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1.
Molecules ; 28(2)2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36677613

RESUMO

These days an extensive amount of the attention of researchers is focused towards exploring bioactive compounds of natural or herbal origin for therapeutic intervention in different ailments of significant importance. One such novel bioactive compound that has a variety of biological properties, including anti-inflammatory and antioxidant activities, is piperine. However, until today, piperine has not been explored for its potential to improve inflammation and enhance healing in acute and chronic wounds. Therefore, the present study aimed to investigate the wound healing potential of piperine hydrogel formulation after topical application. Hydrogels fit the need for a depot system at the wound bed, where they ensure a consistent supply of therapeutic agents enclosed in their cross-linked network matrices. In the present study, piperine-containing carbopol 934 hydrogels mixed with Aloe vera gels of different gel strengths were prepared and characterized for rheological behavior, spreadability, extrudability, and percent (%) content uniformity. Furthermore, the wound healing potential of the developed formulation system was explored utilizing the excision wound healing model. The results of an in vivo study and histopathological examination revealed early and intrinsic healing of wounds with the piperine-containing bioactive hydrogel system compared to the bioactive hydrogel system without piperine. Therefore, the study's findings establish that the piperine-containing bioactive hydrogel system is a promising therapeutic approach for wound healing application that should be diligently considered for clinical transferability.


Assuntos
Alcaloides , Hidrogéis , Ratos , Animais , Hidrogéis/farmacologia , Pele/patologia , Cicatrização , Alcaloides/farmacologia , Alcaloides/uso terapêutico
2.
Molecules ; 28(2)2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36677722

RESUMO

Ephedrae Herba (Ephedra), known as "MaHuang" in China, is the dried straw stem that is associated with the lung and urinary bladder meridians. At present, more than 60 species of Ephedra plants have been identified, which contain more than 100 compounds, including alkaloids, flavonoids, tannins, sugars, and organic phenolic acids. This herb has long been used to treat asthma, liver disease, skin disease, and other diseases, and has shown unique efficacy in the treatment of COVID-19 infection. Because alkaloids are the main components causing toxicity, the safety of Ephedra must be considered. However, the nonalkaloid components of Ephedra can be effectively used to replace ephedrine extracts to treat some diseases, and reasonable use can ensure the safety of Ephedra. We reviewed the phytochemistry, pharmacology, clinical application, and alkaloid toxicity of Ephedra, and describe prospects for its future development to facilitate the development of Ephedra.


Assuntos
Alcaloides , Antineoplásicos , COVID-19 , Medicamentos de Ervas Chinesas , Ephedra , Humanos , Medicamentos de Ervas Chinesas/química , Alcaloides/farmacologia , Ephedra/química , Efedrina/farmacologia
3.
Molecules ; 28(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36677886

RESUMO

Benzoxazole alkaloids exhibit a diverse array of structures and interesting biological activities. Herein we report the identification of a benzoxazole alkaloid-encoding biosynthetic gene cluster (mich BGC) in the marine-derived actinomycete Micromonospora sp. SCSIO 07395 and the heterologous expression of this BGC in Streptomyces albus. This approach led to the discovery of five new benzoxazole alkaloids microechmycin A-E (1-5), and a previously synthesized compound 6. Their structures were elucidated by HRESIMS and 1D and 2D NMR data. Microechmycin A (1) showed moderate antibacterial activity against Micrococcus luteus SCSIO ML01 with the minimal inhibitory concentration (MIC) value of 8 µg mL-1.


Assuntos
Alcaloides , Micromonospora , Micromonospora/genética , Micromonospora/química , Antibacterianos/farmacologia , Antibacterianos/química , Alcaloides/farmacologia , Alcaloides/química , Espectroscopia de Ressonância Magnética , Genômica , Estrutura Molecular
4.
Asian Pac J Cancer Prev ; 24(1): 75-80, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36708554

