Potent Inhibitory Activity Research Articles

In vitro Study on Antioxidant and Antiglycation Activities, and Molecular Docking of Moroccan Medicinal Plants for Diabetes

Background: Moroccan medicinal plants with historical usage to treat diabetes have been analyzed to explore their potential anti-glycation and antioxidant activities through in vitro experiments. These investigations have been complemented by molecular docking. Methods: The present study has examined the in vitro antioxidant and antiglycation properties of six aqueous extracts from six medicinal plants (Ammodaucus leucotrichus, Thymelaea hirsuta, Arbutus unedo, Urtica dioica, Ptychotis verticillata, and Caralluma europaea), and two seeds oils from Argania spinosa and Opuntia dillenii. The antioxidant activity was determined by using the DPPH radical scavenging activity test and β-carotene/linoleic acid bleaching assay. In addition, the antiglycation activity was detected by using the hemoglobin protein model. Results: All studied plant extracts have shown potent antioxidant and antiglycation activity. Furthermore, to confirm the in silico antiglycation activity of the selected medicinal plants, molecular docking techniques were used assuming that binding energy decreases as compound affinity increases; the best molecules responsible for the remarkable antiglycation activity have also been highlighted. Conclusion: Antidiabetic herbal medicines are responsible for the inhibition of oxidative activity and glycation. The molecular docking analysis showed catechin, kaempferol-O-acetylhexoside, luteolin, luteolin-7-O-glucoside, quercetin, and zeaxanthin, to have a high affinity to AGEs receptor and a potent inhibitory activity.

Investigating the optimistic in-vitro and in-vivo therapeutic effects of wild grape: Vitis jacqumantii R. Parker

Vitis jacquemontii R. Parker is a wild grape traditionally used by indigenous people as a substitute for cultivated grapes. However, its therapeutic effects have not been extensively studied. In this study, we investigated the antioxidant, anticholinesterase, analgesic, and antidepressant properties of V. jacquemontii. The antioxidant potential of this wild fruit plant was evaluated using two widely recognized assays: 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2-asino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). In-vitro anticholinesterase effects were determined by assessing butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) inhibition. The analgesic activity was assessed through writhing and tail immersion test models, while the antidepressant effect was evaluated using forced swimming and tail suspension test models. Results revealed the exceptional potential of V. jacquemontii as a valuable natural resource. The fruit extract (VJF-Crd) demonstrated remarkable free radical scavenging abilities, with an impressive IC50 value of 34.96 μg/mL for DPPH and 56.48 μg/mL for ABTS. The leaf extract (VJL-Crd) also exhibited considerable antioxidant properties, with IC50 values of 73.68 μg/mL for DPPH and 86.72 μg/mL for ABTS. Furthermore, VJF-Crd and VJL-Crd extracts displayed potent inhibitory activity against cholinesterase enzymes, with VJF-Crd demonstrating strong inhibition and VJL-Crd showing moderate inhibition. In terms of analgesia, these extracts exhibited dose-dependent responses in various pain models, with significant protection against acetic acid-induced writhing and tail immersion, showcasing their potential as natural pain relievers. Moreover, both VJF-Crd and VJL-Crd extracts displayed a notable decrease in immobility in the forced swimming and tail suspension test models, indicating their potential as natural antidepressants. These findings underscore the untapped potential of V. jacquemontii as a source of valuable chemical constituents. The isolation and identification of phyto-constituents from this plant hold promise for new bioactive compounds, particularly in pain management. This study sheds light on the multifaceted medicinal attributes of V. jacquemontii and opens new avenues for developing natural remedies for different ailments, especially pain management.

Harnessing potential COX-2 engagement for boosting anticancer activity of substituted 2-mercapto-4(3H)-quinazolinones with promising EGFR/VEGFR-2 inhibitory activities

We designed and synthesized new quinazolinone-tethered phenyl thiourea/thiadiazole derivatives 4–26. Based on their structural characteristics, these compounds were proposed to have a multi-target mode of action for their anticancer activities. Using the MTT assay method, antiproliferative effects were assessed against three human cancer cell lines (HEPG-2, MCF-7, and HCT-116). In vitro assessment for enzymatic inhibitory activity of the most active compounds 4, 9 and 20 was done for EGFR, VEGFR-2 and COX-2 as potential targets. The screened compounds showed low micromolar IC50 inhibitory effects against the three targets. Compound 9 demonstrated similar EGFR/VEGFR-2 inhibitory effect to the control drugs and potential inhibitory activity for COX-2 enzyme. In MCF-7 cells, the most active analog 9 caused 41.02% total apoptosis, and arrested the cell cycle at the G2/M phase. Taken as a whole, the findings of this study provide significant new understandings into the relationship between COX inhibition and cancer therapy. Furthermore, the outcomes showcased the encouraging efficacy of these compounds with a multi-target mechanism, making them excellent choices for additional research and development into possible anticancer drug.

