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1.
Bioorg Chem ; 150: 107594, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38941701

RESUMO

Inhibition of human dihydroorotate dehydrogenase (hDHODH) represents a promising strategy for suppressing the proliferation of cancer cells. To identify novel and potent hDHODH inhibitors, a total of 28 piperine derivatives were designed and synthesized. Their cytotoxicities against three human cancer cell lines (NCI-H226, HCT-116, and MDA-MB-231) and hDHODH inhibitory activities were also evaluated. Among them, compound H19, exhibited the strongest inhibitory activities (NCI-H226 IC50 = 0.95 µM, hDHODH IC50 = 0.21 µM). Further pharmacological investigations revealed that H19 exerted anticancer effects by inducing ferroptosis in NCI-H226 cells, with its cytotoxicity being reversed by ferroptosis inhibitors. This was supported by the intracellular growth or decline of ferroptosis markers, including lipid peroxidation, Fe2+, GSH, and 4-HNE. Overall, H19 emerges as a promising hDHODH inhibitor with potential anticancer properties warranting development.

2.
J Ethnopharmacol ; 332: 118352, 2024 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-38762208

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Chrysanthemum morifolium Ramat. is a commonly used Chinese herb and food homologous plant with traditional effects such as anti-inflammatory, antifebrile, antibacterial and antiviral. AIM OF STUDY: Photoaging is one of the main causes of accelerated skin aging. Chrysanthemum morifolium Ramat. has reported to alleviate photodamage. In this study, we investigated the protective effect of the extract of buds of Chrysanthemum morifolium Ramat. (CE) on UVB-induced photoaging and further mechanism. MATERIALS AND METHODS: The extract of buds of chrysanthemum was analyzed by HPLC-Q-TOF-MS/MS. Antioxidant activity was assessed by DPPH and ABTS assay. Cell viability examined by cell counting kit-8 assay. The ROS level was detected by fluorescent probe DCFH-DA. Protein expression evaluated by Western blotting. The skin tissue investigated by immunohistochemistry. RESULTS: CE significantly reversed the decrease of cell viability that induced by UVB in HaCaT and HFF-1 cells. Further analysis showed that CE alleviated photoaging by inhibiting the expression of mitogen-activated protein kinase (MAPK) and activating the NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway to promote the expression of antioxidant enzymes. Moreover, CE effectively improved the reduced skin hydration, disordered collagen and thickening epidermis caused by UVB in mice. CONCLUSIONS: All results demonstrated that CE had therapeutic effect on UVB-induced photoaging and provided theoretical basis for its further developing as a natural functional product with anti-photoaging effect.


Assuntos
Chrysanthemum , Fator 2 Relacionado a NF-E2 , Extratos Vegetais , Envelhecimento da Pele , Raios Ultravioleta , Chrysanthemum/química , Envelhecimento da Pele/efeitos dos fármacos , Envelhecimento da Pele/efeitos da radiação , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Raios Ultravioleta/efeitos adversos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Humanos , Camundongos , Antioxidantes/farmacologia , Antioxidantes/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Elementos de Resposta Antioxidante/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Pele/patologia , Pele/metabolismo , Flores/química , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Células HaCaT , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular
3.
Mol Cancer ; 23(1): 82, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38664722

RESUMO

Triple-negative breast cancer (TNBC) stands as the breast cancer subtype with the highest recurrence and mortality rates, with the lungs being the common site of metastasis. The pulmonary microenvironment plays a pivotal role in the colonization of disseminated tumor cells. Herein, this study highlights the crucial role of exosomal LAP-TGF-ß1, the principal form of exosomal TGF-ß1, in reshaping the pulmonary vascular niche, thereby facilitating TNBC lung metastasis. Although various strategies have been developed to block TGF-ß signaling and have advanced clinically, their significant side effects have limited their therapeutic application. This study demonstrates that in lung metastatic sites, LAP-TGF-ß1 within exosomes can remarkably reconfigure the pulmonary vascular niche at lower doses, bolstering the extravasation and colonization of TNBC cells in the lungs. Mechanistically, under the aegis of the acetyltransferase TIP60, a non-canonical KFERQ-like sequence in LAP-TGF-ß1 undergoes acetylation at the K304 site, promoting its interaction with HSP90A and subsequent transport into exosomes. Concurrent inhibition of both HSP90A and TIP60 significantly diminishes the exosomal burden of LAP-TGF-ß1, presenting a promising therapeutic avenue for TNBC lung metastasis. This study not only offers fresh insights into the molecular underpinnings of TNBC lung metastasis but also lays a foundation for innovative therapeutic strategies.


