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1.
J Ethnopharmacol ; 334: 118588, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39029543

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Sepsis-associated encephalopathy (SAE) is a common and serious complication during the acute phase of and after recovery from sepsis that seriously affects the quality of life of patients. Traditional Chinese medicine (TCM) has been widely used in modern medicine for neurological anomalies and has become a therapeutic tool for the treatment of SAE due to its multitargeting effects and low toxicity and side effects. AIMS OF THE STUDY: This review provides insights into the pathogenesis and treatments of SAE, focusing on the clinical and experimental impacts of TCM formulations and their single components. METHODS: Several known databases such as PubMed, Web of Science, Google Scholar, China National Knowledge Infrastructure (CNKI), and others were extensively explored with keywords and phrases such as "sepsis-associated encephalopathy", "traditional Chinese medicine", "herbs", "SAE", "sepsis", "cerebral" or other relevant terms to obtain literature between 2018 and 2024. RESULTS: Extensive evidence indicated that TCM could decrease mortality and normalize neurological function in patients with sepsis; these effects might be associated with factors such as reduced oxidative stress and downregulated expression of inflammatory factors. CONCLUSIONS: TCM shows notable efficacy in treating SAE, warranting deeper mechanistic studies to optimize its clinical application.


Assuntos
Medicamentos de Ervas Chinesas , Medicina Tradicional Chinesa , Encefalopatia Associada a Sepse , Humanos , Encefalopatia Associada a Sepse/tratamento farmacológico , Medicina Tradicional Chinesa/métodos , Medicamentos de Ervas Chinesas/uso terapêutico , Animais , Sepse/tratamento farmacológico , Sepse/complicações
2.
BMC Cardiovasc Disord ; 24(1): 377, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39030470

RESUMO

BACKGROUD: New-onset atrial fibrillation (NOAF) is a common complication of sepsis and linked to higher death rates in affected patients. The lack of effective predictive tools hampers early risk assessment for the development of NOAF. This study aims to develop practical and effective predictive tools for identifying the risk of NOAF. METHODS: This case-control study retrospectively analyzed patients with sepsis admitted to the emergency department of Xinhua Hospital, Shanghai Jiao Tong University School of Medicine from September 2017 to January 2023. Based on electrocardiographic reports and electrocardiogram monitoring records, patients were categorized into NOAF and non-NOAF groups. Laboratory tests, including myeloperoxidase (MPO) and hypochlorous acid (HOCl), were collected, along with demographic data and comorbidities. Least absolute shrinkage and selection operator regression and multivariate logistic regression analyses were employed to identify predictors. The area under the curve (AUC) was used to evaluate the predictive model's performance in identifying NOAF. RESULTS: A total of 389 patients with sepsis were included in the study, of which 63 developed NOAF. MPO and HOCl levels were significantly higher in the NOAF group compared to the non-NOAF group. Multivariate logistic regression analysis identified MPO, HOCl, tumor necrosis factor-α (TNF-α), white blood cells (WBC), and the Acute Physiology and Chronic Health Evaluation II (APACHE II) score as independent risk factors for NOAF in sepsis. Additionally, a nomogram model developed using these independent risk factors achieved an AUC of 0.897. CONCLUSION: The combination of MPO and its derivative HOCl with clinical indicators improves the prediction of NOAF in sepsis. The nomogram model can serve as a practical predictive tool for the early identification of NOAF in patients with sepsis.


Assuntos
Fibrilação Atrial , Biomarcadores , Ácido Hipocloroso , Peroxidase , Valor Preditivo dos Testes , Sepse , Humanos , Peroxidase/sangue , Masculino , Feminino , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/sangue , Estudos Retrospectivos , Sepse/diagnóstico , Sepse/sangue , Pessoa de Meia-Idade , Idoso , Biomarcadores/sangue , Medição de Risco , Fatores de Risco , China/epidemiologia , Prognóstico , Idoso de 80 Anos ou mais , Estudos de Casos e Controles
3.
J Asian Nat Prod Res ; : 1-11, 2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-39082687

RESUMO

Four new lycoctonine-type C19-diterpenoid alkaloids kamaonensines H-K (1-4) have been isolated from the whole plants of Delphinium kamaonense, together with 12 known compounds (5-16). Interestingly, kamaonensines 1-3 contained a rare nitrone (immine N-oxide) moiety, respectively. Their structures were established by spectroscopic analyses. The active evaluation of compounds (1-16) by LPS induced RAW 264.7 macrophages showed that compounds 4 and 8 displayed strong anti-inflammatory activities. While compounds 11 and 12 also showed strong cytotoxicities by the RAW 264.7 cell viability assay.

