Small molecule α-methylene-γ-butyrolactone, an evolutionarily conserved moiety in sesquiterpene lactones, ameliorates arthritic phenotype via interference DNA binding activity of NF-κB.

Rheumatoid arthritis (RA) is an inflammatory disease accompanied by abnormal synovial microenvironment (SM). Sesquiterpene lactones (SLs) are the main anti-inflammatory ingredients of many traditional herbs utilized in RA treatment. α-Methylene-γ-butyrolactone (α-M-γ-B) is a core moiety that widely exists in natural SLs. This study was designed to investigate the anti-arthritic potential of α-M-γ-B as an independent small molecule in vitro and in vivo. α-M-γ-B exhibited stronger electrophilicity and anti-inflammatory effects than the other six analogs. α-M-γ-B inhibited the production of pro-inflammatory mediators via repolarizing M1 macrophages into M2 macrophages. The transcriptome sequencing suggested that α-M-γ-B regulated the immune system pathway. Consistently, α-M-γ-B attenuated collagen type II-induced arthritic (CIA) phenotype, restored the balance of Tregs-macrophages and remodeled SM via repolarizing the synovial-associated macrophages in CIA mice. Mechanistically, although α-M-γ-B did not prevent the trans-nucleus of NF-κB it interfered with the DNA binding activity of NF-κB via direct interaction with the sulfhydryl in cysteine residue of NF-κB p65, which blocked the activation of NF-κB. Inhibition of NF-κB reduced the M1 polarization of macrophage and suppressed the synovial hyperplasia and angiogenesis. α-M-γ-B failed to ameliorate CIA in the presence of N-acetylcysteine or when the mice were subjected to the macrophage-specific deficiency of Rela. In conclusion, α-M-γ-B significantly attenuated the CIA phenotype by directly targeting NF-κB p65 and inhibiting its DNA binding ability. These results suggest that α-M-γ-B has the potential to serve as an alternative candidate for treating RA. The greater electrophilicity of α-M-γ-B, the basis for triggering strong anti-inflammatory activity, accounts for the reason why α-M-γ-B is evolutionarily conserved in the SLs by medical plants.

Synthesis of Rare Earth Metal Complexes Stabilized by Amine Bridged Bis(phenolato) Ligands and Their Performance in the Polymerization of rac-ß-Butyrolactone.

A series of rare earth alkoxides bearing amine-bridged bis(phenolato) ligands were synthesized through sequential reactions of RE(C5H5)3(THF) (RE = Y, Lu) or Nd[N(SiMe3)2]3 with bis(phenols) LH2 and CF3CH2OH. Complexes REL(OCH2CF3)(THF)n (1-6) bearing different aryl-substituents were obtained in good yields of 59-70%. They were applied in the ring-opening polymerization (ROP) of rac-ß-butyrolactone (rac-BBL), which showed good activity (TOF up to 27,300 h-1), resulting in syndiotactically enriched poly(3-hydroxybutyrate) (PHB) (Pr up to 0.86) with narrow polydispersities (PDI ≤ 1.27). The yttrium complex 3 bearing bulky o-1,1-diphenylethyl substituents outperformed other complexes, suggesting that the smaller ionic radii of metal centers and bulky ortho substituents of ancillary ligands play crucial roles in controlling the activity and stereoselectivity in ROP of rac-BBL. Kinetics of the polymerization of rac-BBL initiated by complex 3 was investigated, which revealed first order dependences on the monomer and initiator concentrations, respectively.

Flexible 2,4-diaminopyrimidine bearing a butyrolactone as Plasmodium falciparum dihydrofolate reductase inhibitors.

Recently, P218, a new flexible antifolate targeting Plasmodium falciparum dihydrofolate reductase (PfDHFR), has entered its clinical trial with good safety profile and effective Pf infection prevention. However, it carries a free carboxyl terminal, which is hydrophilic and prone to metabolic glucuronidation. Here, a new series of P218 analogues carrying butyrolactone has been synthesized with the purpose of enhancing lipophilicity and minimizing metabolic instability. The inhibition constants against the mutant PfDHFR enzymes are in sub-nanomolar level and the antimalarial activity against antifolate-resistant parasites are in the low micromolar range. The crystal structure of the most potent analogue LA1 bound enzyme complex indicates interaction with multiple residues, including Arg122 and Phe116 in the active site. In vitro log D7.4 and kinetic solubility confirmed a higher lipophilicity of this butyrolactone series as compared to P218. These outcomes suggest the possibility to further develop butyrolactone derivatives as non-carboxyl antiplasmodial antifolates.

