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The present review aims to collect the published literature pertaining the recognition of isobaric compounds (isomers or stereoisomers) using the features of tandem mass spectrometry (MS) experiments without any chromatographic separation or chemical modification (derivatization or isotopic enrichment) of the analytes. MS/MS methods possess high selectivity, wide dynamic range and high throughput capabilities. Generally, tandem MS has limited capability for distinguishing isomers that fragment similarly. However, some MS/MS methods have been developed and positively applied to isomers discrimination. Among the literature on this topic, the applications that fit on the review subject can be summarized as follow: (1) chiral discrimination by the kinetic method, (2) the use energy-resolved tandem mass spectra and the survival yield (SY) representation, (3) the kinetics evaluation of the ion-molecule interaction and (4) the postprocessing mathematical algorithm to resolve the isomers in MS/MS signal.
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Free fatty acids (FFA) have gained research interest owing to their functions in both local and systemic immune regulation. Changes in the serum levels of anti-inflammatory short chain fatty acids (SCFA), primarily derived from the gut microbiota, and pro-inflammatory medium (MCFA) and long (LCFA) chain fatty acids, derived from either the gut microbiota or the diet, have been associated with autoimmunity. Circulating FFA were retrospectively analysed by a gas chromatography-mass spectrometry method in the serum of 18 patients with pemphigus vulgaris (PV) at the baseline and 6 months (n = 10) after immunosuppressive treatments, and 18 healthy controls (HC). Circulating FFA were correlated with the Pemphigus Disease Area Index (PDAI) and serum concentrations of interferon-gamma (IFN-γ), Interleukin (IL)-17A, IL-5, IL-10 and IL-21. Principal Component analysis computed on FFA abundances revealed significant differences in the profile of SCFA (p = 0,012), MCFA (p = 0.00015) and LCFA (p = 0,035) between PV patients and HC, which were not significantly changed by immunosuppressive treatments. PV patients showed a significantly lower serum concentration of propionic (p < 0.0005) and butyric (p < 0.0005) acids, SCFA with anti-inflammatory functions, while hexanoic (p < 0.0005) and hexadecanoic (p = 0.0006) acids, pro-inflammatory MCFA and LCFA respectively, were over-represented. Treatments induced a significant decrease of hexanoic (p = 0.035) and a further increase of hexadecanoic (p = 0.046) acids. Positive correlations emerged between IFN-γ and acetic acid (Rho = 0.60), IFN-γ and hexanoic acid (Rho = 0.46), IL-5 and both hexadecanoic acid (Rho = 0.50) and octadecanoic acid (Rho = 0.53), butyric acid and PDAI (Rho = 0.53). PV was associated with a remarked imbalance of circulating FFA compared to HC. The serum alterations of SCFA, MCFA, and LCFA may contribute to promoting inflammation in PV. Deeper insights into the immunomodulatory functions of these molecules may pave the way for personalized dietary interventions in PV patients.
Assuntos
Pênfigo , Humanos , Ácidos Graxos não Esterificados , Interleucina-5 , Estudos Retrospectivos , Ácidos Graxos , Ácidos Graxos Voláteis , Anti-InflamatóriosRESUMO
PURPOSE: Cough represents a natural mechanism that plays an important defensive role in the respiratory tract, but in some conditions, it may become persistent, nonproductive, and harmful. In general, refractory chronic cough (RCC) occurs in about 20% of individuals; hence, we aimed to assess the presence of altered gut-lung communication in RCC patients through a compositional and functional characterization of both gut (GM) and oral microbiota (OM). METHODS: 16S rRNA sequencing was used to characterize both GM and OM composition of RCC patients and healthy controls (HC). PICRUST2 assessed functional changes in microbial communities while gas chromatography was used to evaluate fecal short-chain fatty acid levels and serum-free fatty acid (FFA) abundances. RESULTS: In comparison with HC, RCC patients reported increased saliva alpha-diversity and statistically significant beta-diversity in both GM and OM. Also, a, respectively, significant increased or reduced Firmicutes/Bacteroidota ratio in stool and saliva samples of RCC patients has been shown, in addition to a modification of the abundances of several taxa in both GM and OM. Moreover, a potential fecal over-expression of lipopolysaccharide biosynthesis and lipoic acid metabolism pathways and several differences in serum FFA levels have been reported in RCC patients than in HC. CONCLUSION: Since differences in both GM and OM of RCC patients have been documented, these findings could provide new information about RCC pathogenesis and also pave the way for the development of novel nutritional or pharmacological interventions for the management of RCC through the restoration of eubiotic gut-lung communication.
