ABSTRACT
Ferroptosis is defined as an iron-dependent regulated form of cell death driven by lipid peroxidation. In the past decade, it has been implicated in the pathogenesis of various diseases that together involve almost every organ of the body, including various cancers, neurodegenerative diseases, cardiovascular diseases, lung diseases, liver diseases, kidney diseases, endocrine metabolic diseases, iron-overload-related diseases, orthopedic diseases and autoimmune diseases. Understanding the underlying molecular mechanisms of ferroptosis and its regulatory pathways could provide additional strategies for the management of these disease conditions. Indeed, there are an expanding number of studies suggesting that ferroptosis serves as a bona-fide target for the prevention and treatment of these diseases in relevant pre-clinical models. In this review, we summarize the progress in the research into ferroptosis and its regulatory mechanisms in human disease, while providing evidence in support of ferroptosis as a target for the treatment of these diseases. We also discuss our perspectives on the future directions in the targeting of ferroptosis in human disease.
Subject(s)
Humans , Ferroptosis , Autoimmune Diseases , Cardiovascular Diseases , Iron , Musculoskeletal DiseasesABSTRACT
Hypoxia-inducible factor 1 (HIF-1), as a main transcriptional regulator of metabolic adaptation to changes in the oxygen environment, participates in many physiological and pathological processes in the body, and is closely related to the pathogenesis of many diseases. This review outlines the mechanisms of HIF-1 activation, its signaling pathways, natural inhibitors, and its roles in diseases. This article can provide new insights in the diagnosis and treatment of human diseases, and recent progress on the development of HIF-1 inhibitors.
Subject(s)
Humans , Disease , Hypoxia-Inducible Factor 1/physiology , Oxygen , Signal TransductionABSTRACT
Epigenetic modifications, including those on DNA and histones, have been shown to regulate cellular metabolism by controlling expression of enzymes involved in the corresponding metabolic pathways. In turn, metabolic flux influences epigenetic regulation by affecting the biosynthetic balance of enzyme cofactors or donors for certain chromatin modifications. Recently, non-enzymatic covalent modifications (NECMs) by chemically reactive metabolites have been reported to manipulate chromatin architecture and gene transcription through multiple mechanisms. Here, we summarize these recent advances in the identification and characterization of NECMs on nucleic acids, histones, and transcription factors, providing an additional mechanistic link between metabolism and epigenetics.
ABSTRACT
Epigenetic modifications, including those on DNA and histones, have been shown to regulate cellular metabolism by controlling expression of enzymes involved in the corresponding metabolic pathways. In turn, metabolic flux influences epigenetic regulation by affecting the biosynthetic balance of enzyme cofactors or donors for certain chromatin modifications. Recently, non-enzymatic covalent modifications (NECMs) by chemically reactive metabolites have been reported to manipulate chromatin architecture and gene transcription through multiple mechanisms. Here, we summarize these recent advances in the identification and characterization of NECMs on nucleic acids, histones, and transcription factors, providing an additional mechanistic link between metabolism and epigenetics.
ABSTRACT
Cytochrome P4502J2 (CYP2J2) is widely distributed in various human tissues and takes a part in the metabolism of endogenous compounds and drugs. CYP2J2 can convert arachidonic acid (AA) to expoxyeicosatrienoic acids (EETs), which have various biological effects, implying the important role of CYP2J2 in the regulation of cardiovascular system and promotion of tumor progression and metastasis. Additionally, CYP2J2 plays an indispensable role in the intestinal metabolism of various drugs, such as astemizole, terfenadine and ebastine. In this review, the metabolic function, characteristic of catalysis and tissue distribution of CYP2J2 are discussed with the latest literatures both in China and abroad. The state-of-the-art methods for characterization of CYP2J2 and current trend of substrate discovery as well as its relationship with disease are highlighted. This review gives in-depth understanding of the function of CYP2J2 and its role in disease advance. The information of ligand (substrate and inhibitor) will provide the theoretical guidance and reference to the development of novel drugs for CYP2J2.
