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Hepatocellular carcinoma (HCC), the primary form of liver cancer, is the third leading cause of cancer-related death globally. Hernandonine is a natural alkaloid derived from Hernandia nymphaeifolia that has been shown to exert various biological functions. In a previous study, hernandonine was shown to suppress the proliferation of several solid tumor cell lines without affecting normal human cell lines. However, little is known about the effect of hernandonine on HCC. Therefore, this study aimed to investigate the effect and mechanism of hernandonine on HCC in relation to autophagy. We found that hernandonine inhibited HCC cell growth in vitro and in vivo. In addition, hernandonine elicited autophagic cell death and DNA damage in HCC cells. RNA-seq analysis revealed that hernandonine upregulated p53 and Hippo signaling pathway-related genes in HCC cells. Small RNA interference of p53 resulted in hernandonine-induced autophagic cell death attenuation. However, inhibition of YAP sensitized HCC cells to hernandonine by increasing the autophagy induction. This is the first study to illustrate the complex involvement of p53 and YAP in the hernandonine-induced autophagic cell death in human HCC cells. Our findings provide novel evidence for the potential of hernandonine as a therapeutic agent for HCC treatment.
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A series of flavanols were synthesized to assess their biological activity against human non-small cell lung cancer cells (A549). Among the sixteen synthesized compounds, it was observed that compounds 6k (3.14 ± 0.29 µM) and 6l (0.46 ± 0.02 µM) exhibited higher potency compared to 5-fluorouracil (5-Fu, 4.98 ± 0.41 µM), a clinical anticancer drug which was used as a positive control. Moreover, compound 6l (4'-bromoflavonol) markedly induced apoptosis of A549 cells through the mitochondrial- and caspase-3-dependent pathways. Consequently, compound 6l might be developed as a candidate for treating or preventing lung cancer.
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Antineoplásicos , Apoptose , Flavonóis , Humanos , Flavonóis/farmacologia , Flavonóis/síntese química , Flavonóis/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Células A549 , Caspase 3/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Fluoruracila/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Linhagem Celular TumoralRESUMO
The chemical screening of an octocoral identifed as Junceella fragilis has led to the isolation of five chlorinated briarane-type diterpenoids, including three known metabolites, gemmacolide X (1), frajunolide I (2), and fragilide F (3), along with two new analogs, 12α-acetoxyfragilide F (4) and 12α-acetoxyjunceellin (5). Single-crystal X-ray diffraction analysis was carried out to determine the absolute configurations of 1 and 2, while the structures of new compounds 4 and 5 were ascertained with 2D NMR experiments. Briaranes 1 and 3-5 were active in enhancing alkaline phosphatase (ALP) activity.
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2-Styrylchromones have been shown to possess a broad spectrum of biological activities. Replacing the carbon atom in 2-styrylchromones with a nitrogen atom in the benzene rings forms 2-(pyridylvinyl)chromen-4-ones (aza-2-styrylchromones). We have synthesized a series of novel 2-(pyridylvinyl)chromen-4-ones and their pyridine N-oxides to evaluate them as potential anticancer agents against human non-small-cell lung cancer cells (A549). Among the 18 synthesized molecules, compounds 18 and 8a exhibited comparable inhibitory effects to 5-fluorouracil and showed no toxicity against normal cells.
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Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Fluoruracila , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
The Euphorbiaceae plant Euphorbia neriifolia L. is distributed widely in India, Thailand, Southeastern China, and Taiwan and used as a carminative and expectorant to treat several inflammation-related diseases, such as gonorrhoea, asthma, and cancer. In the course of our search for potential anti-inflammatory agents from the titled plant, 11 triterpenes from the stem of E. neriifolia were isolated and reported in our previous endeavor. Given its rich abundance in triterpenoids, the ethanolic extract in this follow-up exploration has led to the isolation of additional eight triterpenes, including six new euphanes-neritriterpenols H and J-N (1 and 3-7)-one new tirucallane, neritriterpenol I (2), and a known compound, 11-oxo-kansenonol (8). Their chemical structures were elucidated on the basis of spectroscopic data, including 1D- and 2D NMR, and HRESIMS spectra. The absolute stereochemistry of neritriterpenols was determined by single-crystal X-ray diffraction analysis, ICD spectra, and DP4+ NMR data calculations. Compounds 1-8 were also evaluated for their anti-inflammatory activity by using lipopolysaccharide (LPS)-stimulated IL-6 and TNF-α on RAW 264.7 macrophage cells. Intriguingly, the euphane-type triterpenes (1 and 3-8) showed an inhibitory effect on LPS-induced IL-6 but not on TNF-α, while tirucallane-type triterpene 2 showed strong inhibition on both IL-6 and TNF-α.
