Association between polymorphisms of the DNA repair genes RAD51 and OGG1 and risk of cardiovascular disease.

Cardiovascular disease (CVD) is one of the leading causes of mortality worldwide, and multiple single­nucleotide polymorphisms of DNA repair genes have been found to be associated with CVD. The aim of the present study was to assess the effects of the genetic variants of RAD51 recombinase (RAD51) and 8­oxoguanine DNA glycosylase (OGG1) on CVD through genotyping and statistical analysis. Regardless of whether there is a significant association or not, the genotyping data on these two polymorphisms are valuable, because there is limited availability of it in certain populations. A total of 240 blood samples were analyzed and genotyped using TaqMan genotyping; 120 were obtained from cases with a history of CVD, and 120 from cases with no history of CVD. A questionnaire was administered to gather information on age, demographics, sex and clinical features, and confirmation was carried out using medical records. The results of the present study confirmed that the polymorphism rs1052133 in OGG1 had no significant association with CVD. On the other hand, the polymorphism rs1801321 in RAD51 exhibited a significant association with CVD. Collectively, the results of the present study revealed that the polymorphism rs1801321 in RAD51 exhibited a significant association with CVD, however a larger sample size to confirm the present findings, may allow for the early identification of CVD and may aid in the decision­making process concerning treatments for CVD.

FTHL17, PRM2, CABYR, CPXCR1, ADAM29, and CABS1 are highly expressed in colon cancer patients and are regulated in vitro by epigenetic alterations.

Background: Colon cancer is a serious public health issue and a major cause of cancer-related mortality worldwide, including Saudi Arabia. Knowledge of genes associated with colon cancer development and progression is essential for identifying new cancer-specific biomarkers to improve the diagnosis of colon cancer. Methods: The expression levels of FTHL17, PRM2, CABYR, CPXCR1, ADAM29, and CABS1 in 15 adjacent colon cancer and normal colon tissue samples from male patients were investigated using reverse transcription polymerase chain reaction (RT-PCR) and quantitative RT-PCR (qRT-PCR) assays. qRT-PCR analysis was also used to determine whether reducing DNA methyltransferase (via 5-aza-2'-deoxycytidine treatment) or histone deacetylation (via trichostatin treatment) increased the expression levels of the tested genes. Results: The analysis of the 15 colon cancer and adjacent normal colon tissue samples revealed that all six genes were expressed in both groups, but their expression levels were significantly higher in the colon cancer group. Furthermore, the mRNA expression levels of the FTHL17, PRM2, CABYR, CPXCR1, and ADAM29 genes were considerably upregulated after treatment of HCT116 and Caco-2 cells with 5-aza-2'-deoxycytidine and trichostatin. However, the CABS1 gene was activated only with trichostatin treatment. Conclusions: The findings of this study suggest that FTHL17, PRM2, CABYR, CPXCR1, ADAM29, and CABS1 are suitable candidate biomarkers of colon cancer and their expressions are regulated by hypomethylation and hyperacetylation.

Magnetically controlled drug delivery and hyperthermia effects of core-shell Cu@Mn3O4 nanoparticles towards cancer cells in vitro.

