Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.274
Filtrar
1.
Psychopharmacol Bull ; 52(4): 31-51, 2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36339275

RESUMO

Objectives: The aim of this study was to assess the efficacy and tolerability of omega-3 fatty acids (FAs) and inositol alone and in combination for the treatment of pediatric bipolar (BP) spectrum disorder in young children. Methods: Participants were male and female children ages 5-12 meeting DSM-IV diagnostic criteria for a BP spectrum disorder and displaying mixed, manic, or hypomanic symptoms without psychotic features at the time of evaluation. Results: Participants concomitantly taking psychotropic medication were excluded from efficacy analyses. There were significant reductions in YMRS and HDRS mean scores in the inositol and combination treatment groups (all p < 0.05) and in CDRS mean scores in the combination treatment group (p < 0.001), with the largest changes seen in the combination group. Those receiving the combination treatment had the highest rates of antimanic and antidepressant response. The odds ratios for the combination group compared to the omega-3 FAs and inositol groups were clinically meaningful (ORs ≥2) for 50% improvement on the YMRS, normalization of the YMRS (score <12) (vs. inositol group only), 50% improvement on the HDRS, 50% improvement on CDRS (vs. omega-3 FAs group only), and CGI-I Mania, CGI-I MDD, and CGI-I Anxiety scores <2. Conclusion: The antimanic and antidepressant effects of the combination treatment of omega-3 FAs and inositol were consistently superior to either treatment used alone. This combination may offer a safe and effective alternative or augmenting treatment for youth with BP spectrum disorder, but more work is needed to confirm the statistical significance of this finding.


Assuntos
Antipsicóticos , Transtorno Bipolar , Ácidos Graxos Ômega-3 , Adolescente , Masculino , Criança , Humanos , Feminino , Pré-Escolar , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/diagnóstico , Antimaníacos , Antipsicóticos/uso terapêutico , Inositol/farmacologia , Inositol/uso terapêutico , Escalas de Graduação Psiquiátrica , Método Duplo-Cego , Antidepressivos/uso terapêutico , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/uso terapêutico , Mania , Resultado do Tratamento
2.
BMC Oral Health ; 22(1): 437, 2022 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-36192671

RESUMO

BACKGROUND: The relationship between internal root resorption and oxidative stress has not yet been reported. This study aimed to add molecular insight into internal root resorption. The present study was conducted to investigate the effect of hydrogen peroxide (H2O2) as an inducer of oxidative stress on the calcification ability of human dental pulp cells (hDPCs) and the involvement of inositol 1, 4, 5-trisphosphate (IP3). MATERIAL AND METHODS: hDPCs (Lonza, Basel, Switzerland) were exposed to H2O2. Cell viability and reactive oxygen species (ROS) production were then evaluated. To investigate the effect of H2O2 on the calcification ability of hDPCs, real-time PCR for alkaline phosphatase (ALP) mRNA expression, ALP staining, and Alizarin red staining were performed. Data were compared with those of hDPCs pretreated with 2-aminoethyldiphenylborate (2-APB), which is an IP3 receptor inhibitor. RESULTS: H2O2 at concentrations above 250 µM significantly reduced cell viability (P < 0.01). More ROS production occurred in 100 µM H2O2-treated hDPCs than in control cells (P < 0.01). 2-APB significantly decreased the production (P < 0.05). H2O2-treated hDPCs showed significant reductions in ALP mRNA expression (P < 0.01), ALP activity (P < 0.01), and mineralized nodule deposition compared with negative control cells (P < 0.01). 2-APB significantly inhibited these reductions (P < 0.01, P < 0.05 and P < 0.01, respectively). Data are representative of three independent experiments with three replicates for each treatment and values are expressed as means ± SD. CONCLUSION: To the best of our knowledge, this is the first study documenting the involvement of IP3 signaling in the calcification ability of human dental pulp cells impaired by H2O2.


Assuntos
Polpa Dentária , Reabsorção da Raiz , Fosfatase Alcalina/farmacologia , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Humanos , Peróxido de Hidrogênio/farmacologia , Inositol/farmacologia , Receptores de Inositol 1,4,5-Trifosfato/farmacologia , Odontoblastos , Estresse Oxidativo , RNA Mensageiro , Espécies Reativas de Oxigênio
3.
Int J Mol Sci ; 23(19)2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-36232754

RESUMO

Due to the role of cancer stem cells (CSCs) in tumor resistance and glycosphingolipid (GSL) involvement in tumor pathogenesis, we investigated the effect of a newly synthesized compound (3-amino-N-(3-chloro-2-methylphenyl)-5-oxo-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide 1 on the percentage of CSCs and the expression of six GSLs on CSCs and non-CSCs on breast cancer cell lines (MDA-MB-231 and MCF-7). We also investigated the effect of 1 on the metabolic profile of these cell lines. The MTT assay was used for cytotoxicity determination. Apoptosis and expression of GSLs were assessed by flow cytometry. A GC-MS-coupled system was used for the separation and identification of metabolites. Compound 1 was cytotoxic for both cell lines, and the majority of cells died by treatment-induced apoptosis. The percentage of CSCs was significantly lower in the MDA-MB-231 cell line. Treatment with 1 caused a decrease of CSC IV6Neu5Ac-nLc4Cer+ MDA-MB-231 cells. In the MCF-7 cell line, the percentage of GalNAc-GM1b+ CSCs was increased, while the expression of Gg3Cer was decreased in both CSC and non-CSC. Twenty-one metabolites were identified by metabolic profiling. The major impact of the treatment was in glycolysis/gluconeogenesis, pyruvate and inositol metabolism. Compound 1 exhibited higher potency in MBA-MB-231 cells, and it deserves further examination.


