RESUMO
Most human monoclonal antibodies (mAbs) neutralizing SARS-CoV-2 recognize the spike (S) protein receptor-binding domain and block virus interactions with the cellular receptor angiotensin-converting enzyme 2. We describe a panel of human mAbs binding to diverse epitopes on the N-terminal domain (NTD) of S protein from SARS-CoV-2 convalescent donors and found a minority of these possessed neutralizing activity. Two mAbs (COV2-2676 and COV2-2489) inhibited infection of authentic SARS-CoV-2 and recombinant VSV/SARS-CoV-2 viruses. We mapped their binding epitopes by alanine-scanning mutagenesis and selection of functional SARS-CoV-2 S neutralization escape variants. Mechanistic studies showed that these antibodies neutralize in part by inhibiting a post-attachment step in the infection cycle. COV2-2676 and COV2-2489 offered protection either as prophylaxis or therapy, and Fc effector functions were required for optimal protection. Thus, natural infection induces a subset of potent NTD-specific mAbs that leverage neutralizing and Fc-mediated activities to protect against SARS-CoV-2 infection using multiple functional attributes.
Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Substâncias Protetoras/farmacologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Ligação Competitiva , COVID-19/imunologia , COVID-19/virologia , Quimiocinas/metabolismo , Chlorocebus aethiops , Células HEK293 , Humanos , Fragmentos Fab das Imunoglobulinas/metabolismo , Imunoglobulina G/metabolismo , Pulmão/metabolismo , Camundongos Endogâmicos C57BL , Modelos Moleculares , Mutagênese/genética , Testes de Neutralização , Domínios Proteicos , Células VeroRESUMO
Dietary fiber protects against chronic inflammatory diseases by dampening immune responses through short-chain fatty acids (SCFAs). Here we examined the effect of dietary fiber in viral infection, where the anti-inflammatory properties of SCFAs in principle could prevent protective immunity. Instead, we found that fermentable dietary fiber increased survival of influenza-infected mice through two complementary mechanisms. High-fiber diet (HFD)-fed mice exhibited altered bone marrow hematopoiesis, characterized by enhanced generation of Ly6c- patrolling monocytes, which led to increased numbers of alternatively activated macrophages with a limited capacity to produce the chemokine CXCL1 in the airways. Blunted CXCL1 production reduced neutrophil recruitment to the airways, thus limiting tissue immunopathology during infection. In parallel, diet-derived SCFAs boosted CD8+ T cell effector function by enhancing cellular metabolism. Hence, dietary fermentable fiber and SCFAs set an immune equilibrium, balancing innate and adaptive immunity so as to promote the resolution of influenza infection while preventing immune-associated pathology.
Assuntos
Antígenos Ly/imunologia , Linfócitos T CD8-Positivos/imunologia , Fibras na Dieta/farmacologia , Hematopoese/imunologia , Monócitos/imunologia , Infecções por Orthomyxoviridae/imunologia , Imunidade Adaptativa/efeitos dos fármacos , Imunidade Adaptativa/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Fibras na Dieta/administração & dosagem , Ácidos Graxos Voláteis/imunologia , Ácidos Graxos Voláteis/metabolismo , Hematopoese/efeitos dos fármacos , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/farmacologiaRESUMO
OBJECTIVE: Long-term exposure to arsenic has been linked to several illnesses, including hypertension, diabetes, hepatic and renal diseases and cardiovascular malfunction. The aim of the current investigation was to determine whether zingerone (ZN) could shield rats against the hepatotoxicity that sodium arsenite (SA) causes. METHODS: The following five groups of thirty-five male Sprague Dawley rats were created: I) Control; received normal saline, II) ZN; received ZN, III) SA; received SA, IV) SA + ZN 25; received 10 mg/kg body weight SA + 25 mg/kg body weight ZN, and V) SA + ZN 50; received 10 mg/kg body weight SA + 50 mg/kg body weight ZN. The experiment lasted 14 days, and the rats were sacrificed on the 15th day. While oxidative stress parameters were studied by spectrophotometric method, apoptosis, inflammation and endoplasmic reticulum stress parameters were measured by RT-PCR method. RESULTS: The SA disrupted the histological architecture and integrity of the liver and enhanced oxidative damage by lowering antioxidant enzyme activity, such as those of glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), glutathione (GSH) level and increasing malondialdehyde (MDA) level in the liver tissue. Additionally, SA increased the mRNA transcript levels of Bcl2 associated x (Bax), caspases (-3, -6, -9), apoptotic protease-activating factor 1 (Apaf-1), p53, tumor necrosis factor-α (TNF-α), nuclear factor kappa B (NF-κB), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), c-Jun NH2-terminal kinase (JNK), mitogen-activated protein kinase 14 (MAPK14), MAPK15, receptor for advanced glycation endproducts (RAGE) and nod-like receptor family pyrin domain-containing 3 (NLRP3) in the liver tissue. Also produced endoplasmic reticulum stress by raising the mRNA transcript levels of activating transcription factor 6 (ATF-6), protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and glucose-regulated protein 78 (GRP-78). These factors together led to inflammation, apoptosis, and endoplasmic reticulum stress. On the other hand, liver tissue treated with ZN at doses of 25 and 50 mg/kg showed significant improvement in oxidative stress, inflammation, apoptosis and endoplasmic reticulum stress. CONCLUSIONS: Overall, the study's data suggest that administering ZN may be able to lessen the liver damage caused by SA toxicity.