Structural Simplification of Podophyllotoxin: Discovery of γ-Butyrolactone Derivatives as Novel Antiviral Agents for Plant Protection.

Natural products are a valuable resource for the discovery of novel crop protection agents. A series of γ-butyrolactone derivatives, derived from the simplification of podophyllotoxin's structure, were synthesized and assessed for their efficacy against tobacco mosaic virus (TMV). Several derivatives exhibited notable antiviral properties, with compound 3g demonstrating the most potent in vivo anti-TMV activity. At 500 µg/mL, compound 3g achieved an inactivation effect of 87.8%, a protective effect of 71.7%, and a curative effect of 67.7%, surpassing the effectiveness of the commercial plant virucides ningnanmycin and ribavirin. Notably, the syn-diastereomer (syn-3g) exhibited superior antiviral activity compared to the anti-diastereomer (anti-3g). Mechanistic studies revealed that syn-3g could bind to the TMV coat protein and interfere with the self-assembly process of TMV particles. These findings indicate that compound 3g, with its simple chemical structure, could be a potential candidate for the development of novel antiviral agents for crop protection.

Integrated characterization of arabica coffee husk tea using flavoromics, targeted screening, and in silico approaches.

This study aimed to identify the key volatile compounds in two types of processed arabica coffee husk tea, elucidate their olfactory characteristics, and investigate their antioxidant and anti-inflammatory activities. Sensory evaluation indicated differences between the two groups. A total of 64 and 99 compounds were identified in the C and FC groups, respectively, with 5 identified as key aroma compounds (ROAV≥1). Molecular simulations indicated that four common key aroma compounds were successfully docked with OR1A1 and OR5M3 receptors, forming stable complexes. Furthermore, 14 volatile compounds interacted with 140 targets associated with oxidation and inflammation, linking to 919 gene ontology (GO) terms and 135 kyoto encyclopedia of genes and genomes (KEGG) pathways. Molecular simulations revealed that these volatile components showed antioxidant and anti-inflammatory effects by interacting with core receptors through several forces, including van der Waals, Pi-alkyl, and Pi-cation interactions and hydrogen bonds.

Trends in reported GHB-related presentations to Sydney emergency departments between 2012 and 2021.

OBJECTIVES: In overdose, gamma-hydroxybutyrate (GHB) and its precursors can cause decreased levels of consciousness, coma and death. Here, we aim to describe reported exposure to GHB at four EDs in Sydney, New South Wales (NSW), Australia. METHODS: We searched the ED databases of four Sydney metropolitan hospitals for presentations relating to GHB exposure between 2012 and 2021. We calculated annual number of presentations stratified by hospital, age, sex, mode of arrival and triage category. RESULTS: A total of 3510 GHB-related presentations to ED were recorded across the four hospitals. Data for all hospitals were only available from 2015 onwards and between 2015 and 2021; there was a 114% increase in annual presentations (from 228 to 487). Males represented 68.7% of all presentations and the median age was 31 years (range 16-74 years). There was an increase in the proportion of female presentations between 2012 and 2021 (from 27.9% to 37.9%) along with the severity of presentation over the same period, with the proportion of presentations with a triage category 1 increasing from 19.7% to 34.5%. CONCLUSIONS: Increases in recorded absolute number and severity of GHB-related presentations to Sydney EDs are a major public health concern. There may also be shifts in the demographics of those with GHB-related presentations. Renewed efforts are required to understand the drivers of these increases to optimally target harm reduction approaches.

Enzymes with Lactonase Activity against Fungal Quorum Molecules as Effective Antifungals.

Since the growing number of fungi resistant to the fungicides used is becoming a serious threat to human health, animals, and crops, there is a need to find other effective approaches in the eco-friendly suppression of fungal growth. One of the main mechanisms of the development of resistance in fungi, as well as in bacteria, to antimicrobial agents is quorum sensing (QS), in which various lactone-containing compounds participate as signaling molecules. This work aimed to study the effectiveness of action of enzymes exhibiting lactonase activity against fungal signaling molecules. For this, the molecular docking method was used to estimate the interactions between these enzymes and different lactone-containing QS molecules of fungi. The catalytic characteristics of enzymes such as lactonase AiiA, metallo-ß-lactamase NDM-1, and organophosphate hydrolase His6-OPH, selected for wet experiments based on the results of computational modeling, were investigated. QS lactone-containing molecules (butyrolactone I and γ-heptalactone) were involved in the experiments as substrates. Further, the antifungal activity of the enzymes was evaluated against various fungal and yeast cells using bioluminescent ATP-metry. The efficient hydrolysis of γ-heptalactone by all three enzymes and butyrolactone I by His6-OPH was demonstrated for the first time. The high antifungal efficacy of action of AiiA and NDM-1 against most of the tested fungal cells was revealed.

