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1.
Acta Biochim Biophys Sin (Shanghai) ; 52(1): 26-37, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31889181

RESUMO

Chlorine is shown to possess anti-gastric ulcer activity, since it can inactivate Helicobacter pylori, which is regarded as one of the most common risk factors for causing gastric problems. In the current study, the gastroprotective property of a novel dichloro-substituted Schiff base complex, 2, 2'- [-1, 2-cyclohexanediylbis(nitriloethylidyne)] bis(4-chlorophenol) (CNCP), against alcohol-induced gastric lesion in SD rats was assessed. SD rats were divided into four groups, i.e. normal, ulcer control, testing, and reference groups. Ulcer area, gastric wall mucus, and also gastric acidity of the animal stomachs were measured. In addition, antioxidant activity of CNCP was evaluated and its safe dose was identified. Immunohistochemistry staining was also carried to evaluate two important proteins, i.e. Bcl2-associated X protein (Bax) and heat shock protein 70 (HSP70). Moreover, the activities of super oxide dismutase and catalase, as well as the levels of prostaglandin E2 (PGE2) and malondialdehyde (MDA) were also measured. Antioxidant activity of CNCP was approved via the aforementioned experiments. Histological evaluations showed that the compound possesses stomach epithelial defense activity. Additionally, periodic acid-Schiff staining exhibited over-expression of HSP70 and down-expression of Bax protein in the CNCP-treated rats. Moreover, CNCP caused deceased MDA level and elevated PGE2 level, and at the same time increased the activities of the two enzymes.


Assuntos
Antioxidantes/uso terapêutico , Proteínas de Choque Térmico HSP70/metabolismo , Bases de Schiff/toxicidade , Bases de Schiff/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Úlcera Gástrica/tratamento farmacológico , Proteína X Associada a bcl-2/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Catalase/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Clorofenóis/química , Dinoprostona/metabolismo , Modelos Animais de Doenças , Etanol/efeitos adversos , Etanol/farmacologia , Feminino , Fibroblastos/metabolismo , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Testes de Função Renal , Testes de Função Hepática , Masculino , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Bases de Schiff/química , Úlcera Gástrica/induzido quimicamente , Superóxido Dismutase/metabolismo
2.
Chemosphere ; 239: 124709, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31499302

RESUMO

The effect of organic fertilizers on soil phosphorus (P) availability is usually mainly associated with the rate and forms of P applied, while they also alter the soil physical-chemical properties, able to change P availability. We aimed to highlight the impact of pH and organic C modifications in soil on the inorganic P (Pi) sorption capacity and availability as compared to the effect of P accumulation after mineral or organic fertilizers. We conducted a 10-years-old field experiment on an andosol and compared fields that had been amended with mineral or organic (dairy slurry and manure compost) fertilizers against a non-fertilized control. Water and Olsen extractions and Pi sorption experiments were realized on soils sampled after 6 and 10 years of trial. We also realized an artificial and ex situ alkalization of the control soil to isolate the effect of pH on Pi sorption capacity. Organic fertilizer application increased total P, pH, and organic C in soil. Pi-Olsen increased mainly with soil total P (r2 adj = 0.79), while Pi-water increased jointly with soil total P and pH (r2 adj = 0.85). The Pi sorption capacity decreased with organic fertilizer application. Artificial and ex situ alkalization of the control soil showed that Pi sorption capacity decreased with increasing pH. Our study demonstrated that, beyond the P fertilization rate, the increase in organic C content and even more so in pH induced by a decade of organic fertilizer applications in soil decreased the Pi sorption capacity and consequently increased Pi-water in soil.


Assuntos
Fertilizantes , Fósforo/química , Solo/química , Adsorção , Carbono , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Esterco , Minerais , Fósforo/análise , Fósforo/farmacologia , Solo/normas
3.
World J Gastroenterol ; 25(37): 5578-5589, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31602159

RESUMO

Helicobacter pylori (H. pylori) is a gram-negative bacterium that infects approximately 4.4 billion individuals worldwide. However, its prevalence varies among different geographic areas, and is influenced by several factors. The infection can be acquired by means of oral-oral or fecal-oral transmission, and the pathogen possesses various mechanisms that improve its capacity of mobility, adherence and manipulation of the gastric microenvironment, making possible the colonization of an organ with a highly acidic lumen. In addition, H. pylori presents a large variety of virulence factors that improve its pathogenicity, of which we highlight cytotoxin associated antigen A, vacuolating cytotoxin, duodenal ulcer promoting gene A protein, outer inflammatory protein and gamma-glutamyl transpeptidase. The host immune system, mainly by means of a Th1-polarized response, also plays a crucial role in the infection course. Although most H. pylori-positive individuals remain asymptomatic, the infection predisposes the development of various clinical conditions as peptic ulcers, gastric adenocarcinomas and mucosa-associated lymphoid tissue lymphomas. Invasive and non-invasive diagnostic methods, each of them with their related advantages and limitations, have been applied in H. pylori detection. Moreover, bacterial resistance to antimicrobial therapy is a major challenge in the treatment of this infection, and new therapy alternatives are being tested to improve H. pylori eradication. Last but not least, the development of effective vaccines against H. pylori infection have been the aim of several research studies.


