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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.

Shawki, S. M., M. A. Saad, R. M. Rahmo, W. Wadie, and H. S. El-Abhar, "Liraglutide Improves Cognitive and Neuronal Function in 3-NP Rat Model of Huntington's Disease.", Frontiers in pharmacology, vol. 12, pp. 731483, 2021. Abstract

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disease characterized by progressive motor, psychiatric, and cognitive abnormalities. The antidiabetic drug liraglutide possesses a neuroprotective potential against several neurodegenerative disorders; however, its role in Huntington's disease (HD) and the possible mechanisms/trajectories remain elusive, which is the aim of this work. Liraglutide (200 μg/kg, s.c) was administered to rats intoxicated with 3-nitropropionic acid (3-NP) for 4 weeks post HD model induction. Liraglutide abated the 3-NP-induced neurobehavioral deficits (open field and elevated plus maze tests) and histopathological changes. Liraglutide downregulated the striatal mRNA expression of HSP 27, PBR, and GFAP, while it upregulated that of DARPP32. On the molecular level, liraglutide enhanced striatal miR-130a gene expression and TrKB protein expression and its ligand BDNF, while it reduced the striatal protein content and mRNA expression of the death receptors sortilin and p75NTR, respectively. It enhanced the neuroprotective molecules cAMP, p-PI3K, p-Akt, and p-CREB, besides modulating the -GSK-3β/-β-catenin axis. Liraglutide enhanced the antioxidant transcription factor Nrf2, abrogated TBARS, upregulated both Bcl2 and Bcl-XL, and downregulated Bax along with decreasing caspase-3 activity. Therefore, liraglutide exerts a neurotherapeutic effect on 3-NP-treated rats that is, besides the upturn of behavioral and structural findings, it at least partially, increased miR-130a and modulated PI3K/Akt/CREB/BDNF/TrKB, sortilin, and p75NTR, and Akt/GSK-3β/-β-catenin trajectories besides its capacity to decrease apoptosis and oxidative stress, as well as its neurotrophic activity.

Wadie, W., N. S. Abdel-Razek, and H. A. Salem, "Phosphodiesterase (1, 3 & 5) inhibitors attenuate diclofenac-induced acute kidney toxicity in rats.", Life sciences, vol. 277, pp. 119506, 2021. Abstract

Diclofenac, one of the most commonly used non-steroidal anti-inflammatory drugs, leads to severe adverse effects on the kidneys. The aim of the present study was to investigate the potential pretreatment effect of phosphodiesterase (1, 3 & 5) inhibitors on diclofenac-induced acute renal failure in rats. Rats orally received pentoxifylline (100 mg/kg), vinpocetine (20 mg/kg), cilostazol (50 mg/kg), or sildenafil (5 mg/kg) once per day for 6 consecutive days. Diclofenac (15 mg/kg) was injected on day-4, -5 and -6 in all groups except normal control group. The used phosphodiesterase inhibitors significantly reduced the diclofenac-induced elevation in the serum levels of blood urea nitrogen, creatinine and cystatin C. Moreover, the renal tissue contents of tumor necrosis factor (TNF)-α, nuclear factor (NF)-κB as well as the protein expression of toll-like receptor (TLR) 4 and high mobility group box (HMGB) 1 were markedly reduced by the used phosphodiesterase inhibitors, as compared to the diclofenac control. This was reflected on the marked improvement in histopathological changes induced by diclofenac. Sildenafil showed the best protection regarding TNF-α and NF-κB, while cilostazol showed the best results regarding TLR4, HMGB1 and histopathological examination. This study revealed the good protective effect of these phosphodiesterase inhibitors against diclofenac-induced acute renal failure.

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.