Assuntos
Arsenitos , Doença Hepática Induzida por Substâncias e Drogas , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos Sprague-Dawley , Transdução de Sinais , Compostos de Sódio , Fator de Necrose Tumoral alfa , Animais , Masculino , Transdução de Sinais/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Arsenitos/toxicidade , Compostos de Sódio/toxicidade , Ratos , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Caspase 3/metabolismo , Caspase 3/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Proteína X Associada a bcl-2/genética , Estresse Oxidativo/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Chaperona BiP do Retículo Endoplasmático , Endorribonucleases , Complexos Multienzimáticos , Proteínas Serina-Treonina QuinasesRESUMO
BACKGROUND: Inflammation and endothelial barrier dysfunction are the major pathophysiological changes in acute respiratory distress syndrome (ARDS). Sphingosine-1-phosphate receptor 3 (S1PR3), a G protein-coupled receptor, has been found to mediate inflammation and endothelial cell (EC) integrity. However, the function of S1PR3 in ARDS has not been fully elucidated. METHODS: We used a murine lipopolysaccharide (LPS)-induced ARDS model and an LPS- stimulated ECs model to investigate the role of S1PR3 in anti-inflammatory effects and endothelial barrier protection during ARDS. RESULTS: We found that S1PR3 expression was increased in the lung tissues of mice with LPS-induced ARDS. TY-52156, a selective S1PR3 inhibitor, effectively attenuated LPS-induced inflammation by suppressing the expression of proinflammatory cytokines and restored the endothelial barrier by repairing adherens junctions and reducing vascular leakage. S1PR3 inhibition was achieved by an adeno-associated virus in vivo and a small interfering RNA in vitro. Both the in vivo and in vitro studies demonstrated that pharmacological or genetic inhibition of S1PR3 protected against ARDS by inhibiting the NF-κB pathway and improving mitochondrial oxidative phosphorylation. CONCLUSIONS: S1PR3 inhibition protects against LPS-induced ARDS via suppression of pulmonary inflammation and promotion of the endothelial barrier by inhibiting NF-κB and improving mitochondrial oxidative phosphorylation, indicating that S1PR3 is a potential therapeutic target for ARDS.
Assuntos
Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Mitocôndrias , NF-kappa B , Fosforilação Oxidativa , Síndrome do Desconforto Respiratório , Receptores de Esfingosina-1-Fosfato , Animais , Humanos , Masculino , Camundongos , Citocinas/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Inflamação/patologia , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , NF-kappa B/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Receptores de Lisoesfingolipídeo/metabolismo , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/patologia , Receptores de Esfingosina-1-Fosfato/metabolismo , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidoresRESUMO
Liver injury, a major global health issue, stems from various causes such as alcohol consumption, nonalcoholic steatohepatitis, obesity, diabetes, metabolic syndrome, hepatitis, and certain medications. The liver's unique susceptibility to ischemia and hypoxia, coupled with the critical role of the gut-liver axis in inflammation, underscores the need for effective therapeutic interventions. The study highlights E2's interaction with estrogen receptors (ERs) and its modulation of the Toll-like receptor 4 (TLR4) signaling pathway as key mechanisms in mitigating liver injury. Activation of TLR4 leads to the release of pro-inflammatory cytokines and chemokines, exacerbating liver inflammation and injury. E2 down-regulates TLR4 expression, reduces oxidative stress, and inhibits pro-inflammatory cytokines, thereby protecting the liver. Both classic (ERα and ERß) and non-classic [G protein-coupled estrogen receptor (GPER)] receptors are influenced by E2. ERα is particularly crucial for liver regeneration, preventing liver failure by promoting hepatocyte proliferation. Furthermore, E2 exerts anti-inflammatory, antioxidant, and anti-apoptotic effects by inhibiting cytokines such as IL-6, IL-1ß, TNF-α, and IL-17, and by reducing lipid peroxidation and free radical damage. The article calls for further clinical research to validate these findings and to develop estrogen-based treatments for liver injuries. Overall, the research emphasizes the significant potential of E2 as a therapeutic agent for liver injuries. It advocates for extensive clinical studies to validate E2 hepatoprotective properties and develop effective estrogen-based treatments.
