Nrf2/HO-1, NF-κB and PI3K/Akt signalling pathways decipher the therapeutic mechanism of pitavastatin in early phase liver fibrosis in rats.

Liver fibrosis is a common chronic hepatic disease. This study aimed to investigate the effect of pitavastatin (Pit) against thioacetamide (TAA)-induced liver fibrosis. Rats were divided into four groups: (1) control group; (2) TAA group (100 mg/kg, i.p.) three times weekly for 2 weeks; (3 and 4) TAA/Pit-treated group, in which Pit was administered orally (0.4 and 0.8 mg/kg/day) for 2 weeks following TAA injections. TAA caused liver damage manifested by elevated serum transaminases, reduced albumin and histological alterations. Hepatic malondialdehyde (MDA) was increased, and glutathione (GSH) and superoxide dismutase (SOD) were decreased in TAA-administered rats. TAA upregulated the inflammatory markers NF-κB, NF-κB p65, TNF-α and IL-6. Treatment with Pit ameliorated serum transaminases, elevated serum albumin and prevented histopathological changes in TAA-intoxicated rats. Pit suppressed MDA, NF-κB, NF-κB p65, the inflammatory cytokines and PI3K mRNA in TAA-intoxicated rats. In addition, Pit enhanced hepatic antioxidants and boosted the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) mRNA. Moreover, immunohistological studies supported the ability of Pit to reduce liver fibrosis via suppressing p-AKT expression. In conclusion, Pit effectively prevents TAA-induced liver fibrosis by attenuating oxidative stress and the inflammatory response. The hepatoprotective efficacy of Pit was associated with the upregulation of Nrf2/HO-1 and downregulation of NF-κB and PI3K/Akt signalling pathways.

GSK-3ß/Notch-1 Activation Promotes Radiation-Induced Renal Damage: The Role of Gallic Acid in Mitigation of Nephrotoxicity.

Despite the therapeutic advances in treating malignancies, the efficient radiotherapeutic approaches with deprived adverse reactions still represent a potential clinical inquiry. The current study aims to elucidate the role of gallic acid (GA) in modifying the hazardous renal cytotoxicity induced by acute exposure to radiation. The MTT test was used to evaluate the viability of Vero cells exposed to 2 Gy gamma radiation with or without incubation of GA. In an in vivo model, male Wistar rats were divided into four experimental groups (n = 6): Control, Irradiated (IRR, 5 Gy), GA (100 mg/kg, i.p.) + IRR, and Glycogen synthase kinase inhibitor (GSKI, 3 mg/kg, i.p.) + IRR. Based on the MTT toxicity assay, from 0 and up to 5 µM dosages of GA did not demonstrate any cytotoxicity to Vero cells. The optimal GA dose that could protect the cells from radiation was 5 µM. Furthermore, GA exerted a protective effect from gamma radiation on renal tissue as indicated by corrected renal functions, decreased LDH level in serum, and balanced oxidative status, which is indicated by decreased tissue contents of NOx and TBARS with a significant increase of reduced GSH. These outcomes were inferred by the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) expression. The overall molecular impact of radiation in damaging the renal tissue may be explained by modifying the upstream AKT activity and its downstream targets GSK-3ß/Notch-1. Here, we concluded that the anticipated adverse reaction in the course of radiation exposure could be protected by daily administration of GA.

Dynamic expression of H19 and MALAT1 and their correlation with tumor progression biomarkers in a multistage hepatocarcinogenesis model.