Assuntos
Carcinoma de Células Renais , Microbioma Gastrointestinal , Neoplasias Renais , Humanos , Microbioma Gastrointestinal/genética , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/análise , Tosse Crônica , Pulmão/químicaRESUMO
A new series of piperazine derivatives were synthesized and studied with the aim of obtaining dual inhibitors of P-glycoprotein (P-gp) and carbonic anhydrase XII (hCA XII) to synergistically overcome the P-gp-mediated multidrug resistance (MDR) in cancer cells expressing the two proteins, P-gp and hCA XII. Indeed, these hybrid compounds contain both P-gp and hCA XII binding groups on the two nitrogen atoms of the heterocyclic ring. All compounds showed good inhibitory activity on each protein (P-gp and hCA XII) studied individually, and many of them showed a synergistic effect in the resistant HT29/DOX and A549/DOX cell lines which overexpress both the target proteins. In particular, compound 33 displayed the best activity by enhancing the cytotoxicity and intracellular accumulation of doxorubicin in HT29/DOX and A549/DOX cells, thus resulting as promising P-gp-mediated MDR reverser with a synergistic mechanism. Furthermore, compounds 13, 27 and 32 induced collateral sensitivity (CS) in MDR cells, as they were more cytotoxic in resistant cells than in the sensitive ones; their CS mechanisms were extensively investigated.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Inibidores da Anidrase Carbônica , Anidrases Carbônicas , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Piperazinas , Humanos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Piperazinas/farmacologia , Piperazinas/química , Piperazinas/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/síntese química , Anidrases Carbônicas/metabolismo , Doxorrubicina/farmacologia , Doxorrubicina/química , Piperazina/química , Piperazina/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Células HT29 , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Estrutura Molecular , Células A549RESUMO
The tandem mass spectrometry (MS/MS) approach employing an ion trap mass analyzer (IT) was evaluated in isomers recognition. The proposed approach consists of sole, simple, and rapid liquid chromatographic separation (HPLC) without requiring resolution between the analytes. Then, the MS/MS properties were optimized to solve the signal assignment using post-processing data elaboration (LEDA). The IT-MS/MS experiment uses the same site, helium as collision gas, and different time steps to modify the applied conditions on the studied ions. Nevertheless, helium cannot ensure the quick energization of the precursor ion due to its small cross-section. Then, different combinations between excitation amplitude (ExA) and excitation time (ExT) were tested to achieve the activation of the fragmentation channels and the formation of the MS/MS spectrum. Usually, the IT-MS/MS acquisition cycle is longer for other multistage instruments, decreasing the frequency of sample data collection and influencing the chromatographic profile. To solve these problems, two time segments were set up, and the elution conditions were optimized with a compromise between peaks distinction and run time reduction. The developed HPLC-MS/MS method was checked and applied to analyze a series of human plasma samples spiked with an equimolar mixture of pair of isomers.
Assuntos
Hélio , Espectrometria de Massas em Tandem , Humanos , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida/métodos , AlgoritmosRESUMO
Metformin is the most prescribed glucose-lowering drug worldwide; globally, over 100 million patients are prescribed this drug annually. Some different action mechanisms have been proposed for this drug, but, surprisingly, no metabolite of metformin has ever been described. It was considered interesting to investigate the possible reaction of metformin with glucose following the Maillard reaction pattern. The reaction was first performed in in vitro conditions, showing the formation of two adducts that originated by the condensation of the two molecular species with the losses of one or two water molecules. Their structures were investigated by liquid chromatography coupled with mass spectrometry (HPLC-MS), tandem mass spectrometry (MS/MS) and accurate mass measurements (HRMS). The species originated via the reaction of glucose and metformin and were called metformose and dehydrometformose, and some structural hypotheses were conducted. It is worth to emphasize that they were detected in urine samples from a diabetic patient treated with metformin and consequently they must be considered metabolites of the drug, which has never been identified before now. The glucose-related substructure of these compounds could reflect an improved transfer across cell membranes and, consequently, new hypotheses could be made about the biological targets of metformin.
