To assess the role of α3β4* nACh receptors in morphine withdrawal, we used a genetic correlation approach using publically available datasets within the GeneNetwork web resource, genetic knockout and pharmacological tools. Male and female European-American (n = 2772) and African-American (n = 1309) subjects from the Study of Addiction: Genetics and Environment dataset were assessed for possible associations of polymorphisms in the 15q25 gene cluster and opioid dependence. KEY RESULTSBXD recombinant mouse lines demonstrated an increased expression of α3, β4 and α5 nACh receptor mRNA in the forebrain and midbrain, which significantly correlated with increased defecation in mice undergoing morphine withdrawal. Mice overexpressing the gene cluster CHRNA5/A3/B4 exhibited increased somatic signs of withdrawal. Furthermore, α5 and β4 nACh receptor knockout mice expressed decreased somatic withdrawal signs compared with their wild-type counterparts. Moreover, selective α3β4* nACh receptor antagonists, α-conotoxin AuIB and AT-1001, attenuated somatic signs of morphine withdrawal in a dose-related manner. In addition, two human datasets revealed a protective role for variants in the CHRNA3 gene, which codes for the α3 nACh receptor subunit, in opioid dependence and withdrawal. In contrast, we found that the α4β2* nACh receptor subtype is not involved in morphine somatic withdrawal signs.

Aluminum (Al) is an omnipresent mineral element in the environment. The brain is a central target of Al toxicity, being highly susceptible to oxidative damage. Therefore, recognition of drugs or natural products that guard against Al-mediated neuronal cell death is a powerful strategy for prevention and treatment of neurodegenerative disorders. This work aimed to explore the potential of a leaf extract from Harrisonia abyssinica to modulate the neurobehavioral, biochemical and histopathological activities induced experimentally by Al in vivo. Rats subjected to Al treatment displayed a reduction in learning and memory performance in a passive avoidance test accompanied by a decrease in the hippocampal monoamine and glutamate levels in addition to suppression of Bcl2 expression. Moreover, malondialdehyde (MDA), inflammatory markers (TNF-α, IL-1β), apoptotic markers (caspase-3 and expression of Bax) and extracellular regulated kinase (ERK1/2) levels were elevated along with acetylcholinesterase (AChE) activity, histological changes and marked deposition of amyloid β plaques in the hippocampus region of the brain tissues being observed in Al-treated animals. Concomitant administration of the high dose of H. abyssinica (200 mg/kg b.w.) restored nearly normal levels of all parameters measured, rather than the low dose (100 mg/kg b.w.), an effect that was comparable to the reference drug (rivastigmine). Molecular docking revealed the appropriate potential of the extract components to block the active site of AChE and ERK2. In conclusion, H. abyssinica leaf extract conferred neuroprotection against Al-induced neurotoxic effects, most likely due to its high phenolic and flavonoid content.

Background: This study was conducted to assess the therapeutic effect of Myrrh on Diethylnitrosamine (DEN)induced hepatocarcinogenesis (HCC) in male albino rats. Methods: Fifty male albino rats were divided into five groups (10 rats each). Group 1 (control group) received distilled water. Group 2 (positive control) was injected intraperitoneally with DEN (55 mg/kg b.w) twice a week for two weeks, while group 3 (DOX) received doxorubicin i.p (10 mg/ kg b.w) after concomitant with DEN twice a week for four weeks. Groups 4 and 5 received a low dose of Myrrh (250 mg/kg b.w) and a high dose of Myrrh (500 mg/kg b.w) respectively daily for four weeks after the induction with DEN. The sera were used to estimate the liver enzymes (ALT, AST, and ALP), Alpha-fetoprotein (AFP), Total antioxidant capacity (TAC), and Tumor necrosis factor-ἁ (TNF-ἁ). Also, the liver tissues were collected to determine the oxidative stress markers in addition to the histopathological and immunohistochemical investigations. Results: The results showed that the induction of DEN causes a significant increase in the level of liver enzymes (ALT, AST, and ALP), AFP and TNF-ἁ as well as produce oxidative stress indicated by increasing of malondialdehyde (MDA) with the reduction in TAC and glutathione (GSH). Meanwhile, there are noticeable histopathological lesions with loss of hepatic architecture. This was accompanied by a significant increase of immunohistochemical markers; Caspase-3, vascular endothelial growth factor (VEGF), transforming growth factor β1(TGF-β1), and carcinoembryonic antigen (CEA) percentage area. The treatment of DEN rats with DOX reduced the alterations in most parameters. A marked amelioration of all parameters in a dose-dependent manner of Myrrh to the values almost near to those of the control group. Conclusion: Our data revealed that Water extract of Myrrh (C. molmol) has a potential therapeutic effect in attenuation of HCC induced DEN.

The diagnosis of acute kidney injury (AKI) is frequently established on modifications in serum creatinine (SCr). The discriminative and prognostic aptitudes of serum cystatin-C as well as N-acetylglucosaminidase (NAG) and Interleukin-18 (IL-18) were inspected for the estimation of AKI. In this study twelve rats were alienated into two groups: control group received saline, second group received cadmium chloride at a dose (2.4 mg Cd/kg/day, i.p) for 30 days. Blood urea nitrogen (BUN), SCr, and IL-18 serum level were measured in addition to serum and tissue content of cystatin-C and NAG. AKI model showed significant increase in BUN, creatinine, and IL-18. RT-PCR showed upregulation of cystatin-C gene besides significant increase of its level in serum. Additionally, tissue content of NAG was significantly increased. Our findings may provide that grouping of several biomarkers for diagnosis of AKI is a more valuable diagnostic tool than single-marker measurement.

