RESUMO
Despite significant advancements in chemotherapy, effective treatments for advanced cancer stages remain largely elusive due to chemoresistance. Resistance to anticancer agents in cancer cells can arise through various mechanisms, including multi-drug resistance, inhibition of apoptosis, modification of drug targets, and enhancement of DNA repair capabilities. Consequently, there is a critical need for agents that can suppress the molecular signatures responsible for drug resistance. Piperine, an active alkaloid extracted from Piper nigrum L. (black pepper), is one such agent that has been extensively studied for its potential in addressing chronic diseases, including cancer. Piperine's antineoplastic properties are mediated through the regulation of numerous key cellular signaling pathways and the modulation of various biological processes. Its capability to enhance drug bioavailability and counteract mechanisms of drug resistance, such as the inhibition of P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP-1), emphasizes its potential as an adjunct in cancer therapy. Research across various cancer types has demonstrated piperine's role in chemosensitization by targeting P-gp and MRP-1 and altering drug-metabolizing enzymes. This review provides a comprehensive analysis of piperine's pharmacological characteristics and its capacity to modulate several cellular signaling pathways involved in drug resistance. Furthermore, the review emphasizes how piperine, when used in conjunction with other chemotherapeutic agents or natural compounds, can enhance therapeutic effects, leading to improved outcomes in cancer treatment.
Assuntos
Alcaloides , Benzodioxóis , Resistencia a Medicamentos Antineoplásicos , Neoplasias , Piperidinas , Alcamidas Poli-Insaturadas , Alcamidas Poli-Insaturadas/farmacologia , Benzodioxóis/farmacologia , Benzodioxóis/uso terapêutico , Humanos , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Alcaloides/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Animais , Sinergismo Farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Piper nigrum/químicaRESUMO
Piperine, derived from black pepper (Piper nigrum L.), is responsible for the pungent sensation. The diverse bioactivities of piperine underscores its promising potential as a functional food ingredient. This review presents a comprehensive overview of the research progress in extraction, synthesis, pungency transduction mechanism and bioactivities of piperine. Piperine can be extracted through various methods, such as traditional, modern, and innovative extraction techniques. Its synthesis mainly included both chemical and biosynthetic approaches. It exhibits a diverse range of bioactivities, including anticancer, anticonvulsant, antidepressant, anti-inflammatory, antioxidant, immunomodulatory, anti-obesity, neuroprotective, antidiabetic, hepatoprotective, and cardiovascular protective activities. Piperine can bind to TRPV1 receptor to elicit pungent sensation. Overall, the present review can provide a theoretical reference for advancing the potential application of piperine in the field of food science.
Assuntos
Alcaloides , Benzodioxóis , Piper nigrum , Piperidinas , Extratos Vegetais , Alcamidas Poli-Insaturadas , Piper nigrum/química , Alcamidas Poli-Insaturadas/farmacologia , Alcamidas Poli-Insaturadas/química , Benzodioxóis/farmacologia , Benzodioxóis/química , Piperidinas/farmacologia , Piperidinas/química , Alcaloides/farmacologia , Alcaloides/química , Humanos , Animais , Extratos Vegetais/química , Extratos Vegetais/farmacologiaRESUMO
Gastric cancer is one of the most frequent types of neoplasms worldwide, usually presenting as aggressive and difficult-to-manage tumors. The search for new structures with anticancer potential encompasses a vast research field in which natural products arise as promising alternatives. In this scenario, piperine, an alkaloid of the Piper species, has received attention due to its biological activity, including anticancer attributes. The present work proposes three heating-independent, reliable, low-cost, and selective methods for obtaining piperine from Piper nigrum L. (Black pepper). Electronic (SEM) and optical microscopies, X-ray diffraction, nuclear magnetic resonance spectroscopies (13C and 1H NMR), and optical spectroscopies (UV-Vis, photoluminescence, and FTIR) confirm the obtention of piperine crystals. The MTT assay reveals that the piperine samples exhibit good cytotoxic activity against primary and metastasis models of gastric cancer cell lines from the Brazilian Amazon. The samples showed selective cytotoxicity on the evaluated models, revealing higher effectiveness in cells bearing a higher degree of aggressiveness. Moreover, the investigated piperine crystals demonstrated the ability to act as a good cytotoxicity enhancer when combined with traditional chemotherapeutics (5-FU and GEM), allowing the drugs to achieve the same cytotoxic effect in cells employing lower concentrations. These results establish piperine as a promising molecule for therapy investigations in aggressive gastric cancer, both in its isolated form or as a bioenhancer.
