RESUMEN
Platelets are essential component of circulation that plays a major role in hemostasis and thrombosis. During activation and its demise, platelets release platelet-derived microvesicles, with lysophosphatidylcholine (LPC) being a prominent component in their lipid composition. LPC, an oxidized low-density lipoprotein, is involved in cellular metabolism, but its higher level is implicated in pathologies like atherosclerosis, diabetes, and inflammatory disorders. Despite this, its impact on platelet function remains relatively unexplored. To address this, we studied LPC's effects on washed human platelets. A multimode plate reader was employed to measure reactive oxygen species and intracellular calcium using H2DCF-DA and Fluo-4-AM, respectively. Flow cytometry was utilized to measure phosphatidylserine expression, mitochondrial membrane potential (ΔΨm), and mitochondrial permeability transition pore (mPTP) formation using FITC-Annexin V, JC-1, and CoCl2/calcein-AM, respectively. Additionally, platelet morphology and its ultrastructure were observed via phase contrast and electron microscopy. Sonoclot and light transmission aggregometry were employed to examine fibrin formation and platelet aggregation, respectively. The findings demonstrate that LPC induced oxidative stress and increased intracellular calcium in platelets, resulting in increased phosphatidylserine expression and reduced ΔΨm. LPC triggered caspase-independent platelet death and mPTP opening via cytosolic and mitochondrial calcium, along with microvesiculation and reduced platelet counts. LPC increased the platelet's size, adopting a balloon-shaped morphology, causing membrane fragmentation and releasing its cellular contents, while inducing a pro-coagulant phenotype with increased fibrin formation and reduced integrin αIIbß3 activation. Conclusively, this study reveals LPC-induced oxidative stress and calcium-mediated platelet death, necrotic in nature with pro-coagulant properties, potentially impacting inflammation and repair mechanisms during vascular injury.
Asunto(s)
Plaquetas , Calcio , Muerte Celular , Lisofosfatidilcolinas , Estrés Oxidativo , Especies Reactivas de Oxígeno , Humanos , Estrés Oxidativo/efectos de los fármacos , Lisofosfatidilcolinas/farmacología , Lisofosfatidilcolinas/metabolismo , Calcio/metabolismo , Plaquetas/metabolismo , Plaquetas/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Muerte Celular/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Poro de Transición de la Permeabilidad Mitocondrial/metabolismoRESUMEN
Neurological diseases (NDs) are one of the leading causes of disability and the second leading cause of death globally. Among these stroke, Alzheimer's disease (AD), and Parkinson's disease (PD) are the most common NDs. A rise in the absolute number of individuals affected with these diseases indicates that the current treatment strategies in management and prevention of these debilitating diseases are not effective sufficiently. Therefore, novel treatment strategies are being explored to cure these diseases by addressing the causative mechanisms at the molecular level. Advanced therapies like gene therapy (gene editing and gene silencing) and stem cell therapies aim to cure diseases by gene editing, gene silencing and tissue regeneration, respectively. Gene editing results in the deletion of the aberrant gene or insertion of the corrected gene which can be executed using the CRISPR/Cas gene editing tool a promising treatment strategy being explored for many other prevalent diseases. Gene silencing using siRNA silences the gene by inhibiting protein translation, thereby silencing its expression. Stem cell therapy aims to regenerate damaged cells or tissues because of their ability to divide into any type of cell in the human body. Among these approaches, gene editing and gene silencing have currently been applied in vitro and to animal models, while stem cell therapy has reached the clinical trial stage for the treatment of NDs. The current status of these strategies suggests a promising outcome in their clinical translation.
