Optimizing cyclosporine A dose post allogeneic hematopoietic stem cell transplantation in paediatric cancer patients.

BACKGROUND/OBJECTIVES: Cyclosporine A (CSA) dosing has been complicated by considerable intra-patient and inter-patient variability in pharmacokinetics, which is affected by different factors. We aimed to assess the various factors that might affect the CSA dose and its plasma level. PATIENTS AND METHODS: This retrospective study included paediatric cancer patients who underwent allogeneic hematopoietic stem cell transplant at the Children's Cancer Hospital Egypt 57357 from matched related donors with CSA as graft versus host disease prophylaxis. The CSA initial dose was 1.5 mg/kg IV Q12H. Then, it was titrated according to the level and drug toxicity. Cyclosporine A trough levels were assessed two to three times per week using the Emit 2000 cyclosporine-specific assay. Moreover, factors that may affect cyclosporine levels, such as age, sex, weight and the antifungal used, were analyzed to determine their effect on CSA plasma levels. RESULTS: There were 119 patients included in the study. The median age was 10 years; and 43% of them used voriconazole as a prophylactic antifungal. The multivariate analysis revealed that female patients, those >9 years or on voriconazole reached the target level at low initial CSA doses. A higher probability (93%) of reaching the desired plasma level with doses 1.5 mg/kg IV Q12H was observed among patients >9 years, and on voriconazole. While those who were ≤9 years and not on voriconazole required doses >1.5 mg/kg IV Q12H, with an 89% probability of reaching the desired level. CONCLUSION: This study suggests that the initial CSA dose should consider the patient's age and the antifungal used. Patients >9 years and/or on voriconazole may require lower initial CSA doses and could start with 1.5 mg/kg IV Q12H.

Novel therapeutic modalities target cell signaling of Renin-Angiotensin system/NF-κB-induced cell cycle arrest and apoptosis in urethane-induced lung cancer in mice: An in vivo study.

BACKGROUND: Lung cancer has risen to the top of the list of cancer-related deaths worldwide. Aliskiren is a direct renin inhibitor. AIM: This study aims to investigate the impact of cell signaling of Renin-Angiotensin system (RAS)/NF-κB on lung cancer by investigating the potential therapeutic effects of aliskiren for lung cancer treatment in urethane-induced lung cancer in mice. METHODS: Male BALB/c mice were randomly assigned to one of five treatment groups for 150 days, including (1) normal control; (2) aliskiren (25 mg/kg/i.p) daily, (3) urethane at a dose of 1.5 g/kg (i.p) at Day 1 and 60 (nonsmall cell lung cancer[NSCLC] group) (4) NSCLC mice received carboplatin (15 mg/kg/i.p) every other day for the last 4 successive weeks and (5) NSCLC mice treated with aliskiren daily. Tumor size was determined based on blood sampling, and lungs were isolated for biochemical analysis, western blot analysis assay, and histopathological examination. RESULTS: Urethane demonstrated significant changes in all biochemical and molecular parameters and histological patterns. Aliskiren-treated mice had significantly lower levels of NF-κB p65, Bcl-2, cyclin D1, ICAM-1, MMP-2, and Nrf2, with an increase in the catalytic activity of caspase-3 due to its RAS inhibitory mechanism. The combined urethane administration with aliskiren demonstrated a significant improvement in the histopathological examination. CONCLUSION: RAS/NF-B cell signaling is a potential therapeutic target for preventing and treating lung adenocarcinoma, evidenced by the fundamental cytotoxic mechanism and attenuation of metastasis and angiogenesis induced by the treatment of NSCLC mice with aliskiren.

Empagliflozin attenuates neurodegeneration through antioxidant, anti-inflammatory, and modulation of α-synuclein and Parkin levels in rotenone-induced Parkinson's disease in rats.