Assuntos
Alcaloides , Antineoplásicos , Piper nigrum , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Alcaloides/química , Benzodioxóis/química , Piperidinas/química , Alcamidas Poli-Insaturadas/química , Piper nigrum/química , Antineoplásicos/farmacologiaRESUMO
Translation of traditional knowledge of herbs into a viable product for clinical use is still an uphill task. Piperine, a pungent alkaloid molecule derived from Piper nigrum and Piper longum possesses diverse pharmacological effects. Traditionally, pepper is used for arthritis, bronchitis, gastritis, diarrhea, snake bite, menstrual pain, fever, and bacterial infections, etc. The anti-inflammatory, antioxidant and immunomodulatory actions of piperine are the possible mechanisms behind its therapeutic potential. Various in-silico and experimental studies have shown piperine as a possible promising molecule in coronavirus disease (COVID-19), ebola, and dengue due to its immunomodulatory and antiviral activities. The other important clinical applications of piperine are due to its bio enhancing effect on drugs, by modulating, absorption in the gastrointestinal tract, altering activities of transporters like p-glycoprotein substrates, and modulating drug metabolism by altering the expression of cytochrome P450 or UDP-glucuronosyltransferase enzymes. Piperine attracted clinicians in treating patients with arthritis, metabolic syndrome, diabetes, skin infections, gastric and liver disorders. This review focused on systematic, evidence-based insight into the use of piperine in clinical settings and mechanistic details behind its therapeutic actions. Also, highlights a number of clinical trials of piperine at various stages exploring its clinical application in cancer, neurological, respiratory, and viral disease, etc.
Assuntos
Alcaloides , COVID-19 , Piper nigrum , Humanos , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Benzodioxóis/farmacologia , Benzodioxóis/uso terapêutico , Alcamidas Poli-Insaturadas/farmacologia , Alcamidas Poli-Insaturadas/uso terapêutico , Piper nigrum/químicaRESUMO
Volatile organic metabolites (VOMs) present in different spices can provide distinct analytical biosignatures related to organoleptic properties and health benefits. This study aimed to establish the volatilomic fingerprint of six of the most consumed spices all over the world (saffron (Crocus sativus L.), cinnamon (Cinnamomum verum), cumin (Cuminum cyminum L.), black pepper, (Piper nigrum L.), sweet paprika (Capsicum annuum L.), and curry (a mix of different herbs and spices)). Based on headspace solid phase microextraction (HS-SPME) followed by gas chromatography-mass spectrometry (GC-MS) analysis, this is a powerful strategy to explore and establish the spice's volatile pattern and unravel the potential health benefits related to the most important VOMs identified in each spice. This comprehensive knowledge will help in the definition of their authenticity, while simultaneously protecting against potential frauds and adulterations. A total of 162 VOMs were identified. Semi-quantitative assessments revealed that terpenoids and sesquiterpenoids amounted to the major volatile class in the investigated spices, except for cinnamon, where carbonyl compounds are the major group. Most of the studied spices comprised key characteristics of aroma and health bioactive compounds, e.g., dihydrojuneol in saffron, cinnamaldehyde in cinnamon, cuminaldehyde in cumin and curry, and caryophyllene in black pepper. The principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) successfully discriminated the investigated spices, being α-cubebene, 3-methyl butanal, ß-patchoulene and ß-selinene, the most important VOMs (highest VIP's) that contributed to its discrimination. Moreover, some VOMs have a high influence on the spice's bioactive potential, helping to prevent certain diseases including cancer, inflammatory-related diseases, diabetes, and cardiovascular diseases.