RESUMO

OBJECTIVE: Ficus septica is an Indonesian medicinal plant traditionally used to treat various illness, including cancer. The n-hexane insoluble fraction of the ethanolic extract of F. septica leaves (HIFFS) shows a potential anticancer activity against breast cancer cell line T47D. Considering that angiogenesis is a pivotal factor in malignant cancer growth, progression, and invasion, we aimed to investigate the antiangiogenic effect of HIFFS on chicken chorioallantoic membrane (CAM) induced by bFGF. We also evaluated tylophorine, the cytotoxic alkaloid of F. septica. METHODS: Chicken CAM was used to assess the antiangiogenic effect. Fertilized chicken eggs were induced with basic fibroblast growth factor (bFGF) ex ovo. Prior to bFGF induction, HIFFS (2.33, 4.65, 6.98, and 9.30 µg/mL) or tylophorine (9.20 µM) was added (10 µL) to a paper disk and implanted to the CAM. After 48 h of incubation, each treatment group was photographed, and the number of new blood vessel was calculated and compared with that in the solvent-treated group to determine the antiangiogenic activity. Histology of the CAM was evaluated after hematoxylin-eosin and Mallory acid fuchsin staining. RESULTS: We found that HIFFS at low concentrations (2.33, 4.65, 6.98, and 9.30 µg/mL) inhibited angiogenesis activity (31.87, 41.99, 53.65, and 70.08, respectively) in chicken CAM induced by bFGF. Tylophorine (9.20 µM) also showed similar antiangiogenesis activity in the same model. Histopathology analysis revealed that HIFFS and tylophorine reduced the number of new blood vessels in CAM induced by bFGF. CONCLUSION: HIFFS and tylophorine showed antiangiogenic effect on chicken CAM induced by bFGF. This finding emphasized the potential of F. septica as a candidate anticancer agent.


Assuntos
Alcaloides , Antineoplásicos , Ficus , Animais , Galinhas , Membrana Corioalantoide , Fator 2 de Crescimento de Fibroblastos , Alcaloides/farmacologia , Antineoplásicos/farmacologia , Inibidores da Angiogênese/farmacologia , Folhas de Planta
5.
Sci Rep ; 13(1): 1612, 2023 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-36709362

RESUMO

The persistent evolution of drug-resistant influenza strains represents a global concern. The innovation of new treatment approaches through drug screening strategies and investigating the antiviral potential of bioactive natural-based chemicals may address the issue. Herein, we screened the anti-influenza efficacy of some biologically active indole and ß-carboline (ßC) indole alkaloids against two different influenza A viruses (IAV) with varied host range ranges; seasonal influenza A/Egypt/NRC098/2019(H1N1) and avian influenza A/chicken/Egypt/N12640A/2016(H5N1). All compounds were first assessed for their half-maximal cytotoxic concentration (CC50) in MDCK cells and half-maximal inhibitory concentrations (IC50) against influenza A/H5N1. Intriguingly, Strychnine sulfate, Harmalol, Harmane, and Harmaline showed robust anti-H5N1 activities with IC50 values of 11.85, 0.02, 0.023, and 3.42 µg/ml, respectively, as compared to zanamivir and amantadine as control drugs (IC50 = 0.079 µg/ml and 17.59 µg/ml, respectively). The efficacy of the predefined phytochemicals was further confirmed against influenza A/H1N1 and they displayed potent anti-H1N1 activities compared to reference drugs. Based on SI values, the highly promising compounds were then evaluated for antiviral efficacy through plaque reduction assay and consistently they revealed high viral inhibition percentages at non-toxic concentrations. By studying the modes of antiviral action, Harmane and Harmalol could suppress viral infection via interfering mainly with the viral replication of the influenza A/H5N1 virus, whilst Harmaline exhibited a viricidal effect against the influenza A/H5N1 virus. Whereas, Strychnine sulfate elucidated its anti-influenza potency by interfering with viral adsorption into MDCK cells. Consistently, chemoinformatic studies showed that all studied phytochemicals illustrated HB formations with essential peptide cleft through the NH of indole moiety. Among active alkaloids, harmalol displayed the best lipophilicity metrics including ligand efficiency (LE) and ligand lipophilic efficiency (LLE) for both viruses. Compounds geometry and their ability to participate in HB formation are very crucial.