Recent increase in the integration of nanotechnology and nanosciences to the biomedical sector fetches the human wellness through the development of sustainable treatment methodologies for cancerous tumors at all stages of their initiation and progression. This involves the development of multifunctional theranostic probes that effectively support for the early cancer diagnosis, avoiding non-target cell toxicity, controlled and customized anticancer drug release etc. Therefore, to advance the field of nanotechnology-based sustainable cancer treatment, we fabricated and tested the efficacy of anticancer drug-loaded magnetic hybrid nanoparticles (NPs) towards in vitro cell culture systems. The developed conjugate of NPs was incorporated with the functions of both controlled drug delivery and heat-releasing ability using Mn3O4 (manganese oxide) magnetic core with Cu shell encapsulated within trimethyl chitosan (TMC) biopolymer. On characterization, the Cu@Mn3O4-TMC NPs were confirmed to have an approximate size of 130 nm with full agglomeration (as observed by the HRTEM) and crystal size of 92.95 ± 18.38 nm with tetragonal hausmannite phase for Mn3O4 spinel structure (XRD). Also, the UV-Vis and FTIR analysis provided the qualitative and quantitative effects of 5-fluororacil (5-Fu) anticancer drug loading (max 68 %) onto the Cu@Mn3O4-TMC NPs. The DLS analysis indicated for the occurrence of no significant changes to the particle size (around 100 nm) of Cu@Mn3O4-TMC due to the solution dispersion thereby confirming for the aqueous stability of developed NPs. In addition, the magnetization values of Cu@Mn3O4-TMC NPs were measured to be 34 emu/g and a blocking temperature of 42 K. Further tests of magnetic hyperthermia by the Cu@Mn3O4-TMC/5-Fu NPs provided that the heat-releasing capacity (% ΔT at 15 min) increases with that of increased frequency, i.e. 28 % (440 Hz) > 22.6 % (240 Hz) > 18 % (44 Hz), and the highest specific power loss (SPL) value observed to be 488 W/g for water. Moreover, the 5-Fu drug release studies indicate that the release is high at a pH of 5.2 and almost all the loaded drug is getting delivered under the influence of the external magnetic field (430 Hz) due to the influence of both Brownian-rotation and Néel relaxation heat-mediated mechanism. The pharmacokinetic drug release studies have suggested for the occurrence of more than one model, i.e. First-order, Higuchi (diffusion), and Korsemeyer-Peppas (non-Fickian), in addition to hyperthermia. Finally, the in vitro cell culture systems (MCF-7 cancer and MCF-10 non-cancer) helped to differentiate the physiological changes due to the effects of hyperthermia and 5-Fu drug individually and as a combination of both. The observed differences of cell viability losses among both cell types are measured and discussed with the expression of heat shock proteins (HSPs) by the MCF-10 cells as against the MCF-7 cancer cells. We believe that the results generated in this project can be helpful for the designing of new cancer therapeutic models with nominal adverse effects on healthy normal cells and thus paving a way for the treatment of cancer and other deadly diseases in a sustainable manner.

Genetic Variants of HOTAIR Associated with Colorectal Cancer: A Case-Control Study in the Saudi Population.

Genetic polymorphism in long noncoding RNA (lncRNA) HOTAIR is linked with the risk and susceptibility of various cancers in humans. The mechanism involved in the development of CRC is not fully understood but single nucleotide polymorphisms (SNPs) can be used to predict its risk and prognosis. In the present case-control study, we investigated the relationship between HOTAIR (rs12826786, rs920778, and rs1899663) polymorphisms and CRC risk in the Saudi population by genotyping using a TaqMan genotyping assay in 144 CRC cases and 144 age- and sex-matched controls. We found a significant (p < 0.05) association between SNP rs920778 G > A and CRC risk, and a protective role of SNPs rs12826786 (C > T) and rs1899663 (C > A) was noticed. The homozygous mutant "AA" genotype at rs920778 (G > A) showed a significant correlation with the female sex and colon tumor site. The homozygous TT in SNP rs12816786 (C > T) showed a significant protective association in the male and homozygous AA of SNP rs1899663 (C > A) with colon tumor site. These results indicate that HOTAIR can be a powerful biomarker for predicting the risk of colorectal cancer in the Saudi population. The association between HOTAIR gene polymorphisms and the risk of CRC in the Saudi population was reported for the first time here.

Development of Metallo (Calcium/Magnesium) Polyurethane Nanocomposites for Anti-Corrosive Applications.

