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Background Materials and Methods Results Conclusions α‐1 blockers and dutasteride are widely used as agents to treat benign prostatic hyperplasia (BPH); the impact of these drugs on prostatic inflammation is still unclear. Herein, we investigated the impact of α‐1 blockers and dutasteride treatment of BPH in terms of the degree of prostatic inflammation.Tissue specimens were obtained from 143 BPH patients who were administered α‐1 blockers up until their operation. Thirty‐three of the patients had also been treated with dutasteride before the procedure. The degree of prostatic inflammation was quantified histologically by the ratio of high endothelial venule (HEV)‐like vessels. We divided this retrospective cohort into α‐1 blocker monotherapy and combination therapy (α‐1 blockers + dutasteride) groups and evaluated clinical parameters of the two groups in relation to the degree of chronic prostatic inflammation. At the same time, we assessed factors exacerbating chronic prostatic inflammation.Comparison of the monotherapy and combination therapy groups showed no significant differences in the parameters of the urodynamic study or degree of chronic prostatic inflammation, whereas the IPSS total score, voiding subscore, nocturia, intermittency, weak stream, and straining were significantly lower in the combination than the monotherapy group. The duration of α‐1 blockers administration was not correlated with the ratio of HEV‐like vessels, while that of dutasteride was strongly correlated (correlation coefficient = 0.595; p < 0.001). Multiple regression analysis demonstrated that the duration of dutasteride administration was a key factor exacerbating the degree of chronic prostatic inflammation.The present study showed that despite their ameliorating effect on prostatic hyperplasia, dutasteride contributed significantly to chronic prostatic inflammation. [ABSTRACT FROM AUTHOR]

Aim To evaluate the effect of 5 alpha-reductase inhibitor (5-ARI) treatment on prostate cancer detection by multiparametric magnetic resonance imaging (mpMRI). Methods We retrospectively collected data on 429 patients who underwent mpMRI before prostate biopsy in the Urology Department of Giresun University Training and Research Hospital between March 2018 and December 2021. The patients were categorized as those who had never been treated with 5-ARI (n =359) and those who were treated with 5-ARI for more than six months (n =70). The two groups were compared in terms of age, mpMRI findings, and pathology results. Results The number of patients with Prostate Imaging Reporting and Data System (PIRADS) 3 score was significantly higher in the 5-ARI group (37.1% vs 20.6%; P=0.009). The groups did not differ in terms of malignant pathological findings (48.5% in the non-5-ARI vs 47.1% in the 5-ARI group; P =0.505). The detection rates of malignant pathological findings in PIRADS 3 and PIRADS 5 patients were similar between the 5-ARI and non-5-ARI group. However, malignancy detection rate in PIRADS 4 patients was significantly higher in the non-5-ARI group ( P =0.031). In the non-5-ARI group, the sensitivity was 56.4% and the specificity was 79.7%. In the 5-ARI group, the sensitivity was 84.9% and the specificity was 56.8%. Conclusion In patients with suspected prostate cancer, 5-ARI intake may alter lesion mpMRI characteristics and PIRADS distribution on mpMRI. 5-ARI intake should be reported to the radiologist. [ABSTRACT FROM AUTHOR]

To compare the risk of intentional self-harm (ISH) and suicide in older men using 5-α reductase inhibitors (5-ARIs) and alpha-blockers for benign prostatic hyperplasia (BPH). Observational research of older men with BPH suggested an increase in ISH with 5-ARI use compared with nonuse; we aimed to address potential confounding by indication with an active comparator reference group. Using Medicare data linked to the National Death Index (NDI) from 2007-2016, we implemented a retrospective cohort design in males aged ≥65 years who initiated 5-ARI or alpha-blocker use for BPH. ISH was identified using ICD-9-CM and ICD-10-CM diagnosis codes. Suicides were identified through cause-of-death information from the NDI. We used inverse probability of treatment weighted Cox proportional hazards regression to compare time-to-event between treatment groups, with robust variance estimation. The event rates for ISH and suicide, respectively, were 0.314 and 0.308 per 1000 person-years (PY) among 5-ARI users (n = 181,675), and 0.364 and 0.382 per 1000PY among alpha-blocker users (n = 850,476). For 5-ARI use relative to alpha-blocker use, hazard ratios (HRs) for ISH and suicide, respectively, were 0.88 (95% CI:0.62-1.25) and 0.82 (95% CI:0.54-1.24); for the composite outcome (non-fatal ISH or suicide), the HR was 0.88 (95% CI:0.66-1.16). Subgroup and sensitivity analyses supported these results. 5-ARI use was not associated with an increased risk for ISH or suicide compared to alpha-blocker use in older men with BPH. Study limitations included low event rates and potentially low sensitivity for ISH events. [ABSTRACT FROM AUTHOR]

The worrying issue of antibiotic resistance in pathogenic bacteria is aggravated by the scarcity of novel therapeutic agents. Antibiotic adjuvants offer a promising solution due to their cost-effectiveness and high efficacy in addressing this issue, such as the β-lactamase inhibitor sulbactam (a β-lactam adjuvant) and the dihydrofolate reductase inhibitor trimethoprim (a sulfonamide adjuvant). This study aimed to discover potential adjuvants for tetracyclines from a list of previously approved drugs to restore susceptibility to Escherichia coli carrying the tetA gene. We have screened guanethidine, a compound from the Chinese pharmacopoeia, which effectively potentiates the activity of tetracyclines by reversing resistance in tetA-positive Escherichia coli, enhancing its antibacterial potency, and retarding the development of resistance. Guanethidine functions via the inhibition of the TetA efflux pump, thereby increasing the intracellular concentration of tetracyclines. Our findings suggest that guanethidine holds promise as an antibiotic adjuvant. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to explore the suspected adverse drug reaction (ADR) data of five licensed statins in the UK: atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin. A secondary aim was to determine if there are any associations between the polypharmacological properties of the statins and their associated muscle-related side effects. Methods: The chemical database of bioactive molecules with drug-like properties, European Molecular Biology Laboratory (ChEMBL), was used to obtain data on the pharmacological interactions of statins with human proteins. The Medicines and Healthcare Products Regulatory Agency's (MHRA) Yellow Card scheme was used to obtain reports of suspected ADRs from 2018 to 2022. The OpenPrescribing database was used to obtain the prescribing rates for statistical interpretation. Results: The study found no significant difference between the statins association with suspected ADRs across all organ classes (X2, p > 0.05). Fluvastatin was found to have a higher incidence of ADRs/100,000 Rx across multiple system organ classes. Conclusions: No significant difference was found between the suspected ADR incidence of the statins across all system organ classes. [ABSTRACT FROM AUTHOR]

Inhibiting aldose reductase (ALR2, AR) as well as maintaining a concomitant antioxidant (AO) activity via dual-acting agents may be a rational approach to prevent cellular glucotoxicity and at least delay the progression of diabetes mellitus (DM). This study was aimed at evaluating the dual-acting AR inhibitor (ARI) cemtirestat (CMTI) on tissue oxidative stress (OS) and carbonyl stress (CS) biomarkers in rats exposed to fructose alone (F) or fructose plus streptozotocin (D; type-2 diabetic). D and F rats were either untreated or treated daily with low- or high-dose CMTI, ARI drug epalrestat (EPA) or antioxidant stobadine (STB) for 14 weeks. Malondialdehyde (MDA), glutathione S-transferase (GST), nitric oxide synthase (NOS), and catalase (CAT) were increased in the sciatic nerve of F and D. These increases were attenuated by low doses of CMTI and STB in D, but exacerbated by low-dose EPA and high-dose CMTI in F. STB and CMTI and to a lesser extent EPA improved MDA, protein-carbonyl, GST and CAT in the hearts and lungs of F and D. CMTI and STB were more effective than EPA in improving the increased MDA and protein-carbonyl levels in the kidneys of F and especially D. CMTI ameliorated renal GST inhibition in D. In the lungs, hearts, and kidneys of F and D, the GSH to GSSG ratio decreased and caspase-3 activity increased, but partially resolved with treatments. In conclusion, CMTI with ARI/AO activity may be advantageous in overcoming OS, CS, and their undesirable consequences, with low dose efficacy and limited toxicity, compared to ARI or antioxidant alone. [ABSTRACT FROM AUTHOR]

• 5-alpha reductase inhibitors may reduce the risk of bladder cancer. • Androgen suppression therapy could improve the prognosis of bladder cancer. • Androgen deprivation therapy did not reduce the incidence of bladder cancer The influence of androgen suppression therapy (AST) on bladder cancer (BCa) remains controversial, as recent studies have not reached a consensus regarding the relationship between AST and the incidence or prognosis of BCa. We perform an updated systematic review and meta-analysis utilizing the most recent evidence to investigate the potential influence of AST on the incidence and prognosis of BCa. A comprehensive literature search was performed on the PubMed, Medline, Embase, Web of Science, and the Cochrane Library databases to include potentially eligible studies. Hazard ratios (HR) and odds ratios (OR) were used to calculate the incidence and prognosis of BCa. This meta-analysis included 22 studies with 700,755 participants which investigated the impact of AST on the risk and prognosis of BCa. The pooled results revealed no significant relation between AST and a decreased incidence of BCa (OR: 0.92, 95%CI: 0.77-1.09, P = 0.342). Subgroup analysis reported that patients receiving 5-alpha reductase inhibitors (5-ARIs) exhibited a significantly lower risk of BCa (OR: 0.83, 95%CI: 0.75-0.91, P < 0.001), while androgen deprivation therapy did not show a significant reduction (OR: 1.00, 95%CI: 0.46-2.16, P = 0.995). AST may also significantly improve the recurrence-free survival of patients with BCa (HR: 0.69, 95%CI: 0.50-0.95, P = 0.023). We also detected a significant improvement in OS among BCa patients who received 5-ARIs compared to those without 5-ARIs (HR: 0.82, 95%CI: 0.68-0.99, P = 0.037). No significant correlation was found between AST and a decreased BCa incidence, while 5-ARIs have demonstrated efficacy in reducing BCa occurrence. Moreover, patients who received AST demonstrated improved prognosis. [ABSTRACT FROM AUTHOR]