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Metformina , Humanos , Espectrometria de Massas em Tandem , Espectrometria de Massa com Cromatografia Líquida , Membrana Celular , GlucoseRESUMO
Pannexins are an interesting new target in medicinal chemistry, as they are involved in many pathologies such as epilepsy, ischemic stroke, cancer and Parkinson's disease, as well as in neuropathic pain. They are a family of membrane channel proteins consisting of three members, Panx-1, Panx-2 and Panx-3, and are expressed in vertebrates. In the present study, as a continuation of our research in this field, we report the design, synthesis and pharmacological evaluation of new quinoline-based Panx-1 blockers. The most relevant compounds 6f and 6g show an IC50 = 3 and 1.5 µM, respectively, and are selective Panx-1 blockers. Finally, chemical stability, molecular modelling and X-ray crystallography studies have been performed providing useful information for the realization of the project.
Assuntos
Neuralgia , Quinolinas , Animais , Humanos , Modelos Moleculares , Quinolinas/farmacologia , Conexinas/metabolismo , Proteínas do Tecido Nervoso/metabolismoRESUMO
The composition of the gut microbiota (GM) undergoes significant changes during pregnancy, influenced by metabolic status, energy homeostasis, fat storage, and hormonal and immunological modifications. Moreover, dysbiosis during pregnancy has been associated with preterm birth, which is influenced by factors such as cervical shortening, infection, inflammation, and oxidative stress. However, dysbiosis also affects the levels of lipopolysaccharide-binding protein (LBP), short-chain fatty acids (SCFAs), and free fatty acids (FFA) in other tissues and the bloodstream. In this study, we investigated the plasmatic levels of some pro-inflammatory cytokines, such as matrix metalloproteinases-8 (MMP-8), interleukin-8 (IL-8), heat shock protein 70 (Hsp70), and microbial markers in pregnant women with a short cervix (≤25 mm) compared to those with normal cervical length (>25 mm). We examined the differences in the concentration of these markers between the two groups, also assessing the impact of gestational diabetes mellitus. Understanding the relationship between GM dysbiosis, inflammatory mediators, and cervical changes during pregnancy may contribute to the identification of potential biomarkers and therapeutic targets for the prevention and management of adverse pregnancy outcomes, including preterm birth.
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Diabetes Gestacional , Microbioma Gastrointestinal , Nascimento Prematuro , Recém-Nascido , Gravidez , Humanos , Feminino , Gestantes , Colo do Útero , DisbioseRESUMO
Lignans are non-flavonoid polyphenols present in a wide range of foods frequently consumed in the Western world, such as seeds, vegetables and fruits, and beverages such as coffee, tea and wine. In particular, the human gut microbiota (GM) can convert dietary lignans into biologically active compounds, especially enterolignans (i.e., enterolactone and enterodiol), which play anti-inflammatory and anti-oxidant roles, act as estrogen receptor activators and modulate gene expression and/or enzyme activity. Interestingly, recent evidence documenting those dietary interventions involving foods enriched in lignans have shown beneficial and protective effects on various human pathologies, including colorectal and breast cancer and cardiovascular diseases. However, considering that more factors (e.g., diet, food transit time and intestinal redox state) can modulate the lignans bioactivation by GM, there are usually remarkable inter-individual differences in urine, fecal and blood concentrations of enterolignans; hence, precise and validated analytical methods, especially gas/liquid chromatography coupled to mass spectrometry, are needed for their accurate quantification. Therefore, this review aims to summarize the beneficial roles of enterolignans, their interaction with GM and the new methodological approaches developed for their evaluation in different biological samples, since they could be considered future promising nutraceuticals for the prevention of human chronic disorders.