Assuntos
Estradiol , Inflamação , Transdução de Sinais , Receptor 4 Toll-Like , Receptor 4 Toll-Like/metabolismo , Humanos , Transdução de Sinais/efeitos dos fármacos , Animais , Estradiol/farmacologia , Inflamação/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Citocinas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Receptores de Estrogênio/metabolismoRESUMO
Magterpenes A-C (1-3), three unprecedented meroterpenoids featuring a unique 6/6/6/6/6 polycyclic skeleton, were isolated from the ethanol extract of Magnolia officinalis Rehd. et Wils. The compounds were obtained as racemic mixtures that were completely resolved through chiral columns. Their structures were elucidated by extensive analyses of one-dimensional (1D) and 2D nuclear magnetic resonance, high-resolution electrospray ionization mass spectrometry, chemical calculations of 1H/13C NMR, and electronic circular dichroism calculations. The compounds were constructed via two Diels-Alder reactions in the proposed biosynthetic pathway. All isolates were evaluated for their nephroprotective and hepatoprotective activities. The results demonstrated that (+)-1 and (-)-1 possessed promising nephroprotective activities in a dose-dependent manner, while (-)-2 and (+)-3 exhibited moderate hepatoprotective activities.
Assuntos
Magnolia , Terpenos , Magnolia/química , Terpenos/química , Terpenos/farmacologia , Terpenos/isolamento & purificação , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificaçãoRESUMO
Because the chronobiotic and cytoprotective molecule melatonin diminishes with age, its involvement in postmenopausal and senescence pathology has been considered since long. One relevant melatonin target site in aging individuals is bone where melatonin chronobiotic effects mediated by MT1 and MT2 receptors are demonstrable. Precursors of bone cells located in bone marrow are exposed to high quantities of melatonin and the possibility arises that melatonin acts a cytoprotective compound via an autacoid effect. Proteins that are incorporated into the bone matrix, like procollagen type I c-peptide, augment after melatonin exposure. Melatonin augments osteoprotegerin, an osteoblastic protein that inhibits the differentiation of osteoclasts. Osteoclasts are target cells for melatonin as they degrade bone partly by generating free radicals. Osteoclast activity and bone resorption are impaired via the free radical scavenger properties of melatonin. The administration of melatonin in chronobiotic doses (less than 10 mg daily) is commonly used in clinical studies on melatonin effect on bone. However, human equivalent doses allometrically derived from animal studies are in the 1-1.5 mg/kg/day range for a 75 kg human adult, a dose rarely used clinically. In view of the absence of toxicity of melatonin in phase 1 pharmacological studies with doses up to 100 mg in normal volunteers, further investigation is needed to determine whether high melatonin doses have higher therapeutic efficacy in preventing bone loss.
Assuntos
Reabsorção Óssea , Melatonina , Animais , Adulto , Humanos , Melatonina/farmacologia , Melatonina/metabolismo , Osso e Ossos/metabolismo , Osteoclastos , Envelhecimento , Substâncias Protetoras/farmacologia , Ritmo CircadianoRESUMO
Avermectin is one of the widely used anthelmintics in aquaculture and exhibits substantial toxicity to aquatic organisms. Silybin is extensively used for its anti-inflammatory, antioxidant and anti-apoptotic biological properties. Heart is essential for the survival of fish and plays a vital role in pumping blood oxygen and nutrients. Residual avermectin in water poses harm to carp. However, there is still insufficient research on whether silybin can mitigate the toxicity of avermectin to carp heart tissues. In this research, we established a model involving carp subjected to acute avermectin exposure and administered diets containing silybin to explore the potential protective effects of silybin against avermectin-induced cardiotoxicity. The results revealed that avermectin induced oxidative stress, inflammation, endoplasmic reticulum (ER) stress, mitochondrial pathway apoptosis and autophagy in the cardiac tissues of carp. Compared with the avermectin group, silybin significantly reduced ROS accumulation in cardiac tissues, restored antioxidant enzyme activity, inhibited mRNA transcript levels of pro-inflammatory-related factors, and attenuated ER stress, mitochondrial pathway apoptosis and autophagy. Protein-protein interaction (PPI) analysis demonstrated that silybin mitigated avermectin-induced cardiac oxidative stress, inflammation, ER stress, mitochondrial pathway apoptosis and autophagy. Silybin exerted anti-inflammatory effects through the Nuclear Factor kappa B (NF-κB) pathway, antioxidant effects through the Nuclear factor erythroid 2-related factor 2 (Nrf2) - Kelch-like ECH-associated protein 1 (Keap1) pathway, alleviated cardiac ER stress through the Glucose-regulated protein 78 (GRP78)/Activating Transcription Factor 6 (ATF6)/C/EBP homologous protein (CHOP) axis, suppressed apoptosis through the mitochondrial pathway, and inhibited excessive autophagy initiation through the PTEN-induced putative kinase 1 (PINK1)/Parkin RBR E3 ubiquitin protein ligase (PARKIN) signaling pathway. This study provided evidence supporting the protective effect of silybin against avermectin-induced cardiotoxicity in carp, highlighting its potential as a dietary additive to protect fish from adverse effects caused by avermectin exposure.
