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Acute myocardial infarction (AMI) is a prevalent cardiovascular disease with high morbidity and mortality rates worldwide. Pyroptosis is an inflammatory form of programmed cell death that has been linked to various pathological conditions. However, its exact contribution to the onset and progression of heart injury in AMI has not yet fully elucidated. Herein, we established mouse AMI model by ligating the left anterior descending artery and performed transcriptome analysis during the early phase of AMI. Mouse HL-1 and human AC-16 cardiomyocytes were subjected to hypoxia to simulate ischemic injury in vitro. Our results revealed a significant activation of the inflammatory response at 3 h post-ligation, as confirmed by RNA sequencing. We identified the occurrence of NLRP3 inflammasome-mediated pyroptosis in the cardiac tissues of human cases with AMI, as well as in mouse models of AMI and hypoxia-induced cardiomyocytes, using immunohistochemistry staining and Western blotting assays. Concurrently, pharmacological inhibition of NLRP3 inflammasome-mediated pyroptosis with MCC950 and VX-765 effectively decreased hypoxia-induced cardiomyocytes injury, while mitigating myocardial oxidative stress, apoptosis and inflammation caused by hypoxia. Moreover, the circulating levels of gasdermin D (GSDMD), the pyroptosis executor, were remarkably elevated in the plasma of mice with early AMI and in the supernatant of hypoxia-exposed cardiomyocytes in a time-dependent manner using ELISA and Western blotting. Furthermore, the change in circulating GSDMD positively correlated with Creatine Kinase-MB (CK-MB) in the plasma of early-stage AMI mouse. In summary, these findings indicated a critical role for NLRP3 inflammasome-mediated pyroptosis in the progression of AMI, the administration of MCC950 and VX-765 may be attractive candidate therapeutic approaches for cardiac injury caused by acute hypoxia or even AMI. Additionally, the circulating GSDMD exhibits potential as a newly diagnostic biomarker for AMI., Competing Interests: Declaration of competing interest All authors declare no competing interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

FR901464 is a natural product that exhibits antiproliferative activity at single-digit nanomolar concentrations in cancer cells. Its tetrahydropyran-spiroepoxide covalently binds the spliceosome. Through our medicinal chemistry campaign, we serendipitously discovered that a bromoetherification formed a tetrahydrofuran. The tetrahydrofuran analog was three orders of magnitude less potent than the corresponding tetrahydropyran analogs. This study shows the significance of the tetrahydropyran ring that presents the epoxide toward the spliceosome., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: John C. Schmitz reports financial support was provided by UPMC Hillman Cancer Center NCI Cancer Center Support Grant Developmental Funds. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Depression is a psychiatric disorder associated with multiple factors including microglia-mediated neuroinflammation. Although atractylodin exerted a variety of biological activities, however the effect of atractylodin on neuroinflammation-related depression was still unclear. In this study, the lipopolysaccharide (LPS)-induced mouse model was used to explore the antidepressant effects and molecular mechanisms of atractylodin. The results showed that atractylodin increased sugar preference, also reduced immobility time in FST and TST. Further study showed atractylodin reduced the oxidative stress and the activation of microglia in mouse hippocampus, also inhibited the level of cytokine release, especially IL-1β. The results of western blotting showed that atractylodin significantly inhibited the expression of NLRP3 and pro-IL1β via inhibition of NF-κB pathway. Our studies showed that atractylodin upregulated BDNF/Akt pathway in mouse hippocampus. Therefore, this study firstly indicated that atractylodin can ameliorate lipopolysaccharide-induced depressive-like behaviors in mice through reducing neuroinflammation and neuronal damage, and its molecular mechanism may be associated with the decrease of the expression of NLRP3 inflammasome and upregulation of BDNF/Akt pathway., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Although the pathogenesis of choroidal neovascularization (CNV) is largely unknown in age-related macular degeneration (AMD), inflammasomes may contribute to CNV development and progression. To understand the role NLRP3 inflammasomes in CNV, we used Ccr2RFPCx3cr1GFP dual-reporter mice and immunostaining techniques to confirm localization of NLRP3 inflammasomes in the laser-induced CNV (LCNV) lesions. Confocal microscopy was used to image and quantify LCNV volumes. MCC950 was used as NLRP3 inhibitor. ELISA and quantitative RT-PCR were used to confirm the activation of NLRP3 by monitoring the expression of IL-1β protein and mRNA in choroidal tissues from LCNV mice. In addition, NLRP3 (-/-) LCNV mice were used to investigate whether NLRP3 inflammasomes contribute to the development of LCNV lesions. We observed that red fluorescent protein (RFP)-positive monocyte-derived macrophages and GFP-positive microglia-derived macrophages, in addition to other cell types, were localized in LCNV lesions at day 7 post-laser injury. In addition, NLRP3 inflammasomes are associated with LCNV lesions. Inhibition of NLRP3 inflammasomes, using MCC950, caused an increased Ccr2RFP-positive macrophages, Cx3cr1GFP-positive microglia, and other cells, resulting in an increase in total lesion size. NLRP3 (-/-) LCNV mice showed significantly increased lesion size compared with age-matched controls. Inhibition of NLRP3 resulted in decreased IL-1β mRNA and protein expression in the choroidal tissues, suggesting that increased lesion size may not be directly related to IL-1β., (Copyright © 2024 The Authors.)

Microglia are key immune cells in the brain that maintain homeostasis and defend against immune threats. Targeting the dysfunctional microglia is one of the most promising approaches to inhibit neuroinflammation. In the current study, a diverse series of molecular hybrids were designed and screened through molecular docking against two neuroinflammatory targets, namely HMGB1 (2LY4) and HMGB1 Box A (4QR9) proteins. Based on the outcomes of docking scores fifteen compounds; ten furanyl-pyrazolyl acetamides 11(a-j), and five 2,4-thiazolidinyl-furan-3-carboxamide 15(a-e) derivatives were selected for further synthesis, followed by biological evaluation. The selected compounds, 11(a-j) and 15(a-e) were successfully synthesized with moderate to good yields, and structures were confirmed by IR, NMR, and mass spectra. The in-vitro cytotoxicity was evaluated on microglial cells namely BV-2, N-9, HMO6, leukemic HAP1, and human fibroblast cells. Further western-blot analysis revealed that 11h, 11f, 11c, 11j, 15d, 15c, 15e, and 15b compounds significantly suppressed anti-inflammatory markers such as TNF-α, IL-1, IL-6, and Bcl-2. All derivatives were moderate in potency compared to reference doxorubicin and could potentially act as novel anti-neuroinflammatory agents. This study can act as a beacon for further research in the application of furan-pyrazole and furan-2,4-thiazolidinediones as lead moieties for anti-neuroinflammatory and related diseases., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Coordinated morphogenic adaptation of growing plants is critical for their survival and propagation under fluctuating environments. Plant morphogenic responses to light and warm temperatures, termed photomorphogenesis and thermomorphogenesis, respectively, have been extensively studied in recent decades. During photomorphogenesis, plants actively reshape their growth and developmental patterns to cope with changes in light regimes. Accordingly, photomorphogenesis is closely associated with diverse growth hormonal cues. Notably, accumulating evidence indicates that light-directed morphogenesis is profoundly affected by two recently identified phytochemicals, karrikins (KARs) and strigolactones (SLs). KARs and SLs are structurally related butenolides acting as signaling molecules during a variety of developmental steps, including seed germination. Their receptors and signaling mediators have been identified, and associated working mechanisms have been explored using gene-deficient mutants in various plant species. Of particular interest is that the KAR and SL signaling pathways play important roles in environmental responses, among which their linkages with photomorphogenesis are most comprehensively studied during seedling establishment. In this review, we focus on how the phytochemical and light signals converge on the optimization of morphogenic fitness. We also discuss molecular mechanisms underlying the signaling crosstalks with an aim of developing potential ways to improve crop productivity under climate changes., (© 2023 Institute of Botany, Chinese Academy of Sciences.)