Assuntos
Alcaloides , Vírus da Influenza A , Influenza Humana , Animais , Humanos , Antivirais/farmacologia , Estricnina/farmacologia , Harmalina/farmacologia , Ligantes , Vírus da Influenza A/fisiologia , Alcaloides/farmacologia , Influenza Humana/tratamento farmacológico , Sulfatos/farmacologia , Replicação Viral
6.
Mol Med Rep ; 27(2)2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36601753

RESUMO

Oxysophoridine (OSR) is an alkaloid extracted from Sophora alopecuroides L. and exerts beneficial effects in cerebral ischemia/reperfusion (I/R) injury. However, the molecular mechanism underlying the regulatory effects of OSR in cerebral I/R injury remains unclear. In the present study, a cerebral I/R injury rat model was established by occlusion of the right middle cerebral artery. Hematoxylin and eosin and triphenyltetrazolium chloride staining were performed to assess histopathological changes and the extent of cerebral injury to the brain. A Cell Counting Kit­8 and TUNEL assay and western blotting were performed to assess cell viability and apoptosis. Ferroptosis and oxidative stress were evaluated based on ATP and Fe2+ levels and DCFH­DA staining. The protein expression levels of inflammatory factors were assessed using ELISA. The protein expression levels of members of the toll­like receptor (TLR)4/p38MAPK signaling pathway were evaluated using immunofluorescence staining and western blotting. The results demonstrated that OSR decreased brain injury and neuronal apoptosis in the hippocampus in I/R­induced rats. OSR inhibited reactive oxygen species (ROS) production, decreased levels of ATP, Fe2+ and acyl­CoA synthetase long­chain family member 4 (ACSL4) and transferrin 1 protein and increased the protein expression levels of ferritin 1 and glutathione peroxidase 4. Furthermore, OSR blocked TLR4/p38MAPK signaling in brain tissue in the I/R­induced rat. In vitro experiments demonstrated that TLR4 overexpression induced generation of ROS, ATP and Fe2+, which promoted the expression of ferroptosis­associated proteins in hippocampal HT22 neuronal cells. The ferroptosis inducer erastin decreased the effects of OSR on oxygen­glucose deprivation/reoxygenation (OGD/R)­induced cell viability, oxidative stress and inflammatory response. Together, the results demonstrated that OSR alleviated cerebral I/R injury via inhibition of TLR4/p38MAPK­mediated ferroptosis.


Assuntos
Alcaloides , Isquemia Encefálica , Ferroptose , Traumatismo por Reperfusão , Ratos , Animais , Espécies Reativas de Oxigênio/metabolismo , Receptor 4 Toll-Like , Traumatismo por Reperfusão/metabolismo , Alcaloides/farmacologia , Apoptose , Isquemia Encefálica/metabolismo , Trifosfato de Adenosina/farmacologia
7.
Prog Chem Org Nat Prod ; 119: 1-335, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36587292

RESUMO

This book describes a unique class of secondary metabolites, the mono- and dimeric naphthylisoquinoline alkaloids. They occur in lianas of the paleotropical Ancistrocladaceae and Dioncophyllaceae families, exclusively. Their unprecedented structures include stereogenic centers and rotationally hindered, and thus likewise stereogenic, axes. Extended recent investigations on six Ancistrocladus species from Asia, as reported in this review, shed light on their fascinating phytochemical productivity, with over 100 such intriguing natural products. This high chemodiversity arises from a likewise unique biosynthesis from acetate-malonate units, following a novel polyketidic pathway to plant-derived isoquinoline alkaloids. Some of the compounds show most promising antiparasitic activities. Likewise presented are strategies for the regio- and stereoselective total synthesis of the alkaloids, including the directed construction of the chiral axis.


Assuntos
Alcaloides , Antimaláricos , Caryophyllales , Humanos , Antimaláricos/química , Estrutura Molecular , Alcaloides/farmacologia , Alcaloides/química , Antiparasitários , Caryophyllales/química
8.
Phytochemistry ; 207: 113586, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36632950

RESUMO

A phytochemical investigation of the twig extract of Trivalvaria costata (Hook.f. & Thomson) I.M.Turner has identified ten undescribed dimeric aporphine alkaloids, trivalcostatines A-J, one undescribed isoquinoline alkaloid, trivalcostaisoquinoline, and four known aporphine alkaloids. Their structures were elucidated by detailed analysis of NMR and HRESITOFMS data. Three of the dimeric aporphine structures were confirmed by single crystal X-ray diffraction analysis. All of the dimeric aporphine alkaloids were isolated as mixtures of atropisomers. Several of them were resolved by chiral-phase HPLC and the absolute configurations of the pure atropisomers were assigned by calculated and experimental ECD analysis. Bidebilines A and B, heteropsine, and urabaine showed α-glucosidase inhibitory activities with IC50 values in the range of 4.1-11 µM.


