Molecular mechanisms underlying methotrexate-induced intestinal injury and protective strategies.

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.

Role of Nrf2/HO-1, PPAR-γ, and cytoglobin signals in the pathogenesis of methotrexate-induced testicular intoxication in rats and the protective effect of diacerein.

Methotrexate (MTX) is an inhibitor of folic acid reductase used in managing a variety of malignancies. Testicular injury by MTX is one of its serious adverse effects. The current investigation aims to assess the protective effects of diacerein (DIA) on testicular injury by MTX and clarify the possible underlying mechanisms. Testicular injury in rats was induced by a single injection of 20 mg/kg body weight of MTX. DIA was given in 25 mg/kg body weight/day and 50 mg/kg body weight/day doses for 10 days. Compared to the MTX group, DIA attenuated testicular intoxication as evidenced by improvement of testicular histopathological abnormalities and increased serum testosterone and luteinizing hormone. DIA attenuated testicular oxidative stress changes by lowering testicular MDA and boosting GSH content and SOD activity. Moreover, administration of DIA attenuated MTX-induced testicular inflammation, as proved by decreased TNF-α and IL-6. At the molecular level, DIA induced significant upregulation in Nrf2, HO-1, PPAR-γ, and cytoglobin protein expression. The present results proved that DIA, in a dose-dependent manner, exhibited notable amelioration of testicular toxicity induced by MTX through augmentation of anti-inflammatory and antioxidant effects combined by upregulating Nrf2/HO-1, PPAR-γ, and cytoglobin signaling.

The Protective Role of Etoricoxib Against Diethylnitrosamine/2-acetylaminofluorene- Induced Hepatocarcinogenesis in Wistar Rats: The Impact of NF-κB/COX-2/PGE2 Signaling.

BACKGROUND: Liver cancer ranks as the 7th and 5th leading cause of cancer morbidity worldwide in men and women, respectively. Hepatocellular Carcinoma (HCC) is the most common type of liver cancer and is associated with an increasing global burden of Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH). OBJECTIVE: The present study aimed to investigate the possible chemopreventive effect of etoricoxib on diethylnitrosamine (DENA) and 2-acetylaminofluorene (2AAF)-induced HCC in male Wistar rats. METHODS: HCC was induced by DENA (150 mg/kg/week; i.p) for 2 weeks, then 2AAF (20 mg/kg; p.o) every other day for three successive weeks. Etoricoxib (0.6 mg/kg, p.o.) was given to DENA/ 2AAF-administered rats for 20 weeks. RESULTS: Etoricoxib significantly suppressed alpha-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19.9) as liver tumor biomarkers. It also decreased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin levels while increased serum albumin levels. Besides, it alleviated DENA/2AAF-induced histopathological abrasions and inflammatory cell infiltration. Furthermore, etoricoxib showed a potent antioxidant effect, supported by a significant lipid peroxide reduction and elevation in superoxide dismutase activity and GSH content. In addition, Etoricoxib significantly down-regulated the protein expression of interleukin 1 beta (IL-1ß), tumor necrosis factor α (TNFα), nuclear Factor-kappa B (NF-κB), phosphorylated nuclear Factor-kappa B (p-NF-κB), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2). CONCLUSION: In conclusion, the current results proved that etoricoxib possesses an anticarcinogenic effect via its antioxidant, anti-inflammatory, and modulation of NF-κB/COX-2/PGE2 signaling.

Factors determining the amount of residual urine in men with bladder outlet obstruction: Could it be a predictor for bladder contractility?

OBJECTIVE: To determine from urodynamic data what causes an increased postvoid residual urine volume (PVR) in men with bladder outlet obstruction (BOO), urethral resistance or bladder failure, and to determine how to predict bladder contractility from the PVR. PATIENTS AND METHODS: We analysed retrospectively the pressure-flow studies (PFS) of 90 men with BOO. Nine patients could not void and the remaining 81 were divided into three groups, i.e. A (30 men, PVR < 100 mL), B (30 men, PVR 100-450 mL) and C (21 men, PVR > 450 mL). The division was made according to a receiver operating characteristic curve, showing that using a threshold PVR of 450 mL had the best sensitivity and specificity for detecting the start of bladder failure. RESULTS: The filling phase showed an increase in bladder capacity with the increase in PVR and a significantly lower incidence of detrusor overactivity in group C. The voiding phase showed a significant decrease in voided volume and maximum urinary flow rate (Q max) as the PVR increased, while the urethral resistance factor (URF) increased from group A to B to C. The detrusor pressure at Q max (PdetQ max) and opening pressure were significantly higher in group B, which had the highest bladder contractility index (BCI) and longest duration of contraction. Group C had the lowest BCI and the lowest PdetQ max. CONCLUSIONS: In men with BOO, PVR results from increasing outlet resistance at the start and up to a PVR of 450 mL, where the bladder reaches its maximum compensation. At volumes of >450 mL, both the outlet resistance and bladder failure are working together, leading to detrusor decompensation.

Refractory enuresis in children and adolescents: how can urodynamics affect management and what is the optimum test?