Computer-assisted discovery of tyrosinase inhibitors from turmeric and clove: An in silico study on natural skin whitening agents and their potential toxicity

A computational approach was employed to identify potential tyrosinase-related protein 1 (TYRP1) inhibitors from turmeric and clove extracts, with the goal of discovering safer alternatives to the toxic hydroquinone for skin whitening applications. Gas Chromatography–Mass Spectrometry (GC–MS) analysis revealed the phytochemical composition of the plant extracts, which were then evaluated for their binding affinity to TYRP1 through molecular docking simulations. The stability of the resulting hit compounds was assessed via molecular dynamics simulations, and their dermal toxicity profiles were determined using Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis. Density Functional Theory (DFT) calculations were also performed to compare the chemical reactivity of the hit compounds to hydroquinone. The results identified 3,4-dimethoxybenzamidoxime from clove and Ar-turmerone from turmeric as potential inhibitors, exhibiting binding free energies of −6.8 kcal/mol and −6.6 kcal/mol, respectively. These values surpass those of hydroquinone (−5.1 kcal/mol) and the native ligand (−5.5 kcal/mol), suggesting potential inhibitory activity. Notably, 3,4-dimethoxybenzamidoxime exhibited favorable skin permeation properties and passed all toxicity tests, suggesting its potential as a safe and effective replacement for hydroquinone in skin whitening products.

Exploring therapeutic potentials of Tridax procumbens for Glioma: An in-silico approach employed network pharmacology, molecular docking, and molecular dynamics simulation

Glioma is a frequent type of malignant brain tumor, originating from glial cells. Despite advances in understanding the molecular biology and genetics of gliomas, the treatment of high-grade gliomas remains challenging. This study focuses on the identification of potentially active compounds from the medicinal plant Tridax procumbens for the treatment of glioma. Using computational approaches such as virtual screening, ADMET profiling, network pharmacology, molecular docking, and molecular dynamics, ten potential phytocompounds were identified from a total of 106 compounds. Further analysis revealed a network of 170 common genes between the phytochemicals and disease genes, comprising 161 nodes and 2083 edges. Molecular docking experiments demonstrated that luteolin, quercetin, and 6-Hydroxyluteolin 6,3′-dimethyl ether 5-rhamnoside exhibited potential inhibitory activities against two targeted proteins, HSP90 and SRC. Luteolin with HSP90 protein and Quercetin with SRC protein complexes were found to be the highest in docking performance with the least binding affinities −10 kcal mol−1 and −9.3 kcal mol−1 respectively. Molecular dynamics simulations explored Quercetin-SRC and Luteolin-HSP90 interactions over 300 nanoseconds. Quercetin-SRC binding showed dynamic and flexible behavior with an RMSD, RMSF, and radius of gyration of 0.22 nm, 0.35 nm, and 2.12 nm, respectively, whereas Luteolin-HSP90 binding was more stable and less flexible, with an RMSD of 0.14 nm, RMSF of 0.14 nm, a radius of gyration of 1.74 nm, and maintained consistent strong interactions with specific solvent accessibility. The analysis of free binding energy in Quercetin-SRC and Luteolin-HSP90 complexes indicated highly favorable formation driven by altered interactions, with delta total values of −33.74 and −29.26 kcal/mol, respectively. Both phytochemical luteolin and quercetin showed strong inhibitory potential against HSP90 and SRC proteins, indicating their potential as effective therapeutic agent for glioma treatment. This integrated approach emphasizes the significance of these compounds in advancing treatment strategies for glioma. However, pre-clinical and clinical experimentations are required to establish the potential of T. procumbens as a treatment for glioma.

