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2022
Gamal, N. G., R. M. Abdel-Salam, L. N. Gadelrub, O. A. Ahmed-Farid, and M. T. Khayyal, "The herbal preparation STW 5 affects serotonergic pathways in the brain and colon as well as stress parameters in experimental irritable bowel syndrome.", Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society, vol. 34, issue 4, pp. e14301, 2022. Abstract

BACKGROUND: Exposure to stress has been related to disturbance in 5-hydroxytryptamine (5-HT) signaling in the brain-gut axis and is considered as a major predisposing factor for the development of irritable bowel syndrome (IBS). The present study aimed to investigate the possible involvement of 5-HT and some other stress-related parameters in the effectiveness of STW 5 against stress-induced IBS.

METHODS: Rats were subjected to restraint stress (RS) for 1 h/day for 14 consecutive days to induce IBS-like symptoms and were given STW 5 orally at the same time. At the end of the experiment, blood samples were withdrawn, then animals were euthanized and the brain hippocampi, cerebral cortices, as well as colons were isolated for biochemical and histopathological assessments.

RESULTS: RS increased the plasma corticotrophin releasing factor (CRF) with concomitant increase in hippocampal and cortical 5-HT levels, as well as mast cell inflammatory mediators, oxidative stress biomarkers, and histopathological inflammatory changes observed in rat colon. It also decreased the colonic content of 5-HT with consequent decrease in fecal pellet output (FPO). Treatment with STW 5 protected against these changes.

CONCLUSION: The protective effect of STW 5 against RS-induced IBS is related to its ability to normalize the induced changes in 5-HT in the brain-gut axis and counteract the stress-induced oxidative stress and inflammation.

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.

2021
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.

2020
Khayyal, M. T., R. M. El-Hazek, W. A. El-Sabbagh, J. Frank, D. Behnam, and M. Abdel-Tawab, "Micellar solubilization enhances the anti-inflammatory effect of xanthohumol.", Phytomedicine : international journal of phytotherapy and phytopharmacology, vol. 71, pp. 153233, 2020. Abstract

BACKGROUND: Xanthohumol is known to exert anti-inflammatory properties but has poor oral bioavailability. Using advanced micellization technology, it has been possible to markedly enhance its bioavailability.

PURPOSE: In the present study, we compared the chronic anti-inflammatory activities of native and micellar xanthohumol in the rat adjuvant arthritis model, using diclofenac as a reference drug.

METHODS: Adjuvant arthritis was induced by injecting Freund's complete adjuvant into the right hind paw of rats and monitoring paw volume over 3 weeks. The drugs were given daily for 3 weeks, starting from the day of adjuvant inoculation. Serum was collected at the end of the experiment to measure inflammatory and oxidative stress parameters. Statistical comparisons between different groups were carried out by one-way analysis of variance followed by Tukey-Kramer multiple comparison test.

RESULTS: Micellar solubilized xanthohumol showed a better anti-inflammatory activity than its native form. The reduction in paw volume was reflected in corresponding changes in relevant mediators of inflammation like tumor necrosis factor-α, interleukin-6 and C-reactive protein, myloperoxidase and lipid peroxidation markers.

CONCLUSION: The findings confirm that micellar solubilization of xanthohumol enhances its anti-inflammatory activity, probably as a result of improving its bioavailabilty. The solubilized xanthohumol may prove to be a promising adjuvant tool for anti-inflammatory treatment and a potential anti-inflammatory alternative to synthetic drugs.