Assuntos
Anti-Helmínticos , Carpas , Ivermectina , Substâncias Protetoras , Silibina , Silibina/farmacologia , Silibina/uso terapêutico , Estresse do Retículo Endoplasmático , Cardiotoxicidade/tratamento farmacológico , Carpas/fisiologia , Animais , Ivermectina/toxicidade , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Apoptose/efeitos dos fármacos , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Fator 6 Ativador da Transcrição/metabolismo , Fator de Transcrição CHOP/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Inflamação/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Biomarcadores/sangue , Coração/efeitos dos fármacos , Coração/fisiologia , Miocárdio/patologiaRESUMO
Currently, no effective treatment exists for premature ovarian failure (POF). To obtain compounds with protective effects against POF, we aimed to design and synthesize a series of spiroheterocyclic protective agents with a focus on minimizing toxicity while enhancing their protective effect against cisplatin-induced POF. This was achieved through systematic modifications of Michael receptors and linkers within the molecular structure of 1,5-diphenylpenta-1,4-dien-3-one analogs. To assess the cytotoxicity and activity of these compounds, we constructed quantitative conformational relationship models using an artificial intelligence random forest algorithm, resulting in R2 values exceeding 0.87. Among these compounds, j2 exhibited optimal protective activity. It significantly increased the survival of cisplatin-injured ovarian granulosa KGN cells, improved post-injury cell morphology, reduced apoptosis, and enhanced cellular estradiol (E2) levels. Subsequent investigations revealed that j2 may exert its protective effect via a novel mechanism involving the activation of the SIRT1/AKT signal pathway. Furthermore, in cisplatin-injured POF in rats, j2 was effective in increasing body, ovarian, and uterine weights, elevating the number of follicles at all levels in the ovary, improving ovarian and uterine structures, and increasing serum E2 levels in rats with cisplatin-injured POF. In conclusion, this study introduces a promising compound j2 and a novel target SIRT1 with substantial protective activity against cisplatin-induced POF.
Assuntos
Cisplatino , Insuficiência Ovariana Primária , Sirtuína 1 , Feminino , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/tratamento farmacológico , Insuficiência Ovariana Primária/patologia , Insuficiência Ovariana Primária/metabolismo , Sirtuína 1/metabolismo , Sirtuína 1/antagonistas & inibidores , Cisplatino/farmacologia , Animais , Ratos , Humanos , Relação Estrutura-Atividade , Regulação para Cima/efeitos dos fármacos , Ratos Sprague-Dawley , Estrutura Molecular , Substâncias Protetoras/farmacologia , Substâncias Protetoras/química , Substâncias Protetoras/síntese química , Descoberta de Drogas , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Relação Dose-Resposta a Droga , Apoptose/efeitos dos fármacos , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/síntese químicaRESUMO
BACKGROUND: Vanillic acid (VA; 4-hydroxy-3-methoxybenzoic acid) is a flavouring agent found in various natural sources such as olives, fruits, and green tea. While VA exhibits numerous pharmacological effects, its potential protective effects against gastric injury warrants further investigation. Therefore, the primary objective of this study is to elucidate investigate the gastroprotective properties of VA against ethanol-induced gastric injury. METHODS AND RESULTS: Rats were orally administered either saline or VA at different doses (50, 100, and 200 mg/kg/day), with omeprazole (20 mg/kg) serving as a positive control, for fourteen consecutive days before ethanol administration. Blood and gastric tissue samples were collected one hour after ethanol administration for biochemical, molecular, and histological analyses. Pre-treatment with VA before ulcer induction alleviated both macroscopic and microscopic damage. It also increased antioxidant glutathione levels and decreased malondialdehyde and myeloperoxidase activity, along with reducing inflammatory markers such as tumour necrosis factor (TNF)-α, interleukin (IL)-6, and nuclear factor kappa B (NF-κB). Additionally, VA pre-treatment reversed the elevation of Bax mRNA expression and gastric caspase-3 levels induced by gastric damage. It also mitigated the reduction in Bcl-2 mRNA expression. CONCLUSION: These findings suggest that VA exerts protective effects against ethanol-induced gastric injury in rats. It achieves this by augmenting gastric antioxidant capacity and mitigating oxidative, inflammatory, and apoptotic damage.