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Microbioma Gastrointestinal , Lignanas , Humanos , Cromatografia Gasosa-Espectrometria de Massas , Verduras/química , Dieta , Lignanas/químicaRESUMO
This paper proposes a tandem mass spectrometry (MS/MS) approach in isomer recognition by playing in the "energetic dimension" of the experiment. The chromatographic set up (HPLC) was tuned to minimize the run time, without requiring high efficiency or resolution between the isomers. Then, the MS/MS properties were explored to solve the signal assignment by performing a series of energy resolved experiments in order to optimize the parameters, and by applying an interesting post-processing data elaboration tool (LEDA). The reliability of the new approach was evaluated, determining the accuracy and precision of the quantitative results through analysis of the isomer mixture solutions. Next, the proposed method was applied in a chemical stability study of human plasma samples through the simultaneous addition of a pair of isomers. In the studied case, only one of the isomers suffered of enzymatic hydrolysis; therefore, the influence of the stable isomer on the degradation rate of the other was verified. In order to monitor this process correctly, it must be possible to distinguish each isomer present in the sample, quantify it, and plot its degradation profile. The reported results demonstrated the effectiveness of the LEDA algorithm in separating the isomers, without chromatographic resolution, and monitoring their behavior in human plasma samples.
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Algoritmos , Espectrometria de Massas em Tandem , Humanos , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Reprodutibilidade dos Testes , IsomerismoRESUMO
A series of histamine (HST)-related compounds were synthesized and tested for their activating properties on five physiologically relevant human Carbonic Anhydrase (hCA) isoforms (I, II, Va, VII and XIII). The imidazole ring of HST was replaced with different 5-membered heterocycles and the length of the aliphatic chain was varied. For the most interesting compounds some modifications on the terminal amino group were also performed. The most sensitive isoform to activation was hCA I (KA values in the low micromolar range), but surprisingly none of the new compounds displayed activity on hCA II. Some derivatives (1, 3a and 22) displayed an interesting selectivity for activating hCA I over hCA II, Va, VII and XIII.
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Anidrase Carbônica I/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Histamina/química , Histamina/farmacologia , Anidrase Carbônica I/efeitos dos fármacos , Anidrase Carbônica II/efeitos dos fármacos , Anidrase Carbônica II/metabolismo , Anidrase Carbônica V/efeitos dos fármacos , Anidrase Carbônica V/metabolismo , Anidrases Carbônicas/efeitos dos fármacos , Anidrases Carbônicas/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Histamina/análogos & derivados , Histamina/síntese química , Humanos , Imidazóis/química , Isoformas de Proteínas/efeitos dos fármacos , Isoformas de Proteínas/metabolismoRESUMO
Human neutrophil elastase (HNE) is a serine protease that is expressed in polymorphonuclear neutrophils. It has been recognized as an important therapeutic target for treating inflammatory diseases, especially related to the respiratory system, but also for various types of cancer. Thus, compounds able to inhibit HNE are of great interest in medicinal chemistry. In the present paper, we report the synthesis and biological evaluation of a new series of HNE inhibitors with an innovative 1,5,6,7-tetrahydro-4H-indazol-4-one core that was developed as a molecular modification of our previously reported indazole-based HNE inhibitors. Since the 1,5,6,7-tetrahydro-4H-indazol-4-one scaffold can occur in two possible tautomeric forms, the acylation/alkylation reactions resulted in a mixture of the two isomers, often widely unbalanced in favor of one form. Using analytical techniques and NMR spectroscopy, we characterized and separated the isomer pairs and confirmed the compounds used in biological testing. Analysis of the compounds for HNE inhibitory activity showed that they were potent inhibitors, with Ki values in the low nanomolar range (6-35 nM). They also had reasonable stability in aqueous buffer, with half-lives over 1 h. Overall, our results indicate that the 1,5,6,7-tetrahydro-4H-indazol-4-one core is suitable for the synthesis of potent HNE inhibitors that could be useful in the development of new therapeutics for treating diseases involving excessive HNE activity.
