Antisecretory and antioxidative effects of the antidepressants fluvoxamine and mirtazapine on water immersion stress and pyloric ligation-induced gastric ulcer in rats.

Objectives: Although there are numerous drugs available for the treatment of gastric ulcers (GU), these drugs are not always effective. Antidepressant medications have been used for a variety of non-psychiatric indications, including antiulcer activity in various ulcer models. The purpose of this study was to compare the antiulcer effects of fluvoxamine and mirtazapine in two rat GU experimental models and to determine their relationship to antioxidant and antisecretory mechanisms. Materials and Methods: The antiulcer activities of various doses of fluvoxamine and mirtazapine on water immersion restraint stress (WIRS) and pyloric ligation-induced GU in rats have been studied against the positive control antiulcer drug famotidine. Various oxidative stress markers were evaluated. Results: Fluvoxamine and mirtazapine significantly protected against WIRS and pyloric ligation-induced gastric lesions, as evidenced by a dose-dependent decrease in ulcer index, myeloperoxidase (MPO) activity, lipid peroxidation, and an increase in prostaglandin E2, nitric oxide (NO), and reduced glutathione levels, as well as increased antioxidant enzyme activity. In the pyloric ligation model, fluvoxamine and mirtazapine improved GU more than famotidine. Furthermore, a 30 mg/kg dose of mirtazapine significantly improves both NO levels and MPO activity compared to famotidine. Conclusions: The results highlighted the relationship in correlating the antiulcer effect of drugs from different antidepressant classes across two animal GU models, implying that antidepressants that affected both norepinephrine and serotonin levels (mirtazapine) had a more potent antiulcer effect in WIRS-induced gastric model than drugs that only affected serotonin levels (fluvoxamine).

In vitro study of the mechanism of intraneuronal ß-amyloid aggregation in Alzheimer's disease.

Alzheimer's disease (AD) is atrophy of brain cells that lead to decline in the mental capacity and memory. This study investigated the mechanism which postulates that intraneuronal accumulation of amyloid aggregates for pathogenesis of AD. The PC12 cell line was used to examine the amyloid beta (Aß) aggregation in different stages. It was found that dot-blot filter retardation assay for Ub-CTF was 0.25 and 0.2 µM for SS-CTF. In addition, incubation of SS-CTF with 200 µM Aß-42 then bounded with an antibody directed against Aß. It was suggested that most bound Aß-42 in the oligomeric form. Confocal microscope showed that stained with DAPI (blue) in the neuritic plaques, APP-GFP (green) and specific monoclonal M78 (red). Aß oligomeric taken up by neurons and accumulation of misfolded Aß aggregates continue in a perinuclear location. Fluorescence intensities correlate with the priming effect observed on the Aß (p < .001). It was concluded that a new amyloid hypothesis is promising in therapy development to reduce the incidence of disease by inhibition of intraneuronal amyloid aggregation.

Identification of amyloid antibodies for Alzheimer disease - immunotherapy.

The current study identified the specific antibodies that recognise amyloid protein for Alzheimer disease - immunotherapy. The immune-selection of random sequences from a phage display library and sequencing to obtain the random 12 amino acids peptide library for each antibody, and then we analysed these peptides for unique and common sequences, relation to Aß42 sequence and shape and pattern of the amino acid reaction to the antibody to predict the epitopes. Data obtained for 4G8 showed that, the sequence segment related to the putative epitope of 4G8 was LVFFAED. Nine of the ten top sequences contain the sequence RHD corresponding to the Aß sequence from residues 5-7. Peptide 7 has the sequence IRYDTGSYHIH, which has a RYD. It was concluded that, 4G8 and 6E10 can tolerate the binding the sequences that explain it is able to recognise amyloid aggregates.

Strigol1/albumin/chitosan nanoparticles decrease cell viability, induce apoptosis and alter metabolomics profile in HepG2 cancer cell line.

