Risperidone-induced bioenergetic disruption in the isolated human peripheral blood monocytes.

Risperidone (RIS) is a widely used antipsychotic drug with reported alteration in immune response. The current study investigated mitochondrial disruption as the underlying mechanism of RIS-induced immunotoxicity in isolated human peripheral blood monocytes (hPBM). RIS was cytotoxic to hPBM in exposure duration and concentration-dependent patterns. Functionally, RIS was shown to increase the release of IL-6, TNF-α, and IL-8 with a decrease in test particle phagocytosis in concertation and exposure time-based patterns. It was found that RIS decreased ATP production in isolated monocytes' mitochondria, with an estimated EC50 of around 70 µM after 24 h with parallel inhibition of mitochondrial complexes I and III activities and decreased mitochondrial membrane potential and oxygen consumption rates with increased lactate production from by the treated cells in comparison to controls. Structurally, RIS in 100 µM concentration significantly increased the mitochondrial membrane fluidity with significant increase in increased unsaturated/saturated fatty acids ratios of the mitochondrial membranes of the treated cells. Interestingly, water-soluble CoQ10 formulation significantly decreased the cytotoxic effect of RIS and improved the phagocytic activity of RIS-treated cells. To conclude, the current data suggests mitochondrial disruption as the underlying mechanism of RIS-induced immunotoxicity with shown protective effect of water-soluble CoQ10 formulation.

Vitamin D Alleviates Heavy Metal-Induced Cytotoxic Effects on Human Bone Osteoblasts Via the Induction of Bioenergetic Disruption, Oxidative Stress, and Apoptosis.

Cadmium (Cd) and lead (Pb) are heavy metals (HMs) that persistently contaminate the ecosystem, and bioaccumulation in bones is a health concern. We used biochemical and molecular assays to assess the cytoprotective effect of vitamin D (VD) on Cd- and Pd-induced chemical toxicity of human bone osteoblasts in vitro. Exposing Cd and Pb to human osteoblast cultures at concentrations of 0.1-1000 µM for 24-72 h significantly reduced osteoblast viability in an exposure time- and concentration-dependent manner. The cytotoxic effect of Cd on osteoblasts was more severe than Pb's, with 72-h exposure estimated half maximal effective concentration (EC50) of 8 and 12 µM, respectively, and VD (1 and 10 nM) alleviated cytotoxicity. Bioenergetics assays of ATP, mitochondrial membrane potential, and mitochondrial complex I and III activity showed that both Cd and Pb (1 and 10 µM) inhibited cellular bioenergetics after 72-h exposure. Cd and Pb increased lipid peroxidation and reactive oxygen species with reduced catalase/superoxide dismutase antioxidant activities and increased activity of caspases -3, -8, and -9. Co-treatment with VD (1 and 10 nM) counteracted bioenergetic disruption, oxidative damage, and apoptosis in a concentration-dependent manner. These findings suggest that VD is effective in managing the toxic effects of environmental pollutants and in treating bone diseases characterized by oxidative stress, apoptosis, and bioenergetic disruption.

Neurotoxic mechanisms of dexamethasone in SH-SY5Y neuroblastoma cells: Insights into bioenergetics, oxidative stress, and apoptosis.

Despite the known therapeutic uses of dexamethasone (DEX), the specific mechanisms underlying its neurotoxic effects in neuronal cells, particularly in undifferentiated human neuroblastoma (SH-SY5Y) cells, remain inadequately understood. This study aims to elucidate these mechanisms, emphasizing bioenergetics, oxidative stress, and apoptosis, thereby providing novel insights into the cellular vulnerabilities induced by chronic DEX exposure. The findings revealed significant reductions in cell viability, altered membrane integrity with LDH leakage, decreased intracellular ATP production, and the electron transport chain complexes I and III activity inhibition. DEX significantly increased the release of the reactive species and peroxidation of lipids, as well as of Nrf2 expression. At the same time, it simultaneously led to a decline in the activities of the antioxidant catalase and superoxide dismutase enzymes, along with a depletion of glutathione reserves. The apoptosis process was exhibited by a significant elevation of caspases 3 and 8 activities with overexpression of mRNA BAX, inhibition of BCL-2, and a significant upregulation of the BAX/BCL-2 ratio. Assessment of neuronal development genes (GAP43, CAMK2A, CAMK2B, TUBB3, and Wnts) by quantitative PCR assay showed increased expression of CAMK2A, CAMK2B, and Wnt3a with a significant reduction in GAP43 mRNA levels. Collectively, this study proved that DEX was cytotoxic to SH-SY5Y via bioenergetic disruption, mitochondrial dysfunction, oxidative stress, and apoptosis.