Asunto(s)
Enfermedad de Alzheimer , Enfermedad de Parkinson , Accidente Cerebrovascular , Animales , Humanos , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/metabolismo , Sistemas CRISPR-Cas , Edición Génica/métodosRESUMEN
Background: Coronavirus disease 2019, caused by SARS-CoV-2 (SCV-2) was stated as a pandemic on March 11 2020 by World Health Organization (WHO), and since then, it has become a major health issue worldwide. It mainly attacks the respiratory system with various accompanying complications, including cardiac injury, renal failure, encephalitis and Stroke.Materials and Methods: The current systematic review has been compiled to summarize the available literature on SCV-2 induced ischemic Stroke and its subtypes. Further, the mechanisms by which the virus crosses the blood-brain barrier (BBB) to enter the brain have also been explored. The role of CRP and D-dimer as potent prognostic markers was also explored. The literature search was carried out comprehensively on Google scholar, PubMed, SCOP US, Embase and Cochrane databases by following guidelines.Results: All the studies were reviewed thoroughly by authors and disagreements were resolved by consensus and help of the senior authors. The most common subtype of the IS was found to be large artery atherosclerosis in SCV-2 induced IS. Hypertension emerged as the most significant risk factor. The mechanism resulting in elevated levels of CRP and D-dimer have also been discussed. However, there is a scarcity of definitive evidence on how SCV-2 enters the human brain. The available literature based on various studies demonstrated that SCV-2 enters through the nasopharyngeal tract via olfactory cells to olfactory neurons, astrocytes and via choroid plexus through endothelial cells. Further, disruption of gut-brain axis has been also discussed.Conclusion: Data available in the literature is not adequate to come to a conclusion. Therefore, there is a need to carry out further studies to delineate the possible association between SCV-2 induced IS.
Asunto(s)
COVID-19 , Accidente Cerebrovascular Isquémico , Humanos , COVID-19/complicaciones , SARS-CoV-2 , Accidente Cerebrovascular Isquémico/etiología , Células Endoteliales , Internalización del Virus , EncéfaloRESUMEN
BACKGROUND: An emerging component of Unfolded Protein Response (UPR) pathway, cation transport regulator homolog 1 (CHAC1) has been conferred with the ability to degrade intracellular glutathione and induce apoptosis, however, many reports have suggested a role of CHAC1 in cancer progression. Our study aimed to investigate CHAC1 mRNA levels in large breast cancer datasets using online tools and both mRNA and protein levels in different breast cancer cell lines. METHODS AND RESULTS: Analysis of clinical information from various online tools (UALCAN, GEPIA2, TIMER2, GENT2, UCSCXena, bcGenExMiner 4.8, Km Plotter, and Enrichr) was done to elucidate the CHAC1 mRNA expression in large breast cancer patient dataset and its correlation with disease progression. Later, in vitro techniques were employed to explore the mRNA and protein expression of CHAC1 in breast cancer cell lines. Evidence from bioinformatics analysis as well as in vitro studies indicated a high overall expression of CHAC1 in breast tumor samples and had a significant impact on the prognosis and survival of patients. Enhanced CHAC1 levels in the aggressive breast tumor subtypes such as Human Epidermal growth factor receptor 2 (HER2) and Triple Negative Breast Cancer (TNBC) were evident. Our findings hint toward the possible role of CHAC1 in facilitating the aggressiveness of breast cancer and the disease outcome. CONCLUSION: In summary, CHAC1 is constantly up-regulated in breast cancer leading to a poor prognosis. CHAC1, therefore, could be a promising candidate in the analysis of breast cancer diagnosis and prognosis.
Asunto(s)
Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Neoplasias de la Mama/patología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Pronóstico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Neoplasias de la Mama Triple Negativas/genéticaRESUMEN
Background: Platelets are crucial players in thrombus formation during ischemic stroke. Platelet (PLT) count and Mean platelet volume (MPV) are important parameters that affect platelet functions. The current study has been carried out with an aim to evaluate the association of MPV and PLT count with ischemic stroke in a population from the Malwa region of Punjab.Material and Methods: The study included one hundred and fifty ischemic stroke patients. The extent of disability occurs by stroke was measured by mRS. MPV and PLT was evaluated using cell counter. Further, PLT count was confirmed in 50% of patients using flow cytometer. Clot formation rate was evaluated using Sonoclot Coagulation and Platelet Function Analyzer. All the statistical analysis was carried out using SPSS.Results: A significant association of increased MPV (p < 0.02) was found with the ischemic stroke. However, PLT count did not show a significant association with the disease (p < 0.07). Further, a stepwise multiple logistic regression (MLR) analysis controlling the other confounding risk factors evaluated the association of hypertension and MPV with the disease. Patients with higher mRS were found to have high MPV values confirming that higher MPV is correlated with disability occurs by ischemic stroke. MPV was also found to be significantly associated with large artery atherosclerosis (p < 0.001). Clot formation analysis revealed that ischemic stroke patients bear higher clot rate (CR) and Platelet function (PF) values.Conclusions: Elevated MPV is an independent risk factor for Ischemic stroke along with hypertension. In addition, higher MPV associated significantly with stroke disability as well.