4.
Cell Rep ; 43(6): 114316, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38833370

RESUMO

Phosphate (Pi) serves countless metabolic pathways and is involved in macromolecule synthesis, energy storage, cellular signaling, and bone maintenance. Herein, we describe the coordination of Pi uptake and efflux pathways to maintain mammalian cell Pi homeostasis. We discover that XPR1, the presumed Pi efflux transporter, separately supervises rates of Pi uptake. This direct, regulatory interplay arises from XPR1 being a binding partner for the Pi uptake transporter PiT1, involving a predicted transmembrane helix/extramembrane loop in XPR1, and its hitherto unknown localization in a subset of intracellular LAMP1-positive puncta (named "XLPVs"). A pharmacological mimic of Pi homeostatic challenge is sensed by the inositol pyrophosphate IP8, which functionalizes XPR1 to respond in a temporally hierarchal manner, initially adjusting the rate of Pi efflux, followed subsequently by independent modulation of PiT1 turnover to reset the rate of Pi uptake. These observations generate a unifying model of mammalian cellular Pi homeostasis, expanding opportunities for therapeutic intervention.


Assuntos
Homeostase , Fosfatos de Inositol , Humanos , Animais , Fosfatos de Inositol/metabolismo , Receptor do Retrovírus Politrópico e Xenotrópico , Células HEK293 , Organelas/metabolismo , Transporte Biológico , Fosfatos/metabolismo , Camundongos
5.
Anal Bioanal Chem ; 416(14): 3389-3399, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38632130

RESUMO

As one of the most common iron-chelating agents, deferoxamine (DFO) rapidly chelates iron in the body. Moreover, it does not compete for the iron characteristic of hemoglobin in the blood cells, which is common in the clinical treatment of iron poisoning. Iron is a trace element necessary to maintain organism normal life activities. Iron deficiency can lead to anemia, whereas iron overload can cause elevated levels of cellular oxidative stress and cell damage. As a consequence, detection of the iron content in tissues and blood is of great significance. The traditional techniques for detecting the iron content include inductively coupled plasma-mass spectrometry and atomic absorption spectrometry, which cannot be used for imaging purposes. Laser ablation-ICP-MS and synchrotron radiation micro-X-ray fluorescence can map the concentration and distribution of iron in tissues. However, these methods can only be used to measure the total iron levels in blood or tissues. In recent years, due to the deepening understanding of iron metabolism, diseases related to iron overload have attracted increasing attention. Therefore, we took advantage of the properties of DFO in terms of chelating iron and investigated different sampling times following DFO injection in the tail vein of mice. We used mass spectrometry imaging (MSI) technology to detect the DFO and ferrioxamine content in the blood and different tissues to indirectly characterize the non-heme iron content.


Assuntos
Desferroxamina , Ferro , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Animais , Ferro/metabolismo , Ferro/análise , Camundongos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Injeções Intravenosas , Quelantes de Ferro , Masculino , Distribuição Tecidual
6.
Adv Biol Regul ; 91: 101002, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38064879

RESUMO

The inositol pyrophosphates (PP-IPs) are specialized members of the wider inositol phosphate signaling family that possess functionally significant diphosphate groups. The PP-IPs exhibit remarkable functionally versatility throughout the eukaryotic kingdoms. However, a quantitatively minor PP-IP - 1,5 bisdiphosphoinositol tetrakisphosphate (1,5-IP8) - has received considerably less attention from the cell signalling community. The main purpose of this review is to summarize recently-published data which have now brought 1,5-IP8 into the spotlight, by expanding insight into the molecular mechanisms by which this polyphosphate regulates many fundamental biological processes.