Bioenergetics disruption, oxidative stress, and inflammation as underlying mechanisms of tramadol-induced nephrotoxicity.

Tramadol (TR), a commonly prescribed pain reliever for moderate to severe pain, has been associated with kidney damage. This study investigates TR-induced nephrotoxicity mechanisms, focusing on its effects on renal proximal tubular cells (PTCs). The study findings demonstrate that TR disrupts PTC bioenergetic processes, leading to oxidative stress and inflammation. Significant toxicity to PTCs was observed with estimated effective concentration 50 values of 9.8 and 11.5 µM based on 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays, respectively. TR also interferes with the function of PTC transporters, including organic cation uptake transporter 1, organic cation transporter 2, P-glycoprotein, and multidrug resistance protein 2. Furthermore, bioenergetics assays showed that TR reduced the activities of mitochondrial complexes I and III, adenosine triphosphate production, mitochondrial membrane potential, and oxygen consumption rate while increasing lactate release. TR also increased the production of reactive oxygen species, lipid peroxidation thiobarbituric acid reactive substances end products, and the expression of the NRf2 gene while decreasing reduced glutathione (GSH-R) stores and catalase and superoxide dismutase antioxidant activities. Additionally, TR increased the production of inflammatory cytokines (TNF-α and IL-6) and their coding genes expression. Interestingly, the study found that antioxidants like GSH-R, inhibitors of IL-6 and TNF-α, and mitochondrial activating Co-Q10 could protect cells against TR-induced cytotoxicity. The study suggests that TR causes nephrotoxicity by disrupting bioenergetic processes, causing oxidative stress and inflammation, but antioxidants and agents targeting mitochondria may have protective and curative potential.

Differential Effects of Paraquat, Rotenone, and MPTP on Cellular Bioenergetics of Undifferentiated and Differentiated Human Neuroblastoma Cells.

Paraquat (PQ), rotenone (RO), and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are neurotoxicants that can damage human health. Exposure to these neurotoxicants has been linked to neurodegeneration, particularly Parkinson's disease. However, their mechanisms of action have not been fully elucidated, nor has the relative vulnerability of neuronal subtypes to their exposures. To address this, the current study investigated the cytotoxic effects of PQ, RO, and MPTP and their relative effects on cellular bioenergetics and oxidative stress on undifferentiated human neuroblastoma (SH-SY5Y) cells and those differentiated to dopaminergic (DA) or cholinergic (CH) phenotypes. The tested neurotoxicants were all cytotoxic to the three cell phenotypes that correlated with both concentration and exposure duration. At half-maximal effective concentrations (EC50s), there were significant reductions in cellular ATP levels and reduced activity of the mitochondrial complexes I and III, with a parallel increase in lactate production. PQ at 10 µM significantly decreased ATP production and mitochondrial complex III activity only in DA cells. RO was the most potent inhibitor of mitochondrial complex 1 and did not inhibit mitochondrial complex III even at concentrations that induced a 50% loss of cell viability. MPTP was the most potent toxicant in undifferentiated cells. All neurotoxicants significantly increased reactive oxygen species, lipid peroxidation, and nuclear expression of Nrf2, with a corresponding inhibition of the antioxidant enzymes catalase and superoxide dismutase. At a 10 µM exposure to PQ or RO, oxidative stress biomarkers were significant in DA cells. Collectively, this study underscores the importance of mitochondrial dysfunction and oxidative stress in PQ, RO, and MPTP-induced cytotoxicity and that neuronal phenotypes display differential vulnerability to these neurotoxicants.

Role of mitochondrial disruption and oxidative stress in plasticizer phthalate-induced cytotoxicity to human bone osteoblasts.

