Pub Date : 2024-07-03DOI: 10.1007/s13659-024-00460-0
Felaine Anne Sumang, Alan Ward, Jeff Errington, Yousef Dashti
Plants and microbes are closely associated with each other in their ecological niches. Much has been studied about plant–microbe interactions, but little is known about the effect of phytochemicals on microbes at the molecular level. To access the products of cryptic biosynthetic gene clusters in bacteria, we incorporated an organic extract of hibiscus flowers into the culture media of different Actinobacteria isolated from plant rhizospheres. This approach led to the production of broad-spectrum dithiolopyrrolone (DTP) antibiotics, thiolutin (1) and aureothricin (2), by Streptomyces sp. MBN2-2. The compounds from the hibiscus extract responsible for triggering the production of these two DTPs were found to be hibiscus acid dimethyl ester (3) and hydroxycitric acid 1,3-dimethyl ester (4). It was subsequently found that the addition of either Fe2+ or Fe3+ to culture media induced the production of 1 and 2. The Chrome Azurol S (CAS) assay revealed that 3 and 4 can chelate iron, and therefore, the mechanism leading to the production of thiolutin and aureothricin appears to be related to changes in iron concentration levels. This work supports the idea that phytochemicals can be used to activate the production of cryptic microbial biosynthetic gene clusters and further understand plant–microbe interactions.
{"title":"Hibiscus acid and hydroxycitric acid dimethyl esters from Hibiscus flowers induce production of dithiolopyrrolone antibiotics by Streptomyces Strain MBN2-2","authors":"Felaine Anne Sumang, Alan Ward, Jeff Errington, Yousef Dashti","doi":"10.1007/s13659-024-00460-0","DOIUrl":"10.1007/s13659-024-00460-0","url":null,"abstract":"<div><p>Plants and microbes are closely associated with each other in their ecological niches. Much has been studied about plant–microbe interactions, but little is known about the effect of phytochemicals on microbes at the molecular level. To access the products of cryptic biosynthetic gene clusters in bacteria, we incorporated an organic extract of hibiscus flowers into the culture media of different Actinobacteria isolated from plant rhizospheres. This approach led to the production of broad-spectrum dithiolopyrrolone (DTP) antibiotics, thiolutin (<b>1</b>) and aureothricin (<b>2</b>), by <i>Streptomyces</i> sp. MBN2-2. The compounds from the hibiscus extract responsible for triggering the production of these two DTPs were found to be hibiscus acid dimethyl ester (<b>3</b>) and hydroxycitric acid 1,3-dimethyl ester (<b>4</b>). It was subsequently found that the addition of either Fe<sup>2+</sup> or Fe<sup>3+</sup> to culture media induced the production of <b>1</b> and <b>2</b>. The Chrome Azurol S (CAS) assay revealed that <b>3</b> and <b>4</b> can chelate iron, and therefore, the mechanism leading to the production of thiolutin and aureothricin appears to be related to changes in iron concentration levels. This work supports the idea that phytochemicals can be used to activate the production of cryptic microbial biosynthetic gene clusters and further understand plant–microbe interactions.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":718,"journal":{"name":"Natural Products and Bioprospecting","volume":"14 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11219617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-02DOI: 10.1007/s13659-024-00462-y
Rui Ma, Xu-Yao Feng, Jiang-Jiang Tang, Wei Ha, Yan-Ping Shi
Alzheimer’s disease (AD) is a complex neurodegenerative condition. 5α-epoxyalantolactone (5α-EAL), a eudesmane-type sesquiterpene isolated from the herb of Inula macrophylla, has various pharmacological effects. This work supposed to investigate the improved impact of 5α-EAL on cognitive impairment. 5α-EAL inhibited the generation of nitric oxide (NO) in BV-2 cells stimulated with lipopolysaccharide (LPS) with an EC50 of 6.2 μM. 5α-EAL significantly reduced the production of prostaglandin E2 (PGE2) and tumor necrosis factor-α (TNF-α), while also inhibiting the production of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) proteins. The ability of 5α-EAL to penetrate the blood–brain barrier (BBB) was confirmed via a parallel artificial membrane permeation assay. Scopolamine (SCOP)-induced AD mice model was employed to assess the improved impacts of 5α-EAL on cognitive impairment in vivo. After the mice were pretreated with 5α-EAL (10 and 30 mg/kg per day, i.p.) for 21 days, the behavioral experiments indicated that the administration of the 5α-EAL could alleviate the cognitive and memory impairments. 5α-EAL significantly reduced the AChE activity in the brain of SCOP-induced AD mice. In summary, these findings highlight the beneficial effects of the natural product 5α-EAL as a potential bioactive compound for attenuating cognitive deficits in AD due to its pharmacological profile.