Hepatocellular carcinoma (HCC) progresses sequentially in a stepwise pattern. Long noncoding RNA (lncRNA) can regulate the complex cascade of hepatocarcinogenesis. Our study aimed to elucidate the expression profile of H19 and MALAT1 during the different stages of hepatocarcinogenesis and the correlation between H19 and MALAT1 with the genes implicated in the carcinogenesis cascade. We employed a chemically induced hepatocarcinogenesis murine model to mimic the successive stages of human HCC development. Using real-time PCR, we analyzed the expression patterns of H19 and MALAT1, as well as the expression of biomarkers implicated in the Epithelial-Mesenchymal transition (EMT). The protein expression of the mesenchymal marker vimentin was also evaluated using immunohistochemistry in the stepwise induced stages. The histopathological evaluation of the liver tissue sections revealed significant changes during the experiment, with HCC developing at the final stage. Throughout the stages, there was a dynamic significant increase in the expression of H19 and MALAT1 compared to the normal control. Nevertheless, there was no significant difference between each stage and the preceding one. The tumor progression biomarkers (Matrix Metalloproteinases, vimentin, and ß-catenin) exhibited the same trend of steadily increasing levels. However, in the case of Zinc finger E-box-binding homeobox 1 and 2 (ZEB1 and ZEB2), the significant elevation was only detected at the last stage of induction. The correlation between lncRNAs and the tumor progression biomarkers revealed a strong positive correlation between the expression pattern of H19 and MALAT1 with Matrix Metalloproteinases 2 and 9 and vimentin. Our findings imply that genetic and epigenetic alterations influence HCC development in a stepwise progressive pattern.

Potential for cardiac toxicity with methylimidazolium ionic liquids.

Methylimidazolium ionic liquids (MILs) are solvent chemicals used in industry. Recent work suggests that MILs are beginning to contaminate the environment and lead to exposure in the general population. In this study, the potential for MILs to cause cardiac toxicity has been examined. The effects of 5 chloride MIL salts possessing increasing alkyl chain lengths (2 C, EMI; 4 C, BMI; 6 C; HMI, 8 C, M8OI; 10 C, DMI) on rat neonatal cardiomyocyte beat rate, beat amplitude and cell survival were initially examined. Increasing alkyl chain length resulted in increasing adverse effects, with effects seen at 10-5 M at all endpoints with M8OI and DMI, the lowest concentration tested. A limited sub-acute toxicity study in rats identified potential cardiotoxic effects with longer chain MILs (HMI, M8OI and DMI) based on clinical chemistry. A 5 month oral/drinking water study with these MILs confirmed cardiotoxicity based on histopathology and clinical chemistry endpoints. Since previous studies in mice did not identify the heart as a target organ, the likely cause of the species difference was investigated. qRT-PCR and Western blotting identified a marked higher expression of p-glycoprotein-3 (also known as ABCB4 or MDR2) and the breast cancer related protein transporter BCRP (also known as ABCG2) in mouse, compared to rat heart. Addition of the BCRP inhibitor Ko143 - but not the p-glycoproteins inhibitor cyclosporin A - increased mouse cardiomyocyte HL-1 cell sensitivity to longer chain MILs to a limited extent. MILs therefore have a potential for cardiotoxicity in rats. Mice may be less sensitive to cardiotoxicity from MILs due in part, to increased excretion via higher levels of cardiac BCRP expression and/or function. MILs alone, therefore may represent a hazard in man in the future, particularly if use levels increase. The impact that MILs exposure has on sensitivity to cardiotoxic drugs, heart disease and other chronic diseases is unknown.

Immunological insights into the resistance of Nile tilapia strains to an infection with tilapia lake virus.

The emergence of viral diseases affecting fish and causing very high mortality can lead to the disruption of aquaculture production. Recently, this occurred in Nile tilapia aquaculture where a disease caused by a systemic infection with a novel virus named tilapia lake virus (TiLV) caused havoc in cultured populations. With mortality surpassing 90% in young tilapia, the disease caused by TiLV has become a serious challenge for global tilapia aquaculture. In order to partly mitigate the losses, we explored the natural resistance to TiLV-induced disease in three genetic strains of tilapia which were kept at the University of Göttingen, Germany. We used two strains originating from Nilotic regions (Lake Mansala (MAN) and Lake Turkana (ELM)) and one from an unknown location (DRE). We were able to show that the virus is capable of overcoming the natural resistance of tilapia when injected, providing inaccurate mortality results that might complicate finding the resistant strains. Using the cohabitation infection model, we found an ELM strain that did not develop any clinical signs of the infection, which resulted in nearly 100% survival rate. The other two strains (DRE and MAN) showed severe clinical signs and much lower survival rates of 29.3% in the DRE strain and 6.7% in the MAN strain. The disease resistance of tilapia from the ELM strain was correlated with lower viral loads both at the mucosa and internal tissues. Our results suggest that the lower viral load could be caused by a higher magnitude of a mx1-based antiviral response in the initial phase of infection. The lower pro-inflammatory responses also found in the resistant strain might additionally contribute to its protection from developing pathological changes related to the disease. In conclusion, our results suggest the possibility of using TiLV-resistant strains as an ad hoc, cost-effective solution to the TiLV challenge. However, as the fish from the disease-resistant strain still retained significant virus loads in liver and brain and thus could become persistent virus carriers, they should be used within an integrative approach also combining biosecurity, diagnostics and vaccination measures.\.