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Elastase de Leucócito/antagonistas & inibidores , Inibidores de Serina Proteinase/farmacologia , Relação Dose-Resposta a Droga , Humanos , Elastase de Leucócito/metabolismo , Estrutura Molecular , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/química , Relação Estrutura-AtividadeRESUMO
Human neutrophil elastase (HNE) is a potent protease that plays an important physiological role in many processes but is also involved in a variety of pathologies that affect the pulmonary system. Thus, compounds able to inhibit HNE proteolytic activity could represent effective therapeutics. We present here a new series of pyrazolopyridine and pyrrolopyridine derivatives as HNE inhibitors designed as modifications of our previously synthesized indazoles and indoles in order to evaluate effects of the change in position of the nitrogen and/or the insertion of an additional nitrogen in the scaffolds on biological activity and chemical stability. We obtained potent HNE inhibitors with IC50 values in the low nanomolar range (10-50 nM), and some compounds exhibited improved chemical stability in phosphate buffer (t1/2 > 6 h). Molecular modeling studies demonstrated that inhibitory activity was strictly dependent on the formation of a Michaelis complex between the OH group of HNE Ser195 and the carbonyl carbon of the inhibitor. Moreover, in silico ADMET calculations predicted that most of the new compounds would be optimally absorbed, distributed, metabolized, and excreted. Thus, these new and potent HNE inhibitors represent novel leads for future therapeutic development.
Assuntos
Desenvolvimento de Medicamentos , Compostos Heterocíclicos/farmacologia , Elastase de Leucócito/antagonistas & inibidores , Piridinas/farmacologia , Pirróis/farmacologia , Inibidores de Serina Proteinase/farmacologia , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Elastase de Leucócito/metabolismo , Modelos Moleculares , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Pirróis/síntese química , Pirróis/química , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/química , Relação Estrutura-AtividadeRESUMO
Six new monopeptides, seven new dipeptides, and two deprotected monopeptide dihydroquinolinone conjugates were prepared by the benzothiazole-mediated method and their structures were confirmed by nuclear magnetic resonance, mass, infrared spectroscopy, and elemental analysis methods. The human carbonic anhydrase (hCA) I and hCA II enzyme inhibition activities of the compounds were determined using the stopped-flow instrument. The synthesized peptide-dihydroquinolinone conjugates 2, 3, 6, 10, 13, and 15 showed inhibition against the hCA II enzyme in the range of 15.7-65.7 µM. However, none of the compounds showed inhibition of hCA I at a concentration of 100 µM. The antioxidant activities of the compounds were also examined using the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging method at concentrations of 12.5-125 µg/ml, but when compared with the standard antioxidant compounds α-tocopherol and butylated hydroxyanisole (BHA), weak antioxidant activities were detected. The cytotoxic effects of four compounds against the A549 and BEAS-2B cell lines were also investigated. Among the compounds studied, compound 7 was found to be most effective, with the IC50 values on the A549 cells for 48 and 72 h being 26.87 and 9.979 µg/ml, respectively, and the IC50 values on the BEAS-2B cells being >100 µg/ml. None of the tested compounds showed antimicrobial activity in the concentration range (800-1.56 µg/ml) studied.
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Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Quinolonas/farmacologia , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/síntese química , Antioxidantes/química , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica II/antagonistas & inibidores , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Humanos , Concentração Inibidora 50 , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-AtividadeRESUMO
We report here a new drug design strategy for producing membrane-impermeant carbonic anhydrase (CA; EC 4.2.1.1) inhibitors selectively targeting the tumor-associated, membrane-bound human CAs IX and XII over off-target cytosolic isoforms. To date, this approach has only been pursued by including permanent positively charged pyridinium type or highly hydrophilic glycosidic moieties into the structure of aromatic sulfonamide CA inhibitors (CAIs). Aliphatic (propyl and butyl) sulfonic acid tails, deprotonated at physiological pH, were thus incorporated onto a benzenesulfonamide scaffold by a common 1,2,3-triazole linker and different types of spacers. Twenty such derivatives were synthesized and tested for their inhibition of target (hCAs IV, IX, and XII) and off-target CAs (hCAs I and II). Most sulfonate CAIs induced a potent inhibition of hCAs II, IX, and XII up to a low nanomolar KI range (0.9-459.4 nM) with a limited target/off-target CA selectivity of action. According to the drug design schedule, a subset of representative derivatives was assessed for their cell membrane permeability using Caco-2 cells and a developed FIA-MS/MS method. The complete membrane impermeability of the sulfonate tailed CAIs (≥98%) validated these negatively charged moieties as being suitable for achieving, in vivo, the selective targeting of the tumor-associated CAs over off-target ones.
