Quercetin Enhances the Availability of 5-Heptadecylresorcinol by Inhibiting the Expression of P-gp.

5-Heptadecylresorcinol (AR-C17), as the most important active monomer, is found in large quantities in wheat and triticale and plays a variety of health benefits, such as antidiabetic, anti-inflammatory, and antitumor. However, the low bioavailability of AR-C17 due to its low water solubility restricts its application. Moreover, the transport mechanism of AR-C17 is not fully understood. Here, we showed that the transport of AR-C17 in vitro was time- and concentration-dependent, and relatively higher temperature and lower pH obviously promoted the transport of AR-C17. Besides, transporters, especially P-glycoprotein (P-gp), markedly affected the transport of AR-C17 as well. Quercetin, a natural synergist in triticale bran (TB), was confirmed as an inhibitor of P-gp to promote the transport of AR-C17 in this study, and the bioavailability of AR-C17 reached the highest when the concentration ratio of quercetin to AR-C17 was 1:1.

Discovery of novel resorcinol biphenyl ether-based macrocyclic small molecules as PD-1/PD-L1 inhibitors with favorable pharmacokinetics for cancer immunotherapy.

Programmed death protein 1 (PD-1)/programmed death protein ligand 1 (PD-L1) is one of the most promising immune checkpoints (ICs) in tumor immunology and has been actively pursued as a target for anticancer drug discovery. Based on our previous research in small molecule PD-1/PD-L1 modulators, we designed and synthesized a series of resorcinol biphenyl ether-bearing macrocyclic compounds and evaluated their anti-PD-1/PD-L1 activities. Among them, compound 8d exhibited the highest inhibitory activity against PD-1/PD-L1 interaction with IC50 of 259.7 nM in the homogenous time-resolved fluorescence (HTRF) assay. In addition, 8d displayed in vitro immunomodulatory effects by promoting HepG2 cell death in a HepG2/Jurkat cell co-culture model. Furthermore, 8d effectively inhibited tumor growth (TGI = 74.6% at 40 mg/kg) in a melanoma tumor model in mice without causing obvious toxicity. Moreover, 8d exhibited favorable pharmacokinetics [e.g. high stability, reasonable half-life, and good oral bioavailability (F = 21.5%)]. Finally, molecular modeling studies showed that 8d bound to PD-L1 with high affinity. These results suggest that 8d may serve as a starting point for further development of macrocyclic small molecule-based PD-1/PD-L1 inhibitors for cancer treatment.

Maternal transfer of resorcinol-bis(diphenyl)-phosphate perturbs gut microbiota development and gut metabolism of offspring in rats.

Resorcinol-bis(diphenyl)-phosphate (RDP), an emerging organophosphate flame retardant, is increasingly used as a primary alternative for decabromodiphenyl ether and is frequently detected in global environmental matrices. However, the long-term effects of its exposure to humans remain largely unknown. To investigate its intergenerational transfer capacity and health risks, female Sprague Dawley rats were orally exposed to RDP from the beginning of pregnancy to the end of the lactation period. The RDP content, gut microbiota homeostasis, and metabolic levels were determined. RDP accumulation occurred in the livers of maternal rats and offspring and increased with exposure time. 16S rRNA gene sequencing showed that exposure to RDP during pregnancy and/or lactation significantly disrupted gut microbiota homeostasis, as evidenced by decreased abundance and diversity. In particular, the abundance of Turicibacter, Adlercreutzia, and YRC22 decreased, correlating significantly with glycollipic metabolism. This finding was consistent with the reduced levels of short-chain fatty acids, the crucial gut microbial metabolites. Meanwhile, RDP exposure resulted in changes in gut microbiome-related metabolism. Nine critical overlapping KEGG metabolic pathways were identified, and the levels of related differential metabolites decreased. Our results suggest that the significant adverse impacts of RDP on gut microbiota homeostasis and metabolic function may increase the long-term risks related to inflammation, obesity, and metabolic diseases.

Identification of a novel extracellular inhibitor of FGF2/FGFR signaling axis by combined virtual screening and NMR spectroscopy approach.

