The pulmonary protective potential of vanillic acid-loaded TPGS-liposomes: modulation of miR-217/MAPK/NF-κb signalling pathway.

The aim is to investigate the possible pulmonary protective effect of vanillic acid (VA) in liposome-TPGS nanoparticles, to overcome VA's poor bioavailability. VA was successfully extracted. Liposomes were prepared using thin film hydration. Central composite design was adopted for optimisation of liposomes to get the maximum entrapment efficiency (EE%) and the minimum mean diameter, where the liposomes were further modified with TPGS, and tested for PDI, zeta-potential, and in-vitro drug release. In-vivo study on mice with LPS-acute pulmonary toxicity was tested. TPGS-modified VA-liposomes showed EE% of 69.35 ± 1.23%, PS of 201.7 ± 3.23 nm, PDI of 0.19 ± 0.02, and zeta-potential of -32.2 ± 0.32 mv. A sustained drug release of the TPGS-modified VA-liposomes was observed compared to standard VA, and a pulmonary-protective effect through decreasing miR-217 expression with subsequent anti-inflammatory effect through suppression of MAPK and PI3K/NF-κB pathways was also demonstrated in the current study. TPGS-modified VA-liposomes showed an enhanced bioavailability and a sustained drug release with promising pulmonary protective effects against acute pulmonary injury diseases.

Simvastatin ameliorates testosterone-induced prostatic hyperplasia in rats via modulating IGF-1/PI3K/AKT/FOXO signaling.

Benign prostatic hyperplasia (BPH) is characterized by non-malignant enlargement of prostate cells causing many lower urinary tract symptoms. BPH pathogenesis includes androgens receptors signaling pathways, oxidative stress, apoptosis, and possibly changes in IGF-1/PI3K/AKT/FOXO pathway. Altogether, modulating IGF-1/PI3K/AKT/FOXO signaling along with regulating oxidative stress and apoptosis might preserve prostatic cells from increased proliferation. Beyond statins' common uses, they also have anti-inflammatory, antioxidant, and anti-tumor effects. This study aims to determine simvastatin's beneficial effect on testosterone-induced BPH. Rats were randomly allocated into four groups, 9 rats each. The control group received olive oil subcutaneously and distilled water orally for 30 consecutive days. The second group received simvastatin (20 mg/kg, p.o.) dissolved in distilled water. The BPH-induced group received testosterone enanthate (3 mg/kg, s.c.) dissolved in olive oil, and the BPH-induced treated group received both simvastatin and testosterone. Testosterone significantly increased prostate index and severity of histopathological alterations in prostate tissues as well as 5-alpha reductase enzyme level in contrast to simvastatin treatment that reversed the testosterone-induced alterations in these parameters. Likewise, testosterone up-regulated IGF-1/PI3K/AKT signaling pathway and down-regulated FOXO transcription factor. It also decreased apoptotic markers level in prostatic tissue BAX, caspase-3, and caspase-9, while it elevated Bcl-2 level. In addition, it alleviated reduced GSH and GPX5 levels and SOD activity. Simvastatin treatment significantly opposed testosterone's effect on all aforementioned parameters. In conclusion, this study demonstrates that simvastatin is a possible treatment for BPH which may be attributed to its effect on IGF-1/PI3K/AKT/FOXO signaling pathway as well as anti-oxidant and apoptotic effects.

Response surface optimization of a cardioprotective compound through pharmacosomal drug delivery system: in vivo bioavailability and cardioprotective activity potential.

