be significantly related to the patient's blood lipid profile. The main enrichment pathways for distinguishing differential metabolites in different types of leukemia are amino acid metabolism and fatty acid metabolism. All these findings suggested that differential metabolites and lipid profiles might identify different types of leukemia based on existing clinical diagnostic techniques, and their rich metabolic pathways help us to better understand the physiological characteristics of leukemia.
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Alcoholic liver disease (ALD) is caused by alcohol abuse and can progress to hepatitis, cirrhosis, and even hepatocellular carcinoma. Previous studies suggested that Lactobacillus reuteri (L. reuteri) ameliorates ALD, but the exact mechanisms are not fully known. This study created an ALD model in mice, and the results showed L. reuteri significantly alleviating lipid accumulation in the mice. Transcriptome sequencing showed the L. reuteri treatment group had the most enriched metabolic pathway genes. We then studied the farnesoid X receptor (FXR) metabolic pathway in the mice liver tissue. Western blot analysis showed that FXR and carbohydrate response element binding protein (ChREBP) were upregulated and sterol regulatory element binding transcription factor 1 (Srebf1) and Cluster of differentiation (CD36) were downregulated in the L. reuteri-treated group. Subsequently, we administered FXR inhibitor glycine-ß-muricholic acid (Gly-ß-MCA) to mice, and the results show that Gly-ß-MCA could reduce the therapeutic effect of L. ruteri. In conclusion, our study shows L. reuteri improved liver lipid accumulation in mice via the FXR signaling regulatory axis and may be a viable treatment option for ALD.
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Doença Hepática Crônica Induzida por Substâncias e Drogas , Limosilactobacillus reuteri , Hepatopatias Alcoólicas , Animais , Carboidratos/farmacologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/patologia , Etanol/metabolismo , Glicina/farmacologia , Limosilactobacillus reuteri/genética , Lipídeos/farmacologia , Fígado/metabolismo , Hepatopatias Alcoólicas/metabolismo , Camundongos , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais , Esteróis/metabolismo , TranscriptomaRESUMO
BACKGROUND: As a major metabolic site, the liver is an important target organ of endotoxemia. High serum lipopolysaccharide (LPS) levels can cause hepatocyte necrosis and produce cholestasis, which results in severe liver injury. Contrastingly, thiamine (THA) has shown anti-inflammatory effects against severe infections and may be indicated for systemic endotoxemia treatment. Therefore, the present study was conducted to investigate the effective treatment of endotoxemia-induced liver injury with THA and the possible molecular mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: in vivo, We established two models of endotoxemia-induced liver injury at the in vivo level using LPS and bile duct ligation (BDL) + LPS, administering prophylactic THA intraperitoneally to mice. In vitro, the effects of THA on RAW264.7 and THP-1 administration of LPS-induced inflammatory macrophage activation were observed. Metabolomic analysis screening and subsequent validation experiments were also performed. THA has different degrees of preventive therapeutic effects on different causes of endotoxemia-induced liver injury, as evidenced by a decreased alanine aminotransferase (ALT) and decreased inflammatory factors. This study aimed to clarify the specific mechanism. We subsequently found that THA reduced the inflammatory macrophages produced by RAW264.7 and THP-1 in response to LPS. Additionally, THA reduced galactose liver accumulation and improved glucose metabolism. Moreover, Galectin-3 (Gal-3), as a point of interaction between macrophage activation and galactose metabolism mechanisms, was observed to inhibit Gal-3 expression by THA at both in vivo and in vitro levels. CONCLUSIONS: This study revealed that THA may be a viable prophylactic treatment option for the prevention of liver injury occurring in endotoxemia, which is associated with its effects on the modulation of Gal-3 to improve the inflammatory response and the inhibition of galactose metabolism. Additional evidence is provided for its clinical application.
