Kamal Rullah

Introduction: Saurauia bracteosa is a medicinal plant traditionally used by the Batak Toba and Karo ethnic groups of North Sumatra, Indonesia, to manage type 2 diabetes mellitus (T2DM). However, the precise molecular mechanisms responsible for its antidiabetic effect remain unclear. Thus, the purpose of this study was to investigate the mechanisms of action of S. bracteosa leaf extract and assess its potential in treating type 2 diabetes. Methods: Phytochemical profiling was conducted using LC-MS/MS and GC-MS. Key active compounds, including ursolic acid and quercetin, were quantified by UPLC, and their effects on glucose uptake in L6 skeletal muscle cells were evaluated. To learn more about possible molecular pathways, network pharmacology and molecular docking were used. Results: The extract was found to contain triterpenoids and flavonoids such as ursolic acid and quercetin, which significantly enhanced glucose uptake in L6 cells with effects comparable to insulin (P>0.05). Network pharmacology identified multiple gene targets, with pathway enrichment analysis highlighting glycogen synthase kinase-3 beta (GSK3β) as a central protein. Molecular docking confirmed the strong binding affinity of quercetin to GSK3β, supporting its potential role in modulating insulin signaling. Conclusion: These results suggest that GSK3β regulation and enhanced glucose absorption in skeletal muscle cells may be involved in the antidiabetic action of S. bracteosa. This provides a scientific basis for its traditional use and highlights its potential for further development as a natural therapeutic option for diabetes.

2,4,6-Trihydroxy-3-geranyl acetophenone (tHGA) is a bioactive phloroglucinol compound found in the leaves of Melicope pteleifolia (Champ. ex Benth.) T.G.Hartley. Our previous study has proven that tHGA exhibited significant in vitro barrier protective effects against lipopolysaccharide (LPS) induction, mainly by inhibiting endothelial hyperpermeability via attenuation of F-actin cytoskeletal rearrangement, as F-actin cytoskeleton is anchored to junctional proteins such as zonula occluden (ZO)-1, occludin, and vascular endothelial-cadherin (VE-cadherin), and they play collaborative roles in the preservation of endothelial integrity. Therefore, the effects of tHGA on these junctional proteins were further investigated, followed by the dissection of signalling pathways mediated by tHGA in suppressing LPS-induced junctional protein disruption during endothelial hyperpermeability. HUVECs were pretreated with tHGA prior to LPS induction. TEER, immunofluorescence staining, Western Blotting, and RT-qPCR were performed to examine the effects of tHGA on junctional proteins in terms of their integrity, localization, protein expression, and gene expression, respectively. Proinflammatory signalling molecules including MLC, NF-κB p65, p38 MAPK, ERK MAPK, and JNK MAPK were assessed to unravel the underlying signalling pathways, followed by molecular docking on human ROCK1 to predict the molecular target of tHGA. tHGA profoundly preserved junctional integrity by inhibiting both delocalization and downregulation of ZO-1, occludin, and VE-cadherin, via inactivation of MLC, NF-κB p65, p38 MAPK, and ERK MAPK, which are mainly diverged from GEF-H1/RhoA/ROCK pathway. ROCK1 was predicted as the molecular target of tHGA. tHGA should be developed as a potential therapeutic remedy for prevention and/or treatment of permeability-related disorders.

G protein-coupled receptors (GPCRs) are essential cell surface proteins involved in transducing extracellular signals into intracellular responses, regulating various physiological processes. This study validated the use of the Tango assay, a sensitive method for detecting GPCR activation, in Drosophila Schneider 2 (S2) cells, focusing on the human Dopamine Receptor D4 (DRD4). Plasmids encoding the LexA-tagged human DRD4 receptor and a luciferase reporter were co-transfected into Drosophila S2 cells and stimulated with dopamine. Receptor activation was measured by quantifying the luciferase activity. The system showed high specificity for dopamine, with no activation in response to octopamine, a non-ligand for DRD4. Furthermore, the system effectively detects activation by a novel compound. These results demonstrate that Drosophila S2 cells, coupled with the Tango assay, provide a viable model for studying human GPCR function and ligand specificity. This system enables the rapid screening of potential GPCR ligands in a cost-effective cellular model.

Aim: Chromones are promising for anticancer drug development. Methods & results: 12 chromone-based compounds were synthesized and tested against cancer cell lines. Compound 8 showed the highest cytotoxicity (LC₅₀ 3.2 μM) against colorectal cancer cells, surpassing 5-fluorouracil (LC₅₀ 4.2 μM). It suppressed colony formation, induced cell cycle arrest and triggered apoptotic cell death, confirmed by staining and apoptosis markers. Cell death was accompanied by enhanced reactive oxygen species formation and modulation of the autophagic machinery (autophagy marker light chain 3B (LC3B); adenosine monophosphate-activated protein kinase (AMPK); protein kinase B (PKB); UNC-51-like kinase (ULK)-1; and ULK2). Molecular docking and dynamic simulations revealed that compound 8 directly binds to ULK1. Conclusion: Compound 8 is a promising lead for autophagy-modulating anti-colon cancer drugs.