{"title":"5α-Epoxyalantolactone from Inula macrophylla attenuates cognitive deficits in scopolamine-induced Alzheimer’s disease mice model","authors":"Rui Ma, Xu-Yao Feng, Jiang-Jiang Tang, Wei Ha, Yan-Ping Shi","doi":"10.1007/s13659-024-00462-y","DOIUrl":"10.1007/s13659-024-00462-y","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) is a complex neurodegenerative condition. 5<i>α</i>-epoxyalantolactone (5<i>α</i>-EAL), a eudesmane-type sesquiterpene isolated from the herb of <i>Inula macrophylla</i>, has various pharmacological effects. This work supposed to investigate the improved impact of 5<i>α</i>-EAL on cognitive impairment. 5<i>α</i>-EAL inhibited the generation of nitric oxide (NO) in BV-2 cells stimulated with lipopolysaccharide (LPS) with an EC<sub>50</sub> of 6.2 μM. 5<i>α</i>-EAL significantly reduced the production of prostaglandin E2 (PGE<sub>2</sub>) and tumor necrosis factor-α (TNF-α), while also inhibiting the production of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) proteins. The ability of 5<i>α</i>-EAL to penetrate the blood–brain barrier (BBB) was confirmed via a parallel artificial membrane permeation assay. Scopolamine (SCOP)-induced AD mice model was employed to assess the improved impacts of 5<i>α</i>-EAL on cognitive impairment in vivo. After the mice were pretreated with 5<i>α</i>-EAL (10 and 30 mg/kg per day, <i>i.p.</i>) for 21 days, the behavioral experiments indicated that the administration of the 5<i>α</i>-EAL could alleviate the cognitive and memory impairments. 5<i>α</i>-EAL significantly reduced the AChE activity in the brain of SCOP-induced AD mice. In summary, these findings highlight the beneficial effects of the natural product 5<i>α</i>-EAL as a potential bioactive compound for attenuating cognitive deficits in AD due to its pharmacological profile.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":718,"journal":{"name":"Natural Products and Bioprospecting","volume":"14 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11219692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-18DOI: 10.1007/s13659-024-00459-7
Sofya S. Starnovskaya, Liliana E. Nesterenko, Roman S. Popov, Natalya N. Kirichuk, Viktoria E. Chausova, Ekaterina A. Chingizova, Artur R. Chingizov, Marina P. Isaeva, Ekaterina A. Yurchenko, Anton N. Yurchenko
The marine holothurian-derived fungal strain KMM 4401 has been identified as Paragliomastix luzulae using 28S rDNA, ITS regions and the partial TEF1 gene sequences. The metabolite profile of the fungal culture was studied by UPLC-MS technique. The strain KMM 4401 is a source of various virescenoside-type isopimarane glycosides suggested as chemotaxonomic feature for this fungal species. Also Px. luzulae KMM 4401 was proposed as possible source of new bioactive secondary metabolites especially antimicrobials. Moreover, the co-cultures of Px. luzulae KMM 4401 with another marine fungus Penicillium hispanicum KMM 4689 inoculated simultaneously or after two weeks were investigated by same way. It was shown, that P. hispanicum KMM 4689 suppressed the production of most of Px. luzulae KMM 4401 metabolites. On the other hand, the co-cultivation of P. hispanicum KMM 4689 and Px. luzulae KMM 4401 resulted in increasing of production of main deoxyisoaustamide alkaloids of P. hispanicum KMM 4689 on 50–190%.
