Mohamed, Y. S., R. M. Abdelsalam, A. S. Attia, M. T. Abdel-Aziz, and D. M. El-Tanbouly, "Regulation of liver regeneration by prostaglandin E and thromboxane A following partial hepatectomy in rats.", Naunyn-Schmiedeberg's archives of pharmacology, vol. 393, issue 8, pp. 1437-1446, 2020. Abstract

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.

Badawi, H. M., R. M. Abdelsalam, O. M. E. Abdel-Salam, E. R. Youness, N. M. Shaffie, and E. - E. D. S. Eldenshary, "Bee venom attenuates neurodegeneration and motor impairment and modulates the response to L-dopa or rasagiline in a mice model of Parkinson's disease.", Iranian journal of basic medical sciences, vol. 23, issue 12, pp. 1628-1638, 2020. Abstract

OBJECTIVES: This study aimed to investigate the effect of bee venom, a form of alternative therapy, on rotenone-induced Parkinson's disease (PD) in mice. Moreover, the possible modulation by bee venom of the effect of L-dopa/carbidopa or rasagiline was examined.

MATERIALS AND METHODS: Rotenone (1.5 mg/kg, subcutaneously; SC) was administered every other day for two weeks and at the same time mice received the vehicle (DMSO, SC), bee venom (0.065, 0.13, and 0.26 mg/kg; intradermal; ID), L-dopa/carbidopa (25 mg/kg, intraperitoneal; IP), L-dopa/carbidopa+bee venom (0.13 mg/kg, ID), rasagiline (1 mg/kg, IP) or rasagiline+bee venom (0.13 mg/kg, ID). Then, wire hanging and staircase tests were performed and mice were euthanized and brains' striata separated. Oxidative stress biomarkers namely, malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), paraoxonase-1 (PON-1), and total antioxidant capacity (TAC) were measured. Additionally, butyrylcholinesterase (BuChE), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), and dopamine (DA) were evaluated. Brain histopathological changes and caspase-3- expression were done.

RESULTS: Bee venom significantly enhanced motor performance and inhibited rotenone-induced oxidative/nitrosative stress, observed as a reduction in both MDA and NO along with increasing GSH, PON-1, and TAC. Besides, bee venom decreased MCP-1, TNF-α, and caspase-3 expression together with an increase in BuChE activity and DA content.

CONCLUSION: Bee venom alone or in combination with L-dopa/carbidopa or rasagiline alleviated neuronal degeneration compared with L-dopa/carbidopa or rasagiline treatment only. Bee venom via its antioxidant and cytokine reducing potentials might be of value either alone or as adjunctive therapy in the management of PD.

Abo-Zalam, H. B., E. S. El-Denshary, R. M. Abdelsalam, I. A. Khalil, M. M. Khattab, and M. A. Hamzawy, "Therapeutic advancement of simvastatin-loaded solid lipid nanoparticles (SV-SLNs) in treatment of hyperlipidemia and attenuating hepatotoxicity, myopathy and apoptosis: Comprehensive study.", Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, vol. 139, pp. 111494, 2021. Abstract

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.

Abo-Zalam, H. B., R. M. Abdelsalam, R. F. Abdel-Rahman, M. F. Abd-Ellah, and M. M. Khattab, "In Vivo Investigation of the Ameliorating Effect of Tempol against MIA-Induced Knee Osteoarthritis in Rats: Involvement of TGF-β1/SMAD3/NOX4 Cue.", Molecules (Basel, Switzerland), vol. 26, issue 22, 2021. Abstract

Osteoarthritis (OA) is a complex disease characterized by structural, functional, and metabolic deteriorations of the whole joint and periarticular tissues. In the current study, we aimed to investigate the possible effects of tempol on knee OA induced by the chemical chondrotoxic monosodium iodoacetate (MIA) which closely mimics both the pain and structural changes associated with human OA. Rats were administrated oral tempol (100 mg/kg) one week post-MIA injection (3 mg/50 μL saline) at the right knee joints for 21 consecutive days. Tempol improved motor performance and debilitated the MIA-related radiological and histological alterations. Moreover, it subsided the knee joint swelling. Tempol decreased the cartilage degradation-related biomarkers as matrix metalloproteinase-13, bone alkaline phosphatase (bone ALP), and fibulin-3. The superoxide dismutase mimetic effect of tempol was accompanied by decreased NADPH oxidase 4 (NOX4), inflammatory mediators, nuclear factor-kappa B (NF-κB), over-released transforming growth factor-β1 (TGF-β1). Tempol decreased the expression of chemokine (C-C motif) ligand 2 (CCL2). On the molecular level, tempol reduced the phosphorylated protein levels of p38 mitogen-activated protein kinase (MAPK), and small mother against decapentaplegic 3 homologs (SMAD3). These findings suggest the promising role of tempol in ameliorating MIA-induced knee OA in rats via collateral suppression of the catabolic signaling cascades including TGF-β1/SMAD3/NOX4, and NOX4/p38MAPK/NF-κB and therefore modulation of oxidative stress, catabolic inflammatory cascades, chondrocyte metabolic homeostasis.

