The present study was designed to evaluate the potential renoprotective impacts of apocynin (APC) against nephrotoxicity induced by methotrexate (MTX) administration. To fulfill this aim, rats were ...allocated into four groups: control; APC (100 mg/kg/day; orally); MTX (20 mg/kg; single intraperitoneal dose at the end of the 5th day of the experiment); and APC +MTX (APC was given orally for 5 days before and 5 days after induction of renal toxicity by MTX). On the 11th day, samples were collected to estimate kidney function biomarkers, oxidative stress, pro-inflammatory cytokines, and other molecular targets. Compared to the MTX control group, treatment with APC significantly decreased urea, creatinine, and KIM-1 levels and improved kidney histological alterations. Furthermore, APC restored oxidant/antioxidant balance, as evidenced by a remarkable alleviation of MDA, GSH, SOD, and MPO levels. Additionally, the iNOS, NO, p-NF-κB-p65, Ace-NF-κB-p65, TLR4, p-p38-MAPK, p-JAK1, and p-STAT-3 expressions were reduced, while the IκBα, PPAR-γ,
SIRT1
, and
FOXO3
expressions were significantly increased. In NRK-52E cells, MTX-induced cytotoxicity was protected by APC in a concentration-dependent manner. In addition, increased expression of p-STAT-3 and p-JAK1/2 levels were reduced in MTX-treated NRK-52E cells by APC. The in vitro experiments revealed that APC-protected MTX-mediated renal tubular epithelial cells were damaged by inhibiting the JAK/STAT3 pathway. Besides, our in vivo and in vitro results were confirmed by predicting computational pharmacology results using molecular docking and network pharmacology analysis. In conclusion, our findings proved that APC could be a good candidate for MTX-induced renal damage due to its strong antioxidative and anti-inflammatory bioactivities.
Low pathogenic avian influenza (LPAI) H9N2 virus is one of the major poultry pathogens associated with severe economic losses in the poultry industry (broiler, layers, breeders, and grandparents' ...flocks), especially in endemic regions including the Middle East, North Africa, and Asian countries. This work is an attempt to evaluate the efficacy of whole inactivated H9N2 vaccine (MEFLUVAC
H9) in turkey poults kept under laboratory and commercial farm conditions. Here, 10,000 white turkey poults (1-day old) free from maternally derived immunity against H9N2 virus were divided into four groups; G1 involved 10 vaccinated birds kept under biosafety level-3 (BLS-3) as a laboratory vaccinated and challenged group, while G2 had 9970 vaccinated turkeys raised on a commercial farm. Ten of those birds were moved to BLS-3 for daily cloacal and tracheal swabbing to check for the absence of any life-threating disease, before conducting analyses. G3 (10 birds) served as a non-vaccinated challenged control under BSL-3 conditions, while G4 (10 birds) was used as a non-vaccinated and non-challenged control under BSL-3 conditions. Sera were collected on days 7-, 14-, 21-, and 28-post-vaccinations to monitor the humoral immune response using a hemagglutination-inhibition (HI) test. At these same intervals, cloacal and tracheal swabs were also checked for any viral infection. The challenge was conducted 28 days post-vaccination (PV) using AI-H9N2 in BSL-3 by intranasal inoculation of 6-log10 embryo infective dose
(EID
). At 3-, 6-, and 10-days post-challenge, oropharyngeal swabs were taken from challenged birds to quantify viral shedding by quantitative polymerase chain reaction (qRT-PCR). The results of this study showed that vaccinated groups (G1/2) developed HI titers of 1.38, 4.38, 5.88, and 7.25 log
in G1 vs. 1.2, 3.8, 4.9 and 6.2 log
in G2 when measured at 7-, 14-, 21- and 28-days PV, respectively, while undetectable levels were recorded in non-vaccinated groups (G3/4). Birds in G3 showed 90% clinical sickness vs. 10% and 20% in G1/2, respectively, over a 10-day monitoring period following challenge. Vaccinated birds showed a significant reduction in virus shedding in terms of the number of shedders, amount of shed virus and shedding interval over the non-vaccinated challenged birds. Regarding mortality, all groups did not show any mortality, which confirms that the circulating H9N2 virus still has low pathogenicity and cannot cause mortality. However, the virus may cause up to 90% clinical sickness in non-vaccinated birds vs. 10% and 20% in laboratory- and farm-vaccinated birds, respectively, highlighting the role of the vaccine in limiting clinical sickness cases. In conclusion, under the current trial circumstances, MEFLUVAC
-H9 provided protective seroconversion titers, significant clinical sickness protection and significant reduction in virus shedding either in laboratory- or farm-vaccinated groups after a single vaccine dose.
