IC50 Values For Inhibition Research Articles

Identification of novel RANKL inhibitors through in silico analysis

Receptor activator of nuclear factor-κB ligand (RANKL) is considered the principal regulator of osteoclast differentiation. Therefore, strategies interfering with the RANKL-RANK signaling pathway may effectively inhibit osteoclast differentiation and mitigate bone resorption. Consequently, RANKL has become a promising target for new drug design strategies. Despite extensive research on specific drugs and antibodies, only a few have shown efficacy in treating osteoporosis. To address this challenge, we aimed to explore new approaches for designing drugs for osteoporosis. In this study, a 3D quantitative structure–activity relationship (QSAR) pharmacophore model was built for RANKL with reference to known inhibitor IC50 values. The optimal pharmacophore model was then employed as a 3D query to screen databases for novel lead compounds. The obtained compounds were subjected to ADMET and TOPKAT analyses to predict drug pharmacokinetics and toxicity. Molecular docking and de novo evolution approaches were applied to verify the docking binding affinities of the compounds. Five candidate compounds were subjected to further in vitro analyses to assess their anti-osteoporotic effects, among which compound 4 demonstrated significant inhibitory activity, achieving an inhibitory rate of 92.6 % on osteoclastogenesis at a concentration of 10 μM. Subsequent molecular dynamics (MD) simulations to assess the stability and behavior of compound 4 and its evolved variant, ZINC00059014397_Evo, within the RANKL binding site revealed that the variant is a potential therapeutic agent for targeting osteoclasts. This study offers valuable insights for developing next generation RANKL inhibitors for osteoporosis treatments.

Discovery of Novel Antiosteoporosis Leads with Bone Resorption Inhibition and Anabolic Promotion through a Chemotype-Assembly Approach.

Developing a dual-efficiency agent with antiresorptive and anabolic applications is a promising strategy for treating osteoporosis. This study reports the discovery of dual antiosteoporosis agents via a chemotype-assembly approach. Chemotype analysis identified 12 antiresorptive and 12 anabolic chemotypes and 7 dual-function chemotype-assembly rules. Based on these assembly rules, a dual-functional compound S24 was discovered. S24 exhibits osteoclastogenesis inhibition with an IC50 value of 10.28 μM and osteoblast differentiation stimulation at 10 μM. S24 derivatives were designed and synthesized based on the activity relationship of the chemotypes. This yielded a more active compound, S24-14, with an osteoclastogenesis inhibition IC50 value of 0.40 μM and osteoblast differentiation stimulation at 1.0 μM; compound S24-14 also suppressed bone loss in vivo. These results prove that S24-14 can be a potential lead for antiosteoporosis drug development.

Exploring the anticancer properties of indole pyrimidine derivatives: Synthesis, structural insights, docking analysis, and in vitro evaluation

The nitrogen containing heterocyclic and chalcones moiety widely recognized as favorable combination of diagnostic and therapeutic facilities in medicinal chemistry. In particular, indole analogs play a very important medicinal role in pharmacology activities, hence, drugs like pindolol, indomethacin, oxypertine, ellipticine, arbidol and ate viridine are well known in market. In this view, the title compounds 4(a-j) were synthesized in good yield. The purified compounds were explained by spectroscopic procedures (FT-IR, 1H NMR, 13CNMR, and LC-MS), and lastly, all synthetic compounds have in-vitro efficacy assessed against the HeLa human cervical cancer and MCF-7 human breast cancer cell lines, and their efficacy was compared to that of the well-known anticancer drug methotrexate (Methotrexate). Compounds 4a, 4b, 4c, and 4e from the series (4a-j) demonstrated the most notable inhibitory activity. The cytotoxicity evaluation of these newly synthesized compounds revealed that 4a, 4b, 4c, and 4e were the most toxic to HeLa cells, with IC50 values for growth inhibition of 20.41 ± 3.14, 23.54 ± 3.27, 24.77 ± 2.14, and 26.10 ± 1.58, respectively. These compounds exhibited an even stronger growth-inhibitory effect on MCF-7 cells, with IC50 values of 18.84 ± 2.69, 19.45 ± 3.14, 22.83 ± 2.68, and 21.80 ± 1.68, respectively. In comparison, methotrexate (Methotrexate) showed IC50 values of 28.29 ± 1.0 for HeLa cells and 45.08 ± 2.61 for MCF-7 cells. Additionally, compounds 4a, 4b, 4c, and 4e played a crucial role in interacting with the catalytic domain of PDE3, demonstrating IC50 values for PDE3A inhibition of 8.05 ± 1.27, 7.55 ± 2.14, 15.09 ± 1.54, and 17.12 ± 3.14, respectively. These results are compared with Cilostazol, a known PDE inhibitor, which exhibited an IC50 of 0.00368 ± 3.14. In-silico studies revealed that compounds (4a, 4b, and 4c) are comparatively very efficient in binding with PDE3A which was further validated with MMGBSA and MDSs.

