Reductase Inhibitors Research Articles

External validation of the barcelona magnetic resonance imaging predictive model for detecting significant prostate cancer including men receiving 5-alpha reductase inhibitors

PurposeTo 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 methodsA 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.ResultsThe 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.ConclusionsThe BCN-MRI PM has achieved successful validation in Catalonia and, notably, for the first time, in men undergoing 5-ARI treatment.

Safety, Pharmacokinetics, and Pharmacodynamics of the New Aldose Reductase Inhibitor Govorestat (AT-007) After a Single and Multiple Doses in Participants in a Phase 1/2 Study.

In classic galactosemia (CG) patients, aldose reductase (AR) converts galactose to galactitol. In a phase 1/2, placebo-controlled study (NCT04117711), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of govorestat were evaluated after single and multiple ascending doses (0.5-40 mg/kg) in healthy adults (n = 81) and CG patients (n = 14). Levels of govorestat in plasma and cerebrospinal fluid (CSF) and blood levels of galactitol, galactose, and galactose-1-phosphate (Gal-1p) were measured for population PK and PK/PD analyses. Govorestat was well tolerated. Adverse event frequency was comparable between placebo and govorestat. Govorestat PK displayed a 2-compartment model with sequential zero- and first-order absorption, and no effect of demographic factors. Multiple-dose PK of govorestat was linear in the 0.5-40 mg/kg range, and CSF levels increased dose dependently. Elimination half-life was ∼10 h. PK/PD modeling supported once-daily dosing. Change from baseline in galactitol was -15% ± 9% with placebo and -19% ± 10%, -46% ± 4%, and -51% ± 5% with govorestat 5, 20, and 40 mg/kg, respectively, thus was similar for 20 and 40 mg/kg. Govorestat did not affect galactose or Gal-1p levels. In conclusion, govorestat displayed a favorable safety, PK, and PD profile in humans, and reduced galactitol levels in the same magnitude (∼50%) as in a rat model of CG that demonstrated an efficacy benefit on neurological, behavioral, and ocular outcomes.

Synthesis, In Silico Study and Antimalarial Activity of Triazolo[1,5‐a]pyrimidine Derivatives

AbstractThe present study mainly focused on synthesizing novel triazolo[1,5‐a]pyrimidine‐6‐carboxamide derivatives using multicomponent reaction. Synthesized derivatives were duly characterized using spectroscopic methods of analysis FT‐IR and mass spectroscopy, and 1H NMR and 13C NMR confirmed the structure of compounds. Further, the potential of the synthesized compounds against Plasmodium falciparum dihydrofolate reductase (Pf‐DHFR) inhibitors was evaluated by in vitro antimalarial activity, and the results of the study showed moderate to good antimalarial profile of synthesized entities. In silico study of all the synthesized compounds was carried out using Schrödinger LLC‐2020‐3 Software to explain the binding mode and interactions between molecules and pf DHFR enzyme. To study the drug likeliness of molecules, 3D QSAR and Pharmacokinetic studies have been carried out, and the results obtained showed a good pharmacokinetics profile of two compounds, namely AMP‐24 and AMP‐28, having good IC50 values concerning standard drugs. Further, the in vitro enzyme inhibition assay results suggested that the synthesized compound interacts nicely with the enzyme and might be used as a potent antimalarial agent.

In vitro human colonic fermentation of coffee arabinogalactan and melanoidin-rich fractions

Coffee beverage is a source of dietary fiber composed by arabinogalactans, which can also be associated to proteins and phenolic compounds, originating melanoidins. Human colonic in vitro fermentations of coffee fractions, one rich in melanoidins (Mel) and the other in its parental polysaccharide arabinogalactans (AG), were performed in order to evaluate the metabolites produced by microbiota, namely short-chain fatty acids (SCFA), phenolic compounds, and bile acids. After 48 h of fermentation, a higher fermentability of the carbohydrate fraction of AG (62 %) than that of Mel (27 %) was observed, resulting in a SCFA content of 63 mM and 22 mM, respectively. Supplementation with AG and Mel fractions decreased the acetate:propionate ratio from 4.7 (in the absence of coffee fractions) to 2.5 and 3.5, respectively, suggesting a potential inhibition of HMG-CoA reductase, a rate-limiting enzyme for cholesterol synthesis. The fermentation of coffee fractions yielded dihydroferulic and dihydrocaffeic acids, known to have antioxidant properties. In the presence of Mel, it was observed a decrease (from 0.25 to 0.16 mg/mL) in the production of secondary bile acids, whose high content is associated to the development of several diseases, such as colorectal cancer, neurodegenerative and cardiovascular.

