Notable Inhibitory Effect Research Articles

Design, synthesis and antifungal activity of novel 1,4-benzoxazin-3-one derivatives containing an acylhydrazone moiety.

A series of 1,4-benzoxazin-3-one derivatives containing an acylhydrazone moiety were designed, synthesized and evaluated for their in vitro antifungal activities against Gibberella zeae, Pellicularia sasakii, Phytophthora infestans, Capsicum wilt, and Phytophthora capsica. The structures of target compounds were characterized by 1H NMR, 13H NMR, 19F NMR and HRMS. The preliminary antifungal evaluation of all target compounds showed that some target compounds possessed moderate to good activities against G. zeae, P. sasakii, P. infestans and C. wilt. Among them, compounds 5L and 5o exhibited noticeable inhibition effects against G. zeae with the EC50 values (effective concentration for 50% activity) of 20.06 and 23.17μg/ml, respectively, which were even nearly double effective than that of hymexazol (40.51μg/ml). Meanwhile, compound 5q displayed a notable inhibitory effect toward P. sasakii, with the EC50 value of 26.66μg/ml, which was better than that of hymexazol (32.77μg/ml). In addition, compound 5r yielded the EC50 value of 15.37μg/ml against P. infestans, which was less than those of hymexazol (18.35μg/ml) and carbendazim (34.41μg/ml). Eventually, compound 5p showed higher inhibitory effect against C. wilt, with EC50 value of 26.76μg/ml, which was better than that of hymexazol (>50μg/ml).

Evaluation of in vitro enzyme inhibitory, anti-inflammatory, antioxidant, and antibacterial activities of Oldenlandia corymbosa L. and Oldenlandia umbellata L. whole plant extracts

BackgroundOldenlandia corymbosa and Oldenlandia umbellata are well-known medicinal plants in various traditional systems of medicine and used to treat bronchitis, asthma, tuberculosis, constipation, and leprosy. We evaluated the phytochemical content, antioxidant potential, enzyme inhibitory action, anti-inflammatory, and antibacterial activities of the whole plant extracts of O. corymbosa and O. umbellata due to their therapeutic importance. MethodsThe phytochemical analysis includes qualitative analysis and quantification of total phenolics, flavonoids, tannins, flavonols, proanthocyanidins, and vitamin E. Enzyme inhibitory assays were studied using α-amylase and α-glucosidase enzymes and anti-inflammatory activity was determined by egg albumin denaturation assay. Antioxidant potential was estimated using 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis (3-ethyl benzothiozoline-6-sulfonic acid) diammonium salt (ABTS), ferric reducing antioxidant power (FRAP), hydroxyl radical, superoxide, nitric oxide, metal chelating, and phosphomolybdenum assays. Minimum inhibitory concentrations of extracts were studied against ten bacterial strains by the microdilution method. ResultsThe aqueous extract of O.umbellata showed a higher extract yield (5.0%). The highest amount of total phenolics and flavonoids were observed in the ethanolic extract of O.umbellata (77.23±0.46 mg GAE/g) and O.corymbosa (19.01±0.26 mg GAE/g). Ethanolic extract of O.umbellata (IC50 of 31.71±0.32 µg/mL) and aqueous extract of O.corymbosa (30.53±1.83 µg/mL) showed notable α-amylase inhibitory effect and petroleum ether extract of both plants observed good inhibition against α-glucosidase enzyme. Likewise, petroleum ether extract of O.umbellata (IC50 of 57.16±1.88 µg/mL) showed a moderate anti-inflammatory effect. In all extracts, considerable antioxidant potential was recorded specially with aqueous extract in the nitric oxide scavenging assay with an IC50 of 40.72±1.25 µg/mL. Ethanolic extract of O.umbellata and petroleum ether extract of O.corymbosa (MIC of 56.25 µg/mL) showed good antibiotic potency in lower concentrations which proves these two valuable herb's potential in herbal preparations. ConclusionsThe results of the study provide a basis for further studies aiming to evaluate the possibilities of using the O. umbellata and O. corymbosa as natural sources of antioxidants, enzyme inhibitory, and antibacterial agents. Further studies could be directed to exploit these plants in experimental animal models as potential pharmaceutical agents.

Hydroxycoumarins and some Flavonoids from Pistacia atlantica Desf. as Multi-targets Inhibitors for Alzheimer's Disease: Molecular Docking and ADMET Studies.