Assuntos
Alcaloides , Annonaceae , Aporfinas , Estrutura Molecular , Aporfinas/farmacologia , Aporfinas/química , Alcaloides/farmacologia , Alcaloides/química , Annonaceae/química , Espectroscopia de Ressonância Magnética
9.
Vitam Horm ; 121: 355-393, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36707140

RESUMO

Alkaloids derived from natural sources have been shown to have substantial antioxidant activity, suggesting that these natural-product-inspired bioactive entities may have major beneficial influence on human health and food processing sector. The primary process intricates in the etiology of several disorders such as neurodegenerative, inflammatory cardiovascular, and other chronic diseases appear to be either oxidative injury or a cellular damage caused by reactive oxygen species (ROS) or free-radicals. The alkaloid class of bio-heterocycles have been divided into numerous groups based on their biosynthetic precursor and heterocyclic ring systems i.e., piperidine, imidazole, purine, pyrrolizidine, indole, quinolozidine, isoquinoline, tropane, and pyrrolidine alkaloids. Distinct biological properties have been attributed to various compounds belonging to this chemical groups, including antirheumatic, cardiovascular, antispasmodic, anti-ulcer, anti-inflammatory, antibacterial, antinociceptive etc. For many years, natural products and their analogs have been recognized as a possible source of medicinal agents. Recently, research has been concentrated on the synthesis, separation/purification, and identification of new alkaloids derived from a variety of natural sources. This book chapter aims to summarize on the latest developments on the current knowledge on the relationship between the structural features of promising class of bioactive alkaloids with their antioxidant activities.


Assuntos
Alcaloides , Produtos Biológicos , Humanos , Antioxidantes/farmacologia , Produtos Biológicos/farmacologia , Alcaloides/farmacologia , Alcaloides/química , Relação Estrutura-Atividade , Tropanos
10.
Eur J Pharmacol ; 941: 175500, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36627098

RESUMO

Oxymatrine (OMT) is a quinoline alkaloid isolated from the root of the Sophora flavescens that has a variety of biological activities. However, the effect and potential mechanism of OMT on isoproterenol (ISO)-induced heart failure (HF) are not clear. In this study, we found that OMT improved the survival of HL-1 cells induced by ISO. We also demonstrated that OMT significantly inhibited the levels of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). OMT decreased the levels of the TLR4 and reduced the phosphorylation levels of nuclear factor-κB (NF-κB) inhibitor (IκB), p65, c-Jun N-terminal kinases (JNK) and p38. The inhibitory effect of the TLR4 inhibitor TAK242 on HL-1 cells was evaluated. The results showed that the effect of OMT on the phosphorylation levels of IκBα and p65 was enhanced in HL-1 cells treated with TAK242. Using animal models, OMT significantly reduced ISO-induced cardiac injury, myocardial necrosis, interstitial edema, and fibrosis. In addition, OMT attenuated TNF-α and IL-6 and inhibited the expression of TLR4/NF-κB and MAPK pathway-related proteins. This finding suggests that OMT may alleviate HF by interfering with the TLR4/NF-κB and MAPK pathways.


Assuntos
Alcaloides , Insuficiência Cardíaca , Animais , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Isoproterenol/toxicidade , Fator de Necrose Tumoral alfa , Interleucina-6 , Proteínas I-kappa B/metabolismo , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/tratamento farmacológico , Alcaloides/farmacologia , Alcaloides/uso terapêutico
11.
Pharm Biol ; 61(1): 135-143, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36617895

