Mohamed M. Salem

Enhanced DNA binding capacity on up-regulated epidermal wild-type p53 in vitiligo by H2O2-mediated oxidation: a possible repair mechanism for DNA damage

Vitiligo is characterized by a patchy loss of inherited skin color affecting ̃0.5% of individuals of all races. Despite the absence of the protecting pigment and the overwhelming evidence for hydrogen peroxide (H2O2)‐induced oxidative stress in the entire epidermis of these patients, there is neither increased photodamage/skin aging nor a higher incidence for sun‐induced nonmelanoma skin cancer. Here we demonstrate for the first time increased DNA damage via 8‐oxoguanine in the skin and plasma in association with epidermal up‐regulated phosphorylated/acetylated p53 and high levels of the p53 antagonist p76MDM2. Shortpatch base‐excision repair via hOggl, APE1, and polymeraseβ DNA repair is up‐regulated. Overexpression of Bcl‐2 and low caspase 3 and cytochrome c levels argue against increased apoptosis in this disease. Moreover, we show the presence of high epidermal peroxynitrite (ONOO−) levels via nitrotyrosine together with high nitrated p53 levels. We demonstrate by EMSA that nitration of p53 by ONOO− (300×10−6 M) abrogates DNA binding, while H2O2‐oxidized p53 (10−3 M) enhances DNA binding capacity and prevents ONOO−induced abrogation of DNA binding. Taken together, we add a novel reactive oxygen species to the list of oxidative stress inducers in vitiligo. Moreover, we pro!pose up‐regulated wild‐type p53 together with p76MDM2 as major players in the control of DNA damage/repair and prevention of photodamage and nonmelanoma skin cancer in vitiligo.—Salem, M. M. A. E. L., Shalbaf, M., Gibbons, N. C. J., Chavan, B., Thornton, J. M., Schallreuter, K. U. Enhanced DNA binding capacity on up‐regulated epidermal wild‐type p53 in vitiligo by H!O!‐mediated oxidation: a possible repair mechanism for DNA damage. FASEB J. 23, 3790–3807 (2009). www.fasebj.org

Feruhermonins A–C: three daucane esters from the seeds of Ferula hermonis (Apiaceae)

Seventeen daucane esters have been isolated from the seeds of Ferula hermonis Boiss (Apiaceae). Three of these sesquiterpenes, 4β-hydroxy-6α-benzoyl-7-daucen-9-one (1), 4β, 8β-dihydroxy-6α-benzoyl-dauc-9-ene (2), and 4β, 9α-dihydroxy-6α-benzoyl-dauc-7-ene (4), named feruhermonins A–C, respectively, are novel natural products. The structures of these compounds were elucidated unequivocally by a series of 1D and 2D NMR analyses. Although 4β, 8β-dihydroxy-6α-(4-hydroxy-3-methoxybenzoyl)-dauc-9-ene (3) was reported previously, the complete spectroscopic data for this compound are presented here for the first time.

The redox – biochemistry of human hair pigmentation

The biochemistry of hair pigmentation is a complex field involving a plethora of protein and peptide mechanisms. The in loco factory for melanin formation is the hair follicle melanocyte, but it is common knowledge that melanogenesis results from a fine tuned concerted interaction between the cells of the entire dermal papilla in the anagen hair follicle. The key enzyme is tyrosinase to initiate the active pigmentation machinery. Hence, an intricate understanding from transcription of mRNA to enzyme activity, including enzyme kinetics, substrate supply, optimal pH, cAMP signaling, is a must. Moreover, the role of reactive oxygen species on enzyme regulation and functionality needs to be taken into account. So far our knowledge on the entire hair cycle relies on the murine model of the C57BL/6 mouse. Whether this data can be translated into humans still needs to be shown. This article aims to focus on the effect of H2O2‐redox homeostasis on hair follicle pigmentation via tyrosinase, its substrate supply and signal transduction as well as the role of methionine sulfoxide repair via methionine sulfoxide reductases A and B (MSRA and B).

In vivo and in vitro evidence for epidermal H2O2-mediated oxidative stress in piebaldism.

Please cite this paper as: In vivo and in vitro evidence for epidermal H2O2‐mediated oxidative stress in piebaldism. Experimental Dermatology 2010; 19: 883–887.

