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1.
Life Sci ; 285: 120003, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34599936

RESUMO

AIMS: Indole-3-propionic acid (IPA) is a natural product from human microbiota, exhibiting diverse biological activities. The study focused on investigating the antibacterial mode of action(s) triggered by IPA in Escherichia coli. Separate influence of nitric oxide (NO) and each reactive oxygen species, including superoxide anion (O2-), hydrogen peroxide (H2O2), hydroxyl radical (OH-), was specifically analyzed throughout the process. MAIN METHODS: The generation of respective reactive oxygen species (ROS), NO, and ONOO- was conducted using flow cytometer using different dyes. Further analysis of separate influences was held based on usage of each scavenger: sodium pyruvate, thiourea, tiron, and L-NAME. Oxidative cell damage was observed through the detection of glutathione depletion and lipid peroxidation. DNA fragmentation and membrane depolarization were observed by TUNEL and DiBAC4(3) staining agent. Finally, Annexin V/PI and FITC-VAD-FMK were applied to detect apoptosis-like death. KEY FINDINGS: IPA exhibited antibacterial activity in E. coli through the accumulation of ROS, NO, ONOO-, and DNA damage, eventually leading to apoptosis-like death. NO and O2- exerted the most potent influence on oxidative damage of E. coli, whereas H2O2 accounts for the least impact. Moreover, the results reveal the major contribution of ONOO- in IPA-induced apoptosis-like death in E. coli. SIGNIFICANCE: This is the first study that introduces the antibacterial activity and apoptosis-like death induced by IPA and suggests the possibility of being an alternative for current antibiotics. Furthermore, the distinct influence of each ROS and NO was analyzed to investigate their contribution to oxidative damage leading to bacterial apoptosis-like death.


Assuntos
Antibiose , Apoptose , Escherichia coli/fisiologia , Indóis/metabolismo , Microbiota/fisiologia , Óxido Nítrico/fisiologia , Propionatos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fragmentação do DNA , Escherichia coli/efeitos dos fármacos , Glutationa/metabolismo , Indóis/farmacologia , Peroxidação de Lipídeos , Microbiota/efeitos dos fármacos , Propionatos/farmacologia
2.
Molecules ; 26(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34443546

RESUMO

Recent studies found that short-chain fatty acids (SCFAs), which are produced through bacterial fermentation in the gastrointestinal tract, have oncoprotective effects against cervical cancer. The most common SCFAs that are well known include acetic acid, butyric acid, and propionic acid, among which propionic acid (PA) has been reported to induce apoptosis in HeLa cells. However, the mechanism in which SCFAs suppress HeLa cell viability remain poorly understood. Our study aims to provide a more detailed look into the mechanism of PA in HeLa cells. Flow cytometry analysis revealed that PA induces reactive oxygen species (ROS), leading to the dysfunction of the mitochondrial membrane. Moreover, PA inhibits NF-κB and AKT/mTOR signaling pathways and induces LC3B protein levels, resulting in autophagy. PA also increased the sub-G1 cell population that is characteristic of cell death. Therefore, the results of this study propose that PA inhibits HeLa cell viability through a mechanism mediated by the induction of autophagy. The study also suggests a new approach for cervical cancer therapeutics.


Assuntos
Antineoplásicos/farmacologia , Propionatos/farmacologia , Neoplasias do Colo do Útero/patologia , Antineoplásicos/química , Autofagia/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , NF-kappa B/metabolismo , Propionatos/química , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias do Colo do Útero/metabolismo
3.
Food Microbiol ; 100: 103854, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34416957

RESUMO

This study investigated the effects of combinations of acetic or malic acid and various solutes (salt, glucose, glycine, or sucrose) on the survival of Escherichia coli O157:H7 in laboratory broth. Additionally, the effectiveness of combining organic acids and various concentrations of salt (0-18%) or sucrose (0-100%) with different water activity values against E. coli O157:H7 were evaluated. For treatment of 1% malic acid, the addition of 3% salt showed synergistic effect. Whereas, when 3% salt, glucose, glycine, or sucrose was added to 1% acetic acid, the solutes antagonized the action of the acid against E. coli O157:H7. Acetic, lactic, or propionic acid combined with salt at either 7 or 9% or sucrose at 60, 80, or 100% resulted in the highest resistance of E. coli O157:H7. From a result of evaluating the membrane fatty acid (MFA) composition of cells, salt or sucrose significantly increased levels of saturated fatty acids (SFAs) or SFAs and cyclopropane fatty acids, respectively. From the results of this study, the addition of solutes and organic compounds may increase the tolerance of E. coli O157:H7 to acetic, lactic, and propionic acid treatments and that the salt or sucrose significantly affects cell MFA composition.