RESUMEN
Increasing herbal formulations have been used to treat several diseases including cancer. W. somnifera (Ashwagandha) is one such plant the extracts of which have been tested against a number of ailments including cancer, which remains as one of the most dreadful diseases on the globe. The ever-increasing number of cancer related mortality demands the development of novel chemopreventive agents with minimum side effects. Different compounds isolated from various parts of the plant like root, stem, and leaves have been reported to display significant anti-cancerous and immunomodulating properties and thus can be used alone or in combination with other chemotherapeutic drugs for cancer treatment. Through this review, we highlight the importance of W. somnifera in countering the potential oncogenic signaling mediators that are modulated by active constituents of W. somnifera in a variety of cancer types. Further, we hope that active constituents of W. somnifera will be tested in clinical trials so that they can be used as an important adjuvant in the near future for the effective treatment of cancer.
Asunto(s)
Withania , Humanos , Extractos Vegetales/farmacología , Hojas de la Planta , Raíces de PlantasRESUMEN
Stroke is one of the leading causes of death and disability in both developing and developed countries. Biomarkers for stroke and its outcome can greatly facilitate early detection and management of the disease. miRNAs have been explored for their potential as biomarkers for diagnosis, prognosis and brain injury in ischaemic stroke. A substantial body of evidence suggests that miRNAs play key roles in numerous cellular changes following ischaemic stroke including mitochondrial dysfunction, energy failure, cytokine-mediated cytotoxicity, oxidative stress, activation of glial cells, increased intracellular calcium levels inflammatory responses and disruption of the blood-brain barrier (BBB). In addition, targeting specific miRNAs, therapeutic modulation of brain injury and apoptosis can also be achieved. Therefore, the current review has been compiled within an aim to give an overview of the developments exploiting miRNAs at different stages of stroke as prognostic, diagnostic, protective and therapeutic biomarkers.
Asunto(s)
Isquemia Encefálica , Accidente Cerebrovascular Isquémico , MicroARNs , Accidente Cerebrovascular , Biomarcadores , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/terapia , Humanos , MicroARNs/genética , Pronóstico , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/terapiaRESUMEN
Stroke or 'brain attack' is considered to be the major cause of mortality and morbidity worldwide after myocardial infraction. Inspite of the years of research and clinical practice, the pathogenesis of stroke still remains incompletely understood. Omics approaches not only enable the description of a huge number of molecular platforms but also have a potential to recognize new factors associated with various complex disorders including stroke. The most significant development among all other omics technologies over the recent years has been seen by genomics which is a powerful tool for exploring the genetic architecture of stroke. Genomics has decisively established itself in stroke research and by now wealth of data has been generated providing new insights into the physiology and pathophysiology of stroke. However, the efficacy of genomic data is restricted to risk prediction only. Omics approaches not only enable the description of a huge number of molecular platforms but also have a potential to recognize new factors associated with various complex disorders including stroke. The data generated by omics technologies enables clinicians to provide detailed insight into the makeup of stroke in individual patients, which will further help in developing diagnostic procedures to direct therapies. Present review has been compiled with an aim to understand the potential of integrated omics approach to help in characterization of mechanisms leading to stroke, to predict the patient risk of getting stroke by analyzing signature biomarkers and to develop targeted therapeutic strategies.
Asunto(s)
Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Genómica , Metabolómica , Proteómica , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/metabolismoRESUMEN
Platelets are anucleated blood constituents, vital for hemostasis and involved in the pathophysiology of several cardiovascular, neurovascular diseases as well as inflammatory processes and metastasis. Over the past few years, the molecular processes that regulate the function of platelets in hemostasis and thrombosis have emerged revealing platelets to be perhaps more complex than may have been expected. The most understood part of platelets is to respond to a blood vessel injury by altering shape, secreting granule contents, and aggregating. These responses, while advantageous for hemostasis, can become detrimental when they root ischemia or infarction. Only a few transcription and signaling factors involved in platelet biogenesis have been identified till date. Platelets encompass an astonishingly complete array of organelles and storage granules including mitochondria, lysosomes, alpha granules, dense granules, a dense tubular system (analogous to the endoplasmic reticulum of nucleated cells); a highly invaginated plasma membrane system known as the open canalicular system (OCS) and large fields of glycogen. Platelets as a model cells to study neurological disorders have been recommended by several researchers since several counterparts exist between platelets and the brain, which make them interesting for studying the neurobiology of various neurological disorders. This review has been compiled with an aim to integrate the latest research on platelet biogenesis, activation and aggregation focusing on the molecular pathways that power and regulate these processes. The dysregulation of important molecular players affecting fluctuating platelet biology and thereby resulting in neurovascular diseases has also been discussed.
