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1.
Chem Biol Interact ; 401: 111164, 2024 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-39111524

RESUMO

Ganoderic Acid A (GAA) has demonstrated beneficial effects in anti-inflammatory and anti-oxidative stress studies. However, it remains unknown whether GAA exerts positive impacts on bone loss induced by lipopolysaccharide (LPS). This study aims to investigate the influence of GAA on bone loss in LPS-treated rats. The study assesses changes in the viability and osteogenic potential of MC3T3-E1 cells, as well as osteoclast differentiation in RAW264.7 cells in the presence of LPS using CCK-8, ALP staining, AR staining, and Tartrate-resistant acid phosphatase (TRAP) staining. In vitro experiments indicate that LPS-induced inhibition of osteoclasts (OC) and Superoxide Dismutase 2 (SOD2) correlates with heightened levels of inflammation and oxidative stress. Furthermore, GAA has displayed the ability to alleviate oxidative stress and inflammation, enhance osteogenic differentiation, and suppress osteoclast differentiation. Animal experiment also proves that GAA notably upregulates SOD2 expression and downregulates TNF-α expression, leading to the restoration of impaired bone metabolism, improved bone strength, and increased bone mineral density. The collective experimental findings strongly suggest that GAA can enhance osteogenic activity in the presence of LPS by reducing inflammation and oxidative stress, hindering osteoclast differentiation, and mitigating bone loss in LPS-treated rat models.


Assuntos
Diferenciação Celular , Ácidos Heptanoicos , Inflamação , Lanosterol , Lipopolissacarídeos , Osteoclastos , Osteogênese , Estresse Oxidativo , Ratos Sprague-Dawley , Superóxido Dismutase , Animais , Lipopolissacarídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Masculino , Camundongos , Ratos , Células RAW 264.7 , Superóxido Dismutase/metabolismo , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Lanosterol/análogos & derivados , Lanosterol/farmacologia , Lanosterol/uso terapêutico , Ácidos Heptanoicos/farmacologia , Ácidos Heptanoicos/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Reabsorção Óssea/prevenção & controle , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo
2.
Brain Res ; 1842: 149102, 2024 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-38969084

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Accumulation of ß-amyloid (Aß) in the brain has been recognized as a key factor in the onset and progression of Alzheimer's disease (AD).The accumulation of Aß in the brain catalyzes the production of reactive oxygen species (ROS), which in turn triggers oxidative damage to cellular components such as DNA, lipids, and proteins. In the present study, we investigated the protective effect of Ganoderic acid A (GA.A) against Aß42-induced apoptosis in PC12 cells. Changes in mitochondrial membrane potential indicated that GA.A treats mitochondrial dysfunction by decreasing Aß42 deposition and inhibiting neural protofiber tangle formation. Changes in intracellular Ca2+ and caspase-3 indicated that GA.A reduced mitochondrial damage by Aß42 in PC12 cells, thereby decreasing ROS accumulation and reducing Aß protofiber-induced cytotoxicity. These features suggest that GA.A has great potential as an effective neuroprotective drug in the treatment of Alzheimer's disease.


Assuntos
Peptídeos beta-Amiloides , Apoptose , Lanosterol , Potencial da Membrana Mitocondrial , Mitocôndrias , Fármacos Neuroprotetores , Fragmentos de Peptídeos , Espécies Reativas de Oxigênio , Animais , Peptídeos beta-Amiloides/toxicidade , Peptídeos beta-Amiloides/metabolismo , Células PC12 , Ratos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fragmentos de Peptídeos/toxicidade , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Apoptose/efeitos dos fármacos , Lanosterol/farmacologia , Lanosterol/análogos & derivados , Cálcio/metabolismo , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Ácidos Heptanoicos
3.
J Agric Food Chem ; 72(32): 17912-17923, 2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39078661

RESUMO

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a complex gastrointestinal condition influenced by genetic, microbial, and environmental factors, among which the gut microbiota plays a crucial role and has emerged as a potential therapeutic target. Ganoderic acid A (GAA), which is a lanostane triterpenoid compound derived from edible mushroom Ganoderma lucidum, has demonstrated the ability to modulate gut dysbiosis. Thus, we investigated the impact of GAA on IBD using a dextran sodium sulfate (DSS)-induced colitis mouse model. GAA effectively prevented colitis, preserved epithelial and mucus layer integrity, and modulated the gut microbiota. In addition, GAA promoted tryptophan metabolism, especially 3-IAld generation, activated the aryl hydrocarbon receptor (AhR), and induced IL-22 production. Fecal microbiota transplantation validated the mediating role of the gut microbiota in the IBD protection conferred by GAA. Our study suggests that GAA holds potential as a nutritional intervention for ameliorating IBD by influencing the gut microbiota, thereby regulating tryptophan metabolism, enhancing AhR activity, and ultimately improving gut barrier function.


Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Lanosterol , Receptores de Hidrocarboneto Arílico , Triptofano , Animais , Humanos , Masculino , Camundongos , Bactérias/classificação , Bactérias/metabolismo , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/efeitos dos fármacos , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Ácidos Heptanoicos , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/microbiologia , Interleucina 22 , Lanosterol/análogos & derivados , Lanosterol/farmacologia , Camundongos Endogâmicos C57BL , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Triptofano/metabolismo
4.
FASEB J ; 38(14): e23807, 2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-38989570

RESUMO

Specialized proresolving mediators (SPMs) promote local macrophage efferocytosis but excess leukocytes early in inflammation require additional leukocyte clearance mechanism for resolution. Here, neutrophil clearance mechanisms from localized acute inflammation were investigated in mouse dorsal air pouches. 15-HEPE (15-hydroxy-5Z,8Z,11Z,13E,17Z-eicosapentaenoic acid) levels were increased in the exudates. Activated human neutrophils converted 15-HEPE to lipoxin A5 (5S,6R,15S-trihydroxy-7E,9E,11Z,13E,17Z-eicosapentaenoic acid), 15-epi-lipoxin A5 (5S,6R,15R-trihydroxy-7E,9E,11Z,13E,17Z-eicosapentaenoic acid), and resolvin E4 (RvE4; 5S,15S-dihydroxy-6E,8Z,11Z,13E,17Z-eicosapentaenoic acid). Exogenous 15-epi-lipoxin A5, 15-epi-lipoxin A4 and a structural lipoxin mimetic significantly decreased exudate neutrophils and increased local tissue macrophage efferocytosis, with comparison to naproxen. 15-epi-lipoxin A5 also cleared exudate neutrophils faster than the apparent local capacity for stimulated macrophage efferocytosis, so the fate of exudate neutrophils was tracked with CD45.1 variant neutrophils. 15-epi-lipoxin A5 augmented the exit of adoptively transferred neutrophils from the pouch exudate to the spleen, and significantly increased splenic SIRPa+ and MARCO+ macrophage efferocytosis. Together, these findings demonstrate new systemic resolution mechanisms for 15-epi-lipoxin A5 and RvE4 in localized tissue inflammation, which distally engage the spleen to activate macrophage efferocytosis for the clearance of tissue exudate neutrophils.


Assuntos
Lipoxinas , Macrófagos , Neutrófilos , Baço , Animais , Neutrófilos/metabolismo , Neutrófilos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Humanos , Lipoxinas/metabolismo , Lipoxinas/farmacologia , Baço/metabolismo , Baço/citologia , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/farmacologia , Ácido Eicosapentaenoico/metabolismo , Camundongos Endogâmicos C57BL , Fagocitose , Masculino , Inflamação/metabolismo , Ácidos Heptanoicos
5.
J Affect Disord ; 358: 270-282, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38723681

RESUMO

OBJECTIVE: Ganoderic Acid A (GAA), a primary bioactive component in Ganoderma, has demonstrated ameliorative effects on depressive-like behaviors in a Chronic Social Defeat Stress (CSDS) mouse model. This study aims to elucidate the underlying molecular mechanisms through proteomic analysis. METHODS: C57BL/6 J mice were allocated into control (CON), chronic social defeat stress (CSDS), GAA, and imipramine (IMI) groups. Post-depression induction via CSDS, the GAA and IMI groups received respective treatments of GAA (2.5 mg/kg) and imipramine (10 mg/kg) for five days. Behavioral assessments utilized standardized tests. Proteins from the prefrontal cortex were analyzed using LC-MS, with further examination via bioinformatics and PRM for differential expression. Western blot analysis confirmed protein expression levels. RESULTS: Chronic social defeat stress (CSDS) induced depressive-like behaviors in mice, which were significantly alleviated by GAA treatment, comparably to imipramine (IMI). Proteomic analysis identified distinct proteins in control (305), GAA-treated (949), and IMI-treated (289) groups. Enrichment in mitochondrial and synaptic proteins was evident from GO and PPI analyses. PRM analysis revealed significant expression changes in proteins crucial for mitochondrial and synaptic functions (namely, Naa30, Bnip1, Tubgcp4, Atxn3, Carmil1, Nup37, Apoh, Mrpl42, Tprkb, Acbd5, Dcx, Erbb4, Ppp1r2, Fam3c, Rnf112, and Cep41). Western blot validation in the prefrontal cortex showed increased levels of Mrpl42, Dcx, Fam3c, Ppp1r2, Rnf112, and Naa30 following GAA treatment. CONCLUSION: GAA exhibits potential antidepressant properties, with its action potentially tied to the modulation of synaptic functions and mitochondrial activities.