Proximal tubule protein take-up is interceded by 2 receptors, megalin and cubilin. These receptors rescue an assortment of filtered ligands including fundamental vitamins and hormones. The objective of this study was to investigate the potential relation of megalin receptor injury with nuclear factor-kappa B (NF-B) upregulation in acute kidney injury rat model. Twenty four rats were allocated into two groups: control group received saline, while the second group was intoxi-

1. Background: Diethylnitrosamine (DENA) is dietary carcinogen. It is known as cancer initiator in various organs. The present study investigated the destructive changes of DENA in liver and colon and the possible therapeutic effects of doxorubicin (DOX); pyridazine derivative (MDP) and lactobacillus casei (LAB) against DENA induced dysplasia in liver and colon. 2. Methods: 3. Lactobacillus casei were tested for their probiotic properties and prepared for rat administration. Sixty adult male albino rats were divided into six groups. A normal control group received the vehicle; DENA group was injected intraperitoneally (ip) with 55mg/kg body weight twice per week for six weeks. DENA+MDP group received MDP at a dose of 10mg/kg (ip) twice per week for the next 4 weeks after DENA administration; DENA+DOX group received DOX at a dose of 10mg/kg (ip) twice per week for the next 4 weeks after DENA administration; DENA+LAB received LAB orally at a dose of (1.5 x 10 9 CFU) twice per week for the next 4 weeks after DENA administration. DENA+MDP+DOX group received both MDP and DOX as the aforementioned before. Sera, liver and colon were obtained after the end of experiment. Serum aspartate transaminase and alanine transaminase were detected as well as glutathione peroxidase (GSHPX), nitric oxide, tumor necrosis factor (TNF-α), alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA). Histo-pathological studies and immune-histochemical examination of heme oxygenase-1 (HO-1) were done.Morphometric study was performed. All measurements were followed by statistical analysis. 4. Results: DENA induced significant increase in liver enzymes with significant increase in oxidation and inflammation biomarkers and AFP and CEA. Histologically, DENA showed degenerative changes in hepatocytes and dysplastic aberrant crypt foci in colon. Liver and colon displayed increased cytoplasmic and nuclear immune-expression of HO-1. Therapeutic groups showed partial improvement in biochemical parameters and histological structure. However, Lactobacillus casei showed the best result in attenuating pathological and biochemical changes in liver and colon. 5. Conclusion: Lactobacillus casei displayed a potential anti-tumorigenic activity against DENA in liver and colon. This may be exerted via HO-1 modulation and suppression of oxidation and inflammation.

Numerous obstacles challenge the treatment of fungal infections, including the uprising resistance and the low penetration of available drugs. One of the main active agents against fungal infections is itraconazole (ITZ), with activity against a broad spectrum of fungi while having few side effects. The aim of this study was to design ufasomes, oleic acid-based colloidal carriers, that could encapsulate ITZ to improve its penetration power. Employing a 2231 factorial design, the effect of three independent factors (oleic acid amount, cholesterol concentration, and ITZ amount) was investigated and evaluated for the percentage encapsulation efficiency (%EE), particle size (PS), and zeta potential (ZP). Optimization was performed using Design® expert software and the optimized ITZ-loaded ufasomes obtained had %EE of 99.4 ± 0.7%, PS of 190 ± 1 nm, and ZP of −81.6 ± 0.4 mV, with spherical unilamellar morphology and no aggregation. An in vitro microbiological study was conducted to identify the minimum inhibitory concentration of the selected formula against Candida albicans, which was found to be 0.0625 μg/mL. Moreover, the optimized formula reduced the expression of toll-like receptors-4 and pro-inflammatory cytokine IL-1β secretion in the C. albicans-infected fibroblasts, indicating that the proposed ITZ-loaded ufasomes are a promising drug delivery system for ITZ.

Background Gentamicin is one of aminoglycoside antibiotic used for treatment of many infections due to its availability and less cost. The aim of this study aimed to assess the modulation effect of fenugreek seed and its germinated seeds on pancreatic and testicular toxicity induced by gentamicin in male Swiss albino mice. Forty male albino mice were divided into four treatment groups as follows: (1) control group, (2) gentamicin treated group, (3) gentamicin-fenugreek treated group and (4) gentamicin-germinated fenugreek treated group. Pancreatic and testicular tissues were collected for histopathological examinations, histochemical, and biochemical analysis as well as genetic study. Results Administration of gentamicin resulted in histopathological damage in pancreatic and testicular tissues as well as decreased glutathione peroxides, catalase and total antioxidant activity content in both pancreatic and testicular tissues compared to control group. Histopathological changes and antioxidant/oxidative alterations as well as DNA damage observed in gentamicin treated animals found were moderate improvement by fenugreek seeds administration and marked improvement by treatment with germinated fenugreek seeds. Conclusions Treated with gentamicin induced histopathological lesions, antioxidant/oxidant imbalance and DNA damage in the pancreatic and testicular. Treatment with germinated fenugreek seeds was more effective than fenugreek seeds in amelioration of pancreatic and testicular lesions, preventing high appearance of carbohydrate and accumulation of collagen fibers as well as oxidative damage and genotoxicity induced by gentamicin administration.