Antioxidant, anti-inflammatory and epigenetic potential of curcumin in Alzheimer's disease.

Alzheimer's disease (AD) constitutes a multifactorial neurodegenerative pathology characterized by cognitive deterioration, personality alterations, and behavioral shifts. The ongoing brain impairment process poses significant challenges for therapeutic interventions due to activating multiple neurotoxic pathways. Current pharmacological interventions have shown limited efficacy and are associated with significant side effects. Approaches focusing on the early interference with disease pathways, before activation of broad neurotoxic processes, could be promising to slow down symptomatic progression of the disease. Curcumin-an integral component of traditional medicine in numerous cultures worldwide-has garnered interest as a promising AD treatment. Current research indicates that curcumin may exhibit therapeutic potential in neurodegenerative pathologies, attributed to its potent anti-inflammatory and antioxidant properties. Additionally, curcumin and its derivatives have demonstrated an ability to modulate cellular pathways via epigenetic mechanisms. This article aims to raise awareness of the neuroprotective properties of curcuminoids that could provide therapeutic benefits in AD. The paper provides a comprehensive overview of the neuroprotective efficacy of curcumin against signaling pathways that could be involved in AD and summarizes recent evidence of the biological efficiency of curcumins in vivo.

Generation of iPSC lines (KAIMRCi003A, KAIMRCi003B) from a Saudi patient with Dravet syndrome carrying homozygous mutation in the CPLX1 gene and heterozygous mutation in SCN9A.

The most prevalent form of epileptic encephalopathy is Dravet syndrome (DRVT), which is triggered by the pathogenic variant SCN1A in 80% of cases. iPSCs with different SCN1A mutations have been constructed by several groups to model DRVT syndrome. However, no studies involving DRVT-iPSCs with rare genetic variants have been conducted. Here, we established two DRVT-iPSC lines harboring a homozygous mutation in the CPLX1 gene and heterozygous mutation in SCN9A gene. Therefore, the derivation of these iPSC lines provides a unique cellular platform to dissect the molecular mechanisms underlying the cellular dysfunctions consequent to CPLX1 and SCN9A mutations.

Withania somnifera mitochondrial atp4 gene editing alters the ATP synthase b subunit, independent of salt stress.

Numerous studies have shown that stress in plant cells and organelles with transport electron chains is related to RNA editing. The ATP synthase complex present in mitochondria plays a crucial role in cellular respiration and consists of several subunits. Among them is the b subunit, which is encoded by the mitochondrial atp4 gene. Computing-based analysis of the effects of RNA editing of the Withania somnifera atp4 gene in mitochondria leading to alterations in the b subunit of ATP synthase. Using the CLC Genomic Workbench 3, RNA editing analysis between the control and salt stress conditions was not significantly different. Depending on RNA editing, the tertiary structure model revealed a change in the states of the b subunit, reflecting differences in the central stalk and F1-catalytic domain. The study found that polar edits in the N-terminus of the b subunit allow for efficient H + ion selectivity and introduce a new coiled-coil alpha-helical structure that may help stabilize the complex. The most noteworthy finding of this study was the strong impact of these editing events on the tertiary structure of the b subunit, which has the potential to affect the ATPase activity and indicate that the editing in this subunit aimed to restore the original active protein and not as a response to salt stress.

Comprehensive Review of Ustekinumab Utilization in Inflammatory Bowel Diseases: Insights from the ClinicalTrials.gov Registry.

Background: Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are chronic inflammatory conditions affecting the gastrointestinal tract. To achieve and sustain remission, effective treatment strategies are necessary. Ustekinumab, a biologic agent targeting interleukin-12 and interleukin-23, has emerged as a significant therapeutic option for moderate to severe IBD. Aim: To gain insights into the utilization of Ustekinumab for IBD, we conducted a comprehensive review of the ClinicalTrials.gov registry. Methods: A comprehensive search of the ClinicalTrials.gov was conducted to find all clinical trials involving the use of Ustekinumab in IBD patients. As of December 30th, 2022, 69 clinical trials were identified that included IBD and Ustekinumab. The study list was saved, and those clinical trials that fitted the definition of targeted therapy were included in the review. Results: The results showed that Ustekinumab was associated with significant improvements in the clinical response and remission rates, in both Crohn's disease and ulcerative colitis patients. Additionally, the safety profile of Ustekinumab was generally favourable, with low rates of adverse events reported. In terms of study design, most of the relevant studies found in the database were interventional studies. The investigation focused on completed studies and found that there were a limited number of clinical trials with interventional measures. Conclusion: Ustekinumab appears to be a promising treatment option for patients with IBD, with the potential to provide significant clinical benefits and a favourable safety profile. Further research is warranted to confirm these findings and explore optimal dosing and treatment regimens.

