RESUMO
Potassium channels have recently emerged as suitable target for the treatment of epileptic diseases. Among potassium channels, KCNT1 channels are the most widely characterized as responsible for several epileptic and developmental encephalopathies. Nevertheless, the medicinal chemistry of KCNT1 blockers is underdeveloped so far. In the present review, we describe and analyse the papers addressing the issue of KCNT1 blockers' development and identification, also evidencing the pros and the cons of the scientific approaches therein described. After a short introduction describing the epileptic diseases and the structure-function of potassium channels, we provide an extensive overview of the chemotypes described so far as KCNT1 blockers, and the scientific approaches used for their identification.
Assuntos
Química Farmacêutica , Epilepsia , Bloqueadores dos Canais de Potássio , Humanos , Bloqueadores dos Canais de Potássio/química , Bloqueadores dos Canais de Potássio/uso terapêutico , Bloqueadores dos Canais de Potássio/farmacologia , Química Farmacêutica/métodos , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Relação Estrutura-Atividade , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Canais de Potássio de Domínios Poros em Tandem/antagonistas & inibidores , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Canais de Potássio de Domínios Poros em Tandem/química , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Canais de Potássio Ativados por SódioRESUMO
Films and fibers of syndiotactic polystyrene (sPS), being amorphous or exhibiting nanoporous crystalline (NC) or dense crystalline phases, were loaded with salicylic acid (SA), a relevant non-volatile antimicrobial molecule. In the first section of the paper, sPS/SA co-crystalline (CC) δ form is characterized, mainly by wide angle X-ray diffraction (WAXD) patterns and polarized Fourier transform infrared (FTIR) spectra. The formation of sPS/SA δ CC phases allows the preparation of sPS fibers even with a high content of the antibacterial guest, which is also retained after repeated washing procedures at 65 °C. A preparation procedure starting from amorphous fibers is particularly appropriate because involves a direct formation of the CC δ form and a simultaneous axial orientation. The possibility of tuning drug amount and release kinetics, by simply selecting suitable crystalline phases of a commercially available polymer, makes sPS fibers possibly useful for many applications. In particular, fibers with δ CC forms, which retain SA molecules in their crystalline phases, could be useful for antimicrobial textiles and fabrics. Fibers with the dense γ form which easily release SA molecules, because they are only included in their amorphous phases, could be used for promising SA-based preparations for antibacterial purposes in food processing and preservation and public health. Finally, using a cell-based assay system and antibacterial tests, we investigated the cellular activity, toxicity and antimicrobial properties of amorphous, δ CC forms and dense γ form of sPS fibers loaded with different contents of SA.
Assuntos
Poliestirenos , Ácido Salicílico , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Poliestirenos/química , Difração de Raios X , Antibacterianos/farmacologiaRESUMO
The endoplasmic reticulum (ER) is a dynamic structure, playing multiple roles including calcium storage, protein synthesis and lipid metabolism. During cellular stress, variations in ER homeostasis and its functioning occur. This condition is referred as ER stress and generates a cascade of signaling events termed unfolded protein response (UPR), activated as adaptative response to mitigate the ER stress condition. In this regard, calcium levels play a pivotal role in ER homeostasis and therefore in cell fate regulation since calcium signaling is implicated in a plethora of physiological processes, but also in disease conditions such as neurodegeneration, cancer and metabolic disorders. A large body of emerging evidence highlighted the functional role of TRP channels and their ability to promote cell survival or death depending on endoplasmic reticulum stress resolution, making them an attractive target. Thus, in this review we focused on the TRP channels' correlation to UPR-mediated ER stress in disease pathogenesis, providing an overview of their implication in the activation of this cellular response.