Assuntos
Comportamento Animal , Depressão , Modelos Animais de Doenças , Lanosterol , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal , Proteômica , Derrota Social , Estresse Psicológico , Animais , Camundongos , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Masculino , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Lanosterol/análogos & derivados , Lanosterol/farmacologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Imipramina/farmacologia , Proteína Duplacortina , Ácidos Heptanoicos
6.
Adv Ther ; 41(7): 2808-2825, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38771476

RESUMO

INTRODUCTION: Fixed-dose combinations (FDCs) of angiotensin II receptor blockers, calcium channel blockers, and statins are conventional therapeutic interventions prescribed for cardiovascular diseases. This study aimed at drawing a comparison between the pharmacokinetics and safety of an FDC and the corresponding individual formulations in healthy subjects. METHODS: A randomized, open-label, single-dose, three-sequence, three-period, partially repeated crossover study was conducted with a cohort of healthy volunteers. A 14-day washout period was maintained between each of the three periods. In this study, candesartan cilexetil, amlodipine, and atorvastatin was administered orally as FDCs of 16/10/40 mg in study 1 and 16/5/20 mg in study 2. The maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of candesartan, amlodipine, and atorvastatin were estimated as the geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the FDC to individual formulations. If the within-subject coefficient of variation (CVwr) of Cmax was greater than 0.3, the bioequivalence (BE) range calculated using the reference-scaled average bioequivalence was used to assess whether the 90% CI was within the BE range. RESULTS: The GMRs (90% CIs) for the AUClast for candesartan and amlodipine were 0.9612 (0.9158-1.0089)/0.9965 (0.9550-1.0397) and 1.0033 (0.9800-1.0271)/1.0067 (0.9798-1.0344), and the GMRs (90% CIs) for Cmax were 0.9600 (0.8953-1.0294)/0.9851 (0.9368-1.0359) and 1.0198 (0.9950-1.0453)/1.0003 (0.9694-1.0321) in studies 1 and 2, respectively. The extended BE ranges calculated from the CVwr of the Cmax of atorvastatin were 0.7814-1.2797 and 0.7415-1.3485, respectively. The GMRs (90% CIs) for the AUClast of atorvastatin were 1.0532 (1.0082-1.1003)/1.0252 (0.9841-1.0680), and the GMRs (90% CIs) for Cmax were 1.0630 (0.9418-1.1997)/0.9888 (0.8792-1.1120) in studies 1 and 2, respectively. CONCLUSION: The Cmax and AUClast values of candesartan cilexetil/amlodipine/atorvastatin 16/10/40 mg and 16/5/20 mg, respectively, were within the BE ranges. There were no clinically significant differences in safety between the two formulations. TRIAL REGISTRATION: ClinicalTrials.gov identifier, study 1: NCT04478097; study 2: NCT04627207.


Assuntos
Anlodipino , Atorvastatina , Benzimidazóis , Compostos de Bifenilo , Estudos Cross-Over , Combinação de Medicamentos , Tetrazóis , Humanos , Compostos de Bifenilo/farmacocinética , Compostos de Bifenilo/administração & dosagem , Anlodipino/farmacocinética , Anlodipino/administração & dosagem , Benzimidazóis/farmacocinética , Benzimidazóis/administração & dosagem , Tetrazóis/farmacocinética , Tetrazóis/administração & dosagem , Masculino , Adulto , Feminino , Atorvastatina/farmacocinética , Atorvastatina/administração & dosagem , Adulto Jovem , Área Sob a Curva , Pessoa de Meia-Idade , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores dos Canais de Cálcio/farmacocinética , Bloqueadores dos Canais de Cálcio/administração & dosagem , Equivalência Terapêutica , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/administração & dosagem , Ácidos Heptanoicos/farmacocinética , Ácidos Heptanoicos/administração & dosagem , Voluntários Saudáveis
7.
Clin Med (Lond) ; 24(3): 100217, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38710328

RESUMO

Statin-induced immune-mediated necrotising myopathy (IMNM) is an inflammatory myopathy that can present as proximal muscle weakness and, in some cases, as dysphagia and respiratory distress. In this report, we present a case of statin-induced IMNM in a 78-year-old male. The patient had significantly high levels of creatinine kinase and myoglobinuria and experienced gradual weakness in the proximal muscles for 1 month after initiating a 20 mg dose of Atorvastatin 10 months before admission. Rapid clinical improvement was observed with the use of high-dose glucocorticoids in conjunction with methotrexate.