Long-term corrosion protection of metals might be provided by nanocomposite coatings having synergistic qualities. In this perspective, rapeseed oil-based polyurethane (ROPU) and nanocomposites with calcium and magnesium ions were designed. The structure of these nanocomposites was established through Fourier-transform infrared spectroscopy (FT-IR). The morphological studies were carried out using scanning electron microscopy (SEM) as well as transmission electron microscopy (TEM). Their thermal characteristics were studied using thermogravimetric analysis (TGA). Electrochemical experiments were applied for the assessment of the corrosion inhibition performance of these coatings in 3.5 wt. % NaCl solution for 7 days. After completion of the test, the results revealed a very low icorr value of 7.73 × 10-10 A cm-2, a low corrosion rate of 8.342 × 10-5 mpy, impedance 1.0 × 107 Ω cm2, and phase angle (approx 90°). These findings demonstrated that nanocomposite coatings outperformed ordinary ROPU and other published methods in terms of anticorrosive activity. The excellent anti-corrosive characteristic of the suggested nanocomposite coatings opens up new possibilities for the creation of advanced high-performance coatings for a variety of metal industries.

Green Synthesis of Silver Nanoparticles Using Aerial Part Extract of the Anthemis pseudocotula Boiss. Plant and Their Biological Activity.

Green syntheses of metallic nanoparticles using plant extracts as effective sources of reductants and stabilizers have attracted decent popularity due to their non-toxicity, environmental friendliness and rapid nature. The current study demonstrates the ecofriendly, facile and inexpensive synthesis of silver nanoparticles (AP-AgNPs) using the extract of aerial parts of the Anthemis pseudocotula Boiss. plant (AP). Herein, the aerial parts extract of AP performed a twin role of a reducing as well as a stabilizing agent. The green synthesized AP-AgNPs were characterized by several techniques such as XRD, UV-Vis, FT-IR, TEM, SEM and EDX. Furthermore, the antimicrobial and antibiofilm activity of as-prepared AP-AgNPs were examined by a standard two-fold microbroth dilution method and tissue culture plate methods, respectively, against several Gram-negative and Gram-positive bacterial strains and fungal species such as Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), multidrug-resistant Pseudomonas aeruginosa (MDR-PA) and Acinetobacter baumannii (MDR-AB), methicillin-resistant S. aureus (MRSA) and Candida albicans (C. albicans) strains. The antimicrobial activity results clearly indicated that the Gram-negative bacteria MDR-PA was most affected by AgNPs as compared to other Gram-negative and Gram-positive bacteria and fungi C. albicans. Whereas, in the case of antibiofilm activity, it has been found that AgNPs at 0.039 mg/mL, inhibit biofilms formation of Gram-negative bacteria i.e., MDR-PA, E. coli, and MDR-AB by 78.98 ± 1.12, 65.77 ± 1.05 and 66.94 ± 1.35%, respectively. On the other hand, at the same dose (i.e., 0.039 mg/mL), AP-AgNPs inhibits biofilm formation of Gram-positive bacteria i.e., MRSA, S. aureus and fungi C. albicans by 67.81 ± 0.99, 54.61 ± 1.11 and 56.22 ± 1.06%, respectively. The present work indicates the efficiency of green synthesized AP-AgNPs as good antimicrobial and antibiofilm agents against selected bacterial and fungal species.

Association of HER1 and HER2 Gene Variants in the Predisposition of Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) is a major health concern worldwide. A series of sequential accumulation of genetic and epigenetic changes are responsible for the initiation and progression of diseases via the normal > adenoma > carcinoma sequence. Genetic variants in crucial cancer-causing genes are known to mediate the risk of cancer. OBJECTIVE: In this case-control study, we examined single nucleotide polymorphism (SNP) in HER1 (rs763317 and rs3752651) and HER2 (rs1136201 and rs1058808) genes to assess their role in the susceptibility of CRC in a Saudi population. METHODS: TaqMan allelic discrimination assay was utilized to identify the genotypes in 163 normal and 143 CRC patients. RESULTS: In the overall analysis, the rs3752651 and rs1136201 were significantly associated with the risk of CRC. Although none of the examined SNPs had any impact on the age at which CRC was diagnosed, interestingly, three SNPs showed a significant association based on gender. The rs3752651 conferred significant protection only in men, whereas rs1136201 diminished the risk and rs1058808 considerably increased the susceptibility of CRC only in women. CONCLUSIONS: Our result suggests that these SNPs in HER1 and HER2 after validation in larger cohorts of different ethnicities may be utilized as genetic screening markers for predicting colorectal cancer predisposition.