ABSTRACT
Abstract Gyrate atrophy of the choroid and retina (GACR) is a hereditary form of progressive blindness caused by homozygosity for loss-of-function mutations in the ornithine aminotransferase gene (Oat). The high levels of circulating ornithine that lead to ophthalmic symptoms in young adults are also displayed by 2 ornithine aminotransferase (OAT)-deficient mouse models of GACR. Here, we have developed an inexpensive and quantitative bacteria-based test for detecting hyperornithinemia in blood or urine samples from these mutant mice, a test that we suggest could be used to facilitate the identification and treatment of OAT-deficient humans before the onset of visual impairment.
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Collaborative Cross mice ( CC mice) are series of inbred mice strains generated from hybrid strains of mice with different genetic background which used for human complex diseases and genetic diversity diseases studies. Genetic diversity of CC mice can reflect different mouse subspecies, the single nucleotide polymorphism is four times than traditional inbred mice. CC mice are more and more widely used in the field of life science and medical research. Based on information retrieval of CC mice, we introduced the related information resources of CC mice origin, database, application tools, and research results, to promote CC mice resources to be used widely in China.
ABSTRACT
La Brucelosis es una enfermedad infecciosa, transmisible mediante la ingestión de alimentos contaminados. Se discuten dos casos clínicos, cuya manifestación común fue un “rash” eritematoso generalizado, asociado a un síndrome febril sin foco aparente. Ambos con historia de exposición a quesos artesanales. Mediante el antecedente epidemiológico, la clínica y los datos de laboratorio confirmaron el diagnóstico de brucelosis, iniciándose tratamiento antibiótico. Se expone la evolución de cada paciente y se realiza una breve revisión bibliográfica del tema.
Brucellosis is an infectious disease whose transmition is by the ingestion of contaminated foods. We discuss two cases characterized by generalized erythematous rash and febrile syndrome without an apparent focus. Both had a history of exposure to artisanal cheeses. Epidemiological, clinical and laboratory data confirmed the diagnosis, initiating antibiotic treatment. We follow up each patient and performed a brief review of the literature.
ABSTRACT
Introduction: Common variable immunodeficiency (CVID) is an immunological disorder characterized by defective antibody production. Objectives: To study lymphocytes number, surface activation molecules, cell markers, lymphoproliferative response, cytokine production, and cell death. Methods: A study was led on thirty four patients with CVID selected from the Division of Clinical Immunology and Allergies of the Faculty of Medicine of São Paulo University (FMUSP), Brazil. Peripheral mononuclear blood cells (PBMC) of CVID patients and healthy individuals were evaluated in regard to the expression of cell surface markers, activation molecules, lymphoproliferative response, cytokine synthesis and apoptosis. Results: CVID patients showed decrease in T and B lymphocyte counts, CD25, CD69, CD40L, and CD70 expression, and low synthesis levels of IL-4 and IL-5. Furthermore, their lymphocytes were more susceptible to apoptosis following activation. Conclusion: The higher susceptibility to apoptosis following activation may also be responsible for the decrease in the expression of activation molecules and CD40L, in cytokine synthesis, and in levels of circulating T and B cells.
Introdução: A imunodeficiência comum variável (CVID) é uma enfermidade imune caracterizada pela produção deficiente de anticorpos. Objetivo: Avaliar o número de linfócitos, moléculas de ativação, resposta linfoproliferativa, produção de citocinas e morte celular. Métodos: Foram selecionados 34 pacientes com CVID na Divisão de Imunologia Clínica e Alergia da Faculdade de Medicina da Universidade de São Paulo (FMUSP), Brasil. Células mononucleares obtidas a partir de sangue periférico (PBMC) foram isoladas para avaliação de marcadores de superfície celular, moléculas de ativação, resposta linfoproliferativa, quantificação de citocinas e apoptose. Resultados: Os pacientes analisados apresentaram diminuição na contagem de linfócitos T e B, expressão de CD25, CD69, CD40L, CD70, e baixa produção de IL-4 e IL-5. Os linfócitos se apresentaram mais suscetíveis à apoptose pós-ativação. Conclusão: A maior susceptibilidade à apoptose pós-ativação pode ser responsável pela diminuição na expressão de moléculas de ativação e CD40L, síntese de citocinas e linfócitos T e B circulantes.