The aberrant activation of the fibroblast growth factor 2 (FGF2)/fibroblast growth factor receptor (FGFR) signalling pathway drives severe pathologies, including cancer development and angiogenesis-driven pathologies. The perturbation of the FGF2/FGFR axis via extracellular allosteric small inhibitors is a promising strategy for developing FGFR inhibitors with improved safety and efficacy for cancer treatment. We have previously investigated the role of new extracellular inhibitors, such as rosmarinic acid (RA), which bind the FGFR-D2 domain and directly compete with FGF2 for the same binding site, enabling the disruption of the functional FGF2/FGFR interaction. To select ligands for the previously identified FGF2/FGFR RA binding site, NMR data-driven virtual screening has been performed on an in-house library of non-commercial small molecules and metabolites. A novel drug-like compound, a resorcinol derivative named RBA4 has been identified. NMR interaction studies demonstrate that RBA4 binds the FGF2/FGFR complex, in agreement with docking prediction. Residue-level NMR perturbations analysis highlights that the mode of action of RBA4 is similar to RA in terms of its ability to target the FGF2/FGFR-D2 complex, inducing perturbations on both proteins and triggering complex dissociation. Biological assays proved that RBA4 inhibited FGF2 proliferative activity at a level comparable to the previously reported natural product, RA. Identification of RBA4 chemical groups involved in direct interactions represents a starting point for further optimization of drug-like extracellular inhibitors with improved activity.

Benvitimod inhibits MCM6-meditated proliferation of keratinocytes by regulating the JAK/STAT3 pathway.

BACKGROUND: Benvitimod (Tapinarof), as a small-molecule topical therapeutical aryl hydrocarbon receptor (AHR)-modulating agent, is in clinical development for treating psoriasis and atopic dermatitis. Benvitimod reduces proinflammatory cytokines in psoriasis by specifically binding and activation of AHR. However, whether benvitimod can inhibit keratinocyte proliferation remains unclear. Minichromosome maintenance protein 6 (MCM6) is a key element of the prereplication complex (pre-RC) assembly which is one of the essential steps in the initiation of DNA replication for cell proliferation. OBJECTIVES: This study aimed to determine whether benvitimod could reduce the excessive proliferation of psoriatic keratinocytes by inhibiting MCM6. METHODS: We examined the inhibitory effect of benvitimod on MCM6-mediated proliferation of keratinocytes by HaCaT cells in vitro and an IMQ-induced psoriatic model of mice in vivo. RESULTS: Epidermal MCM6 expression was enhanced in the skin lesions of psoriatic patients. The experiments further revealed that MCM6 was required for the proliferation of keratinocytes and governed by the IL-22/STAT3 pathway. In addition, the antiproliferation effect of benvitimod is achieved by the inhibition of p-JAK1 and p-JAK2, which further restrained the activation of STAT3 in keratinocytes. Lastly, benvitimod could repressed imiquimod-induced skin lesions and the expression of epidermal MCM6 and p-STAT3 in mice. Moreover, knockdown of AHR in keratinocytes enhanced the activation of JAK1 and JAK2. CONCLUSION: The findings reveal that benvitimod could decrease MCM6-mediated proliferation of keratinocytes by affecting the JAK/STAT3 pathway, thereby serving as a new treatment modality for psoriasis.

Resorcinol-based hemiindigoid derivatives as human tyrosinase inhibitors and melanogenesis suppressors in human melanoma cells.

Human tyrosinase (hsTYR) catalyzes the key steps of melanogenesis, making it a privileged target for reducing melanin production in vivo. However, very few hsTYR inhibitors have been reported so far in the literature, whereas thousands of mushroom tyrosinase (abTYR) inhibitors are known. Yet, as these enzymes are actually very different, including at their active sites, there is an urgent need for new true hsTYR inhibitors in order to enable human-directed pharmacological and dermocosmetic applications without encountering the inefficiency and toxicity issues currently triggered by kojic acid or hydroquinone. Starting from the two most active compounds reported to date, i.e. a 2-hydroxypyridine-embedded aurone and thiamidol, we combined herein key structural elements and developed new nanomolar hsTYR inhibitors with cell-based activity. From a complete series of thirty-eight synthesized derivatives, excellent inhibition values were obtained for two compounds in both human melanoma cell lysates and purified hsTYR assays, and a promising improvement was observed in whole cell experiments.

