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المصدر: Pflügers Archiv - European Journal of Physiology. 473:1667-1683
مصطلحات موضوعية: medicine.hormone, Stromal cell, Physiology, Clinical Biochemistry, Kidney development, Kidney, urologic and male genital diseases, Endothelins, Endothelin-1, Endothelin receptors, Kidney fibrosis, Unilateral ureter occlusion, Adenine-induced nephropathy, Mice, Fibrosis, Physiology (medical), medicine, Renal fibrosis, Animals, 570 Biowissenschaften, Biologie, RNA, Messenger, Chemistry, Adenine, Receptor, Endothelin A, medicine.disease, Receptor, Endothelin B, Endothelin 1, Up-Regulation, medicine.anatomical_structure, Gene Expression Regulation, cardiovascular system, Cancer research, Kidney Diseases, ddc:570, Endothelin receptor, Gene Deletion, Ureteral Obstruction
الوصف: Renal interstitial fibrosis is characterized by the development of myofibroblasts, originating from resident renal and immigrating cells. Myofibroblast formation and extracellular matrix production during kidney damage are triggered by various factors. Among these, endothelins have been discussed as potential modulators of renal fibrosis. Utilizing mouse models of adenine nephropathy (AN) and unilateral ureter occlusion (UUO), this study aimed to investigate the contribution of endothelin signaling in stromal mesenchymal resident renal interstitial cells. We found in controls that adenine feeding and UUO caused marked upregulations of endothelin-1 (ET-1) gene expression in endothelial and in tubular cells and a strong upregulation of ETA-receptor (ETA-R) gene expression in interstitial and mesangial cells, while the gene expression of ETB-receptor (ETB-R) did not change. Conditional deletion of ETA-R and ETB-R gene expression in the FoxD1 stromal cell compartment which includes interstitial cells significantly reduced renal ETA-R gene expression and moderately lowered renal ETB-R gene expression. ET receptor (ET-R) deletion exerted no apparent effects on kidney development nor on kidney function. Adenine feeding and UUO led to similar increases in profibrotic and proinflammatory gene expression in control as well as in ETAflflETBflfl FoxD1Cre+ mice (ET-Ko). In summary, our findings suggest that adenine feeding and UUO activate endothelin signaling in interstitial cells which is due to upregulated ETA-R expression and enhanced renal ET-1 production Our data also suggest that the activation of endothelin signaling in interstitial cells has less impact for the development of experimentally induced fibrosis.
وصف الملف: application/pdf
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المؤلفون: Denny Sakkas, Daniel J. Needleman, Jaimin S. Shah, Xingbo Yang, Tim Sanchez, William Conway, Marta Venturas
المصدر: Human Reproduction. 37:411-427
مصطلحات موضوعية: Fluorescence-lifetime imaging microscopy, Embryonic Development, Reproductive technology, Biology, Embryo Culture Techniques, Human fertilization, medicine, Inner cell mass, Animals, Humans, Blastocyst, Zona pellucida, reproductive and urinary physiology, Mammals, urogenital system, Adenine, Rehabilitation, Obstetrics and Gynecology, Embryo, Aneuploidy, Cell biology, Autofluorescence, medicine.anatomical_structure, Microscopy, Fluorescence, Reproductive Medicine, embryonic structures
الوصف: STUDY QUESTION Can non-invasive metabolic imaging via fluorescence lifetime imaging microscopy (FLIM) detect variations in metabolic profiles between discarded human blastocysts? SUMMARY ANSWER FLIM revealed extensive variations in the metabolic state of discarded human blastocysts associated with blastocyst development over 36 h, the day after fertilization and blastocyst developmental stage, as well as metabolic heterogeneity within individual blastocysts. WHAT IS KNOWN ALREADY Mammalian embryos undergo large changes in metabolism over the course of preimplantation development. Embryo metabolism has long been linked to embryo viability, suggesting its potential utility in ART to aid in selecting high quality embryos. However, the metabolism of human embryos remains poorly characterized due to a lack of non-invasive methods to measure their metabolic state. STUDY DESIGN, SIZE, DURATION We conducted a prospective observational study. We used 215 morphologically normal human embryos from 137 patients that were discarded and donated for research under an approved institutional review board protocol. These embryos were imaged using metabolic imaging via FLIM to measure the autofluorescence of two central coenzymes, nicotinamide adenine (phosphate) dinucleotide (NAD(P)H) and flavine adenine dinucleotide (FAD+), which are essential for cellular respiration and glycolysis. PARTICIPANTS/MATERIALS, SETTING, METHODS Here, we used