Curcumin attenuates cytoplasmic/endoplasmic reticulum stress, apoptosis and cholinergic dysfunction in diabetic rat hippocampus.

Diabetes mellitus (DM) is associated with the increased risk of the central nervous system complications as cerebrovascular disease, impaired cognition, dementia and neurodegeneration. Curcumin is a polyphenol with anti-oxidant, anti-inflammatory, anti-hyperlipidemic, and anti-cancer effects. Therefore, the present study was aimed to focus on the mechanistic insights of diabetes-induced hippocampal neurodegeneration in addition to shedding the light on the modulatory effect of curcumin. Twenty-eight male Wistar rats were randomly divided into four groups. Type I DM was induced by a single intra-peritoneal injection of streptozotocin (STZ) (65 mg/kg b.w.). Curcumin (100 mg/kg b.w.) was given to the diabetic group after the induction and for eight weeks. Hippocampal glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF-4), Bcl2 and choline acetyl transferase (ChAT) genes expression were assessed. Heat shock protein 70 (HSP70), Bcl-2-Associated X protein (Bax), Interferon-γ (INF-γ) and CCAAT-enhancer-binding protein homologous protein (CHOP) levels in the hippocampus were immunoassayed, in addition to the assessment of glycemic and redox status. Curcumin significantly improved blood glucose level, redox status, cellular stress, and decreased INF-γ and Bax levels, down-regulated GRP78 and ATF-4 expression, meanwhile, up-regulated Bcl2 and ChAT expression in hippocampus. Histological findings proved the biochemical and molecular findings. Our results support curcumin as a potential neuro-protective agent against diabetes induced hippocampal neurodegeneration.

Heat shock protein 47 as indispensible participant in liver fibrosis: Possible protective effect of lactoferrin.

Lactoferrin (LF) was previously suggested to have a protective effect against liver fibrosis by preventing hepatic stellate cells (HSCs) activation. The effect of LF on heat shock protein 47 (HSP47) has not yet been studied so this study was designed to investigate LF effect on HSP47 as a potential target for management of liver fibrosis and comparing it with silymarin (SM) in a thioacetamide (TAA)-induced liver fibrosis model. Rats were divided into four groups; normal control, TAA (TAA-treated), LF (LF + TAA-treated), and SM (SM + TAA-treated). After 6 weeks, both LF and SM improved the grade of cirrhosis, reduced collagen fibers deposition, inactivated HSCs, significantly decreased elevated liver enzymes, HSP47, hydroxyproline content, transforming growth factor-beta 1, matrix metalloproteinase-2, 8-hydroxydeoxyguanosine, malondialdehyde, nitric oxide levels and the percentage of alpha smooth muscle actin positive HSCs compared with TAA group. Moreover, LF significantly increased the total antioxidant capacity compared with TAA group. It could be concluded that LF is a promising antifibrotic drug and could be considered as one of the HSP47 inhibitors but SM is still more potent. © 2018 IUBMB Life, 70(8):795-805, 2018.

Fabrication and In-Vivo Evaluation of Polyvinyl pyrrolidone/Poloxamer 188 Hybrid Nanofibers of Deflazacort.

The superior flexibility, efficient drug loading, high surface-to-volume ratio, ease of formulation, and cost-controlled production are considered exceptional advantages of nanofibers (NFs) as a smart delivery system. Deflazacort (DEF) is an anti-inflammatory and immunosuppressant agent. It is categorized as a poorly soluble class II drug. In this study, DEF-loaded polymeric nanofibrous using the electrospinning technique mats, Polyvinyl pyrrolidone (PVP) with or without Poloxamer 188 (PX) were used as mat-forming polymers. Microscopical imaging, drug content (%), and in vitro dissolution studies were conducted for all NFs formulae (F1-F7). All NFs improved the DEF dissolution compared to the unprocessed form, with the superiority of the PVP/PX hybrid. The optimized formula (F7) exhibited an average diameter of 655.46 ± 90.4 nm and % drug content of 84.33 ± 5.58. The dissolution parameters of DEF loaded in PVP/PX NFs (F7) reflected a release of 95.3 % ± 3.1 and 102.6 % ± 1.7 after 5 and 60 min, respectively. NFs (F7) was investigated for drug-polymer compatibility using Fourier-Transform Infrared Spectroscopy (FTIR), Powder X-ray diffraction analysis (PXRD), and Differential Scanning Calorimetry (DSC). In vivo anti-inflammatory study employing male Sprague-Dawley rats showed a significant reduction of rat paw edema for F7 (p < 0.05) compared with unprocessed DEF with a normal epidermal and dermal skin structure comparable to the healthy negative control. Immunohistochemical and morphometric data displayed similarities between the immune reaction of F7 and the negative healthy control. The finding of this work emphasized that DEF loaded in PVP/PX NFs could be considered a useful strategy for enhancing the therapeutic performance of DEF.