Resorcinol alleviates alpha-terpineol-induced cell death in Schizosaccharomyces pombe via increased activity of the antioxidant enzyme Sod2.

Alpha-terpineol, popular monoterpenoid alcohol, is known to cause cytotoxicity in a few cancer cells or to have antioxidant activity, but underlying mechanisms or apoptotic processes in yeast cell death should be understood. We used the fission yeast (Schizosaccharomyces pombe) as a unicellular model to monitor cellular toxicology and physiological mechanisms for the involvement of alpha-terpineol in cell death. Alpha-terpineol caused Reactive oxygen species (ROS) overproduction and following cytotoxicity and apoptosis in a dose-dependent manner. The effect of oxidative stress was proved using sod1 and sod2 mutants (antioxidant-limited cells), and the results showed that apoptosis was caused by alpha-terpineol-driven oxidation. In addition, resorcinol, a herbal extract from medicinal plants, showed protective activity against alpha-terpineol cytotoxicity. Survival rates, apoptotic cell death ratios, oxidation levels, and antioxidant gene expressions were completely altered; surprisingly sod1 and sod2 levels dramatically increased. However, sod2 was highly upregulated in response to resorcinol treatment with alpha-terpineol. The potential role of the Sod2 enzyme was proved using sod2 mutant cells that do not have a mitochondrial radical-clearing activity. Consequently, the dose-dependent and ROS-mediated cytotoxic/apoptotic effects of alpha-terpineol and the Sod2-dependent protective and antioxidant effects of resorcinol were demonstrated in unicellular model organism S. pombe by this study.

Insilico Docking Study of Isoxazole Indole Linked Resorcinol Derivatives as Promising Selective Estrogen Receptor Modulators & Anticancer Drugs.

A series of 9 compounds with isoxazole-indole-γ-resorcylic acid scaffold, segregated into B1 & A1 series, wherein, B1 comprises compounds:1,3,4,5, & 9 and A1comprises compounds: 2,6,7, & 8 , on the basis of variable substituents at the indole , resorcinol and isoxazole end of the scaffold as in Fig. 1, were designed and docked with human estrogen receptor:1ERRα. The binding affinity (BA) and the interacting amino acids compared with reference selective estrogen receptor modulators (SERMs) such as Raloxifene, Estradiol, Bazedoxifene, Bisphenol, Genistein, Daidzein, Ormiloxifene,Tamoxifen,6-hydroxy-naphthalen-2yl-benzo(D)-isoxazol-6-ol(1)(WAY-397) using PyRx software and their ADME properties predicted with SWISS ADME online tool. Significant similarities and minor differences in the binding pattern between the key interacting aminoacids such as Arg 394,Glu 353, Asp 351, Leu 346, Leu 525, Trp 383,Phe 404 ,Ala 350, Leu 387, Met 421 responsible for ER agonist/antagonist activity found in the binding cavity of a 1 Errα -Bazedoxifene/1 Errα -raloxifene/1 Errα -estradiol docked complex AND 1 Errα -isoxazole-indole- resorcinol docked complex indicate their promising potential to serve as potent ER agonists in bone or ER antagonists against breast cancer and other cancer diseases. The Compounds with Highest BA is of the order: BA (A1series)>B1 series & BA(6)=BA(8)>BA(7)>BA(2)>BA(9)=BA(1)>BA(3)>BA(4)=BA(5).

Analysis of the multi-physiological and functional mechanism of wheat alkylresorcinols based on reverse molecular docking and network pharmacology.