Assuntos
Antineoplásicos , Neoplasias da Mama , Quinolinas , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Glucose/metabolismo , Glicoesfingolipídeos/metabolismo , Humanos , Inositol/farmacologia , Células-Tronco Neoplásicas/metabolismo , Piridinas/metabolismo , Piridinas/farmacologia , Piruvatos/metabolismo , Quinolinas/farmacologia
4.
Int J Mol Sci ; 23(19)2022 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-36233170

RESUMO

Airway remodeling in asthma involves the hyperproliferation of airway smooth muscle (ASM) cells. However, the molecular signals that regulate ASM growth are not completely understood. Gq-coupled G protein-coupled receptor and receptor tyrosine kinase signaling regulate ASM cell proliferation via activation of phospholipase C, generation of inositol triphosphate (IP3) and diacylglycerol (DAG). Diacylglycerol kinase (DGK) converts DAG into phosphatidic acid (PA) and terminates DAG signaling while promoting PA-mediated signaling and function. Herein, we hypothesized that PA is a pro-mitogenic second messenger in ASM, and DGK inhibition reduces the conversion of DAG into PA resulting in inhibition of ASM cell proliferation. We assessed the effect of pharmacological inhibition of DGK on pro-mitogenic signaling and proliferation in primary human ASM cells. Pretreatment with DGK inhibitor I (DGKI) significantly inhibited platelet-derived growth factor-stimulated ASM cell proliferation. Anti-mitogenic effect of DGKI was associated with decreased mTOR signaling and expression of cyclin D1. Exogenous PA promoted pro-mitogenic signaling and rescued DGKI-induced attenuation of ASM cell proliferation. Finally, house dust mite (HDM) challenge in wild type mice promoted airway remodeling features, which were attenuated in DGKζ-/- mice. We propose that DGK serves as a potential drug target for mitigating airway remodeling in asthma.


Assuntos
Remodelação das Vias Aéreas , Asma , Animais , Asma/metabolismo , Proliferação de Células , Ciclina D1/metabolismo , Diacilglicerol Quinase/genética , Diacilglicerol Quinase/metabolismo , Diglicerídeos/metabolismo , Humanos , Inositol/farmacologia , Camundongos , Mitógenos/farmacologia , Miócitos de Músculo Liso/metabolismo , Ácidos Fosfatídicos/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Fator de Crescimento Derivado de Plaquetas/farmacologia , Proteínas Tirosina Quinases/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fosfolipases Tipo C/metabolismo
5.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 53(5): 798-804, 2022 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-36224681

RESUMO

Objective: To investigate the effect of hydrogen sulfide (H 2S) on reactive oxygen species (ROS)-mediated endoplasmic reticulum stress in myocardial injury caused by sepsis. Methods: A sepsis model was induced in Sprague-Dawley (SD) rats by cecal ligation and puncture (CLP). The rats were randomly divided into sham operation (sham) group, sepsis (CLP) group, and sepsis+sodium hydrosulfide (NaHS) (CLP+NaHS) group. The left ventricular function of the rats was observed with echocardiography and their plasma H 2S levels were measured. Lactate dehydrogenase (LDH), malondialdehyde (MDA), glutathione (GSH) levels were measured and HE staining was done to evaluate the level of myocardial oxidative stress in rats. HE staining was done to observe the morphological changes of rat myocardium, and transmission electron microscope was used to observe the ultrastructure of myocardial mitochondria. Western blot was done to examine changes in the expression of two endogenous hydrogen sulfide synthases, cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfur transferase (3-MST), and changes in the expression of endoplasmic reticulum stress (ERS) marker proteins, including phosphorylated (p) protein kinase R-like endoplasmic reticulum kinase (p-PERK), p-eukaryotic translation initiation factor 2α (p-eIF2α), p-inositol requires enzyme 1α (IRE1α), recombinant activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP). TUNEL staining was performed to observe the changes of cardiomyocyte apoptosis in rats. Results: Left ventricular ejection fraction (LVEF), left ventricular shortening fraction (LVFS) and plasma H 2S decreased in septic rats ( P<0.05). Plasma H 2S exhibited linear correlation with LVEF and LVFS ( r 2=0.62 and r 2=0.64, all P<0.05). The ROS levels were significantly elevated in rats of the CLP group. In addition, these rats showed increased level of LDH ( P<0.05), increased expression of MDA ( P<0.05), and decreased expression of GSH ( P<0.05). Inflammatory cell infiltration and cardiomyocyte edema were observed in HE staining. Transmission electron microscopic observation revealed significant mitochondrial damage, observable mitochondrial edema, and cristae structure dissolution. The Western blot results showed that the expression levels of CSE and 3-MST decreased ( P<0.05), while the ERS marker proteins, including p-PERK, p-eIF2, IRE1α, ATF4, and CHOP, were expressed at increased levels ( P<0.05). TUNEL staining showed significant increase of apoptosis in cardiomyocytes ( P<0.05). After NaHS treatment, LVEF and LVFS increased ( P<0.05) and plasma H 2S increased in septic rats ( P<0.05). Myocardial oxidative stress levels decreased. HE staining and transmission electron microscopy showed improved myocardial morphology. Mitochondrial damage was reduced and CSE and 3-MST levels were significantly increased ( P<0.05). The expression of p-PERK, p-eIF2α, p-IRE1α, and CHOP proteins decreased ( P<0.05). A decrease in cardiomyocyte apoptosis levels was observed by TUNEL staining ( P<0.05). Conclusion: H 2S reduces septic cardiomyocyte apoptosis by inhibiting ROS-mediated ERS, thereby improving myocardial dysfunction in sepsis.