Assuntos
Capsicum , Crocus , Cuminum , Piper nigrum , Compostos Orgânicos Voláteis , Crocus/química , Cuminum/química , Cromatografia Gasosa-Espectrometria de Massas/métodos , Piper nigrum/química , Especiarias/análise , Terpenos/análise , Compostos Orgânicos Voláteis/análiseRESUMO
India is the largest producer in the world of black pepper and it is the center of origin for Piper. The present study gives a comparative account of the chemical composition of the Piper nigrum and its wild putative parent the P. trichostachyon. Microextractions were performed and the quantification of six phenolic compounds (namely epicatechin, gallic acid, catechol, chlorogenic acid, caffeic acid, and catechin), piperine from leaves, petioles, and the fruits of both the species, were accomplished using the RP-UFLC system. The polyphenols (phenolic, flavonoid) and their antioxidant activities were also estimated. Among the six phenolic compounds studied, only three were detected and quantified. The polyphenol content correlating to the antioxidant activities was higher in the P. trichostachyon, whereas the piperine content was 108 times greater in the P. nigrum fruits. The Piper trichostachyon comparatively showed a higher content of polyphenols. The microextractions reduced the solvent consumption, the quantity of the plant material, and the amount of time used for the extraction. The first report on the TPC, TF, and the antioxidant activity of the P. trichostachyon has been described, and it also forms a scientific basis for its use in traditional medicine. The petioles of both species are good sources of phenolic compounds. A quantitative chemical analysis is a useful index in the identification and comparison of the species.
Assuntos
Catequina , Piper nigrum , Piper , Alcaloides , Antioxidantes/farmacologia , Benzodioxóis , Catecóis , Ácido Clorogênico , Flavonoides , Ácido Gálico , Fenóis , Piper nigrum/química , Piperidinas , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Alcamidas Poli-Insaturadas , SolventesRESUMO
Emulgel is a new innovatory technique for drug development permitting controlled release of active ingredients for topical administration. We report a stable emulgel of 4% Piper nigrum extract (PNE) prepared using 80% ethanol. The PNE-loaded formulation had an antioxidant activity of 84% and tyrosinase inhibition was 82%. Prepared formulation rendered spherical-shaped globules with high zeta potential (-45.5 mV) indicative of a stable system. Total phenolic contents were 58.01 mg GAE/g of dry extract whereas total flavonoid content was 52.63 mg QE/g of dry extract. Sun protection factor for PNE-loaded emulgel was 7.512 and formulation was stable without any evidence of physical and chemical changes following 90 days of storage. Gas chromatography-mass spectroscopy (GC-MS) revealed seventeen bioactive compounds in the PNE including monoterpenoids, triterpenoids, a tertiary alcohol, fatty acid esters, and phytosterols. In silico studies of GC-MS identified compounds show higher binding affinity in comparison to standard kojic acid indicating tyrosinase inhibition. It can be concluded that PNE-loaded emulgel had prominent antioxidant and tyrosinase inhibition and can be utilized as a promising topical system for anti-aging skin formulation.
Assuntos
Fitosteróis , Piper nigrum , Triterpenos , Alérgenos , Antioxidantes/química , Antioxidantes/farmacologia , Preparações de Ação Retardada , Etanol , Álcoois Graxos , Flavonoides , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase , Monoterpenos , Piper nigrum/química , Extratos Vegetais/química , SementesRESUMO
The active compounds isolated from Black pepper have anticancer effects, but the bioactivity of Black pepper essential oil (BP-EO) is rarely studied. BP-EO has poor stability and a suitable dose form should be prepared for in vivo delivery. Triple negative breast cancer (TNBC) has attracted more and more attention due to its high mitotic index, high metastasis rate and poor prognosis. In this study, the composition of BP-EO was analyzed by gas chromatography-mass spectrometry (GC-MS), and nanoparticles (NPs) loaded with BP-EO were prepared by nanoprecipitation method using Eudragit L100 as a carrier. We investigated the preparation, characterization, stability and in vitro release of nanoparticles. MTT assay, cell wound healing, Transwell invasion assay and Western blot were used to study the anti-tumor effect and mechanism of MDA-MB-231 cells. The GC-MS analysis identified a total of 33 compounds among which alkenes account for 63.55%. The prepared BP-EO NPs exhibited nanoscale morphology, good stability and pH-responsive and sustained release character which is suitable for in vivo delivery. BP-EO NPs significantly inhibited the proliferation, migration and invasion of MDA-MB-231 cells. Furthermore, BP-EO NPs significantly inhibited the expressions of Wnt and ß-catenin and significantly activated the expression of GSK-3ß in MDA-MB-231 cells. Therefore, BP-EO NPs prepared in this study provide a new effective strategy for the treatment of TNBC. PRACTICAL APPLICATIONS: Black pepper is rich in essential oil and has excellent antioxidant and antibacterial activities. However, the anti-tumor activity of BP-EO has not been studied. In this study, we found that BP-EO has excellent anticancer activity. To achieve effective encapsulation of black pepper essential oil and an excellent anti-triple negative breast cancer activity, nanoparticles loaded with BP-EO were prepared using Eudragit L100 as the carrier by the nanoprecipitation method. The in vitro study revealed that BP-EO NPs inhibited proliferation, migration and invasion of MDA-MB-231 cells via inhibiting the Wnt/ß-Catenin signaling pathway. This study provides new ideas and innovations for the treatment of invasive triple negative breast cancer in the future. At the same time, we will further reveal the application potential, pharmacokinetic characteristics and precise mechanism of BP-EO NPs in vivo in subsequent studies.