Mitragyna speciosa Korth (kratom) is a tropical indigenous tree of Southeast Asia. It is commonly consumed by the people due to its various pharmacological properties. The leaves of this plant are traditionally used for the treatment of several diseases including pain, fever, cough, anxiety, depression, obesity, diarrhoea, wound healing, diabetes, hypertension as well as for the prevention of cancer and improvement of sexual performance. Phytochemical investigations have confirmed the presence of more than forty alkaloids along with the presence of other bioactive secondary metabolites. Among the alkaloids isolated, mitragynine and 7-hydroxymitragynine along with their derivatives have been widely evaluated and reported to possess various pharmacological effects. Hence, the aim of this review is to shed light on the traditional uses of kratom and the scientific studies to justify the folkloric claims and active principles responsible for the various medicinal effects associated with the leaves of this plant. This review highlights the potential benefits and toxicities associated with M. speciosa leaves along with the phytochemistry. Moreover, the existing gaps in the field of M. speciosa study have been identified along with the future directions to further avail the benefits of this plant species.

Targeting lipopolysaccharide (LPS)/toll-like receptor 4 signaling in mononuclear phagocytes has been explored for the treatment of inflammation and inflammation-related disorders. However, only a f... Graphical abstract

Pinocembrin (PCB), a flavonoid known for its anti‐inflammatory properties, has been approved for various clinical trial applications. To evaluate deeper into the anti‐inflammatory potential of the specific enantiomer of natural PCB, we conducted the first investigation into the efficacy of the pure enantiomer (2S)‐PCB in modulating inflammatory mediators induced by lipopolysaccharide (LPS) in both murine RAW 264.7 and human U937 macrophage cell lines. This particular compound was isolated from Goniothalamus macrophyllus (Annonaceae), a native plant of Indonesia. This plant has been used traditionally as an herbal medicine to alleviate inflammation. (2S)‐PCB was isolated from the stem bark of G. macrophyllus by defatting with n‐hexane followed by maceration with methanol. Purification was performed using several chromatographic techniques. The absolute configuration was determined using electronic circular dichroism (ECD) spectroscopy. This compound was then tested for its inhibitory activity on prostaglandin E₂ (PGE₂) and subjected to docking simulations. The results indicated that (2S)‐PCB significantly suppressed the production of PGE₂ induced by LPS in both RAW 264.7 and U937 cell lines. The docking simulations revealed that (2S)‐PCB reduced PGE₂ levels by suppressing mitogen‐activated protein kinase (MAPK) activation through inhibiting p38 and extracellular signal‐regulated kinases (ERK). These findings suggest that the compound may prevent worsening of septic shock caused by bacterial infection.

Dengue hemorrhagic fever (DHF) is severe dengue with a hallmark of vascular leakage. β-tryptase has been found to promote vascular leakage in DHF patients, which could be a potential target for DHF treatment. This study aims to develop a theoretical background for designing and selecting human β-tryptase inhibitors through computational studies. Thirty-four α-keto-[1,2,3]-oxadiazoles scaffold-based compounds were used to generate 2D-QSAR models and for molecular docking studies with β-tryptase (PDB Code 4A6L). In addition, molecular dynamics (MD) simulation and molecular mechanics generalised born surface area (MM-GBSA) analysis on the binding of the reported most active compound, compound 11e, towards β-tryptase were performed. Finally, a structure-based pharmacophore model was generated. The selected 2D-QSAR models have statistically proven good models by internal and external validation as well as the y-randomization test. The docking results of compound 11e showed lower CDOCKER energy than the 4A6L co-crystallised ligand and a similar binding pattern as the 4A6L co-crystallised ligand. From molecular dynamics simulation, 4A6L in compound 11e bound state has RMSD below 2 Å throughout the 500 ns simulation, indicating the docked complex is stable. Besides, MM-GBSA analysis suggested the 4A6L-compound 11e docked complex (−66.04 Kcal/mol) is structurally as stable as the 4A6L-native ligand co-crystallized structure (−66.84 Kcal/mol). The best pharmacophore model identified features included hydrogen bond acceptor, ionic interaction, hydrophobic interaction, and aromatic ring, which contribute to the inhibitory potency of a compound. This study supplied insight and knowledge for developing novel chemical compounds with improved inhibition of β-tryptase. Communicated by Ramaswamy H. Sarma