Hepatocellular carcinoma is one of the most common causes of cancer-related deaths globally. Bioavailable, effective and safe therapeutic agents are urgently needed for cancer treatment. This study evaluated the metabolomics profiling, anti-proliferative and pro-apoptotic effects of strigol/albumin/chitosan nanoparticles (S/A/CNP) on HepG2 cell line. The diameter of S/A/CNP was (5 ±â€¯0.01) nm. The IC50 was 180.4 nM and 47.6 nM for Strigol1 and S/A/CNP, respectively, after incubation for 24 h with HepG2 cells. By increasing the concentration of S/A/CNP, there was chromatin condensation, degranulation in the cytoplasm and shrinking in cell size indicating pro-apoptotic activity. Metabolomics profiling of the exposed cells by LC/MS/MS revealed that S/A/CNP up-regulated epigenetic intermediates (spermine and spermidine) and down-regulated energy production pathway and significantly decreased glutamine (P < 0.001). These findings demonstrated that S/A/CNP has anti-proliferative, apoptotic effects and modulate energetic, and epigenetic metabolites in the hepatocellular carcinoma cell line (HepG2).

Antiatherogenic Effects of Quercetin in the THP-1 Macrophage Model In Vitro, With Insights Into Its Signaling Mechanisms Using In Silico Analysis.

Background: Atherosclerosis (AS), a major risk factor for stroke and brain tissue destruction, is an inflammatory disease of the blood vessels, and the underlying pathology is inflammation mediated by various chemokines and cytokines. Quercetin, a natural flavonol, is reported to have both anti-inflammatory and antioxidant properties. As such, in the present study, we evaluated the antiatherogenic effects of quercetin in a human THP-1 cell line in vitro and also the signaling mechanisms using in silico analysis. Materials and Methods: THP-1 macrophages exposed to different concentrations of quercetin (5-100 µM for 24 h) were tested for cytotoxicity. Real-time gene expression assay for intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) was carried out following treatment with quercetin at 15 and 30 µM for 24 h either in the absence or presence of interferon (IFN-γ) for 3 h to induce inflammation. Monocyte migration and cholesterol efflux were also assessed. Results: Quercetin did not exert any cytotoxic effects on THP-1 cells at the various concentrations tested. The gene expression assay showed a significant decrease in ICAM-1 (by 3.05 and 2.70) and MCP-1 (by 22.71 and 27.03), respectively. Quercetin at 15 µM decreased THP-1 monocyte migration by 33% compared to the MCP-1-treated cells. It also increased cholesterol efflux significantly by1.64-fold and 1.60-fold either alone or in combination with IFN-γ, respectively. Ingenuity Pathway Analysis of the molecular interactions of quercetin identified canonical pathways directly related to lipid uptake and cholesterol efflux. Furthermore, CD36, SR-A, and LXR-α also demonstrated significant increases by 72.16-, 149.10-, and 29.68-fold, respectively. Conclusion: Our results from both in vitro and in silico studies identified that quercetin inhibited the THP-1 monocyte migration, MCP-1, and ICAM-1 and increased cholesterol efflux probably mediated via the LXR/RXR signaling pathway. Therefore, quercetin will help prevent cell infiltration in atherosclerotic plaques and reduce the risk of stroke or brain destruction.

Role of heme oxygenase-1, cytokines, and vascular endothelial growth factor in murine Schistosoma mansoni.

OBJECTIVES: Among tropical diseases, schistosomiasis caused by Schistosoma mansoni is the second major cause of morbidity and mortality worldwide. Inflammation was considered as an adverse event that contributes to the pathology associated with schistosomiasis. Heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) have been implicated in the process of angiogenesis. The current study aimed to evaluate the effect of S. mansoni infection on HO-1 gene expression, IL-4, IL-12, and VEGF to address the role of these factors in the pathogenesis of schistosomiasis. METHODS: Thirty mice divided equally into three groups comprised a non-infected control group and two S. mansoni-infected groups. Infected animals were studied at 8 and 12 weeks post-infection. Serum IL-4, IL-12, and VEGF were measured. HO-1 mRNA was detected by RT-PCR of liver homogenates and HO activity was assessed as percentage of carboxy hemoglobin. RESULTS: S. mansoni-infected mice showed a progressive increase in serum IL-4 and VEGF and decrease in IL-12 levels. In addition, HO-1 expression and activity were increased in infected mice compared to control group with the maximum increase at egg deposition stage. CONCLUSION: Our results suggested that the body response to acute stage of S. mansoni infection by elevating the expression of the stress gene HO-1 and that VEGF may serve as a new indicator of progression of S. mansoni associated angiogenesis which regulates granuloma and/or fibrosis development in the liver of infected mice. Understanding the role of HO-1 and VEGF in pathogenesis of S. mansoni may provide a new pharmacological target.