non-invasive FLIM to measure the metabolic state of human blastocysts. We first studied spatial patterns in the metabolic state within human blastocysts and the association of the metabolic state of the whole blastocysts with stage of expansion, day of development since fertilization and morphology. We explored the sensitivity of this technique in detecting metabolic variations between blastocysts from the same patient and between patients. Next, we explored whether FLIM can quantitatively measure metabolic changes through human blastocyst expansion and hatching via time-lapse imaging. For all test conditions, the level of significance was set at P MAIN RESULTS AND THE ROLE OF CHANCE We found that FLIM is sensitive enough to detect significant metabolic differences between blastocysts. We found that metabolic variations between blastocyst are partially explained by both the time since fertilization and their developmental expansion stage (P LIMITATIONS, REASONS FOR CAUTION Although we observed significant variations in metabolic parameters, our data are taken from human blastocysts that were discarded and donated for research and we do not know their clinical outcome. Moreover, the embryos used in this study are a mixture of aneuploid, euploid and embryos of unknown ploidy. WIDER IMPLICATIONS OF THE FINDINGS This work reveals novel aspects of the metabolism of human blastocysts and suggests that FLIM is a promising approach to assess embryo viability through non-invasive, quantitative measurements of their metabolism. These results further demonstrate that FLIM can provide biologically relevant information that may be valuable for the assessment of embryo quality. STUDY FUNDING/COMPETING INTEREST(S) Supported by the Blavatnik Biomedical Accelerator Grant at Harvard University. Becker and Hickl GmbH and Boston Electronics sponsored research with the loaning of equipment for FLIM. D.J.N. is an inventor on patent US20170039415A1. TRIAL REGISTRATION NUMBER N/A.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fa555f6ee328c97f8eef16428036e048
https://doi.org/10.1093/humrep/deab283 -
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المؤلفون: Yoshiro Matsui, Satoshi Sugimoto, Yasushige Shingu, Satoru Wakasa, Hidetsugu Asai, Tomoji Yamakawa, Torsten Doenst
المصدر: The Journal of Thoracic and Cardiovascular Surgery. 163:e33-e40
مصطلحات موضوعية: Cardiomyopathy, Dilated, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Rat model, Myocardial Ischemia, Autophagy-Related Proteins, 030204 cardiovascular system & hematology, Ventricular Function, Left, 03 medical and health sciences, 0302 clinical medicine, Recurrence, Internal medicine, Autophagy, medicine, Animals, Myocyte, Myocytes, Cardiac, Myocardial infarction, Cardiomyoplasty, Ischemic cardiomyopathy, Ventricular Remodeling, business.industry, Adenine, Cardiovascular Agents, medicine.disease, Rats, medicine.anatomical_structure, 030228 respiratory system, Echocardiography, Heart failure, Cardiology, Surgery, Cardiology and Cardiovascular Medicine, Ligation, business, Microtubule-Associated Proteins, Artery
الوصف: Objectives Myocardial autophagy has been recognized as an important factor in heart failure. It is not known whether changes in ventricular geometry by left ventriculoplasty influence autophagy in ischemic cardiomyopathy. We hypothesized that myocardial autophagy plays an important role in left ventricular (LV) redilation after ventriculoplasty. Methods Four weeks after ligation of the left anterior descending artery, ventriculoplasty or sham operation was performed. The animals were euthanized at 2 days (early) or 28 days (late) after the second operation. Ventricular autophagy was evaluated by protein expression of microtubule-associated protein light chain 3 II, an autophagosome marker. Cardiomyocyte area was assessed by histologic examination. LV function was evaluated by echocardiography. To examine the implications of autophagy, an autophagy inhibitor (3-methyladenine) was injected intraperitoneally for 3 weeks before sacrifice. Results The LV was reduced in size early and redilated late after ventriculoplasty. LV systolic function was improved early and later worsened after ventriculoplasty. Light chain 3 II expression decreased early after ventriculoplasty and increased in the late period. Myocyte area increased from the early to late stage after ventriculoplasty. Autophagic inhibition exaggerated the increased myocyte hypertrophy and LV redilation. Conclusions In a rat model of myocardial infarction, autophagy decreased early after ventriculoplasty and increased again during LV redilation. These results provide new insights into the mechanism underlying the late failure of ventriculoplasty.
