Abdullah Alghasham

Therapeutic targets for rheumatoid arthritis: Progress and promises

Abstract Recent therapeutic advancements in understanding of molecular and cellular mechanisms of rheumatoid arthritis (RA) have highlighted the strategies that aim to inhibit the harmful effects of up-regulated cytokines or other inflammatory mediators and to inhibit their associated signaling events. The utility of cytokine as therapeutic targets in RA has been unequivocally demonstrated by the success of tumor necrosis factor (TNF)-α blockade in clinical practice. Partial and non-responses to TNF-α blocking agents, however, together with the increasing clinical drive to remission induction, requires that further therapeutic targets be identified. Numerous proinflammatory mediators with their associated cell signaling events have now been demonstrated in RA, including interleukin (IL)-1 and IL-12 superfamilies. Continued efforts are ongoing to target IL-6, IL-15 and IL-17 in clinical trials with promising data emerging. In the present review, we focus on IL-7, IL-18, IL-32 and IL-10 family of cytokines (IL-19, IL-20 and IL-22) as they are implicated in contributing to the pathogenesis of RA, which could be targeted and offer new therapeutic options for RA therapy. Recent evidences also suggest that multiligand receptor for advanced glycation end products (RAGE), several adipokines and various components of immune system play a critical role in the pathophysiology of RA; therefore we have also highlighted them as therapeutic targets for RA therapy. Components of subcellular pathways, involve in nuclear transcription factor (NF)-κB, mitogen-activated protein kinases (MAPKs) and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway have also been discussed and offer several novel potential therapeutic opportunities for RA.

Cucurbitacins – A Promising Target for Cancer Therapy

During the last decades a large number of cucurbitacins have been isolated from various plant species belonging to other plant families than Cucurbitaceae. Although the roots and the fruits of plant belong to these Cucurbitaceae species are very bitter, they have been used as folk medicines in some countries because of their wide spectrum of pharmacological activities such as anti-inflammation and anticancer effects. In the last ten years, cucurbitacins had been shown to inhibit proliferation and induced apoptosis utilizing a long array of in vitro and in vivo cancer cell models. Several molecular targets for cucurbitacins have been discovered, such as fibrous-actin, signal transducer and activator of transcription (STAT), cyclooxygenase-2, etc. This review aimed at elucidating the natural sources of some cucurbitacin compounds, their chemical structure and derivatives, physical properties, biological activities and mechanism by which they reduce the proliferation human cancer cells. This widens our armaments against a devastating disease that we are failing to face.

Effect of cadmium-polluted water on plasma levels of tumor necrosis factor-α, interleukin-6 and oxidative status biomarkers in rats: Protective effect of curcumin

UNLABELLED The present study was designed to investigate the effect of CdCl₂-polluted drinking water (40 mg CdCl₂/L) on the level of TNF-α and IL-6, as well as oxidative status biomarkers in plasma of rats. The possible protective effect of oral administration of curcumin (50 mg/kg body weight/day) was assessed. Results illustrated that Cd exposure significantly elevated the plasma levels of TNF-α and IL-6 (p<0.001) as compared to normal rats. Also, Cd administration resulted in a significant elevation in the lipid peroxidation and markedly reduction in the activities of SOD and catalase as well as the level of glutathione and total antioxidant capacity in plasma. The co-treatment of Cd with curcumin significantly reduced the levels of TNF-α and IL-6 and ameliorated the alteration in oxidative status biomarkers induced by Cd. Negative correlation between IL-6 or TNF-α was and the plasma activities of catalase, SOD and the level of total antioxidant capacity were found in rats exposed to Cd. CONCLUSION Cadmium toxicity induced the release of TNF-α and IL-6 which is associated with systemic oxidative stress. This may be involved in the mechanism of the Cd toxicity. On the other hand, the findings suggest the curative action of curcumin against Cd toxicity.