Subject(s)
Humans , Common Variable Immunodeficiency/blood , Apoptosis , Antibodies/blood , B-Lymphocytes , T-Lymphocytes , Case-Control Studies , Cytokines , Cell Death , Signaling Lymphocytic Activation Molecule FamilyABSTRACT
Purpose: The human vascular endothelial growth factor (VEGF)-A gene transcribes a signaling protein involved in the regulation of angiogenesis, vasculogenesis and endothelial cell growth. Two insertion/deletion (I/D) simple nucleotide polymorphisms (SNPs, rs34357231 & rs35569394) in the promoter region of the gene have been significantly associated with several human diseases. These SNPs were computationally examined with respect to changes in punitive transcriptional factor binding sites (TFBS) and these changes were discussed in relation to the diseases. Methods: The JASPAR CORE and ConSite databases were instrumental in identifying the TFBS. The Vector NTI Advance 11.5 computer program was employed in locating all the TFBS in the VEGFA gene from 2.7 kb upstream of the transcriptional start site to 1.6 kb past the 3’UTR. The JASPAR CORE database was also involved in computing each nucleotide occurrence (%) within the TFBS. Results: Regulatory SNPs (rSNPs) in the promoter region of the VEGFA gene alter the DNA landscape for potential transcriptional factors (TFs) to attach resulting in changes in TFBS. The VEGFA-deletion (D) allele of these SNPs has been found to be a risk factor for diabetic retinopathy, diabetic microvascular complications in patients with type 1 diabetes mellitus, breast cancer in north Indian patients, and bladder cancer. The changes in TFs associated with the TFBS are examined with respect to these human diseases. Conclusion: The VEGFA-insertion (I) allele provides punitive TFBS for the AR, EGR1 & 2, KLF5 and SP1 TFs whose BS do not occur with the VEGFA-D allele. These TFs have been linked to prostate cancer, cancer suppression and oncogenic processes and if not regulating the VEGFA gene may pose a risk for disease.
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In recent years,many kinds of animal models of human diseases with different genetic background were developed.Some were established in China,others were imported from abroad.Precious were these animal models,their biological features could be lost for various reasons,for instance,reverse from mutation,lost of modified or constructed gene,etc.This study provided some suggestions for scientific management of the animal models to in terms of quarantine inspection,specific feeding method and methods to maintain gene stability,so as to preserve their biological features.
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The recent advent of next-generation sequencing technologies has dramatically changed the nature of biomedical research. Human genetics is no exception-it has never been easier to interrogate human patient genomes at the nucleotide level to identify disease-associated variants. To further facilitate the efficiency of this approach, whole exome sequencing (WES) was first developed in 2009. Over the past three years, multiple groups have demonstrated the power of WES through robust disease-associated variant discoveries across a diverse spectrum of human diseases. Here, we review the application of WES to different types of inherited human diseases and discuss analytical challenges and possible solutions, with the aim of providing a practical guide for the effective use of this technology.
Subject(s)
Humans , Exome , Genetics, Medical , GenomeABSTRACT
itamin D plays a crucial role in human health and diseases.Researches have showed that 50％ of the population have a risk for vitamin D deficiency in the world.Vitamin D deficiency is caused by the lack of sunlight or by deficient dietary supplement.It does not only lead to rickets and osteomalacia, can also cause cancers, cardiovascular disease, endocrine system diseases, autoimmune diseases, nervous system diseases and tuberculosis susceptibility.
