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.

Histopathology and electron microscopy evaluation of the sildenafil effect on diabetic rats' retinae.

PURPOSE: Although there is increasing evidence that phosphodiesterase-5 (PDE-5) inhibitors modify the effect of diabetes on different tissues, its effect on diabetic retinopathy is not well studied. METHODS: Forty male Sprague-Dawley (SD) rats were divided into four groups: group I = control group that received no treatment; group II (diabetic group), in which diabetes was induced by a single streptozotocin injection; group III (sildenafil small dose, SSD), in which diabetes was similarly introduced (however, rats received daily oral 1 mg/kg sildenafil citrate (SC) for 3 months); and group IV (sildenafil large dose, SLD), which was as in group 3, but SC was 2.5 mg/kg. After 3 months, globes were removed and retinae were dissected; one globe from each rat was examined by light microscopy (LM), and the other by electron microscopy (EM). RESULTS: In contrast to the control group, diabetic rats in group II demonstrated well-established diabetic changes in the form of capillary congestion, decreased cell population, hyaline changes of capillary walls, and degenerated nerve fiber layer by LM. Similarly, EM demonstrated photoreceptor degeneration, mitochondrial cristolysis, and vacuolated depleted cells among other features in group II. These diabetic features were less prominent in group III and nearly absent in group IV. CONCLUSION: SC use in the early stages of DR may prevent/delay diabetic retinopathy development or progression in diabetic rat models, an effect that seems to be dose-related.

Chronic sildenafil citrate use decreases retinal vascular endothelial growth factor expression in diabetic rats: a pilot study.

BACKGROUND: Sildenafil citrate (SC) attenuates endothelial dysfunction. However, its effects on diabetic retinopathy (DR), which is mainly a microvascular disease, remain unclear. Vascular endothelial growth factor (VEGF) is known to be a critical mediator of DR. Therefore, we investigated the effects of SC on diabetic retina by measuring VEGF levels. METHODS: In this study, twenty-eight rats were divided into the following groups: group I, the control group; group II, rats with streptozotocin-induced diabetes; group III, rats with streptozotocin-induced diabetes receiving daily oral sildenafil at 1 mg/kg; and group IV, rats with streptozotocin-induced diabetes receiving high-dose daily sildenafil at 2.5 mg/kg. After 3 months, VEGF was measured in the retina specimen in one eye and the vitreous body in the other eye by immunohistochemistry and enzyme-linked immunosorbent assay, respectively. RESULTS: We found that VEGF expression in the retina was low in all rats from groups I and IV and in 30% of rats from group III; 80% of rats in group II demonstrated high VEGF expression in the retinae (P < 0.001). VEGF concentrations in the vitreous body samples were 32 ± 2, 61 ± 4, 44 ± 5, and 36 ± 3 pg/l in groups I-IV, respectively (P < 0.001). CONCLUSION: VEGF decreased significantly in the eyes of diabetic rats after chronic oral sildenafil citrate treatment. SC may have a modifying/attenuating effect on DR. However, further studies are needed to evaluate its use as an adjunctive treatment.

AICAR Ameliorates Non-Alcoholic Fatty Liver Disease via Modulation of the HGF/NF-κB/SNARK Signaling Pathway and Restores Mitochondrial and Endoplasmic Reticular Impairments in High-Fat Diet-Fed Rats.

Non-alcoholic fatty liver disease (NAFLD) is a global health problem characterized by altered lipid and redox homeostasis, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. The AMP-dependent kinase (AMPK) agonist 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) has been shown to improve the outcome of NAFLD in the context of AMPK activation, yet the underlying molecular mechanism remains obscure. This study investigated the potential mechanism(s) of AICAR to attenuate NAFLD by exploring AICAR's effects on the HGF/NF-κB/SNARK axis and downstream effectors as well as mitochondrial and ER derangements. High-fat diet (HFD)-fed male Wistar rats were given intraperitoneal AICAR at 0.7 mg/g body weight or left untreated for 8 weeks. In vitro steatosis was also examined. ELISA, Western blotting, immunohistochemistry and RT-PCR were used to explore AICAR's effects. NAFLD was confirmed by steatosis score, dyslipidemia, altered glycemic, and redox status. HGF/NF-κB/SNARK was downregulated in HFD-fed rats receiving AICAR with improved hepatic steatosis and reduced inflammatory cytokines and oxidative stress. Aside from AMPK dominance, AICAR improved hepatic fatty acid oxidation and alleviated the ER stress response. In addition, it restored mitochondrial homeostasis by modulating Sirtuin 2 and mitochondrial quality gene expression. Our results provide a new mechanistic insight into the prophylactic role of AICAR in the prevention of NAFLD and its complications.