Phthalates are frequently utilized in a wide range of products such as plasticizers with reported negative effects on bones. The current study evaluated the effect of butyl cyclohexyl phthalate on the human osteoblasts via different assays. MTT and lactate dehydrogenase assays were used to examine the in-vitro cytotoxic effect of butyl cyclohexyl phthalate on human bone osteoblasts in concentrations 0.1, 1, 10, and 100 µM for 12 to 72 h postexposures. Incubation of osteoblasts with butyl cyclohexyl phthalate significantly reduced cell viability based on its concentrations and durations of exposure. In parallel, osteoblast secretion of procollagen type 1, osteocalcin, as well as alkaline phosphatase was significantly decreased by butyl cyclohexyl phthalate in concentrations (1 or 2 µM). Butyl cyclohexyl phthalate decreased ATP synthesis and mitochondrial complexes I and III activities, with increased lactate production, all of which were detrimental to cellular bioenergetics. The cellular redox defense systems were significantly depleted by increased lipid peroxidation, elevated reactive oxygen species, decreased catalase and superoxide dismutase enzymes activities, and decreased intracellular reduced glutathione (GSH). Redox stress was also induced. Interestingly, preincubating osteoblasts with reduced GSH before exposing them to butyl cyclohexyl phthalate significantly lowered the cytotoxicity of the butyl cyclohexyl phthalate, suggesting that antioxidants may play a helpful protective effect.

Genetic Variants in the Mitochondrial Thymidylate Biosynthesis Pathway Increase Colorectal Cancer Risk.

We assess the contributions of genetic variants for the enzymes involved in capecitabine metabolism to colorectal cancer (CRC) development risk. In this case-control study, DNA samples were collected from 66 patients (King Abdulaziz University Hospital) and 65 controls (King Fahad General Hospital) between April and November 2022 to be used in PCR-RFLP. The chi-square (χ2) test at a significance level of p ˂ 0.05 was used to estimate genotype and allele frequencies. The Lys27Gln variant of cytidine deaminase (CDA) showed a risk ratio (RR) of 1.47 for heterozygous (AC) carriers, with genotype distributions for patients (χ2 = 1.97) and controls (χ2 = 14.7). Homozygous (AA) Ala70Thr carriers demonstrated a three-fold higher risk, with genotype distributions for patients (χ2 = 3.85) and controls (χ2 = 4.23). Genotype distributions of the 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T variant for patients were (χ2 = 22.43) and for controls were (χ2 = 0.07); for the MTHFR A1298C variant, they were (χ2 = 54.44) for patients and (χ2 = 4.58) for controls. Heterozygous (AC) carriers of the A1298C variant demonstrated highly significant protection against CRC development (RR = 0.2, p = 0.001), while a two-fold higher risk for CRC was estimated for homozygous genotype (CC) carriers. In conclusion, the heterozygous genotype of CDA Lys27Gln, the homozygous genotype of CDA Ala70Thr, and the homozygous genotype of MTHFR A1298C were associated with CRC development risk. The heterozygous genotype of MTHFR A1298C variant provided highly significant protection against CRC development. Further examinations using a larger population size are needed to reliably confirm our findings.

5­Fluorouracil and capecitabine therapies for the treatment of colorectal cancer (Review).

Although 5­fluorouracil (5­FU)­based chemotherapy is the major treatment for colorectal cancer, it has disadvantages such as systemic toxicity, lack of effectiveness and selectivity, and development of resistance. Capecitabine, a prodrug form of 5­FU, was designed to overcome these drawbacks, to fulfill the need for more convenient therapy, and to improve safety, tolerability and intratumor drug concentration levels through a tumor­specific conversion to the active 5­FU drug. The purpose of the present review is to provide a comprehensive comparison between 5­FU therapy and capecitabine. In the current review, anticancer drug classification was discussed and the development of capecitabine from the original fluorinated analogue (5­FU) to overcome its drawbacks was explained. Specifically, 5­FU is compared with capecitabine therapy regarding various properties, including drug metabolism, cellular mechanism, effect on the apoptosis pathway and cell cycle phases, safety and tolerability. Moreover, three metabolizing enzymes required for the activation of capecitabine to 5­FU were discussed. Capecitabine, as monotherapy or in combination with other chemotherapies, exhibited improved drug efficacy and survival. However, the changes that mediate the chemoresistance of capecitabine treatment were classified as intracellular, extracellular or cell surface factors, or cell­phenotype state. Future studies should examine the efficacy of capecitabine combined with novel and safe drugs other than chemotherapeutic agents that play a role in the inhibition of tumor initiation, progression and metastasis.

An Investigation of the Neurotoxic Effects of Malathion, Chlorpyrifos, and Paraquat to Different Brain Regions.