Sodium-glucose co-transporter 2 (SGLT 2) inhibitors are a relatively new antidiabetic drug with antioxidant and anti-inflammatory properties. Therefore, this study aimed to investigate whether SGLT 2 inhibitors have a neuroprotective effect in PD. Twenty-four Wistar rats were randomized into four groups. The first one (control group) received dimethyl sulfoxide (DMSO) as a vehicle (0.2 mL/48 hr, S.C). The second group (positive control) received rotenone (ROT) (2.5 mg/kg/48 hr, S.C) for 20 successive days, whereas the third and fourth groups received empagliflozin (EMP) (1 and 2 mg/kg/day, orally), respectively. The two groups received rotenone (2.5 mg/kg/48 hr S.C) concomitantly with EMP for another 20 days on the fifth day. By the end of the experimental period, behavioral examinations were done. Subsequently, rats were sacrificed, blood samples and brain tissues were collected for analysis. ROT significantly elevated oxidative stress and proinflammatory markers as well as α-synuclein. However, dopamine (DP), antioxidants, tyrosine hydroxylase (TH), and Parkin were significantly decreased. Groups of (EMP + ROT) significantly maintained oxidative stress and inflammatory markers elevation, maintained α-synuclein and Parkin levels, and elevated TH activity and dopamine level. In both low and high doses, EMP produced a neuroprotective effect against the PD rat model, with the high dose inducing a more significant effect.

Neuroprotective role of camphor against ciprofloxacin induced depression in rats: modulation of Nrf-2 and TLR4.

BACKGROUND: Depression affects people feeling to be anxious, worried, and restless. They also lose interest in activities, concentrating and appetite, they finally may attempt suicide. Depression is the second chronic disease, as a source of the global burden of disease, after heart disease. Its prevalence elevated seven times during the COVID-19. AIM: The current study was designed to evaluate camphor neuroprotective role against rats' ciprofloxacin-induced depression. MATERIALS AND METHODS: Depression was induced by administration of ciprofloxacin (50 mg/kg; orally) for 21 days. Wister albino male rats were divided into five groups. Group I (normal control): rats were given normal saline. Group II: rats received camphor (10 mg/kg; i.p.) for 21 days. Group III (depression control): rats received ciprofloxacin only. Groups IV and V: rats received camphor (5 and 10 mg/kg; i.p.) for 21 days concurrent with ciprofloxacin. Behavior tests as forced swimming test, activity cage, and rotarod were estimated. Oxidative stress and antioxidant biomarkers as malondialdehyde (MDA), nitric oxide (NO), catalase, and nuclear factor erythroid 2-related factor 2 (Nrf-2) besides inflammatory biomarkers as Toll-like receptor 4 (TLR4) and tumor necrosis factor alpha (TNF-α) as well as neurotransmitters were determined. Finally, histopathological examination was done. RESULTS: Camphor increased catalase and Nrf-2 activities, decreased NO, MDA, TNF-α, TLR4 serum levels, and elevating brain contents of serotonin, dopamine, gamma-amino butyric acid (GABA) and P190-RHO GTP protein with normal neuronal cells of the frontal cortex. CONCLUSION: Camphor has neuroprotective effect via modulation of Nrf-2 and TLR4 against ciprofloxacin-induced depression in rats.

Polydatin protects against ovalbumin-induced bronchial asthma in rats; involvement of urocortin and surfactant-D expression.

Context: Prevalence of bronchial asthma massively increases worldwide, while the frequent therapies are still not sufficient. Polydatin, a naturally occurring glycoside, was known as to have anti-inflammatory and anti-oxidant effects. Objective: The current study aimed to investigate the possible protective effect of polydatin against experimental bronchial asthma in rats. Material and methods: Bronchial asthma was induced by ovalbumin (OVA) sensitization and challenge. Rats were randomly allocated into five groups; Group I (normal control group); Group II (asthma control group) received OVA; Group III (reference standard treatment group) received dexamethasone (1 mg/kg/day); Group IV (treatment group) received polydatin (200/mg/kg); and Group V (polydatin control group). The inflammatory biomarkers interleukin-4 (IL-4), IL-5, IL-13, tumor necrosis factor-alpha, interferon-gamma and absolute eosinophil count in bronchoalveolar lavage fluid (BALF), as well as serum immunoglobulin E were assessed, coupled with the oxido-nitrative stress biomarkers malondialdehyde and glutathione reduced levels and superoxide dismutase activity in the lung tissue, besides inducible nitric oxide synthase level in BALF. Western blot analysis of surfactant-D and immunohistochemical assay of urocortin (UCN) expression in the lung was performed. Results: Polydatin significantly reduced the inflammatory mediators and restored the normal values of oxidative and nitrosative stress biomarkers. It also significantly reduced the expression of surfactant-D and UCN as compared to asthma control. The histopathological study strongly augmented the biochemical results. Discussion and conclusions: Polydatin may be a promising protective agent against experimentally induced bronchial asthma. Modulation of SP-D and UCN expressions seems to mediate such protective effects.