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Sinulariolide (SC-1) is a natural product extracted from the cultured-type soft coral Sinularia flexibilis and possesses anti-inflammation, anti-proliferative, and anti-migratory in several types of cancer cells. However, the molecular pathway behind its effects on inflammation remains poorly understood. Since inflammatory cytokines such as TGFß, TNFα, IL-1, IL-6, and IL-8 activate transcription factors such as Smads, NF-κB, STAT3, Snail, Twist, and Zeb that drive the epithelial-to-mesenchymal transition (EMT), in this study, we focus on the investigation in effects of SC-1 on TGFß-induced interleukin-6 (IL-6) releases in an in vitro cell culture model. We showed that both intracellular IL-6 expression and secretion were stimulated by TGFß and associated with strong upregulation of IL-6 mRNA and increased transcription in A549 cells. SC-1 blocked TGFß-induced secretion of IL-6 while showing no effect on the induction of fibronectin and plasminogen activator inhibitor-1 genes, indicating that SC-1 interferes with only a subset of TGFß activities. In addition, SC-1 inhibits TGFß-induced IL-6 by suppressing p38 MAPK signaling and subsequently inhibits NF-κB and its nuclear translocation without affecting the canonical Smad pathway and receptor turnover. Overall, these data suggest that p38 may involve in the inhibition of SC-1 in IL-6 release, thus illustrating an inhibitory effect for SC-1 in the suppression of inflammation, EMT phenotype, and tumorigenesis.
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Antozoários , Carcinoma , Animais , NF-kappa B/metabolismo , Interleucina-6/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Fator de Crescimento Transformador beta/genética , Antozoários/metabolismoRESUMO
Background and aim: Sepsis causes an uncontrolled systemic response characterized by excessive inflammation and immune suppression, leading to multiple organ failure and death. An effective therapeutic strategy for sepsis-related syndromes is urgently needed. Hypericum sampsonii Hance (HS) is a folk herbal plant used to treat arthritis and dermatitis, but the anti-inflammatory properties of HS and its related compounds have rarely been investigated. In this study, we aimed to explore the anti-inflammatory effects of HS. Experimental procedure: Models of bacterial lipopolysaccharide (LPS)-induced activated macrophages and endotoxemia mice were used, in which the TLR4/NF-κB signaling pathway is upregulated to trigger inflammatory responses. The HS extract (HSE) was delivered into LPS-induced endotoxemia mice via oral administration. Three compounds were purified using column chromatography and preparative thin layer chromatography and were validated by physical and spectroscopic data. Results: HSE suppressed NF-κB activation and proinflammatory molecules (TNF-α, IL-6, iNOS) in LPS-activated RAW 264.7 macrophages. Furthermore, oral administration of HSE (200 mg/kg) to LPS-treated mice improved the survival rate, restored body temperature, decreased TNF-α and IL-6 in serum, and reduced IL-6 expression in bronchoalveolar lavage fluid (BALF). In lung tissues, HSE reduced LPS-induced leukocyte infiltration and the expression of proinflammatory molecules (TNF-α, IL-6, iNOS, CCL4 and CCL5). Three pure compounds isolated from HSE, including 2,4,6-trihydroxybenzophenone-4-O-geranyl ether, 1-hydroxy-7 methoxyxanthone and euxanthone, were demonstrated to exhibit anti-inflammatory activities in LPS-stimulated RAW 264.7 macrophages. Conclusion: The present study demonstrated the anti-inflammatory effects of HS in vitro and in vivo. Further clinical studies of HS in human sepsis are warranted.
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Three new triterpenoids-spergulagenin B (1), spergulagenin C (2), and spergulagenin D (3)-were isolated from the aerial part of Glinus oppositifolius, along with 17 known compounds (4-20). The structures of these new compounds were identified by spectroscopic and MS analyses. Compounds 3, 5, 19, and 20 were evaluated for inhibition of nitric oxide production in LPS-stimulated RAW 264.7 cells with IC50 values of 17.03, 18.21, 16.30, and 12.64 µM, respectively. Compounds 3, 5, and 20 exhibited inhibitory effects on LPS-induced nitric oxide production in RAW 264.7 cells with IC50 values of 18.35 ± 1.34, 17.56 ± 1.41, and 14.27 ± 1.29 µM, respectively.