The present study aimed to identify new selective inhibitors for acetylcholinesterase, butyrylcholinesterase, monoacylglycerol lipase, beta-secretase, and Asparagine endopeptidase, the targets enzymes in Alzheimer's disease. The inhibitory effect of P. atlantica Desf. methanol extracts against AChE were determined using Ellman's method. The molecular docking study is achieved using Autodock Vina. The structures of the molecules 3-methoxycarpachromene, masticadienonic acid, 7-ethoxycoumarin, 3',5,7- trihydroxy-4'-methoxyflavanone and 5,6,7,4'-tetrahydroxyflavonol-3-O-rutinoside and the five enzymes were obtained from the PubChem database and Protein databank. ADMET parameters were checked to confirm their pharmacokinetics using swiss-ADME and ADMET-SAR servers. P. atlantica Desf. methanol extracts showed a notable inhibitory effect against AChE (IC50 = 0.26 ± 0.004 mg/ml). The molecular docking results of 3-methoxycarpachromene, masticadienonic acid, 7-ethoxycoumarin, 3',5,7-trihydroxy-4'-methoxyflavanone and 5,6,7,4'-tetrahydroxyflavonol-3-Orutinoside with the five enzymes show significant affinities of these molecules towards Alzheimer disease targets, where they could form several interactions, such as hydrogen bonds and hydrophobic interactions with the studied enzymes. The shortest hydrogen bond is 1.7 A° between masticadienonic acid and Arg128 of the active site of BACE, while the lowest free energy is -11.2 of the complex 5,6,7,4'-tetrahydroxyflavonol-3-O-rutinoside -HuBchE. To the best of our knowledge, these molecules' potential anti-Alzheimer disease effect is studied in this paper for the first time. The docking studies of this work show that 3-methoxycarpachromene and masticadienonic acid, 7-ethoxycoumarin, 3',5,7-Trihydroxy-4'-methoxyflavanone and 5,6,7,4'-tetrahydroxyflavonol- 3-O-rutinoside have good affinities towards the enzymes involved in Alzheimer pathology, which confirm the ability of these molecules to inhibit the studied enzymes namely: HuAChE, HuBChE, BACE, MAGL, and AEP. These molecules might become drug candidates to prevent Alzheimer's disease.

Phytochemical Analysis and Antibacterial Activity of Methanol and Ethyl Acetate Extracts of Detarium microcarpum Guill. & Perr.

This research aimed to investigate the phytoconstituents and antibacterial effects of methanol and ethyl acetate stem bark extracts of Detarium microcarpum (DM). The phytochemicals were detected and quantified while the antibacterial activity against Escherichia coli, Staphylococcus aureus, and Salmonella typhi was established determining the zone of inhibition (ZI), minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC). Phytochemical screening showed alkaloids (16.33% ±0.88) were present in the methanol extract only while saponins and flavonoids were detected in concentrations of 31.00% ±2.31 and 21.01% ±2.33 respectively for the methanol extract and 21.67% ±1.76 and 38.01% ±1.16, for the ethyl acetate. The methanol extract exhibited the highest ZI on S. aureus (21.3 mm ±1.11) with its least inhibition observed on E. coli (6.5 mm ±0.77) while the ethyl acetate extract demonstrated the highest ZI on S. typhi (19.1 mm ±2.01). S. typhi exhibited more sensitivity to DM extracts at the least concentrations of 12.5 mg/ml (methanol) and 25 mg/ml (ethyl acetate) while the MBC results showed that the 12.5 mg/ml and 25 mg/ml were the effective respective concentration for methanol and ethyl acetate extracts against S. typhi. Conclusively, DM exhibited an antibacterial effect against the test organisms with notable inhibitory and bactericidal effects.

The marine natural product, dicitrinone B, induces apoptosis through autophagy blockade in breast cancer.

Being a highly conserved catabolic process, autophagy is induced by various forms of cellular stress, and its modulation has considerable potential as a cancer therapeutic approach. In the present study, it was demonstrated that dicitrinone B (DB), a rare carbon-bridged citrinin dimer, may exert anticancer effects by blocking autophagy at a late stage, without disrupting lysosomal function in MCF7 breast cancer and MDA-MB-231 triple-negative breast cancer cells. Furthermore, it was discovered that DB significantly enhanced intracellular reactive oxygen species (ROS) production and that the removal of ROS was followed by the attenuation of autophagy inhibition. In addition, DB exerted notable inhibitory effects on the proliferation and promoting effects on the apoptosis of MCF7 and MDA-MB-231 cells. In combination with conventional chemotherapeutic drugs, DB exhibited a further enhanced synergistic effect than when used as a single agent. Overall, the data of the present study demonstrate that DB may prove to be a promising autophagy inhibitor with anticancer activity against breast cancer.