Epigenetic immunomodulatory effect of eugenol and astaxanthin on doxorubicin cytotoxicity in hormonal positive breast Cancer cells.

BACKGROUND: Hormonal receptor positive (HR+) breast cancer is the most commonly diagnosed molecular subtype of breast cancer; which showed good response to doxorubicin (DOX)-based chemotherapy. Eugenol (EUG) and astaxanthin (AST) are natural compounds with proved epigenetic and immunomodulatory effects in several cancer cell lines. This study has been initiated to investigate the molecular mechanism (s) whereby EUG and AST could enhance DOX cytotoxicity in MCF7 cells. METHODS: Cytotoxic activity of DOX alone and combined with either 1 mM EUG or 40 µM AST was performed using sulphorhodamine-B assay in MCF7 cells. Global histones acetylation and some immunological markers were investigated using ELISA, western blotting and quantitative RT-PCR techniques. Functional assay of multidrug resistance was performed using rhodamine 123 and Hoechst 3342 dyes. Flow cytometry with annexin V and propidium iodide were used to assess the change in cell cycle and apoptosis along with the expression of some differentiation, apoptosis and autophagy proteins. RESULTS: DOX alone resulted in concentration-dependent cytotoxicity with IC50 of 0.5 µM. Both EUG and AST significantly increased DOX cytotoxicity which is manifested as a significant decrease in DOX IC50 from 0.5 µM to 0.088 µM with EUG and to 0.06 µM with AST. Combinations of DOX with 1 mM EUG or 40 µM AST significantly increased the level of histones acetylation and histone acetyl transferase expression, while reduced the expression of aromatase and epidermal growth factor receptor (EGFR) when compared with 0.25 µM DOX alone. Also both combinations showed higher uptake of rhodamine but lower of Hoechst stains, along with increased the percentage of caspase 3, and decreased the expression of CK7 and LC3BI/II ratio. EUG combination induced IFγ but reduced TNFα causing shifting of cells from G2/M to S and G0/ G1 phases. Combination of DOX with EUG induced apoptosis through the higher BAX/ BCl2 ratio, while with AST was through the increase in caspase 8 expressions. CONCLUSION: EUG and AST potentiated the anticancer activity of DOX through epigenetic histones acetylation along with the immunonomodulation of different apoptotic approaches in MCF7 cells.

Ultrasonographic and biochemical assessments as early prediction of polycystic ovarian syndrome in obese women.

BACKGROUND: Polycystic ovary syndrome (PCOS) is considered as a common cause of hormonal disturbance and obesity. The diagnosis of PCOS was done by different methods including clinical signs as anovulation, hyperandrogenism, biochemical markers and ultrasounographic investigation. This study investigated comparative outcomes of ultrasonographic and biochemical markers for early prediction of PCOS in obese women. SUBJECTS AND METHODS: Seventy-five patients were clinically diagnosed with obese, PCOS and obese with PCOS and twenty-five normal age matched subjects were enrolled as control. Abdominal and transvaginal ultrasonographic for assessment of ovarian properties. In addition, BMI, serum free testosterone, dehydroepiandrosterone (DHEA), insulin, glycosylated hemoglobin (HbA1c) and LDL-c levels were evaluated. RESULT: In obese patients with PCOs (20%) ovaries revealed normal appearance in morphology while the rest (80%) showed PCOs in the form of cysts of 2-8 mm in diameter peripherally arranged around stroma. A significant elevation of free testosterone, DHEA and insulin in obese with or without PCOS compared with obese group (p<0.001). A positive correlation with hormonal abnormalities of increased HA1c, LDL-c, free testosterone, DHEA and insulin compared with obese only. CONCLUSION: According to our study findings, ovarian morphology combined with biochemical markers is more reliable for early prediction and diagnosis of PCOS for interpretation and management.

