Behtash Nezami | Case Western Reserve University-University Hospitals (original) (raw)

Papers by Behtash Nezami

The Journal of Physiology, 2016

Consumption of high-fat diets (HFD) is associated with myenteric neurodegeneration associated wit... more Consumption of high-fat diets (HFD) is associated with myenteric neurodegeneration associated with delayed colonic transit and constipation. We examined the hypothesis that both HFD&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s inherent increase in plasma free fatty acids (FFA) and HFD-induced alteration in gut microbiota contribute to the pathophysiology of these disorders. C57BL/6 mice were fed a Western diet (WD, 35% kcal from fat- enriched in palmitate) or a purified regular diet (RD, 16.9% kcal from fat) for 3, 6, 9 and 12 weeks. Gut microbiota dysbiosis was investigated by fecal LPS measurement and metabolomics (LTQ-FTMS) analysis. Plasma FFA and LPS, colonic and ileal nitrergic myenteric neurons quantifications and motility were assessed. Compared to RD-fed control mice, WD-fed mice gained significantly more weight without blood glucose alteration. Dysbiosis was exhibited after 6 weeks of feeding as reflected by increased fecal LPS and bacterial metabolites and concomitant higher plasma FFA. Numbers of nitrergic myenteric neurons were reduced in the proximal colon after 9 and 12 weeks of WD and associated with delayed colonic transit. WD-fed TLR4(-/-) mice did not exhibit myenteric cell loss or dysmotility. Finally, LPS [0.5 to 2 ng/ml] and palmitate [20 and 30 μM] acted synergistically to induce neuronal cell death in vitro which was prevented by the NOS inhibitor L-NAME. In conclusion, WD-feeding results in increased levels of FFA and microbiota that, even in absence of hyperglycemia or overt endotoxemia, synergistically induce TLR4-mediated neurodegeneration and dysmotility. This article is protected by copyright. All rights reserved.

American Journal of Physiology - Gastrointestinal and Liver Physiology, 2015

Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, Jan 30, 2015

Moderate macrovesicular steatosis (>30%), which is present in almost 50% of livers considered ... more Moderate macrovesicular steatosis (>30%), which is present in almost 50% of livers considered for transplantation increases the risk of primary graft dysfunction. Our previously published data showed that glial cell line-derived neurotrophic factor (GDNF) is protective against high-fat diet (HFD)-induced hepatic steatosis in mice. Hence, we hypothesized that perfusion of steatotic livers with GDNF may reduce liver fat content prior to transplantation. Livers from 8 weeks regular diet (RD) and HFD-fed mice were perfused ex-vivo for 4 hours with either vehicle, GDNF, or a previously described defatting cocktail. Liver's residual fat was quantified colorimetrically using a triglyceride assay kit, and by Oil Red-O and Nile Red/Hoechst staining. Liver tissue injury was assessed using an LDH activity assay. In vitro induction of lipolysis in HepG2 cells was assessed by measuring glycerol and free fatty acid release. Oil Red-O staining showed significantly more steatosis in liver fr...

Neurogastroenterology & Motility, 2012

Gut microbiota have recently been implicated in the pathogenesis of the obesity and its related m... more Gut microbiota have recently been implicated in the pathogenesis of the obesity and its related metabolic diseases. Avariety of factors including diet, genetic background, environment and host innate and adaptive immune responses define an individual's gut microbiota. In this review we outline potential mechanisms by which gut microbiota can contribute to the development of obesity focusing on specific processes such as microbial energy extraction, microbiota inducedinflammation and regulation of appetite. We review the current understanding of each of these processes on regulating metabolism and examine potential therapeutic strategies for the treatment or prevention of the metabolic syndrome. We explore the hypothesis that alteration in gut microbiota may be an initial event leading to altered feeding behavior and/or systemic inflammation, ultimately leading to weight gain and the metabolic syndrome.