Asunto(s)
Plaquetas/fisiología , Trastornos Cerebrovasculares/sangre , Enfermedades del Sistema Nervioso/sangre , Biogénesis de Organelos , Activación Plaquetaria/fisiología , Transducción de Señal/fisiología , Humanos , Agregación Plaquetaria/fisiologíaRESUMEN
Human epidermal growth factor receptor 2 positive (HER2+) breast cancer (BC) is an aggressive BC subtype characterized by HER2 overexpression/amplification. Genomic alterations of HER2 and others have been reported to be associated with, HER2 overexpression and prediction of trastuzumab-response. Here, we aimed at identifying germline and somatic alterations associated with HER2+ BC and evaluating their association with clinical outcome in response to trastuzumab therapy given to HER2+ BC patients. Global Sequencing Array (GSA) and polymerase chain reaction-restriction length polymorphism (PCR-RFLP) techniques were used to determine alterations in HER2 and other HER2-interacting as well as signaling-related genes in HER2+ BC. In addition, 20 formalin fixed paraffin-embedded tissue samples were also evaluated by GSA for identifying significant variations associated with HER + BC as well as response to trastuzumab therapy. A germline variant in HER2 (I655V) was found to be significantly associated with the risk of the disease (p < 0.01). A nonsense mutation in PTPN11 (K99X), a pathogenic CCND1 splice site variant (P241P), a hotspot missense mutation in PIK3CA (E542K) and a hotspot missense mutation in TP53 (R249S); were observed in 25%, 75%, 30% and 40% of the HER2+ BC tissue samples, respectively. Mutant CCND1 (P241P) and PIK3CA (E542K) were found to be significantly associated with reduced disease-free survival (DFS) in patients treated with trastuzumab (p: 0.018 and 0.005, respectively). These results indicate that HER2, PTPN11, CCND1 and PIK3CA genes are important biomarkers in HER2+ BC. Moreover, the patients harboring mutant CCND1 and PIK3CA exhibit a poorer clinical outcome as compared to those carrying wild-type CCND1 and PIK3CA.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Genoma Humano , Mutación/genética , Receptor ErbB-2/genética , Trastuzumab/uso terapéutico , Estudios de Casos y Controles , Supervivencia sin Enfermedad , Femenino , Células Germinativas/metabolismo , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Modelos Biológicos , Especificidad de Órganos , Factores de Riesgo , Trastuzumab/farmacología , Resultado del TratamientoRESUMEN
Purpose/Aim of the study: The aim of this review is to summarize the role of genetic variants affecting mean platelet volume (MPV) and platelet count (PLT) leading to higher platelet reactivity and in turn to thrombotic events like stroke and cardiovascular diseases. MATERIALS AND METHODS: A search was conducted in PUBMED, MEDLINE, EMBASE, PROQUEST, Science Direct, Cochrane Library, and Google Scholar related to the studies focussing on genome-wide association studies (GWAS), whole exome sequencing (WES), whole genome sequencing (WGS), phenome-wide association studies (PheWAS) and multi-omic analysis that have been employed to identify the genetic variants influencing MPV and PLT. RESULTS: Antiplatelet agents underscore the crucial role of platelets in the pathogenesis of stroke. Higher platelet reactivity in terms of mean platelet volume (MPV) and platelet count (PLT) contributes significantly to the interindividual variation in platelet reaction at the site of vessel wall injury. Some individuals encounter thrombotic events as platelets get occluded at the site of vessel wall injury whereas others heal the injury without occluding the circulation. Evidence suggests that MPV and PLT have a strong genetic component. High throughput techniques including genome-wide association studies (GWAS), whole exome sequencing (WES), whole genome sequencing (WGS), phenome-wide association studies (PheWAS) and multi-omic analysis have identified different genetic variants influencing MPV and PLT. CONCLUSIONS: Identification of complex genetic cross talks affecting PLT and MPV might help to develop novel treatment strategies in treating neurovascular diseases like stroke.