Transcription factor KLF16 activates MAGT1 to regulate the tumorigenesis and progression of breast cancer.

Breast cancer is the most frequent cause of cancer-related mortality among women worldwide. The present study aimed to explore the role of magnesium transporter protein 1 (MAGT1) in breast cancer and to illustrate the potential underlying molecular mechanisms. Bioinformatic analysis was performed to explore the association between MAGT1 expression and patients with breast cancer. MTT, colony formation, wound healing and Transwell assays were performed to examine the proliferative, migratory and invasive abilities of MCF-7 cells. Western blot analysis was conducted to determine the corresponding protein expression. Chromatin immunoprecipitation and luciferase reporter assays were carried out to reveal the interaction between MAGT1 and the Kruppel-like factor 16 (KLF16). In addition, an experimental animal model was established by the subcutaneous injection of MCF-7 cells into BALB/c nude mice, and tumor weight and size were measured. The results revealed that MAGT1 expression was upregulated in breast cancer. MAGT1 knockdown significantly suppressed the MCF-7 cell proliferative, migratory and invasive abilities, and downregulated the protein expression of Ki67, proliferating cell nuclear antigen, MMP2 and MMP9. MAGT1 knockdown also markedly suppressed tumor growth in vivo. Moreover, KLF6 could bind to the MAGT1 promoter and positively regulate MAGT1 expression. The inhibitory effects of KLF6 knockdown on cell proliferation, migration and invasion in vitro, and tumor growth in vivo were partly abolished by MAGT1 overexpression. On the whole, the findings of the present study suggest that MAGT1 knockdown exerts notable inhibitory effects on the progression of breast cancer, providing a potential therapeutic target for the treatment of breast cancer.

Norcantharidin Nanostructured Lipid Carrier (NCTD-NLC) Suppresses the Viability of Human Hepatocellular Carcinoma HepG2 Cells and Accelerates the Apoptosis.

Malignant tumors have become the main cause of harm to human life and health. Development for new antitumor drugs and the exploration to drug carriers are becoming the concerned focus. In this study, we exploited our experiments to explore the effect of NCTD-NLC on liver cancer cells: the HepG2 cells cultured in vitro were given with NCTD-NLC administration; then, the estimation on cellular proliferation and apoptosis was accomplished through MTT and flow cytometry. Six hours after the administration, we performed the High Performance Liquid Chromatography (HPLC) detection to estimate the NCTD content in the heart, liver, spleen, lung, kidney and plasma of rats. Then, our outcomes showed that NCTD-NLC had a notable inhibitory effect on HepG2 cells, leading to a gradually decreased cellular viability. Cell viability was negatively correlated with NCTD-NLC concentration. Along with the concentration increasing, significantly increasing cellular apoptosis and gradually decreasing cellular viability were observed. The apoptosis rate was positively correlated with the concentration of NCTD-NLC. On the basis of the data we obtained, we found that the group with NCTD-NLC tail vein injection had an obvious advantage in drug delivery when compared with other groups. Through the tumorigenesis test to nude mice, we found that the tumor inhibition rate of the NCTD-NLC tail vein injection group had a 27.48% elevation in contrast to the NCTD gavage group, and it was also the group with the best tumor inhibition efficiency. In conclusion, the NCTD-NLC prepared in this study had a mighty inhibitory effect towards HepG2 cellular viability and an accelerating work on apoptosis. Tail vein injection of NCTD-NLC has the best drug delivery effect.

Interferon regulatory factor 5‑induced upregulation of zinc‑finger protein 217 promotes pancreatic carcinoma progression.