Assuntos
Atorvastatina , Inibidores de Hidroximetilglutaril-CoA Redutases , Miosite , Humanos , Masculino , Idoso , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Miosite/induzido quimicamente , Miosite/tratamento farmacológico , Atorvastatina/uso terapêutico , Atorvastatina/efeitos adversos , Metotrexato/uso terapêutico , Metotrexato/efeitos adversos , Pirróis/efeitos adversos , Pirróis/uso terapêutico , Imunossupressores/uso terapêutico , Imunossupressores/efeitos adversos , Ácidos Heptanoicos/efeitos adversos , Ácidos Heptanoicos/uso terapêutico , Necrose/induzido quimicamente , Glucocorticoides/uso terapêutico , Doenças Musculares/induzido quimicamente , Doenças Musculares/tratamento farmacológico
8.
J Am Heart Assoc ; 13(9): e033780, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38686894

RESUMO

BACKGROUND: Hypertension and hypercholesterolemia are important risk factors for cardiovascular disease, and treatment with fixed-dose combination (FDC) regimens is recommended by current guidelines. However, the clinical outcomes of different FDC dosages remain unknown. This study aimed to examine the clinical outcomes of FDC regimens and the free combination of amlodipine and atorvastatin at different dosages. METHODS AND RESULTS: Patients with concurrent hypertension and hypercholesterolemia treated daily with an FDC of 5 mg amlodipine and 10 mg atorvastatin (5/10 fixed group), and FDC of 5 mg amlodipine and 20 mg atorvastatin (5/20 fixed group), or free combination of 5 mg amlodipine and 20 mg atorvastatin (5/20 free group) were identified from the National Health Insurance Research Database of Taiwan. The primary outcome was the composite cardiovascular outcomes, including cardiovascular death, acute myocardial infarction, stroke, and coronary intervention. A total of 9095 patients were eligible for inclusion. The incidence of primary outcome per 1000 person-years was 16.6 in the 5/10 fixed group, 12.6 in the 5/20 fixed group, and 16.5 in the 5/20 free group (5/20 fixed versus 5/20 free: hazard ratio [HR], 0.76 [95% CI, 0.64-0.91]; 5/20 fixed versus 5/10 fixed: HR, 0.76 [95% CI, 0.63-0.90]). CONCLUSIONS: Among patients with concomitant hypertension and hypercholesterolemia, treatment with an FDC of amlodipine and high-dose atorvastatin led to a lower risk of a composite of cardiovascular outcomes than treatment with the free combination or a similar FDC with a lower dose of atorvastatin.


Assuntos
Anlodipino , Atorvastatina , Combinação de Medicamentos , Ácidos Heptanoicos , Hipercolesterolemia , Hipertensão , Pirróis , Humanos , Anlodipino/administração & dosagem , Anlodipino/efeitos adversos , Masculino , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/complicações , Hipercolesterolemia/epidemiologia , Hipertensão/tratamento farmacológico , Hipertensão/complicações , Hipertensão/epidemiologia , Feminino , Pessoa de Meia-Idade , Atorvastatina/administração & dosagem , Idoso , Taiwan/epidemiologia , Resultado do Tratamento , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/efeitos adversos , Estudos Retrospectivos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/uso terapêutico , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos
10.
Eur J Med Chem ; 270: 116367, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38581732

RESUMO

Breast cancer is one of the most common female malignant tumors, with triple-negative breast cancer (TNBC) being the most specific, highly invasive, metastatic and associated with a poor prognosis. Our previous study showed that the natural product ganoderic acid A (GAA) has a certain affinity for MDM2. In this study, two series of novel GAA PROTACs C1-C10 and V1-V10 were designed and synthesized for the treatment of breast cancer. The antitumor activity of these compounds was evaluated against four human tumor cell lines (MCF-7, MDA-MB-231, SJSA-1, and HepG2). Among them, V9 and V10 showed stronger anti-proliferative effects against breast cancer cells, and V10 showed the best selectivity in MDA-MB-231 cells (TNBC), which was 5-fold higher than that of the lead compound GAA. Preliminary structure-activity analysis revealed that V-series GAA PROTACs had better effects than C-series, and the introduction of 2O-4O PEG linkers could significantly improve the antitumor activity. Molecular docking, surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), and Western blot researches showed that both V9 and V10 could bind with MDM2, and degrade the protein through the ubiquitin-proteasome system. Molecular dynamics simulation (MD) revealed that V10 is a bifunctional molecule that can bind to von Hippel-Lindau (VHL) at one end and target MDM2 at the other. In addition, V10 promoted the upregulation of p21 in p53-mutant MDA-MB-231 cells, and induced apoptosis via down-regulation of the bcl-2/bax ratio and the expression of cyclin B1. Finally, in vivo experiments showed that, V10 also exhibited good tumor inhibitory activity in xenografted TNBC zebrafish models, with an inhibition rate of 27.2% at 50 µg/mL. In conclusion, our results suggested that V10 has anti-tumor effects on p53-mutant breast cancer in vitro and in vivo, and may be used as a novel lead compound for the future development of TNBC.