RESUMO

CONTEXT: Alkaloid-enriched extract of Huperzia serrata (Thunb.) Trevis (Lycopodiaceae) (HsAE) can potentially be used to manage neuronal disorders. OBJECTIVE: This study determines the anti-neuroinflammatory effects of HsAE on lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and the underlying mechanisms. MATERIALS AND METHODS: BV-2 cells were pre- or post-treated with different concentrations of HsAE (25-150 µg/mL) for 30 min before or after LPS induction. Cell viability was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and no cytotoxicity was found. Nitric oxide (NO) concentration was determined using Griess reagent. The levels of prostaglandin E2 (PGE2), tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 were determined using enzyme-linked immunosorbent assay. The levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 and the phosphorylation of mitogen-activated protein kinase (MAPK) were analyzed using western blotting. RESULTS: HsAE reduced LPS-induced NO production with half-maximal inhibitory concentration values of 99.79 and 92.40 µg/mL at pre- and post-treatment, respectively. Pre-treatment with HsAE at concentrations of 50, 100, and 150 µg/mL completely inhibited the secretion of PGE2, TNF-α, IL-6, and IL-1ß compared to post-treatment with HsAE. This suggests that prophylactic treatment is better than post-inflammation treatment. HsAE decreased the expression levels of iNOS and COX-2 and attenuated the secretion of pro-inflammatory factors by downregulating the phosphorylation of p38 and extracellular signal-regulated protein kinase in the MAPK signaling pathway. DISCUSSION AND CONCLUSIONS: HsAE exerts anti-neuroinflammatory effects on LPS-stimulated BV-2 cells, suggesting that it may be a potential candidate for the treatment of neuroinflammation in neurodegenerative diseases.


Assuntos
Alcaloides , Huperzia , Lipopolissacarídeos/farmacologia , Huperzia/metabolismo , Interleucina-6/metabolismo , Doenças Neuroinflamatórias , Dinoprostona/metabolismo , Microglia , Fator de Necrose Tumoral alfa/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Alcaloides/farmacologia , Alcaloides/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo
12.
BMC Vet Res ; 19(1): 4, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36624444

RESUMO

Post-weaning diarrhea in piglets is a major problem, resulting in a significant loss in pig production. This study aimed to investigate the effects of piperine, an alkaloid abundantly found in black peppers, on biological activities related to the pathogenesis of post-weaning diarrhea using a porcine duodenal enteroid model, a newly established intestinal stem cell-derived in vitro model recapitulating physiology of porcine small intestinal epithelia. Porcine duodenal enteroid models were treated with disease-relevant pathological inducers with or without piperine (8 µg/mL and/or 20 µg/mL) before measurements of oxidative stress, mRNA, and protein expression of proinflammatory cytokines, nuclear factor-kappa B (NF-κB) nuclear translocation, barrier leakage, and fluid secretion. We found that piperine (20 µg/mL) inhibited H2O2-induced oxidative stress, TNF-α-induced mRNA, and protein expression of proinflammatory cytokines without affecting NF-κB nuclear translocation, and prevented TNF-α-induced barrier leakage in porcine duodenal enteroid monolayers. Importantly, piperine inhibited fluid secretion induced by both forskolin and heat-stable toxins (STa) in a three-dimensional model of porcine duodenal enteroids. Collectively, piperine possesses both anti-inflammatory and anti-secretory effects in porcine enteroid models. Further research and development of piperine may provide novel interventions for the treatment of post-weaning porcine diarrhea.


Assuntos
Alcaloides , NF-kappa B , Suínos , Animais , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa , Desmame , Peróxido de Hidrogênio , Diarreia/tratamento farmacológico , Diarreia/veterinária , Alcaloides/farmacologia , Citocinas , RNA Mensageiro
13.
Funct Integr Genomics ; 23(1): 35, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36629976

RESUMO

Rohitukine is a chromone alkaloid and precursor of potent anticancer drugs flavopiridol, P-276-00, and 2,6-dichloro-styryl derivative (11d) (IIIM-290). The metabolite is reported to possess anticancer, anti-inflammatory, antiadipogenic, immunomodulatory, gastroprotective, anti-implantation, antidyslipidemic, anti-arthritic, and anti-fertility properties. However, the physiological role of rohitukine in plant system is yet to be explored. Here, we studied the effect of rohitukine isolated from Dysoxylum gotadhora on Arabidopsis thaliana. The A. thaliana plants grown on a medium fortified with different rohitukine concentrations showed a significant effect on the growth and development. The root growth of A. thaliana seedlings showed considerable inhibition when grown on medium containing 1.0 mM of rohitukine. Transcriptomic analysis indicated the expression of 895 and 932 genes in control and treated samples respectively at a cut-off of FPKM ≥ 1 and P-value < 0.05. Gene ontology (GO) analysis revealed the upregulation of genes related to photosynthesis, membrane transport, antioxidation, xenobiotic degradation, and some transcription factors (TFs) in response to rohitukine. Conversely, rohitukine downregulated several genes including RNA helicases and those involved in nitrogen compound metabolism. The RNA-seq result was also validated by real-time qRT-PCR analysis. In light of these results, we discuss (i) likely ecological importance of rohitukine in parent plant as well as (ii) comparison between responses to rohitukine treatment in plants and mammals.