Vanillic acid (VA) is a phenolic compound with potential antioxidant activity, which improves ischemia-induced myocardial degeneration, by reducing oxidative stress; however, it suffers poor bioavailability owing to its poor solubility. VA-loaded pharmacosomes were optimized using a central composite design, where the effect of phosphatidylcholine:VA molar ratio and the precursor concentration were studied. An optimized formulation (O1) was prepared and tested for the release rate of VA, in vivo bioavailability, and cardioprotective potential on myocardial infarction-induced rats. The optimized formulation showed a particle size of 229.7 nm, polydispersity index of 0.29, and zeta potential of - 30 mV. O1 showed a sustained drug release for 48 h. The HPLC-UV method was developed for the determination of VA in plasma samples using protein precipitation. The optimized formulation showed a great improvement in the bioavailability as compared to VA. The residence time of the optimized formula was 3 times longer than VA. The optimized formulation showed a more potent cardioprotective effect as compared to VA, via inhibition of the MAPK pathway with subsequent inhibition of PI3k/NF-κB signaling, in addition to its antioxidant effect. The optimized formulation showed normalization of many oxidative stress and inflammatory biomarkers. Thus, a VA-loaded pharmacosome formulation with promising bioavailability and cardioprotective activity potential was prepared.

Modulation of the miR-122/Sirt-6/ACE2 axis on experimentally-induced myocardial infarction.

Myocardial infarction (MI) is a progressive myocardial necrosis that can lead to a number of life-threatening complications. MiRNAs have a crucial role in the pathogenesis of many cardiovascular diseases. Remarkably, miR-122 targets the sirtuin-6 (Sirt-6) gene, which is an essential regulator of cardiovascular function and is considered a partial angiotensin converting enzyme 2 (ACE2) activator. Modulation of this axis is supposed to contribute to MI pathogenesis. The current study aims to investigate the cardioprotective effects of xanthenone through targeting the miR-122/Sirt-6/ACE2 axis on experimentally-induced MI in rats. Xanthenone was administered for 14 days and isoprenaline was injected in the last 2 days of the experiment. Xanthenone treatment resulted in a significant downregulation of miR-122, which further upregulated Sirt-6 and thus activated the adenosine monophosphate-activated protein kinase (AMPK). AMPK increases ACE2 levels and results in a decrease in the level of its substrate angiotensin II resulting in the normalization of the inflammatory cytokines and the cardiac biomarkers. Finally, by targeting the miR-122/Sirt-6/AMPK/ACE2 axis, xanthenone has the potential to be a promising cardioprotective agent against MI.

Dasatinib ameliorates thioacetamide-induced liver fibrosis: modulation of miR-378 and miR-17 and their linked Wnt/ß-catenin and TGF-ß/smads pathways.

Hepatic stellate cells activation (HSCs) plays a crucial role in the pathogenesis of liver fibrosis. Specific microRNAs have been suggested to affect the activation of HSCs via various signalling pathways including TGF-ß/smads and Wnt/ß-catenin pathways. Dasatinib is a multitarget inhibitor of many tyrosine kinases has recently studied for its anti-fibrotic effects in a variety of fibrous diseases. This study investigated the role of modulation of miRNA-378 and miRNA-17 in the pathogenesis of liver fibrosis through altering Wnt/ß-catenin and TGF-ß/smads pathways and evaluated the beneficial effect of the tyrosine kinase inhibitor, dasatinib, in thioacetamide-induced liver fibrosis model in mice. Treatment with dasatinib down-regulated miRNA-17 expression, leading to the restoration of WiF-1 and smad-7 which cause the inhibition of both Wnt/ß-catenin and TGF-ß/smads signalling. In addition, it upregulated miRNA-378 leading to the decrease of Wnt-10 which contributes to the suppression of activated HSCs.

The Hepatoprotective Effect of Piperine Against Thioacetamide-Induced Liver Fibrosis in Mice: The Involvement of miR-17 and TGF-ß/Smads Pathways.

