Reductase Inhibitors Research Articles

Regulatory effects of statins on CCL2/CCR2 axis in cardiovascular diseases: new insight into pleiotropic effects of statins

BackgroundHMG-CoA reductase inhibitors are well-known medications in the treatment of cardiovascular disorders due to their pleiotropic and lipid-lowering properties. Herein, we reviewed the effects of statins on the CCL2/CCR2 axis.MethodScopus and Pubmed databases were systematically searched using the following keywords:” Hydroxymethylglutaryl CoA Reductase Inhibitors”,” HMG-CoA Reductase Inhibitors”,” Statins”, “CCL2, Chemokine”, “Monocyte Chemoattractant Protein-1” and “Chemokine (C-C Motif) Ligand 2”. Evidence investigating the role of statin on MCP-1 in CVD was identified and bibliographies were completely evaluated to gather further related studies.ResultsThe anti-inflammatory effects of statins on the CCL2/CCR2 pathway have been widely investigated. Despite inconclusive results, a great body of research supports the regulatory roles of statins on this pathway due to their pleiotropic effects. By disrupting the CCL2/CCR2 axis, statins attenuate the infiltration of monocytes and macrophages into the zone of inflammation and hence down-regulate the inflammatory cascades in various CVDs including atherosclerosis, cardiac remodeling, and stroke, among others.ConclusionCCL2 plays a major role in the pathogenesis of cardiovascular disorders. Down-regulation of CCL2 is proposed as one of the pleiotropic properties of statins. However, more investigations are required to elucidate which statin in what dose exerts a more potent effect on CCL2/CCR2 pathway.

Molecular modeling, synthesis and biological evaluation of caffeic acid based Dihydrofolate reductase inhibitors

Dihydrofolate reductase (DHFR) is an enzyme that plays a crucial role in folate metabolism, which is essential for cell growth and division. DHFR has been identified as a molecular target for numerous diseases due to its significance in various biological processes. DHFR inhibitors can disrupt folate metabolism by inhibiting DHFR, leading to the inhibition of cell growth. So, a series of caffeic acid derivatives were designed, synthesized, characterized and evaluated for their in vitro ability to inhibit DHFR, as well as their antimicrobial and anticancer properties. Among all synthesized compounds, compound CE11 exhibited the highest DHFR inhibitory activity, with an IC50 value of 0.048 µM, which is approximately four times more potent than methotrexate. Compound CE11 exhibited similar docking performance to methotrexate, binding to the same site and engaging key residues such as Glh30, Phe31, Phe34, and Ser59. It also fit snugly in the hydrophobic pocket of modeled protein. Moreover, substantial hydrophobic interactions were noted between the ligand and the hydrophobic amino acid residues of DHFR. This effectively secured the derivative within the restricted substrate cavity. Furthermore, compound CE11 demonstrated a significant anticancer activity against MCF-7 breast cancer cell line, with an IC50 value of 5.37 ± 0.16 µM. Compounds CE3 and CE15 displayed better antibacterial activity compared to trimethoprim and comparable to ampicillin against the gram-positive bacteria S. aureus. Moreover, compounds CE3 and CE15 have shown better antibacterial activity than standard trimethoprim, ampicillin and tetracycline against the gram-negative bacteria, particularly P. aeruginosa and E. coli. Molecular docking analysis of CE3 revealed that it firmly entrapped into the active site of enzyme through hydrophobic interaction with hydrophobic residues. Additionally, it forms hydrogen bonds with important amino acid residues Ala7, Asn18, and Thr121 with excellent docking score and binding energy (-9.9, -71.77 kcal/mol). These interactions might be contributed to the significant DHFR inhibition and antimicrobial activity. The generated model holds potential value in facilitating the development of a novel category of DHFR inhibitors as anticancer and antimicrobial agents.