Assuntos
Ácido Acético/farmacologia , Escherichia coli O157/efeitos dos fármacos , Escherichia coli O157/crescimento & desenvolvimento , Glucose/metabolismo , Malatos/farmacologia , Propionatos/farmacologia , Cloreto de Sódio/metabolismo , Sacarose/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Meios de Cultura/química , Meios de Cultura/metabolismo , Escherichia coli O157/metabolismo , Ácidos Graxos/metabolismo , Glicina/metabolismo
4.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064070

RESUMO

C60 fullerene as a potent free radical scavenger and antioxidant could be a beneficial means for neurodegenerative disease prevention or cure. The aim of the study was to define the effects of C60 administration on mitochondrial dysfunction and oxidative stress disorders in a 3-nitropropionic acid (3-NPA)-induced rat model of Huntington's disease. Animals received 3-NPA (30 mg/kg i.p.) once a day for 3 consecutive days. C60 was applied at a dose of 0.5 mg/kg of body weight, i.p. daily over 5 days before (C60 pre-treatment) and after 3-NPA exposure (C60 post-treatment). Oxidative stress biomarkers, the activity of respiratory chain enzymes, the level of antioxidant defense, and pro- and antiapoptotic markers were analyzed in the brain and skeletal muscle mitochondria. The nuclear and cytosol Nrf2 protein expression, protein level of MnSOD, γ-glutamate-cysteine ligase (γ-GCLC), and glutathione-S-transferase (GSTP) as Nrf2 targets were evaluated. Our results indicated that C60 can prevent 3-NPA-induced mitochondrial dysfunction through the restoring of mitochondrial complexes' enzyme activity, ROS scavenging, modulating of pro/antioxidant balance and GSH/GSSG ratio, as well as inhibition of mitochondria-dependent apoptosis through the limitation of p53 mitochondrial translocation and increase in Bcl-2 protein expression. C60 improved mitochondrial protection by strengthening the endogenous glutathione system via glutathione biosynthesis by up-regulating Nrf2 nuclear accumulation as well as GCLC and GSTP protein level.


Assuntos
Fulerenos/fisiologia , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Nitrocompostos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Propionatos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Glutationa/metabolismo , Masculino , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
5.
Toxicol Appl Pharmacol ; 426: 115615, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102242

RESUMO

Current therapies for preeclampsia (PE) and its complications are limited and defective. Considering the importance of endothelin (ET) and thromboxane A2 (TXA2) signaling in PE pathophysiology, we tested the hypothesis that prenatal blockade of endothelin ETA or thromboxane TXA2 receptors favorably reprograms preeclamptic cardiovascular and renal insults. PE was induced by daily oral administration of L-NAME (50 mg/kg) to pregnant rats for 7 consecutive days starting from gestational day 14. The effects of co-exposure to atrasentan (ETA receptor blocker, 10 mg/kg/day) or terutroban (TXA2 receptor blocker, 10 mg/kg/day) on cardiovascular and renal anomalies induced by PE were assessed on gestational day 20 (GD20) and at weaning time and compared with those evoked by the sympatholytic drug α-methyldopa (α-MD, 100 mg/kg/day), a prototypic therapy for PE management. Among all drugs, terutroban was basically the most potent in ameliorating PE-evoked increments in blood pressure and decrements in creatinine clearance. Cardiorenal tissues of PE rats exhibited significant increases in ETA and TXA2 receptor expressions and these effects disappeared after treatment with atrasentan and to a lesser extent by terutroban or α-MD. Atrasentan was also the most effective in reversing the reduced ETB receptor expression in renal tissues of PE rats. Signs of histopathological damage in cardiac and renal tissues of PE rats were mostly improved by all therapies. Together, pharmacologic elimination of ETA or TXA2 receptors offers a relatively better prospect than α-MD in controlling perinatal cardiorenal irregularities sparked by PE.