Assuntos
Mucosa Gástrica/microbiologia , Infecções por Helicobacter/terapia , Helicobacter pylori/patogenicidade , Gastropatias/terapia , Antiácidos/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Vacinas Bacterianas/uso terapêutico , Farmacorresistência Bacteriana , Quimioterapia Combinada , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/transmissão , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/imunologia , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Probióticos/administração & dosagem , Inibidores da Bomba de Prótons/uso terapêutico , Gastropatias/diagnóstico , Gastropatias/microbiologia , Resultado do Tratamento , Fatores de Virulência/metabolismo
4.
Nat Commun ; 10(1): 4731, 2019 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-31636264

RESUMO

Compounds with specific cytotoxic activity in senescent cells, or senolytics, support the causal involvement of senescence in aging and offer therapeutic interventions. Here we report the identification of Cardiac Glycosides (CGs) as a family of compounds with senolytic activity. CGs, by targeting the Na+/K+ATPase pump, cause a disbalanced electrochemical gradient within the cell causing depolarization and acidification. Senescent cells present a slightly depolarized plasma membrane and higher concentrations of H+, making them more susceptible to the action of CGs. These vulnerabilities can be exploited for therapeutic purposes as evidenced by the in vivo eradication of tumors xenografted in mice after treatment with the combination of a senogenic and a senolytic drug. The senolytic effect of CGs is also effective in the elimination of senescence-induced lung fibrosis. This experimental approach allows the identification of compounds with senolytic activity that could potentially be used to develop effective treatments against age-related diseases.


Assuntos
Apoptose/efeitos dos fármacos , Glicosídeos Cardíacos/farmacologia , Senescência Celular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Células A549 , Animais , Antibióticos Antineoplásicos/farmacologia , Bleomicina/farmacologia , Neoplasias da Mama , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Digoxina/farmacologia , Feminino , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Camundongos , Osteoartrite , Ouabaína/farmacologia , Proscilaridina/farmacologia , Fibrose Pulmonar , Ensaios Antitumorais Modelo de Xenoenxerto
5.
World J Gastroenterol ; 25(34): 5097-5104, 2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31558859

RESUMO

The survival and replication cycle of Helicobacter pylori (H. pylori) is strictly dependant on intragastric pH, since H. pylori enters replicative phase at an almost neutral pH (6-7), while at acid pH (3-6) it turns into its coccoid form, which is resistant to antibiotics. On these bases, it is crucial to increase intragastric pH by proton pump inhibitors (PPIs) when an antibiotic-based eradicating therapy needs to be administered. Therefore, several tricks need to be used to optimize eradication rate of different regimens. The administration of the highest dose as possible of PPI, by doubling or increasing the number of pills/day, has shown to be able to improve therapeutic outcome and has often proposed in rescue therapies, even if specific trials have not been performed. A pre-treatment with PPI before starting antibiotics does not seem to be effective, therefore it is discouraged. However, the choice of PPI molecule could have a certain weight, since second-generation substances (esomeprazole, rabeprazole) are likely more effective than those of first generation (omeprazole, lansoprazole). A possible explanation is due to their metabolism, which has been proven to be less dependent on cytochrome P450 (CYP) 2C19 genetic variables. Finally, vonoprazan, a competitive inhibitor of H+/K+-ATPase present on luminal membrane of gastric parietal cells has shown the highest efficacy, due to both its highest acid inhibition power and rapid pharmacologic effect. However current data come only from Eastern Asia, therefore its strong power needs to be confirmed outside this geographic area in Western countries as well as related to the local different antibiotic resistance rates.


Assuntos
Antibacterianos/administração & dosagem , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/efeitos dos fármacos , Inibidores da Bomba de Prótons/administração & dosagem , Relação Dose-Resposta a Droga , Quimioterapia Combinada/métodos , Mucosa Gástrica/química , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/microbiologia , ATPase Trocadora de Hidrogênio-Potássio/metabolismo , Infecções por Helicobacter/microbiologia , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Resultado do Tratamento
6.
Med Hypotheses ; 131: 109320, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443769

RESUMO

In animal experiments, neuroprotective, anticonvulsive and antidepressant-like properties have been increasingly attributed to administrations of ascorbic acid (AA, vitamin C) in at least medium (low millimolar) doses, which however await validation in well controlled clinical studies. In mammalian cortical and subcortical neurons, small to modest acidification (<0.4-0.5 pH-units) is belonging to the key strategies for controlling local excitability and is associated with neuroprotection, e.g. by limiting excitotoxicity. Such acidifications are furthermore involved in the mechanisms of some anticonvulsants and antidepressants. As AA-transport and regulation of intracellular pH (pHi) are closely interwoven on the level of special transmembrane solute carriers, I suppose that the aforementioned beneficial AA-effects might be based upon a discrete "hormetic" acidification of cortical and or subcortical neurons via an AA-mediated weakening of their pHi-regulation. This assumption is supported by findings in non-neuronal cells suggesting both, intracellular acidification and inhibition of a core-element of the pHi-regulation apparatus by millimolar AA. In mammalian subcortical neurons, there is already first evidence of a modest acidification after adding low millimolar AA.


