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The interaction potential of Cynara scolymus L., Mikania glomerata Spreng.,Rhamnus purshiana DC and Uncaria tomentosa (Willd. Ex Roem. & Schult.) with conventional drugs metabolized by the CYP3A4 metabolic route was tested in HeLa cell lines, using the in vitro model of the hPXR. The herbal medicines C. scolymus (1.5 mg/mL dry extract) did not affect the receptor. On the other hand, M. glomerata (5.5 mg/mL dry extract), R. purshiana (1.5 mg/mL dry extract), and U. tomentosa (2.0 mg/mL dry extract) showed to be hPXR agonist, suggesting a potential interaction with the conventional drugs metabolized by the same isoforms of the CYP superfamily. The results from this study contribute to the use safer and more effective of these herbal medicines.
Se evaluó el potencial de interacción de Cynara scolymus L., Mikania glomerata Spreng., Rhamnus purshiana DC y Uncaria tomentosa (Willd. Ex Roem. & Schult.) con fármacos convencionales metabolizados por la ruta metabólica CYP3A4 en líneas celulares HeLa, utilizando el modelo in vitro del hPXR. Las hierbas medicinales C. scolymus (1,5 mg/mL de extracto seco) no afectaron al receptor. Por otro lado, M. glomerata (5.5 mg/mL de extracto seco), R. purshiana (1.5 mg/mL de extracto seco) y U. tomentosa (2.0 mg/mL de extracto seco) mostraron ser agonistas de hPXR, lo que sugiere una potencial interacción con los fármacos convencionales metabolizados por las mismas isoformas de la superfamilia CYP. Los resultados de este estudio contribuyen a un uso más seguro y eficaz de estos medicamentos a base de hierbas medicinales.
Assuntos
Rhamnus , Unha-de-Gato , Cynara scolymus , Mikania , Interações Ervas-Drogas , Plantas Medicinais , Técnicas In Vitro , Indutores do Citocromo P-450 CYP3A/químicaRESUMO
Mandevilla Lindl. is an important genus of the Apocynaceae family, not only as ornamental plants but also for its medicinal uses. In Brazil, Mandevilla species are indicated to treat asthma and skin infections, their anti-inflammatory potential and wound healing properties are also reported in the literature. Concerning their chemical composition, this group of plants is a conspicuous producer of pregnane glycosides. Mandevilla dardanoi is an endemic species from the Brazilian semiarid region not studied by any phytochemical methods. In view of the medicinal potential of Mandevilla species, this study aimed to isolate new pregnane glycosides from M. dardanoi. To achieve this main goal, modern chromatography techniques were employed. Five new pregnane glycosides, dardanols A-E, were isolated from the roots of M. dardanoi by HPLC. Their structures were determined using extensive 1D and 2D-NMR and mass spectrometry (MSn and HRESIMS) data. The cytotoxicity and the anti-inflammatory potential of these compounds were evaluated. The first was evaluated by measuring proinflammatory cytokines and nitric oxide production by stimulated macrophages. Dardanols were able to inhibit the production of nitric oxide and reduce IL-1ß and TNF-α. The current work demonstrates the chemodiversity of Brazilian semiarid species and contributes to amplifying knowledge about the biological potential of the Mandevilla genus.
