Farag, M. M., H. B. El-Nassan, H. A. Merey, B. M. Eltanany, M. M. Galal, W. Wadie, D. M. El-Tanbouly, M. A. Khattab, L. A. Rashed, and A. N. ElMeshad, "Comparative pharmacodynamic study delineating the efficacy of amantadine loaded nano-emulsified organogel via intranasal versus transdermal route in rotenone-induced Parkinson ", Journal of Drug Delivery Science and Technology, vol. 86, pp. 104765, 2023.
Abdel-Latif, R. T., W. Wadie, Y. Abdel-Mottaleb, D. M. Abdallah, N. N. El-Maraghy, and H. S. El-Abhar, "Reposition of the anti-inflammatory drug diacerein in an colorectal cancer model.", Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society, vol. 30, issue 1, pp. 72-90, 2022. Abstract

Excessive interleukin (IL)-6 production is a driver for malignancy and drug resistance in colorectal cancer (CRC). Our study investigated a seven-week post-treatment with the anti-inflammatory drug, Diacerein (Diac), alone or in combination with 5-fluorouracil (5-FU), using a 1,2-dimethylhydrazine (DMH) rat model of CRC. Diac alone and 5-FU+Diac reduced serum levels of carcino-embryonic antigen (CEA), while all regimens decreased serum levels of colon cancer-specific antigen (CCSA), a more specific CRC biomarker. Additionally, Diac, 5-FU and their combination suppressed colonic content/gene expression of IL-6, its downstream oncogene, Kirsten rat sarcoma viral oncogene homolog (K-Ras), and consequently Notch intracellular domain and nuclear factor-kappa B (NF-κB) p65. In turn, NF-κB downstream factors, , matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF), c-Myc, and B-cell lymphoma-2 (Bcl-2) were also downregulated, while E-cadherin was elevated. Additionally, the drugs reduced the immunoreactivity of CD31 to prove their anti-angiogenic effect, while the TUNEL assay confirmed the apoptotic effect. The apoptotic effect was confirmed by transferase dUTP nick-end labeling assay. Moreover, these drugs inhibited colon content of -Akt, β-catenin, and cyclin D1 immunoreactivity. The drugs also activated the tumor suppressor glycogen synthase kinase 3- β (GSK3-β) and upregulated the expression of the Nur77 gene, which represents the second arm of IL-6 signaling. However, only 5-FU upregulated miR-200a, another K-Ras downstream factor. The cytotoxic and migration/invasion assays verified the molecular trajectories. Accordingly, we evaluated the antineoplastic effect of Diac alone and its possible chemosensitization effect when added to 5-FU. This combination may target critical oncogenic pathways, including the IL-6/K-Ras/Notch/NF-κB p65 axis, -Akt/GSK3-β/β-catenin/cyclin D-1 hub, and Nur77.

Mahmoud, N., M. - E. F. Hegazy, W. Wadie, M. Elbadawi, E. Fleischer, A. Klinger, G. Bringmann, M. T. Khayyal, and T. Efferth, "Naphthoquinone derivatives as P-glycoprotein inducers in inflammatory bowel disease: 2D monolayers, 3D spheroids, and in vivo models.", Pharmacological research, vol. 179, pp. 106233, 2022. Abstract

Inflammatory bowel disease (IBD) represents a chronic inflammation of the gastrointestinal tract characterized by an overreaction of immune responses and damage at the intestinal mucosal barrier. P-glycoprotein (P-gp) plays a key role to protect the intestinal barrier from xenobiotic accumulation and suppressing excessive immune responses. Therefore, induction/activation of P-gp function could serve as a novel therapeutic target to treat IBD. This study aimed to evaluate the potential therapeutic values of naphthoquinone derivatives (NQ-1 - NQ-8) as P-gp modulators to counterbalance intestinal inflammation. The data indicate that NQ-2, NQ-3, and NQ-4 act as P-gp inducers/activators and are recognized as substrates for P-gp. The three derivatives possess anti-inflammatory effects mediated by suppression of NF-κB and HDAC6 activity in Caco2 monolayer cells. Besides, they reversed LPS-induced intestinal barrier dysfunction by enhancing the expression of P-gp and ZO-1 tight junction proteins in a Caco-2 spheroid model. NQ-2, NQ-3, and NQ-4 showed a robust inhibitory effect on IL-1β maturation in LPS-primed THP-1 cells. This effect may contribute to alleviate the inflammatory cascades associated with IBD. Distinctively, NQ-2 and NQ-3 exerted anti-NLRP3 inflammasome activity evidenced by the inhibition of CASP-1 activity and the promotion of autophagy. Both compounds induced disruptions of the microtubule network in transfected U2OS-GFP-α-tubulin cells. Treatment with NQ-2 remarkably attenuated dextran sulfate sodium (DSS)-induced colitis in rats by suppressing changes in colon length, colon mass index, and intestinal histopathology scores. Thus, 1,4-naphthoquinone derivatives such as NQ-2 may provide potential therapeutic anti-inflammatory effects for IBD patients and for other NLRP3-associated inflammatory diseases.

