RESUMO
Diabetes mellitus is a major public health concern, often leading to undiagnosed micro- and macrovascular complications, even in patients with controlled blood glucose levels. Recent evidence suggests that empagliflozin and metformin have renoprotective effects in addition to their hypoglycemic action. This study investigated the potential protective effect of empagliflozin and metformin on diabetic renal complications. Forty-two adult male Sprague Dawley rats were randomized into six groups: normal control, diabetic control, metformin (250 mg/kg), empagliflozin (10 mg/kg), and combination therapy groups. Type 2 diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (40 mg/kg) following two weeks of 10% fructose solution in their drinking water. Blood glucose, creatinine, urea nitrogen, inflammatory markers (IL-6, TNF-α), and renal tissue caspase-3 were assessed after eight weeks. Blood glucose, urea, creatinine, serum IL-6, TNF-α, and tissue caspase-3 were significantly decreased in the treatment groups compared to the diabetic group. The histopathological findings revealed that treatment with empagliflozin and/or metformin improved the damage in the renal tissue caused by diabetes-induced nephropathy. Moreover, co-administration of empagliflozin and metformin resulted in even better outcomes. Our data revealed that empagliflozin and metformin could improve renal function and decrease inflammation and apoptosis in diabetic animals, delaying the progression of diabetic nephropathy. Combined treatment with metformin and empagliflozin proved to have an additive protective action on renal tissue.
Assuntos
Compostos Benzidrílicos , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Glucosídeos , Metformina , Ratos Sprague-Dawley , Metformina/farmacologia , Metformina/uso terapêutico , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/uso terapêutico , Animais , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Glucosídeos/administração & dosagem , Masculino , Ratos , Nefropatias Diabéticas/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada , Glicemia , Rim/efeitos dos fármacos , Rim/patologiaRESUMO
Ulcerative colitis is a public health issue with a rising worldwide incidence. It has been found that current medications for treating UC may cause varying degrees of damage to male fertility. Our previous study demonstrated that cyanidin-3-O-glucoside (C3G) treatment could effectively restore reproductive damage in a mouse model of DSS induced colitis. However, the underlying mechanism of C3G alleviates UC induced male reproductive disorders remain scarce. The aim of this study is to discover the molecular mechanisms of C3G on the amelioration of UC stimulated reproductive disorders. The targeted genes toward UC-induced reproductive injury upon C3G treatments were explored by transcriptomic analysis. Hematological analysis, histopathological examination, and real time transcription-polymerase chain reaction (RT-PCR) analysis were applied for conjoined identification. Results showed that C3G may effectively target for reducing pro-inflammatory cytokine IL-6 in testis through cytokine-cytokine receptor interaction pathway. Transcriptome sequencing found that a series of genetic pathways involved in the protective effects of C3G on male reproduction were identified by gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Further results presented that C3G could effectively restore mRNA expression levels of Ly6a and Col1a1, closely linked with UC induced male reproductive damage pathways. Sufficient results implied that Ly6a and Col1a1 may be treated as the promising therapeutic targets for the mechanism of C3G in treating UC induced reproductive impairment. C3G administration might be an effective dietary supplementation strategy for male reproduction improvement.
Assuntos
Antocianinas , Citocinas , Glucosídeos , Transcriptoma , Masculino , Animais , Antocianinas/farmacologia , Glucosídeos/farmacologia , Camundongos , Citocinas/metabolismo , Citocinas/genética , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Interleucina-6/metabolismo , Interleucina-6/genética , Perfilação da Expressão Gênica , Modelos Animais de Doenças , Infertilidade Masculina/tratamento farmacológico , Reprodução/efeitos dos fármacosRESUMO
This study explored how high hydrostatic pressure (HHP) and proteins (i.e., BSA and HSA) influence the color and chemical stability of cyanidin-3-O-glucoside (C3G) at neutral pH. HHP treatments (100-500 MPa, 0-20 min, 25 °C) did not affect C3G content in phosphate buffer (PB) and MOPS buffer. However, significant color loss of C3G occurred in PB due to pressure-induced pH reduction (e.g., from 7 to 4.8 at 500 MPa), which accelerated the hydration of C3G, converting it from colored to colorless species. Consequently, MOPS buffer was employed for subsequent stability experiments to assess the impact of protein and HHP on the thermal, storage, and UV light stability of C3G. Initially, rapid color loss occurred during heating and storage, primarily due to the reversible hydration of C3G until equilibrium with colorless species was reached, followed by slower parallel degradation. HSA increased the fraction of colored species at equilibrium but accelerated thermal degradation, while BSA had minimal effects. UV light irradiation accelerated the degradation of C3G colored species, causing direct degradation without conversion to colorless species, a process further intensified by the presence of proteins. HHP exhibited a negligible effect on C3G stability regardless of protein addition. These findings provide insights into anthocyanin stability under HHP and protein interactions, contributing to the development of future formulation and processing strategies for improved stability and broader applications.