Background: The evidence base pertaining to the efficacy of monotherapies for androgenetic alopecia (AGA), the most common form of hair loss, is ever expanding—and this warrants a formal comparison therapies' effect on a frequent basis. Aims: The objective of the current study was to determine the comparative effect of relevant monotherapies for male AGA. Patients/Methods: Our aim was achieved by conducting Bayesian network meta‐analysis (NMA), under a random effects model, for two outcomes: 6‐month change in (1) total and (2) terminal hair density in adult (i.e., aged 18 years and above) men with AGA; these analyses were preceded by a systematic search of the peer‐reviewed literature for suitable data. Interventions' surface under the cumulative ranking curve (SUCRA) and pairwise relative effects (quantified as mean differences) were estimated through the NMAs. Results: We determined the comparative effect of 20 active comparators and a control (i.e., placebo/vehicle). "Dutasteride 0.5 mg once daily for 24 weeks" was ranked the most effective in terms of 6‐month change in (1) total hair density (SUCRA = 87%) and terminal hair density (SUCRA = 98%). Our results showed that interventions' effectiveness can be dose dependent. Conclusions: Our updated analyses of the up‐to‐date evidence regarding monotherapies for male AGA showed that the oral form of 5‐alpha reductase inhibitors are more effective than oral minoxidil and other newer agents like Botox, microneedling, and photobiomodulation. Our findings can better inform clinical decision making and design of future research studies. [ABSTRACT FROM AUTHOR]

Background: Type II diabetes mellitus is posing a severe health threat throughout the globe due to its associated pathophysiological risks and high mortality rate. Carbohydrate catabolic enzymes, including α-amylase, α-glucosidase and aldose reductase, play an important role in the development of diabetes. The natural or synthetic inhibitors of these enzymes are crucial in reducing diabetes and its related complications. Tinosporacordifolia is a plant of great significance in Ayurveda due to its unique biological activities, including anti-diabetic properties. The present study aims to identify the active constituents of T. cordifolia leaves and evaluate the in vitro inhibitory potential of its ethanol extract constituents against α-amylase, α-glucosidase and aldose reductase activities. Results: The ethanolic leaf extract of T. cordifolia inhibited the activities of α-amylase, α-glucosidase and aldose reductase in a dose-dependent manner. It was on par with the standard inhibitors acarbose and quercetin. At 5 mg/ml, the noted % inhibition values of extract were 69.27 ± 0.17, 67.8 ± 0.26 and 62.55 ± 0.24, respectively, for α-amylase, α-glucosidase and aldose reductase. Using GC-MS analysis, neophytadiene, γ-sitosterol, phytol, phytyl palmitate, and phytyl acetate were identified as prominent constituents of the ethanolic extract. Based on molecular docking and ADME analysis, γ-sitosterol was found as the major reactive phytoconstituent, which showed the highest inhibitory potential against α-amylase, α-glucosidase and aldose reductase activities. Conclusions: The present study identified γ-sitosterol as triplet inhibitor of α-amylase, α-glucosidase and aldose reductase and affirmed the ethno-medicinal significance of T. cordifolia leaves in the development of new anti-diabetic leads. [ABSTRACT FROM AUTHOR]

Alteration of cell metabolism is one of the essential characteristics of tumor growth. Cancer stem cells (CSCs) are the initiating cells of tumorigenesis, proliferation, recurrence, and other processes, and play an important role in therapeutic resistance and metastasis. Thus, identification of the metabolic profiles in prostate cancer stem cells (PCSCs) is critical to understanding prostate cancer progression. Using untargeted metabolomics and lipidomics methods, we show distinct metabolic differences between prostate cancer cells and PCSCs. Urea cycle is the most significantly altered metabolic pathway in PCSCs, the key metabolites arginine and proline are evidently elevated. Proline promotes cancer stem‐like characteristics via the JAK2/STAT3 signaling pathway. Meanwhile, the enzyme pyrroline‐5‐carboxylate reductase 1 (PYCR1), which catalyzes the conversion of pyrroline‐5‐carboxylic acid to proline, is highly expressed in PCSCs, and the inhibition of PYCR1 suppresses the stem‐like characteristics of prostate cancer cells and tumor growth. In addition, carnitine and free fatty acid levels are significantly increased, indicating reprogramming of fatty acid metabolism in PCSCs. Reduced sphingolipid levels and increased triglyceride levels are also observed. Collectively, our data illustrate the comprehensive landscape of the metabolic reprogramming of PCSCs and provide potential therapeutic strategies for prostate cancer. [ABSTRACT FROM AUTHOR]

Pre‐clinical evidence suggests that 5‐alpha reductase inhibitors (5ARi's), prescribed in the treatment of benign prostatic hyperplasia, reduce colorectal and gastro‐oesophageal cancer incidence via action on the male hormonal pathway. However, few studies to date have investigated this association at the population level. Our study aimed to investigate the risk of colorectal and gastro‐oesophageal cancers with the use of 5ARi's. We conducted a retrospective cohort study of new users of 5ARi's and alpha‐blockers among patients with benign prostatic hyperplasia in the UK Clinical Practice Research Datalink. Patients were followed until a first ever diagnosis of colorectal or gastro‐oesophageal cancer, death from any cause or end of registration with the general practice or 31st of December 2017. Cox proportional hazards models with inverse probability of treatment weights were used to calculate weighted hazard ratios (HR) and 95% confidence intervals (CIs) of incident colorectal cancer or gastro‐oesophageal cancer associated with the use of 5ARi's compared to alpha‐blockers. During a mean follow‐up of 6.6 years, we found no association between the use of 5ARi's and colorectal (HR: 1.13, 95% CI 0.91–1.41) or gastro‐oesophageal (HR 1.14, 95% CI 0.76–1.63) cancer risk compared to alpha‐blockers. Sensitivity analysis showed largely consistent results when varying lag periods, using multiple imputations, and accounting for competing risk of death. Our study found no association between the use of 5ARi's and risk of colorectal or gastro‐oesophageal cancer in men with benign prostatic hyperplasia. [ABSTRACT FROM AUTHOR]

Adjustment of the cellular metabolism of pro‐inflammatory macrophages is essential for their bactericidal function; however, it underlies the development of many human diseases if induced chronically. Therefore, intervention of macrophage metabolic polarisation has been recognised as a potent strategy for their treatment. Although many small‐molecule inhibitors affecting macrophage metabolism have been identified, their in vivo administration requires a tool for macrophage‐specific delivery to limit their potential side effects. Here, we establish Drosophila melanogaster as a simple experimental model for in vivo testing of macrophage‐specific delivery tools. We found that yeast‐derived glucan particles (GPs) are suitable for macrophage‐specific delivery of small‐molecule inhibitors. Systemic administration of GPs loaded with atorvastatin, the inhibitor of hydroxy‐methyl‐glutaryl‐CoA reductase (Hmgcr), leads to intervention of mevalonate pathway specifically in macrophages, without affecting HMGCR activity in other tissues. Using this tool, we demonstrate that mevalonate pathway is essential for macrophage pro‐inflammatory polarisation and individual's survival of infection. [ABSTRACT FROM AUTHOR]

Background: Many observational studies have examined the association between statins and the incidence of Parkinson's disease (PD) in high‐risk populations. On the other hand, clinical trials as well as other observational studies investigated the safety and efficacy of statins in slowing disease progression in PD patients. However, the evidence has been inconclusive in both questions. To that end, we conducted this systematic review and meta‐analysis to synthesize evidence on the role of statins in decreasing the risk of PD among high‐risk populations and as a possible disease‐modifying agent for patients with PD. Methods: A comprehensive literature search of electronic databases including PubMed, Scopus, Cochrane, and Web of Science has been performed. Relevant studies were chosen and data were extracted and analyzed using RevMan software version 5.4.1. Results: Twenty‐five studies (14 cohort, 9 case–control, and 2 randomized controlled trials) have been included in the present systematic review. Of them, 21 studies reported the association between statins and PD risk. Statins were found to significantly reduce the risk of developing PD (pooled RR 0.86, 95% CI [0.77–0.95], p < 0.005). Four studies investigated statins as a disease‐modifying agent. The pooled mean difference (MD) in the UPDRS‐III from baseline to endpoint did not differ significantly between the statin and control groups (MD −1.34 points, 95% CI [−3.81 to 1.14], p = 0.29). Conclusion: Although epidemiological observational studies showed that statin use was associated with a reduced risk of PD, current evidence is insufficient to support the role of statins in slowing the progression of PD. These findings are limited by the fact that most of the included studies are observational studies which carry a high risk of confounding bias which highlights the need for future well‐designed RCTs. [ABSTRACT FROM AUTHOR]