Unveiling potent bioactive compounds and anti-angiogenic pathways in Gekko swinhonis Guenther for gastric cancer therapy

Ethnopharmacological relevanceGekko swinhonis Guenther, commonly referred to as Gecko in the following text, belongs to the genus Gekko within the family Gekko. Its dried whole body is a widely utilized traditional Chinese medicine, demonstrating significant efficacy in the treatment of gastrointestinal malignancies, particularly gastric cancer (GC). Nevertheless, the composition of the gecko is complex, necessitating further research into its active ingredients for the treatment of GC. Aim of the studyIsolation and characterization of the most active components in Gecko based on their anti-GC mechanisms of vascular endothelial cell inhibition and anti-neovascularization. Materials and methodsWe utilized the enzymatic hydrolysate of Geckos to investigate its effectiveness and underlying mechanisms. Initially, we assessed its efficacy in ectopic and in-situ GC tumor-bearing mouse models. Subsequently, we evaluated the effectiveness of peptides, aliphatics, and small molecules derived from Gecko using CCK-8 and 3D tumor spheroid assays. The activities of peptides S1-S4 were further examined through these experiments. Finally, we screened, synthesized, and investigated five potential peptides for their pharmacodynamics in the CCK-8 assay and in the in-situ GC model mice. ResultsThe Gecko can inhibit the formation of blood vessels in the tumor microenvironment, providing a localized treatment for GC. The peptide components significantly inhibit vascular endothelial cells and impede the formation of new blood vessels, with the S2 peptide sections (0.3 KD - 3 KD) demonstrating the most potent inhibitory activity against angiogenesis. One of the active peptides effectively suppresses the growth of in-situ GC in nude mice through angiogenesis inhibition and also modulates immunity, all while exhibiting excellent biosafety. ConclusionsWe have achieved a significant breakthrough in the local treatment of GC using Gecko. Through pharmacodynamic experiments and a systematic process of isolation and identification, we identified the most effective anti-GC ingredients of Gecko, based on their mechanisms of inhibiting vascular endothelial cells and promoting anti-angiogenesis. Furthermore, we synthesized a lead peptide that demonstrates promising therapeutic efficacy and safety.

Synthesis of Indol-3-yl Morpholino Derivatives Containing a Hydrazone Moiety as Potential Antiplant Virus Agents.

A series of indol-3-yl morpholino derivatives containing a hydrazone moiety were designed and synthesized using indole-3-carboxylic acid as the starting material. The antiviral activities of the synthesized compounds were systematically evaluated. Compound D35, optimized using the comparative molecular field analysis (CoMFA) model, exhibited the most potent inhibitory activity against Tobacco mosaic virus (TMV) in vivo with a 50% effective concentration (EC50) value of 69.9 mg/L and exceeded that of Ningnanmycin (142.4 mg/L). Molecular docking and molecular dynamics simulations revealed that compound D35 could form stable interactions with the TMV coat protein (CP), exhibiting a lower binding energy of -9.37 kcal/mol compared to that of Ningnanmycin (-8.55 kcal/mol). Microscale thermophoresis (MST) experiments further confirmed the stronger binding affinity of compound D35 for the TMV CP than Ningnanmycin. Additionally, transmission electron microscopy (TEM) demonstrated that compound D35 effectively disrupts the TMV particles and inhibits their spread. These collective findings strongly suggest that compound D35 has the potential to serve as a lead compound for the development of novel antiviral agents.

Synthesis of new bis(pyrazolo[1,5-a]pyrimidines) linked to different spacers with potential MurB inhibitory activity utilizing 1H-pyrazole-3,5-diamines

Recently, there has been an increased interest in developing new antibacterial agents that target the MurB inhibition, which is necessary for bacterial survival. We developed a two-step tandem protocol to synthesize 15 new bis(pyrazolo[1,5-a]pyrimidines), which are attached to alkane cores by amide linkages. The protocol involved reacting the appropriate bis(2-cyanoacetamides) with dimethylformamide-dimethylacetal in toluene at 80 °C for 3-4 h. The crude bis(2-cyano-3-(dimethylamino)acrylamides) was collected, then reacted with 3,5-diamino-1H-pyrazoles. The reaction gave the desired products in 82-92% yields after 5-6 h of heating at reflux in pyridine. Bis(2,7-diamino-3-(4-methoxybenzyl)pyrazolo[1,5-a]pyrimidine-6-carboxamides) demonstrated comparable efficacy to ciprofloxacin. Their MIC and MBC ranged from 2.8-3.0 and 5.7-6.0 µM, respectively, against S. aureus and E. coli. Moreover, these products displayed promising MurB inhibitory activity with IC50 ranging from 7.8 to 8.0 µM.