Objective: To evaluate the effects of NLRP3 inflammasome inhibition or knockout in experimental apical periodontitis (AP) induced in mice., Methods: The experimental AP was induced by pulpal exposure. To evaluate NLRP3-specific inhibitor medication (MCC950), WT mice received intraperitoneal injections, while the control received PBS (n = 10). In addition, to evaluate NLRP3 knockout, 35 wild-type (WT) and 35 NLRP3 -/- mice were divided into a control group (without pulpal exposure, n = 5) and three experimental groups: after 2, 14 and 42 days after pulpal exposure (n = 10). Microscopic and molecular analyzes were carried out using a significance level of 5%., Results: Exposure to MCC950 did not affect the periapical lesion size after 14 days (P = 0.584). However, exposed mice had a lower expression of IL-1β, IL-18 and caspase-1 (P = 0.010, 0.016 and 0.002, respectively). Moreover, NLRP3 -/- mice showed a smaller periapical lesion after 14 and 42 days (P = 0.023 and 0.031, respectively), as well as a lower expression of IL-1β after 42 days (P < 0.001), of IL-18 and caspase-1 after 14 (P < 0.001 and 0.035, respectively) and 42 days (P = 0.002 and 0.002, respectively). NLRP3 -/- mice also showed a lower mRNA for Il-1β, Il-18 and Casp1 after 2 (P = 0.002, 0.036 and 0.001, respectively) and 14 days (P = 0.002, 0.002 and 0.001, respectively)., Conclusions: NLRP3 inflammasome inhibition or knockout can attenuate the inflammatory events that result in the periapical lesion (AP) formation after pulpal exposure in mice., Clinical Relevance: The NLRP3 inflammasome may be a therapeutic target for AP, and new approaches may verify the impact of its inhibition (through intracanal medications or filling materials) on the bone repair process and treatment success., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Myocarditis substantially increases the risk of ventricular arrhythmia. Approximately 30% of all ventricular arrhythmia cases in patients with myocarditis originate from the right ventricular outflow tract (RVOT). However, the role of NLRP3 signaling in RVOT arrhythmogenesis remains unclear., Methods: Rats with myosin peptide-induced myocarditis (experimental group) were treated with an NLRP3 inhibitor (MCC950; 10 mg/kg, daily for 14 days) or left untreated. Then, they were subjected to electrocardiography and echocardiography. Ventricular tissue samples were collected from each rat's RVOT, right ventricular apex (RVA), and left ventricle (LV) and examined through conventional microelectrode and histopathologic analyses. In addition, whole-cell patch-clamp recording, confocal fluorescence microscopy, and Western blotting were performed to evaluate ionic currents, intracellular Ca 2+ transients, and Ca 2+ -modulated protein expression in individual myocytes isolated from the RVOTs., Results: The LV ejection fraction was lower and premature ventricular contraction frequency was higher in the experimental group than in the control group (rats not exposed to myosin peptide). Myocarditis increased the infiltration of inflammatory cells into cardiac tissue and upregulated the expression of NLRP3; these observations were more prominent in the RVOT and RVA than in the LV. Furthermore, experimental rats treated with MCC950 (treatment group) improved their LV ejection fraction and reduced the frequency of premature ventricular contraction. Histopathological analysis revealed higher incidence of abnormal automaticity and pacing-induced ventricular tachycardia in the RVOTs of the experimental group than in those of the control and treatment groups. However, the incidences of these conditions in the RVA and LV were similar across the groups. The RVOT myocytes of the experimental group exhibited lower Ca 2+ levels in the sarcoplasmic reticulum, smaller intracellular Ca 2+ transients, lower L-type Ca 2+ currents, larger late Na + currents , larger Na + -Ca 2+ exchanger currents, higher reactive oxygen species levels, and higher Ca 2+ /calmodulin-dependent protein kinase II levels than did those of the control and treatment groups., Conclusion: Myocarditis may increase the rate of RVOT arrhythmogenesis, possibly through electrical and structural remodeling. These changes may be mitigated by inhibiting NLRP3 signaling., (© 2024. The Author(s).)

Plasma cell mastitis (PCM) is a sterile inflammatory condition primarily characterized by periductal inflammation and ductal ectasia. Currently, there is a lack of non-invasive or minimally invasive treatment option other than surgical intervention. The NLRP3 inflammasome has been implicated in the pathogenesis and progression of various inflammatory diseases, however, its involvement in PCM has not yet been reported. In this study, we initially observed the pronounced upregulation of NLRP3 in both human and mouse PCM tissue and elucidated the mechanism underlying the attenuation of PCM through inhibition of NLRP3. We established the PCM murine model and collected samples on day 14, when inflammation reached its peak, for subsequent research purposes. MCC950, an NLRP3 inhibitor, was utilized to effectively ameliorate PCM by significantly reducing plasma cell infiltration in mammary tissue, as well as attenuate the expression of pro-inflammatory cytokines including IL-1β, TNF-α, IL-2, and IL-6. Mechanistically, we observed that MCC950 augmented the function of myeloid-derived suppressor cells (MDSCs), which in turn inhibited the infiltration of plasma cells. Furthermore, it was noted that depleting MDSCs greatly compromised the therapeutic efficacy of MCC950. Collectively, our findings suggest that the administration of MCC950 has the potential to impede the progression of PCM by augmenting MDSCs both numerically and functionally, ultimately treating PCM effectively. This study provides valuable insights into the utilization of pharmacological agents for PCM treatment., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Inhibition of the NLRP3 inflammasome is a promising strategy for the development of new treatments for inflammatory diseases. MCC950 is a potent and selective small-molecule inhibitor of the NLRP3 pathway and has been validated in numerous species and disease models. Although the capacity of MCC950 to block NLRP3 signaling is well-established, it is still critical to identify the mechanism of action and molecular targets of MCC950 to inform and derisk drug development. Quantitative proteomics performed in disease-relevant systems provides a powerful method to study both direct and indirect pharmacological responses to small molecules to elucidate the mechanism of action and confirm target engagement. A comprehensive target deconvolution campaign requires the use of complementary chemical biology techniques. Here we applied two orthogonal chemical biology techniques: compressed Cellular Thermal Shift Assay (CETSA) and photoaffinity labeling chemoproteomics, performed under biologically relevant conditions with LPS-primed THP-1 cells, thereby deconvoluting, for the first time, the molecular targets of MCC950 using chemical biology techniques. In-cell chemoproteomics with inlysate CETSA confirmed the suspected mechanism as the disruption of inflammasome formation via NLRP3. Further cCETSA (c indicates compressed) in live cells mapped the stabilization of NLRP3 inflammasome pathway proteins, highlighting modulation of the targeted pathway. This is the first evidence of direct MCC950 engagement with endogenous NLRP3 in a human macrophage cellular system using discovery proteomics chemical biology techniques, providing critical information for inflammasome studies.

Objective: To study the effect of arctigenin(ARG) on adriamycin(ADM) resistance of leukemia cell line K562/A02 and the underlying mechanism., Methods: Human leukemia cell line K562 and ADM-resistant cell line K562/A02 were cultured and treated with 2.5-50 µmol/L ADM. Cell proliferation was measured using CCK-8 method, and half maximal inhibitory concentration (IC 50 ) was calculated. K562/A02 cells were treated with different concentrations of ARG (1, 2, 4, 8, 16 mmol/L) to detect the effect of ARG on K562/A02 cells, and a suitable concentration (2 mmol/L) was selected for subsequent experiments. K562/A02 cells were treated with 2 mmol/L ARG and 5 µmol/L ADM, and cell apoptosis was detected by flow cytometry, the expression of P-gp, MRP, cleaved caspase-3, Bax, Bcl-2 proteins and the TLR4/NF-κB signaling pathway-related proteins were measured by Western blot. TLR4 overexpression plasmid was transfected into K562/A02 cells which were co-treated with ARG and ADM, then drug sensitivity and cell apoptosis were measured., Results: The IC 50 value of ADM on K562/A02 cells was 36.57 µmol/L, which was significantly higher than that on K562 cells (1.30 µmol/L). ARG with a concentration of ≤2 mmol/L did not have a significant effect on K562/A02 cells. 2 mmol/L ARG significantly reduced the IC 50 of ADM on K562/A02 cells. In 5 µmol/L ADM-treated K562/A02 cells, compared with the control group, the apoptosis rate of K562/A02 cells in the ARG group was significantly increased, the expressions of cleaved caspase-3, Bax proteins were significantly upregulated, the expressions of P-gp, MRP, Bcl-2, TLR4, MyD88, and p-NF-κB proteins were significantly downregulated, and the differences were statistically significant ( P < 0.05). After transfection with TLR4 overexpression plasmid, the sensitivity of ARG-treated K562/A02 cells to ADM was reduced ( P < 0.05), the cell apoptosis was decreased, and the expressions of P-gp, MRP, Bcl-2 and TLR4/NF-κB signaling pathway-related proteins were significantly elevated, while the expressions of cleaved caspase-3 and Bax proteins were significantly decreased (all P < 0.05)., Conclusion: ARG may reverse the resistance of human leukemia cell line K562/A02 to ADM by inhibiting TLR4/NF-κB signaling pathway.