Assuntos
Sulfeto de Hidrogênio , Sepse , Animais , Ratos , Fator 4 Ativador da Transcrição/farmacologia , Apoptose , Cistationina gama-Liase/farmacologia , Estresse do Retículo Endoplasmático , Endorribonucleases/farmacologia , Fator de Iniciação 2 em Eucariotos/farmacologia , Glutationa , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/uso terapêutico , Inositol/farmacologia , Lactato Desidrogenases , Malondialdeído , Proteínas Serina-Treonina Quinases , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Sepse/complicações , Sepse/tratamento farmacológico , Volume Sistólico , Sulfetos , Enxofre/farmacologia , Função Ventricular Esquerda
6.
Eur J Pharmacol ; 933: 175274, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36108736

RESUMO

Oxidative stress and endoplasmic reticulum (ER) stress promote atherogenesis while transcription factor EB (TFEB) inhibits atherosclerosis. Since reducing oxidative stress with antioxidants have failed to reduce atherosclerosis possibly because of aggravation of ER stress, we studied the effect of TFEB on ER stress in human coronary artery endothelial cells. ER stress was measured using the secreted alkaline phosphatase assay. Expression and phosphorylation of key mediators of unfolded protein response (UPR). TFEB, inositol-requiring enzyme 1α (IRE1α), phospho-IRE1α, protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), phospho-PERK, and activating transcription factor 6 (ATF6) expression were measured by Western blot. The effect of TFEB gain- and loss-of-function on ER stress were assessed with a plasmid expressing a constitutively active form of TFEB and via siRNA-mediated silencing, respectively. Treatment with tunicamycin (TM) and thapsigargin (TG) increased TFEB expression by 42.8% and 42.3%, respectively. In HCAEC transfected with the TFEB siRNA, treatment with either TM, TG or high-dextrose increased IRE1α and PERK phosphorylation and ATF6 levels significantly more compared to cells transfected with the control siRNA and treated similarly. Furthermore, transient transfection with a plasmid expressing a constitutively active form of TFEB reduced ER stress. Increased expression of TFEB inhibited ER stress in HCAEC treated with pharmacologic (TM and TG) and physiologic (high-dextrose) ER stress inducers, while TFEB knockout aggravated ER stress caused by these ER stress inducers. TFEB-mediated ER stress reduction may contribute to its anti-atherogenic effects in HCAEC and may be a novel target for drug development.


Assuntos
Aterosclerose , Estresse do Retículo Endoplasmático , Fator 6 Ativador da Transcrição/genética , Fator 6 Ativador da Transcrição/metabolismo , Fosfatase Alcalina/metabolismo , Vasos Coronários/metabolismo , Endorribonucleases/genética , Endorribonucleases/metabolismo , Células Endoteliais/metabolismo , Glucose/farmacologia , Humanos , Inositol/farmacologia , Proteínas Serina-Treonina Quinases/genética , RNA Interferente Pequeno/metabolismo , Tapsigargina/farmacologia , Tunicamicina/farmacologia , Resposta a Proteínas não Dobradas , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo
7.
J Dairy Sci ; 105(11): 9191-9205, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36114053

RESUMO

Adipose tissue of ketotic dairy cows exhibits greater lipolytic rate and signs of inflammation, which further aggravate the metabolic disorder. In nonruminants, the endoplasmic reticulum (ER) is a key organelle coordinating metabolic adaptations and cellular functions; thus, disturbances known as ER stress lead to inflammation and contribute to metabolic disorders. Enhanced activity of diacylglycerol O-acyltransferase 1 (DGAT1) in murine adipocytes undergoing lipolysis alleviated ER stress and inflammation. The aim of the present study was to investigate the potential role of DGAT1 on ER stress and inflammatory response of bovine adipose tissue in vivo and in vitro. Adipose tissue and blood samples were collected from cows diagnosed as clinically ketotic (n = 15) or healthy (n = 15) following a veterinary evaluation based on clinical symptoms and serum concentrations of ß-hydroxybutyrate, which were 4.05 (interquartile range = 0.46) and 0.52 mM (interquartile range = 0.14), respectively. Protein abundance of DGAT1 was greater in adipose tissue of ketotic cows. Among ER stress proteins measured, ratios of phosphorylated PKR-like ER kinase (p-PERK) to PERK and phosphorylated inositol-requiring enzyme 1 (p-IRE1) to IRE1, and protein abundance of cleaved ATF6 protein were greater in adipose tissue of ketotic cows. Furthermore, ratios of phosphorylated RELA subunit of NF-κB (p-RELA) to RELA and phosphorylated c-jun N-terminal kinase (p-JNK) to JNK were greater, whereas protein abundance of NF-κB inhibitor α (NFKBIA) was lower in adipose tissue of ketotic cows. In addition, mRNA abundance of proinflammatory cytokines including TNF and IL-6 was greater in adipose tissue of ketotic cows. To better address mechanistic aspects of these responses, primary bovine adipocytes isolated from the harvested adipose tissue of healthy cows were subjected to lipolysis-stimulating conditions via incubation with 1 µM epinephrine (EPI) for 2 h. In another experiment, adipocytes were cultured with DGAT1 overexpression adenovirus and DGAT1 small interfering RNA for 48 h, respectively, followed by EPI (1 µM) exposure for 2 h. Treatment with EPI led to greater ratios of p-PERK to PERK, p-IRE1 to IRE1, p-RELA to RELA, p-JNK to JNK, and cleaved ATF6 protein, whereas EPI stimulation inhibited protein abundance of NFKBIA. Furthermore, treatment with EPI upregulated the secretion of proinflammatory cytokines into culture medium, including TNF-α and IL-6. Overexpression of DGAT1 in EPI-treated adipocytes attenuated ER stress, the activation of NF-κB and JNK signaling pathways, and the secretion of inflammatory cytokines. In contrast, silencing DGAT1 further aggravated EPI-induced ER stress and inflammatory responses. Overall, these data indicated that activation of DGAT1 may act as an adaptive mechanism to dampen metabolic dysregulation in adipose tissue. As such, it contributes to relief from ER stress and inflammatory responses.