Assuntos
Exossomos , Neoplasias Pulmonares , Fator de Crescimento Transformador beta1 , Neoplasias de Mama Triplo Negativas , Exossomos/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/genética , Fator de Crescimento Transformador beta1/metabolismo , Acetilação , Animais , Feminino , Camundongos , Linhagem Celular Tumoral , Microambiente Tumoral
4.
Talanta ; 274: 125975, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38599114

RESUMO

Sirtuin1 (SIRT1), an NAD+-dependent histone deacetylase, plays a crucial role in regulating molecular signaling pathways. Recently, inhibition of SIRT1 rather than its activation shows the therapeutic potential for central nervous system disorder, however, the discovered SIRT1 inhibitors remains limited. In this work, a dual recognition-based strategy was developed to screen SIRT1 inhibitors from natural resources in situ. This approach utilized a Ni-modified metal-organic framework (Ni@Tyr@UiO-66-NH2) along with cell lysate containing an engineered His-tagged SIRT1 protein, eliminating the need for purified proteins, pure compounds, and protein immobilization. The high-performance Ni@Tyr@UiO-66-NH2 was synthesized by modifying the surface of UiO-66-NH2 with Ni2+ ions to specifically capture His-tagged SIRT1 while persevering its enzyme activity. By employing dual recognition, in which Ni@Tyr@UiO-66-NH2 recognized SIRT1 and SIRT1 recognized its ligands, the process of identifying SIRT1 inhibitors from complex matrix was vastly streamlined. The developed method allowed the efficient discovery of 16 natural SIRT1 inhibitors from Chinese herbs. Among them, 6 compounds were fully characterized, and suffruticosol A was found to have an excellent IC50 value of 0.95 ±â€¯0.12 µM. Overall, an innovative dual recognition-based strategy was proposed to efficiently identify SIRT1 inhibitors in this study, offering scientific clues for the development of drugs targeting CNS disorders.


Assuntos
Medicamentos de Ervas Chinesas , Estruturas Metalorgânicas , Níquel , Sirtuína 1 , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/metabolismo , Níquel/química , Estruturas Metalorgânicas/química , Humanos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Avaliação Pré-Clínica de Medicamentos
5.
Int Immunopharmacol ; 131: 111789, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38484668

RESUMO

Physalin H (PH), a withanolide isolated from Physalisangulata L. has been reported to have anti-inflammatory effect. However, its impact on acute lung injury (ALI) remains unexplored. In this study, we observed that PH significantly alleviated inflammation in LPS-stimulated macrophages by suppressing the release of proinflammatory cytokines (TNF-α, IL-1ß, and IL-6) and down-regulating the expression of the inflammation-related genes. RNA sequencing analysis revealed a significant up-regulation of the NRF2 pathway by PH. Further investigation elucidated that PH attenuated the ubiquitination of NRF2 by impeding the interaction between NRF2 and KEAP1, thereby facilitating NRF2 nuclear translocation and up-regulating the expression of target genes. Consequently, it regulated redox system and exerted anti-inflammatory effect. Consistently, PH also significantly alleviated pathological damage and inflammation in LPS-induced ALI mice model, which could be reversed by administration of an NRF2 inhibitor. Collectively, these results suggest that PH ameliorates ALI by activating the KEAP1/NRF2 pathway. These findings provide a foundation for further development of pH as a new anti-inflammatory agent for ALI therapy.