The aim of the present study was to investigate the molecular mechanisms of zinc-finger protein 217 (ZNF217) in pancreatic carcinoma (PC) progression. ZNF217-associated expression and survival data from patients with PC were retrieved from the Gene Expression Profiling Interactive Analysis server. The mRNA expression level of ZNF217 was detected by reverse transcription-quantitative PCR. Cell Counting Kit-8, colony formation, wound-healing and Transwell assays were conducted to assess cellular proliferation, migratory and invasive abilities. Proliferation was also examined by immunofluorescence detection of Ki67 expression, and chromatin immunoprecipitation (ChIP) and luciferase reporter assays were performed to detect the interaction between ZNF217 and interferon regulatory factor 5 (IRF5). ZNF217 was found to be significantly upregulated in tumor tissues and cancer cell lines, which was associated with a poor survival rate in patients with PC. ZNF217 silencing markedly suppressed cellular proliferation and migratory and invasive abilities, as well as decreased the expression of Ki67. IRF5 was also upregulated in PC tumor tissues and was shown to positively regulate the activity of the ZNF217 promoter and its mRNA expression levels. Furthermore, ChIP assays demonstrated that IRF5 bound to the promoter region of ZNF217 in vitro. In conclusion, ZNF217 silencing exerted notable inhibitory effects on the progression of PC. Thus, ZNF217 may serve as a potential target for developing novel therapeutic strategies for PC.

Antibacterial mechanism of Protocatechuic acid against Yersinia enterocolitica and its application in pork

Protocatechuic acid (PCA) has adequate antibacterial activity against foodborne pathogens; however, its antibacterial mechanism has been rarely investigated. Therefore, this study attempts to elucidate the antibacterial mechanism of PCA against Yersinia enterocolitica . The corresponding results showed that PCA had a satisfactory antibacterial effect on Y. enterocolitica with a minimum inhibitory concentration (MIC) of 2.5 mg/mL. Accordingly, depolarization of the cell membrane, reduction of intracellular pH (pH in ) and adenosine triphosphate (ATP), leakage of K + and destruction of cell morphology were observed in this study, which indicated that PCA changed the membrane permeability of Y. enterocolitica . According to the metabolomics analysis, PCA induced the differential expression of the metabolites of Y. enterocolitica . In addition, enrichment analysis of metabolic pathways demonstrated that PCA disordered energy metabolism and amino acid biosynthesis of Y. enterocolitica . PCA also exhibited a notable inhibitory effect on Y. enterocolitica in pork. According to the corresponding findings, PCA may possess potential antibacterial properties in controlling Y. enterocolitica contamination within food industry. • Protocatechuic acid showed high antibacterial activity against Y. enterocolitica. • Protocatechuic acid destroyed the cell membrane structure of Y. enterocolitica. • Protocatechuic acid disordered energy metabolism and amino acid metabolism. • Protocatechuic acid extended the shelf life of chilled pork.

Mapping Regulatory Elements within 5' and 3' UTRs of SIGLEC15 with a Use of Reporter System

Siglec-15 is an immune suppressor with broad upregulation on various cancer types and has emerged as a potential target for cancer immunotherapy. However, it remains unclear how SIGLEC15 expression is controlled in normal or cancer cells. In this work, we utilized reporter assays to evaluate the impact of the 5' UTR and the 3' UTR of SIGLEC15 mRNA on gene expression. We found that the 3' UTR dramatically reduced reporter protein production, whereas the 5' UTR showed modest inhibitory effect. Quantification of steady-state mRNA revealed the good coupling of protein amount and mRNA abundance that was associated with the 3' UTR. In contrast, the 5' UTR had little effect on mRNA abundance compared with the empty control. By measuring mRNA half-life, we showed that the 3' UTR markedly promoted mRNA degradation. Testing shortened 3' UTR fragments demonstrated five out of the six having notable inhibitory effect, with the one spanning 993-1317 had the most robust activity. More interestingly, the 993-1317 region contains a predicted 43-nt stem-loop structure that showed apparent inhibitory activity in four cell lines tested. These results suggested that the 3' UTR inhibited reporter gene expression by accelerating mRNA decay possibly via multiple cis-regulatory elements, but the 5' UTR repressed gene expression by inhibiting translation. Thus, our findings provided a clue to the molecular mechanism underlying the regulation of SIGLEC15 expression.

Expression Landscape and Functional Roles of HOXA4 and HOXA5 in Lung Adenocarcinoma.