Asunto(s)
Isquemia Encefálica , Estudio de Asociación del Genoma Completo , Volúmen Plaquetario Medio , Recuento de Plaquetas , Accidente Cerebrovascular , Isquemia Encefálica/sangre , Isquemia Encefálica/genética , Humanos , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/genéticaRESUMEN
ß-hemoglobin disorders, such as ß-thalassemia and sickle cell anemia are among the most prevalent inherited genetic disorders worldwide. These disorders are caused by mutations in the gene encoding hemoglobin-ß (HBB), a vital protein found in red blood cells (RBCs) that carries oxygen from lungs to all parts of the human body. As a consequence, there has been an enduring interest in this field in formulating therapeutic strategies for the treatment of these diseases. Currently, there is no cure available for hemoglobin disorders, although, some patients have been treated with bone marrow transplantation, whose scope is limited because of the difficulty in finding a histocompatible donor and also due to transplant-associated clinical complications that can arise during the treatment. On account of these constraints, reactivation of fetal hemoglobin (HbF) synthesis holds immense promise and is a viable strategy to alleviate the symptoms of ß-hemoglobin disorders. Development of new genomic tools has led to the identification of important natural genetic modifiers of hemoglobin switching which include BCL11A, KLF1, HBSIL-MYB, LRF, LSD1, LDB1, histone deacetylases 1 and 2 (HDAC1 and HDAC2). miRNAs are also promising therapeutic targets for development of more effective strategies for the induction of HbF production. Many new small molecule pharmacological inducers of HbF production are already under pre-clinical and clinical development. Furthermore, recent advancements in gene and cell therapy includes targeted genome editing and iPS cell technologies, both of which utilizes a patient's own cells, are emerging as extremely promising approaches for significantly reducing the burden of ß-hemoglobin disorders.
Asunto(s)
Anemia de Células Falciformes/terapia , Hemoglobina Fetal/genética , Terapia Genética/métodos , Fármacos Hematológicos/uso terapéutico , Hemoglobinas Anormales/genética , Mutación , Talasemia beta/terapia , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/genética , Animales , Hemoglobina Fetal/biosíntesis , Edición Génica , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Fenotipo , Talasemia beta/sangre , Talasemia beta/genéticaRESUMEN
The aim of current study was to evaluate the genetic variation in all the genes encoding pro- and anti-inflammatory cytokines in association with breast cancer development in patients from Malwa region of Punjab. The importance of the levels of interleukin (IL)-17, tumor necrosis factor, interferon γ, IL-10, IL-6, IL-4, and IL-2 with respect to clinicopathological data, prognosis, and disease-free survival was also determined in these patients. Two hundred and fifty female breast cancer patients and 250 age-matched controls were screened for variations in cytokine-encoding genes using global screening array microchip. The level of cytokines was estimated in 150 patients and 60 age-matched controls using BD™ Cytometric Bead Array (CBA) Human Th1/Th2/Th17 cytokine kit by BD Accuri flow cytometer. The difference in cytokine levels was evaluated by Mann-Whitney test. No significant variation in the genes encoding various cytokines was found between patients and controls. Out of the seven cytokines evaluated, the levels of IL-6 and IL-17a were found to be significantly high in patients in comparison with controls ( p = 0.001 and 0.02, respectively). The elevated levels of these cytokines are also associated significantly with poor outcome. We did not find any specific variation in the genes encoding various cytokines between patients and controls. However, there was a significant difference in the serum levels of IL-6 and IL-17a between patients and controls, and the elevated levels of these two cytokines associated significantly with poor outcome in breast cancer patients and, therefore, can be used as prognostic markers.
