Dr. Rania Mohsen AbdElSalam

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.

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.

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.

Recombinant human myelin basic protein (rhMBP) was previously produced in the milk of transgenic cows. Differences in molecular recognition of either hMBP or rhMBP by surface-immobilized anti-hMBP antibodies were demonstrated. This indicated differences in immunological response between rhMBP and hMBP. Here, the activity of free and controlled release rhMBP poly(ε-caprolactone) nanoparticles (NPs), as a therapeutic vaccine against multiple sclerosis (MS) was demonstrated in experimental autoimmune encephalomyelitis (EAE) animal model. Following optimization of nanoformulation, discrete spherical, rough-surfaced rhMBP NPs with high entrapment efficiency and controlled release pattern were obtained. Results indicated that rhMBP was loaded into and electrostatically adsorbed onto the surface of NPs. Subcutaneous administration of free or rhMBP NPs before EAE-induction reduced the average behavioral score in EAE mice and showed only mild histological alterations and preservation of myelin sheath, with rhMBP NPs showing increased protection. Moreover, analysis of inflammatory cytokines (IFN-γ and IL-10) in mice brains revealed that pretreatment with free or rhMBP NPs significantly protected against induced inflammation.

IN CONCLUSION: i) rhMBP ameliorated EAE symptoms in EAE animal model, ii) nanoformulation significantly enhanced efficacy of rhMBP as a therapeutic vaccine and iii) clinical investigations are required to demonstrate the activity of rhMBP NPs as a therapeutic vaccine for MS.

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.

Stroke remains a debilitating disease with high incidence of morbidity and mortality, where many reports provide promising venues for prevention/treatment of such ailment. Glibenclamide, a selective blocker of KATP channels, was reported to protect against ischemia and ischemia-reperfusion (IR) injury in several experimental models. Hence, the present study aimed to investigate the possible involvement of free radicals as well as inflammatory and anti-inflammatory mediators in the hippocampus of rats exposed to IR. To this end, male Wistar rats were divided into 3 groups: group I served as sham operated controls; group II was subjected to 15 min ischemia by occlusion of both common carotid arteries, followed by 60 min reperfusion; group III was injected with glibenclamide (1mg/kg, i.p.) 10 min before ischemic-reperfusion injury. IR increased lipid peroxides, myeloperoxidase activity, TNF-α and PGE(2), while decreasing glutathione, total antioxidant capacity, nitric oxide and IL-10 levels in the hippocampus. Glibenclamide reversed all the former alterations, thus highlighting a potential therapeutic utility for this sulphonyl urea in IR brain injury via modulating oxidative stress and inflammatory mediators.