Assuntos
Nanopartículas , Óleos Voláteis , Piper nigrum , Neoplasias de Mama Triplo Negativas , Humanos , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Piper nigrum/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Glicogênio Sintase Quinase 3 betaRESUMO
Dexamethasone acts as an immunosuppressive drug and has been used recently in the management of specific coronavirus disease 2019 (COVID-19) cases; however, various adverse effects could limit its use. In this work, we studied the mitigation effects of black pepper oil (BP oil) on glycemic parameters, dyslipidemia, oxidative and nitrosative stress and pancreatic fibrosis in dexamethasone-treated rats. Animals were divided into five groups that were treated with vehicle, dexamethasone (10 mg/kg, SC) or black pepper oil (BP oil, 0.5 mL, or 1 mL/kg) or metformin (50 mg/kg) plus dexamethasone for 4 consecutive days. Serum insulin, blood glucose, total cholesterol, triglycerides, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) were higher in the dexamethasone group vs the control group and decreased in BP oil and metformin groups relative to the dexamethasone group. Pancreatic nitric oxide, inducible nitric oxide synthase and malondialdehyde levels were increased in the dexamethasone group vs the control group and decreased in BP oil and metformin groups relative to the dexamethasone group. Pancreatic endothelial nitric oxide synthase and reduced glutathione were declined in the dexamethasone group vs the control group. They were increased in BP oil and metformin groups relative to the dexamethasone group. Moreover, the pancreatic islets diameter and collagen deposition were assessed and found to be higher in the dexamethasone group vs the control group. BP oil and metformin groups showed to regress this effect. In conclusion, BP oil may alleviate hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia and pancreatic structural derangements and fibrosis by suppressing oxidative stress, increasing endogenous antioxidant levels, modulating nitric oxide signaling, preventing pancreatic stellate cells transition and collagen deposition.
Assuntos
Dexametasona , Metformina , Pâncreas , Piper nigrum , Óleos de Plantas , Animais , Glicemia , Dexametasona/efeitos adversos , Dexametasona/farmacologia , Dislipidemias/tratamento farmacológico , Fibrose , Resistência à Insulina , Metformina/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Piper nigrum/química , Óleos de Plantas/farmacologia , Óleos de Plantas/uso terapêutico , Ratos , Ratos Wistar , Tratamento Farmacológico da COVID-19RESUMO
This study aimed to evaluate the piperine content, essential oil composition, and multi-elemental composition of black pepper samples according to different drying methods and harvest season. Differences in essential oil composition and B, Ca, K, Mg, and S were noted according to sampling campaign, indicating secondary metabolism plant alterations. Mechanical drying resulted in essential oil composition changes due to high temperature exposure during processing. Increases in Fe and Cr contents when employing mechanical dryers with direct heating were also observed, due to direct contact with metallic structures and particulate material from the burning process. The As and Pb contents of several samples were higher than the maximum permissible limits, reaching 0.46 and 0.56 mg kg-1, respectively, thus surpassing legislation safety limitations for human consumption.