Assuntos
Antocianinas , Cor , Glucosídeos , Pressão Hidrostática , Antocianinas/química , Glucosídeos/química , Concentração de Íons de Hidrogênio , Raios Ultravioleta , Soroalbumina Bovina/químicaRESUMO
Anthocyanins are water-soluble pigments, but they tend to be unstable in aqueous solutions. Modification of their molecular structure offers a viable approach to alter their intrinsic properties and enhance stability. Aromatic and aliphatic acid methyl esters were used as acyl donors in the enzymatic acylation of cyanidin-3-O-glucoside (C3G), and their analysis was conducted using ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). The highest conversion rate achieved was 96.41 % for cyanidin-3-O-(6â³-feruloyl) glucoside. Comparative evaluations of stability revealed that aromatic acyl group-conjugated C3G exhibited superior stability enhancement compared with aliphatic acyl group derivatives. The stability of aliphatic C3G decreased with increasing carbon chain length. The molecular geometries of different anthocyanins were optimized, and energy level calculations using density functional theory (DFT) identified their sites with antioxidant activities. Computational calculations aligned with the in vitro antioxidant assay results. This study provided theoretical support for stabilizing anthocyanins and broadened the application of acylated anthocyanins as food colorants and nutrient supplements.
Assuntos
Antocianinas , Glucosídeos , Antocianinas/química , Acilação , Glucosídeos/química , Antioxidantes/química , Ésteres/química , Espectrometria de Massas , Estrutura Molecular , Cromatografia Líquida de Alta PressãoRESUMO
BACKGROUND: Salidroside (SAL), derived from Rhodiola, shows protective effects in pulmonary arterial hypertension (PAH) models, but its mechanisms are not fully elucidated. OBJECTIVES: Investigate the therapeutic effects and the mechanism of SAL on PAH. METHODS: Monocrotaline was used to establish a PAH rat model. SAL's impact on oxidative stress and inflammatory responses in lung tissues was analyzed using immunohistochemistry, ELISA, and Western blot. Untargeted metabolomics explored SAL's metabolic regulatory mechanisms. RESULTS: SAL significantly reduced mean pulmonary artery pressure, right ventricular hypertrophy, collagen deposition, and fibrosis in the PAH rats. It enhanced antioxidant enzyme levels, reduced inflammatory cytokines, and improved NO bioavailability by upregulating endothelial nitric oxide synthase (eNOS), soluble guanylate cyclase (sGC), cyclic guanosine monophosphate (cGMP), and protein kinase G (PKG) and decreases the expression of endothelin-1 (ET-1). Metabolomics indicated SAL restored metabolic balance in PAH rats, particularly in arginine metabolism. CONCLUSIONS: SAL alleviates PAH by modulating arginine metabolism, enhancing NO synthesis, and improving pulmonary vascular remodeling.
Assuntos
Arginina , Glucosídeos , Óxido Nítrico , Fenóis , Hipertensão Arterial Pulmonar , Animais , Glucosídeos/farmacologia , Fenóis/farmacologia , Fenóis/uso terapêutico , Óxido Nítrico/metabolismo , Ratos , Masculino , Arginina/metabolismo , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/metabolismo , Ratos Sprague-Dawley , Modelos Animais de Doenças , Estresse Oxidativo/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Disponibilidade Biológica , Remodelação Vascular/efeitos dos fármacosRESUMO
With the rapid development of traditional Chinese medicine and the continuous discovery of various anticancer effects of salidroside (sal), it is known that sal inhibits tumor proliferation, invasion and migration by inducing apoptosis and autophagy, regulating the cell cycle, modulating the tumor microenvironment, and controlling cancer-related signaling pathways and molecules. The microRNA (miRNA)-mRNA signaling axis can regulate the expression of target mRNAs by altering miRNA expression, thereby affecting the growth cycle, proliferation, and metabolism of cancer cells. Studies have shown that sal can influence the occurrence and progression of various malignant tumors through the miRNA-mRNA signaling axis, inhibiting the progression of lung cancer, gastric cancer, and nasopharyngeal carcinoma, with a notable time and dose dependence in its antitumor effects. Summarizing the specific mechanism of sal regulating miRNA-mRNA signaling axis to inhibit tumors in recent years can provide a new theoretical basis, diagnosis, and therapeutic methods for the research on prevention and treatment of tumors.