Design, molecular docking, synthesis and in vitro evaluation of anti-influenza activity of oseltamivir carboxamides and their hybrid molecules with hydroxamic acid

Background The influenza virus is a highly contagious respiratory disease that causes seasonal outbreaks and occasionally, unpredictable pandemics with high morbidity and mortality rates. This problem is exacerbated by the lack of drugs with potential antiviral activity against all types of influenza strains, including resistant strains. Therefore, there is an urgent need to develop novel antiviral agents. Methods The synthesis of new oseltamivir carboxamides with amino acids and the subsequent synthesis of hybrid molecules with hydroxamic acid were considered. Two series are presented as series one; oseltamivir carboxamides with L-serine, L-isoleucine, L-phenylalanine, L-tyrosine and series two included hydroxamates of series one. This approach may provide promising candidates with potential anti-influenza activity. The in vitro cytotoxic activity against Madin-Darby Canine Kidney (MDCK), type (NBL-2) - CCL-34 cells using the MTT ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used to determine the half maximal inhibitory concentrations (IC50) of the investigated compounds. The percent inhibition of neuraminidase was plotted against concentrations and the IC50 values were calculated by non-linear logistic curve fitting. Results The compounds were subjected to molecular docking using the GOLD suite (version 5.7.1) to predict the binding affinities for neuraminidase (3CL0). The docking scores are presented as PLP fitness and are comparable to those of oseltamivir. Oseltamivir-Phenylalanine recorded the highest docking score (72.23 kcal/mol), while, oseltamivir acid was recorded (56.24 kcal/mol). The ADMET parameters were generated using the Swiss ADME server to predict successful candidates with reasonable oral absorption and safety margins. All compounds are safer than oseltamivir and their IC50 values for neuraminidase inhibition were variable. The hybrids showed a lower percentage of viable cells. Oseltamivir-phenylalanine had the highest inhibitory activity against neuraminidase (3.03 μM), when compared with oseltamivir (67.22 μM). Conclusion Oseltamivir-phenylalanine showed remarkable and very significant activity, and the hybrid molecules were surprisingly less effective on neuraminidase than oseltamivir carboxamides.

A Cyclic Tripeptide-based Human SIRT3 Inhibitor

Background: Among the seven human sirtuins SIRT1-7, SIRT3 is not lesser functionally understood. However, the identification of its inhibitors has not been quite a success. Objective: In the current study, we intended to see if we were able to develop cyclic tripeptide-based human SIRT3 inhibitors that would harbor the catalytic mechanism-based pan-SIRT1/2/3 inhibitory warhead Ne-thioacetyl-lysine. Methods: In the current study, we prepared the corresponding N-terminus-to-side chain cyclic analog of two of our previously reported linear tripeptidic human SIRT3 inhibitors whose chemical structures both harbor the catalytic mechanism-based pan-SIRT1/2/3 inhibitory warhead N(epsilon)-thioacetyl-lysine at the central position and subjected the analogs to the same sirtuin inhibition assay under the same assay condition as those employed previously in our laboratory for the two parent linear tripeptidic SIRT3 inhibitors. Results: We found that analog 2 exhibited an enhanced SIRT3 inhibitory potency than its linear tripeptidic parent (i.e. compound 2a) and displayed a SIRT3 inhibitory IC50 value of ~340 nM which is smaller than its inhibitory IC50 values against other sirtuins with the following folds: ~2-fold versus SIRT1, ~7.7- fold versus SIRT2, and >68-353-fold versus SIRT5-7. Conclusion: The successful identification of the human SIRT3 inhibitor 2 in the current study would help the further functional dissection and pharmacological exploitation of the SIRT3 deacetylation reaction.