Evaluation of genotoxicity induced by exposure to antineoplastic drugs in lymphocytes of oncology nurses and pharmacists.

The hazards of handling antineoplastic drugs have been raised and discussed in several studies. Introduction of new antineoplastics together with abuse of safety standards have contributed to the exposure risk for personnel who handle these substances. Interactions of antineoplastic drugs with biological structures vary according to the drug(s) and the individual's genetic susceptibility. This study was carried out to evaluate the genome damage induced by exposure to antineoplastic drugs in nurses (n = 20) and pharmacists (n = 18) working in the Oncology Department of Tanta Cancer Center. Thirty subjects matched in age, gender and smoking habit were selected as controls. Both chromosomal aberration analysis and micronucleus assay were used to evaluate genome damage in peripheral blood lymphocytes of the study subjects. The numbers of aberrant lymphocytes, as well as chromosomal aberration and micronuclei frequencies, were significantly increased in exposed personnel in comparison to matched controls. Compared with pharmacists, nurses showed notably higher level of chromosome damage. On the other hand, no significant difference in micronuclei frequency was observed between nurses and pharmacists. Correlation analyses pointed to the influence of age and duration of occupational exposure on the level of chromosome damage among exposed subjects. The results of this study confirmed that handling antineoplastic drugs without appropriate precautions imposed a genotoxic risk for exposed healthcare workers. These results address the need for regular biomonitoring of exposed personnel. In addition, they call attention to the need for proper implementation of intervention measures aiming to eliminate or significantly reduce worker exposure and prevent untoward biological effects.

A new trend in the medication of hepatocyte cytoxicity in mice: protective role of probiotic bacteria.

Liver toxicity is affected by several factors, including certain medications, fumes emission from factories, materials used in industries, and exposure to chemicals such as carbon tetrachloride (CCl4). Some preselected probiotic bacteria strains have been widely employed in different medical researches due to their antioxidant, anticancer, antimicrobial, anti-inflammatory characters, and hepatoprotective factor. The present study was aimed to evaluate the protective role of probiotic bacteria (Lactobacillus plantarum DSMZ 20174) and their ameliorative effects against CCl4-induced hepatotoxicity in mice. The cell cycle of hepatocytes and the expression of transforming growth factor-ß (TGF-ß) were assessed by flow cytometry as indicators for apoptosis. The antioxidant activity of probiotic bacteria was estimated by measuring lipid peroxidation (LPO) and scavenging 2,2-diphenyl-1-picryl-hydrazyl (DPPH). The results showed that the treatment of CCl4-administered mice by supernatant from Lactobacillus plantarum DSMZ 20174 induced an amelioration in CCl4-induced increases in serum activity of the liver enzymes and decreases in LPO and DPPH. After treatment with probiotics, the liver histopathological studies showed abundant infiltration and accumulation of mononuclear cells and fibroblast, indicating a positive effect ameliorating the damage previously induced by CCl4. In sum, the results of the present work indicate the protective effects of Lactobacillus plantarum against hepatotoxicity through antioxidant effects.

Evaluation of the effect of combined intralesional injection of prostaglandin F2α with narrow band UVB phototherapy in treatment of resistant cases of vitiligo.

