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Cardiovascular disease (CVD) is one of the main causes of death in Saudi Arabia. Cardiac remodeling plays a critical role in the pathophysiology of heart failure. Major focus of our study was to identify crucial genes involved in the pathological remodeling of the heart caused by pressure overload. We utilized various in-silico tools to analyze and interpret microarray data obtained from the Gene Expression Omnibus (GEO) database (GSE120739), including GEO2R analysis, Metascape analysis, WebGestalt analysis, and IPA (Ingenuity pathway analysis). Our findings indicate that certain genes, including Cartilage Oligomeric Matrix Protein (COMP), collagen type VIII alpha 1 chain (COL8A1) and Lysyl Oxidase (LOX) under the influence caused by knockdown of KDM3A, were down regulated by the extracellular matrix pathway. Moreover, genes, such as Acyl-CoA Thioesterase 1 (ACOT1) were up regulated by the fatty acid metabolism pathway. Overexpression of lysine-specific demethylase 3A (KDM3A) leads to the up regulation of fibrosis-related genes COMP, COL8A1, and LOX and the down regulation of ACOT1, result in enhanced fibrosis and heart failure. Our results suggest that COMP, COL8A1, LOX, and ACOT1 warrant further investigation in the development of cardiac fibrosis and as potential biomarkers for causing heart failure.
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We identified the PACS2 gene responsible for the multifunctional sorting protein that play a role in nuclear gene expression as well as pathway traffic regulation. Diseases associated with PACS2 include early infantile epileptic encephalopathy (EIEE66), alacrima, achalasia, and mental retardation syndrome. Whole exome sequencing (WES) technique was used for the identification of variants that may lead to the disease. We identified a consanguineous Saudi family segregating developmental delay, mental retardation and epilepsy. Our results showed a heterozygous missense variant PACS2 gene leading to intellectual disability, epilepsy and cause epileptic encephalopathies (EIEE66) disorder. WES data was analyzed and identified variants were further confirmed by Sanger sequencing validation technique. We identified a heterozygous missense c.625G>A p.Glu209Lys in exon-6 of PACS2. The detected heterozygous mutation in the exon-6 region of PACS2 gene change the protein features and may cause disease. Further, explain the possibility that PACS2 gene play important role to cause intellectual disability, epilepsy and epileptic encephalopathies in this Saudi family.
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Partner and localiser of BRCA2 (PALB2), also known as FANCN, is a key tumour suppressor gene in maintaining genome integrity. Monoallelic mutations of PALB2 are associated with breast and overian cancers, while bi-allelic mutations cause Fanconi anaemia (FA). In the present study, whole exome sequencing (WES) identified a novel homozygous missense variant, NM_024675.3: c.3296C>G (p.Thr1099Arg) in PALB2 gene (OMIM: 610355) that caused FA with mild pulmonary valve stenosis and dysmorphic and atypical features, including lymphangiectasia, non-immune hydrops fetalis and right-sided pleural effusion in a preterm female baby. WES results were further validated by Sanger sequencing. WES improves the screening and detection of novel and causative genetic variants to improve management of disease. To the best of our knowledge, the present study is the first reported FA case in a Saudi family with phenotypic atypical FA features. The results support the role of PALB2 gene and pathogenic variants that may cause clinical presentation of FA. Furthermore, the present results may establish a disease database, providing a groundwork for understanding the key genomic regions to control diseases resulting from consanguinity.