Lipid-Lowering Therapy Associated Erectile Dysfunction and Testicular Pain: A Rare Case Report

Lipid-lowering therapy (LLT) includes a diverse group of pharmaceuticals designed to reduce blood levels of cholesterol and triglyceride (TG), helping to prevent cardiovascular diseases like myocardial infarction and stroke. LLT includes treatment with several lipid-lowering drugs (LLD), including hydroxymethylglutaryl (HMG-CoA) reductase inhibitors (statin), PCSK9 Inhibitors, cholesterol-absorbing inhibitors (Ezetimibe), Bile Acid Sequestrants, Fibrates, Niacin (Vitamin B3), Omega-3 Fatty Acids, Bempedoic Acid, and combination therapy. The efficacy and safety of these molecules vary widely. Statins are the first-line LLD for treating hypercholesterolemia and are widely used for cardiovascular disease prevention. Common side effects include muscle-related issues such as myalgia, muscle atrophy, and, rarely, rhabdomyolysis. However, adverse effects on male reproductive health are infrequent and often underreported. Other medication classes employed in LLT mostly share many of the ADRs seen with statins, although individual classes may have unique ADRs depending on the pharmacokinetics and pharmacodynamics. Here, we are reporting a unique case of a 50-year-old male patient with no prior history of sexual dysfunction or testicular issues and other comorbidities or habits, who developed loss of libido, erectile dysfunction (ED) and testicular pain with most of the LLD, which promptly resolved on discontinuation of the LLT. This case highlights the importance of considering potential reproductive side effects when prescribing LLT and monitoring male patients for symptoms of sexual dysfunction.

Insights through molecular modeling into the structural requirement of Phenyl(6-phenylpyrazin-2-yl)methanone derivatives as aldose reductase inhibitors

Aldose reductase, play an important role in the pathogenesis of diabetic complications such as neuropathy, nephropathy and retinopathy. Therefore design of aldose reductase inhibitors has received considerable attention. In the present study molecular insights were explored through docking and QSAR. The quantification of the structural features of Phenyl(6-phenylpyrazin-2-yl)methanone analogs inferred that atomic Senderson electronegativity, van der Waals volume and charge distribution on the molecule are decisive for the aldose reductase inhibitory activity. Moreover, docking study depicted that benzonoid system of scaffold is crucial for - interaction with the side chain of key aromatic amino acids i.e. TRP111 and TRP20. These structural insights might provide significant roadmap for continuing search of potential ARIs prior to synthesis.

Quantitative Structure Activity Relationship Analysis of Benzimidazole Derivatives as Aldose Reductase Inhibitors

Hyperglycemia is involved in the pathogenesis of diabetic neuropathy, retinopathy, nephropathy, and macro-vascular disease via multiple mechanisms, of which increased aldose reductase activity. Aldose reductase inhibitors, when administered from the onset of hyperglycemia, prevent the progression of polyol accumulation–linked complication. In this work, we report quantitative structure activity relationship analysis performed on the Triazino[4,3-α]benzimidazole acetic acid derivatives as aldose reductase inhibitors. The molecular modeling study was performed by using the software BioMed CAChe 6.0 and the regression analysis by SYSTAT 10.2. Various physicochemical parameters belonging to different classes viz. hydrophobic, steric and electronic etc. were calculated. QSAR models were generated using 17 compounds. The model showed a good correlative and predictive ability having convention coefficient (r2) of 0.846 and cross-validated correlation coefficient (q2) of 0.6866 by LOO external validation method. Based on the developed QSAR model, it may be concluded that aldose reductase inhibition activity of benzimidazole acetic acid derivatives is strongly influenced by the thermodynamic and electronic nature of the substituents. QSAR model shows that LOGP, LUMO energy, and steric energy are negatively affecting the biological activity. For a molecule to have higher aldose reductase activity, compound should be less lipophilic and should have more electronegative groups or atoms than electropositive groups or atoms present in the compound.

Statin Use in Children and Adolescents - Dos, Don'ts and Practical Tips.