Hemorrhagic fever in Saudi Arabia: challenge to public health, effective management and future considerations.

BACKGROUND: Viral hemorrhagic fevers (VHF) refers to a group of febrile illnesses caused by different viruses that result in high mortality in animals and humans. Many risk factors like increased human-animal interactions, climate change, increased mobility of people and limited diagnostic facility have contributed to the rapid spread of VHF. MATERIALS: The history of VHFs in the Saudi Arabian Peninsula has been documented since the 19th century, in which many outbreaks have been reported from the southwestern region of Saudi Arabia. Despite presence of regional network of experts and technical organizations, which expedite support and respond during outbreaks, there are some more challenges that need to be addressed immediately. Gaps in funding, exhaustive and inclusive response plans and improved surveillance systems are some areas of concern in the region which can be dealt productively. This review primarily focusses on the hemorrhagic fevers that are caused by three most common viruses namely, the Alkhurma hemorrhagic fever virus, Rift valley fever virus, and Dengue fever virus. CONCLUSION: In summary, effective vector control, health education, possible use of vaccine and concerted synchronized efforts between different government organizations and private research institutions will help in planning effective outbreak-prevention and response strategies in future.

m-Coumaric acid attenuates non-catalytic protein glycosylation in the retinas of diabetic rats.

In this study, we investigated the inhibitory effects of m-coumaric acid on the glycosylation of proteins in the retinas of diabetic rats. Male rats were divided into two main groups, Group I (normal control) and Group II (diabetic); Group II was further divided into four subgroups: Group IIa (diabetic control), Group IIb (diabetic rats were given m-coumaric acid orally [150 mg/kg, body weight (bw)/day]), Group IIc (diabetic rats were given HCA m-coumaric acid orally [300 mg/kg bw/day]), and Group IId (diabetic rats were given insulin [10 units/kg bw/day]) as a positive control). The treatment lasted for six weeks, and the data obtained suggested that m-coumaric acid reduced glucose and glycated hemoglobin levels, which further decreased the formation of glucose-derived advanced glycation end products. Hence, it protected the tissues from the detrimental effects of hyperglycemia and enhanced antioxidant activity. In conclusion, m-coumaric acid could be a potential candidate to prevent the onset and progression of retinopathy in diabetic patients.

Evaluation of in vitro chondrocytic differentiation: A stem cell research initiative at the King Abdulaziz University, Kingdom of Saudi Arabia.

Mesenchymal stem cells (MSCs) from various sources have been used in cartilage differentiation with variable success. Therefore, it is of interest to evaluate the in vitro differentiation potential of the hWJSCs derived from the human umbilical cords into chondrocytes at the stem cell research facility at the King Abdulaziz University. hWJSCs are an attractive choice for tissue engineering and regenerative medical applications including cartilage regeneration. We evaluated the hWJSCs using classical histological and cartilage related gene expression studies. Some of the known parameters were re-examined for consistency at the current laboratory conditions. Early passages (P1-P4) showed short fibroblastic morphology and high expression of MSC related surface markers namely CD29 (99.9%), CD44 (97.8%), CD73 (99.6%), CD90 (95.1%) and CD105 (98.9%). MTT assay showed time dependent increase in hWJSCs proliferation by 61.06% and 206.31% at 48h and 72h respectively. Toluidine blue histology showed that hWJSCs were successfully differentiated into chondrocytes in chondrocytic differentiation medium for 21 days. Differentiated hWJSCs also showed significantly increased expression of collagen type II, aggrecan and SOX9 compared to the undifferentiated control. It should be noted that the determination of the average cell yield, the population doubling time and histological staining wtih alcian blue and/or safronin O is required in future studies for improved evaluation of differentiation. Painless derivation, abundance of stem cells that are hypo-immunogenic and safety issues makes this method advantages to MSCs derived from other sources.

Serum proteins C and S levels as early biomarkers for kidney dysfunction in hemophilic patients.