Assuntos
Lesão Pulmonar Aguda , Fator 2 Relacionado a NF-E2 , Secoesteroides , Camundongos , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Lipopolissacarídeos/farmacologia , Transdução de Sinais , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Anti-Inflamatórios/efeitos adversos , Inflamação/tratamento farmacológico , Pulmão/patologia
6.
Front Endocrinol (Lausanne) ; 15: 1291775, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38419957

RESUMO

Objective: To investigate the diagnostic efficiency and prognostic value of 68Ga-Pentixafor PET/CT in comparison with adrenal vein sampling (AVS) for functional lateralization in primary aldosteronism (PA). Histology and long-term clinical follow-up normally serve as the gold standard for such diagnosis. Methods: We prospectively recruited 26 patients diagnosed with PA. All patients underwent 68Ga-Pentixafor PET/CT and AVS. Postsurgical biochemical and clinical outcomes of patients with unilateral primary aldosteronism (UPA), as diagnosed by PET/CT or AVS, were assessed by applying standardized Primary Aldosteronism Surgical Outcome (PASO) criteria. Immunohistochemistry (IHC) was performed to detect the expression of aldosterone synthase (CYP11B2) and CXCR4. Results: On total, 19 patients were diagnosed with UPA; of these, 13 patients were lateralized by both PET/CT and AVS, four patients were lateralized by PET-only, and two by AVS-only. Seven subjects with no lateralization on AVS and PET received medical therapy. All patients achieved complete biochemical success except one with nodular hyperplasia lateralized by AVS alone. The consistency between PET/CT and AVS outcomes was 77% (20/26). Moreover, CYP11B2-positive nodules were all CXCR4-positive and showed positive findings on PET. Patients who achieved complete biochemical and clinical success had a higher uptake on PET as well as stronger expression levels of CXCR4 and CYP11B2. Conclusion: Our analysis showed that 68Ga-Pentixafor PET/CT could enable non-invasive diagnosis in most patients with PA and identify additional cases of unilateral and surgically curable PA which could not be classified by AVS. 68Ga-Pentixafor PET/CT should be considered as a first-line test for the future classification of PA.


Assuntos
Complexos de Coordenação , Hiperaldosteronismo , Peptídeos Cíclicos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Glândulas Suprarrenais/metabolismo , Radioisótopos de Gálio/metabolismo , Citocromo P-450 CYP11B2/metabolismo , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/cirurgia , Hiperaldosteronismo/metabolismo
7.
J Pharm Biomed Anal ; 242: 116037, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38387130

RESUMO

Identifying medicinally relevant compounds from natural resources generally involves the tedious work of screening plants for the desired activity before capturing the bioactive molecules from them. In this work, we created a paper-based ligand fishing platform to vastly simplify the discovery process. This paper-based method exploits the enzymatic cascade reaction between α-glucosidase (GAA), glucose oxidase (GOx), and horseradish peroxidase (HRP), to simultaneously screen the plants and capture the GAA inhibitors from them. The designed test strip could capture ligands in tandem with screening the plants, and it features a very simply operation based on direct visual assessment. Multiple acylated flavonol glycosides from the leaves of Quercus variabilis Blume were newly found to possess GAA inhibitory activities, and they may be potential leads for new antidiabetic medications. Our study demonstrates the prospect of the newly discovered GAA ligands as potential bioactive ingredients as well as the utility of the paper-based ligand fishing method.


