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Steroid 5α-reductase (5αR) converts testosterone into dihydrotestosterone (DHT), a potent androgen driving prostate cell proliferation via the androgen receptor (AR). Both 5αR and AR play crucial roles in androgen-mediated disorders, making them key therapeutic targets in drug development. Current treatments target these enzymes individually and often cause significant side effects, highlighting the need for safer alternatives. Through in silico screening, 13 pyrrolizidine alkaloids of Heliotropium indicum (HI) were assessed for their inhibitory potential against 5αR and AR. Using machine learning, six alkaloids showed promising pIC50 values. The accuracy of the models was assessed using key statistical parameters, including the score, correlation coefficient for training sets (R 2 ), correlation coefficient for test sets (Q 2 ), standard deviation (SD), and root mean square error (RMSE). For 5αR, the results were 0.763 (R 2 ), 0.781 (Q 2 ), 0.748 (score), 0.362 (SD), and 0.832 (RMSE), while for AR, the values were 0.817 (R 2 ), 0.783 (Q 2 ), 0.713 (score), 0.427 (SD), and 0.782 (RMSE), indicating reliability. Europine-N-oxide (-10.27 kcal/mol) and Heliotridine-N-oxide (-9.72 kcal/mol) displayed stronger 5αR binding than Finasteride, while Heliotrine (-10.09 kcal/mol) and Europine-N-oxide (-8.76 kcal/mol) outperformed Enzalutamide in AR binding. Key hydrogen bonds and MD simulations confirmed stable interactions. Pharmacokinetic screening revealed favorable drug-like profiles, including good solubility and absorption with minimal CYP enzyme inhibition. These findings suggest that HI alkaloids are promising multi-target inhibitors for BPH treatment, warranting further in vivo validation and optimization., Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00280-7., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Objectives: Chagas Disease, caused by the parasite Trypanosoma cruzi , remains a significant public health concern, particularly in Latin America. The current standard treatment for Chagas Disease, benznidazole, is associated with various side effects, necessitating the search for alternative therapeutic options. In this study, we aimed to identify potential therapeutics for Chagas Disease through a comprehensive computational analysis., Methods: A library of compounds derived from Cananga odorata was screened using a combination of pharmacophore modeling, structure-based screening, and quantitative structure-activity relationship (QSAR) analysis. The pharmacophore model facilitated the efficient screening of the compound library, while the structure-based screening identified hit compounds with promising inhibitory potential against the target enzyme, sterol-14-alpha demethylase., Results: The QSAR model predicted the bioactivity of the hit compounds, revealing one compound to exhibit superior activity compared to benznidazole. Evaluation of the physicochemical, pharmacokinetic, toxicity, and medicinal chemistry properties of the hit compounds indicated their drug-like characteristics, oral bioavailability, ease of synthesis, and reduced toxicity profiles., Conclusion: Overall, our findings present a promising avenue for the discovery of novel therapeutics for Chagas Disease. The identified hit compounds possess favorable drug-like properties and demonstrate potent inhibitory effects against the target enzyme. Further in vitro and in vivo studies are warranted to validate their efficacy and safety profiles., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Benign Prostate Cancer (BPC), a prevalent condition predominantly affecting elderly males, manifests with voiding difficulties and urinary retention. A library of compounds from Trigonella foenum-graecum , commonly known as fenugreek was used in this study. We aimed to explore its potential anti-cancer effects by computationally assessing its inhibitory activity on the androgen receptor (AR). For in-silico drug assessment, we employed Maestro 12.8, part of the Schrödinger Suite, to identify the most promising candidates acting as androgen receptor antagonists in the treatment of BPC. Subsequently, 59 fenugreek compounds were retrieved from the PubChem database and subjected to molecular docking against the active site of the target protein, 1E3G. 100-nanosecond molecular dynamics (MD) simulations were performed to assess the stability and compactness of the AR-ligand complexes. Notably, the AR-kaempferol complex exhibited the least fluctuation within the AR active site throughout the simulation trajectory, followed by chlorogenic acid and the reference ligand, hydroxyflutamide. The MM/GBSA values revealed the compounds' maximum free binding energy (-103.3 ± 6, -87.4 ± 23, -68.5 ΔG bind ) for chlorogenic acid, kaempferol, and hydroxyflutamide, respectively. These findings suggest their potential as promising leads for drug development. Further lead optimization and comprehensive studies on the top-ranked ligands identified in this investigation are warranted to advance their potential as therapeutic agents for BPC treatment.Communicated by Ramaswamy H. Sarma.