2019
Khayyal, M. T., M. H. Kreuter, M. Kemmler, P. Altmann, D. H. Abdel-Naby, and M. A. El-Ghazaly, "Effect of a chamomile extract in protecting against radiation-induced intestinal mucositis.", Phytotherapy research : PTR, vol. 33, issue 3, pp. 728-736, 2019.
Khayyal, M. T., F. K. El-Baz, M. R. Meselhy, G. H. Ali, and R. M. El-Hazek, "Intestinal injury can be effectively prevented by in gamma irradiated rats.", Heliyon, vol. 5, issue 5, pp. e01814, 2019. Abstract

is one of the most common microalgae that is used as human food. It is isolated from the salty lakes in El-Fayoum and Lake of Bardawil-Sinai in Egypt and can withstand very high concentrations of salt: The potentiality of , a unicellular biflagellate green alga to protect against intestinal injury induced after radiation exposure was studied. was given orally in doses of 100 and 200 mg/kg to male Wistar rats for 5 days before exposure to 6 Gray (Gy) gamma radiation and continued for a further two days. Rats were sacrificed 24 h later and intestinal segments were dissected out. One segment was examined histologically and another was used to prepare homogenates to assess relevant biochemical parameters reflecting intestinal injury. Radiation exposure led to a rise in the histological damage score, an increase in tissue tumor necrosis factor (TNF-α), interleukin (IL-1β) and thiobarbituric acid reactive substances (TBARS) but a reduction in tissue reduced glutathione (GSH) and in serum citrulline. Pretreatment with either dose of effectively reduced the severity of intestinal mucositis induced by gamma radiation.

Khayyal, M. T., D. H. Abdel-Naby, and M. A. El-Ghazaly, "Propolis extract protects against radiation-induced intestinal mucositis through anti-apoptotic mechanisms.", Environmental science and pollution research international, 2019. Abstract

Intestinal mucositis is a common side effect during radiotherapy that could be largely prevented by compounds possessing anti-inflammatory or anti-oxidant properties, including extracts of propolis containing a high proportion of flavonoids. A specially formulated aqueous extract of propolis (PWE) has been prepared in such a way to preclude the inclusion of flavonoids but contain mostly organic aromatic acids to study whether it would still protect against radiation-induced intestinal mucositis and to study the possible involvement of apoptotic pathways. Rats were exposed to a gamma radiation dose of 8 Gy from a Cesium-137 source in order to inflict intestinal mucositis. Three days before exposure, rats were given PWE orally and treatment continued for 2 more days. Twenty-four hours later, rats were sacrificed, the small intestine was excised, and sections were examined histologically. Different parameters for apoptosis, inflammation, and oxidative stress were determined in the serum and in intestinal homogenates. Radiation exposure led to histological and biochemical signs of intestinal damage. This was associated with an increase in apoptotic indicators and derangement in oxidative stress parameters. All deranged parameters were largely prevented by PWE. The findings provide evidence that the protective effect of PWE against intestinal radiation damage involves not only its anti-inflammatory and anti-oxidant effects but also its anti-apoptotic properties as well.

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.

2018
MT, K., E. - H. RM, E. - S. WA, F. J, B. D, and A. - T. M, "Micellar solubilisation enhances the antiinflammatory activities of curcumin and boswellic acids in rats with adjuvant-induced arthritis.", Nutrition, vol. 54, pp. 189-196, 2018.
2015
Abdel-Aziz, H., M. Schneider, W. Neuhuber, A. M. Kassem, S. Khailah, J. Müller, H. G. E. deen, A. Khairy, M. T. Khayyal, A. Shcherbakova, et al., "GPR84 and TREM-1 signaling contribute to the pathogenesis of reflux esophagitis.", Molecular medicine (Cambridge, Mass.), 2015 Nov 24. Abstract