Indole–thiazolidinedione–triazole hybrids: synthesis, molecular docking, absorption, distribution, metabolism and excretion (ADME) profiling, and biological evaluation as α-amylase inhibitors

Abstract A novel series of hybrid indole–thiazolidinedione–triazole derivatives (6a-l) were synthesized and assessed for their in vitro inhibitory activity against porcine pancreatic α-amylase. The synthetic procedure consists of 3 steps. A crucial step in this process involves the generation of novel target molecules using a Cu(I)-catalyzed azide–alkyne cycloaddition reaction. The α-amylase inhibition IC50 value of the targeted compounds ranged from 0.51 ± 0.02 to 7.99 ± 0.28 μM as compared with 0.68 ± 0.02 μM with acarbose as the standard drug. Using the Autodock technique, all the derivatives 6a-l were subjected to molecular docking investigations against porcine pancreatic α-amylase (PDB ID: 1OSE). Moreover, it was discovered that the docked compounds had excellent binding affinities that ranged from −10.1 to −10.8 kcal/mol as compared with the standard −7.9 kcal/mol. Additionally, a comprehensive analysis of the physicochemical and pharmacokinetic properties associated with absorption, distribution, metabolism and excretion (ADME) was conducted for all the synthesized compounds.

New Thiazole Derivatives: Carbonic Anhydrase I–II and Cholinesterase Inhibition Profiles, Molecular Docking Studies

AbstractThiosemicarbazone derivative was obtained by the addition of thiosemicarbazide to 5‐nitro‐thiophene‐2‐carbaldehyde. The addition–cyclization of the 2‐bromoacetophenone derivative to thiosemicarbazone derivative gave the new thiazole derivatives (2 a‐k). Acetylcholinesterase (AChE), butyrylcholinesterase (BChE), antioxidant, and human carbonic anhydrase (hCA) I and II isoform inhibitory activities of the thiazole derivatives 2 a‐k were investigated. The effects of thiazole derivatives on carbonic anhydrase I and II (hCA I–II) isoenzymes were examined in vitro using the esterase method. IC50 values for enzyme inhibition were found to be 2.661–22.712 μM for hCA I and 5.372–26.813 μM for hCA II. All derivatives reduced the activities of carbonic anhydrase I and II isoenzymes and were new potential inhibitor molecule candidates. These compounds were found to have minimal effects on AChE and BChE. The antioxidant properties of the target compounds were determined using DPPH and ferric ion‐chelating assays. In particular, compounds 2 k and 2 h had the highest antioxidant effect in the series with IC50 values of 30.11±0.008 μM and 30.21±0.006 μM, respectively. ADMET properties of the compounds found to be effective were evaluated and their interactions with the enzyme were determined by molecular docking.

Uncovering the antiinflammatory potential of Lactiplantibacillus Plantarum fermented Cannabis Sativa L seeds

Inflammation acts as a dual role in disease initiation and progression, while Cannabis sativa L. (hemp) seeds, known for their abundance of anti-inflammatory phytochemicals, present a promising food source. Additionally, fermentation may optimize the food matrix, thereby augmenting its developmental prospects. This study explores the anti-inflammatory potential of hemp seeds fermented with 10 different probiotic strains. Among these, Lactiplantibacillus plantarum fermented hemp seeds (FHS) demonstrated a significant anti-inflammatory ability, accompanied by a reduction in the expression of critical inflammatory markers such as TLR4, NF-κBp65, and iNOS. Moreover, there is a noteworthy dose-dependent inhibition of inflammatory cytokines TNF-α, IL-6, IL-1β, and NO within a concentration range of 50 to 500 µg/mL. Subsequently, metabolomics analysis using UHPLC-QTOF-MS highlighted significant metabolic alterations in FHS compared to raw hemp seeds (RHS). Through multivariate, univariate, and correlation analyses, indolelactic acid (IA) and homovanillic acid (HVA) emerged as the main anti-inflammatory metabolites in FHS. Validation via HPLC confirmed the concentration of IA and HVA in RHS and FHS and both organic acids demonstrated lower IC50 values for TNF-α, IL-1β, IL-6, IL-18, and NO inhibition, showcasing their potent anti-inflammatory abilities. Furthermore, in vitro gastro-intestinal digestion coupled with the Caco-2 cell monolayer model validates the uptake and bioaccessibility of FHS, further affirming IA and HVA as major anti-inflammatory compounds. Overall, this research sets the stage for the development of novel hemp seed-based products targeting inflammation-associated disorders.