Replacing protein via enteral nutrition in a stepwise approach in critically ill patients: the REPLENISH randomized clinical trial protocol.

BACKGROUND: Protein intake is recommended in critically ill patients to mitigate the negative effects of critical illness-induced catabolism and muscle wasting. However, the optimal dose of enteral protein remains unknown. We hypothesize that supplemental enteral protein (1.2 g/kg/day) added to standard enteral nutrition formula to achieve high amount of enteral protein (range 2-2.4 g/kg/day) given from ICU day 5 until ICU discharge or ICU day 90 as compared to no supplemental enteral protein to achieve moderate amount enteral protein (0.8-1.2 g/kg/day) would reduce all-cause 90-day mortality in adult critically ill mechanically ventilated patients. METHODS: The REPLENISH (Replacing Protein Via Enteral Nutrition in a Stepwise Approach in Critically Ill Patients) trial is an open-label, multicenter randomized clinical trial. Patients will be randomized to the supplemental protein group or the control group. Patients in both groups will receive the primary enteral formula as per the treating team, which includes a maximum protein 1.2 g/kg/day. The supplemental protein group will receive, in addition, supplemental protein at 1.2 g/kg/day starting the fifth ICU day. The control group will receive the primary formula without supplemental protein. The primary outcome is 90-day all-cause mortality. Other outcomes include functional and quality of life assessments at 90 days. The trial will enroll 2502 patients. DISCUSSION: The study has been initiated in September 2021. Interim analysis is planned at one third and two thirds of the target sample size. The study is expected to be completed by the end of 2025. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04475666 . Registered on July 17, 2020.

The first report describes features of the chloroplast genome of Withania frutescens.

Genomic studies not only help researcher not only to identify genomic features in organisms, but also facilitate understanding of evolutionary relationships. Species in the Withania genus have medicinal benefits, and one of them is Withania frutescens, which is used to treat various diseases. This report investigates the nucleotides and genic features of chloroplast genome of Withania frutescens and trying to clarify the evolutionary relationship with Withania sp and family Solanaceae. We found that the total size of Withania frutescens chloroplast genome was 153.771 kb (the smallest chloroplast genome in genus Withania). A large single-copy region (91.285 kb), a small single-copy region (18.373 kb) form the genomic region, and are distinct from each other by a large inverted repeat (22.056 kb). 137 chloroplast genes are found including 4 rRNAs, 38 tRNAs and 83 protein-coding genes. The Withania frutescens chloroplast genome as well as four closest relatives was compared for features such as structure, nucleotide composition, simple sequence repeats (SSRs) and codon bias. Compared to other Withania species, Withania frutescens has unique characteristics. It has the smallest chloroplast genome of any Withania species, isoleucine is the major amino acid, and tryptophan is the minor, In addition, there are no ycf3 and ycf4 genes, fourth, there are only fifteen replicative genes, while in most other species there are more. Using fast minimum evolution and neighbor joining, we have reconstructed the trees to confirm the relationship with other Solanacaea species. The Withania frutescens chloroplast genome is submitted under accession no. ON153173.

Meta-analysis of whole-genome gene expression datasets assessing the effects of IDH1 and IDH2 mutations in isogenic disease models.

Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are oncogenic drivers to a variable extent in several tumors, including gliomas, acute myeloid leukemia (AML), cholangiocarcinoma, melanoma, and thyroid carcinoma. The pathobiological effects of these mutations vary considerably, impeding the identification of common expression profiles. We performed an expression meta-analysis between IDH-mutant (IDHmut) and IDH-wild-type (IDHwt) conditions in six human and mouse isogenic disease models. The datasets included colon cancer cells, glioma cells, heart tissue, hepatoblasts, and neural stem cells. Among differentially expressed genes (DEGs), serine protease 23 (PRSS23) was upregulated in four datasets, i.e., in human colon carcinoma cells, mouse heart tissue, mouse neural stem cells, and human glioma cells. Carbonic anhydrase 2 (CA2) and prolyl 3-hydroxylase 2 (P3H2) were upregulated in three datasets, and SOX2 overlapping transcript (SOX2-OT) was downregulated in three datasets. The most significantly overrepresented protein class was termed intercellular signal molecules. An additional DEG set contained genes that were both up- and downregulated in different datasets and included oxidases and extracellular matrix structural proteins as the most significantly overrepresented protein classes. In conclusion, this meta-analysis provides a comprehensive overview of the expression effects of IDH mutations shared between different isogenic disease models. The generated dataset includes biomarkers, e.g., PRSS23 that may gain relevance for further research or clinical applications in IDHmut tumors.