Statins, known as hydroxymethylglutaryl coenzyme A reductase (HMG-CoA) inhibitors, are primarily used to lower blood lipids, preventing and treating cardiovascular diseases. Research indicates that statins exhibit multiple effects in the prevention and treatment of colorectal cancer. They function by inhibiting the MVA pathway, suppressing inflammation, enhancing cellular immunity, and influencing the gut microbiota, positively impacting the onset and progression of colorectal cancer. Clinical studies have additionally uncovered that statin drugs can augment the effectiveness of chemotherapy, immunotherapy, and adjuvant therapies, acting as both preventive and adjunctive measures for colorectal cancer. This article critically reviews the research progress on statins in colorectal cancer, aiming to establish a theoretical foundation for exploring innovative treatment options. [ABSTRACT FROM AUTHOR]

Objectives: While the impact of treatment with 5-alpha Reductase Inhibitors (5-ARI) on the risk of cancer-related mortality in men with prostate cancer (PC) has been extensively studied, little is known about the impact of preoperative 5-ARI use on patient-reported outcomes (PROs) following radical prostatectomy (RP). Methods: Within our prospectively maintained institutional database of 5899 patients treated with RP for PC (2008– 2021), 99 patients with preoperative 5-ARI therapy were identified. A 1:4 propensity-score matched analysis of 442 men (n = 90 5-ARI, n = 352 no 5-ARI) was conducted. Primary endpoint was continence recovery using daily pad usage and ICIQ-SF. Health-related quality of life (HRQOL) was assessed using the validated EORTC QLQ-C30 and PR25 questionnaires. Multivariable Cox-regression-models tested the effect of preoperative 5-ARI treatment on continence-recovery (p < 0.05). Results: Patients were followed up perioperatively, followed by annual assessments up to 60mo postoperatively. Preoperative mean ICIQ-SF score (2.2 vs. 0.9) was significantly higher in the 5-ARI cohort (p = 0.006). 24mo postoperatively, 68.6% (no 5-ARI) vs. 55.7% (5-ARI) had full continence recovery (p = 0.002). Multivariable Cox regression analysis, revealed preoperative 5-ARI treatment as an independent predictor for impaired continence recovery (HR 0.50, 95% CI 0.27–0.94, p = 0.03) In line, general HRQOL was significantly higher for patients without 5-ARI only up to 24mo postoperatively (70.6 vs. 61.2, p = 0.045). There was no significant impact of preoperative 5-ARI treatment on erectile function, biochemical recurrence-free survival and metastasis-free survival. Conclusions: Pre-RP 5-ARI treatment was associated with impaired continence outcomes starting 24mo postoperatively, suggesting that preoperative 5-ARI treatment can impair the long-term urinary function recovery following RP. [ABSTRACT FROM AUTHOR]

GSTs catalyze detoxification reactions of harmful xenobiotics via conjugation with glutathione (GSH) while glutathione reductase (GR) is the sole enzyme that acts in the recovery reaction of GSH from oxidized glutathione (GSSG). In this study, in vitro inhibitory impacts of 3‐amino‐benzoic acid methyl ester compounds on GR and GST were investigated. For this firstly, GR and GST were obtained from human blood with specific activity of 6.26 EU/mg protein and 8.57 EU/mg protein respectively. Then, inhibition studies were performed. It was found that methyl 3‐amino‐5‐chlorobenzoate had the highest inhibitory effect on hGR with Ki value of 0.524±0.109 μM) and methyl 3‐amino‐4‐nitrobenzoate was the most effective inhibitor on hGST with Ki value of 37.05±4.487 μM. Besides, molecular docking analysis was used to estimate the binding energies of molecules. Methyl 3‐amino‐4‐nitrobenzoate and methyl 3‐amino‐4‐chlorobenzoate were predicted to have the highest binding affinity into GR and GST receptors respectively. [ABSTRACT FROM AUTHOR]

Purpose: To validate the Barcelona-magnetic resonance imaging predictive model (BCN-MRI PM) for clinically significant prostate cancer (csPCa) in Catalonia, a Spanish region with 7.9 million inhabitants. Additionally, the BCN-MRI PM is validated in men receiving 5-alpha reductase inhibitors (5-ARI). Materials and methods: A population of 2,212 men with prostate-specific antigen serum level > 3.0 ng/ml and/or a suspicious digital rectal examination who underwent multiparametric MRI and targeted and/or systematic biopsies in the year 2022, at ten participant centers of the Catalonian csPCa early detection program, were selected. 120 individuals (5.7%) were identified as receiving 5-ARI treatment for longer than a year. The risk of csPCa was retrospectively assessed with the Barcelona-risk calculator 2 (BCN-RC 2). Men undergoing 5-ARI treatment for less than a year were excluded. CsPCa was defined when the grade group was ≥ 2. Results: The area under the curve of the BCN-MRI PM in 5-ARI naïve men was 0.824 (95% CI 0.783–0.842) and 0.849 (0.806–0.916) in those receiving 5-ARI treatment, p 0.475. Specificities at 100, 97.5, and 95% sensitivity thresholds were to 2.7, 29.3, and 39% in 5-ARI naïve men, while 43.5, 46.4, and 47.8%, respectively in 5-ARI users. The application of BCN-MRI PM would result in a reduction of 23.8% of prostate biopsies missing 5% of csPCa in 5-ARI naïve men, while reducing 25% of prostate biopsies without missing csPCa in 5-ARI users. Conclusions: The BCN-MRI PM has achieved successful validation in Catalonia and, notably, for the first time, in men undergoing 5-ARI treatment. [ABSTRACT FROM AUTHOR]

Progression to symptomatic heart failure is a complication of type 2 diabetes; heart failure onset in this setting is commonly preceded by deterioration in exercise capacity. This study sought to determine whether AT-001, a highly selective aldose reductase inhibitor, can stabilize exercise capacity among individuals with diabetic cardiomyopathy (DbCM) and reduced peak oxygen uptake (V o 2). A total of 691 individuals with DbCM meeting inclusion and exclusion criteria were randomized to receive placebo or ascending doses of AT-001 twice daily. Stratification at inclusion included region of enrollment, cardiopulmonary exercise test results, and use of sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists. The primary endpoint was proportional change in peak V o 2 from baseline to 15 months. Subgroup analyses included measures of disease severity and stratification variables. The mean age was 67.5 ± 7.2 years, and 50.4% of participants were women. By 15 months, peak V o 2 fell in the placebo-treated patients by −0.31 mL/kg/min (P = 0.005 compared to baseline), whereas in those receiving high-dose AT-001, peak V o 2 fell by −0.01 mL/kg/min (P = 0.21); the difference in peak V o 2 between placebo and high-dose AT-001 was 0.30 (P = 0.19). In prespecified subgroup analyses among those not receiving sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists at baseline, the difference between peak V o 2 in placebo vs high-dose AT-001 at 15 months was 0.62 mL/kg/min (P = 0.04; interaction P = 0.10). Among individuals with DbCM and impaired exercise capacity, treatment with AT-001 for 15 months did not result in significantly better exercise capacity compared with placebo. (Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy [ARISE-HF]; NCT04083339) [Display omitted] [ABSTRACT FROM AUTHOR]

Background: There are current clinical observations that atorvastatin may promote subdural hematoma resorption. We aimed to assess the causal effects of lipid-lowering agents 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors, Proproteinconvertase subtilisin/kexin type 9 (PCSK9) inhibitors and Niemann-Pick C1-like protein 1 (NPC1L1) inhibitors on traumatic subdural hematomas. Methods: We used genetic instruments to proxy lipid-lowering drug exposure, with genetic instruments being genetic variants within or near low-density lipoprotein (LDL cholesterol)-associated drug target genes. These were analyzed by using a two-sample Mendelian randomization (MR) study. Results: A causal relationship was found between HMGCR inhibitors and traumatic subdural hematoma (Inverse variance weighted (β = -0.7593341 (Odds Ratio (OR) = 0.4679779), p = 0.008366947<0.05)). However, no causal relationship was found between PCSK9 inhibitors and NPC1L1 inhibitors and traumatic subdural hematoma (PCSK9 inhibitors: Inverse variance weighted (β = 0.23897796 (OR = 1.2699505), p = 0.1126327), NPC1L1 inhibitors: Inverse variance weighted (β = -0.02118558 (OR = 0.9790373), p = 0.9701686)). Sensitivity analysis of the data revealed good stability of the results. Conclusions: This two-sample MR study suggests a potential causal relationship between HMGCR inhibition (atorvastatin) and traumatic subdural hemorrhage. [ABSTRACT FROM AUTHOR]

