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Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa. Cholesterol metabolism is involved in the progression of aggressive prostate cancer (PCa). Here the authors show that miR-205 downregulation promotes cholesterol synthesis and androgen receptor signalling in PCa through enhancing the expression of the rate-limiting enzyme of cholesterol synthesis, squalene epoxidase.

Purpose: Females with polycystic ovary syndrome (PCOS) are found to have hormonal and metabolic alterations. This study investigated the efficacy of the favonolignan silibinin in restoring the metabolic alterations associated with letrozole-induced PCOS in rats. Methods: The study allocated 42 albino rats into two groups. The first group was a normal control group (n=12) in which only the vehicle was given. The second group, the PCOS group (n=30), received letrozole (1 mg/kg/day) orally for 21 days. On day 21, six animals from the first group and six animals from the second group were sacrificed to confirm the development of PCOS, and the rest of the animals (n=24) in the second group were distributed equally into four groups: the PCOS group received vehicle, the metformin (MET) group received 300 mg/kg metformin orally, and the low-dose silibinin (LD-100) and high-dose silibinin (HD-200) groups received 100 and 200 mg/kg silibinin intraperitoneally, respectively. Blockade of the estrus cycle in the diestrus phase, hyperglycemia, and body weight elevation were related to a positive PCOS induction. An oral glucose tolerance test (OGTT) was also carried out for all animals on day 21 and on the last day of the experiment (day 40) to investigate the effect of silibinin on insulin resistance. The rats' lipid profile, insulin level, estrus cycle patterns, body weight, and weights of the ovaries and uterus were also measured on day 40. Results: A 19-day silibinin treatment led to the restoration of regular estrus cyclicity, reduced the glucose spike in OGTT analysis, and alleviated insulin resistance in PCOS rats. There was a statistically non-significant decrement in insulin level and lipid profile in the treatment groups. Conclusion: Silibinin favonolignan ameliorated some metabolic and reproductive alterations associated with PCOS. This could be related to the decreased insulin resistance, and antiandrogenic and phytoestrogenic activity of silibinin. Further study with longer term therapy is recommended to clarify more potential effects of silibinin and its mechanism of action in PCOS. Keywords: metabolic alteration, impaired glucose tolerance, lipid profile, silibinin

The study aimed to investigate whether zofenopril (ZOF), thymoquinone (TQ), or their co-administration effectively ameliorates urotoxicity and nephrotoxicity following cyclophosphamide (CPH) treatment. A total of 48 Wister Albino female rats were divided into six groups each of eight rats; negative control (NC), positive control (PC), mesna (MS), ZOF, TQ, and ZOF+TQ groups. Normal saline, mesna, ZOF-15mg/kg, TQ-80mg/kg, and their combination were given orally for 19 days to the groups NC, MS, ZOF, TQ, and ZOF+TQ respectively. On the 17 day, a single dose of CPH 200 mg/kg was given intraperitoneally for all the groups except the NC group. Urine was collected over 24 hours before animal scarification for urinalysis. After scarification, blood, and kidney tissue were obtained for assessment of conventional kidney function parameters, novel kidney injury biomarkers, pro-inflammatory cytokines, oxidative status, complete blood count (CBC), and histopathological examination. CPH disturbed the urinary excretion of urea, creatinine, and protein, and significantly elevated novel biomarkers for kidney injury including cystatin-C (Cys-C) (p=0.019) and markedly kidney injury molecule-1 (KIM-1) (p=0.27), the semiquantitative measurement of hematuria revealed significant elevation of hematuria score (p=0.0002), urine pus and protein (p=0.0005). Additionally, CBC-derived inflammatory biomarkers including neutrophil-lymphocyte ratio (NLR) (p=0.001), neutrophil-monocyte ratio (NMR) (p=0.0004), pro-inflammatory cytokine interleukin (IL)-6 (p=0.016) and tumor necrosis factor (TNF)-α (p<=0.007), total antioxidant capacity (TAC) (p<0.0001) were significantly increased. Evidence of obvious histopathological structural alteration was noticed in kidney tissue and bladder urothelium in CPH-treated animals. ZOF, TQ, and their co-treatment significantly prevented these deleterious effects associated with CPH treatment. This study demonstrated that ZOF and TQ provided uroprotective and nephroprotective effects against CPH-induced nephrotoxicity by reducing kidney injury biomarkers, and CBC-derived inflammatory markers, restoring antioxidant capacity, and improving histopathological outcomes. The suggested mechanism involves the anti-inflammatory and antioxidant activity of TQ and the sulfhydryl-angiotensin converting enzyme inhibitor ZOF.