NOTCH Single Nucleotide Polymorphisms in the Predisposition of Breast and Colorectal Cancers in Saudi Patients.

Breast cancer (BC) is a heterogeneous disease and is one of the most common malignancy affecting women worldwide while colorectal cancer (CRC) is estimated to be the third common cancer and second leading cause of cancer related death globally. Both BC and CRC involve multiple genetic and epigenetic alterations in genes belonging to various signaling pathways including NOTCH that has been implicated in the development of these cancers. We investigated four single nucleotide polymorphisms, each in genes encoding NOTCH1-4 receptors for their role in susceptibility to breast and colorectal cancers in Saudi population. In this case-control study, TaqMan genotypic analysis of rs3124591 in NOTCH1 and rs3820041 in NOTCH4 did not exhibit association with breast as well as colorectal cancers. However, a strong association of rs11249433 which is in close proximity to NOTCH2 was observed with breast cancer susceptibility especially with those having an early onset of the disease. Interestingly, the rs1043994 located in NOTCH3 showed gender preference and was found to be significantly associated with colorectal cancers in males. Validation of these findings in bigger populations of different ethnicities may prove beneficial in identifying rs11249433 and rs1043994 as genetic screening markers for early detection of breast and colorectal carcinomas, respectively.

Mn3O4 nanoparticles: Synthesis, characterization and their antimicrobial and anticancer activity against A549 and MCF-7 cell lines.

Due to their inexpensive and eco-friendly nature, and existence of manganese in various oxidation states and their natural abundance have attained significant attention for the formation of Mn3O4 nanoparticles (Mn3O4 NPs). Herein, we report the preparation of Mn3O4 nanoparticles using manganese nitrate as a precursor material by utilization of a precipitation technique. The as-prepared Mn3O4 nanoparticles (Mn3O4 NPs) were characterized by using X-ray powder diffraction (XRD), UV-Visible spectroscopy (UV-Vis), High-Resolution Transmission electron microscopy (HRTEM), Field emission scanning electron microscopy (FESEM), Thermal gravimetric analysis (TGA) and Fourier-transform infrared spectroscopy (FT-IR). The antimicrobial properties of the as-synthesized Mn3O4 nanoparticles were investigated against numerous bacterial and fungal strains including S. aureus, E. coli, B. subtilis, P. aeruginosa, A. flavus and C. albicans. The Mn3O4 NPs inhibited the growth of S. aureus with a minimum inhibitory concentration (MIC) of 40 µg/ml and C. albicans with a MIC of 15 µg/ml. Furthermore, the Mn3O4 NPs anti-cancer activity was examined using MTT essay against A549 lung and MCF-7 breast cancer cell lines. The Mn3O4 NPs revealed significant activity against the examined cancer cell lines A549 and MCF-7. The IC50 values of Mn3O4 NPs with A549 cell line was found at concentration of 98 µg/mL and MCF-7 cell line was found at concentration of 25 µg/mL.

A novel biocompatible formate bridged 1D-Cu(ii) coordination polymer induces apoptosis selectively in human lung adenocarcinoma (A549) cells.