Novel herbicide from an optimized Bacillus altitudinis D30202 solvent extract

AbstractThe herbicidal activity of the fermentation broth, filtrate, and extracts of Bacillus altitudinis D30202 was evaluated against seed germination and seedling growth of wild oat (Avena fatua L.). The bacterial culture filtrate exhibited greater inhibition of the wild oat weed than the fermentation broth. The filtrate was also extracted with organic solvents. The herbicidal potency of the extracts on the growth of wild oat plants was as follows: chloroform (100% inhibition of germination) > n‐butanol (93.8%) > ethyl acetate (66.7%) > petroleum ether (6.3%) > aqueous phase (2.1%); so the chloroform extract was evaluated further. It inhibited wild oat radicle growth by 100%, and plumule growth by 97.9%, while spraying young plants with a 5 mg/mL extract caused severe desiccation of the leaves, stalk wilting, and plant death. IC50 values for inhibition of plumule and radicle growth and germination were 0.64–0.72 mg/mL. Scanning electron microscopy and transmission electron microscopy revealed changes in the microstructure of the leaves and root tips, and degradation of organelles following chloroform extract treatment. The 5 mg/mL extract had no adverse impact on the growth or health of highland barley (Hordeum vulgare L.), corn (Zea mays), and broad bean (Vicia faba L.), indicating that this novel bioherbicide is suitable for control of wild oat weeds in the production of these food crops (while having a minor impact on the health of pea plants and being phytotoxic to wheat plants).

Synthesis of new N-(5,6-methylenedioxybenzothiazole-2-yl)-2-[(substituted)thio/piperazine]acetamide/propanamide derivatives and evaluation of their AChE, BChE, and BACE-1 inhibitory activities.

In this study, the synthesis of N-(5,6-methylenedioxybenzothiazole-2-yl)-2-[(substituted)thio/piperazine]acetamide/propanamide derivatives (3a-3k) and to investigate their acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and β-secretase 1 (BACE-1) inhibition activity were aimed. Mass, 1H NMR, and 13C NMR spectra were utilized to determine the structure of the synthesized compounds. Compounds 3b, 3c, 3f, and 3j showed AChE inhibitory activity which compound 3c (IC50 = 0.030 ± 0.001 µM) showed AChE inhibitory activity as high as the reference drug donepezil (IC50 = 0.0201 ± 0.0010 µM). Conversely, none of the compounds showed BChE activity. Compounds 3c and 3j showed the highest BACE-1 inhibitory activity and IC50 value was found as 0.119 ± 0.004 µM for compound 3j whereas IC50 value was 0.110 ± 0.005 µM for donepezil, which is one of the reference substance. Molecular docking studies have been carried out using the data retrieved from the server of the Protein Data Bank (PDBID: 4EY7 and 2ZJM). Using in silico approach behavior active compounds (3c and 3j) and their binding modes clarified.