Naphthoquinone Derivatives from the Endophytic Fungus Fusarium solani Induce Pancreatic Cancer Cells Apoptosis via Targeting EGFR-Mediated PI3K/Akt Pathway.

Seven new polyketide compounds, four naphthoquinone derivatives, neofusarubins A-D (1, 3, 5, and 18) and three graminin-like compounds, fusofuranones A-C (19-21), together with 14 known naphthoquinone derivatives, were isolated from the solid fermentation of Fusarium solani, an endophytic fungus obtained from medicinal plant as tea, Camellia chrysantha. The structures of new compounds were elucidated based on chemical evidence and spectral data analysis (1D and 2D-NMR, HR-ESI-MS, ECD, SC-XRD). Among the isolated compounds tested, 2-acetonyl-3-methyl-5-hydroxy-7-methoxy-naphthazarin (11) exhibited the most potent inhibitory activity against pancreatic cancer in PANC-1, MiaPaCa-2, and BxPC-3 cells. Network pharmacology analysis revealed that compound 11 inhibited cell proliferation and promotion of apoptosis by targeting epidermal growth factor receptor (EGFR), which were confirmed by cellular thermal shift assay (CETSA), microscale thermophoresis (MST) and EGFR stably knockdown cells model assay, respectively. In addition, molecular mechanism studies in vitro showed that 11 could suppress the growth of pancreatic cancer cells by targeting EGFR and effectively inhibit downstream PI3K/Akt signaling pathway. Collectively, these findings provide a new EGFR targeting natural product for the treatment of pancreatic cancer.

Enzyme Inhibitory Activities and RP-HPLC Analysis of Geranium and Erodium Species.

The genera Geranium and Erodium (Geraniaceae) have been documented to possess diverse ethnopharmacological uses, including diabetes mellitus. Relevant to their ethnopharmacological use, the current study aimed to evaluate the α-glucosidase, α-amylase, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzyme inhibitory activity of ethanol extracts from 46 samples belonging to thirty-one species of Geranium (20) and Erodium (11) collected throughout Türkiye. The majority of the extracts displayed a marked α-glucosidase and α-amylase inhibitory activity. Besides, 23 extracts out of 46 exhibited a concentration-dependent inhibitory effect over 50 % towards AChE. The highest AChE inhibition was found in G. subcaulescens collected from Konya with an IC50 value of 4.73±2.96 μg/mL. E. somanum, E. leucanthum, and E. sipthorpianum exhibited the most potent α-glucosidase inhibitory activity, while E. birandianum and E. pelargoniiflorum were the most active extracts against AChE and BChE, respectively. Three extracts that had inhibitory activity over 50 % against four of the enzymes were selected and proceeded to RP-HPLC analysis. Geraniin and ellagic acid were identified as major compounds in the active extracts. Most species screened in the current study were examined for the first time against α-glucosidase, α-amylase, AChE, and BChE.

Phytosterols as inhibitors of New Delhi metallo-β-lactamase (NDM-1): an in silico study.

The global emergence of New Delhi metallo-β-lactamase-1 (NDM-1) poses a formidable challenge to antibiotic therapy, as it confers resistance to a wide range of β-lactam antibiotics. This study aims to identify potential inhibitors of NDM-1 and thereby restore the effectiveness of the current antibiotics. Employing a comprehensive computational approach integrating molecular docking and molecular dynamics (MD) simulations, a library of phytosterols was screened to identify promising candidates for inhibiting NDM-1 activity. Using the binding energy of meropenem, a frontline carbapenem antibiotic, as a reference, avenasterol, brassicasterol, and stigmasterol emerged as top phytosterol candidates for further investigation. Subsequent MD simulations confirmed the stability of NDM-1 complexes with avenasterol and stigmasterol over the simulation period, indicating their potential efficacy. These findings suggest that avenasterol and stigmasterol may effectively inhibit NDM-1 activity, warranting validation through in vitro and in vivo studies. Furthermore, these phytosterols hold promise as lead compounds for developing novel NDM-1 inhibitors. Their natural origin and potential inhibitory activity against NDM-1 offer compelling avenues for developing alternative antibacterial therapies to combat multidrug-resistant infections. This study underscores the utility of computational methods in drug discovery and highlights the potential of phytosterols as valuable candidates for addressing antibiotic resistance.