Liver fibrosis is characterized by a series of events including activation of quiescent hepatic stellate cells (HSCs) into proinflammatory, contractile, and fibrogenic myofibroblasts, which is the primary trigger for the fibrogenesis process. HSC activation involves many signaling pathways such as the TGF-ß/smads pathway. Specific microRNAs have been identified to play a crucial role in the activation of HSCs via various signaling pathways. Piperine has recently been studied as a promising anti-fibrotic agent against pancreatic fibrosis through altering the TGF-ß1/Smad pathway. Hence, the current study evaluated the beneficial effects of piperine in thioacetamide-induced liver fibrosis in mice through the modulation of miRNA-17 and TGF-ß/smads pathways. Mice were allocated into three groups randomly. Thioacetamide was used to induce liver fibrosis for 6 weeks. Starting from the fourth week of the experiment, mice were treated with piperine daily for 21 days. Piperine treatment resulted in a significant downregulation of miRNA-17 expression, leading to the restoration of smad-7 accompanied with marked inhibition of TGF-ß/smads signaling with further suppression of the activated HSCs and collagen deposition in the hepatocytes. In conclusion, piperine has the potential to be a promising therapeutic drug for the treatment of liver fibrosis through inhibiting the TGF-ß/smads pathway.

The Protective Effect of Korean Red Ginseng Against Rotenone-Induced Parkinson's Disease in Rat Model: Modulation of Nuclear Factor-κß and Caspase-3.

OBJECTIVE: Korean red ginseng was reported to have many biological effects like the antioxidant and the anti-inflammatory activities. Oxidative stress and neuro-inflammation play major roles in the pathogenesis of Parkinson's disease (PD). The current study aimed to investigate the protective effects of ginseng on rotenone-induced PD in rats. METHODS: Rats were randomly allocated into 4 groups: normal rats, rotenone control, ginseng+rotenone and ginseng only treated rats. The severity of PD was evaluated through locomotor activity perceived in the open field test, histological examination and immunohistochemical detection of amyloid-ß in brain tissues, in addition to the biochemical assessment of tyrosine hydroxylase activity in brain tissues. Moreover, the following parameters were investigated for studying the possible mechanisms of ginseng neuroprotective effect: nuclear factor-κß (NF-κß), tumor necrosis factor-alpha (TNF-α), caspase- 3, lipid peroxides and reduced glutathione (GSH). RESULTS: Ginseng exhibited potent neuroprotective effect that was reflected upon the histopathological examination, marked improvement in the locomotor activity and through its ability to suppress the amyloid- ß deposition in the cortex and striatum along with significant increase in the tyrosine hydroxylase activity. Ginseng successfully inhibited the NF-κß inflammatory pathway in brain tissues beside the inhibition of other oxidative stress and inflammatory mediators. Furthermore, it exhibited antiapoptotic effect via the inhibition of caspase-3 expression. CONCLUSION: Ginseng could be a promising treatment in PD. It can suppress dopaminergic neuron degeneration through variable mechanisms mainly via inhibition of NF-κß pathway in addition to inhibition of oxidative stress and apoptosis.

Amitriptyline attenuates bleomycin-induced pulmonary fibrosis: modulation of the expression of NF-κß, iNOS, and Nrf2.

Amitriptyline is a tricyclic antidepressant that was suggested to have antifibrotic potential. The current study aimed to investigate the modulatory effects of amitriptyline on bleomycin-induced pulmonary fibrosis in rats. Rats were randomly assigned into 4 groups: normal control, bleomycin control, amitriptyline+bleomycin, and amitriptyline only treated group. Lung injury was evaluated through the histological examination and immunohistochemical detection of α-smooth muscle actin (α-SMA) in lung tissue, in addition to the biochemical assessment of pulmonary contents of hydroxyproline and transforming growth factor beta-1 (TGF-ß1). In addition, the following parameters were investigated for studying the possible mechanisms of amitriptyline antifibrotic effect: inducible nitric oxide synthase (iNOS), nuclear factor-κß (NF-κß), tumor necrosis factor-alpha (TNF-α), serpine-1, p53, nuclear factor erythroid 2-related factor 2 (Nrf2), lipid peroxides, and reduced glutathione (GSH). Amitriptyline exhibited potent antifibrotic effect that was reflected upon the histopathological examination and through its ability to suppress all the fibrotic parameters. Amitriptyline successfully suppressed the expression of NF-κß, Nrf2, iNOS, and p53 in lung tissues besides the inhibition of other oxidative stress and inflammatory mediators. Amitriptyline could be a promising treatment to pulmonary fibrosis. Amitriptyline not only prevents the depression and its drawbacks in patients suffering from pulmonary fibrosis but also it can suppress fibrosis through variable mechanisms mainly via inhibition of NF-κß/TNF-α/TGF-ß pathway in addition to inhibition of Nrf2 and iNOS expression.