Assuntos
Anticonvulsivantes/farmacologia , Antidepressivos/farmacologia , Ácido Ascórbico/farmacologia , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Líquido Intracelular/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/tratamento farmacológico , Animais , Anticonvulsivantes/uso terapêutico , Antidepressivos/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Ácido Ascórbico/uso terapêutico , Encéfalo/citologia , Proteínas de Transporte/metabolismo , Cátions/metabolismo , Ácido Desidroascórbico/metabolismo , Transtorno Depressivo/tratamento farmacológico , Epilepsia/tratamento farmacológico , Humanos , Líquido Intracelular/química , Mamíferos , Alvo Mecanístico do Complexo 1 de Rapamicina/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Oxirredução
7.
Eur J Pharm Sci ; 138: 105012, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31330259

RESUMO

New 6-triazolyl-substituted sulfocoumarins were described as potent inhibitors of the transmembrane human carbonic anhydrase isoforms, CAIX and CAXII. These membrane associated enzymes that maintain pH and CO2 homeostasis are involved in cancer progression, invasion, and resistance to therapy. Recently, it was shown that CAXII expression associates with the expression of P-glycoprotein in multidrug resistant cancer cells. CAXII regulates P-glycoprotein activity by maintaining high intracellular pHi. In this study, the activity of three new sulfocoumarins was evaluated in three sensitive and corresponding multidrug resistant cancer cell lines with increased P-glycoprotein expression (non-small cell lung carcinoma, colorectal carcinoma and glioblastoma). Compound 3 showed the highest potential for cancer cell growth inhibition in all tested cell lines. Flow cytometric analyses showed that compound 3 induced intracellular acidification, cell cycle arrest in G2/M phase and necrosis in non-small cell lung carcinoma cells. Compound 3 demonstrated irreversible, concentration- and time-dependent inhibition of P-glycoprotein activity in multidrug resistant non-small cell lung carcinoma cells. The suppression of P-glycoprotein activity was accompanied with increased P-glycoprotein expression suggesting a compensatory mechanism of multidrug resistant cancer cells. In addition, compound 3 was able to sensitize multidrug resistant non-small cell lung carcinoma cells to doxorubicin. Overall, results imply that compound 3 has multidrug resistance modulating effect through intracellular acidification and subsequent inhibition of P-glycoprotein activity.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Anidrase Carbônica IX/antagonistas & inibidores , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Neoplasias/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Neoplasias/metabolismo , Fenótipo
8.
J Dermatol ; 46(6): 457-465, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31106905

RESUMO

The pH of the skin surface increases with age and thus reduces epidermal barrier function. Aged skin needs appropriate skin care to counterbalance age-related pH increase and improve barrier function. This confirmatory randomized study investigated the efficacy of water-in-oil (w/o) emulsions with either pH 4 or pH 5.8 in 20 elderly subjects after 4 weeks of treatment. After the treatment, the skin was challenged with a sodium dodecyl sulphate (SDS) solution in order to analyze barrier protection properties of both formulations. The pH 4 w/o emulsion resulted in a significantly lower skin pH compared with the pH 5.8 w/o emulsion and an improved skin hydration after 4-week treatment. Further, the pH 4 emulsion led to more pronounced improvements in length of intercellular lipid lamellae, lamellar organization as well as lipid levels than the pH 5.8 emulsion. Following SDS-induced barrier damage to the skin, the pH of all test areas increased, but the area treated with the pH 4 emulsion showed the lowest increase compared with baseline. In addition, even after the SDS challenge the skin area treated with the pH 4 emulsion still maintained a significantly increased length of intercellular lipid lamellae compared with the beginning of the study. This study provides evidence that topical application of a w/o emulsion with pH 4 reacidifies the skin in elderly and has beneficial effects on skin moisturization, regeneration of lipid lamellae and lipid content. Application of a pH 4 emulsion can improve the epidermal barrier as well as the stratum corneum organization in aged skin.