Anthrax lethal toxin exerts potent metabolic inhibition of the cardiovascular system.

Bacillus anthracis causes anthrax through a combination of bacterial infection and toxemia. As a major virulence factor of B. anthracis, anthrax lethal toxin (LT) is a zinc-dependent metalloproteinase, exerting its cytotoxicity through proteolytic cleavage of the mitogen-activated protein kinase kinases, thereby shutting down the MAPK pathways. Anthrax lethal toxin induces host lethality mostly by targeting the cardiovascular system. Although the enzymatic activity and the molecular targets of LT have long been known, the detailed mechanisms underlying cellular/tissue/organ toxicity are still poorly understood. In this work, we sought to investigate the mechanism of LT-induced cellular damage in the cardiovascular system. We demonstrate for the first time that anthrax lethal toxin has potent inhibitory effects on the central metabolism of cardiomyocytes and endothelial cells. This is likely due to the observed downregulating of c-Myc expression through the toxin-induced inhibition of the ERK pathway. Since c-Myc is a master transcription factor controlling the expression of many rate-limiting metabolic enzymes in glycolysis and the tricarboxylic acid cycle, LT's downregulation of c-Myc may lead to the observed bioenergetic collapse, particularly, in cardiomyocytes. Since cardiac cell contraction requires continuous production of large amounts of ATP, potent inhibition of the bioenergetics of cardiomyocytes would be incompatible with life. Thus, LT-induced lethality through targeting cardiomyocytes and endothelial cells appears to be a consequence of a bioenergetic collapse, likely due to the toxin's potent inhibitory activity on the MEK-ERK-c-Myc-metabolic/bioenergetic axis within these target cells of cardiovascular system.IMPORTANCEAnthrax lethal toxin (LT) is a major virulence factor of Bacillus anthracis, the causative pathogen of anthrax disease. Anthrax lethal toxin is a metalloproteinase that cleaves and inactivates MEKs, thereby shutting down MAPK pathways, leading to host mortality primarily through targeting of the cardiovascular system. However, the detailed mechanisms underlying the toxin's cellular and tissue toxicity are still poorly understood. Here, we found that anthrax lethal toxin has potent inhibitory activity on glycolysis and oxidative phosphorylation of cardiomyocytes and endothelial cells. These effects appear to be the consequence of downregulation of c-Myc, a master transcription factor that controls many rate-limiting enzymes of glycolysis and the tricarboxylic acid cycle. With the high demand on energy for cardiac contraction, the potent inhibition of cardiomyocyte metabolism by LT would be incompatible with life. This work provides critical insights into why the cardiovascular system is the major in vivo target of LT-induced lethality.

In Silico Investigation Targeting the IL-6/JAK-1/TNF-α Pathway in Rheumatoid arthritis: Matricaria chamomilla L. Compounds

Chamomile, emphasized as an herbal remedy with healing potential for human health, is used in traditional medicine. In this study, the potential of compounds derived from Matricaria chamomilla L. against IL-6, JAK-1 and TNF-[Formula: see text] target proteins associated with rheumatoid arthritis (RA) was compared with known inhibitors. The drug-likeness and ADME/T properties of these compounds were investigated using online tools, and molecular docking and molecular dynamics simulations of the selected structures were examined. IL-6, JAK-1 and TNF-[Formula: see text] formed stable complexes with apigenin, quercetin and galaxolide, respectively, demonstrating that these compounds exhibit potential inhibitory activity against RA.

Therapeutic Potential of Ramalin Derivatives with Enhanced Stability in the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) remains a significant public health challenge with limited effective treatment options. Ramalin, a compound derived from Antarctic lichens, has shown potential in the treatment of AD because of its strong antioxidant and anti-inflammatory properties. However, its instability and toxicity have hindered the development of Ramalin as a viable therapeutic agent. The primary objective of this study was to synthesize and evaluate novel Ramalin derivatives with enhanced stabilities and reduced toxic profiles, with the aim of retaining or improving their therapeutic potential against AD. The antioxidant, anti-inflammatory, anti-BACE-1, and anti-tau activities of four synthesized Ramalin derivatives (i.e., RA-Hyd-Me, RA-Hyd-Me-Tol, RA-Sali, and RA-Benzo) were evaluated. These derivatives demonstrated significantly improved stabilities compared to the parent compound, with RA-Sali giving the most promising results. More specifically, RA-Sali exhibited a potent BACE-1 inhibitory activity and effectively reduced tau phosphorylation, a critical factor in AD pathology. Despite exhibiting reduced antioxidant activities compared to the parent compound, these derivatives represent a potential multi-targeted approach for AD treatment, marking a significant step forward in the development of stable and effective AD therapeutics.