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(1) Background: Dyggve-Melchior-Clausen Syndrome is a skeletal dysplasia caused by a defect in the DYM gene (OMIM number 607461). Pathogenic variants in the gene have been reported to cause Dyggve-Melchior-Clausen (DMC; OMIM 223800) dysplasia and Smith-McCort (SMC; OMIM 607326) dysplasia. (2) Methods: In the present study, large consanguineous families with five affected individuals with osteochondrodysplasia phenotypes were recruited. The family members were analyzed by polymerase chain reaction for homozygosity mapping using highly polymorphic microsatellite markers. Subsequent to linkage analysis, the coding exons and exon intron border of the DYM gene were amplified. The amplified products were then sent for Sanger sequencing. The structural effect of the pathogenic variant was analyzed by different bioinformatics tools. (3) Results: Homozygosity mapping revealed a 9 Mb homozygous region on chromosome 18q21.1 harboring DYM shared by all available affected individuals. Sanger sequencing of the coding exons and exon intron borders of the DYM gene revealed a novel homozygous nonsense variant [DYM (NM_017653.6):c.1205T>A, p.(Leu402Ter)] in affected individuals. All the available unaffected individuals were either heterozygous or wild type for the identified variant. The identified mutation results in loss of protein stability and weekend interactions with other proteins making them pathogenic (4) Conclusions: This is the second nonsense mutation reported in a Pakistani population causing DMC. The study presented would be helpful in prenatal screening, genetic counseling, and carrier testing of other members in the Pakistani community.
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Enanismo , Discapacidad Intelectual , Osteocondrodisplasias , Humanos , Osteocondrodisplasias/genética , Péptidos y Proteínas de Señalización Intracelular , Enanismo/genética , Discapacidad Intelectual/genéticaRESUMEN
The lack of precise molecular signatures limits the early diagnosis of non-small cell lung cancer (NSCLC). The present study used gene expression data and interaction networks to develop a highly accurate model with the least absolute shrinkage and selection operator (LASSO) for predicting NSCLC. The differentially expressed genes (DEGs) were identified in NSCLC compared with normal tissues using TCGA and GTEx data. A biological network was constructed using DEGs, and the top 20 upregulated and 20 downregulated hub genes were identified. These hub genes were used to identify signature genes with penalized logistic regression using the LASSO to predict NSCLC. Our model's development involved the following steps: (i) the dataset was divided into 80% for training (TR) and 20% for testing (TD1); (ii) a LASSO logistic regression analysis was performed on the TR with 10-fold cross-validation and identified a combination of 17 genes as NSCLC predictors, which were used further for development of the LASSO model. The model's performance was assessed on the TD1 dataset and achieved an accuracy and an area under the curve of the receiver operating characteristics (AUC-ROC) of 0.986 and 0.998, respectively. Furthermore, the performance of the LASSO model was evaluated using three independent NSCLC test datasets (GSE18842, GSE27262, GSE19804) and achieved high accuracy, with an AUC-ROC of >0.99, >0.99, and 0.95, respectively. Based on this study, a web application called NSCLCpred was developed to predict NSCLC.
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BACKGROUND: Traumatic brain injury (TBI) is a serious issue and a leading cause of death and disability worldwide. Caregivers of TBI patients experience psychological distress and a variety of social and financial issues. The present study aims to investigate the caregiver's burden and the factors that influence this burden. Furthermore, the present study will find out the association of religious practice, religious coping relations and psychological distress among caregivers of children affected with TBI. METHODS: A cross-sectional survey was conducted on 302 caregivers of children with TBI using Duke University Religion Index (DURL) for religious practice. General Health Questionaire-12 (GHQ-12) was used for anxiety and depression and Brief Religious Coping Scale (RCOPE) was used for coping strategies. The caregivers were conveniently chosen from different regions of Khyber Pakhtunkhwa province and data was collected from different tertiary care hospitals in Peshawar. RESULTS: Forty-nine (49) % of caregivers score ≥ 3 on GHQ suffer from psychological distress with a Mean of 20.957 ± 4.175). Positive coping methods were mostly used by caregivers than negative coping have a low level of distress with a Mean Positive Coping (P-COPE ) of 6.93 ± 0.41, Mean of Negative Coping (N-COPE) 0.486 ± 1.023. In religious practice, caregivers mostly participate in Organized Reliogious Activities (ORA) or some Non-Organized Reliogious Activities (NORA) with a Mean ORA of 4.20 ± 1.27, and NORA Mean of 4.17 ± 1.37 used by the caregivers. Coping methods were related to Caregiver psychological distress (GHQ-12 and P-COPE co-relation scores are (ρ -0.022, p b 0.05); GHQ-12 scores and N-COPE (ρ + 0.221=, p b 0.001). There is a negative correlation between GHQ 12 and PCOPE, while GHQ12 is positively correlated with NCOPE. CONCLUSION: According to this study, there is a significant association between religious coping methods, religious practice, and psychological distress among caregivers of children with traumatic brain injury.