{"title":"Metabolite profiles of Paragliomastix luzulae (formerly named as Acremonium striatisporum) KMM 4401 and its co-cultures with Penicillium hispanicum KMM 4689","authors":"Sofya S. Starnovskaya, Liliana E. Nesterenko, Roman S. Popov, Natalya N. Kirichuk, Viktoria E. Chausova, Ekaterina A. Chingizova, Artur R. Chingizov, Marina P. Isaeva, Ekaterina A. Yurchenko, Anton N. Yurchenko","doi":"10.1007/s13659-024-00459-7","DOIUrl":"10.1007/s13659-024-00459-7","url":null,"abstract":"<div><p>The marine holothurian-derived fungal strain KMM 4401 has been identified as <i>Paragliomastix luzulae</i> using 28S rDNA, ITS regions and the partial <i>TEF1</i> gene sequences. The metabolite profile of the fungal culture was studied by UPLC-MS technique. The strain KMM 4401 is a source of various virescenoside-type isopimarane glycosides suggested as chemotaxonomic feature for this fungal species. Also <i>Px. luzulae</i> KMM 4401 was proposed as possible source of new bioactive secondary metabolites especially antimicrobials. Moreover, the co-cultures of <i>Px. luzulae</i> KMM 4401 with another marine fungus <i>Penicillium hispanicum</i> KMM 4689 inoculated simultaneously or after two weeks were investigated by same way. It was shown, that <i>P. hispanicum</i> KMM 4689 suppressed the production of most of <i>Px. luzulae</i> KMM 4401 metabolites. On the other hand, the co-cultivation of <i>P. hispanicum</i> KMM 4689 and <i>Px. luzulae</i> KMM 4401 resulted in increasing of production of main deoxyisoaustamide alkaloids of <i>P. hispanicum</i> KMM 4689 on 50–190%.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":718,"journal":{"name":"Natural Products and Bioprospecting","volume":"14 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s13659-024-00459-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141334867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-11DOI: 10.1007/s13659-024-00457-9
Song-Yu Hou, Bing-Chao Yan, Han-Dong Sun, Pema-Tenzin Puno
Cyclobutanes are distributed widely in a large class of natural products featuring diverse pharmaceutical activities and intricate structural frameworks. The [2 + 2] cycloaddition is unequivocally the primary and most commonly used method for synthesizing cyclobutanes. In this review, we have summarized the application of the [2 + 2] cycloaddition with different reaction mechanisms in the chemical synthesis of selected cyclobutane-containing natural products over the past decade.
{"title":"Recent advances in the application of [2 + 2] cycloaddition in the chemical synthesis of cyclobutane-containing natural products","authors":"Song-Yu Hou, Bing-Chao Yan, Han-Dong Sun, Pema-Tenzin Puno","doi":"10.1007/s13659-024-00457-9","DOIUrl":"10.1007/s13659-024-00457-9","url":null,"abstract":"<div><p>Cyclobutanes are distributed widely in a large class of natural products featuring diverse pharmaceutical activities and intricate structural frameworks. The [2 + 2] cycloaddition is unequivocally the primary and most commonly used method for synthesizing cyclobutanes. In this review, we have summarized the application of the [2 + 2] cycloaddition with different reaction mechanisms in the chemical synthesis of selected cyclobutane-containing natural products over the past decade.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":718,"journal":{"name":"Natural Products and Bioprospecting","volume":"14 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11166626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141299682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-04DOI: 10.1007/s13659-024-00458-8
Yuru Shi, Xiaoqian Zhang, Shengji Pei, Yuhua Wang
Adenosma buchneroides Bonati, also known as fleagrass, is an important medicinal plant used by the Akha (Hani) people of China for treating inflammation-related skin swelling, acne, and diarrhoea, among other conditions. In this study, we aimed to evaluate the anti-inflammatory activities and explore the molecular mechanisms of fleagrass on treating skin swelling and acne. The results demonstrated that fleagrass inhibited the enzymatic activities of 5-LOX and COX-2 in vitro, and decreased the release of NO, IL-6, TNF-α, and IL-10 in the LPS-induced RAW264.7 macrophages. The levels of proteins associated with the nuclear factor-kappa B (NF-κB) pathway were examined by western blotting and immunofluorescence, demonstrating that fleagrass downregulated the expression of TLR4, MyD88, NF-κB/p65, and iNOS and blocked the nuclear translocation of NF-κB/p65. Furthermore, fleagrass exhibited acute anti-inflammatory activity in paw oedema models. The results confirm that fleagrass exhibits remarkable anti-inflammatory activity and can be used in alleviating inflammation, suggesting that fleagrass has the potential to be a novel anti-inflammatory agent.