Design, synthesis, anti-inflammatory evaluation and molecular docking of novel thiophen-2-ylmethylene-based derivatives as potential TNF-α production inhibitors.

Inflammation is considered to be an alarming signal for the progress of varied biological complications. Based on the previous reports in the literature that proved the noticeable efficacy of thiophene scaffold as well as nitrogen heterocyclic based compounds against acute and chronic inflammatory disease, a new set of thiophen-2-ylmethylene-based derivatives incorporated with various nitrogenous heterocyclic rings was synthesized and evaluated for their in vivo anti-inflammatory efficiency via applying formalin-induced paw edema bioassay using celecoxib as a standard drug. Compounds 6 and 11a displayed fast onset as well as long duration of anti-inflammatory potency better than that of celecoxib. However, compounds 4a, 7a, 7b and 9b exhibited moderate anti-inflammatory efficiency compared with celecoxib. Ulcerogenic activity and histopathology studies were also carried out. Moreover, the analgesic evaluation of some bioactive candidates revealed that compound 6 showed a promising and long acting analgesic effect exceeding that of the reference drug. While, compounds 4a and 7a displayed mild analgesic activity. Furthermore, the inhibitory effects of some potent anti-inflammatory derivatives on the production of tumor necrosis factor-alpha (TNF-α) were tested. The obtained results revealed that compounds 6 and 11a displayed a remarkable inhibitory effect on the production of TNF-α greater than that of celecoxib. Otherwise, compounds 4a and 7a showed nearly the same inhibitory effect as celecoxib. Finally, the molecular docking study was performed for the tested derivatives 4a, 4b, 6, 7a, 9a and 11a to understand the binding interactions with the active site of TNF-α.

Antineoplastic activity of Salmonella Typhimurium outer membrane nanovesicles.

Nano-sized Gram-negative bacterial outer membrane vesicles possess unique structural and immunostimulatory effects that could be exploited to regress tumors by alerting the host immune system and reversing the immunosuppressive tumor microenvironment. The current study was conducted to investigate the antitumor activity of the outer membrane vesicles (ST-OMVs) of Salmonella Typhimurium ATCC 14028, in vitro in human colorectal carcinoma (HTC116), breast cancer (MCF-7), and hepatocellular carcinoma (HepG2) cell lines and in vivo in Ehrlich solid carcinoma-bearing mice model either as a mono-immunotherapy or as an adjuvant to a commonly used conventional chemotherapy. In addition, we investigated the safety of ST-OMVs. Adult Swiss albino female mice with transplanted Ehrlich solid carcinoma were treated with either ST-OMVs, paclitaxel or a combination of both. Tumor volume, growth inhibition rate, quantitative RT-PCR of Bax and VEGF genes expression, histopathology and immune-expression of caspase-3, Beclin-1, CD49b and Ki-67 were all analyzed. Our results showed that ST-OMVs significantly decreased tumor volume, significantly increased tumor growth inhibition rate, up-regulated the immunohistochemical expression of caspase-3, Beclin-1, and CD49b (enhanced recruitment of NK cells). Furthermore, ST-OMVs down-regulated the expression of Ki-67, increased Bax gene expression and decreased VEGF gene expression as detected by qRT-PCR analysis. Histologically, ST-OMVs promoted apoptosis, decreased tumor invasion and mitotic activities. Moreover, ST-OMVs showed a remarkable cytotoxic activity in various investigated in vitro cancer cell lines. Our findings demonstrate potential antitumor activity of ST-OMVs that might be used as a promising safe antitumor immunotherapy or an adjuvant to conventional chemotherapeutic drugs, resolving some of their problems.