Assuntos
Apocynaceae , Óxido Nítrico , Anti-Inflamatórios/farmacologia , Apocynaceae/química , Glicosídeos/química , Glicosídeos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Plantas , Pregnanos/química , Pregnanos/farmacologia , Fator de Necrose Tumoral alfaRESUMO
Pregnanes and pregnane glycosides or their esters are well-studied secondary metabolites, many of them exhibit immunomodulator, anticancer, antidiabetic, antarthritic, antiulcer, anti-nociceptive, hypolipidemic, anti-inflammatory, and antibacterial properties. Pregnane glycosides are widely distributed in the families Apocyanaceae and Asclepiadaceae. Plant members of the genus Caralluma R.Br., Apocynaceae, are among the most studied species because of uses in traditional medicine or as food. They are a rich source of pregnane glycosides, as russelioside B. However, the bioactivity profile of this pregnane glycoside has not been reviewed until now. The present review aims to summarize the most important pharmacological and therapeutic applications of russelioside B with specific emphasis on the mechanism of actions associated with its administration in preclinical models. Russelioside B has many pharmacological effects including antidiabetic, anti-obesity, anti-nociceptive, antiulcer, anti-inflammatory, anti-arthritis effects, and antibiofilm, and wound healing activities. Despite its outstanding pharmacotherapeutic potential, russelioside B has never been tested in clinical trials. This review indicates that russelioside B is a potentially promising bioactive candidate, but further deeper mechanistic studies and clinical trials are needed in the future to elucidate its interaction with receptors of specific genes. Supplementary Information: The online version contains supplementary material available at 10.1007/s43450-022-00245-x.
RESUMO
Pregnane derivatives have been studied mainly for their 5α-reductase activity. However, the anti-inflammatory activities of such compounds are still poorly explored. In the search for new anti-inflammatory agents, seven new pregnane derivatives 6a-g, with cinnamic acid esters at C-3 were prepared and fully characterized. The anti-inflammatory activity of compounds was assessed in TPA induced mice ear model. From them, compound 6 b was the most active to reduce edema, with an ED50 of 0.017 mg/ear. Also, Molecular Docking and Molecular Dynamics studies were performed to identify a potential molecular target related to the inflammatory process. The in vivo results suggest that 6 b could be a potent anti-inflammatory compound, while in silico studies suggest its interaction with some critical enzymes in the inflammatory response.
Assuntos
Anti-Inflamatórios , Edema , Camundongos , Animais , Simulação de Acoplamento Molecular , Anti-Inflamatórios/farmacologia , Edema/tratamento farmacológico , Simulação de Dinâmica Molecular , Pregnanos/uso terapêutico , Relação Estrutura-AtividadeRESUMO
Chlorpyrifos (CPF) is an organophosphate pesticide, commonly detected in water and food. Despite CPF toxicity on aquatic species has been extensively studied, few studies analyze the effects of CPF on fish transcriptional pathways. The Pregnane X receptor (PXR) is a nuclear receptor that is activated by binding to a wide variety of ligands and regulates the transcription of enzymes involved in the metabolism and transport of many endogenous and exogenous compounds. We evaluated the mRNA expression of PXR-regulated-genes (PXR, CYP3A27, CYP2K1, ABCB1, UGT, and ABCC2) in intestine and liver of the rainbow trout, Oncorhynchus mykiss, exposed in vivo to an environmentally relevant CPF concentration. Our results demonstrate that the expression of PXR and PXR-regulated genes is increased in O. mykiss liver and intestine upon exposure to CPF. Additionally, we evaluated the impact of CPF on other cellular pathway involved in xenobiotic metabolism, the Aryl Hydrocarbon Receptor (AhR) pathway, and on the expression and activity of different biotransformation enzymes (CYP2M1, GST, FMO1, or cholinesterases (ChEs)). In contrast to PXR, the expression of AhR, and its target gene CYP1A, are reduced upon CPF exposure. Furthermore, ChE and CYP1A activities are significantly inhibited by CPF, in both the intestine and the liver. CPF activates the PXR pathway in O. mykiss in the intestine and liver, with a more profound effect in the intestine. Likewise, our results support regulatory crosstalk between PXR and AhR pathways, where the induction of PXR coincides with the downregulation of AhR-mediated CYP1A mRNA expression and activity in the intestine.