Alkylresorcinols (ARs) are phenolic lipids present in the bran part of whole grain wheat and rye, which possess antioxidant, anti-inflammatory, anti-cancer and anti-tumor properties. The physiological activities of ARs have been proven to be diverse; however, the specific molecular mechanisms are still unclear. In this study, reverse virtual screening and network pharmacology were used to explore the potential molecular mechanisms of the physiological function of ARs and their endogenous metabolites. The Metascape database was used for GO enrichment and KEGG pathway analysis. Furthermore, molecular docking was used to investigate the interactions between active compounds and potential targets. The results showed that the bioavailability of most ARs and their endogenous metabolites was 0.55 and 0.56, while the bioavailability of certain endogenous metabolites was only 0.11. Multiplex analysis was used to screen 73 important targets and 4 core targets (namely, HSP90AA1, EP300, HSP90AB1 and ERBB2) out of the 163 initial targets. The important targets involved in the key KEGG pathway were pathways in cancer (hsa05200), lipid and atherosclerosis (hsa05417), Th17 cell differentiation (hsa04659), chemical carcinogenesis-receptor activation (hsa05207), and prostate cancer (hsa05215). The compounds involved in the core targets were AR-C21, AR-C19, AR-C17, 3,5-DHPHTA-S, 3,5-DHPHTA-G, 3,5-DHPPTA, 3,5-DHPPTA-S, 3,5-DHPPTA-G, 3,5-DHPPTA-Gly and 3,5-DHPPA-G. The interaction force between them was mainly related to hydrogen bonds and van der Waals. Overall, the physiological activities of ARs are not only related to their multiple targets, but may also be related to the synergistic effect of their endogenous metabolites.

Design, synthesis, and biological evaluation of novel dual inhibitors of heat shock protein 90/mammalian target of rapamycin (Hsp90/mTOR) against bladder cancer cells.

In this study, a novel class of thieno [2,3-d] pyrimidine derivatives containing resorcinol and morpholine fragments as Hsp90/mTOR dual inhibitors was designed, synthesized, and evaluated. In vitro anti-tumor assay results: the obtained compounds demonstrated effectiveness in suppressing the enzymatic activities of the Hsp90 and mTOR and inhibiting the proliferation of J82, T24, and SW780 cancer cell lines. Among these dual inhibitors, the most potent compound 17o, confirmed remarkable inhibitory activities on Hsp90, mTOR, and SW780 cell. Furthermore, the molecular dynamics simulation and a panel of mechanism studies revealed that inhibitor 17o suppressed the proliferation of SW780 cells through the over-activation of the PI3K/AKT/mTOR pathway regulated by mTOR inhibition and apoptosis regulated by the mitochondrial pathway. In subcutaneous J82 xenograft models, the compound 17o also presented considerable in vivo anti-tumor activity. Therefore, our investigations highlight that a new-found dual Hsp90/mTOR inhibitor by rational drug design strategies could be a promising lead compound for targeted bladder cancer therapy and deserves further studies.

Anti-breast Adenocarcinoma and Anti-urease Anti-tyrosinase Properties of 5-Pentylresorcinol as Natural Compound with Molecular Docking Studies.

5-Pentylresorcinol is a type of the group of resorcinol compounds that is resorcinol in that has hydrogen atom at position 5 is replaced by a pentyl group. It has a role as a lichen metabolite. This compound showed excellent to good inhibitory activities against studied these enzymes with IC50 values of 65.96 µM for urease and 34.81 µM for tyrosinase. Standard compounds for enzymes had IC50 values of 1.94±0.24 µM against urease and 84.36±5.17 µM against tyrosinase. The IC50 of 5-pentylresorcinol against MCF7 cell line was 165.72 µg/mL; against Hs 578Bst cell line was 102.14 µg/mL; against Hs 319.T cell line was 12.34 µg/mL; and against UACC-3133 cell line was 73.07 µg/mL, respectively. The chemical activities of 5-pentylresorcinol against urease and tyrosinase were evaluated using the molecular modeling study. The anti-cancer activity of 5-pentylresorcinol was also investigated by treating the compound on the BRCT repeat region from the breast cancer-associated protein (BRCA1), and their interactions were assessed utilizing the molecular docking calculations. The results revealed the probable interactions and their characteristics at an atomic level. The docking scores of 5-pentylresorcinol against urease, tyrosinase, and BRCA1 are -3.073, -5.262, and -3.238 (kcal/mol), respectively.

Sesquiterpene and Sorbicillinoid Glycosides from the Endophytic Fungus Trichoderma longibrachiatum EN-586 Derived from the Marine Red Alga Laurencia obtusa.