Assuntos
Atrasentana/uso terapêutico , Antagonistas do Receptor de Endotelina A/uso terapêutico , Cardiopatias/prevenção & controle , Nefropatias/prevenção & controle , Naftalenos/uso terapêutico , Pré-Eclâmpsia/tratamento farmacológico , Propionatos/uso terapêutico , Receptores de Tromboxano A2 e Prostaglandina H2/antagonistas & inibidores , Animais , Atrasentana/farmacologia , Antagonistas do Receptor de Endotelina A/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Cardiopatias/genética , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/genética , Nefropatias/patologia , Nefropatias/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Naftalenos/farmacologia , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/patologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Propionatos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/genética , Receptores de Tromboxano A2 e Prostaglandina H2/genética
6.
Immunology ; 164(2): 292-304, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33999409

RESUMO

Allergic diseases are caused by dysregulated Th2 immune responses involving multiple effector cells including basophils. Short chain fatty acids (SCFAs), mainly acetate, propionate and butyrate, exert immunomodulatory functions via activation of its receptors GPR41 and GPR43, and inhibition of the histone deacetylases (HDACs) activity. In allergic diseases, SCFAs suppress the activity of mast cells, eosinophils and type 2 innate lymphoid cells (ILC2) but enhance the function of Th2 cells. Here, we aimed to elucidate the function of SCFAs on human basophils. Human basophils were purified from healthy donors by flow cytometric sorting. The surface proteins, apoptosis and degranulation of basophils were analyzed by flow cytometric analysis. The mRNA expression was assayed using real-time PCR. Interleukin 4 (IL-4) and IL-13 were measured by ELISA. Histone acetylation was examined by western blot. GPR41 was expressed by basophils and was enhanced by IL-3. Acetate induced intracellular calcium influx in basophils which was suppressed by blocking GPR41. Propionate and butyrate, but not acetate, induced the expression of CD69 and IL-13. In addition, propionate and butyrate enhanced IgE-mediated basophil degranulation but inhibited basophil survival and IL-4 secretion. Propionate and butyrate induced histone acetylation of basophils and suppression of HDACs activity mimicked the effects of propionate and butyrate on human basophils. Our findings demonstrate that propionate and butyrate may play a complex role in regulating basophil apoptosis, activation and degranulation via inhibiting HDACs activity. The in vivo effects of SCFAs on the regulation of basophil-associated allergic diseases need to be further explored.


Assuntos
Apoptose/efeitos dos fármacos , Basófilos/efeitos dos fármacos , Butiratos/farmacologia , Histonas/metabolismo , Interleucina-13/metabolismo , Propionatos/farmacologia , Apoptose/imunologia , Basófilos/imunologia , Basófilos/metabolismo , Células Cultivadas , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/metabolismo , Ácidos Graxos Voláteis , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Humanos , Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo
7.
Biomed Pharmacother ; 139: 111618, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33901871

RESUMO

Holoparasitic plants of the Orobanchaceae, including Cistanche, Orobanche, and Phelipanche spp, are known for their richness of phenylpropanoid glycosides (PPGs). Many PPG compounds have been found to possess a wide spectrum of activities, such as antimicrobial, anti-inflammatory, antioxidant, and memory-enhancing. To better explore the bioactivity potential of European broomrapes (O. caryophyllacea - OC, P. arenaria - PA, P. ramosa - PR) and ten single isolated phenylpropanoid constituents, we investigated their antiradical action, protective effect against oxidation in plasma in vitro system, and influence on coagulation parameters. The tested extracts showed a scavenging activity of 50-70% of Trolox's power. The OC extract, rich in acteoside, had over 20% better antiradical potential than PR extract which was the only one containing PPGs lacking a B-ring catechol moiety in the acyl unit. Moreover, it was found that only eight tested PPGs demonstrated antioxidant potential in human plasma treated with H2O2/Fe; however, the three tested PPGs possessed anticoagulant potential in addition to antioxidant properties. It appears that the structure of PPGs, especially the presence of acyl and catechol moieties, is mainly related to their antioxidant properties. The anticoagulant potential of these compounds is also related to their chemical structure. Selected PPGs exhibit the potential for treating cardiovascular diseases associated with oxidative stress.


Assuntos
Anticoagulantes/farmacologia , Antioxidantes/farmacologia , Orobanchaceae/química , Propionatos/farmacologia , Adulto , Compostos de Bifenilo/química , Catecóis/química , Catecóis/farmacologia , Cromanos/farmacologia , Cistanche , Feminino , Sequestradores de Radicais Livres/farmacologia , Glicosídeos/farmacologia , Hemostasia/efeitos dos fármacos , Humanos , Masculino , Orobanche/química , Picratos/química , Extratos Vegetais/farmacologia , Propionatos/química , Substâncias Protetoras/farmacologia , Espectrofotometria Ultravioleta , Relação Estrutura-Atividade
8.
J Biochem Mol Toxicol ; 35(7): e22791, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33880814