Assessment of 3‐Amino‐Benzoic Acid Methyl Ester Derivatives as Glutathione S‐Transferase and Glutathione Reductase Inhibitor: Supported by Molecular Docking Studies

Assessment of 3‐Amino‐Benzoic Acid Methyl Ester Derivatives as Glutathione S‐Transferase and Glutathione Reductase Inhibitor: Supported by Molecular Docking Studies

Anti-Inflammatory Effect of Atorvastatin and Rosuvastatin on Monosodium Urate-Induced Inflammation through IL-37/Smad3-Complex Activation in an In Vitro Study Using THP-1 Macrophages.

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.

Evaluation of Tamsulosin 0.4 mg versus 0.8 mg in Management of Patients Suffering from Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia

Abstract Introduction Lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) are common among older men. Beside watchful waiting and surgery, medical therapy includes alpha adrenergic blockers, 5 alpha reductase inhibitors, and phytotherapy. Alpha blockers are considered to be the main treatment for BPH-associated LUTS depending on the evidence that prostatic smooth muscle contraction is responsible for bladder outlet obstruction via alpha adrenergic receptor- mediated mechanism. Tamsulosin is a super selective alpha blocker. Improvement of LUTS can be assessed by maximum flow rate (Qmax), average flow rate (Qavg), post void residual (PVR) urine volume and international prostate symptom score questionnaire (IPSS). Objectives To compare the efficacy and the safety of Tamsulosin 0.4 mg/day and 0.8 mg/day in patients suffering from lower urinary tract symptoms due to benign prostatic hyperplasia. Patients and Methods A Prospective Interventional, double-blinded, controlled study was carried out on 93 patients who met the criteria and divided randomly into 2 groups; group A for Tamsulosin 0.4 mg/day and group B for Tamsulosin 0.8 mg/day. International prostate symptom score, Post void residual urine volume, and maximum flow rate of urine were assessed before and after 4 weeks of treatment. Results Both study groups showed a significant reduction in storage sub-score but only frequency was significantly reduced in group B (P &amp;lt; 0.001). On the other hand, Tamsulosin 0.8 mg was superior to Tamsulosin 0.4 mg regarding voiding sub score except for straining (P = 0.325). Accordingly, the total international prostate symptom score was significantly improved in group B (P &amp;lt; 0.001). Furthermore, maximum flow rate and post-void residual urine volume were notably improved with Tamsulosin 0.8 mg compared to Tamsulosin 0.4 mg (P &amp;lt; 0.001). Although the adverse events; such as headache, orthostatic hypotension, and retrograde ejaculation were more frequent, but not significant, to occur with Tamsulosin 0.8 mg, only dizziness was noted to be significant. Conclusion Tamsulosin 0.8 mg has shown better outcomes in treating patients who suffer from lower urinary tract symptoms due to benign prostatic hyperplasia than Tamsulosin 0.4 mg, and besides that, it is well tolerated.

Associations between Suspected Adverse Drug Reactions of HMG-CoA Reductase Inhibitors and Polypharmacology Using a National Registry Approach

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 &gt; 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.

In silico studies of Ruellia tuberosa L. compounds as aldose reductase, dipeptidyl peptidase 4, and α-glucosidase inhibitors against type 2 diabetes mellitus

Context: The search for a safe and effective anti-diabetic medication has escalated due to the unfavorable side effects of synthetic drugs and the geometric rise in diabetes mellitus cases. Ruellia tuberosa is an important medicinal plant that can potentially reduce postprandial hyperglycemia. Aims: To identify the inhibition of aldose reductase, dipeptidyl peptidase 4 (DPP-4), and α-glucosidase for anti-diabetic drug discovery from Ruellia tuberosa bioactive compounds using computational methods, including molecular docking, binding free energy estimates and ADMET predictions. Methods: A molecular docking study of betulin, betulinic acid, cirsiliol, cirsimarin, cirsimaritin, and pedalitin with aldose reductase, DPP-4, and α-glucosidase inhibitors was done using Glide XP-docking module. The adsorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction was carried out by the QikProp module, and ligand binding energy was ascertained by the prime molecular mechanics with generalized born and surface area (MM/GBSA) module, Schrodinger suite 2020-2. Results: The molecular docking and complexes' MM/GBSA show specific interactions and high binding free energies. The ADMET prediction demonstrates the excellent safety profile, pharmacokinetic characteristics, and favorable drug-likeness of betulin, betulinic acid, cirsiliol, cirsimarin, cirsimaritin, and pedalitin. This study shows the inhibition potential of Ruellia tuberosa compounds against aldose reductase, DPP-4, and α-glucosidase inhibitors. Conclusions: Therefore, for this chemical to be developed further into novel pharmaceuticals for treating type 2 diabetes mellitus, optimization and experimental research are required.