Targeting the Oxytocin System to Ameliorate Early Life Depressive-Like Behaviors in Maternally-Separated Rats.

Oxytocin (OXT) -"the love hormone"- has been involved in the anti-depressant activity of some selective serotonin reuptake inhibitors (SSRIs). The exact mechanism underlying the OXT pathway in depression is not fully clear. This study aimed to investigate the effect of OXT analogue, carbetocin (CBT) and the SSRI, escitalopram (ESCIT) on depressive-like behaviors following maternal separation (MS). It is worthy to mention that intranasal CBT has been approved by U.S. Food and Drug Administration (FDA) for Prader-Willi syndrome. Adolescent Wistar albino maternally-separated rats were given CBT, (100 µg/animal/d via inhalation route), and, ESCIT, (20 mg kg-1, per os ( p.o.)) either alone or in combination for 7 d. Repeated 3-h MS demonstrated increased immobility time in forced swim test (FST) and decreased locomotor activity in open field test. MS elevated plasma level of adrenocortico-trophic hormone (ACTH) but notably reduced plasma OXT, with no effect on hippocampal OXT-R expression. Following MS, hippocampal contents of 5-hydroxytryptamine receptors (5HT1A-R), serotonin transporter (SERT) were increased. CBT and ESCIT corrected the behavioral dysfunction in FST and suppressed the high levels of ACTH. Additionally, both treatments boosted OXT level, reduced 5HT1A-R and normalized SERT contents, which reflects increased availability of serotonin. Finally, CBT markedly ameliorated the histopathological damage induced by MS and suppressed the increased glial fibrillary acidic protein. CBT and ESCIT manage depressive-like behavior by positively affecting serotonergic and oxytocinergic systems. Targeting OXT system -using CBT- ameliorated depressive like behaviors induced by maternal separation most probably via enhancing OXT plasma levels, attenuating hormonal ACTH and restoring the expression of hippocampal oxytocin and serotonin mechanisms.

Poly(ADP-Ribose) Polymerase 1 Promotes Inflammation and Fibrosis in a Mouse Model of Chronic Pancreatitis.

Chronic pancreatitis (CP) is an inflammatory disease of the pancreas characterized by ductal obstructions, tissue fibrosis, atrophy and exocrine and endocrine pancreatic insufficiency. However, our understanding is very limited concerning the disease's progression from a single acute inflammation, via recurrent acute pancreatitis (AP) and early CP, to the late stage CP. Poly(ADP-ribose) polymerase 1 (PARP1) is a DNA damage sensor enzyme activated mostly by oxidative DNA damage. As a co-activator of inflammatory transcription factors, PARP1 is a central mediator of the inflammatory response and it has also been implicated in acute pancreatitis. Here, we set out to investigate whether PARP1 contributed to the pathogenesis of CP. We found that the clinically used PARP inhibitor olaparib (OLA) had protective effects in a murine model of CP induced by multiple cerulein injections. OLA reduced pancreas atrophy and expression of the inflammatory mediators TNFα and interleukin-6 (IL-6), both in the pancreas and in the lungs. Moreover, there was significantly less fibrosis (Masson's trichrome staining) in the pancreatic sections of OLA-treated mice compared to the cerulein-only group. mRNA expression of the fibrosis markers TGFß, smooth muscle actin (SMA), and collagen-1 were markedly reduced by OLA. CP was also induced in PARP1 knockout (KO) mice and their wild-type (WT) counterparts. Inflammation and fibrosis markers showed lower expression in the KO compared to the WT mice. Moreover, reduced granulocyte infiltration (tissue myeloperoxidase activity) and a lower elevation of serum amylase and lipase activity could also be detected in the KO mice. Furthermore, primary acinar cells isolated from KO mice were also protected from cerulein-induced toxicity compared to WT cells. In summary, our data suggest that PARP inhibitors may be promising candidates for repurposing to treat not only acute but chronic pancreatitis as well.

Oral and Topical Anti-Inflammatory and Antipyretic Potentialities of Araucaria bidiwillii Shoot Essential Oil and Its Nanoemulsion in Relation to Chemical Composition.