Zaky, D. A., W. M. Eldehna, A. M. El Kerdawy, D. M. Abdallah, H. S. El Abhar, and W. Wadie, "Recombinant human growth hormone improves the immune status of rats with septic encephalopathy: The role of VEGFR2 in the prevalence of endoplasmic reticulum stress repair module.", International immunopharmacology, vol. 101, issue Pt B, pp. 108370, 2021. Abstract

Septic encephalopathy results from the intense reaction of the immune system to infection. The role of growth hormone (GH) signaling in maintaining brain function is well established; however, the involvement of the vascular endothelial growth factor receptor-2 (VEGFR2) in the potential modulatory effect of GH on septic encephalopathy-associated endoplasmic reticulum stress (ERS) and blood-brain barrier (BBB) permeability is not well-understood. Therefore, after the induction of mid-grade sepsis by cecal ligation/perforation, rats were subcutaneously injected with recombinant human GH (rhGH)/somatropin alone or preceded by the VEGFR2 antagonist WAG-4S for 7 days. rhGH/somatropin reduced bodyweight loss and plasma endotoxin, maintained the hyperthermic state, and improved motor/memory functions. Additionally, rhGH/somatropin increased the junctional E-cadherin and β-catenin pool in the cerebral cortex to enhance the BBB competency, effects that were abolished by VEGFR2 blockade. Also, it activated cortical VEGFR2/mammalian target of the Rapamycin (mTOR) axis to mitigate ERS. The latter was reflected by the deactivation of the inositol-requiring enzyme-1α (IRE1α)/spliced X-box binding protein-1 (XBP1s) trajectory and the reduction in the protein levels of the death markers, C/EBP homologous protein (CHOP)/growth arrest and DNA damage-153 (GADD153), c-jun-N-terminal kinase (JNK), and caspase-3 with the simultaneous augmentation of expression of the unfolded protein response transducer proteinkinaseR-like ERkinase (PERK). Furthermore, rhGH/somatropin suppressed the phosphorylation of eukaryotic initiation factor-2α (eIF2α), upregulated the gene expression of activating transcription factor-4 (ATF4), GADD34, and glucose-regulated protein-78/binding immunoglobulin (GRP78/Bip). Moreover, it increased the glutathione level and reduced lipid peroxidation in the cerebral cortex. The VEGFR2 antagonist reversed the effect of rhGH/somatropin on PERK and IRE1α and boosted the apoptotic markers but neither affected p-eIF2α nor GADD34. Hence, we conclude that VEGFR2 activation by rhGH/somatropin plays a crucial role in assembling the BBB adherens junctions via its antioxidant capacity, ERS relief, and reducing endotoxemia in septic encephalopathy.

Al-Shorbagy, M. Y., W. Wadie, and D. M. El-Tanbouly, "Trimetazidine Modulates Mitochondrial Redox Status and Disrupted Glutamate Homeostasis in a Rat Model of Epilepsy.", Frontiers in pharmacology, vol. 12, pp. 735165, 2021. Abstract

Mitochondrial oxidative status exerts an important role in modulating glia-neuron interplay during epileptogenesis. Trimetazidine (TMZ), a well-known anti-ischemic drug, has shown promising potential against a wide range of neurodegenerative disorders including epilepsy. Nevertheless, the exact mechanistic rationale behind its anti-seizure potential has not been fully elucidated yet. Herein, the impact of TMZ against mitochondrial oxidative damage as well as glutamate homeostasis disruption in the hippocampus has been investigated in rats with lithium/pilocarpine (Li/PIL) seizures. Animals received 3 mEq/kg i.p. LiCl followed by PIL (single i.p.; 150 mg/kg) 20 h later for induction of seizures with or without TMZ pretreatment (25 mg/kg; i.p.) for five consecutive days. Seizure score and seizure latency were observed. Mitochondrial redox status as well as ATP and uncoupling protein 2 was recorded. Moreover, glutamate homeostasis was unveiled. The present findings demonstrate the TMZ-attenuated Li/PIL seizure score and latency. It improved mitochondrial redox status, preserved energy production mechanisms, and decreased reactive astrocytes evidenced as decreased glial fibrillary acidic protein immune-stained areas in hippocampal tissue. In addition, it modulated phosphorylated extracellular signal-regulated kinases (-ERK1/2) and p-AMP-activated protein kinase (-AMPK) signaling pathways to reflect a verified anti-apoptotic effect. Consequently, it upregulated mRNA expression of astroglial glutamate transporters and reduced the elevated glutamate level. The current study demonstrates that TMZ exhibits robust anti-seizure and neuroprotective potentials. These effects are associated with its ability to modulate mitochondrial redox status, boost -ERK1/2 and -AMPK signaling pathways, and restore glutamate homeostasis in hippocampus.