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Background: The whole of humanity has suffered dire consequences related to the novel coronavirus disease 2019 (COVID-19). Vaccination of the world base population is considered the most promising and challenging approach to achieving herd immunity. As healthcare organizations took on the extensive task of vaccinating the entire U.S. population, digital health companies expanded their automated health platforms in order to help ease the administrative burdens of mass inoculation. Although some software companies offer free applications to large organizations, there are prohibitive costs for small clinics such as the Good Health Associates Clinic (GHAC) for integrating and implementing new self-scheduling software into our e-Clinical Works (ECW) Electronic Health Record (EHR). These cost burdens resulted in a search that extended beyond existing technology, and in investing in new solutions to make it easier, more efficient, more cost-effective, and more scalable. Objective: In comparison to commercial entities, primary care clinics (PCCs) have the advantage of engaging the population for vaccination through personalized continuity of clinical care due to good rapport between their patients and the PCC team. In order to support the overall national campaign to prevent COVID-19 infections and restore public health, the GHAC wanted to make COVID-19 vaccination accessible to its patients and to the communities it serves. We aimed to achieve a coordinated COVID-19 vaccination drive in our community through our small primary care clinic by developing and using an easily implementable, cost-effective self-registration and scheduling web-based mobile platform, using the principle of "C.D.S. Five Rights". Results: Overall, the Moderna vaccination drive using our developed self-registration and scheduling web portal and SMS messaging mobile platform improved vaccination uptake (51%) compared to overall vaccination uptake in our town, county (36%), and state (39%) during April-July 2021. Conclusions: Based on our experience during this COVID-19 vaccination drive, we conclude that PCCs have significant leverage as "invaluable warriors", along with government and media education available, to engage patients for vaccination uptake; this leads to national preventive health spread in our population, and reduces expenses related to acute illness and hospitalization. In terms of cost-effectiveness, small PCCs are worthy of government-sponsored funding and incentives, including mandating EHR vendors to provide free (or minimal fee) software for patient self-registration and scheduling, in order to improve vaccination drive access. Hence, improved access to personalized informative continuity of clinical care in the PCC setting is a "critical link" in accelerating similar cost-effective campaigns in patient vaccine uptake.
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Multidrug resistance (MDR) is one of the major therapeutic challenges that limits the efficacy of chemotherapeutic response resulting in poor prognosis of ovarian cancer (OC). The multidrug resistance protein 1 (MRP1) is a membrane-bound ABC transporter involved in cross resistance to many structurally and functionally diverse classes of anticancer drugs including doxorubicin, taxane, and platinum. In this study, we utilize homology modelling and molecular docking analysis to determine the binding affinity and the potential interaction sites of MRP1 with Carboplatin, Gemcitabine, Doxorubicin, Paclitaxel, and Topotecan. We used AutoDock Vina scores to compare the binding affinities of the anticancer drugs against MRP1. Our results depicted Carboplatin < Gemcitabine < Topotecan < Doxorubicin < Paclitaxel as the order of binding affinities. Paclitaxel has shown the highest binding affinity whereas Carboplatin displayed the lowest affinity to MRP1. Interestingly, our data showed that Carboplatin, Paclitaxel, and Topotecan bind specifically to Asn510 residue in the transmembrane domains 1 of the MRP1. Our results suggest that Carboplatin could be an appropriate therapeutic choice against MRP1 in OC as it couples weakly with Carboplatin. Further, our findings also recommend opting Carboplatin with Gemcitabine as a combinatorial chemotherapeutic approach to overcome MDR phenotype associated with recurrent OC.