Protective effects of vitamin D and losartan in complete Freund's adjuvant-induced arthritis in rats.

The current study was designed to explore the protecting effects of vitamin D and losartan in treatment of rheumatoid arthritis (RA). Animals were allotted to five groups: Group I received vehicles only (vehicle control). Group II was administered complete Freund's adjuvant (CFA) and did not receive any medication. The remaining three groups (III, IV, V) were given CFA followed by treatment with leflunomide, vitamin D or losartan, respectively for two weeks. Compelling increment in tumor necrosis factor (TNF-α), interleukin 6 (IL-6), rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), malondialdehyde (MDA) level, white blood cells (WBCs), total cholesterol (TC) and triglycerides (TGs) was revealed in arthritic rats. This was associated with marked decline in glutathione (GSH) level, red blood cells (RBCs), hemoglobin (Hb), Platelets (Plts), hematocrit (Hct) and high density lipoprotein cholesterol (HDL). vitamin D or losartan significantly decreased TNF α, IL-6, RF, ESR, MDA, TC, TGs, WBCs and significantly increased RBCs, Hb, Hct, Plts and HDL. It could be concluded that vitamin D and losartan are able to repress the alterations associated with adjuvant-induced arthritis (AIA). This preserving effect might be partially attributed to antiarithritic, hypolipidemic and antianemic properties.

Evaluation of the possible nephroprotective effects of vitamin E and rosuvastatin in amikacin-induced renal injury in rats.

Amikacin (AMIK) is an aminoglycoside antibiotic that possesses considerable nephrotoxic adverse effects. This study examined the protective effects of vitamin E (VIT. E) or rosuvastatin (ROSU) against AMIK-induced nephrotoxicity. For this purpose, eight groups of rats were used. Two control groups received saline and vehicle, AMIK group (1.2 g/kg, i.p.), VIT. E group (1000 mg/kg; p.o.), ROSU group (10 mg/kg; p.o.), AMIK + VIT. E group, AMIK + ROSU group, and combination group. The results showed that AMIK significantly increased serum levels of urea and creatinine. Meanwhile, serum levels of total protein and albumin were decreased. The kidney content of malondialdehyde was increased, whereas glutathione content and catalase activity were decreased. Tumor necrosis factor-α and nuclear transcriptional factor levels were increased. Conversely, administration of VIT. E and/or ROSU with AMIK ameliorated such damage and reduced DNA fragmentation, apoptosis, and necrosis. In conclusion, co-administration of VIT. E, ROSU, or their combination alleviated AMIK-induced nephrotoxicity.

Vitamin E mitigates cisplatin-induced nephrotoxicity due to reversal of oxidative/nitrosative stress, suppression of inflammation and reduction of total renal platinum accumulation.

Cisplatin (CP) is one of the most effective chemotherapeutic agents. Unfortunately, CP-induced nephrotoxicity hampered its use. This study aims to investigate the effect of vitamin E (Vit E) on CP-induced nephrotoxicity. Male white albino rats were divided to four group's six rats each and received either, 1% tween 80 in normal saline or Vit E (75 mg/kg) per day for 14 consecutive days or a single injection of CP (6 mg/kg) alone or CP (6 mg/kg) together with Vit E (75 mg/kg per day for 14 consecutive days). Five days after the CP injection, rats were euthanized; blood samples were collected; kidneys were dissected; and biochemical, immunohistochemical, and histological examinations were performed. Our results revealed that CP treatment significantly increased serum levels of creatinine and urea. Moreover, reduced glutathione (GSH) content as well as superoxide dismutase (SOD) and catalase (CAT) activities were significantly reduced with concurrent increase in kidney malondialdehyde (MDA) content following CP treatment. Vit E successfully lowered serum levels of urea and creatinine, enhanced creatinine clearance and diuresis, and normalized relative kidney/body weight. Furthermore, Vit E successfully normalized renal MDA and nitrite concentrations, elevated GSH level, and restored CAT and SOD activities in renal tissues. Histopathological examination of rat kidney revealed that Vit E significantly mitigated CP-induced renal damage. Importantly, administration of Vit E reduced kidney total platinum concentration indicating a role of platinum renal accumulation on the ability of Vit E to protect against CP nephrotoxicity.