An unusual sesquiterpene glycoside trichoacorside A (1) and two novel sorbicillinoid glycosides sorbicillisides A (2) and B (3), together with a known compound sorbicillin (4), were isolated and identified from the culture extract of an endophytic fungus Trichoderma longibrachiatum EN-586, obtained from the marine red alga Laurencia obtusa. Trichoacorside A (1) is the first representative of a glucosamine-coupled acorane-type sesquiterpenoid. Their structures were elucidated based on detailed interpretation of NMR and mass spectroscopic data. The absolute configurations were determined by X-ray crystallographic analysis, chemical derivatization, and DP4+ probability analysis. The antimicrobial activities of compounds 1-4 against several human, aquatic, and plant pathogens were evaluated.

Topical application of TAK1 inhibitor encapsulated by gelatin particle alleviates corneal neovascularization.

Rationale: Corneal neovascularization (CoNV) is a severe complication of various types of corneal diseases, that leads to permanent visual impairment. Current treatments for CoNV, such as steroids or anti-vascular endothelial growth factor agents, are argued over their therapeutic efficacy and adverse effects. Here, we demonstrate that transforming growth factor-ß (TGF-ß)-activated kinase 1 (TAK1) plays an important role in the pathogenesis of CoNV. Methods: Angiogenic activities were assessed in ex vivo and in vitro models subjected to TAK1 inhibition by 5Z-7-oxozeaenol, a selective inhibitor of TAK1. RNA-Seq was used to examine pathways that could be potentially affected by TAK1 inhibition. A gelatin-nanoparticles-encapsulated 5Z-7-oxozeaenol was developed as the eyedrop to treat CoNV in a rodent model. Results: We showed that 5Z-7-oxozeaenol reduced angiogenic processes through impeding cell proliferation. Transcriptome analysis suggested 5Z-7-oxozeaenol principally suppresses cell cycle and DNA replication, thereby restraining cell proliferation. In addition, inhibition of TAK1 by 5Z-7-oxozeaenol blocked TNFα-mediated NFκB signalling, and its downstream genes related to angiogenesis and inflammation. 5Z-7-oxozeaenol also ameliorated pro-angiogenic activity, including endothelial migration and tube formation. Furthermore, topical administration of the gelatin-nanoparticles-encapsulated 5Z-7-oxozeaenol led to significantly greater suppression of CoNV in a mouse model compared to the free form of 5Z-7-oxozeaenol, likely due to extended retention of 5Z-7-oxozeaenol in the cornea. Conclusion: Our study shows the potential of TAK1 as a therapeutic target for pathological angiogenesis, and the gelatin nanoparticle coupled with 5Z-7-oxozeaenol as a promising new eyedrop administration model in treatment of CoNV.

A new resorcinol derivative from the bark of Aegiceras floridum (Primulaceae).

Chemical investigation of the Vietnamese plant Aegiceras floridum Roem. & Schult. (Primulaceae) led to the isolation of the new compound 3-methoxy-5-nonylphenol (1) along with five known ones 2,8,10-trihydroxy-6H-benzo[c]chromen-6-one (2), 2-hydroxy-5-methoxy-3-nonylbenzo-1,4-quinone (3), 5-(3-hydroxypropyl)-7-methoxy-3-(methylbenzofuran-2-yl)-3-methoxyphenol (4), 2,8-dihydroxy-7-methoxy-3,9-diundecyldibenzofuran-1,4-dione (5) and 10-hydroxy-4-methoxy-2,11-diundecylgomphilactone (6). The structures were elucidated by analysis of their HRESIMS and NMR data as well as the comparison of their NMR data with those reported in the literature. The cytotoxic activity of selected isolated compounds against some cancer cell lines such as human epithelial carcinoma (HeLa), human lung cancer (NCI-H460), liver hepatocellular carcinoma (HepG2), human breast cancer (MCF-7), and acute T cell leukemia (Jurkat) was evaluated. Among them, 3 showed moderate activities against MCF-7 with an IC50 of 17.77 µM and NCI-H460 with an IC50 of 25.02 µM. The result of DPPH radical scavenging activity assay indicated that compounds 2-4 and 6 revealed weak antioxidant activity.