Elgohary, R., R. M. Abdelsalam, O. M. E. Abdel-Salam, M. M. Khattab, N. A. Salem, Z. A. El-Khyat, and F. A. Morsy, "Protective effect of cannabinoids on gastric mucosal lesions induced by water immersion restrain stress in rats.", Iranian journal of basic medical sciences, vol. 24, issue 9, pp. 1182-1189, 2021. Abstract

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.

El-Safty, H., A. Ismail, R. M. Abdelsalam, A. E. El-Sahar, and M. A. Saad, "Dapagliflozin diminishes memory and cognition impairment in Streptozotocin induced diabetes through its effect on Wnt/β-Catenin and CREB pathway.", Brain research bulletin, vol. 181, pp. 109-120, 2022. Abstract

Diabetic neuropathy is a chronic condition that affects a significant number of individuals with diabetes. Streptozotocin injection intraperitoneally to rodents produces pancreatic islet β-cell destruction causing hyperglycemia, which affect the brain leading to memory and cognition impairment. Dapagliflozin may be able to reverse beta-cell injury and alleviate this impairment. This effect may be via neuroprotective effect or possible involvement of the antioxidant, and anti-apoptotic properties. Forty rats were divided into four groups as follows: The normal control group, STZ-induced diabetes group, STZ-induced diabetic rats followed by treatment with oral dapagliflozin group and normal rats treated with oral dapagliflozin. Behavioral tests (Object location memory task and Morris water maze) were performed. Serum biomarkers (blood glucose and insulin) were measured and then the homeostatic model assessment for insulin resistance (HOMA-IR) was calculated. In the hippocampus the followings were determined; calmodulin, ca-calmodulin kinase Ⅳ (CaMKIV), protein kinase A (PKA) and cAMP-responsive element-binding protein to determine the transcription factor CREB and its signaling pathway also Wnt signaling pathway and related parameters (WnT, B-catenin, lymphoid enhancer binding factor LEF, glycogen synthase kinase 3β). Moreover, nuclear receptor-related protein-1, acetylcholine and its hydrolyzing enzyme acetylcholine esterase, oxidative stress parameter malondialdehyde (MDA) and apoptotic parameter caspase-3 were determined. STZ was able to cause destruction to pancreatic β-cells which was reflected on glucose levels causing diabetes. Diabetic neuropathy was clear in the rats performing the behavioral tests. Memory and cognition parameters in the hippocampus were negatively affected. Oxidative stress and apoptotic parameter were elevated while the electrical activity was declined. Dapagliflozin was able to reverse the previously mentioned parameters and behavior. Thus, to say dapagliflozin significantly showed neuroprotective action along with antioxidant, and anti-apoptotic properties.

Khalifa, M., R. M. Abdelsalam, M. M. Safar, and H. F. Zaki, "Phosphodiesterase (PDE) III inhibitor, Cilostazol, improved memory impairment in aluminum chloride-treated rats: modulation of cAMP/CREB pathway.", Inflammopharmacology, 2022. Abstract

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.

Hussien, Y. A., D. I. N. A. F. Mansour, S. A. Nada, S. S. Abd El-Rahman, R. M. Abdelsalam, A. S. Attia, and D. M. El-Tanbouly, "Linagliptin attenuates thioacetamide-induced hepatic encephalopathy in rats: Modulation of C/EBP-β and CX3CL1/Fractalkine, neuro-inflammation, oxidative stress and behavioral defects.", Life sciences, vol. 295, pp. 120378, 2022. Abstract

The degree of neuroinflammation is correlated mainly with cognitive and motor dysfunctions associated with hepatic encephalopathy (HE). The current study was conducted to explore the possible protective potential of the antidiabetic drug; linagliptin (LNG; 10 or 20 mg/kg) against HE induced by thioacetamide (TAA) in rats. Animals received two consecutive intraperitoneal injections of TAA (200 mg/kg) on alternate days. Neurobehavioral tests were performed 24 h after the last injection, and rats were sacrificed 24 h later (48 h). The higher LNG dose more effectively protected against TAA-induced changes. Administration of LNG for 15 days before TAA notably mitigated TAA-induced acute liver injury and HE, as verified by the marked improvement in motor coordination, locomotor activity, and cognition function. LNG maintained both brain and liver weight indices and retracted the hyperammonemia with a prominent suppression in liver transaminases. This was accompanied by an evident modulation of hepatic and hippocampal oxidative stress markers; GSH and MDA. LNG attenuated both liver and hippocampal pro-inflammatory cytokine; IL-1β while augmented the anti-inflammatory one; IL-10. It noticeably reduced hepatic and hippocampal COX-2 and TNF-α and maintained hepatic and brain architectures. It also induced a marked decrease in the inflammation-regulated transcription factor, C/EBP-β, with a profound increase in hippocampi's anti-inflammatory chemokine, CX3CL1/Fractalkine. LNG modulated TAA-induced disturbances in hippocampal amino acids; glutamate, and GABA with a significant increase in hippocampal BDNF. In conclusion, the regulatory effect of LNG on neuroinflammatory signaling underlines its neuroprotective effect against progressive encephalopathy accompanying acute liver injury.