Protective effects of apigenin and myricetin against cisplatin-induced nephrotoxicity in mice.

CONTEXT: Currently, the outcomes of the use of cisplatin in cancer therapy is limited by nephrotoxicity. OBJECTIVE: This study aims to investigate the nephroprotective role of apigenin and myricetin against cisplatin-induced nephrotoxicity in mice. MATERIALS AND METHODS: Adult female Wistar Albino mice were divided into eight groups (n = 8). Group I served as normal control. Groups II, III and IV received apigenin (3 mg/kg, i.p.), myricetin (3 mg/kg, i.p.) or their combination respectively, for seven days. Group V served as positive control group, received vehicles for seven days and cisplatin (7.5 mg/kg, i.p.) for three days starting at day five. Groups VI, VII and VIII received apigenin, myricetin or their combination, respectively for seven days as well as cisplatin injection for three days starting at day five. by the end of the experimental period, a biochemical study involving, nephrotoxicity markers [serum creatinine (Cr) and blood urea nitrogen (BUN)], apoptotic marker [caspase 3], inflammatory mediators [tumour necrosis factor alpha (TNF-α), interleukin 6 (IL-6), cyclooxygenase I and II (COXI, COXII)] and oxidative stress biomarkers [malondialdehyde (MDA), reduced glutathione (GSH) and catalase] was conducted. In addition, renal histopathological alterations were evaluated. RESULTS: Apigenin, myricetin and their combination significantly reduced blood BUN, serum Cr, caspase-3TNF-α, IL-6, COXI and COXII, MDA levels and significantly increased GSH level and catalase activity parallel to, histopathological improvement in kidney tissues. DISCUSSION AND CONCLUSION: Apigenin and myricetin exhibited a protective and promising preventive strategy against cisplatin-induced nephrotoxicity due to their antioxidant and anti-inflammatory effects.

Investigating the tamoxifen/high-fat diet synergy: a promising paradigm for nonalcoholic steatohepatitis induction in a rat model.

Non-alcoholic steatohepatitis (NASH) is a severe liver condition characterized by excessive fat deposition, ballooning, and lobular inflammation. This investigation was conducted to estimate the capability of concomitant tamoxifen administration (TAM) with a high fat diet (HFD) to induce a reliable NASH model that mimics human NASH features. Rats were administered TAM (25 mg/kg/day p.o.) and consumed HFD for 5 weeks. A time-course investigation was conducted to determine the optimal time for NASH development. Liver function indices, hepatic lipid profile factors, oxidative stress biomarkers, and inflammatory mediators were estimated. Additionally, macroscopic and microscopic changes were examined. Compared with the time-matched control group receiving vehicle alone, TAM/HFD significantly impaired liver function indices represented as marked elevation in ALT, AST, and ALP serum levels. TAM/HFD significantly increased lipid profile factors including high TG and TC hepatic levels. Additionally, TAM/HFD remarkably raised hepatic levels of TNF-α and IL-17 and significantly decreased IL-10. The combination also increases the oxidative status evidenced by high content of MDA as well as low activity of GPx and SOD. Accordingly, the combination of TAM and HFD for 5 weeks collaboratively promotes NASH development by initiating compromised hepatocyte functionality, elevated lipid levels, oxidative stress, and liver inflammation.

The impact of PPAR-γ/Nrf-2/HO-1, NF-κB/IL-6/ Keap-1, and Bcl-2/caspase-3/ATG-5 pathways in mitigation of DOX-induced cardiotoxicity in an animal model: The potential cardioprotective role of oxyresveratrol and/or dapagliflozin.