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OBJECTIVES: To assess survival and prognostic factors among women with epithelial ovarian cancer in Western Saudi Arabia. METHODS: A retrospective cohort study was carried out between October 2000 and May 2018, reviewing clinical and pathology data of all women who underwent staging or debulking surgery for epithelial ovarian cancer. Analysis of disease-free survival (DFS), overall survivals (OS) and the associated factors used Kaplan-Meier method in addition to cox multivariate regression. RESULTS: A total of 144 patients were included (median age=49.5 years), with a median follow-up time was 3.4 years. Majority (59.7%) of the patients were diagnosed at an advanced stage (III or IV). The mean (95% CI) DFS was 82.3 (67.8-96.8) months, OS was 96.2 (81.3-111.2) months, and the 5-year survival rate was estimated as 38.9%. Univariate analysis showed that older age, clear cell or papillary carcinoma subtypes, serous type, advanced International Federation of Gynecology and Obstetrics (FIGO) stage and the presence of residual disease were associated with poorer DFS and OS (log rank <0.05). Cox regression showed FIGO stage and residual disease >1cm as the strongest prognostic factors independently associated with DFS and OS. CONCLUSION: Improving early diagnosis and achieving optimal cytoreduction are the most critical challenges to achieve significant positive impact on survival of women with epithelial ovarian cancer.
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Neoplasias Ováricas , Anciano , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/terapia , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/cirugía , Pronóstico , Estudios Retrospectivos , Arabia Saudita/epidemiologíaRESUMEN
Colorectal cancer (CRC) is one of the most important causes of morbidity and mortality in the developed world and is gradually more frequent in the developing world including Saudi Arabia. According to the Saudi Cancer Registry report 2015, CRC is the most common cancer in men (14.9%) and the second most prevalent cancer. Oncogenic mutations in the KRAS gene play a central role in tumorigenesis and are mutated in 30-40% of all CRC patients. To explore the prevalence of KRAS gene mutations in the Saudi population, we collected 80 CRC tumor tissues and sequenced the KRAS gene using automated sequencing technologies. The chromatograms presented mutations in 26 patients (32.5%) in four different codons, that is, 12, 13, 17, and 31. Most of the mutations were identified in codon 12 in 16 patients (61.5% of all mutations). We identified a novel mutation c.51 G>A in codon 17, where serine was substituted by arginine (S17R) in four patients. We also identified a very rare mutation, c.91 G>A, in which glutamic acid was replaced by lysine (E31K) in three patients. In conclusion, our findings further the knowledge about KRAS mutations in different ethnic groups is indispensable to fully understand their role in the development and progression of CRC.
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Neoplasias Colorrectales/genética , Mutación/genética , Proteínas Proto-Oncogénicas p21(ras) , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Moleculares , Proteínas Proto-Oncogénicas p21(ras)/química , Proteínas Proto-Oncogénicas p21(ras)/genética , Arabia Saudita , Adulto JovenRESUMEN
Colorectal cancer (CRC) is graded as one of the most common cancer. It accounts for the second leading cause of cancer deaths worldwide. The present study intends to investigate the role and importance of different biochemical variables in the development of colorectal cancer.In this cross-sectional study we recruited ninety-one patients diagnosed with colorectal cancer and fifty-three age-sex matched controls from June 2017 to June 2018. Different variables i.e. SOD, GSH, CAT, MDA, TGF, VEGF, TNF, ILs, MMPs, etc., were estimated with the help of their respective methods. Our findings suggest a significant increase in the levels of different inflammatory and stress-related markers. The NFκB, TGF-ß, VEGFß, 8OHdG, IsoP-2α were significantly found to be increased in patients with colon cancer (0.945 ± 0.067 µg/ml, 18.59 ± 1.53 pg/ml, 99.35 ± 4.29 pg/ml, 21.26 ± 1.29 pg/ml, 102.25 ± 4.25 pg/ml) as compared to controls (0.124 ± 0.024 µg/ml, 8.26 ± 0.88 pg/ml, 49.58 ± 2.62 pg/ml, 0.93 ± 0.29 pg/ml, 19.65 ± 3.19 pg/ml). Notably, the levels of different antioxidants were shown to be significantly lower in patients of colon cancer. The present study concluded that excessive oxidative stress and lipid peroxidation result in a decrease in the antioxidative capacity of cells which may influence diverse signaling cascades including NF-KB, which results in DNA modification and gene transcription that ultimately involved in the progression of colon cancer.
