فهرست مطالب sadaf nezamoleslami

Several factors contribute to the development of gastric erosions, including corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs), alcohol, and stress. These factors can cause or worsen gastrointestinal ulcers by activating inflammatory pathways or by altering gastric mucosal blood flow. Dapsone is an antimicrobial compound with anti-inflammatory properties. The aim of this study was to evaluate the protective effects of dapsone against gastric erosions-induced by alcohol, stress, or indomethacin. Gastric damage was induced in male rats in different three experimental models:  ethanol (5 ml/kg, p.o.)-, water-immersion stress-, and indomethacin (30 mg/kg, p.o.)- induced ulcer. Rats in each of these three experimental models were divided into 5 groups: Normal group, 2. Control group (gastric damage + vehicle), 3. Gastric damage+ dapsone 1 mg/kg, 4. Gastric damage+ dapsone 3 mg/kg, 5. Gastric damage+ dapsone 10 mg/kg. In this study, the J- score ulcer index and histopathological assessment were performed. In addition, inflammatory cytokines levels, NF-κB expression and MPO activity were determined. Dapsone reduced the tissue injuries and erosion area in all three experimental groups compared to the control group. In addition, serum levels of inflammatory cytokines, TNF-alpha and IL-1β were reduced in the dapsone treatment groups. The expression of NF-κB and tissue concentration of myeloperoxidase (a marker of neutrophil activation) was also reduced in rats given dapsone. To conclude, dapsone exhibits significant protective effects against the development of experimental gastric erosions in rats and these effects seem to be related to its anti-inflammatory and antioxidant properties.

Drug-induced cholestasis is the main type of liver disorder accompanied by high morbidity and mortality. Evidence for the role of hepatobiliary pumps in the cholestasis patho-mechanism is constantly increasing. Recognition of the interactions of chemical agents with these transporters at the initial phases of drug discovery can help develop new drug candidates with low cholestasis potential. This review delivers an outline of the role of these transport proteins in bile creation. It addresses the pathophysiological mechanism for drug-induced cholestasis. In-vitro models, including cell-based and membrane-based approaches and In-vivo models such as genetic knockout animals, are considered. The benefits and restrictions of each model are discussed in this review. Current understandings into the cellular and molecular process that control the activity of hepatobiliary pumps have directed to a better understanding of the pathophysiology of drug-induced cholestasis. A combination of in-vitro monitoring for transport interaction, in-silico predicting systems, and consideration of and metabolic and physicochemical properties must cause more effective monitoring of possible liver problems.

Epileptic seizure is phenomenon of abnormal synchronous neuronal discharge of a set of neurons in brain as a result of neuronal excitation. Evidence shows the nitric oxide (NO) involvement in neuronal excitability. Moreover, the role of NO-mediated cyclic guanosine monophosphate (cGMP) activation in seizure pathogenesis is well-established. Sumatriptan is a selective agonist of 5-Hydroxytryptamine1B/D auto-receptor, has been reassessed for its neuroprotection. This study was aimed to explore the anticonvulsant effect of sumatriptan through possible involvement of NO-cGMP pathway in mice. For this purpose, the protective effect of sumatriptan on PTZ-induced clonic seizure threshold (CST) was measured using NO-cGMP pathway inhibitors including N(G)-nitro-L-arginine (L-NNA, 1, 5, and 10 mg/kg), 7-nitroindazole (7-NI, 30, 45, and 60 mg/kg), aminoguanidine (AG, 30, 50, and 100 mg/kg), methylene blue (MB, 0.1, 0.5, and 1 mg/kg) and sildenafil (5, 10, and 20 mg/kg). The involvement of nitrergic system was further confirmed by measurement of nitrite levels by Griess reaction. The gene expression of neuronal nitric oxide synthase (nNOS) and subunits of soluble guanylyl cyclase (sGC) was studied using qRT-PCR analysis. Acute administration of sumatriptan (1.2 and 0.3 mg/kg) in combination with subeffective doses of NOS, sGC, and phosphodiesterase 5 inhibitors significantly reversed the PTZ-induced CST (P≤0.001). The nitrite level in prefrontal cortex was significantly attenuated by sumatriptan (P≤0.01). Furthermore, sumatriptan downregulated the PTZ-induced mRNA expression of nNOS, and α1, α2, and β1 genes in cerebral cortex of mice (P≤0.0001). In conclusion, the anticonvulsant activity of sumatriptan at least, in part, is mediated through inhibiting NO-cGMP pathway.

Cirrhotic cardiomyopathy refers to cardiac muscle dysfunction caused by liver cirrhosis. Seemingly, free radicals and inflammatory factors play a critical role in the pathophysiology of cardiomyopathy. Curcumin has the anti-inflammatory, antioxidant, and anticancer properties . However, the therapeutic indications of this compound are limited due to its low absorption, rapid metabolism, and low bioavailability. Curcumin nanomicelle is a form of nanoparticle developed to overcome the poor kinetic profile of curcumin and enhance its bioavailability and therapeutic effects. The present study aimed to develop an experimental model of cirrhosis induced by biliary duct ligation in rats.

The animals were kept until 28 days after the bile duct ligation and received curcumin or curcumin nanomicelle via oral gavage at various doses during days 7-28. After the intervention, the effects of curcumin and curcumin nanomicelle on cardiovascular function, some inflammatory and antioxidant biomarkers, and histopathological changes were assessed.

According to the findings, cardiac electrophysiology function and contractile force improved only in the curcumin nanomicelle groups. In addition, curcumin nanomicelle significantly reduced inflammatory factors and increased antioxidant enzymes. In the histopathological studies, cardiac tissue damage and destruction were observed to decrease in the curcumin nanomicelle groups.

Therefore, it was concluded that curcumin nanomicelle plays a protective role in cirrhotic cardiomyopathy by reducing inflammatory and oxidative factors and improving the cardiac function. Furthermore, curcumin nanomicelle exhibited more significant therapeutic effects compared to the curcumin treatment groups.

Drug repositioning is one of the common strategies of new indications and therapeutic targets for already known drugs.  Drug repositioning is known by various names in textbooks such as drug re-proposing, re-profiling, re-tasking and therapeutic switching. Drugs may act through multiple molecular targets. Although perhaps designed for specificity, modulate several targets. This “Poly-pharmacology” may also be essential for efficacy. This “off-targets” may also lead to side-effect. Repositioning vs traditional drug discovery reduces time, reduces risk, and reduces cost.  Bleeding disorder observation of aspirin (a wonder drug) over the years (1891) was made repeatedly leading to the suggestion by Craven (1953) that aspirin might be used for the prevention of thrombosis. The historically unintentional, serendipitous, or constrained research effort is now being replaced by systematic, high-throughput and rational pursuit of new therapeutic uses for marketed drugs, drugs in development, or as a drug salvaging strategy.