Antioxidants given concurrently with chemotherapy offer an effective strategy for reducing the negative effects of the drug. One remaining obstacle to the use of doxorubicin (DOX) in chemotherapy is cardiotoxicity. Using vitamin E (Vit. E) as a reference standard, our study focuses on the potential preventive benefits of oxyresveratrol (ORES) and/or dapagliflozin (DAPA) against DOX-induced cardiac injury. Acute cardiotoxicity was noticed after a single intravenous injection of a male rat's tail vein with 10 mg/kg of DOX. Oral doses of ORES (80 mg/kg), DAPA (10 mg/kg), and Vit. E (1 g/kg) were given, respectively. Pretreatment of animals with Vit. E, ORES and/or DAPA revealed a considerable alleviation of heart damage, as evidenced by histopathological change mitigation and a notable drop in serum AST, LDH, CK, CK-MB, and cardiac contents of MDA and NO2-. Also, serum TAC, tissue GSH, and SOD showed substantial increases. Additionally, tissue caspase-3, serum IL-6, and TNF-α were considerably reduced. Moreover, a downregulation in cardiac gene expression of ATG-5, Keap-1, and NF-κB in addition to an upregulation of Bcl-2 gene expression and HO-1, Nrf-2, and PPAR-γ protein expression clearly appeared. Ultimately, ORES and/or DAPA have an optimistic preventive action against severe heart deterioration caused by DOX.

"Cerastes snake venom as a promising approach in the management of complete Freund's adjuvant-induced rheumatoid arthritis in rats: Involvement of RANKL and JAK/STAT pathway".

ETHNOPHARMACOLOGICAL RELEVANCE: Cerastes is a snake found mainly in the Egyptian desert. Many studies were performed to explain the possible snake venom's pharmacological therapeutic effect in different autoimmune diseases. One of the most common auto-immune diseases is rheumatoid arthritis. Rheumatoid arthritis is characterized by a high release of pro-inflammatory and immune-modulatory cytokines. The reduction of these markers can indicate how effective is the administered drug. AIM OF THE STUDY: This study aims to explore the potential pharmacological effects of cerastes venom in experimentally-induced RA in rats using Complete Freund's adjuvant - via different mechanisms - by assessing various tissue and serum parameters. MATERIALS AND METHODS: The rats were assigned to negative control group, cerastes control group, positive control group, dexamethasone-treated group, infliximab-treated group, and cerastes-treated group. The study ended on the 20th day when serum and tissue samples were prepared for further evaluation of reduced glutathione, malondialdehyde, rheumatoid factor, tumor necrosis factor-α, interleukin-6, and nuclear factor kappa-light-chain-enhancer of activated B cells as well as relative expression of phosphorylated Janus-kinase, phosphorylated signal transducers and activators of transcription, nuclear factor erythroid 2-related factor 2, and receptor activator of nuclear factor Kappa-B ligand. In addition, a histopathological examination of different groups' knees joints, and spleen was done. RESULTS: The results showed a significant improvement of arthritis induced in the cerastes-treated group in contrast to the positive control group in all assessed parameters. In addition, significant improvement of arthritis was observed in the histopathological examination of different groups' knees joints, and spleen. CONCLUSION: These results revealed that cerastes snake venom has potent anti-inflammatory and immunomodulatory effects and can be used in the management of arthritis.

A novel protective modality against rotenone-induced Parkinson's disease: A pre-clinical study with dulaglutide.

Parkinson's disease (PD) drugs treat symptoms without inhibiting progression. In recent years, finding novel therapeutic medications that can halt disease progression has become crucial. Research on antidiabetic medicines is valuable in these investigations because of the parallels between the two disorders. Using Rotenone (ROT), a frequently used PD model, the possible neuroprotective benefits of Dulaglutide (DUL), an extended-acting glucagon-like peptide-1 agonist, were considered. Twenty-four rats were randomly assigned to 4 groups to complete this experiment (n = 6). 0.2 ml of the vehicle (1 ml of dimethyl sulfoxide (DMSO) diluted in sunflower oil) was administered to the standard control group subcutaneously with a 48-hour pause. The second group was administered ROT 2.5 mg/kg SC every 48 h for 20 days as a positive control group. The third and fourth groups were administered one dose of DUL each week (0.05 and 0.1 mg/kg SC, respectively) to their regimens. The mice received ROT (2.5 mg/kg SC) every 48 h for 20 days after receiving DUL for the initial dose (96 h later). The current study focused on the DUL's ability to preserve usual behavioral function, enhance antioxidant and anti-inflammatory pathways, inhibit alpha-synuclein (α-syn), and increase parkin levels. It is concluded that DUL acts as an antioxidant and an anti-inflammatory to protect against ROT-induced PD. However, more studies are required to support this finding.