Assuntos
Glucosídeos , MicroRNAs , Fenóis , RNA Mensageiro , Transdução de Sinais , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fenóis/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Neoplasias Gástricas/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Microambiente Tumoral/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , AnimaisRESUMO
BACKGROUND: Gender is a significant risk factor for late-onset Alzheimer's disease (AD), often attributed to the decline of estrogen. The plant estrogen secoisolariciresinol diglucoside (SDG) has demonstrated anti-inflammatory and neuroprotective effects. However, the protective effects and mechanisms of SDG in female AD remain unclear. METHODS: Ten-month-old female APPswe/PSEN1dE9 (APP/PS1) transgenic mice were treated with SDG to assess its potential ameliorative effects on cognitive impairments in a female AD model through a series of behavioral and biochemical experiments. Serum levels of gut microbial metabolites enterodiol (END) and enterolactone (ENL) were quantified using HPLC-MS. Correlation analysis and broad-spectrum antibiotic cocktail (ABx) treatment were employed to demonstrate the involvement of END and ENL in SDG's cognitive improvement effects in female APP/PS1 mice. Additionally, an acute neuroinflammation model was constructed in three-month-old C57BL/6J mice treated with lipopolysaccharide (LPS) and subjected to i.c.v. injection of G15, an inhibitor of G protein-coupled estrogen receptor (GPER), to investigate the mediating role of the estrogen receptor GPER in the cognitive benefits conferred by SDG. RESULTS: SDG administration resulted in significant improvements in spatial, recognition, and working memory in female APP/PS1 mice. Neuroprotective effects were observed, including enhanced expression of CREB/BDNF and PSD-95, reduced ß-amyloid (Aß) deposition, and decreased levels of TNF-α, IL-6, and IL-10. SDG also altered gut microbiota composition, increasing serum levels of END and ENL. Correlation analysis indicated significant associations between END, ENL, cognitive performance, hippocampal Aß-related protein mRNA expression, and cortical neuroinflammatory cytokine levels. The removal of gut microbiota inhibited END and ENL production and eliminated the neuroprotective effects of SDG. Furthermore, GPER was found to mediate the inhibitory effects of SDG on neuroinflammatory responses. CONCLUSION: These findings suggest that SDG promotes the production of gut microbial metabolites END and ENL, which inhibit cerebral ß-amyloid deposition, activate GPER to enhance CREB/BDNF signaling pathways, and suppress neuroinflammatory responses. Consequently, SDG exerts neuroprotective effects and ameliorates cognitive impairments associated with AD in female mice.
Assuntos
Doença de Alzheimer , Fator Neurotrófico Derivado do Encéfalo , Butileno Glicóis , Disfunção Cognitiva , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Microbioma Gastrointestinal , Glucosídeos , Camundongos Transgênicos , Doenças Neuroinflamatórias , Receptores de Estrogênio , Receptores Acoplados a Proteínas G , Animais , Feminino , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Camundongos , Microbioma Gastrointestinal/efeitos dos fármacos , Butileno Glicóis/farmacologia , Butileno Glicóis/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Receptores de Estrogênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Modelos Animais de DoençasRESUMO
Diabetes mellitus is a metabolic disorder caused by a dysfunction in insulin action or secretion, leading to an elevation in blood glucose levels. It is a highly prevalent condition and as a result, the NHS spends 10 % of its entire budget on diabetes mellitus care, that is equivalent to £10 billion a year. Diabetes mellitus has been linked with vascular and neurological complications which may be associated with the progression of neurodegeneration and Alzheimer's disease. Chronic hyperglycaemia increases the production of the reactive oxidant species (ROS) such as methylglyoxal (MGO). MGO has been linked with vascular complications, neuropathy and cytotoxicity. The main aim of this study was to investigate the potential beneficial effect of antidiabetic agents such as metformin and dapagliflozin on human brain neuronal cells (SH-SY5Y) treated with MGO. SH-SY5Y cells were cultured in DMEM/F12 media and subjected overnight incubation with one of the following treatment conditions: Control (untreated); MGO (1 µM); MGO (100 µM); metformin (100 µM) + MGO (100 µM); and dapagliflozin (10 µM) + MGO (100 µM). Several assays were conducted to explore the effect of the treatment groups on the SH-SY5Y cells. These included: MTT assay; LDH assay, peroxynitrite fluorescence assay, and laser scanning confocal microscopy. MGO (100 µM) led to significant cell injury and damage and significantly reduced the survival of the cells by approximately 50-75 %, associated with significant increase in peroxynitrite. The addition of metformin (100 µM) or dapagliflozin (10 µM) represented significant protective effects on the cells and prevented the cell damage caused by the high MGO concentration. As a result, the findings of this research reveal that MGO-induced cell damage may partly be mediated by the generation of peroxynitrite, while the antidiabetic agents such as metformin and dapagliflozin prevent brain cell death, which potentially may play prophylactic roles against the risk of dementia in diabetic patients.