Assuntos
Cetose , Doenças dos Roedores , Feminino , Bovinos , Animais , Camundongos , Ácido 3-Hidroxibutírico , Diacilglicerol O-Aciltransferase/metabolismo , Estresse do Retículo Endoplasmático , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Cetoses/metabolismo , Cetoses/farmacologia , RNA Interferente Pequeno/metabolismo , Interleucina-6/metabolismo , Cetose/veterinária , Tecido Adiposo/metabolismo , Citocinas/metabolismo , Inflamação/veterinária , Inflamação/metabolismo , Proteínas Serina-Treonina Quinases , Proteínas de Choque Térmico/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Epinefrina/farmacologia , RNA Mensageiro/metabolismo , Inositol/metabolismo , Inositol/farmacologia , Doenças dos Roedores/metabolismo
8.
J Inorg Biochem ; 236: 111972, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36087434

RESUMO

Excessive organophosphate flame retardant (OPFR) use in consumer products has been reported to increase human disease susceptibility. However, the adverse effects of tris(2-chloroethyl) phosphate (TCEP) (a chlorinated alkyl OPFR) on the heart remain unknown. In this study, we tested whether cardiac fibrosis occurred in animal models of TCEP (10 mg/kg b.w./day) administered continuously by gavage for 30 days and evaluated the specific role of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA). First, we confirmed that TCEP could trigger cardiac fibrosis by histopathological observation and cardiac fibrosis markers. We further verified that cardiac fibrosis occurred in animal models of TCEP exposure accompanied by SERCA2a, SERCA2b and SERCA2c downregulation. Notably, inductively coupled plasma-mass spectrometry (ICP-MS) analysis revealed that the cardiac concentrations of Ca2+ increased by 45.3% after TCEP exposure. Using 4-Isopropoxy-N-(2-methylquinolin-8-yl)benzamide (CDN1163, a small molecule SERCA activator), we observed that Ca2+ overload and subsequent cardiac fibrosis caused by TCEP were both alleviated. Simultaneously, the protein levels of endoplasmic reticulum (ER) markers (protein kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring protein 1α (IRE1α), eukaryotic initiation factor 2 α (eIF2α)) were upregulated by TCEP, which could be abrogated by CDN1163 pretreatment. Furthermore, we observed that CDN1163 supplementation prevented overactive autophagy induced by TCEP in the heart. Mechanistically, TCEP could lead to Ca2+ overload by inhibiting the expression of SERCA, thereby triggering ER stress and overactive autophagy, eventually resulting in cardiac fibrosis. Together, our results suggest that the Ca2+ overload/ER stress/autophagy axis can act as a driver of cardiotoxicity induced by TCEP.


Assuntos
Endorribonucleases , Retardadores de Chama , Aminoquinolinas , Animais , Autofagia , Benzamidas/metabolismo , Cálcio/metabolismo , Retículo Endoplasmático , Estresse do Retículo Endoplasmático , Endorribonucleases/metabolismo , Endorribonucleases/farmacologia , Fator de Iniciação 2 em Eucariotos/metabolismo , Fator de Iniciação 2 em Eucariotos/farmacologia , Fibrose , Retardadores de Chama/metabolismo , Retardadores de Chama/farmacologia , Humanos , Inositol/metabolismo , Inositol/farmacologia , Organofosfatos , Fosfatos/metabolismo , Fosfinas , Proteínas Serina-Treonina Quinases , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/farmacologia
9.
Int J Mol Sci ; 23(17)2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36077373

RESUMO

Opportunistic pathogen Candida albicans causes systemic infections named candidiasis. Due to the increasing number of multi-drug resistant clinical isolates of Candida sp., currently employed antifungals (e.g., azoles) are insufficient for combating fungal infection. One of the resistance mechanisms toward azoles is increased expression of plasma membrane (PM) transporters (e.g., Cdr1p), and such an effect was observed in C. albicans clinical isolates. At the same time, it has been proven that a decrease in PMs sphingolipids (SLs) content correlates with altered sensitivity to azoles and diminished Cdr1p levels. This indicates an important role for SL in maintaining the properties of PM and gaining resistance to antifungal agents. Here, we prove using a novel spot variation fluorescence correlation spectroscopy (svFCS) technique that CaCdr1p localizes in detergent resistant microdomains (DRMs). Immunoblot analysis confirmed the localization of CaCdr1p in DRMs fraction in both the C. albicans WT and erg11Δ/Δ strains after 14 and 24 h of culture. We also show that the C. albicanserg11Δ/Δ strain is more sensitive to the inhibitor of SLs synthesis; aureobasidin A (AbA). AbA treatment leads to a diminished amount of SLs in C. albicans WT and erg11Δ/Δ PM, while, for C. albicanserg11Δ/Δ, the general levels of mannose-inositol-P-ceramide and inositol-P-ceramide are significantly lower than for the C. albicans WT strain. Simultaneously, the level of ergosterol in the C. albicans WT strain after adding of AbA remains unchanged, compared to the control conditions. Analysis of PM permeabilization revealed that treatment with AbA correlates with the disruption of PM integrity in C. albicanserg11Δ/Δ but not in the C. albicans WT strain. Additionally, in the C. albicans WT strain, we observed lower activity of H+-ATPase, correlated with the delocalization of both CaCdr1p and CaPma1p.


