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Despite its broad applications, cisplatin affords considerable nephro- and hepatotoxicity through triggering inflammatory and oxidative stress cascades. The aim of the current investigation was to study the possible protective effects of tangeretin on cisplatin-induced hepatotoxicity. The impact of tangeretin on cisplatin-evoked hepatic dysfunction and histopathologic changes along with oxidative stress, inflammatory and apoptotic biomarkers were investigated compared to silymarin. Tangeretin pre-treatment significantly improved liver function tests (ALT and AST), inhibited cisplatin-induced lipid profile aberrations (total cholesterol and triglycerides) and diminished histopathologic structural damage in liver tissues. Tangeretin also attenuated cisplatin-induced hepatic inflammatory events as indicated by suppression of tumor necrosis factor-α (TNF-α) and enhancement of interleukin-10 (IL-10). Meanwhile, it lowered malondialdehyde (MDA), nitric oxide (NO) and nuclear factor erythroid 2-related factor 2 (NRF-2) levels with restoration of glutathione (GSH), and glutathione peroxidase (GPx). Regarding mitogen-activated protein kinase (MAPK) pathway, tangeretin attenuated cisplatin-induced increase in phospho-p38, phospho-c-Jun N-terminal kinase (p-JNK) and phospho-extracellular signal-regulated kinase (p-ERK1/2) in liver tissues. In addition, tangeretin downregulated Bax expression with augmentation of Bcl-2 promoting liver cell survival. Our results highlight the protective effects of tangeretin against cisplatin-induced acute hepatic injury via the concerted modulation of inflammation, oxidative stress, MAPKs and apoptotic pathways.

Background Irinotecan is a chemotherapeutic agent used to treat a variety of tumors, including colorectal cancer (CRC). In the intestine, it is transformed into SN-38 by gut microbial enzymes, which is responsible for its toxicity during excretion. Objective Our study highlights the impact of Irinotecan on gut microbiota composition and the role of probiotics in limiting Irinotecan-associated diarrhea and suppressing gut bacterial β-glucuronidase enzymes. Material and methods To investigate the effect of Irinotecan on the gut microbiota composition, we applied 16S rRNA gene sequencing in three groups of stool samples from healthy individuals, colon cancer, and Irinotecan treated patients ( n  = 5/group). Furthermore, three Lactobacillus spp.; Lactiplantibacillus plantarum (L. plantarum) , Lactobacillus acidophilus (L. acidophilus) , Lacticaseibacillus rhamnosus ( L. rhamnosus) were used in a single and mixed form to in-vitro explore the effect of probiotics on the expression of β-glucuronidase gene from E. coli . Also, probiotics were introduced in single and mixed forms in groups of mice before the administration of Irinotecan, and their protective effects were explored by assessing the level of reactive oxidative species (ROS) as well as studying the concomitant intestinal inflammation and apoptosis. Results The gut microbiota was disturbed in individuals with colon cancer and after Irinotecan treatment. In the healthy group, Firmicutes were more abundant than Bacteriodetes, which was the opposite in the case of colon-cancer or Irinotecan treated groups. Actinobacteria and Verrucomicrobia were markedly present within the healthy group, while Cyanobacteria were noted in colon-cancer and the Irinotecan-treated groups. Enterobacteriaceae and genus Dialister were more abundant in the colon-cancer group than in other groups. The abundance of Veillonella , Clostridium , Butryicicoccus, and Prevotella were increased in Irinotecan-treated groups compared to other groups. Using Lactobacillus spp. mixture in mice models significantly relieved Irinotecan-induced diarrhea through the reduction of both β-glucuronidase expression and ROS, in addition to guarding gut epithelium against microbial dysbiosis and proliferative crypt injury. Conclusions Irinotecan-based chemotherapy altered intestinal microbiota. The gut microbiota participates greatly in determining both the efficacy and toxicity of chemotherapies, of which the toxicity of Irinotecan is caused by the bacterial ß-glucuronidase enzymes. The gut microbiota can now be aimed and modulated to promote efficacy and decrease the toxicity of chemotherapeutics. The used probiotic regimen in this study lowered mucositis, oxidative stress, cellular inflammation, and apoptotic cascade induction of Irinotecan.