Spectroscopic and computational studies on the binding interaction of biologically active thioridazine and perphenazine with human Matrix metalloproteinases 9

Matrix metaloproteinase (MMP)-9, as a neuroinflammation-facilitating element, plays a significant role in neurodegenerative disorders and could be considered an inflammation control target. This study is intended to survey the effects of thioridazine (TRZ) and phenothiazines (PRZ) as neuroleptic drugs on the performance of recombinant human MMP-9 (rhMMP-9) by using experimental (ultraviolet visible (UV–vis), fluorescence, synchronous fluorescence, fluorescence resonance energy transfer (FRET) spectroscopy, circular dichroism (CD), surface plasmon resonance (SPR), and theoretical techniques (molecular docking). For this purpose, rhMMP-9 was expressed and purified by utilizing recombinant E. coli bacteria. The kinetic analysis illustrated that the different concentrations of TRZ and PRZ could considerably decrease the catalytic function of rhMMP-9 through competitive and mixed inhibition mechanisms, respectively. The results illustrated the higher affinity of TRZ-MMP-9 with an inhibitory IC50 value of 10.7 µM in comparison with PRZ (12.1 µM) following the conformational alteration of the enzyme. In addition, hydrophobic binding and hydrogen bonds/van der Waals forces were suggested for TRZ-MMP-9 and PRZ-MMP-9, respectively. Finally, the molecular docking study demonstrated that TRZ and PRZ bind to the cavity in the catalytic and fibronectin domains, respectively, which supports the experimental data. This study provides some experimental and structural insights into the possible anti-inflammatory mechanisms of TRZ and PRZ drugs that suggest both drugs could be used as anti-MMP-9 drugs in neuroinflammatory conditions.

α-Glucosidase inhibitory potential of Oroxylum indicum using molecular docking, molecular dynamics, and in vitro evaluation

BackgroundAccording to the International Diabetes Federation, there will be 578 million individuals worldwide with diabetes by 2030 and 700 million by 2045. One of the promising drug targets to fight diabetes is α-glucosidase (AG), and its inhibitors may be used to manage diabetes by reducing the breakdown of complex carbohydrates into simple sugars. The study aims to identify and validate potential AG inhibitors in natural sources to combat diabetes. MethodsComputational techniques such as structure-based virtual screening and molecular dyncamic simulation were employed to predict potential AG inhibitors from compounds of Oroxylum indicum. Finally, in silico results were validated by in vitro analysis using n-butanol fraction of crude methanol extracts. ResultsThe XP glide scores of top seven hits OI_13, OI_66, OI_16, OI_44, OI_43, OI_20, OI_78 and acarbose were –14.261, –13.475, –13.074, –13.045, –12.978, –12.659, –12.354 and –12.296 kcal/mol, respectively. These hits demonstrated excellent binding affinity towards AG, surpassing the known AG inhibitor acarbose. The MM-GBSA dG binding energies of OI_13, OI_66, and acarbose were −69.093, −62.950, and −53.055 kcal/mol, respectively. Most of the top hits were glycosides, indicating that active compounds lie in the n-butanol fraction of the extract. The IC50 value for AG inhibition by n-butanol fraction was 248.1 μg/ml, and for that of pure acarbose it was 89.16 μg/ml. The predicted oral absorption rate in humans for the top seven hits was low like acarbose, which favors the use of these compounds as anti-diabetes in the small intestine. ConclusionIn summary, the study provides promising insights into the use of natural compounds derived from O. indicum as potential AG inhibitors to manage diabetes. However, further research, including clinical trials and pharmacological studies, would be necessary to validate their efficacy and safety before clinical use.

Design, Synthesis, Formulation, and Bioevaluation of Trisubstituted Triazines as Highly Selective mTOR Inhibitors for the Treatment of Human Breast Cancer.

The aberrant activation of the PI3K/mTOR signaling pathway is implicated in various human cancers. Thus, the development of inhibitors targeting mTOR has attracted considerable attention. In this study, we used a structure-based drug design strategy to discover a highly potent and kinase-selective mTOR inhibitor 24 (PT-88), which demonstrated an mTOR inhibitory IC50 value of 1.2 nM without obvious inhibition against another 195 kinases from the kinase profiling screening. PT-88 displayed selective inhibition against MCF-7 cells (IC50: 0.74 μM) with high biosafety against normal cells, in which autophagy induced by mTOR inhibition was implicated. After successful encapsulation in a lipodisc formulation, PT-88 demonstrated favorable pharmacokinetic and biosafety profiles and exerted a large antitumor effect in an MCF-7 subcutaneous bearing nude mice model. Our study shows the discovery of a highly selective mTOR inhibitor using a structure-based drug discovery strategy and provides a promising antitumor candidate for future study and development.