Acute or chronic exposures to pesticides have been linked to neurotoxicity and the potential development of neurodegenerative diseases (NDDs). This study aimed to consider the neurotoxicity of three widely utilized pesticides: malathion, chlorpyrifos, and paraquat within the hippocampus (HC), corpus striatum (CS), cerebellum (CER), and cerebral cortex (CC). Neurotoxicity was evaluated at relatively low, medium, and high pesticide dosages. All pesticides inhibited acetylcholinesterase (AChE) and neuropathy target esterase (NTE) in each of the brain regions, but esterase inhibition was greatest in the HC and CS. Each of the pesticides also induced greater disruption to cellular bioenergetics within the HC and CS, and this was monitored via inhibition of mitochondrial complex enzymes I and II, reduced ATP levels, and increased lactate production. Similarly, the HC and CS were more vulnerable to redox stress, with greater inhibition of the antioxidant enzymes catalase and superoxide dismutase and increased lipid peroxidation. All pesticides induced the production of nuclear Nrf2 in a dose-dependent manner. Collectively, these results show that pesticides disrupt cellular bioenergetics and that the HC and CS are more susceptible to pesticide effects than the CER and CC.

General insight into cancer: An overview of colorectal cancer (Review).

Cancer is currently among the leading causes of mortality globally. Colorectal cancer (CRC) ranks second among the most common types of cancer in terms of mortality worldwide. This type of cancer arises from mutations in the colonic and rectal epithelial tissues that target oncogenes, tumor suppressor genes and genes related to DNA repair mechanisms. The aim of the present review was to provide an explanation of CRC classification, which is carried out according to the histological subtype, location and molecular pathways implicated in its development. The pathogenic mechanisms implicated in CRC may involve one of three different molecular pathways: Chromosomal instability, microsatellite instability and cytosine preceding guanine island methylator phenotype. In addition, a variety of mutated genes associated with CRC, which affect certain signaling pathways, including DNA mismatch repair, cell cycle checkpoints and apoptotic pathways, were discussed. Moreover, a brief description of the risk factors and the symptoms associated with CRC was also provided. Finally, the treatment approaches to CRC were outlined.

Biochemical and histological effects of five weeks ingestion of Zamzam water on the liver and kidneys of Wistar rats.

Zamzam water is a natural alkaline water which has become alkaline as a result of the natural environment. It comes from what is considered as one of the oldest springs in the world. The water contains high concentrations of alkaline minerals as well as trace and heavy metals. The aim of the current study is to evaluate the effects of five weeks ingestion of Zamzam water on the liver and kidney functions of rats. Adult female Wistar rats weighing 150-200 g were divided into two groups, with 15 rats in each. The control group was supplied daily by bottled water and the Zamzam water group was supplied daily by 500 ml of Zamzam water for five weeks. The rats were weighed weekly and, at the end of the experiment, blood samples were collected from all rats for the biochemical determination of serum levels of aspartate transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), urea, creatinine, albumin, and uric acid, using calorimetric methods. Liver and kidney tissues were fixed in 10% neutral buffered-formalin solution and further embedded in wax blocks for routine hematoxylin and eosin (H&E) staining and were examined for histopathological changes using a light microscope. The results of the current study showed that there was a significant increase (P < 0.05) in the weight of the Zamzam group when compared to the control group after five weeks of ingestion. Liver and kidney function tests did not show any significant difference when compared with the controls (P > 0.05). In addition, histological examination of the liver and kidney tissues did not show any toxicological changes. In conclusion, the results showed that the ingestion of Zamzam water did not alter serum levels of kidney function tests and liver enzymes; and did not result in a noticeable change in the liver and kidney histology. Thus, the high concentrations of elements in Zamzam water do not induce hepatotoxicity or nephrotoxicity and the water is considered safe for long-term consumption.

Roles of oxidative stress, apoptosis, and inflammation in metal-induced dysfunction of beta pancreatic cells isolated from CD1 mice.

The diabetogenic effects of metals including lead (Pb), mercury (Hg), cadmium (Cd), and molybdenum (Mo) have been reported with poorly identified underlying mechanisms. The current study assessed the effect of metals on the roles of oxidative stress, apoptosis, and inflammation in beta pancreatic cells isolated from CD-1 mice, via different biochemical assays. Data showed that the tested metals were cytotoxic to the isolated cells with impaired glucose stimulated insulin secretion (GSIS). This was associated with increased reactive oxygen species (ROS) production, lipid peroxidation, antioxidant enzymes activities, active proapoptotic caspase-3 (cas-3), inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels in the intoxicated cells. Furthermore, antioxidant-reduced glutathione (GSH-R), cas-3 inhibitor z-VAD-FMK, IL-6 inhibitor bazedoxifene (BZ), and TNF-α inhibitor etanercept (ET) were found to significantly decrease metal-induced cytotoxicity with improved GSIS in metals' intoxicated cells. In conclusion, oxidative stress, apoptosis, and inflammation can play roles in metals-induced diabetogenic effect.