{"title":"Ethnopharmacological study on Adenosma buchneroides Bonati inhibiting inflammation via the regulation of TLR4/MyD88/NF-κB signaling pathway","authors":"Yuru Shi, Xiaoqian Zhang, Shengji Pei, Yuhua Wang","doi":"10.1007/s13659-024-00458-8","DOIUrl":"10.1007/s13659-024-00458-8","url":null,"abstract":"<div><p><i>Adenosma buchneroides</i> Bonati, also known as fleagrass, is an important medicinal plant used by the Akha (Hani) people of China for treating inflammation-related skin swelling, acne, and diarrhoea, among other conditions. In this study, we aimed to evaluate the anti-inflammatory activities and explore the molecular mechanisms of fleagrass on treating skin swelling and acne. The results demonstrated that fleagrass inhibited the enzymatic activities of 5-LOX and COX-2 in vitro, and decreased the release of NO, IL-6, TNF-α, and IL-10 in the LPS-induced RAW264.7 macrophages. The levels of proteins associated with the nuclear factor-kappa B (NF-κB) pathway were examined by western blotting and immunofluorescence, demonstrating that fleagrass downregulated the expression of TLR4, MyD88, NF-κB/p65, and iNOS and blocked the nuclear translocation of NF-κB/p65. Furthermore, fleagrass exhibited acute anti-inflammatory activity in paw oedema models. The results confirm that fleagrass exhibits remarkable anti-inflammatory activity and can be used in alleviating inflammation, suggesting that fleagrass has the potential to be a novel anti-inflammatory agent.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":718,"journal":{"name":"Natural Products and Bioprospecting","volume":"14 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11150230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141236256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01DOI: 10.1007/s13659-024-00456-w
Liz E. Lescano, Mario O. Salazar, Ricardo L. E. Furlan
The generation of chemically engineered essential oils (CEEOs) prepared from bi-heteroatomic reactions using ammonium thiocyanate as a source of bioactive compounds is described. The impact of the reaction on the chemical composition of the mixtures was qualitatively demonstrated through GC–MS, utilizing univariate and multivariate analysis. The reaction transformed most of the components in the natural mixtures, thereby expanding the chemical diversity of the mixtures. Changes in inhibition properties between natural and CEEOs were demonstrated through acetylcholinesterase TLC autography, resulting in a threefold increase in the number of positive events due to the modification process. The chemically engineered Origanum vulgare L. essential oil was subjected to bioguided fractionation, leading to the discovery of four new active compounds with similar or higher potency than eserine against the enzyme. The results suggest that the directed chemical transformation of essential oils can be a valuable strategy for discovering new acetylcholinesterase (AChE) inhibitors.
{"title":"Chemically engineered essential oils prepared through thiocyanation under solvent-free conditions: chemical and bioactivity alteration","authors":"Liz E. Lescano, Mario O. Salazar, Ricardo L. E. Furlan","doi":"10.1007/s13659-024-00456-w","DOIUrl":"10.1007/s13659-024-00456-w","url":null,"abstract":"<div><p>The generation of chemically engineered essential oils (CEEOs) prepared from bi-heteroatomic reactions using ammonium thiocyanate as a source of bioactive compounds is described. The impact of the reaction on the chemical composition of the mixtures was qualitatively demonstrated through GC–MS, utilizing univariate and multivariate analysis. The reaction transformed most of the components in the natural mixtures, thereby expanding the chemical diversity of the mixtures. Changes in inhibition properties between natural and CEEOs were demonstrated through acetylcholinesterase TLC autography, resulting in a threefold increase in the number of positive events due to the modification process. The chemically engineered <i>Origanum vulgare</i> L. essential oil was subjected to bioguided fractionation, leading to the discovery of four new active compounds with similar or higher potency than eserine against the enzyme. The results suggest that the directed chemical transformation of essential oils can be a valuable strategy for discovering new acetylcholinesterase (AChE) inhibitors.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":718,"journal":{"name":"Natural Products and Bioprospecting","volume":"14 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11143095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141183255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer cells generally exhibit ‘iron addiction’ phenotypes, which contribute to their vulnerability to ferroptosis inducers. Ferroptosis is a newly discovered form of programmed cell death caused by iron-dependent lipid peroxidation. In the present study, pacidusin B, a dichapetalin-type triterpenoid from Phyllanthus acidus (L.) Skeels (Euphorbiaceae), induces ferroptosis in the HT1080 human fibrosarcoma cell line. Cells treated with pacidusin B exhibited the morphological characteristic ‘ballooning’ phenotype of ferroptosis. The biochemical hallmarks of ferroptosis were also observed in pacidusin B-treated cells. Both oxidative stress and ER stress play significant roles in pacidusin B-induced ferroptosis. The activation of the PERK-Nrf2-HO-1 signaling pathway led to iron overload, while inhibition of GPX4 further sensitized cancer cells to ferroptosis. Furthermore, the molecular docking study showed that pacidusin B docked in the same pocket in xCT as the ferroptosis inducer erastin. These results revealed that pacidusin B exerts anticancer effects via inducing ER-mediated ferroptotic cell death.