We review treatment criteria in the pediatric population, provide practical advice on how and when to prescribe statins, and share tips to improve compliance. Although long-term outcome studies of cardiovascular-related events, such as myocardial infarction (MI) and stroke, are lacking in this population, statin therapy initiated during adolescence has been shown to be safe and effective for up to 20years of continuous use. HMG-CoA reductase inhibitors (statins) are the most effective class of drugs for lowering low-density lipoprotein cholesterol (LDL-C) in children and adolescents.

Evaluation of UCP1162, a potent propargyl-linked inhibitor of dihydrofolate reductase with potential application to cancer and autoimmune disease

Cellular resistance can limit the effectiveness of antifolate drugs for the treatment of cancer and autoimmune diseases. Here we examine the biochemical and cellular effects of a propargyl linked, non-classical antifolate that shows exceptional potency and resilience in the background of methotrexate resistance, UCP1162. UCP1162 inhibited the human DHFR enzyme with affinity and kinetics comparable to methotrexate (MTX). UCP1162 also inhibited cancer cell proliferation and bound cellular DHFR at low nanomolar concentrations. Leucovorin suppressed the cellular effects of UCP1162, consistent with UCP1162 working as an antifolate. Like other antifolates, UCP1162 reduced acute inflammation in mice and inhibited FLS cell growth and motility. Single cell RNA-seq showed that MTX and UCP1162 generated overlapping gene expression changes after a 48-hour exposure. However, while leukemia cells (CCRF-CEM) resistant to MTX could be readily selected, UCP1162-resistant cells could not be obtained. Long-term exposure to UCP1162 resulted in static culture expressing stem cell genes (CD34, ABCG2, ABCB1), adaptive genes (TCN2, CDKN1A), and genes that might serve as therapeutic targets (TPBG/5T4, TNFRSF10A, ACE). These findings suggest that UCP1162 is a unique tool for studying cellular responses to long-term antifolate treatment and holds promise as a lead compound capable of overcoming some forms of antifolate resistance.

Quassinoids from Eurycoma longifolia as Potential Dihydrofolate Reductase Inhibitors: A Computational Study.

Quassinoids are degraded triterpene compounds that can be obtained from various species of the Simaroubaceae plant family, including Eurycoma longifolia. Quassinoids are the major compounds in E. longifolia, and they are known to have various medicinal potentials, such as anticancer and antimalarial properties. Dihydrofolate reductase (DHFR) was reported to be one of the important targets for certain anticancer and antimalarial drugs. Twelve quassinoids from E. longifolia were identified to have anticancer effects based on their IC50 values. This study aimed to evaluate the interactions of these twelve quassinoids with DHFR via Autodock 4.2 software and Biovia Discovery Studio Visualiser. Twelve quassinoids from E. longifolia and their interactions with DHFR were evaluated via Autodock 4.2 software and Biovia Discovery Studio Visualiser. Their drug-likeness and pharmacokinetic properties were also assessed using the ADMETlab 2.0 program. The molecular docking results showed that eleven quassinoids showed better docking scores than methotrexate, in which the binding energy (BE) of these quassinoids ranged from - 7.87 to -9.58 kcal/mol. Their inhibition constant (Ki) ranged from 0.095 to 1.71 μM. At the same time, the BE and Ki values for methotrexate were -7.80 kcal/mol and 1.64 μM, respectively. From the analysis, 6-dehydrolongilactone and eurycomalide B are among the twelve compounds that showed great potential as hit-to-lead compounds based on the docking score on DHFR, drug-likeness, and ADMET properties. These results suggest a great potential to pursue validation studies via in vitro and in vivo models.