Drug-drug interaction between danshensu and irbesartan and its potential mechanism

To uncover the effect of danshensu on irbesartan pharmacokinetics and its underlying mechanisms. To investigate the effect of danshensu on the pharmacokinetics of irbesartan, Sprague-Dawley rats (n = 6) were orally administered 30 mg/kg irbesartan alone (control group) or pre-treated with 160 mg/kg danshensu (experimental group). The effect of danshensu on the metabolic stability of irbesartan in RLMs was examined by LC-MS/MS method. The effect of danshensu on CYP2C9 activity was also determined. Danshensu markedly increased the AUC(0-t) (9573 ± 441 vs. 16157 ± 559 μg/L*h) and C max (821 ± 24 vs. 1231 ± 44 μg/L) of irbesartan. Danshensu prolonged the t 1/2 (13.39 ± 0.98 vs. 16.04 ± 1.21 h) and decreased the clearance rate (2.27 ± 0.14 vs. 1.19 ± 0.10 L/h/kg) of irbesartan. Danshensu enhanced the metabolic stability of irbesartan in vitro with prolonged t 1/2 (36.34 ± 11.68 vs. 48.62 ± 12.03 min) and reduced intrinsic clearance (38.14 ± 10.24 vs. 28.51 ± 9.06 μL/min/mg protein). Additionally, the IC50 value for CYP2C9 inhibition by danshensu was 35.74 μM. Danshensu enhanced systemic exposure of irbesartan by suppressing CYP2C9. The finding can also serve as a guidance for further investigation of danshensu-irbesartan interaction in clinical practice.

Anticancer Activity of the Thai Herbal Formula “Kerra” Versus Afatinib and Doxorubicin In Vitro

One of the greatest challenges impeding the achievement of global health goals and afflicting millions of people each year is cancer. Prevailing cancer treatment options come with inherent risks, and significant adverse effects, and can result in financial burdens. Nowadays, many turn to alternative medicine, which have played an integral part in the treatment of a myriad of diseases especially when other approaches are ineffective or unable to be deployed. However, an opulent number of herbs seldom have reliable evidence derived from research to support their claims of phytochemical properties contributing to the alleviation of illnesses. Kerra is a Thai herbal formula that possesses immunomodulatory properties and anti-tumor activities which provides a safe, efficacious, and holistic treatment for cancer. Kerra offers therapeutic benefits without resulting in severe adverse effects, ameliorates overall welfare and quality of life for advanced care patients, and is cost-effective, allowing them to be vastly accessible for widespread use, particularly in areas facing disparities due to insufficient economic stability. This study explores the in vitro anticancer effect of the Kerra formula utilizing cytotoxicity assays on six cancer cell lines, compared to afatinib, a targeted therapy for non-small cell lung carcinoma, and doxorubicin, a chemotherapeutic agent. Anticancer activity was determined by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay and the half-maximal inhibitory concentrations (IC50) were calculated for the A431, A549, HepG2, HCT-116, NCI-H1975, MCF-7, and HeLa cell lines. Kerra showed the best effectiveness against HCT-116 and A431. The IC50 values showing inhibition of the growth of colorectal carcinoma (HCT-116 cell line) by Kerra, afatinib, and doxorubicin are 72.96, 3.574, and 63.39 µg/ml, respectively. The IC50 values for inhibition of epidermoid carcinoma (A431 cell line) by Kerra and afatinib are 96.1 and 2.449 µg/ml, respectively. The findings revealed the Kerra extract can inhibit the growth of different types of cancer cells. From our results, Kerra may be advantageous to use in conjunction with conventional cancer interventions, offer an economical solution, and improve the quality of life remarkably for end-stage cancer patients by mitigating severe adverse events.