Objective: The onset of insulin resistant diabetes has been associated with a high-sucrose diet in vertebrates and invertebrates. However, various parts of Spondias mombin reportedly possess antidiabetic potential. However, the antidiabetic efficacy of S. mombin stem bark in high-sucrose diet-induced Drosophila melanogaster model has not been explored. In this study, the antidiabetic and antioxidant effects of the solvent fractions of S. mombin stem bark were evaluated using in vitro, in vivo , and in silico methods., Methods: Successive fractionation of S. mombin stem bark ethanol extract was performed; the resulting fractions were subjected to in vitro antioxidant and antidiabetic assays using standard protocols. The active compounds identified from the high-performance liquid chromatography (HPLC) study of the n-butanol fraction were docked against the active site of Drosophila α-amylase using AutoDoc Vina. The n-butanol and ethyl acetate fractions of the plant were incorporated into the diet of diabetic and nondiabetic flies to study the in vivo antidiabetic and antioxidant properties., Results: The results obtained revealed that n-butanol and ethyl acetate fractions had the highest in vitro anti-oxidant capacity by inhibiting 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing antioxidant power, and hydroxyl radical followed by significant inhibition of α-amylase. HPLC analysis revealed the identification of eight compounds with quercetin having the highest peak followed by rutin, rhamnetin, chlorogenic acid, zeinoxanthin, lutin, isoquercetin, and rutinose showing the lowest peak. The fractions restored the glucose and antioxidant imbalance in diabetic flies, which is comparable with the standard drug (metformin). The fractions were also able to upregulate the mRNA expression of insulin-like peptide 2, insulin receptor, and ecdysone-inducible gene 2 in diabetic flies. The in silico studies revealed the inhibitory potential of active compounds against α-amylase with isoquercetin, rhamnetin, rutin, quercetin, and chlorogenic acid having higher binding affinity than the standard drug (acarbose)., Conclusion: Overall, the butanol and ethyl acetate fractions of S. mombin stem bark ameliorate type 2 diabetes in Drosophila . However, further studies are needed in other animal models to confirm the antidiabetes effect of the plant., (© 2023 [The Author/The Authors].)

Doxorubicin (DOX) has been linked with impairment in cardiovascular function and redox balance. In the present study, the effect of Phyllanthus amarus (PA) and Momordica charantia (MC) leaves on some biomolecules [Angiotensin-I converting enzyme (ACE), arginase, acetylcholinesterase (AChE), adenosine deaminase (ADA), lactate dehydrogenase (LDH)] and antioxidant [catalase (CAT), superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA)] linked with cardiac function in DOX-stressed rats was evaluated. Animals were grouped and pretreated with PA and MC leaf extracts at different doses (200 and 400 mg/kg/bwt orally), while DOX (15 mg/kg/bwt) was administered intraperitoneally on the last day of the experiment. Result revealed an increase of ACE, arginase, AChE, ADA, LDH activities and MDA level as well as a significant reduction in CAT and SOD activities, and GSH level in the rats treated with DOX compared to the control. However, these were significantly mitigated in the rats pretreated with PA and MC dose dependently. Chemical characterization of the leaf extracts via high performance liquid chromatography revealed the presence of some phenolic compounds which included kaempferol, catechin, epicatechin, ellagic acid, gallic acid quercetin, isoquercitrin and rutin. These findings revealed a significant improvement in redox imbalance and other biomolecules associated with cardiac function, which was altered by DOX. This improvement could be linked to the presence of cardioprotective agents present in PA and MC, thereby making these plants therapeutic agents for the treatment of cardiovascular complications associated with drugs such as DOX.