Assuntos
Cálcio , Estresse do Retículo Endoplasmático , Cálcio/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Resposta a Proteínas não Dobradas , Retículo Endoplasmático/metabolismo , Sinalização do CálcioRESUMO
Transient receptor potential melastatin type 8 (TRPM8) is a target for the treatment of different physio-pathological processes. While TRPM8 antagonists are reported as potential drugs for pain, cancer, and inflammation, to date only a limited number of chemotypes have been investigated and thus a limited number of compounds have reached clinical trials. Hence there is high value in searching for new TRPM8 antagonistic to broaden clues to structure-activity relationships, improve pharmacological properties and explore underlying molecular mechanisms. To address this, the EDASA Scientific in-house molecular library has been screened in silico, leading to identifying twenty-one potentially antagonist compounds of TRPM8. Calcium fluorometric assays were used to validate the in-silico hypothesis and assess compound selectivity. Four compounds were identified as selective TRPM8 antagonists, of which two were dual-acting TRPM8/TRPV1 modulators. The most potent TRPM8 antagonists (BB 0322703 and BB 0322720) underwent molecular modelling studies to highlight key structural features responsible for drug-protein interaction. The two compounds were also investigated by patch-clamp assays, confirming low micromolar potencies. The most potent compound (BB 0322703, IC50 1.25 ± 0.26 µM) was then profiled in vivo in a cold allodinya model, showing pharmacological efficacy at 30 µM dose. The new chemotypes identified showed remarkable pharmacological properties paving the way to further investigations for drug discovery and pharmacological purposes.
Assuntos
Canais de Cátion TRPM/antagonistas & inibidores , Animais , Descoberta de Drogas/métodos , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Relação Estrutura-AtividadeRESUMO
Different molecular mechanisms contribute to the development of multidrug resistance in cancer, including increased drug efflux, enhanced cellular repair mechanisms and alterations of drug metabolism or drug targets. ABCG2 is a member of the ATP-binding cassette superfamily transporters that promotes drug efflux, inducing chemotherapeutic resistance in malignant cells. In this context, the development of selective ABCG2 inhibitors might be a suitable strategy to improve chemotherapy efficacy. Thus, through a multidisciplinary approach, we identified a new ABCG2 selective inhibitor (8), highlighting its ability to increase mitoxantrone cytotoxicity in both hepatocellular carcinoma (EC50from 8.67 ± 2.65 to 1.25 ± 0.80 µM) and transfected breast cancer cell lines (EC50from 9.92 ± 2.32 to 2.45 ± 1.40 µM). Moreover, mitoxantrone co-administration in both transfected and non-transfected HEK293 revealed that compound 8 notably lowered the mitoxantrone EC50, demonstrating its efficacy along with the importance of the ABCG2 extrusion pump overexpression in MDR reversion. These results were corroborated by evaluating the effect of inhibitor 8 on mitoxantrone cell uptake in multicellular tumor spheroids and via proteomic experiments.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Antineoplásicos , Neoplasias , Humanos , Antineoplásicos/química , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Células HEK293 , Mitoxantrona/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , ProteômicaRESUMO
BACKGROUND: Transient Receptor Potential Melastatin-8 (TRPM8) is a non-selective cation channel activated by cold temperature and by cooling agents. Several studies have proved that this channel is involved in pain perception. Although some studies indicate that TRPM8 inhibition is necessary to reduce acute and chronic pain, it is also reported that TRPM8 activation produces analgesia. These conflicting results could be explained by extracellular Ca2+-dependent desensitization that is induced by an excessive activation. Likely, this effect is due to phosphatidylinositol 4,5-bisphosphate (PIP2) depletion that leads to modification of TRPM8 channel activity, shifting voltage dependence towards more positive potentials. This phenomenon needs further evaluation and confirmation that would allow us to understand better the role of this channel and to develop new therapeutic strategies for controlling pain. EXPERIMENTAL APPROACH: To understand the role of TRPM8 in pain perception, we tested two specific TRPM8-modulating compounds, an antagonist (IGM-18) and an agonist (IGM-5), in either acute or chronic animal pain models using male Sprague-Dawley rats or CD1 mice, after systemic or topical routes of administration. RESULTS: IGM-18 and IGM-5 were fully characterized in vivo. The wet-dog shake test and the body temperature measurements highlighted the antagonist activity of IGM-18 on TRPM8 channels. Moreover, IGM-18 exerted an analgesic effect on formalin-induced orofacial pain and chronic constriction injury-induced neuropathic pain, demonstrating the involvement of TRPM8 channels in these two pain models. Finally, the results were consistent with TRPM8 downregulation by agonist IGM-5, due to its excessive activation. CONCLUSIONS: TRPM8 channels are strongly involved in pain modulation, and their selective antagonist is able to reduce both acute and chronic pain.