Assuntos
Cosméticos/administração & dosagem , Epiderme/metabolismo , Envelhecimento da Pele/efeitos dos fármacos , Perda Insensível de Água/efeitos dos fármacos , Administração Cutânea , Idoso , Método Duplo-Cego , Emulsões , Epiderme/efeitos dos fármacos , Epiderme/ultraestrutura , Espaço Extracelular/diagnóstico por imagem , Espaço Extracelular/metabolismo , Feminino , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Óleos/química , Permeabilidade/efeitos dos fármacos , Envelhecimento da Pele/fisiologia , Dodecilsulfato de Sódio/farmacologia , Resultado do Tratamento , Água/química
9.
J Am Soc Nephrol ; 30(6): 946-961, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31097611

RESUMO

BACKGROUND: Antagonists of the V1a vasopressin receptor (V1aR) are emerging as a strategy for slowing progression of CKD. Physiologically, V1aR signaling has been linked with acid-base homeostasis, but more detailed information is needed about renal V1aR distribution and function. METHODS: We used a new anti-V1aR antibody and high-resolution microscopy to investigate Va1R distribution in rodent and human kidneys. To investigate whether V1aR activation promotes urinary H+ secretion, we used a V1aR agonist or antagonist to evaluate V1aR function in vasopressin-deficient Brattleboro rats, bladder-catheterized mice, isolated collecting ducts, and cultured inner medullary collecting duct (IMCD) cells. RESULTS: Localization of V1aR in rodent and human kidneys produced a basolateral signal in type A intercalated cells (A-ICs) and a perinuclear to subapical signal in type B intercalated cells of connecting tubules and collecting ducts. Treating vasopressin-deficient Brattleboro rats with a V1aR agonist decreased urinary pH and tripled net acid excretion; we observed a similar response in C57BL/6J mice. In contrast, V1aR antagonist did not affect urinary pH in normal or acid-loaded mice. In ex vivo settings, basolateral treatment of isolated perfused medullary collecting ducts with the V1aR agonist or vasopressin increased intracellular calcium levels in ICs and decreased luminal pH, suggesting V1aR-dependent calcium release and stimulation of proton-secreting proteins. Basolateral treatment of IMCD cells with the V1aR agonist increased apical abundance of vacuolar H+-ATPase in A-ICs. CONCLUSIONS: Our results show that activation of V1aR contributes to urinary acidification via H+ secretion by A-ICs, which may have clinical implications for pharmacologic targeting of V1aR.


Assuntos
Equilíbrio Ácido-Base/efeitos dos fármacos , Receptores de Vasopressinas/efeitos dos fármacos , Vasopressinas/farmacologia , Equilíbrio Ácido-Base/genética , Animais , Células Cultivadas/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Imunofluorescência , Células HEK293/efeitos dos fármacos , Células HEK293/metabolismo , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Imuno-Histoquímica , Túbulos Renais Coletores/citologia , Túbulos Renais Coletores/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Ratos Brattleboro , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real/métodos , Receptores de Vasopressinas/genética , Sensibilidade e Especificidade , Urinálise/métodos
10.
Cells ; 8(5)2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31108937

RESUMO

ß-site APP-cleaving enzyme 1 (BACE1) initiates amyloid precursor protein (APP) cleavage and ß-amyloid (Aß) production, a critical step in the pathogenesis of Alzheimer's disease (AD). It is thus of considerable interest to investigate how BACE1 activity is regulated. BACE1 has its maximal activity at acidic pH and GFP variant-pHluorin-displays pH dependence. In light of these observations, we generated three tandem fluorescence-tagged BACE1 fusion proteins, named pHluorin-BACE1-mCherry, BACE1-mCherry-pHluorin and BACE1-mCherry-EGFP. Comparing the fluorescence characteristics of these proteins in response to intracellular pH changes induced by chloroquine or bafilomycin A1, we found that pHluorin-BACE1-mCherry is a better pH sensor for BACE1 because its fluorescence intensity responds to pH changes more dramatically and more quickly. Additionally, we found that (pro)renin receptor (PRR), a subunit of the v-ATPase complex, which is critical for maintaining vesicular pH, regulates pHluorin's fluorescence and BACE1 activity in pHluorin-BACE1-mCherry expressing cells. Finally, we found that the expression of Swedish mutant APP (APPswe) suppresses pHluorin fluorescence in pHluorin-BACE1-mCherry expressing cells in culture and in vivo, implicating APPswe not only as a substrate but also as an activator of BACE1. Taken together, these results suggest that the pHluorin-BACE1-mCherry fusion protein may serve as a useful tool for visualizing active/inactive BACE1 in culture and in vivo.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Proteínas Luminescentes/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Linhagem Celular Tumoral , Cloroquina/farmacologia , Feminino , Fluorescência , Células HEK293 , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Macrolídeos/farmacologia , Masculino , Camundongos , Receptores de Superfície Celular/metabolismo , Transfecção , ATPases Vacuolares Próton-Translocadoras/metabolismo
11.
Biochim Biophys Acta Proteins Proteom ; 1867(6): 595-603, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30954577