Ibrahim, W. W., R. H. Sayed, E. S. R. A. A. A. KANDIL, and W. Wadie, "Niacin mitigates blood-brain barrier tight junctional proteins dysregulation and cerebral inflammation in ketamine rat model of psychosis: Role of GPR109A receptor.", Progress in neuro-psychopharmacology & biological psychiatry, vol. 119, pp. 110583, 2022. Abstract

Dysregulated inflammatory responses and blood-brain barrier (BBB) dysfunction are recognized as central factors in the development of psychiatric disorders. The present study was designed to evaluate the effect of niacin on BBB integrity in ketamine-induced model of psychosis. Meanwhile, mepenzolate bromide (MPN), a GPR109A receptor blocker, was used to investigate the role of this receptor on the observed niacin's effect. Male Wistar rats received ketamine (30 mg/kg/day, i.p) for 5 consecutive days and then niacin (40 mg/kg/day, p.o), with or without MPN (5 mg/kg/day, i.p), was given for the subsequent 15 days. Three days before the end of experiment, rats were behaviorally tested using open field, novel object recognition, social interaction, and forced swimming tests. Niacin significantly ameliorated ketamine-induced behavioral deficits, amended gamma aminobutyric acid and glutamate concentration, decreased tumor necrosis factor-α and matrix metallopeptidase 9 levels, and increased netrin-1 contents in the hippocampus of rats. Niacin also augmented the hippocampal expression of ZO-1, occludin, and claudin-5 proteins, indicating the ability of niacin to restore the BBB integrity. Moreover, the histopathologic changes in hippocampal neurons were alleviated. Since all the beneficial effects of niacin in the present investigation were partially abolished by the co-administration of MPN; GPR109A receptor was proven to partially mediate the observed antipsychotic effects of niacin. These data revealed that GPR109A-mediated signaling pathways might represent potential targets for therapeutic interventions to prevent or slow the progression of psychosis.

Shendy, H. M., S. S. Mohamed, E. A. Abd El-Haleim, O. Galal, W. Wadie, A. Helal, and M. T. Khayyal, "Rice bran extract mitigates depressive-like behavior in dextran sulfate sodium-induced colitis: Involvement of the gut-brain axis and Sirt1 signaling pathway.", Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, vol. 184, pp. 114386, 2024. Abstract

Inflammatory bowel disease (IBD) patients frequently suffer from depressive disorders as well. The present study was carried out to explore whether treatment with a standardized rice bran extract (RBE) could affect depression-like behavior in rats with dextran sulfate sodium (DSS)-induced colitis. Male Wistar rats were treated with RBE (100 mg/kg/day; p.o.) for 2 weeks. During the second week, colitis was induced by feeding the rats with 5 % (w/v) DSS in drinking water. RBE protected against DSS-induced body weight loss as well as against the macro- and microscopic inflammatory changes of the colon. Additionally, RBE mitigated DSS-induced dysregulation in blood-brain barrier tight junctional proteins, preserved the hippocampal histopathological architecture and improved the animal behavior in the forced swimming test. This was associated with modulation of hippocampal oxidative stress marker; GSH as well as hippocampal pro-inflammatory mediators; NF-ĸB and IL-1β. Treatment with RBE also led to a profound increase in the hippocampal levels of Sirt1, PGC-1α, Nrf2, and HO-1, which were drastically dropped by DSS. In conclusion, the study revealed the protective effect of RBE against DSS-induced depressive-like behavior through modulation of different parameters along the gut-brain axis and up-regulated the Sirt1/PGC-1α/Nrf2/HO-1 signaling pathway.