Asunto(s)
Neoplasias de la Mama/sangre , Citocinas/sangre , Interleucina-17/sangre , Interleucina-6/sangre , Adulto , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Humanos , Inflamación/sangre , Inflamación/genética , Inflamación/patología , Interferón gamma/sangre , Interleucina-10/sangre , Interleucina-17/genética , Interleucina-2/sangre , Interleucina-6/genética , Masculino , Persona de Mediana Edad , Pronóstico , Factor de Necrosis Tumoral alfa/sangreRESUMEN
PURPOSE: Cyclophosphamide and doxorubicin (adjuvant chemotherapy) are commonly used to treat breast cancer patients. Variation in the genes involved in pharmacodynamics and pharmacokinetics of these drugs plays an important role in prediction of drug response and survival. The present study was carried out with an aim to evaluate the variation in all the genes involved in pharmacokinetic and pharmacodynamics pathways of cyclophosphamide and doxorubicin, and correlate specific variants with disease outcome in breast cancer patients from the Malwa region of Punjab. METHODS: A total of 250 confirmed breast cancer patients were involved in the study. Genotyping was performed on an Illumina Infinium HD assay platform using a Global Screening Array (GSA) microchip. GenomeStudio (Illumina, Inc.) was used for data preprocessing and a p value less than or equal to 5 × 10-8 was considered statistically significant. To rule out the influence of confounding risk factors, a step-wise multivariate regression analysis was carried out to evaluate the association of genotype with overall clinical outcome. RESULTS: Two gene variants, CYP2C19 (G681A) and ALDH1A1*2 (17 bp deletion), were found to be significantly associated with the disease outcome, including overall survival, recurrence and metastasis, in breast cancer patients on adjuvant therapy. Both these genes are involved in the pharmacokinetics of cyclophosphamide. However, none of the variants in the genes involved in pharmacokinetics and pharmacodynamics of doxorubicin were found to have any significant impact on disease outcome in the studied group. CONCLUSION: CYP2C19 (G681A) variant and ALDH1A1*2 emerged as two important biomarkers associated with bad outcome in breast cancer patients on adjuvant therapy.
Asunto(s)
Aldehído Deshidrogenasa/genética , Neoplasias de la Mama/tratamiento farmacológico , Ciclofosfamida/administración & dosificación , Citocromo P-450 CYP2C19/genética , Doxorrubicina/administración & dosificación , Adulto , Anciano , Familia de Aldehído Deshidrogenasa 1 , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacocinética , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/farmacocinética , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Quimioterapia Adyuvante/métodos , Ciclofosfamida/farmacocinética , Doxorrubicina/farmacocinética , Femenino , Genotipo , Humanos , India , Análisis por Micromatrices/métodos , Persona de Mediana Edad , Análisis de Regresión , Retinal-Deshidrogenasa , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Primordial dwarfism is a group of genetic disorders which include Seckel Syndrome, Silver-Russell Syndrome, Microcephalic Osteodysplastic Primordial Dwarfism types I/III, II and Meier-Gorlin Syndrome. This genetic disorder group is characterized by intra-uterine growth retardation and post-natal growth abnormalities which occur as a result of disorganized molecular and genomic changes in embryonic stage and, thus, it represents a unique area to study growth and developmental abnormalities. Lot of research has been carried out on different aspects; however, a consolidated review that discusses an overall spectrum of this disorder is not accessible. Recent research in this area points toward important molecular and cellular mechanisms in human body that regulate the complexity of growth process. Studies have emerged that have clearly associated with a number of abnormal chromosomal, genetic and epigenetic alterations that can predispose an embryo to develop PD-associated developmental defects. Finding and associating such fundamental changes to its subtypes will help in re-examination of alleged functions at both cellular and developmental levels and thus reveal the intrinsic mechanism that leads to a balanced growth. Although such findings have unraveled a subtle understanding of growth process, we further require active research in terms of identification of reliable biomarkers for different subtypes as an immediate requirement for clinical utilization. It is hoped that further study will advance the understanding of basic mechanisms regulating growth relevant to human health. Therefore, this review has been written with an aim to present an overview of chromosomal, molecular and epigenetic modifications reported to be associated with different subtypes of this heterogenous disorder. Further, latest findings with respect to clinical and molecular genetics research have been summarized to aid the medical fraternity in their clinical utility, for diagnosing disorders where there are overlapping physical attributes and simultaneously inform about the latest developments in PD biology.