Assuntos
Alcaloides , Antineoplásicos , Arabidopsis , Animais , Arabidopsis/genética , Antineoplásicos/farmacologia , Cromonas/farmacologia , Cromonas/uso terapêutico , Alcaloides/farmacologia , Perfilação da Expressão Gênica , Transcriptoma , Regulação da Expressão Gênica de Plantas , Mamíferos
14.
Int J Biol Macromol ; 227: 736-748, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36549615

RESUMO

Piperine is an alkaloid mostly found in the fruits of several species of the Piper genus, and its anti-inflammatory potential is already known. However, its therapeutic applications still need to be better explored due to the low aqueous solubility of this active. To overcome this drawback, the objective of this work was to evaluate the efficiency of the nanoencapsulation of the compound as well as its incorporation into hyaluronic acid/alginate-based biomembranes. Polymeric nanoparticles composed of Eudragit S100 and Poloxamer 188 were obtained by the nanoprecipitation technique, obtaining spherical nanosized particles with an average diameter of 122.1 ± 2.0 nm, polydispersity index of 0.266, and encapsulation efficiency of 76.2 %. Hyaluronic acid/sodium alginate membranes were then prepared and characterized. Regarding permeation, a slow passage rate was observed until the initial 14 h, when an exponential increase in the recovered drug concentration began to occur. The in vivo assay showed a reduction in inflammation up to 43.6 %, and no cytotoxicity was observed. The results suggested the potential of the system developed for the treatment of inflammatory skin diseases.


Assuntos
Alcaloides , Dermatite , Nanopartículas , Humanos , Ácido Hialurônico , Alginatos , Alcaloides/farmacologia , Tamanho da Partícula
15.
Chem Biodivers ; 20(1): e202200871, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36529680

RESUMO

Seven benzophenanthridine alkaloids (1-7) were obtained from the 75 % EtOH extract of Eomecon chionantha, and exhibited moderate biological activity against MCF-7 cells. 8,12-dimethoxysanguinarine (1, DSG) strongly decreased the cell viability of MCF-7 cell lines with an IC50 value of 7.12 µΜ. Based on RNA-sequencing measure and KEGG pathway enrichment analysis results, the significant differentially expressed genes (DEGs) were associated with Pathways in Cancer and PI3 K-AKT signaling pathways in DSG treated group. The potential molecular regulatory mechanisms underlying the effect of DSG induces necroptosis in MCF-7 cells via molecular docking, TEM analysis, and ROS measurement. Besides, DEGs of bone metastasis-related genes such as PI3 K, IGF1R, Notch, and Wnt mRNA were significantly downregulated in the DSG-treated group on MCF-7 cells. DSG might be selected as a bone metastasis proteins inhibitor of IL-1ß, IL-6, IκBα, IGF1R, Notch, NF-κB, PTHrp, PI3 K, PKB/AKT, PTEN, TNF-α, and Wnt via molecular docking. DSG suppressed bone metastasis by regulating the expression levels of IL-1ß, IL-6, PTH, CROSS, TP1NP, and OSTEOC on MCF-7 cells using ELISA measurement. Thus, our findings reveal that DSG could be a lead compound for suppressing tumor cells to bone metastasis in breast cancer cells.


Assuntos
Alcaloides , Antineoplásicos , Humanos , Células MCF-7 , Proteínas Proto-Oncogênicas c-akt/metabolismo , Benzofenantridinas/farmacologia , Interleucina-6 , Simulação de Acoplamento Molecular , Alcaloides/farmacologia , Antineoplásicos/farmacologia
16.
Chem Commun (Camb) ; 59(3): 326-329, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36511292

RESUMO

Veratrazine A (1), a steroidal alkaloid with a unique 6/5/5 triheterocyclic scaffold as the side chain, was isolated from Veratrum stenophyllum, and its structure was established via spectroscopic analyses and X-ray diffraction. A plausible biosynthetic pathway for 1 is proposed. Bioassy exhibits moderate anti-inflammatory activities in vitro and in vivo.