Graphical Abstract
癌细胞通常表现出 "铁成瘾 "表型，这导致它们容易受到铁变态反应诱导剂的影响。铁中毒是一种新发现的细胞程序性死亡形式，由铁依赖性脂质过氧化引起。在本研究中，pacidusin B（一种来自 Phyllanthus acidus (L.) Skeels（大戟科）的二矢车菊苷型三萜类化合物）可诱导 HT1080 人纤维肉瘤细胞系发生铁氧化。用 pacidusin B 处理的细胞表现出铁细胞凋亡的形态特征 "气球 "表型。在经 pacidusin B 处理的细胞中也观察到了铁突变的生化特征。氧化应激和ER应激在pacidusin B诱导的铁突变中都起着重要作用。PERK-Nrf2-HO-1 信号通路的激活导致铁超载，而 GPX4 的抑制则进一步使癌细胞对铁变态反应敏感。此外，分子对接研究表明，pacidusin B 与铁变态反应诱导剂麦拉宁对接在 xCT 的同一个口袋中。这些结果表明，pacidusin B通过诱导ER介导的铁凋亡细胞死亡发挥抗癌作用。
{"title":"Pacidusin B isolated from Phyllanthus acidus triggers ferroptotic cell death in HT1080 cells","authors":"Guangyu Zhu, Dian Luo, Yueqin Zhao, Zhengrui Xiang, Chao Chen, Na Li, Xiaojiang Hao, Xiao Ding, Yingjun Zhang, Yuhan Zhao","doi":"10.1007/s13659-024-00454-y","DOIUrl":"10.1007/s13659-024-00454-y","url":null,"abstract":"<div><p>Cancer cells generally exhibit ‘iron addiction’ phenotypes, which contribute to their vulnerability to ferroptosis inducers. Ferroptosis is a newly discovered form of programmed cell death caused by iron-dependent lipid peroxidation. In the present study, pacidusin B, a dichapetalin-type triterpenoid from <i>Phyllanthus acidus</i> (L.) Skeels (Euphorbiaceae), induces ferroptosis in the HT1080 human fibrosarcoma cell line. Cells treated with pacidusin B exhibited the morphological characteristic ‘ballooning’ phenotype of ferroptosis. The biochemical hallmarks of ferroptosis were also observed in pacidusin B-treated cells. Both oxidative stress and ER stress play significant roles in pacidusin B-induced ferroptosis. The activation of the PERK-Nrf2-HO-1 signaling pathway led to iron overload, while inhibition of GPX4 further sensitized cancer cells to ferroptosis. Furthermore, the molecular docking study showed that pacidusin B docked in the same pocket in xCT as the ferroptosis inducer erastin. These results revealed that pacidusin B exerts anticancer effects via inducing ER-mediated ferroptotic cell death.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":718,"journal":{"name":"Natural Products and Bioprospecting","volume":"14 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11116305/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141079591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
N-Hydroxyapiosporamide (N-hydap), a marine product derived from a sponge-associated fungus, has shown promising inhibitory effects on small cell lung cancer (SCLC). However, there is limited understanding of its metabolic pathways and characteristics. This study explored the in vitro metabolic profiles of N-hydap in human recombinant cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs), as well as human/rat/mice microsomes, and also the pharmacokinetic properties by HPLC–MS/MS. Additionally, the cocktail probe method was used to investigate the potential to create drug-drug interactions (DDIs). N-Hydap was metabolically unstable in various microsomes after 1 h, with about 50% and 70% of it being eliminated by CYPs and UGTs, respectively. UGT1A3 was the main enzyme involved in glucuronidation (over 80%), making glucuronide the primary metabolite. With a favorable bioavailability of 24.0%, N-hydap exhibited a higher distribution in the lungs (26.26%), accounting for its efficacy against SCLC. Administering N-hydap to mice at normal doses via gavage did not result in significant toxicity. Furthermore, N-hydap was found to affect the catalytic activity of drug metabolic enzymes (DMEs), particularly increasing the activity of UGT1A3, suggesting potential for DDIs. Understanding the metabolic pathways and properties of N-hydap should improve our knowledge of its drug efficacy, toxicity, and potential for DDIs.