Different parts of Araucaria bidiwillii (bunya pin) trees, such as nuts, seeds, bark, and shoots, are widely used in cooking, tea, and traditional medicines around the world. The shoots essential oil (EO) has not yet been studied. Herein, the chemical profile of A. bidiwillii shoots EO (ABSEO) was created by GC-MS analysis. Additionally, the in vivo oral and topical anti-inflammatory effect against carrageenan-induced models, as well as antipyretic potentiality of ABSEO and its nanoemulsion were evaluated. Forty-three terpenoid components were identified and categorized as mono- (42.94%), sesqui- (31.66%), and diterpenes (23.74%). The main compounds of the ABSEO were beyerene (20.81%), α-pinene (16.21%), D-limonene (14.22%), germacrene D (6.69%), ß-humulene (4.14%), and sabinene (4.12%). The ABSEO and its nanoemulsion exhibited significant inflammation suppression in carrageenan-induced rat paw edema model, in both oral (50 and 100 mg/kg) and topical (5% in soyabean oil) routes, compared to the control and reference drugs groups. All the results demonstrated the significant inflammation reduction via the inflammatory cytokines (IL-1ß and IL8), nitrosative (NO), and prostaglandin E2 (PGE2) supported by the histopathological studies and immunohistochemical assessment of MMP-9 and NF-κß levels in paw tissues. Moreover, the oral administration of ABSEO and its nanoemulsion (50 and 100 mg/kg) exhibited antipyretic activity in rats, demonstrated by the inhibition of hyperthermia induced by intramuscular injection of brewer's yeast. These findings advised that the use of ABSEO and its nanoemulsion against numerous inflammatory and hyperthermia ailments that could be attributed to its active constituents.

Co-infection of Salmonella enteritidis with H9N2 avian influenza virus in chickens.

Salmonella and avian influenza virus are important pathogens affecting the poultry industry and human health worldwide. In this experimental study, we evaluated the consequences of co-infection of Salmonella enteritidis (SE) with H9N2 avian influenza virus (H9N2-AIV) in chickens. Four groups were included: control group, H9N2-AIV group, H9N2-AIV + SE group, and SE group. Infected chickens were intranasally inoculated with H9N2-AIV at 21 days of age and then orally administered SE on the same day. The birds were monitored for clinical signs, mortality rates, and alterations in body weight. Sera, intestinal fluids, oropharyngeal, and cloacal swabs, and tissue samples were collected at 2, 6, 10, and 14 days post-infection (dpi). Significant increases in clinical signs and mortality rates were observed in the H9N2-AIV + SE group. Moreover, chickens with co-infection showed a significant change in body weight. SE faecal shedding and organ colonization were significantly higher in the H9N2-AIV + SE group than in the SE group. H9N2-AIV infection compromised the systemic and mucosal immunity against SE, as evidenced by a significant decrease in lymphoid organ indices as well as systemic antibody and intestinal immunoglobulin A (IgA) responses to SE and a significant increase in splenic and bursal lesion scores. Moreover, SE infection significantly increased shedding titres and duration of H9N2-AIV. In conclusion, this is the first report of co-infection of SE with H9N2-AIV in chickens, which leads to increased pathogenicity, SE faecal shedding and organ colonization, and H9N2-AIV shedding titre and duration, resulting in substantial economic losses and environmental contamination, ultimately leading to increased zoonoses.

Differences in the tissue tropism to chicken oviduct epithelial cells between avian coronavirus IBV strains QX and B1648 are not related to the sialic acid binding properties of their spike proteins.

The avian coronavirus (AvCoV) infectious bronchitis virus (IBV) is a major poultry pathogen. A characteristic feature of IBV is the occurrence of many different strains belonging to different serotypes, which makes a complete control of the disease by vaccinations a challenging task. Reasons for differences in the tissue tropism and pathogenicity between IBV strains, e.g. a predilection for the kidneys or the oviduct are still an open question. Strains of the QX genotype have been major pathogens in poultry flocks in Asia, Europe and other parts of the world. They are the cause of severe problems with kidney disease and reproductive tract disorders. We analysed infectivity and binding properties of the QX strain and compared them with those of the nephropathogenic strain B1648. As most IBV strains do not infect permanent cell lines and show infection only in primary chicken cells of the target organs, we developed a culture system for chicken oviduct explants. The epithelial cells of the oviduct showed a high susceptibility to infection by the QX strain and were almost resistant to infection by the nephropathogenic B1648 strain. Binding tests with isolated primary oviduct epithelial cells and soluble S1 proteins revealed that S1 proteins of two IBV strains bound with the same efficiency to oviduct epithelial cells. This attachment was sialic acid dependent, indicating that the sugar binding property of IBV spike proteins is not the limiting factor for differences in infection efficiency for the oviduct of the corresponding viruses.