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Biomarcadores de Tumor/sangre , Neoplasias Colorrectales , Antioxidantes/análisis , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Estudios Transversales , Citocinas/sangre , Progresión de la Enfermedad , Humanos , Inflamación/metabolismo , Malondialdehído/sangre , Estrés Oxidativo/fisiologíaRESUMEN
In spite of the significant advancements in the treatment modalities, 30% of advanced stage ovarian cancer (OC) patients do not respond to the standard chemotherapeutic regimen and most of the responders finally relapse over time due to the escalation of multidrug resistance (MDR) Phenomenon. Our present study evaluated chemotherapeutic sensitivity response among 47 ovarian tumor patients of which we found 37 (78.8%) sensitive and remaining 10 (21.2%) resistant. Among the resistant, seven tumor samples were found to be platinum resistant or refractory to platinum (CB/TX), one to carboplatin, and two to 5FU. Notably, all these resistant cases were observed in the disease recurrence group of patients identified at stage III or IV. The stage III resistant cases revealed heterozygous mutation (C/T) in exon 12 (C1236T) and 26 (C3435T) and increased level of mRNA, whereas homozygous mutation (T/T) was found at stage IV tumor patients. The genotypic difference was found to be significant (p = 0.03) for exon 12, and p = 0.003 for exon 26 mutant genotypes. No significant association between genotypes of different exons with tumor stages and tumor grade was observed (p > 0.05). However, a significant association was observed between the genotype of exon-12 and histopathology of tumor tissue (p = 0.028). Statistically, the chemotherapy response was found to be significantly associated with the tumor stage (p = 0.019). We also observed a significant difference in PFS (P = 0.019) and OS (P = 0.047) between tumor grades 1 and 3. Notably, the highest mRNA expression was observed in resistant tumor sample T-32, where interestingly we found homozygosity TT in all of the exons 12, 21, and 26. Thus, we suggest that exons 12 (C1236T) and exon 26 (C3435T) polymorphism may play a role in inducing drug resistance by altering the expression level of the MDR1 gene. To summarize, we suggest that the expression of MDR1 in OC is influenced by tumor stage and genotype variants as well as by chemotherapeutic drugs. Thus our findings suggest that inter individual variability in platinum based therapy may be anticipated by MDR1 genotypes. Further studies on a large number of samples shall eventually lead to provide beneficial information for the individualized chemotherapy.
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OBJECTIVE: To study the putative effects of Advanced Oxidation Protein Products (AOPPs) and Advanced Glycation End Products (AGEs) in the development and progression of cardiovascular disease (CVD). METHODOLOGY: AGEs, AOPPs, e-NOS, lipid profile, circulating stress and inflammatory biomarkers were evaluated among fifty cardiovascular patients and fifty controls. Independent student's t-test was done for statistical analysis. RESULTS: The malondialdehyde mean level in CVD patients (5.45â¯nmol/ml) was significantly higher than control (1.36â¯nmol/ml) (p valueâ¯=â¯0.018). Nitric oxide in CVD patients (55.72â¯ng/ml) was remarkably increased as compared to normal subjects (19.19â¯ng/ml). A significant change in the mean serum level of AGEs in CVD patients (2.74â¯ng/ml) and normal individuals (0.85â¯ng/ml) was recorded (p valueâ¯=â¯0.000). The AOPPs also showed significant increased levels in CVD group (132.07â¯ng/ml) in comparison with normal subjects (83.05â¯ng/ml) (p valueâ¯=â¯0.011). The mean eNOS serum level in CVD group (15.50â¯U/L) was higher than control group (11.28â¯U/L) (p valueâ¯=â¯0.004). Cardiovascular disease patients, in comparison with healthy controls, showed increased level of total cholesterol (5.48â¯mmol/L vs 4.45â¯mmol/L), triglycerides (2.59â¯mmol/L vs 1.24â¯mmol/L), and low density lipoprotein (2.47â¯mmol/L vs 2.31â¯mmol/L) along with decrease in high density lipoprotein (1.39â¯mmol/L vs 1.74â¯mmol/L). The mean MMP-11 serum levels in CVD group (98.69â¯ng/ml) was almost double of control group (45.60â¯ng/ml) (p valueâ¯=â¯0.017). The mean serum level of TNF-α and IL1-α were 32.16â¯pg/ml and 6.64â¯pg/ml in CVD patient. The significant decreasing trend of SOD (p valueâ¯=â¯0.041), CAT (p valueâ¯=â¯0.018), GSH (p valueâ¯=â¯0.036) and GRx (p valueâ¯=â¯0.029) but increasing drift of GPx (0.023) level was observed in CVD patients. CONCLUSION: This study provides strong evidence that CVD patients presented with elevated oxidative stress, enhanced inflammation and lipid profile in their serum. Therefore, the study strongly approves that AGEs, AOPPs, inflammatory and lipoxidative biomarkers hold predictive potential in causing and aggravating the disease, thus by controlling these factors CVD progression can be inhibited.