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Molluginaceae , Triterpenos , Animais , Camundongos , Molluginaceae/química , Triterpenos/farmacologia , Triterpenos/química , Óxido Nítrico , Lipopolissacarídeos/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Células RAW 264.7 , Estrutura MolecularRESUMO
The mold Monascus, also called red yeast rice, anka, or koji, has been used as the natural food coloring agent and food additives for more than 1000 years in Asian countries. It has also been used in Chinese herbology and traditional Chinese medicine due to its easing digestion and antiseptic effects. However, under different culture conditions, the ingredients in Monascus-fermented products may be changed. Therefore, an in-depth understanding of the ingredients, as well as the bioactivities of Monascus-derived natural products, is important. Here, through the thorough investigation into the chemical constituents of M. purpureus wmd2424, five previously undescribed compounds, monascuspurins A-E (1-5), were isolated from the EtOAc extract of mangrove-derived fungus Monascus purpureus wmd2424 cultured in RGY medium. All the constituents were confirmed via HRESIMS and 1D- and 2D-NMR spectroscopy. Their antifungal activity was also evaluated. Our results showed that four constituents (compounds 3-5) possessed mild antifungal activity against Aspergillus niger, Penicillium italicum, Candida albicans, and Saccharomyces cerevisiae. It is worth mentioning that the chemical composition of the type strain Monascus purpureus wmd2424 has never been studied.
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Monascus , Oryza , Antifúngicos/farmacologia , Antifúngicos/metabolismo , Monascus/metabolismo , Fungos , Aditivos Alimentares/metabolismo , Corantes , Fermentação , Oryza/microbiologiaRESUMO
The chemical screening of a cultured soft coral, Briareum violaceum, led to the isolation of eight natural, briarane-related diterpenoids, including three unreported metabolites, briavioids E-G (1-3), and five known briaranes, briacavatolides B (4) and C (5), briaexcavatin L (6), briaexcavatolide U (7) and briarenol K (8). The structures of briaranes 1-8 were established using spectroscopic methods. The absolute configuration of briavioid A (9), obtained in a previous study, was reported for the first time in this study by a single-crystal X-ray diffraction analysis using a copper radiation source. The anti-inflammatory activity of briaranes 1 and 2 and briaranes 4-8 was evaluated by screening their inhibitory ability against the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins in lipopolysaccharide (LPS)-induced RAW 264.7 macrophage cells.
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Antozoários , Diterpenos , Animais , Camundongos , Anti-Inflamatórios/farmacologia , Células RAW 264.7 , Macrófagos/metabolismo , Diterpenos/farmacologia , Antozoários/química , Óxido Nítrico Sintase Tipo II/metabolismo , Ciclo-Oxigenase 2/metabolismoRESUMO
In our continued search for bioactive metabolites from cultures of rare Actinobacteria resources from all over Taiwan and various natural ecological environments, an active antimicrobial strain of Acrocarpospora punica 04107M was collected in Taitung County in Taiwan and prepared from soil. The bioassay-guided fractionation of the BuOH extract of a culture broth from A. punica 04107M led to the isolation of five previously undescribed compounds: Acrocarposporins A−E (Compounds 1−5). All the constituents were confirmed by HRESIMS and 1D- and 2D-NMR spectroscopy. Their antifungal activity was also evaluated. Our results showed that four constituents (Compounds 1, 2, 4, and 5) possessed mild antifungal activity against Aspergillus niger, Penicillium italicum, Candida albicans, and Saccharomyces cerevisiae. It is worth mentioning that the chemical composition of Acrocarpospora punica 04107M has never been studied. This is the first report on diterpenoid metabolites from the genus Acrocarpospora.
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Selenium is an essential micronutrient that is beneficial to human health. Selenium-containing drugs have been developed as antioxidants, anti-inflammatory, and anticancer agents. However, the synthesis of selenium-containing chalcones has not been fully explored. Therefore, we report the synthesis of novel selenophene-based chalcone analogs and reveal their biological activities as anticancer agents. Among the seven synthesized molecules, compounds 6, 8, and 10 exhibited anticancer activity with IC50 values of 19.98 ± 3.38, 38.23 ± 3.30, and 46.95 ± 5.68 µM, respectively, against human colorectal adenocarcinoma (HT-29) cells. Clonogenic assays and Western blot analysis tests further confirmed that compound 6 effectively induced apoptosis in HT-29 cells through mitochondrial- and caspase-3-dependent pathways.