Objective: The pleiotropic effect of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) is responsible for potent defense against inflammatory response. This study evaluated the inhibitory effects of HMG-CoA reductase inhibitors on the monosodium urate (MSU)-induced inflammatory response through the regulation of interleukin-37 (IL-37) expression. Methods: Serum was collected from patients with gout (n = 40) and from healthy controls (n = 30). The mRNA and protein expression of the target molecules IL-1β, IL-37, caspase-1, and Smad3 were measured in THP-1 macrophages stimulated with MSU, atorvastatin, or rosuvastatin using a real-time quantitative polymerase chain reaction and Western blot assay. Transfection with IL-1β or Smad3 siRNA in THP-1 macrophages was used to verify the pharmaceutical effect of statins in uric-acid-induced inflammation. Results: Serum IL-37 levels in gout patients were significantly higher than in controls (p < 0.001) and was associated with the serum uric acid level (r = 0.382, p = 0.008). THP-1 cells stimulated with MSU markedly induced IL-37 mRNA expression and the transition of IL-37 from the cytoplasm to the nucleus. Recombinant IL-37 treatment dose-dependently inhibited activation of caspase-1 and IL-1β in MSU-induced inflammation. Atorvastatin and rosuvastatin attenuated caspase-1 activation and mature IL-1β expression but augmented translocation of IL-37 from the cytoplasm to the nucleus. Atorvastatin and rosuvastatin induced phosphorylation of Smad3 in THP-1 cells treated with MSU crystals. Statins potently attenuated translocation of IL-37 from the cytoplasm to the nucleus in THP-1 macrophages transfected with Smad3 siRNA compared to cells with negative control siRNA. Conclusions: This study revealed that statins inhibit the MSU-induced inflammatory response through phosphorylated Smad3-mediated IL-37 expression in THP-1 macrophages. [ABSTRACT FROM AUTHOR]

Statins, also known as HMG-CoA reductase inhibitors, are widely prescribed drugs for the prevention and treatment of cardiovascular diseases. In addition to their lipid-lowering effects, these compounds have been found to possess immune-modulating properties. Macrophages, which are crucial phagocytic cells in the body, can be divided into two main subsets: M1 (proinflammatory) and M2 (anti-inflammatory). While there is evidence suggesting that statins exert an anti-inflammatory action on macrophages and promote their polarization towards the M2 subset, recent studies have identified the proinflammatory impact of statins on macrophages, leading to polarization towards the M1 subset. For example, statins have been shown to inhibit NF-κB activation to promote anti-inflammatory responses. On the other hand, statins can induce NFκB/AP-1 activation and increase IL-1β secretion in macrophages to promote pro-inflammatory responses. This review aims to provide a comprehensive overview of both in vivo and in vitro studies that have investigated the effects of statins on macrophage polarization and inflammatory responses in various diseases. Furthermore, this review seeks to evaluate the underlying mechanisms involved in these effects. By summarizing the existing evidence, this review contributes to our understanding of the complex interactions between statins and macrophages in different disease contexts. [ABSTRACT FROM AUTHOR]

Background: We previously demonstrated that the hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (statins) play an important role in the regulation of alloimmune responses. However, little is known regarding the effects of statin on allograft protection or donor-specific antibodies (DSA). In this study, we investigated the graft-protective and immunomodulatory effects of rosuvastatin in a model of fully major histocompatibility complex-mismatched murine cardiac allograft transplantation. Methods: CBA mice underwent transplantation of C57BL/6 (B6) hearts and received 50 and 500 μg/kg/day of rosuvastatin from the day of transplantation until seven days after the completion of transplantation. To confirm the requirement for regulatory T cells (Tregs), we administered an anti-interleukin-2 receptor alpha antibody (PC-61) to rosuvastatin-treated CBA recipients. Additionally, histological and fluorescent staining, cell proliferation analysis, flow cytometry, and DSA measurements were performed. Results: CBA recipients with no treatment rejected B6 cardiac graft acutely (median survival time [MST], 7 days). CBA mice treated with 500 μg/kg/day of rosuvastatin prolonged allograft survival (MSTs, 77 days). Fluorescent staining studies showed that rosuvastatin-treated recipients had strong aggregation of CD4+Foxp3+ cells in the myocardium and around the coronary arteries of cardiac allografts two weeks after grafting. Flow cytometry studies performed two weeks after transplantation showed an increased number of splenic CD4+CD25+Foxp3+ T cells in rosuvastatin-treated recipients. The addition of rosuvastatin to mixed leukocyte cultures suppressed cell proliferation by increasing the number of CD4+CD25+Foxp3+ Tregs. Additionally, Tregs suppressed DSA production in rosuvastatin-treated recipients. Conclusion: Rosuvastatin treatment may be a complementary graft-protective strategy for suppressing DSA production in the acute phase, driven by the promotion of splenic and graft-infiltrating CD4+CD25+Foxp3+ Tregs. [ABSTRACT FROM AUTHOR]

Novel therapeutic approaches are needed for the treatment of Ewing sarcoma tumors. We previously identified that Ewing sarcoma cell lines are sensitive to drugs that inhibit protein translation. However, translational and therapeutic approaches to inhibit protein synthesis in tumors are limited. In this work, we identified that reactive oxygen species, which are generated by a wide range of chemotherapy and other drugs, inhibit protein synthesis and reduce the level of critical proteins that support tumorigenesis in Ewing sarcoma cells. In particular, we identified that both hydrogen peroxide and auranofin, an inhibitor of thioredoxin reductase and regulator of oxidative stress and reactive oxygen species, activate the repressor of protein translation 4E-BP1 and reduce the levels of the oncogenic proteins RRM2 and PLK1 in Ewing and other sarcoma cell lines. These results provide novel insight into the mechanism of how ROSinducing drugs target cancer cells via inhibition of protein translation and identify a mechanistic link between ROS and the DNA replication (RRM2) and cell cycle regulatory (PLK1) pathways. [ABSTRACT FROM AUTHOR]

The aim of the study is to develop the synthesis of a novel series of potent anti-tubercular (anti-TB) activity of 1,3-diphenylpyrazole-based spirooxindolopyrrolizidine derivatives via an efficient green approach achieved by using an ionic liquid ([Bmim]BF4) under ultrasonication. The title compounds 4a–4ad with a general molecular formula CaHbX(0–2)NcOd (X = F/Cl/Br) were produced with high yields in shorter reaction time and well characterized by using spectral techniques; and finally single crystal X-ray diffraction method (4b). The newly synthesized compounds were evaluated for their in vitro anti-TB activity against Mycobacterium tuberculosis H37Rv strain. Among all, six compounds 4e (C36H29N5O4), 4g (C34H28N4O3), 4q (C36H28F2N4O2), 4r (C36H28ClFN4O2), 4y (C36H29BrN4O2) and 4z (C36H28BrFN4O2) exhibited significant anti-TB activity with MIC value 6.25 μg mL−1, when compared to the standard drug ethambutol (MIC:1.56 μg mL−1). In silico molecular docking studies were performed against M. tuberculosis enoyl–acyl carrier protein reductase inhibitor. The compounds 4o, 4p, 4y and 4aa were exhibited least binding energies −12.58, −12.61, −12.58 and −12.57 kcal mol−1, respectively. These results reveal that the produced compounds might be used for the future generation of novel anti-TB drugs. [ABSTRACT FROM AUTHOR]

Background Persistent inflammation affects people with HIV (PWH) despite antiretroviral therapy (ART). Selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRIs, SNRIs), HMG-CoA reductase-inhibitors (statins), and angiotensin-converting enzyme inhibitors (ACEIs) have immunomodulant properties. We evaluated the potential impact of these drugs on inflammation and neurodegeneration in PWH. Methods Cross-sectional single-center (United States) analysis in 184 PWH on ART with plasma HIV RNA < 200 copies/mL. All participants had 10 biomarkers measured in blood and cerebrospinal fluid (CSF). To reduce dimensionality, hierarchical clustering and principal components (PCs) analysis were employed. The analyses were adjusted for duration of the drugs and clinical conditions. Results Participants were mostly middle-aged men, with median CD4+ T cells of 620/µL. In adjusted models, SSRI use was associated with 3 PCs: higher CSF and plasma Aβ42 and CSF CCL2 (aβ=.14, P =.040); lower CSF 8-oxo-dG, total tau, and sCD14 (aβ=−.12, P =.042); and higher plasma sCD14 with lower sCD40L (aβ=.15, P =.042). SNRI use was associated with higher values of CSF and plasma neopterin and CSF sTNFR-II (aβ=.22, P =.004). Statins and ACEIs showed no association. Conclusions SSRIs and SNRIs had distinct biomarker signatures. SSRIs were associated with reduced neurodegeneration, immune activation, and oxidative stress in CSF, suggesting a role of SSRIs as adjunctive therapy in PWH. [ABSTRACT FROM AUTHOR]