AJP: Gastrointestinal and Liver Physiology, 2013

The enteric nervous system (ENS), referred to as the &amp;amp;amp;amp;amp;amp;amp;amp;amp... more The enteric nervous system (ENS), referred to as the &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;second brain,&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; comprises a vast number of neurons that form an elegant network throughout the gastrointestinal tract. Neuropeptides produced by the ENS play a crucial role in the regulation of inflammatory processes via cross talk with the enteric immune system. In addition, neuropeptides have paracrine effects on epithelial secretion, thus regulating epithelial barrier functions and thereby susceptibility to inflammation. Ultimately the inflammatory response damages the enteric neurons themselves, resulting in deregulations in circuitry and gut motility. In this review, we have emphasized the concept of neurogenic inflammation and the interaction between the enteric immune system and enteric nervous system, focusing on neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP). The alterations in the expression of NPY and VIP in inflammation and their significant roles in immunomodulation are discussed. We highlight the mechanism of action of these neuropeptides on immune cells, focusing on the key receptors as well as the intracellular signaling pathways that are activated to regulate the release of cytokines. In addition, we also examine the direct and indirect mechanisms of neuropeptide regulation of epithelial tight junctions and permeability, which are a crucial determinant of susceptibility to inflammation. Finally, we also discuss the potential of emerging neuropeptide-based therapies that utilize peptide agonists, antagonists, siRNA, oligonucleotides, and lentiviral vectors.

World Journal of Gastroenterology

To investigate the anti-oxidant and anti-neutrophil recruitment effects of rectal d-alpha (d-alph... more To investigate the anti-oxidant and anti-neutrophil recruitment effects of rectal d-alpha (d-alpha) tocopherol administration on mild and moderately active ulcerative colitis (UC). Fifteen patients with mild and moderately active ulcerative colitis were enrolled in an open-label study of d-alpha tocopherol enema (8000 U/d) for 12 wk. All patients were receiving concomitant therapy with 5-aminosalicylic acid derivatives (5-ASA) and/or immunomodulator medications. Endoscopic evaluation was performed at baseline and after 4th and 12th weeks. Disease activity was measured with the Mayo disease activity index (DAI) and remission was defined as DAI of < or = 2 with no blood in stool. Clinical response was defined as a DAI reduction of > or = 2. At the end of 12th week, the average DAI score significantly decreased compared to the beginning of the study (2.3 +/- 0.37 vs 8 +/- 0.48, P < 0.0001). One patient was withdrawn after 3 wk for being unavailable to follow-up. On the 4th wee...

International Urology and Nephrology, 2014

To present a new approach for management of cutaneous vesicostomy (CV) prolapse, with special emp... more To present a new approach for management of cutaneous vesicostomy (CV) prolapse, with special emphasis on normal appearing vesicostomy may be malfunctioning. To introduce the application of temporary stoma-free drainage as a diagnostic and therapeutic tool. From December 2000 to September 2006, 66 children (61 males and 5 females) with CV were studied. The mean age at vesicostomy was 7 months (range 1-30), and the main underlying disease was posterior urethral valves (in 45 children, 68%). Indications for CV included significant hydroureteronephrosis (HUN) and recurrent urinary tract infection. Patients were followed up for complications and were treated based on our institutional approach. All patients with persistent upper tract dilatation and micturition per urethra underwent temporary bladder (via stoma) free drainage. Patients with stomal stenosis were managed either by a revision surgery or by simple dilatation and intermittent catheterization. Purse string suturing was applied in mucosal prolapses as the first choice. The complications were observed in 21 patients (31%), including twelve stomal stenosis, nine severe mucosal prolapses, and two recurrent urinary infections. HUN and significant voiding per urethra persisted following initial CV in 19 out of 66 patients (29%), eleven of which having normal appearing CVs. Seventeen of these patients were managed by temporary stoma-free drainage (accompanied by purse string suturing in mucosal prolapse), and two patients with severe stenosis underwent surgical revision. Temporary stoma-free drainage improved HUN in 94% of patients (16 of 17). Voiding per urethra is an indicator of CV malfunction, and temporary stoma-free drainage can be a diagnostic and therapeutic option in such children. A seemingly open CV may still be malfunctioning, and ureterovesical or intravesical obstructions should be considered if HUN does not improve following temporary stoma-free drainage.