Asunto(s)
Enanismo/genética , Retardo del Crecimiento Fetal/genética , Trastornos del Crecimiento/genética , Animales , Aberraciones Cromosómicas , Epigénesis Genética/genética , Marcadores Genéticos/genética , HumanosRESUMEN
BACKGROUND & OBJECTIVES: The amount of foetal haemoglobin that persists in adulthood affects the clinical severity of haemoglobinopathies including ß-thalassaemia major and sickle cell anaemia (SCA). The present study was undertaken to analyse ß-thalassaemia as well as SCA patients for the single nucleotide polymorphism (SNP), rs11886868 (T/C) in BCL11A gene and to evaluate the association between this polymorphism and severity of ß-thalassaemia major and SCA. METHODS: a total of 620 samples (420 ß-thalassaemia major and 200 SCA cases) were analysed before blood transfusion using basic screening tests like complete blood analysis and osmotic fragility and further confirmed by high performance liquid chromatography (HPLC), amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and reverse dot blot techniques. All patients were transfusion dependent. Patients with ß-thalassaemia and SCA were classified into mild, moderate, severe according to the severity score based on Hb levels, age of onset, age at which patients received their first blood transfusion, the degree of growth retardation and splenectomy. ß-thalassaemia as well as SCA patients were analysed for the SNP, rs11886868 (T/C) in BCL11A gene and association between this polymorphism and severity of ß-thalassaemia major as well as SCA was evaluated. RESULTS: There was a significant difference in genotypic and allelic frequencies of BCL11A gene polymorphism between mild and moderate and mild and severe cases in both the groups. A significant (P<0.001) difference was observed in the mean HbF levels between the three genotypes in different severity groups. HbF levels were found to be high in CC genotype bearing individuals followed by TC and TT in ß-thalassaemia major as well as SCA. INTERPRETATION & CONCLUSIONS: This study confirms that the T/C variant (rs11886868) of the BCL11A gene causing downregulation of BCL11A gene expression in adult erythroid precursors results in the induction of HbF and ameliorates the severity of ß-thalassaemia as well as SCA.
Asunto(s)
Anemia de Células Falciformes/genética , Proteínas Portadoras/genética , Predisposición Genética a la Enfermedad , Proteínas Nucleares/genética , Talasemia beta/genética , Adolescente , Adulto , Anemia de Células Falciformes/patología , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Proteínas Represoras , Índice de Severidad de la Enfermedad , Talasemia beta/patologíaRESUMEN
Stroke is a severe complication and a leading cause of death worldwide and genetic studies among different ethnicities has provided the basis for involvement of phosphodiesterase 4D (PDE4D) gene in cerebrovascular diseases. Recent advancements have evaluated the role of this gene in stroke and these studies have provided a stronger support for the involvement of this gene in stroke development and few studies also suggest that it may influence outcome. Furthermore, case-control studies and meta-analysis studies have provided strong evidence for certain variants in PDE4D to predispose to stroke only among certain ethnicities. Thus, this review focuses on recent progress made in PDE4D gene research involving genetic, molecular and pharmacological aspect. A strong conclusion has emerged that clearly indicates a pivotal role played by this gene in ischemic stroke globally. Studies have also noticeably highlighted that PDE4D gene/pathway can be a suitable drug target for managing stroke; however, a more comprehensive research is still required to understand the molecular and cellular intricacies this gene plays in stroke development, progression and its outcome.
Asunto(s)
Isquemia Encefálica/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Accidente Cerebrovascular/genética , HumanosRESUMEN
In the present study, we investigated the association of insertion/deletion polymorphism of ACE gene with genetic predisposition to hemorrhagic stroke and also determined the mean ACE activity levels in ischemic and hemorrhagic stroke patients. Two hundred hemorrhagic stroke, 200 ischemic stroke patients and 200 gender and age matched controls were recruited for the study. We found statistically significant difference in the genotypic distribution between hemorrhagic patients and controls for dominant, co-dominant and recessive models. Significant difference was observed in the allelic frequencies between hemorrhagic patients and controls. Multiple logistic regression analysis confirmed these findings [adjusted OR for DD genotype was 2.46 (95 % CI 1.43-4.21) and p = 0.001] and [adjusted OR for ID genotype was 5.45 (95 % CI 2.6-10.4) and p = 0.001]. We have already established the association of this polymorphism in ischemic stroke patients. Comparing hemorrhagic with ischemic stroke, we found a significant difference in genotypic distribution between the two [for II vs. DD, χ (2) = 4.75; p = 0.03, OR = 0.5 (95 % CI 0.27-0.93) and for DD vs. ID, χ (2) = 5.1; p = 0.02, OR = 1.8 (95 % CI 1.1-3.3)]. Our results indicate that DD genotype and D allele are important risk factors for the development of stroke. Individuals harboring DD genotype of ACE I/D polymorphism are more predisposed to hemorrhagic stroke than ischemic stroke. Further, the mean ACE activity level was found to be significantly higher in hemorrhagic and ischemic stroke in comparison with controls, but there was no significant difference in the levels found between the two types of stroke.