RESUMO

Methanotrophs play a prominent role in the global carbon cycle, by oxidizing the potent greenhouse gas methane to CO2. Methane is first converted into methanol by methane monooxygenase. This methanol is subsequently oxidized by either a calcium-dependent MxaF-type or a lanthanide-dependent XoxF-type methanol dehydrogenase (MDH). Electrons from methanol oxidation are shuttled to a cytochrome redox partner, termed cytochrome cL. Here, the cytochrome cL homolog from the thermoacidophilic methanotroph Methylacidiphilum fumariolicum SolV was characterized. SolV cytochrome cGJ is a fusion of a XoxG cytochrome and a periplasmic binding protein XoxJ. Here we show that XoxGJ functions as the direct electron acceptor of its corresponding XoxF-type MDH and can sustain methanol turnover, when a secondary cytochrome is present as final electron acceptor. SolV cytochrome cGJ (XoxGJ) further displays a unique, red-shifted absorbance spectrum, with a Soret and Q bands at 440, 553 and 595 nm in the reduced state, respectively. VTVH-MCD spectroscopy revealed the presence of a low spin iron heme and the data further shows that the heme group exhibits minimal ruffling. The midpoint potential Em,pH7 of +240 mV is similar to other cytochrome cL type proteins but remarkably, the midpoint potential of cytochrome cGJ was not influenced by lowering the pH. Cytochrome cGJ represents the first example of a cytochrome from a strictly lanthanide-dependent methylotrophic microorganism.


Assuntos
Citocromos c/química , Citocromos c/metabolismo , Verrucomicrobia/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Citocromos c/genética , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Elementos da Série dos Lantanídeos/metabolismo , Óperon , Verrucomicrobia/genética
12.
Int J Mol Sci ; 20(5)2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30836626

RESUMO

A deeper understanding of the detailed mechanism of in vivo tissue healing is necessary for the development of novel regenerative therapies. Among several external factors, environmental pH is one of the crucial parameters that greatly affects enzyme activity and cellular biochemical reactions involving tissue repair and homeostasis. In this study, in order to analyze the microenvironmental conditions during bone healing, we first measured the pH in vivo at the bone healing site using a high-resolution fiber optic pH microsensor directly in femur defects and tooth extraction sockets. The pH was shown to decrease from physiological 7.4 to 6.8 during the initial two days of healing (inflammatory phase). In the same initial stages of the inflammatory phase of the bone healing process, mesenchymal stem cells (MSCs) are known to migrate to the healing site to contribute to tissue repair. Therefore, we investigated the effect of a short-term acidic (pH 6.8) pre-treatment on the stemness of bone marrow-derived MSCs (BMSCs). Interestingly, the results showed that pre-treatment of BMSCs with acidic pH enhances the expression of stem cell markers (OCT-4, NANOG, SSEA-4), as well as cell viability and proliferation. On the other hand, acidic pH decreased BMSC migration ability. These results indicate that acidic pH during the initial stages of bone healing is important to enhance the stem cell properties of BMSCs. These findings may enable the development of novel methods for optimization of stem cell function towards tissue engineering or regenerative medicine.


Assuntos
Ácidos/farmacologia , Regeneração Óssea/genética , Osteogênese/efeitos dos fármacos , Engenharia Tecidual/métodos , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Regeneração Óssea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Microambiente Celular/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Proteína Homeobox Nanog/genética , Fator 3 de Transcrição de Octâmero/genética , Medicina Regenerativa , Antígenos Embrionários Estágio-Específicos/genética , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Cicatrização/genética
13.
Intern Med ; 58(12): 1723-1726, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30799357

RESUMO

A 40-year-old man suffered from short bowel syndrome. Since a large amount of intestinal output and watery diarrhea hampered his quality of life, we tried to control the intestinal output by reducing the secretion of gastric acid with lansoprazole. Because the small intestine was only 10 cm in length and effective absorption of oral lansoprazole was doubtful, we monitored his intragastric pH for 24 hours and confirmed that the holding time above pH 3.0 was 14.5 hours (60.4%). He spent his home life eating porridge during the day, and receiving total parenteral nutrition of 1,100 mL/day at night while taking lansoprazole as an oral tablet (30 mg) once a day.


Assuntos
Antiulcerosos/uso terapêutico , Ácido Gástrico/metabolismo , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Lansoprazol/uso terapêutico , Síndrome do Intestino Curto/tratamento farmacológico , Adulto , Humanos , Masculino , Qualidade de Vida
14.
J Anim Sci ; 97(3): 1347-1363, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30753501