Wadie, W., G. S. Ahmed, A. M. A. N. I. N. SHAFIK, and M. El-Sayed, "Effects of insulin and sitagliptin on early cardiac dysfunction in diabetic rats.", Life sciences, vol. 299, pp. 120542, 2022. Abstract

AIMS: Cardiac affection is common in diabetic patients. Although insulin exerts a cardioprotective role, it may not be enough to totally prevent this affection. The current study aimed to compare the cardioprotective effect of insulin alone or combined with sitagliptin in a rat model of type 1 diabetes mellitus.

MATERIALS AND METHODS: Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ; 60 mg/kg). Diabetic rats were treated with insulin (3 IU), insulin (6 IU), or insulin (3 IU) + sitagliptin (10 mg/kg) for 42 days.

KEY FINDINGS: Diabetic rats exhibited significant systolic and diastolic cardiac affection with significant elevation of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6) and brain natriuretic peptide (BNP) levels. Treatment with insulin prevented the deterioration of diabetes-induced cardiac condition, an effect that was significantly potentiated by the combined use of sitagliptin.

SIGNIFICANCE: The combined use of sitagliptin and insulin significantly improved the cardioprotective effect of insulin and prevented the early cardiac dysfunction in STZ diabetic rats.

Wadie, W., S. S. Mohamed, E. A. Abd El-Haleim, and M. T. Khayyal, "Niacin modulates depressive-like behavior in experimental colitis through GPR109A-dependent mechanisms.", Life sciences, vol. 330, pp. 122004, 2023. Abstract

AIMS: Depression is one of the common neurological comorbidities in patients with inflammatory bowel disease (IBD). The current study aimed to investigate the potential impact of niacin on colitis-induced depressive-like behavior in rats.

MATERIALS AND METHODS: Animals were given 5 % dextran sulfate sodium (DSS) in drinking water for one week to induce colitis. Niacin (80 mg/kg), with or without mepenzolate bromide (GPR109A blocker), was administered once per day throughout the experimental period. Rats were tested for behavioral changes using open field and forced swimming tests.

KEY FINDINGS: Niacin significantly ameliorated DSS-induced behavioral deficits and alleviated macroscopic and microscopic colonic inflammatory changes. It also augmented the hippocampal levels of ZO-1, occludin, and claudin-5 proteins, indicating the ability of niacin to restore the blood-brain barrier (BBB) integrity. Moreover, niacin decreased hippocampal IL-1ꞵ and NF-ĸB contents but increased GSH, Sirt-1, Nrf-2, HO-1 concentrations. All these beneficial effects were partially abolished by the co-administration of mepenzolate bromide.

SIGNIFICANCE: The neuroprotective effect of niacin against DSS-induced depressive-like behavior was partially mediated through GPR109A-mediated mechanisms. Such mechanisms are also involved in modulating neuronal oxidative stress and inflammation via Sirt-1/Nrf-2/HO-1 signaling pathways.

Zaky, D. A., W. Wadie, W. M. Eldehna, A. M. El Kerdawy, D. M. Abdallah, and H. S. El Abhar, "Modulation of endoplasmic reticulum stress response in gut-origin encephalopathy: Impact of vascular endothelial growth factor receptor-2 manipulation.", Life sciences, vol. 252, pp. 117654, 2020. Abstract

BACKGROUND: Septic encephalopathy, the most frequent complication of sepsis, is orchestrated by a complex interplay of signals that leads to high mortality rates among intensive care unit patients. However, the role of the vascular endothelial growth factor receptor-2 (VEGFR2) in endoplasmic reticulum stress response (ERSR), during septic encephalopathy, is still elusive.

AIM: This study was aimed to examine the effect of an in-house designed/synthesized VEGFR2 antagonist, named WAG4S, on septic encephalopathy using cecal ligation and perforation (CLP).

MAIN METHODS: Rats were intraperitoneally injected with WAG-4S (1 mg/kg/d) for 7 days post-CLP.

KEY FINDINGS: In septic animals, VEGFR2 antagonism declined the expression of cortical p-VEGFR2 and p-mammalian target of rapamycin complex-1 (p-mTORC1). It also worsened the behavioral and histopathological alterations beyond CLP. However, and contrary to CLP, WAG-4S decreased the p-protein kinase R-like ER kinase (p-PERK) and eukaryotic initiation factor-2α (p-eIF2α) expression. Moreover, VEGFR2 blockade upregulated the mRNA expression of activating transcription factor-4 (ATF4), binding immunoglobulin protein/glucose-regulated protein-78 (Bip/GRP78), growth arrest and DNA damage-34 (GADD34) and spliced X-box binding protein-1 (XBP1s) above CLP. Similarly, it boosted inositol requiring enzyme-1α (IRE1α) activation and redox imbalance. In the same context, WAG-4S augmented the protein levels of CLP-induced ERSR apoptotic markers, namely C/EBP homologous protein (CHOP/GADD153), c-jun N-terminal kinase (JNK) and caspase-3.