Background: Simvastatin (Sim), a hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been widely used in prevention and treatment of cardiovascular diseases. Studies have suggested that Sim exerts anti-fibrotic effects by interfering fibroblast proliferation and collagen synthesis. This study was to determine whether Sim could alleviate silica-induced pulmonary fibrosis and explore the underlying mechanisms. Methods: The rat model of silicosis was established by the tracheal perfusion method and treated with Sim (5 or 10 mg/kg), AICAR (an AMPK agonist), and apocynin (a NOX inhibitor) for 28 days. Lung tissues were collected for further analyses including pathological histology, inflammatory response, oxidative stress, epithelial mesenchymal transformation (EMT), and the AMPK-NOX pathway. Results: Sim significantly reduced silica-induced pulmonary inflammation and fibrosis at 28 days after administration. Sim could reduce the levels of interleukin (IL)-1β, IL-6, tumor necrosis factor-α and transforming growth factor-β1 in lung tissues. The expressions of hydroxyproline, α-SMA and vimentin were down-regulated, while E-cad was increased in Sim-treated rats. In addition, NOX4, p22pox, p40phox, p-p47phox/p47phox expressions and ROS levels were all increased, whereas p-AMPK/AMPK was decreased in silica-induced rats. Sim or AICAR treatment could notably reverse the decrease of AMPK activity and increase of NOX activity induced by silica. Apocynin treatment exhibited similar protective effects to Sim, including down-regulating of oxidative stress and inhibition of the EMT process and inflammatory reactions. Conclusions: Sim attenuates silica-induced pulmonary inflammation and fibrosis by downregulating EMT and oxidative stress through the AMPK-NOX pathway. [ABSTRACT FROM AUTHOR]

Benign prostatic hyperplasia (BPH) is a widespread male disease, affecting more than 50 % of men over the age of 60 years. Inhibition of the enzyme 5α-reductase is a common treatment strategy for this condition. Such potential can be found in willow flowers (Epilobium spp.), which are known in folk medicine for treating of prostate ailments, mainly benign prostatitis, hypertrophy and prostatitis. Smallflower hairy willowherb (E. parviflorum), which is rare, is the most recommended for treating BPH. The aim. The aim of the study was to investigate the qualitative and quantitative content of polyphenols in five Epilobium species (E. adenocaulon Hausskn., E. hirsutum L., E. montanum L., E. parviflorum Schreb. and E. palustre L.) growing in Estonia, to find the most promising species in terms of chemical composition to alleviate BPH. Materials and Methods. The qualitative and quantitative analyses of polyphenols in herbs of Epilobium spp. were performed using HPLC/MS. All five species were collected from the pond's shore in Pilkuse village (Otepää municipality, Valga county, Estonia) in July 2008. Research results. It was found that 20 % ethanol was optimal for extracting polyphenolic compounds from the herb Epilobium spp. with subsequent UV chromatogram analysis at 350 nm. In the analyzed Epilobium species, 12 polyphenolic compounds were identified. Oenothein B, myricetin rhamnoside and myricetin glucoside were the principal polyphenolic compounds among other identified constituents in the Epilobium spp. herbs. E. montanum had the highest content of oenothein B. The highest was the total content of myricetin glycosides for all five compared species, the total content of quercetin glycosides was slightly lower, and the total content of kaempferol glycosides was the lowest. Conclusions. The content of polyphenols is highest in E. adenocaulon and the lowest in E. parviflorum. Thus, E. parviflorum does not offer the best therapeutic potential for the to relief of BPH in terms of the quantitative content of polyphenolic compounds [ABSTRACT FROM AUTHOR]

Benign prostatic hyperplasia (BPH) is a widespread male disease, affecting more than 50 % of men over the age of 60 years. Inhibition of the enzyme 5α-reductase is a common treatment strategy for this condition. Such potential can be found in willow flowers (Epilobium spp.), which are known in folk medicine for treating of prostate ailments, mainly benign prostatitis, hypertrophy and prostatitis. Smallflower hairy willowherb (E. parviflorum), which is rare, is the most recommended for treating BPH. The aim. The aim of the study was to investigate the qualitative and quantitative content of polyphenols in five Epilobium species (E. adenocaulon Hausskn., E. hirsutum L., E. montanum L., E. parviflorum Schreb. and E. palustre L.) growing in Estonia, to find the most promising species in terms of chemical composition to alleviate BPH. Materials and Methods. The qualitative and quantitative analyses of polyphenols in herbs of Epilobium spp. were performed using HPLC/MS. All five species were collected from the pond's shore in Pilkuse village (Otepää municipality, Valga county, Estonia) in July 2008. Research results. It was found that 20 % ethanol was optimal for extracting polyphenolic compounds from the herb Epilobium spp. with subsequent UV chromatogram analysis at 350 nm. In the analyzed Epilobium species, 12 polyphenolic compounds were identified. Oenothein B, myricetin rhamnoside and myricetin glucoside were the principal polyphenolic compounds among other identified constituents in the Epilobium spp. herbs. E. montanum had the highest content of oenothein B. The highest was the total content of myricetin glycosides for all five compared species, the total content of quercetin glycosides was slightly lower, and the total content of kaempferol glycosides was the lowest. Conclusions. The content of polyphenols is highest in E. adenocaulon and the lowest in E. parviflorum. Thus, E. parviflorum does not offer the best therapeutic potential for the to relief of BPH in terms of the quantitative content of polyphenolic compounds [ABSTRACT FROM AUTHOR]

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Human dihydrofolate reductase (hDHFR) is an essential cellular enzyme, and inhibiting its activity is a promising strategy for cancer therapy. We have chosen the trimethoprim molecule (TMP) as a model compound in our search for a new class of hDHFR inhibitors. We incorporated an amide bond, a structural element typical of netropsin, a ligand that binds selectively in the minor groove of DNA, into the molecules of TMP analogs. In this work, we present previously obtained and evaluated eleven benzamides (JW1–JW8; MB1, MB3, MB4). Recently, these compounds were specifically projected as potential inhibitors of the enzymes acetylcholinesterase (AChE) and β-secretase (BACE1). JW8 was most active against AChE, with an inhibitory concentration of AChE IC50 = 0.056 µM, while the IC50 for donepezil was 0.046 µM. This compound was also the most active against the BACE1 enzyme. The IC50 value was 9.01 µM compared to that for quercetin, with IC50 = 4.89 µM. All the benzamides were active against hDHFR, with IC50 values ranging from 4.72 to 20.17 µM, and showed activity greater than TMP (55.26 µM). Quantitative results identified the derivatives JW2 and JW8 as the most promising. A molecular modeling study demonstrates that JW2 interacts strongly with the key residue Gly-117, while JW8 interacts strongly with Asn-64 and Arg-70. Furthermore, JW2 and JW8 demonstrate the ability to stabilize the hDHFR enzyme, despite forming fewer hydrogen bonds with the protein compared to reference ligands. It can be concluded that this class of compounds certainly holds great promise for good active leads in medicinal chemistry. [ABSTRACT FROM AUTHOR]

AKR1B1 and AKR1B10 are important members of aldo–keto reductase family which plays a significant role in cancer progression by modulating cellular metabolism. These enzymes are involved in various metabolic processes, including the synthesis and metabolism of hormones, detoxification of reactive aldehydes, and the reduction of various endogenous and exogenous compounds. This study aimed to explore the potential of strychnine as an anticancer agent by targeting AKR1B1 and AKR1B10 via drug repurposing approach. To assess the drug-like properties of strychnine, a physiologically based pharmacokinetic (PKPB) model and High Throughput Pharmacokinetics (HTPK) approach were employed. The obtained results fell within the expected range for drug molecules, confirming its suitability for further investigation. Additionally, density functional theory (DFT) studies were conducted to gain insight into the electronic properties contributing to the drug molecule's reactivity. Building upon the promising DFT results, molecular docking analysis using the AutoDock tool was performed to examine the binding interactions between strychnine and the proposed targets, AKR1B1 and AKR1B10. Findings from the molecular docking studies suggested a higher probability of strychnine acting as an inhibitor of AKR1B1 and AKR1B10 with docking scores of − 30.84 and − 29.36 kJ/mol respectively. To validate the stability of the protein–ligand complex, Molecular Dynamic Simulation (MDS) studies were conducted, revealing the formation of a stable complex between the enzymes and strychnine. This comprehensive approach sheds light on the potential effectiveness of strychnine as a treatment for breast, lung, liver, and pancreatic cancers, as well as related malignancies. The novel insights gained from the physiologically based pharmacokinetic modeling, density functional theory, molecular docking, and molecular dynamics simulations collectively support the prospect of strychnine as a promising molecule for anticancer therapy. Further investigations are warranted to validate these findings and explore the therapeutic potential of strychnine in preclinical and clinical settings. [ABSTRACT FROM AUTHOR]

Aims: The objective of this meta‐analysis was to determine whether maternal exposure to folate antagonists is associated with increased rates of congenital heart disease in offspring. Methods: A comprehensive search for articles in the MEDLINE (PubMed) and EMBASE databases published up to 21 August 2023 was performed. The search strategy was not limited by study design but only for articles in the English language. Results: Analysis of 6 cohort studies and 5 cross‐sectional studies, published between 1976 and 2020, showed significant increase in rate of congenital heart disease (odds ratio 1.55, 95% confidence interval, 1.28–1.87) when exposed to folate antagonists compared with the control. Further subgroup analysis showed the increased rate for exposure to both dihydrofolate reductase inhibitors and antiepileptic drugs separately. No differences were observed when analyses were stratified by timing of study. Conclusion: Administration of folate antagonists within the 12‐week period preceding conception and throughout the second and third months of gestation exhibited a statistically significant elevation in the susceptibility to congenital heart diseases. Notably, the protective effect of folic acid supplementation was reported in cases of congenital heart disease linked to dihydrofolate reductase inhibitors but not that associated with antiepileptic drugs. [ABSTRACT FROM AUTHOR]