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المؤلفون: Wenchao Wei, Chi Chun Wong, Xiang Zhang, Jun Yu, Weixin Liu, Feixue Wang, Yunfei Zhou, Dabin Liu, Joseph J.Y. Sung
المصدر: Cellular and Molecular Gastroenterology and Hepatology, Vol 13, Iss 1, Pp 257-274 (2022)
Cellular and Molecular Gastroenterology and Hepatologyمصطلحات موضوعية: medicine.medical_treatment, Nonalcoholic Steatohepatitis, AST, aspartate aminotransferase, RC799-869, IL12, interleukin 12, Non-alcoholic Fatty Liver Disease, TBARS, thiobarbituric acid reactive substances, NK cell, natural killer cell, NF-κB, nuclear factor kappa B, Original Research, Activated Natural Killer Cell, JAK-STAT, Janus kinase-signal transducer and activator of transcription, Chemistry, Gastroenterology, JAK-STAT signaling pathway, ELISA, enzyme-linked immunosorbent assay, TG, triglycerides, Diseases of the digestive system. Gastroenterology, Killer Cells, Natural, medicine.anatomical_structure, Cytokine, Interleukin 12, LPS, lipopolysaccharide, FITC, fluorescein isothiocyanate, GM-CSF, granulocyte-macrophage colony-stimulating factor, NASH, nonalcoholic steatohepatitis, CDHF, choline-deficient high-fat diet, MFI, mean fluorescent intensity, CCL5, Natural killer cell, ROS, reactive oxygen species, ALT, alanine aminotransferase, medicine, KEGG, Kyoto encyclopedia of genes and genomes, Humans, MoMF, monocyte derived macrophage, MCD, methionine- and choline-deficient, IFN-γ, interferon gamma, Hepatology, nutritional and metabolic diseases, NADPH, nicotinamide adenine dinucleotide phosphate, medicine.disease, NKG2D, Ig, immunoglobulin, JAK/STAT, Cancer research, NAFLD, nonalcoholic fatty liver disease, Steatohepatitis, HCC, hepatocellular carcinoma, NKT cell, natural killer T cell, Natural Killer Cell
الوصف: Background & Aims Hepatic immune microenvironment plays a pivotal role in the development of nonalcoholic steatohepatitis (NASH). However, the role of natural killer (NK) cells, accounting for 10%–20% of liver lymphocytes, in NASH is still unclear. In this study, we aim to investigate the functional significance of NK cells in NASH evolution. Methods NASH was induced in mice fed methionine- and choline-deficient diet (MCD), choline-deficient high-fat diet (CD-HFD), or high-fat diet with streptozotocin injection (STAM model). NK cell deficient mice (Nfil3-/-) and neutralization antibody (PK136) were used in this study. Results Activated liver NK cells were identified with increased expression of NKG2D, CD107a, and interferon-γ but decreased inhibitory NKG2A. With NK cell deficiency Nfil3-/- mice, the absence of NK cells ameliorated both MCD- and CDHF- induced NASH development with significantly decreased hepatic triglycerides, peroxides, alanine aminotransferase, and aspartate aminotransferase compared with Nfil3+/+ mice. Further molecular analysis unveiled suppressed pro-inflammatory cytokines and associated signaling. Mechanistically, NK cells isolated from NASH liver secreted higher levels of pro-inflammatory cytokines (interferon-γ, interleukin 1β, interleukin 12, CCL4, CCL5, and granulocyte-macrophage colony-stimulating factor), which could activate hepatic JAK-STAT1/3 and nuclear factor kappa B signaling and induce hepatocyte damage evidenced by elevated reactive oxygen species and apoptosis rate. Moreover, neutralization antibody PK136-dependent NK cell depletion can significantly alleviate MCD-induced steatohepatitis with suppressed cytokine levels and JAK-STAT1/3 activity. Conclusions NK cells in NASH liver are activated with a more pro-inflammatory cytokine milieu and promote NASH development via cytokine-JAK-STAT1/3 axis. Modulation of NK cells provides a potential therapeutic strategy for NASH.