SIGNIFICANCE: In conclusion, the PERK/eIF2α axis inhibition, during septic encephalopathy, is VEGFR2-independent, whereas the activated IRE1α/XBP1s/CHOP/JNK/caspase-3 cue promotes the ERSR execution module through VEGFR2 inhibition. This has turned VEGFR2 into a potential therapeutic target for ameliorating such an ailment.

Wadie, W., A. H. Mohamed, M. A. Masoud, H. A. Rizk, and H. M. Sayed, "Protective impact of lycopene on ethinylestradiol-induced cholestasis in rats.", Naunyn-Schmiedeberg's archives of pharmacology, vol. 394, issue 3, pp. 447-455, 2021. Abstract

Protection against cholestasis and its consequences are considered an essential issue to improve the quality of a patient's life and reduce the number of death every year from liver diseases. Lycopene, a natural carotenoid, has antioxidant scavenger capacity and inhibits inflammation in many experimental models. The present study aimed to elucidate the potential protective effects of lycopene, in comparison to silymarin, in a rat model of cholestatic liver. Animals were daily injected with 17α-ethinylestradiol (EE; 5 mg/kg) for 18 successive days. Silymarin (100 mg/kg) and lycopene (10 mg/kg) were orally administered once per day through the experimental period. Lycopene significantly decreased the EE-induced rise in the serum levels of total bile acid and total bilirubin as well as the activities of alanine aminotransaminase, aspartate aminotransaminase, alkaline phosphatase, and gamma-glutamyl transaminase. Moreover, lycopene reduced the hepatic levels of thiobarbituric acid reactive substances and tumor necrosis factor-α as well as the hepatic activity of myeloperoxidase that were markedly elevated by EE. Lycopene increased the hepatic levels of total protein and albumin and reduced glutathione. In addition, lycopene improved the hepatic histopathological changes induced by EE. These protective effects of lycopene were comparable to that of silymarin. In conclusion, lycopene was effective in protecting against estrogen-induced cholestatic liver injury through its antioxidant and anti-inflammatory activities. Therefore, lycopene might be a potentially effective drug for protection against cholestasis in susceptible women during pregnancy, administration of oral contraceptives, or postmenopausal replacement therapy.

Mohamed, S. S., N. F. Abdeltawab, W. Wadie, L. A. Ahmed, R. M. Ammar, S. Rabini, H. Abdel-Aziz, and M. T. Khayyal, "Effect of the standard herbal preparation, STW5, treatment on dysbiosis induced by dextran sodium sulfate in experimental colitis.", BMC complementary medicine and therapies, vol. 21, issue 1, pp. 168, 2021. Abstract

BACKGROUND: The standardized herbal preparation, STW 5, is effective clinically in functional gastrointestinal disorders and experimentally in ulcerative colitis (UC). The present study explores whether the beneficial effect of STW 5 involves influencing the intestinal microbiota.

METHODS: UC was induced in Wistar rats by feeding them 5% dextran sodium sulfate (DSS) in drinking water for 7 days. Rats were treated concurrently with STW 5 and sacrificed 24 h after last drug administration. Fecal samples were used to determine changes in the abundance of selected microbial phyla and genera using real-time PCR.

RESULTS: Induction of UC led to dysbiosis and changes in the gut microbiota. The changes included an increase in some genera of the Firmicutes, namely Enterococcus, and a decrease in others, namely Blautia, Clostridium, and Lactobacillus. DSS further induced a marked increase in the abundance of Bacteroidetes and Proteobacteria as well as in the relative abundance of Actinobacteria and its genus Bifidobacterium. Methanobrevibacter levels (phylum Euryarchaeota) were also increased. Microbial dysbiosis was associated with changes in various parameters of colonic inflammation. STW 5 effectively guarded against those changes and significantly affected the indices of edema and inflammation in the UC model. Changes in colon length, colon mass index, inflammatory and apoptotic markers, and histological changes induced by DSS were also prevented.

CONCLUSIONS: Dysbiosis plays a contributing role in the development of DSS-induced UC. Derangements in the microbial flora and associated inflammatory processes were largely prevented by STW 5, suggesting that this effect might contribute towards its beneficial usefulness in this condition.

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