محمد درویش خادم

Inhibition of inflammatory processes in various diseases can have effective therapeutic applications. The effective function of cis-aconitate decarboxylase (CAD) enzyme, a product of IRG1 gene, in the inflammatory processes of various diseases has been recently proven in clinical studies. In humans, the enzyme (CAD) catalyzes cis-aconitic acid to itaconic acid.

In this work, with the help of bioinformatics tools, functional hotspots were identified and their position in ACOD1 structure was investigated. Then, the effects of all mutation modes at these points were investigated and more dangerous mutations were selected. Interactions of selected mutant enzymes with other proteins were evaluated and visualized.

During the analysis of different mutations in functional hotspots of ACOD1 enzyme, it was found that 9 mutations (A247C, A248T, A101C, L156P, A244P, N248C, N248F, E150Y, E150W) in the seven predicted hotspots had the most destructive effects in terms of function. And decreased the stability and interaction of ACOD1 enzyme with other proteins.

From the bioinformatic analysis of the results of the predicted SNPs of the functional hot spots of the human ACOD1 gene, finally, among all the studied mutations, 9 mutations were obtained that had more destructive effects on the ACOD1 enzyme function. which researchers can use to investigate their role and effectiveness in clinical processes and as diagnostic markers in cancer diseases related to inflammation or as possible drug targets. This insilico study provides a possible path to clarify the study of molecular mechanisms involved in inflammatory processes caused by IRG1 gene mutation and its protein product (ACOD1).

The covid 19 pandemic since it was first discovered in late 2019 has made a great impact on human health worldwide. At present, no specific drug and treatment methods have been discovered to treat this disease. On the other hand, excessive inflammation due to high cytokines secretion in Covid-19 patients results in fatal effects including organ failure and death. Therefore, to define a better understanding of the pathophysiology of this virus, scientists are trying to use a variety of methods such as examining some available anti-inflammatory drugs or evaluating Insilico inhibitory compounds as IL-6 receptor (IL-6R) inhibitors to modulate parts of the immune system.

In this study, after designing Insilico, docking was performed between inhibitory ligands and IL6R. Subsequently, the appropriated ligand was evaluated for toxicity and allergy, and ADME prediction (absorption, distribution, metabolism, and excretion).

The results of the molecular docking showed that between the non-polar parts of the designed inhibitory ligand composition, mainly with parts of IL-6R protein containing amino acids of Arg118, Thr120, ser122 hydrogen interaction took place. The amino acids of Arg118, Ser122, Trp115, Thr120, Glu96, , Pro121, Val93, Thr125 and Pro94 also demonstrate ester interactions.
Discussion and

Docking results demonstrated that out of 100 studied ligands, [03] unknown (24) has more suitable binding energy (-114.648) with the IL-6R than other ligands and this energy level indicates a favorable interaction between this inhibitory compound and IL-6R through amino acids of Ser122, Arg118, Trp115, Glu96, Thr120, Pro121, Val93, Pro94, and Thr125. Clinical studies are needed to prove the inhibitory effect of this ligand on the IL6R.

Scorpion envenomation is a main general health problem in developing countries, especially in tropical and subtropical regions. Hemiscorpius lepturus as a member of the Hemiscorpiidae family is cause of the most scorpion sting lethality in Iran. In the present study, the oxidative stress and antioxidant defense in serum of envenomated sheep with the venom of Hemiscorpius lepturus were investigated. Nine sheep were randomly divided into three groups (three in each). Groups A, B and C received 0.10, 0.05 and 0.01 mg kg-1 of H. lepturus venom subcutaneously, respectively. Blood sampling were performed 30 min before envenomation (control) and 30 min, 1, 2, 3 and 6 hr after envenomation and serum levels of total antioxidant capacity (TAC), malonedialdehyde (MDA) and protein carbonyl (PCO) were determined. The TAC was significantly increased at the doses of 0.10 mg kg-1 (at 3 hr) and 0.05 mg kg-1 (at 6 hr) compared to pre-injection time. However, no significant differences were observed in serum levels of MDA and PCO in different groups. It can be concluded that the dose of 0.01 mg kg-1 of venom had no effect on stress factors of serum, but according to increased level of TAC at the doses of 0.05 and 0.10 and no significant changes in serum levels of MDA and PCO, the oxidative damage has been prevented by the antioxidant defense system response.

Scorpionism is a common problem that occurs in tropical and subtropical countries. Hemiscorpius lepturus is one of the most dangerous scorpion species, endemic in Khuzestan. The aim of the current study was to clarify the possible histopathological implications due to injection of H. lepturus scorpion venom in sheep. The study performed on 12 native male sheep in which the age and weight average were about 6 months and 20.72±1.61 Kg respectively. Four groups (3 rams in each group) were chosen randomly (1 group as control and the other 3, as experimental groups). Three doses of H. lepturus venom included: 0.01, 0.05 and 0.1 mg/kg BW were injected subcutaneously into the three experimental groups and just 1 mL of distilled water were injected to control group as the same way. After death or after 72 hours, the animals were subjected to necropsy. In most animals, histopathological evidence of lesions, were confined in the liver and skeletal muscles (injection site), whereas the other injuries such as in brain and urinary bladder lesions were at minimum. Lesions such as petechiae (at necropsy), hemorrhage and congestion (in histopathology), which may due to vascular injuries were seen in various organs (such as liver, kidney, lung, bowel and heart). These findings may be due to vascular injuries. Vascular injuries were also the reason of edema in many organs. The results showed that the pathological lesions were existed at least in two parts of the studied organs in the sheep receiving venom. Existence of the leisons imply that the venom of H. lepturus scorpion is dangerous in sheep and serious complications such as death will take place.

Considering the possibility of increased renal toxicity induced by streptomycin in tea and coffee, which contain methylxanthines such as caffeine, we aimed to investigate the histopathological changes in the kidney and liver of rats. We also evaluated some serum parameters after the concurrent use of streptomycin and caffeine. This experimental study was performed on 25 female Wistar rats, with the average weight of 200 g; the rats were divided in five groups. Group I was regarded as the control group, group II received streptomycin (25 mg/kg), group III was administered streptomycin+caffeine (5 mg/kg), group IV received caffeine (5 mg/kg) and group V received streptomycin + vitamin C (100 mg/kg) for a period of 21 days. Afterwards, the rats were anesthetized with ether and blood samples were obtained from the heart. Serum creatinine, blood urea nitrogen, sodium and potassium levels were measured in rats. After preparing and sectioning renal and hepatic tissues for pathological examinations, they were stained by hematoxylin and eosin (H&E); the samples were examined, using a light microscope. Serum creatinine and potassium levels were not significantly different between the groups, while urea nitrogen level in group V (15±07 mg/dL) was significantly lower than the values reproted in groups I and IV (p<0.05). Sodium level increased in group II (139. 8±0.2 mEq/L) and group IV (140±0.447 mEq/L), while a significant reduction was reported in group V (137.25±0.75 mEq/L) (p<0.05). According to the findings, hepatic and renal damages were severe after the concomitant use of streptomycin and caffeine. However, vitamin C reduced the induced damages. As the results indicated, caffeine could aggravate renal injuries, induced by streptomycin, while vitamin C had an alleviating effect.