Copper compounds are promising candidates for next-generation metal anticancer drugs. Therefore, we synthesized and characterized a formate bridged 1D coordination polymer [Cu(L)(HCOO)2]n, (L = 2-methoxy-6-methyl-3-((quinolin-8-ylimino)methyl)chroman-4-ol), PCU1, wherein the Cu(ii) center adopts a square pyramidal coordination environment with adjacent CuCu distances of 5.28 Å. Primarily, in vitro DNA interaction studies revealed a metallopolymer which possesses high DNA binding propensity and cleaves DNA via the oxidative pathway. We further analysed its potential on cancerous cells MCF-7, HeLa, A549, and two non-tumorigenic cells HEK293 and HBE. The selective cytotoxicity potential of PCU1 against A549 cells driven us to examine the mechanistic pathways comprehensively by carrying out various assays viz, cell cycle arrest, Annexin V-FTIC/PI assay, autophagy, intercellular localization, mitochondrial membrane potential 'MMP', antiproliferative assay, and gene expression of TGF-ß and MMP-2.

Targeted sequencing of crucial cancer causing genes of breast cancer in Saudi patients.

Breast cancer is the most common cancer among women worldwide, causing 15% of cancer-related deaths among women. Breast cancer incidence rate is increasing in most countries. In Saudi Arabia, breast cancer constitutes nearly 22% of the newly diagnosed cancer cases in women. Breast cancer incidence in the women population of Saudi Arabia is 25.9%, with 18.2% mortality. In this study, targeted sequencing of 164 selected genes was performed on germline and somatic DNA derived from the blood and tissue samples of 50 breast cancer patients using customized panel on Ion torrent platform. This study focused on the identification of genetic variations of different cancer-causing genes, raising the hope for identification of personalized prognosis. After final filtration and validation, we found protein-truncating, non-synonymous missense, and splice site mutations in the known susceptibility genes for breast cancer. We identified a total of 14 point mutations and one deletion in BRCA1, BRCA2, and RAD50 genes from the BRCA panel analysis of breast cancer samples. In the customized panel analysis, we identified 37 potential mutations in 25 breast cancer risk associated genes. Out of these, most mutations were observed in TP53. After filtration, we observed 7 mutations in TP53 genes (n = 7:- one stop gain (p.R81X), four non-synonymous (p.R81X, p.Y88C, p.R141H, and p.V25D), and two deletions (c.59delC and c.327delC)). Among the mutations detected in our study, TP53 (p.R81X), VHL (p.E52X), and BRCA2 (p.K3326X) mutations, which lead to an aberrant transcript with a premature stop codon, were reported for the first time in breast cancer patients from Saudi Arabia. Our study will help in identifying the damaging mutations and predisposing genes in Saudi breast cancer patients.

Whole exome sequencing of a Saudi family and systems biology analysis identifies CPED1 as a putative causative gene to Celiac Disease.

Celiac disease (CD) is a gastrointestinal disorder whose genetic basis is not fully understood. Therefore, we studied a Saudi family with two CD affected siblings to discover the causal genetic defect. Through whole exome sequencing (WES), we identified that both siblings have inherited an extremely rare and deleterious CPED1 genetic variant (c.241 A > G; p.Thr81Ala) segregating as autosomal recessive mutation, suggesting its putative causal role in the CD. Saudi population specific minor allele frequency (MAF) analysis has confirmed its extremely rare prevalence in homozygous condition (MAF is 0.0004). The Sanger sequencing analysis confirmed the absence of this homozygous variant in 100 sporadic Saudi CD cases. Genotype-Tissue Expression (GTEx) data has revealed that CPED1 is abundantly expressed in gastrointestinal mucosa. By using a combination of systems biology approaches like protein 3D modeling, stability analysis and nucleotide sequence conservation analysis, we have further established that this variant is deleterious to the structural and functional aspects of CPED1 protein. To the best of our knowledge, this variant has not been previously reported in CD or any other gastrointestinal disease. The cell culture and animal model studies could provide further insight into the exact role of CPED1 p.Thr81Ala variant in the pathophysiology of CD. In conclusion, by using WES and systems biology analysis, present study for the first-time reports CPED1 as a potential causative gene for CD in a Saudi family with potential implications to both disease diagnosis and genetic counseling.

Two novel SNPs in genes involved in immune response and their association with mandibular residual ridge resorption.