Assuntos
Óleos Voláteis , Piper nigrum , Alcaloides , Benzodioxóis , Humanos , Óleos Voláteis/química , Piper nigrum/química , Piperidinas , Alcamidas Poli-Insaturadas/química , Estações do AnoRESUMO
CONTEXT: Many natural extracts have been shown to minimize the toxicity of doxorubicin (Dox). Low piperine Piper nigrum L. (Piperaceae) extract (PFPE) is a natural extract containing many types of antioxidants that may reduce Dox toxicities. OBJECTIVE: To evaluate the effect of PFPE in attenuating the side effects of Dox. MATERIALS AND METHODS: Tumour-bearing Sprague Dawley rats were divided into five groups including normal, vehicle, 100 mg/kg BW of PFPE plus 2 mg/kg BW of Dox (P100 + Dox), 100 mg/kg BW of PFPE plus 2 mg/kg BW of Dox (P200 + Dox) and Dox. Rats were treated with Dox and/or PFPE three times/week for 4 weeks. Tumour burden, blood parameters, weight of internal organs and immunological data were investigated. RESULTS: The addition of 200 mg/kg PFPE significantly restored the levels of AST from 174.60 ± 45.67 U/L in the Dox group near to normal levels at 109.80 ± 4.99 U/L. The combination of PFPE and Dox also decreased the levels of CXCL7, TIMP-1, sICAM-1 and l-selectin about 1.4-1.6-fold compared to Dox group. Feeding rats with 200 mg/kg BW of PFPE combination with Dox slightly increased Th1 from 161.67 ± 14.28 cells in Dox group to 200.75 ± 5.8 cells meanwhile suppressed Treg from 3088 ± 78 cells in Dox to 2561 ± 71 cells. DISCUSSION AND CONCLUSIONS: This study showed that PFPE ameliorated Dox toxicity in many aspects indicating the role of antioxidant and other substances in the extract on toxicity attenuation. This suggested the using of PFPE may be valuable for Dox treated patients.
Assuntos
Alcaloides/farmacologia , Benzodioxóis/farmacologia , Doxorrubicina/toxicidade , Piper nigrum/química , Piperidinas/farmacologia , Extratos Vegetais/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Alcaloides/administração & dosagem , Alcaloides/isolamento & purificação , Animais , Antibióticos Antineoplásicos/toxicidade , Antioxidantes/administração & dosagem , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Benzodioxóis/administração & dosagem , Benzodioxóis/isolamento & purificação , Relação Dose-Resposta a Droga , Feminino , Neoplasias Mamárias Experimentais/tratamento farmacológico , Piperidinas/administração & dosagem , Piperidinas/isolamento & purificação , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Alcamidas Poli-Insaturadas/administração & dosagem , Alcamidas Poli-Insaturadas/isolamento & purificação , Ratos , Ratos Sprague-DawleyRESUMO
Ethanol extracts of two types of pepper (sweet and hot) were separated into fractions with increasing lipophilicity. After drying the extracts and fractions, their chemical composition, anti-radical activity in the DPPH radical system, and cytotoxic activity against PC-3 and HTC-116 cells were determined. A detailed qualitative analysis of the fractions was performed with the LC-QTOF-MS method. It was found that the chemical composition of pepper fractions did not always reflect their biological activity. The highest antiradical activity was detected in the fraction eluted with 40% methanol from sweet pepper. The highest total content of phenolic compounds was found in an analogous fraction from hot pepper, and this fraction showed the strongest cytotoxic effect on the PC-3 tumour line. The LC-MS analysis identified 53 compounds, six of which were present only in sweet pepper and four only in hot pepper. The unique chemical composition of the extracts was found to modulate their biological activity, which can only be verified experimentally.
Assuntos
Capsicum/química , Extratos Vegetais/química , Antioxidantes/química , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Fenóis/química , Piper nigrum/química , Verduras/químicaRESUMO
In the present study, we have used seed extract of P. nigrum as an effective reducing agent for the synthesis of silver nanoparticles (Ag NPs) and silver based chitosan nanocomposite (Ag/CS NC). The silver nanoparticles were characterized by UV-vis spectroscopy, X-ray diffraction (XRD), scanning electron microscope (SEM), transmission electron microscope (TEM) and Fourier transform infrared spectroscopy (FTIR). The appearance of a surface plasmon resonance (SPR) peak located at 430 nm reveals the formation of silver nanoparticles. The TEM analysis indicates that the attained silver nanoparticles were mostly in spherical shapes with sizes ranging between 15 and 38 nm. The high resolution liquid chromatography with mass spectroscopy (HR-LCMS) analysis was performed to screen the phytochemical constituents of P. nigrum seed extract. The silver nanoparticles synthesized by P. nigrum seed extract exhibited effective antibacterial activity against Bacillus subtilis (B. subtilis) and Escherichia coli (E. coli). In addition, the silver nanoparticles showed potent cytotoxicity against hazardous human cancer cell lines MDA-MB-231, PANC-1, SKOV-3, PC-3 and Hela. The observation of bright spots in the TEM dark field images represents the presence of Ag in CS suspension. Besides, the Ag/CS NC coated cotton fabric substantially showed remarkable antibacterial activity against B. subtilis and E. coli.