Pharmacophore-Based Virtual Screening, Quantum Mechanics Calculations, and Molecular Dynamics Simulation Approaches Identified Potential Natural Antiviral Drug Candidates against MERS-CoV S1-NTD.

Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly infectious zoonotic virus first reported into the human population in September 2012 on the Arabian Peninsula. The virus causes severe and often lethal respiratory illness in humans with an unusually high fatality rate. The N-terminal domain (NTD) of receptor-binding S1 subunit of coronavirus spike (S) proteins can recognize a variety of host protein and mediates entry into human host cells. Blocking the entry by targeting the S1-NTD of the virus can facilitate the development of effective antiviral drug candidates against the pathogen. Therefore, the study has been designed to identify effective antiviral drug candidates against the MERS-CoV by targeting S1-NTD. Initially, a structure-based pharmacophore model (SBPM) to the active site (AS) cavity of the S1-NTD has been generated, followed by pharmacophore-based virtual screening of 11,295 natural compounds. Hits generated through the pharmacophore-based virtual screening have re-ranked by molecular docking and further evaluated through the ADMET properties. The compounds with the best ADME and toxicity properties have been retrieved, and a quantum mechanical (QM) based density-functional theory (DFT) has been performed to optimize the geometry of the selected compounds. Three optimized natural compounds, namely Taiwanhomoflavone B (Amb23604132), 2,3-Dihydrohinokiflavone (Amb23604659), and Sophoricoside (Amb1153724), have exhibited substantial docking energy >-9.00 kcal/mol, where analysis of frontier molecular orbital (FMO) theory found the low chemical reactivity correspondence to the bioactivity of the compounds. Molecular dynamics (MD) simulation confirmed the stability of the selected natural compound to the binding site of the protein. Additionally, molecular mechanics generalized born surface area (MM/GBSA) predicted the good value of binding free energies (ΔG bind) of the compounds to the desired protein. Convincingly, all the results support the potentiality of the selected compounds as natural antiviral candidates against the MERS-CoV S1-NTD.

Infant Oral Healthcare and Anticipatory Guidance Practices among Dentists in a Pediatric Care Shortage Area.

OBJECTIVES: To assess dentists' practices and barriers towards infant oral healthcare (IOH) and anticipatory guidance (AG) in eastern Saudi Arabia. METHODS: A regional, cross-sectional survey was distributed to 340 (323 general dentists (GPs) and 17 pediatric dentists (PDs)) working in a governmental setting in eastern Saudi Arabia. A 23 close-ended, pilot-tested questionnaire was developed. The questionnaire asked about dentists' IOH and AG practices. A five-point Likert scale question assessed barriers interfering with AG practices. Descriptive and multivariate logistic regressions were used. RESULTS: Participation rate was 98.5% (335/340). Only 18% of GPs indicated performing IOH exams, while 100% of PDs do. About 90% of GPs would see children on a first visit when they are ≥3 years old, whereas 60% of PDs reported seeing one-year-old children. Older practitioners and those performing AG were more likely to perform IOH (OR = 1.8, CI = 1.06-3.1, and OR = 3.84, CI = 1.93-7.65, resp.). The majority of respondents (94%) felt their training did not prepare them to practice AG. "Parents bringing their children for the first time for emergency or existing conditions" was cited by 99% of respondents as a barrier to performing AG. CONCLUSION: Increasing the awareness of GPs and parents about the importance of IOH and AG is crucial in improving children's oral health. Collaboration with pediatricians for early referral of children is equally important in increasing the awareness on prevention principles.

Pharmacoinformatics and molecular dynamics simulation-based phytochemical screening of neem plant (Azadiractha indica) against human cancer by targeting MCM7 protein.