Aims: Elevated levels of endogenous opioids play a pivotal role in several deleterious consequenc... more Aims: Elevated levels of endogenous opioids play a pivotal role in several deleterious consequences of cholestasis. Renal dysfunction occurs in cholestasis but its exact mechanism is still unknown. In this study, we investigated the role of endogenous opioids in cholestasis induced nephrotoxicity. Main methods: Thirty-five rats were divided into five groups. In groups 1 and 2 BDL rats received either daily subcutaneous 20 mg/kg of naltrexone or its vehicle, for 7 days after BDL. In groups 3 and 4, BDL or Sham rats received no injections. In group 5, normal rats received subcutaneous injections of 20 mg/kg/day of naltrexone for 7 days. At the 7th day, 24 h urine was collected to measure urinary N-acetyl-β-Dglucosaminidase (NAG) as an early marker of renal tubular injury. Kidney samples were then collected for light and electron microscopic studies. Key findings: BDL significantly increased NAG activity compared to sham groups. Naltrexone significantly reversed NAG activity to normal levels in BDL animals. Naltrexone treatment in BDL animals also significantly reversed ALT and AST to their normal levels. In light and electron microscopic studies, there were significant structural alterations in BDL samples, which were mostly prevented in naltrexone treated BDL animals. Significance: Significant changes in urinary NAG activity and renal morphology of cholestatic rats were reversed by naltrexone treatment. These results suggest a possible role for endogenous opioids in inducing cholestatic nephrotoxicity.

World Journal of Urology, 2008

We assessed the effectiveness of sildenafil administration during ischemic period in a rat model ... more We assessed the effectiveness of sildenafil administration during ischemic period in a rat model of testicular torsion/detorsion (T/D). Sprague-Dawley rats were divided into four groups (n = 10). In those animals that underwent T/D, right testes were rotated 720 degrees for 1 h. Base line group was for basal normal values. Sham operated group was served as a control group. T/D group underwent 1 h testicular torsion. Sildenafil group received sildenafil (0.7 mg/kg) intraperitoneally 30 min after initiation of ischemic period. For measurement of lipid peroxidation and antioxidant enzyme activities, right testes of five animals in each group were excised after 4-h reperfusion. Germ cell apoptosis indices were determined 24 h following detorsion in right testes of remaining five animals in each group. Malondialdehyde (MDA) levels in T/D group were significantly higher versus control and base line groups. Moreover, testicular MDA values in sildenafil group were significantly lower than T/D. There were also significant decreases in catalase and superxide dismutase activities in T/D group compared with control and base line groups. These values were significantly higher in sildenafil group versus T/D. Germ cell apoptosis indices were significantly higher in both groups that experienced T/D in comparison to control and base line groups; however, sildenafil treatment significantly reduced the apoptosis in sildenafil group compared with T/D group. Sildenafil administration during testicular torsion decreased ischemia/reperfusion cellular damage. The results of biochemical studies suggest that, reduction of oxidative stress by sildenafil may have a major role in its cytoprotective effects.

Seizure, 2010

Although there is evidence that diabetes affects seizure susceptibility, the underlying mechanism... more Although there is evidence that diabetes affects seizure susceptibility, the underlying mechanism has not been completely understood. Several studies also suggest a pivotal role for K(ATP) channels in the seizure modulation. The aim of the present study was to evaluate the seizure threshold induced by pentylenetetrazole in diabetic mice at different times (3 days, 1-8 weeks) after induction of diabetes with streptozocin and to examine the possible role of ATP-sensitive potassium (K(ATP)) channels in this manner. Our data showed a time-dependent alteration in the threshold in diabetic mice, reaching a peak on week 2 after streptozocin injection and declining significantly afterwards. The seizure threshold in 8-week diabetic mice was even lower than control levels, though the difference was not significant. The K(ATP) channel opener cromakalim (0.1-30microg/kg, i.p.) significantly increased the seizure threshold in control mice. Although the K(ATP) channel blocker glibenclamide (0.5, 1mg/kg) had no effect, it prevented the effects of the potent dose of cromakalim (30microg/kg) on seizure threshold in control mice. Glibenclamide (1mg/kg, i.p.) also decreased the seizure threshold in 2-week diabetic mice to the control levels which was blocked by pre-treatment with cromakalim (10microg/kg, i.p.). Cromakalim (10microg/kg, i.p.) significantly increased the seizure threshold in 8-week diabetic mice which was inhibited by pre-treatment with glibenclamide (1mg/kg, i.p.). We demonstrated a time-dependent alteration in the pentylenetetrazole-induced seizure threshold in diabetic mice. This phenomenon might be due to the probable alteration in the K(ATP) channel functioning during the diabetic condition.