RESUMO

The increasing drug efflux through the ATP-binding cassette (ABC) transporters is the most plausible mechanism that mediates resistance to the anticancer phytochemicals, such as benzyl isothiocyanate (BITC), as well as chemotherapy drugs. To identify a potential component to overcome this resistance by combinatory utilization, we focused on multidrug resistance-associated proteins (MRPs) pumping various drug metabolites with glutathione as well as the organic anions. The pharmacological treatment of an MRP inhibitor, MK571, significantly potentiated the BITC-induced antiproliferation, coincided with the enhanced accumulation of BITC and glutathione in human colorectal cancer HCT-116 cells. MK571 also enhanced the apoptosis induction as well as activation of the mitogen-activated protein kinases and caspase-3, whereas it did not affect their basal levels. These results suggested that, since MRPs might play a pivotal role in the BITC efflux, MK571 potentiates the BITC-induced antiproliferation in human colorectal cancer cells through inhibition of the glutathione-dependent BITC efflux.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Colorretais , Isotiocianatos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Propionatos/farmacologia , Quinolinas/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Células HCT116 , Humanos , Isotiocianatos/farmacocinética , Isotiocianatos/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo
9.
Viruses ; 13(3)2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807769

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of novel coronavirus disease 2019 (COVID-19), has become a severe threat to global public health. There are currently no antiviral therapies approved for the treatment or prevention of mild to moderate COVID-19 as remdesivir is only approved for severe COVID-19 cases. Here, we evaluated the antiviral potential of a Propylamylatin formula, which is a mixture of propionic acid and isoamyl hexanoates. The Propylamylatin formula was investigated in gaseous and liquid phases against 1 mL viral suspensions containing 105 PFU of SARS-CoV-2. Viral suspensions were sampled at various times post-exposure and infectious virus was quantified by plaque assay on Vero E6 cells. Propylamylatin formula vapors were effective at inactivating infectious SARS-CoV-2 to undetectable levels at room temperature and body temperature, but the decline in virus was substantially faster at the higher temperature (15 min versus 24 h). The direct injection of liquid Propylamylatin formula into viral suspensions also completely inactivated SARS-CoV-2 and the rapidity of inactivation occurred in an exposure dependent manner. The overall volume that resulted in 90% viral inactivation over the course of the direct injection experiment (EC90) was 4.28 µls. Further investigation revealed that the majority of the antiviral effect was attributed to the propionic acid which yielded an overall EC90 value of 11.50 µls whereas the isoamyl hexanoates provided at most a 10-fold reduction in infectious virus. The combination of propionic acid and isoamyl hexanoates was much more potent than the individual components alone, suggesting synergy between these components. These findings illustrate the therapeutic promise of the Propylamylatin formula as a potential treatment strategy for COVID-19 and future studies are warranted.


Assuntos
Antivirais/farmacologia , Caproatos/farmacologia , Propionatos/farmacologia , SARS-CoV-2/efeitos dos fármacos , Animais , COVID-19/virologia , Chlorocebus aethiops , Composição de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Humanos , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Células Vero , Replicação Viral/efeitos dos fármacos
10.
Int J Mol Sci ; 22(5)2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33671042

RESUMO

Short-chain fatty acids (e.g., butyrate and propionate) are able to diminish endothelial cell activation. The aim of this study was to investigate whether intracellular IL-33 mediates the effects of butyrate and propionate on TNFα-induced IL-8 production and vascular cell adhesion molecule-1 (VCAM-1) expression. In addition, it was investigated whether regulating NF-κB and MAPK signaling pathways are involved. Intracellular IL-33 was measured in human endothelial cells (HUVECs) pre-incubated for 24 h with butyrate (0.1 mM or 5 mM), propionate (0.3 mM or 10 mM), or trichostatin A (TSA, 0.5 µM) prior to TNFα (1 ng/mL) stimulation (24 h). The effects of butyrate, propionate, and TSA on TNFα-induced IL-8, vascular cell adhesion molecule-1 (VCAM-1), NF-κB, and MAPK signaling pathways in normal HUVECs and IL-33 siRNA (siIL-33)-transfected HUVECs were compared to study the role of IL-33 in the protective effects of butyrate and propionate. Endogenous IL-33 was highly expressed in the perinuclear in HUVECs, which was significantly reduced by TNFα stimulation. The TNFα-induced reduction in IL-33 was prevented by pre-incubation with butyrate or propionate. Butyrate (0.1 mM), propionate (0.3 mM), and TSA inhibited the IL-8 production and activation of NF-κB. Interestingly, this effect was not observed in siIL-33-transfected HUVECs. The effects of butyrate (5 mM), propionate (10 mM), and TSA (0.5 µM) on VCAM-1 expression and activation of MAPK signaling pathways were not affected by siIL-33 transfection. In conclusion, we showed that the inhibitory effects of butyrate and propionate on TNFα-induced IL-8 production were mediated by the HDACs/IL-33/NF-κB pathway, while their effects on VCAM-1 expression might be associated with the HDACs/MAPK signaling pathway, independently of IL-33.