Three new annonaceous acetogenins, annotemoyin L ( 1 ), annotemoyin Y ( 2 ) and annotemoyin X, ( 3 ) were isolated from the seeds of Annona squamosa Linn. Their structures were ascertained by chemical methods and spectral data. The cytotoxic activities of compounds against three multidrug-resistant cancer cell lines were evaluated, and compound 3 exerted strong cytotoxicity against SMMC 7721/ADR (IC 50 0.163 μM), A549/T (IC 50 0.064 μM) and MCF-7/ADR (IC 50 0.057 μM).

N 6 -[(Furan-2-yl)methyl]adenosine (kinetin riboside) and its seven synthesized analogues were examined for the ability to inhibit the growth of five human carcinoma cell lines and for comparison of normal human lung fibroblast cell line (MRC-5). Out of the compounds evaluated, 8-azakinetin riboside was shown to exhibit significant cytotoxic activity for 72 h treatment against ovarian OVCAR-3 and pancreatic MIA PaCa-2 cancer cells (IC 50  = 1.1 μM) with an observed weaker effect against MRC-5 cells (IC 50  = 4.6 μM). Kinetin riboside, as well as its N 6 -[(furan-3-yl)methyl]- and N 6 -[(thien-2-yl)methyl]- counterparts, also exhibited cytotoxic activities at low micromolar levels but were non-selective over MRC-5 cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Herein, we report the results of anticancer screening of two 2-phenylbenzo[b]furan derivatives functionalised at the 3-position with 4-hydroxy-3,5-dimethoxybenzoyl (BF2) or 3,4,5-trimethoxybenzoyl (BF3) against 60 different cancer cell lines. The results confirmed the anticancer potential of the tested compounds against different cancer cell types, especially colon cancer, brain cancer and melanoma. BF3 was defined as the most potent (also as a tubulin polymerisation inhibitor). Its anticancer activity against melanoma cell lines that originated from different stages, i.e., primary skin-derived A375 and metastatic WM9/MDA-MB-435S, was evaluated (as the clinical success of melanoma therapy strictly depends on the disease stage). Moreover, to determine the BF3 mode of action and its effect on cell proliferation, intracellular microtubule networks, cell cycle phase distribution and apoptosis were evaluated. Our study revealed that BF3 inhibited cell proliferation in a dose-dependent manner, with IC 50 yielding 0.09 ± 0.01 μM, 0.11 ± 0.01 μM and 0.18 ± 0.05 μM for A375, MDA-MB435S and WM9, respectively. The strong antiproliferative activity of compound BF3 correlated well with its inhibitory effect on tubulin polymerisation. Molecular docking proved that BF3 belongs to the colchicine binding site inhibitors (CBSIs), and experimental studies revealed that it disturbs cell cycle progression leading to G2/M arrest and apoptosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) remains an incurable neurodegenerative condition that poses a threat to humanity. Immune signaling in the brain, particularly the NLR family pyrin domain containing 3 (NLRP3), is currently targeted for AD treatment. Based on the crystal structure of the NACHT domain of NLRP3 and its renowned inhibitor MCC950, we designed and synthesized nineteen sulfonylurea compounds and evaluated their capacity to inhibit caspase-1 and interleukin-1β (IL-1β). Of these, nine were selected for measuring their IC 50 for caspase-1 and cytotoxicity analysis. Finally, three compounds were chosen to assess their inhibitory effect on IL-1β in mice. The results showed that compound 5m had a superior ability to reduce IL-1β levels in the brain compared to MCC950 at a lower dosing concentration, indicating that 5m has the potential to penetrate the blood-brain barrier (BBB) and inhibit inflammation both in vitro and in vivo. Docking studies of compound 5m on NLRP3 revealed a binding mode similar to MCC950. These findings suggest that compound 5m holds promise as an NLRP3 inhibitor for AD treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Epilepsy is one of the most common serious chronic brain disorders, affecting up to 70 million people worldwide. Vascular disruption, including blood-brain barrier impairment and pathological angiogenesis, exacerbates its occurrence. However, its underlying mechanisms remain elusive. MCC950 is a specific small-molecule inhibitor that selectively blocks NLRP3 inflammatory vesicle activation across the blood-brain barrier, limits downstream IL-1β maturation and release, and exerts therapeutic effects across multiple diseases. In the present study, an epilepsy model was established by intraperitoneal administration of Kainic acid to adult male C57BL/6J wild-type mice. The results revealed that the epilepsy susceptibility of MCC950-treated mice was decreased, and neural damage following seizure episodes was reduced. In addition, immunofluorescence staining, RT-qPCR, and Western blot demonstrated that MCC950 inhibited the expression of the NLRP3 inflammasome and its related proteins in microglia, whereas microangiogenesis was found to be increased in the cerebral cortex and hippocampus of epileptic mice, and these effects could be reversed by MCC950. Furthermore, neurobehavioral impairment was observed in the epileptic mouse model, and MCC950 similarly alleviated the aforementioned pathological process. To the best of our knowledge, this is the first study to establish that pathological microangiogenesis is associated with NLRP3/IL-1β signaling pathway activation in a Kainic acid-induced epilepsy mouse model and that MCC950 administration attenuates the above-mentioned pathological changes and exerts neuroprotective effects. Therefore, MCC950 is a promising therapeutic agent for the treatment of epilepsy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Uric acid is a product of purine nucleotide metabolism, and high concentrations of uric acid can lead to hyperuricemia, gout and other related diseases. Xanthine oxidase, the only enzyme that catalyzes xanthine and hypoxanthine into uric acid, has become a target for drug development against hyperuricemia and gout. Inhibition of xanthine oxidase can reduce the production of uric acid, so xanthine oxidase inhibitors are used to treat hyperuricemia and related diseases, including gout. In recent years, researchers have obtained new xanthine oxidase inhibitors through drug design, synthesis, or separation of natural products. This paper summarizes the research on xanthine oxidase inhibitors since 2015, mainly including natural products, pyrimidine derivatives, triazole derivatives, isonicotinamide derivatives, chalcone derivatives, furan derivatives, coumarin derivatives, pyrazole derivatives, and imidazole derivatives, hoping to provide valuable information for the research and development of novel xanthine oxidase inhibitors., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Alzheimer's disease (AD) is a neurodegenerative disorder caused by accumulation of amyloid-β oligomers (AβO) in the brain, neuroinflammation, oxidative stress, and cognitive decline. Grandisin, a tetrahydrofuran neolignan, exhibits relevant anti-inflammatory and antioxidant properties. Interestingly, grandisin-based compounds were shown to prevent AβO-induced neuronal death in vitro. However, no study has assessed the effect of these compounds on the AD animal model. This study focuses on a triazole grandisin analogue (TGA) synthesized using simplification and bioisosteric drug design, which resulted in improved potency and solubility compared with the parent compound. This study aimed to investigate the possible in vivo effects of TGA against AβO-induced AD. Male C57/Bl6 mice underwent stereotaxic intracerebroventricular AβO (90 μM) or vehicle injections. 24 h after surgery, animals received intraperitoneal treatment with TGA (1 mg/kg) or vehicle, administered on a 14 day schedule. One day after treatment completion, a novel object recognition task (NORT) was performed. Memantine (10 mg/kg) was administered as a positive control. NORT retention sessions were performed on days 8 and 16 after AβO injection. Immediately after retention sessions, animals were euthanized for cortex and hippocampus collection. Specimens were subjected to oxidative stress and cytokine analyses. TGA reduced the level of cortex/hippocampus lipoperoxidation and prevented cognitive impairment in AβO-injected mice. Additionally, TGA reduced tumor necrosis factor (TNF) and interferon-γ (IFN-γ) levels in the hippocampus. By contrast, memantine failed to prevent cortex/hippocampus lipid peroxidation, recognition memory decline, and AβO-induced increases in TNF and IFN-γ levels in the hippocampus. Thus, memantine was unable to avoid the AβO-induced persistent cognitive impairment. The results showed that TGA may prevent memory impairment by exerting antioxidant and anti-inflammatory effects in AβO-injected mice. Moreover, TGA exhibited a persistent neuroprotective effect compared to memantine, reflecting an innovative profile of this promising agent against neurodegenerative diseases, such as AD.