"Residual ridge resorption" (RRR) is a multifactorial condition involving bone resorption of the residual ridge. We investigated 10 single nucleotide polymorphisms (SNPs) in seven genes with the aim of identifying the genetic factors associated with RRR susceptibility. The study group included 96 RRR patients and 96 controls. Age at first edentulism, duration of edentulism, and bone height were recorded. Saliva was collected from the subjects for DNA extraction. Genotype analysis was performed on the 'SequenomMassARRAYiPLEX'. The genotype and allele frequencies calculated in patients and controls were compared. We found that rs1800896 in the IL10 gene and rs5743289 in NOD2 gene showed significant association with RRR. Within the RRR group, genotypes for each SNP were separated, and we observed that the age at first edentulism and bone height showed variations in the different genotypes of the ten studied SNPs. This study showed an association between SNPs in IL10 and NOD2 genes. It also revealed that the genotypes of the different SNPs influence bone resorption and health. Additionally, age at first edentulism and bone height were much lower in some genotypes. This study demonstrates the need for larger multicenter trials to confirm these findings. Finally, we suggest that the results of this study may be utilized for developing novel genetic diagnostic tests and for identifying Saudi individuals who may be more susceptible to RRR development following dental extraction.

Frequent Activation of Notch Signaling Pathway in Colorectal Cancers and Its Implication in Patient Survival Outcome.

Colorectal cancer is a major health concern as it ranks third in incidence and second major cause of cancer-related deaths worldwide. A leading cause of treatment failure has been attributed to cancer stem cells that can invariably resist existing chemotherapeutic regimens. Notch signaling pathway has been involved in the maintenance of stem cells besides being crucial in cell fate decision and embryonic development. This pathway has also been implicated in several human malignancies including colorectal cancer. We investigated mRNA expression of four Notch receptors (Notch1-4), five ligands (Jag1, Jag2, Dll1, Dll3, and Dll4), and four target genes (Hes1, Hes5, Hey1, and Hey2) using highly specific TaqMan gene expression assays in colorectal adenomas and cancers. Upregulated expression of Notch receptors ranged between 29 and 73% in colorectal cancers and between 11 and 56% in adenomas. Expression of Notch3 and Notch4 receptors was significantly higher in colorectal cancers compared to normal and adenoma tissues. The Jagged and Delta-like ligands were overexpressed between 25 and 52% in colorectal cancers, while in adenomas, it ranged between 0 and 33%. Combining the data for upregulation of receptors and ligands suggests that 86% colorectal cancers and 56% adenomas exhibited overexpression of Notch pathway genes in our cohort. Notch target genes were upregulated between 24 and 33% in colorectal cancers and between 11 and 22% in adenomas. Collating upregulation of Notch receptors and ligands with the target genes showed concordance in 58% colorectal tumors. Additionally, we evaluated expression of Notch receptors, ligands, and target genes with prognosis using the TCGA mRNA expression dataset. Patients overexpressing Notch3, Notch4, and Hey1 had significantly poorer overall survival relative to those having lower levels of these genes. Taken together, Notch signaling components are aberrantly overexpressed in colorectal tumors, and development of therapeutics targeting the Notch pathway may prove to be beneficial in the management of colorectal cancers.

Antimicrobial resistance, mechanisms and its clinical significance.