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In recent years, genetic studies have yielded great progress in elucidating causes of male infertility. This investigation aims to identify frequent genetic abnormalities, that is, sex chromosome aneuploidies and Y-chromosome microdeletions among infertile men in Western Saudi Arabia. From a population of infertile patients, 88 male patients with either azoospermia or severe oligozoospermia (sperm concentration <5 million/ml) were selected. In addition to a thorough clinical workup, karyotypes and Y-chromosomal microdeletions were investigated. Among those 88 infertile patients, we detected six patients with Klinefelter syndrome, two with 47 XYY syndrome and two with Y-chromosome microdeletions AZFb,c. While the prevalence of sex chromosome aneuploidies was in the range of globally investigated populations, the microdeletions appeared to be less frequent in Western Saudi Arabia compared to other regions of the world. All genetically abnormal cases showed sperm concentration <1 million/ml, and hence, this appears to be the threshold for warranting genetic investigations in Western Saudi Arabia. Since Klinefelter and 47 XYY syndromes were only discovered late in life, upon an infertility investigation, sex chromosome aneuploidies due to their many-fold comorbidities require earlier medical attention. A neonatal screening programme is suggested for detection of these aneuploidies in Saudi Arabia for the general health benefit of these patients.
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Aneuploidia , Infertilidad Masculina/epidemiología , Síndrome de Klinefelter/epidemiología , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/epidemiología , Adulto , Deleción Cromosómica , Cromosomas Humanos Y/genética , Pruebas Genéticas/métodos , Necesidades y Demandas de Servicios de Salud , Humanos , Incidencia , Infertilidad Masculina/diagnóstico , Infertilidad Masculina/genética , Cariotipificación , Síndrome de Klinefelter/diagnóstico , Síndrome de Klinefelter/genética , Masculino , Tamizaje Masivo/métodos , Tamizaje Masivo/organización & administración , Persona de Mediana Edad , Estudios Prospectivos , Arabia Saudita/epidemiología , Aberraciones Cromosómicas Sexuales , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/diagnóstico , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/genética , Recuento de EspermatozoidesRESUMEN
Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder, characterized by the deposition of amyloid-ß within the brain parenchyma resulting in a significant decline in cognitive functions. The pathophysiological conditions of the disease are recognized by the perturbation of synaptic function, energy and lipid metabolism. In Addition deposition of amyloid plaques also triggers inflammation upon the induction of microglia. Peroxisome proliferatoractivated receptors (PPARs) are ligand-activated transcription factors known to play important role in the regulation of glucose absorption, homeostasis of lipid metabolism and are further known to involved in repressing the expression of genes related to inflammation. Therefore, agonists of this receptor represent an attractive therapeutic target for AD. Recently, both clinical and preclinical studies showed that use of Peroxisome proliferator-activated receptor gamma (PPARγ) agonist improves both learning and memory along with other AD related pathology. Thus, PPARγ signifies a significant new therapeutic target in treating AD. In this review, we have shed some light on the recent progress of how, PPARγ agonist selectively modulated different cellular targets in AD and its amazing potential in the treatment of AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Antipsicóticos/uso terapéutico , PPAR gamma/agonistas , PPAR gamma/metabolismo , Animales , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/metabolismo , Tiazolidinedionas/uso terapéuticoRESUMEN