Assuntos
Difosfatos , Fosfatos de Inositol , Humanos , Transdução de Sinais/fisiologia
7.
Bioorg Chem ; 140: 106841, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37683541

RESUMO

Four monoterpenoid indole alkaloid dimers (MIADs), axidimins A-D (1-4), which possesses unprecedented apidosperma-aspidosperma-type skeletons, along with twelve known MIAs were isolated from Melodinus axillaris. Their structures were established by comprehensive analysis of the HRESIMS, NMR, ECD calculation and DP4 + analysis. A possible biosynthetic pathway for axidimins A-D was proposed. In vitro, axidimins C and D exhibited significant cytotoxicities against HCT116 cells with IC50 values of 5.3 µM and 3.9 µM, respectively. The results obtained from flow cytometry and Western blot analysis clearly demonstrated that axidimins C and D significantly induced a reverse G2/M phase arrest and apoptosis of HCT116 cells. The potential mechanism of axidimins C and D on HCT116 cells were thoroughly discussed through the utilization of network pharmacology and molecular docking research. Subsequently, the selected targets were validated using Western blot and CETSA analysis, confirming that axidimins C and D exert its cytotoxic effects through the activation of the p38 MAPK pathway, ultimately leading to HCT116 cells death. This study provides evidence indicating that axidimins C and D have the potential to induce cell cycle arrest and apoptosis in HCT116 cells by modulating the p38 MAPK signaling pathway. These findings offer a novel perspective for the development of anti-colorectal cancer drugs.


Assuntos
Apocynaceae , Alcaloides de Triptamina e Secologanina , Humanos , Células HCT116 , Simulação de Acoplamento Molecular , Apoptose , Pontos de Checagem do Ciclo Celular , Alcaloides Indólicos , Mitose , Monoterpenos/farmacologia , Polímeros
8.
Chem Biodivers ; 20(10): e202301270, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37697440

RESUMO

In the investigation of Meehania fargesii, eighteen triterpenoids were isolated and identified, including a previously unknown compound with an 13,27-cycloursane skeleton, using techniques like 1D and 2D NMR, and HR-MS. Furthermore, the cytotoxicity of these compounds were evaluated against HCT116, MCF-7, and AGS cell lines using the CCK-8 method to examine their structure-activity relationship. Remarkably, compounds 13 and 16 exhibited higher cytotoxicity across all three cell lines compared to the positive drug. Western blot analysis revealed that these compounds activated apoptosis in HCT116 cells by promoting the Bax protein and inhibiting the Bcl-2 protein. This suggests that compounds 13 and 16 have potential as apoptosis-inducing agents in HCT116 cells.

9.
Chem Biodivers ; 20(7): e202300696, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37269051

RESUMO

Through a phytochemical investigation of Abrus mollis Hance, a folk medicinal plant in China, we isolated and identified three undescribed compounds, including two flavonoids and one amides alkaloid, along with nine known from this plant. Their structures were elucidated by analyses of 1D, 2D NMR, HR-ESI-MS, ECD, and DP4+ analysis. Furthermore, we evaluated the hepatoprotective effects of all twelve compounds on D-GalN-induced Brl-3 A cells. According to the results, at a concentration of 25 µM, the cell survival rates were observed to be 71.92±0.34 %, 70.03±1.29 %, and 69.11±1.90 % for compound 2, 4, and 11, respectively. Further experimental studies showed that compound 2 (EC50 5.76±0.37 µM) showed more significant protective activity than the bicyclol.


Assuntos
Abrus , Alcaloides , Flavonoides/química , Extratos Vegetais/química , Abrus/química , Amidas/farmacologia , Alcaloides/farmacologia
10.
Brain Cogn ; 168: 105972, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37079997

RESUMO

Pain elicits the desire for a reward to alleviate the unpleasant sensation. This may be a consequence of facilitated neural activities in the reward circuit. However, the temporal modulation of pain on reward processing remains unclear. We addressed this issue by recording electroencephalogram when participants received win or loss feedback in a simple gambling task. Pain treatment was conducted on 33 participants with topical capsaicin cream and on 33 participants with hand cream as a control. Results showed that pain generally increased the P300 amplitude for both types of feedback but did not affect feedback-related negativity (FRN). A significant interaction effect of treatment (painful, non-painful) and outcome (win, loss) was observed on delta oscillation as pain only enhanced the power of win feedback. In addition, the FRN and theta oscillation responded more to loss feedback, but this effect was unaffected by pain. These findings indicate that pain may enhance secondary value representation and evaluation processes of rewards, but does not influence primary distinction of reward or reward expectation. The temporal unfolding of how pain affects reward-related neural activities highlights the prominent impact of pain on high-level cognitive processes associated with reward.