Assuntos
Clorpirifos , Inseticidas , Oncorhynchus mykiss , Animais , Clorpirifos/toxicidade , Inseticidas/toxicidade , Fígado , Oncorhynchus mykiss/genética , Receptor de Pregnano X/genética , Receptores de Hidrocarboneto Arílico/genéticaRESUMO
La epilepsia es una enfermedad neurológica frecuente que afecta a cerca de 50.000 millones de personas en el mundo. En Chile, la prevalencia estimada es de 10.8 a 17 por 1.000 habitantes. La primera opción para su tratamiento son los fármacos antiepilépticos (FAE) los cuales logran un aceptable control de enfermedad en la mayoría de los casos, sin embargo, tienen la potencialidad de desencadenar una serie de efectos adversos destacando entre ellos el desarrollo de hipocalcemia (HC) secundaria a hipovitaminosis D (HD), alteración que por lo general es leve y asintomática. Presentamos el caso de una mujer perimenopausica con antecedente de epilepsia en tratamiento con anticonvulsivante que desarrolla hipocalcemia severa. Además revisamos los mecanismos descritos a través de los cuales los FAE afectan el metabolismo de esta vitamina.
Epilepsy is a common neurological disease that affects about 50,000 million people in the world. The estimated prevalence is 10.8 to 17 per 1.000 inhabitants in Chile. The first option for its treatment are antiepileptic drugs (AEDs) which achieve an acceptable control of the disease in most cases, however, they have the potential to trigger a series of adverse effects (AE) highlighting among them the development of hypocalcemia (HC) secondary to hypovitaminosis D (HD), an alteration that is generally mild and asymptomatic. We present the case of a perimenopausal woman with a history of epilepsy under treatment with an anticonvulsant who develops severe hypocalcemia. We also review the mechanisms described through which AEDs affect the metabolism of this vitamin.
Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/induzido quimicamente , Epilepsia/tratamento farmacológico , Anticonvulsivantes/efeitos adversos , Vitamina D/metabolismo , Epilepsia/metabolismo , Hipercalcemia/etiologiaRESUMO
Allopregnanolone (3α,5α-tetrahydroprogesterone; pharmaceutical formulation: brexanolone) is a neurosteroid that has recently been approved for the treatment of postpartum depression, promising to fill part of a long-lasting gap in the effectiveness of pharmacotherapies for depressive disorders. In this review, we explore the experimental research that characterized the antidepressant-like effects of allopregnanolone, with a particular focus on the neurotrophic adaptations induced by this neurosteroid in preclinical studies. We demonstrate that there is a consistent decrease in allopregnanolone levels in limbic brain areas in rodents submitted to stress-induced models of depression, such as social isolation and chronic unpredictable stress. Further, both the drug-induced upregulation of allopregnanolone or its direct administration reduce depressive-like behaviors in models such as the forced swim test. The main drugs of interest that upregulate allopregnanolone levels are selective serotonin reuptake inhibitors (SSRIs), which present the neurosteroidogenic property even in lower, non-SSRI doses. Finally, we explore how these antidepressant-like behaviors are related to neurogenesis, particularly in the hippocampus. The protagonist in this mechanism is likely the brain-derived neurotrophic factor (BFNF), which is decreased in animal models of depression and may be restored by the normalization of allopregnanolone levels. The role of an interaction between GABA and the neurotrophic mechanisms needs to be further investigated.
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Currently one of the problems facing global development is the availability of water. Although water is abundant the planet only a small portion is for human use and consumption. The problem is exacerbated due to different factors, mainly: meteorological phenomena, the presence of contaminants in the water and the increase in the number of inhabitants. Potential effects of pollutants not only can affect freshwater biota but also can be implicated in cancer development and neurodegenerative diseases in humans. The study was conducted in the Madín Dam, a reservoir of economic importance for the geographical area in which it is located, as well as catering to the population of nearby areas, and is a place where recreational activities such as fishing and kayaking are carried out. The aim of this study was to identify the toxic effects that the pollutants present in the water of the Madín Dam can generate on a human cell line (SH SY5Y) evaluating the cell viability and the participation of the Aril Hydrocarbon Receptor (AhR) and Pregnane X receptor (PXR) through of the expression of the CYP1A1 and CYP3A4 (canonical genes). In one of the five sites analyzed, cell viability was up to 50%, in this site a decrease in the normal expression of CYP1A1 was observed (pâ¯<â¯0.05) and the CYP3A4 gene was not expressed in the cells SH SY5Y. These results show that the SH SY5Y cell line is a good biomarker for assessing the human toxicity of environmental pollutants and relating it to neurodegenerative diseases.