Effects of environmental metals on mitochondrial bioenergetics of the CD-1 mice pancreatic beta-cells.

Environmental metals are believed to have diabetogenic effects without any clear underlying mechanisms. The study investigated the effects of metals, lead (Pb), mercury (Hg), cadmium (Cd), and molybdenum (Mo), on the bioenergetics of isolated pancreatic ß-cells from CD-1 mice via different functional and structural techniques. The tested metals caused significant decrease in ATP production in concentration and exposure duration-dependent pattern; Cd was the most potent cytotoxic metal. In ATP assay estimated effective concentration 50 (EC50) (25, 40, 20, and 100 µM for Pb, Hg, Cd, and Mo, respectively), the metals also significantly inhibited the glucose-stimulated insulin secretion (GSIS), mitochondrial complexes activity, mitochondrial membranes potential, and oxygen consumption rates of the treated cells with parallel increases in their lactate production and in the mitochondrial swelling and permeation of their inner mitochondrial membranes to potassium (K+) and hydrogen (H+) ions. In addition, Cd, Pb, and Hg produced significant increases in mitochondrial membrane fluidity (MMF) with significant decreases in saturated/unsaturated fatty acid ratios. In 10 µM concentration, away from Mo, the three metals showed inhibitory effects on the mitochondrial functions to variable degrees. Only Cd showed significant effect on MMF and fatty acid ratios at a concentration of 10 µM. In conclusion, the tested metals significantly affected the bioenergetics of the pancreatic ß-cells with significant effect on GSIS. Cd showed the most significant functional and structural effects on their mitochondria followed by Pb, then Hg, while Mo was almost safe up to 10 µM concentration. Hence, bioenergetic mitochondrial disruption can be considered as an underlying mechanism of the diabetogenic effects of the tested metals.

High Expression of Pd-1 in Circulating Cells of Patients With Advanced Colorectal Cancer Receiving Adjuvant Therapy.

Among all cancer types, colorectal cancer is the third most common in men and the second most common in women globally. Generally, the risk of colorectal cancer increases with age, and colorectal cancer is modulated by various genetic alterations. Alterations in the immune response serve a significant role in the development of colorectal cancer. In primary cancer types, immune cells express a variety of inhibitory molecules that dampen the immune response against tumor cells. Additionally, few reports have demonstrated that classical chemotherapy promotes the immunosuppressive microenvironment in both tissues and immune cells. This study assessed the expression levels of genes using RT-qPCR associated with the immune system, including interferon-γ, programmed death-1, ß2-microglobulin, human leukocyte antigen-A, CD3e, CD28 and intracellular adhesion molecule 1, in patients with colorectal cancer, as these genes are known to serve important roles in immune regulation during cancer incidence. Gene expression analysis was performed with the whole blood cells of patients with colorectal cancer and healthy volunteers. Compared with the normal controls, programmed death-1was highly expressed in patients with advanced-stage colorectal cancer. Furthermore, the expression of programmed death-1 was higher in patients receiving adjuvant therapy, which suggests the therapy dampened the immune response against tumor cells. The results of the present study indicate that classical adjuvant therapies, which are currently used for patients with colorectal cancer, should be modulated, and a combination of classical therapy with anti-programmed death-1 antibody should be conducted for improved management of patients with colorectal cancer.

Association between MDR1 polymorphisms and XELIRI and XELOX chemoresistance in Saudi patients with colorectal cancer.