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Antineoplásicos , Chalcona , Chalconas , Selênio , Humanos , Chalconas/farmacologia , Selênio/farmacologia , Relação Estrutura-Atividade , Proliferação de Células , Antineoplásicos/farmacologia , Apoptose , Ensaios de Seleção de Medicamentos Antitumorais , Linhagem Celular Tumoral , Estrutura MolecularRESUMO
Two new chromones named cnidimol G (1) and cnidimol H (2), one new coumarin, 7-methoxy-8-(3-methoxy-3-methyl-2-oxobutyl)coumarin (3), and twenty known compounds were isolated from MeOH extract of the fruit of Cnidium monnieri (L.) Cusson. The structures of compounds were elucidated by extensive spectroscopic analyses including 1 D and 2 D NMR, HRESIMS, IR and UV. Anti-inflammatory activity of the selected isolated compounds were evaluated. Compounds 1 and 8 exhibited inhibitory activities against nitric oxide production.
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Cnidium , Frutas , Cnidium/química , Frutas/química , Cromonas/farmacologia , Cromonas/análise , Extratos Vegetais/química , Cumarínicos/químicaRESUMO
Hepatocellular carcinoma (HCC) is the most common form of liver cancer, with the second highest mortality rate in all cancer. Energy reprogramming is one of the hallmarks of cancer, and emerging evidence showed that targeting glycolysis is a promising strategy for HCC treatment. Cryptocaryone has been shown to display promising anti-cancer activity against numerous types of cancer. Previous study also indicated that cryptocaryone induces cytotoxicity by inhibiting glucose transport in cancer cells, but the detailed mechanism still needs to be elucidated. Therefore, this study aimed to investigate the relationship between the anti-cancer effect and glycolytic metabolism of cryptocaryone in human HCC cells. In this study, we found that cryptocaryone potently induced growth inhibition by apoptotic cell death in HCC cells. Cryptocaryone also suppressed the ATP synthesis, lactate production and glycolytic capacity of HCC cells. Mechanistic investigations showed that phosphorylation of Akt and c-Src, as well as the expression of HK1 were impeded by cryptocaryone. Moreover, cryptocaryone markedly increased the expression level of transcription factor FoxO1. Importantly, clinical database analysis confirmed the negative correlation between HK1 and FoxO1. High expression levels of HK-1 were positively correlated with poorer survival in patients with HCCs. These results suggest that cryptocaryone may promote cell apoptosis by inhibiting FoxO1-mediated aerobic glycolysis through Akt and c-Src signaling cascades in human HCC cells. This is the first study to indicate that cryptocaryone exerts anti-cancer property against human HCC cells. Cryptocaryone is a potential natural product worthy of further development into a promising candidate for HCC treatment.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Pironas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Tumoral , Transdução de Sinais , Glicólise , ApoptoseRESUMO
Three norsesquiterpenoids, pathyspirolactones A (1) and B (2), and napalilactone (3), featuring a γ-spirolactone moiety, were isolated from the cultured octocoral Paralemnalia thyrsoides. The structures of 1-3 were determined by analyzing spectroscopic data, DP4+ computation, specific optical rotation, and X-ray diffraction. In addition, we explored the absolute configurations of pathyspirolactone A (1) and its conformation of the cyclohexane ring to resolve the stereochemical confusion of those of norsesquiterpenoid compounds. Furthermore, we proved that pathyspirolactone B (2) was the first bromine-containing norsesquiterpenoid reported from octocorals.
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The root bark of Morus alba L. (Mori Cortex) is used to treat diuresis and diabetes in Chinese traditional medicine. We evaluated different solvent extracts and bioactive components from the root bark of Morus alba L. for their antioxidant, anti-α-glucosidase, antityrosinase, and anti-inflammatory activities. Acetone extract showed potent antioxidant activity, with SC50 values of 242.33 ± 15.78 and 129.28 ± 10.53 µg/mL in DPPH and ABTS radical scavenging assays, respectively. Acetone and ethyl acetate extracts exhibited the strongest anti-α-glucosidase activity, with IC50 values of 3.87 ± 1.95 and 5.80 ± 2.29 µg/mL, respectively. In the antityrosinase assay, the acetone extract showed excellent activity, with an IC50 value of 7.95 ± 1.54 µg/mL. In the anti-inflammatory test, ethyl acetate and acetone extracts showed significant anti-nitric oxide (NO) activity, with IC50 values of 10.81 ± 1.41 and 12.00 ± 1.32 µg/mL, respectively. The content of the active compounds in the solvent extracts was examined and compared by HPLC analysis. Six active compounds were isolated and evaluated for their antioxidant, anti-α-glucosidase, antityrosinase, and anti-inflammatory properties. Morin (1) and oxyresveratrol (3) exhibited effective antioxidant activities in DPPH and ABTS radical scavenging assays. Additionally, oxyresveratrol (3) and kuwanon H (6) showed the highest antityrosinase and anti-α-glucosidase activities among all isolates. Morusin (2) demonstrated more significant anti-NO and anti-iNOS activities than the positive control, quercetin. Our study suggests that the active extracts and components from root bark of Morus alba should be further investigated as promising candidates for the treatment or prevention of oxidative stress-related diseases, hyperglycemia, and pigmentation disorders.