Eicosapentaenoic Acid and Vitamin E Against Doxorubicin Induced Cardiac and Renal Damages: Role of Cytochrome c and iNOS.

BACKGROUND: The current study aimed to evaluate the mechanisms involved in protection against doxorubicin-induced cardiac and renal toxicities upon treatment with eicosapentaenoic acid and vitamin E. METHODS: Rats were randomly assigned to 4 groups: normal control, doxorubicin inducted control, eicosapentaenoic acid treated group and a final group pretreated with vitamin E. Lipid peroxidation, reduced glutathione (GSH) and tumor necrosis factor-alpha (TNF-α) contents as well as glutathione peroxidase (GPx), superoxide dismutase (SOD) and myeloperoxidase (MPO) activities were assessed. Moreover, hearts were used for immunohistochemical detection of the pro-apoptotic protein cytochrome c expression, while the kidneys were used for detection of inducible nitric oxide synthase (iNOS) expression. RESULTS: Eicosapentaenoic acid and vitamin E produced significant protection from doxorubicin-induced cardiac and renal toxicities. The suggested mechanisms for protection included decreased cytochrome c and iNOS expression as well as markedly decreased lipid peroxides and TNF-α contents accompanied with increased GSH content as compared to the doxorubicin control group. Moreover, there was marked increase in GPx and SOD activities accompanied by significant suppression of MPO activity. CONCLUSION: The present study demonstrated the potent protective effects of eicosapentaenoic acid and vitamin E from doxorubicin induced cardiac and renal toxicities through their potent anti-oxidant, anti-inflammatory and anti-apoptotic properties. Hence, eicosapentaenoic acid and vitamin E could be promising protective agents against doxorubicintoxicity.

Pyrrolidinedithiocarbamate attenuates bleomycin-induced pulmonary fibrosis in rats: Modulation of oxidative stress, fibrosis, and inflammatory parameters.

OBJECTIVE: The current study aimed to investigate the modulatory effects of pyrrolidinedithiocarbamate (PDTC; 100 mg/kg) on bleomycin-induced pulmonary fibrosis (5 mg/kg; intratracheal) in rats. MATERIALS AND METHODS: Rats were randomly assigned to three groups: normal control, bleomycin control, and PDTC-treated groups. Lung injury was evaluated through histological examination, immunohistochemical detection of inducible nitric oxide synthase (iNOS) in lung tissue and evaluating the total and differential leucocytes count in bronchoalveolar lavage fluid. Lung tissue was used for biochemical assessment of lung content of hydroxyproline, transforming growth factor beta-1 (TGF-ß1), tumor necrosis factor-alpha (TNF-α) as well as analysis of lipid peroxides, reduced glutathione (GSH), and total nitrite contents. RESULTS: PDTC attenuated bleomycin-induced pulmonary fibrosis as evidenced by histological observations, decreased iNOS expression and prevention of bleomycin-induced altered total and differential leukocytes count. Additionally, PDTC caused a significant decrease in lung contents of hydroxyproline, TGF-ß1, TNF-α, lipid peroxides, and total nitrite coupled with increase in lung GSH content as compared to bleomycin control group. CONCLUSION: PDTC attenuated bleomycin-induced pulmonary fibrosis in rats via its anti-inflammatory, antioxidant, and antifibrotic activities.