Shouman, M. M., R. M. Abdelsalam, M. M. Tawfick, S. A. Kenawy, and M. M. El-Naa, "Antisense Tissue Factor Oligodeoxynucleotides Protected Diethyl Nitrosamine/Carbon Tetrachloride-Induced Liver Fibrosis Through Toll Like Receptor4-Tissue Factor-Protease Activated Receptor1 Pathway.", Frontiers in pharmacology, vol. 12, pp. 676608, 2021. Abstract

Tissue factor (TF) is a blood coagulation factor that has several roles in many non-coagulant pathways involved in different pathological conditions such as angiogenesis, inflammation and fibrogenesis. Coagulation and inflammation are crosslinked with liver fibrosis where protease-activated receptor1 (PAR1) and toll-like receptor4 (TLR4) play a key role. Antisense oligodeoxynucleotides are strong modulators of gene expression. In the present study, antisense TF oligodeoxynucleotides (TFAS) was evaluated in treating liver fibrosis via suppression of TF gene expression. Liver fibrosis was induced in rats by a single administration of N-diethyl nitrosamine (DEN, 200 mg/kg; i. p.) followed by carbon tetrachloride (CCl4, 3 ml/kg; s. c.) once weekly for 6 weeks. Following fibrosis induction, liver TF expression was significantly upregulated along with liver enzymes activities and liver histopathological deterioration. Alpha smooth muscle actin (α-SMA) and transforming growth factor-1beta (TGF-1β) expression, tumor necrosis factor-alpha (TNF-α) and hydroxyproline content and collagen deposition were significantly elevated in the liver. Blocking of TF expression by TFAS injection (2.8 mg/kg; s. c.) once weekly for 6 weeks significantly restored liver enzymes activities and improved histopathological features along with decreasing the elevated α-SMA, TGF-1β, TNF-α, hydroxyproline and collagen. Moreover, TFAS decreased the expression of both PAR1 and TLR4 that were induced by liver fibrosis. In conclusion, we reported that blockage of TF expression by TFAS improved inflammatory and fibrotic changes associated with CCl4+DEN intoxication. In addition, we explored the potential crosslink between the TF, PAR1 and TLR4 in liver fibrogenesis. These findings offer a platform on which recovery from liver fibrosis could be mediated through targeting TF expression.

Abd-ElRaouf, A., A. S. Nada, N. E. - D. A. Mohammed, H. A. Amer, S. S. Abd-ElRahman, R. M. Abdelsalam, and H. A. Salem, "Low dose gamma irradiation attenuates cyclophosphamide-induced cardiotoxicity in rats: role of NF-κB signaling pathway.", International journal of radiation biology, vol. 97, issue 5, pp. 632-641, 2021. Abstract

PURPOSE: Cyclophosphamide (Cyp) is one of the most commonly used, wide spectrum chemotherapeutic agents. Cyp has multi-organ toxicities that are dose limiting, thus it's mostly used in chemotherapeutic combinations. Radiation is well known as a hazardous sort of energy, recent studies are interested in studying the beneficial therapeutic effects of low-dose gamma radiation. This study examined the protective effect of two different doses/dose-rates of irradiation either alone or combined with telmisartan against Cyp-induced cardiotoxicity.

MATERIALS AND METHODS: Rats were divided into seven groups; (1): Control, (2): Cyp, (3-4): 0.05 Gy low dose rate (LDR) irradiation, 0.25 Gy high dose rate (HDR) irradiation, respectively, prior to Cyp dose, (5-7): telmisartan either alone or with 0.05 Gy LDR-irradiation or 0.25 Gy HDR-irradiation, respectively, prior to Cyp dose. The current investigation studied the effect of Cyp alone or combined with different treatment regimens on serum cTn-I and LDH, nuclear factor-κB (NF-κB) pathway (p65/IκB/IKK-α/IKK-ß) in the myocardium. Pro-inflammatory cytokines IL-1ß, IL-6 and TNF-α were assessed in addition to histopathological examination of the heart.

RESULTS: Low-dose irradiation attenuated cardiac enzymes, pro-inflammatory cytokines, NF-κB content, and histology, in both low and HDRs. Furthermore, the combination of low-dose irradiation with telmisartan (an angiotensin-II receptor type-1 blocker and a known cardio-protective drug) offered the best histological results.

CONCLUSIONS: Low-dose irradiation-induced amelioration is partially but not completely through canonical activation of NF-κB, and may have another atypical pathway. While telmisartan probably ameliorates NF-κB totally through canonical pathway.