Gastro-esophageal reflux disease (GERD) is one of the most common disorders in gastroenterology. Patients present with or without increased acid exposure indicating a non-uniform etiology. Thus the common treatment with proton pump inhibitors (PPIs) fails to control symptoms in up to 40% of patients.To further elucidate the pathophysiology of the condition and explore new treatment targets, transcriptomics, proteomics and histological methods were applied to a surgically induced sub-chronic reflux esophagitis model in Wistar rats after treatment with either omeprazole (PPI) or STW5, a herbal preparation shown to ameliorate esophagitis without affecting refluxate pH. The normal human esophageal squamous cellline HET-1A and human endoscopic biopsies were used to confirm our findings to the G-protein coupled receptor (GPR) 84 in human tissue.Both treatments reduced reflux-induced macroscopic and microscopic lesions of the esophagi as well as known pro-inflammatory cytokines. Proteomic and transcriptomic analyses identified CINC1-3, MIP-1/3α, MIG, RANTES and IL-1β as prominent mediators in GERD. Most regulated cyto-/chemokines are linked to the TREM-1 signaling pathway. The fatty acid receptor GPR84 was up-regulated in esophagitis but significantly decreased in treated groups, a finding supported by Western blot and immunohistochemistry in both rat tissue and HET-1A cells. GPR84 was also found to be significantly up-regulated in patients with grade B reflux esophagitis.The expression of GPR84 in esophageal tissue and its potential involvement in GERD are reported for the first time. IL-8 (CINC1-3) and the TREM-1 signaling pathway are proposed, besides GPR84, to play an important role in the pathogenesis of GERD.

Abdel-Aziz, H., M. Schneider, W. Neuhuber, A. M. Kassem, S. Khailah, J. Müller, H. G. E. deen, A. Khairy, M. T. Khayyal, A. Shcherbakova, et al., "GPR84 and TREM-1 signaling contribute to the pathogenesis of reflux esophagitis.", Molecular medicine (Cambridge, Mass.), 2015 Nov 24. Abstract

Gastro-esophageal reflux disease (GERD) is one of the most common disorders in gastroenterology. Patients present with or without increased acid exposure indicating a non-uniform etiology. Thus the common treatment with proton pump inhibitors (PPIs) fails to control symptoms in up to 40% of patients.To further elucidate the pathophysiology of the condition and explore new treatment targets, transcriptomics, proteomics and histological methods were applied to a surgically induced sub-chronic reflux esophagitis model in Wistar rats after treatment with either omeprazole (PPI) or STW5, a herbal preparation shown to ameliorate esophagitis without affecting refluxate pH. The normal human esophageal squamous cellline HET-1A and human endoscopic biopsies were used to confirm our findings to the G-protein coupled receptor (GPR) 84 in human tissue.Both treatments reduced reflux-induced macroscopic and microscopic lesions of the esophagi as well as known pro-inflammatory cytokines. Proteomic and transcriptomic analyses identified CINC1-3, MIP-1/3α, MIG, RANTES and IL-1β as prominent mediators in GERD. Most regulated cyto-/chemokines are linked to the TREM-1 signaling pathway. The fatty acid receptor GPR84 was up-regulated in esophagitis but significantly decreased in treated groups, a finding supported by Western blot and immunohistochemistry in both rat tissue and HET-1A cells. GPR84 was also found to be significantly up-regulated in patients with grade B reflux esophagitis.The expression of GPR84 in esophageal tissue and its potential involvement in GERD are reported for the first time. IL-8 (CINC1-3) and the TREM-1 signaling pathway are proposed, besides GPR84, to play an important role in the pathogenesis of GERD.

Khayyal, M. T., R. M. El-Hazek, and M. A. El-Ghazaly, "Propolis aqueous extract preserves functional integrity of murine intestinal mucosa after exposure to ionizing radiation.", Environmental toxicology and pharmacology, vol. 40, issue 3, pp. 901-6, 2015 Nov. Abstract

The ability of a specially prepared water propolis extract (PWE) to preserve the functional activity of the intestinal mucosa after radiation exposure was studied. PWE was given orally (650mg/kg) to rats five days prior to irradiation by 6Gy and continued for further two days. Rats were sacrificed 24h later, intestinal segments were examined histologically and homogenates were used to assess relevant biochemical parameters reflecting intestinal injury. Irradiation led to a rise in the histological damage score, a rise in tissue TNF-α and TBARS, and a decrease in sucrase, alkaline phosphatase, GSH and cholecystokinin as well as a decrease in plasma citrulline. The findings reflect a decrease in intestinal functional activity. PWE preserved the intestinal integrity and largely protected against the changes induced in the histology damage score and all parameters measured, possibly as a result of the antioxidant and anti-inflammatory action of its caffeic acid content.