Assessment of novel biomarkers of renal dysfunction associated with lower urinary tract symptoms in men with benign prostatic hyperplasia

Introduction. The problem of diagnostics and treatment of patients with complex lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) remains highly relevant. Clinical diagnostic methods do not always allow timely prediction of changes in renal, upper and lower urinary tract function with different types of treatment intervention. The search for potential biomarkers allowing minimally invasive assessment of the bladder and renal function condition seems to be a promising direction of scientific research.Objective. To identify potential urine and serum biomarkers allowing to assess renal function in patients with LUTS/BPH.Materials & methods. The study included 69 patients with LUTS/BPH and subsequently divided them into two groups. Group 1 included 48 patients with moderate LUTS who received combination therapy with alpha-1 adrenergic blockers (AABs) and 5-alpha reductase inhibitors (5ARIs). Group 2 included 21 patients with severe LUTS/BPH. Patients of group 2 underwent surgical treatment: transurethral resection of the prostate. In addition to standard research methods (IPSS, voiding diaries, laboratory, urodynamic and radiation techniques), to search for potential biomarkers in serum and urine, concentrations of: insulin-like growth factor binding protein-7 (IGFBP7), B-Cross Laps, Cystatin C, OPN, trefoil factor (TFF3), uromodulin, Clusterin, lactate dehydrogenase (LDH). The follow-up period for patients was 12 months.Results. The study noted that IGFBP7, Cystatin C, TFF3 in the blood serum, as well as LDH, Clusterin in the urine are associated with the severity of LUTS/BPH. Serum biomarker levels were initially higher in patients with severe LUTS compared to patients with moderate LUTS (group 1). The levels of these substrates decreased in patients of all groups during treatment (conservative therapy, surgical interventions for BPH). When assessing urinary biomarkers, the greatest decrease in Clusterin level by the end of follow-up was registered in group 1 patients, the least pronounced in group 2 patients. The initial value of LDH was twice higher in group 2 vs group 1 and progressively decreased after surgical treatment of bladder outlet obstruction.Conclusion. Biomarkers used to assess renal dysfunction in the development of LUTS/BPH are a promising area of scientific research. Panels of new markers will enable to predict renal dysfunction in patients with moderate-to-severe LUTS, which will improve the quality of medical care for this category of patients.

Isolation of phytoconstituents from an extract of Murraya paniculata with cytotoxicity and antioxidant activities and in silico evaluation of their potential to bind to aldose reductase (AKR1B1)

The study on Murraya paniculata (Orange Jasmine) stem bark extract found it to have antioxidant and cytotoxic proper-ties. The structures of the isolated phytoconstituents were determined using NMR spectroscopy. Compounds were evaluated for their potential to be aldose reductase inhibitors using molecular docking and dynamics (MD) simulations. Phytochemical screening of methanolic crude extract was performed from which different fractions of the extract were screened for antioxidant activity using the DPPH radical scavenging method and cytotoxicity using the brine shrimp lethality bioassay. The aqueous fraction showed strong antioxidant activity as compared to the standard butylated hy-droxytoluene, whereas pet ether, dichloromethane, chloroform and methanolic extract exhibited moderate antioxidant activity. Activities in the DPPH assay ranged from 17 to 63 µg/ml and all fractions showed cytotoxic activity. Five identified phytochemical compounds (1-5) include ergosterol endoperoxide (1), the coumarin derivatives 7-methoxy-8-(3-methylbut-2-enyl)-1-benzopyran-2-one (2) and 5,7-dimethoxy-8-(3-methylbut-2-enyl)-1-benzopyran-2-one (3) and a mixture of β-sitosterol (4), and stigmasterol (5). Among them ergosterol endoperoxide has been isolated from the stem bark of the M. paniculata for the first time. MD simulations of the identified compounds indicated their potential to bind to the aldose reductase (AKR1B1) protein. Predicted binding affinities of the compounds based on the site identification the ligand competitive saturation (SILCS) technology was −15.04, −8.85, −9.83, −11.95, and −11.75 kcal/mol for 1 through 5, respectively. The present results are anticipated to lead to further study of the activities of the five compounds including experimental evaluation of their inter-actions with AKR1B1.