Background Hearing deficit is one of the side effects of 1st generation iron chelators in β-thalassemia, however the risk of hearing deficits following 2nd generation iron chelators is not well known. Aim To assess hearing status of Transfusion Dependent β-thalassemia children on oral iron chelating agents and detect risk factors for hearing impairment. Methods This is a cross-sectional study recruited sixty children and adolescent with confirmed diagnosis of transfusion dependent β-thalassemia. Demographic and clinical characteristics collected, audiological testing were performed by the same audiologist using the same equipment for all patients including tympanometry, pure tone audiometry, speech audiometry, transient evoked otoacoustic emissions and distortion product otoacoustic emissions. Results Recruited children and adolescents with transfusion dependent β-thalassemia were 32 (53.3%) boys and 28 (46.7%) girls and their mean age was 11.34 ± 3.08, majority of patients 48 (80%) were on single Deferasirox. Our study revealed that among the 60 children evaluated, 16.6% exhibited some form of hearing loss. Sensorineural hearing loss (SNHL) was observed in 6.6% of the participants, while 10% had conductive hearing loss (CHL). Bilateral SNHL in 5% and bilateral CHL in 8.3% of all the cases. Hearing impairment was mild in nature, but predominantly affected high-frequency ranges, the most affected frequencies being 4000 Hz and 8000 Hz. There was no significant difference between studied thalassemia children with and without hearing impairment regarding gender, age at study entry, age at diagnosis, duration of disease and duration or dose of chelating agent ( P  > 0.05). Our study revealed significant difference between studied thalassemia children with and without hearing impairment regarding age of starting blood transfusion ( p -value = 0.024), affected patients started blood transfusion at older age, also statistically significant difference in both groups regarding median serum ferritin was found ( p -value = 0.028), lower levels were found in affected patients. Conclusion No significant effect of using oral iron chelation drugs was observed on frequency and type of hearing loss among the studied patients but instead the age at starting regular blood transfusion did. Screening of such group of patients for hearing impairment at diagnosis and at regular periods is recommended.

Background The effects of safflower oil and vitamin C (Vit. C) inclusion in broiler chicken diets on the growth performance, apparent ileal digestibility coefficient “AID%” of amino acids, intestinal histology, behavior, carcass traits, fatty acid composition of the breast muscle, antioxidant and immune status for a 35-day feeding period were evaluated. A total of 300 three-day-old Ross chicks (58.25 g ± 0.19) were randomly allotted in a 2 × 3 factorial design consisting of two levels of vitamin C (0 and 400 mg/kg diet) and three levels of safflower oil (0, 5, and 10 g/kg diet). Results An increase in the final body weight, total body weight gain, total feed intake, and the relative growth rate ( P  <  0.05) were reported by safflower oil and vitamin C inclusion. Dietary supplementation of safflower oil and vitamin C had a positive effect ( P <  0.05 ) on the ingestive, resting, and feather preening behavior. Vitamin C supplementation increased ( P <  0.05 ) the AID% of lysine, threonine, tryptophan, arginine, and valine. Safflower inclusion (10 g/kg) increased ( P <  0.05 ) the AID% of methionine and isoleucine. Safflower oil inclusion increased ( P <  0.05 ) the levels of stearic acid, linoleic acid, saturated fatty acids, and omega-3 fatty acids (ω-3) in the breast muscle. In contrast, the supplementation of only 10 g of safflower oil/kg diet increased ( P = 0.01 ) the omega-3/omega-6 (ω-3/ω-6) fatty acids ratio. Vit. C supplementation increased ( P <  0.05 ) the CAT serum levels, SOD, and GSH enzymes. Dietary supplementation of safflower oil and vitamin C improved the intestinal histology. They increased the villous height and width, crypt depth, villous height/crypt depth ratio, mucosal thickness, goblet cell count, and intra-epithelium lymphocytic lick cell infiltrations. The serum levels of IgA and complement C3 were increased ( P <  0.01 ) by Vit. C supplementation and prominent in the 400 vit. C +  10 safflower Oil group. Conclusion A dietary combination of safflower oil and vitamin C resulted in improved growth rate, amino acids AID%, intestinal histology, welfare, immune and antioxidant status of birds, and obtaining ω-3 and linoleic acid-enriched breast muscles. The best inclusion level was 400 vit. C +  10 safflower Oil.