Background: Current therapies for polycystic ovary syndrome (PCOS) are accompanied by unwanted effects. Silibinin; a flavonolignan has pleiotropic activities and favorable safety profile. Purpose: To investigate the efficacy of silibinin on estrous cyclicity, inflammation, oxidative stress and ovarian morphology in letrozole-induced PCOS in rats. Methods: Forty-eight female Wistar albino rats were divided into 2 sets. Rats of the first set (n = 12), assigned as a negative control (NC) received only the vehicle, rats of the second set (n = 36), assigned as PCOS rats, were given letrozole 1mg/Kg orally for 21 days. On day 21, six rats from the first set and six rats from the second set were euthanized for confirmation of PCOS-induction. The remaining animals from the first set assigned as group 1, those in the second set (n = 30) were equally divided into 5 groups and treated daily for 19 days as follows: group 2 (positive control) received only the vehicle, group 3 treated with metformin 300mg/Kg orally, groups 4 and 5 treated respectively with 100 and 200 mg/Kg silibinin intraperitoneally (IP), and group 6 treated with a combination of metformin 300mg/Kg orally and silibinin 100mg/Kg IP. On day 40, blood samples were examined for luteinizing hormone (LH), testosterone (TS) and estradiol (EST) levels, the anti-inflammatory and antioxidant parameters, ovarian and uterine morphology. Results: Silibinin alone or in combination with metformin was found to be effective in restoring the regularity of estrous cycle by ameliorating the abnormal alterations of LH, TS, EST, tumor necrosis factor (TNF)-[alpha], and oxidative status and by resuming the appearance of corpora lutea and decreasing or even total absence of cystic follicles in the ovaries. Conclusion: Silibinin was effective in restoring estrous regularities and alleviating hormonal and histomorphological abnormalities of the ovarian and uterine tissues, this could be due to its anti-androgenic, anti-inflammatory and antioxidant properties. Keywords: inflammation, estrous cycle, PCOS, silybin, testosterone

Four serotypes recovered from clinically diarrheic human faecal samples ( Salmonella Muenster, Salmonella Florian, Salmonella Omuna and Salmonella Noya) were investigated for the presence of 11 virulence genes ( inv A , avr A, ssa Q, mgt C, sii D, sop B, gip A, sod C1, sop E1, spv C, and bcf C) and their association with antibiotic resistance. The 4 Salmonella serotypes lacked virulence genes gip A and spv C. Resistance to 7 of the 14 antimicrobials was detected. The frequency of resistance, to lincomycin and streptomycin (100% of the Salmonella Muenster [2/5], Salmonella Florian [1/5], Salmonella Omuna [1/5], and Salmonella Noya [1/5] isolates), chloramphenicol (100% of the Salmonella Muenster [2/5] and Salmonella Florian [1/5] isolates) and trimethoprim–sulfamethoxazole (100% of the Salmonella Florian [1/5] and Salmonella Omuna [1/5] isolates) was an outstanding feature. With the rest of the antibiotics, the four Salmonella serotypes exhibited a great diversity in their resistance patterns. Overall, the four Salmonella serotypes were resistant to more than one antimicrobial. The antimicrobials to which the Salmonella Muenster, Salmonella Florian, and Salmonella Omuna isolates were resistant, contributed to five different antimicrobial resistance profiles. The virulence associated genes inv A, ssa Q, sii D, sop B, and bcf C genes were 100% associated with certain antimicrobial resistance phenotypes (streptomycin and lincosamide) not recorded previously, and secondly, the presence of inv A, avr A, ssa Q, mgt C, sii D, sop B, and bcf C was associated with resistance to chloramphenicol. The results of this study will help in understanding the spread of virulence genotypes and antibiotic resistance in Salmonella in the region of study.

