Dr. Rania Mohsen AbdElSalam

Liver fibrosis is one of the most serious consequences of S. mansoni infection. The aim of the present study was to investigate the potential anti-fibrotic effect of human Wharton's jelly-derived mesenchymal stem cells (WJMSCs) combined with praziquantel (PZQ) in S. mansoni-infected mice. S. mansoni-infected mice received early (8(th) week post infection) and late (16(th) week post infection) treatment with WJMSCs, alone and combined with oral PZQ. At the 10(th) month post infection, livers were collected for subsequent flow cytometric, histopathological, morphometric, immunohistochemical, gene expression, and gelatin zymographic studies. After transplantation, WJMSCs differentiated into functioning liver-like cells as evidenced by their ability to express human hepatocyte-specific markers. Regression of S. mansoni-induced liver fibrosis was also observed in transplanted groups, as evidenced by histopathological, morphometric, and gelatin zymographic results besides decreased expression of three essential contributors to liver fibrosis in this particular model; alpha smooth muscle actin, collagen-I, and interleukin-13. PZQ additionally enhanced the beneficial effects observed in WJMSCs-treated groups. Our results suggest that combining WJMSCs to PZQ caused better enhancement in S. mansoni-induced liver fibrosis, compared to using each alone.

Hepatic ischemia-reperfusion (IR) injury is a clinical problem that leads to cellular damage and organ dysfunction mediated mainly via production of reactive oxygen species and inflammatory cytokines. Vinpocetine has long been used in cerebrovascular disorders. This study aimed to explore the protective effect of vinpocetine in IR injury to the liver. Ischemia was induced in rats by clamping the common hepatic artery and portal vein for 30 min followed by 30 min of reperfusion. Serum transaminases and liver lactate dehydrogenase (LDH) activities, liver inflammatory cytokines, oxidative stress biomarkers, and liver histopathology were assessed. IR resulted in marked histopathology changes in liver tissues coupled with elevations in serum transaminases and liver LDH activities. IR also increased the production of liver lipid peroxides, nitric oxide, and inflammatory cytokines interleukin-1β and interleukin-6, in parallel with a reduction in reduced glutathione and interleukin-10 in the liver. Pretreatment with vinpocetine protected against liver IR-induced injury, in a dose-dependent manner, as evidenced by the attenuation of oxidative stress as well as inflammatory and liver injury biomarkers. The effects of vinpocetine were comparable with that of curcumin, a natural antioxidant, and could be attributed to its antioxidant and anti-inflammatory properties.

This study set out to optimize simvastatin (SV) in lipid nanoparticles (SLNs) to improve bioavailability, efficacy and alleviate adverse effects. Simvastatin-loaded solid lipid nanoparticles (SV-SLNs) were prepared by hot-melt ultrasonication method and optimized by box-Behnken experimental design. Sixty Wister albino rats were randomly assigned into six groups and treated daily for 16 weeks: control group, the group fed with 20 g of high-fat diet (HFD), group treated with vehicle (20 mg/kg, P.O.) for last four weeks, group treated with HFD and SV (20 mg/kg, P.O.) / or SV-SLNs (20 mg/kg/day, P.O.) / or SV-SLNs (5 mg/kg, P.O.) at last four weeks. Blood, liver tissues, and quadriceps muscles were collected for biochemical analysis, histological and immunohistochemical assays. The optimized SV-SLNS showed a particle-size 255.2 ± 7.7 nm, PDI 0.31 ± 0.09, Zeta-potential - 19.30 ± 3.25, and EE% 89.81 ± 2.1%. HFD showed severe changes in body weight liver functions, lipid profiles, atherogenic index (AIX), albumin, glucose, insulin level, alkaline phosphatase as well as muscle injury, oxidative stress biomarkers, and protein expression of caspase-3. Simvastatin treatment in animals feed with HFD showed a significant improvement of all tested parameters, but it was associated with hepatotoxicity, myopathy, and histological changes in quadriceps muscles. SV-SLNs exhibited a significant improvement of all biochemical, histological examinations, and immunohistochemical assays. SV-SLNs (5 mg/kg) treatment returns all measured parameters to control itself. These results represent that SV-SLNs is a promising candidate as a drug carrier for delivering SV with maximum efficacy and limited adverse reaction.