Design, synthesis and antifungal activity of novel α-methylene-γ-butyrolactone derivatives containing benzothiophene moiety.

BACKGROUND: The discovery of agricultural fungicide candidates from natural products is one of the key strategies for developing environment friendly agricultural fungicides with high efficiency, high selectivity and unique modes-of-action. Based on previous work, a series of novel α-methylene-γ-butyrolactone (MBL) derivatives containing benzothiophene moiety were designed and synthesized. RESULTS: The majority of the proposed compounds displayed moderate to considerable antifungal efficacy against the tested pathogenic fungi and oomycetes, some exhibiting broad spectrum antifungal activity. Notably, compounds 2 (3-F-Ph) and 7 (4-Cl-Ph) showed excellent antifungal activity against Rhizoctonia with half maximal effective concentration (EC50) values of 0.94 and 0.99 mg L-1, respectively, comparable to the commercial fungicide tebuconazole (EC50 = 0.96 mg L-1), and also displayed significant inhibitory effects against V alsa mali with EC50 values of 2.26 and 1.67 mg L-1, respectively - better than famoxadone and carabrone. The in vivo protective and curative effects against R. solani of compound 2 were 57.2% and 53.7% at 100 mg L-1, respectively, which were equivalent to tebuconazole (51.6% and 52.4%). Further investigations found that compound 2 altered the ultrastructure of R. solani cell, significantly increased the relative conductivity of the cells, and reduced the activity of complex III in a dose-dependent manner. Molecular docking results showed that compound 2 matched well with the Qo pocket. CONCLUSION: The results revealed that MBL derivatives containing benzothiophene moiety are promising antifungal candidates and provide a new backbone structure for further optimization of novel fungicides. © 2024 Society of Chemical Industry.

Insights into additional lactone-based signaling circuits in Streptomyces: existence of acyl-homoserine lactones and LuxI/LuxR homologs in six Streptomyces species.

Acyl-homoserine lactones (AHLs), mediating pivotal physiological activities through quorum sensing (QS), have conventionally been considered limited to Gram-negative bacteria. However, few reports on the existence of AHLs in Gram-positive bacteria have questioned this conception. Streptomyces, as Gram-positive bacteria already utilizing a lactone-based QS molecule (i.e., gamma-butyrolactones), are yet to be explored for producing AHLs, considering their metabolic capacity and physiological distinction. In this regard, our study examined the potential production of AHLs within Streptomyces by deploying HPLC-MS/MS methods, which resulted in the discovery of multiple AHL productions by S. griseus, S. lavendulae FRI-5, S. clavuligerus, S. nodosus, S. lividans, and S. coelicolor A3(2). Each of these Streptomyces species possesses a combination of AHLs of different size ranges, possibly due to their distinct properties and regulatory roles. In light of additional lactone molecules, we further confirm that AHL- and GBL-synthases (i.e., LuxI and AfsA enzyme families, respectively) and their receptors (i.e., LuxR and ArpA) are evolutionarily distinct. To this end, we searched for the components of the AHL signaling circuit, i.e., AHL synthases and receptors, in the Streptomyces genus, and we have identified multiple potential LuxI and LuxR homologs in all 2,336 Streptomyces species included in this study. The 6 Streptomyces of interest in this study also had at least 4 LuxI homologs and 97 LuxR homologs. In conclusion, AHLs and associated gene regulatory systems could be more widespread within the prokaryotic realm than previously believed, potentially contributing to the control of secondary metabolites (e.g., antibiotics) and their complex life cycle, which leads to substantial industrial and clinical applications.

A gene cluster encoding a nonribosomal peptide synthetase-like enzyme catalyzes γ-aromatic butenolides.