Preliminary molecular study for DIVA trial of antigenically characterized circulating bovine herpesvirus subtype 1.1 in Egypt.

Using marker vaccines to control bovine alphaherpesvirus-1 (BoHV-1) is a novel strategy for differentiation between infected and vaccinated animals (DIVA). In this study, multiplex real-time PCR targeting gD and gE genes was applied for BoHV-1 screening on 60 clinical samples from cattle with a history of vaccination, in some cases by US2-deleted marker vaccines, that were suffering from severe respiratory symptoms. Conventional PCR targeting the gC and US2 flanking region was done for molecular characterization and identification of the US2-deleted vaccine strain. Six samples were positive for BoHV-1 by both RT-PCR and conventional PCR. Surprisingly, a conventional PCR DIVA trial based on the US2 gene revealed that only one sample that exhibited the US2 gene was a wild virus, while others that did not exhibit the US2 gene were vaccine viruses. Phylogenetic characterization classifies the samples as BoHV-1.1. This finding reveals the circulation of vaccine virus in field-diseased animals, which threatens the eradication program.

Do Nanoparticles of Calcium Disodium EDTA Minimize the Toxic Effects of Cadmium in Female Rats?

The present study aims to investigate the ability of CaNa2EDTA (ethylenediaminetetraacetic acid) macroparticles and nanoparticles to treat cadmium-induced toxicity in female rats and to compare their efficacies. Forty rats were divided into 4 equal groups: control, cadmium, cadmium + CaNa2EDTA macroparticles and Cd + CaNa2EDTA nanoparticles. Cadmium was added to the drinking water in a concentration of 30 ppm for 10 weeks. CaNa2EDTA macroparticles and nanoparticles (50 mg/kg) were intraperitoneally injected during the last 4 weeks of the exposure period. Every two weeks, blood and urine samples were collected for determination of urea, creatinine, metallothionein and cadmium concentrations. At the end of the experiment, the skeleton of rats was examined by X-ray and tissue samples from the kidney and femur bone were collected and subjected to histopathological examination. Exposure to cadmium increased the concentrations of urea and creatinine in the serum and the concentrations of metallothionein and cadmium in serum and urine of rats. A decrease in bone mineralization by X-ray examination in addition to various histopathological alterations in the kidney and femur bone of Cd-intoxicated rats were also observed. Treatment with both CaNa2EDTA macroparticles and nanoparticles ameliorated the toxic effects induced by cadmium on the kidney and bone. However, CaNa2EDTA nanoparticles showed a superior efficacy compared to the macroparticles and therefore can be used as an effective chelating antidote for treatment of cadmium toxicity.

Appraisal of the Pre-Emptive Effect of Lactoferrin Against Chromium-Induced Testicular Toxicity in Male Rats.

Lactoferrin (LCF), a potent naturally occurring antioxidant, is a crucial component in preventing potassium dichromate (PDC) toxicity. The goal of the current work was to study the potential efficacy of LCF in preventing PDC(CrVI)-induced testicular toxicity and oxidative injury in rats. Six groups of male rats of Wistar stain were randomly categorized into: group 1, which served as the control; group 2 and 3 received LCF (200 and 300 mg/kg orally, respectively); group 4 received PDC (2 mg/kg i.p.); group 5 and 6 pretreated with LCF, followed by PDC as in group 4 with 90 min apart for 28 days. PDC-intoxicated rats showed a significantly altered spermogram with abnormal sperm morphology. PDC significantly upregulated serum FSH and downregulated testosterone levels. Additionally, PDC decreased the levels of testicular key antioxidant biomarkers (catalase (CAT), superoxide dismutase (SOD), and glutathione (GSH)) with elevated lipid peroxidation marker (TBARS) and testicular chromium content. Moreover, it upregulated testicular proinflammatory cytokines, IL-1, IL-6, IL-10, and TNF-α, induced histopathological changes in testes with significant immunohistochemical expression of FasL and moderate expression of Nrf2. Pretreatment with LCF significantly mitigated PDC-induced testicular toxicity by enhancing spermogram, improving hormonal levels, restoring testicular oxidant/antioxidant balance, and decreasing testicular IL-1, IL6, IL-10, and TNFα levels, and amending both FasL and Nrf2 immunohistochemical-expression. Additionally, LCF improved testicular histopathological picture and spermatogenesis. Our results highlight the importance of LCF as a superior protective modulator of PDC-induced testicular injury.