Assuntos
Antineoplásicos , Inibidores de Glicosídeo Hidrolases , Inibidores de Glicosídeo Hidrolases/farmacologia , Ligantes , Hipoglicemiantes , Glicosídeos , alfa-Glucosidases
8.
Eur J Med Chem ; 268: 116250, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38417218

RESUMO

Ferritinophagy is a cellular process to release redox-active iron. Excessive activation of ferritinophagy ultimately results in ferroptosis characterized by ROS accumulation which plays important roles in the development and progression of cancer. Sinomenine, a main bioactive alkaloid from the traditional Chinese medicine Sinomenum acutum, inhibits the proliferation of cancer cells by promoting ROS production. Herein, new compounds were designed and synthesized through the stepwise optimization of sinomenine. Among them, D3-3 induced the production of lipid ROS, and significantly promoted colorectal cancer cells to release the ferrous ion in an autophagy-dependent manner. Moreover, D3-3 enhanced the interaction of FTH1-NCOA4, indicating the activation of ferritinophagy. In vivo experiments showed that D3-3 restrained tumor growth and promoted lipid peroxidation in the HCT-116 xenograft model. These findings demonstrated that D3-3 is an inducer of ferritinophagy, eventually triggering ferroptosis. Compound D3-3, as the first molecule to be definitively demonstrated to induce ferritinophagy, is worth further evaluation as a promising drug candidate in the treatment of colorectal cancer.


Assuntos
Neoplasias Colorretais , Ferritinas , Morfinanos , Humanos , Espécies Reativas de Oxigênio/metabolismo , Ferro/metabolismo , Autofagia , Neoplasias Colorretais/tratamento farmacológico
9.
Fitoterapia ; 174: 105843, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38301937

RESUMO

In this research, five new indolequinazoline alkaloids (1-5), along with six known indolequinazoline alkaloids (6-11) were obtained from the fruits of Tetradium ruticarpum. Their structures were elucidated through comprehensive spectroscopic data of 1D and 2D NMR, HRESIMS and ECD spectra. Additionally, all isolates were assayed for their SIRT1 inhibitory activities in vitro and compounds 2, 7, 10 and 11 exhibited activities with IC50 values ranged from 43.16 to 118.35 µM.


Assuntos
Alcaloides , Evodia , Evodia/química , Frutas/química , Estrutura Molecular , Alcaloides/análise , Espectroscopia de Ressonância Magnética
10.
J Med Chem ; 67(4): 2758-2776, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38295524

RESUMO

The coexistence of ferroptosis and other modes of death has great advantages in the treatment of cancers. A series of glutathione peroxidase 4 (GPX4) and cyclin-dependent kinase (CDK) dual inhibitors were designed and synthesized, given the synergistic anticancer effect of ML162 (GPX4 inhibitor) in combination with indirubin-3'-oxime (IO) (CDK inhibitor). Compound B9 exhibited the highest potential cytotoxic activity against all four cell lines and displayed excellent inhibitory activity against GPX4 (IC50 = 542.5 ± 0.9 nM) and selective inhibition of CDK 4/6 (IC50 = 191.2 ± 8.7, 68.1 ± 1.4 nM). Mechanism research showed that B9 could simultaneously induce ferroptosis and arrest cells at the G1 phase in both MDA-MB-231 cells and HCT-116 cells. Compared with ML162 and IO, B9 showed much stronger cancer cell growth inhibition in vivo. These results proved that developing potent GPX4/CDK dual inhibitors is a promising strategy for the malignant cancer therapy.


Assuntos
Compostos de Anilina , Antineoplásicos , Tiofenos , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia
11.
J Nat Prod ; 87(1): 38-49, 2024 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-38207331

RESUMO

Physalis angulata var. villosa is a plant possessing abundant withanolides, but in-depth research is lacking. In our ongoing study of P. angulata var. villosa, 15 previously undescribed withanolides (1-15), along with 21 known analogs (16-36), were isolated from the whole plant. The structures of the withanolides (1-15) were elucidated based on analysis of their 1D and 2D NMR, HRESIMS, and ECD data. Additionally, the application of γ-gauche effects with the help of ROESY correlations led to the formulation of empirical rules for withanolides with 14-OH/15-OAc to rapidly determine the 14-OH orientations, making it possible to propose configurational revisions of 19 previously reported analogs (1'-19'). Withanolides 1, 4-6, and 10 showed potent cytotoxic activities against three human cancer cell lines (HCT-116, MDA-MB-231, and A549).