Four new resorcinol derivatives with neuroprotective activities from Xylaria nigripes.

Four new resorcinol derivatives, namely (-)/(+)-xylarinig A (1), as well as xylarinigs B (2) and C (3), were isolated from the ethyl acetate extracts of the solid fermentation of Xylaria nigripes. Their structures were established by comprehensive spectroscopic analysis combined with electronic circular dichroism (ECD) calculations. Compound 1 is an optical mixture, and was resoluted into optical pure enatiomers (+)-1 and (-)-1 by chiral HPLC. The neuroprotective effects of 1-3 against the damage of PC12 cells induced by oxygen and glucose deprivation (OGD) were evaluated.

A heat shock protein 90 inhibitor reduces oncoprotein expression and induces cell death in heterogeneous glioblastoma cells with EGFR, PDGFRA, CDK4, and NF1 aberrations.

AIMS: Glioblastoma (GBM) is a highly malignant brain tumor. After treatment with the first-line drug temozolomide, only 50% of patients are responsive. Recent literature shows that the difficulty in treating GBM is mainly due to the heterogeneity of its four major cellular states, which are characterized by differences in EGFR, PDGFRA, CDK4, and NF1. Therefore, development of a multitarget drug is a potential strategy for treating heterogeneous GBM. MAIN METHODS: In this study, the antitumor ability of a potent heat shock protein 90 inhibitor, NVP-AUY922 (AUY922), was evaluated in GBM cell lines (U-87 MG and T98G cells) and patient-derived GBM cell lines [P#5 and P#5 temozolomide-resistant (TMZ-R) cells]. KEY FINDINGS: We found that AUY922 significantly reduced cell viability and colony formation in four GBM cell lines. AUY922 also significantly induced apoptosis by increasing PARP1 cleavage and the number of annexin V-positive cells. The autophagy indicators as MAP1LC3B cleavage and MAP1LC3B puncta were increased after AUY922 treatment. AUY922-induced cell death could be partially reversed by pharmacological inhibition of either apoptotic inhibitor or autophagy inhibitor. Moreover, AUY922 reduced the mRNA and protein expressions of EGFR, PDGFRA, CDK4, and NF1, which contribute to the four cellular state subtypes in GBM cells. In addition, the downstream signaling proteins of these four proteins, AKT/p-AKT, MAPK/p-MAPK, and BRAF, were downregulated after AUY922 treatment. SIGNIFICANCE: Taken together, AUY922 led to GBM cell death via apoptosis and autophagy, and reduced the mRNA and protein expression of EGFR, PDGFRA, CDK4, and NF1in heterogeneous GBM cells.

Discovery of Resorcinol-Based Polycyclic Structures as Tyrosinase Inhibitors for Treatment of Parkinson's Disease.

Tyrosinase is involved in the synthesis of neuromelanin in the substantia nigra, which is closely correlated with the pathogenesis of Parkinson's disease. Herein, we identified S05014 (l-Tyr, IC50 = 6.25 ± 1.43 nM; l-Dopa, IC50 = 0.64 ± 0.40 µM) as a highly effective tyrosinase inhibitor. It could inhibit the tyrosinase function from different origins and decrease the expression of tyrosinase. S05014 presented good medication safety and inhibited melanogenesis in a dose-dependent manner. Moreover, as a resorcinol derivative, S05014 could scavenge the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical and significantly reduce the overproduction of LPS-induced reactive oxidative species (ROS), indicating its antioxidative profile. S05014 exhibited an excellent neuroprotective effect against methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) impairment in vitro and could remarkably alleviate movement abnormalities and exploratory activities in vivo. Altogether, S05014 is considered as a promising inhibitor for tyrosinase, melanogenesis, and oxidative stress and has great potential to be utilized in anti-Parkinsonian syndrome. From this point of view, tyrosinase inhibition has been further confirmed to be a novel strategy to improve locomotor capacity and treat Parkinson's disease.

Abnormal cannabidiol ameliorates inflammation preserving pancreatic beta cells in mouse models of experimental type 1 diabetes and beta cell damage.