The Palliative and Antioxidant Effects of Hesperidin against Lead-Acetate-Induced Testicular Injury in Male Wistar Rats.

Lead (Pb)-induced reprotoxicity is a detrimental consequence of Pb exposure, which results in abnormal spermatogenesis, testicular degeneration, and pathogenic sperm changes. The association between impaired male reproductive function and Pb-induced oxidative stress (OS) has been demonstrated, with consequent testicular antioxidant deficiency. The current study investigated the protective role of the natural antioxidant hesperidin (HSD) against lead-acetate (PbAc)-induced testicular toxicity. Male Wistar rats (n = 40) were randomly divided into four experimental groups: Group I (negative control) received 2.0 mL/kg BW 0.9% saline; Group II received 100 mg/kg BW PbAc; Group III received 100 mg/kg BW HSD; and Group IV received HSD two hours before PbAc using the abovementioned doses. The treatments were administered daily for 30 consecutive days. The results showed that HSD treatment significantly restored PbAc-induced decrease in body, epididymal, and testicular weights as well as in semen parameters, reproductive hormones, and testicular markers of OS. Reduced MDA levels and improved testicular histopathological findings were also observed. Collectively, this study sheds light on the preventive role of HSD against PbAc-induced testicular injury, which is mediated via the suppression of OS and the modulation of reproductive hormones as well as the plausibility of HSD being used as a supplementary therapeutic option for recovery.

Protective effect of acrocarpus fraxinifolius extract against hepatic fibrosis induced by Gamma irradiation and carbon tetrachloride in albino rats.

PURPOSE: Liver fibrosis is considered as one of the ultimate outcomes of chronic liver disorders, characterized by outrageous cell proliferation and abnormal deposition of extracellular matrix, resulting in sever pathological distortions in the architecture and performance of liver tissues. The present study aimed to investigate the protective properties of aqueous methanol extract of Acrocarpus fraxinifolius leaves (AFL) against liver fibrosis induced by dual toxicity of γ-irradiation and carbon tetrachloride (CCl4) in rats. METHODS: The animals were exposed to 2 Gy irradiation once/week concurrently with intraperitoneal administration of CCl4 (0.2 mL/100 g body weight) for seven weeks. Afterwards, liver toxicity and fibrosis were assessed biochemically at cellular and molecular as well as histopathological levels. RESULTS: The livers of intoxicated rats showed distinct structural and functional changes, compared with the normal rats. The administration of AFL (500 mg/kg, p.o) significantly ameliorated the histopathological manifestations of fibrotic liver evidenced by mitigated steatosis progression, necrosis, fibrotic septa, apoptotic bodies, and immunochistochemical studies of alpha-smooth muscle actin. Also, AFL increased the final body weight, total protein, albumin levels and albumin/globulin ratio. While, the absolute liver weight, liver enzymes, total cholesterol and triglycerides were reduced. A significant modulation was observed in hydroxyproline, transforming growth factor-ß and collagen-1expression. Furthermore, AFL exerted a direct effect on liver fibrosis by promoting extracellular matrix degradation via overexpression of the tissue inhibitor metalloproteinase-1, coupled with decease of metalloproteinase-9 activity. CONCLUSIONS: Our findings suggested that AFL effectively improved the architecture of fibrotic liver and modified the biochemical markers of liver fibrosis.

Novel naringin tablet formulations of agro-resides based nano/micro crystalline cellulose with neuroprotective and Alzheimer ameliorative potentials.