Comparative Histological Study of Therapeutic Effect of Mesenchymal Stem Cells versus Mesenchymal Stem Cells Co-Cultured with Liver Tissue on Carbon Tetrachloride-Induced Hepatotoxicity in Adult Male Albino Rats.

Context: Liver diseases are major causes of morbidity and mortality. Mesenchymal stem cells (MSCs) have immunomodulatory, anti-inflammatory, and antifibrotic effects, so they can be used in the treatment of liver diseases. MSCs co-cultured with diseased liver tissue improve the homing capacity, survival rate, and paracrine effects of the MSCs, as well as the ability to enhance liver function. Aims: This work aimed to study the therapeutic effect of MSCs versus MSCs co-cultured with liver tissue on carbon tetrachloride (CCl4)-induced hepatotoxicity in adult male albino rats. Settings and Design: Twenty adult male albino rats were divided into four equal groups; Group I (control group), Group II received CCl4 intraperitoneally (i.p.), Group III received CCl4 i.p. and then injected with MSCs intravenously (i.v.), and Group IV received CCl4 i.p. and then injected with co-cultured MSCs i.v. Materials and Methods: Finally, liver specimens were processed for light microscopy (LM) and electron microscopy (EM). Statistical analysis was carried out to assess histological scoring, area percentage of collagen fibers, number of glial fibrillary acidic protein-positive cells, and biochemical analysis of alanine aminotransferase and aspartate aminotransferase. Statistical Analysis Used: Statistical analysis of (histological scoring, area % of collagen fibers, and biochemical analysis) was done by using one-way analysis of variance (ANOVA) test using graphpad software (SanDiego, CA, USA). The means ± standard deviations were used for statistical analysis. Results: LM of Group II revealed loss of hepatic architecture and diffuse fibrosis with dilated congested blood vessels, bile ductular proliferation, and cellular infiltrations. Vacuolated cytoplasm with or without pyknotic nuclei was observed in addition to micro- and macro-steatosis. EM demonstrated disfigured hepatocytes with abnormal organelles surrounding atypical nucleus. Group III showed restoration of the normal liver architecture with greater extent in Group IV. Statistical analysis confirmed the microscopic findings. Conclusions: Co-cultured MSCs with diseased liver tissue augmented the therapeutic effects of MSCs in treating hepatotoxicity induced by CCl4 in adult male albino rats.

The clinical and electron microscopic evaluation of the impact of pulsed dye laser techniques on solar lentigines (randomized clinical trial).

BACKGROUND: Solar lentigines are skin lesions manifested by benign dark pigmentation causing a cosmetic problem in many patients. Several treatment modalities used for the management of solar lentigines. Side effects and rates of recurrence may be associated with them. OBJECTIVE: Treating solar lentigines with two different techniques of pulsed dye laser (PDL) and evaluation of the results both clinically and via the examination of ultrastructural changes by electron microscopy. PATIENTS AND METHODS: This study was conducted on 22 subjects with solar lentigines and having Fitzpatrick III-IV skin types, was managed by the use of PDL after enrolling them into two groups. Group I (one stacked PDL was used) and Group II (treated by stacked PDL in two sessions, 1 month apart). At baseline and 6 months after treatment, two punch biopsies with a diameter of 2 mm were taken from all patients. All taken biopsies were prepared for light and electron microscopic examinations. RESULTS: Both PDL techniques induced significant better clinical and histological outcomes. No one demonstrated any postoperative complications such as post-inflammatory hyperpigmentation and scarring. CONCLUSIONS: The two techniques of PDL are efficient for solar lentigines treatment.

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.

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.

Thyroidectomy induces thyroglobulin formation by parotid salivary glands in rats.