Poster 109: Association of Anti-hypertensive and Statin Medication Usage With Post-Operative Stiffness After Arthroscopic Rotator Cuff Repair: A Retrospective Cohort Study

Objectives: Postoperative stiffness following arthroscopic rotator cuff repair (aRCR) is a major cause of morbidity reported in up to 23% of patients. Angiotensive converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), medications commonly used to treat hypertension, affect TGF-β, an essential regulator of both the inflammatory process and tissue healing that has been linked to the development of tissue fibrosis. Statins, a class of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have downstream cytokine effects thought to impact bone formation and resorption. The purpose of this study is to: determine if there is an association between ACEi, ARB, or statin usage and post-operative range of motion (ROM) following aRCR, determine if ACEi, ARB, or statin usage has any association with post-operative patient-reported outcome measures (PROMs) following aRCR, and to determine if ACEi, ARB, or statin usage has any association with the need for follow-up shoulder procedures following primary repair. Methods: This was an IRB approved retrospective cohort study examining all patients at a single institution undergoing primary aRCR from 1/1/2016 – 12/31/2019. Patients were identified by CPT codes and included if they had a minimum of 1-year postoperative follow-up and documented ROM outcomes. Patients with concomitant adhesive capsulitis, calcific tendinosis, glenohumeral arthritis, labral tears, prior history of shoulder surgery, previous history of humeral fractures, workman’s compensation claims, age under 18, irreparable rotator cuff tear, history of substance abuse, or on dialysis were excluded. Patients were then separated into four groups based on usage of ACEi, ARBs, statins, or control. Demographic information, medication usage, concurrent diagnoses, and follow-up procedures were collected via chart review. Physician and physiotherapy notes were examined to determine ROM (flexion, abduction, internal rotation (IR), and external rotation (ER)) (Figure 1). PROMs were assessed through the American Shoulder and Elbow Surgeons (ASES), Single Assessment Numeric Evaluation (SANE) and Simple Shoulder Test (SST). Results: After applying inclusion/exclusion criteria, 125 patients were included in the case group (ACEi 45 patients, ARB 27 patients, statins 53 patients) and 217 controls. No significant differences were found between groups with regard to demographics. Preoperatively, patients on ACEi or ARBs had significantly decreased active flexion (p=.022), IR (p=.002), and abduction (p&lt;.001). Patients on statins had significantly decreased active abduction (85° vs. 130°, p=0.015), ER (40° vs. 50°, p=0.008), and IR (4 vs. 5, p=0.011). Postoperatively, patients on ACEi or ARBs had significantly decreased 6-month active ER (p=.015) that resolved by 12 months, and 6-month active abduction (p=.047) that also resolved by 12 months. Patients on statin medication had significantly increased 6-week active abduction (95° vs. 58°, p=0.017) that normalized to the control group by 3 month. All other ROM measurements at different time points were not significant. There was a significant decrease in postoperative SST scores in those taking ACEi or ARBs (p=.004), with no significance found in the other PROM scores at the 1-year mark. No significant differences were found in complications or reoperation rates between groups. Conclusions: Patients on ACEi or ARB medications are at an increased risk of decreased ROM before and 6 months after aRCR. Sub-analyses revealed that this effect was more pronounced with ACEi than with ARBs. Patients on statin medications are at an increased risk of decreased ROM before arthroscopic rotator cuff repair but increased ROM in the early postoperative period, especially abduction. Surgeons should use this information to guide patient education and rehabilitation perioperatively after arthroscopic rotator cuff repair.

The Role of Aldose Reductase in Polyol Pathway: An Emerging Pharmacological Target in Diabetic Complications and Associated Morbidities.