Resveratrol shows remarkable anti-inflammatory activities in experimental models. This study aims to evaluate the effect of resveratrol, as an adjuvant with meloxicam (Mlx), on the pain and functional activity during a 90-day period and monitor the adverse effects on kidney and liver functions, lipid profile, and hematological markers. This study was a double-blind, placebo-controlled, randomized multi-center study that involved 110 patients with knee osteoarthritis (OA) and was performed at Sulaimani City, Iraq, from December 2016 to September 2017. To assess the effects of Mlx with or without resveratrol, pain severity and functional disability were evaluated at baseline and after 90 days using the Western Ontario and McMaster Universities Osteoarthritis Index. Fasting blood was collected to evaluate the lipid profile markers, hematological picture, and liver and kidney functions, in addition to vitamin D level. Resveratrol significantly improves pain, functions, and associated symptoms compared with placebo. The clinical and biochemical markers indicated that 500 mg/day of resveratrol, as an adjuvant with Mlx, is safe and well tolerated by the knee OA patients. Resveratrol, as an \"add-on\" medication with Mlx, was superior in terms of safety and efficacy to Mlx alone for the treatment of pain and improvement of physical function in patients with knee OA.

Traditional liberal theories of jurisprudence consider the \"rule of law\" as a collection of rules and principles created without the help of rhetoric. From this perspective the judicial system is ideally a neutral forum wherein experts interpret rather than create the law. This essay claims that this orthodox view of the relationship between law and rhetoric needs extensive revision, and argues the need for a critical legal rhetoric that examines the ways in which the law is constituted and enacted beyond the domain of Supreme Court decision making. By illustrating how the rights talk found in appellate decisions can serve as sword, shield, and menace, this essay invites critics to consider seriously the participatory role that ordinary citizens take in the creation of their own legal culture. The author contends that in the case of reproductive rights, extra-judicial public arguments provided part of the fragmentary materials that called into question the rule of law which allowed for the compulsory sterilization of thousands of Americans.

SARS-CoV-2 virus is transmitted in closed settings to people in contact with COVID-19 patients such as healthcare workers and household contacts. However, household person-to-person transmission studies are limited. Households participating in an ongoing cohort study of influenza incidence and prevalence in rural Egypt were followed. Baseline enrollment was done from August 2015 to March 2017. The study protocol was amended in April 2020 to allow COVID-19 incidence and seroprevalence studies. A total of 290 households including 1598 participants were enrolled and followed from April to October 2020 in four study sites. When a participant showed respiratory illness symptoms, a serum sample and a nasal and an oropharyngeal swab were obtained. Swabs were tested by RT-PCR for SARS-CoV-2 infection. If positive, the subject was followed and swabs collected on days three, six, nine, and 14 after the first swab day and a serum sample obtained on day 14. All subjects residing with the index case were swabbed following the same sampling schedule. Sera were collected from cohort participants in October 2020 to assess seroprevalence. Swabs were tested by RT-PCR. Sera were tested by Microneutralization Assay to measure the neutralizing antibody titer. Incidence of COVID-19, household secondary attack rate, and seroprevalence in the cohort were determined. The incidence of COVID-19 was 6.9% and the household secondary attack rate was 89.8%. Transmission within households occurred within two-days of confirming the index case. Infections were asymptomatic or mild with symptoms resolving within 10 days. The majority developed a neutralizing antibody titer by day 14 post onset. The overall seroprevalence among cohort participants was 34.8%. These results suggest that within-household transmission is high in Egypt. Asymptomatic or mild illness is common. Most infections seroconvert and have a durable neutralizing antibody titer.