Assuntos
Ácidos Heptanoicos , Lanosterol/análogos & derivados , Proteínas Proto-Oncogênicas c-mdm2 , Neoplasias de Mama Triplo Negativas , Animais , Feminino , Humanos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Proteína Supressora de Tumor p53/metabolismo , Simulação de Acoplamento Molecular , Peixe-Zebra/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Apoptose
12.
Int J Med Mushrooms ; 26(2): 11-23, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38421693

RESUMO

Ganoderic acid A (GAA) is one of the major triterpenoids in Ganoderma lucidum (GL). Accumulating evidence has indicated that GAA demonstrates multiple pharmacological effects and exhibits treatment potential for various neurological disorders. Here, the effects and mechanisms of GAA in the treatment of neurological disorders were evaluated and discussed through previous research results. By summarizing previous research results, we found that GAA may play a neuroprotective role through various mechanisms: anti-inflammatory, anti-oxidative stress, anti-apoptosis, protection of nerve cells, and regulation of nerve growth factor. Therefore, GAA is a promising natural neuroprotective agent and this review would contribute to the future development of GAA as a novel clinical candidate drug for treating neurological diseases.


Assuntos
Ácidos Heptanoicos , Lanosterol/análogos & derivados , Doenças do Sistema Nervoso , Fármacos Neuroprotetores , Humanos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Lanosterol/farmacologia , Lanosterol/uso terapêutico , Doenças do Sistema Nervoso/tratamento farmacológico
13.
Chemosphere ; 352: 141379, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38316277

RESUMO

Perfluorinated compounds (PFCs), organofluoride compounds comprising carbon-fluorine and carbon-carbon bonds, are used as water and oil repellents in textiles and pharmaceutical tablets; however, they are associated with potential neurotoxic effects. Moreover, the impact of PFCs on neuronal survival, activity, and regulation within the brain remains unclear. Additionally, the mechanisms through which PFCs induce neuronal toxicity are not well-understood because of the paucity of data. This study elucidates that perfluorooctanoic acid (PFOA) and perfluoroheptanoic acid (PFHpA) exert differential effects on the survival and activity of primary cortical neurons. Although PFOA triggers apoptosis in cortical neurons, PFHpA does not exhibit this effect. Instead, PFHpA modifies dendritic spine morphogenesis and synapse formation in primary cortical neuronal cultures, additionally enhancing neural activity and synaptic transmission. This research uncovers a novel mechanism through which PFCs (PFHpA and PFOA) cause distinct alterations in dendritic spine morphogenesis and synaptic activity, shedding light on the molecular basis for the atypical behaviors noted following PFC exposure. Understanding the distinct effects of PFHpA and PFOA could guide regulatory policies on PFC usage and inform clinical approaches to mitigate their neurotoxic effects, especially in vulnerable population.


Assuntos
Fluorocarbonos , Ácidos Heptanoicos , Síndromes Neurotóxicas , Poluentes Químicos da Água , Humanos , Poluentes Químicos da Água/análise , Fluorocarbonos/toxicidade , Fluorocarbonos/análise , Caprilatos/toxicidade , Neurônios/química , Carbono
14.
Sci Rep ; 14(1): 3416, 2024 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-38341447

RESUMO

Synthetic ester oils are widely used in many applications due to their ideal cleaning properties, lubricating performance and assured polarity. The majority of esters oils are more biodegradable. than any other base stock. For instance, oil soluble polyalkyleneglycols (PAGs) or polyalphaolephins (PAOs), are only biodegradable in the lower viscosity grades. The goal of this study is to create some synthetic base oils by two major protocols; the first is esterifying valeric acid with various glycols (ethylene glycol, propylene glycol, butylene glycol and poly (ethylene glycol 400). The second involves esterification of propanoic acid, heptanoic acid, or octanoic acid with ethylene glycol. The reaction yield varies between 85 and 94%. The chemical composition of the prepared esters was examined using various spectroscopic methods (Fourier-transform infrared (FT-IR) and proton nuclear magnetic resonance (1H-NMR) spectroscopy. The thermal properties investigation by thermo gravimetric analysis (TGA) showed pronounced thermal stability of the prepared esters. The biodegradability was verified versus two bacterial isolates (B1, B2). The results showed that percentage of degradation of the lube oil was in the range of 34% to 84% after 3 days of incubation. Moreover, the rheological study revealed that the prepared esters exhibited Newtonian rheological behaviours. Viscosity examination displayed that the esters based on ethylene glycol, such as (A), had the highest VI: 179 values when compared to those based on higher glycols. Viscosity and viscosity index results showed slight increase as the number of carbon atoms in the acid chain increases. At last, most of the synthesized esters possessed pour points ≤ - 32 °C: ≤ - 40 except in case of using higher acids like heptanoic acid and octanoic acid in preparation the pour point increases to - 9 °C and - 15 °C.