{"title":"Metabolism characterization and toxicity of N-hydap, a marine candidate drug for lung cancer therapy by LC–MS method","authors":"Jindi Lu, Weimin Liang, Yiwei Hu, Xi Zhang, Ping Yu, Meiqun Cai, Danni Xie, Qiong Zhou, Xuefeng Zhou, Yonghong Liu, Junfeng Wang, Jiayin Guo, Lan Tang","doi":"10.1007/s13659-024-00455-x","DOIUrl":"10.1007/s13659-024-00455-x","url":null,"abstract":"<div><p><i>N</i>-Hydroxyapiosporamide (<i>N</i>-hydap), a marine product derived from a sponge-associated fungus, has shown promising inhibitory effects on small cell lung cancer (SCLC). However, there is limited understanding of its metabolic pathways and characteristics. This study explored the in vitro metabolic profiles of <i>N</i>-hydap in human recombinant cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs), as well as human/rat/mice microsomes, and also the pharmacokinetic properties by HPLC–MS/MS. Additionally, the cocktail probe method was used to investigate the potential to create drug-drug interactions (DDIs). <i>N</i>-Hydap was metabolically unstable in various microsomes after 1 h, with about 50% and 70% of it being eliminated by CYPs and UGTs, respectively. UGT1A3 was the main enzyme involved in glucuronidation (over 80%), making glucuronide the primary metabolite. With a favorable bioavailability of 24.0%, <i>N</i>-hydap exhibited a higher distribution in the lungs (26.26%), accounting for its efficacy against SCLC. Administering <i>N</i>-hydap to mice at normal doses via gavage did not result in significant toxicity. Furthermore, <i>N</i>-hydap was found to affect the catalytic activity of drug metabolic enzymes (DMEs), particularly increasing the activity of UGT1A3, suggesting potential for DDIs. Understanding the metabolic pathways and properties of <i>N</i>-hydap should improve our knowledge of its drug efficacy, toxicity, and potential for DDIs.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":718,"journal":{"name":"Natural Products and Bioprospecting","volume":"14 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11109052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-21DOI: 10.1007/s13659-024-00449-9
Gleb V. Borkunov, Elena V. Leshchenko, Dmitrii V. Berdyshev, Roman S. Popov, Ekaterina A. Chingizova, Nadezhda P. Shlyk, Andrey V. Gerasimenko, Natalya N. Kirichuk, Yuliya V. Khudyakova, Viktoria E. Chausova, Alexandr S. Antonov, Anatoly I. Kalinovsky, Artur R. Chingizov, Ekaterina A. Yurchenko, Marina P. Isaeva, Anton N. Yurchenko
Four extracts of the marine-derived fungus Penicillium velutinum J.F.H. Beyma were obtained via metal ions stress conditions based on the OSMAC (One Strain Many Compounds) strategy. Using a combination of modern approaches such as LC/UV, LC/MS and bioactivity data analysis, as well as in silico calculations, influence metal stress factors to change metabolite profiles Penicillium velutinum were analyzed. From the ethyl acetate extract of the P. velutinum were isolated two new piperazine derivatives helvamides B (1) and C (2) together with known saroclazin A (3) (4S,5R,7S)-4,11-dihydroxy-guaia-1(2),9(10)-dien (4). Their structures were established based on spectroscopic methods. The absolute configuration of helvamide B (1) as 2R,5R was determined by a combination of the X-ray analysis and by time-dependent density functional theory (TD-DFT) calculations of electronic circular dichroism (ECD) spectra. The cytotoxic activity of the isolated compounds against human prostate cancer PC-3 and human embryonic kidney HEK-293 cells and growth inhibition activity against yeast-like fungi Candida albicans were assayed.