Novel dihydropyrazole 5-8, 10 and pyrazole derivatives 12, 14, 15, 17 were synthesized. The structures of the newly synthesized compounds were elucidated by spectral and elemental analyses. The anti-inflammatory activity of all new compounds was evaluated using the carrageenan-induced rat paw edema test using indomethacin and celecoxib as reference drugs. The most active derivatives as anti-inflammatory agents were accordingly tested for their analgesic activity using the p-benzoquinone-induced writhing method in mice and results revealed that these compounds had also good analgesic activity. The ulcerogenic liability of the selected compounds was also evaluated. Results showed that the selected derivatives had anti-inflammatory activity comparable to or slightly lower than the reference drugs, reaching about 82% inhibition with a considerable gastric safety profile.

The most epidemic liver disorder non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis and inflammation with hepatocellular damage. Recently, it is predictable to be the extensive cause for liver transplantation. The absence of an approved therapeutic agent for NASH is the reason for investigating saroglitazar (SAR) which showed promising effects as a dual PPAR-α/γ agonist in recent studies on NASH. Here, we aimed to investigate the effect of SAR on NASH induced in rats by the administration of high-fat emulsion (HFE) and small doses of lipopolysaccharides (LPS) for 5 weeks. Rats were divided into three groups: negative control group (saline and standard rodent chow), model group (HFE(10 ml/kg/day, oral gavage) + LPS(0.5 mg/kg/week, i.p)), and SAR-treated group (HFE(10 ml/kg/day, oral gavage) + LPS(0.5 mg/kg/week, i.p.) + SAR(4 mg/kg/day, oral gavage) starting at week 3.Treatment with SAR successfully ameliorated the damaging effects of HFE with LPS, by counteracting body weight gain and biochemically by normalization of liver function parameters activity, glucose, insulin, homeostasis model of assessment (HOMA-IR) score, lipid profile levels, and histopathological examination. Significant changes in adipokine levels were perceived, resulting in a significant decline in serum leptin and tumor necrosis factor-α (TNF-α) level concurrent with adiponectin normalization. The positive effects observed for SAR on NASH are due to the downregulation of the LPS/TLR4 pathway, as indicated by the suppression of hepatic Toll-like receptor 4 (TLR4), NF-κB, TNF-α, and transforming growth factor-β1 (TGF-β1) expression. In conclusion, this work verified that SAR ameliorates NASH through deactivation of the hepatic LPS/TLR4 pathway and inhibition of adipocyte dysfunction.

3-Nitropropionic acid (3-NP)-induced neurotoxicity is an experimental model which mimics the pathology and motor abnormalities seen in Huntington's disease (HD) in human. The present investigation was directed to estimate the role of rho kinase (ROCK) inhibition in the possible protective effect of fasudil and simvastatin in 3-NP-induced striatal neurodegeneration in rats. Animals were injected s.c. with 3-NP (20 mg/kg/day) for 1 week with or without administration of fasudil (10 mg/kg/day, p.o.) or simvastatin (20 mg/kg/day, p.o.). At the end of experiment, motor and behavioral abnormalities were evaluated. Animals were then sacrificed for measurement of mitochondrial membrane potential as well as succinate dehydrogenase (SDH) and caspase-3 activities in striatum. Moreover, tumor necrosis factor-alpha (TNF-α) level and protein expressions of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), ROCK, phosphorylated-Akt (p-Akt), endothelial and inducible nitric oxide synthase (eNOS and iNOS), Bax, and Bcl-2 were estimated. Finally, histological changes as demonstrated by striatum injury score, glial activation, and percentage of altered mitochondria were assessed. Both fasudil and simvastatin effectively inhibited 3-NP-induced behavioral, biochemical, and histological changes through inhibition of ROCK activity. However, fasudil provided more amelioration in histological changes, mitochondrial membrane potential and SDH activity in addition to p-Akt and PGC-1α protein expressions. The present study highlights a significant role of ROCK/p-Akt/eNOS pathway in the protective effects of fasudil and simvastatin on neurotoxicity and mitochondrial dysfunction induced by 3-NP in rats. Thus, specific inhibition of ROCK may be considered a promising new approach in the management of HD.