Assuntos
Apoptose , Etanol , NF-kappa B , Transdução de Sinais , Úlcera Gástrica , Ácido Vanílico , Animais , NF-kappa B/metabolismo , Etanol/toxicidade , Etanol/efeitos adversos , Ratos , Apoptose/efeitos dos fármacos , Ácido Vanílico/farmacologia , Transdução de Sinais/efeitos dos fármacos , Masculino , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/lesões , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Substâncias Protetoras/farmacologia , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genética , Glutationa/metabolismoRESUMO
BACKGROUND: Baicalein is the main active flavonoid in Scutellariae Radix and is included in shosaikoto, a Kampo formula used for treating hepatitis and jaundice. However, little is known about its hepatoprotective effects against hepatic ischemia-reperfusion injury (HIRI), a severe clinical condition directly caused by interventional procedures. We aimed to investigate the hepatoprotective effects of baicalein against HIRI and partial hepatectomy (HIRI + PH) and its potential underlying mechanisms. METHODS AND RESULTS: Male Sprague-Dawley rats received either baicalein (5 mg/kg) or saline intraperitoneally and underwent a 70% hepatectomy 15 min after hepatic ischemia. After reperfusion, liver and blood samples were collected. Survival was monitored 30 min after hepatic ischemia and hepatectomy. In interleukin 1ß (IL-1ß)-treated primary cultured rat hepatocytes, the influence of baicalein on inflammatory mediator production and the associated signaling pathway was analyzed. Baicalein suppressed apoptosis and neutrophil infiltration, which are the features of HIRI + PH treatment-induced histological injury. Baicalein also reduced the mRNA expression of the proinflammatory cytokine tumor necrosis factor-α (TNF-α). In addition, HIRI + PH treatment induced liver enzyme deviations in the serum and hypertrophy of the remnant liver, which were suppressed by baicalein. In the lethal HIRI + PH treatment group, baicalein significantly reduced mortality. In IL-1ß-treated rat hepatocytes, baicalein suppressed TNF-α and chemokine mRNA expression as well as the activation of nuclear factor-kappa B (NF-κB) and Akt. CONCLUSIONS: Baicalein treatment attenuates HIRI + PH-induced liver injury and may promote survival. This potential hepatoprotection may be partly related to suppressing inflammatory gene induction through the inhibition of NF-κB activity and Akt signaling in hepatocytes.
Assuntos
Apoptose , Modelos Animais de Doenças , Flavanonas , Hepatectomia , Hepatócitos , Interleucina-1beta , Fígado , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Animais , Flavanonas/farmacologia , Flavanonas/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Hepatectomia/métodos , Masculino , Ratos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Apoptose/efeitos dos fármacos , Interleucina-1beta/metabolismo , NF-kappa B/metabolismo , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Here, the protective effect of antioxidant Idebenone (IDB) on renovascular hypertension was studied. The two-kidney one-clip (2K-1C) model of renal hypertension was established. The rats were divided into 3 groups: sham-operation group, 2K-1C renal hypertensive rats' model group and model treated with IDB group. The mean arterial blood pressure (MBP) of rats was measured and pathological condition of kidney was observed by H&E staining. The change of renal damage biomarkers (Cre, BUN, urine proteins), inflammatory factors (IL-6, IL-1ß and TNF-α), oxidative stress ratio and key factors (MDA, SOD and CAT) were assessed by kits. The apoptosis key proteins (BAD, BAX, Caspase9, GSK-3ß) were detected via Western blot. The 2K-1C model of renal hypertension was established. IDB reduced the MBP, Cre, BUN, urine proteins and improved the pathological condition of 2K-1C kidney. IDB restrained the inflammation factors (IL-6, IL-1ß and TNF-α) and oxidative stress in kidney of renal hypertensive rats' model. Besides, IDB suppressed the expression of apoptosis key factors (BAD, BAX, Caspase9, GSK-3ß) in kidney of renal hypertensive rats' model. IDB protects the kidneys of rats with renovascular arterial hypertension by inhibiting inflammation, oxidative stress, and apoptosis. These findings might provide medication guidance for IDB in renovascular arterial hypertension.