Graphical abstractURL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2c28da1742a020c4b72f0c4a997351c0
http://www.sciencedirect.com/science/article/pii/S2352345X21001867 -
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المؤلفون: Masashi Yoshida, Masafumi Kakei, Shunsuke Funazaki, Kazuo Hara, Masanobu Kawakami, Katsuya Dezaki, Shuichi Nagashima, Hodaka Yamada
المصدر: Journal of Diabetes Investigation, Vol 13, Iss 1, Pp 34-41 (2022)
Journal of Diabetes Investigationمصطلحات موضوعية: Blood Glucose, Male, Basic Science and Research, endocrine system, Imeglimin, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, TRPM Cation Channels, Nicotinamide adenine dinucleotide, Pharmacology, Cyclic ADP-ribose, Diseases of the endocrine glands. Clinical endocrinology, Islets of Langerhans, Mice, chemistry.chemical_compound, Transient receptor potential channel, Insulin Secretion, Internal Medicine, Animals, Hypoglycemic Agents, Medicine, TRPM2, ADP-ribosyl Cyclase, Triazines, business.industry, Pancreatic islets, Insulin, Articles, General Medicine, RC648-665, Transient receptor potential melastatin 2, medicine.anatomical_structure, chemistry, Cyclic ADP ribose, Original Article, NAD+ kinase, business, Signal Transduction
الوصف: Aims/Introduction Imeglimin is a novel oral hypoglycemic agent that improves blood glucose levels through multiple mechanisms of action including the enhancement of glucose‐stimulated insulin secretion (GSIS), however, the details of this mechanism have not been clarified. In the process of GSIS, activation of the transient receptor potential melastatin 2 (TRPM2) channel, a type of non‐selective cation channel (NSCCs) in β‐cells, promotes plasma membrane depolarization. The present study aimed to examine whether imeglimin potentiates GSIS via the TRPM2 channel in β‐cells. Materials and Methods Pancreatic islets were isolated by collagenase digestion from male wild‐type and TRPM2‐knockout (KO) mice. Insulin release and nicotinamide adenine dinucleotide (NAD+) production in islets were measured under static incubation. NSCC currents in mouse single β‐cells were measured by patch‐clamp experiments. Results Batch‐incubation studies showed that imeglimin enhanced GSIS at stimulatory 16.6 mM glucose, whereas it did not affect basal insulin levels at 2.8 mM glucose. Imeglimin increased the glucose‐induced production of NAD+, a precursor of cADPR, in islets and the insulinotropic effects of imeglimin were attenuated by a cADPR inhibitor 8‐Br‐cADPR. Furthermore, imeglimin increased NSCC current in β‐cells, and abolished this current in TRPM2‐KO mice. Imeglimin did not potentiate GSIS in the TRPM2‐KO islets, suggesting that imeglimin’s increase of NSCC currents through the TRPM2 channel is causally implicated in its insulin releasing effects. Conclusions Imeglimin may activate TRPM2 channels in β‐cells via the production of NAD+/cADPR, leading to the potentiation of GSIS. Developing approaches to stimulate cADPR‐TRPM2 signaling provides a potential therapeutic tool to treat type 2 diabetes.