Khayyal, M. T., R. M. El-Hazek, and M. A. El-Ghazaly, "Propolis aqueous extract preserves functional integrity of murine intestinal mucosa after exposure to ionizing radiation.", Environmental toxicology and pharmacology, vol. 40, issue 3, pp. 901-6, 2015 Nov. Abstract

The ability of a specially prepared water propolis extract (PWE) to preserve the functional activity of the intestinal mucosa after radiation exposure was studied. PWE was given orally (650mg/kg) to rats five days prior to irradiation by 6Gy and continued for further two days. Rats were sacrificed 24h later, intestinal segments were examined histologically and homogenates were used to assess relevant biochemical parameters reflecting intestinal injury. Irradiation led to a rise in the histological damage score, a rise in tissue TNF-α and TBARS, and a decrease in sucrase, alkaline phosphatase, GSH and cholecystokinin as well as a decrease in plasma citrulline. The findings reflect a decrease in intestinal functional activity. PWE preserved the intestinal integrity and largely protected against the changes induced in the histology damage score and all parameters measured, possibly as a result of the antioxidant and anti-inflammatory action of its caffeic acid content.

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, 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.

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.

El-Ghazaly, M. A., R. M. El-Hazek, and M. T. Khayyal, "Protective effect of the herbal preparation, STW 5, against intestinal damage induced by gamma radiation in rats.", International journal of radiation biology, vol. 91, issue 2, pp. 150-6, 2015 Feb. Abstract

PURPOSE: STW 5 (marketed as Iberogast(®), Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany) is a herbal preparation reported to possess anti-inflammatory properties and antioxidant activity. We investigated the effect of STW 5 against intestinal injury induced after whole body exposure to ionizing radiation (IR).

MATERIALS AND METHODS: Intestinal mucositis was induced in rats by irradiation at a level of 6 Gy. STW 5 (5 ml/kg) was delivered orally for 5 days before irradiation and 2 days after. Rats were sacrificed, jejunum homogenates were tested to assess biochemical parameters indicating intestinal injury and jejunum segments were exposed to semi-quantitative histological examination.

RESULTS: IR led to an increase in overall damage severity (ODS) score associated with a significant rise in tumor necrosis factor (TNF-α) and thiobarbituric acid reactive substances (TBARS) by 46% and 50% (p ≤ 0.05), respectively, whereas the reduced glutathione (GSH), sucrase and alkaline phosphatase enzyme activities were significantly decreased by 68%, 76% and 25% (p ≤ 0.05), respectively, in intestinal homogenates. IR led to a reduction of plasma citrulline. Pre-treatment with STW 5 guarded against the changes in ODS score and in all parameters measured.

CONCLUSION: Pre-treatment with STW 5 has the potential to decrease the severity of radiation-induced mucositis.

El-Ghazaly, M. A., R. M. El-Hazek, and M. T. Khayyal, "Protective effect of the herbal preparation, STW 5, against intestinal damage induced by gamma radiation in rats.", International journal of radiation biology, vol. 91, issue 2, pp. 150-6, 2015 Feb. Abstract

PURPOSE: STW 5 (marketed as Iberogast(®), Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany) is a herbal preparation reported to possess anti-inflammatory properties and antioxidant activity. We investigated the effect of STW 5 against intestinal injury induced after whole body exposure to ionizing radiation (IR).