Assuntos
Apoptose , Hipertensão Renovascular , Rim , Estresse Oxidativo , Ubiquinona , Animais , Estresse Oxidativo/efeitos dos fármacos , Hipertensão Renovascular/tratamento farmacológico , Hipertensão Renovascular/metabolismo , Apoptose/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Masculino , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Ubiquinona/uso terapêutico , Ratos , Ratos Sprague-Dawley , Pressão Sanguínea/efeitos dos fármacos , Antioxidantes/farmacologia , Modelos Animais de Doenças , Substâncias Protetoras/farmacologiaRESUMO
Triterpenoids are a type of specialized metabolites that exhibit a wide range of biological activities. However, the availability of some minor triterpenoids in nature is limited, which has hindered our understanding of their pharmacological potential. To overcome this limitation, heterologous biosynthesis of triterpenoids in yeast has emerged as a promising and time-efficient production platform for obtaining these minor compounds. In this study, we analyzed the transcriptomic data of Enkianthus chinensis to identify one oxidosqualene cyclase (EcOSC) gene and four CYP716s. Through heterologous expression of these genes in yeast, nine natural pentacyclic triterpenoids, including three skeleton products (1-3) produced by one multifunctional OSC and six minor oxidation products (4-9) catalyzed by CYP716s, were obtained. Of note, we discovered that CYP716E60 could oxidize ursane-type and oleanane-type triterpenoids to produce 6ß-OH derivatives, marking the first confirmed C-6ß hydroxylation in an ursuane-type triterpenoid. Compound 9 showed moderate inhibitory activity against NO production and dose-dependently reduced IL-1ß and IL-6 production at the transcriptional and protein levels. Compounds 1, 2, 8, and 9 exhibited moderate hepatoprotective activity with the survival rates of HepG2 cells from 61% to 68% at 10 µM.
Assuntos
Anti-Inflamatórios , Sistema Enzimático do Citocromo P-450 , Transferases Intramoleculares , Triterpenos , Triterpenos/farmacologia , Triterpenos/química , Humanos , Sistema Enzimático do Citocromo P-450/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Estrutura Molecular , Saccharomyces cerevisiae , Hidroxilação , Células Hep G2 , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Substâncias Protetoras/farmacologia , Substâncias Protetoras/químicaRESUMO
Stachybatranones A-F (1a/1b and 2-6) and three known analogues, namely methylatranones A and B (7 and 8) and atranone B (9), were isolated and identified from a toxigenic fungus Stachybotrys chartarum. Their structures and absolute configurations were elucidated via the extensive spectroscopic data, comparison of the experimental electronic circular dichroism (ECD) data, and single-crystal X-ray diffraction analyses. Structurally, compounds 2-6 belonged to a rare class of C-alkylated dolabellanes, featuring a unique five-membered hemiketal ring and a γ-butyrolactone moiety both fused to an 11-membered carbocyclic system, while compound 1 (1a/1b) represented the first example of a 5-11-6-fused atranone possessing a 2,3-butanediol moiety. The cardiomyocyte protective activity assay revealed that compounds 1-9 ameliorated cold ischemic injury at 24 h post cold ischemia (CI), with compounds 1 and 4 acting in a dose-dependent manner. Moreover, compound 1 prevented cold ischemia induced dephosphorylation of PI3K and AKT acting in a dose-dependent manner. In this study, a new class of natural products were found to protect cardiomyocytes against cold ischemic injury, providing a potential option for the development of novel cardioprotectants in heart transplant medicine.
Assuntos
Miócitos Cardíacos , Stachybotrys , Stachybotrys/química , Animais , Miócitos Cardíacos/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade , Relação Dose-Resposta a Droga , Ratos , Descoberta de Drogas , Produtos Biológicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Substâncias Protetoras/farmacologia , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificaçãoRESUMO
Phenylarsine oxide (PAO) is a known environmental pollutant and skin keratinocytes are most seriously affected. Baicalin (BCN) was reported to have antioxidant and anti-inflammatory effects, but its protective effect against PAO toxicity is unknown. This study aimed at exploring whether baicalin can reverse the toxicity of human epidermal keratinocytes that are subjected to PAO exposure and underlying mechanisms. In silico analysis from a publicly accessible HaCaT cell transcriptome dataset exposed to chronic Arsenic showed significant differential expression of several genes, including the genes related to DNA replication. Later, we performed in vitro experiments, in which HaCaT cells were exposed to PAO (500 nM) in the existence of BCN (10-50 µM). Treatment of PAO alone induces the JNK, p38 and caspase-3 activation, which were engaged in the apoptosis induction, while the activity of AKT was significantly inhibited, which was engaged in the suppression of apoptosis. PAO suppressed SIRT3 expression and induced intracellular reactive oxygen species (ROS), causing a marked reduce in cell viability and apoptosis. However, BCN treatment restored the PAO-induced suppression of SIRT3 and AKT expression, reduced intracellular ROS generation, and markedly suppressed both caspase-3 activation and apoptosis induction. However, the protective effect of BCN was significantly attenuated after pretreatment with nicotinamide, an inhibitor of SIRT3. These findings indicate that BCN protects against cell death induced by PAO via inhibiting excessive intracellular ROS generation via restoring SIRT3 activity and reactivating downstream AKT pathway. In this study, we firstly shown that BCN is an efficient drug to prevent PAO-induced skin cytotoxicity, and these findings need to be confirmed by in vivo and clinical investigations.