Preoperative Embolization of Extra-axial Hypervascular Tumors with Onyx

Objective Preoperative endovascular embolization of intracranial tumors is performed to mitigate anticipated intraoperative blood loss. Although the usage of a wide array of embolic agents, particularly polyvinyl alcohol (PVA), has been described for a variety of tumors, literature detailing the efficacy, safety and complication rates for the usage of Onyx is relatively sparse. Materials and Methods We reviewed our single institutional experience with pre-surgical Onyx embolization of extra-axial tumors to evaluate its efficacy and safety and highlight nuances of individualized cases. Results Five patients underwent pre-surgical Onyx embolization of large or giant extra-axial tumors within 24 hours of surgical resection. Four patients harbored falcine or convexity meningiomas (grade I in 2 patients, grade II in 1 patient and grade III in one patient), and one patient had a grade II hemangiopericytoma. Embolization proceeded uneventfully in all cases and there were no complications. Conclusion This series augments the expanding literature confirming the safety and efficacy of Onyx in the preoperative embolization of extra-axial tumors, underscoring its advantage of being able to attain extensive devascularization via only one supplying pedicle.

Carotid artery stenting vs. carotid endarterectomy in the management of carotid artery stenosis: Lessons learned from randomized controlled trials

Background: Carotid artery stenosis, both symptomatic and asymptomatic, has been well studied with several multicenter randomized trials. The superiority of carotid endarterectomy (CEA) to medical therapy alone in both symptomatic and asymptomatic carotid artery stenosis has been well established in previous trials in the 1990s. The consequent era of endovascular carotid artery stenting (CAS) has offered another option for treating carotid artery stenosis. A series of randomized trials have now been conducted to compare CEA and CAS in the treatment of carotid artery disease. The large number of similar trials has created some confusion due to inconsistent results. Here, the authors review the trials that compare CEA and CAS in the management of carotid artery stenosis. Methods: The PubMed database was searched systematically for randomized controlled trials published in English that compared CEA and CAS. Only human studies on adult patients were assessed. The references of identified articles were reviewed for additional manuscripts to be included if inclusion criteria were met. The following terms were used during search: carotid stenosis, endarterectomy, stenting. Retrospective or single-center studies were excluded from the review. Results: Thirteen reports of seven large-scale prospective multicenter studies, comparing both interventions for symptomatic or asymptomatic extracranial carotid artery stenosis, were identified. Conclusions: While the superiority of intervention to medical management for symptomatic patients has been well established in the literatures, careful selection of asymptomatic patients for intervention should be undertaken and only be pursued after institution of appropriate medical therapy until further reports on trials comparing medical therapy to intervention in this patient group are available.

Ginseng oligopeptides protect against irradiation-induced immune dysfunction and intestinal injury

Intestinal injury and immune dysfunction are commonly encountered after irradiation therapy. While the curative abilities of ginseng root have been reported in prior studies, there is little known regarding its role in immunoregulation of intestinal repairability in cancer patients treated with irradiation. Our current study aims to closely examine the protective effects of ginseng-derived small molecule oligopeptides (Panax ginseng C. A. Mey.) (GOP) against irradiation-induced immune dysfunction and subsequent intestinal injury, using in vitro and in vivo models. Expectedly, irradiation treatment resulted in increased intestinal permeability along with mucosal injury in both Caco-2 cells and mice, probably due to disruption of the intestinal epithelial barrier, leading to high plasma lipopolysaccharide (LPS) and pro-inflammatory cytokines levels. However, when the cells were treated with GOP, this led to diminished concentration of plasma LPS and cytokines (IL-1 and TNF-α), suggesting its dampening effect on inflammatory and oxidative stress, and potential role in restoring normal baseline intestinal permeability. Moreover, the Caco-2 cells treated with GOP showed high trans-epithelial electrical resistance (TEER) and low FITC-dextran paracellular permeability when compared to the control group. This could be explained by the higher levels of tight junction proteins (ZO-1 and Occludin) expression along with reduced expression of the apoptosis-related proteins (Bax and Caspase-3) noticed in the GOP-treated cells, highlighting its role in preserving intestinal permeability, through prevention of their degradation while maintaining normal levels of expression. Further confirmatory in vivo data showed that GOP-treated mice exhibited high concentrations of lymphocytes (CD3+, CD4+, CD8+) in the intestine, to rescue the irradiation-induced damage and restore baseline intestinal integrity. Therefore, we propose that GOP can be used as an adjuvant therapy to attenuate irradiation-induced immune dysfunction and intestinal injury in cancer patients.

Middle Meningeal Artery Arising from the Basilar Artery

Various anomalies for the origin of the middle meningeal artery (MMA) have been described in the literature. However, origin of the MMA from the basilar trunk is an extremely rare variant. We report on a 54-year-old female who presented with frequent headaches; magnetic resonance imaging showed a right parietal meningioma. The abnormal origin of the middle meningeal artery from the basilar artery was diagnosed by angiography performed for preoperative embolization of the tumor. We report on the case with a review of the embryologic basis, possible explanations for this aberrant origin, and its clinical implications.