Multidrug resistance member 1 (MDR1) is located on chromosome 7 and encodes P-glycoprotein, which is universally accepted as a drug resistance biomarker. MDR1 polymorphisms can alter protein expression or function, which has been previously reported to associate with various types of malignancies, such as colorectal cancer (CRC). Therefore, the present study aimed to determine the effects of MDR1 polymorphisms on drug responses of Saudi patients with CRC. DNA samples were obtained from 62 patients with CRC and 100 healthy controls. Genotypes and allele frequencies of MDR1 single nucleotide polymorphisms (SNPs) G2677T and T1236C were determined using the PCR-restriction fragment length polymorphism procedure. The results showed no significant differences in the genotype distribution and allele frequency of T1236C between patients with CRC and controls. However, G2677T was found to serve a highly significant role in protecting against the progression of CRC. In addition, none of the genotypes in SNPs T1236C and G2677T was found to affect chemoresistance to XELIRI and XELOX. In conclusion, although T1236C in the MDR1 gene is not associated with CRC risk, G2677T protects against the development of CRC. Neither of the MDR1 SNPs tested were associated with the risk of chemoresistance. Therefore, these two SNPs cannot be used as molecular markers for predicting drug response in patients with CRC.

TaqI and ApaI Variants of Vitamin D Receptor Gene Increase the Risk of Colorectal Cancer in a Saudi Population.

BACKGROUND: Polymorphisms in the gene encoding the vitamin D receptor (VDR) affect the protective role of vitamin D against many types of cancers, including colorectal cancer (CRC). OBJECTIVE: The objective of this study was to assess the effect of four major polymorphisms of the VDR gene (ApaI, TaqI, BsmI and FokI) on the risk of CRC in a Saudi population. MATERIALS AND METHODS: This case-control study recruited 132 CRC patients from the oncology clinics at King Abdulaziz University Hospital and 124 healthy controls from the blood bank at King Fahad General Hospital, Jeddah, Saudi Arabia, between September 2017 and August 2018. All participants were Saudis and aged 20-80 years. Genomic DNA samples were extracted from the peripheral blood cells and amplified with polymerase chain reaction. The resulting fragments were digested with different endonucleases to reveal the genotypes using the restriction fragment length polymorphism technique. The genotype distribution and allele frequency, odds ratio (OR), risk ratio (RR) and P values were determined with contingency table analysis following Hardy-Weinberg equilibrium equation. RESULTS: For the ApaI single-nucleotide polymorphism (SNP) (rs7975232), only the heterozygous (Aa) genotype increased the risk of CRC (OR = 3.4, RR = 2.3, and P < 0.0001), whereas the TaqI SNP (rs731236) carriers with either the heterozygous (Tt) or homozygous (tt) genotype displayed an increased risk for the disease (OR = 6.18, RR = 4, P < 0.0001; OR = 3, RR = 2.4, P = 0.02, respectively). In contrast, heterozygous (Bb) and homozygous (bb) carriers of the BsmI SNP (rs1544410) had significantly lower risk for CRC (P < 0.0001). Finally, for the FokI SNP (rs2228570), there was no association with CRC risk. CONCLUSION: This study found that VDR SNPs ApaI and TaqI increase the risk of CRC, whereas BsmI reduces the risk of CRC in the selected Saudi population. Therefore, ApaI and TaqI SNPs could potentially be used as a diagnostic biomarker for CRC. However, the molecular mechanisms by which these variants increase or decrease the risk of CRC need to be investigated.

Increased expressions of cellular ATP-binding cassette transporters may be a promising diagnostic marker for colorectal cancer.

OBJECTIVES: To measure the blood expression levels of related drug-resistant ATP-binding cassette (ABC) transporters in colorectal cancer (CRC) patients and to assess these examined transporters for whether they present signi cant expression in connection with the tumor appearance of CRC. METHODS: In this case-control study, the messenger ribonucleic acids were isolated from the blood of 62 CRC patients who were recruited from King Abdulaziz University Hospital Oncology Clinic and 46 controls from King Fahad General Hospital Blood Bank (Jeddah, Saudi Arabia) from September 2016 to March 2017. The Biomedical Ethics Unit at King Abdulaziz University, Jeddah, Saudi Arabia approved this study. The expressions of ABC transporters were measured using quantitative polymerase chain reaction. GraphPad Prism 5 and REST 2009 Software were used to correlate the expressions with clinicopathological independent stages and body mass index. A p-value of less than 0.05 was considered significant. RESULTS: The results showed that the 3 ABC transporters, particularly ABCC1 (p less than 0.0001), were highly expressed in the blood of CRC patients compared with controls. However, none of the 3 transporters was related to the progression of CRC, age, gender, or body mass index. CONCLUSION: The expressions of ABC transporters were found to be significantly higher in CRC patients, and they may act as diagnostic markers and should potentially be tested for their contribution to drug sensitivity in CRC patients.