Assuntos
Alcaloides , Antineoplásicos , Veratrum , Alcaloides/farmacologia , Alcaloides/química , Extratos Vegetais/química , Veratrum/química , Esteroides/farmacologia , Anti-Inflamatórios , Estrutura Molecular
17.
Pharmacol Ther ; 241: 108335, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36567056

RESUMO

Metal-based complexes have occupied a pioneering niche in the treatment of many chronic diseases, including various types of cancers. Despite the phenomenal success of cisplatin for the treatment of many solid malignancies, a limited number of metallo-drugs are in clinical use against cancer chemotherapy till date. While many other prominent platinum and non­platinum- based metallo-drugs (e.g. NAMI-A, KP1019, carboplatin, oxaliplatin, titanocene dichloride, casiopeinas® etc) have entered clinical trials, many have failed at later stages of R&D due to deleterious toxic effects, intrinsic resistance and poor pharmacokinetic response and low therapeutic efficacy. Nonetheless, research in the area of medicinal inorganic chemistry has been increasing exponentially over the years, employing novel target based drug design strategies aimed at improving pharmacological outcomes and at the same time mitigating the side-effects of these drug entities. Over the last few decades, natural products became one of the key structural motifs in the anticancer drug development. Many eminent researchers in the area of medicinal chemistry are devoted to develop new 3d-transition metal-based anticancer drugs/repurpose the existing bioactive compounds derived from myriad pharmacophores such as coumarins, flavonoids, chromones, alkaloids etc. Metal complexes of natural alkaloids and their analogs such as luotonin A, jatrorrhizine, berberine, oxoaporphine, 8-oxychinoline etc. have gained prominence in the anticancer drug development process as the naturally occurring alkaloids can be anti-proliferative, induce apoptosis and exhibit inhibition of angiogenesis with better healing effect. While some of them are inhibitors of ERK signal-regulated kinases, others show activity based on cyclooxygenases-2 (COX-2) and telomerase inhibition. However, the targets of these alkaloid complexes are still unclear, though it is well-established that they demonstrate anticancer potency by interfering with multiple pathways of tumorigenesis and tumor progression both in vitro and in vivo. Over the last decade, many significant advances have been made towards the development of natural alkaloid-based metallo-drug therapeutics for intervention in cancer chemotherapy that have been summarized below and reviewed in this article.


Assuntos
Alcaloides , Antineoplásicos , Complexos de Coordenação , Neoplasias , Humanos , Antineoplásicos/efeitos adversos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Complexos de Coordenação/uso terapêutico , Sistemas de Liberação de Medicamentos , Alcaloides/farmacologia , Alcaloides/uso terapêutico
18.
J Nat Prod ; 86(1): 45-51, 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36524671

RESUMO

Burkitt's lymphoma (BL) has a particularly extremely poor prognosis and the fastest growth rate among human tumors, and the development of new drugs for the treatment of BL is urgently needed. In this study, the cytotoxic properties of 3,7-bis(3,5-dimethylphenyl)-aaptamine (AP-51), a new semisynthetic alkaloid derived from the marine natural product aapatamine, were investigated using BL cell lines. Our results showed that AP-51 inhibited the proliferation of Daudi and Raji cells with IC50 values of 3.48 and 2.07 µM, respectively. Flow cytometry and Western blot analyses showed that AP-51 initiated G0/G1 phase arrest by modulating the expression of cyclin-dependent kinases (CDKs). AP-51 also induced apoptosis, as demonstrated by nuclear fragmentation, downregulation of BCL-XL and Mcl-1, and upregulation of cleaved caspase-9, cleaved caspase-3, cleaved-PARP, and cytochrome c, the markers of apoptosis regulated via the mitochondrial pathway. When it comes to mitochondria, AP-51 treatment also significantly increased the levels of intracellular mitochondrial superoxide, decreased ATP content, and reduced the expression of ATP synthase, as well as the expression of the mitochondrial respiratory chain complexes. Finally, AP-51 treatment significantly inhibited the PI3K/AKT/mTOR signaling pathway, which was shown to be associated with the induction of apoptosis. Collectively, these findings indicated that AP-51 initiated cell cycle arrest, induced apoptosis, caused mitochondrial dysfunction, and decreased the phosphorylation of PI3K/AKT/mTOR signaling pathway-related proteins and the protein levels of C-MYC, suggesting that AP-51 has therapeutic potential as a possible treatment for Burkitt's lymphoma.