OBJECTIVE: After failure of medical and behavioral therapy in enuresis, the usual next step is to investigate using urodynamics. The aim of this study was to determine the actual benefit and optimal method of urodynamics in the treatment of refractory enuresis. METHODS: This prospective randomized study included 56 patients: 17 males and 39 females with an age range of 7-16 years. All had tried multiple courses of medical treatment for enuresis for at least 6 months without response. Thirty patients underwent investigation by cystometrogram, uroflowmetry and electromyogram (UFM/EMG), while 26 patients underwent pressure/flow/EMG (P/F/EMG) studies. RESULTS: Bladder filling abnormalities were found in 25 out of the 56 patients (44.6%) and included low bladder capacity in 39%, hypocompliance in 32%, and detrusor overactivity in 45%. With regard to voiding dysfunction, 70% of the UFM/EMG group had detrusor‒sphincter dyssynergia and 67% of the P/F/EMG group had bladder outlet obstruction. CONCLUSIONS: Urodynamics can help in cases of refractory enuresis by detecting dysfunctional voiding, which is present in a large percentage of these patients. This can be diagnosed by UFM/EMG, rather than P/F/EMG, as a non-invasive test. UFM alone may be misleading. Alpha adrenergic blockers may be of benefit in treating these patients.

Different urodynamic patterns in female bladder outlet obstruction: Can urodynamics alone reach the diagnosis?

OBJECTIVE: To define the different urodynamic patterns in female bladder outlet obstruction (BOO) and to assess whether urodynamics alone can be relied on for the diagnosis. PATIENTS AND METHODS: This prospective study included 60 clinically obstructed women and 27 with stress urinary incontinence as a control group. All patients had pressure-flow studies and were divided into four groups. Group A (control group, 27 patients) and group B (22) had a maximum urinary flow rate (Q max) of >15 mL/s and a detrusor pressure at Q max (P det Q max) of <30 or >30 cm H2O, respectively. Group C (20 patients) and group D (18) had a Q max of <15 mL/s and a P det Q max of >30 or <30 cm H2O, respectively. RESULTS: The mean Q max for groups A, B, C, and D were 21.8, 21.9, 10.8 and 9.9 mL/s, respectively, while the mean P det Q max was 20.8, 40.4, 48.7, and 18.7 cm H2O, respectively. The residual urine volume was <100 mL in groups A and B but >100 mL in groups C and D. When compared with group A, groups B-D had a significant difference in vesical pressure, groups B and C had a significant difference in P det Q max, while Q max, the maximum voided volume and residual urine volume were significantly different in groups C and D. Group A was obviously unobstructed, group B might have early obstruction, group C had compensated obstruction, while group D can be considered to have late de-compensated obstruction. CONCLUSIONS: BOO in females has three different urodynamic patterns, i.e. early, compensated and late obstruction. However, urodynamics should be combined with the clinical presentation and residual urine volume for an accurate diagnosis.

Prostate specific antigen reference ranges in Saudi men.

OBJECTIVE: The aim of this study is to find out the age-specific and population-specific values of prostate specific antigen (PSA) among Saudi men. Normal values for different age groups between 40 and 89 years will be obtained. METHODS: The study was conducted in King Fahd Hospital of the University, Al-Khobar, Kingdom of Saudi Arabia. The total free and percent free PSA were measured for Saudi men who were free of prostate cancer by digital rectal examination (DRE) and with PSA value of <4 ng/ml. Transrectal ultrasonography and needle biopsy were performed in those with suspicious DRE or PSA >4 ng/ml. A total of 567 cancer free Saudi men were included in this study. All men were divided into 5 groups; each 10 years interval starting from the age of 40 years. RESULTS: The mean values of total PSA were 0.87 for men 40-49 years, 1.36 for men 50-59 years, 1.81 for men 60-69 years, 2.32 for men 70-79 years and 2.36 for men 80-89 years. The percent free PSA was >30% in all age groups. When those with PSA <4 ng/ml were considered, the percent free PSA was the same and only 16.6% of them had a ratio of < or =18%. The upper limit of normal PSA was near to that of Chinese and Korean. CONCLUSION: Normal mean PSA values for Saudi men are lower than the reported values. The percent free PSA for men having PSA <4 ng/ml is applicable. Racial variations of PSA values were observed.

Study of pelvicaliceal anatomy by helical computerized tomography. Is it feasible?

OBJECTIVE: To evaluate the role of 3-dimensional images produced by computerized tomography (CT), using intravenous contrast to study pelvicaliceal anatomy. This might be of help in endourological procedures. METHODS: The study was conducted in King Fahd Hospital of the University, King Faisal University, Dammam, Kingdom of Saudi Arabia. The study took place from July 2002 through to October 2002. Helical CT was carried out for patients who were investigated using excretory urography for any reason, after obtaining a written consent. A CT was carried out to the kidneys only within 10 minutes (between the 5 and 15 minute films of excretory urography). Images were reprocessed by 3-dimension construction after subtracting all structures except for the pelvicaliceal system. Thirty-six normal kidneys were studied. RESULTS: The upper pole was drained by a single caliceal infundibulum in all 36 (100%) kidneys. The middle segment of the kidney was drained by 2 infundibula in 32 (89%) kidneys. Four (11%) kidneys had no middle caliceal infundibula. The lower pole was drained by 2 caliceal infundibula in 23 (64%) and a single infundibulum in 13 (36%) kidneys. The minor calices draining each renal segment were seen clearly. CONCLUSION: Three-dimensional images derived by helical CT are feasible for evaluating the anatomy of pelvicaliceal system, and, can be of help in endourological procedures.