RESUMO

The objective of this trial was to determine the benefits of supplementing active dried yeast (ADY; 3 × 1010 CFU/d of Saccharomyces cerevisiae) in diets of growing and finishing steers on ruminal pH and liver health, and evaluate the relationship of these variables with performance traits. Growing beef steers (n = 120) were blocked by weight (i.e., heavy and light) and allocated to 1 of 4 pens in an automated feed intake monitoring system. Steers were fed either control (CON; no ADY) or ADY supplemented in 4 sequential diets: grower diet from days 0 to 70, 2 step up diets (STEP1 and STEP2) for 7 d each, and finishing diet from days 85 to 164. Indwelling rumen boli were administered to monitor rumen pH during days 56 to 106 during the dietary transition. An exchange of pen assignment, within block, occurred on day 70 resulting in 4 final treatment (TRT) assignments: steers fed CON before and after the exchange (CC; n = 30), steers fed CON before and ADY after the exchange (CY; n = 30), steers fed ADY before and CON after the exchange (YC; n = 30), and steers fed ADY (YY; n = 30). Ruminal parameters were analyzed as a randomized complete block design with repeated measures of day, diet and TRT as fixed effects, and block as random effects, using 2 approaches: preliminary analysis of the means or drift analysis (DA; units change from basal values over time). Ruminal pH duration (DUR) below 6.0 (P = 0.05) and 5.8 (P = 0.05) was greater for CY steers than CC steers. Acidosis bout prevalence (pH < 5.6 for 180 consecutive minutes; P < 0.01) and bout DUR (P = 0.05) were greater for CY than other TRT groups. The DA indicated that the ruminal pH variables range, variance, and amplitude of steers in the YC group drifted further from basal pH values than CY and YY steers during the dietary transition (P ≤ 0.02), indicating that removing ADY during the dietary transition was not favorable, but including ADY may reduce ruminal fluctuation. Steers with fewer days experiencing bouts (DEB) had numerically greater ADG (P = 0.11) and tended to have greater G:F (P = 0.06). Liver abscess severity negatively affected ADG (P = 0.04). However, liver abscess severity was not affected by DEB (P = 0.90). There is evidence to suggest that the addition of the specific ADY strain in the diets of beef cattle during the dietary transition may aid in ruminal stabilization, but our study did not find evidence that acidosis bouts were related to abscess prevalence or severity.


Assuntos
Acidose/veterinária , Ração Animal/análise , Doenças dos Bovinos/prevenção & controle , Suplementos Nutricionais , Abscesso Hepático/veterinária , Fermento Seco/farmacologia , Acidose/epidemiologia , Acidose/prevenção & controle , Animais , Bovinos , Doenças dos Bovinos/epidemiologia , Dieta/veterinária , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/fisiologia , Abscesso Hepático/epidemiologia , Abscesso Hepático/prevenção & controle , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Masculino , Prevalência , Distribuição Aleatória , Rúmen/metabolismo
15.
J Vet Intern Med ; 33(2): 544-550, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30746763

RESUMO

BACKGROUND: Famotidine is commonly administered to cats. Prolonged famotidine administration results in decreased efficacy in humans, dogs, and cows, but the long-term effects in cats are unknown. OBJECTIVES: To compare the effect of 2 oral administration frequencies of famotidine, twice daily (Group 1) and twice daily every second day (Group 2), on intragastric pH and serum gastrin concentrations in cats. We hypothesized a diminished effect on intragastric pH would be observed over time in Group 1 but not Group 2. ANIMALS: Sixteen healthy cats. METHODS: Randomized, 2-factor repeated measures crossover design. Cats received 0.5-1.24 mg/kg (median, 0.87 mg/kg) famotidine twice daily or twice daily every second day for 14 consecutive days. Intragastric pH monitoring was used to record intragastric pH on treatment days 1-3 and 11-13. Mean pH and mean percentage time (MPT) intragastric pH was ≥3 and 4 were compared between and within treatment groups by analysis of variance. RESULTS: Significant treatment group by time interactions were observed for mean intragastric pH, MPT intragastric pH ≥3 and 4 (P = .009, P = .02, P = .005, respectively). Interaction post hoc tests identified significant decreases in mean intragastric pH (P = .001), MPT ≥3 (P = .001), and MPT ≥4 (P = .001) on day 13 compared to day 1 in Group 1 but not in Group 2. CONCLUSIONS AND CLINICAL IMPORTANCE: Oral famotidine administration results in a diminished effect on intragastric pH in healthy cats when given twice daily every day.


Assuntos
Antiulcerosos/farmacologia , Gatos/metabolismo , Famotidina/farmacologia , Ácido Gástrico/metabolismo , Administração Oral , Animais , Antiulcerosos/administração & dosagem , Estudos Cross-Over , Esquema de Medicação/veterinária , Famotidina/administração & dosagem , Feminino , Determinação da Acidez Gástrica/veterinária , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Masculino , Distribuição Aleatória
16.
Pharmacol Res Perspect ; 7(1): e00454, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30705757