Assuntos
Compostos Benzidrílicos , Glucosídeos , Hipoglicemiantes , Metformina , Neurônios , Aldeído Pirúvico , Humanos , Compostos Benzidrílicos/farmacologia , Aldeído Pirúvico/toxicidade , Metformina/farmacologia , Glucosídeos/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Hipoglicemiantes/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/citologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neuroblastoma/patologia , Neuroblastoma/metabolismoRESUMO
BACKGROUND: One in 7 adults have chronic kidney disease (CKD), which is associated with high morbidity and mortality and substantial health care costs, especially in more advanced disease. Our data from a US commercial payer show rising per-member-per-year costs for renal and cardiac complications associated with CKD. OBJECTIVE: To predict the clinical and economic impact of treatment with or without dapagliflozin from the perspective of a US commercial payer using a cost-offset model (COM). METHODS: The COM used real-world cost and member count data from a US employer-sponsored commercial payer and results of the double-blind, randomized, phase 3 Dapagliflozin and Prevention of Adverse Outcomes in CKD clinical trial (NCT03036150) to predict the incidence of clinical events, including a greater than or equal to 50% decline in estimated glomerular filtration rate (eGFR), end-stage kidney disease, and hospitalization for heart failure, and their associated costs over a 3-year period. The COM compared a hypothetical scenario of the experience with or without dapagliflozin in members with CKD stages 2-4, aged younger than 65 years. RESULTS: In the simulated populations of 130 members, the COM projected 9 events of a greater than or equal to 50% decline in estimated glomerular filtration rate for the experience with dapagliflozin vs 15 events for the experience without dapagliflozin (6 fewer events; number needed to treat [NNT] = 20, amounting to estimated cumulative cost offsets of $0.57 million [M] over a 3-year period). The COM projected similar results for end-stage kidney disease (8 events with dapagliflozin vs 14 events without dapagliflozin; NNT = 24, amounting to $1.92 M in cumulative cost offsets) and for hospitalization for heart failure (13 events with dapagliflozin vs 33 events without dapagliflozin; NNT = 7, amounting to $0.79 M in cumulative cost offsets). These projections translated to total mean, cumulative cost offsets of $3.89 M for all clinical events evaluated over the 3-year period (36.6% reduction with dapagliflozin vs without dapagliflozin), and net mean, cumulative cost offsets of $2.58 M over the 3-year period (24.2% reduction with dapagliflozin vs without dapagliflozin) after factoring in a discounted wholesale acquisition cost for dapagliflozin expenditure ($1.31 M over 3 years). Thus, the net mean, cumulative cost offsets were $19,843 per member over 3 years, representing a 197% return on investment for dapagliflozin expenditure. CONCLUSIONS: Results of our COM suggest that dapagliflozin can reduce clinical events and their associated costs over a 3-year period when compared with a scenario without dapagliflozin. Cost offsets increased with each year, indicating that US commercial payers can substantially reduce costs associated with CKD morbidity and mortality.
Assuntos
Compostos Benzidrílicos , Análise Custo-Benefício , Glucosídeos , Insuficiência Renal Crônica , Humanos , Compostos Benzidrílicos/uso terapêutico , Compostos Benzidrílicos/economia , Glucosídeos/economia , Glucosídeos/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/economia , Estados Unidos , Pessoa de Meia-Idade , Masculino , Feminino , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/economia , Taxa de Filtração Glomerular , Adulto , Método Duplo-Cego , Idoso , Custos de Cuidados de Saúde/estatística & dados numéricos , Modelos EconômicosRESUMO
Deoxynivalenol-3-glucoside (D3G), the masked form of the important mycotoxin deoxynivalenol (DON), displays potential toxicity but is difficult to control owing to the lack of rapid detection methods. Herein, an innovative molecularly imprinted polymer (MIP)-based electrochemical sensor was developed for the rapid detection of D3G. MIP, an efficient recognition element for D3G, was electropolymerized using o-phenylenediamine based on a surface functional monomer-directing strategy for the first time. CeO2, which contains both Ce3+ and Ce4+ oxidation states, was introduced as a nanozyme to catalyze H2O2 reduction, while Mn doping generated more oxygen vacancies and considerably improved the catalytic activity. Mn-CeO2 also served as a promising substrate material because of its large surface area and excellent conductivity. Under optimal conditions, a good linear relationship was observed for D3G detection over the concentration range of 0.01-50 ng/mL. The proposed sensor could detect D3G down to 0.003 ng/mL with excellent selectivity, even distinguishing its precursor DON in complex samples. The sensor exhibited acceptable stability with high reproducibility and accuracy, and could successfully determine D3G in grain samples. To the best of our knowledge, this is the first electrochemical sensing platform for rapid D3G detection that can easily be expanded to other masked mycotoxins.