Background: Chronic renal failure (CRF) is defined by a significant decline in renal function that results in decreased salt filtration and inhibition of tubular reabsorption, which ultimately causes volume enlargement. This study evaluated the potential renopreventive effects of the NLRP3 inflammasome inhibitor MCC950 in adenine-induced CRF in rats due to conflicting evidence on the effects of MCC950 on the kidney., Methods: Since the majority of the kidney tubular abnormalities identified in people with chronic renal disease are comparable to those caused by adding 0.75 percent of adenine powder to a rat's diet each day for four weeks, this method has received broad approval as a model for evaluating kidney damage. Throughout the test, blood pressure was checked weekly and at the beginning. Additionally, oxidative stress factors, urine sample examination, histological modifications, and immunohistochemical adjustments of caspase-3 and interleukin-1 beta (IL-1) levels in renal tissues were carried out., Results: Results revealed that MCC950, an inhibitor of the NLRP3 inflammasome, had a renopreventive effect, which was demonstrated by a reduction in blood pressure readings and an improvement in urine, serum, and renal tissue indicators that indicate organ damage. This was also demonstrated by the decrease in neutrophil gelatinase-associated lipocalin tubular expression (NGAL). The NLRP3 inflammasome inhibitor MCC950 was found to significantly alleviate the worsening renal cellular alterations evidenced by increased expression of caspase-3 and IL-1, according to immunohistochemical tests., Conclusion: The NLRP3 inflammasome inhibitor MCC950 demonstrated renopreventive effects in the CRF rat model, suggesting that it might be used as a treatment strategy to stop the progression of CRF., (© 2023. The Author(s).)

Ethnopharmacological Relevance: Arctium lappa L. is a common specie of Asteraceae. Its main active ingredient, Arctigenin (AG), in mature seeds exerts pharmacological effects on the Central Nervous System (CNS)., Aim of the Study: To review studies on the specific effects of the AG mechanism on various CNS diseases and elucidate signal transduction mechanisms and their pharmacological actions., Materials and Methods: This investigation reviewed the essential role of AG in treating neurological disorders. Basic information on Arctium lappa L. was retrieved from the Pharmacopoeia of the People's Republic of China. The related articles from 1981 to 2022 on the network database (including CNKI, PubMed, and Wan Fang and so on) were reviewed using AG and CNS diseases-related terms such as Arctigenin and Epilepsy., Results: It was confirmed that AG has a therapeutic effect on Alzheimer's disease, Glioma, infectious CNS diseases (such as Toxoplasma and Japanese Encephalitis Virus), Parkinson's disease, Epilepsy, etc. In these diseases, related experiments such as a Western blot analysis revealed that AG could alter the content of some key factors (such as the reduction of Aβ in Alzheimer's disease). However, in-vivo AG's metabolic process and possible metabolites are still undetermined., Conclusion: Based on this review, the existing pharmacological research has indeed made objective progress to elucidate how AG prevents and treats CNS diseases, especially senile degenerative disease such as Alzheimer's diseases. It was revealed that AG could be used as a potential nervous system drug as it has a wide range of effects in theory with markedly high application value, especially in the elder group. However, the existing studies are limited to in-vitro experiments; therefore, little is known about how AG metabolizes and functions in-vivo, limiting its clinical application and requiring further research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In terrestrial plants, strigolactones act as multifunctional endo- and exo-signals. On microalgae, the strigolactones determine akin effects: induce symbiosis formation with fungi and bacteria and enhance photosynthesis efficiency and accumulation of biomass. This work aims to synthesize and identify strigolactone mimics that promote photosynthesis and biomass accumulation in microalgae with biotechnological potential. Novel strigolactone mimics easily accessible in significant amounts were prepared and fully characterized. The first two novel compounds contain 3,5-disubstituted aryloxy moieties connected to the bioactive furan-2-one ring. In the second group of compounds, a benzothiazole ring is connected directly through the cyclic nitrogen atom to the bioactive furan-2-one ring. The novel strigolactone mimics were tested on Chlorella sorokiniana NIVA-CHL 176. All tested strigolactones increased the accumulation of chlorophyll b in microalgae biomass. The SL-F3 mimic, 3-(4-methyl-5-oxo-2,5-dihydrofuran-2-yl)-3 H -benzothiazol-2-one ( 7 ), proved the most efficient. This compound, applied at a concentration of 10 -7 M, determined a significant biomass accumulation, higher by more than 15% compared to untreated control, and improved the quantum yield efficiency of photosystem II. SL-F2 mimic, 5-(3,5-dibromophenoxy)-3-methyl-5 H -furan-2-one ( 4 ), applied at a concentration of 10 -9 M, improved protein production and slightly stimulated biomass accumulation. Potential utilization of the new strigolactone mimics as microalgae biostimulants is discussed., Competing Interests: The authors declare no conflict of interest.

Skeletal muscle is essential for locomotion and plays a crucial role in energy homeostasis. It is regulated by nutrition, genetic factors, physical activity and hormones. Furan fatty acids (FuFAs) are minor fatty acids present in small quantities in food from plants and animals origin. Recently, we showed that a preventive nutritional supplementation with furan fatty acid in a DIO mouse model reduces metabolic disorders. The present study was designed to determine the influence of FuFA-F2 extracted from Hevea brasiliensis latex on skeletal muscle phenotype. In C2C12 myotubes we found that FuFA-F2 whatever the concentration used increased protein content. We revealed that in C2C12 myotubes FuFA-F2 (10 µM) increases protein synthesis as shown by the stimulation of mTOR phosphorylation. Next, to confirm in vivo our results C57Bl6 mice were supplemented by oral gavage with vehicle or FuFA-F2 (20 mg/kg) for 3 and a half weeks. We found that mice supplemented with FuFA-F2 had a greater lean mass than the control mice. In line with this observation, we revealed that FuFA-F2 increased muscle mass and promoted more oxidative muscle metabolism in mice as attested by cytochrome c oxidase activity. In conclusion, we demonstrated that FuFA-F2 stimulates muscle anabolism in mice in vitro and in vivo, mimicking in part physical activity. This study highlights that in vivo FuFA-F2 may have health benefits by increasing muscle mass and oxidative metabolism., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Masson SAS.)

The inhibition of CXC chemokine receptor 2 (CXCR2), a key inflammatory mediator, is a potential strategy in the treatment of several pulmonary diseases and cancers. The complexity of endogenous chemokine interaction with the orthosteric binding site has led to the development of CXCR2 negative allosteric modulators (NAMs) targeting an intracellular pocket near the G protein binding site. Our understanding of NAM binding and mode of action has been limited by the availability of suitable tracer ligands for competition studies, allowing direct ligand binding measurements. Here, we report the rational design, synthesis, and pharmacological evaluation of a series of fluorescent NAMs, based on navarixin ( 2 ), which display high affinity and preferential binding for CXCR2 over CXCR1. We demonstrate their application in fluorescence imaging and NanoBRET binding assays, in whole cells or membranes, capable of kinetic and equilibrium analysis of NAM binding, providing a platform to screen for alternative chemophores targeting these receptors.

The NLRP3 inflammasome is a critical component of innate immunity involved in the pathophysiology of various inflammatory diseases. In this study, we designed and synthesized a series of NLRP3 inflammasome inhibitors based on MCC950. Specifically, we optimized the furan moiety, which is considered to be potentially associated with drug-induced liver injury. The representative inhibitor N14 , 4-(2-(dimethylamino)ethyl)- N -((1,2,3,5,6,7-hexahydro- s -indacen-4-yl)carbamoyl)benzenesulfonamide, not only maintains the NLRP3 inhibitory activity of MCC950 with IC 50 of 25 nM but also demonstrates improved tolerability in human hepatic cells line and mouse primary hepatocytes. In addition, N14 exhibits superior pharmacokinetic properties, with an oral bioavailability of 85.2%. In vivo studies demonstrate that N14 is more effective than MCC950 in multiple NLRP3-related animal model diseases, including nonalcoholic steatohepatitis, lethal septic shock, and colitis. Our research has provided a lead compound that directly targets the NLRP3 inflammasome and can be developed as a novel therapeutic candidate for NLRP3-driven diseases.