Assuntos
Apoptose , Arsenicais , Sobrevivência Celular , Flavonoides , Queratinócitos , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Flavonoides/farmacologia , Flavonoides/química , Arsenicais/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Estrutura Molecular , Relação Dose-Resposta a Droga , Substâncias Protetoras/farmacologia , Substâncias Protetoras/química , Relação Estrutura-Atividade , Pele/efeitos dos fármacos , Pele/patologiaRESUMO
Plastic pollution is an emerging environmental issue, with microplastics and nanoplastics raising health concerns due to bioaccumulation. This work explored the impact of polystyrene nanoparticle (PS-NPs) exposure during prepuberty on male reproductive function post maturation in rats. Rats were gavaged with PS-NPs (80 nm) at 0, 3, 6, 12 mg/kg/day from postnatal day 21 to 95. PS-NPs accumulated in the testes and reduced sperm quality, serum reproductive hormones, and testicular coefficients. HE staining showed impaired spermatogenesis. PS-NPs disrupted the blood-testis barrier (BTB) by decreasing junction proteins, inducing inflammation and apoptosis. Transcriptomics identified differentially expressed genes related to metabolism, lysosome, apoptosis, and TLR4 signaling. Molecular docking revealed Cordycepin could compete with polystyrene for binding to TLR4. Cordycepin alleviated oxidative stress and improved barrier function in PS-NPs treated Sertoli cells. In conclusion, prepubertal PS-NPs exposure induces long-term reproductive toxicity in male rats, likely by disrupting spermatogenesis through oxidative stress and BTB damage. Cordycepin could potentially antagonize this effect by targeting TLR4 and warrants further study as a protective agent. This study elucidates the mechanisms underlying reproductive toxicity of PS-NPs and explores therapeutic strategies.
Assuntos
Barreira Hematotesticular , Desoxiadenosinas , Nanopartículas , Poliestirenos , Espermatogênese , Testículo , Animais , Masculino , Desoxiadenosinas/farmacologia , Barreira Hematotesticular/efeitos dos fármacos , Poliestirenos/toxicidade , Nanopartículas/toxicidade , Espermatogênese/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/metabolismo , Simulação de Acoplamento Molecular , Microplásticos/toxicidade , Receptor 4 Toll-Like/metabolismo , Apoptose/efeitos dos fármacos , Maturidade Sexual/efeitos dos fármacos , Substâncias Protetoras/farmacologiaRESUMO
Potassium bromate (KBrO3) is a common dietary additive, pharmaceutical ingredient, and significant by-product of water disinfection. p-coumaric acid (PCA) is a naturally occurring nutritional polyphenolic molecule with anti-inflammatory and antioxidant activities. The goal of the current investigation was to examine the protective effects of p-coumaric acid against the liver damage caused by KBrO3. The five groups of animals-control, KBrO3 (100 mg/kg bw), treatment with KBrO3 along with Silymarin (100 mg/kg bw), KBrO3, followed by PCA (100 mg/bw, and 200 mg/kg bw) were randomly assigned to the animals. Mice were slaughtered, and blood and liver tissues were taken for assessment of the serum biochemical analysis for markers of liver function (alanine transaminase, aspartate transaminase, alkaline phosphatase, albumin, and protein), lipid markers and antioxidant markers (TBARS), glutathione peroxidase [GSH-Px], glutathione (GSH), and markers of hepatic oxidative stress (CAT), (SOD), as well as histological H&E stain, immunohistochemical stain iNOS, and COX-2 as markers of inflammatory cytokines. PCA protects against acute liver failure by preventing the augmentation of blood biochemical markers and lipid profiles. In mice liver tissues, KBrO3 increases lipid indicators and depletes antioxidants, leading to an increase in JNK, ERK, and p38 phosphorylation. Additionally, PCA inhibited the production of pro-inflammatory cytokines and reduced the histological alterations in KBrO3-induced hepatotoxicity. Notably, PCA effectively mitigated KBrO3-induced hepatic damage by obstructing the TNF-α/NF-kB-mediated inflammatory process signaling system. Additionally, in KBrO3-induced mice, PCA increased the intensities of hepatic glutathione (GSH), SOD, GSH-Px, catalase, and GSH activities. Collectively, we demonstrate the molecular evidence that PCA eliminated cellular inflammatory conditions, mitochondrial oxidative stress, and the TNF-α/NF-κB signaling process, thereby preventing KBrO3-induced hepatocyte damage.