Assuntos
Potenciais Evocados , Jogo de Azar , Humanos , Eletroencefalografia , Recompensa , Jogo de Azar/psicologia , Dor , Retroalimentação Psicológica
11.
Phytochemistry ; 203: 113382, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36007663

RESUMO

The phytochemical study on Euphorbia fischeriana, a folk medicinal plant in China, led to the isolation of eight undescribed glycosides, including two diterpene glycosides, three acetophenone glycosides and three tannins together with eight known ones. Their planar structures were elucidated by extensive analyses of 1D, 2D NMR experiments and HRESIMS. The absolute configurations were determined by NOESY experiments, ECD calculations. All undescribed compounds were evaluated for their cytotoxicity and antibacterial activities in vitro. Two diterpene glycosides (1-2) showed cytotoxic activity with IC50 values ranging from 5.4 to 16.2 µM toward Hep-G2, Hep-3B, A549, NCI-H460 and AGS cells. Tannins (6-8) showed the significant antibacterial activity with MIC values in the range of 1.56-6.25 µg/mL.


Assuntos
Antineoplásicos Fitogênicos , Diterpenos , Euphorbia , Acetofenonas/farmacologia , Antibacterianos/farmacologia , Antineoplásicos Fitogênicos/química , Diterpenos/química , Euphorbia/química , Glicosídeos/análise , Glicosídeos/farmacologia , Estrutura Molecular , Compostos Fitoquímicos/análise , Extratos Vegetais/química , Raízes de Plantas/química , Taninos/análise
12.
Artigo em Inglês | MEDLINE | ID: mdl-35497917

RESUMO

Mesangial proliferative glomerulonephritis (MesPGN) is a common renal disease that lacks effective drug intervention. Aconiti Lateralis Radix (Fuzi), a natural Chinese medical herb, is found with significant therapeutic effects on various diseases in the clinic. However, its effects on MesPGN have not been reported. This study is aimed to discuss the therapeutic effects of the aqueous extract of Aconiti Lateralis Radix (ALR) and the polysaccharides of Aconiti Lateralis Radix (PALR) on MesPGN as well as the underlying mechanism. In this study, we, firstly, studied the anti-MesPGN mechanism of ALR and PALR. ALR and PALR inhibit the proliferation of the mesangial cells through the PI3K/AKT/mTOR pathway, induce the G0/G1 phase of block and apoptosis, inhibit the activity of Cyclin E and CDK2, increase the expression of Bax, cleaved caspase-8/caspase-8, and cleaved caspase-3/caspase-3 proteins, and effectively inhibit the growth of the mesangial cells. Overall, our data suggest that ALR and PALR may be potential candidates for MesPGN and that PALR is more effective than ALR.

13.
Cell Rep ; 36(12): 109706, 2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34551291

RESUMO

The serine synthesis pathway (SSP) involving metabolic enzymes phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) drives intracellular serine biosynthesis and is indispensable for cancer cells to grow in serine-limiting environments. However, how SSP is regulated is not well understood. Here, we report that activating transcription factor 3 (ATF3) is crucial for transcriptional activation of SSP upon serine deprivation. ATF3 is rapidly induced by serine deprivation via a mechanism dependent on ATF4, which in turn binds to ATF4 and increases the stability of this master regulator of SSP. ATF3 also binds to the enhancers/promoters of PHGDH, PSAT1, and PSPH and recruits p300 to promote expression of these SSP genes. As a result, loss of ATF3 expression impairs serine biosynthesis and the growth of cancer cells in the serine-deprived medium or in mice fed with a serine/glycine-free diet. Interestingly, ATF3 expression positively correlates with PHGDH expression in a subset of TCGA cancer samples.


Assuntos
Fator 3 Ativador da Transcrição/metabolismo , Neoplasias/patologia , Serina/biossíntese , Fator 3 Ativador da Transcrição/deficiência , Fator 3 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Animais , Vias Biossintéticas/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Nus , Neoplasias/metabolismo , Fosfoglicerato Desidrogenase/genética , Fosfoglicerato Desidrogenase/metabolismo , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Estabilidade Proteica , Serina/deficiência , Transaminases/genética , Transaminases/metabolismo , Transplante Heterólogo , Fatores de Transcrição de p300-CBP/metabolismo
14.
J Tradit Chin Med ; 40(4): 613-620, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32744028