P-glycoprotein (P-gp) is one of the drug efflux transporters that triggers multidrug resistance (MDR) in cells. Herein, by utilizing the strategies of active skeleton splicing and structural optimization on the lead compound 5 m, a total of 50 novel 2,5-disubstituted furan derivatives were designed, synthesized, and screened for P-gp inhibitory activity. The structure-activity relationship analysis enabled the identification of an important pharmacophore N-phenylbenzamide, which resulted in the discovery of a promising drug lead compound Ⅲ-8. Ⅲ-8 possesses broad-spectrum reversal activity and low toxicity in MCF-7/ADR cells. Western blot and Rh123 accumulation assay demonstrated that Ⅲ-8 displayed the reversal activity by inhibiting P-gp efflux. Molecular docking analysis indicated a potent affinity of Ⅲ-8 to P-gp by forming H-bond interactions with residues Asn 721 and Met 986. Ⅲ-8 was determined to be a highly effective and safe P-gp inhibitor in an MCF-7/ADR xenograft mouse model., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Two silver(I) complexes with biologically relevant heterocyclic ligands, pyrrole and furan-2- carboxylic acid, were synthesized and their composition was confirmed using elemental, spectral, thermal and structural analyses. The {[Ag(Py2c)]} n (AgPy2c, Py2c = pyrrole-2-carboxylate) and {[Ag(Fu2c)]} n (AgFu2c, Fu2c = furan-2-carboxylate) solubility and stability in biological test stock solution were confirmed by 1 H NMR spectroscopy. The X-ray analysis has enabled us to determine typical argentophilic interactions and bridging carboxylate coordination mode of both ligands. Potentiometric data analysis by BSTAC program resulted in the determination of the stability constant of only one species, i.e., the ML (M = Ag + , L = Fu2c - ), log β ML  = 0.59 ± 0.04. Antimicrobial and anticancer tests were performed against selected microorganisms and cell lines with new silver(I) complexes and compared with AgSD (silver(I) sulfadiazine) and cisplatin. From their microbial toxicity point of view, selectivity was determined against lactobacilli (AgPy2c is 8× more effective against S. aureus and E. coli and AgFu2c is 8× more effective against E. coli and 4× against S. aureus). AgFu2c significant anticancer activity was determined against Jurkat cell lines (IC 50  = 8.00 μM) and was similar to cisPt (IC 50  = 6.3 μM) similarly to its selectivity (SI (AgFu2c) = 7.3, SI (cisPt) = 6.4, SI = selectivity index). In addition, cell cycle arrest was observed already in the Sub-G0 phase during a flow cytometry experiment. To evaluate the AgPy2c and AgFu2c bioavailability we also discuss their Lipinski's Rule of Five., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

The novel series of furan-bearing pyrazolo[3,4-b]pyridines were designed as cyclin-dependent kinase 2 (CDK2) inhibitors and as p53-murine double minute 2 (MDM2) inhibitors. The newly synthesized compounds were screened for their antiproliferative activity toward hepatocellular carcinoma (HepG2) and breast cancer (MCF7) cell lines. The most active compounds on both cell lines were additionally evaluated for their in vitro CDK2 inhibitory activity. Compounds 7b and 12f displayed enhanced activity (half-maximal inhibitory concentration [IC 50 ] = 0.46 and 0.27 µM, respectively) in comparison to the standard roscovitine (IC 50  = 1.41 ± 0.03 µM), in addition to, cell cycle arrest at S phase and G1/S transition phase in MCF7 cells treated with both compounds, respectively. Moreover, the most active spiro-oxindole derivative against MCF7 cell line, 16a, exhibited enhanced inhibitory activity against p53-MDM2 interaction in vitro (IC 50  = 3.09 ± 0.12 µM) compared to nutlin, and increased the levels of both p53 and p21 by nearly fourfold in comparison to the negative control. Molecular docking studies demonstrated the plausible interaction patterns of the most potent derivatives 17b and 12f in the CDK2 binding pocket and the spiro-oxindole 16a with p53-MDM2 complex, respectively. Consequently, the new chemotypes 7b, 12f, and 16a can be presented as promising antitumor hits for further studies and optimization., (© 2023 Wiley Periodicals LLC.)

Background: The primary objective of this study was to characterize the pharmacological and behavioral activity of 2 novel compounds, DM497 [(E)-3-(thiophen-2-yl)- N -(p-tolyl)acrylamide] and DM490 [(E)-3-(furan-2-yl)- N -methyl- N -(p-tolyl)acrylamide], structural derivatives of PAM-2, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor (nAChR)., Methods: A mouse model of oxaliplatin-induced neuropathic pain (2.4 mg/kg, 10 injections) was used to test the pain-relieving properties of DM497 and DM490. To assess possible mechanisms of action, the activity of these compounds was determined at heterologously expressed α7 and α9α10 nAChRs, and voltage-gated N-type calcium channel (Ca V 2.2) using electrophysiological techniques., Results: Cold plate tests indicated that 10 mg/kg DM497 was able to decrease neuropathic pain in mice induced by the chemotherapeutic agent oxaliplatin. In contrast, DM490 induced neither pro- nor antinociceptive activity but inhibited DM497's effect at equivalent dose (30 mg/kg). These effects are not a product of changes in motor coordination or locomotor activity. At α7 nAChRs, DM497 potentiated whereas DM490 inhibited its activity. In addition, DM490 antagonized the α9α10 nAChR with >8-fold higher potency than that for DM497. In contrast, DM497 and DM490 had minimal inhibitory activity at the Ca V 2.2 channel. Considering that DM497 did not increase the mouse exploratory activity, an indirect anxiolytic mechanism was not responsible for the observed antineuropathic effect., Conclusions: The antinociceptive activity of DM497 and the concomitant inhibitory effect of DM490 are mediated by opposing modulatory mechanisms on the α7 nAChR, whereas the involvement of other possible nociception targets such as the α9α10 nAChR and Ca V 2.2 channel can be ruled out., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Anesthesia Research Society.)