Assuntos
Candida albicans , Ergosterol , Proteínas de Membrana Transportadoras/metabolismo , ATPases Translocadoras de Prótons/metabolismo , Esfingolipídeos/metabolismo , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Azóis/farmacologia , Candida albicans/citologia , Candida albicans/efeitos dos fármacos , Candida albicans/metabolismo , Membrana Celular/química , Membrana Celular/metabolismo , Ceramidas/metabolismo , Farmacorresistência Fúngica , Ergosterol/metabolismo , Proteínas Fúngicas/metabolismo , Inositol/farmacologia , Proteínas de Membrana Transportadoras/análise , Testes de Sensibilidade Microbiana
10.
J Cell Mol Med ; 26(20): 5303-5314, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36111515

RESUMO

Doxorubicin (Dox), an anthracycline antibiotic with potent antitumor effects, has limited clinical applications due to cumulative cardiotoxicity. Ca2+ /calmodulin-dependent protein kinase II (CaMKII) is implicated in the pathological progression of Dox-induced cardiotoxicity. This study examined the hypothesis that CaMKII exacerbates Dox-induced cardiotoxicity by promoting endoplasmic reticulum stress and apoptosis through regulation of the inositol-requiring enzyme 1α (IRE1α)/spliced X-box binding protein 1 (XBP1s) pathway. Our results demonstrated that CaMKII activation and IRE1α/XBP1s pathway were involved in Dox-treated hearts. CaMKII inhibition with KN-93 ameliorated Dox-induced cardiac dysfunction and pathological myocardial changes. In addition, CaMKII inhibition prevented Dox-induced endoplasmic reticulum stress and apoptosis. Moreover, CaMKII inhibition increased the expression of IRE1α and XBP1s in Dox-treated hearts. The IRE1α inhibitor 4µ8C blocked the protective effect of CaMKII inhibition against Dox-induced cardiotoxicity. Mechanistically, 4µ8C prevented the effects of CaMKII inhibition on Dox-induced endoplasmic reticulum stress and apoptosis by inhibiting the expression of IRE1α and XBP1s. Additionally, treatment with rhADAMTS13 decreased the protein level of thrombospondin 1 (TSP1) and the phosphorylation of CaMKII in Dox-treated human AC16 cardiomyocytes. Taken together, these results demonstrate that the ADAMTS13-TSP1 axis regulates CaMKII activation and exacerbates Dox-induced cardiotoxicity by triggering endoplasmic reticulum stress and apoptosis by inhibiting the IRE1α/XBP1s pathway.


Assuntos
Cardiotoxicidade , Estresse do Retículo Endoplasmático , Antibacterianos/toxicidade , Apoptose , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cardiotoxicidade/patologia , Doxorrubicina/toxicidade , Endorribonucleases/metabolismo , Humanos , Inositol/farmacologia , Miócitos Cardíacos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Trombospondina 1/metabolismo , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/metabolismo
11.
Nat Metab ; 4(9): 1166-1184, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36123394

RESUMO

Adipose tissue undergoes thermogenic remodeling in response to thermal stress and metabolic cues, playing a crucial role in regulating energy expenditure and metabolic homeostasis. Endoplasmic reticulum (ER) stress is associated with adipose dysfunction in obesity and metabolic disease. It remains unclear, however, if ER stress-signaling in adipocytes mechanistically mediates dysregulation of thermogenic fat. Here we show that inositol-requiring enzyme 1α (IRE1α), a key ER stress sensor and signal transducer, acts in both white and beige adipocytes to impede beige fat activation. Ablation of adipocyte IRE1α promotes browning/beiging of subcutaneous white adipose tissue following cold exposure or ß3-adrenergic stimulation. Loss of IRE1α alleviates diet-induced obesity and augments the anti-obesity effect of pharmacologic ß3-adrenergic stimulation. Notably, IRE1α suppresses stimulated lipolysis and degrades Ppargc1a messenger RNA through its RNase activity to downregulate the thermogenic gene program. Hence, blocking IRE1α bears therapeutic potential in unlocking adipocytes' thermogenic capacity to combat obesity and metabolic disorders.