Investigating the influence of XAV-939, a tankyrase inhibitor, on the density and gating of erg-mediated K+ currents in mouse MA-10 Leydig tumor cells

XAV-939(XAV) is a chemical compound that inhibits the activity of tankyrase. However, the precise way in which XAV alters membrane ionic currents is not well understood. In this study,our goal was to examine the impact of XAV on the ionic currents in mouse MA-10 Leydig cells, specifically focusing on the magnitude, gating properties,and voltage-dependent hysteresis of erg-mediated K+currents(IK(erg)). In our whole-cell current recordings we observed that the addition of XAV inhibited the density of IK(erg) in a concentration-dependent manner with an IC50 of 3.1 μM. Furthermore we found that continued exposure to XAV, further addition of neither liraglutide nor insulin-like growth factor-1 counteracted XAV-mediated inhibition of IK(erg). Additionally the presence of XAV suppressed the mean current versus voltage relationship of IK(erg) across the entire voltage-clamp step analyzed. This compound shifted the steady-state activation curve of IK(erg) to a less negative potential by approximately 12 mV. The presence of XAV increased the time constant of deactivating IK(erg) in MA-10 cells. The voltage-dependent clockwise hysteresis of IK(erg) responding to prolonged upright isosceles-triangular ramp voltage became diminished by adding XAV; moreover subsequent addition of NS3623 effectively reversed XAV-induced decrease of hysteretic area of IK(erg). XAV also inhibited the proliferation of this cell line and the IC50 value of XAV-induced inhibition of cell proliferation was 2.8M. Overall the suppression of IK(erg) by XAV may serve as a significant ionic mechanism that contribute to the functional properties of MA-10 cells. However, it is important to note that this effect cannot be attributed solely to the inhibition of tankyrase.

Enhanced Enzyme Inhibitory Effects of the Nanohybrid Eggplant Extract: An Unusual Pharmaceutical Form for Medicinal Plant

Objective: Recently, biosynthesis/synthesis of nanoflowers has become very attractive for chemical and pharmaceutical sciences, and enhanced enzyme activities. Various plant extracts and their active compounds are effectively used as organic component for novel nanoflowers synthesis. Solanum melongena L., commonly known as eggplant in English, a vegetable and medicinal plant belongs to Solanaceae family has several advantages in materials synthesis due to cheap and obtained easily. The aim of this study is to compare the enzyme ((alpha-glucosidase (AGase), alpha-amylase (AAase), tyrosinase (Tyr), acetylcholinesterase (AChE) and butyryl cholinesterase (BChE)) inhibitory effects of the eggplant’ calyx extract and its Solanum-inorganic hybrid nanoflower (Sm-ihNFs) via in vitro experimental methods. 
 Methods: The hybrid nanoflower was formed (NF) with organic molecules, eggplant extract (Sm), and inorganic compounds, copper to enhance the catalytic activities. The inhibition capacities of the eggplant extract, and its hybrid nanoflower were evaluated on selected enzymes (AGase, AAase, Tyr, AChE and BChE) which play significant roles physiologically by in vitro tests in this study. 
 Results: According to inhibition percentages and IC50 values, Sm-ihNFs showed higher inhibitory activities on enzymes other than ache than the plain crude plant extract. Among all the enzymes that were studied, Sm-ihNFs demonstrated significantly higher alpha-glucosidase and alpha-amylase inhibition activities compared to acarbose. And when compared to galanthamine hydrobromide Sm-ihNFs showed higher enzyme inhibition and significant IC50 value. 
 Conclusion: It was thought that Sm-ihNFs prepared from eggplant extract may have promising potential for antidiabetic drug formulations in the future. The hybrid nanoflowers will be promising and guide for the future work in terms of pharmaceutical and cosmeceutical industry.

Comparative UHPLC-MS/MS-based untargeted metabolomics analysis, antioxidant, and anti-diabetic activities of six walnut cultivars