The expression of aldose reductase leads to a variety of biological and pathological effects. It is a multifunctional enzyme which has a tendency to reduce aldehydes to the corresponding sugar.alcohol. In diabetic conditions, the aldose reductase enzyme converts glucose into sorbitol using nicotinamide adenine dinucleotide phosphate as a cofactor. It is a key enzyme in polyol pathway which is a surrogate course of glucose metabolism. The polyol pathway has a significant impact on the aetiology of complications in individuals with end-stage diabetes. The exorbitant level of sorbitol leads to the accumulation of intracellular reactive oxygen species in diabetic heart, neurons, kidneys, eyes and other vasculatures, leading to many complications and pathogenesis. Recently, the pathophysiological role of aldose reductase has been explored with multifarious perspectives. Research on aldose reductase suggest that besides implying in diabetic complications, the enzyme also turns down the lipid-derived aldehydes as well as their glutathione conjugates. Although aldose reductase has certain lucrative role in detoxification of toxic lipid aldehydes, its overexpression leads to intracellular accumulation of sorbitol which is involved in secondary diabetic complications, such as neuropathy, cataractogenesis, nephropathy, retinopathy and cardiovascular pathogenesis. Osmotic upset and oxidative stress are produced by aldose reductase via the polyol pathway. The inhibition of aldose reductase alters the activation of transcription factors like NF-ƙB. Moreover, in many preclinical studies, aldose reductase inhibitors have been observed to reduce inflammation-related impediments, such as asthma, sepsis and colon cancer, in diabetic subjects. Targeting aldose reductase can bestow a novel cognizance for this primordial enzyme as an ingenious strategy to prevent diabetic complications and associated morbidities. In this review article, the significance of aldose reductase is briefly discussed along with their prospective applications in other afflictions.

Preparation and Characterization of Dutasteride Nanoparticles as Oral Fast-Dissolving Film

Background: Dutasteride, is a drug whose mechanism of action is inhibition of the enzyme 5-alpha reductase. It has been approved for use in the treatment of benign prostatic hyperplasia. Dutasteride has low solubility and high permeability, which classifies it as Biopharmaceutics classification system class II, according to the Biopharmaceutics Classification System. It has a water solubility of only 0.038 ng/mL and a slow dissolving rate, resulting in its exclusive availability in the market as a formulation contained within soft gelatin capsules. Objective: The aim of this study involves two parts. First, is the enhancement of dutasteride dissolution rate, by the creation of dutasteride nanosuspension, and second is the enhancement of patient compliance by the transformation of this nanosuspension to oral fast-dissolving film, which is characterized by its fast disintegration, stability, and ease of administration. Methods: The solvent anti/solvent precipitation method was used to formulate dutasteride nanosuspension. In addition, dutasteride nanoparticles oral fast dissolving films were prepared by using the solvent casting method. To compare the in vitro release patterns of pure dutasteride film and selected dutasteride nanoparticles film, the statistical analysis for the dissolution investigation was conducted using the model-independent technique (employing similarity factor f2) utilizing a DD solver. The selected dutasteride nanoparticle film was supposed to be the test material, while the pure dutasteride film was supposed to serve as the reference. Results: dutasteride nanosuspension demonstrated a high enhancement of the dissolution rate. In addition, the prepared dutasteride nanoparticles oral fast-dissolving film exhibited a further increase in the rate of dissolution and fast disintegration, and the administration is easy, all of these properties making it a promising dosage form. Conclusion: Nanosuspension is an excellent approach for enhancing the solubility, dissolution rate, and effectiveness of drugs with limited aqueous solubility such as dutasteride. In addition, the oral fast-dissolving film can be considered a promising dosage form that will increase patient compliance due to its high dissolution rate, fast disintegration, and easy administration.

Long-Term Water Vapor Thermal Therapy Outcomes Across a Broad Range of Prostate Volumes.