Assuntos
Analgésicos , Percepção da Dor/efeitos dos fármacos , Dor , Canais de Cátion TRPM , Analgésicos/química , Analgésicos/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Dor/tratamento farmacológico , Dor/metabolismo , Dor/patologia , Dor/fisiopatologia , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPM/antagonistas & inibidores , Canais de Cátion TRPM/metabolismoRESUMO
Bovine lactoferrin C-lobe is able to prevent both influenza virus hemagglutination and cell infection. In particular, it was demonstrated that the fragment 418SKHSSLDCVLRP429 is a potent antiviral peptide. Therefore, we tried to increase the stability of this fragment through side-chain lactam cyclization of the peptide, S[KHSSLD]CVLRP (1). However, classic strategy involving solid-supported cyclization of the linear precursor, containing orthogonal allyl/alloc-based protection for the key amino and carboxyl residues, did not provide the desired cyclic peptide. Here, we report the identification of problematic stretches during the sequence assembly process and the optimization of the different parameters involved in the construction of 1. Results indicated a significant influence of ß-protecting group of both aspartic acid and adjacent cysteine residues on the formation of side products. Therefore, the identification of suitable ß-protecting groups of these residues allowed us to optimize the synthesis of designed lactam-bridged cyclic peptide.
Assuntos
Lactamas/química , Lactoferrina/síntese química , Peptídeos Cíclicos/química , Animais , Ácido Aspártico/química , Bovinos , Ciclização , Cisteína/química , Lactoferrina/químicaRESUMO
Humulus lupulus L. (hop) is highly interesting from a nutraceutical perspective. The hop phytocomplex contains a wide range of bioactive metabolites, and its characterization is challenging. To tackle such a task, for the first time we applied and compared a combined approach consisting of online comprehensive two-dimensional liquid chromatography with tandem mass spectrometry and direct infusion Fourier transform ion cyclotron mass spectrometry. A reversed phase × reversed phase approach with a shifted gradient in the second dimension ensured selectivity and two-dimensional space coverage. Hyphenation with an ion trap time-of-flight analyzer led to the identification of 83 compounds in 70 min, comprising a novel quercetin derivative and six unknown bitter acids. On the other hand, the direct infusion method was able to identify 40 analytes (except isomers) with high mass accuracy (≤ 0.1 ppm) in less than 1 min analysis time. The developed approach can be used in a complementary way, combining the separation capability and high informative spectra of two-dimensional liquid chromatography tandem mass spectrometry with the ultra-high mass accuracy of direct infusion, for potential compound discovery or the accurate profiling of bioactive compounds in different hop cultivars as well as for monitoring processing and storage of hop-based products.
Assuntos
Humulus/química , Internet , Extratos Vegetais/análise , Quercetina/análise , Cromatografia Líquida , Espectrometria de Massas , Estrutura Molecular , Espectrometria de Massas em TandemRESUMO
Arthrospira platensis, better known as Spirulina, is one of the most important microalgae species. This cyanobacterium possesses a rich metabolite pattern, including high amounts of natural pigments. In this study, we applied a combined strategy based on Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FT-ICR-MS) and Ultra High-Performance Liquid Chromatography (UHPLC) for the qualitative/quantitative characterization of Spirulina pigments in three different commercial dietary supplements. FT-ICR was employed to elucidate the qualitative profile of Spirulina pigments, in both direct infusion mode (DIMS) and coupled to UHPLC. DIMS showed to be a very fast (4 min) and accurate (mass accuracy ≤ 0.01 ppm) tool. 51 pigments were tentatively identified. The profile revealed different classes, such as carotenes, xanthophylls and chlorophylls. Moreover, the antioxidant evaluation of the major compounds was assessed by pre-column reaction with the DPPH radical followed by fast UHPLC-PDA separation, highlighting the contribution of single analytes to the antioxidant potential of the entire pigment fraction. ß-carotene, diadinoxanthin and diatoxanthin showed the highest scavenging activity. The method took 40 min per sample, comprising reaction. This strategy could represent a valid tool for the fast and comprehensive characterization of Spirulina pigments in dietary supplements, as well as in other microalgae-based products.