Assuntos
Antibacterianos/farmacologia , Quitosana/química , Química Verde , Nanopartículas Metálicas/química , Nanocompostos/química , Piper nigrum/química , Extratos Vegetais/farmacologia , Prata/farmacologia , Bacillus subtilis/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Fibra de Algodão , Escherichia coli/efeitos dos fármacos , Humanos , Nanopartículas Metálicas/ultraestrutura , Testes de Sensibilidade Microbiana , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Sementes/química , Espectrometria por Raios X , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios XRESUMO
Trans-(-)-kusunokinin, an anticancer compound, binds CSF1R with low affinity in breast cancer cells. Therefore, finding an additional possible target of trans-(-)-kusunokinin remains of importance for further development. Here, a computational study was completed followed by indirect proof of specific target proteins using small interfering RNA (siRNA). Ten proteins in breast cancer were selected for molecular docking and molecular dynamics simulation. A preferred active form in racemic trans-(±)-kusunokinin was trans-(-)-kusunokinin, which had stronger binding energy on HER2 trans-(+)-kusunokinin; however, it was weaker than the designed HER inhibitors (03Q and neratinib). Predictively, trans-(-)-kusunokinin bound HER2 similarly to a reversible HER2 inhibitor. We then verified the action of (±)-kusunokinin compared with neratinibon breast cancer cells (MCF-7). (±)-Kusunokinin exhibited less cytotoxicity on normal L-929 and MCF-7 than neratinib. (±)-Kusunokinin and neratinib had stronger inhibited cell proliferation than siRNA-HER2. Moreover, (±)-kusunokinin decreased Ras, ERK, CyclinB1, CyclinD and CDK1. Meanwhile, neratinib downregulated HER, MEK1, ERK, c-Myc, CyclinB1, CyclinD and CDK1. Knocking down HER2 downregulated only HER2. siRNA-HER2 combination with (±)-kusunokinin suppressed HER2, c-Myc, CyclinB1, CyclinD and CDK1. On the other hand, siRNA-HER2 combination with neratinib increased HER2, MEK1, ERK, c-Myc, CyclinB1, CyclinD and CDK1 to normal levels. We conclude that trans-(±)-kusunokinin may bind HER2 with low affinity and had a different action from neratinib.
Assuntos
Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Lignanas/metabolismo , Lignanas/farmacologia , Piper nigrum/química , Extratos Vegetais/metabolismo , Extratos Vegetais/farmacologia , Receptor ErbB-2/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Técnicas de Silenciamento de Genes , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Quinolinas/farmacologia , RNA Interferente Pequeno/genética , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , TransfecçãoRESUMO
Global prevalence of type 2 diabetes (T2D) is rising and may affect 700 million people by 2045. Totum-63 is a polyphenol-rich natural composition developed to reduce the risk of T2D. We first investigated the effects of Totum-63 supplementation in high-fat diet (HFD)-fed mice for up to 16 wk and thereafter assessed its safety and efficacy (2.5 g or 5 g per day) in 14 overweight men [mean age 51.5 yr, body mass index (BMI) 27.6 kg·m-2] for 4 wk. In HFD-fed mice, Totum-63 reduced body weight and fat mass gain, whereas lean mass was unchanged. Moreover, fecal energy excretion was higher in Totum-63-supplemented mice, suggesting a reduction of calorie absorption in the digestive tract. In the gut, metagenomic analyses of fecal microbiota revealed a partial restoration of HFD-induced microbial imbalance, as shown by principal coordinate analysis of microbiota composition. HFD-induced increase in HOMA-IR score was delayed in supplemented mice, and insulin response to an oral glucose tolerance test was significantly reduced, suggesting that Totum-63 may prevent HFD-related impairments in glucose homeostasis. Interestingly, these improvements could be linked to restored insulin signaling in subcutaneous adipose tissue and soleus muscle. In the liver, HFD-induced steatosis was reduced by 40% (as shown by triglyceride content). In the subsequent study in men, Totum-63 (5 g·day-1) improved glucose and insulin responses to a high-carbohydrate breakfast test (84% kcal carbohydrates). It was well tolerated, with no clinically significant adverse events reported. Collectively, these data suggest that Totum-63 could improve glucose homeostasis in both HFD-fed mice and overweight individuals, presumably through a multitargeted action on different metabolic organs.NEW & NOTEWORTHY Totum-63 is a novel polyphenol-rich natural composition developed to reduce the risk of T2D. Totum-63 showed beneficial effects on glucose homeostasis in HFD-fed mice, presumably through a multitargeted action on different metabolic organs. Totum-63 was well tolerated in humans and improved postprandial glucose and insulin responses to a high-carbohydrate breakfast test.