Structure-Based Design of Covalent SARS-CoV-2 Papain-like Protease Inhibitors.

The COVID-19 pandemic is caused by SARS-CoV-2, a highly transmissible and pathogenic RNA betacoronavirus. Like other RNA viruses, SARS-CoV-2 continues to evolve with or without drug selection pressure, and many variants have emerged since the beginning of the pandemic. The papain-like protease, PLpro, is a cysteine protease that cleaves viral polyproteins as well as ubiquitin and ISG15 modifications from host proteins. Leveraging our recently discovered Val70Ub binding site in PLpro, we designed covalent PLpro inhibitors by connecting cysteine reactive warheads to the biarylphenyl PLpro inhibitors via flexible linkers. Several leads displayed potent enzymatic inhibition (IC50 = 0.1-0.3 μM) and antiviral activity (EC50 = 0.09-0.96 μM). Fumaramide inhibitors Jun13567 (15), Jun13728 (16), and Jun13714 (18) showed favorable in vivo pharmacokinetic properties with intraperitoneal injection. The X-ray crystal structure of PLpro with Jun13567 (15) validated our design strategy, revealing covalent conjugation between the catalytic Cys111 and the fumaramide warhead. The results suggest these covalent PLpro inhibitors are promising SARS-CoV-2 antiviral drug candidates.

Potassium Phosphate-Mediated Synthesis of C4-Phosphorylated Quinolines via Cascade Cycloisomerization of Ynones.

A cascade phosphorylation cycloisomerization of readily accessible ynones and diphenylphosphine oxides facilitated by potassium phosphate is described, allowing for the straightforward synthesis of C4-phosphorylated quinoline scaffolds. The formation of a C-P bond and a C-N bond is achieved in a single procedure without the need for pre-assembled quinoline cores prior to phosphorylation. This transformation operates without the requirement for metals or oxidants and exhibits excellent compatibility with various functional groups. Furthermore, antimicrobial activity evaluation demonstrated that the synthesized C4 phosphorylated quinoline derivatives exhibited potent inhibitory activity against Staphylococcus aureus.

Curcumin derivative C210 induces Epstein–Barr virus lytic cycle and inhibits virion production by disrupting Hsp90 function

Lytic induction therapy was devised to selectively combat malignancies associated with Epstein–Barr virus (EBV) by triggering viral reactivation from latency. At present, the major challenges of lytic induction therapy are to maximize reactivating efficiencies and meanwhile minimize infectious virion production. C210, a novel curcumin derivative with potent Hsp90 inhibitory activity, was explored for EBV-reactivating and virion-producing effects in EBV-positive nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC) cell lines. And the molecular mechanisms underlying these effects were determined. Follow C210 treatment, EBV lytic RNAs and proteins were upregulated, but infectious virions were not produced. Knockdown of heat shock protein 90 (Hsp90) induced expression of lytic RNAs and proteins, and diminished C210-driven EBV lytic induction. Pretreatment with an X box binding protein 1 (XBP1) inhibitor reduced C210-induced EBV lytic RNA. Furthermore, we demonstrated that C210 inhibited the binding of Hsp90 with its clients, signal transducer and activator of transcription 3 (STAT3) and xeroderma pigmentosum group B-complementing protein (XPB), which subsequently promoted their proteasomal degradation. Degradation of STAT3 by C210 enhanced the EBV-reactivating and anticancer capacity of suberoylanilide hydroxamic acid (SAHA). Depletion of XPB blocked SAHA-induced expression of late viral genes and production of infectious virions. These results elucidate a novel Hsp90 inhibitor targeting EBV lytic phase and extend the research on lytic induction strategy, which may offer reference value in the treatment of EBV-positive malignancies.

A first-in-human, randomized study of the safety, pharmacokinetics and pharmacodynamics of povetacicept, an enhanced dual BAFF/APRIL antagonist, in healthy adults.