Assuntos
Endorribonucleases , Inositol , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Proteínas Serina-Treonina Quinases , Adipócitos/metabolismo , Adrenérgicos/farmacologia , Animais , Endorribonucleases/genética , Endorribonucleases/metabolismo , Inositol/farmacologia , Camundongos , Obesidade/genética , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Estabilidade de RNA , RNA Mensageiro , Termogênese/genética
12.
Molecules ; 27(18)2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36144793

RESUMO

Eight new inositol derivatives, solsurinositols A-H (1-8), were isolated from the 70% EtOH extract of the leaves of Solanum capsicoides Allioni. Careful isolation by silica gel column chromatography followed by preparative high-performance liquid chromatography (HPLC) allowed us to obtain analytically pure compounds 1-8. They shared the same relative stereochemistry on the ring but have different acyl groups attached to various hydroxyl groups. This was the first time that inositol derivatives have been isolated from this plant. The chemical structures of compounds 1-8 were characterized by extensive 1D nuclear magnetic resonance (NMR) and 2D NMR and mass analyses. Meanwhile, the in vitro anti-inflammatory activity of all compounds was determined using lipopolysaccharide (LPS)-induced BV2 microglia, and among the isolates, compounds 5 (IC50 = 11.21 ± 0.14 µM) and 7 (IC50 = 14.5 ± 1.22 µM) were shown to have potential anti-inflammatory activity.


Assuntos
Solanum , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Inositol/química , Inositol/farmacologia , Lipopolissacarídeos/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta , Sílica Gel , Solanum/química
13.
Neuroscience ; 501: 72-84, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35961525

RESUMO

Swimming training (ST) can mitigate functional disorders in neurological diseases, but the effect and mechanism of ST in improving the neurological function of intracerebral haemorrhage (ICH) have not been reported. Our study aimed to explore the protective effect of early ST on ICH mice and its relationship with the serine-threonine kinase (Akt)/glycogen synthase kinase 3ß (GSK3ß) pathway. Our findings showed that the ICH model mice had poor behavioural manifestations in the Y maze test and open field test compared to the ST group and sham group. The modified neurological severity score was increased in the ICH mice, and 7 days of ST intervention significantly attenuated the neurological deficits. The ratios of myo-inositol/creatine, lactate/creatine and glutamate/creatine were decreased, and the ratios of N-acetylaspartate/creatine and choline/creatine were increased in the ICH mice with ST intervention. ST intervention decreased the expression of Iba1 and GFAP. Seven days of ST significantly increased the expression of p-Akt/Akt compared to that in the ICH mice. Furthermore, the Akt kinase inhibitor GSK690693 exacerbated neurological impairment, increased the expression of Iba1, GFAP and Bax/Bcl-2, and reversed the anti-apoptotic effects and anti-glia activation of ST, which was associated with the inhibition of p-Akt/Akt and p-GSK3ß/GSK3ß expression. These results indicated that the protective role of ST in ICH was mediated via the Akt/GSK3ß pathway. In conclusion, ST displayed neuroprotection by inhibiting apoptosis and glial activation in ICH mice by activating the Akt/GSK3ß signalling pathway.


Assuntos
Fármacos Neuroprotetores , Proteínas Serina-Treonina Quinases , Animais , Apoptose , Hemorragia Cerebral/metabolismo , Colina/farmacologia , Creatina/farmacologia , Glutamatos , Glicogênio Sintase Quinase 3 beta , Inositol/farmacologia , Lactatos/farmacologia , Camundongos , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2 , Natação , Proteína X Associada a bcl-2
14.
J Biol Chem ; 298(9): 102363, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35963434

RESUMO

Inositol is an essential metabolite that serves as a precursor for structural and signaling molecules. Although perturbation of inositol homeostasis has been implicated in numerous human disorders, surprisingly little is known about how inositol levels are regulated in mammalian cells. A recent study in mouse embryonic fibroblasts demonstrated that nuclear translocation of inositol hexakisphosphate kinase 1 (IP6K1) mediates repression of myo-inositol-3-P synthase (MIPS), the rate-limiting inositol biosynthetic enzyme. Binding of IP6K1 to phosphatidic acid (PA) is required for this repression. Here, we elucidate the role of PA in IP6K1 repression. Our results indicate that increasing PA levels through pharmacological stimulation of phospholipase D (PLD) or direct supplementation of 18:1 PA induces nuclear translocation of IP6K1 and represses expression of the MIPS protein. We found that this effect was specific to PA synthesized in the plasma membrane, as endoplasmic reticulum-derived PA did not induce IP6K1 translocation. Furthermore, we determined that PLD-mediated PA synthesis can be stimulated by the master metabolic regulator 5' AMP-activated protein kinase (AMPK). We show that activation of AMPK by glucose deprivation or by treatment with the mood-stabilizing drugs valproate or lithium recapitulated IP6K1 nuclear translocation and decreased MIPS expression. This study demonstrates for the first time that modulation of PA levels through the AMPK-PLD pathway regulates IP6K1-mediated repression of MIPS.


Assuntos
Ácidos Fosfatídicos , Fosfolipase D , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Fibroblastos/metabolismo , Glucose , Humanos , Inositol/metabolismo , Inositol/farmacologia , Lítio , Mamíferos/metabolismo , Camundongos , Ácidos Fosfatídicos/metabolismo , Fosfolipase D/genética , Fosfolipase D/metabolismo , Fosfotransferases (Aceptor do Grupo Fosfato) , Ácido Valproico
15.
Int J Mol Sci ; 23(15)2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35955788

RESUMO

Classic Galactosemia (CG) is a devastating inborn error of the metabolism caused by mutations in the GALT gene encoding the enzyme galactose-1 phosphate uridylyltransferase in galactose metabolism. Severe complications of CG include neurological impairments, growth restriction, cognitive delays, and, for most females, primary ovarian insufficiency. The absence of the GALT enzyme leads to an accumulation of aberrant galactose metabolites, which are assumed to be responsible for the sequelae. There is no treatment besides the restriction of dietary galactose, which does not halt the development of the complications; thus, additional treatments are sorely needed. Supplements have been used in other inborn errors of metabolism but are not part of the therapeutic regimen for CG. The goal of this study was to test two generally recognized as safe supplements (purple sweet potato color (PSPC) and myo-inositol (MI)) that may impact cellular pathways contributing to the complications in CG. Our group uses a GalT gene-trapped mouse model to study the pathophysiology in CG, which phenocopy many of the complications. Here we report the ability of PSPC to ameliorate dysregulation in the ovary, brain, and liver of our mutant mice as well as positive results of MI supplementation in the ovary and brain.