BACKGROUND: Hemophilia is an inherited genetic disease characterized by the inability to coagulate blood after injury. The rationale of the current study was to evaluate serum proteins S and C and correlate to kidney function test in hemophilic patients for early diagnosis of abnormality in renal function. SUBJECTS AND METHODS: This study was conducted on 80 males subjects divided into four groups. Group I: Control: Healthy subjects. Group II: Renal dysfunction (serum Creatinine >2mg/dl): Group III: Hemophilic patients. Group IV: Hemophilic patients with renal disorder. Serum urea, creatinine, sodium, potassium, protein C and protein S level were determined. RESUTS: Protein C and S levels showed a significant decrease in hemophilic/and with renal dysfunction (P < 0.001, p<0.001). The level of plasma protein C and S levels were positively correlated with increased urinary albumin (P < 0.01). Urinary albumin was increased about 15 folds in hemophilic patients with renal dysfunction and nephrotic patients as compared with the control group. The cut-off value in 90% patients at the hemophilic patients with renal dysfunction 70%. Positive correlations were observed between urinary albumin (r=0.66), and creatinine (r=0.73). CONCLUSION: These biomarkers showed good predictive values with regard to ROC-AUC (0.41 and 0.75 for Proteins C and S, respectively).

EFFICIENCY OF BORAGE SEEDS OIL AGAINST GAMMA IRRADIATION-INDUCED HEPATOTOXICITY IN MALE RATS: POSSIBLE ANTIOXIDANT ACTIVITY.

BACKGROUND: Borage (Borago officinal L.) is an annual herbaceous plant of great interest because its oil contains a high percentage of γ-linolenic acid (GLA). The present work was carried out to detect fatty acids composition of the oil extracted from borage seeds (BO) and its potential effectiveness against γ-irradiation- induced hepatotoxicity in male rats. MATERIALS AND METHODS: GC-MS analysis of fatty acids methyl esters of BO was performed to identify fatty acids composition. Sixty rats were divided into five groups (12 rats each): Control, irradiated; rats were exposed to (6.5 Gy) of whole body γ-radiation, BO (50 mg/kg b.wt), irradiated BO post-treated and irradiated BO prepost-treated. Six rats from each group were sacrificed at two time intervals 7 and 15 days post-irradiation. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT) levels, lipids profile, as well as serum and hepatic reduced glutathione (GSH) and lipid peroxide (malondialdehyde) (MDA) levels were assessed. Histopathological examination of liver sections were also carried out. RESULTS: The results showed that the high contents of BO extracted by cold pressing, were linoleic acid (34.23%) and GLA (24.79%). Also, oral administration of BO significantly improved serum levels of liver enzymes, lipids profile, as well as serum and hepatic GSH and MDA levels (p<0.001) as compared with irradiated rats after 15 days post irradiation. Moreover, it exerted marked amelioration against irradiation-induced histopathological changes in liver tissues. The improvement was more pronounced in irradiated BO prepost-treated group than irradiated BO post-treated. CONCLUSION: BO has a beneficial role in reducing hepatotoxicity and oxidative stress induced by radiation exposure. Therefore, BO may be used as a beneficial supplement for patients during radiotherapy treatment.

PROTECTIVE ROLE OF CARNITINE SYNERGIZED WITH VITAMIN E AGAINST ISOPROTERENOL INDUCED CARDIAC INFARCTION IN RATS.