The combined angiotensin receptor neprilysin inhibitor is a promising cardioprotective pharmacological agent. This study investigated the beneficial effects of thiorphan (TH)/irbesartan (IRB), in ...myocardial ischemia–reperfusion (IR) injury, compared to each of nitroglycerin and carvedilol. Male Wistar rats were divided into five groups (10 rats/group): Sham, untreated I/R, TH/IRB + IR (0.1/10 mg/kg), nitroglycerin + IR (0.2 mg/kg), and carvedilol + IR (10 mg/kg). Mean arterial blood pressure, cardiac functions and arrhythmia incidence, duration and score were assessed. Cardiac levels of creatine kinase‐MB (CK‐MB), oxidative stress, endothelin‐1, ATP, Na+/K+ ATPase pump activity and mitochondria complexes activities were measured. Histopathological examination, Bcl/Bax immunohistochemistry studies and electron microscopy examination of left ventricle were performed. TH/IRB preserved the cardiac functions and mitochondrial complexes activities, mitigated cardiac damage, reduced oxidative stress and arrhythmia severity, improved the histopathological changes and decreased cardiac apoptosis. TH/IRB showed a comparable effect to each of nitroglycerin and carvedilol in alleviating the IR injury consequences. TH/IRB showed significant preservation of mitochondrial complexes activity I and II compared to nitroglycerin. TH/IRB significantly increased LVdP/dtmax and decreased oxidative stress, cardiac damage and endothelin‐1 along with increasing the ATP content, Na+/K+ ATPase pump activity and mitochondrial complexes activity when compared to carvedilol. TH/IRB showed a cardioprotective effect in reducing IR injury that is comparable to each of nitroglycerin and carvedilol that could be explained in part by its ability to preserve mitochondrial function, increase ATP, decrease oxidative stress as well as endothelin 1.
Male reproductive toxicity is becoming of growing significance due to clinical chemotherapy usage. Methotrexate (MTX) is an anti-folate used on a large scale for different tumors and autoimmune ...conditions. Despite its wide clinical use, MTX is associated with severe testicular intoxication. The exact underlying mechanism is unclear.
Our study was conducted to explore the pathogenesis mechanism of MTX-induced testicular damage and the potential testicular protective effects of apocynin (APO) on testicular injury induced by single i.p. MTX (20 mg/kg). APO was administered orally (100 mg/kg) for ten days.
As compared to rats given MTX alone, co-administration of MTX with APO demonstrated multiple beneficial effects evidenced by a marked increase in testosterone, FSH, and LH and significantly restored testes histopathological alterations. Mechanistically, APO restored antioxidant status through up-regulation of Nrf2, cytoglobin, PPAR-γ, SIRT1, AKT, and p-AKT, while effectively lowering Keap-1. Moreover, APO significantly attenuated inflammation by down-regulating NF-κB-p65, iNOS, and TLR4 expressions confirmed by in-silico evidence. Additionally, network pharmacology analysis, a bioinformatics approach, was used to decipher various cellular processes' molecular mechanisms.
The current investigation proves the beneficial effects of APO in MTX-associated testicular damage through activation of cytoglobin, Keap-1/Nrf2/AKT, PPAR-γ, SIRT1, and suppressing of TLR4/NF-κB-p65 signal. Our data collectively encourage extending the investigation to the clinical setting to explore APO effects in MTX-treated patients.
Illustrated diagram explores the molecular mechanism of APO against MTX-induced testicular damage. Display omitted
•Apocynin abrogates MTX-induced testicular damage.•Apocynin regulates testicular Keap-1/Nrf2/AKT expression after MTX treatment.•Apocynin suppresses testicular iNOS/NF-κB/TLR4 expression.•In-silico and network pharmacology analysis confirmed biochemical and histological results.
Cyclophosphamide (CP) is a medication used as an anticancer drug and to suppress the immune system. However, its clinical applications are restricted because of the toxic and adverse side effects. ...The present study investigated the protective effect of acetovanillone (AV), a natural NADPH oxidase inhibitor, against acute lung injury (ALI) induced by CP. Rats were administered AV (100 mg/kg) for 10 days and a single injection of CP (200 mg/kg) at day 7. At the end of the experiment, the animals were sacrificed, and lung samples were collected for analyses. CP caused ALI manifested by the histopathological alterations. Lipid peroxidation and NADPH oxidase activity were increased, whereas GSH and antioxidant enzymes were decreased in the lung of CP‐intoxicated rats. Oral administration of AV prevented CP‐induced lung injury and oxidative stress and enhanced antioxidant defenses. AV downregulated Keap1 and upregulated Nrf2, GCLC, HO‐1, and SOD3 mRNA. In addition, AV boosted the expression of PI3K, Akt, mTOR, and cytoglobin. In vitro, AV showed a synergistic anticancer effect when combined with CP. In conclusion, AV protected against CP‐induced ALI by attenuating oxidative stress and boosting Nrf2/HO‐1 and PI3K/Akt/mTOR signaling. Therefore, AV might represent a promising adjuvant to prevent lung injury in patients receiving CP.