Assuntos
Anti-Inflamatórios/farmacologia , Butiratos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Interleucina-33/metabolismo , Propionatos/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Histona Desacetilases/metabolismo , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases , NF-kappa B/metabolismo , Transdução de Sinais , Molécula 1 de Adesão de Célula Vascular/metabolismo
11.
J Physiol Biochem ; 77(2): 321-329, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33704695

RESUMO

Lysophosphatidic acid (LPA) acts through the activation of G protein-coupled receptors, in a Ca2+-dependent manner. We show the effects of LPA on the plasma membrane Ca2+-ATPase (PMCA) from kidney proximal tubule cells. The Ca2+-ATPase activity was inhibited by nanomolar concentrations of LPA, with maximal inhibition (~50%) obtained with 20 nM LPA. This inhibitory action on PMCA activity was blocked by Ki16425, an antagonist for LPA receptors, indicating that this lipid acts via LPA1 and/or LPA3 receptor. This effect is PKC-dependent, since it is abolished by calphostin C and U73122, PKC, and PLC inhibitors, respectively. Furthermore, the addition of 10-8 M PMA, a well-known PKC activator, mimicked PMCA modulation by LPA. We also demonstrated that the PKC activation leads to an increase in PMCA phosphorylation. These results indicate that LPA triggers LPA1 and/or LPA3 receptors at the BLM, inducing PKC-dependent phosphorylation with further inhibition of PMCA. Thus, LPA is part of the regulatory lipid network present at the BLM and plays an important role in the regulation of intracellular Ca2+ concentration that may result in significant physiological alterations in other Ca2+-dependent events ascribed to the renal tissue.


Assuntos
Cálcio/metabolismo , Membrana Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Lisofosfolipídeos/farmacologia , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Receptores de Ácidos Lisofosfatídicos/genética , Animais , Fracionamento Celular , Membrana Celular/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Estrenos/farmacologia , Regulação da Expressão Gênica , Transporte de Íons/efeitos dos fármacos , Isoxazóis/farmacologia , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Naftalenos/farmacologia , Fosforilação/efeitos dos fármacos , ATPases Transportadoras de Cálcio da Membrana Plasmática/antagonistas & inibidores , ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismo , Cultura Primária de Células , Propionatos/farmacologia , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Pirrolidinonas/farmacologia , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais , Suínos , Acetato de Tetradecanoilforbol/farmacologia , Fosfolipases Tipo C/antagonistas & inibidores , Fosfolipases Tipo C/genética , Fosfolipases Tipo C/metabolismo
12.
Future Med Chem ; 13(8): 691-700, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33715419

RESUMO

Aim: To identify virtual bioisosteric replacements of two GPR40 agonists. Materials & methods: Bioinformatic docking of candidate molecules featuring a wide range of carboxylic acid bioisosteres into complex with GPR40 was performed using TAK-875 and GW9508 templates. Results: This study suggests that 2,6-difluorophenol and squaric acid motifs are the preferred bioisosteric groups for conferring GPR40 affinity. Conclusion: This study suggests that compounds 10 and 20 are worthy synthetic targets.


Assuntos
Benzofuranos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/química , Metilaminas/farmacologia , Propionatos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Sulfonas/farmacologia , Animais , Benzofuranos/metabolismo , Ciclobutanos/química , Humanos , Hipoglicemiantes/farmacologia , Metilaminas/metabolismo , Simulação de Acoplamento Molecular , Fenóis/química , Propionatos/metabolismo , Ligação Proteica , Conformação Proteica , Sulfonas/metabolismo
13.
J Enzyme Inhib Med Chem ; 36(1): 377-383, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33525941

RESUMO

A classical drug repurposing approach was applied to find new putative GPR40 allosteric binders. A two-step computational protocol was set up, based on an initial pharmacophoric-based virtual screening of the DrugBank database of known drugs, followed by docking simulations to confirm the interactions between the prioritised compounds and GPR40. The best-ranked entries showed binding poses comparable to that of TAK-875, a known allosteric agonist of GPR40. Three of them (tazarotenic acid, bezafibrate, and efaproxiral) affect insulin secretion in pancreatic INS-1 832/13 ß-cells with EC50 in the nanomolar concentration (5.73, 14.2, and 13.5 nM, respectively). Given the involvement of GPR40 in type 2 diabetes, the new GPR40 modulators represent a promising tool for therapeutic intervention towards this disease. The ability to affect GPR40 was further assessed in human breast cancer MCF-7 cells in which this receptor positively regulates growth activities (EC50 values were 5.6, 21, and 14 nM, respectively).