Background: The role of HOXA family genes in the occurrence and progression of a variety of human cancers has been scatteredly reported. However, there is no systematic study on the differential expression, prognostic significance and potential molecular mechanism of HOXA4 and HOXA5 in LUAD.Methods: In-house immunohistochemistry (IHC), multi-center microarrays, RT-qPCR and RNA-seq data were incorporated for comprehensively evaluating the expression and prognostic value of HOXA4 and HOXA5 in LUAD. The mechanism of HOXA4 and HOXA5 in the formation and development of LUAD was analyzed from multiple aspects of immune correlations, upstream transcriptional regulation, functional states of single cells and co-expressed gene network. The functional roles of HOXA4 and HOXA5 in LUAD were validated by in vitro experiments.Results: As a result, in 3201 LUAD samples and 2494 non-cancer lung samples, HOXA4 and HOXA5 were significantly downexpressed (P < 0.05). The aberrant expression of HOXA5 was significantly correlated with the clinical progression of LUAD (P < 0.05). HOXA5 showed remarkable prognostic value for LUAD patients (P < 0.05). The expression of HOXA4 and HOXA5 in LUAD were negatively correlated with tumor purity and positively correlated with the infiltration of various immune cells such as B cells, T cells and macrophages. HOXA4 and HOXA5 overexpression had notable inhibitory effect on the proliferation, migration and invasion of LUAD cells.Conclusions: In conclusion, the identified downexpressed HOXA4 and HOXA5 had significant distinguishing ability for LUAD samples and affected the cellular functions of LUAD cells. The low expression of HOXA5 indicated worse overall survival of LUAD patients. Therefore, the two HOXA family genes especially HOXA5 may serve as potential biomarkers for LUAD.

Identification and characterization of bisbenzimide compounds that inhibit human cytomegalovirus replication.

The shortcomings of current anti-human cytomegalovirus (HCMV) drugs has stimulated a search for anti-HCMV compounds with novel targets. We screened collections of bioactive compounds and identified a range of compounds with the potential to inhibit HCMV replication. Of these compounds, we selected bisbenzimide compound RO-90-7501 for further study. We generated analogues of RO-90-7501 and found that one compound, MRT00210423, had increased anti-HCMV activity compared to RO-90-7501. Using a combination of compound analogues, microscopy and biochemical assays we found RO-90-7501 and MRT00210423 interacted with DNA. In single molecule microscopy experiments we found RO-90-7501, but not MRT00210423, was able to compact DNA, suggesting that compaction of DNA was non-obligatory for anti-HCMV effects. Using bioinformatics analysis, we found that there were many putative bisbenzimide binding sites in the HCMV DNA genome. However, using western blotting, quantitative PCR and electron microscopy, we found that at a concentration able to inhibit HCMV replication our compounds had little or no effect on production of certain HCMV proteins or DNA synthesis, but did have a notable inhibitory effect on HCMV capsid production. We reasoned that these effects may have involved binding of our compounds to the HCMV genome and/or host cell chromatin. Therefore, our data expand our understanding of compounds with anti-HCMV activity and suggest targeting of DNA with bisbenzimide compounds may be a useful anti-HCMV strategy.

Insights into the enhanced degradation of flumequine by UV/ClO2 integrated process: Kinetics, mechanisms and DBPs-related toxicity in post-disinfection

The enhanced elimination of flumequine by combined UV/ClO2 advanced oxidation processes (AOPs) and disinfection by-products (DBPs)-related toxicity during post-disinfection were investigated. The efficient removal of flumequine by UV/ClO2 could be depicted with pseudo first order kinetics. The roles of main reactive species were identified by quenching experiments and EPR spectrum. The contributing proportions of UV photolysis, singlet oxygen (1O2), OH and reactive chlorine species (RCS) were calculated to be 11.37%, 14.72%, 19.79% and 54.12%, respectively. Then key influence factors including UV intensity, ClO2 dosages, pH and water matrices (co-present anions and nature organic matter (NOM)) were examined comprehensively. The degradation rate of flumequine (kobs) gradually increased with ClO2 dosage and UV intensity, but decreased obviously as pH ascended. The coexistence of Cl− showed negligible impact on kobs while HCO3− displayed notable inhibitory effect. However, kobs was greatly depressed by the NOM presence and the negative correlations between kobs and organic indexes were verified. Based on FT-ICR-MS analysis, the UV/ClO2 destruction pathways of flumequine were proposed to involve hydroxylation, decarboxylation, demethylation and defluorination. Comparatively, although UV/Cl2 showed better removal efficiency and lower energy requirement than UV/ClO2, the latter process induced much less toxicity connected with DBPs in post-oxidation. The results implied that the oxidation characteristics of 1O2 (non-radical pathway) varied greatly from those of OH and RCS, which may lead to the distinct advantage of UV/ClO2 in DBPs control. Take flumequine as an example, this paper is devoted to better comprehending the UV/ClO2 integrated technique. The findings may also shed light on the feasibility of UV/ClO2 and UV/Cl2 AOPs systems in tradeoffs among factors including removal effectiveness, operational cost and toxicity concerns of the treated waters containing emerging contaminants.