Assuntos
Cério , Técnicas Eletroquímicas , Manganês , Tricotecenos , Tricotecenos/análise , Tricotecenos/química , Cério/química , Manganês/química , Polímeros Molecularmente Impressos/química , Impressão Molecular , Polímeros/química , Reprodutibilidade dos Testes , Grão Comestível/química , Limite de Detecção , Glucosídeos/química , Glucosídeos/análise , Contaminação de Alimentos/análise , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/análiseRESUMO
Rehmannia glutinosa produces many phenylethanoid glycoside (PhG) compounds, including salidroside, which not only possesses various biological activities but also is a core precursor of some medicinal PhGs, so it is very important to elucidate the species' salidroside biosynthesis pathway to enhance the production of salidroside and its derivations. Although some plant copper-containing amine oxidases (CuAOs), phenylacetaldehyde reductases (PARs) and UDP-glucose glucosyltransferases (UGTs) are thought to be vital catalytic enzymes involved in the downstream salidroside biosynthesis pathways, to date, none of these proteins or the associated genes in R. glutinosa have been characterized. To verify a postulated R. glutinosa salidroside biosynthetic pathway starting from tyrosine, this study identified and characterized a set of R. glutinosa genes encoding RgCuAO, RgPAR and RgUGT enzymes for salidroside biosynthesis. The functional activities of these proteins were tested in vitro by heterologous expression of these genes in Escherichia coli, confirming these catalytic abilities in these corresponding reaction steps of the biosynthetic pathway. Importantly, four enzyme-encoding genes (including the previously reported RgTyDC2 encoding tyrosine decarboxylase and the RgCuAO1, RgPAR1 and RgUGT2 genes) were cointegrated into Saccharomyces cerevisiae to reconstitute the R. glutinosa salidroside biosynthetic pathway, achieving an engineered strain that produced salidroside and validating these enzymes' catalytic functions. This study elucidates the complete R. glutinosa salidroside biosynthesis pathway from tyrosine metabolism in S. cerevisiae, establishing a basic platform for the efficient production of salidroside and its derivatives.
Assuntos
Vias Biossintéticas , Glucosídeos , Fenóis , Rehmannia , Saccharomyces cerevisiae , Fenóis/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Glucosídeos/biossíntese , Glucosídeos/metabolismo , Rehmannia/genética , Rehmannia/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismoRESUMO
Tyrosol is a natural phenolic compound with antioxidant, anti-inflammatory and other biological activities, serving as an important precursor of high-value products such as hydroxytyrosol and salidroside. Therefore, the green and efficient biosynthesis of tyrosol and its derivatives has become a research hotspot in recent years. Building cell factories by metabolic engineering of microorganisms is a potential industrial production way, which has low costs and environmental friendliness. This paper introduces the biosynthesis pathway of tyrosol and presents the key regulated nodes in the de novo synthesis of tyrosol in Escherichia coli and Saccharomyces cerevisiae. In addition, this paper reviews the recent advances in metabolic engineering for the production of hydroxytyrosol and salidroside. This review can provide a reference for engineering the strains for the high-yield production of tyrosol and its derivatives.
Assuntos
Escherichia coli , Engenharia Metabólica , Álcool Feniletílico , Saccharomyces cerevisiae , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/metabolismo , Engenharia Metabólica/métodos , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Escherichia coli/metabolismo , Escherichia coli/genética , Fenóis/metabolismo , Glucosídeos/biossíntese , Glucosídeos/metabolismo , Microbiologia IndustrialRESUMO
Chronic kidney disease (CKD) is a complication of diabetes that affects circulating drug concentrations and elimination of drugs from the body. Multiple drugs may be prescribed for treatment of diabetes and co-morbidities, and CKD complicates the pharmacotherapy selection and dosing regimen. Characterizing variations in renal drug clearance using models requires large clinical datasets that are costly and time-consuming to collect. We propose a flexible approach to incorporate impaired renal clearance in pharmacokinetic (PK) models using descriptive statistics and secondary data with mechanistic models and PK first principles. Probability density functions were generated for various drug clearance mechanisms based on the degree of renal impairment and used to estimate the total clearance starting from glomerular filtration for metformin (MET) and dapagliflozin (DAPA). These estimates were integrated with PK models of MET and DAPA for simulations. MET renal clearance decreased proportionally with a reduction in estimated glomerular filtration rate (eGFR) and estimated net tubular transport rates. DAPA total clearance varied little with renal impairment and decreased proportionally to reported non-renal clearance rates. Net tubular transport rates were negative to partially account for low renal clearance compared with eGFR. The estimated clearance values and trends were consistent with MET and DAPA PK characteristics in the literature. Dose adjustment based on reduced clearance levels estimated correspondingly lower doses for MET and DAPA while maintaining desired dose exposure. Estimation of drug clearance rates using descriptive statistics and secondary data with mechanistic models and PK first principles improves modeling of CKD in diabetes and can guide treatment selection.