Water vapor thermal therapy (WVTT) is a minimally invasive therapy designed to treat lower urinary tract symptoms associated with benign prostatic hyperplasia. Long-term outcomes with large (>80 cc) and small (<30 cc) prostate volumes (PVs) remain limited. We report 48-month outcomes for a multiethnic cohort of WVTT-treated men, stratified by PV. In this single-center retrospective study, patients were stratified by PV: < 30 cc, 30 to 80 cc, or > 80 cc. Outcome measures, including International Prostate Symptom Score, quality of life, International Index of Erectile Function, medication usage, and adverse events, were analyzed at baseline and at 1-, 3-, 6-, 12-, 24-, 36-, and/or 48-month follow-up. Two hundred fifty-two patients met inclusion; 35 (13.9%) had PVs < 30 cc, 196 (77.8%) had PVs 30 to 80 cc, and 21 (8.3%) had PVs > 80 cc. Most patients were Asian (33.7%) or non-Hispanic Black (29.4%). International Prostate Symptom Score and quality of life improved in all cohorts from baseline at all follow-ups (all P < .05), with no differences between cohorts. International Index of Erectile Function-Orgasmic Function and -Erectile Function domains improved in 30 to 80 cc patients at 48 months. Alpha blocker and/or 5-alpha reductase inhibitor usage decreased at all follow-ups in < 30 cc and 30 to 80 cc patients and remained durable to only 6 months for > 80 cc patients. No significant differences in adverse events or reoperation rates were observed between cohorts. Our study suggests WVTT to be efficacious, durable, and safe in managing lower urinary tract symptoms across PVs, although PV > 80 cc patients may require benign prostatic hyperplasia medication at long-term follow-up. Further research is desired to clarify WVTT's role regarding sexual function and in treating men with larger PVs.

Molecular docking analysis of Ficus religiosa L. fruit extracts with HMG-COA reductase inhibitors, anti-hyperlipidemic effects of its in Albino wistar rats, triggered by Triton-X 100 and High fat diet

Hyperlipidemia is the major risk factor for coronary artery disease in various patients suffering with cardiovascular disorders. Literature claims that flavonoids and phenolic compounds are able to reduce hyperlipidemia. Aim of the present study is to establish antihyperlipidemic activity of Ficus religiosa L. fruits extract with molecular docking approach and perform in-vivo study.Extraction has performed by Soxhlet apparatus with methanol for 72 h. Further, the extract has subjected to phytochemical tests followed by GC-MS analysis. Molecular docking study has been conducted to screening the compounds in extract which have affinity to HMG-COA reductase (PDB ID: 1HWK) receptor with reference to Atorvastatin. Anti-hyperlipidemic activity of the extract has investigated by studying in vivo effects on Triton-X 100 and High fat diet induced animal model. The animals were divided in 5 groups of 6 each. The extract has administered at a dose of 1000 mg/kg (p.o) and 500 mg/kg (p.o) to both models. Atorvastatin was used as standard.The GC-MS result of Ficus religiosa L. fruits has demonstrated the presence of phenols, flavonoids. Molecular docking study has been performed to identify the anti-oxidant compounds in the extracts. The extract has shown a significant decrease in the levels of Body weight, serum cholesterol, glucose, triglyceride, LDL, VLDL and significant increase in the level of serum HDL. The result of the research has showed that Ficus religiosa L. fruits possess antihyperlipidemic activity in both groups; the results were statistically significant compared to Atorvastatin.

Unveiling potent inhibitors for schistosomiasis through ligand-based drug design, molecular docking, molecular dynamics simulations and pharmacokinetics predictions.

Schistosomiasis is a neglected tropical disease which imposes a considerable and enduring impact on affected regions, leading to persistent morbidity, hindering child development, diminishing productivity, and imposing economic burdens. Due to the emergence of drug resistance and limited management options, there is need to develop additional effective inhibitors for schistosomiasis. In view of this, quantitative structure-activity relationship studies, molecular docking, molecular dynamics simulations, drug-likeness and pharmacokinetics predictions were applied to 39 Schistosoma mansoni Thioredoxin Glutathione Reductase (SmTGR) inhibitors. The chosen QSAR model demonstrated robust statistical parameters, including an R2 of 0.798, R2adj of 0.767, Q2cv of 0.681, LOF of 0.930, R2test of 0.776, and cR2p of 0.746, confirming its reliability. The most active derivative (compound 40) was identified as a lead candidate for the development of new potential non-covalent inhibitors through ligand-based design. Subsequently, 12 novel compounds (40a-40l) were designed with enhanced anti-schistosomiasis activity and binding affinity. Molecular docking studies revealed strong and stable interactions, including hydrogen bonding, between the designed compounds and the target receptor. Molecular dynamics simulations over 100 nanoseconds and MM-PBSA free binding energy (ΔGbind) calculations validated the stability of the two best-designed molecules. Furthermore, drug-likeness and pharmacokinetics prediction analyses affirmed the potential of these designed compounds, suggesting their promise as innovative agents for the treatment of schistosomiasis.