Minichromosome maintenance complex component 7 (MCM7) belongs to the minichromosome maintenance family that is important for the initiation of eukaryotic DNA replication. Overexpression of the MCM7 protein is relative to cellular proliferation and responsible for aggressive malignancy in various cancers. Mechanistically, inhibition of MCM7 significantly reduces the cellular proliferation associated with cancer. To date, no effective small molecular candidate has been identified that can block the progression of cancer induced by the MCM7 protein. Therefore, the study has been designed to identify small molecular-like natural drug candidates against aggressive malignancy associated with various cancers by targeting MCM7 protein. To identify potential compounds against the targeted protein a comprehensive in silico drug design including molecular docking, ADME (Absorption, Distribution, Metabolism and Excretion), toxicity, and molecular dynamics (MD) simulation approaches has been applied. Seventy phytochemicals isolated from the neem tree (Azadiractha indica) were retrieved and screened against MCM7 protein by using the molecular docking simulation method, where the top four compounds have been chosen for further evaluation based on their binding affinities. Analysis of ADME and toxicity properties reveals the efficacy and safety of the selected four compounds. To validate the stability of the protein-ligand complex structure MD simulations approach has also been performed to the protein-ligand complex structure, which confirmed the stability of the selected three compounds including CAS ID:105377-74-0, CID:12308716 and CID:10505484 to the binding site of the protein. In the study, a comprehensive data screening process has performed based on the docking, ADMET properties, and MD simulation approaches, which found a good value of the selected four compounds against the targeted MCM7 protein and indicates as a promising and effective human anticancer agent.

Effect of hypothyrodism's medication (T4) on implant osstointegration: A case series and literature search.

INTRODUCTION: Hypothyroidism reduces the recruitment, maturation, and activity of bone cells, decreasing bone resorption and formation. Several investigations have reported that T4 replacement therapy is associated with a significant decrease in bone mineral density in various skeletal parts, while others have failed to corroborate these results. The present study describes both a literature review and our own experience with dental implants in patients with hypothyroidism undergoing T4 replacement therapy. CASE PRESENTATION: The study included two parts: a literature review and case series. The literature review included 12 articles documenting the success rate of osseointegrated dental implants in patients with hypothyroidism. The clinical cases were chosen from King Saud University Dental College, Riyadh. The patients' identity was only available to the main researcher. The inclusion criteria for the clinical cases were: T4-treated hypothyroidism, age 20-60 years, and use of dental implants with a follow-up period of 6-12 months after loading. The exclusion criteria were: any other medical condition alongside hypothyroidism, syndromic hypothyroidism, pregnancy, current smoking, bruxism, and hypothyroidism caused by surgical excision combined with radiotherapy. The following parameters were assessed: insertion torque (IT), crestal bone height (CBH), mesial bone width (MBW), and distal bone width (DBW) at different time points, probing depth, and signs of infection. DISCUSSION: Seventeen dental implants placed in patients with T4-treated hypothyroidism showed median IT success (42.4 N⋅cm; range: 35-45 N⋅cm). The median crestal bone loss was measured at 6-12 months after loading was 0.6 mm (range: 0.5-0.7. mm). Conversely, the median bone loss differences in MBW and DBW at 6-12 months after loading were 0.3 mm and 0.2 mm, respectively. CONCLUSION: After a 1-year follow-up, patients with T4-treated hypothyroidism who had received dental implants fulfilled the criteria for successful implants.

Genetic relationship between Hashimoto`s thyroiditis and papillary thyroid carcinoma with coexisting Hashimoto`s thyroiditis.