Antimicrobial agents play a key role in controlling and curing infectious disease. Soon after the discovery of the first antibiotic, the challenge of antibiotic resistance commenced. Antimicrobial agents use different mechanisms against bacteria to prevent their pathogenesis and they can be classified as bactericidal or bacteriostatic. Antibiotics are one of the antimicrobial agents which has several classes, each with different targets. Consequently, bacteria are endlessly using methods to overcome the effectivity of the antibiotics by using distinct types of mechanisms. Comprehending the mechanisms of resistance is vital for better understanding and to continue use of current antibiotics. Which also helps to formulate synthetic antimicrobials to overcome the current mechanism of resistance. Also, encourage in prudent use and misuse of antimicrobial agents. Thus, decline in treatment costs and in the rate of morbidity and mortality. This review will be concentrating on the mechanism of actions of several antibiotics and how bacteria develop resistance to them, as well as the method of acquiring the resistance in several bacteria and how can a strain be resistant to several types of antibiotics. This review also analyzes the prevalence, major clinical implications, clinical causes of antibiotic resistance. Further, it evaluates the global burden of antimicrobial resistance, identifies various challenges and strategies in addressing the issue. Finally, put forward certain recommendations to prevent the spread and reduce the rate of resistance growth.

Exome sequencing and metabolomic analysis of a chronic kidney disease and hearing loss patient family revealed RMND1 mutation induced sphingolipid metabolism defects.

Mitochondrial disorders (MIDs) shows overlapping clinical presentations owing to the genetic and metabolic defects of mitochondria. However, specific relationship between inherited mutations in nuclear encoded mitochondrial proteins and their functional impacts in terms of metabolic defects in patients is not yet well explored. Therefore, using high throughput whole exome sequencing (WES), we screened a chronic kidney disease (CKD) and sensorineural hearing loss (SNHL) patient, and her family members to ascertain the mode of inheritance of the mutation, and healthy population controls to establish its rare frequency. The impact of mutation on biophysical characteristics of the protein was further studied by mapping it in 3D structure. Furthermore, LC-MS tandem mass spectrophotometry based untargeted metabolomic profiling was done to study the fluctuations in plasma metabolites relevant to disease causative mutations and kidney damage. We identified a very rare homozygous c.631G > A (p.Val211Met) pathogenic mutation in RMND1 gene in the proband, which is inherited in an autosomal recessive fashion. This gene is involved in the mitochondrial translational pathways and contribute in mitochondrial energy metabolism. The p.Val211Met mutation is found to disturb the structural orientation (RMSD is -2.95 Å) and stability (ΔΔG is -0.552 Kcal/mol) of the RMND1 protein. Plasma metabolomics analysis revealed the aberrant accumulation of metabolites connected to lipid and amino acid metabolism pathways. Of these metabolites, pathway networking has discovered ceramide, a metabolite of sphingolipids, which plays a role in different signaling cascades including mitochondrial membrane biosynthesis, is highly elevated in this patient. This study suggests that genetic defects in RMND1 gene alters the mitochondrial energy metabolism leading to the accumulation of ceramide, and subsequently promote dysregulated apoptosis and tissue necrosis in kidneys.

Genetic variants in the WNT signaling pathway are protectively associated with colorectal cancer in a Saudi population.

The Wnt/ß-catenin signaling pathway has been etiologically implicated in the development and progression of colorectal cancer. We studied thirteen single nucleotide polymorphisms (SNPs) located in SFRP3 (rs7775), CTNNB1 (ß-catenin) [rs4135385, rs13072632], APC (rs454886, rs459552), LRP6 (rs2075241, rs2284396), DKK4 (rs3763511), DKK3 (rs6485350), TCF4 (rs12255372) and AXIN2 (rs3923086, rs3923087, rs4791171) in patients with colorectal cancer (n = 122) and controls (n = 110). Evaluation of WNT pathway SNPs showed protective association for rs4135385, located in ß-catenin. Additionally, variants in SFRP3 (rs7775) and LRP6 (rs2284396) which did not show any association in the overall analysis were significantly associated with female and old aged colorectal cancer patients, respectively.

Association between polymorphisms in PRNCR1 and risk of colorectal cancer in the Saudi population.