Assuntos
Antineoplásicos Fitogênicos , Physalis , Vitanolídeos , Humanos , Vitanolídeos/farmacologia , Vitanolídeos/química , Physalis/química , Extratos Vegetais/química , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Linhagem Celular , Estrutura Molecular
12.
Heliyon ; 9(11): e22186, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38045189

RESUMO

Distiller's grains, byproducts of the brewing process, represent a valuable resource for extracting natural phenolic compounds due to their significant global production. This study presents the first evidence of the protective effects of Moutai distiller's grain polyphenol extract (MDGP) on dextran sulfate sodium (DSS)-induced colitis in mice. These protective effects manifest predominantly through the amelioration of general colitis indices and histopathological improvements. Utilizing liquid chromatography-high-resolution electrospray ionization mass spectrometry (LC-HR-ESI-MS), the main components of MDGP were identified as rutin, quercetin, naringenin, and dihydroquercetin. Moreover, a novel mechanism was elucidated by which rutin, the primary active component of MDGP, alleviates DSS-induced colitis. Assessment of intestinal barrier function, microbial sequencing, fecal transplantation, and antibiotic depletion experiments revealed that rutin suppresses the abundance of pathogenic bacteria (Helicobacter, Klebsiella, and Veillonella) while promoting the proliferation of beneficial bacteria (Ruminococcus_torques_group, Lachnoclostridium, and norank_f__Muribaculaceae). This modulation culminates in elevated butyric acid concentrations within short-chain fatty acids (SCFAs), amplified integrity of tight (ZO-1, occludin) and adherent (E-cadherin, ß-catenin) junctional complexes, fortified intestinal barrier function, and diminished intestinal inflammation.This investigation accentuates the innovative therapeutic potential of MDGP and its main active component, rutin, in assuaging DSS-induced intestinal inflammation and fortifying the intestinal barrier through a mechanism predominantly mediated by the intestinal microbiota. Such insights potentially elevate the prominence of distiller's grains in the realm of functional food development.

13.
Bioorg Chem ; 141: 106899, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37797457

RESUMO

Drug-induced liver injury (DILI), induced by overdose or chronic administration of drugs, has become the leading cause of acute liver failure. Therefore, an accurate diagnostic method for DILI is critical to improve treatment efficiency. The production of γ-glutamyltranspeptidase (GGT) is closely related to the progression of drug-induced hepatotoxicity. KL-Glu exhibits a prominent GGT-activated NIR fluorescence (734 nm) with a large Stokes shift (137 nm) and good sensitivity/selectivity, making it favorable for real-time detection of endogenous GGT activity. Using this probe, we evaluated the GGT up-regulation under the acetaminophen-induced liver injury model. Moreover, KL-Glu was successfully used to assess liver injury induced by the natural active ingredient triptolide and the effective amelioration upon treatment with N-acetyl cysteine (NAC) or Glutathione (GSH) in cells and in vivo by fluorescent trapping the fluctuation of GGT for the first time. Therefore, the fluorescent probe KL-Glu can be used as a potential tool to explore the function of GGT in the progression of DILI and for the early diagnosis and prognostic evaluation of DILI.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Corantes Fluorescentes , Humanos , Linhagem Celular , Células Hep G2 , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , gama-Glutamiltransferase , Glutationa
14.
Eur J Med Chem ; 261: 115829, 2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-37801824

RESUMO

Glutathione peroxidase 4 (GPX4) is an essential antioxidant enzyme that negatively regulates ferroptosis. To exploit novel GPX4 inhibitors, we designed and synthesized 32 indirubin derivatives. Compound 31 exhibited the strongest antitumor activity against HCT-116 cells (IC50 = 0.49 ± 0.02 µM). Further studies suggested that 31 could induce ferroptosis in colon cancer cells and its cytotoxic activity could be reversed by ferroptosis inhibitors. Mechanism research showed that 31 promoted the degradation of GPX4, causing the accumulation of lipid ROS to induce ferroptosis. Animal experiments also proved that 31 could inhibit the growth of colon cancer cells in vivo and reduce the expression of GPX4 in tumor tissues. These results indicated that compound 31 had potential as a novel ferroptosis inducer agent for colon cancer.