Assuntos
Ésteres , Ácidos Heptanoicos , Ésteres/química , Caprilatos , Espectroscopia de Infravermelho com Transformada de Fourier , Polietilenoglicóis/química , Óleos de Plantas/química
15.
J Pharm Pharmacol ; 76(4): 354-367, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38330446

RESUMO

OBJECTIVES: Reportedly, ganoderic acid A (GA-A) increases the sensitivity of hepatocellular carcinoma cells to cisplatin (DDP) chemotherapy. Therefore, this study aims to fathom the influence of GA-A on lung cancer cells. METHODS: After the construction of A549/DDP cells through exposure to DDP, the effects of GA-A on A549 and A549/DDP cells were revealed by cellular functional assays, western blot and quantitative reverse transcription PCR (qRT-PCR). The DDP-resistant lung cancer tumor was established in vivo, followed by further validation of the mechanism of GA-A. RESULTS: GA-A suppressed the viability, migration, and invasion while downregulating Beclin and autophagy marker LC3II/LC3I levels and upregulating P62 levels in A549 and A549/DDP cells. These effects were reversed by circFLNA overexpression. Also, GA-A reinforced the sensitivity of A549/DDP cells to DDP, elevated the apoptosis and regulated the circFLNA/miR-486-3p/cytochrome P450 family 1 subfamily A member 1 (CYP1A1)/X-ray repair cross-complementing 1 (XRCC1) axis. The reversal effects of circFLNA overexpression on GA-A-induced viability and apoptosis of A549/DDP cells could all be counteracted in the presence of 3MA. GA-A inhibited lung cancer tumor growth and blocked autophagy. CONCLUSION: GA-A suppresses autophagy by regulating the circFLNA/miR-486-3p/CYP1A1/XRCC1 axis to strengthen the sensitivity of lung cancer cells to DDP.


Assuntos
Antineoplásicos , Autofagia , Carcinoma Pulmonar de Células não Pequenas , Ácidos Heptanoicos , Lanosterol , Neoplasias Pulmonares , MicroRNAs , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/farmacologia , Citocromo P-450 CYP1A1/efeitos dos fármacos , Citocromo P-450 CYP1A1/metabolismo , Resistencia a Medicamentos Antineoplásicos , Ácidos Heptanoicos/farmacologia , Ácidos Heptanoicos/uso terapêutico , Lanosterol/análogos & derivados , Lanosterol/farmacologia , Lanosterol/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , MicroRNAs/efeitos dos fármacos , MicroRNAs/metabolismo , RNA Circular/efeitos dos fármacos , RNA Circular/metabolismo , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/efeitos dos fármacos , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/metabolismo
16.
Eur Heart J Cardiovasc Pharmacother ; 10(4): 307-315, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-38196131

RESUMO

AIMS: Objective methods to determine statin adherence are requested to improve lipid management. We have recently established a method to detect reduced adherence to atorvastatin therapy with cut-off values based on the sum of atorvastatin and its major metabolites in the blood. We aimed to validate this method in patients with and without cardiovascular disease, and optimize previous cut-off values. METHODS AND RESULTS: The pharmacokinetic study included 60 participants treated with atorvastatin 20 mg (N = 20), 40 mg (N = 20), and 80 mg (N = 20). Atorvastatin was then stopped and blood samples collected from day zero to day four. Quantification of the parent drug and its metabolites in blood plasma was performed with a liquid chromatography-tandem mass spectrometry assay. The cut-off values for reduced adherence were validated and optimized by calculating diagnostic sensitivity and specificity. Our candidate cut-off value of dose-normalized six-component sum of atorvastatin plus metabolites <0.10 nM/mg provided a sensitivity of 97% and a specificity of 93% for detecting ≥2 omitted doses. An optimized cut-off <0.062 nM/mg provided a sensitivity of 90% and a specificity of 100%. An alternative simplified two-component metabolite sum with a cut-off value <0.05 nM/mg provided a sensitivity of 98% and a specificity of 76%. An optimized cut-off <0.02 nM/mg provided a sensitivity of 97% and a specificity of 98%. CONCLUSION: This validation study confirms that our direct method discriminates reduced adherence from adherence to atorvastatin therapy with high diagnostic accuracy. The method may improve lipid management in clinical practice and serve as a useful tool in future studies.