Assuntos
Galactosemias , Ipomoea batatas , Animais , Cor , Feminino , Galactose/metabolismo , Galactosemias/genética , Inositol/farmacologia , Inositol/uso terapêutico , Ipomoea batatas/metabolismo , Camundongos , UTP-Hexose-1-Fosfato Uridililtransferase/metabolismo
16.
Andrologia ; 54(10): e14528, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35841196

RESUMO

In this study, the influence of myoinositol (MYO) as an antioxidant on the inhibition of the negative impacts of cryopreservation on sperm quality in men with Asthenospermia was investigated. In this prospective study, each semen sample from 25 cases was separated into three groups: Fresh, Control (with freezing medium), Myoinositol (2 mg/ml). According to the World Health Organization criteria (WHO) (2010), total motility, progressive sperm motility, viability, normal morphology, and DNA integrity were assessed. In addition, the hypo-osmotic swelling (HOS) test and mitochondrial membrane potential (MMP) were used. Total antioxidant capacity (TAC), malondialdehyde (MDA), and antioxidant enzyme activity were determined by the ELISA method. In contrast to the fresh samples, lipid peroxidation, DNA integrity damage, DNA fragmentation, HOST, and MMP had significant enhancement in the control samples. Sperm quality was significantly decreased (p < 0.05). Mean percentage viability, normal morphology, total motility, progressive motility, and DNA integrity were significantly enhanced in the MYO group in comparison to the control group (p < 0.05). The MDA and TAC levels and DNA damage in the MYO group were significantly lower compared to the control group (p < 0.05). The findings confirm that sperm quality in patients with Asthenospermia is improved by the administration of 2 mg/ml of myoinositol together with the freezing medium after sperm cryopreservation.


Assuntos
Astenozoospermia , Preservação do Sêmen , Antioxidantes/farmacologia , Criopreservação/métodos , DNA , Humanos , Inositol/farmacologia , Masculino , Malondialdeído , Estudos Prospectivos , Sêmen , Preservação do Sêmen/métodos , Motilidade Espermática , Espermatozoides
17.
J Clin Pharm Ther ; 47(11): 1759-1767, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35775148

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Vitamin D and myo-inositol reduce thyroid antibody titers in subjects with autoimmune thyroiditis. No previous study has investigated interactions between these agents. The aim of the current study was to determine whether the impact of exogenous vitamin D on thyroid autoimmunity and thyroid function in women with Hashimoto's thyroiditis depends on myo-inositol supplementation. METHODS: The study population consisted of three thyroid antibody- and insulin sensitivity-matched groups of women with autoimmune thyroiditis and high-normal or slightly elevated TSH levels. Forty-one women (21 in group A and 20 in group C) had been treated for at least 6 months with myo-inositol (group A), while 21 women (group B) had not received myo-inositol preparations. Over the entire study period (6 months), groups A and C continued treatment with myo-inositol (2 g daily), while groups A and B received exogenous vitamin D (4000 IU daily). Plasma titers of thyroid peroxidase and thyroglobulin antibodies, as well as plasma concentrations of glucose, insulin, TSH, free thyroid hormones, prolactin, and 25-hydroxyvitamin D (25-OH-D) were assessed at entry and 6 months later. Moreover, baseline and follow-up values of the structure parameters of thyroid homeostasis were calculated RESULTS AND DISCUSSION: In groups A and B, vitamin D improved insulin sensitivity and increased 25-OH-D levels. Although follow-up antibody titers in both these groups were lower than baseline ones, the impact of vitamin D on thyroid peroxidase and thyroglobulin antibodies was stronger in group A than in group B. Only in group A, vitamin D decreased TSH levels and increased SPINA-GT. There were no differences between baseline and follow-up free values of glucose, thyroid hormones, prolactin, Jostel's index, and SPINA-GD. The impact of vitamin D treatment on antibody titers correlated with treatment-induced changes in 25-OH-D levels and the degree of improvement in insulin sensitivity. In group C, glucose homeostasis markers, antibody titers and hormone levels remained at a similar level throughout the study period. WHAT IS NEW AND CONCLUSION: The obtained results suggest that the impact of vitamin D on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity in subjects with autoimmune thyroiditis is more pronounced if they receive myo-inositol.