Structural changes in parotid gland (PG) were previously reported following ablation of thyroid gland. However, the functional alterations (especially for proteins) have not been elucidated yet. Herein, we investigated the effect of rat thyroidectomy on PG structure and protein content and studied the ability of thyroxin-supplementation to alleviate the associated structural and functional changes. Male young adult 4-month old albino rats (n = 48) were allocated equally into 4 groups (control, sham-operated, thyroidectomized, and thyroxin-supplemented). PGs were examined histologically, and their proteins expression and localization were analyzed using western blot (WB) and immunohistochemistry (IHC), respectively at 3 w and 5 w post-surgery. Functionally, PGs of thyroidectomized rats formed a newly expressed 300 KDa protein, which was confirmed to be thyroglobulin (TG) by WB and IHC, with higher expression at 5 w. TG was localized in the interstitium, within capillaries, in the cytoplasm of the intralobular ductal cells, in the secretory products within the ductal lumen, and in the cytoplasm of individual small cells at the periphery of the acini. This functional change accompanied by structural changes in PGs (presence of dark and light acinar cells, TG-like colloid material, and high periductal vasculature). Noteworthy, PG of the thyroxin-supplemented depicted vanishment of TG. From these data, it could be concluded that thyroidectomy could alter the morphology and function of the parotid that induce a thyroid-like reprogramming of the parotid to secrete TG and thyroxin supplementation could alleviate this effect.

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.

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.

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.

Ginger and vitamin C as protective agents against oxidative stress and liver injury induced by methyl parathion

Methyl parathion is one of the highly toxic organophosphorus (OP) compounds. It induces hepatotoxicity, which might be related to generation of reactive oxygen species. This study was carried out to investigate the protective roles of vitamins C and ginger against hepatotoxicity induced by methyl parathion in male albino rats.Sixty male albino rats were randomly divided into 6 groups (ten rats each). Group I was considered as controls. Animals of groups II, III and IV were given methyl parathion (2 mg/kg), ginger (200 mg/kg) and vitamin C (100 mg/kg) respectively. Groups V and VI were given ginger (200 mg/kg) and vitamin C (100 mg/kg) respectively 2 hours before methyl parathion administration. All animals were treated orally, once daily, for four weeks. Blood and liver samples were obtained for biochemical, immunohistochemistry and histopathological examinations.Administration of either ginger or vitamin C along with methyl parathion significantly reduced the alanine aminotransferase (ALT) and malondialdehyde (MDA) levels in rats compared to those only treated with methyl parathion. Treatment with either ginger or vitamin C in combination with methyl parathion resulted in increased level of reduced glutathione compared to the methyl parathion treated group. However, oral ginger significantly increased glutathione-S-transferase levels compared to the control group, and this may outbalance the protective value of ginger over vitamin C to guard against liver injury and oxidative stress. The immunohistochemical and histopathological examinations showed that ginger or vitamin C combination with methyl parathion resulted in less hepatocytes degeneration and milder portal tract infiltration compared to the methyl parathion group.In conclusion, pre-treatment with either ginger or vitamin C appears to alleviate methyl parathion-inducted hepatotoxicity. However, their protective role is still limited and needs further investigation

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Morphometric and ultrastructural analysis of tramadol effects on epididymis: an experimental study.

The effect of tramadol addiction on epididymal structure was not investigated before. Therefore, this experimental study was carried out to investigate the effect of chronic tramadol use on the epididymal structure using light and electron microscopies. Thirty adult Wister Albino male rats were divided into two groups: control group (five rats) and tramadol-treated group (25 rats), which was further subdivided into five subgroups that received tramadol orally at 4.5, 9, 45, 90, and 135 mg/kg/day, respectively, for 18 weeks. Epididymal tissues were dissected and processed for histopathological examination. Morphometric analysis showed significantly reduced mean values of epididymal ducts' diameters and epithelial height in the tramadol-treated group compared with the control group. Light microscopic examination revealed degeneration and necrosis of epididymal cells in the tramadol-treated group. Electron microscopic (EM) examination showed ultrastructure alterations in a dose-dependent manner. In conclusion, tramadol can adversely affect all epididymal cells, which subsequently deteriorate epididymal function and may affect sperm maturation, leading to subfertility.

Anti-fibrotic potential of human umbilical cord mononuclear cells and mouse bone marrow cells in CCl4- induced liver fibrosis in mice.