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Citocromo P-450 CYP1A1/metabolismo , Linhagem Celular Tumoral , Poluentes Ambientais , Humanos , México , Receptores de Hidrocarboneto ArílicoRESUMO
Considerable progress has been made in learning about the physiology and biochemistry of the sebaceous glands and several of the diseases that affect this component of the skin. Of these diseases, acne has particular importance. It is associated with adolescence, and because of the hormonal changes that take place in this stage, when it is severe it can cause depression. Moreover, in a considerable proportion of acne sufferers both adolescent and adult, it can produce tumors and deformation of the sebaceous glands. This seriously affects the sufferers to the point where it may limit their professional activities because they do not want to be seen in public. Several important issues from classic studies on the sebaceous gland will be reviewed in this document to report the state of the art of current treatments for the pathology of these glands. The sebaceous gland is an intracrine organ, capable of synthesizing and metabolizing different steroidal hormones. The role of each of the enzymes involved in these processes of the skin will be analyzed. The presence of different hormone receptors in the scientific literature will be also reviewed, due to the role of the sebaceous gland in lipogenesis at different ages. We also describe the mechanism of action of androgens and progestins in relation to coregulators recruited for lipogenesis in this gland. We propose several new steroidal compounds based on their mechanism of action to block lipogenesis in the sebaceous glands. These molecules offer potential for new treatment options for skin diseases.
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Acne Vulgar/metabolismo , Glândulas Sebáceas/metabolismo , Sebo/metabolismo , Esteroides/biossíntese , Acne Vulgar/complicações , Acne Vulgar/psicologia , Adolescente , Adulto , Animais , Vias Biossintéticas , Depressão/etiologia , Depressão/metabolismo , Feminino , Humanos , Lipogênese , Masculino , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/metabolismoRESUMO
The multidrug resistance-associated protein 2 (MRP2/ABCC2) is a transporter that belongs to the ATP-binding cassette (ABC) superfamily. In the intestine, it is localized to the apical membrane of the enterocyte and plays a key role in limiting the absorption of xenobiotics incorporated orally. MRP2 may also play a role in systemic clearance of xenobiotics available from the serosal side of the intestine. MRP2 transports a wide range of substrates, mainly organic anions conjugated with glucuronic acid, glutathione and sulfate and its expression can be modulated by xenobiotics at transcriptional- and post-transcriptional levels. Transcriptional regulation is usually mediated by a group of nuclear receptors. The pregnane X receptor (PXR) is a major member of this group. Relevant drugs described to up-regulate intestinal MRP2 via PXR are rifampicin, spironolactone and carbamazepine, among others. The constitutive androstane receptor (CAR, NR1I3) was also reported to modulate MRP2 expression, phenobarbital being a typical activator. Dietary compounds, including micronutrients and other natural products, are also capable of regulating intestinal MRP2 expression transcriptionally. We have given them particular attention since the composition of the food ingested daily is not necessarily supervised and may result in interactions with therapeutic drugs. Post-transcriptional regulation of MRP2 activity by xenobiotics, e.g. as a consequence of inhibitory actions, is also described in this review. Unfortunately, only few studies report on drug-drug or nutrient-drug interactions as a consequence of modulation of intestinal MRP2 activity by xenobiotics. Future clinical studies are expected to identify additional interactions resulting in changes in efficacy or safety of therapeutic drugs.