BACKGROUND: Cancer patients when treated with different chemotherapeutic drugs often develop mild to severe sight threatening diseases during or after chemotherapy. The mechanism involved in the pathogenesis of ocular toxicities is poorly understood. Oxidative stress, inflammation and MMPs (angiogenic factor) are involved in the progression of chemotherapy related ocular disorders. MATERIALS AND METHODS: The concentration of oxidative stress markers such as MDA, NO and levels of different antioxidant molecules such as SOD, CAT, GSH, GPx, GPr, VIT A, VIT E and VIT C present in the serum of chemotherapy treated patients (nâ¯=â¯50) and in normal persons (nâ¯=â¯20) were estimated by the direct spectrophotometric method while the concentration of TNF-α and MMP-9 activity were determined using human TNF-α and MMP-9 ELISA kits. RESULTS: The concentration of SOD and CAT (0.356⯱â¯0.05⯵g/dl and 1.26⯱â¯0.01⯵mol/mol of protein) was significantly lower as compared to that (1.09⯱â¯0.03⯵g/dl and 3.99⯱â¯0.04⯵mol/mol of protein) in controls. The levels of GPx (0.06⯱â¯0.01â¯mmol/dl) in the cancer patients were much lower than those in the controls (0.78⯱â¯0.06â¯mmol/dl). Lower level of GSH (0.96⯱â¯0.003⯵g/dl) in serum of the diseased group was observed as compared to healthy group (7.26⯱â¯1.40⯵g/dl). The level of Vit A, Vit C and Vit E was lower in systemic circulation of cancer patients (109.99⯱â¯6.35⯵g/ml, 1.26⯱â¯0.36⯵g/ml and 1.29⯱â¯0.191⯵g/ml) as compared to control subjects (166.35⯱â¯14.26⯵g/ml, 3.25⯱â¯0.099⯵g/ml and 6.354⯱â¯2.26⯵g/ml) respectively. The concentration of nitric oxide was significantly higher in the cancer patients (45.26⯱â¯6.35â¯ng/ml) than that in the normal subjects (16.35⯱â¯3.26â¯ng/ml). The higher concentration of MDA (8.65⯱â¯3.26â¯nmol/ml) was observed in the patients than normal ones (1.254⯱â¯0.065â¯nmol/ml). The quantity of TNF-α was significantly higher in chemotherapy treated patients (32.68⯱â¯4.33â¯pg/ml) as compared to the control group (20.979⯱â¯1.98â¯pg/ml). Significantly higher concentration of MMP-9 (40.26⯱â¯3.26â¯ng/ml) was observed in the cancer patients than the controls (7.256⯱â¯1.95â¯ng/ml). CONCLUSION: Lower levels of antioxidant enzymes and non-enzymatic small molecules and higher levels of oxidative stress and inflammatory clinical parameters such as NO, MDA, TNF-α and MMP-9 may be involved in the pathogenesis of systemic chemotherapy related ocular complications such as cataract, glaucoma, blepharitis, retinitis pigmentosa, macular degeneration, pterygium and retinal degeneration.
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The screening of plants for medicinal purposes represents an effort to discover newer, safer, and possibly more effective drugs. Design of the present study was made aiming to the optimization of the antibacterial activity of ethanolic extracts of Eucalyptus tereticornis (leaves) and Nigella sativa (seeds) against bacteria belongings to both Gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Escherichia coli) spectrum by using response surface methodology. 20 g powder of each E. tereticornis (leaf) and N. sativa (seeds) were mixed with 200ml of ethanol at room temperature, and then it was centrifuged at 4000 rpm for 10 min to separate the supernatants, and allowed to dry in order to obtain ethanol free extracts. A fresh bacterial culture of 100µl of test microorganism was inoculated onto media and spread homogeneously. The antimicrobial activity of ethanolic extracts showed that all the concentrations tested were effective against the test microorganisms. The diameters of zones of inhibition exhibited by S. aureus PCSIR-83 were in the range of 0-28mm, E. coli PCSIR-102 (0-28mm) and B. subtilis PCSIR-05 (15-26mm). The combination of N. sativa (15mg/µl) and E. tereticornis (20mg/µl) were found most effective at pH 9.0 and temperature 35°C. Our results clearly indicate that Gram positive bacteria showed more sensitivity than Gram-negative bacteria.