Sea cucumber-derived fungi have attracted much attention due to their capacity to produce an incredible variety of secondary metabolites. Genome-wide information on Aspergillus micronesiensis H39 obtained using third-generation sequencing technology (PacBio-SMRT) showed that the strain contains nonribosomal peptide synthetase (NRPS)-like gene clusters, which aroused our interest in mining its secondary metabolites. 11 known compounds (1-11), including two γ-aromatic butenolides (γ-AB) and five cytochalasans, were isolated from A. micronesiensis H39. The structures of the compounds were determined by NMR and ESIMS, and comparison with those reported in the literature. From the perspective of biogenetic origins, the γ-butyrolactone core of compounds 1 and 2 was assembled by NRPS-like enzyme. All of the obtained compounds showed no inhibitory activity against drug-resistant bacteria and fungi, as well as compounds 1 and 2 had no anti-angiogenic activity against zebrafish.

Unveiling Synergistic Potency: Exploring Butyrolactone I to Enhance Gentamicin Efficacy against Methicillin-Resistant Staphylococcus aureus (MRSA) Strain USA300.

Staphylococcus aureus, including MRSA strains, poses significant health risks, imposing a significant disease burden and mortality. We investigate butyrolactone I (BL-1), a marine-derived metabolite from Aspergillus terreus, enhancing aminoglycoside efficacy against MRSA. A promising synergy is observed with BL-1 and various aminoglycosides, marked by low fractional inhibitory concentration indexes (FICIs < 0.5). Comprehensive studies utilizing USA300 MRSA and gentamicin reveal a remarkable one-fourth reduction in minimum inhibitory concentration (MIC) with 20 µg/mL BL-1. A relative abundance assay indicates that BL-1 enhances gentamicin uptake while restraining extracellular presence, involving intricate transmembrane signaling and molecular interactions. RNA-Seq analysis yielded an unexpected revelation, unveiling a distinctive gene expression profile and distinguishing it from other treatment approaches. Furthermore, meticulous analyses validated the extensive perturbations induced by BL-1 exposure, affecting diverse biological functions, encompassing glycolysis, amino acid metabolisms, substance transmembrane transport, and virulence generation. These valuable insights inspired further confirmation of bacterial virulence and the modulation of membrane permeability resulting from BL-1 treatment. Phenotypic validations corroborated our observations, revealing reduced membrane permeability and hemolytic toxicity, albeit demanding a deeper comprehension of the intricate interplay underlying these actions. Our study contributes crucial mechanistic insights to the development of therapeutic strategies against this notorious pathogen and the judicious employment of aminoglycosides. Additionally, it elucidates marine-derived metabolites' ecological and functional roles, exemplified by fungal quorum sensing signals. These compounds could give producers a competitive edge, inhibiting microorganism proliferation and suggesting novel approaches for combating resistant pathogens.

Production of Optically Pure (S)-3-Hydroxy-γ-butyrolactone from d-Xylose Using Engineered Escherichia coli.

Biocatalysis has advantages in asymmetric synthesis due to the excellent stereoselectivity of enzymes. The present study established an efficient biosynthesis pathway for optically pure (S)-3-hydroxy-γ-butyrolactone [(S)-3HγBL] production using engineered Escherichia coli. We mimicked the 1,2,4-butanetriol biosynthesis route and constructed a five-step pathway consisting of d-xylose dehydrogenase, d-xylonolactonase, d-xylonate dehydratase, 2-keto acid decarboxylase, and aldehyde dehydrogenase. The engineered strain harboring the five enzymes could convert d-xylose to 3HγBL with glycerol as the carbon source. Stereochemical analysis by chiral GC proved that the microbially synthesized product was a single isomer, and the enantiomeric excess (ee) value reached 99.3%. (S)-3HγBL production was further enhanced by disrupting the branched pathways responsible for d-xylose uptake and intermediate reduction. Fed-batch fermentation of the best engineered strain showed the highest (S)-3HγBL titer of 3.5 g/L. The volumetric productivity and molar yield of (S)-3HγBL on d-xylose reached 50.6 mg/(L·h) and 52.1%, respectively. The final fermentation product was extracted, purified, and confirmed by NMR. This process utilized renewable d-xylose as the feedstock and offered an alternative approach for the production of the valuable chemical.

Improving the Enantioselectivity of CHMOBrevi1 for Asymmetric Synthesis of Podophyllotoxin Precursor.