LncRNA Prostate cancer non-coding RNA (PRNCR1) is downregulated in many types of cancer. The current case-control study was performed on 144 patients with colorectal cancer and 130 matching controls. Genotyping was performed using TaqMan assays for four Single Nucleotide Polymorphisms (SNPs) in PRNCR1. RNAsnp Web Server was used to detect variations in the secondary structure for each SNP. The genotyping analysis for SNP rs1456315 showed increased association with colorectal cancer with the homozygous CC variant allele (OR: 2.09; χ2 = 4.95; CI: 1.08-4.02; p = 0.02), the minor allele frequency, and additive genotype, respectively (OR: 1.55; χ2 = 6.24; CI: 1.09-2.19; p = 0.01) & (OR: 1.64; χ2 = 4.04; CI: 1.01-2.67; p = 0.04). A risk association was also observed among younger age patients (≤57) and in female patients as well as in patients with tumors of the colon. For the other SNPs tested (rs16901946, rs13252298, rs1016343), no significant association was observed. The secondary structure of the rs1456315 mutant is different from that of the wild-type. Our findings suggest that the upregulation of PRNCR1 and its variants is associated with increased risk of colorectal cancer in Saudi patients, indicating that PRNCR1 might be a unique and valuable signature for predicting the risk of colorectal cancer in a Saudi population.

Toll-like receptor 4 polymorphisms in Saudi population with cardiovascular diseases.

BACKGROUND: Toll-like receptors play a substantial role in innate immunity and the effects of TLR4 genetic variants on cardiovascular diseases are still largely unknown. Therefore, we aimed to investigate the effects of TLR4 polymorphisms on cardiovascular diseases risk in the Saudi population. METHODS: Three tag single-nucleotide polymorphisms (rs2770150, rs10759931, and rs4986790) in TLR4 were studied on 222 unrelated patients with cardiovascular diseases and 190 healthy volunteers. RESULTS: We found that, in patients over 60 years old, the frequency of the TT genotype in rs2770150 and the variant allele G in rs10759931 were higher compared to the control group. Based on gender, the genotype frequency of rs2770150 increases the risk for cardiovascular diseases in female patients by 3.6-fold. The allele frequency for the G allele of rs10759931 increased the risk for CVDs in male patients by more than 1.5-fold. Furthermore, the genotype frequency of rs2770150 had a significant association with cardiovascular diseases in patients without hypertension and G allele of rs10759931 significantly increased the risk of cardiovascular diseases in patients that smoked. After Bonferroni correction only patients without hypertension showed significant risk of CVD with rs2770150. CONCLUSION: A deeper understanding of the genetic variability of TLR4 will enable us to better identification of biomarkers for early detection and prognosis, and also enhance the decision-making process of treatments for cardiovascular diseases.

TDG Gene Polymorphisms and Their Possible Association with Colorectal Cancer: A Case Control Study.

Genetic alterations that might lead to colorectal cancer involve essential genes including those involved in DNA repair, inclusive of base excision repair (BER). Thymine DNA glycosylase (TDG) is one of the most well characterized BER genes that catalyzes the removal of thymine moieties from G/T mismatches and is also involved in many cellular functions, such as the regulation of gene expression, transcriptional coactivation, and the control of epigenetic DNA modification. Mutation of the TDG gene is implicated in carcinogenesis. In the present study, we aimed to investigate the association between TDG gene polymorphisms and their involvement in colon cancer susceptibility. One hundred blood samples were obtained from colorectal cancer patients and healthy controls for the genotyping of seven SNPs in the TDG gene. DNA was extracted from the blood, and the polymorphic sites (SNPs) rs4135113, rs4135050, rs4135066, rs3751209, rs1866074, and rs1882018 were investigated using TaqMan genotyping. One of the six TDG SNPs was associated with an increased risk of colon cancer. The AA genotype of the TDG SNP rs4135113 increased the risk of colon cancer development by more than 3.6-fold, whereas the minor allele A increased the risk by 1.6-fold. It also showed a 5-fold higher risk in patients over the age of 57. SNP rs1866074 showed a significant protective association in CRC patients. The GA genotype of TDG rs3751209 was associated with a decreased risk in males. There is a significant relationship between TDG gene function and colorectal cancer progression.