Assuntos
Atorvastatina , Inibidores de Hidroximetilglutaril-CoA Redutases , Adesão à Medicação , Atorvastatina/farmacocinética , Atorvastatina/uso terapêutico , Atorvastatina/sangue , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Idoso , Ácidos Heptanoicos/farmacocinética , Ácidos Heptanoicos/administração & dosagem , Ácidos Heptanoicos/sangue , Ácidos Heptanoicos/uso terapêutico , Pirróis/farmacocinética , Pirróis/sangue , Pirróis/administração & dosagem , Espectrometria de Massas em Tandem , Cromatografia Líquida , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/prevenção & controle , Reprodutibilidade dos Testes , Relação Dose-Resposta a Droga
17.
Ecotoxicol Environ Saf ; 272: 116017, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38290316

RESUMO

BACKGROUND AND OBJECTIVE: Per- and polyfluoroalkyl substances (PFASs) have been shown to be persistent and bioaccumulative. An elevated danger of pregnancy complications perhaps connected with exposure to PFASs, but the potential effects remain elusive. The objective of this study is to investigate the possible association between PFASs exposure and pregnancy complications, drawing upon existing evidence. METHODS: Electronic databases of PubMed, Qvid Medline, Embase, and Web of Science were searched thoroughly to identify eligible research published prior to November 28, 2023, examining the relationship between PFASs and pregnancy-related complications. To evaluate the quality of observational studies incorporated into the article, the Strengthening Reporting of Observational Studies in Epidemiology (STROBE) tool was utilized. The main outcomes assessed in this study included gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), gestational hypertension (GH), and preeclampsia (PE). RESULTS: Twenty-five relevant studies involving 30079 participants were finally selected from four databases. The combined estimates indicate that prenatal exposure to perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorobutane sulfonic acid (PFBS), and perfluoroenanthic acid (PFHpA) is associated with gestational diabetes mellitus (GDM) (PFOA: OR = 1.45, 95%CI: 1.07-1.94, P = 0.015; PFHxS: OR = 1.16, 95%CI: 1.00-1.36, P = 0.055; PFBS: OR = 1.44, 95%CI: 1.16-1.79, P = 0.001; PFHpA: OR = 1.41, 95%CI: 1.10-1.82, P = 0.008). The exposure to PFBS is positively associated with HDP (OR = 1.27, 95%CI: 1.14-1.41, P < 0.001), while both PFOA and PFHpA demonstrate statistically significant positive correlations with GH (PFOA: OR = 1.09, 95%CI: 1.00-1.19, P = 0.049; PFHpA: OR = 1.43, 95%CI: 1.15-1.78, P = 0.001). Negative correlations were observed for prenatal perfluorododecanoic acid (PFDoA) exposure and GH (OR = 0.71, 95%CI: 0.57-0.87, P = 0.001). However, no compelling evidence was identified to link PFASs exposure with the risk of PE. CONCLUSION: According to the meta-analysis findings, exposure to PFASs may be linked to GDM, HDP, and GH, but it does not significantly raise the risk of PE alone. Further research with larger sample size is required to verify this potential association and explore the biological mechanisms.


Assuntos
Ácidos Alcanossulfônicos , Caprilatos , Diabetes Gestacional , Poluentes Ambientais , Fluorocarbonos , Ácidos Heptanoicos , Hipertensão Induzida pela Gravidez , Pré-Eclâmpsia , Ácidos Sulfônicos , Gravidez , Feminino , Humanos , Diabetes Gestacional/induzido quimicamente , Diabetes Gestacional/epidemiologia , Poluentes Ambientais/toxicidade , Hipertensão Induzida pela Gravidez/epidemiologia , Pré-Eclâmpsia/induzido quimicamente , Pré-Eclâmpsia/epidemiologia , Fluorocarbonos/toxicidade , Ácidos Alcanossulfônicos/toxicidade
18.
Chem Biol Drug Des ; 103(1): e14382, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37984927

RESUMO

Osteoarthritis (OA) is a prevalent degenerative pathology, however, there exists a lack of cost-effective pharmacological interventions that efficaciously inhibit its progression. ganoderic acid A (GAA), a triterpenoid derived from Ganoderma lucidum, possesses antiapoptotic and -inflammatory effects. Our objective was to better understand the therapeutic effects of GAA on OA as well as to elucidate the underlying mechanisms of its action. To establish an OA cell model in vitro, chondrocytes (CHONs) were treated with interleukin (IL)-1ß. Subsequently, the investigation was conducted afterward according to the following indicators: cell viability, apoptosis, inflammation, and extracellular matrix (ECM) degradation. Western blotting analysis (WB) was employed to assess both endoplasmic reticulum (ER) stress and proteins associated with the nuclear factor-kappa B (NF-κB) signaling pathway. Furthermore, based on molecular docking studies, GAA exhibits a significant binding competence to p65. OA mouse models were constructed by performing a destabilization medial meniscus (DMM) operation. Moreover, histopathology and immunohistochemistry were used to determine the GAA therapeutic effect in reducing OA in vivo. Our findings revealed that GAA has antiapoptotic, anti-inflammatory, and anti-ECM degradation effects by inhibiting the ER stress and NF-κB axis in CHONs in vitro. Furthermore, our findings suggest that GAA may attenuate the progression of osteoarthritis in vivo. GAA can protect CHONs by regulating apoptosis, ECM changes, and inflammation thereby preventing OA progression. These promising results indicate that GAA may be a therapeutic agent for OA treatment.