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Antígenos de Neoplasias/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Desenho de Fármacos/métodos , Neoplasias/tratamento farmacológico , Espectrometria de Massas em Tandem/métodos , Células CACO-2 , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Ácidos Sulfônicos/farmacologiaRESUMO
Persistent infection with High Risk-Human Papilloma Viruses (HR-HPVs) is a primary cause of cervical cancer worldwide. Vaginal-dysbiosis-associated bacteria were correlated with the persistence of HR-HPVs infection and with increased cancer risk. We obtained strains of the most represented bacterial species in vaginal microbiota and evaluated their effects on the survival of cervical epithelial cells and immune homeostasis. The contribution of each species to supporting the antiviral response was also studied. Epithelial cell viability was affected by culture supernatants of most vaginal-dysbiosis bacteria, whereas Lactobacillus gasseri or Lactobacillus jensenii resulted in the best stimulus to induce interferon-γ (IFN-γ) production by human mononuclear cells from peripheral blood (PBMCs). Although vaginal-dysbiosis-associated bacteria induced the IFN-γ production, they were also optimal stimuli to interleukin-17 (IL-17) production. A positive correlation between IL-17 and IFN-γ secretion was observed in cultures of PBMCs with all vaginal-dysbiosis-associated bacteria suggesting that the adaptive immune response induced by these strains is not dominated by TH1 differentiation with reduced availability of IFN-γ, cytokine most effective in supporting virus clearance. Based on these results, we suggest that a vaginal microbiota dominated by lactobacilli, especially by L. gasseri or L. jensenii, may be able to assist immune cells with clearing HPV infection, bypasses the viral escape and restores immune homeostasis.
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Antibiose , Disbiose , Homeostase , Lactobacillus/fisiologia , Mucosa/imunologia , Mucosa/microbiologia , Vagina/imunologia , Vagina/microbiologia , Sobrevivência Celular , Citocinas/biossíntese , Células Epiteliais/metabolismo , Ácidos Graxos Voláteis/biossíntese , Feminino , Humanos , Vagina/metabolismoRESUMO
Myocardial fibrosis is an endogenous response to different cardiac insults that may become maladaptive over time and contribute to the onset and progression of heart failure (HF). Fibrosis is a direct and indirect target of established HF therapies, namely inhibitors of the renin-angiotensin-aldosterone system, but its resilience to therapy warrants a search for novel, more targeted approaches to myocardial fibrosis. Pirfenidone is a drug approved for idiopathic pulmonary fibrosis, a severe form of idiopathic interstitial pneumonias. Pirfenidone is a small synthetic molecule with high oral bioavailability, exerting an antifibrotic activity, but also anti-oxidant and anti-inflammatory effects. These effects have been attributed to the inhibition of several growth factors (in particular transforming growth factor-ß, but also platelet-derived growth factor and beta fibroblast growth factor), matrix metalloproteinases, and pro-inflammatory mediators (such as interleukin-1ß and tumour necrosis factor-α), and possibly also an improvement of mitochondrial function and modulation of lymphocyte activation. Given the activation of similar profibrotic pathways in lung and heart disease, the crucial role of fibrosis in several cardiac disorders, and the wide spectrum of activity of pirfenidone, this drug has been evaluated with interest as a potential treatment for cardiac disorders. In animal studies, pirfenidone has shown cardioprotective effects across different species and in a variety of models of cardiomyopathy. In the present review we summarize the pharmacological characteristics of pirfenidone and the data from animal studies supporting its cardioprotective effects.