Assuntos
Reposicionamento de Medicamentos , Ácidos Fíbricos/farmacologia , Insulina/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Retinoides/farmacologia , Regulação Alostérica/efeitos dos fármacos , Compostos de Anilina/farmacologia , Animais , Bezafibrato/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Propionatos/farmacologia , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-Atividade
14.
Life Sci ; 270: 119138, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33524422

RESUMO

AIMS: Sodium propionate (SP) has been reported to possess an anti-inflammatory and anti-apoptotic potential by inhibiting certain signaling pathways and helps in reducing the pathological damages of the mammary gland. However, the effects of sodium propionate on attenuating Lipopolysaccharide (LPS)-induced inflammatory condition and cell damage in bovine mammary epithelial cells (bMECs) are not comprehensively studied yet. Therefore, the aim of the current investigation was to evaluate the protective effects of sodium propionate on LPS-induced inflammatory conditions and to clarify the possible underlying molecular mechanism in bMECs. MAIN METHODS: The effects of increasing doses of SP on LPS-induced inflammation, oxidative stress and apoptosis was studied in vitro. Furthermore, the underlying protective mechanisms of SP on LPS-stimulated bMECs was investigated under different experimental conditions. KEY FINDINGS: The results reveled that increased inflammatory cytokines, chemokines and those of tight junction's mRNA expression was significantly attenuated dose-dependently by propionate. Biochemical analysis revealed that propionate pretreatment modulated the LPS-induced intercellular reactive oxygen species (ROS) accumulation, oxidative and antioxidant factors and apoptosis rate. Furthermore, we investigated that the LPS activated nuclear factor-kB (NF-kB), caspase/Bax apoptotic pathways and Histone deacetylases (HDAC) was significantly attenuated by propionate in bMECs. SIGNIFICANCE: Our results suggest that sodium propionate is a potent agent for ameliorating LPS-mediated cellular disruption and limiting detrimental inflammatory responses, partly via maintaining blood milk barrier integrity, inhibiting HDAC activity and NF-kB signaling pathway.


Assuntos
Leite/efeitos dos fármacos , Propionatos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Bovinos , Células Cultivadas , China , Citocinas/metabolismo , Células Epiteliais/metabolismo , Feminino , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/metabolismo , Leite/metabolismo , NF-kappa B/metabolismo , Propionatos/metabolismo , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos
15.
Molecules ; 26(3)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525625

RESUMO

Worldwide obesity is a public health concern that has reached pandemic levels. Obesity is the major predisposing factor to comorbidities, including type 2 diabetes, cardiovascular diseases, dyslipidemia, and non-alcoholic fatty liver disease. The common forms of obesity are multifactorial and derive from a complex interplay of environmental changes and the individual genetic predisposition. Increasing evidence suggest a pivotal role played by alterations of gut microbiota (GM) that could represent the causative link between environmental factors and onset of obesity. The beneficial effects of GM are mainly mediated by the secretion of various metabolites. Short-chain fatty acids (SCFAs) acetate, propionate and butyrate are small organic metabolites produced by fermentation of dietary fibers and resistant starch with vast beneficial effects in energy metabolism, intestinal homeostasis and immune responses regulation. An aberrant production of SCFAs has emerged in obesity and metabolic diseases. Among SCFAs, butyrate emerged because it might have a potential in alleviating obesity and related comorbidities. Here we reviewed the preclinical and clinical data that contribute to explain the role of butyrate in this context, highlighting its crucial contribute in the diet-GM-host health axis.