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Epidemiological studies have linked herbicides and Parkinson's disease (PD), with the strongest associations resulting from long exposure durations. Paraquat (PQ), an herbicide, induces PD-like syndromes and has widely been accepted as a PD mimetic. Currently, there is still no cure to prevent the progression of PD, and the search for effective therapeutic ways is urgent. Recently, the impairing activity of sirtuins (SIRTs), such as SIRT1, may correlate with PD etiology. However, the nonspecificity of SIRT1 agonists has made the protective mechanisms against PD unclear and hampered the therapeutic application of SIRT1. Thus, this study investigated the protective mechanism and therapeutic potential of SRT1720, a more specific agonist for SIRT1 synthesized by Sirtris, in alleviating the toxicity of PQ-induced cellular and animal models of PD. Here we show that SRT1720 alleviates PQ-induced toxicity in cell and animal models. Genetic silencing and pharmacological inhibition of SIRT1 attenuated SRT1720's protection against PQ-induced toxicity. Moreover, SRT1720 not only attenuated PQ-induced increased oxidative stress and mitochondrial free radical formations but also decreased mitochondrial membrane potential. Furthermore, SRT1720 reversed PQ-induced decreased PGC-1α levels and mitochondrial biogenesis. Although PQ and SRT1720 elevated NRF2 and antioxidative enzyme levels, only PQ decreased antioxidative enzyme activity but not SRT1720. NRF2 and PGC-1α silencing attenuated SRT1720 protection against PQ-induced toxicity. SRT1720 targeted SIRT1 and activated downstream PGC-1α and NRF2 signalings to prevent PQ-induced toxicity involving oxidative stress and mitochondrial dysfunction. Thus, SRT1720 might have therapeutic potential in preventing PD.
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Herbicidas , Doença de Parkinson , Animais , Paraquat/farmacologia , Sirtuína 1/genética , Sirtuína 1/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo , Herbicidas/toxicidade , Herbicidas/metabolismoRESUMO
The authors wish to make the following changes to their paper [...].
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The authors wish to make the following changes to their paper [...].
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Polygonatum sibiricum (Asparagaceae) is often used as an herbal drug in the traditional medicine of Southeast Asia. Its rhizome, called "Huang Jing", is used in traditional Chinese medicine as an immune system stimulant, hypolipidemic agent, anti-aging agent, anti-fatigue agent, and cardiovascular protectant. We investigated the antioxidant, anti-acetylcholinesterase (AChE), anti-inflammatory, and anti-α-glucosidase effects of various solvent extracts and major bioactive components of Polygonatum sibiricum (PS) and processed Polygonatum sibiricum (PPS). Dichloromethane extract of PS showed stronger antioxidant effects by DPPH, ABTS, and FRAP assays, and EtOAc extract displayed relatively high antioxidant activity by a superoxide radical scavenging test. Moreover, acetone, EtOAc, and dichloromethane extracts displayed a significant anti-α-glucosidase effect. EtOH and CH2Cl2 extracts showed effective AChE inhibitory activity. In addition, dichloromethane extract showed the best inhibition against lipopolysaccharide (LPS)-induced nitric oxide (NO) accumulation in RAW264.7 macrophages. HPLC analysis was used to investigate and compare the content of major active components of various solvent extracts of PS and PPS. Rutin showed the most effective scavenging of DPPH and ABTS free radicals, while scopoletin and isoquercetin displayed the strongest anti-α-glucosidase and anti-AChE effect, respectively. Rutin showed the best inhibition against LPS-induced NO production and also inhibited inducible nitric oxide synthase (iNOS) expression in Western blot. The molecular docking of AChE and iNOS revealed that active components could have a better antagonistic effect than positive controls (common inhibitors). This study shows that the active extracts and components of Polygonatum sibiricum have the potential to be further developed as a natural anti-AChE, anti-α-glucosidase, antioxidant and anti-inflammatory agent.