Acrylamide-derived compounds have been previously shown to act as modulators of members of the Cys-loop transmitter-gated ion channel family, including the mammalian GABA A receptor. Here we have synthesized and functionally characterized the GABAergic effects of a series of novel compounds (termed "DM compounds") derived from the previously characterized GABA A and the nicotinic α 7 receptor modulator (E)-3-furan-2-yl- N -p-tolyl-acrylamide (PAM-2). Fluorescence imaging studies indicated that the DM compounds increase apparent affinity to the transmitter by up to 80-fold in the ternary αβγ GABA A receptor. Using electrophysiology, we show that the DM compounds, and the structurally related (E)-3-furan-2-yl- N -phenylacrylamide (PAM-4), have concurrent potentiating and inhibitory effects that can be isolated and observed under appropriate recording conditions. The potentiating efficacies of the DM compounds are similar to those of neurosteroids and benzodiazepines (ΔG ∼ -1.5 kcal/mol). Molecular docking, functionally confirmed by site-directed mutagenesis experiments, indicate that receptor potentiation is mediated by interactions with the classic anesthetic binding sites located in the transmembrane domain of the intersubunit interfaces. Inhibition by the DM compounds and PAM-4 was abolished in the receptor containing the α 1(V256S) mutation, suggestive of similarities in the mechanism of action with that of inhibitory neurosteroids. Functional competition and mutagenesis experiments, however, indicate that the sites mediating inhibition by the DM compounds and PAM-4 differ from those mediating the action of the inhibitory steroid pregnenolone sulfate. SIGNIFICANCE STATEMENT: We have synthesized and characterized the actions of novel acrylamide-derived compounds on the mammalian GABA A receptor. We show that the compounds have concurrent potentiating effects mediated by the classic anesthetic binding sites, and inhibitory actions that bear mechanistic resemblance to but do not share binding sites with, the inhibitory steroid pregnenolone sulfate., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Ocular neovascularization is a leading cause of blindness and visual impairment. While intravitreal anti-VEGF agents can be effective, they do have several drawbacks, such as endophthalmitis and drug resistance. Additional studies are necessary to explore alternative therapeutic targets., Methods: Bioinformatics analysis and quantitative RT-PCR were used to detect and verify the FSCN1 expression levels in oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) mice model. Transwell, wound scratching, tube formation, three-dimensional bead sprouting assay, rhodamine-phalloidin staining, Isolectin B4 staining and immunofluorescent staining were conducted to detect the role of FSCN1 and its oral inhibitor NP-G2-044 in vivo and vitro. HPLC-MS/MS analysis, cell apoptosis assay, MTT assay, H&E and tunnel staining, visual electrophysiology testing, visual cliff test and light/dark transition test were conducted to assess the pharmacokinetic and security of NP-G2-044 in vivo and vitro. Co-Immunoprecipitation, qRT-PCR and western blot were conducted to reveal the mechanism of FSCN1 and NP-G2-044 mediated pathological ocular neovascularization., Results: We discovered that Fascin homologue 1 (FSCN1) is vital for angiogenesis both in vitro and in vivo, and that it is highly expressed in oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV). We found that NP-G2-044, a small-molecule inhibitor of FSCN1 with oral activity, can impede the sprouting, migration, and filopodia formation of cultured endothelial cells. Oral NP-G2-044 can effectively and safely curb the development of OIR and CNV, and increase efficacy while overcoming anti-VEGF resistance in combination with intravitreal aflibercept (Eylea) injection., Conclusion: Collectively, FSCN1 inhibition could serve as a promising therapeutic approach to block ocular neovascularization., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Arctigenin (ARG) has potent antifatigue activity, but its clinical application has been restricted for its poor water solubility. In this study, seven ARG derivatives containing different amino acids coupled via an ethoxy linker were synthesized, and tested for their solubility, as well as activities to improve exercise performance in mice. All of the derivatives showed improved solubility compared to that of ARG. Derivative Z-A-6 exhibited the highest activity, showing that the mice ran a 4.88-fold greater distance in the running wheel test and swam a 2.86-fold greater time in the swimming test than those in the blank control group. Z-A-6 treatment increased the plasma superoxide dismutase and catalase concentrations as well as reduced lactic acid and blood urea nitrogen accumulation during exercise. Z-A-6 treatment enhanced the phosphorylation of adenosine monophosphate-activated protein kinase, and no acute toxicity was observed. The results will contribute to the development of potential antifatigue agents., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Quorum sensing inhibitors (QSIs) are a class of compounds that can reduce the pathogenicity of bacteria without affecting bacterial growth. In this study, we designed and synthesized four series of 4-fluorophenyl-5-methylene-2(5 H )-furanone derivatives and evaluated their QSI activities. Among them, compound 23e not only showed excellent inhibitory activity against various virulence factors but also significantly enhanced the inhibitory activity of antibiotics ciprofloxacin and clarithromycin against two strains of Pseudomonas aeruginosa in vitro . What is even more exciting is that it remarkably increased the antibacterial effect in vivo in combination with ciprofloxacin in the bacteremia model infected with P. aeruginosa PAO1. Moreover, 23e had little hemolytic activity to mouse erythrocytes. Further, the results of GFP reporter fluorescence strain inhibition and β-galactosidase activity inhibition experiments demonstrated that 23e simultaneously targeted the three quorum sensing systems in P. aeruginosa . As a result, compound 23e could be used as an effective QSI for further development against bacterial infections.

A series of carbamothioyl-furan-2-carboxamide derivatives were synthesized using a one-pot strategy. Compounds were obtained in moderate to excellent yields (56-85%). Synthesized derivatives were evaluated for their anti-cancer (HepG2, Huh-7, and MCF-7 human cancer cell lines) and anti-microbial potential. Compound p-tolylcarbamothioyl)furan-2-carboxamide showed the highest anti-cancer activity at a concentration of 20 μg/mL against hepatocellular carcinoma, with a cell viability of 33.29%. All compounds showed significant anti-cancer activity against HepG2, Huh-7, and MCF-7, while indazole and 2,4-dinitrophenyl containing carboxamide derivatives were found to be less potent against all tested cell lines. Results were compared with the standard drug doxorubicin. Carboxamide derivatives possessing 2,4-dinitrophenyl showed significant inhibition against all bacterial and fungal strains with inhibition zones (I.Z) in the range of 9-17 and MICs were found to be 150.7-295 μg/mL. All carboxamide derivatives showed significant anti-fungal activity against all tested fungal strains. Gentamicin was used as the standard drug. The results showed that carbamothioyl-furan-2-carboxamide derivatives could be a potential source of anti-cancer and anti-microbial agents.

A new decalin-containing secondary metabolite, wakodecaline C, was isolated from a fungus Pyrenochaetopsis sp. RK10-F058 by screening structurally interesting metabolites based on LC/MS profiling. The structure including the absolute configuration was determined by a combination of spectroscopic methods including NMR and mass spectrometry, chemical reaction, and calculation of ECD spectra. Wakodecaline C has unique structural features containing a tetrahydrofuran-fused decalin skeleton and tetramic acid moiety, which are connected through a double bond. The compound showed moderate cytotoxicity against HL-60 cells and antimalarial activity against the Plasmodium falciparum 3D7 strain., (© 2023. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.)

Seven previously undescribed tetrahydrofuran lignans with different configurations and unusual isopentenyl substitutions, nitidumlignans D-J (corresponding to compounds 1, 2, 4, 6, 7, 9 and 10), along with 14 known lignans, were isolated from Zanthoxylum nitidum. Notably, compound 4 is an uncommon naturally occurring furan-core lignan derived from tetrahydrofuran aromatization. The antiproliferation activity of the isolated compounds (1-21) was determined in various human cancer cell lines. The structure-activity study revealed that the steric positioning and chirality of the lignans exert important effects on their activity and selectivity. In particular, compound 3 (sesaminone) exhibited potent antiproliferative activity in cancer cells, including acquired osimertinib-resistant non-small-cell lung cancer (HCC827-osi) cells. Compound 3 also inhibited colony formation and induced the apoptotic death of HCC827-osi cells. The underlying molecular mechanisms revealed that 3 downregulated the activation of the c-Met/JAK1/STAT3 and PI3K/AKT/mTOR signaling pathways in the HCC827-osi cells. In addition, the combination of 3 and osimertinib exhibited synergistic effects on the antiproliferative activity against HCC827-osi cells. Overall, these findings inform the structure elucidation of novel lignans isolated from Z. nitidum, and sesaminone was identified as a potential compound for exerting antiproliferative effects on osimertinib-resistant lung cancer cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Arctigenin is the active ingredient of the traditional medicines Arctium lappa and Fructus Arctii and has been extensively investigated for its diverse pharmacological functions, including its novel anti-austerity activity. Although several mechanisms have been proposed, the direct target of arctigenin to induce anti-austerity activity remains unclear. In this study, we designed and synthesized photo-crosslinkable arctigenin probes and utilized them in the chemoproteomic profiling of potential target proteins directly in living cells. Vacuolar protein sorting-associated protein 28 (VPS28), a key subunit of the ESCRT-I complex implicated in phagophore closure, was successfully identified. Unexpectedly, we found that arctigenin degraded VPS28 via the ubiquitin-proteasome pathway. We also demonstrated that arctigenin induces a prominent phagophore closure-blockade phenotype in PANC-1 cells. To the best of our knowledge, this is the first report of a small molecule acting as a phagophore-closure blocker and a VPS28 degrader. The arctigenin-modulating phagophore closure provides a new druggable target for cancers that rely heavily on autophagy activation and may also be used for other diseases associated with the ESCRT system., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Five integrasone derivatives, integrasone C ( 1 ), isointegrasone C ( 2 ), integrasone D1 ( 3 ), integrasone D2 ( 4 ), and integrasone E ( 5 ), were isolated from the culture broth of Lepteutypa sp. KT4162. Neither conventional NMR analyses nor DFT (density functional theory)-based computationally assisted chemical shift discussions were sufficient to elucidate the relative configuration of the 1,4-epoxydiol moiety. A combined analysis using the calculated n J CH values and HMBC spectra was helpful to establish the relative configuration. The absolute configurations of 1 - 5 were determined using DFT-based ECD (electronic circular dichroism) spectral analysis. Biological assays of these compounds revealed that 2 potently inhibits HIV-1 integrase without cytotoxicity.