Imeglimin may activate TRPM2 channels in β‐cells via the production of NAD+/cADPR, leading to the potentiation of GSIS. -
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المؤلفون: Sadayoshi Ito, Mariko Miyazaki, Hiroshi Sato, Akiyo Sekimoto, Emiko Sato, Yuji Oe, Nobuyuki Takahashi, Shohei Mitsui, Naoko Shibata, Kiyomi Kisu
المصدر: The American Journal of Pathology. 191:283-293
مصطلحات موضوعية: 0301 basic medicine, medicine.medical_specialty, Nitric Oxide Synthase Type III, Exacerbation, 030204 cardiovascular system & hematology, medicine.disease_cause, Pathology and Forensic Medicine, Mice, 03 medical and health sciences, chemistry.chemical_compound, Ectopic calcification, 0302 clinical medicine, Enos, medicine.artery, Internal medicine, medicine, Animals, Renal Insufficiency, Chronic, Aorta, Uremia, Kidney, biology, business.industry, Adenine, Calcinosis, Phosphorus, biology.organism_classification, medicine.disease, Diet, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, chemistry, Mice, Inbred DBA, business, Nicotinamide adenine dinucleotide phosphate, Oxidative stress, Kidney disease
الوصف: Ectopic calcification is a risk of cardiovascular disease in chronic kidney disease (CKD) patients, and impaired endothelial nitric oxide synthase (eNOS) is involved in the CKD complications. However, whether eNOS dysfunction is a cause of ectopic calcification in CKD remains to be elucidated. To address this issue, we investigated the role of eNOS in ectopic calcification in mice with renal injury caused by an adenine and high-phosphorus (Ade + HP) diet. DBA/2J mice, a calcification-sensitive strain, were fed Ade + HP for 3 weeks. Expression levels of eNOS-related genes were reduced significantly in their calcified aorta. C57BL/6J is a calcification-resistant strain, and wild-type mice showed mild calcified lesions in the aorta and kidney when given an Ade + HP diet for 4 weeks. In contrast, a lack of eNOS led to the development of severe aortic calcification accompanied by an increase in runt-related transcription factor 2, an osteochondrogenic marker. Increased renal calcium deposition and the tubular injury score were remarkable in mice lacking eNOS-fed Ade + HP. Exacerbation of ectopic calcification by a lack of eNOS is associated with increased oxidative stress markers such as nicotinamide adenine dinucleotide phosphate oxidases. In conclusion, eNOS is critically important in preventing ectopic calcification. Therefore, the maintenance of eNOS is useful to reduce cardiovascular disease events and to improve prognosis in CKD patients.
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المؤلفون: Kaneez Fatima, Abha Meena, Suaib Luqman, Nusrat Masood, Zahoor Ahmad Wani
المصدر: Journal of Advanced Research
مصطلحات موضوعية: TRIG, Triglyceraldehyde, Skin Neoplasms, Cell, DOXO, Doxorubicin, Hyaluronidase, Pharmacology, NaOH, Sodium hydroxide, Polymerization, MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, Mice, 0302 clinical medicine, BIL, Bilirubin total & direct, Neomenthol, PEP A, pepstatin A, Cancer biomarker, MEF, Mean erythrocyte fragility, HYAL, Hyaluronidase, PBS, Phosphate buffer saline, CM-H2DCFDA, Chloromethyl derivative of dichloro fluorescin diacetate, HA, Hyaluronic acid, Epidermoid carcinoma, Human epidermoid carcinoma, 030220 oncology & carcinogenesis, RBC, Red