Assuntos
Butiratos/farmacologia , Obesidade/tratamento farmacológico , Substâncias Protetoras/farmacologia , Acetatos/farmacologia , Animais , Fibras na Dieta/metabolismo , Metabolismo Energético/efeitos dos fármacos , Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Obesidade/metabolismo , Propionatos/farmacologia
16.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33540803

RESUMO

Distinct from ovarian estradiol, the steroid hormone 17ß-estradiol (E2) is produced in the brain and is involved in numerous functions, particularly acting as a neurosteroid. However, the physiological role of E2 and the mechanism of its effects are not well known. In hippocampal slices, 17ß-estradiol has been found to cause a modest increase in fast glutamatergic transmission; because some of these effects are rapid and acute, they might be mediated by membrane-associated receptors via nongenomic action. Moreover, activation of membrane estrogen receptors can rapidly modulate neuron function in a sex-specific manner. To further investigate the neurological role of E2, we examined the effect of E2, as an estrogen receptor (ER) agonist, on synaptic transmission in slices of the prefrontal cortex (PFC) and hippocampus in both male and female mice. Whole-cell recordings of spontaneous excitatory postsynaptic currents (sEPSC) in the PFC showed that E2 acts as a neuromodulator in glutamatergic transmission in the PFC in both sexes, but often in a cell-specific manner. The sEPSC amplitude and/or frequency responded to E2 in three ways, namely by significantly increasing, decreasing or having no response. Additional experiments using an agonist selective for ERß, diarylpropionitrile (DPN) showed that in males the sEPSC and spontaneous inhibitory postsynaptic currents sIPSC responses were similar to their E2 responses, but in females the estrogen receptor ß (ERß) agonist DPN did not influence excitatory transmission in the PFC. In contrast, in the hippocampus of both sexes E2 potentiated the gluatmatergic synaptic transmission in a subset of hippocampal cells. These data indicate that activation of E2 targeting probably a estrogen subtypes or different downstream signaling affect synaptic transmission in the brain PFC and hippocampus between males versus females mice.


Assuntos
Estradiol/farmacologia , Receptor alfa de Estrogênio/fisiologia , Hipocampo/metabolismo , Córtex Pré-Frontal/metabolismo , Transmissão Sináptica/fisiologia , Animais , Receptor alfa de Estrogênio/agonistas , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Feminino , GABAérgicos/farmacologia , Hipocampo/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Cinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nitrilas/farmacologia , Técnicas de Patch-Clamp , Córtex Pré-Frontal/efeitos dos fármacos , Propionatos/farmacologia , Caracteres Sexuais , Transmissão Sináptica/efeitos dos fármacos
17.
Biochem Biophys Res Commun ; 548: 91-97, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33636640

RESUMO

Autotaxin (ATX) and its product lysophosphatidic acid (LPA) have been implicated in lung fibrosis and cancer. We have studied their roles in DNA damage induced by carcinogenic crystalline silica particles (CSi). In an earlier study on bronchial epithelia, we concluded that ATX, via paracrine signaling, amplifies DNA damage. This effect was seen at 6-16 h. A succeeding study showed that CSi induced NLRP3 phosphorylation, mitochondrial depolarization, double strand breaks (DSBs), and NHEJ repair enzymes within minutes. In the current study we hypothesized a role for the ATX-LPA axis also in this rapid DNA damage. Using 16HBE human bronchial epithelial cells, we show ATX secretion at 3 min, and that ATX inhibitors (HA130 and PF8380) prevented both CSi-induced mitochondrial depolarization and DNA damage (detected by γH2AX and Comet assay analysis). Experiments with added LPA gave similar rapid effects as CSi. Furthermore, Rac1 was activated at 3 min, and a Rac1 inhibitor (NSC23766) prevented mitochondrial depolarization and genotoxicity. In mice the bronchial epithelia exhibited histological signs of ATX activation and signs of DSBs (53BP1 positive nuclei) minutes after a single inhalation of CSi. Our data indicate that CSi rapidly activate the ATX-LPA axis and within minutes this leads to DNA damage in bronchial epithelial cells. Thus, ATX mediates very rapid DNA damaging effects of inhaled particles.


Assuntos
Dano ao DNA , Diester Fosfórico Hidrolases/metabolismo , Mucosa Respiratória/patologia , Dióxido de Silício/química , Proteínas rac1 de Ligação ao GTP/metabolismo , Animais , Cristalização , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Isoxazóis/farmacologia , Lisofosfolipídeos/farmacologia , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Propionatos/farmacologia , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Receptores de Ácidos Lisofosfatídicos/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores
18.
J Hosp Infect ; 111: 69-77, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33545216