Hyperuricemia is an abnormal metabolic condition characterized by an increase in uric acid levels in the blood. It is the cause of gout, manifested by inflammatory arthritis, pain and disability. This study examined the possible ameliorative impacts of parsley (PAR) and celery (CEL) as hypouricemic agents at biochemical, molecular and cellular levels. PAR and CEL alone or in combination were orally administered to hyperuricemic (HU) mice and control mice for 10 consecutive days. Serum levels of uric acid and blood urea nitrogen (BUN), xanthine oxidase activity, antioxidants, inflammatory (IL-1β and TNF-α) and anti-inflammatory cytokines (IL-10) were measured. mRNA expression of urate transporters and uric acid excretion genes in renal tissues were examined using qRT-PCR (quantitative real time PCR). Normal histology and immunoreactivity of transforming growth factor-beta 1 (TGF-β1) in kidneys was examined. Administration of PAR and CEL significantly reduced serum BUN and uric acids in HU mice, ameliorated changes in malondialdehyde, catalase, and reduced glutathione, glutathione peroxidase (GPX), IL-1β, TNF-α and IL-10 in hyperuricemic mice. Both effectively normalized the alterations in mURAT-1, mGLUT-9, mOAT-1 and mOAT-3 expression, as well as changes in TGF-β1 immunoreactivity. Interestingly, combined administration of PAR and CEL mitigated all examined measurements synergistically, and improved renal dysfunction in the hyperuricemic mice. The study concluded that PAR and CEL can potentially reduce damaging cellular, molecular and biochemical effects of hyperuricemia both individually and in combination.

Nigella sativa oil (NSO) possesses antioxidant activity. However, its protective role against the hazards of fungicides has been poorly studied. Therefore, the present work aimed at determining the ameliorative potential of NSO against hepatotoxicity induced by carbendazim (CBZ) and/or mancozeb (MNZ) in female rats. In the present study, about 120 adult female Sprague-Dawley rats were randomly divided into eight equal groups. One group of animals was kept as a negative control (Gp. 1); groups 2, 3 and 4 orally received CBZ (200 mg/kg body wt) and/or MNZ (300 mg/kg body wt) daily for 2 weeks (positive groups). In order to assess the hepatoprotective potential of NSO, in comparison with NSO-treated rats (Gp. 5), groups 6, 7 and 8 were CBZ- and/or MNZ-exposed groups pre-treated orally with NSO (2 ml/kg body wt) daily for 2 weeks (prophylactic groups). All groups were kept further for 15 days without medications to observe the withdrawal effect. At the end of exposure and withdrawal periods, the body weight of all experimental rats was recorded and blood samples were collected for hematological, clinico-biochemical, and micronucleus assays. The animals were then sacrificed, and the liver and bone marrow were harvested for oxidative stress bioassay, chromosomal aberrations, DNA fragmentation, and histopathological examinations. The results suggested that pre-treatment with NSO remarkably diminished CBZ- and MNZ-induced macrocytic hypochromic anemia, leukocytosis, lymphocytosis, eosinophilia, and neutropenia. Besides, it also minimized the elevated liver enzymes, lipid peroxidation, micronucleus incidence, DNA damage, and chromosomal aberration frequency. Conversely, NSO significantly stimulated the CBZ- and/or MNZ-induced antioxidant system suppression. The NSO also normalized the hepatic structural architecture. As far as withdrawal effect is concerned, there was almost disappearance of the bad effects of these fungicides and the values were close to the normal range especially with the use of NSO. Ultimately, the results revealed that N. sativa oil is an effective hepatoprotective agent due to its genoprotective and free radical scavenging activities.