BACKGROUND: Vitiligo is a chronic cutaneous disease characterized with hypopigmented patches that leave psychological impact on the patients. There is increasing need for new treatment modalities to shorten the duration of treatment of vitiligo with the least side effects. OBJECTIVE: To explore the effect of intralesional injection of prostaglandin F2α on the outcome of narrow band ultraviolet rays B (NBUVB) for patients with stable vitiligo. PATIENTS AND METHODS: The study included 27 stable vitiligo patients with overall symmetrical lesions. For each patient, one patch was treated with NBUVB alone (control side), while another symmetrical patch was treated with combined intralesional injection of prostaglandin F2α with NBUVB therapy, weekly for 3 months. RESULTS: There was statistically significant improvement in the repigmentation in the combination group compared with NBUVB group. Side effects were minimal. CONCLUSION: Intralesional injection of prostaglandin F2α in combination with NBUVB therapy could be considered as safe and tolerable technique for treatment of vitiligo, it shortens the duration of NBUVB therapy. Longer follow up is needed.

Metformin ameliorated methotrexate-induced hepatorenal toxicity in rats in addition to its antitumor activity: two birds with one stone.

Methotrexate (MTX) is a drug used in treatment of various malignancies. Unfortunately, it leads to life-threatening complications including hepatorenal toxicity. Previous studies revealed the protective effects of metformin (MET) on hepatorenal toxicity in other models in addition to its anticancer effects. The current study investigates the effect of MET on MTX-induced hepatorenal toxicity and the possible mechanisms involved in this toxicity which can be overwhelmed by MET. Thirty male rats were divided into 3 groups: normal control, MTX treated and MET/MTX treated. After 7 days, MTX induced hepatorenal toxicity as proved by histological examinations and biochemical analysis of liver and kidney functions. Also, it led to significant increase in hepatic and renal malondialdehyde levels, significant decrease in hepatic and renal total antioxidant capacity levels and Na+/K+-ATPase activities and significant up regulation of mRNA expressions of nuclear factor kappa-light-chain-enhancer of activated B cells, cyclooxygenase-2 and caspase 3 compared with the control group. While, MET could significantly reduce hepatorenal toxicity and counteract the effects of MTX on all measured parameters. In conclusion, MET can be an effective adjuvant to MTX chemotherapy that could ameliorate its hepatorenal toxicity through antioxidant, anti-inflammatory and anti-apoptotic mechanisms.

Upregulation of Toll-like receptor 2 and nuclear factor-kappa B expression in experimental colonic schistosomiasis.

Role of different mediators was described in the development of the granulomatous response and fibrosis observed in intestinal schistosomiasis. However, both Toll-like receptor 2 (TLR2) and nuclear factor kappa B (NF-κB) have not yet been investigated in intestinal schistosomiasis. This study aimed to characterize the role of TLR2 and NF-κB in the pathogenesis of intestinal schistosomiasis. Experimental animals were divided into two groups; group I: non-infected control group and group II: mice infected subcutaneously with S. mansoni cercariae. Colon samples were taken from infected mice, every two weeks, starting from the 6th week postinfection (PI) till 18th week PI. Samples were subjected to histopathological and immunohistochemical studies. Colon of S. mansoni infected mice showed histopathological changes in the form of mucosal degeneration, transmural mononuclear cellular infiltration and granulomas formation. Immunostained sections revealed significant increase in TLR2 and NF-κB positive cells in all layers of the colon, cells of the granuloma and those of the lymphoid follicles 10 weeks PI. All these changes decreased gradually starting from 12 weeks PI onward to be localized focally at 18 weeks PI. In conclusion, recruitment and activation of inflammatory cells to the colonic mucosa in intestinal schistosomiasis are multifactorial events involving TLR2 that can trigger the NF-κB pathways. Hence, down-regulation of both TLR2 and NF-κB could be exploited in the treatment of colonic schistosomiasis.

Neurotrophic and antioxidant effects of silymarin comparable to 4-methylcatechol in protection against gentamicin-induced ototoxicity in guinea pigs.