Therapeutic agents targeting the tumor necrosis factor (TNF) superfamily cytokines B-cell activating factor (BAFF, BLyS) and/or A PRoliferation Inducing Ligand (APRIL) have demonstrated clinical effectiveness in multiple autoimmune diseases, such as systemic lupus erythematosus, lupus nephritis, and immunoglobulin A nephropathy (IgAN). However, their clinical utility can often be limited by incomplete and/or prolonged times to clinical response and inconvenient dosing regimens, which may be improved by more potent dual inhibition of both cytokines. Povetacicept (ALPN-303; TACI vTD-Fc) is a crystallizable fragment (Fc) fusion protein of an engineered transmembrane activator and CAML interactor (TACI) domain which mediates more potent inhibitory activity than wild-type TACI-Fc or BAFF- or APRIL-specific antibodies and demonstrates superior pharmacokinetic and pharmacodynamic activity in multiple preclinical disease models. In this first-in-human study in healthy adults, povetacicept was well-tolerated as single ascending doses of up to 960 mg administered intravenously or subcutaneously. Dose-dependent pharmacokinetics were observed. Coverage of BAFF and APRIL was observed for 2-3 weeks and ≥4 weeks after doses of 80 mg and ≥240 mg, respectively. Maximal pharmacodynamic effects were observed at dose levels ≥80 mg for a single dose, associated with on-target reductions in antibody-secreting cells as well as in all circulating immunoglobulin isotypes, including the IgAN disease-related biomarker galactose-deficient-immunoglobulin A1 (Gd-IgA1), and were superior to results reported for wild-type TACI-Fc. These data strongly support further development of povetacicept for the treatment of B-cell-mediated automimmune diseases.

Antioxidant potential and xanthine oxidase inhibition of flavonol glycosides from Phyllanthus emblica L. leaves

Context: Hyperuricemia is the cause of gout in the inflammatory joint condition. The xanthine oxidase enzyme is a therapeutic target for gout treatment because it plays a role in the generation of uric acid. Allopurinol is used to treat gout. It prevents the xanthine oxidase enzyme from producing as much uric acid. When selecting a medication, one must consider the various adverse effects of allopurinol. Phyllanthus emblica plants are among the medicinal plants that can be used as an alternative treatment for gout. Aims: To evaluate isolated compounds from the Phyllanthus emblica as antihyperuricemia candidates. Methods: The isolated compounds were characterized using High-Performance Liquid Chromatography Analysis and Thin Layer Chromatography-Densitometry. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) and cupric ion (CUPRAC) antioxidant capacity procedures were used to develop the antioxidant activity index. The ability to inhibit xanthine oxidase was determined using a spectrophotometer. Results: Compound 1 was indicated as rutin having antioxidant capacity with an antioxidant activity index (AAI) DPPH value of 7.89 ± 0.03 and AAI CUPRAC value of 15.83 ± 0.04 stronger than compound 2 (quercitrin) with an AAI DPPH value of 3.72 ± 0.01 and AAI CUPRAC 3.24 ± 0.03. The IC50 for quercitrin's inhibition of xanthine oxidase is 23.85 ± 2.04, which was higher than rutin’s IC50 value of 32.77 ± 4.49 µg/mL. Conclusions: Flavonol glycosides present in the ethanol extract of Phyllanthus emblica leaves gave potent xanthine oxidase inhibitory activity stronger than the extract. Quercitrin gave stronger xanthine oxidase inhibitory activity, but this compound has weaker antioxidant capacity compared to rutin.

Discovery of Novel SIRT3 Inhibitors for the Cancer Differentiation Therapy by Structural Modification.

Inhibition of SIRT3 triggered differentiation of multiple myeloma (MM) cells. In discovery of potent SIRT3 inhibitors for cancer differentiation therapy, structural modification was performed on the previously developed lead compound S27. A total of 49 compounds divided into two series were designed and synthesized. In the enzyme inhibitory assay, several molecules (A7, A13, B15, and B26) exhibited potent SIRT3 inhibitory activity and selectivity. Significantly, representative compounds, especially A7, promoted differentiation of MM cells from cancer phenotype to normal cells, accompanied by increased expression of antigen CD49e, human immunoglobulin light chain λ-IgLG and κ-IgLG. Additionally, molecule A7 reversed growth factor IL-6 induced MM cell proliferation, improved the antiproliferative activity of Ixazomib and increased the apoptotic rate of MM cells treated with Ixazomib. Collectively, potent SIRT3 inhibitors with MM cell differentiation potency were developed for the cancer therapy used alone or in combination.