The Future of Carica papaya Leaf Extract as an Herbal Medicine Product.

Carica papaya (papaya) leaf extract has been used for a long time in a traditional medicine to treat fever in some infectious diseases such as dengue, malaria, and chikungunya. The development of science and technology has subsequently made it possible to provide evidence that this plant is not only beneficial as an informal medication, but also that it has scientifically proven pharmacological and toxicological activities, which have led to its formal usage in professional health care systems. The development of formulations for use in nutraceuticals and cosmeceuticals has caused this product to be more valuable nowadays. The use of good manufacturing practice (GMP) standards, along with the ease of registering this product facilitated by policies of the national government, will absolutely increase the value of papaya leaf extract as a vital nutraceutical and cosmeceutical products in the near future. In this article, we review the potential of papaya leaf extract to be a high-value commodity in terms of its health effects as well as its industrial benefits.

Arylamide as Potential Selective Inhibitor for Matrix Metalloproteinase 9 (MMP9): Design, Synthesis, Biological Evaluation, and Molecular Modeling.

Previous studies have reported that compounds bearing an arylamide linked to a heterocyclic planar ring have successfully inhibited the hemopexin-like domain (PEX9) of matrix metalloproteinase 9 (MMP9). PEX9 has been suggested to be more selectively targeted than MMP9's catalytic domain in a degrading extracellular matrix under some pathologic conditions, especially in cancer. In this study, we aim to synthesize and evaluate 10 arylamide compounds as MMP9 inhibitors through an enzymatic assay as well as a cellular assay. The mechanism of inhibition for the most active compounds was investigated via molecular dynamics simulation (MD). Molecular docking was performed using AutoDock4.0 with PEX9 as the protein model to predict the binding of the designed compounds. The synthesis was carried out by reacting aniline derivatives with 3-bromopropanoyl chloride using pyridine as the catalyst at room temperature. The MMP9 assay was conducted using the FRET-based MMP9 kits protocol and gelatin zymography assay. The cytotoxicity assay was done using the MTT method, and the MD simulation was performed using AMBER16. Assay on MMP9 demonstrated activities of three compounds (2, 7, and 9) with more than 50% inhibition. Further inhibition on MMP9 expressed by 4T1 showed that two compounds (7 and 9) inhibited its gelatinolytic activity more than 50%. The cytotoxicity assay against 4T1 cells results in the inhibition of the cell growth with an EC50 of 125 µM and 132 µM for 7 and 9, respectively. The MD simulation explained a stable interaction of 7 and 9 in PEX9 at 100 ns with a free energy of binding of -8.03 kcal/mol and -6.41 kcal/mol, respectively. Arylamides have potential effects as selective MMP9 inhibitors in inhibiting breast cancer cell progression.

Molecular insights into the inhibitory potential of anthocyanidins on glucokinase regulatory protein.

Computational methods were used to investigate six anthocyanidins exhibiting antidiabetic activity by inhibiting glucokinase regulatory protein (GKRP) activity. Density functional theory was used to optimise the geometry of anthocyanidins and calculate their quantum chemical properties. A blind docking method was employed to conduct a molecular docking study, which revealed that delphinidin (Del), cyanidin (Cya), and pelargonidin (Pel) as potential GKRP inhibitors with the lowest binding free energy of -8.7, -8.6, and -8.6 kcal/mol, corresponding to high binding affinity. The molecular dynamics study further verified the blind docking results by showing high GKRP-F1P complex stability and high binding affinity calculated through the MM/GBSA method, upon the binding of pelargonidin. The lower RMSF values of pivotal GK-interacting residues for GKRP-F1P-Pel compared to GKRP-F1P, as a positive control, indicating pelargonidin ability to maintain the inactive conformation of GKRP through the inhibition of GK binding. The key residues that control the binding of the F1P to GKRP and anthocyanidin to GKRP-F1P were also identified in this study. Altogether, pelargonidin is anthocyanidins-derived natural products that have the most potential to act as inhibitors of GKRP and as antidiabetic nutraceuticals.

Single Nucleotide Polymorphism in the 3' Untranslated Region of PRKAA2 on Cardiometabolic Parameters in Type 2 Diabetes Mellitus Patients Who Received Metformin.

Purpose: This study aimed to explore the association of rs857148 A>C as 3'UTR variants with blood pressure, HbA1c profile, and lipid profiles as cardiometabolic parameters among patients with T2DM receiving metformin. Patients and Methods: This cross-sectional analytic research was conducted with 114 consecutively selected patients with T2DM. Polymerase chain reaction-restriction fragment length polymorphism was conducted to determine rs857148. A total of 108 patients fulfilled inclusion and exclusion criteria. Results: Genotype distribution agreed with the Hardy Weinberg Equation for Equilibrium (p>0.05) but wildtype allele was found as the minor allele. Subjects with CC genotype and C allele had enhanced HbA1c levels (OR=7.12; 95% CI=1.05-48.26; p=0.04; OR=1.66; 95% CI=1.06-2.60; p=0.03, respectively). It was confirmed by dominant model whereas subjects with AA tended to have reduced HbA1c compared to AC+CC genotype (OR=0.15; 95% CI=0.02-0.97; p=0.047). AC genotype had significant correlation to total cholesterol (OR=1.05; 95% CI=1.01-1.10; p=0.03) compared to AA genotype. Conclusion: We conclude that polymorphism of rs87148, specifically CC genotype and C allele, has a significant association with HbA1c and total cholesterol after considering oral hypoglycemia agent dose, age, gender, and combination therapy, compared to AA genotype. Future studies that involve a larger sample population and more rigorous selection criteria are required.

An Update on the Anticancer Activity of Xanthone Derivatives: A Review.

The annual number of cancer deaths continues increasing every day; thus, it is urgent to search for and find active, selective, and efficient anticancer drugs as soon as possible. Among the available anticancer drugs, almost all of them contain heterocyclic moiety in their chemical structure. Xanthone is a heterocyclic compound with a dibenzo-γ-pyrone framework and well-known to have "privileged structures" for anticancer activities against several cancer cell lines. The wide anticancer activity of xanthones is produced by caspase activation, RNA binding, DNA cross-linking, as well as P-gp, kinase, aromatase, and topoisomerase inhibition. This anticancer activity depends on the type, number, and position of the attached functional groups in the xanthone skeleton. This review discusses the recent advances in the anticancer activity of xanthone derivatives, both from natural products isolation and synthesis methods, as the anticancer agent through in vitro, in vivo, and clinical assays.