Liver fibrosis is the consequence of hepatocyte injury that leads to the activation of hepatic stellate cells (HSC). The treatment of choice is Liver transplantation; however, it has many problems such as surgery-related complications, immunological rejection and high costs associated with the procedure. Stem cell-based therapy would be a potential alternative, so the aim of this study is to investigate the therapeutic potential of human umbilical cord mononuclear cells (MNC) and mouse bone marrow cells (BMC) against carbon tetrachloride (CCl4) induced liver fibrosis in mice and compare it with that of silymarin. In the present study, male albino mice (N=60) were divided into six groups (10 mice each), the first group served as the normal control group while the remaining five groups were rendered fibrotic by intraperitoneal injections of CCl4 and being left for 6 weeks to develop hepatic fibrosis. Thereafter, the mice were divided into CCl4 group, CCl4 group receiving MNC or BMC or silymarin or MNC and silymarin combination. After the specified treatment period, animals were then euthanized, blood and tissue samples were collected for measurement of alanine aminotransferase(ALT), aspartate aminotransferase(AST), malondialdehyde(MDA), reduced glutathione(GSH), collagen, Laminin, transforming growth factor ß1(TGFß1), tumor necrosis factor alpha(TNFα). MNC, BMC, and the combination therapy showed a significant decrease in ALT, AST, MDA, collagen, Laminin, TGFß1, and TNFα and a significant increase in GSH. The data displayed a similar regression of fibrosis with the histological and immunohistological parameters. In conclusion, MNC, BMC and the combination therapy showed a potential therapeutic effect against liver fibrosis via reducing oxidative stress, inflammatory mediators, and fibrogenic markers.

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.

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.

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.

Histological and immunohistochemical study of the effect of gold nanoparticles on the brain of adult male albino rat.

Gold nanoparticles (GNPs) have numerous medical applications as in biological imaging, cancer treatment and in implants (pacemakers and stents). Many conflicting results about GNPs safety and its accumulation in liver, kidney and brain were recorded. This work was carried out to study the histological effect of long period exposure to gold nanoparticle on the brain of adult male albino rat. Twenty adult male albino rats were divided into two equal groups: The first one served as a control group and the second one received 400 µg/kg/day GNPs by gastric tube once daily for eight weeks. Brain specimens were collected at the end of the experiment for histological and immunohistochemical studies using caspase-3 and glial fibrillary acidic protein (GFAP). GNPs treated group revealed wide spread histological alterations and deposition of gold nanoparticle aggregates in the neurons of cerebral cortex and hippocampus and also in the epithelium of choroid plexus with hyalinization of the wall of some blood vessels and disruption of the capillaries. All these changes were associated with localized positive caspase 3 reaction. Various degrees of astrogliosis were evidenced by astrocytic proliferation and increase size of their cell body with increase number and length of their processes. It could be concluded that repeated exposure of adult male albino rats to gold nanoparticles induced its deposition in the brain in association with histological alterations and various degrees of astrogliosis.

Resveratrol protects against experimental induced Reye's syndrome by prohibition of oxidative stress and restoration of complex I activity.

This study was designed to investigate whether resveratrol could provide protection against Reye's syndrome induced by 4-pentenoic acid in Wistar albino rats. Compared with rats with untreated Reye's syndrome, 1 h pretreatment by low dose resveratrol (10 mg/kg by oral gavage) resulted in marked amelioration in liver functions in the form of significant decrease in serum transaminases (AST, ALT) and plasma ammonia levels, shortening of prothrombin time, and increase in serum albumin levels. In addition, resveratrol prohibited oxidative stress markers, as indicated by a significant increase in GSH and decrease in MDA, with restoration of complex I activity in liver tissues. The classical histopathological presentation in Reye's syndrome of microvesicular steatosis by light microscope and mitochondria distortion by electron microscope has been improved by resveratrol pretreatment. The efficient protection by resveratrol was determined by normalization in serum levels of AST and albumin, as well as complex I activity, GSH, and MDA. In conclusion, pretreatment by resveratrol in low doses could protect against Reye's syndrome partially via prohibition of oxidative stress and restoration of complex I activity. This may provide the opportunity to reconsider aspirin therapy for infants and young children. However, the verification of such results in clinical practice remains a challenge.