Assuntos
Alcaloides , Antineoplásicos , Linfoma de Burkitt , Poríferos , Humanos , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proliferação de Células , Linhagem Celular Tumoral , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Poríferos/metabolismo , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Mitocôndrias/metabolismo , Trifosfato de Adenosina , Apoptose
19.
Phytochemistry ; 207: 113564, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36535411

RESUMO

Twenty-six structurally diverse Amaryllidaceae alkaloids, including ten undescribed compounds named zephyranines A-I and 6-O-ethylnerinine, two undescribed natural products zephyranthine-6-one and 3-O-deacetyl-sternbergine, were isolated from whole plants of Zephyranthes candida. Their structures were determined by HRESIMS, 1D and 2D NMR, CD data analysis, NMR and ECD calculations, and single-crystal X-ray diffraction analysis. All structures were classified into nine framework types: 10b,11-seco-crinine, graciline, crinine, homolycorine, trisphaeridine, lycorine, galasine, tazettine, and belladine. Zephyranine A represents the first naturally occurring 10b,11-seco-crinine type alkaloid, and zephyranine B is the sixth graciline type alkaloid. 6-O-ethylnerinine is an artifact from the extraction and isolation. All isolates were evaluated for their acetylcholinesterase (AChE) inhibitory and anti-inflammatory activities. Zephyranines A, G, and H exhibited moderate AChE inhibitory activities, with IC50 values of 8.2, 39.0, and 10.8 µM, respectively. Zephyranine B, haemanthamine, haemanthidine, 11-hydroxyvittatine, and 8-demethoxy-10-O-methylhostasine exhibited potent anti-inflammatory activity on the LPS-induced NO production in RAW264.7 mouse macrophages with IC50 values of 21.3, 4.6, 12.2, 5.6, and 17.4 µM, respectively. Structure-activity-relationship analysis and docking studies indicated that interactions with the key Trp286 and Tyr337 residues are required for potent AChE inhibitors.


Assuntos
Alcaloides , Alcaloides de Amaryllidaceae , Amaryllidaceae , Camundongos , Animais , Acetilcolinesterase , Alcaloides de Amaryllidaceae/farmacologia , Alcaloides de Amaryllidaceae/química , Alcaloides/farmacologia , Alcaloides/química , Amaryllidaceae/química , Anti-Inflamatórios/farmacologia , Candida , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química
20.
Mar Drugs ; 20(12)2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36547885

RESUMO

Two new guanidine alkaloids, batzelladines O (1) and P (2), were isolated from the deep-water marine sponge Monanchora pulchra. The structures of these metabolites were determined by NMR spectroscopy, mass spectrometry, and ECD. The isolated compounds exhibited cytotoxic activity in human prostate cancer cells PC3, PC3-DR, and 22Rv1 at low micromolar concentrations and inhibited colony formation and survival of the cancer cells. Batzelladines O (1) and P (2) induced apoptosis, which was detected by Western blotting as caspase-3 and PARP cleavage. Additionally, induction of pro-survival autophagy indicated as upregulation of LC3B-II and suppression of mTOR was observed in the treated cells. In line with this, the combination with autophagy inhibitor 3-methyladenine synergistically increased the cytotoxic activity of batzelladines O (1) and P (2). Both compounds were equally active in docetaxel-sensitive and docetaxel-resistant prostate cancer cells, despite exhibiting a slight p-glycoprotein substrate-like activity. In combination with docetaxel, an additive effect was observed. In conclusion, the isolated new guanidine alkaloids are promising drug candidates for the treatment of taxane-resistant prostate cancer.


Assuntos
Alcaloides , Antineoplásicos , Poríferos , Neoplasias da Próstata , Animais , Masculino , Humanos , Guanidina/farmacologia , Guanidina/química , Docetaxel/farmacologia , Guanidinas/farmacologia , Guanidinas/química , Poríferos/química , Apoptose , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/química , Neoplasias da Próstata/tratamento farmacológico , Autofagia , Alcaloides/farmacologia , Alcaloides/química
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