RESUMO

OBJECTIVE: To determine the effect of Wenyang Huazhuo Fang (WHF), a Traditional Chinese Medicine decoction, on renal function in a rat model of doxorubicin-induced nephropathy, and to elucidate the underlying mechanism. METHODS: Sprague-Dawley rats were randomly divided into six groups: control, doxorubicin-nephropathy, and prednisone-treated (6.45 mg·kg-1·d-1) doxorubicin nephropathy groups, as well as high- (7.26 g·kg-1·d-1, medium- (2.42 g·kg-1·d-1, and low-dose (0.81 g·kg-1·d-1 WHF-treated doxorubicin-nephropathy groups. The nephropathy rat model was established by two tail vein injections of doxorubicin, followed by prednisone or WHF treatment for 8 weeks. Body weights were monitored and urinary protein was measured every 2 weeks. After the end of the treatment period, the rats were euthanized. Serum biochemical indicators were determined and renal morphological alterations were assessed using histological staining. The expression of transient receptor potential cation channel subfamily C member 6 (TRPC6), stromal interaction molecule 1 (STIM1), and calcium release-activated calcium channel protein 1 (Orai1) was detected using western blotting, and their mRNA levels were examined using quantitative real-time reverse transcription-polymerase chain reaction. RESULTS: WHF treatment was found to significantly ameliorate weight loss, proteinuria, hypoalbuminemia, and dyslipidemia in doxorubicin-nephropathy rats. The protein and mRNA levels of TRPC6, STIM1, and Orai1 were partially, but significantly suppressed by prednisone or WHF treatment. CONCLUSION: Treatment with WHF significantly ameliorates renal injury in a rat model of doxorubicin-induced nephropathy, which could be at least partially related to repression of the TRPC6 pathway.


Assuntos
Doxorrubicina/efeitos adversos , Medicamentos de Ervas Chinesas/administração & dosagem , Nefropatias/prevenção & controle , Substâncias Protetoras/administração & dosagem , Canais de Cátion TRPC/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/genética , Nefropatias/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPC/genética
15.
Proc Natl Acad Sci U S A ; 117(32): 19245-19253, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32727897

RESUMO

Regulation of enzymatic 5' decapping of messenger RNA (mRNA), which normally commits transcripts to their destruction, has the capacity to dynamically reshape the transcriptome. For example, protection from 5' decapping promotes accumulation of mRNAs into processing (P) bodies-membraneless, biomolecular condensates. Such compartmentalization of mRNAs temporarily removes them from the translatable pool; these repressed transcripts are stabilized and stored until P-body dissolution permits transcript reentry into the cytosol. Here, we describe regulation of mRNA stability and P-body dynamics by the inositol pyrophosphate signaling molecule 5-InsP7 (5-diphosphoinositol pentakisphosphate). First, we demonstrate 5-InsP7 inhibits decapping by recombinant NUDT3 (Nudix [nucleoside diphosphate linked moiety X]-type hydrolase 3) in vitro. Next, in intact HEK293 and HCT116 cells, we monitored the stability of a cadre of NUDT3 mRNA substrates following CRISPR-Cas9 knockout of PPIP5Ks (diphosphoinositol pentakisphosphate 5-kinases type 1 and 2, i.e., PPIP5K KO), which elevates cellular 5-InsP7 levels by two- to threefold (i.e., within the physiological rheostatic range). The PPIP5K KO cells exhibited elevated levels of NUDT3 mRNA substrates and increased P-body abundance. Pharmacological and genetic attenuation of 5-InsP7 synthesis in the KO background reverted both NUDT3 mRNA substrate levels and P-body counts to those of wild-type cells. Furthermore, liposomal delivery of a metabolically resistant 5-InsP7 analog into wild-type cells elevated levels of NUDT3 mRNA substrates and raised P-body abundance. In the context that cellular 5-InsP7 levels normally fluctuate in response to changes in the bioenergetic environment, regulation of mRNA structure by this inositol pyrophosphate represents an epitranscriptomic control process. The associated impact on P-body dynamics has relevance to regulation of stem cell differentiation, stress responses, and, potentially, amelioration of neurodegenerative diseases and aging.