The atypical cannabinoid Abn-CBD improves the inflammatory status in preclinical models of several pathologies, including autoimmune diseases. However, its potential for modulating inflammation in autoimmune type 1 diabetes (T1D) is unknown. Herein we investigate whether Abn-CBD can modulate the inflammatory response during T1D onset using a mouse model of T1D (non-obese diabetic- (NOD)-mice) and of beta cell damage (streptozotocin (STZ)-injected mice). Six-week-old female NOD mice were treated with Abn-CBD (0.1-1 mg/kg) or vehicle during 12 weeks and then euthanized. Eight-to-ten-week-old male C57Bl6/J mice were pre-treated with Abn-CBD (1 mg/kg of body weight) or vehicle for 1 week, following STZ challenge, and euthanized 1 week later. Blood, pancreas, pancreatic lymph nodes (PLNs) and T cells were collected and processed for analysis. Glycemia was also monitored. In NOD mice, treatment with Abn-CBD significantly reduced the severity of insulitis and reduced the pro-inflammatory profile of CD4+ T cells compared to vehicle. Concomitantly, Abn-CBD significantly reduced islet cell apoptosis and improved glucose tolerance. In STZ-injected mice, Abn-CBD decreased circulating proinflammatory cytokines and ameliorated islet inflammation reducing intra-islet phospho-NF-κB and TXNIP. Abn-CBD significantly reduced 2 folds intra-islet CD8+ T cells and reduced Th1/non-Th1 ratio in PLNs of STZ-injected mice. Islet cell apoptosis and intra-islet fibrosis were also significantly reduced in Abn-CBD pre-treated mice compared to vehicle. Altogether, Abn-CBD reduces circulating and intra-islet inflammation, preserving islets, thus delaying the progression of insulitis. Hence, Abn-CBD and related compounds emerge as new candidates to develop pharmacological strategies to treat the early stages of T1D.

Synthesis and Antimicrobial Activity of δ-Viniferin Analogues and Isosteres.

The natural stilbenoid dehydro-δ-viniferin, containing a benzofuran core, has been recently identified as a promising antimicrobial agent. To define the structural elements relevant to its activity, we modified the styryl moiety, appended at C5 of the benzofuran ring. In this paper, we report the construction of stilbenoid-derived 2,3-diaryl-5-substituted benzofurans, which allowed us to prepare a focused collection of dehydro-δ-viniferin analogues. The antimicrobial activity of the synthesized compounds was evaluated against S. aureus ATCC29213. The simplified analogue 5,5'-(2-(4-hydroxyphenyl)benzofuran-3,5-diyl)bis(benzene-1,3-diol), obtained in three steps from 4-bromo-2-iodophenol (63% overall yield), emerged as a promising candidate for further investigation (MIC = 4 µg/mL).

Aureonitol Analogues and Orsellinic Acid Esters Isolated from Chaetomium elatum and Their Antineuroinflammatory Activity.

Overexpression of various pro-inflammatory factors in microglial cells tends to induce neurodegenerative diseases, for which there is no effective therapy available. Aureonitol (1) and seven analogues, including six previously undescribed [elatumenol A-F (2-4, 6-8, respectively)], along with two new orsellinic acid esters [elatumone A and B (9 and 10)], were isolated from Chaetomium elatum. The structures of the compounds were established through comprehensive analysis of spectroscopic data, including high-resolution mass spectra and one- and two-dimensional NMR, and absolute configurations determined by the Mosher method, dimolybdenum tetraacetate-induced circular dichroism, and theoretical calculations including electronic circular dichroism and NMR. Metabolites 3, 4, 7, and 8 exhibited antineuroinflammatory activity by attenuating the production of inflammatory mediators, such as nitric oxide, interleukin-6, interleukin-1ß, tumor necrosis factor-α, and reactive oxygen species. Western blot results indicated 8 decreases the level of inducible nitric oxide synthase and cyclooxygenase-2 and suppresses the expression of Toll-like receptor 4 and nuclear factor kappa-B (NF-κB) as well as the phosphorylation of the inhibitor of NF-κB and p38 mitogen-activated protein kinases in lipopolysaccharide-activated BV-2 microglial cells.