Proteasome inhibitors are used in the therapy of several cancers, and clinical trials are underway for their use in the treatment of glioblastoma (GBM). However, GBM becomes resistant to chemotherapy relatively rapidly. Recently, the overexpression of ribonucleotide reductase (RNR) genes was found to mediate therapy resistance in GBM. The use of combinations of chemotherapeutic agents is considered a promising direction in cancer therapy. The present work aimed to evaluate the efficacy of the combination of proteasome and RNR inhibitors in yeast and GBM cell models. We have shown that impaired proteasome function results in increased levels of RNR subunits and increased enzyme activity in yeast. Co-administration of the proteasome inhibitor bortezomib and the RNR inhibitor hydroxyurea was found to significantly reduce the growth rate of S. cerevisiae yeast. Accordingly, the combination of bortezomib and another RNR inhibitor gemcitabine reduced the survival of DBTRG-05MG compared to the HEK293 cell line. Thus, yeast can be used as a simple model to evaluate the efficacy of combinations of proteasome and RNR inhibitors. [ABSTRACT FROM AUTHOR]

Introduction: Tuberculosis (TB), an infectious disease caused by the bacterium Mycobacterium Tuberculosis (MTB), continues to be a global health problem. Alpinia galanga (Linn.) of the Zingiberaceae family has antitubercular properties, and their mode of action in in-vitro as well as in-vivo conditions is well established. This knowledge of the active phytochemicals of Alpinia galanga has been utilised to identify new potent drugs for MTB. Aim: To perform molecular docking studies of various phytochemicals of Alpinia galanga and their derivatives with ß-ketoacyl reductase (MabA) of MTB. Materials and Methods: The present study is an in-silico study conducted in the Bioinformatics facility of the Central Research Laboratory of Tagore Medical College and Hospital, Chennai, Tamil Nadu, India from November 2022 to April 2023. The receptor protein was downloaded from the Research Collaboratory for Structural Bioinformatics (RCSB) database. The phytochemicals in. sdf format were downloaded from the PubChem database. The derivatives were prepared by Chemsketch software. Docking was performed using AutoDock Vina with PyRx as the GUI (Graphical User Interface). Postdocking analysis was performed in LigPlot+. Results: Phytochemicals from Alpinia galanga were obtained from the PubChem database and docked with MabA of MTB. The derivatives were further subjected to docking analyses. From the docking study, two molecules, namely, (1E,6Z)-2,4-diamino-6-fluoro-1,7-bis(4-hydroxyphenyl)-1-sulfanylhepta-1,6-diene-3,5-dione and (2E,6Z,10E)-2,6,9,9-tetrakis(hydroxymethyl) cycloundeca-2,6,10-trien-1-one-ethane (1/1), were found to have good binding energy values. Conclusion: The present study helped us find drug-like molecules that can inhibit the MabA of MTB. Two compounds derived from the phytochemicals of A. galanga were found to have an effective binding capacity to the drug target in-silico. Hence, the outcome of present study has provided a therapeutic strategy for TB, especially for strains of MTB that are drug-resistant. [ABSTRACT FROM AUTHOR]

Statins are effective drugs in reducing cardiovascular morbidity and mortality by inhibiting cholesterol synthesis. These effects are primarily beneficial for the patient's vascular system. A significant number of statin users suffer from muscle complaints probably due to mitochondrial dysfunction, a mechanism that has recently been elucidated. This has raised our interest in exploring the effects of statins on cardiac muscle cells in an era where the elderly and patients with poorer functioning hearts and less metabolic spare capacity start dominating our patient population. Here, we investigated the effects of statins on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-derived CMs). hiPSC-derived CMs were exposed to simvastatin, atorvastatin, rosuvastatin, and cerivastatin at increasing concentrations. Metabolic assays and fluorescent microscopy were employed to evaluate cellular viability, metabolic capacity, respiration, intracellular acidity, and mitochondrial membrane potential and morphology. Over a concentration range of 0.3–100 µM, simvastatin lactone and atorvastatin acid showed a significant reduction in cellular viability by 42–64%. Simvastatin lactone was the most potent inhibitor of basal and maximal respiration by 56% and 73%, respectively, whereas simvastatin acid and cerivastatin acid only reduced maximal respiration by 50% and 42%, respectively. Simvastatin acid and lactone and atorvastatin acid significantly decreased mitochondrial membrane potential by 20%, 6% and 3%, respectively. The more hydrophilic atorvastatin acid did not seem to affect cardiomyocyte metabolism. This calls for further research on the translatability to the clinical setting, in which a more conscientious approach to statin prescribing might be considered, especially regarding the current shift in population toward older patients with poor cardiac function. [ABSTRACT FROM AUTHOR]

Neurosteroids have been implicated in the pathophysiology of post‐traumatic stress disorder (PTSD). Allopregnanolone is reduced in subsets of individuals with PTSD and has been explored as a novel treatment strategy. Both direct trauma exposure and witnessed trauma are risk factors for PTSD; however, the role of neurosteroids in the behavioral outcomes of these unique experiences has not been explored. Here, we investigate whether observational fear is associated with a reduced capacity for endogenous neurosteroidogenesis and the relationship with behavioral outcomes. We demonstrated that mice directly subjected to a threat (foot shocks) and those witnessing the threat have decreased plasma levels of allopregnanolone. The expression of a key enzyme involved in endogenous neurosteroid synthesis, 5α‐reductase type 2, is decreased in the basolateral amygdala, which is a major emotional processing hub implicated in PTSD. We demonstrated that genetic knockdown or pharmacological inhibition of 5α‐reductase type 2 exaggerates the behavioral expression of fear in response to witnessed trauma, whereas oral treatment with an exogenous, synthetic neuroactive steroid gamma‐aminobutyric acid‐A receptor positive allosteric modulator with molecular pharmacology similar to allopregnanolone (SGE‐516 [tool compound]) decreased the behavioral response to observational fear. These data implicate impaired endogenous neurosteroidogenesis in the pathophysiology of threat exposure, both direct and witnessed. Further, these data suggest that treatment with exogenous 5α‐reduced neurosteroids or targeting endogenous neurosteroidogenesis may be beneficial for the treatment of individuals with PTSD, whether resulting from direct or witnessed trauma. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) is characterized by impaired vascular endothelial function that may be improved by hydroxy-methylglutaryl-CoA (HMG-CoA) reductase enzyme inhibition. Thus, using a parallel, double-blind, placebo-controlled design, this study evaluated the efficacy of 30-day atorvastatin administration (10 mg daily) on peripheral vascular function and biomarkers of inflammation and oxidative stress in 16 patients with HFpEF [Statin: n = 8, 74 ± 6 yr, ejection fraction (EF) 52–73%; Placebo: n = 8, 67 ± 9 yr, EF 56–72%]. Flow-mediated dilation (FMD) and sustained-stimulus FMD (SS-FMD) during handgrip (HG) exercise, reactive hyperemia (RH), and blood flow during HG exercise were evaluated to assess conduit vessel function, microvascular function, and exercising muscle blood flow, respectively. FMD improved following statin administration (pre, 3.33 ± 2.13%; post, 5.23 ± 1.35%; P < 0.01), but was unchanged in the placebo group. Likewise, SS-FMD, quantified using the slope of changes in brachial artery diameter in response to increases in shear rate, improved following statin administration (pre: 5.31e−5 ± 3.85e−5 mm/s−1; post: 8.54e−5 ± 4.98e−5 mm/s−1; P = 0.03), with no change in the placebo group. Reactive hyperemia and exercise hyperemia responses were unchanged in both statin and placebo groups. Statin administration decreased markers of lipid peroxidation (malondialdehyde, MDA) (pre, 0.652 ± 0.095; post, 0.501 ± 0.094; P = 0.04), whereas other inflammatory and oxidative stress biomarkers were unchanged. Together, these data provide new evidence for the efficacy of low-dose statin administration to improve brachial artery endothelium-dependent vasodilation, but not microvascular function or exercising limb blood flow, in patients with HFpEF, which may be due in part to reductions in oxidative stress. NEW & NOTEWORTHY: This is the first study to investigate the impact of statin administration on vascular function and exercise hyperemia in patients with heart failure with preserved ejection fraction (HFpEF). In support of our hypothesis, both conventional flow-mediated dilation (FMD) testing and brachial artery vasodilation in response to sustained elevations in shear rate during handgrip exercise increased significantly in patients with HFpEF following statin administration, beneficial effects that were accompanied by a decrease in biomarkers of oxidative damage. However, contrary to our hypothesis, reactive hyperemia and exercise hyperemia were unchanged in patients with HFpEF following statin therapy. These data provide new evidence for the efficacy of low-dose statin administration to improve brachial artery endothelium-dependent vasodilation, but not microvascular reactivity or exercising muscle blood flow in patients with HFpEF, which may be due in part to reductions in oxidative stress. [ABSTRACT FROM AUTHOR]