RESUMO

BACKGROUND: Up to 50% of all long-term catheterized individuals experience recurrent episodes of urinary catheter infections and blockages, leading to urine retention, pyelonephritis and septicaemia if the catheter is left in situ. We have previously reported the synergistic activity of weak organic acid (WOA) combinations against nosocomial uropathogens. AIM: To investigate the efficacy of selected WOAs, citric acid and propionic acid, alone and in combination, on prevention of crystalline biofilm formation and catheter blockages. METHODS: Static crystallization assays and dynamic in vitro bladder model assays, with scanning electron microscopy, were performed for determination of bacterial viability, urinary pH and time to catheter blockage. FINDINGS: The rate of encrustation around the catheter eyeholes was reduced in the presence of the citric acid/propionic acid combination, extending the time to blockage three-fold. CONCLUSION: Synergistic WOA combinations identified herein represent promising alternatives to antibiotics to combat the global healthcare burden of catheter-associated urinary tract infections and related blockages.


Assuntos
Obstrução do Cateter , Ácido Cítrico/farmacologia , Propionatos/farmacologia , Cateterismo Urinário , Infecções Urinárias , Biofilmes , Cateteres de Demora , Humanos , Microscopia Eletrônica de Varredura , Infecções Urinárias/prevenção & controle
19.
Sci Rep ; 11(1): 2118, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33483531

RESUMO

Lung fibrosis, or the scarring of the lung, is a devastating disease with huge unmet medical need. There are limited treatment options and its prognosis is worse than most types of cancer. We previously discovered that MK-0429 is an equipotent pan-inhibitor of αv integrins that reduces proteinuria and kidney fibrosis in a preclinical model. In the present study, we further demonstrated that MK-0429 significantly inhibits fibrosis progression in a bleomycin-induced lung injury model. In search of newer integrin inhibitors for fibrosis, we characterized monoclonal antibodies discovered using Adimab's yeast display platform. We identified several potent neutralizing integrin antibodies with unique human and mouse cross-reactivity. Among these, Ab-31 blocked the binding of multiple αv integrins to their ligands with IC50s comparable to those of MK-0429. Furthermore, both MK-0429 and Ab-31 suppressed integrin-mediated cell adhesion and latent TGFß activation. In IPF patient lung fibroblasts, TGFß treatment induced profound αSMA expression in phenotypic imaging assays and Ab-31 demonstrated potent in vitro activity at inhibiting αSMA expression, suggesting that the integrin antibody is able to modulate TGFß action though mechanisms beyond the inhibition of latent TGFß activation. Together, our results highlight the potential to develop newer integrin therapeutics for the treatment of fibrotic lung diseases.


Assuntos
Anticorpos/metabolismo , Fibroblastos/metabolismo , Integrina alfaV/metabolismo , Fibrose Pulmonar/metabolismo , Animais , Anticorpos/imunologia , Bleomicina , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Fibroblastos/citologia , Humanos , Integrina alfaV/imunologia , Masculino , Camundongos Endogâmicos C57BL , Naftiridinas/farmacologia , Propionatos/farmacologia , Ligação Proteica , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/prevenção & controle
20.
Sci Rep ; 11(1): 595, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436729

RESUMO

This paper proposes the use of astrocytes to realize Boolean logic gates, through manipulation of the threshold of [Formula: see text] ion flows between the cells based on the input signals. Through wet-lab experiments that engineer the astrocytes cells with pcDNA3.1-hGPR17 genes as well as chemical compounds, we show that both AND and OR gates can be implemented by controlling [Formula: see text] signals that flow through the population. A reinforced learning platform is also presented in the paper to optimize the [Formula: see text] activated level and time slot of input signals [Formula: see text] into the gate. This design platform caters for any size and connectivity of the cell population, by taking into consideration the delay and noise produced from the signalling between the cells. To validate the effectiveness of the reinforced learning platform, a [Formula: see text] signalling simulator was used to simulate the signalling between the astrocyte cells. The results from the simulation show that an optimum value for both the [Formula: see text] activated level and time slot of input signals [Formula: see text] is required to achieve up to 90% accuracy for both the AND and OR gates. Our method can be used as the basis for future Neural-Molecular Computing chips, constructed from engineered astrocyte cells, which can form the basis for a new generation of brain implants.


Assuntos
Astrócitos/metabolismo , Sinalização do Cálcio , Cálcio/metabolismo , Simulação por Computador , Mecanotransdução Celular , Receptores Acoplados a Proteínas G/metabolismo , Astrócitos/efeitos dos fármacos , Células Cultivadas , Humanos , Indóis/farmacologia , Ativação do Canal Iônico , Lógica , Modelos Biológicos , Propionatos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/genética
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