Assuntos
Compostos Benzidrílicos , Taxa de Filtração Glomerular , Glucosídeos , Hipoglicemiantes , Metformina , Modelos Biológicos , Insuficiência Renal Crônica , Compostos Benzidrílicos/farmacocinética , Compostos Benzidrílicos/administração & dosagem , Metformina/farmacocinética , Metformina/administração & dosagem , Glucosídeos/farmacocinética , Glucosídeos/administração & dosagem , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Simulação por Computador , MasculinoRESUMO
A previous study showed that high-glucose (HG) conditions induce mitochondria fragmentation through the calcium-mediated activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) in H9C2 cells. This study tested whether empagliflozin could prevent HG-induced mitochondria fragmentation through this pathway. We found that exposing H9C2 cells to an HG concentration decreased cell viability and increased cell apoptosis and caspase-3. Empagliflozin could reverse the apoptosis effect of HG stimulation on H9C2 cells. In addition, the HG condition caused mitochondria fragmentation, which was reduced by empagliflozin. The expression of mitochondria fission protein was upregulated, and fusion proteins were downregulated under HG stimulation. The expression of fission proteins was decreased under empagliflozin treatment. Increased calcium accumulation was observed under the HG condition, which was decreased by empagliflozin. The increased expression of ERK 1/2 under HG stimulation was also reversed by empagliflozin. Our study shows that empagliflozin could reverse the HG condition, causing a calcium-dependent activation of the ERK 1/2 pathway, which caused mitochondria fragmentation in H9C2 cells.
Assuntos
Apoptose , Compostos Benzidrílicos , Cálcio , Glucose , Glucosídeos , Sistema de Sinalização das MAP Quinases , Mitocôndrias , Apoptose/efeitos dos fármacos , Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Glucose/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Cálcio/metabolismo , Animais , Ratos , Linhagem Celular , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Caspase 3/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismoRESUMO
Patients with type 2 diabetes mellitus are frequently hospitalized for heart failure. The ratio of early diastolic mitral inflow velocity to early diastolic mitral annulus velocity (E/e'), measured by echocardiography, is a simple and convenient indicator of diastolic dysfunction. Various large clinical trials have reported that sodium glucose transporter-2 inhibitor therapy reduced cardiovascular events and hospitalizations in heart failure patients. We examined the effect of tofogliflozin on various physiological and cardiac function. A retrospective analysis was performed on elderly patients aged 65 years or older with type 2 diabetes mellitus attending Himi Municipal Hospital who were taking oral tofogliflozin 20 mg/day. Measurement of physiological and hormonal variables, blood sampling, and echocardiographic evaluations at 0, 1, 3, and 6 months were performed on those with ejection fraction (EF) of 40% or greater at the time of treatment. Statistical analysis was performed using t-tests and mixed-effects models, with brain natriuretic peptide less than or not less than 100 pg/mL, estimated glomerular filtration rate (eGFR) less than or not less than 50 mL/min/1.73 m2, and diuretics administered or not. Hypoglycemic effects were observed at 0, 1, 3, and 6 months. At each time point, EF was retained and E/e' was significantly reduced. On the other hand, most physiological parameters and laboratory results showed no clinical abnormalities. Mixed-effects models showed time-dependent reduction of E/e' in high/low brain natriuretic peptide, high/low eGFR, with or without diuretics between baseline and at 6 months. The interaction with time was significant in high/low eGFR. Tofogliflozin was shown to improve E/e', a measure of diastolic function, while maintaining EF, with hypoglycemic effects and no clinical side effects.
Assuntos
Compostos Benzidrílicos , Diabetes Mellitus Tipo 2 , Glucosídeos , Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Volume Sistólico , Humanos , Estudos Retrospectivos , Idoso , Masculino , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/uso terapêutico , Compostos Benzidrílicos/farmacologia , Feminino , Glucosídeos/administração & dosagem , Glucosídeos/uso terapêutico , Glucosídeos/farmacologia , Volume Sistólico/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Idoso de 80 Anos ou mais , Ecocardiografia , Taxa de Filtração Glomerular/efeitos dos fármacosRESUMO
During the development of animal organs, various adverse stimuli or toxic environments can induce oxidative stress and delay ovarian development. Paeoniflorin (PF), the main active ingredient of the traditional Chinese herb Paeonia lactiflora Pall., has protective effects on various diseases by preventing oxidative stress. However, the mechanism by which PF attenuates oxidative damage in mouse ovaries remains unclear. We evaluated the protective effects of PF on ovaries in an H2O2-induced mouse oxidative stress model. The H2O2-induced mouse ovarian oxidative stress model was used to explore the protective effect of PF on ovarian development. Histology and follicular development were observed. We then detected related indicators of cell apoptosis, oxidative stress, and autophagy in mouse ovaries. We found that PF inhibited H2O2-induced ovarian cell apoptosis and ferroptosis and promoted granulosa cell proliferation. PF prevented oxidative stress by increasing nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression levels. In addition, the autophagic flux of ovarian cells was activated and was accompanied by increased lysosomal biogenesis. Moreover, PF-mediated autophagy was involved in clearing mitochondria damaged by H2O2. Importantly, PF administration significantly increased the number of primordial follicles, primary follicles, secondary follicles, and antral follicles. PF administration improved ovarian sizes compared with the H2O2 group. The present study suggested that PF administration reversed H2O2-induced ovarian developmental delay and promoted follicle development. PF-activated mitophagy is crucial for preventing oxidative stress and improving mitochondrial quality.