MATERIALS AND METHODS: Intestinal mucositis was induced in rats by irradiation at a level of 6 Gy. STW 5 (5 ml/kg) was delivered orally for 5 days before irradiation and 2 days after. Rats were sacrificed, jejunum homogenates were tested to assess biochemical parameters indicating intestinal injury and jejunum segments were exposed to semi-quantitative histological examination.

RESULTS: IR led to an increase in overall damage severity (ODS) score associated with a significant rise in tumor necrosis factor (TNF-α) and thiobarbituric acid reactive substances (TBARS) by 46% and 50% (p ≤ 0.05), respectively, whereas the reduced glutathione (GSH), sucrase and alkaline phosphatase enzyme activities were significantly decreased by 68%, 76% and 25% (p ≤ 0.05), respectively, in intestinal homogenates. IR led to a reduction of plasma citrulline. Pre-treatment with STW 5 guarded against the changes in ODS score and in all parameters measured.

CONCLUSION: Pre-treatment with STW 5 has the potential to decrease the severity of radiation-induced mucositis.

Khayyal, M. T., A. M. Agha, H. F. Zaki, A. El-Sahar, and H. Abdel-Aziz, "Mechanisms Involved in the Anti-inflammatory and Vascular Effects of Iberis amara Extract.", Planta medica, vol. 81, issue 12-13, pp. 1097-102, 2015 Aug. Abstract

The anti-inflammatory potential and vasoprotective effects of an Iberis amara extract in a rat model of arthritis were investigated. I. amara, or bitter candytuft, has long been known for its anti-inflammatory properties on account of its active constituents, including cucurbitacins, kaempferol, and sinapic acid. The present study was intended to explore more in depth its anti-inflammatory activity in both acute (carrageenan rat paw edema) and chronic (adjuvant-induced arthritis) models of inflammation. An extract of I. amara dose-dependently reduced the extent of edema in both models. In the chronic model, this was associated with a reduction in the inflammation mediators tumor necrosis factor-α, interleukin-1β, and prostaglandin E2 and in the antioxidant biomarkers malondialdehyde and total nitrate/nitrite. Because arthritis was reported both clinically and experimentally to contribute towards different vascular complications, it was of interest to study ex vivo the sensitivity of aortic rings in our experimental setup towards norepinephrine, acetylcholine, and sodium nitroprusside. The aortic rings from arthritic rats showed no change in sensitivity to norepinephrine, but showed a reduced sensitivity to sodium nitroprusside and acetylcholine. To show whether the treatment of the arthritis would restore endothelial function, I. amara extract was shown to markedly reduce the reactivity to norepinephrine, but not to appreciably affect the reactivity towards sodium nitroprusside and it had a tendency towards normalizing reactivity to acetylcholine. Taken collectively, the findings imply an improvement in endothelial function and lend support to the use of the extract in rheumatic inflammatory conditions to help safeguard the integrity of the endothelium and reduce the risk of vascular complications.

Khayyal, M. T., A. M. Agha, H. F. Zaki, A. El-Sahar, and H. Abdel-Aziz, "Mechanisms Involved in the Anti-inflammatory and Vascular Effects of Iberis amara Extract.", Planta medica, vol. 81, issue 12-13, pp. 1097-102, 2015 Aug. Abstract

The anti-inflammatory potential and vasoprotective effects of an Iberis amara extract in a rat model of arthritis were investigated. I. amara, or bitter candytuft, has long been known for its anti-inflammatory properties on account of its active constituents, including cucurbitacins, kaempferol, and sinapic acid. The present study was intended to explore more in depth its anti-inflammatory activity in both acute (carrageenan rat paw edema) and chronic (adjuvant-induced arthritis) models of inflammation. An extract of I. amara dose-dependently reduced the extent of edema in both models. In the chronic model, this was associated with a reduction in the inflammation mediators tumor necrosis factor-α, interleukin-1β, and prostaglandin E2 and in the antioxidant biomarkers malondialdehyde and total nitrate/nitrite. Because arthritis was reported both clinically and experimentally to contribute towards different vascular complications, it was of interest to study ex vivo the sensitivity of aortic rings in our experimental setup towards norepinephrine, acetylcholine, and sodium nitroprusside. The aortic rings from arthritic rats showed no change in sensitivity to norepinephrine, but showed a reduced sensitivity to sodium nitroprusside and acetylcholine. To show whether the treatment of the arthritis would restore endothelial function, I. amara extract was shown to markedly reduce the reactivity to norepinephrine, but not to appreciably affect the reactivity towards sodium nitroprusside and it had a tendency towards normalizing reactivity to acetylcholine. Taken collectively, the findings imply an improvement in endothelial function and lend support to the use of the extract in rheumatic inflammatory conditions to help safeguard the integrity of the endothelium and reduce the risk of vascular complications.