Pralatrexate represses the resistance of HCC cells to molecular targeted agents via the miRNA-34a/Notch pathway

Metabolism-related pathways are important targets for intervention in the treatment of hepatocellular carcinoma (HCC), but few studies have reported on the combination of inhibitors of folate metabolism-related enzymes and molecularly targeted drugs for HCC. The results of the present work are the first to reveal the effects of an inhibitor of dihydrofolate reductase (DHFR), pralatrexate, on the sensitivity of HCC cells to molecularly targeted agents examined using multiple assays. In HCC cells, knockdown of DHFR or treatment with pralatrexate enhanced the sensitivity of HCC cells to molecularly targeted agents, such as sorafenib, regorafenib, lenvatinib, cabozantinib, or anlotinib. Mechanically, pralatrexate decreased the methylation rates of miRNA-34a’s promoter region to enhance the expression of miRNA-34a. Treatment with pralatrexate inhibited the expression of Notch and its downstream factors by enhancing the expression of miRNA-34a in HCC cells. In clinical specimens, the expression of miRNA-34a was negatively correlated with DHFR expression, while DHFR expression was positively correlated with the Notch intracellular domain (NICD) and downstream factors of the Notch pathway. The expression of miRNA-34a was negatively correlated with DHFR expression, while the methylation rates of miRNA-34a’s promoter were positively related to DHFR. The effect of pralatrexate on the metabolic profile of HCC cells is very different from that of small molecule inhibitors related to glycolipid metabolism. Therefore, pralatrexate upregulates the sensitivity of HCC cells to molecularly targeted drugs. These results expand our understanding of folate metabolism and HCC and can help provide more options for HCC treatment.

Results of the ACTION-Galactosemia Kids Study to Evaluate the Effects of Govorestat in Pediatric Patients with Classic Galactosemia.

To evaluate the pharmacodynamic effects and clinical outcomes of orally administered once-daily govorestat (AT-007), a central nervous system penetrant aldose reductase inhibitor, the double-blind placebo-controlled ACTION-Galactosemia Kids study (NCT04902781) randomly assigned 47 participants (2-17 years old) with Classic Galactosemia to 18 months of govorestat or placebo (2:1) treatment. Mean change in galactitol was compared between the treatment groups at each post-baseline timepoint using a t-test, with a mixed model for repeated measures (MMRM) analysis as a sensitivity analysis. Changes from baseline in clinical outcomes were compared between treatment groups also using a t-test with two different MMRM models as sensitivity models, one including baseline clinical outcome score. The pharmacodynamic effect of govorestat was assessed by correlating galactitol level at 3 months with change from baseline in clinical measures at 18 months using a Pearson correlation. Govorestat treatment resulted in a rapid and sustained reduction in plasma galactitol. Govorestat treatment stabilized or improved clinical measures of behavior, daily living skills, adaptive skills, cognition, tremor, and fine motor skills, which declined over time in the placebo group. Govorestat treatment did not demonstrate a benefit compared with placebo on speech outcomes or gross motor skills, which improved in both treatment groups over 18 months. Govorestat was safe and well tolerated, with adverse events well balanced between the active and placebo groups. Aldose reductase inhibition with govorestat represents a potential opportunity to lower galactitol and improve clinical outcomes in children with Classic Galactosemia.

Oxidative Stress Mechanism by Gold Compounds: A Close Look at Total ROS Increase and the Inhibition of Antioxidant Enzymes.

The antitumor activity of various gold compounds is a promising field of investigation, attracting researchers seeking potential clinical candidates. To advance this research, they explore the complex mechanisms of action of these compounds. Since the discovery of the strong inhibition of thioredoxin reductase by auranofin, the primary mechanism explored has been the inhibition of this enzyme. This inhibition disrupts the redox balance in cells, promoting oxidative stress and triggering cell death. In this review, we analyzed studies from the past decade that measured cellular ROS increase and examined the coordination structures of gold compounds. We also correlate ROS increase with the inhibition of redox-regulating enzymes, thioredoxin reductase, and glutathione reductase, to elucidate the relationship between these cellular effects and chemical structures. Our data compilation reveals that different structures exhibit varying efficacy: some significantly increase ROS production and inhibit thioredoxin reductase or glutathione reductase, while others elevate ROS levels without affecting these target enzymes, suggesting alternative mechanisms of action. This review consolidates critical evidence, enhancing our understanding of the mechanisms by which these gold complexes act and providing valuable insights for developing new therapeutic strategies against tumor cells.