RESUMO

Despite intensive treatments including temozolomide (TMZ) administration, glioblastoma patient prognosis remains dismal and innovative therapeutic strategies are urgently needed. A systems pharmacology approach was undertaken to investigate TMZ pharmacokinetics-pharmacodynamics (PK-PD) incorporating the effect of local pH, tumor spatial configuration and micro-environment. A hybrid mathematical framework was designed coupling ordinary differential equations describing the intracellular reactions, with a spatial cellular automaton to individualize the cells. A differential drug impact on tumor and healthy cells at constant extracellular pH was computationally demonstrated as TMZ-induced DNA damage was larger in tumor cells as compared to normal cells due to less acidic intracellular pH in cancer cells. Optimality of TMZ efficacy defined as maximum difference between damage in tumor and healthy cells was reached for extracellular pH between 6.8 and 7.5. Next, TMZ PK-PD in a solid tumor was demonstrated to highly depend on its spatial configuration as spread cancer cells or fragmented tumors presented higher TMZ-induced damage as compared to compact tumor spheroid. Simulations highlighted that smaller tumors were less acidic than bigger ones allowing for faster TMZ activation and their closer distance to blood capillaries allowed for better drug penetration. For model parameters corresponding to U87 glioma cells, inter-cell variability in TMZ uptake play no role regarding the mean drug-induced damage in the whole cell population whereas this quantity was increased by inter-cell variability in TMZ efflux which was thus a disadvantage in terms of drug resistance. Overall, this study revealed pH as a new potential target to significantly improve TMZ antitumor efficacy.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Temozolomida/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Simulação por Computador , Citoplasma/química , Dano ao DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Espaço Extracelular/química , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Modelos Biológicos , Modelos Químicos , Esferoides Celulares , Temozolomida/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos
17.
Cell Death Dis ; 10(1): 25, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30631035

RESUMO

Acidosis is a significant feature of the tumor microenvironment in glioma, and it is closely related to multiple biological functions of cancer stem cells. Here, we found that the self-renewal ability, the mitochondrial activity and ATP production were elevated in stem cell-like glioma cells (SLCs) under acidic microenvironment, which promoted and maintained the stemness of SLCs. Under acidosis, 25-hydroxy vitamin D3-24-hydroxylase (CYP24A1) was upregulated and catalyzed the fast degradation of 1α,25(OH)2D3. We further revealed that the active form of vitamin D (1α,25(OH)2D3) could inhibit the expression of stemness markers, attenuate acidosis-induced increase of self-renewal ability and mitochondrial respiration in stem cell-like glioma cells. Our study indicates that the acidosis-CYP24A1-vitamin D pathway may be a key regulator of the cancer stem cell phenotype in malignant glioma and point out the potential value for the utilization of vitamin D to target cancer stem cells and to restrain the growth of malignant glioma in the future.


Assuntos
Acidose/metabolismo , Neoplasias Encefálicas/metabolismo , Calcitriol/metabolismo , Glioma/metabolismo , Mitocôndrias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Vitamina D3 24-Hidroxilase/metabolismo , Acidose/induzido quimicamente , Acidose/genética , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Autorrenovação Celular/efeitos dos fármacos , Meios de Cultura Livres de Soro/química , Glioma/patologia , Xenoenxertos , Humanos , Ácido Clorídrico/farmacologia , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/genética , Fenótipo , Hidróxido de Sódio/farmacologia , Transcriptoma , Microambiente Tumoral/efeitos dos fármacos , Vitamina D3 24-Hidroxilase/genética
18.
J Cell Sci ; 132(3)2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30617110

RESUMO

The dipeptide glycyl-l-phenylalanine 2-naphthylamide (GPN) is widely used to perturb lysosomes because its cleavage by the lysosomal enzyme cathepsin C is proposed to rupture lysosomal membranes. We show that GPN evokes a sustained increase in lysosomal pH (pHly), and transient increases in cytosolic pH (pHcyt) and Ca2+ concentration ([Ca2+]c). None of these effects require cathepsin C, nor are they accompanied by rupture of lysosomes, but they are mimicked by structurally unrelated weak bases. GPN-evoked increases in [Ca2+]c require Ca2+ within the endoplasmic reticulum (ER), but they are not mediated by ER Ca2+ channels amplifying Ca2+ release from lysosomes. GPN increases [Ca2+]c by increasing pHcyt, which then directly stimulates Ca2+ release from the ER. We conclude that physiologically relevant increases in pHcyt stimulate Ca2+ release from the ER in a manner that is independent of IP3 and ryanodine receptors, and that GPN does not selectively target lysosomes.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Cálcio/metabolismo , Citosol/efeitos dos fármacos , Dipeptídeos/farmacologia , Retículo Endoplasmático/efeitos dos fármacos , Transporte Biológico , Sistemas CRISPR-Cas , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Catepsina C/genética , Catepsina C/metabolismo , Linhagem Celular Tumoral , Citosol/metabolismo , Retículo Endoplasmático/metabolismo , Edição de Genes , Expressão Gênica , Técnicas de Silenciamento de Genes , Células HEK293 , Células HeLa , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Receptores de Inositol 1,4,5-Trifosfato/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Leucócitos/citologia , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Glicoproteínas de Membrana Associadas ao Lisossomo/genética , Glicoproteínas de Membrana Associadas ao Lisossomo/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Ploidias , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo
19.
Int J Surg ; 62: 5-11, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30639574