Design, synthesis of novel peripherally tetra-chalcone substituted phthalocyanines and their inhibitory effects on acetylcholinesterase and carbonic anhydrases (hCA I and II)

In this work, phthalocyanine precursor (3), tetra-chalcone substituted metal-free (4) and metallo phthalocyanines (5, 6, 7) were synthesized for the first time and surveyed interactions against acetylcholinesterase (AChE, which are associated with Alzheimer's disease) and human CA isoenzymes I and II (hCA I and hCA II, which are ubiquitous cytosolic isoforms). The structures of the novel phthalonitrile (3) and phthalocyanines (4-7) were designated by FT-IR, NMR, UV-Vis, and mass spectroscopy. These phthalocyanines inhibited hCA I with inhibition constants in the range of 0.5621-0.6413 μM and hCA II with inhibition constants in the range of 0.4823-0.6117 μM. On the other hand, these phthalocyanines indicated notable inhibitory effect against AChE.

Cadinane-type sesquiterpenes with potential anti-inflammatory and anti-HIV activities from the stems and leaves of Mappianthus iodoides

Eight cadinane-type sesquiterpenes, including a new cadinane-type sesquiterpene, named as mappianiodene (1), and seven known analogues (2–8), were isolated and identified from the stems and leaves of Mappianthus iodoides. The chemical structure and absolute configurations of 1 was elucidated by extensive spectral methods and the known compounds were identified by comparing their experimental spectral data with the reported spectral data in the literature. The anti-inflammatory and anti-HIV activities of those isolated cadinane-type sesquiterpenes were tested. As a result, cadinane-type sesquiterpenes 1–8 displayed notable inhibitory effects on NO (nitric oxide) production with IC50 values equivalent to that of the hydrocortisone. Moreover, compounds 1–8 exhibited pronounced anti-HIV-1 reverse transcriptase (RT) activities with the EC50 values in range of 0.17 to 9.28 µM.

Thymol-functionalized hollow mesoporous silica spheres nanoparticles: preparation, characterization and bactericidal activity

Antimicrobial natural products show good antimicrobial activities; however, some of them have unpleasant odor or high volatility that limits their application in food industry. One of solutions is to introduce them in inorganic media. In this study, hollow mesoporous silica sphere (HS) was used to encapsulate natural organic antimicrobial agent thymol, and antimicrobial activity of the resulted antimicrobial agent (HST) was tested. Materials characterization revealed that the thymol was successfully introduced into the cavities of HS, and the inorganic host exhibited a high loading capacity of 1320 mg g−1. In addition, the antibacterial activities were tested by double-fold dilution method, the minimum bactericidal concentrations of HST against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) were decreased compared with that of thymol. Furthermore, scanning electron microscopy observation confirmed that HST indeed showed a notable inhibitory effect against E. coli and S. aureus by disrupting cell membrane structure.

Prenylated coumarins from the fruits of Artocarpus heterophyllus with their potential anti-inflammatory and anti-HIV activities

A phytochemical investigation on the fruits of Artocarpus heterophyllus led to the isolation and characterisation of a new prenylated coumarin, artoheteronin (1), together with six known analogues (2−7). The chemical structure of 1 was elucidated using extensive spectral methods and the known compounds (2−7) were identified by comparing their spectral data with those reported in the literature. All known compounds (2–7) were isolated from the genus Artocarpus for the first time. The anti-inflammatory and anti-HIV activities of all isolated prenylated coumarins (1–7) were assessed in vitro. As a result, compounds 1–7 displayed notable inhibitory effects against nitric oxide (NO) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells in vitro with the IC50 values in range of 0.58 ± 0.06 to 6.29 ± 0.12 μM. Meanwhile, compounds 1–7 exhibited notable anti-HIV-1 reverse transcriptase (RT) activities possessing EC50 values in the range of 0.18 to 9.12 µM.