The implication of prostaglandin E (PGE) and thromboxane A (TXA) in the striking process of liver regeneration has been previously reported. However, their exact roles and downstream signals have not been utterly revealed. Therefore, the present study was conducted to explore whether inhibition of cyclooxygenase-2 (COX-2)-derived PGE by celecoxib and blocking of TXA action by seratrodast could alter the progression of liver regeneration after 70% partial hepatectomy (PHx) in rats. Celecoxib (20 mg/kg/day) and seratrodast (2 mg/kg/day) were given orally 1 h before PHx and then daily till the end of experiment (1, 3, or 7 days after the operation). Interestingly, celecoxib-treated rats showed a further increase in interleukin-6, p65 nuclear factor κB, and phosphorylated signal transducer and activator of transcription 3 as compared with PHx control rats. Furthermore, the liver contents of growth factors as well as β-catenin and cyclin D1protein expressions were also enhanced by celecoxib. Accordingly, celecoxib significantly improved hepatic proliferation as indicated by the increase in Ki67 expression and liver index. Contrariwise, seratrodast hindered the normal regeneration process and completely abolished the proliferative effect of celecoxib. In conclusion, TXA has a major role in liver regeneration that could greatly mediate the triggering effect of celecoxib on hepatocytes proliferation following PHx.

OBJECTIVES: This study aimed to determine the impact of cannabinoid agonists and antagonists on the mucosal lesion progress in the stomach induced by water-immersion restraint stress (WIRS).

MATERIALS AND METHODS: Rats subjected to WIRS for 4 hr were treated with Dimethyl sulfoxide (DMSO), CBR1 agonist (NADA, 1 mg/kg), CBR1 antagonist (Rimonabant, 1 mg/kg), CBR2 agonist (GW405833 1 mg/kg) or CBR2 antagonist (AM630, 1 mg/kg SC) 30 min before WIRS. Microscopic lesions, oxidative stress, inflammatory cytokines biomarkers, and (Myeloperoxidase) MPO in gastric tissues were determined.

RESULTS: Results indicated development of severe gastric lesions with a substantial increase in the contents of (nitric oxide) NO, (malondialdehyde) MDA, (interleukin-1 beta) IL-1β, MPO, (tumor necrosis factor-alpha) TNF-α, and a significant fall in the content of GSH and the activity of PON-1 after WIRS.

CONCLUSION: Treatment with NADA and AM630 protected gastric tissues against ulcers as demonstrated by a decrease in the contents of MDA, TNF-α, MPO, and IL-1β along with an increase in the content of PON-1 activity and GSH in the stomach tissues. On the other hand, treatment with SR141716A or GW405833 showed no protective effects on ulcers development. It seems that cannabinoids exert their antioxidant potential and anti-inflammatory effects against WIRS-induced gastric ulcers by activation of CB1R.

Ischemic preconditioning (IPC), comprising exposure to sub-lethal short term ischemic events, has been shown to exert adaptive responses in many organs including the brain, thus guarding against exacerbations of ischemia reperfusion (IR). However, the mechanisms involved in the early phase of such a protection remain elusive; hence, the present study aimed to investigate the modulatory effect of preconditioning against IR induced injury on infarct size, free radicals, inflammatory/anti-inflammatory markers, caspase-3 and heat shock protein (HSP)70 in the rat hippocampus. To this end, male Wistar rats were divided into 3 groups, (1) sham operated (SO) control; (2) IPC, animals were subject to 3 episodes of ischemia (5 min) followed by reperfusion (10 min), afterwards rats underwent ischemia (15 min) followed by reperfusion (60 min); (3) IR animals were subjected to 15 min global ischemia followed by 60 min reperfusion. IR produced cerebral infarction accompanied by an imbalance in the hippocampal redox status, neutrophil infiltration, elevation in tumor necrosis factor (TNF)-α and prostaglandin (PG)E₂, besides reduction in interleukin (IL)-10 and nitric oxide (NO) levels. IPC reverted all changes except for PGE₂; however, neither HSP70 nor caspase-3 expression was altered following IR or IPC. The current study points thus towards the activation of the antioxidant system, anti-inflammatory pathway, as well as NO in the early phase of preconditioning protection.