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.

Ibrahim, A. B., H. F. Zaki, W. W. Ibrahim, M. M. Omran, and S. A. Shouman, "Evaluation of tamoxifen and simvastatin as the combination therapy for the treatment of hormonal dependent breast cancer cells.", Toxicology reports, vol. 6, pp. 1114-1126, 2019. Abstract

Tamoxifen (TAM) is a nonsteroidal antiestrogen drug, used in the prevention and treatment of all stages of hormone-responsive breast cancer. Simvastatin (SIM), a lipid-lowering agent, has been shown to inhibit cancer cell growth. The study aimed at investigating the impact of using SIM with TAM in estrogen receptor-positive (ER+) breast cancer cell line, T47D, as well as in mice-bearing Ehrlich solid tumor. The cell line was treated with different concentrations of TAM or/and SIM for 72 h. The effects of treatment on cytotoxicity, oxidative stress markers, apoptosis, angiogenesis, and metastasis were investigated. Our results showed that the combination treatment decreased the oxidative stress markers, glucose uptake, VEGF, and MMP 2 &9 in the cell line compared to TAM- treated cells. Drug interaction of TAM and SIM was synergistic in T47D by increasing the apoptotic makers Bax/BCL-2 ratio and caspase 3 activity. Additionally, , the combination regimen resulted in a non-significant decrease in the tumor volume compared to TAM treated group. Moreover, the combined treatment decreased the protein expression of TNF-α, NF-kB compared to control. In conclusion, our results suggest that SIM may serve as a promising treatment with TAM for improving the efficacy against estrogen receptor-positive (ER+) breast cancer.

Abdo, S. A., W. Wadie, R. M. Abdelsalam, and M. M. Khattab, "Potential Anti-Inflammatory Effect of Escitalopram in Iodoacetamide-Induced Colitis in Depressed Ovariectomized Rats: Role of α7-nAChR.", Inflammation, vol. 42, issue 6, pp. 2056-2064, 2019. Abstract

Escitalopram, a drug of choice in the treatment of depression, was recently shown to possess an anti-inflammatory activity. The aim of the present study was to elucidate the effect of escitalopram on peripheral inflammatory cascades in iodoacetamide-induced colitis associated with depressive behavior in ovariectomized rats. Moreover, the role of α-7 nicotinic acetylcholine receptor in mediating the anti-colitic effect of escitalopram was examined using a nicotinic receptor antagonist methyllycaconitine citrate. Colitis was induced by intracolonic injection of 4% iodoacetamide in ovariectomized rats. Escitalopram (10 mg/kg/day, i.p.) was then injected for 1 week and several parameters including macroscopic (colon mass index and ulcerative area), microscopic (histopathology and scoring), and biochemical (myeloperoxidase and tumor necrosis factor-α) were determined. Colitis induction in ovariectomized rats resulted in a marked increase in colon mass index, ulcerative area, histopathological scoring, myeloperoxidase activity and tumor necrosis factor-α levels. These effects were ameliorated by escitalopram, even in the presence of methyllycaconitine indicating that α-7 nicotinic acetylcholine receptor does not mediate the anti-inflammatory effect of escitalopram. The present study revealed the beneficial effect of escitalopram in iodoacetamide induced colitis in ovariectomized rats and suggests that it may represent a new therapeutic agent for the treatment of inflammatory bowel disease, especially in patients with or at high risk of depressive behavior.

Fahim, V. F., W. Wadie, A. N. Shafik, and M. I. Attallah, "Role of simvastatin and insulin in memory protection in a rat model of diabetes mellitus and dementia.", Brain research bulletin, vol. 144, pp. 21-27, 2019. Abstract

OBJECTIVES: The memory protective role of simvastatin and/or insulin, in a rat model of diabetes mellitus (DM) and dementia was examined.

METHODS: DM was induced by an intraperitoneal injection of streptozotocin. Diabetic rats were divided into untreated; insulin treated; simvastatin treated with 10 and 20 mg/kg/day; and combined insulin plus simvastatin treatment in the previous doses. Treatment started after blood glucose elevation and persisted for 6 weeks. Morris water maze and Y maze tests were held to detect behavioral changes. Serum glucose, cholesterol and insulin levels, the hippocampi insulin, amyloid beta (Aß) 1-42 and oxidative stress markers were measured.