This study aimed to prepare micro/nanocrystalline cellulose-loaded naringin (NAR) tablets and evaluate their neuro-protective/therapeutic potentials in Alzheimer's disease (AD) model. Micro/nanocellulose was prepared from different agro-wastes, and the different cellulose preparations were then used to formulate eight oral tablets of naringin micro/nanoparticles by direct compression. AD-like symptoms were induced in adult male Sprague Dawley rats by co-administration of 150 mg/kg AlCl3 and 300 mg/kg D-galactose (oral administration/one week), and NAR tablets were assessed for neuroprotective/therapeutic potentials in terms of behavioral changes, levels of neurodegenerative and inflammatory markers, brain redox status, neurotransmitter tones, and cortex/hippocampus histopathological alterations. NAR treatments have significantly reversed the neurotoxic effect of AlCl3 as demonstrated by improved spatial and cognitive memory functions and promoted antioxidant defense mechanisms in treated AD animals. Also, the neurodegeneration was markedly restrained as reflected by marked histopathological enhancement, and prevention/amelioration of neuropsychiatric disorders, besides the restorative effect on dysregulated neurotransmitters tone. Both NAR tablet forms showed an overall higher ameliorative effect compared to the DPZ reference drug. The formulated tablets represent promising neuroprotective/therapeutic agents for Alzheimer's disease.

Chrysin loaded nanovesicles ameliorated diabetic peripheral neuropathy. Role of NGF/AKT/GSK-3ß pathway.

Diabetic peripheral neuropathy (DPN) is a common diabetic complication. Chrysin (CHY) has many biological properties but poor oral bioavailability. This study investigates the effect of CHY and CHY-loaded nanovesicles (CHY-NVs) on streptozotocin (STZ)-induced DPN in rats. CHY-NVs were prepared by using film hydration method. The formula with the best entrapment efficiency%, lowest particle size, highest zeta potential, and highest in vitro CHY released profile was selected, characterized by Differential scanning calorimetry, Fourier transformation infrared spectroscopy analysis, and examined by Transmission electron microscope. Acute toxicity test, pharmacokinetic study and experimental model of diabetes mellitus were performed on the selected formulation. Wistar rats were considered diabetic by administration of a single intraperitoneal dose of STZ (50 mg/kg). 48 h after STZ administration, hyperglycemic rats were randomly assigned into four groups, one group of untreated hyperglycemic rats and the other three groups received daily oral doses of unloaded NVs, CHY-NVs (25 mg/kg), and CHY-NVs (50 mg/kg), respectively for 21 days. Moreover, five additional groups of healthy rats received: distilled water (control), free CHY, unloaded NVs, and CHY-NVs respectively for 21 days. CHY and CHY-NVs maintained body weight and reduced STZ-induced behavioral changes in rotarod, hind paw cold allodynia, tail cold allodynia, tail flick, and hot plate tests. CHY and CHY-NVs lowered blood glucose, glycated hemoglobin, elevated serum reduced glutathione (GSH), and reduced plasma malondialdehyde (MDA) levels. CHY-NVs elevated phosphatidylinositol 3-kinase (Pi3k), phosphorylated protein kinase B (p-AKT), and reduced nuclear factor kappa B (NF-κB), interleukin-6 (IL-6) in sciatic nerve homogenate. CHY and CHY-NVs increased nerve growth factor (NGF) and decreased glycogen synthase kinase-3ß (GSK-3ß) gene expressions in the sciatic nerve. In conclusion, CHY and CHY-NVs ameliorated STZ-induced DPN behavioral and histopathological changes via attenuating hyperglycemia, exerting anti-oxidant, anti-inflammatory effects, activating NGF/p-AKT/GSK-3ß pathway, and its anti-apoptotic effect. The best pharmacokinetic profile and therapeutic effect was observed in rats treated with CHY-loaded NVs.

Retraction notice to "Dobera glabra (Forssk.) Poir. (Salvadoraceae); Phenolic constituents of the aqueous leaves extract and evaluation of its anti-inflammatory, analgesic activities" [Heliyon 7 (2021) e06205].

[This retracts the article DOI: 10.1016/j.heliyon.2021.e06205.].