Leurieus quinquestriatus scorpion venom ameliorates adjuvant-induced arthritis in rats: Modulating JAK/STAT/RANKL signal transduction pathway.

Leurieus quinquestriatus (LQ) is a type of Egyptian scorpions. Prior studies have established the potential use of scorpion venoms in treating several autoimmune diseases. Therefore, the current study investigates the possible pharmacological effect of LQ venom in CFA-induced arthritis - through different mechanisms - by assessing different serum and tissue parameters. This study was divided into two phases: phase I was conducted to determine the lowest therapeutic dose of LQ scorpion venom, whereas phase II investigated the potential therapeutic effect of the chosen dose of LQ venom on induced arthritis through different mechanisms. The Wistar albino rats were divided equally and randomly into normal control group, LQ control group, arthritis control group, infliximab-treated group, and LQ-treated group. On day 20, blood and tissue samples were collected for further analysis of serum and tissue biomarkers as well as histopathological examination. The results revealed a potential therapeutic effect of LQ venom on arthritic-induced rats through a significant decrease in Rheumatoid Factor, Janus Kinase, Signal transducers and activators of transcription, Receptor activator of nuclear factor Kappa-B ligand, Tumor Necrosis Factor-alpha, Interleukin-6, Nuclear factor kappa-light-chain-enhancer of activated B cells and Malondialdehyde by 57%, 66%, 64%, 62%, 75%, 59%, 38%, and 69%, respectively as well as a significant increase in reduced glutathione, and Nuclear factor erythroid 2-related factor 2 by 102% and 360%, respectively. Histopathological examination of knee joint and spleen also revealed a substantial improvement, indicating the possible utilization of LQ venom in the treatment of rheumatoid arthritis.

Ameliorate impacts of scopoletin against vancomycin-induced intoxication in rat model through modulation of Keap1-Nrf2/HO-1 and IκBα-P65 NF-κB/P38 MAPK signaling pathways: Molecular study, molecular docking evidence and network pharmacology analysis.

Nephrotoxicity is an indication for the damage of kidney-specific detoxification and excretion mechanisms by exogenous or endogenous toxicants. Exposure to vancomycin predominantly results in renal damage and losing the control of body homeostasis. Vancomycin-treated rats (200 mg/kg/once daily, for seven consecutive days, i.p.) revealed significant increase in serum pivotal kidney function, oxidative stress, and inflammatory biomarkers. Histologically, vancomycin showed diffuse acute tubular necrosis, denudation of epithelium and infiltration of inflammatory cells in the lining tubular epithelium in cortical portion. In the existing study, the conservative consequences of scopoletin against vancomycin nephrotoxicity was investigated centering on its capacity to alleviate oxidative strain and inflammation through streamlining nuclear factor (erythroid-derived-2) like 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling and prohibiting the nuclear factor kappa B (NF-κB)/mitogen-activated protein kinase (p38 MAPK) pathway. With respect to vancomycin group, scopoletin pretreatment (50 mg/kg/once daily, i.p.) efficiently reduced kidney function, oxidative stress biomarkers and inflammatory mediators. Moreover, histological and immunohistochemical examination of scopoletin-treated group showed remarkable improvement in histological structure and reduced vancomycin-induced renal expression of iNOS, NF-κB and p38 MAPK. In addition, scopoletin downregulated (Kelch Like ECH Associated Protein1) Keap1, P38MAPK and NF-κB expression levels while upregulated renal expression levels of regulatory protein (IκBα), Nrf2 and HO-1. Furthermore, molecular docking and network approach were constructed to study the prospect interaction between scopoletin and the targeted proteins that streamline oxidative stress and inflammatory pathways. The present investigations elucidated that scopoletin co-treatment with vancomycin may be a rational curative protocol for mitigation of vancomycin-induced renal intoxication.

Diallyl Disulfide Attenuates Methotrexate-Induced Hepatic Oxidative Injury, Inflammation and Apoptosis and Enhances its Anti-Tumor Activity.