Assuntos
Hidrolases Anidrido Ácido/metabolismo , Fosfatos de Inositol/metabolismo , Capuzes de RNA/metabolismo , RNA Mensageiro/metabolismo , Hidrolases Anidrido Ácido/genética , Células HEK293 , Humanos , Fosfotransferases (Aceptor do Grupo Fosfato)/genética , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo , Capuzes de RNA/genética , Estabilidade de RNA , RNA Mensageiro/genética
16.
Proc Natl Acad Sci U S A ; 117(7): 3568-3574, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32019887

RESUMO

Homeostasis of cellular fluxes of inorganic phosphate (Pi) supervises its structural roles in bones and teeth, its pervasive regulation of cellular metabolism, and its functionalization of numerous organic compounds. Cellular Pi efflux is heavily reliant on Xenotropic and Polytropic Retrovirus Receptor 1 (XPR1), regulation of which is largely unknown. We demonstrate specificity of XPR1 regulation by a comparatively uncharacterized member of the inositol pyrophosphate (PP-InsP) signaling family: 1,5-bis-diphosphoinositol 2,3,4,6-tetrakisphosphate (InsP8). XPR1-mediated Pi efflux was inhibited by reducing cellular InsP8 synthesis, either genetically (knockout [KO] of diphosphoinositol pentakisphosphate kinases [PPIP5Ks] that synthesize InsP8) or pharmacologically [cell treatment with 2.5 µM dietary flavonoid or 10 µM N2-(m-trifluorobenzyl), N6-(p-nitrobenzyl) purine], to inhibit inositol hexakisphosphate kinases upstream of PPIP5Ks. Attenuated Pi efflux from PPIP5K KO cells was quantitatively phenocopied by KO of XPR1 itself. Moreover, Pi efflux from PPIP5K KO cells was rescued by restoration of InsP8 levels through transfection of wild-type PPIP5K1; transfection of kinase-dead PPIP5K1 was ineffective. Pi efflux was also rescued in a dose-dependent manner by liposomal delivery of a metabolically resistant methylene bisphosphonate (PCP) analog of InsP8; PCP analogs of other PP-InsP signaling molecules were ineffective. High-affinity binding of InsP8 to the XPR1 N-terminus (Kd = 180 nM) was demonstrated by isothermal titration calorimetry. To derive a cellular biology perspective, we studied biomineralization in the Soas-2 osteosarcoma cell line. KO of PPIP5Ks or XPR1 strongly reduced Pi efflux and accelerated differentiation to the mineralization end point. We propose that catalytically compromising PPIP5K mutations might extend an epistatic repertoire for XPR1 dysregulation, with pathological consequences for bone maintenance and ectopic calcification.


Assuntos
Fosfatos de Fosfatidilinositol/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Virais/metabolismo , Transporte Biológico , Células HEK293 , Humanos , Fosfatos/metabolismo , Fosfotransferases (Aceptor do Grupo Fosfato)/genética , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Virais/genética , Transdução de Sinais , Receptor do Retrovírus Politrópico e Xenotrópico
17.
Adv Biol Regul ; 75: 100674, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31776069

RESUMO

The inositol pyrophosphates (PP-InsPs) are a unique subgroup of intracellular signals with diverse functions, many of which can be viewed as reflecting an overarching role in metabolic homeostasis. Thus, considerable attention is paid to the enzymes that synthesize and metabolize the PP-InsPs. One of these enzyme families - the diphosphoinositol pentakisphosphate kinases (PPIP5Ks) - provides an extremely rare example of separate kinase and phosphatase activities being present within the same protein. Herein, we review the current state of structure/function insight into the PPIP5Ks, the separate specialized activities of the two metazoan PPIP5K genes, and we describe a phylogenetic analysis that places PPIP5K evolutionary origin within the Excavata, the very earliest of eukaryotes. These different aspects of PPIP5K biology are placed in the context of a single, overriding question. Why are they bifunctional: i.e., what is the particular significance of the ability to turn PP-InsP signaling on or off from two separate 'switches' in a single protein?