Assuntos
Doença de Hashimoto , Resistência à Insulina , Tireoidite Autoimune , Humanos , Feminino , Iodeto Peroxidase , Autoimunidade , Projetos Piloto , Tireoidite Autoimune/tratamento farmacológico , Tireoglobulina , Prolactina , Vitamina D , Hormônios Tireóideos , Tireotropina , Inositol/farmacologia , Glucose
18.
J Cardiovasc Pharmacol ; 80(4): 574-582, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35881905

RESUMO

ABSTRACT: Inositol 1, 4, 5-trisphosphate (IP3) signaling-mediated calcium release drives the contraction of vascular smooth muscles and hence regulates blood vessel volume and blood pressure. Melatonin supplementation has been suggested to be beneficial for hypertension. To determine whether the blood pressure-lowering effect of melatonin was accounted for by IP3 signaling, we evaluated the vasoconstriction response and IP3 signaling in isolated mouse thoracic aortic rings during melatonin incubation. C57BL/6 mice were given intraperitoneal injections daily with melatonin, and the systolic blood pressure and contractility of aortic rings from melatonin-treated mice were decreased, and the contraction suppression effect of melatonin was attributed to the impaired expression of contractile proteins in vascular smooth muscle cells rather than IP3 signaling. Our results further showed that melatonin increased the expression of γ-secretase, which could cleave and release the notch intracellular domain, and the notch intracellular domain prevented the transcription of contractile genes by interfering with the interaction between serum response factor and myocardin, the master regulator of contractile protein. In this article, we report a novel mechanism by which melatonin regulates smooth muscle contractility that does not depend on IP3 signaling.


Assuntos
Melatonina , Vasoconstrição , Secretases da Proteína Precursora do Amiloide/metabolismo , Secretases da Proteína Precursora do Amiloide/farmacologia , Animais , Cálcio/metabolismo , Proteínas Contráteis/metabolismo , Proteínas Contráteis/farmacologia , Inositol/metabolismo , Inositol/farmacologia , Melatonina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Contração Muscular , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Proteínas Nucleares , Fator de Resposta Sérica/metabolismo , Fator de Resposta Sérica/farmacologia , Transativadores
19.
Int J Mol Sci ; 23(13)2022 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-35805938

RESUMO

Mutations in LRRK2 and GBA1 are key contributors to genetic risk of developing Parkinson's disease (PD). To investigate how LRRK2 kinase activity interacts with GBA and contributes to lysosomal dysfunctions associated with the pathology of PD. The activity of the lysosomal enzyme ß-Glucocerebrosidase (GCase) was assessed in a human neuroglioma cell model treated with two selective inhibitors of LRKK2 kinase activity (LRRK2-in-1 and MLi-2) and a GCase irreversible inhibitor, condutirol-beta-epoxide (CBE), under 24 and 72 h experimental conditions. We observed levels of GCase activity comparable to controls in response to 24 and 72 h treatments with LRRK2-in-1 and MLi-2. However, GBA protein levels increased upon 72 h treatment with LRRK2-in-1. Moreover, LC3-II protein levels were increased after both 24 and 72 h treatments with LRRK2-in-1, suggesting an activation of the autophagic pathway. These results highlight a possible regulation of lysosomal function through the LRRK2 kinase domain and suggest an interplay between LRRK2 kinase activity and GBA. Although further investigations are needed, the enhancement of GCase activity might restore the defective protein metabolism seen in PD.


Assuntos
Glucosilceramidase , Doença de Parkinson , Linhagem Celular , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Glioma/metabolismo , Glucosilceramidase/genética , Glucosilceramidase/metabolismo , Humanos , Inositol/análogos & derivados , Inositol/farmacologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/antagonistas & inibidores , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Mutação , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia
20.
Psychopharmacology (Berl) ; 239(9): 2955-2974, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35776189

RESUMO

RATIONALE: Discovering biomarkers of major depressive disorder (MDD) can give a deeper understanding of this mood disorder and improve the ability to screen for, diagnose, and treat MDD. OBJECTIVES: In this study, metabolomics was used in unraveling metabolite fluctuations of MDD and drug outcome by creating specific metabolomic fingerprints. We report metabolomic patterns of change of the hippocampus of adult male Wistar rats following chronic social isolation (CSIS) (6 weeks), an animal model of depression, and/or chronic tianeptine (Tian) treatment (10 mg kg-1 per day) (lasting 3 weeks of 6-week CSIS), monitored by using comprehensive GC × GC-MS. RESULTS: The comparative metabolomic analysis highlighted the role of gamma aminobutyric acid (GABA), iso-allocholate, and unsaturated fatty acid metabolism alterations following the CSIS, which was corroborated with moderate to strong negative Pearson's correlation of GABA, docosahexaenoic, 9-hexadecenoic acid, 5,8,11,14-eicosatetraynoic, and arachidonic acids with immobility behavior in the forced swim test. The antidepressant effect of Tian restored GABA levels, which was absent in Tian resilient rats. Tian decreased myo-inositol and increased TCA cycle intermediates, amino acids, and cholesterol and its metabolite. As key molecules of divergence between Tian effectiveness and resilience, metabolomics revealed myo-inositol, GABA, cholesterol, and its metabolite. A significant moderate positive correlation between myo-inositol and immobility was revealed. Tian probably acted by upregulating NMDAR's and α2 adrenergic receptors (AR) or norepinephrine transporter in both control and stressed animals. CONCLUSION: Metabolomics revealed several dysregulations underlying CSIS-induced depressive-like behavior and responsiveness to Tian, predominantly converging into NMDAR-mediated glutamate and myo-inositol signalization and GABA inhibitory pathways.


Assuntos
Transtorno Depressivo Maior , Animais , Colesterol/metabolismo , Transtorno Depressivo Maior/metabolismo , Ácidos Graxos/metabolismo , Ácidos Graxos/farmacologia , Hipocampo , Inositol/metabolismo , Inositol/farmacologia , Masculino , Ratos , Ratos Wistar , Tiazepinas , Ácido gama-Aminobutírico/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...