BACKGROUND: Methotrexate (MTX) is used potently for a wide range of diseases. However, hepatic intoxication by MTX hinders its clinical use. OBJECTIVES: The present study was conducted to investigate the diallyl disulfide (DADS) ability to ameliorate MTX-induced hepatotoxicity. METHODS: Thirty-two rats were randomly divided into four groups: normal control, DADS (50 mg/kg/day, orally), MTX (single i.p. injection of 20 mg/kg) and DADS+MTX. Liver function biomarkers, histopathological examinations, oxidative stress, inflammation, and apoptosis biomarkers were investigated. Besides, an in vitro cytotoxic activity study was conducted to explore the modulatory effects of DADS on MTX cytotoxic activity using Caco-2, MCF-7, and HepG2 cells. RESULTS: DADS significantly reduced the increased serum activities of ALT, AST, ALP, and LDH. These results were confirmed by the alleviation of liver histopathological changes. It restored the decreased GSH content and SOD activity, while significantly decreased MTX-induced elevations in both MDA and NO2 - contents. The hepatoprotective effects were mechanistically mediated through the up-regulation of hepatic Nrf-2 and the down-regulation of Keap-1, P38MAPK, and NF- κB expression levels. In addition, an increase in Bcl-2 level with a decrease in the expression of both Bax and caspase-3 was observed. The in vitro study showed that DADS increased MTX antitumor efficacy. CONCLUSION: DADS potently alleviated MTX-induced hepatotoxicity through the modulation of Keap-1/Nrf-2, P38MAPK/NF-κB and apoptosis signaling pathways and effectively enhanced the MTX cytotoxic effects, which could be promising for further clinical trials.

Prevalence and Predictors of Persistent Symptoms After Clearance of SARS-CoV-2 Infection: A Multicenter Study from Egypt.

Background and Aim: Little is known about the persistence of symptoms after clearance of SARS-CoV-2 infection. Our study aimed to assess persistent symptoms in COVID-19 patients after clearance of SARS-CoV-2 infection. Methodology: A multi-center survey was conducted on first wave COVID-19 patients with confirmed SARS-CoV-2 infection. Sociodemographic and clinical characteristics, including presenting symptoms and persistent symptoms after viral clearance and possible factors contributing to persistence of such symptoms, were collected using an online multicomponent questionnaire. Descriptive and inferential statistical analysis was performed to detect the most persisting symptoms and factors contributing to their persistence. Results: Overall, 538 patients were enrolled. Mean age was 41.17 (±SD 14.84), 54.1% were males, and 18.6% were smokers. Hypertension and diabetes were the most reported co-morbidities. Mild symptoms were reported in 61.3% of patients, 51.3% were admitted to hospital and 6.5% were admitted to the intensive care unit. Our study identified 49 types of persisting symptoms. Fatigue (59.1%), sense of fever (46.5%), anorexia (24.3%) and diarrhea (24.3%) were the most commonly reported persisting symptoms followed by loss of taste and smell (22.3%), headache (21.4%), cough (20.8) and dyspnea (21%). The use of hydroxychloroquine, azithromycin and multivitamins were significantly associated with persistence of symptoms (OR = 8.03, 8.89 and 10.12, respectively). Conclusion: Our study revealed that in COVID-19 recovered patients, many patients reported persistence of at least one symptom, particularly fatigue and sense of fever. Follow-up of patients after discharge from hospital is recommended until complete resolution of symptoms.

Repurposing of sildenafil as antitumour; induction of cyclic guanosine monophosphate/protein kinase G pathway, caspase-dependent apoptosis and pivotal reduction of Nuclear factor kappa light chain enhancer of activated B cells in lung cancer.

OBJECTIVES: Lung cancer is one of the most frequent types of cancers that lead to death. Sildenafil is a potent inhibitor of phosphodiesterase-5 and showed potential anticancer effects, which has not yet been fully evaluated. Thus, this study aims to investigate the potential anticancer effect of sildenafil in urethane-induced lung cancer in BALB/c mice. METHODS: Five-week-old male BALB/c mice were treated with either (i) normal saline only, (ii) sildenafil only 50 mg kg-1/ P.O every other day for the last four successive weeks, (iii) urethane 1.5 gm kg-1 i.p (at day 1 and day 60), (iv) carboplatin after urethane induction, or (v) sildenafil after urethane induction. KEY FINDINGS: It was shown that sildenafil significantly increased the levels of cGMP and Caspase-3 with a reduction of NF-κB, Bcl-2, Cyclin D1, intercellular adhesion molecule 1, matrix metalloproteinase-2 levels and normalisation of Nrf2 along with pronounced improvement in the histological patterns. CONCLUSIONS: These results indicated that sildenafil markedly induces cell cycle arrest, apoptosis and inhibits the metastatic activity through activation of cyclic guanosine monophosphate/protein kinase G pathway and down-regulation of cyclin D1 and nuclear factor kappa light chain enhancer of activated B cells with downstream anti-apoptotic gene Bcl-2, which underscores the critical importance of future using sildenafil in the treatment of lung cancer.