Hashimoto's thyroiditis (HT) is present in the background of around 30% of papillary thyroid carcinomas (PTCs). The genetic predisposition effect of this autoimmune condition is not thoroughly understood. We analyzed the microarray expression profiles of 13 HT, eight PTCs with (w/) coexisting HT, six PTCs without (w/o) coexisting HT, six micro PTCs (mPTCs), and three normal thyroid (TN) samples. Based on a false discovery rate (FDR)-adjusted p-value ≤ 0.05 and a fold change (FC) > 2, four comparison groups were defined, which were HT vs. TN; PTC w/ HT vs. TN; PTC w/o HT vs. TN; and mPTC vs. TN. A Venn diagram displayed 15 different intersecting and non-intersecting differentially expressed gene (DEG) sets, of which a set of 71 DEGs, shared between the two comparison groups HT vs. TN ∩ PTC w/ HT vs. TN, harbored the relatively largest number of genes related to immune and inflammatory functions; oxidative stress and reactive oxygen species (ROS); DNA damage and DNA repair; cell cycle; and apoptosis. The majority of the 71 DEGs were upregulated and the most upregulated DEGs included a number of immunoglobulin kappa variable genes, and other immune-related genes, e.g., CD86 molecule (CD86), interleukin 2 receptor gamma (IL2RG), and interferon, alpha-inducible protein 6 (IFI6). Upregulated genes preferentially associated with other gene ontologies (GO) were, e.g., STAT1, MMP9, TOP2A, and BRCA2. Biofunctional analysis revealed pathways related to immunogenic functions. Further data analysis focused on the set of non-intersecting 358 DEGs derived from the comparison group of HT vs. TN, and on the set of 950 DEGs from the intersection of all four comparison groups. In conclusion, this study indicates that, besides immune/inflammation-related genes, also genes associated with oxidative stress, ROS, DNA damage, DNA repair, cell cycle, and apoptosis are comparably more deregulated in a data set shared between HT and PTC w/ HT. These findings are compatible with the conception of a genetic sequence where chronic inflammatory response is accompanied by deregulation of genes and biofunctions associated with oncogenic transformation. The generated data set may serve as a source for identifying candidate genes and biomarkers that are practical for clinical application.

Antihyperglycemic, Antioxidant and Antiapoptotic Effect of Rhizophora Mucronata and Avicennia Marina in Streptozotocin-induced Diabetic Rats.

INTRODUCTION: Diabetes mellitus is a common disease worldwide. It is considered as the third leading cause of death, in the developed countries followed by heart diseases and cancer. AIM: The aim of this study was to assess the effectiveness of the aqueous fraction of R. mucronata and A. marina leaves grown in Saudi Arabia alone or in combination as antidiabetic agents and explore its effect on the antioxidants status. METHODS: One hundred and twenty male Wistar albino rats were divided into 8 groups were utilized in this study. Streptozotocin (STZ) was utilized for induction of diabetes. The effects of daily oral administration of aqueous extract from the leaves of R. mucronata (400 mg/kg BW), A. marina (400 mg/kg BW) and the combination of both plant extracts for 6 weeks were evaluated on blood glucose, insulin, tissues' antioxidants as well as pancreatic immunohistochemistry in normal, (STZ)-induced diabetic rats. RESULTS: Oral administration of the plants extracts significantly reduced (p ≤ 0.001) serum glucose, insulin and improved the antioxidants status in the liver compared to the untreated rats. Immunohistochemically, the pancreas of diabetic rats treated with R. mucronata revealed a few islets ß-cells (2-3%/ HPF) with positive caspase-3. CONCLUSION: The extract of R. mucronata exhibited a promising antidiabetic, antioxidant and tissue enhancing effects compared with A. marina alone or in combination.

Molecular evolution of cytochrome C oxidase-I protein of insects living in Saudi Arabia.

The study underpins barcode characterization of insect species collected from Saudi Arabia and explored functional constraints during evolution at the DNA and protein levels to expect the possible mechanisms of protein evolution in insects. Codon structure designated AT-biased insect barcode of the cytochrome C oxidase I (COI). In addition, the predicted 3D structure of COI protein indicated tyrosine in close proximity with the heme ligand, depicted substitution to phenylalanine in two Hymenopteran species. This change resulted in the loss of chemical bonding with the heme ligand. The estimated nucleotide substitution matrices in insect COI barcode generally showed a higher probability of transversion compared with the transition. Computations of codon-by-codon nonsynonymous substitutions in Hymenopteran and Hemipteran species indicated that almost half of the codons are under positive evolution. Nevertheless, codons of COI barcode of Coleoptera, Lepidoptera and Diptera are mostly under purifying selection. The results reinforce that codons in helices 2, 5 and 6 and those in loops 2-3 and 5-6 are mostly conserved and approach strong purifying selection. The overall results argue the possible evolutionary position of Hymenopteran species among those of other insects.

Investigation of Impact Strength and Hardness of UHMW Polyethylene Composites Reinforced with Nano-Hydroxyapatite Particles Fabricated by Friction Stir Processing.