{"title":"New piperazine derivatives helvamides B–C from the marine-derived fungus Penicillium velutinum ZK-14 uncovered by OSMAC (One Strain Many Compounds) strategy","authors":"Gleb V. Borkunov, Elena V. Leshchenko, Dmitrii V. Berdyshev, Roman S. Popov, Ekaterina A. Chingizova, Nadezhda P. Shlyk, Andrey V. Gerasimenko, Natalya N. Kirichuk, Yuliya V. Khudyakova, Viktoria E. Chausova, Alexandr S. Antonov, Anatoly I. Kalinovsky, Artur R. Chingizov, Ekaterina A. Yurchenko, Marina P. Isaeva, Anton N. Yurchenko","doi":"10.1007/s13659-024-00449-9","DOIUrl":"10.1007/s13659-024-00449-9","url":null,"abstract":"<div><p>Four extracts of the marine-derived fungus <i>Penicillium velutinum</i> J.F.H. Beyma were obtained via metal ions stress conditions based on the OSMAC (One Strain Many Compounds) strategy. Using a combination of modern approaches such as LC/UV, LC/MS and bioactivity data analysis, as well as in silico calculations, influence metal stress factors to change metabolite profiles <i>Penicillium velutinum</i> were analyzed. From the ethyl acetate extract of the <i>P. velutinum</i> were isolated two new piperazine derivatives helvamides B (<b>1</b>) and C (<b>2</b>) together with known saroclazin A (<b>3</b>) (4<i>S</i>,5<i>R</i>,7<i>S</i>)-4,11-dihydroxy-guaia-1(2),9(10)-dien (<b>4</b>). Their structures were established based on spectroscopic methods. The absolute configuration of helvamide B (<b>1</b>) as 2<i>R</i>,5<i>R</i> was determined by a combination of the X-ray analysis and by time-dependent density functional theory (TD-DFT) calculations of electronic circular dichroism (ECD) spectra. The cytotoxic activity of the isolated compounds against human prostate cancer PC-3 and human embryonic kidney HEK-293 cells and growth inhibition activity against yeast-like fungi <i>Candida albicans</i> were assayed.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":718,"journal":{"name":"Natural Products and Bioprospecting","volume":"14 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11106049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-14DOI: 10.1007/s13659-024-00452-0
Antonio Evidente
Among microorganisms, fungi are the ones that have the most imagination in producing secondary metabolites with the most varied structural differences, which are produced through different biosynthetic pathways. Therefore, they synthesize secondary metabolites classifiable into numerous families of natural compounds such as amino acids, alkaloids, anthraquinones, aromatic compounds, cyclohexene epoxides, furanones, macrolides, naphthoquinones, polyketides, pyrones, terpenes, etc. They also produced metabolites with very complex structures that can not be classified in the known families of natural compounds. Many fungal metabolites show different biological activities with potential applications in agriculture, food chemistry, cosmetics, pharmacology and medicine. This review is focused on the fungal secondary metabolites with anticancer activity isolated in the last ten years. For some metabolites, when described, their biosynthetic origin, the mode of action and the results of structure activity relationships studies are also reported.
{"title":"Advances on anticancer fungal metabolites: sources, chemical and biological activities in the last decade (2012–2023)","authors":"Antonio Evidente","doi":"10.1007/s13659-024-00452-0","DOIUrl":"10.1007/s13659-024-00452-0","url":null,"abstract":"<div><p>Among microorganisms, fungi are the ones that have the most imagination in producing secondary metabolites with the most varied structural differences, which are produced through different biosynthetic pathways. Therefore, they synthesize secondary metabolites classifiable into numerous families of natural compounds such as amino acids, alkaloids, anthraquinones, aromatic compounds, cyclohexene epoxides, furanones, macrolides, naphthoquinones, polyketides, pyrones, terpenes, etc. They also produced metabolites with very complex structures that can not be classified in the known families of natural compounds. Many fungal metabolites show different biological activities with potential applications in agriculture, food chemistry, cosmetics, pharmacology and medicine. This review is focused on the fungal secondary metabolites with anticancer activity isolated in the last ten years. For some metabolites, when described, their biosynthetic origin, the mode of action and the results of structure activity relationships studies are also reported.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":718,"journal":{"name":"Natural Products and Bioprospecting","volume":"14 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11093966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号