Effect of students’ learning styles on classroom performance in problem-based learning

Introduction: Since problem-based learning (PBL) sessions require a combination of active discussion, group interaction, and inductive and reflective thinking, students with different learning styles can be expected to perform differently in the PBL sessions. Methodology: Using “Learning Style Inventory Questionnaire,” students were divided into separate active and reflective learner groups. Tutors were asked to observe and assess the students’ behavioral performance during the PBL sessions for a period of 5 weeks. A questionnaire of 24 items was developed to assess students’ behavioral performance in PBL sessions. Results: Active students tended to use multiple activities to obtain the needed information were more adjusted to the group norms and regulation and more skillful in using reasoning and problem-solving skills and in participation in discussion. On the other hand, reflective students used independent study more, listened actively and carefully to others and used previously acquired information in the discussion more frequently. Formative assessment quizzes did not indicate better performance of either group. There were no significant gender differences in PBL behavioral performance or quizzes’ scores. Conclusion: Active and reflective learners differ in PBL class behavioral performance but not in the formative assessment. We recommend that students should be informed about their learning style and that they should learn strategies to compensate for any lacks in PBL sessions through self-study. Also, educational planners should ensure an adequate mix of students with different learning styles in the PBL groups to achieve PBL desired objectives.

Comparison of double- and single-dose methotrexate protocols for treatment of ectopic pregnancy

To compare efficacy between double‐dose methotrexate and single‐dose methotrexate for treatment of tubal ectopic pregnancy (EP).

Neuroprotective and anti-stress effect of A68930 in acute and chronic unpredictable stress model in rats

The neurorescuing effect of A68930 (a potent selective D(1) agonist) and its role on the regulation of hypothalamus-pituitary-adrenal (HPA)-axis have been investigated. Acute (AS) and chronic unpredictable (CUS) stress models were used to evaluate the effect of A68930 on HPA-axis regulation in relation to the change in the fiber density and number of immunoreactive (ir) neurons of tyrosine hydroxylase (TH) and glucocorticoid receptor (GR) in the dopamine (DA) and GR rich brain regions in rats. CUS caused a significant decrease in the number of TH ir neurons in the striatum, medial forebrain bundle, ventral tegmental area and substansia nigra and GR in the cortex, striatum and hippocampus as compared to the non-stress controls (NS). Administration of A68930 (0.25mg/kg i.p.) significantly normalized these CUS-induced alterations. We also examined the role of A68930 on stress-induced brain oxidative status. AS enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the cortex and striatum, while CUS reduced the activities of SOD and catalase (CAT) in the cortex, striatum and hippocampus, when compared with NS. Increased GSH-Px activity, with reduced glutathione and increased lipid peroxidation was observed in both AS and CUS in selected brain regions as compared to NS. Administration of A68930 normalized the antioxidant enzyme activities, replenished GSH and decreased the extent of lipid peroxidation. In conclusion, present findings suggest that the stress-induced immunoreactivity of TH and GR in distinct brain regions are modulated by A68930 leading to the normalization of HPA-axis response. Ours results show the therapeutic importance of DA D(1) agonist in stress-induced dopaminergic-related neurological disorders. A68930 also influenced the brain antioxidant machinery probably through the restoration of stress-induced changes in the dopaminergic system and its crosstalk with GR.

Central dopaminergic system and its implications in stress-mediated neurological disorders and gastric ulcers: short review.

For decades, it has been suggested that dysfunction of dopaminergic pathways and their associated modulations in dopamine levels play a major role in the pathogenesis of neurological disorders. Dopaminergic system is involved in the stress response, and the neural mechanisms involved in stress are important for current research, but the recent and past data on the stress response by dopaminergic system have received little attention. Therefore, we have discussed these data on the stress response and propose a role for dopamine in coping with stress. In addition, we have also discussed gastric stress ulcers and their correlation with dopaminergic system. Furthermore, we have also highlighted some of the glucocorticoids and dopamine-mediated neurological disorders. Our literature survey suggests that dopaminergic system has received little attention in both clinical and preclinical research on stress, but the current research on this issue will surely identify a better understanding of stressful events and will give better ideas for further efficient antistress treatments.