BACKGROUND: The current study aimed to evaluate the role of carnitine in combination with vitamin E in protection against myocardial infarction induced by isoproterenol (ISO) in rats. MATERIALS AND METHODS: Rats were grouped into 5 (each 10 rats): Group I. Control fed a standard diet. Group III: Rats were injected with vitamin E (100 IU/kg bw, i.p) daily. Group IV: Rats were given carnitine (20 mg/kg bw, i.p) daily. Group V: Rats were injected with both vitamin E (100 IU/kg bw, i.p) and carnitine (20 mg/kg bw, i.p) daily. On 7th, 8th, and 9th day, rats in groups (II-V) were injection i.p with ISO (55mg/kg b.w for successive three days). The treatment with carnitine and vitamin E were continuous for 21 days. RESULTS: Canirine combined with vitamin E significantly increased coronary flow (CF) (P<0.001) in rats injected with ISO. The recovery of rate pressure product (RPP) and left ventricular developed pressure (LVDP) were significantly improved in treated rats in comparison to untreated. The rats administrated with ISO resulted in a significant elevation of serum enzymes (CK-MB and LDH) compared with control group (p<0.001). However, it returned to about normal. ISO administration resulted in a significant elevation in the levels of malondialdehyde (MDA) and nitric oxide (NO) as compared with control (p<0.001) and a significant reduction in the activities of GSPxase and GSRase (p<0.001) compared with control group. The levels of cardiac inflammatory markers interleukine-6 (IL-6) and tumor necrosis factor (TNF-α) were markedly elevated in rats injected with ISO compared with control group. Vitamin E combined with carnitine reversed these effects. However, pretreatment with vitamin E or carnitine or combined together showed a significant reduction in MDA and NO (p<0.001) and a significant elevation in the activities of GSPxase and GSRase (p<0.001) as compared to ISO injected group. The combined effect was more significant than individual ones. CONCLUSION: Vitamin E combined with carnitine exerts potential protective effect against MI through suppression of inflammatory mediators and enhancement of antioxidant activity.

Analysis of SNPs of MC4R, GNB3 and FTO gene polymorphism in obese Saudi subjects.

BACKGROUND: The goal of this study was to analyze the association between the FTO rs17817449 (G>T), G protein beta3 subunit (GNB3) C825T and Melanocortin 4 receptor (MC4R) A822G single nucleotide polymorphism (SNP) with obesity in Saudi subjects. METHODS: The subjects were divided into 2 groups according to BMI: Obese (BMI> 29.9) and non- obese control (BMI<24.9). Genotyping of the target genes were determined by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism analysis (RFLP). RESULTS: We demonstrated the association of the FTO genotype TT with increased weight, BMI and leptin levels in both males and females. However, there was no association of genotype TT with fasting blood glucose, triglycerides and cholesterol levels. Regarding GNB3 rs5443 polymorphism, the likelihood of obesity was linked to the TT genotype which was also associated with increased leptin levels. On the other hand, the SNP of MC4R A822G did not exhibit any significant association with obesity among studied subjects and showed only the presence of homozygous AA genotype. CONCLUSION: The polymorphism of FTO gene rs17817449 and GNB3 gene rs5443 (C825T) may be a genetic determinant of obesity in Saudi population whereas impact of MC4R Asn274Ser change could not be detected.

Changes in erythrocyte ATPase activity under different pathological conditions.

BACKGROUND: Studies have shown that Na+-K+ ATPase activity was altered in disrupted red blood cell membranes and this enzyme is believed to be the site of active transport of Na+ and K+ in intact red blood cells. The enzyme is often referred to as Na+-K+ pump because it pumps Na+ out and K+ into the cell against gradients with the concomitant hydrolysis of intracellular ATP. OBJECTIVE: The aim of this study was to find out the possibility of using Na+-K+-ATPase activity as a biomarker for the diagnosis of individuals with different physiological conditions. MATERIALS AND METHODS: The activity of Na+-K+ ATPase was determined in blood samples collected from different pathological and physiological conditions such as pregnancy, smoking, diabetes and renal dysfunction compared with healthy subjects matched for age and sex. RESULTS: The Na+-K+ ATPase activity in pregnancy (0.094 ± 0.0051 µM Pi/min. mg protein), smoking (0.064 ± 0.0011 µM), diabetes (0.047 µM 0.002 µM) and kidney disease (0.069 ± 0.0014 µM) was higher compared to the measurements in healthy individuals (0.0081 ± 0.0031 µM). CONCLUSION: Na+-K+ATPase specific activity is a biomarker for the diagnosis of individuals with different physiological diseases.

Protein Kinase C Is Involved in the Induction of ATP-Binding Cassette Transporter A1 Expression by Liver X Receptor/Retinoid X Receptor Agonist in Human Macrophages.