Assuntos
Glucosídeos , Peróxido de Hidrogênio , Mitofagia , Ovário , Estresse Oxidativo , Animais , Feminino , Estresse Oxidativo/efeitos dos fármacos , Glucosídeos/farmacologia , Camundongos , Ovário/efeitos dos fármacos , Ovário/metabolismo , Mitofagia/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Monoterpenos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Proliferação de Células/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/metabolismoRESUMO
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have a variety of cardiovascular and renoprotective effects and have been developed as novel agents for the treatment of heart failure. However, the beneficial mechanisms of SGLT2i on cardiac tissue need to be investigated further. In this study, we established a mouse model of acute myocardial infarction (AMI) using coronary artery constriction surgery and investigated the role of dapagliflozin (DAPA) in protecting cardiomyocytes from hypoxic injury induced by AMI. In vitro experiments were done using hypoxic cultured H9c2 ventricular cells to verify this potential mechanism. Expression of the SIRT family and related genes and proteins was verified by qPCR, Western blotting and immunofluorescence staining, and the intrinsic potential mechanism of cardiomyocyte death due to AMI and hypoxia was comprehensively investigated by RNA sequencing. The RNA sequencing results of cardiomyocytes from AMI mice showed that the SIRT family may be mainly involved in the mechanisms of hypoxia-induced cardiomyocyte death. In vitro hypoxia-induced ventricular cells showed the role of dapagliflozin in conferring resistance to hypoxic injury in cardiomyocytes. It showed that SIRT1/3/6 were downregulated in H9c2 cells in a hypoxic environment, and the addition of dapagliflozin significantly increased the gene and protein expression of SIRT1, 3 and 6. We then verified the underlying mechanisms induced by dapagliflozin in hypoxic cardiomyocytes using RNA-seq, and found that dapagliflozin upregulated the hypoxia-induced gene downregulation, which includes ESRRA, EPAS1, AGTRAP, etc., that associated with SIRTs-related and apoptosis-related signaling to prevent H9c2 cell death. This study provides laboratory data for SGLT2i dapagliflozin treatment of AMI and confirms that dapagliflozin can be used to treat hypoxia-induced cellular necrosis in cardiomyocytes, in which SIRT1 and SIRT3 may play an important role. This opens up further opportunities for SGLT2i in the treatment of heart disease.
Assuntos
Compostos Benzidrílicos , Glucosídeos , Infarto do Miocárdio , Miócitos Cardíacos , Transdução de Sinais , Sirtuína 1 , Inibidores do Transportador 2 de Sódio-Glicose , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Animais , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Compostos Benzidrílicos/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Camundongos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Sirtuína 1/metabolismo , Sirtuína 1/genética , Transdução de Sinais/efeitos dos fármacos , Masculino , Sirtuína 3/metabolismo , Sirtuína 3/genética , Sirtuínas/metabolismo , Sirtuínas/genética , Linhagem Celular , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Hipóxia Celular/efeitos dos fármacos , Ratos , Apoptose/efeitos dos fármacosRESUMO
KEY MESSAGE: We revealed the intrinsic transformation molecular mechanism of gastrodin by two ß-d-glucosidases (GeBGL1 and GeBGL9) during the processing of Gastrodia elata. Gastrodia elata is a plant resource with medicinal and edible functions, and its active ingredient is gastrodin. However, the intrinsic transformation molecular mechanism of gastrodin in G. elata has not been verified. We speculated that ß-d-glucosidase (BGL) may be the key enzymes hydrolyzing gastrodin. Here, we identified 11 GeBGL genes in the G. elata genome. These genes were unevenly distributed on seven chromosomes. These GeBGL proteins possessed motifs necessary for catalysis, namely, TF(I/M/L)N(T)E(Q)P and I(V/L)T(H/S)ENG(S). These GeBGLs were divided into five subgroups together with homologous genes from Arabidopsis thaliana, rice, and maize. Quantitative real-time PCR analysis showed GeBGL genes expression was tissue-specific. Gene cloning results showed two mutation sites in the GeBGL1 gene compared with the reference genome. And, the GeBGL4 gene has two indel fragments, which resulted in premature termination of translation and seemed to turn into a pseudogene. Furthermore, protein expression and enzyme activity results proved that GeBGL1 and GeBGL9 have the activity of hydrolyzing gastrodin into 4-hydroxybenzyl alcohol. This study revealed the function of ß-d-glucosidase in degrading active compounds during the G. elata processing for medicinal purposes. These results offer a theoretical foundation for elevating the standard and enhancing the quality of G. elata production.