Assuntos
Antioxidantes/química , Suplementos Nutricionais , Pigmentos Biológicos/química , Spirulina/química , Cromatografia Líquida de Alta Pressão , Radicais Livres/antagonistas & inibidores , Concentração Inibidora 50 , Espectrometria de MassasRESUMO
An acid- and oxidant-promoted intramolecular cyclization of a tetrahydro-ß-carboline-based dipeptide has been developed to prepare new indole-fused aminoacetals. This approach involves N-acyliminium formation from readily available precursors and cyclization under mild reaction conditions. The diastereoselectivity in the formation of the products is influenced by the specific substituents of the starting reagents, which has been rationalized analyzing the energy profile of the related reactions and the relative stability of the proposed structures based on DFT computational methods.
RESUMO
The p53-MDM2 interaction is a well-known protein-protein contact, and its disruption is a key event for p53 activation and induction of its oncosuppressor response. The design of small molecules that can block the p53-MDM2 interaction and reactivate the p53 function is a promising strategy for cancer therapy. To date, several compounds have been identified as p53-MDM2 inhibitors, and X-ray structures of MDM2 complexed with several ligands are available in the Brookhaven Protein Data Bank. These data have been exploited to compile a hierarchical virtual screening protocol. The first steps were aimed at selecting a focused library, which was submitted in parallel to docking and pharmacophore model alignment. Selected compounds were subjected to inhibition assays of both cellular vitality (MTT) and p53-MDM2 interaction (ELISA and co-immunoprecipitation), disclosing four nanomolar inhibitors.
Assuntos
Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Humanos , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica/efeitos dos fármacos , Conformação Proteica em alfa-Hélice , Proteínas Proto-Oncogênicas c-mdm2/química , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/química , Interface Usuário-ComputadorRESUMO
G protein-coupled receptor kinase 2 (GRK2) plays a central role in the cellular transduction network. In particular, during chronic heart failure GRK2 is upregulated and believed to contribute to disease progression. Thereby, its inhibition offers a potential therapeutic solution to several pathological conditions. In the present study, we performed a SAR study and a NMR conformational analysis of peptides derived from HJ loop of GRK2 and able to selectively inhibit GRK2. From Ala-scan and D-Ala point replacement, we found that Arg residues don't affect the inhibitory properties, while a D-amino acid at position 5 is key to the activity. Conformational analysis identified two ß-turns that involve N-terminal residues, followed by a short extended region. These information can help the design of peptides and peptido-mimetics with enhanced GRK2 inhibition properties.
Assuntos
Quinase 2 de Receptor Acoplado a Proteína G , Peptídeos , Peptídeos/metabolismo , Fosforilação , Estrutura Secundária de ProteínaRESUMO
Gain-of-function (GoF) variants in KCNT1 channels cause severe, drug-resistant forms of epilepsy. Quinidine is a known KCNT1 blocker, but its clinical use is limited due to severe drawbacks. To identify novel KCNT1 blockers, a homology model of human KCNT1 was built and used to screen an in-house library of compounds. Among the 20 molecules selected, five (CPK4, 13, 16, 18, and 20) showed strong KCNT1-blocking ability in an in vitro fluorescence-based assay. Patch-clamp experiments confirmed a higher KCNT1-blocking potency of these compounds when compared to quinidine, and their selectivity for KCNT1 over hERG and Kv7.2 channels. Among identified molecules, CPK20 displayed the highest metabolic stability; this compound also blocked KCNT2 currents, although with a lower potency, and counteracted GoF effects prompted by 2 recurrent epilepsy-causing KCNT1 variants (G288S and A934T). The present results provide solid rational basis for future design of novel compounds to counteract KCNT1-related neurological disorders.