Association of MTHFR C677T and A1298C Gene Polymorphisms with Hypertension

OBJECTIVES To check for the association of genetic polymorphisms related to the methylenetetrahydrofolate reductase (MTHFR) gene namely C677T and A1298C with hypertension in Saudi affected subjects from Qassim region. SUBJECTS AND METHODS Participants included 123 Saudi hypertensive cases (83 males and 40 females) in addition to 250 (142 males and 108 females) unrelated healthy controls from the same locality. Their age mean ±SD was 50.93 ± 15.43 years. For all subjects, DNA was extracted followed by real-time PCR amplifications for characterization of genotypes and alleles related to MTHFR C677T and A1298C gene polymorphisms RESULTS Total cases showed significantly higher carriage rate for the mutant allele 677T compared to controls (40.7% vs. 26%, OR=1.9, 95% CI= 1.2-3.1) with a lower frequency of the wild type 677CC genotype (59.3% vs. 74%, p=0.004). The same was observed among cases-subgroups of hypertension associated with obesity with a notably higher odds ratio (OR=2.6, 95% CI=1.3-5.01, p=0.004). Total cases showed also significantly higher frequency of mutant 1298 C allele carriage rate compared to controls (59.3% vs. 42.4%, OR=1.98, 95% CI= 1.3-3.1) with a lower frequency of the normal AA genotype (40.7% vs. 57.6%, p=0.003). The same was observed among cases-subgroups of hypertension associated with both diabetes and obesity and among cases of hypertension with obesity, also with higher odds ratio (OR=2.6 and 2.2 respectively). CONCLUSION This work showed that genetic polymorphisms related to the MTHFR gene are associated with the risk of hypertension particularly when accompanied with obesity and diabetes among Saudi subjects.

CYP2J2 −50 G/T and ADRB2 G46A Gene Polymorphisms in Saudi Subjects with Hypertension

BACKGROUND Hypertension is a result of complex factors including multiple genetic polymorphisms. OBJECTIVE This study aims to check for the association of genetic polymorphisms of the cytochrome P450 2J2 (CYP 2J2) and beta-2-adrenergic receptor (ADRB2) genes with hypertension among Saudi subjects. SUBJECTS AND METHODS This study included 116 cases with documented hypertension of at least 1 year duration. Their data were compared to that of 250 unrelated healthy nonhypertensive subjects from the same locality. For all participants, DNA was extracted and analyzed using real time polymerase chain reaction technique for the identification of genotypic and allelic variants of the CYP2J2 -50 G/T and ADRB2 G46A genes. RESULTS Hypertensive cases showed a significantly higher frequency of mutant CYP2J2 -50 T allele carriage (TT and GT genotypes) compared with controls (odds ratio [OR]=3.7, p=0.0003). The same was observed among subgroups of hypertension associated with diabetes and obesity (OR=3.6, p=0.007) and cases with isolated hypertension (OR=8.4, p=0.0002). On the other hand, hypertensive cases, whether being isolated or associated with obesity and/or diabetes, showed a nonsignificant difference from controls in relation to all genotypic variants related to the ADRB2 G46A polymorphism (p>0.05). CONCLUSION This study showed positive association of CYP2J2 gene polymorphism with hypertension among Saudi cases.

ACE I/D and eNOS E298D gene polymorphisms in Saudi subjects with hypertension

Background: Hypertension has a multifactorial background based on genetic and environmental interactive factors. Objectives: We aimed to test for the association of the angiotensin-converting enzyme (ACE) and endothelial nitric oxide synthase (eNOS) gene polymorphisms with hypertension. Subjects and methods: Participants included 120 Saudi patients with hypertension and 250 normal healthy controls. For all participants, DNA was processed for characterization of ACE I/D and eNOS E298D gene polymorphisms. Results: Hypertensive cases showed a significantly higher frequency of the ACE mutant D allele carriage (98.3% vs. 92.4%, p = 0.028, OR = 4.8). Cases with hypertension associated with diabetes and obesity showed 100% mutant D allele carriage. Regarding the eNOS E298D polymorphism, the frequency of the mutant D allele carriage was only observed to be higher among cases with hypertension associated with diabetes and obesity, in comparison with controls, yet not reaching statistical significance (41.2% vs. 34%, p > 0.05). Conclusions: There is increased frequency of ACE and eNOS mutant allele carriage among Saudi patients affected with hypertension, particularly if accompanied by obesity and diabetes.