Three new benzo[ b ]naphtho[2,1- d ]furans, usambarins A-C ( 1 - 3 ), five new 2-phenylnaphthalenes, usambarins D-H ( 4 - 8 ), a new flavan ( 9 ), and a new phenyl-1-benzoxepin ( 10 ) as well as two known compounds ( 11 and 12 ) were isolated from the extract of the stem and roots of Streblus usambarensis (Moraceae). The structures were deduced using NMR spectroscopic and mass spectrometric analyses, and those of compounds 1 and 4 were confirmed by X-ray crystallography. Usambarin D ( 4 ) demonstrated moderate antibacterial activity (MIC 9.0 μM) against Bacillus subtilis , while none of the tested compounds were effective against Escherichia coli .

A new chalcone series has been developed that may be useful in the treatment of lung cancer. The new series was confirmed by the different spectral tools. MTT assay was used to detect the cytotoxic effect of the novel chalcones against lung cancer cell line (A549). Molecular docking studies were performed on the most two effective chalcones 7b and 7c. Different molecular techniques were utilized to study the activity and the effect of two chalcones 7b and 7c on apoptosis of A549 cell line., (© 2022. The Author(s).)

Nine undescribed phloroglucinol derivatives (dryatraols A-I) with five different backbones and three known dimeric acylphloroglucinols were isolated from the rhizome of Dryopteris atrata (Wall. Ex Kunze) Ching (Dryopteridaceae). Dryatraol A contains an unprecedented carbon skeleton-a butyrylphloroglucinol and a rulepidanol-type sesquiterpene are linked via a furan ring to form a 6/5/6/6 ring system. Dryatraols B and C are the first examples of monomeric phloroglucinols coupled with the aristolane-type sesquiterpene through the C-C bond. Dryatraol D features a rare spiro [benzofuran-2',5″-furan] backbone. Dryatraols E-I are five undescribed adducts with a butyrylphloroglucinol or filicinic acid incorporated into the germacrene-type sesquiterpene via a pyran ring. These undescribed structures were determined by comprehensively analysing the spectroscopic data, X-ray diffraction results, and electronic circular dichroism calculations. The result of in vitro antiviral activity evaluation indicated that dryatraol C displayed the strongest antiviral effect against both respiratory syncytial virus and influenza A virus (H1N1), with IC 50 values of 11.9 μM and 5.5 μM, respectively. Dryatraols F-H exhibited considerable inhibitory activity against herpes simplex virus type 1 (HSV-1), with IC 50 values ranging from 2.6 to 6.3 μM. Analysis of the inhibitory mechanism using a time-of-addition assay revealed that dryatraol G may inhibit the replication of HSV-1 by interfering with the late stage of the viral life cycle., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Two pairs of side-chain epimeric 3-methoxycarbonyl-dihydrofuran-4-ones with structures purported for thiocarboxylics C 1/2 and gregatins G 1/2 , isolated from Penicillium sp. Sb62, were synthesised for the first time in five steps and 17-25 % yield. Key steps were a Suzuki cross-coupling, a Yamaguchi esterification, and a base-induced Knoevenagel-type condensation. The optimum protecting group for the 10-OH group in the dienyl side-chain, orthogonal to necessary protecting groups on O-10 of the furanone, was found to be t-butyldiphenylsilyl (TBDPS). The specific rotations of our synthetic products deviated markedly from those reported for the natural isolates. In contrast to the isolates, the synthetic products were not active against Escherichia coli and Staphylococcus aureus bacteria., (© 2023 The Authors. Chemistry & Biodiversity published by Wiley-VHCA AG, Zurich, Switzerland.)

The high potency of the tetrahydrofuran-containing acetogenins (THF-ACGs) against a broad range of human cancer cell lines has stimulated interest in structurally simpler mimetics. In this context, we have previously reported THF-ACG mimetics in which the THF and butenolide moieties of a mono-THF-ACG were replaced with carbohydrate and thiophene residues, respectively. In the present study, towards the targeting of these carbohydrate analogues to prostate cancer (PCa), we synthesized prodrugs in which a parent thiophene or butenolide congener was conjugated through a self-immolative linker to 2-[3-(1,3-dicarboxypropyl)ureido] pentanedioic acid (DUPA), a highly specific ligand for prostate-specific membrane antigen (PSMA), which is overexpressed on prostate tumors. Both prodrugs were found to be more active against receptor positive LNCaP than receptor-negative PC-3 cells, with 2.5 and 12 times greater selectivity for the more potent thiophene analog and the less active butenolide congener, respectively. This selectivity for LNCaP over PC-3 contrasted with the behavior of the parent drugs, which showed similar or significantly higher activity for PC-3 compared to LNCaP. These data support the notion that higher activity of these DUPA-derived prodrugs against LNCaP cells is connected to their binding to PSMA and suggest that the conjugation of PSMA ligands to this family of cytotoxic agents may be effective for targeting them to PCa.

Background: Arctigenin (ATG), a dibenzyl butyrolactone lignan compound, is one of the major bioactive components from the medicinal plant Arctium lappa. ATG possesses remarkable therapeutic potential against a wide range of human diseases, such as cancers, immune disorders and chronical diseases. The molecular mechanisms behind the biological effects of ATG have been intensively studied., Purpose: This review aims to systematically summarize the updated knowledge of the proteins and signaling pathways behind the curative property of ATG, and further analyze the potential connections between them., Method: SciFinder, Pubmed, Web of Science and Cochrane Library databases were queried for publications reporting the therapeutic properties of ATG. "Arctigenin", "disease", "cancer", "inflammation", "organ damage", "infection", "toxicity" and "pharmacokinetics" were used as the searching titles., Result: 625 publications were identified and 95 met the inclusion criteria and exclusion criteria. 42 studies described the molecular mechanisms implicated in ATG treatments. Several proteins including phosphodiesterase subtype 4D (PDE4D), estrogen receptor (ER) β, protein phosphatase 2A (PP2A), phosphoinositide 3-kinase (PI3K) and transmembrane protein 16A (TMEM16A) are targeted by ATG in different settings. The frequently described signaling pathways are TLR4/NF-κB, PI3K/AKT/mTOR, AMP-activated protein kinase (AMPK) and nuclear factor erythroid 2-related factor 2 (Nrf-2) signalings., Conclusion: Inhibition of PI3K/AKT pathway and activation of AMPK signaling play the pivotal roles in the therapeutic effects of ATG. PI3K/AKT and AMPK signaling widely link to other signaling pathways, modulating various biological processes such as anti-inflammation, anti-oxidative stress, anti-fibrosis, anti-ER stress, anti-steatosis and pro-apoptosis, which constitute the curative mechanisms of ATG against multiple human diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no potential financial competing interests that may in any way gain or lose financially from the publication of this manuscript at present or in the future. Additionally, no non-financial competing interests are involved in the manuscript., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

The role of nucleotide-binding oligomerization domainlike receptor pyrin domain containing 3 (NLRP3) inflammasome in cerebral ischemia-reperfusion (I/R) induced neuroinflammation and neuronal pyroptosis has been widely recognized. Latest studies revealed that NLRP3 inflammasome engage in not only pyroptosis but also other types of cell death. Ferroptosis has been proved to be closely associated with cerebral I/R injury. In this study, our objectives were to verify the inhibitory effect of the NLRP3-specific inhibitor MCC950 on cerebral I/R-mediated neuronal pyroptosis, and to explore the regulation and possible mechanism of MCC950 on cerebral I/R-mediated neuronal ferroptosis. Our data showed that the NLRP3-specific inhibitor, MCC950, effectively reversed the I/R-mediated NLRP3 inflammasome activation and neuronal pyroptosis. Furthermore, we found that I/R increased iron concentrations and levels of malondialdehyde (MDA), downregulated glutathione peroxidase 4 (GPX4) expression, and upregulated long chain fatty acid-CoA ligase 4 (FACL4) and prostaglandin endoperoxide synthase 2 (PTGS2) expression. Interestingly, these changes were also reversed by the MCC950. Finally, in vitro, we found that MCC950 significantly reduced ROS levels in OGD/R treated HT22 cells. In conclusion, pharmaceutical inhibition of NLRP3 by MCC950 attenuates I/R-induced neuronal ferroptosis, possibly by reducing ROS accumulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Geraniol, a monoterpene, and furan are structural motifs that exhibit antifouling activity. In this study, monoterpene-furan hybrid molecules with potentially enhanced antifouling activity were designed and synthesized. The nine synthetic hybrids showed antifouling activity against the cypris larvae of the barnacle Balanus ( Amphibalanus ) amphitrite with EC 50 values of 1.65-4.70 μg mL -1 . This activity is higher than that of geraniol and the reference furan compound. This hybridization approach to increase antifouling activity is useful and can also be extended to other active structural units.