RESUMO

BACKGROUND: Phenylephrine is the first-line vasoactive drug in the cesarean section under spinal anesthesia. The rate of hypotension remains high after intravenous preventive use of phenylephrine. However, few studies have investigated the effect of preventive intramuscular phenylephrine via a longer period of usage on fetal and maternal outcomes. METHODS: A total of 99 healthy parturients undergoing elective cesarean delivery were randomly allocated into three groups: M group (preventive intramuscular use of 5 mg phenylephrine), V group (preventive intravenous use of 100 µg phenylephrine), and P group (0.9% normal saline placebo). Rescue phenylephrine, ephedrine and atropine were used intraoperatively to adjust blood pressure and heart rate. The primary outcome was umbilical artery pH. RESULTS: Significant differences in umbilical artery pH (M group: 7.32 ±â€¯0.05 versus V group: 7.25 ±â€¯0.04 versus P group: 7.21 ±â€¯0.03, P < 0.05), fetal acidosis (M group: 3% [n = 33] versus V group: 15% [n = 33] versus P group: 30% [n = 33], P = 0.01) and maternal intraoperative hypotension (M group: 12% [33] versus V group: 39% [33] versus P group: 73% [33], P < 0.0001) were identified among the groups. Multiple linear regression analysis demonstrated that treating arms, neonatal birthweight and the interval from the end of anesthesia to baby delivery were associated with umbilical artery pH. CONCLUSION: Compared with the preventive intravenous use of phenylephrine and placebo, preventive intramuscular phenylephrine exhibited a better neonatal acid-base status and more stable maternal hemodynamics in elective cesarean under spinal anesthesia.


Assuntos
Anestesia Obstétrica/efeitos adversos , Raquianestesia/efeitos adversos , Cesárea/métodos , Hipotensão/prevenção & controle , Fenilefrina/administração & dosagem , Vasoconstritores/administração & dosagem , Adulto , Anestesia Obstétrica/métodos , Pressão Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Procedimentos Cirúrgicos Eletivos , Efedrina/uso terapêutico , Feminino , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Hipotensão/etiologia , Recém-Nascido , Injeções Intramusculares , Injeções Intravenosas , Complicações Intraoperatórias/prevenção & controle , Fenilefrina/farmacologia , Fenilefrina/uso terapêutico , Gravidez , Resultado da Gravidez , Artérias Umbilicais/metabolismo , Vasoconstritores/farmacologia , Vasoconstritores/uso terapêutico
20.
Curr Drug Targets ; 20(1): 111-121, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30124148

RESUMO

The H+-gated (proton) currents are widely present in brain sensory neuronal system and various studies identified the structural units and deciphered the physiological and pathological function of ion channels. The normal neuron requires an optimal pH to carry out its functions. In acidosis, the ASICs (Acid-sensing Ion Channels) are activated in both the CNS (central nervous system) and PNS (peripheral nervous system). ASICs are related to degenerin channels (DEGs), epithelial sodium cation channels (ENaCs), and FMRF-amide (Phe-Met-Arg-Phe-NH2)-gated channels (FaNaC). Its activation leads physiologically to pain perception, synaptic plasticity, learning and memory, fear, ischemic neuronal injury, seizure termination, neuronal degeneration, and mechanosensation. It detects the level of acid fluctuation in the extracellular environment and responds to acidic pH by increasing the rate of membrane depolarization. It conducts cations like Na+ (Sodium) and Ca2+ (Calcium) ions across the membrane upon protonation. The ASICs subtypes are characterized by differing biophysical properties and pH sensitivities. The subtype ASIC1 is involved in various CNS diseases and therefore focusing on its specific functional properties will guide in drug design methods. The review highlights the cASIC1 (Chicken ASIC1) crystal structures, involvement in physiological environment and limitations of currently available inhibitors. In addition, it details the mutational data available to design an inhibitor against hASIC1 (Human ASIC1).


Assuntos
Bloqueadores do Canal Iônico Sensível a Ácido/química , Canais Iônicos Sensíveis a Ácido/química , Doenças do Sistema Nervoso Central/tratamento farmacológico , Desenho de Fármacos , Neurônios/efeitos dos fármacos , Bloqueadores do Canal Iônico Sensível a Ácido/farmacologia , Bloqueadores do Canal Iônico Sensível a Ácido/uso terapêutico , Canais Iônicos Sensíveis a Ácido/genética , Canais Iônicos Sensíveis a Ácido/metabolismo , Animais , Doenças do Sistema Nervoso Central/genética , Doenças do Sistema Nervoso Central/patologia , Cristalografia por Raios X , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Neurônios/patologia , Mutação Puntual , Domínios Proteicos/efeitos dos fármacos , Domínios Proteicos/genética , Relação Estrutura-Atividade
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