Assuntos
Bromatos , Ácidos Cumáricos , Fígado , Propionatos , Animais , Camundongos , Ácidos Cumáricos/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Substâncias Protetoras/farmacologiaRESUMO
As a critical cause of human dysfunctionality, hepatic failure leads to approximately two million deaths per year and is on the rise. Considering multiple inflammatory, oxidative, and apoptotic mechanisms behind hepatotoxicity, it urges the need for finding novel multi-targeting agents. Curcumin is a phenolic compound with anti-inflammatory, antioxidant, and anti-apoptotic roles. Curcumin possesses auspicious health benefits and protects against several diseases with exceptional safety and tolerability. This review focused on the hepatoprotective mechanisms of curcumin. The need to develop novel delivery systems of curcumin (e.g., nanoparticles, self-micro emulsifying, lipid-based colloids, solid lipid nanoparticles, cyclodextrin inclusion, phospholipid complexes, and nanoemulsions) is also considered.
Assuntos
Curcumina , Curcumina/farmacologia , Curcumina/química , Humanos , Animais , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Antioxidantes/farmacologia , Antioxidantes/química , Fígado/efeitos dos fármacos , Fígado/patologia , Substâncias Protetoras/farmacologia , Substâncias Protetoras/química , Nanopartículas , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
Non-alcoholic fatty liver disease (NAFLD), with a global prevalence of 25%, continues to escalate, creating noteworthy concerns towards the global health burden. NAFLD causes triglycerides and free fatty acids to build up in the liver. The excessive fat build-up causes inflammation and damages the healthy hepatocytes, leading to non-alcoholic steatohepatitis (NASH). Dietary habits, obesity, insulin resistance, type 2 diabetes, and dyslipidemia influence NAFLD progression. The disease burden is complicated due to the paucity of therapeutic interventions. Obeticholic acid is the only approved therapeutic agent for NAFLD. With more scientific enterprise being directed towards the understanding of the underlying mechanisms of NAFLD, novel targets like lipid synthase, farnesoid X receptor signalling, peroxisome proliferator-activated receptors associated with inflammatory signalling, and hepatocellular injury have played a crucial role in the progression of NAFLD to NASH. Phytocompounds have shown promising results in modulating hepatic lipid metabolism and de novo lipogenesis, suggesting their possible role in managing NAFLD. This review discusses the ameliorative role of different classes of phytochemicals with molecular mechanisms in different cell lines and established animal models. These compounds may lead to the development of novel therapeutic strategies for NAFLD progression to NASH. This review also deliberates on phytomolecules undergoing clinical trials for effective management of NAFLD.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Compostos Fitoquímicos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Humanos , Animais , Compostos Fitoquímicos/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismoRESUMO
BACKGROUND: The liver serves as a metabolic hub within the human body, playing a crucial role in various essential functions, such as detoxification, nutrient metabolism, and hormone regulation. Therefore, protecting the liver against endogenous and exogenous insults has become a primary focus in medical research. Consequently, the potential hepatoprotective properties of multiple 4-phenyltetrahydroquinolines inspired us to thoroughly study the influence of four specially designed and synthesized derivatives on carbon tetrachloride (CCl4)-induced liver injury in rats. METHODS AND RESULTS: Seventy-seven Wistar albino male rats weighing 140 ± 18 g were divided into eleven groups to investigate both the toxicity profile and the hepatoprotective potential of 4-phenyltetrahydroquinolines. An in-vivo hepatotoxicity model was conducted using CCl4 (1 ml/kg body weight, a 1:1 v/v mixture with corn oil, i.p.) every 72 h for 14 days. The concurrent treatment of rats with our newly synthesized compounds (each at a dose of 25 mg/kg body weight, suspended in 0.5% CMC, p.o.) every 24 h effectively lowered transaminases, preserved liver tissue integrity, and mitigated oxidative stress and inflammation. Moreover, the histopathological examination of liver tissues revealed a significant reduction in liver fibrosis, which was further supported by the immunohistochemical analysis of α-SMA. Additionally, the expression of the apoptotic genes BAX and BCL2 was monitored using real-time PCR, which showed a significant decrease in liver apoptosis. Further investigations unveiled the ability of the compounds to significantly decrease the expression of autophagy-related proteins, Beclin-1 and LC3B, consequently inhibiting autophagy. Finally, our computer-assisted simulation dockingonfirmed the obtained experimental activities. CONCLUSION: Our findings suggest that derivatives of 4-phenyltetrahydroquinoline demonstrate hepatoprotective properties in CCl4-induced liver damage and fibrosis in rats. The potential mechanism of action may be due to the inhibition of autophagy in liver cells.