This study targeted to examine the protective effects of acetovanillone (AV) against methotrexate (MTX)‐induced hepatotoxicity. Thirty‐two rats were allocated into four groups of eight animals; Group ...1: Normal; Group 2: administered AV (100 ml/kg; P.O.) for 10 days; Group 3: challenged with MTX (20 mg/kg, i.p; single dose); Group 4: administered AV 5 days before and 5 days after MTX. For the first time, this study affords evidence for AV's hepatoprotective effects on MTX‐induced hepatotoxicity. The underlined mechanisms behind its hepatic protection include counteracting MTX‐induced oxidative injury via down‐regulation of NADPH oxidase and up‐regulation of Nrf2/ARE, SIRT1, PPARγ, and cytoglobin signals. Additionally, AV attenuated hepatic inflammation through down‐regulation of IL‐6/STAT‐3 and NF‐κB/AP‐1 signaling. Network pharmacology analysis exhibited a high enrichment score between the interacting proteins and strongly suggested the intricate and essential role of the target proteins regulating MTX‐induced oxidative damage and inflammatory perturbation. Besides, AV increased the in vitro cytotoxic activity of MTX toward PC‐3, HeLa, and K562 cancer cell lines. On the whole, our investigation suggested that AV might be regarded as a promising adjuvant for the amelioration of MTX hepatotoxicity and/or increased its in vitro antitumor efficacy, and it could be used in patients receiving MTX.
Taxol, a diterpenoid was initially isolated from the bark of Taxus brevifolia, approved by FDA in 1994 as a powerful drug for metastatic ovarian carcinoma, breast and lung cancer. However, due to ...limitations in the production of this drug based on this plant source, the productive potentiality of fungi of this compound opened a new avenue for its commercial production. In this study, among the twenty fungal isolates screened for Taxol production, Aspergillus terreus had the highest potentiality to produce Taxol (131.2 microg/ml). The productivity of Taxol by A. terreus has been maximized by nutritional optimization using inhibitors and growth regulators. The yield of Taxol by A. terreus was maximally obtained (0.663microg/ml) by growing the fungal isolate on potato dextrose broth medium, amended with addition of biotin at 150 microg/ml for 20 days. The chemical structure Taxol extracted of A. terreus has been verified by proton and carbon NMR, IR and UV analyses. The activity of A. terreus Taxol has been assessed towards multiple cell lines, displaying a strong anticancer activity. In conclusion, the productivity of Taxol by A. terreus has been greatly improved upon using biotin as chemical modulator, that open a new avenue for commercializing the Taxol yield by fungi. Keywords: Aspergillus terreus; Taxol; Nutritional optimization, Inhibitors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Hemorrhagic cystitis is a potentially deadly complication associated with radiation therapy and chemotherapy. This study explored the protective effect of edaravone (ED) on cyclophosphamide ...(CP)‐induced hemorrhagic cystitis, oxidative stress, and inflammation in rats. The animals received 20 mg/kg ED for 10 days and a single injection of 200 mg/kg CP on day 7. CP induced tissue injury manifested by the diffuse necrotic changes, disorganization of lining mucosa, focal hemorrhagic patches, mucosal/submucosal inflammatory cells infiltrates, and edema. CP increased malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor‐alpha, and interleukin 6 (IL‐6), decreased IL‐10, and upregulated toll‐like receptor 4 (TLR‐4), nuclear factor‐kappa B (NF‐κB) p65, Janus kinase 1 (JAK1), and signal transducer and activator of transcription 3 (STAT3) in the urinary bladder of rats. ED effectively prevented the histopathological alterations, decreased MDA, NO, and inflammatory mediators, and downregulated TLR‐4, NF‐κB, JAK1, and STAT3 in CP‐induced rats. Treatment with ED upregulated ikβ kinase β, IL‐10, nuclear factor‐erythroid 2 related factor 2 (Nrf2), and cytoglobin, and boosted glutathione, superoxide dismutase, and glutathione S‐transferase. Molecular docking simulations revealed the ability of ED to bind TLR‐4, NF‐κB, JAK1, and STAT3. In vitro, ED increased the cytotoxic activity of CP against HeLa, Caco‐2, and K562 cell lines. In conclusion, ED prevented CP‐induced hemorrhagic cystitis in rats by attenuating oxidative stress, suppressing TLR‐4/NF‐κB, and JAK1/STAT3 signaling and boosted Nrf2, cytoglobin, and antioxidants.
Ivermectin (IVM) has been used in veterinary practice to control different parasitic infestations over the past two decades. This study aimed to re-assess the acaricidal effects of IVM, as well as to ...evaluate its efficacy against
(
by determining the mortality rate, γ-aminobutyric acid (GABA) level, and oxidative/antioxidative homeostasis (malondialdehyde MDA levels and glutathione S-transferase GST activities).
Adult female
(
were picked from cattle farms in El-Beheira Governorate, Egypt. Ticks were equally allocated to seven experimental groups to assess the acaricidal potential of IVM chemotherapeutics in controlling
. (
.)
. IVM was prepared at three concentrations (11.43, 17.14, and 34.28 µM of IVM).
Mortality rate was calculated among the treated ticks. In addition, GABA, GST, and MDA biomarker levels were monitored. The data revealed a noticeable change in GST activity, a detoxification enzyme found in
. (
.)
, through a critical elevation in mortality percentage.
IVM-induced potent acaricidal effects against
. (
.)
by repressing GST activity for the initial 24 h after treatment. Collectively, this paper reports the efficacy of IVM in a field population of
. (
.)
in Egypt.
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