blood cell, DMEM, Dulbecco’s minimal essential media, SRB, Sulphorhodamine B, BUN, Blood urea nitrogen, FACS, Fluorescence-Activated Cell Sorting, AKLP, Alkaline phosphatase, Hyaluronoglucosaminidase, NADPH, Nicotinamide adenine dinucleotide phosphate hydrogen, TMPD, N,N,N′,N′-tetramethyl-p-phenylenediamine, Article, 03 medical and health sciences, In vivo, Ehrlich Ascites Carcinoma, BE, Binding energy, Humans, CATD, Cathepsin D, LDH, Lactate dehydrogenase, COX-2, Cyclooxygenase 2, FOX, Ferrous oxidation-xylenol orange, DMSO, Dimethyl sulfoxide, mTOR, Mammalian target of rapamycin, In vitro, Ab/Am, Antibiotic/antimycotic, NRU, Neutral red uptake, EC50, Half maximal effective concentration, 030104 developmental biology, IC50, Half maximal inhibitory concentration, EAC, Ehlrich Ascites Carcinoma, RPMI, Roswell park memorial institute, ROS, Reactive oxygen species, 0301 basic medicine, HDL, High density lipoprotein, TNBS, Trinitrobenzenesulphonic acid, PI3K, Phosphotidyl inositol-3 kinase, URIC, Uric acid, DNA, Deoxyribonucleic acid, GAPDH, Glyceraldehyde 3-phosphate dehydrogenase, HEPES, N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid, Tubulin, OECD, Organization for Economic Co-operation and Development, SGPT, Alanine aminotransferase, LOX-5, Lipoxygenase-5, DFMO, α-difluoro methyl ornithine, Multidisciplinary, WBC, White blood cell, Chemistry, ELISA, enzyme-linked immunosorbent assay, PKB/Akt, Protein kinase B, AA, Arachidonic acid, RNase A, Ribonuclease A, TPR, Total protein, Molecular Docking Simulation, medicine.anatomical_structure, TCA, Tricarboxylic acid, CHOL, Cholesterol, Ki, Inhibitory constant, medicine.drug, ODC, Ornithine decarboxylase, DHFR, Dihydrofolatereductase, BSA, Bovine serum albumin, PDB, Protein Data Bank, medicine, Animals, MMP, Mitochondrial membrane potential, DCFDA, 2′,7′ dichloro fluorescin diacetate, RNA, Ribonucleic acid, RIPA, Radio immune precipitation assay buffer, EDTA, Ethylene diamine tetra acetic acid, IC50, TPA, 12-O-Tetradecanoylphorbol-13-acetate, ComputingMethodologies_COMPUTERGRAPHICS, TRPM8, Transient receptor potential member 8, Cell Proliferation, HDAC, Histone deacetylase, MTX, Methotrexate, OF, Osmotic fragility, PI, Propidium iodide, FDA, Food and Drug Administration, HEK293 Cells, PDT, Podophyllotoxin, Cell culture, NAC, N-acetyl cysteine, SGOT, Aspartate aminotransferase, CRTN, Creatinine, FBS, Fetal bovine serum, PCR, Polymerase chain reaction, Rh123, Rhodamine 123, Ex vivo, IDT, Integrated DNA Technologies
الوصف: Graphical abstract
Introduction Neomenthol, a cyclic monoterpenoid, is a stereoisomer of menthol present in the essential oil of Mentha spp. It is used in food as a flavoring agent, in cosmetics and medicines because of its cooling effects. However, neomenthol has not been much explored for its anticancer potential. Additionally, targeting hyaluronidase, Cathepsin-D, and ODC by phytochemicals is amongst the efficient approach for cancer prevention and/or treatment. Objectives To investigate the molecular and cell target-based antiproliferative potential of neomenthol on human cancer (A431, PC-3, K562, A549, FaDu, MDA-MB-231, COLO-205, MCF-7, and WRL-68) and normal (HEK-293) cell lines. Methods The potency of neomenthol was evaluated on human cancer and normal cell line using SRB, NRU and MTT assays. The