Development of an at-line coupling of LC-QTOF-ESI-MS/MS to steroid 5-alpha reductase inhibition assay, a fast bioactive targeting and guided purification of natural complex sample, Impatiens balsamina Linn.

This study provides a rapid and accurate method for screening steroid 5-alpha reductase (S5αR) inhibitors in Impatiens balsamina Linn (IB). using at-line LC-QTOF-ESI-MS/MS coupling S5αR inhibitory assay. IB (Balsaminaceae) is an annual herbaceous plant cultivated in tropical and subtropical regions. It has been used in traditional Chinese and Thai medicine for treatment of hair loss and various skin conditions, potentially through anti-androgenic mechanisms. A combined approach of S5αR inhibitory assay and LC-QTOF-ESI-MS/MS was developed to rapidly screen for target biomarkers and guide their isolation using preparative HPLC. The toxicity of both the extract and isolated biomarkers was evaluated on skin cells, keratinocytes, and fibroblasts. Eight bioactive compounds were identified as two naphthoquinone, two fatty acid derivatives, three nitrogenous compounds and one aromatic derivative. The most potent bioactive markers, identified as 2-methoxy-1,4-naphthoquinone (2MN) and impateinol, were targeted and isolated using preparative HPLC, yielding 5.0 % and 3.5 %, respectively. These compounds exhibited S5αR inhibitory activity higher than that of finasteride drug by 10 and 2 times, respectively. Both the isolated biomarkers and the extract demonstrated a broad therapeutic index. The developed method in this study proved to be both rapid and accurate, making it suitable for screening and targeting S5αR inhibitors in herbal plants or complex matrix samples. It facilitated the fast-guided isolation of bioactive compounds, highlighting its potential for future applications in drug discovery research.

In-silico study and in-vitro validations for an affinity of mangiferin with aldose reductase: Investigating potential in tackling diabetic retinopathy

Type II Diabetes mellitus (T2DM) and associated complications primarily diabetic retinopathy cases are rising with an alarming rate. Prolong hyperglycemia along with the aldose reductase (AR) activity play a pivotal role in the development of oxidative stress in the aqueous humor and diabetic retinopathy. AR catalyzes conversion of glucose into sorbitol and or fructose get diffuse into lens leading to impaired electrolyte balance and cataract formation. Here in the study, affinity of mangiferin was evaluated first using in silico approaches (Docking studies) and then validated via isothermal titration calorimetry. Here in the present study aim was to check the does mangiferin do have affinity with AR, does mangiferin inhibit the AR and polyol pathway as key pathway involve in the diabetic retinopathy. Both in silico and laboratory investigations were carried out to explore the affinity of mangiferin with the aldose reductase. Swiss target prediction study showed that the AR is prime target of mangiferin in the human proteome. The molecular docking study and affinity searches were performed to seek the bonding pattern and forces involved. Docking (affinity 34.37 kcal/mol) for AR pose 1 was reported superior over the AR pose 2 (affinity −35.46 kcal/mol) against mangiferin. Mangiferin showed significant AR inhibition where IC50 reported 67.711 µg/ml and highest inhibition was reported at 300 µg/ml i.e. 86.44 %. On the contrary, Quercetin showed much higher inhibition of aldose reductase at similar concentration i.e. 94.47 % at 300 µg/ml with IC50 59.6014 µg/ml. Here, AR pose 1 showed higher affinity with the mangiferin and confirmed via Isothermal Titration Calorimetry clearly showed higher binding affinity parameters. Binding affinity of AR pose 1 with the mangiferin was higher as showed with affinity parameter determined via ITC i.e. floating association constant (Ka) reported 6.47×106, binding enthalpy (ΔH) −46.11 kJ/mol and higher binding sites (n) i.e. 1.84. Findings demonstrates that the mangiferin is promising AR inhibitor with the ADME prediction (CLR 1.119 ml/min and t1/2 1.162 h).