Structural analogues of existing anti-viral drugs inhibit SARS-CoV-2 RNA dependent RNA polymerase: A computational hierarchical investigation

The Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became a pandemic, resulting in an exponentially increased mortality globally and scientists all over the world are struggling to find suitable solutions to combat it. Multiple repurposed drugs have already been in several clinical trials or recently completed. However, none of them shows any promising effect in combating COVID-19. Therefore, developing an effective drug is an unmet global need. RdRp (RNA dependent RNA polymerase) plays a pivotal role in viral replication. Therefore, it is considered as a prime target of drugs that may treat COVID-19. In this study, we have screened a library of compounds, containing approved RdRp inhibitor drugs that were or in use to treat other viruses (favipiravir, sofosbuvir, ribavirin, lopinavir, tenofovir, ritonavir, galidesivir and remdesivir) and their structural analogues, in order to identify potential inhibitors of SARS-CoV-2 RdRp. Extensive screening, molecular docking and molecular dynamics show that five structural analogues have notable inhibitory effects against RdRp of SARS-CoV-2. Importantly, comparative protein-antagonists interaction revealed that these compounds fit well in the pocket of RdRp. ADMET analysis of these compounds suggests their potency as drug candidates. Our identified compounds may serve as potential therapeutics for COVID-19.

Isoquercitrin induces apoptosis and autophagy in hepatocellular carcinoma cells via AMPK/mTOR/p70S6K signaling pathway.

Hepatocellular carcinoma (HCC) is an aggressive malignancy with high rates of metastasis and relapse. Isoquercitrin (ISO), a natural flavonoid present in the Chinese bayberry and other plant species, reportedly exerts notable inhibitory effects on tumor cell proliferation, though the mechanism is unknown. In the present study, we exposed HepG2 and Huh7 human liver cancer cells to ISO and examined the roles of autophagy and apoptosis in ISO-mediated cell death. We found that ISO exposure inhibited cell viability and colony growth, activated apoptotic pathway, and triggered dysregulated autophagy by activating the AMPK/mTOR/p70S6K pathway. Autophagy inhibition using 3-methyladenine (3-MA) or Atg5-targeted siRNA decreased the Bax/Bcl-2 ratio, caspase-3 activation, and PARP cleavage and protected cells against ISO-induced apoptosis. Moreover, autophagy inhibition reversed the upregulation of AMPK phosphorylation and downregulation of mTOR and p70S6K phosphorylation elicited by ISO. By contrast, application of a broad-spectrum caspase inhibitor failed to inhibit autophagy in ISO-treated cells. These data indicate that ISO simultaneously induced apoptosis and autophagy, and abnormal induction of autophagic flux contributed to ISO-triggered caspase-3-dependent apoptosis.

MiR-223-3p inhibits rTp17-induced inflammasome activation and pyroptosis by targeting NLRP3.

The incidence of syphilis caused by Treponema pallidum subsp pallidum (T pallidum) infection is accompanied by inflammatory injuries of vascular endothelial cells. Studies have revealed that T pallidum infection could induce inflammasome activation and pyroptosis in macrophages. MicroRNA‐223‐3p (miR‐223‐3p) was reported to be a negative regulator in inflammatory diseases. The present study aimed to explore whether miR‐223‐3p regulates T pallidum‐induced inflammasome activation and pyroptosis in vascular endothelial cells, and determine the mechanisms which underlie this process. MiR‐223‐3p levels in syphilis and control samples were determined. The biological function of miR‐223‐3p in the NLRP3 inflammasome and pyroptosis was evaluated in T pallidum‐infected human umbilical vein endothelial cells (HUVECs). We observed a dramatic decrease in miR‐223‐3p levels in syphilis patients (n = 20) when compared to healthy controls (n = 20). Moreover, miR‐223‐3p showed a notable inhibitory effect on recombinant Tp17 (rTP17)‐induced caspase‐1 activation, resulting in decrease in IL‐1β production and pyroptosis, which was accompanied by the release of lactate dehydrogenase (LDH) in HUVECs. Additionally, the dual‐luciferase assay confirmed that NLRP3 is a direct target of miR‐223‐3p. Moreover, NLRP3 overexpression or knockdown largely blocked the effects of miR‐223‐3p on T pallidum‐induced inflammasome activation and pyroptosis in HUVECs. Most importantly, a notable negative correlation was observed between miR‐223‐3p and NLRP3, caspase‐1, and IL‐1β, respectively, in the serum of syphilis patients and healthy controls. Taken together, our results reveal that miR‐223‐3p targets NLRP3 to suppress inflammasome activation and pyroptosis in T pallidum‐infected endothelial cells, implying that miR‐223‐3p could be a potential target for syphilis patients.