RESULTS: Insulin increased the time spent in the target quadrant in the Morris water maze test and the percentage of alternations in the Y maze test, despite the mild improvements in brain parameters demonstrated by amyloid beta 1-42, malondialdehyde and reduced glutathione levels; while simvastatin in both doses improved brain parameters with no positive impact on behavioral tests. Insulin combined with simvastatin 20 mg/kg/day was effective in enhancing the behavioral tests and the measured brain parameters.

CONCLUSIONS: Treatment with insulin and simvastatin could provide a promising memory protective effect in diabetics.

Ibrahim, A. B., H. F. Zaki, W. Wadie, M. M. Omran, and S. A. Shouman, "Simvastatin Evokes An Unpredicted Antagonism For Tamoxifen In MCF-7 Breast Cancer Cells.", Cancer management and research, vol. 11, pp. 10011-10028, 2019. Abstract

Purpose: Tamoxifen (TAM) is a non-steroidal antiestrogen drug, used in the prevention and treatment of all stages of hormone-responsive breast cancer. Simvastatin (SIM) is a lipid-lowering agent and has been shown to inhibit cancer cell growth. The study aimed to investigate the effect of the combination of TAM and SIM in the treatment of estrogen receptor positive (ER+) breast cancer cell line, MCF-7, and in mice-bearing Ehrlich solid tumors.

Methods: MCF-7 cells were treated with different concentrations of TAM or/and SIM for 72 hours and the effects of the combination treatment on cytotoxicity, oxidative stress markers, apoptosis, angiogenesis, and metastasis were investigated using different techniques. In addition, tumor volume, oxidative markers, and inflammatory markers of the combined therapy were explored in mice bearing solid EAC tumors.

Results: The results showed that treatment of MCF-7 cells with the combination of 10 µM TAM, and 2 µM SIM significantly inhibited the increase in oxidative stress markers, LDH, and NF-kB induced by TAM. In addition, there was a significant decrease in the total apoptotic ratio, caspase-3 activity, and glucose uptake, while there was a non-significant change in Bax/bcl-2 ratio compared to the TAM-treated group. Using the isobologram equation, the drug interaction was antagonistic with combination index, CI=1.18. On the other hand, the combination regimen decreased VEGF, and matrix metalloproteinases, MMP 2&9 compared to TAM-treated cells. Additionally, in vivo, the combination regimen resulted in a non-significant decrease in the tumor volume, decreased oxidative markers, and the protein expression of TNF-α, and NF-B compared to the TAM treated group.

Conclusion: Although the combination regimen of TAM and SIM showed an antagonistic drug interaction in MCF-7 breast cancer, it displayed favorable antiangiogenic, anti-metastatic, and anti-inflammatory effects.

Khayyal, M. T., W. Wadie, E. A. Abd El-Haleim, K. A. Ahmed, O. Kelber, R. M. Ammar, and H. Abdel-Aziz, "STW 5 is effective against nonsteroidal anti-inflammatory drugs induced gastro-duodenal lesions in rats.", World journal of gastroenterology, vol. 25, issue 39, pp. 5926-5935, 2019. Abstract

BACKGROUND: Proton pump inhibitors are often used to prevent gastro-intestinal lesions induced by nonsteroidal anti-inflammatory drugs. However, they are not always effective against both gastric and duodenal lesions and their use is not devoid of side effects.

AIM: To explore the mechanisms mediating the clinical efficacy of STW 5 in gastro-duodenal lesions induced by nonsteroidal anti-inflammatory drugs (NSAIDs), exemplified here by diclofenac, in a comparison to omeprazole.

METHODS: Gastro-duodenal lesions were induced in rats by oral administration of diclofenac (5 mg/kg) for 6 successive days. One group was given concurrently STW 5 (5 mL/kg) while another was given omeprazole (20 mg/kg). A day later, animals were sacrificed, stomach and duodenum excised and divided into 2 segments: One for histological examination and one for measuring inflammatory mediators (tumor necrosis factor α, interleukins-1β and 10), oxidative stress enzyme (heme oxygenase-1) and apoptosis regulator (B-cell lymphoma 2).

