Mansour, S. M., R. N. Shamma, K. A. Ahmed, N. A. Sabry, G. Esmat, A. A. Mahmoud, and A. Maged, "Safety of inhaled ivermectin as a repurposed direct drug for treatment of COVID-19: A preclinical tolerance study.", International immunopharmacology, vol. 99, pp. 108004, 2021. Abstract

INTRODUCTION: SARS-CoV-2 replication in cell cultures has been shown to be inhibited by ivermectin. However, ivermectin's low aqueous solubility and bioavailabilityhinders its application in COVID-19 treatment. Also, it has been suggested that best outcomes for this medication can be achieved via direct administration to the lung.

OBJECTIVES: This study aimed at evaluating the safety of a novel ivermectin inhalable formulation in rats as a pre-clinical step.

METHODS: Hydroxy propyl-β-cyclodextrin(HP-β-CD) was used to formulate readily soluble ivermectin lyophilized powder. Adult male rats were used to test lung toxicity for ivermectin-HP-β-CD formulations in doses of 0.05, 0.1, 0.2, 0.4 and 0.8 mg/kg for 3 successive days.

RESULTS: The X-ray diffraction for lyophilized ivermectin-HP-β-CD revealed its amorphous structure that increased drug aqueous solubility 127-fold and was rapidly dissolved within 5 s in saline.Pulmonary administration of ivermectin-HP-β-CD in dosesof 0.2, 0.4 and 0.8 mg/kgshowed dose-dependent increase in levels of TNF-α, IL-6, IL-13 and ICAM-1 as well as gene expression of MCP-1, protein expression of PIII-NP and serum levels of SP-D paralleled by reduction in IL-10. Moreover, lungs treated with ivermectin (0.2 mg/kg) revealed mild histopathological alterations, while severe pulmonary damage was seen in rats treated with ivermectin at doses of 0.4 and 0.8 mg/kg. However, ivermectin-HP-β-CD formulation administered in doses of 0.05 and 0.1 mg/kg revealed safety profiles.

CONCLUSION: The safety of inhaledivermectin-HP-β-CD formulation is dose-dependent. Nevertheless, use of low doses(0.05 and 0.1 mg/kg) could be considered as a possible therapeutic regimen in COVID-19 cases.

Yacoub, A. S., H. O. Ammar, M. Ibrahim, S. M. Mansour, and N. M. El Hoffy, "Artificial intelligence-assisted development of forming nanoparticles for arthritis therapy via intra-articular delivery.", Drug delivery, vol. 29, issue 1, pp. 1423-1436, 2022. Abstract

Intra-articular (IA) injection is grasping much interest due to the poor drug bioavailability at the targeted site of action which minimizes the effect of the orally administered moiety. Based on the integral role of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of Rheumatoid Arthritis (RA), much effort is exerted to develop novel localized drug delivery systems to increase their bioavailability and minimize their side effects. Artificial intelligence (AI) is acquiring an increasing role in the design of experiments being an effective tool for saving both time and resources. Hence, the aim of this work was to develop, characterize and optimize targeted forming nano particles (ISNs) for IA delivery of piroxicam using Design Expert as an AI-based application where a 3 full factorial experimental design was adopted. Morphological investigation, injectability, rheological studies, Fourier Transform Infrared Radiation (FTIR) as well as biological, histopathological, and biochemical examinations were performed to evaluate the optimized-ISNs. The optimized formulation, exhibiting a nano-sized particle size with a dense core, showed significant improvement in the histopathological findings compared to both the oral solution and the placebo. Additionally, the once-a-week IA administration of the optimized-ISNs proved a significant reduction in the protein expression of both STAT-3 and RANKL and the levels of anti-CCP and MCP-1 by almost 54 and 73%, respectively, coupled with a marked decline in the content of IL-17, MMP-3, NF-κB and TNF-α as compared to the positive control. In conclusion, the use of ISNs for intra-articular injection has demonstrated their effectiveness in piroxicam delivery for RA treatment.