Assuntos
Glicemia/efeitos dos fármacos , Hiperglicemia/prevenção & controle , Extratos Vegetais/farmacologia , Adulto , Animais , Glicemia/metabolismo , Chrysanthemum/química , Cynara scolymus/química , Controle Glicêmico/métodos , Homeostase/efeitos dos fármacos , Humanos , Hiperglicemia/sangue , Hiperglicemia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Olea/química , Sobrepeso/sangue , Sobrepeso/tratamento farmacológico , Sobrepeso/metabolismo , Projetos Piloto , Piper nigrum/química , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Período Pós-Prandial/efeitos dos fármacos , Pesquisa Translacional Biomédica , Vaccinium myrtillus/químicaRESUMO
Piper nigrum is extensively utilized because of its antioxidation, antiallergic, antitumor, antiinflammatory, antidiarrhea, and gastrointestinal protection. We attempted to indicate whether the Piper nigrum extract (PNE) could alleviate ovalbumin (OVA)-induced food allergy, and to explore its potential mechanism. An OVA-induced food allergy mouse model was established, and different concentrations of PNE were administrated. Symptoms of food allergy, levels of immunoglobulin E (IgE), mucosal mast cell protease-1 (mMCP-1), and intestine pathological changes were assessed. Additionally, the expressions of T helper (Th) 2, Th17 and regulatory T (Treg)-associated cytokines and the proportion of Th17 and Treg cells in CD4+ T cells were measured. We found PNE attenuated symptoms of food allergy and decreased the levels of IgE and mMCP-1. In PNE group, the infiltration degree of inflammatory cells was ameliorated and the villi of small intestine were more complete. Moreover, the expressions of Th2 and Th17 cell-associated cytokines were down-regulated by PNE pretreatment, while the levels of Treg cell-associated cytokines were up-regulated. PNE decreased the number of Th17 cells, while increased the Tregs cells. PNE treatment dose-dependently improved the Th17/Treg balance. PNE plays a protective role in OVA-induced food allergy through inhibiting Th2 cell response and regulating the Th17/Treg balance.
Assuntos
Antialérgicos/farmacologia , Hipersensibilidade Alimentar/prevenção & controle , Piper nigrum/química , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Citocinas/metabolismo , Feminino , Imunoglobulina E/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina , Linfócitos T Reguladores/metabolismo , Células Th17/imunologia , Células Th2/imunologiaRESUMO
Lipid oxidation products generated during meat digestion may contribute to the apparent epidemiological link between red meat intake and the risk of cardiovascular diseases and colorectal cancer. The aim of this work was to assess the lipid oxidation inhibitory activity of black, green, and pink pepper during cooking and in vitro digestion of meat. Peppers were characterized for their phenolic profiles by LC-ESI-MS and the antioxidant properties. Pink pepper showed the highest phenolic content and antioxidant activities. Then, the peppers were added to meat either before or after cooking, and the meat was subjected to in vitro digestion. Pink pepper added before cooking was the most effective, with an inhibition of 80% and 72% in lipid hydroperoxides and TBA-RS formation after digestion, respectively. These findings suggest that peppers, particularly pink pepper, can be used to minimize lipid oxidation in the gastro-intestinal tract and for the design of healthy dietary patterns.