(R)-ß-piperonyl-γ-butyrolactones are key building blocks for the synthesis of podophyllotoxin, which have demonstrated remarkable potential in cancer treatment. Baeyer-Villiger monooxygenases (BVMOs)-mediated asymmetric oxidation is a green approach to produce chiral lactones. While several BVMOs were able to oxidize the corresponding cyclobutanone, most BVMOs gave the (S) enantiomer while Cyclohexanone monooxygenase (CHMO) from Brevibacterium sp. HCU1 gave (R) enantiomer, but with a low enantioselectivity (75 % ee). In this study, we use a strategy called "focused rational iterative site-specific mutagenesis" (FRISM) at residues ranging from 6 Šfrom substrate. The mutations by using a restricted set of rationally chosen amino acids allow the formation of a small mutant library. By generating and screening less than 60 variants, we achieved a high ee of 96.8 %. Coupled with the cofactor regeneration system, 9.3 mM substrate was converted completely in a 100-mL scale reaction. Therefore, our work reveals a promising synthetic method for (R)-ß-piperonyl-γ-butyrolactone with the highest enantioselectivity, and provides a new opportunity for the chem-enzymatic synthesis of podophyllotoxin.

Discovery of novel salicylaldehyde derivatives incorporating an α-methylene-γ-butyrolactone moiety as fungicidal agents.

BACKGROUND: Plant diseases caused by phytopathogenic fungi and oomycetes pose a serious threat to ensuring crop yield and quality. Finding novel fungicidal candidates based on natural products is one of the critical methods for developing effective and environmentally friendly pesticides. In this study, a series of salicylaldehyde derivatives containing an α-methylene-γ-butyrolactone moiety were designed, synthesized, and their fungicidal activities were evaluated. RESULTS: The bioassay studies indicated that compound C3 displayed an excellent in vitro activity against Rhizoctonia solani with a half-maximal effective concentration (EC50 ) value of 0.65 µg/mL, higher than that of pyraclostrobin (EC50 = 1.44 µg/mL) and comparable to that of carbendazim (EC50 = 0.33 µg/mL). For Valsa mali and Phytophthora capsici, compound C3 also showed good fungicidal activities with EC50 values of 0.91 and 1.33 µg/mL, respectively. In addition, compound C3 exhibited promising protective in vivo activity against R. solani (84.1%) at 100 µg/mL, which was better than that of pyraclostrobin (78.4%). The pot experiment displayed that compound C3 had 74.8% protective efficacy against R. solani at 200 µg/mL, which was comparable to that of validamycin (78.2%). The antifungal mode of action research indicated that compound C3 could change the mycelial morphology and ultrastructure, increase cell membrane permeability, affect respiratory metabolism by binding to complex III, and inhibit the germination and formation of sclerotia, thereby effectively controlling the disease. CONCLUSION: The present study provides support for the application of these salicylaldehyde derivatives as promising potential pesticides with remarkable and broad-spectrum fungicidal activities against phytopathogenic fungi and oomycetes in crop protection. © 2023 Society of Chemical Industry.

Heterocycle-Substituted α-Methylene-γ-Butyrolactones Derivatives Synthesis, Antifungal Activity, and 3D-QSAR.

Developing fungicides from active botanical skeletons is one of the effective methods to tackle the resistance of plant pathogens. Based on our previous discoveries, a series of novel α-methylene-γ-butyrolactone (MBL) derivatives containing heterocycles and phenyl rings were designed according to the antifungal molecule carabrone first discovered in plant Carpesium macrocephalum. The target compounds were synthesized, and the inhibitory activity against pathogenic fungi as well as the mechanism of action were then systematically investigated. Several compounds showed promising inhibitory activities against a variety of fungi. The most potent compound 38 exhibited the EC50 value of 0.50 mg/L against Valsa mali (V. mali), which was more effective than that of commercial fungicide famoxadone. The protective effect of compound 38 against V. mali on apple twigs was superior to that of famoxadone, with an inhibition rate of 47.9% at 50 mg/L. The physiological and biochemical results showed that compound 38 inhibits V. mali by causing cell deformation and contraction, reducing the number of intracellular mitochondria, thickening the cell wall, as well as increasing the permeability of the cell membrane. Based on three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses, it was shown that the introduction of the bulky and negatively charged groups favored the antifungal activity of the novel MBL derivatives. These findings suggest that compound 38 can be a potential candidate for novel fungicides worthy of further investigation further.

Promising Cytotoxic butenolides from the Soybean endophytic fungus Aspergillus terreus: a combined molecular docking and in-vitro studies.