RESULTS: Diclofenac caused overt histological damage in both tissues, associated with parallel changes in all parameters measured. STW 5 and omeprazole effectively prevented these changes, but STW 5 superseded omeprazole in protecting against histological damage, particularly in the duodenum.

CONCLUSION: The findings support the therapeutic usefulness of STW 5 and its superiority over omeprazole as adjuvant therapy to NSAIDs to protect against their possible gastro-duodenal side effects.

El-Abhar, H., M. A. E. A. Fattah, W. Wadie, and D. M. El-Tanbouly, "Cilostazol disrupts TLR-4, Akt/GSK-3β/CREB, and IL-6/JAK-2/STAT-3/SOCS-3 crosstalk in a rat model of Huntington's disease.", PLoS One, vol. 13, issue 9, pp. 1-16, 2018.
Wazea, S. A., W. Wadie, A. K. Bahgat, and H. S. El-Abhar, "Galantamine anti-colitic effect: Role of alpha-7 nicotinic acetylcholine receptor in modulating Jak/STAT3, NF-κB/HMGB1/RAGE and p-AKT/ Bcl-2 pathways", Scientific Reports , vol. 8, issue 5110, pp. 1-10, 2018.
Soliman, S. M., W. Wadie, S. A. Shouman, and A. A. Ainshoka, "Sodium selenite ameliorates both intestinal and extra-intestinal changes in acetic acid-induced colitis in rats", Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 391, issue 6, pp. 639-647, 2018.
Wadie, W., and D. M. El-Tanbouly, "Vinpocetine mitigates proteinuria and podocytes injury in a rat model of diabetic nephropathy.", European journal of pharmacology, vol. 814, pp. 187-195, 2017 Nov 05. Abstract

Podocyte injury and glomerular basement membrane thickening have been considered as essential pathophysiological events in diabetic nephropathy. The aim of this study was to investigate the possible beneficial effects of vinpocetine on diabetes-associated renal damage. Male Wistar rats were made diabetic by injection of streptozotocin (STZ). Diabetic rats were treated with vinpocetine in a dose of 20mg/kg/day for 6 weeks. Treatment with vinpocetine resulted in a marked decrease in the levels of blood glucose, glycosylated haemoglobin, creatinine, blood urea nitrogen, urinary albumin and albumin/creatinine ratio along with an elevation in creatinine clearance rate. The renal contents of advanced glycation end-products, interleukin-10, tissue growth factor-β, nuclear factor (NF)-κB and Ras-related C3 botulinum toxin substrate 1 (Rac 1) were decreased. Renal nephrin and podocin contents were increased and their mRNA expressions were replenished in vinpocetine-treated rats. Moreover, administration of vinpocetine showed improvements in oxidative status as well as renal glomerular and tubular structures. The current investigation revealed that vinpocetine ameliorated the STZ-induced renal damage. This beneficial effect could be attributed to its antioxidant and antihyperglycemic effects parallel to its ability to inhibit NF-κB which eventually modulated cytokines production as well as nephrin and podocin proteins expression.

Salem, H. A., and W. Wadie, "Effect of Niacin on Inflammation and Angiogenesis in a Murine Model of Ulcerative Colitis.", Scientific reports, vol. 7, issue 1, pp. 7139, 2017 Aug 02. Abstract

Butyrate and niacin are produced by gut microbiota, however butyrate has received most attention for its effects on colonic health. The present study aimed at exploring the effect of niacin on experimental colitis as well as throwing some light on the ability of niacin to modulate angiogenesis which plays a crucial role of in the pathogenesis of inflammatory bowel disease. Rats were given niacin for 2 weeks. On day 8, colitis was induced by intrarectal administration of iodoacetamide. Rats were sacrificed on day 15 and colonic damage was assessed macroscopically and histologically. Colonic myeloperoxidase (MPO), tumour necrosis factor (TNF)-α, interleukin (IL)-10, vascular endothelial growth factor (VEGF), angiostatin and endostatin levels were determined. Niacin attenuated the severity of colitis as demonstrated by a decrease in weight loss, colonic wet weight and MPO activity. Iodoacetamide-induced rise in the colonic levels of TNF-α, VEGF, angiostatin and endostatin was reversed by niacin. Moreover, niacin normalized IL-10 level in colon. Mepenzolate bromide, a GPR109A receptor blocker, abolished the beneficial effects of niacin on body weight, colon wet weight as well as colonic levels of MPO and VEGF. Therefore, niacin was effective against iodoacetamide-induced colitis through ameliorating pathologic angiogenesis and inflammatory changes in a GPR109A-dependent manner.