The impact strength and surface properties of polymeric materials are of critical importance in various engineering applications. Friction stir processing (FSP) is a novel method for the fabrication of composite materials with superior mechanical properties. The main objective of this study is to investigate the impact strength and Rockwell hardness of UHMW polyethylene composites reinforced with nano-hydroxyapatite particles fabricated through FSP. The spindle speed (ω), tool traverse speed (f), volume fraction (v) of strengthening material and shoulder temperature (T) were key processing parameters. The analysis of variance (ANOVA) indicated that the selected processing parameters were significant. Microscopic investigations unveiled that high levels of (v, f) and low levels of (T, ω) caused agglomeration of the reinforcing particles and induced voids and channels, which consequently reduced the impact strength and hardness of the manufactured composite. However, medium conditions of processing parameters exhibited better distribution of particles with minimum defects, and hence resulted in better mechanical properties. Finally, the models to predict the impact strength and hardness are proposed and verified. Sets of process parameters favorable to maximize the impact strength and Rockwell hardness were worked out, which were believed to increase the impact strength, Rockwell hardness number, and ultimate tensile strength by 27.3%, 5.7%, and 11.2%, respectively.

Endophytic bacteria isolated from Solanum nigrum L., alleviate cadmium (Cd) stress response by their antioxidant potentials, including SOD synthesis by sodA gene.

Cadmium (Cd) is a toxic heavy metal and an abiotic stressor to plants; however, inoculation of endophytic bacteria can raise resistance in plants against Cd, as well as improve plant growth. In the present study, two endophytic bacterial strains were isolated from Solanum nigrum, identified as Serratia sp. IU01 and Enterobacter sp. IU02 by 16S DNA sequencing. Both IU01 and IU02 were tolerant up to 9.0 mM of Cd in culture broth and successive increase in Cd concentration from 0 mM to 9.0 mM, led to an increase in the SOD enzyme activity of the isolates. Both strains were capable of indole-3-acetic acid (IAA) synthesis and phosphate solubilization, detected through gas spectrometry-mass chromatography (GC-MS) and Pikovskaya agar medium respectively. Brassica juncea plants stressed with 0-25 mg/kg Cd showed retardation in all growth attributes, however, inoculation of strain IU01 and IU02 significantly promoted the plant growth attributes as compared to control. Moreover, antioxidant enzymes and metabolites against reactive oxygen species (ROS) including polyphenol oxidase (PPO), peroxidase (POD), catalase (CAT), superoxide dismutase (SOD), alcohol dehydrogenase (ADH), reduced glutathione (GSH), malondialdehyde (MDA), flavonoid and polyphenolic contents were also significantly relieved by inoculation of IU01 and IU02 in plant exposed to different concentration of Cd stress as compared to control plants. Phytohormone production, phosphate solubilization, and/or antioxidative support of IU01 and IU02 might be responsible for growth promotion and Cd resistance in the plant.

Public health and veterinary important flies (order: Diptera) prevalent in Jeddah Saudi Arabia with their dominant characteristics and identification key.

Order Diptera of class insecta is of immense importance for the public and animal health and hygiene. Many dipteran flies are potential vectors of dreadful diseases. Therefore, it is required to have a simple characterization method and identification key for the field workers and entomologists. The present study fulfill the need and focus on the identification to generate a base line data with the help of original photographs. Nine families with 16 species of dipteran flies (other than mosquitoes) from Jeddah region of Saudi Arabia are included in this work. Major families which are more prevalent and common in this region are Muscidae, Calliphoridae, Sarcophagidae and Phoridae.

Association of HCV mutated proteins and host SNPs in the development of hepatocellular carcinoma.

Hepatitis C virus plays a significant role in the development of hepatocellular carcinoma (HCC) globally. The pathogenic mechanisms of hepatocellular carcinoma with HCV infection are generally linked with inflammation, cytokines, fibrosis, cellular signaling pathways, and liver cell proliferation modulating pathways. HCV encoded proteins (Core, NS3, NS4, NS5A) interact with a broad range of hepatocytes derived factors to modulate an array of activities such as cell signaling, DNA repair, transcription and translational regulation, cell propagation, apoptosis, membrane topology. These four viral proteins are also implicated to show a strong conversion potential in tissue culture. Furthermore, Core and NS5A also trigger the accretion of the ß-catenin pathway as a common target to contribute viral induced transformation. There is a strong association between HCV variants within Core, NS4, and NS5A and host single nucleotide polymorphisms (SNPs) with the HCC pathogenesis. Identification of such viral mutants and host SNPs is very critical to determine the risk of HCC and response to antiviral therapy. In this review, we highlight the association of key variants, mutated proteins, and host SNPs in development of HCV induced HCC. How such viral mutants may modulate the interaction with cellular host machinery is also discussed.