The escalating global prevalence of diabetes mellitus (DM) over the past two decades has led to a persistent high incidence of diabetic retinopathy (DR), necessitating screening for early symptoms and proper treatment. Effective management of DR aims to decrease vision impairment by controlling modifiable risk factors including hypertension, obesity, and dyslipidemia. Moreover, systemic medications and plant-based therapy show promise in advancing DR treatment. One of the key mechanisms related to DR pathogenesis is the polyol pathway, through which aldose reductase (AR) catalyzes the conversion of glucose to sorbitol within various tissues, including the retina, lens, ciliary body and iris. Elevated glucose levels activate AR, leading to osmotic stress, advanced glycation end-product formation, and oxidative damage. This further implies chronic inflammation, vascular permeability, and angiogenesis. Our comprehensive narrative review describes the therapeutic potential of aldose reductase inhibitors in treating DR, where both synthetic and natural inhibitors have been studied in recent decades. Our synthesis aims to guide future research and clinical interventions in DR management. [ABSTRACT FROM AUTHOR]

The most important dose-limiting factor of the anthracycline idarubicin is the high risk of cardiotoxicity, in which the secondary alcohol metabolite idarubicinol plays an important role. It is not yet clear which enzymes are most important for the formation of idarubicinol and which inhibitors might be suitable to suppress this metabolic step and thus would be promising concomitant drugs to reduce idarubicin-associated cardiotoxicity. We, therefore, established and validated a mass spectrometry method for intracellular quantification of idarubicin and idarubicinol and investigated idarubicinol formation in different cell lines and its inhibition by known inhibitors of the aldo–keto reductases AKR1A1, AKR1B1, and AKR1C3 and the carbonyl reductases CBR1/3. The enzyme expression pattern differed among the cell lines with dominant expression of CBR1/3 in HEK293 and MCF-7 and very high expression of AKR1C3 in HepG2 cells. In HEK293 and MCF-7 cells, menadione was the most potent inhibitor (IC50 = 1.6 and 9.8 µM), while in HepG2 cells, ranirestat was most potent (IC50 = 0.4 µM), suggesting that ranirestat is not a selective AKR1B1 inhibitor, but also an AKR1C3 inhibitor. Over-expression of AKR1C3 verified the importance of AKR1C3 for idarubicinol formation and showed that ranirestat is also a potent inhibitor of this enzyme. Taken together, our study underlines the importance of AKR1C3 and CBR1 for the reduction of idarubicin and identifies potent inhibitors of metabolic formation of the cardiotoxic idarubicinol, which should now be tested in vivo to evaluate whether such combinations can increase the cardiac safety of idarubicin therapies while preserving its efficacy. [ABSTRACT FROM AUTHOR]

Aldose reductase 2 (ALR2), an activated enzyme in the polyol pathway by hyperglycemia, has long been recognized as one of the most promising targets for complications of diabetes, especially in diabetic peripheral neuropathy (DPN). However, many of the ALR2 inhibitors have shown serious side effects due to poor selectivity over aldehyde reductase (ALR1). Herein, we describe the discovery of a series of benzothiadiazine acetic acid derivatives as potent and selective inhibitors against ALR2 and evaluation of their anti-DPN activities in vivo. Compound 15c, carrying a carbonyl group at the 3-position of the thiadiazine ring, showed high potent inhibition against ALR2 (IC50 = 33.19 nmol/L) and ∼16,109-fold selectivity for ALR2 over ALR1. Cytotoxicity assays ensured the primary biosafety of 15c. Further pharmacokinetic assay in rats indicated that 15c had a good pharmacokinetic feature (t 1/2 = 5.60 h, area under the plasma concentration time curve [AUC(0-t)] = 598.57 ± 216.5 μg/mL * h), which was superior to epalrestat (t 1/2 = 2.23 h, AUC[0-t] = 20.43 ± 3.7 μg/mL * h). Finally, in a streptozotocin-induced diabetic rat model, 15c significantly increased the nerve conduction velocities of impaired sensory and motor nerves, achieved potent inhibition of d-sorbitol production in the sciatic nerves, and significantly increased the paw withdrawal mechanical threshold. By combining the above investigations, we propose that 15c might represent a promising lead compound for the discovery of an antidiabetic peripheral neuropathy drug. Article Highlights: Benzothiadiazine acetic acid derivatives show potent and selective inhibition against aldose reductase 2. The leading compounds 15a, 15c, and 15f had low cytotoxicity on the human-derived neuroblastoma cell line SH-SY5Y and the primary dorsal root ganglion cells and had a good pharmacokinetic feature. Compound 15c significantly increased the nerve conduction velocities of impaired sensory nerves, decreased the d-sorbitol level in the sciatic nerves, and increased the paw withdrawal mechanical threshold. Compound 15c may serve as a potential antidiabetic peripheral neuropathy drug. [ABSTRACT FROM AUTHOR]

Background: Lipid pathways play a crucial role in psoriatic arthritis development, and some lipid-lowering drugs are believed to have therapeutic benefits due to their anti-inflammatory properties. Traditional observational studies face issues with confounding factors, complicating the interpretation of causality. This study seeks to determine the genetic link between these medications and the risk of psoriatic arthritis. Methods: This drug target study utilized the Mendelian randomization strategy. We harnessed high-quality data from population-level genome-wide association studies sourced from the UK Biobank and FinnGen databases. The inverse variance-weighted method, complemented by robust pleiotropy methods, was employed. We examined the causal relationships between three lipid-lowering agents and psoriatic arthritis to unveil the underlying mechanisms. Results: A significant association was observed between genetically represented proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and a decreased risk of psoriatic arthritis (odds ratio [OR]: 0.51; 95% CI 0.14–0.88; P < 0.01). This association was further corroborated in an independent dataset (OR 0.60; 95% CI 0.25–0.94; P = 0.03). Sensitivity analyses affirmed the absence of statistical evidence for pleiotropic or genetic confounding biases. However, no substantial associations were identified for either 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors or Niemann–Pick C1-like 1 inhibitors. Conclusions: This Mendelian randomization analysis underscores the pivotal role of PCSK9 in the etiology of psoriatic arthritis. Inhibition of PCSK9 is associated with reduced psoriatic arthritis risk, highlighting the potential therapeutic benefits of existing PCSK9 inhibitors. [ABSTRACT FROM AUTHOR]

Background: Due to encouraging pre‐clinical data and supportive observational studies, there has been growing interest in applying cardiovascular drugs (including aspirin, angiotensin‐converting enzyme [ACE] inhibitors, statins, and metformin) approved to treat diseases such as hypertension, hyperlipidemia, and diabetes mellitus to the field of oncology. Moreover, given growing costs with cancer care, these medications have offered a potentially more affordable avenue to treat or prevent recurrence of cancer. We sought to investigate the anti‐cancer effects of drugs repurposed from cardiology or anti‐inflammatories to treat cancer. We specifically evaluated the following drug classes: HMG‐CoA reductase inhibitors (statins), cyclo‐oxygenase inhibitors, aspirin, metformin, and both angiotensin receptor blockers (ARBs) and angiotensin‐converting enzyme inhibitors. We also included non‐steroidal anti‐inflammatory drugs (NSAIDs) because they exert a similar mechanism to aspirin by blocking prostaglandins and reducing inflammation that is thought to promote the development of cancer. Methods: We performed a systematic literature review using PubMed and Web of Science with search terms including "aspirin," "NSAID," "statin" (including specific statin drug names), "metformin," "ACE inhibitors," and "ARBs" (including specific anti‐hypertensive drug names) in combination with "cancer." Searches were limited to human studies published between 2000 and 2023. Main Outcomes and Measures: The number and percentage of studies reported positive results and pooled estimates of overall survival, progression‐free survival, response, and disease‐free survival. Results: We reviewed 3094 titles and included 67 randomized clinical trials. The most common drugs that were tested were metformin (n = 21; 30.9%), celecoxib (n = 20; 29.4%), and simvastatin (n = 8; 11.8%). There was only one study that tested cardiac glycosides and none that studied ACE inhibitors. The most common tumor types were non‐small‐cell lung cancer (n = 19; 27.9%); breast (n = 8; 20.6%), colorectal (n = 7; 10.3%), and hepatocellular (n = 6; 8.8%). Most studies were conducted in a phase II trial (n = 38; 55.9%). Most studies were tested in metastatic cancers (n = 49; 72.1%) and in the first‐line setting (n = 36; 521.9%). Four studies (5.9%) were stopped early because of difficulty with accrual. The majority of studies did not demonstrate an improvement in either progression‐free survival (86.1% of studies testing progression‐free survival) or in overall survival (94.3% of studies testing overall survival). Progression‐free survival was improved in five studies (7.4%), and overall survival was improved in three studies (4.4%). Overall survival was significantly worse in two studies (3.8% of studies testing overall survival), and progression‐free survival was worse in one study (2.8% of studies testing progression‐free survival). Conclusions and Relevance: Despite promising pre‐clinical and population‐based data, cardiovascular drugs and anti‐inflammatory medications have overall not demonstrated benefit in the treatment or preventing recurrence of cancer. These findings may help guide future potential clinical trials involving these medications when applied in oncology. [ABSTRACT FROM AUTHOR]