El-Tanbouly, D. M., W. Wadie, and R. H. Sayed, "Modulation of TGF-β/Smad and ERK signaling pathways mediates the anti-fibrotic effect of mirtazapine in mice.", Toxicology and applied pharmacology, vol. 329, pp. 224-230, 2017 08 15. Abstract

Serotonin (5-HT) has been implicated as a key driver of liver fibrosis, acting via 5-HT2 receptor activation in the hepatic stellate cells. The current study was conducted to investigate the effects of mirtazapine, a 5-HT2A antagonist, in a mouse model of liver fibrosis. Mice received thioacetamide (TAA, 150mg/kg/biweekly, ip) for nine successive weeks for induction of liver fibrosis. Administration of mirtazapine significantly improved the plasma aminotransferases, reduced hepatic 5-HT concentration and ameliorated TAA-induced liver fibrosis, as demonstrated by reduced portal blood pressure, liver procollagen I content and α alpha smooth muscle actin expression. Moreover, hepatic collagen deposition was markedly decreased in mirtazapine-treated mice as evaluated by Masson's trichrome staining. Mirtazapine provided an antifibrotic environment by decreasing the liver content of transforming growth factor-β1 (TGF-β1), and protein kinase C as well as the expression of phosphorylated-Smad3 (p-Smad) and phosphorylated extracellular signal-regulated kinases 1 and 2 (p-ERK1/2). Additionally, oxidative stress was largely mitigated by mirtazapine as manifested by decreased liver lipid peroxidation and NADPH oxidase 1 along with glutathione replenishment. The current study indicates that mirtazapine suppressed 5-HT-mediated TGF-β1/Smad3 and ERK1/2 signaling pathways as well as oxidative stress that contribute to the progression of liver fibrosis.

Abdel-Aziz, H., W. Wadie, H. F. Zaki, J. Müller, O. Kelber, T. Efferth, and M. T. Khayyal, "Novel sequential stress model for functional dyspepsia: Efficacy of the herbal preparation STW5.", Phytomedicine : international journal of phytotherapy and phytopharmacology, vol. 22, issue 5, pp. 588-95, 2015 May 15. Abstract

BACKGROUND: Many screening procedures for agents with potential usefulness in functional dyspepsia (FD) rely on animals exposed to stress early in life (neonatal maternal separation, NMS) or in adulthood (restraint stress, RS).

PURPOSE: Since many clinical cases of FD have been associated with stress in early life followed by stress in adulthood, a sequential model simulating the clinical situation is described. To explore the validity of the model, the efficacy of STW5, a multicomponent herbal preparation of proven usefulness in FD, was tested.

STUDY DESIGN/METHODS: A sequential stress model established where rats are exposed to NMS after birth followed later by RS in adulthood. Stress hormones and ghrelin were measured in plasma, while responsiveness of stomach fundus strips to smooth muscle stimulants and relaxants was assessed ex-vivo. The effectiveness of treatment with STW5 a few days before and during exposure to RS in preventing changes induced by the stress model is reported and compared to its efficacy when used in animals subjected to RS alone.

RESULTS: Responses to both stimulants and relaxants were reduced to various extents in the studied models, but treatment with STW5 tended to normalize gastric responsiveness. Plasma levels of ghrelin, corticosterone releasing factor, and corticosterone were raised by RS as well as the sequential model. Treatment with STW5 tended to prevent the deranged parameters.

CONCLUSION: The sequential stress model has a place in drug screening for potential usefulness in FD as it simulates more the clinical setting. Furthermore, the findings shed more light on the mechanisms of action of STW5 in FD.