Assuntos
Epilepsia , Humanos , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/química , Animais , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/genética , Relação Estrutura-Atividade , Células HEK293 , Simulação por Computador , Canais de Potássio Ativados por SódioRESUMO
In this paper we present the design, synthesis, and biological evaluation of a new series of peptidomimetics acting as potent anti-SARS-CoV-2 agents. Starting from our previously described Main Protease (MPro) and Papain Like Protease (PLPro) dual inhibitor, CV11, here we disclose its high inhibitory activity against cathepsin L (CTSL) (IC50 = 19.80 ± 4.44 nM), an emerging target in SARS-CoV-2 infection machinery. An in silico design, inspired by the structure of CV11, led to the development of a library of peptidomimetics showing interesting activities against CTSL and Mpro, allowing us to trace the chemical requirements for the binding to both enzymes. The screening in Vero cells infected with 5 different SARS-CoV-2 variants of concerns, highlighted sub-micromolar activities for most of the synthesized compounds (13, 15, 16, 17 and 31) in agreement with the enzymatic inhibition assays results. The compounds showed lack of activity against several different RNA viruses except for the 229E and OC43 human coronavirus strains, also characterized by a cathepsin-L dependent release into the host cells. The most promising derivatives were also evaluated for their chemical and metabolic in-vitro stability, with derivatives 15 and 17 showing a suitable profile for further preclinical characterization.
Assuntos
COVID-19 , Peptidomiméticos , Chlorocebus aethiops , Humanos , Animais , Catepsina L , SARS-CoV-2 , Peptidomiméticos/farmacologia , Inibidores de Proteases/farmacologia , Células Vero , Peptídeo Hidrolases , Antivirais/farmacologia , Simulação de Acoplamento MolecularRESUMO
Haspin is an emerging, but rather unexplored, divergent kinase involved in tumor growth by regulating the mitotic phase. In this paper, the in-silico design, synthesis, and biological characterization of a new series of substituted indoles acting as potent Haspin inhibitors are reported. The synthesized derivatives have been evaluated by FRET analysis, showing very potent Haspin inhibition. Then, a comprehensive in-cell investigation highlighted compounds 47 and 60 as the most promising inhibitors. These compounds were challenged for their synergic activity with paclitaxel in 2D and 3D cellular models, demonstrating a twofold improvement of the paclitaxel antitumor activity. Compound 60 also showed remarkable selectivity when tested in a panel of 70 diverse kinases. Finally, in-silico studies provided new insight about the chemical requirements useful to develop new Haspin inhibitors. Biological results, together with the drug-likeness profile of 47 and 60, make these derivatives deserving further studies.
Assuntos
Indóis , Indóis/farmacologia , Indóis/química , Indóis/síntese química , Humanos , Relação Estrutura-Atividade , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Paclitaxel/farmacologia , Paclitaxel/química , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
The cannabinoid system is one of the most investigated neuromodulatory systems because of its involvement in multiple pathologies such as cancer, inflammation, and psychiatric diseases. Recently, the CB2 receptor has gained increased attention considering its crucial role in modulating neuroinflammation in several pathological conditions like neurodegenerative diseases. Here we describe the rational design of pyrrole-based analogues, which led to a potent and pharmacokinetically suitable CB2 full agonist particularly effective in improving cognitive functions in a scopolamine-induced amnesia murine model. Therefore, we extended our study by investigating the interconnection between CB2 activation and neurotransmission in this experimental paradigm. To this purpose, we performed a MALDI imaging analysis on mice brains, observing that the administration of our lead compound was able to revert the effect of scopolamine on different neurotransmitter tones, such as acetylcholine, serotonin, and GABA, shedding light on important networks not fully explored, so far.
Assuntos
Canabinoides , Receptor CB2 de Canabinoide , Camundongos , Animais , Pirróis/farmacologia , Canabinoides/farmacologia , Neurotransmissores/farmacologia , Derivados da Escopolamina , Agonistas de Receptores de Canabinoides/farmacologia , Receptor CB1 de CanabinoideRESUMO
It is well known that resveratrol (RSV) displayed cancer-preventing and anticancer properties but its clinical application is limited because of a low bioavailability and a rapid clearance from the circulation. Aim of this work was to synthesize pharmacologically active resveratrol analogs with an enhanced structural rigidity and bioavailability. In particular, we have synthesized a library of 2,3-thiazolidin-4-one derivatives in which a thiazolidinone nucleus connects two aromatic rings. Some of these compounds showed strong inhibitory effects on breast cancer cell growth. Our results indicate that some of thiazolidin-based resveratrol derivatives may become a new potent alternative tool for the treatment of human breast cancer.
Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Estilbenos/química , Estilbenos/farmacologia , Tiazolidinedionas/química , Tiazolidinedionas/farmacologia , Antineoplásicos Fitogênicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Resveratrol , Estilbenos/síntese química , Tiazolidinedionas/síntese químicaRESUMO
Resveratrol (3,4',5 tri-hydroxystilbene), a natural plant polyphenol, has gained interest as a non-toxic agent capable of inducing tumor cell death in a variety of cancer types. However, therapeutic application of these beneficial effects remains very limited due to its short biological half-life, labile properties, rapid metabolism and elimination. Different studies were undertaken to obtain synthetic analogs of resveratrol with major bioavailability and anticancer activity. We have synthesized a series 3-chloro-azetidin-2-one derivatives, in which an azetidinone nucleus connects two aromatic rings. Aim of the present study was to investigate the effects of these new 3-chloro-azetidin-2-one resveratrol derivatives on human breast cancer cell lines proliferation. Our results indicate that some azetidin-based resveratrol derivatives may become new potent alternative tools for the treatment of human breast cancer.
Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Azetidinas/química , Azetidinas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Estilbenos/química , Estilbenos/farmacologia , Células 3T3 , Animais , Azetidinas/síntese química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Camundongos , Resveratrol , Estilbenos/síntese químicaRESUMO
Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are the most common causes of chronic liver disease and are increasingly emerging as a global health problem. Such disorders can lead to liver damage, resulting in the release of pro-inflammatory cytokines and the activation of infiltrating immune cells. These are some of the common features of ALD progression in ASH (alcoholic steatohepatitis) and NAFLD to NASH (non-alcoholic steatohepatitis). Hepatic steatosis, followed by fibrosis, lead to a continuous progression accompanied by angiogenesis. This process creates hypoxia, which activates vascular factors, initiating pathological angiogenesis and further fibrosis. This forms a vicious cycle of ongoing damage and progression. This condition further exacerbates liver injury and may contribute to the development of comorbidities, such as metabolic syndrome as well as hepatocellular carcinoma. Increasing evidence suggests that anti-angiogenic therapy may have beneficial effects on these hepatic disorders and their exacerbation. Therefore, there is a great interest to deepen the knowledge of the molecular mechanisms of natural anti-angiogenic products that could both prevent and control liver diseases. In this review, we focus on the role of major natural anti-angiogenic compounds against steatohepatitis and determine their potential therapeutic benefits in the treatment of liver inflammation caused by an imbalanced diet.
Assuntos
Hepatopatias Alcoólicas , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Fígado/metabolismo , Fibrose , Hepatopatias Alcoólicas/metabolismo , Dieta Hiperlipídica , Neoplasias Hepáticas/metabolismo , Inflamação/metabolismoRESUMO
Acute pancreatitis (AP) is a potentially life-threatening illness characterized by an exacerbated inflammatory response with limited options for pharmacological treatment. Here, we describe the rational development of a library of soluble epoxide hydrolase (sEH) inhibitors for the treatment of AP. Synthesized compounds were screened in vitro for their sEH inhibitory potency and selectivity, and the results were rationalized by means of molecular modeling studies. The most potent compounds were studied in vitro for their pharmacokinetic profile, where compound 28 emerged as a promising lead. In fact, compound 28 demonstrated a remarkable in vivo efficacy in reducing the inflammatory damage in cerulein-induced AP in mice. Targeted metabololipidomic analysis further substantiated sEH inhibition as a molecular mechanism of the compound underlying anti-AP activity in vivo. Finally, pharmacokinetic assessment demonstrated a suitable profile of 28 in vivo. Collectively, compound 28 displays strong effectiveness as sEH inhibitor with potential for pharmacological AP treatment.