Diabetes mellitus continues to be a menace, being one of the five major causes of death in the world. In this study, the common fruit fly, Drosophila melanogaster, a well-studied genetic model organism for understanding molecular mechanisms of human diseases, and Artocarpus camansi (breadnut), an underutilized fruit, was used. This study was aimed at investigating the antihyperglycemic potentials of Artocarpus camansi fruit in sucrose-induced diabetic Drosophila melanogaster. Phytochemical screening was carried out after the fruit has been pulverized and freeze-dried. Total phenol content and total flavonoid content were carried out in vitro on the aqueous extract of Artocarpus camansi, and the result obtained showed that its phenol content is low, and its flavonoid content increases at increasing concentrations. Alpha-amylase inhibitory activity was carried out in vivo on sucrose-induced diabetic Drosophila melanogaster tissue. Gene expression profiling of Insulin-like peptide-2 (ILP-2), Insulin-like receptor (InR) and Ecdysone inducible gene L2 (Imp-L2) was carried out on trizol homogenate of Drosophila melanogaster tissue. In this study, Drosophila melanogaster was divided into nine groups. Group1 served as the basal control as they were fed with normal basal diet, group II served as the negative control which were fed with basal diet and 0.5 mL sucrose/100 mL distilled water, group III served as the positive control which were fed with basal diet 0.5 mL sucrose/100 mL distilled water and metformin, groups IV and V which were fed with basal diet and 0.1 and 1% Artocarpus camansi respectively, groups VI and VII were fed with basal diet, sucrose and 0.1 and 1% Artocarpus camansi respectively, groups VIII and IX served the purpose of the synergistic effect which were fed with basal diet, sucrose, metformin and 0.1 and 1% Artocarpus camansi respectively. All the groups were left for seven days. The experiment was conducted for 3 months and the fruit fly meals were changed every 5 days. Gene expression profiling results showed that the dietary inclusion of fruit downregulated the expression of ILP-2 and InR and upregulated the expression of Imp-L2 when the diabetic group were compared with the normal control. The results suggest that Artocarpus camansi fruit could possess antihyperglycemic properties and its use as a nutraceutical in the alleviation of diabetes should be encouraged., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Impaired liver function is associated with decreased hepatic delta-aminolevulinic acid dehydratase (δ-ALAD) activity in diabetes mellitus. Hence, this study described the effect of dietary jute leaf (Corchorus olitorius) on hepatic δ-ALAD activity in high-fat fed combined with low-dose streptozotocin administered diabetic rats. Animals were fed diets containing 35% fat for 14 days prior to a single administration of low-dose (35 mg/kg body weight) streptozotocin to induce diabetes. Thereafter, the animals were randomly placed in groups and fed 100 mg/g jute leaf-supplemented diets for 30 days. The result showed that jute leaf supplementation significantly (p < 0.05) reversed the decreased hepatic δ-ALAD activity, increased hepatic catalase and SOD activity accompanying the decrease in serum AST and AST activities. This finding suggests that restoration of hepatic δ-ALAD activity, modulation of hepatic function biomarkers, and increase in antioxidant status could be possible underlying events mediating the hepatoprotective effect of jute leaf in diabetic conditions. PRACTICAL APPLICATIONS: Decrease in hepatic δ-ALAD activity has been associated with diabetes-induced hepatotoxicity arising from prolonged and uncontrolled hyperglycemia. Therefore, increased δ-ALAD activity represents improved hepatic function in diabetic situations. Antidiabetic properties of jute leaf have been demonstrated but information on its effect on hepatic δ-ALAD is lacking. Thus, this study revealed that dietary supplementation of jute leaf restored hepatic δ-ALAD activities and improved liver antioxidant status in diabetic rats which is an indication of its hepatoprotective properties., (© 2019 Wiley Periodicals, Inc.)

Context: Plants have historically been used to treat neurodegerative diseases which include Alzheimer's disease., Objective: This study investigated the antioxidant properties and inhibitory effect of aqueous extracts of Securidaca longipendunculata root and Olax subscropioidea leaf on the cholinergic system in rat brain in vitro., Materials and Methods: Aqueous extracts (1:20 w/v) of S. longipendunculata root and O. subscropioidea leaf was prepared and the ability of the extract to inhibit the activities of acetylcholinesterase and butyrylcholinesterase was evaluated as well as antioxidants as typified by 2,2-azino-bis-(3-ethylbenthiazoline-6-sulphonic acid (ABTS • ) radical scavenging ability and Fe chelation spectophotometrically., Results: ABTS • radical scavenging ability showed that S. longipendunculata (0.075 Mmol TEAC/100 g) had a higher scavenging ability than O. subscropioidea (0.07 Mmol TEAC/100 g). Also, the Fe 2+  chelating ability of both extracts revealed that S. longipendunculata (IC 50  =   105.57 g/mL) had a significantly (p < 0.05) higher Fe 2+  chelating ability than O. subscropioidea (IC 50  =   255.84 g/mL). Extracts of S. longipendunculata and O. subscropioidea inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities. However, S. longipendunculata (IC 50  =   108.02 g/mL) has the higher AChE inhibitory activity than O. subscropioidea (IC 50  =   110.35 g/mL). Also, both extracts inhibit BChE activity in vitro but S. longipendunculata (IC 50  =   82.55 g/mL) had a higher BChE inhibitory activity than O. subscropioidea (IC 50  =   108.44 g/mL)., Discussion and Conclusions: The mechanism by which S. longipendunculata root and O. subscropioidea leaf perform their anti-Alzheimer's disease activity may be by their inhibition on the key enzymes linked to this disease.

Background: This study investigated the effects of Padauk leaf on brain malondialdehyde (MDA) content, acetylcholinesterase (AChE) activities, ectonucleotidases and adenosine deaminase (ADA) activities in the platelet of high fat diet and streptozotocin (STZ)-induced diabetic rats., Methods: The animals were divided into six groups (n=7): normal control rats; diabetic rats+high fat diet (HFD); diabetic rats+HFD+Metformin; diabetic rats+HFD+acarbose; diabetic rats+HFD+10% Padauk leaf; normal rats+basal diet+10% Padauk leaf. After 30days of experiment comprising of acclimatization, dietary manipulation, pre-treatment with STZ and supplementation with Padauk leaf, the animals were sacrificed and the rats' brain and blood were collected for subsequent analysis., Results: The results demonstrated that the elevated MDA content and AChE activity in the diabetic rats were significantly reduced when compared with the control rats. Furthermore, the increased NTPDases, 5'-nucleotidase and ADA activities in the diabetic rats were significantly reduced when compared with the control rats., Conclusion: This study demonstrated that Padauk leaf exhibited modulatory effects on purinergic and cholinergic enzymes involved in the prevention of platelet abnormality and consequent vascular complications in diabetic state., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)