Graft protective effects and donor-specific antibody suppression by CD4+CD25+Foxp3+ regulatory T cell induced by HMG-CoA reductase inhibitor rosuvastatin in a murine heart transplant model

BackgroundWe 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.MethodsCBA 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.ResultsCBA 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.ConclusionRosuvastatin 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.

Pro-Oxidant Auranofin and Glutathione-Depleting Combination Unveils Synergistic Lethality in Glioblastoma Cells with Aberrant Epidermal Growth Factor Receptor Expression.

Glioblastoma (GBM) is the most prevalent and advanced malignant primary brain tumor in adults. GBM frequently harbors epidermal growth factor receptor (EGFR) wild-type (EGFRwt) gene amplification and/or EGFRvIII activating mutation. EGFR-driven GBM relies on the thioredoxin (Trx) and/or glutathione (GSH) antioxidant systems to withstand the excessive production of reactive oxygen species (ROS). The impact of EGFRwt or EGFRvIII overexpression on the response to a Trx/GSH co-targeting strategy is unknown. In this study, we investigated Trx/GSH co-targeting in the context of EGFR overexpression in GBM. Auranofin is a thioredoxin reductase (TrxR) inhibitor, FDA-approved for rheumatoid arthritis. L-buthionine-sulfoximine (L-BSO) inhibits GSH synthesis by targeting the glutamate-cysteine ligase catalytic (GCLC) enzyme subunit. We analyzed the mechanisms of cytotoxicity of auranofin and the interaction between auranofin and L-BSO in U87MG, U87/EGFRwt, and U87/EGFRvIII GBM isogenic GBM cell lines. ROS-dependent effects were assessed using the antioxidant N-acetylsteine. We show that auranofin decreased TrxR1 activity and increased ROS. Auranofin decreased cell vitality and colony formation and increased protein polyubiquitination through ROS-dependent mechanisms, suggesting the role of ROS in auranofin-induced cytotoxicity in the three cell lines. ROS-dependent PARP-1 cleavage was associated with EGFRvIII downregulation in U87/EGFRvIII cells. Remarkably, the auranofin and L-BSO combination induced the significant depletion of intracellular GSH and synergistic cytotoxicity regardless of EGFR overexpression. Nevertheless, molecular mechanisms associated with cytotoxicity were modulated to a different extent among the three cell lines. U87/EGFRvIII exhibited the most prominent ROS increase, P-AKT(Ser-473), and AKT decrease along with drastic EGFRvIII downregulation. U87/EGFRwt and U87/EGFRvIII displayed lower basal intracellular GSH levels and synergistic ROS-dependent DNA damage compared to U87MG cells. Our study provides evidence for ROS-dependent synergistic cytotoxicity of auranofin and L-BSO combination in GBM in vitro. Unraveling the sensitivity of EGFR-overexpressing cells to auranofin alone, and synergistic auranofin and L-BSO combination, supports the rationale to repurpose this promising pro-oxidant treatment strategy in GBM.

Formulation Development and Evaluation of Atorvastatin Calcium Extended-Release Tablets

Atorvastatin calcium is an antihyperlipidemic agent that acts as HMG- COA reductase inhibitor. The objectives of the current research are to evaluate Atorvastatin calcium release from sustained-release tablets. FTIR analysis reveals that drug and polymer have no interaction. The tablets were created utilizing the wet granulation process by using various concentrations of polymer like HPMC. The prepared extended-release tablets have been assessed for friability, thickness, drug content, hardness, and in-vitro drug release studies. From the release analysis at high concentrations demonstrate better release than HPMC low concentration. The in-vitro release data findings indicate that HPMC polymer exhibits a better release rate at 18 hours showing 97.63.

Identification of lipid-modifying drug targets for autoimmune diseases: insights from drug target mendelian randomization