Assuntos
Ácidos Heptanoicos , Lanosterol/análogos & derivados , NF-kappa B , Osteoartrite , Camundongos , Animais , NF-kappa B/metabolismo , Simulação de Acoplamento Molecular , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Condrócitos/metabolismo , Estresse do Retículo Endoplasmático , Interleucina-1beta/metabolismo , Células Cultivadas
19.
Aging (Albany NY) ; 15(23): 13669-13679, 2023 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-38048213

RESUMO

Mild cognitive impairment (MCI) is a common symptom observed in people over 60 years old and is found to be aggravated by hypercholesterolemia. Severe neuroinflammation induced by BBB dysfunction and monocyte infiltration might be responsible for neuron damage and cognitive impairment. Atorvastatin is a lipid-lowering drug that is widely applied for the treatment of cardiovascular diseases. However, the potential function of Atorvastatin in hypercholesterolemia-induced MCI remains uncertain. Our research will explore the potential therapeutic function of Atorvastatin in memory deficits induced by chronic hypercholesterolemia. ApoE-/- mice were utilized to mimic the state of chronic hypercholesterolemia and were divided into four groups. Animals in the WT and ApoE-/-groups were orally administered with normal saline, while WT mice in the Atorvastatin group and ApoE-/- mice in the ApoE-/-+ Atorvastatin group were orally administered with 10 mg/kg/day Atorvastatin. Markedly increased plasma cholesterol levels reduced RI in the long-term memory test and the spatial short-term memory test, declined mobility in the open field test, and downregulated PSD-95 and BDNF were observed in ApoE-/- mice, all of which were signally reversed by Atorvastatin. Moreover, the percentages of brain Ly6Chi CD45+ cells and CD3+ CD45+ cells, as well as the blood Ly6Chi CD45+ cells, plasma IL-12/IL-23 levels and IL-17 level were found notably increased in ApoE-/- mice, all of which were largely repressed by Atorvastatin. Lastly, the increased BBB permeability, decreased ZO-1 and occludin levels, and reduced KLF2 level were markedly abolished by Atorvastatin. Collectively, Atorvastatin mitigated memory deficits and brain monocyte infiltration in ApoE-/- mice.


Assuntos
Ácidos Heptanoicos , Hipercolesterolemia , Hiperlipidemias , Humanos , Camundongos , Animais , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Hipercolesterolemia/complicações , Hipercolesterolemia/tratamento farmacológico , Monócitos/metabolismo , Ácidos Heptanoicos/farmacologia , Ácidos Heptanoicos/uso terapêutico , Pirróis/farmacologia , Hiperlipidemias/tratamento farmacológico , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Encéfalo/metabolismo
20.
J Health Popul Nutr ; 42(1): 143, 2023 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-38098069

RESUMO

OBJECTIVES: To compare the efficacy and safety of Shanhuang Jiangzhi tablets and atorvastatin in reducing blood lipid levels. METHODS: Patients with hyperlipidaemia admitted to the cardiac centre between January 2019 and December 2020 were included in the study. A total of 1063 patients with hyperlipidaemia took either Shanhuang Jiangzhi tablets (n = 372) or atorvastatin (n = 691) and met the inclusion and exclusion criteria. Clinical data, including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol, were retrospectively evaluated after propensity score matching (PSM) analysis. The adverse events were also recorded during the therapy process. RESULTS: Following PSM analysis, both groups were well matched across all parameters. Compared with the baseline, Shanhuang Jiangzhi tablets had greater effects on TC, TG and LDL-C, and the difference was statistically significant (p < 0.001). Furthermore, the results showed that Shanhuang Jiangzhi tablets are similar to atorvastatin in reducing TC and LDL-C, and all p-values were > 0.05. However, the decrease of TG was greater in the Shanhuang Jiangzhi group (p < 0.001). Clinical adverse reactions of Shanhuang Jiangzhi tablets are rare and have no statistical significance compared with atorvastatin (p = 0.682). CONCLUSIONS: Shanhuang Jiangzhi tablets have a higher hypotriglyceridaemic performance than atorvastatin and an equivalent ability to lower TC and LDL-C. In addition, Shanhuang Jiangzhi tablets are a low-risk option for lowering blood lipids.


Assuntos
Anticolesterolemiantes , Ácidos Heptanoicos , Hiperlipidemias , Humanos , Atorvastatina/efeitos adversos , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/induzido quimicamente , LDL-Colesterol/uso terapêutico , Anticolesterolemiantes/efeitos adversos , Estudos Retrospectivos , Ácidos Heptanoicos/efeitos adversos , Pirróis/efeitos adversos , Lipídeos/uso terapêutico , Triglicerídeos , HDL-Colesterol/uso terapêutico , Resultado do Tratamento
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