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The great discovery of microRNAs (miRNAs) has revolutionized current cell biology and medical science. miRNAs are small conserved non-coding RNA molecules that post-transcriptionally regulate gene expression by targeting the 3' untranslated region of specific messenger RNAs for degradation or translational repression. New members of the miRNA family are being discovered on a daily basis and emerging evidence has demonstrated that miRNAs play a major role in a wide range of developmental process including cell proliferation, cell cycle, cell differentiation, metabolism, apoptosis, developmental timing, neuronal cell fate, neuronal gene expression, brain morphogenesis, muscle differentiation and stem cell division. Moreover, a large number of studies have reported links between alterations of miRNA homeostasis and pathological conditions such as cancer, psychiatric and neurological diseases, cardiovascular disease, and autoimmune disease. Interestingly, in addition, miRNA deficiencies or excesses have been correlated with a number of clinically important diseases ranging from cancer to myocardial infarction. miRNAs can repress the gene translation of hundreds of their targets and are therefore well-positioned to target a multitude of cellular mechanisms. As a consequence of extensive participation in normal functions, it is quite logical to ask the question if abnormalities in miRNAs should have importance in human diseases. Great discoveries and rapid progress in the past few years on miRNAs provide the hope that miRNAs will in the near future have a great potential in the diagnosis and treatment of many diseases. Currently, an explosive literature has focussed on the role of miRNA in human cancer and cardiovascular disease. In this review, I briefly summarize the explosive current studies about involvement of miRNA in various human cancers and cardiovascular disease.
Subject(s)
Humans , 3' Untranslated Regions , Apoptosis , Autoimmune Diseases , Brain , Cardiovascular Diseases , Cell Cycle , Cell Differentiation , Cell Proliferation , Gene Expression , Heart Diseases , Homeostasis , Logic , MicroRNAs , Morphogenesis , Muscles , Myocardial Infarction , Neurons , Repression, Psychology , RNA, Messenger , RNA, Untranslated , Stem CellsABSTRACT
O cerrado é fonte de moléculas químicas com grande potencial medicamentoso. As moléculas produzidas pelo metabolismo secundário das plantas, em resposta às condições ambientais adversas, sempre foram fornecedoras ou inspiradoras dos princípios ativos medicamentosos. O Laboratório de Farmacognosia da Universidade de Brasília criou um Banco de Extratos de Plantas e Substâncias do Bioma Cerrado, que é avaliado sobre modelos biológicos in vitro e in vivo como parasitos, bactérias, fungos, células cancerígenas, inibidores de alfa-amilase humana e de insetos-praga ou vetores de doenças. Estudos químicos dos extratos ativos, guiados pelos testes biológicos permitem eleger, desde seu isolamento e caracterização, moléculas-alvo para a busca de fármacos inovadores. A formação de mestres e doutores, em parceria com diversos laboratórios da Universidade de Brasília e de outras instituições científicas na mesma área do conhecimento, contribui para a aquisição de moléculas químicas com perspectivas futuras de aplicação industrial e para o incremento da produção científica e tecnológica do País.
The Cerrado lands are sources of chemical molecules with great medical potential. Vegetal secondary-metabolism- derived molecules, produced as a response to adverse environmental conditions, were always a source or an inspiration for the medical active components. The Laboratory of Farmacognosy of the University of Brasília has created a Plant Extracts and Substances of the Cerrado Biome Data Bank, evaluated on biological in vitro and in vivo models such as parasites, bacteria and fungi, cancer cells, human alfa-amylase inhibitors and plague insects, or disease vectors. Chemical studies of active extracts guided by the biological trials allow the election, from their isolation and characterization, of target molecules in the search of innovative drugs. The graduation of masters and doctors, a partnership with several laboratories of the UnB and other institutions in the same knowledge area, contributes to the acquisition of chemical molecules with future perspectives of industrial applications and to the growth of the countrys technological and scientific production.
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Culicoides paraensis (Goeldi), a common and widespread American bloodsucking midge that has been incriminated in the transmission of Mansonellosis and Oropouche Fever of humans in South America, is redescribed and figured. All published records are listed and new distribution is based on examination of extensive collections from throughout its range. Three closely related species of the subgenus Haematomyidium that have been confused with C. paraensis are briefly redescribed and figured, and a key is presented for their identification.