Do 5-Alpha Reductase Inhibitors Influence the Features of Suspicious Lesions on Magnetic Resonance Imaging and Targeted Biopsy Results for Prostate Cancer Diagnosis?

5-alpha reductase inhibitors (5-ARIs) change hormonal pathways and reduce prostate size. We evaluated the effects of 5-ARIs on prostatic multiparametric magnetic resonance imaging (mpMRI) suspicious findings and in the identification of prostate cancer using targeted biopsies. We conducted a retrospective study including 600 consecutive patients who, between 2017 and 2021, underwent combined transperineal fusion biopsies. Primary outcomes were Prostate Imaging Reporting and Data System version 2 (PIRADS v2) scores and the identification of clinically significant prostate cancer from suspicious lesions (targeted CSPC). Outcomes were compared between patients treated with 5-ARIs for a minimum of 6 months and the other patients. Patients treated with 5-ARIs were older (p < 0.001) with higher rates of previous prostate biopsies (p = 0.004). PIRADS scores were 3, 4, and 5 in 15 (29%), 28 (54%), and 9 (17%) patients among the 5-ARI group and 130 (24%), 308 (56%), and 110 (20%) patients among the others, and the scores were not different between the groups (p = 0.69). The targeted CSPC identification rate among 5-ARI patients was 31%, not different compared to the non-5-ARI group (p = 1). Rates of targeted CSPC for each PIRADS score were not affected by 5-ARI treatment. The 5-ARI was not associated with neither PIRADS ≥ 4 score nor targeted CSPC on logistic regression analyses (OR = 0.76, 95% CI 0.4-1.4 and OR = 1.02, 95% CI 0.5-1.9, respectively). 5-ARI treatment is not associated with PIRADS score alterations or targeted biopsy results. Patients treated by 5-ARIs with suspicious lesions should not be addressed differently during the mpMRI-related diagnostic process.

Exploring Teucrium aureo-candidum Essential Oil as a Promising Alternative to Triclosan for Targeting Enoyl-Acyl Carrier Protein Reductase: Chemical Composition, Antibacterial Activity, and Molecular Docking Study.

The chemical composition of the essential oil isolated from the aerial parts of Teucrium aureo-candidum, an endemic aromatic shrub collected from Moghrar and Djeniene Bourezg in the Nâama region (Algeria), was determined for the first time using GC/FID and GC/MS. A total of 45 constituents were identified, representing 87.73% of the oil. Characterized by unique chemical variability, it was primarily composed of sesquiterpene hydrocarbons (29.53%) and oxygenated sesquiterpenes (30.06%), with the major compounds being γ-cadinene (5.24%), δ-cadinene (4.24%), α-muurolene (4.04%), τ-muurolol (11.35%), and α-cadinol (3.30%). However, monoterpene hydrocarbons and oxygenated monoterpenes accounted for 23.98% and 1.64%, respectively, contributing to a relatively low fraction. The essential oil demonstrated notable antibacterial activity, particularly against Gram-positive bacteria. Due to safety concerns associated with triclosan, a known inhibitor of the Enoyl-Acyl Carrier Protein Reductase (FabI) enzyme, the essential oil components from this plant were explored as alternatives through a combination of experimental approaches and in silico molecular docking studies. The results revealed that α-cadinol, spathulenol, caryophyllene, and α-muurolene exhibited strong FabI inhibition, with better bioavailability and lower toxicity than triclosan, highlighting their potential in combating antibiotic-resistant bacteria.

Dissecting the Cell-Killing Mechanisms of Hydroxyurea Using Spot Assays.

Hydroxyurea is an inhibitor of ribonucleotide reductase and is commonly used in laboratories to induce replication stress or arrest cells in the S phase for cell cycle or checkpoint studies. However, hydroxyurea also causes side effects such as oxidative stress, particularly under chronic exposure conditions. This complicates the interpretation of the cell-killing mechanisms, particularly in a previously uncharacterized mutant, and thus hampers the analyses. Here, we describe a few easy and simple spot assays in fission yeast that allow dissecting the cell-killing mechanisms of hydroxyurea.