Serum visfatin concentration and its relationship with sex hormones in obese Saudi women.

Objective: Visfatin is an adipokine secreted mainly by adipose tissue and has been implicated in obesity. It also mimics the effects of insulin and its expression is hormonally regulated by hormones. Serum visfatin concentrations were evaluated in Saudi women of different body weights to determine its relationships with sex hormones and obesity-induced insulin resistance (IR) in women in Saudi Arabia. Methods: In this cross-sectional study, 83 healthy Saudi women of different body weights were recruited between 2014 and 2016, from King Abdulaziz University staff and students. They were divided into three groups according to their body mass indexes (BMIs). Anthropometric measurements were recorded for all of the participants. Blood samples were collected to assess the biochemical variables, including glucose, insulin, lipid profile, visfatin, sex hormone-binding globulin (SHBG), and sex hormones levels. Results: Obese women exhibited significantly higher blood pressure (BP), glucose, insulin, IR, lipid profile, and visfatin levels than overweight and lean women. However, lean women had significantly higher high-density lipoprotein-cholesterol (HDL)-C, estradiol (E2), luteinizing hormone (LH), and SHBG levels than overweight and obese women. Positive correlations were observed between visfatin levels and waist and hip circumferences, BMI, diastolic BP, systolic BP (SBP) insulin, IR, and LDL-C levels (P < 0.001 - P < 0.05). Negative correlations were observed between visfatin levels and HDL-C, SHBG, LH, and E2 levels (P < 0.001 - P < 0.05). Conclusions: The results of this study revealed that E2 and SHBG concentrations were decreased in obese women, while visfatin levels were increased in obese women with high IR levels. This suggests that visfatin levels and sex hormones interact synergistically with obesity with regard to the IR risk in obese women.

Assessment of insertion/deletion polymorphism of ACE gene as a genetic risk marker for preeclampsia in pregnant women.

OBJECTIVE: To investigate the possible associations of angiotensin converting enzyme insertion or deletion genotypes and alleles with the risk of preeclampsia in Arab women. METHODS: The case-control study was conducted from January 2016 to December 2017 at King Abdulaziz University Hospital and Maternity & Children Hospital, Jeddah, Saudi Arabia, and comprised pregnant women withpreeclampsia as cases and normal pregnant women as controls. Deoxyribonucleic acid was extracted and angiotensin-converting enzyme gene was amplified by polymerase chain reaction analysis and characterised through gel electrophoresis. RESULTS: Of the 162 women, 68(42%) were cases and 94(58%) controls. The mean values of age, body mass index, and systolic and diastolic blood pressure were significantly different among the cases than the controls (p<0.05), but mean gestational age did not significantly differ between the groups (p>0.05). The distribution of the polymorphic variants of the angiotensin converting enz yme gene insertion/deletion was not significantly different between the groups (p>0.05). Also, genotype distribution and allelic frequencies were not significantly different between the groups (p>0.05). CONCLUSIONS: For insertion/deletion polymorphism, no significant differences were detected in the genotype and allele frequencies or any of the inheritance models between preeclampsia patients and controls.

Serum vitamin D receptor (VDR) levels as a potential diagnostic marker for colorectal cancer.

Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity worldwide, and there has been a significant increase in the incidence of CRC in recent decades. Therefore, there is an urgent need to identify blood biomarkers that can be used for early diagnosis. It is not yet clear whether the level of vitamin D and its receptor, vitamin D receptor (VDR), in the blood are helpful factors in the diagnosis of CRC. Therefore, the study focuses on determining the VDR serum level's contribution and other chemical parameters to the risk of CRC. A total of 189 Saudi participants (66 CRC patients and 123 control patients) aged 20-80 years old were enrolled in this case-control study. A serum sample was collected from each participant, and the levels of VDR and other bone profile tests were determined using ELISA or chemiluminescent assays. P values < 0.05 were considered statistically significant. The results showed a highly significant reduction in the levels of total vitamin D (P < 0.0001), VDR (P < 0.0001), vitamin D3 (P < 0.05), and calcium (P < 0.0001) in the serum of CRC patients compared to the controls. However, the alkaline phosphatase level was higher in CRC patients compared to the controls (P < 0.0001). None of the blood markers showed a significant correlation to the progression of CRC (P > 0.05). More investigation is needed to elucidate different physiological processes that can be affected by these blood biomarkers, therefore changing the carcinogenesis of CRC.