HTLV-1 Associated Neurological Disorders.

Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus which is endemic to certain regions of the world and infects around 10-20 million people. HTLV-1 is the etiologic agent of Adult T cell leukemia/lymphoma and HTLV-1 associated neurological disorders including mainly HTLV-1 associated myelopathy/Tropical spastic paraparesis. The involvement of the central nervous diseases occurs among: HTLV-1 infected patients from endemic areas, HIV positive individuals and drug users. The ability of HTLV-1 to cause associated neuropathies starts with the virus crossing the blood brain barrier (BBB), then entering and infecting the cells of the central nervous system. As a consequence, to the viral attack, HTLV-1 infected lymphocytes produce pro-inflammatory cytokines like tumor necrosis factor alpha, Interleukin 1 beta and interleukin 6 which further disrupts the BBB. Different serological tests have been used in the diagnosis of HTLV-1. These include: ELISA, Western Blotting (WB), Immunofluorescence, Particle Agglutination and Polymerase Chain Reaction which is used as a confirmatory test. Danazol, pentoxifylline, azathioprine and vitamin C have been used in the treatment of the HTLV-1 associated neurological disorders. Other antiviral drugs (lamivudine, zidovudine), monoclonal antibodies (Daclizumab) and therapeutic agents (valporic acid, interferons) have also been evaluated. No known drug, so far, has been shown to be efficacious. The aim of this review is to present the complexities of HTLV-1 associated neurological disorders and their current ongoing treatment. In addition to discussing future possible therapeutic strategies, by targeting HTVL-1 viral components and gene/s products, for the treatment of those neurological conditions.

Cyclin D1 as a therapeutic target of renal cell carcinoma- a combined transcriptomics, tissue microarray and molecular docking study from the Kingdom of Saudi Arabia.

BACKGROUND: Renal cell carcinoma (RCC) is a seventh ranked malignancy with poor prognosis. RCC is lethal at metastatic stage as it does not respond to conventional systemic treatments, and there is an urgent need to find out promising novel biomarkers for effective treatment. The goal of this study was to evaluate the biomarkers that can be potential therapeutic target and predict effective inhibitors to treat the metastatic stage of RCC. METHODS: We conducted transcriptomic profiling to identify differentially expressed genes associated with RCC. Molecular pathway analysis was done to identify the canonical pathways and their role in RCC. Tissue microarrays (TMA) based immunohistochemical stains were used to validate the protein expression of cyclinD1 (CCND1) and were scored semi-quantitatively from 0 to 3+ on the basis of absence or presence of staining intensity in the tumor cell. Statistical analysis determined the association of CCND1 expression with RCC. Molecular docking analyses were performed to check the potential of two natural inhibitors, rutin and curcumin to bind CCND1. RESULTS: We detected 1490 significantly expressed genes (1034, upregulated and 456, downregulated) in RCC using cutoff fold change 2 and p value < 0.05. Hes-related family bHLH transcription factor with YRPW motif 1 (HEY1), neuropilin 2 (NRP2), lymphoid enhancer-binding factor 1 (LEF1), and histone cluster 1 H3h (HIST1H3H) were most upregulated while aldolase B, fructose-bisphosphate (ALDOB), solute carrier family 12 (SLC12A1), calbindin 1 (CALB1) were the most down regulated genes in our dataset. Functional analysis revealed Wnt/ß-catenin signaling as the significantly activated canonical pathway (z score = 2.53) involving cyclin D1 (CCND1). CCND1 was overexpressed in transcriptomic studies (FC = 2.26, p value = 0.0047) and TMA results also showed the positive expression of CCND1 in 53 % (73/139) of RCC cases. The ligands - rutin and curcumin bounded with CCND1 with good affinity. CONCLUSION: CCND1 was one of the important upregulated gene identified in microarray and validated by TMA. Docking study showed that CCND1 may act as a potential therapeutic target and its inhibition could focus on the migratory, invasive, and metastatic potential of RCC. Further in vivo and in vitro molecular studies are needed to investigate the therapeutic target potential of CCND1 for RCC treatment.