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Antibacterianos/farmacología , Eucalyptus/química , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Nigella sativa/química , Extractos Vegetales/farmacología , Antibacterianos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Etanol/química , Pruebas de Sensibilidad Microbiana , Extractos Vegetales/aislamiento & purificación , Proyectos de InvestigaciónRESUMEN
BACKGROUND: Despite having extensive research, the apparent pathogenic mechanism of Alzheimer's disease (AD), Parkinson's disease (PD) and other neurodegenerative diseases (NDs) have not yet fully understood. The Heat Shock Protein 90 (HSP90), a ubiquitous molecular chaperone, found to have an important role in averting protein misfolding and aggregation through inhibition of apoptotic activity in neuro-inflammatory diseases. Various researchers have confirmed its role in maintaining aberrant neuronal protein's functional stability to a great capacity. It is also involved in regulating the activity of the heat shock factor-1 (HSF-1), a vital regulator of the heat shock response mechanism that cells employ to protect themselves against stress conditions. This quality makes the HSP90 an ideal candidate for novel inhibitory target for therapeutic modality in NDs. METHODS: An extensive literature search was conducted for relevant studies on PubMed, ScienceDirect, Springer- Link etc. The articles were carefully read in their entirety to determine whether they contained information on the topic of interest. Additionally, the reference sections of these articles were searched manually to get more relevant and eligible studies. RESULTS: We have taken an attempt to reveal how HSP90 play important roles with key neuronal proteins involved in supporting the AD and PD pathology. We have further on structure-function relationship of HSP90 to understand its efficacy as a new target in AD and PD by utilizing new generation of HSP90 inhibitors such as geldanamycin and its derivatives, 17-AAG, 17-DMAG, IPI-504, radicicol and its derivatives. HSP90 inhibition leads to suppress atypical neuronal activity by assisting in improving protein aggregation and its related toxicity. Further, the formation of neuronal aggregates is also influenced by HSP90 inhibitors and provides protection from toxicity of protein through HSF-1 activation and HSP70 induction in AD. CONCLUSION: HSP90 inhibition has emerged as a potential target in treating diverse array of diseases especially NDs. In spite of a large amount of research in this direction, the clear cut molecular mechanisms of HSPs associated with neuroprotection are still poorly elucidated and hence more focus is needed toward HSPs and its inhibitory mechanism. The development of HSP90 inhibitors that induce heat-shock response without cytotoxicity for treatment of NDs are still in its early stage. A panel of novel designed research and clinical trial studies are greatly needed to establish the therapeutic reliability and efficacy of HSPs in order to provide best cure for NDs.
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Enfermedad de Alzheimer/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Enfermedad de Parkinson/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/química , Humanos , Macrólidos/farmacología , Neoplasias/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Conformación ProteicaRESUMEN
The purpose of the current study was to find out the possible changes polymorphic site at the promoter region of IL-18 gene in Saudi CAD patients. We have also measured serum IL-18 level to find out, the likely association between its level and polymorphic site. The present study included total 197 subjects (98 confirmed CAD patients both men and women and 99 healthy control individuals). Serum concentration of IL-18 was measured by enzyme linked immuno-sorbent assay. For SNPs analysis, sanger method of DNA sequencing was followed. We observed variable numbers of SNPs at -137 C/G, -607 A/C, and -656 T/G promoter sites in our studied samples. However, the observed changes in the number of SNP hotspots were found to be non-significant compared with control. IL-18 level was found to be significantly (P < 0.001) elevated in CAD patients compared with control individuals. The highest rise of around 36% (P < 0.001) in IL-18 level was recorded in unstable angina (UA) patients. Moreover, the group belonging to UA and non-ST segment elevation myocardial infarction (NSTEMI) showed only 6% rise. On the basis of our result, inflammation seems to have a role in the pathogenesis of CAD but not leading to the significant changes at the genetic level. J. Cell. Biochem. 118: 1849-1854, 2017. © 2017 Wiley Periodicals, Inc.