Assuntos
Cardiotônicos , Piridonas , Animais , Cardiotônicos/efeitos adversos , Cardiotônicos/farmacocinética , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Fibrose , Coração/efeitos dos fármacos , Humanos , Miocárdio/patologia , Piridonas/efeitos adversos , Piridonas/farmacocinética , Piridonas/farmacologia , Piridonas/uso terapêuticoRESUMO
PURPOSE: We evaluated the effect of low-calorie mediterranean (MD) and vegetarian (VD) diets on gut microbiome (GM) composition and short-chain-fatty acids (SCFA) production. METHODS: We performed next generation sequencing (NGS) of 16S rRNA and SCFA analysis on fecal samples of 23 overweight omnivores (16 F; 7 M) with low-to-moderate cardiovascular risk. They were randomly assigned to a VD or MD, each lasting 3 months, with a crossover study design. RESULTS: Dietary interventions did not produce significant diversity in the GM composition at higher ranks (family and above), neither between nor within MD and VD, but they did it at genus level. MD significantly changed the abundance of Enterorhabdus, Lachnoclostridium and Parabacteroides, while VD significantly affected the abundance of Anaerostipes, Streptococcus, Clostridium sensu stricto, and Odoribacter. Comparison of the mean variation of each SCFA between MD and VD showed an opposite and statistically significant trend for propionic acid (+ 10% vs - 28%, respectively, p = 0.034). In addition, variations of SCFA were negatively correlated with changes of some inflammatory cytokines such as VEGF, MCP-1, IL-17, IP-10 and IL-12, only after MD. Finally, correlation analyses showed a potential relationship-modulated by the two diets-between changes of genera and changes of clinical and biochemical parameters. CONCLUSIONS: A short-term dietary intervention with MD or VD does not induce major change in the GM, suggesting that a diet should last longer than 3 months for scratching the microbial resilience. Changes in SCFA production support their role in modulating the inflammatory response, thus mediating the anti-inflammatory and protective properties of MD.
Assuntos
Dieta Mediterrânea , Microbioma Gastrointestinal , Estudos Cross-Over , Dieta Vegetariana , Humanos , RNA Ribossômico 16S/genéticaRESUMO
New dipeptide-dihydroquinolinone derivatives were successfully synthesised by benzotriazole mediated nucleophilic acyl substitution reaction and their structures were elucidated by spectroscopic and analytic techniques. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was determined against four human (h) isoforms, hCA I, hCA II, hCA IX and hCA XII. While all compounds showed moderate to good in vitro CA inhibitory properties against hCA IX and hCA XII with inhibition constants in the micromolar level (37.7-86.8 and 2.0-8.6 µM, respectively), they did not show inhibitory activity against hCA I and hCA II up to 100 µM concentration. The antioxidant capacity of the peptide-dihydroquinolinone conjugates was determined using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging method. Most of the synthesised compounds showed low antioxidant activities compared to the control antioxidant compounds BHA and α-tocopherol.
Assuntos
Antioxidantes/farmacologia , Compostos de Bifenilo/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Dipeptídeos/farmacologia , Picratos/antagonistas & inibidores , Quinolonas/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Dipeptídeos/química , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-AtividadeRESUMO
A series of amino acid-sulphonamide conjugates was prepared through benzotriazole mediated coupling reactions and characterised by 1H-NMR, 13C-NMR, MS, and FTIR spectroscopic techniques as well as elemental analysis. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was determined against four human (h) isoforms, hCA I, hCA II, hCA VA, and hCA XII. Most of the synthesised compounds showed effective in vitro CA inhibitory properties. The new amino acid-sulphonamide conjugates showed potent inhibitory activity against hCA II, some of them at subnanomolar levels, exhibiting more effective inhibitory activity compared to the standard drug acetazolamide. Some of these sulphonamides were also found to be effective inhibitors of hCA I, hCA VA, and hCA XII, with activity from the low to high nanomolar range.