Purpose: The purpose of this paper is to understand the effect of hydrolysis by pepsin and pancreatin on the angiotensin-I-converting enzyme (ACE) inhibitory activity of bioactive peptide from pigeon pea tempe and the absorption of pigeon pea tempe peptide by using the everted gut sac method. Design/methodology/approach: The tempe was prepared by inoculating Raprima (Rhizopus oligosporus) on hulled-cooked pigeon pea for 48 h. The extraction was performed using the ultrasonic method at 40 kHz frequency and 100% ultrasonic power for 10 min. The extracted protein was placed in simulated gastrointestinal digestion using consecutive pepsin–pancreatin for 240 min. The hydrolysates were fractionated using a dialysis tube, and its absorption was assessed using the everted Sprague–Dawley rat gut sac. Findings: The tempe protein from the hydrolyzed pigeon pea exhibited higher ACE inhibitory (71.53%) activity than that from the boiled pigeon pea (53.04%) (p = 0.028). The bioactive peptide of the digested pigeon pea tempe consisted of low-molecular-weight peptides (<1 kDa). The fraction also showed the highest ACE inhibition activity among the others (IC50 = 0.61 mg/mL, p = 0.021). Bioactive peptides from pigeon pea tempe were absorbed well in the small intestine, mainly in the jejunum. The activity of the absorbed peptides did not change considerably. Originality/value: The activity of bioactive peptide of pigeon pea tempe was comparatively stable during digestion. It exhibited activity even after absorption in the small intestine. Thus, pigeon pea tempe can serve as an antihypertensive peptide source and alternative food for maintaining/reducing blood pressure.

Targeted therapies that selectively inhibit certain molecules in cancer cells have been considered promising for cancer treatment. In lung cancer, evidence has suggested that mesenchymal-epithelial transition factor (c-Met) oncoprotein drives cancer progression through its signaling transduction pathway. In this paper, we report the downregulation of c-Met by artonin F, a flavonoid isolated from Artocarpus gomezianus. Artonin F was found to be dominantly toxic to lung cancer cells by mediating apoptosis. With regard to its mechanism of action, artonin F downregulated c-Met expression, consequently suppressed the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin signaling, increased Bax expression, decreased Bcl-2 expression, and activated caspase-3. The depletion of c-Met was mediated by ubiquitin-proteasomal degradation following co-treatment with artonin F, with the proteasome inhibitor MG132 reversing its c-Met-targeting effect. The immunoprecipitation analysis revealed that artonin F significantly promoted the formation of the c-Met–ubiquitin complex. Given that ubiquitin-specific protease 8 (USP8) prevents c-Met degradation by deubiquitination, we performed a preliminary in silico molecular docking and observed that artonin F blocked the catalytic site of USP8. In addition, artonin F interacted with the catalytic residues of palmitoylating enzymes. By acting as a competitive inhibitor, artonin F could reduce the degree of palmitoylation of c-Met, which affected its stability and activity. In conclusion, c-Met is critical for cancer cell survival and the failure of chemotherapeutic regimens. This novel information on the c-Met downregulating effect of artonin F will be beneficial for the development of efficient anticancer strategies or targeted therapies.

The ErbB2 signaling pathway plays a crucial role in cancer stem cells (CSCs), governing cancer aggressiveness and proliferation. Targeting ErbB2 holds promise for advancing cancer therapeutics. Resveratrol (RES) and its derivatives have been noted for their ability to target proteins that are involved in CSCs. In this investigation, we synthesize novel derivatives of RES, aim at elucidating structure-activity relationships (SARs) that could enhance the anticancer properties of the RES analogues, and explore their capacities to suppress CSCs. YI-12, an O-benzyl-substituted 1,3-diphenylpropane, demonstrated the most potent anticancer activity against lung cancer cells (A549 and H460), showing high potential inhibiting cancer colony formation. Interestingly, not only does YI-12 suppress CSCs-related proteins, indicated by decreased expression of CSC-enhancing molecules such as CD133-, OCT4-, and CSC-related protein β-catenin, but it also induces apoptosis in CSC-rich spheroids after treatment. Additionally, molecular docking and bioinformatic analysis suggest ErbB2 as a potential target of the compound with a strong binding affinity (-6.709 kcal/mol) compared to the reference compound TAK-285 (-5.563 kcal/mol). YI-12's capability to bind and inhibit ErbB2 leads to the suppression of PI3K and AKT. In conclusion, we highlight the novel resveratrol derivative YI-12 for its ability to inhibit CSCs through the ErbB2 signaling pathway. This compound represents a promising structure that should be further developed for potential use in anticancer therapy.

Acquired Immune Deficiency Syndrome (AIDS), caused by Human Immunodeficiency Virus type-1 (HIV-1), remains a global health crisis. Despite advances in antiretroviral therapy, drug resistance, particularly to protease inhibitors, persists as a significant challenge. Darunavir, a second-generation protease inhibitor, has reduced efficacy against resistant HIV-1 variants, underscoring the development of new inhibitors. This study combines machine learning (ML) and quantitative structure–activity relationship (QSAR) models to design potent HIV-1 protease inhibitors using phenol-based and polyphenol-based P2 ligands. QSAR models, including genetic function approximation (GFA), multiple linear regression (MLR), random forest (RF), gradient boosting regressor (GBR), and Extreme Gradient Boosting (XGBoost), were developed to analyze molecular descriptors. GBR exhibited the highest accuracy (R ² = 0.911 and 0.994) with GFA and PI-selected descriptors, respectively. SHAP analysis highlighted key contributions to pIC₅₀ predictions, including electronic charge at C53, low dipole moments, and shortened bond length (C53-O54). Five potent inhibitors (B01-B05) were predicted, outperforming HIV-1 protease inhibitors. Furthermore, molecular docking suggested that B03 and B05 exhibit strong binding interactions with wild-type and variants, particularly through hydrophobic and hydrogen bonding interactions, with key residues including D25, G27, D29, D30, D25′, and D30′. This integrated QSAR-ML and structure-based analysis offers promising candidates for addressing drug resistance.