Walnuts are important stone fruits that are commonly consumed as food or used in food products. However, most studies have focused on specific compounds found in walnuts. Therefore, this study aimed to compare untargeted UHPLC-MS/MS metabolite profiles and determine the antioxidant and antidiabetic properties of six walnut cultivars. A total of 135 metabolites belonging to fourteen different classes were identified including amino acids, lipids, carboxylic acids and amides, phenyl alcohols and aldehydes, ketones, flavonoids, oxygenated hydrocarbons, glycosides, phenolic acids, hydrocarbons, sugar alcohols and acids, and vitamins. The main classes of metabolites were amino acids, lipids, oxygenated hydrocarbons, carboxylic acids and amides, phospholipids, and phenolic acids. The six cultivars were divided into two groups based on PCA, and PLS-DA score with significant differences in the number of distinct metabolites between the two groups. Hierarchical cluster analysis further confirmed these groups by comparing the similarities and differences of all metabolites in the six cultivars. Pathway enrichment analysis revealed that the most prominent metabolic pathways in walnuts were related to amino acids, followed by flavonoids and vitamins. The antioxidant and antidiabetic effects of walnuts varied significantly among the cultivars. Group A, which had higher levels of upregulated metabolites, showed greater IC50 values for ABTS, and DPPH scavenging, as well as α-glucosidase activities. On the other hand, walnuts 4, 5, and 6 in group B had more downregulated metabolites and higher IC50 values for α-amylase inhibition. These findings suggest that walnuts contain key metabolites with antioxidant and antidiabetic properties, which occur at cultivar-dependent levels.

The preparation and anti-atherosclerotic effects of different low-molecular weights fucoidan

Fucoidan, a marine-derived sulfated polysaccharide, exhibits a broad spectrum of biological activities. However, its high molecular weight and viscosity often restrict these benefits. In this study, a new fucoidanase-producing microbial strain Kosakonia oryzendophytica LH-58 was isolated from freshwater for the first time. Three low-molecular-weight fucoidans were synthesized through enzymatic hydrolysis, and their antioxidant, hypoglycemic, hypolipidemic, and anticoagulant properties were evaluated in vitro. With the hydrolysis of fucoidan by fucoidanase, there was no significant change in the composition of monosaccharides, and the sulfate content decreased slightly. Interestingly, reduced molecular weight enhanced antioxidant activity, though anticoagulant efficacy diminished. In vitro experiments demonstrated that a higher molecular weight of fucoidan significantly prolonged activated partial thromboplastin and thrombin times. The fraction F1, with a weight-average molecular weight exceeding 10 kDa, displayed superior hypoglycemic and lipid-lowering effects compared to its counterparts. The IC50 values for F1's inhibition of α-amylase and α-glucosidase were 0.81 mg/mL and 0.94 mg/mL, respectively, while its binding rates to sodium taurocholate and sodium glycocholate were 50.11% ± 2.32% and 54.58% ± 2.71%, respectively. This study also offers a methodological reference for the swift identification of functional polysaccharides to prevent atherosclerosis.

A Novel Ultrafiltrate Extract of Propolis Exerts Anti-inflammatory Activity through Metabolic Rewiring.

Thousands of years ago, humans started to use propolis because of its medicinal properties, and modern science has successfully identified several bioactive molecules within this resinous bee product. However, a natural propolis extract which has been removed the adhesive glue and preserved propolis bioactive compounds is urgently needed to maximise the therapeutic opportunities. In this study, a novel ultrafiltrate fraction from Brazilian green propolis, termed P30K, was demonstrated with anti-inflammatory properties, both in vitro and in vivo. Total flavonoids and total phenolic acids content in P30K were 244.6 mg/g and 275.8 mg/g respectively, while the IC50 value of inhibition of cyclooxygenase-2 (COX-2) was 8.30 μg/mL. The anti-inflammatory activity of P30K was furtherly corroborated in experimental models of lipopolysaccharides (LPS)-induced acute liver and lung injury. Mechanistically, integrated GC-MS and LC-MS based serum metabolomics analysis revealed that P30K modulated citrate cycle (TCA), pyruvate, glyoxylate and dicarboxylate metabolism pathways to inhibit secretion of pro-inflammatory cytokines. Results of network pharmacology and molecular docking suggested that P30K targeted catechol-O-methyltransferases (COMT), 11β-hydroxysteroid dehydrogenases (HSD11B1), and monoamine oxidases (MAOA and MAOB) to promote cellular metabolomic rewiring. Collectively, our work reveals P30K as an efficient therapeutic agent against inflammatory conditions and its efficacy is related to metabolic rewiring.