Assuntos
Evolução Molecular , Fosfatos de Inositol , Fosfotransferases (Aceptor do Grupo Fosfato) , Transdução de Sinais , Animais , Humanos , Fosfatos de Inositol/genética , Fosfatos de Inositol/metabolismo , Fosfotransferases (Aceptor do Grupo Fosfato)/genética , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo
18.
Cell Death Differ ; 27(6): 1807-1818, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31796886

RESUMO

Blocking p53 ubiquitination through disrupting its interaction with MDM2 or inhibiting the MDM2 catalytic activity is the central mechanism by which the tumor suppressor p53 is activated in response to genotoxic challenges. Although MDM2 is first characterized as the major E3 ubiquitin ligase for p53, it can also catalyze the conjugation of ubiquitin moieties to other proteins (e.g., activating transcription factor 3, or ATF3). Here we report that ATF3 can act as an ubiquitin "trap" and competes with p53 for MDM2-mediated ubiquitination. While ATF3-mediated p53 stabilization required ATF3 binding to the MDM2 RING domain, we demonstrated that ATF3 ubiquitination catalyzed by MDM2 was indispensable for p53 activation in response to DNA damage. Moreover, a cancer-derived ATF3 mutant (R88G) devoid of ubiquitination failed to prevent p53 from MDM2-mediated degradation and thus was unable to activate the tumor suppressor. Therefore, we have identified a previously-unknown mechanism that can activate p53 in the genotoxic response.


Assuntos
Fator 3 Ativador da Transcrição/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular Tumoral , Dano ao DNA , Humanos , Ligação Proteica , Ubiquitinação
19.
Int J Biol Macromol ; 108: 550-557, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29233709

RESUMO

Diabetes has become a global and serious health issues which causes a variety of complications. This study aims to explore the hypoglycemic effect of Crassostrea gigas polysaccharide (CGPS) and the dynamic changes in the endogenous small molecule metabolites of urine from normal group, model group and CGPS high dose group by metabolomic approach (UPLC-Q-TOF-MS). In our study, the CGPS treatment could reduce the fasting blood glucose levels and recover the triglycerides (TG), total cholesterol (TC) and glycosylated serum protein (GSP) levels in serum of diabetic mice. Urine samples in normal group, model group and CGPS high dose group were dispersed in the PLS-DA score plots. Nineteen metabolites in urine such as l-carnitine, hippuric acid, pantothenate and ornithine were selected as potential therapeutic biomarkers and related metabolic pathways of CGPS for treating diabetes. They were mainly involved in amino acid metabolism, carbohydrate metabolism and purine metabolism. These data suggested that CGPS has antidiabetic activity and urine metabolites provided new understanding of CGPS for treating diabetes and its complications.


Assuntos
Crassostrea/química , Diabetes Mellitus Experimental/metabolismo , Metaboloma , Metabolômica , Polissacarídeos/farmacologia , Animais , Biomarcadores , Glicemia , Cromatografia Líquida de Alta Pressão , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Feminino , Lipídeos/sangue , Masculino , Metabolômica/métodos , Camundongos , Polissacarídeos/administração & dosagem , Polissacarídeos/química , Ratos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
20.
Mediators Inflamm ; 2017: 7659023, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28250578

RESUMO

Obesity has been associated with osteoarthritis (OA) due to increased mass and metabolic factors which are independent of the biomechanical contribution to joint load. Resveratrol, a natural polyphenolic compound, exerts protective effects on OA through its anti-inflammatory property. However, the mechanism of resveratrol on obesity-related OA is unclear. To investigate the effect and possible mechanism of oral resveratrol on obesity-related OA, we fed C57BL/6J mice with a high-fat diet (HFD) for 16 weeks to establish obesity-related OA model; then two doses (22.5 mg/kg and 45 mg/kg) of resveratrol were given by gavage for additional 12 weeks. Mice with HFD significantly increased body weights compared to the control mice, while resveratrol treatment did not cause obvious weight loss. Histological assessments showed that resveratrol at 45 mg/kg significantly improved OA symptoms. Levels of serum IL-1ß and leptin were decreased by resveratrol treatment and positively correlated with Mankin scores. Moreover, resveratrol significantly inhibited the expression of TLR4 and TRAF6 in cartilage. These results suggest that HFD induced obesity can lead to the occurrence of OA, and resveratrol may alleviate OA pathology by decreasing the levels of systematic inflammation and/or inhibiting TLR4 signaling pathway in cartilage. Thus, resveratrol might be a promising therapeutic treatment for obesity-related OA.


Assuntos
Osteoartrite/tratamento farmacológico , Estilbenos/uso terapêutico , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Western Blotting , Dieta Hiperlipídica/efeitos adversos , Ensaio de Imunoadsorção Enzimática , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Osteoartrite/metabolismo , Resveratrol , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Estilbenos/administração & dosagem
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