Assuntos
Culinária , Digestão , Peroxidação de Lipídeos , Carne/análise , Piper nigrum/química , Animais , Antioxidantes , Cor , Humanos , Fenóis/análiseRESUMO
SCOPE: Processed meat intake has been associated with adverse health outcomes. However, little is known about the type of processed meat more particularly responsible for these effects. This study aims to identify novel biomarkers for processed meat intake. METHODS AND RESULTS: In a controlled randomized cross-over dietary intervention study, 12 healthy volunteers consume different processed and non-processed meats for 3 consecutive days each. Metabolomics analyses are applied on post-intervention fasting blood and urine samples to identify discriminating molecular features of processed meat intake. Nine and five pepper alkaloid metabolites, including piperine, are identified as major discriminants of salami intake in urine and plasma, respectively. The associations with processed meat intake are tested for replication in a cross-sectional study (n = 418) embedded within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Three of the serum metabolites including piperine are associated with habitual intake of sausages and to a lesser extent of total processed meat. CONCLUSION: Pepper alkaloids are major discriminants of intake for sausages that contain high levels of pepper used as ingredient. Further work is needed to assess if pepper alkaloids in combination with other metabolites may serve as biomarkers of processed meat intake.
Assuntos
Alcaloides/sangue , Alcaloides/urina , Carne , Piper nigrum/química , Benzodioxóis/sangue , Benzodioxóis/urina , Estudos Transversais , Feminino , Manipulação de Alimentos , Humanos , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Piperidinas/sangue , Piperidinas/urina , Alcamidas Poli-Insaturadas/sangue , Alcamidas Poli-Insaturadas/urinaRESUMO
In the present study, α-amylase and α-glucosidase inhibitory effect and antioxidant activity of capsaicin and piperine from the ethanolic extract of Capsicum chinense (EECch) and Piper nigrum (EEPn) fruits were investigated. Results revealed that EECch exhibited the highest phenolic (154 mg GAE/100 g of tissue) and flavonoid content (75 mg RtE/100 g of tissue) in comparison with EEPn. The predominant compound detected in EECch and EEPn by GC-EIMS analysis was the capsaicin and piperine, respectively. The capsaicin and piperine showed the highest α-amylase and α-glucosidase inhibitory effect and antioxidant activity rather than extracts. The EEPn (IC50= 216 µg/mL) and piperine (IC50= 105 µg/mL) present a highest α-amylase inhibitory effect, while the EECch (IC50= 225 µg/mL) and capsaicin (IC50= 117 µg/mL) showed highest anti-α-glucosidase activity. Molecular docking established that capsaicin and piperine bind at the α-glucosidase and α-amylase through hydrophobic interactions, hydrogen bond, and charge interactions with amino acid residues. The enzyme inhibitory activity and antioxidant properties exhibited by EECch and EEPn could be attributed to the capsaicin and piperine content and other compounds present such as phenolic compounds and flavonoids. These fruits are potential sources of natural antioxidant agents and α-amylase and α-glucosidase inhibitors.
Assuntos
Alcaloides/farmacologia , Benzodioxóis/farmacologia , Capsaicina/farmacologia , Capsicum/química , Inibidores Enzimáticos/farmacologia , Piper nigrum/química , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , alfa-Amilases/antagonistas & inibidores , Frutas/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Extratos Vegetais/químicaRESUMO
The persistent activation of intestinal mechanistic target of rapamycin complex 1 (mTORC1) triggered by mucosal stress has been linked to deregulation of the gut immune response resulting in intestinal inflammation and cell death. The present study investigated the regulatory properties of food-derived mTORC1 modulators, curcumin, and piperine, toward the polarization of stimulated macrophages and the differentiation of monocytes at two mTORC1 activity levels (baseline and elevated). To that end, we created stable human THP-1 monocytes exhibiting normal or constitutively active mTORC1. Curcumin or its combination with piperine, but not piperine alone, suppressed mTORC1 kinase activity, curtailed lipopolysaccharide-mediated inflammatory response of THP-1 macrophages, and repressed macrophage activation by inhibiting signaling pathways involved in M1 (mTORC1) and M2 (mTORC2 and cAMP response element binding protein) polarization. The effects of piperine in the curcumin/piperine combination were modest overall, indicating it was curcumin that modulated differentiating monocytes into acquiring a M0 macrophage phenotype characterized by low inflammatory cytokine output.