DDDR-32. EXPLORING ANDROGENIC MODULATION IN GLIOBLASTOMA: POTENCY AND SELECTIVITY OF NOVEL NORETHINDRONE DERIVATIVES

Abstract BACKGROUND Glioblastoma (GBM) represents the most frequently diagnosed malignant CNS tumor in adults and remains incurable. Despite the identification of several oncogenic drivers contributing to tumor formation, targeted therapy with brain-penetrant inhibitors has afforded little progress in survival outcomes. Interestingly, gender has been shown to increase the incidence of GBM, with men having roughly a 50-60% increase in incidence compared to women in the US. This statistic led to research on the involvement of and subsequent inhibition of androgen synthesis and signaling in cell culture models and tumor samples. METHODS To further investigate the potential involvement of steroidal hormones in GBM proliferation, our lab synthesized a series of norethindrone (NE) derivatives with varied molecular weights, steric bulk, and lipophilicity to modulate the androgenic activity of NE. The small library was tested in several GBM cell lines, including U87, A172, and T98G cells, using cell viability assays. RESULTS One derivative, a lipophilically modified version of NE synthesized via a one-pot click reaction, was shown to have improved potency compared with parental NE (&amp;gt;5-fold). The lipophilic NE derivative had IC50 value of 22 uM, 15 uM, and 35 uM in the U87, A172, and T98G cells, respectively. This molecule was tested in immortalized normal human astrocyte (NHA) cells and found to have an IC50 value of 34 uM suggesting some selectivity. DISCUSSION Given this derivative’s activity in GBM models and modest selectivity, we plan to screen it in additional GBM cell lines (LN-18 and U251) and eventually in glioma stem cell models. Future research will focus on identifying key targets involved in the mechanism of action, including the impact of lipophilic addition to the steroid nucleus and its effect on androgenic activity and downstream signaling. We will investigate these effects using RPPA and co-treatments with androgen receptor antagonists and 5-alpha reductase inhibitors.

Repurposing of Statins Against Superficial Fungal Infections

In a few decades fungal infections will become a major worldwide health concern. Research reveal that the fungal strain becomes resistant to current medications in cases of HIV infections, corona infections and environmental factors particularly in people with impaired immune systems. The amount of organ transplants and medication used for therapy all have contributed to an increase in the immunocompromised population. The fungal infections are becoming a more significant cause of mortality and morbidity. An estimated 1.5 million fatal consequences are caused by fungal pathogens annually. In a few decades, fungal infections will become a major worldwide health concern, so that unprecedented rates of fungal resistance to currently available antifungal medicines has been observed.The drug repurposing approaches lowers costs and time by investigating previously approved medicines with known safety and pharmacokinetics toxicity profile for novel therapeutic effects.The HMG – CoA reductase inhibitors drugs statins shows antifungal properties against tinea spp. group of common fungus that causes superficial infections. We have evaluated statins for their antifungal potential by insilico studies &amp; Invitro studies &amp; validate results with standard drugs itraconazole &amp; ketoconazole.The docking studies shows highest binding energy shown by atorvastatin among all statin were used for docking studies pravastatin , atorvastatin, simavastatin ,fluvastatin &amp; rosuvastatin . against fungal protein (PDB ID:5V5Z) &amp; human protein (PDB ID: 3LD6) was found to be -13.52 &amp;13.4 kcal/mole .The invitro studies shows MIC values for atorvastatin against Trichophyton rubrum , Microsporum canis &amp; Epidermatophyton flocossum fungal strains found between 125 μg/ml to 150 125 μg/ml where as for standard drugs was found between 12.5 μg/ml to 25 μg/ml. Following insilico &amp; invitro research atorvastatin determined and may be used for the treatment of fungal infections.