Hamouda, H. A., S. M. Mansour, and M. F. Elyamany, "Vitamin D Combined with Pioglitazone Mitigates Type-2 Diabetes-induced Hepatic Injury Through Targeting Inflammation, Apoptosis, and Oxidative Stress.", Inflammation, vol. 45, issue 1, pp. 156-171, 2022. Abstract

Inflammation is a major pathophysiological factor in development of type-2 diabetes mellitus (T2DM). Vitamin D (VITD) plays an imperative role in modulation of several inflammatory responses. The current study aimed to investigate the possible beneficial effects of coadministration of VITD with pioglitazone (PIO), a PPAR-γ agonist, in fructose/streptozotocin (F/STZ) T2DM model in male Wistar rats. T2DM was induced by maintaining rats on 10% (w/v) fructose in drinking water for 9 weeks with an intraperitoneal injection of sub-diabetogenic dose of STZ (35 mg/kg) by the end of the fourth week. One week after STZ injection, PIO (10 mg/kg/day) alone or with VITD (500 IU/kg/day) was administered orally to diabetic rats till the end of the experiment. Blood samples were collected, livers were homogenized to determine biochemical parameters, and samples of livers were fixed in 10% formalin in saline for histological examination. Administration of PIO alone improved diabetes-induced inflammatory and oxidative states besides controlling hyperglycemia and decreasing apoptosis. Coadministration of VIT D with PIO promoted additional improvement in glycemic and lipid profiles, provided further control on diabetic-induced hepatic inflammation evident by downregulating TLR2, TLR4, and IKK-β while upregulating IκB-α expression and reducing inflammatory cytokines namely; NF-κB, TNF-α, IL-6, and IL-1β, decreasing apoptosis and oxidative stress by hampering caspase-3 and MDA contents, respectively, and improved liver histology than PIO alone. These beneficial effects of VIT D may expand its use by diabetics combined with antidiabetic drugs due to its anti-inflammatory, antioxidant, and antiapoptotic properties.

Mansour, S. M., S. A. Abd El-Aal, H. S. El-Abhar, K. A. Ahmed, and M. M. Awny, "Repositioning of Ticagrelor: Renoprotection mediated by modulating renin-angiotensin system, inflammation, autophagy and galectin-3.", European journal of pharmacology, vol. 918, pp. 174793, 2022. Abstract

Aside from being an antiplatelet, ample studies revealed the anti-ischemic cardioprotective effect of Ticagrelor (Tica) mediated via different mechanisms; however, its protective potential against renal ischemia reperfusion (I/R) has been rarely investigated, which is the aim of the current study. Animals were divided into sham, I/R (45 min/24 h) and I/R pretreated with Tica (30 mg/kg) for one week, after a pilot study using 30 and 150 mg/kg of Tica. The pre-administration of Tica (30 mg/kg) guarded against the harmful impact of I/R insult and improved renal histological structure and function validated by reducing cystatin-C, neutrophil gelatinase-associated lipocalin, interleukin-18 and the classical markers, blood urea nitrogen and creatinine. On the molecular level, Tica signified its anti-inflammatory capacity by inhibiting nuclear factor κB and tumor necrosis factor-α, while it enhanced the autophagy process evidenced by increasing the protein expression of Beclin-1 and microtubule-associated protein light chain 3 II and abating the lysosomal marker cathepsin-D. Besides, Tica augmented cell survival by inhibiting galectin-3 and caspase-3 activity. Additionally, Tica modulated the renin-angiotensin system (RAS), where it decreased angiotensin II and downregulated the gene expression of prorenin and endothelin-1 receptors, but increased the activity of angiotensin converting enzyme-2 and the renal content of angiotensin 1-7. Our study is the first to highlight the renal anti-ischemic potential of Tica via enhancing autophagy, modulating the RAS, and decreasing both inflammation and cell demise.

Salem, M. A., B. Budzyńska, J. Kowalczyk, N. S. El Sayed, and S. M. Mansour, "Tadalafil and bergapten mitigate streptozotocin-induced sporadic Alzheimer's disease in mice via modulating neuroinflammation, PI3K/Akt, Wnt/β-catenin, AMPK/mTOR signaling pathways.", Toxicology and applied pharmacology, vol. 429, pp. 115697, 2021. Abstract