Diallyl disulfide ameliorates methotrexate-induced nephropathy in rats: Molecular studies and network pharmacology analysis.

Methotrexate (MTX) is a promising chemotherapeutic agent. Its medical use is limited by induced nephropathy. Our study was designed to explore the reno-protective effect of diallyl disulfide (DADS), an organosulfur compound of garlic oil, on MTX-induced nephropathy. Adult rats were randomly divided into 4 groups; normal control, DADS (50 mg kg-1  day-1 , p.o.), MTX (20 mg/kg, i.p.) and DADS+MTX. DADS significantly decreased serum creatinine, urea, uric acid, and albumin levels with an improvement of final body weight. Additionally, DADS markedly attenuated MTX-induced elevations in renal MDA and NO2- contents with an increase in GSH content and SOD activity. Mechanistically, DADS effectively down-regulated mRNA expression level of renal p38 and NF-κB. Additionally, DADS positively regulated the NRF2 gene with a remarkable inhibition of Keap-1 gene. Furthermore, DADS up-regulated BCL2 protein and remarkably suppressed the expression of both BAX and caspase-3 proteins. Overall, DADS has favorable renal protection against MTX-induced nephropathy via modulation of Keap-1/NRF2, p38/NF-κB, and BCL2/BAX/caspase-3 signaling. PRACTICAL APPLICATIONS: Diallyl disulfide is one of the organosulfur compounds of garlic oil. Our study demonstrated that DADS substantially alleviated the decline of kidney function and renal injury induced by MTX. The antioxidative, anti-inflammatory, and anti-apoptotic properties may constitute an important part of its therapeutic applications via regulation of p38/NF-κB, Keap-1/NRF2, and BCL2/BAX/caspase-3 signaling pathways. Therefore, DADS could be a potential therapeutic adjunct in cancer chemotherapy to decrease the associated side effects of MTX. It should be further explored clinically as a protective agent for MTX-treated cancer patients.

Hepatoprotective effects of phytochemicals berberine and umbelliferone against methotrexate-induced hepatic intoxication: experimental studies and in silico evidence.

Chemotherapeutic drugs are used effectively to manage wide types of malignancies, but their therapeutic use is limited due to their associated hepatic intoxication. The current study sheds light on the effect of phytochemicals berberine (BBR) and umbelliferone (UMB) on methotrexate (MTX)-induced hepatic intoxication. Forty-eight rats were allocated to normal, BBR (50 mg/kg orally for 10 days), UMB (30 mg/kg orally for 10 days), MTX (20 mg/kg at the 5th day), BBR+MTX, and UMB+MTX. With regard to MTX, the results of this investigation reveal potent amelioration of MTX hepatotoxicity by BBR and UMB through reduction of the elevated serum levels of ALT, ALP, AST, and LDH confirmed by the attenuation of histopathological abrasion in liver tissues. BBR and UMB markedly restored antioxidant status. More importantly, BBR resulted in reducing P38 mitogen-activated protein kinase (P38MAPK), nuclear factor kappa-B (NF-κB), and Kelch-like ECH-associated protein 1 (Keap-1) genes and enhanced mRNA expression of Nrf-2 (P < 0.05). Interestingly, in silico studies via molecular docking pinpointed the binding modes of BBR and UMB to the binding pocket residues of P38MAPK, NF-κB, and Keap-1 and demonstrated a promising inhibition of Keap-1, P38MAPK, and NF-κB. BBR and UMB reduced the expression of pro-apoptotic protein Bax and apoptotic protein caspase-3 as well as increased the expression of anti-apoptotic protein Bcl-2. Therefore, BBR and UMB may denote promising therapeutic agents that can avert hepatic intoxication in patients receiving MTX.