Hagl, S., R. Grewal, I. Ciobanu, A. Helal, M. T. Khayyal, W. E. Muller, and G. P. Eckert, "Rice bran extract compensates mitochondrial dysfunction in a cellular model of early Alzheimer's disease.", Journal of Alzheimer's disease : JAD, vol. 43, issue 3, pp. 927-38, 2015. Abstract

Mitochondrial dysfunction plays an important role in brain aging and has emerged to be an early event in Alzheimer's disease (AD), contributing to neurodegeneration and the loss of physical abilities seen in patients suffering from this disease. We examined mitochondrial dysfunction in a cell culture model of AD (PC12APPsw cells) releasing very low amyloid-β (Aβ40) levels and thus mimicking early AD stages. Our data show that these cells have impaired energy metabolism, low ATP levels, and decreased endogenous mitochondrial respiration. Furthermore, protein levels of PGC1α as well as of Mitofusin 1 were decreased. PC12APPsw cells also showed increased mitochondrial content, probably due to an attempt to compensate the impaired mitochondrial function. Recent data showed that stabilized rice bran extract (RBE) protects from mitochondrial dysfunction in vivo Pharmacol Res. (2013) 76C, 17-27. To assess the effect of RBE on mitochondrial function, we treated PC12APPsw cells for 24 h with RBE. Key components of RBE are oryzanols, tocopherols, and tocotrienols, all substances that have been found to exert beneficial effects on mitochondrial function. RBE incubation elevated ATP production and respiratory rates as well as PGC1α protein levels in PC12APPsw cells, thus improving the impaired mitochondrial function assessed in our cell culture AD model. Therefore, RBE represents to be a promising nutraceutical for the prevention of AD.

Hagl, S., R. Grewal, I. Ciobanu, A. Helal, M. T. Khayyal, W. E. Muller, and G. P. Eckert, "Rice bran extract compensates mitochondrial dysfunction in a cellular model of early Alzheimer's disease.", Journal of Alzheimer's disease : JAD, vol. 43, issue 3, pp. 927-38, 2015. Abstract

Mitochondrial dysfunction plays an important role in brain aging and has emerged to be an early event in Alzheimer's disease (AD), contributing to neurodegeneration and the loss of physical abilities seen in patients suffering from this disease. We examined mitochondrial dysfunction in a cell culture model of AD (PC12APPsw cells) releasing very low amyloid-β (Aβ40) levels and thus mimicking early AD stages. Our data show that these cells have impaired energy metabolism, low ATP levels, and decreased endogenous mitochondrial respiration. Furthermore, protein levels of PGC1α as well as of Mitofusin 1 were decreased. PC12APPsw cells also showed increased mitochondrial content, probably due to an attempt to compensate the impaired mitochondrial function. Recent data showed that stabilized rice bran extract (RBE) protects from mitochondrial dysfunction in vivo Pharmacol Res. (2013) 76C, 17-27. To assess the effect of RBE on mitochondrial function, we treated PC12APPsw cells for 24 h with RBE. Key components of RBE are oryzanols, tocopherols, and tocotrienols, all substances that have been found to exert beneficial effects on mitochondrial function. RBE incubation elevated ATP production and respiratory rates as well as PGC1α protein levels in PC12APPsw cells, thus improving the impaired mitochondrial function assessed in our cell culture AD model. Therefore, RBE represents to be a promising nutraceutical for the prevention of AD.