Sporadic Alzheimer's disease (SAD) is a slowly progressive neurodegenerative disorder. This study aimed to investigate neuroprotective potential of tadalafil (TAD) and bergapten (BG) in SAD-induced cognitive impairment in mice. SAD was induced by single injection of streptozotocin (STZ; 3 mg/kg, ICV). STZ resulted in AD-like pathologies including Aβ deposition, tau aggregation, impaired insulin and Wnt/β-catenin signaling, as well as autophagic dysfunction and neuroinflammation. Administration of TAD or BG at doses of 20 and 25 mg/kg, respectively, for 21 consecutive days attenuated STZ-induced hippocampal insult, preserved neuronal integrity, and improved cognitive function in the Morris water maze and object recognition tests paralleled by reduction in Aβ expression by 79 and 89% and tau hyperphosphorylation by 60 and 61%, respectively. TAD and BG also enhanced protein expression of pAkt, pGSK-3β, beclin-1 and methylated protein phosphatase 2A (PP2A) and gene expression of cyclin D1, while raised BDNF immunoreactivity. Furthermore, TAD and BG boosted hippocampal levels of cGMP, PKG, Wnt3a, and AMPK and reduced expression of β-catenin and mTOR by 74% and 51%, respectively. TAD and BG also halted neuroinflammation by reducing IL-23 and IL-27 levels, as well as protein expression of NF-κB by 62% & 61%, respectively. In conclusion, this study offers novel insights on the neuroprotective effects of TAD or BG in the management of SAD as evidenced by improved cognitive function and histological architecture. This could be attributed to modulation of the crosstalk among PI3K/Akt/GSK-3β, PP2A, mTOR/autophagy, cGMP/PKG, and Wnt/β-catenin signaling cascades and mitigation of neuroinflammation.

Mohammed, R. A., and S. M. Mansour, "Sodium hydrogen sulfide upregulates cystathionine β-synthase and protects striatum against 3-nitropropionic acid-induced neurotoxicity in rats.", The Journal of pharmacy and pharmacology, vol. 73, issue 3, pp. 310-321, 2021. Abstract

OBJECTIVES: Hydrogen sulfide (H2S) is a neuromodulator that plays a protective role in multiple neurodegenerative diseases including Alzheimer's (AD) and Parkinson's (PD). However, the precise mechanisms underlying its effects against Huntington's disease (HD) are still questioned.This study aimed to examine the neuroprotective effects of sodium hydrogen sulfide (NaHS; H2S donor) against 3-nitropropionic acid (3NP)-induced HD like pathology in rats. Methods: Male Wistar rats were randomly allocated into four groups; (1) normal control receiving saline; (2) NaHS control receiving (0.5 mg/kg/day, i.p.) for 14 days; (3,4) receiving 3NP (10 mg/kg/day, i.p.) for 14 days, with NaHS 30 min later in group 4.

KEY FINDINGS: NaHS improved cognitive and locomotor deficits induced by 3NP as confirmed by the striatal histopathological findings. These former events were biochemically supported by the increment in cystathionine β-synthase (CBS) gene expression, reduction of glutamate (Glu), dopamine (DA), malondialdehyde (MDA), tumour necrosis factor-alpha (TNF-α), cytochrome-c, cleaved caspase-3 and pc-FOS indicating antioxidant, anti-inflammatory as well as anti-apoptotic effects. Furthermore, NaHS pretreatment improved cholinergic dysfunction and increased brain-derived neurotropic factor (BDNF) and nuclear factor erythroid-2-related factor 2 (Nrf2).

CONCLUSIONS: These findings suggest that appropriate protection with H2S donors might represent a novel approach to slow down HD-like symptoms.

Mansour, S. M., S. Aly, S. H. M. Hassan, and H. F. Zaki, "Protective effect of sitagliptin and whole-body γ-irradiation in diabetes-induced cardiac injury", Can J Physiol Pharmacol ., 2021.
Shahin, H., B. P. Vinjamuri, A. A. Mahmoud, S. M. Mansour, M. B. Chougule, and L. Chablani, "Formulation and optimization of sildenafil citrate-loaded PLGA large porous microparticles using spray freeze-drying technique: A factorial design and in-vivo pharmacokinetic study.", International journal of pharmaceutics, vol. 597, pp. 120320, 2021. Abstract

The oral administration of sildenafil citrate (SC) for the treatment of pulmonary arterial hypertension is associated with several drawbacks. The study aimed to design and formulate SC-loaded inhalable poly (lactic-co-glycolic acid) [PLGA] large porous microparticles (LPMs) for pulmonary delivery. A factorial design was used to study the effect of the composition of LPMs on physicochemical properties. The study also evaluated the effect of glucose and L-leucine concentration on the formulation. The developed LPMs demonstrated an acceptable yield% (≤48%), large geometric particle size (>5µm) with a spherical and porous surface, and sustained drug release (up to 48 h). Increasing the concentration of poly(ethyleneimine) from 0.5% to 1% in SC-loaded LPMs led to an increase in entrapment efficiency from ~3.02% to ~94.48%. The optimum LPMs showed adequate aerodynamic properties with a 97.68 ± 1.07% recovery, 25.33 ± 3.32% fine particle fraction, and low cytotoxicity. Intratracheal administration of LPMs demonstrated significantly higher lung deposition, systemic bioavailability, and longer retention time (p < 0.05) compared to orally administered Viagra® tablets. The study concluded that SC-loaded LPMs could provide better therapeutic efficacy, reduced dosing frequency, and enhanced patient compliance.