Introduction: Atorvastatin is "HMG-COA" reductase inhibitors" that is widely used for management of hyperlipidemia particularly in patients with risk of cardio and cerebrovascular stroke. Similar to other medications, atorvastatin has adverse effect and recent studies showing that atorvastatin may affect the function of the pancreas. The aim of this work is to assess the functional and the structural changes of endocrine and exocrine parts of pancreas of female rats that were treated with atorvastatin and to assess the possible defensive role of propolis. Methods and Result: Four groups of female albino rats (ten animals in each) were treated as follow: Group I regarded as control and received nothing, group II received 100 mg/kg propolis by oral gavage, Group III treated with atorvastatin at a dose of 80 mg/kg orally while group IV was treated with propolis and atorvastatin as same dose as GII and GIII respectively. After three months, blood was drown from tail's vein for biochemical assessment, then animals were sacrificed and pancreas were removed and processed for light microscopic examination. The results indicated that atorvastatin significantly elevate blood glucose, pancreatic enzyme as well as oxidative stress biomarkers of pancreas these finding were confirmed by histological changes in both endocrine and exocrine portion which include degeneration, vascular congestion, hemorrhage and inflammatory cells infiltration of pancreatic tissue. However, administration of propolis concomitantly with atorvastatin improved both the biochemical and the histological changes. Conclusion: Propolis has protective effect against atorvastatin induced pancreatic dysfunction. [ABSTRACT FROM AUTHOR]

Metastatic melanoma has a very poor prognosis. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibitors, are cholesterol-lowering agents with a potential for cancer treatment. The inhibition of HMGCR by statins, however, induces feedback, which paradoxically upregulates HMGCR expression via sterol regulatory element-binding protein-2 (SREBP2). Dipyridamole, an antiplatelet agent, is known to inhibit SREBP2 upregulation. We aimed to demonstrate the efficacy of statin–dipyridamole combination treatment in both human and spontaneously occurring canine melanoma cell lines. The half maximal inhibitory concentration (IC50) of atorvastatin showed a 68–92% reduction when combined with dipyridamole, compared with that of atorvastatin alone. In some melanoma cell lines, cell proliferation was suppressed to almost zero by the combination treatment (≥3 μM atorvastatin). Finally, the BRAF inhibitor, vemurafenib, further potentiated the effects of the combined statin–dipyridamole treatment in BRAF V600E mutation-bearing human melanoma cell lines. In conclusion, the inexpensive and frequently prescribed statin–dipyridamole combination therapy may lead to new developments in the treatment of melanoma and may potentiate the effects of vemurafenib for the targeted therapy of BRAF V600E-mutation bearing melanoma patients. The concordance between the data from canine and human melanoma cell lines reinforces this possibility. [ABSTRACT FROM AUTHOR]

Cervical cancer is among the most frequently observed cancer types in females. New therapeutic targets are needed because of the side impacts of existing cancer drugs and the inadequacy of treatment methods. Thioredoxin reductase 1 (TrxR1) is often overexpressed in many cancer cells, and targeting TrxR1 has become an attractive target for cancer therapy. This study investigated the anticancer impacts of diffractaic and vulpinic acids, lichen secondary metabolites, on the cervical cancer HeLa cell line. XTT findings demonstrated showed that diffractaic and vulpinic acids suppressed the proliferation of HeLa cells in a dose- and time-dependent manner and IC50 values were 22.52 μg/ml and 66.53 μg/ml at 48 h, respectively. Each of these lichen metabolites significantly suppressed migration. Diffractaic acid showed an increase in both the BAX/BCL2 ratio by qPCR analysis and the apoptotic cell population via flow cytometry analysis on HeLa cells. Concerning vulpinic acid, although it decreased the BAX/BCL2 ratio in this cells, it increased apoptotic cells according to the flow cytometry analysis results. Diffractaic and vulpinic acids significantly suppressed TrxR1 enzyme activity rather than the gene and protein expression levels in HeLa cells. This research demonstrated for the first time, that targeting TrxR1 with diffractaic and vulpinic acids was an effective therapeutic strategy for treating cervical cancer. [ABSTRACT FROM AUTHOR]

Concerns exist regarding the effects of 5-alpha reductase inhibitors (5-ARIs) on multipa-rametric magnetic resonance imaging (mpMRI) and clinically significant prostate cancer (csPCa) detection. Our objective is to analyze the effect of 5-ARI on the prostate imaging–reporting and data system (PI-RADS) distribution and csPCa and insignificant PCa (iPCa) detection. Among 2212 men with serum prostate-specific antigen levels of >3.0 ng/mL and/or suspicious digital rectal examinations who underwent mpMRI and targeted and/or systematic biopsies, 120 individuals exposed to 5-ARI treatment for over a year were identified. CsPCa was defined when the grade group (GG) was >2. The overall csPCa and iPCa detection rates were 44.6% and 18.8%, respectively. Since logistic regression revealed independent predictors of PCa, a randomized matched group of 236 individuals was selected for analysis. The PI-RADS distribution was comparable with 5-ARI exposure (p 0.685). The CsPCa detection rates in 5-ARI-naïve men and 5-ARI-exposed men were 52.6% and 47.4%, respectively (p 0.596). IPCa was detected in 37.6 and 62.5%, respectively (p 0.089). The tumor GG distribution based on 5-ARI exposure was similar (p 0.149) to the rates of csPCa and iPCa across the PI-RADS categories. We conclude that exposure to 5-ARI in suspected PCa men did not change the PI-RADS distribution and the csPCa and iPCa detection rates. [ABSTRACT FROM AUTHOR]

Background: The chemokine ligand CCL2 and its cognate receptor CCR2 have been implicated in the pathogenesis of a wide variety of diseases. Hence, the inhibition of the CCL2/CCR2 signaling pathway has been of great attention in recent studies. Among suggested medications, statins known as HMG-COA reductase inhibitors with their pleiotropic effects are widely under investigation. Method: A comprehensive literature search on Scopus and PubMed databases was conducted using the keywords 'CCL2', 'CCR2', 'monocyte chemoattractant protein-1', 'HMG-COA reductase inhibitor', and 'statin'. Both experimental and clinical studies measuring CCL2/CCR2 expressions following statin therapy were identified excluding the ones focused on cardiovascular diseases. Results: Herein, we summarized the effects of statins on CCL2 and CCR2 expression in various pathologic conditions including immune-mediated diseases, nephropathies, diabetes, rheumatic diseases, neuroinflammation, inflammatory bowel diseases, gynecologic diseases, and cancers. Conclusion: For the most part, statins play an inhibitory role on the CCL2–CCR2 axis which implies their potential to be further developed as therapeutic options in non-cardiovascular diseases either alone or in combination with other conventional treatments. However, the existing literature mostly focused on experimental models and is therefore inadequate to reach a conclusion. [ABSTRACT FROM AUTHOR]

Heart disease has become the leading cause of death in the world in the last 15 years. This disease has several primary risk factors, one of which is hypercholesterolemia. Cholesterol biosynthesis in the liver is influenced by the activity of the rate-limiting enzyme, HMG-CoA reductase. Traditional herbal medicine provides alternative treatment for hypercholesterolemia. Both pulai and papaya leaves were reported as HMG-CoA reductase inhibitors. There has been very limited study however, on the efficacy of a mixture of aqueous extracts of the two in inhibiting HMG-CoA reductase. This study aims to determine the activity of a mixture of water extracts of both pulai and papaya leaves. The activity of the enzyme HMG-CoA reductase was measured by Abcam® kit No. Ab204701 by spectrophotometric method at 334 nm. The results showed that the three extracts of the combination of pulai and papaya leaves had four times better inhibitory action than the single extract (p0.05). The results of the phytochemical literature study showed that the aqueous extract contained flavonoids, alkaloids, tannins, and saponins. [ABSTRACT FROM AUTHOR]

Cisplatin is a frequently used chemotherapeutic medicine for cancer treatment. Permanent hearing loss is one of the most serious side effects of cisplatin, but there are few FDA-approved medicines to prevent it. We applied high-through screening and target fishing and identified aldose reductase, a key enzyme of the polyol pathway, as a novel target for treating cisplatin ototoxicity. Cisplatin treatment significantly increased the expression level and enzyme activity of aldose reductase in the cochlear sensory epithelium. Genetic knockdown or pharmacological inhibition of aldose reductase showed a significant protective effect on cochlear hair cells. Cisplatin-induced overactivation of aldose reductase led to the decrease of NADPH/NADP+ and GSH/GSSG ratios, as well as the increase of oxidative stress, and contributed to hair cell death. Results of target prediction, molecular docking, and enzyme activity detection further identified that Tiliroside was an effective inhibitor of aldose reductase. Tiliroside was proven to inhibit the enzymatic activity of aldose reductase via competitively interfering with the substrate-binding region. Both Tiliroside and another clinically approved aldose reductase inhibitor, Epalrestat, inhibited cisplatin-induced oxidative stress and subsequent cell death and thus protected hearing function. These findings discovered the role of aldose reductase in the pathogenesis of cisplatin-induced deafness and identified aldose reductase as a new target for the prevention and treatment of hearing loss. [Display omitted] • Abnormal activation of aldose reductase plays an important role in platinum-induced hearing impairment. • Genetic knockdown or pharmacological inhibition of aldose reductase strongly ameliorated cisplatin ototoxicity. • Drug screening identified Tiliroside as an effective natural inhibitor of aldose reductase. • Tiliroside and Epalrestat have the potential as clinically therapeutic drugs for cisplatin-induced ototoxicity. [ABSTRACT FROM AUTHOR]