Abdel-Aziz, H., W. Wadie, O. Scherner, T. Efferth, and M. T. Khayyal, "Bacteria-Derived Compatible Solutes Ectoine and 5α-Hydroxyectoine Act as Intestinal Barrier Stabilizers to Ameliorate Experimental Inflammatory Bowel Disease.", Journal of natural products, vol. 78, issue 6, pp. 1309-15, 2015 Jun 26. Abstract

Earlier studies showed that the compatible solute ectoine (1) given prophylactically before induction of colitis by 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats prevented histological changes induced in the colon and the associated rise in inflammatory mediators. This study was therefore conducted to investigate whether ectoine (1) and its 5α-hydroxy derivative (2) would also be effective in treating an already established condition. Two days after inducing colitis in rats by instilling TNBS/alcohol in the colon, animals were treated orally once daily for 1 week with either 1 or 2 (50, 100, 300 mg/kg). Twenty-four hours after the last drug administration rats were sacrificed. Ulcerative lesions and colon mass indices were reduced by 1 and 2 in a bell-shaped manner. Best results were obtained with 100 mg/kg ectoine (1) and 50 mg/kg 5α-hydroxyectoine (2). The solutes normalized the rise in myeloperoxidase, TNFα, and IL-1β induced by TNBS but did not affect levels of reduced glutathione or ICAM-1, while reducing the level of fecal calprotectin, an established marker for inflammatory bowel disease. The findings indicate that the naturally occurring compatible solutes ectoine (1) and 5α-hydroxyectoine (2) possess an optimum concentration that affords maximal intestinal barrier stabilization and could therefore prove useful for better management of human inflammatory bowel disease.

H, A. - A., W. W, Scherner O, E. T, and K. MT., "Bacteria-Derived Compatible Solutes Ectoine and 5α-Hydroxyectoine Act as Intestinal Barrier Stabilizers to Ameliorate Experimental Inflammatory Bowel Disease.", J Nat Prod. 2015, vol. 78, issue 6, pp. 1309-15., 2015.
H, A. - A., W. W, Z. HF, Müller J, K. O, E. T, and K. MT, "Novel sequential stress model for functional dyspepsia: Efficacy of the herbal preparation STW5.", Phytomedicine., vol. 22, issue (5), pp. 588-595., 2015.
Abdel-Aziz, H., W. Wadie, D. M. Abdallah, G. Lentzen, and M. T. Khayyal, "Novel effects of ectoine, a bacteria-derived natural tetrahydropyrimidine, in experimental colitis.", Phytomedicine : international journal of phytotherapy and phytopharmacology, vol. 20, issue 7, pp. 585-91, 2013 May 15. Abstract

Evidence suggests an important role of intestinal barrier dysfunction in the etiology of inflammatory bowel disease (IBD). Therefore stabilizing mucosal barrier function constitutes a new therapeutic approach in its management. Ectoine is a compatible solute produced by aerobic chemoheterotrophic and halophilic/halotolerant bacteria, where it acts as osmoprotectant and effective biomembrane stabilizer, protecting the producing cells from extreme environmental stress. Since this natural compound was also shown to prevent inflammatory responses associated with IBD, its potential usefulness was studied in a model of colitis. Groups of rats were treated orally with different doses of ectoine (30-300 mg/kg) or sulfasalazine (reference drug) daily for 11 days. On day 8 colitis was induced by intracolonic instillation of 2,4,6-trinitrobenzenesulfonic acid, when overt signs of lesions develop within the next 3 days. On day 12, blood was withdrawn from the retro-orbital plexus of the rats and the animals were sacrificed. The colon was excised and examined macroscopically and microscopically. Relevant parameters of oxidative stress and inflammation were measured in serum and colon homogenates. Induction of colitis led to marked weight loss, significant histopathological changes of the colon, and variable changes in levels of myeloperoxidase, reduced glutathione, malondialdehyde, and all inflammatory markers tested. Treatment with ectoine ameliorated the inflammatory changes in TNBS-induced colitis. This effect was associated with reduction in the levels of TNF-α, IL-1β, ICAM-1, PGE2 and LTB4. The findings suggest that intestinal barrier stabilizers from natural sources could offer new therapeutic measures for the management of IBD.

H, A. - A., W. W, A. DM, Lentzen G, and K. MT, "Novel effects of ectoine, a bacteria-derived natural tetrahydropyrimidine, in experimental colitis.", Phytomedicine, vol. 20, issue 7, pp. 585-591, 2013.