Mohammed, R. A., and S. M. Mansour, "Sodium hydrogen sulfide upregulates cystathionine β-synthase and protects striatum against 3-nitropropionic acid-induced neurotoxicity in rats.", The Journal of pharmacy and pharmacology, vol. 73, issue 3, pp. 310-321, 2021. Abstract

OBJECTIVES: Hydrogen sulfide (H2S) is a neuromodulator that plays a protective role in multiple neurodegenerative diseases including Alzheimer's (AD) and Parkinson's (PD). However, the precise mechanisms underlying its effects against Huntington's disease (HD) are still questioned.This study aimed to examine the neuroprotective effects of sodium hydrogen sulfide (NaHS; H2S donor) against 3-nitropropionic acid (3NP)-induced HD like pathology in rats. Methods: Male Wistar rats were randomly allocated into four groups; (1) normal control receiving saline; (2) NaHS control receiving (0.5 mg/kg/day, i.p.) for 14 days; (3,4) receiving 3NP (10 mg/kg/day, i.p.) for 14 days, with NaHS 30 min later in group 4.

KEY FINDINGS: NaHS improved cognitive and locomotor deficits induced by 3NP as confirmed by the striatal histopathological findings. These former events were biochemically supported by the increment in cystathionine β-synthase (CBS) gene expression, reduction of glutamate (Glu), dopamine (DA), malondialdehyde (MDA), tumour necrosis factor-alpha (TNF-α), cytochrome-c, cleaved caspase-3 and pc-FOS indicating antioxidant, anti-inflammatory as well as anti-apoptotic effects. Furthermore, NaHS pretreatment improved cholinergic dysfunction and increased brain-derived neurotropic factor (BDNF) and nuclear factor erythroid-2-related factor 2 (Nrf2).

CONCLUSIONS: These findings suggest that appropriate protection with H2S donors might represent a novel approach to slow down HD-like symptoms.

Mansour, S. M., H. S. El-Abhar, and A. A. Soubh, "MiR-200a inversely correlates with Hedgehog and TGF-β canonical/non-canonical trajectories to orchestrate the anti-fibrotic effect of Tadalafil in a bleomycin-induced pulmonary fibrosis model.", Inflammopharmacology, vol. 29, issue 1, pp. 167-182, 2021. Abstract

Few reports have documented the ability of phosphodiesterase-5 inhibitors (PDE-5-Is) to ameliorate idiopathic pulmonary fibrosis (IPF) mainly by their anti-inflammatory/antioxidant capacities, without unveiling the possible molecular mechanisms involved. Because of the recent role of miR-200 family and Sonic Hedgehog (SHH) trajectory in IPF, we have studied their impact on the anti-fibrotic potential of tadalafil against bleomycin-induced pulmonary fibrosis. Animals were allocated into normal-control, bleomycin-fibrotic control, and bleomycin post-treated with tadalafil or dexamethasone, as the reference drug. On the molecular level, tadalafil has reverted the bleomycin effect on all the assessed parameters. Tadalafil upregulated the gene expression of miR-200a, but decreased the smoothened (SMO) and the transcription factors glioma-associated oncogene homolog (Gli-1, Gli-2), members of SHH pathway. Additionally, tadalafil ebbed transforming growth factor (TGF)-β, its canonical (SMAD-3/alpha smooth muscle actin [α-SMA] and Snail), and non-canonical (p-Akt/p-Forkhead box O3 (FOXO3) a) pathways. Besides, a strong negative correlation between miR-200a and the analyzed pathways was proved. The effect of tadalafil was further confirmed by the improved lung structure and the reduced Ashcroft score/collagen deposition. The results were comparable to that of dexamethasone. In conclusion, our study has highlighted the involvement of miR-200a in the anti-fibrotic effect of tadalafil with the inhibition of SHH hub and the pro-fibrotic pathways (TGF-β/ SMAD-3/α-SMA, Snail and p-AKT/p-FOXO3a). Potential anti-fibrotic effect of tadalafil. Modulation of miR200a/SHH/canonical and non-canonical TGF-β trajectories. → : stimulatory effect; ┴: inhibitory effect.

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