Hagl, S., R. Grewal, I. Ciobanu, A. Helal, M. T. Khayyal, W. E. Muller, and G. P. Eckert, "Rice bran extract compensates mitochondrial dysfunction in a cellular model of early Alzheimer's disease.", Journal of Alzheimer's disease : JAD, vol. 43, issue 3, pp. 927-38, 2015. Abstract

Mitochondrial dysfunction plays an important role in brain aging and has emerged to be an early event in Alzheimer's disease (AD), contributing to neurodegeneration and the loss of physical abilities seen in patients suffering from this disease. We examined mitochondrial dysfunction in a cell culture model of AD (PC12APPsw cells) releasing very low amyloid-β (Aβ40) levels and thus mimicking early AD stages. Our data show that these cells have impaired energy metabolism, low ATP levels, and decreased endogenous mitochondrial respiration. Furthermore, protein levels of PGC1α as well as of Mitofusin 1 were decreased. PC12APPsw cells also showed increased mitochondrial content, probably due to an attempt to compensate the impaired mitochondrial function. Recent data showed that stabilized rice bran extract (RBE) protects from mitochondrial dysfunction in vivo Pharmacol Res. (2013) 76C, 17-27. To assess the effect of RBE on mitochondrial function, we treated PC12APPsw cells for 24 h with RBE. Key components of RBE are oryzanols, tocopherols, and tocotrienols, all substances that have been found to exert beneficial effects on mitochondrial function. RBE incubation elevated ATP production and respiratory rates as well as PGC1α protein levels in PC12APPsw cells, thus improving the impaired mitochondrial function assessed in our cell culture AD model. Therefore, RBE represents to be a promising nutraceutical for the prevention of AD.

2014
Khayyal, M. T., D. H. Abdel-Naby, H. Abdel-Aziz, and M. A. El-Ghazaly, "A multi-component herbal preparation, STW 5, shows anti-apoptotic effects in radiation induced intestinal mucositis in rats.", Phytomedicine : international journal of phytotherapy and phytopharmacology, vol. 21, issue 11, pp. 1390-9, 2014 Sep 25. Abstract

PURPOSE: Intestinal mucositis is a common adverse effect in patients undergoing radiotherapy and constitutes a treatment-limiting condition. Since no agents are yet known that can adequately guard against its development, the search continues to find safe and effective measures. The present study was intended to investigate whether the herbal preparation, STW 5, could offer a potentially effective agent in this respect.

METHODS: Intestinal mucositis was induced in rats by exposing them to whole body gamma-irradiation (6 Gy). Rats were treated orally with STW 5 (5 or 10 ml/kg) for five days before and two days after irradiation. One day later, rats were sacrificed and segments of small intestine were examined histologically. Intestinal homogenates and serum samples were used to assess relevant parameters for apoptosis and different markers for inflammation and oxidative stress.

RESULTS: Exposure to radiation produced dose-dependent extents of intestinal injury associated with apoptotic changes with high radiation levels. Apoptosis was associated with an increase in cytosolic calcium, depletion of mitochondrial cytochrome c, B-cell lymphoma-2 and complex I. Oxidative stress parameters (reduced glutathione, thiobarbituric acid reactive substance and total nitrate/nitrite) were deranged. Inflammation markers (tumor necrosis factor and myeloperoxidase) and indices of intestinal damage (serum diamine oxidase) were increased. STW 5 protected to a large extent against histological changes and counteracted the deranged parameters.

CONCLUSION: The findings provide experimental evidence for the potential beneficial use of STW5 in protecting against the development of radiation-induced intestinal mucositis and associated changes in tissue biomarkers.