Asunto(s)
Isquemia Encefálica/enzimología , Isquemia Encefálica/genética , Hemorragias Intracraneales/enzimología , Hemorragias Intracraneales/genética , Peptidil-Dipeptidasa A/genética , Accidente Cerebrovascular/enzimología , Accidente Cerebrovascular/genética , Femenino , Eliminación de Gen , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutagénesis Insercional , Peptidil-Dipeptidasa A/metabolismo , Polimorfismo GenéticoRESUMEN
OBJECTIVE: Several studies have implicated the role of interleukin-1 in various chronic diseases including periodontitis. The present study was carried out with an aim to evaluate the role of interleukin 1ß polymorphisms, namely +3954C/T, -511C/T and -31T/C, in the development of chronic periodontitis. MATERIALS AND METHODS: Twenty-nine chronic periodontitis patients and 31 healthy controls of North Indian origin from Chhattisgarh were recruited for the study. The genotypes for the three variants were determined using the PCR-RFLP technique and the strength of association between genotypes and periodontitis was determined by odds ratio with 95% confidence interval (CI) and chi-square analysis. RESULTS: Analysis for the +3954 allelic and genotypic frequencies of the polymorphism revealed a significant difference in the CT genotype between periodontitits patients and controls (p = 0.03). A significant difference was also observed in the allelic frequencies between the two groups (p = 0.02). For the -511 site, TT genotype revealed a significant association with the disease (p = 0.01). A significant association was also found following the co-dominant model (p = 0.007). However, the -31 polymorphism revealed no significant difference between patients and controls. CONCLUSIONS: In conclusion, the present study suggests a strong association of the TT genotype of -511 and CT genotype of +3954 variant of interleukin 1ß with chronic periodontitis. However, the -31 variant did not show a significant association with the disease.
Asunto(s)
Periodontitis Crónica/inmunología , Interleucina-1beta/genética , Polimorfismo Genético/genética , Adulto , Estudios de Casos y Controles , Periodontitis Crónica/genética , Citosina , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Genotipo , Haplotipos , Humanos , India , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo de Longitud del Fragmento de Restricción/genética , TiminaRESUMEN
Certain minerals and trace elements are essential for the development of healthy nervous system. Altered serum levels of these elements may lead to the development of various diseases including epilepsy. The present study was designed to evaluate the association of serum calcium, magnesium, zinc and copper in the development of genetic generalized epilepsy [GGE; erstwhile known as idiopathic generalized epilepsy (IGE)] as well as idiopathic intractable epilepsy (IIE), in which seizures persist despite treatment with at least two or three antiepileptic drugs tolerated at reasonable dosage. 200 GGE patients and equal number of healthy controls were recruited for study with their written informed consent. The patients were further divided into responders and non-responders based on their response to antiepileptic drugs. Copper and zinc levels were assayed by atomic absorption spectrophotometer whereas calcium and magnesium were analyzed by Human Star 600 fully automated biochemistry analyzer. The patients with GGE had significant low levels of calcium, magnesium and zinc (1.85 ± 0.33, 0.69 ± 0.13 mmol/L and 11.33 ± 3.32 µmol/L respectively) and the corresponding values for controls were 2.27 ± 0.22, 0.89 ± 0.15, 12.71 ± 3.24 (p < 0.05). Significant high levels of copper were found in patients as compared to controls (26.69 ± 8.79 µmol/L; 16.64 ± 3.64) (p < 0.05). Significantly decreased levels of zinc were noted in non-responders (10.38 ± 2.99) compared to responders (12.62 ± 3.30) (p < 0.05). No significant difference was observed in serum calcium, magnesium and copper levels between responders and non-responders. In conclusion, low levels of calcium, magnesium, zinc and high levels of copper were found to be associated with GGE. Further, the patients with IIE were also found to have low levels of zinc.