Context: Phytocompounds xanthatin and 8-epi-xanthatin, obtained from Xanthium chinese Mill, showed antitumoral activity in vitro related to the microtubules destabilizing properties of these phytocompounds. Five binding sites for microtubule destabilizing agents have been characterized on tubulin by high-resolution X-ray crystallography: vinca domain, colchicine, pironetin, maytansine site, and more recently, the seventh site. This work aims to develop a comprehensive computational strategy to understand and eventually predict the interaction between xanthatin and 8-epi-xanthatin with the destabilizing-antimitotic binding domain of the tubulin heterodimer. In addition, we propose a putative binding site for these phytocompounds into the microtubule destabilizing binding sites on the tubulin heterodimer. Xanthanolides showed higher stability in the colchicine and pironetin binding sites, whit a greater affinity for the former. In addition, we found that xanthanolides and non-classical colchicine binding site inhibitors share a high structural similarity., Methods: The 3D structures for xanthatin and 8-epi-xanthatin were obtained using DFT with the hybrid functional B3LYP and the base 6-31G (d,p), implemented in Gaussian 09. The 3D coordinates for tubulin proteins were downloaded from PDB. The complexes tubulin-xanthanolides were predicted using a Monte-Carlo iterated search combined with the BFGS gradient-based optimizer implemented in the AutoDock Vina. The xanthanolides-tubulin complexes were energy minimized by molecular dynamics simulations at vacuum, and their stabilities were evaluated by solvated molecular dynamics simulations during 100 ns. All molecular dynamics simulations were performed using the conjugate gradient method implemented in NAMD2 and CHARMM36 forcefield., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Chemotherapy results in long-term effects on cognitive dysfunction called chemotherapy-induced cognitive impairment (CICI) in cancer survivors. However, little is known about the potential molecular mechanisms of CICI. This study aimed to determine the role and potential underlying mechanisms of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in cognitive impairments induced by chemotherapeutic agents commonly used in breast cancer. The cognitive effects of chemotherapy were investigated in a rat model using the cocktail of doxorubicin and cyclophosphamide. The NLRP3 pathway was found to be differentially expressed after chemotherapy by iTRAQ-based proteomic analysis of normal and chemotherapeutic hippocampi. Treatment with the NLRP3 inhibitor MCC950 following chemotherapy significantly reduced cognitive impairment and decreased the expression of NLRP3, caspase-1 and ASC. Chemotherapy led to increased expression of the glial response markers Iba-1 and GFAP and the axonal injury markers NF-L and NF-M, an elevated number of apoptotic cells and enhanced microstructural damage to axons and mitochondria, while MCC950 treatment alleviated the glial response, cell death and axonal injury. The protective effect of MCC950 was related to the NLRP3 pathway and levels of inflammatory cytokines (TNF-α, IL-1β, IL-18, IL-6, IL-4, and IL-10) and oxidative stress-responsive markers (SOD, MDA, CAT and GSH). The results indicate that CICI is associated with NLRP3 pathway-induced oxidative damage and the inflammatory response and provide a potential therapeutic target to treat cognitive impairment after chemotherapy (doxorubicin and cyclophosphamide)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: More than 20% of the US population suffers from laryngopharyngeal reflux. Although dietary/lifestyle modifications and alginates provide benefit to some, there is no gold standard medical therapy. Increasing evidence suggests that pepsin is partly, if not wholly, responsible for damage and inflammation caused by laryngopharyngeal reflux. A treatment specifically targeting pepsin would be amenable to local, inhaled delivery, and could prove effective for endoscopic signs and symptoms associated with nonacid reflux. The aim herein was to identify small molecule inhibitors of pepsin and test their efficacy to prevent pepsin-mediated laryngeal damage in vivo., Methods: Drug and pepsin binding and inhibition were screened by high-throughput assays and crystallography. A mouse model of laryngopharyngeal reflux (mechanical laryngeal injury once weekly for 2 weeks and pH 7 solvent/pepsin instillation 3 days/week for 4 weeks) was provided inhibitor by gavage or aerosol (fosamprenavir or darunavir; 5 days/week for 4 weeks; n = 3). Larynges were collected for histopathologic analysis., Results: HIV protease inhibitors amprenavir, ritonavir, saquinavir, and darunavir bound and inhibited pepsin with IC 50 in the low micromolar range. Gavage and aerosol fosamprenavir prevented pepsin-mediated laryngeal damage (i.e., reactive epithelia, increased intraepithelial inflammatory cells, and cell apoptosis). Darunavir gavage elicited mild reactivity and no discernable protection; aerosol protected against apoptosis., Conclusions: Fosamprenavir and darunavir, FDA-approved therapies for HIV/AIDS, bind and inhibit pepsin, abrogating pepsin-mediated laryngeal damage in a laryngopharyngeal reflux mouse model. These drugs target a foreign virus, making them ideal to repurpose. Reformulation for local inhaled delivery could further improve outcomes and limit side effects., Level of Evidence: NA. Laryngoscope, 133:S1-S11, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

Although the overall survival of advanced soft-tissue sarcoma (STS) patients has increased in recent years, the median progression-free survival is lower than 5 months, meaning that there is an unmet need in this population. Among second-line treatments for advanced STS, eribulin is an anti-microtubule agent that has been approved for liposarcoma. Here, we tested the combination of eribulin with gemcitabine in preclinical models of L-sarcoma. The effect in cell viability was measured by MTS and clonogenic assay. Cell cycle profiling was studied by flow cytometry, while apoptosis was measured by flow cytometry and Western blotting. The activity of eribulin plus gemcitabine was evaluated in in vivo patient-derived xenograft (PDX) models. In L-sarcoma cell lines, eribulin plus gemcitabine showed to be synergistic, increasing the number of hypodiploid events (increased subG1 population) and the accumulation of DNA damage. In in vivo PDX models of L-sarcomas, eribulin combined with gemcitabine was a viable scheme, delaying tumour growth after one cycle of treatment, being more effective in leiomyosarcoma. The combination of eribulin and gemcitabine was synergistic in L-sarcoma cultures and it showed to be active in in vivo studies. This combination deserves further exploration in the clinical context.

Chemotherapy of human immunodeficiency virus type-1 (HIV-1) has significantly developed over the last three decades. The emergence of drug-resistant variants is, however, still a severe problem. The RNase H activity of HIV-1 reverse transcriptase is an attractive target for a new class of antiviral drugs because there is no approved inhibitor. The nitro-furan-carbonyl and nitro-thiophene-carbonyl groups are potent scaffolds for the HIV-1 RNase H inhibitor. In this work, the binding structures of six inhibitory compounds were obtained by X-ray crystal analysis in a complex with a recombinant protein of HIV-1 RNase H domain. Every inhibitory compound was found to be bound to the catalytic site with the furan- or thiophene-ring coordinated to two divalent metal ions at the binding pocket. All the atoms in nitro, furan, carbonyl, and two metals were aligned in the nitro-furan derivatives. The straight line connecting nitro and carboxyl groups was parallel to the plane made by two metal ions and a furan O atom. The binding modes of the nitro-thiophene derivatives were slightly different from those of the nitro-furan ones. The nitro and carbonyl groups deviated from the plane made by two metals and a thiophene S atom. Molecular dynamics simulations suggested that the furan O or thiophene S atom and carbonyl O atom were firmly coordinated to the metal ions. The simulations made the planar nitro-furan moiety well aligned to the line connecting the two metal ions. In contrast, the nitro-thiophene derivatives were displaced from the initial positions after the simulations. The computational findings will be a sound basis for developing potent inhibitors for HIV-1 RNase H activity.