BACKGROUND: Despite that gentamicin is a very effective aminoglycoside, its potential ototoxicity which is of irreversible nature makes a challenge and limitation for its use. This study was designed to investigate possible neurotrophic and antioxidant effects of silymarin comparable to 4-methylcatechol in protection against gentamicin-induced ototoxicity. METHODS AND RESULTS: Twenty pigmented guinea pigs were divided into four equal groups, where group I served as normal control group. The other groups received gentamicin (120 mg/kg/day, ip) for 19 days where group II given vehicle of 1% CMC, group III and group IV were pre-treated 2h before gentamicin by 4-methylcatechol (10 µg/kg, ip) and silymarin (100mg/kg, oral gavage), respectively. The main findings indicated that silymarin exhibited restoration of nerve growth factor (NGF) levels and increased tropomyosin-related kinase receptors-A (Trk-A) m-RNA expression in cochlear tissue and preservation of hair cells of organ of Corti by scanning electron microscopy (SEM) with significant decrease in auditory brainstem response (ABR) threshold compared to 4-methylcatechol. Only silymarin caused significant amelioration in oxidative stress state by reducing malondialdehyde (MDA) levels and increasing catalase activity. CONCLUSIONS: Silymarin exerts superiority over 4-methylcatechol when recommended as protective agent against gentamicin ototoxicity based on its efficient neurotrophic and antioxidant activities.

GC-MS Based Plasma Metabolomics for Identification of Candidate Biomarkers for Hepatocellular Carcinoma in Egyptian Cohort.

This study evaluates changes in metabolite levels in hepatocellular carcinoma (HCC) cases vs. patients with liver cirrhosis by analysis of human blood plasma using gas chromatography coupled with mass spectrometry (GC-MS). Untargeted metabolomic analysis of plasma samples from participants recruited in Egypt was performed using two GC-MS platforms: a GC coupled to single quadruple mass spectrometer (GC-qMS) and a GC coupled to a time-of-flight mass spectrometer (GC-TOFMS). Analytes that showed statistically significant changes in ion intensities were selected using ANOVA models. These analytes and other candidates selected from related studies were further evaluated by targeted analysis in plasma samples from the same participants as in the untargeted metabolomic analysis. The targeted analysis was performed using the GC-qMS in selected ion monitoring (SIM) mode. The method confirmed significant changes in the levels of glutamic acid, citric acid, lactic acid, valine, isoleucine, leucine, alpha tocopherol, cholesterol, and sorbose in HCC cases vs. patients with liver cirrhosis. Specifically, our findings indicate up-regulation of metabolites involved in branched-chain amino acid (BCAA) metabolism. Although BCAAs are increasingly used as a treatment for cancer cachexia, others have shown that BCAA supplementation caused significant enhancement of tumor growth via activation of mTOR/AKT pathway, which is consistent with our results that BCAAs are up-regulated in HCC.

Intervention of mitochondrial dysfunction-oxidative stress-dependent apoptosis as a possible neuroprotective mechanism of α-lipoic acid against rotenone-induced parkinsonism and L-dopa toxicity.

The current study evidenced hypothesis that mitochondrial dysfunction-oxidative stress-dependent apoptotic pathways play a critical role in degeneration of dopaminergic neurons in Parkinson's disease. Model of rotenone-induced parkinsonism in rats produced decrease in striatal complex I activity and reduced glutathione with increase in nitrites concentration and caspase-3 activity. This was confirmed by significant correlation of catalepsy score with neurochemical parameters. Moreover, electron microscopic examination of striatal neurons displayed ultrastructure affection as hyperchromatic nuclei and disrupted mitochondria that are typical features of undergoing apoptosis. Administration of L-dopa as replacement therapy, although caused symptomatic improvement in catalepsy score, but further worsening in neurochemical parameters. Therefore, efforts are not only to improve effect of L-dopa, but also to introduce drugs provide antiparkinsonian and neuroprotective effects. In this study, α-lipoic acid exhibited noticeable neuroprotective effects by a mechanism via intervention of mitochondrial dysfunction-oxidative stress-dependent apoptotic pathways. Combination of α-lipoic acid efficiently halting deleterious toxic effects of L-dopa, revealed normalization of catalepsy score in addition to amelioration of neurochemical parameters and apparent preservation of striatal ultrastructure integrity, indicating benefit of both symptomatic and neuroprotective therapy. In conclusion, α-lipoic acid could be recommended as a disease-modifying therapy when given with L-dopa early in course of Parkinson's disease.