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Doença Hepática Crônica Induzida por Substâncias e Drogas , Colestase , Endotoxemia , Animais , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Colestase/complicações , Endotoxemia/tratamento farmacológico , Galactose/metabolismo , Lipopolissacarídeos/farmacologia , Fígado , Ativação de Macrófagos , Camundongos , Tiamina/metabolismo , Tiamina/farmacologia , Tiamina/uso terapêuticoRESUMO
The complex etiology and pathogenesis of retained placenta (RP) bring huge challenges for researchers and clinical veterinarians in investigating the pathogenesis and treatment schedule. This study aims to investigate the pathogenesis of RP in dairy cows by plasma metabolomics. As subjects, 10 dairy cows with RP and 10 healthy dairy cows were enrolled according to strict enrollment criteria. Imbalanced antioxidant capacity, reduced Th1/Th2 cytokine ratio, and deregulation of total bilirubin (T-bil), alkaline phosphatase (ALP), and reproductive hormones were shown in dairy cows with RP by detecting biochemical indicators, oxidation and antioxidant markers, and cytokines in serum. Plasma metabolites were detected and analyzed by a liquid chromatography-mass spectrometry (LC-MS) system coupled with multivariate statistical analysis software. A total of 23 potential biomarkers were uncovered in the plasma of dairy cows with RP. The metabolic pathways involved in these potential biomarkers are interconnected, and the conversion, utilization, and excretion of nitrogen were disturbed in dairy cows with RP. Moreover, these potential biomarkers are involved in the regulation of antioxidant capacity, inflammation, and autocrine or paracrine hormone. All of these findings suggest that an imbalance of these potential biomarkers might be responsible for the imbalanced antioxidant capacity, reduced Th1/Th2 cytokine ratio, and deregulation of reproductive hormones in dairy cows with RP. The regulation of metabolic pathways involved in these potential biomarkers represents a promising therapeutic strategy for RP.
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The purpose of this study is to investigate the protective effect of γ-oryzanol (ORY) against hepatic ischemia reperfusion (HIR) injury and the potential protective mechanisms of ORY. ORY is an important biologically active ingredient isolated from rice bran oil, which has anti-inflammatory and antiapoptotic effects. However, it is still unknown whether ORY can protect the liver from the HIR damage. In this study, ORY was administered orally for seven days, after which the animals were subjected to liver ischemia for 60 minutes and reperfused for 6 hours. Related indicators were analyzed. The results showed that ORY pretreatment significantly reduced the levels of AST and ALT, relieved hepatocellular damage and apoptosis, and attenuated the exhaustion of SOD and GSH and accumulation of MDA and MPO. Interestingly, ORY treatment could significantly decreased ER stress. Furthermore, ORY pretreatment remarkably reduced the protein expressions of HMGB1, NLRP3, caspase-1 (p20), and IL-1ß to protect the liver from I/R-induced inflammasome activation and apoptosis. In conclusion, we demonstrated the potential effect of ORY in modulating oxidative stress, endoplasmic reticulum stress, and inflammasome activation during HIR.
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Estresse do Retículo Endoplasmático/efeitos dos fármacos , Proteína HMGB1/metabolismo , Inflamassomos/efeitos dos fármacos , Fígado/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fenilpropionatos/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Suplementos Nutricionais , Modelos Animais de Doenças , Humanos , Hipolipemiantes/farmacologia , Fígado/efeitos dos fármacos , Masculino , CamundongosRESUMO
Long non-coding RNAs (lncRNAs) play a significant role in multiple human cancers as competing endogenous RNAs (ceRNAs). However, a systematic mRNA-microRNA (miRNA)-lncRNA network linked to kidney renal clear cell carcinoma (KIRC) prognosis has not been described. In this study, we aimed to identify the prognosis-related ceRNA regulatory network and analyzed its relationship with immune cell infiltration to predict KIRC patient survival. The MMP25-AS1/hsa-miR-10a-5p/SERPINE1 ceRNA network related to the prognosis of KIRC was obtained through bioinformatics analysis based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Meanwhile, we constructed a three-gene-based survival predictor model, which could be referential for future clinical research. Methylation analyses suggested that the abnormal upregulation of the SERPINE1 likely resulted from hypomethylation. Furthermore, the immune infiltration analysis showed that the MMP25-AS1/hsa-miR-10a-5p/SERPINE1 axis could affect the changes in the tumor immune microenvironment and the development of KIRC by affecting the expression of chemokines (CCL4, CCL5, CXCL13, and XCL2). Tumor Immune Dysfunction and Exclusion (TIDE) analysis indicated that the high expression of SERPINE1 might be related to tumor immune evasion in KIRC. In summary, the current study constructing the MMP25-AS1/hsa-miR-10a-5p/SERPINE1 ceRNA network might be a novel significant prognostic factor associated with the diagnosis and prognosis of KIRC.
