Statins were reported to lower the Coenzyme Q10 (CoQ10) content upon their inhibition of HMG-CoA reductase enzyme and both are known to possess neuroprotective potentials; therefore, the aim is to assess the possible use of CoQ10 as an adds-on therapy to rosuvastatin to improve its effect using global I/R model. Rats were allocated into sham, I/R, rosuvastatin (10 mg/kg), CoQ10 (10 mg/kg) and their combination. Drugs were administered orally for 7 days before I/R. Pretreatment with rosuvastatin and/or CoQ10 inhibited the hippocampal content of malondialdehyde, nitric oxide, and boosted glutathione and superoxide dismutase. They also opposed the upregulation of gp91phox, and p47phox subunits of NADPH oxidase. Meanwhile, both agents reduced content/expression of TNF-α, iNOS, NF-κBp65, ICAM-1, and MPO. Besides, all regimens abated cytochrome c, caspase-3 and Bax, but increased Bcl-2 in favor of cell survival. On the molecular level, they increased p-Akt and its downstream target p-FOXO3A, with the inhibition of the nuclear content of FOXO3A to downregulate the expression of Bim, a pro-apoptotic gene. Additionally, both treatments downregulate the JNK3/c-Jun signaling pathway. The effect of the combination regimen overrides that of either treatment alone. These effects were reflected on the alleviation of the hippocampal damage in CA1 region inflicted by I/R. Together, these findings accentuate the neuroprotective potentials of both treatments against global I/R by virtue of their rigorous multi-pronged actions, including suppression of hippocampal oxidative stress, inflammation, and apoptosis with the involvement of the Akt/FOXO3A/Bim and JNK3/c-Jun/Bax signaling pathways. The study also nominates CoQ10 as an adds-on therapy with statins.

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Both hydrogen sulfide (H2S) and mesenchymal stem cells (MSCs) extracted microvesicles (MVs) are potent anti‐inflammatory molecules. They play an essential role in lowering the production of tumor necrosis factor‐alpha (TNF‐α). The latter could strongly stimulate MiR‐155 that contributes to neurodegeneration and Alzheimer's disease (AD). miR‐155 could repress the expression of inositol 5‐phosphatase‐1 (SHIP‐1) leading eventually to activation of Akt kinase and neurofibrillary development in AD. The current study was conducted to evaluate the role of miR‐155 in a rat model of lipopolysaccharide (LPS)‐induced AD and to investigate the effect of using MVs and H2S that were given either separately or combined in regulating pro‐inflammatory signaling. Thirty female Wistar albino rats aged 6 months to 1 year were equally divided into five groups; control group, LPS‐induced AD group, LPS + MVs group, LPS + NaHS group, and LPS + MVs and NaHS group. The increased miR‐155 level was associated with decreased SHIP‐1 level and positively correlated with TNF‐α. In addition, treatment with MVs and/or NaHS resulted in attenuation of inflammation, decreasing miR‐155, pAkt levels, and downregulation of apoptosis along with improvement of the hippocampal and cortical histopathological alterations. LPS enhanced production of malondialdehyde (MDA) and reduced glutathione (GSH) levels indicating oxidative stress‐induced neural damage, whereas MVs and NaHS could mitigate oxidative damage and accelerate antioxidant capacity via increasing catalase enzyme. In conclusion, downregulation of TNF‐α, miR‐155, and pAkt and increased SHIP‐1 could improve the neuro‐inflammatory state and cognitive function of LPS‐induced Alzheimer's disease.

The main focus of our study is to assess the anti-cancer activity of cimetidine and vitamin C via combating the tumor supportive role of mast cell mediators (histamine, VEGF, and TNF-α) within the tumor microenvironment and their effect on the protein kinase A(PKA)/insulin receptor substrate-1(IRS-1)/phosphatidylinositol-3-kinase (PI3K)/serine/threonine kinase-1 (AKT)/mammalian target of rapamycin (mTOR) cue in Ehrlich induced breast cancer in mice. In vitro study was carried out to evaluate the anti-proliferative activity and combination index (CI) of the combined drugs. Moreover, the Ehrlich model was induced in mice via subcutaneous injection of Ehrlich ascites carcinoma cells (EAC) in the mammary fat pad, and then they were left for 9 days to develop obvious solid breast tumor. The combination therapy possessed the best anti-proliferative effect, and a CI < 1 in the MCF7 cell line indicates a synergistic type of drug interaction. Regarding the in vivo study, the combination abated the elevation in the tumor volume, and serum tumor marker carcinoembryonic antigen (CEA) level. The serum vascular endothelial growth factor (VEGF) level and immunohistochemical staining for CD34 as markers of angiogenesis were mitigated. Additionally, it reverted the state of oxidative stress and inflammation. Meanwhile, it caused an increment in apoptosis, which prevents tumor survival. Furthermore, it tackled the elevated histamine and cyclic adenosine monophosphate (cAMP) levels, preventing the activation of the (PKA/IRS-1/PI3K/AKT/mTOR) cue. Finally, we concluded that the synergistic combination provided a promising anti-neoplastic effect via reducing the angiogenesis, oxidative stress, increasing apoptosis,as well as inhibiting the activation of PI3K/AKT/mTOR cue, and suggesting its use as a treatment option for breast cancer.

Transient global ischemia continues to be an important clinical problem with limited treatment options. The present study aimed to investigate the possible protective effects of celecoxib [a selective cyclooxygenase (COX-2) inhibitor] and N-omega-nitro-L-arginine methyl ester (L-NAME) [a nonselective nitric oxide synthase (NOS) inhibitor] against global ischemia-reperfusion (IR) induced biochemical and histological alterations in the rat hippocampus. Global ischemia was induced by bilateral clamping of the common carotid arteries for 60 minutes. Hippocampal cysteinyl aspartate-specific protease-3 (caspase-3) activity, nitrite/nitrate contents (NOX), as well as COX-2 immunoreactivity in the hippocampal Cornu Ammonis 1 (CA1) subregion were dramatically increased 24 hours after global ischemia. After 72-hour of reperfusion, ischemia induced a selective, extensive neuronal loss in the hippocampus CA1 subregion. Celecoxib (3 and 5 mg/kg, intraperitoneally; i.p.), administered 30 minutes before ischemia and at 6, 12, and 22 hours of 24-hour reperfusion, caused significant reductions in hippocampal caspase-3 activity as well as the number of COX-2 immunoreactive (COX-2 ir) neurons in the CA1 subregion. Further, celecoxib (3 or 5 mg/kg, i.p.), administered 30 minutes before ischemia and at 6, 12, 22, and 48 hours of 72-hour reperfusion, provided a notable histological protection of hippocampal CA1 neurons. Meanwhile, L-NAME (3 mg/kg, i.p.), administered twice (immediately after ischemia and 45 minutes after starting the reperfusion period), effectively reduced the elevated NOX level, decreased hippocampal caspase-3 activity and COX-2 immumoreactivity, and ameliorated ischemia-induced damage in the hippocampal CA1 subregion. The present study indicates that celecoxib and L-NAME might be neuroprotective agents of potential benefit in the treatment of cerebral ischemia.

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