Ischemia-reperfusion (I/R) injury is a pathological process which magnifies with the ensuing inflammatory response and endures with the increase of oxidants especially during reperfusion. The present study was conducted to assess the possible modulatory effects of plumbagin, the active constituent extracted from the roots of traditional medicinal plant Plumbago zeylanica L., on the dire role of high mobility group box 1 (HMGB1) as well as the associated inflammation, oxidative stress and apoptotic cell death following hepatic I/R. Four groups of rats were included: sham-operated, sham-operated treated with plumbagin, I/R (30 min ischemia and 1 h reperfusion) and I/R treated with plumbagin. Pretreatment with plumbagin markedly improved hepatic function and structural integrity compared to the I/R group, as manifested by depressed plasma transaminases and lactate dehydrogenase (LDH) activities as well as alleviated tissue pathological lesions. Plumbagin prominently hampered HMGB1 expression and subsequently quelled inflammatory cascades, as nuclear factor κB (NF-κB), tumor necrosis factor-alpha (TNF-α) and myeloperoxidase (MPO) activity. It also interrupted reactive oxygen species (ROS)-HMGB1loop as evident by restored liver reduced glutathione (GSH), elevated glutathione peroxidase (GPx) activity, along with decreased liver lipid peroxidation. Simultaneously, plumbagin significantly ameliorated apoptosis by amending the mRNA expressions of both anti-apoptotic (Bcl-2) and pro-apoptotic (Bax). The present results revealed that plumbagin is endowed with hepatoprotective activity ascribed to its antioxidant, anti-inflammatory and anti-apoptotic properties which are partially mediated through dampening of HMGB1 expression.

BACKGROUND: Pinocembrin is a major flavonoid molecule isolated from honey and propolis. It has versatile pharmacological and biological activities including antimicrobial, anti-inflammatory, antioxidant, and anticancer activities as well as neuroprotective effects against cerebral ischemic injury. The purpose of the current study was to determine the possible mechanisms of neuroprotection elicited by pinocembrin with specific emphasis on chronic prophylactic use before the induction of global cerebral ischemia reperfusion.

METHODS: Global cerebral ischemia-reperfusion (I/R) was induced by bilateral carotid artery occlusion for 15min followed by 60min reperfusion period. Animals were randomly allocated into 3 groups (n=28): Sham operated, I/R control and rats treated with pinocembrin (10mg/kg, po) daily for 7 days then I/R was induced 1h after the last dose of pinocembrin. After reperfusion rats were killed by decapitation, brains were removed and both hippocampi separated and the following biochemical parameters were estimated; lactate dehydrogenase activity, oxidative stress markers (lipid peroxides, nitric oxide and reduced glutathione), inflammatory markers (myeloperoxidase, tumor necrosis factor-alpha, nuclear factor kappa-B, interleukin-6 and interleukin-10), apoptotic biomarkers (caspase 3 and cytochrome C), neurotransmitters (glutamate, gamma aminobutyric acid) and infarct size were assessed.

RESULTS: Pinocembrin ameliorated damage induced by I/R through suppressing oxidative stress, inflammatory and apoptotic markers as well as mitigating glutamate and lactate dehydrogenase activity. One of the more significant findings to emerge from this study is that pinocembrin normalized the infarct size elevated by I/R.

CONCLUSIONS: Pinocembrin showed a neuroprotective effects through antioxidant, anti-inflammatory and antiapoptotic mechanisms.

BACKGROUND: Phosphodiestrase (PDE) enzymes are suggested to play a leading role in fibrogenesis of liver where studies showed the possible implication of PDE 1 & 4 in liver injury proposing them as possible targets for treating liver fibrosis.

AIM: The present study was designed to investigate, for the first time, the possible therapeutic effects of selective inhibitors of PDE-1 (vinpocetine) and PDE-4 (roflumilast) in liver fibrosis induced by diethylnitrosamine (DEN) in rats.

MAIN METHODS: Rats were given DEN (100 mg/kg, i.p.) once weekly for 6 weeks to induce liver fibrosis. Vinpocetine (10 mg/kg/day) or roflumilast (0.5 mg/kg/day) was then orally administered for 2 weeks.

KEY FINDINGS: Vinpocetine significantly suppressed the contents of hydroxyproline, transforming growth factor-beta 1 (TGF-β1), nuclear factor-kappa B (NF-κB) whereas roflumilast normalized them. Moreover, tumor necrosis factor-alpha (TNF-α) content and protein expressions of toll-like receptor 4 (TLR4) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were markedly decreased whereas cAMP response element binding (CREB) protein expression was significantly elevated by both treatments. Additionally, vinpocetine and roflumilast up-regulated the gene expression of bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) receptor where roflumilast showed better results. PDE1 and 4 activities were inhibited by vinpocetine and roflumilast, respectively. The superior results offered by roflumilast could be related to the higher cAMP level obtained relative to vinpocetine.

SIGNIFICANCE: Our study manifested the up-regulation of PDE enzymes (1 & 4) in liver fibrosis and addressed the therapeutic role of vinpocetine and roflumilast as PDEIs through a cAMP-mediated TLR4 inflammatory and fibrogenic signaling pathways.