Assuntos
Álcoois Benzílicos , Gastrodia , Regulação da Expressão Gênica de Plantas , Glucosídeos , Proteínas de Plantas , Gastrodia/genética , Gastrodia/metabolismo , Álcoois Benzílicos/metabolismo , Glucosídeos/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Glicosídeo Hidrolases/genética , Glicosídeo Hidrolases/metabolismo , Filogenia , Genoma de PlantaRESUMO
Rhodiola rosea, a long-lived herbaceous plant from the Crassulaceae group, contains the active compound salidroside, recognized as an adaptogen with significant therapeutic potential for bone metabolism. Salidroside promotes osteoblast proliferation and differentiation by activating critical signaling pathways, including bone morphogenetic protein-2 and adenosine monophosphate-activated protein kinase, essential for bone formation and growth. It enhances osteogenic activity by increasing alkaline phosphatase activity and mineralization markers, while upregulating key regulatory proteins including runt-related transcription factor 2 and osterix. Additionally, salidroside facilitates angiogenesis via the hypoxia-inducible factor 1-alpha and vascular endothelial growth factor pathway, crucial for coupling bone development with vascular support. Its antioxidant properties offer protection against bone loss by reducing oxidative stress and promoting osteogenic differentiation through the nuclear factor erythroid 2-related factor 2 pathway. Salidroside has the capability to counteract the negative effects of glucocorticoids on bone cells and prevents steroid-induced osteonecrosis. Additionally, it exhibits multifaceted anti-inflammatory actions, notably through the inhibition of tumor necrosis factor-alpha and interleukin-6 expression, while enhancing the expression of interleukin-10. This publication presents a comprehensive review of the literature on the impact of salidroside on various aspects of bone tissue metabolism, emphasizing its potential role in the prevention and treatment of osteoporosis and other diseases affecting bone physiology.
Assuntos
Osso e Ossos , Glucosídeos , Osteoblastos , Osteogênese , Osteoporose , Fenóis , Glucosídeos/farmacologia , Humanos , Fenóis/farmacologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Animais , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Rhodiola/química , Transdução de Sinais/efeitos dos fármacos , Antioxidantes/farmacologia , Diferenciação Celular/efeitos dos fármacos , Anti-Inflamatórios/farmacologiaRESUMO
Objective: This study aimed to evaluate the efficacy and safety of polyethylene glycol loxenatide (PEG-Loxe) compared to those of dapagliflozin in patients with mild-to-moderate diabetic kidney disease (DKD), a prevalent microvascular complication of type 2 diabetes mellitus (T2DM). The study is set against the backdrop of increasing global diabetes incidence and the need for effective DKD management. Methods: This study constituted a single-center, randomized, open-label, clinical trial. The trial included patients with mild-to-moderate DKD and suboptimal glycemic control. Eligible participants were randomly allocated to one of the two groups for treatment with either PEG-Loxe or dapagliflozin. The primary endpoint was the change in UACR from baseline at 24 weeks. Results: Overall, 106 patients were randomized and 80 patients completed the study. Following 24 weeks of treatment, the PEG-Loxe group exhibited a mean percent change in baseline UACR of -29.3% (95% confidence interval [CI]: -34.8, -23.7), compared to that of -31.8% in the dapagliflozin group (95% CI: -34.8, -23.7). Both PEG-Loxe and dapagliflozin showed similar efficacy in reducing UACR, with no significant difference between the groups (p = 0.336). The HbA1c levels decreased by -1.30% (95% CI: -1.43, -1.18) in the PEG-Loxe group and by -1.29% (95% CI: -1.42, -1.17) in the dapagliflozin group (p = 0.905). The TG levels decreased by -0.56 mmol/L (95% CI: -0.71, -0.42) in the PEG-Loxe group and -0.33 mmol/L (95% CI: -0.48, -0.19) in the dapagliflozin group (p = 0.023). Differences in TC, HDL-C, LDL-C, SBP, and DBP levels between the groups were not statistically significant (all p > 0.05). Safety profiles were consistent with previous findings, with gastrointestinal adverse events being more common in the PEG-Loxe group. Conclusions: PEG-Loxe is as effective as dapagliflozin in improving urine protein levels in patients with mild-to-moderate DKD and offers superior benefits in improving lipid profiles. These findings support the use of PEG-Loxe in DKD management, contributing to evidence-based treatment options. Clinical Trial Registration: www.chictr.org.cn, identifier ChiCTR2300070919.