Assuntos
Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Xenobióticos/farmacologia , Animais , Receptor Constitutivo de Androstano , Humanos , Mucosa Intestinal/metabolismo , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/químicaRESUMO
Pregnane derivatives are studied as agents for the treatment of different hormone-dependent diseases. The biological importance of these steroids is based on their potential use against cancer. In this study, we report the synthesis, characterization and biological activity of two pregnane derivatives with a triazole (3ß-hydroxy-21-(1H-1,2,4-triazol-1-yl)pregna-5,16-dien-20-one; T-OH) or imidazole (3ß-hydroxy-21-(1H-imidazol-1-yl)pregna-5,16-dien-20-one; I-OH) moieties at C-21. These derivatives were synthesized from 16-dehydropregnenolone acetate. The activity on cell proliferation of the compounds was measured on three human cancer cells lines: prostate cancer (PC-3), breast cancer (MCF7) and lung cancer (SK-LU-1). The cytotoxic and antiproliferative effects of T-OH and I-OH were assessed by using SBR and XTT methods, respectively. The gene expressions were evaluated by real time PCR. In addition, results were complemented by docking studies and transactivation assays using an expression vector to progesterone and androgen receptor. Results show that the two compounds inhibited the three cell lines proliferation in a dose-dependent manner. Compound I-OH downregulated the gene expression of the cyclins D1 and E1 in PC-3 and MFC7 cells; however, effect upon Ki-67, EAG1, BIM or survivin genes was not observed. Docking studies show poor interaction with the steroid receptors. Nevertheless, the transactivation assays show a weak antagonist effect of I-OH on progesterone receptor but not androgenic or antiandrogenic actions. In conclusion, the synthesized compounds inhibited cell proliferation as well as genes key to cell cycle of PC-3 and MCF7 cell lines. Therefore, these compounds could be considered a good starting point for the development of novel therapeutic alternatives to treat cancer.
Assuntos
Antineoplásicos/síntese química , Imidazóis/síntese química , Pregnadienos/síntese química , Triazóis/síntese química , Antineoplásicos/farmacologia , Apoptose , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Imidazóis/farmacologia , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Pregnadienos/farmacologia , Triazóis/farmacologia , Vitamina D3 24-Hidroxilase/metabolismoRESUMO
The pregnane X receptor (PXR) (nuclear receptor NR1I2) is a ligand activated transcription factor, mediating responses to diverse xenobiotic and endogenous chemicals. The properties of PXR in fish are not fully understood. Here we report on cloning and characterization of full-length PXR of zebrafish, Danio rerio, and pxr expression in vivo. Initial efforts gave a cDNA encoding a 430 amino acid protein identified as zebrafish pxr by phylogenetic and synteny analysis. The sequence of the cloned Pxr DNA binding domain (DBD) was highly conserved, with 74% identity to human PXR-DBD, while the ligand-binding domain (LBD) of the cloned sequence was only 44% identical to human PXR-LBD. Sequence variation among clones in the initial effort prompted sequencing of multiple clones from a single fish. There were two prominent variants, one sequence with S183, Y218 and H383 and the other with I183, C218 and N383, which we designate as alleles pxr*1 (nr1i2*1) and pxr*2 (nr1i2*2), respectively. In COS-7 cells co-transfected with a PXR-responsive reporter gene, the full-length Pxr*1 (the more common variant) was activated by known PXR agonists clotrimazole and pregnenolone 16α-carbonitrile but to a lesser extent than the full-length human PXR. Activation of full-length Pxr*1 was only 10% of that with the Pxr*1 LBD. Quantitative real time PCR analysis showed prominent expression of pxr in liver and eye, as well as brain and intestine of adult zebrafish. The pxr was expressed in heart and kidney at levels similar to that in intestine. The expression of pxr in liver was weakly induced by ligands for mammalian PXR or constitutive androstane receptor (NR1I3). The results establish a foundation for PXR studies in this vertebrate model. PXR allelic variation and the differences between the full-length PXR and the LBD in reporter assays have implications for assessing the action of PXR ligands in zebrafish.