Assuntos
Neoplasias do Colo , Ferroptose , Animais , Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Neoplasias do Colo/tratamento farmacológico
15.
Eur J Drug Metab Pharmacokinet ; 48(4): 363-376, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37344636

RESUMO

BACKGROUND AND OBJECTIVES: The oral bioavailability of withangulatin A (WA) is low and may undergo first-pass metabolism because of the presence of two esters bonds. This study aimed to identify the hydrolysis behavior and mechanism of WA, thus enriching its structure-pharmacokinetic relationship. METHODS: The in vivo pharmacokinetic studies of WA in rats were first investigated, followed by in vitro assays including metabolic stability, phenotyping identification and metabolic kinetics assays. After screening out the responsible enzymes with higher catalytic capacity, molecular docking study was performed to demonstrate the interaction mode between WA and metabolic enzymes. Then, metabolites in human serum albumin (HSA) were identified by LC-TOF-MS/MS. RESULTS: In rats, the oral bioavailability of WA was only 2.83%. In vitro, WA was hydrolyzed in both rat and human plasma and could not be inhibited by selective esterase inhibitors. Physiologic concentration of HSA not recombinant human carboxylesterases (rhCES) could significantly hydrolyze WA, and it had a similar hydrolytic capacity with human plasma to WA. Furthermore, WA could stably bind to HSA by forming hydrogen bonds with Lys199 and Arg410, accompanied by the metabolic reaction of the lactone ring opening. CONCLUSION: The study showed that WA underwent obvious hydrolysis in rat and human plasma, which implied a strong first-pass effect. Serum albumin rather than common esterases primarily contributed to the hydrolytic metabolism of WA in plasma.


Assuntos
Esterases , Albumina Sérica , Ratos , Humanos , Animais , Esterases/metabolismo , Hidrólise , Albumina Sérica/metabolismo , Simulação de Acoplamento Molecular , Espectrometria de Massas em Tandem , Albumina Sérica Humana
16.
Chem Biodivers ; 20(6): e202300263, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37141509

RESUMO

The Complexity-to-Diversity (CtD) strategy was applied to synthesize a 23-member compound collection from the natural product drupacine, including 21 novel compounds. An unusual benzo [d] cyclopenta [b] azepin skeleton was constructed by Von Braun reaction to cleave C-N bond of drupacine. Moreover, compound 10 has potential cytotoxicity to human colon cancer cells with low toxicity to the normal human colon mucosal epithelial cell lines.


Assuntos
Produtos Biológicos , Neoplasias do Colo , Harringtoninas , Humanos , Produtos Biológicos/farmacologia , Harringtoninas/química , Linhagem Celular
17.
Chem Biodivers ; 20(4): e202300195, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36932465

RESUMO

Six new withanolides, angulasteroidins A-F (1-6), along with twelve known analogs (7-18) were isolated from the whole plants of Physalis angulata. Their structures were elucidated by analysis of 1D and 2D NMR, ECD and IR spectra, HR-ESI-MS data, and ECD calculation. Compounds 1 and 6 were rare 1-10 seco withanolides. Compounds 2-4, 7-9, and 15 exhibited significant inhibitory activity on the production of nitric oxide in the LPS-activated RAW 264.7 mouse macrophage cell lines with IC50 values ranging from 0.23 to 9.06 µM.