AIM: This study aimed to use one strain many compounds approach (OSMAC) to investigate the cytotoxic potential of Aspergillus terreus associated with soybean versus several cancer cell lines, by means of in-silico and in vitro approaches. METHODS AND RESULTS: Fermentation of the isolated strain was done on five media. The derived extracts were investigated for their inhibitory activities against three human cancer cell lines; mammary gland breast cancer (MCF-7), colorectal adenocarcinoma (Caco-2), and hepatocellular carcinoma (HepG2) using MTT Assay. The fungal mycelia fermented in Modified Potato Dextrose Broth (MPDB) was the most cytotoxic extract against HepG2, MCF-7, and Caco-2 cell lines with IC50 4.2 ± 0.13, 5.9 ± 0.013 and 7.3 ± 0.004 µg mL-1, respectively. MPDB extract was scaled up resulting in the isolation of six metabolites; three fatty acids (1, 2, and 4), one sterol (3) and two butenolides (5 and 6) by column chromatography. The isolated compounds (1-6) were screened through a molecular docking approach for their binding aptitude to various active sites. butyrolactone-I (5) revealed a significant interaction within the CDK2 active site, while aspulvinone E (6) showed promising binding affinity to FLT3 and EGFR active sites that was confirmed by in vitro CDK2, FLT3 and EGFR inhibitory activity. Finally, the in vitro cytotoxic activities of butyrolactone-I (5) and aspulvinone E (6) revealed the antiproliferative activity of butyrolactone-I (5), against HepG2 cell line (IC50 = 17.85 ± 0.32 µM). CONCLUSION: Molecular docking analysis and in vitro assays suggested the CDK2/A2 inhibitory potential of butyrolactone-I (5) in addition to the promising interaction abilities of aspulvinone E (6) with EGFR and FLT3 active sites as a possible mechanism of their biological activities.

Corrigendum: Coral-derived endophytic fungal product, butyrolactone-I, alleviates LPS induced intestinal epithelial cell inflammatory response through TLR4/NF-κB and MAPK signaling pathways: An in vitro and in vivo studies.

[This corrects the article DOI: 10.3389/fnut.2021.748118.].

Two new secondary metabolites isolated from the fungus Penicillium virgatum T49-A.

The extensively chemical investigation of the EtOAc extract of the soil fungus Penicillium virgatum T49-A has successfully led to the isolation of two undescribed secondary metabolites penivirtone A (1) and peniviramide B (2) together with six known compounds. Their chemical structures including the absolute configurations of the two new compounds were comprehensively established by extensive analyses of NMR and HRESIMS spectra as well as ECD powered by theoretical calculations. Moreover, the cytotoxic and antibacterial activities of compounds 1-2 were also evaluated, whereas the two novel compounds showed no notable cytotoxic and antibacterial activities.

Costunolide covalently targets NACHT domain of NLRP3 to inhibit inflammasome activation and alleviate NLRP3-driven inflammatory diseases.

The NLRP3 inflammasome's core and most specific protein, NLRP3, has a variety of functions in inflammation-driven diseases. Costunolide (COS) is the major active ingredient of the traditional Chinese medicinal herb Saussurea lappa and has anti-inflammatory activity, but the principal mechanism and molecular target of COS remain unclear. Here, we show that COS covalently binds to cysteine 598 in NACHT domain of NLRP3, altering the ATPase activity and assembly of NLRP3 inflammasome. We declare COS's great anti-inflammasome efficacy in macrophages and disease models of gouty arthritis and ulcerative colitis via inhibiting NLRP3 inflammasome activation. We also reveal that the α-methylene-γ-butyrolactone motif in sesquiterpene lactone is the certain active group in inhibiting NLRP3 activation. Taken together, NLRP3 is identified as a direct target of COS for its anti-inflammasome activity. COS, especially the α-methylene-γ-butyrolactone motif in COS structure, might be used to design and produce novel NLRP3 inhibitors as a lead compound.

A review on multi-therapeutic potential of (-)-cubebin: experimental evidences.

Lignans are a large category of polyphenolic compounds that have low molecular weight and are widely distributed in the plant kingdom. They have been recognized for their potential antioxidizing and antiproliferative action. One of the most important lignans is cubebin which is abundantly isolated from the leaves and seeds of Piper cubeba and Piper nigrum. Cubebin possesses numerous biological actions such as antileukemic, trypanocidal, antimycobacterial, analgesic, anti-inflammatory, histamine antagonist, antifungal, and antispasmodic. This review discusses the in vitro and in vivo pharmacological studies on cubebin related to biochemistry and pharmacological applications and it ensures that it widely shows therapeutic potential. We expect that these therapeutic actions will set a new track in the formation of novel biological agents by the derivatization of cubebin. This review will assuredly fascinate countless researchers to begin further experimentation that might lead to novel agents for the treatment and prevention of diseases.