molecular target based study of neomenthol was carried out in cell-free and cell-based test systems. Further, the potency of neomenthol was confirmed by quantitative real-time PCR analysis and molecular docking studies. The in vivo anticancer potential of neomenthol was performed on mice EAC model and the toxicity examination was accomplished through in silico, ex vivo and in vivo approaches. Results Neomenthol exhibits a promising activity (IC50 17.3 ± 6.49 μM) against human epidermoid carcinoma (A431) cells by arresting the G2/M phase and increasing the number of sub-diploid cells. It significantly inhibits hyaluronidase activity (IC50 12.81 ± 0.01 μM) and affects the tubulin polymerization. The expression analysis and molecular docking studies support the in vitro molecular and cell target based results. Neomenthol prevents EAC tumor formation by 58.84% and inhibits hyaluronidase activity up to 10% at 75 mg/kg bw, i.p. dose. The oral dose of 1000 mg/kg bw was found safe in acute oral toxicity studies. Conclusion Neomenthol delayed the growth of skin carcinoma cells by inhibiting the tubulin polymerization and hyaluronidase activity, which are responsible for tumor growth, metastasis, and angiogenesis. -
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المؤلفون: Fang Liu, Yuejiao Guo, Chenggang Huang, Xiaoting Tian, Qiang Xiong, Qiang Tian, Mingcang Chen
المصدر: Journal of Separation Science. 44:4384-4394
مصطلحات موضوعية: Male, Spectrometry, Mass, Electrospray Ionization, Arginine, Renal function, Filtration and Separation, Pharmacology, Analytical Chemistry, Rats, Sprague-Dawley, chemistry.chemical_compound, Metabolomics, Metabolome, medicine, Animals, Renal Insufficiency, Chronic, Chromatography, High Pressure Liquid, Kidney, Creatinine, business.industry, Adenine, Albumin, Reproducibility of Results, medicine.disease, Rats, medicine.anatomical_structure, chemistry, business, Kidney disease
الوصف: Chronic kidney disease is an increasingly serious public health problem worldwide. Our recent studies have shown that Huangjinsan has a renal protective effect on chronic kidney disease, but the specific mechanism by which this effect occurs is not clear. To study the therapeutic effect of Huangjinsan on chronic kidney disease and to explore its possible mechanism of action through nontargeted metabolomics methods, a chronic kidney disease rat model was induced by adenine, and the Huangjinsan extract was given by oral gavage. Body weight, the kidney index, pathological sections, and a series of biochemical indicators were measured. High-performance liquid chromatography quadrupole time-of-flight mass spectrometry was used to analyze the changes in the plasma metabolome. Huangjinsan significantly reduced indicators of kidney damage, including total protein, albumin, the total protein to creatinine ratio, and the albumin to creatinine ratio in urine, as well as IL-2, MCP-1α, and blood urea levels in plasma. Based on nontargeted metabolomics, 13 metabolites related to chronic kidney disease were discovered. These metabolites are closely related to glycerophospholipid metabolism, arginine and proline metabolism, and sphingolipid metabolism. We found that Huangjinsan can restore the renal function of adenine-induced chronic kidney disease by regulating the metabolic profile.