The transcription of the ATP-binding cassette transporter A1 (ABCA1) gene, which plays a key anti-atherogenic role, is known to be induced by agonists of liver X receptors (LXRs). LXRs form obligate heterodimers with retinoid X receptors (RXRs) and interact with their recognition sequences in the regulatory regions of key genes implicated in the control of cholesterol, fatty acid and glucose homeostasis. We have previously shown a novel role for c-Jun N-terminal kinase (JNK) and phosphoinositide 3-kinase (PI3K) in the LXRs-mediated induction of macrophage gene expression. Protein kinase C (PKC) is often found to regulate the action of nuclear receptors and cross talk between this kinase family and JNK and/or PI3K has been shown in several settings. We have therefore investigated a potential role for PKC in the action of LXR/RXR agonist 22-(R)-hydroxycholesterol (22-(R)-HC)/9-cis-retinoic acid (9cRA) in THP-1 macrophages, including the induction of ABCA1 expression. The pan PKC inhibitor bisindoylmaleimide was found to attenuate the induction of ABCA1 protein expression, the activation of the JNK signaling pathway and the stimulation of activator protein-1 (AP-1) DNA binding activity in macrophages treated with 22-(R)-HC and 9cRA. The role of PKC in the action of these ligands was confirmed further by the use of more isotype-specific inhibitors. These studies therefore reveal a potentially important role for PKC in the action of 22-(R)-HC and 9cRA in human macrophages. This article is protected by copyright. All rights reserved.

Protein Kinase C Is Involved in the Induction of ATP-Binding Cassette Transporter A1 Expression by Liver X Receptor/Retinoid X Receptor Agonist in Human Macrophages.

The transcription of the ATP-binding cassette transporter A1 (ABCA1) gene, which plays a key anti-atherogenic role, is known to be induced by agonists of liver X receptors (LXRs). LXRs form obligate heterodimers with retinoid X receptors (RXRs) and interact with their recognition sequences in the regulatory regions of key genes implicated in the control of cholesterol, fatty acid and glucose homeostasis. We have previously shown a novel role for c-Jun N-terminal kinase (JNK) and phosphoinositide 3-kinase (PI3K) in the LXRs-mediated induction of macrophage gene expression. Protein kinase C (PKC) is often found to regulate the action of nuclear receptors and cross talk between this kinase family and JNK and/or PI3K has been shown in several settings. We have, therefore, investigated a potential role for PKC in the action of LXR/RXR agonist 22-(R)-hydroxycholesterol (22-(R)-HC)/9-cis-retinoic acid (9cRA) in THP-1 macrophages, including the induction of ABCA1 expression. The pan PKC inhibitor bisindoylmaleimide was found to attenuate the induction of ABCA1 protein expression, the activation of the JNK signaling pathway and the stimulation of activator protein-1 (AP-1) DNA binding activity in macrophages treated with 22-(R)-HC and 9cRA. The role of PKC in the action of these ligands was confirmed further by the use of more isotype-specific inhibitors. These studies, therefore, reveal a potentially important role for PKC in the action of 22-(R)-HC and 9cRA in human macrophages.

Relationship between soil cobalt and vitamin B12 levels in the liver of livestock in Saudi Arabia: role of competing elements in soils.

OBJECTIVE: This study aimed to analyze the agricultural soils from different regions in Saudi Arabia for cobalt and related metals as Cu(2+), Ni(2+), Cr(3+), Zn(2+) and Pb(2+). MATERIALS AND METHODS: Liver and muscle tissues of livestock grazing on the selected areas were analyzed for the content of Co and vitamin B12. RESULTS: Our results indicated that the levels of Co in surface soil (0-15 cm) were higher than in sub-surface soil (>15 cm-45 cm). In contrast, Pb and Zn were higher in sub-surface soil than in surface soil. A significant positive correlation existed between the levels of Co and vitamin B12 in the liver of livestock. However, Co was not detected in muscle tissues while vitamin B12 was present at very low levels in comparison with the levels found in the liver. The results indicated that Zn(2+), Pb(2+) compete with Co in soil, which eventually affected the levels of vitamin B12 in liver. CONCLUSION: It was recommended that survey of heavy metals in grazing fields of cattle should consider inclusion of multiple elements that compete with the bioavailability of essential elements in plants and animals for the prevention of deficiency of essential elements such as Co.