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Oxidative stress is recognized as free radical dyshomeostasis, which has damaging effects on proteins, lipids and DNA. However, during cell differentiation and proliferation and other normal physiological processes, free radicals play a pivotal role in message transmission and are considered important messengers. Organisms maintain free radical homeostasis through a sophisticated regulatory system in which these "2-faced" molecules play appropriate roles under physiological and pathological conditions. Reactive oxygen species (ROS), including a large number of free radicals, act as redox signalling molecules in essential cellular signalling pathways, including cell differentiation and proliferation. However, excessive ROS levels can induce oxidative stress, which is an important risk factor for diabetes, cancer and cardiovascular disease. An overall comprehensive understanding of ROS is beneficial for understanding the pathogenesis of certain diseases and finding new therapeutic treatments. This review primarily focuses on ROS cellular localization, sources, chemistry and molecular targets to determine how to distinguish between the roles of ROS as messengers and in oxidative stress.
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Espécies Reativas de Oxigênio/química , Espécies Reativas de Oxigênio/metabolismo , Animais , Regulação da Expressão Gênica , Oxirredução , Espécies Reativas de NitrogênioRESUMO
The complex etiology, higher morbidity and mortality, poor prognosis, and expensive cost of calf diarrhea have made it a catastrophic disease in the dairy industry. This study aims to assess the biomarkers in calves with diarrhea and to predict the biomarkers related to the pathway. As subjects, nine calves with diarrhea and nine healthy calves were enrolled, according to strict enrollment criteria. The serum metabolites were detected by a liquid chromatographic tandem mass spectrometry (LC-MS/MS), and then analyzed by online multivariate statistical analysis software to further screen the biomarkers. In addition, the biomarkers involved in the metabolic pathways of calves with diarrhea and healthy calves were analyzed. In the serum of calves with diarrhea, nine biomarkers were found to which several biomarkers exhibited a certain relation. Moreover, these biomarkers were involved in important metabolic pathways, including protein digestion and absorption, ABC transporters, aminoacyl-tRNA biosynthesis, mineral absorption, and fatty acid biosynthesis. All these findings suggested that the imbalance of these markers was closely related to the occurrence and development of calf diarrhea. The targeted regulation of metabolic pathways involved in these biomarkers may facilitate the diagnosis, treatment, and discussion of the mechanism of calf diarrhea.
RESUMO
Aspirin eugenol ester (AEE) is a new potential drug with anti-inflammatory and antioxidant stress pharmacological activity. Paraquat (PQ) is an effective and commercially important herbicide that is widely used worldwide. However, paraquat is highly toxic and can cause various complications and acute organ damage, such as liver, kidney and lung damage. The purpose of this study was to investigate whether AEE has a protective effect on hepatotoxicity induced by PQ in vivo and in vitro. Cell viability, apoptosis rate, mitochondrial function and intracellular oxidative stress were detected to evaluate the protective effect of AEE on PQ-induced BRL-3A (normal rat hepatocytes) cytotoxicity in vitro. In vivo, AEE pretreatment could attenuate oxidative stress and histopathological changes in rat liver induced by PQ. The results showed that AEE could reduce the hepatotoxicity induced by PQ in vivo and in vitro. AEE reduced PQ-induced hepatotoxicity by inhibitingoxidative stress and maintaining mitochondrial function. This study proved that AEE is an effective antioxidant and can reduce the hepatotoxicity of PQ.