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المؤلفون: Yu Nie, Haojie Jin, Baohui Xu, Jihong Meng, Lixiang Xue, Feng Wang, Yafang Wang, Yan Wang, Xiaomu Tan, Heng Zhao, Yang Yao, Cuixia Yang
المصدر: Theranostics
مصطلحات موضوعية: Male, medicine.medical_specialty, Macrophage, Macrophage polarization, Medicine (miscellaneous), Sult2b1, Cholesterol Sulfate, Monocytes, Brain Ischemia, chemistry.chemical_compound, Mice, Immune system, Neuroinflammation, Internal medicine, SULT2B1, Medicine, Animals, Humans, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), Stroke, Ischemic Stroke, Inflammation, Mice, Knockout, business.industry, Cholesterol, Monocyte, Macrophages, Infarction, Middle Cerebral Artery, Recovery of Function, Macrophage Activation, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, medicine.anatomical_structure, Endocrinology, chemistry, Neuroinflammatory Diseases, Cholesterol Esters, Microglia, Sulfotransferases, business, Nicotinamide adenine dinucleotide phosphate, Research Paper, Signal Transduction
الوصف: Rationale: Stroke is a leading causes of human death worldwide. Ischemic damage induces the sterile neuroinflammation, which directly determines the recovery of patients. Lipids, a major component of the brain, significantly altered after stroke. Cholesterol sulfate, a naturally occurring analog of cholesterol, can directly regulate immune cell activation, indicating the possible involvement of cholesterol metabolites in neuroinflammation. Sulfotransferase family 2b member 1 (Sult2b1) is the key enzyme that catalyzes the synthesis of cholesterol sulfate. This study aimed to investigate the function of Sult2b1 and cholesterol sulfate in the neuroinflammation after ischemic stroke. Methods and Results: Sult2b1-/- and wild-type mice were subjected to transient middle cerebral artery occlusion. Our data showed that Sult2b1-/- mice had larger infarction and worse neurological scores. To determine whether immune cells were involved in the worsening stroke outcome in Sult2b1-/- mice, bone marrow transplantation, immune cell depletion, and adoptive monocyte transfer were performed. Combined with CyTOF and immunofluorescence techniques, we demonstrated that after stroke, the peripheral monocyte-derived macrophages were the dominant cell type promoting the pro-inflammatory status in Sult2b1-/-mice. Using primary bone marrow-derived macrophages, we showed that cholesterol sulfate could attenuate the pro-inflammatory polarization of macrophages under both normal and oxygen-glucose deprivation conditions by regulating the levels of nicotinamide adenine dinucleotide phosphate (NADPH), reactive oxygen species (ROS), and activating the AMP-activated protein kinase (AMPK) - cAMP responsive element-binding protein (CREB) signaling pathway. Conclusions: Sult2b1-/- promoted the polarization of macrophages into pro-inflammatory status. This trend could be attenuated by adding cholesterol sulfate, which promotes the polarization of macrophages into anti-inflammatory status by metabolic regulation. In this study, we established an inflammation-metabolism axis during the macrophage polarization after ischemic stroke.
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المؤلفون: Joseph E. Kaserman, Lauren Young, Andrew A. Wilson, Yvonne Aratyn-Schaus, Packer Michael, Carlos Villacorta-Martin, Gregoire Francine, Jonathan Lindstrom-Vautrin, Rhiannon B Werder
المصدر: Molecular Therapy. 29:3219-3229
مصطلحات موضوعية: Induced Pluripotent Stem Cells, Gene Expression, Alpha (ethology), medicine.disease_cause, alpha 1-Antitrypsin Deficiency, Drug Discovery, Genetics, medicine, Humans, Secretion, Induced pluripotent stem cell, Molecular Biology, Cells, Cultured, Gene Editing, Pharmacology, Mutation, Alpha 1-antitrypsin deficiency, Chemistry, Adenine, RNA, Cell Differentiation, Endoplasmic Reticulum Stress, medicine.disease, Molecular biology, medicine.anatomical_structure, alpha 1-Antitrypsin, Hepatocyte, Hepatocytes, Unfolded protein response, Molecular Medicine, CRISPR-Cas Systems, Biomarkers
الوصف: Alpha-1 antitrypsin deficiency (AATD) is most commonly caused by the Z mutation, a single-base substitution that leads to AAT protein misfolding and associated liver and lung disease. In this study, we apply adenine base editors to correct the Z mutation in patient induced pluripotent stem cells (iPSCs) and iPSC-derived hepatocytes (iHeps). We demonstrate that correction of the Z mutation in patient iPSCs reduces aberrant AAT accumulation and increases its secretion. Adenine base editing (ABE) of differentiated iHeps decreases ER stress in edited cells, as demonstrated by single-cell RNA sequencing. We find ABE to be highly efficient in iPSCs and do not identify off-target genomic mutations by whole-genome sequencing. These results reveal the feasibility and utility of base editing to correct the Z mutation in AATD patient cells.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::30a607aaccda9c5ddc82338a01c7fef4
https://doi.org/10.1016/j.ymthe.2021.06.021
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