The most prevalent type of dementia is Alzheimer's disease (AD), which is currently incurable. Existing treatments for Alzheimer's disease, such as acetylcholinesterase inhibitors, are only effective for symptom relief. Disease-modifying medications for Alzheimer's disease are desperately required, given the enormous burdens that the disease places on individuals and communities. Phosphodiesterase (PDE) inhibitors are gaining a lot of attention in the research community because of their potential in treating age-related cognitive decline. Cilostazol is a selective PDE III inhibitor used as antiplatelet agent through cAMP response element-binding (CREB) protein phosphorylation pathway (cAMP/CREB). The neuroprotective effect of cilostazol in AD-like cognitive decline in rats was investigated in this study. After 2 months of intraperitoneal administration of 10 mg/kg aluminum chloride, Morris water maze and Y-maze (behavioral tests) were performed. After that, histological and biochemical examinations of the hippocampal region were carried out. Aluminum chloride-treated rats showed histological, biochemical, and behavioral changes similar to Alzheimer's disease. Cilostazol improved rats' behavioral and histological conditions, raised neprilysin level while reduced levels of amyloid-beta protein and phosphorylated tau protein. It also decreased the hippocampal levels of tumor necrosis factor-alpha, nuclear factor-kappa B, FAS ligand, acetylcholinesterase content, and malondialdehyde. These outcomes demonstrate the protective activity of cilostazol versus aluminum-induced memory impairment.

Nonionic surfactant (NIS) vesicles (niosomes) formed from self-assembly of hydrated synthetic NIS monomers are capable of entrapping a variety of drugs and have been evaluated as an alternative to liposomes. Nystatin (NYS) is a polyene antifungal drug that has been used in the treatment of cutaneous, vaginal and oral fungal infections since the 1950s. The aim of this work is to encapsulate NYS in niosomes to obtain a safe and effective formula administered parenterally for neutropenic patients. NYS niosomes were prepared by the thin-film hydration method using Span 60 or Span 40 and cholesterol (CHOL). Stearylamine and dicetyl phosphate were added as the positive and negative charge-inducing agents (CIA), respectively. Two molar ratios were used, namely NIS/CHOL/CIA (1:1:0.1 and 2:1:0.25). Neutral and positively charged niosomes gave the highest encapsulation efficiencies. NYS niosomes were characterized using transmission electron microscopy, differential scanning calorimetry and dynamic light scattering. The release of neutral and negatively charged NYS niosomes was estimated, and it showed a slow sustained release profile. A 25-kGy γ-irradiation dose was sufficient to sterilize the investigated vesicles. NYS niosomes exerted less nephrotoxicity and hepatotoxicity in vivo, showed higher level of drug in vital organs and revealed pronounced efficacy in elimination of the fungal burden in experimental animals infected with Candida albicans compared with those treated with free NYS. Niosomal encapsulation thus provided means for parenteral administration of NYS, reducing its toxicity and making it a more active antifungal agent.

One-third of cancer patients undergoing chemotherapy treatment often display symptoms of depression leading to poor adherence and decreased quality of life. Thus, this study aimed to investigate the possible protective effect of nebivolol against cisplatin-associated depressive symptoms in adult male rats. Nebivolol is a highly cardioselective β-adrenergic receptor blocker that possesses endothelium-dependent vasodilator properties and antioxidant capacities. Animals were allocated into four groups. Group one was given aqueous solution of carboxymethyl cellulose and served as control, group two was given nebivolol (10 mg/kg p.o., daily), group three was given cisplatin (2 mg/kg i.p. once per week) for 10 consecutive weeks and group four was treated with cisplatin concomitantly with nebivolol as per above schedule. Cisplatin-treated rats showed an increase in both depressive-like behaviors in open-field and forced swimming tests. In addition, histopathological examination revealed cortical encephalomalacia along with hippocampal neuronal degeneration and kidney dysfunction. In parallel, cisplatin administration prominently reduced GABA and elevated glutamate levels in the cortical and hippocampal tissues. Furthermore, it resulted in a significant decline in cortical and hippocampal brain-derived neurotrophic factor and nitric oxide contents concomitantly with a marked decrease in endothelial- and an increase in inducible-nitric oxide synthase genes expression. On the other hand, treatment with nebivolol effectively mitigated the aforementioned cisplatin-associated behavioral, biochemical, and histopathological alterations without changing its antitumor activity as evidenced by sulforhodamine B cell survival assay. Taken together, our results suggest that nebivolol may offer a promising approach for alleviating depressive symptoms associated with the use of cisplatin.