Assuntos
Physalis , Vitanolídeos , Animais , Camundongos , Relação Estrutura-Atividade , Vitanolídeos/farmacologia , Vitanolídeos/química , Óxido Nítrico , Células RAW 264.7 , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Physalis/química , Physalis/metabolismo , Estrutura Molecular
18.
Chem Biodivers ; 20(2): e202201067, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36598403

RESUMO

Taiwania cryptomerioides Hayata is an endangered relict plant belonging to Taxodiaceae, and it is also an endemic plant to China. The decay-resistant of Taiwania timber can provide highly quality wood for building and furniture. Plenty of regenerative of leaves of T. cryptomerioides also has been used as a resource for the discovery of new dimeric diterpenoids. In a search for structurally diverse dimeric diterpenoids and potent bioactive isolates, ten new heterodimeric diterpenoids, taiwaniadducts K-T (1-4, 6, 8-11, and 14), along with five known ones (5, 7, 12, 13, and 15), were isolated from the leaves of T. cryptomerioides. These new compounds were defined by comprehensive spectroscopic analyses, putative biosynthetic pathways, and the values of optical. Biologically, anti-multidrug resistance (MDR) activities of compounds were evaluated. Compounds 4 and 10 exerted a 9.18-fold potentiation effect on bortezmib (BTZ) susceptibility at a tested concentration (20 µM) better than the positive control verapamil. The research of the leaves of T. cryptomerioides not only added the new data to the structural diversity and activities of dimeric diterpenoids but also could provide support for the medical and industrial application of the leaves of this endangered relict plant.


Assuntos
Cupressaceae , Diterpenos , Diterpenos/química , Extratos Vegetais/química , Madeira , Análise Espectral , Cupressaceae/química , Estrutura Molecular
19.
Int Immunopharmacol ; 115: 109689, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36621330

RESUMO

SQSTM1/p62 sequesters intracellular aberrant proteins and mediates their selective autophagic degradation. p62 oligomerization posttranslational modification enhances its sequestration function and positively regulates the KEAP1-NRF2 redox pathway. However, the regulation of p62 covalent oligomerization has yet been poorly characterized. Here, we identified a natural small-molecule sesquiterpene, Iso-seco-tanapartholide (IST) modified p62 cysteine residues, which induced p62 to form crosslinked oligomers between TBS and TBS or TBS and PB1 domains in a covalently non-disulfide-linked manner. Using LC-MS/MS analysis and complementary approaches, we revealed that Cys residues of p62 were necessary for IST-induced covalent oligomer. This oligomerization promoted p62 recruitment of KEAP1 for degradation by autophagosomes and released NRF2 to the nucleus to activate the expression of downstream genes with anti-oxidant and anti-inflammatory capacities. Accordingly, IST-mediated p62/NRF2 activation conferred protection from oxidative and inflammatory destruction of rheumatoid arthritis in vitro and in vivo. In contrast, p62-knockdown cells displayed a reduced anti-oxidant response and increased pro-inflammatory cytokine secretion in response to TNF-α stimulation. Hence, our findings uncover an unrecognized role of IST in the regulation of p62 oligomerization and provide a new strategy for the treatment of rheumatoid arthritis.


Assuntos
Artrite Reumatoide , Transdução de Sinais , Humanos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Artrite Reumatoide/tratamento farmacológico , Autofagia , Cromatografia Líquida , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Oxirredução , Estresse Oxidativo , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismo , Espectrometria de Massas em Tandem , Proteínas Adaptadoras de Transdução de Sinal/metabolismo
20.
Nat Prod Res ; 37(21): 3639-3646, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-35848378

RESUMO

(±)-Patulinervones A (1) and B (2), two diastereomers of spiro-lignans sharing an unprecedented dimethyl-spiro[furan-2,2'-furo[2,3-b]furan] 5/5/5 tricyclic moiety were isolated from the leaves of Melicope patulinervia (Merr. & Chun) C.C. Huang. Their structures were established by extensive spectroscopic data and electronic circular dichroism (ECD) analyses. The racemates (±)-1 and 2 and their enantiomers exhibited α-glucosidase inhibitory effect with IC50 values range of 10.08 ± 1.24 - 25.58 ± 1.97 µM.

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