The effect of phenolic-rich onion extract (PROE), as a feed additive, was evaluated on the growth, carcass traits, behavior, welfare, intestinal histology, amino acid ileal digestibility \"AID%,\" and the immune status of broiler chicks for 35 days. A total number of 400, 1-day-old broiler chicks (45.38 g ± 1.35) were allocated to four different treatments with 10 replicates each (100 chicks/treatment) consisting of: T1, basal diet without additives (control treatment) (PROE0); T2, basal diet + phenolic-rich onion extract (1 g/kg diet) (PROE1); T3, basal diet + phenolic-rich onion extract (2 g/kg diet) (PROE2); and T4, basal diet + phenolic-rich onion extract (3 g/kg diet) (PROE3). An increase in the final body weight \"FBW,\" bodyweight gain \"BWG,\" and feed consumption was observed ( < 0.05) at different PROE levels. Also, the thymus and bursa percentages were increased in the PROE2 and PROE3 treatments ( < 0.05). The chicks fed on PROE supplemented diets had increased frequency of feeding and drinking and showed comfortable behavior ( < 0.05) with lesser aggression ( < 0.05). Additionally, an increase was observed in the antioxidant enzyme activity, phagocytic %, phagocytic index, and serum lysozyme activity in PROE supplemented treatments, with the best outcome reported in the PROE3 treatment ( < 0.01). IgM was increased in the birds fed with PROE2 and PROE3 diets ( < 0.01). PROE supplementation increased the AID% of lysine and methionine ( <0.01), PROE3 treatment increased the AID% of threonine ( < 0.05), and PROE2 and PROE3 treatments increased the AID% of leucine and isoleucine ( < 0.05). Besides, PROE2, and PROE3 treatments increased the villus height and width, mucosal thickness, and goblet cell count from the duodena, jejuna, and ilea ( < 0.05) compared to control treatment. Based on these results, we concluded that the dietary addition of phenolic-rich onion extracts can improve the growth rate of broiler chicken by improving the AID% of amino acids and intestinal histology. Also, it can improve the welfare, antioxidant enzymes activity, and immune status of the birds. Phenolic-rich onion extracts can be used as a natural growth promoter in the poultry feed for good health and improved performance.

Methotrexate (MTX) is a folic acid reductase inhibitor that manages various malignancies as well as immune-mediated inflammatory chronic diseases. Despite being frequently prescribed, MTX’s severe multiple toxicities can occasionally limit its therapeutic potential. Intestinal toxicity is a severe adverse effect associated with the administration of MTX, and patients are significantly burdened by MTX-provoked intestinal mucositis. However, the mechanism of such intestinal toxicity is not entirely understood, mechanistic studies demonstrated oxidative stress and inflammatory reactions as key factors that lead to the development of MTX-induced intestinal injury. Besides, MTX causes intestinal cells to express pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which activate nuclear factor-kappa B (NF-κB). This is followed by the activation of the Janus kinase/signal transducer and activator of the transcription3 (JAK/STAT3) signaling pathway. Moreover, because of its dual anti-inflammatory and antioxidative properties, nuclear factor erythroid-2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) has been considered a critical signaling pathway that counteracts oxidative stress in MTX-induced intestinal injury. Several agents have potential protective effects in counteracting MTX-provoked intestinal injury such as omega-3 polyunsaturated fatty acids, taurine, umbelliferone, vinpocetine, perindopril, rutin, hesperidin, lycopene, quercetin, apocynin, lactobacillus, berberine, zinc, and nifuroxazide. This review aims to summarize the potential redox molecular mechanisms of MTX-induced intestinal injury and how they can be alleviated. In conclusion, studying these molecular pathways might open the way for early alleviation of the intestinal damage and the development of various agent plans to attenuate MTX-mediated intestinal injury. Graphical Abstract

Background. Transforming growth factor-beta (TGF-β) and hepatocyte growth factor (HGF) are inflammatory cytokines which function as key regulators of immunological homeostasis and inflammatory responses. They have been linked to inflammatory bowel diseases (IBD). In this study, we aim to assess the levels of TGF-β and HGF and other inflammatory markers in patients with IBD and correlate them with the disease activity. Study Design. A cross-sectional study involving 100 patients with ulcerative colitis (UC) and 100 patients with Crohn’s disease (CD) and 50 control subjects. TGF-β and HGF levels were measured and correlated with disease activity. Results and Conclusion. Serum levels of TGF-β and HGF were significantly higher in IBD patients compared with the control group. In the UC group, the levels of HGF and TGF-β were significantly higher than in the CD group. Levels of TGF-β and HGF correlate with the activity of IBD.