BackgroundsA growing body of evidence has highlighted the interactions of lipids metabolism and immune regulation. Nevertheless, there is still a lack of evidence regarding the causality between lipids and autoimmune diseases (ADs), as well as their possibility as drug targets for ADs.ObjectivesThis study was conducted to comprehensively understand the casual associations between lipid traits and ADs, and evaluate the therapeutic possibility of lipid-lowering drug targets on ADs.MethodsGenetic variants for lipid traits and variants encoding targets of various lipid-lowering drugs were derived from Global Lipid Genetics Consortium (GLGC) and verified in Drug Bank. Summary data of ADs were obtained from MRC Integrative Epidemiology Unit (MER-IEU) database and FinnGen consortium, respectively. The causal inferences between lipid traits/genetic agents of lipid-lowering targets and ADs were evaluated by Mendelian randomization (MR), summary data-based MR (SMR), and multivariable MR (MVMR) analyses. Enrichment analysis and protein interaction network were employed to reveal the functional characteristics and biological relevance of potential therapeutic lipid-lowering targets.ResultsThere was no evidence of causal effects regarding 5 lipid traits and 9 lipid-lowering drug targets on ADs. Genetically proxied 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibition was associated with a reduced risk of rheumatoid arthritis (RA) in both discovery (OR [odds ratio] = 0.45, 95%CI: 0.32, 0.63, P = 6.79 × 10− 06) and replicate datasets (OR = 0.37, 95%CI: 0.23, 0.61, P = 7.81 × 10− 05). SMR analyses supported that genetically proxied HMGCR inhibition had causal effects on RA in whole blood (OR = 0.48, 95%CI: 0.29, 0.82, P = 6.86 × 10− 03) and skeletal muscle sites (OR = 0.75, 95%CI: 0.56, 0.99, P = 4.48 × 10− 02). After controlling for blood pressure, body mass index (BMI), smoking and drinking alchohol, HMGCR suppression showed a direct causal effect on a lower risk of RA (OR = 0.33, 95%CI: 0.40, 0.96, P = 0.042).ConclusionsOur study reveals causal links of genetically proxied HMGCR inhibition (lipid-lowering drug targets) and HMGCR expression inhibition with a decreased risk of RA, suggesting that HMGCR may serve as candidate drug targets for the treatment and prevention of RA.

Відбір пробіотичних мікроорганізмів та їх композицій як основи для лінійки функціональних продуктів харчування з гіпохолестеринемічними властивостями

In modern clinical practice, the main methods for correcting elevated serum cholesterol levels are drugs that block the activity of the enzyme hydroxymethylglutaracyl-CoA-reductase (HMG-CoA-reductase) – statins or drugs that inhibit the absorption of cholesterol and sterols in the intestines ezetimibe. All hypocholesterolemic drugs are rather expensive and have side effects, the main of which is hepatotoxicity. During mono- and combined therapy with HMG-CoA reductase inhibitors and ezetimibe, cases of increased activity of alanine and asparagine transaminases (biochemical indicator of cytolytic syndrome), disorders of the digestive and respiratory systems, the central and peripheral nervous systems, and the sense organs along with weight gain, etc. have been found. Scientific literature has increasingly reported on the ability of lactic acid bacteria to lower serum cholesterol. The ability of certain strains of representatives of the normal microbiota to assimilate and precipitate deconjugated bile acids, as well as to destroy, bind, and assimilate cholesterol, is the basis of their hypocholesterolemic activity (the ability to reduce the level of serum cholesterol). A high level of cholesterol, both in the total blood serum and in low-density lipoproteins, is one of the main risk factors for coronary heart disease, atherosclerosis, cerebrovascular atherosclerosis, hypertension, tumors of the digestive tract, etc. The aim of the study was to establish the hypocholesterolemic activity in vitro and in vivo of previously selected highly effective probiotic strains of lactic- and bifidobacteria for the further creation on their basis of a line of effective functional food with hypocholesterolemic activity for the prevention and concomitant treatment of pathological conditions associated with high cholesterol levels. Methods. Bacterial hypocholesterolemic activity in vitro was determined according to Rudel L.L. and in vivo – on the mice model that was designed by us. Two schemes of the administration of probiotic strains – the prophylactic and therapeutic ones–were developed. Results showed that Lactobacillus acidophilus IMV B-7279 and Bifidobacterium animalis IMV B-7286 strains, as well as the Bifidobacterium animalis IMV B-7286: Bifidobacterium animalis IMV B-7285 (1:1) composition were the most effective probiotics used for treatment of mice with hypercholesterolemia. The cholesterol-lowering activity of all studied probiotic strains and their compositions ranged between 40–78 %. At the same time, it should be noted that the hypocholesterolemic activity of the other studied strains was not lower, and in some cases even higher than that of most of the drugs currently used for cholesterinosis. Conclusions. The obtained results allow us to assert that it is necessary to develop a series of functional foods and probiotics based on the studied strains and their compositions in an encapsulated form, for the prevention and treatment of diseases associated with the negative manifestations of high cholesterol levels.