RESUMO
Salvianolic acid A (SalA), a bioactive compound extracted from Salvia miltiorrhiza, has garnered considerable interest for its potential in ameliorating the post-stroke neuroinflammation. This review delineates the possible molecular underpinnings of anti-inflammatory and neuroprotective roles of SalA, offering a comprehensive analysis of its therapeutic efficacy in preclinical studies of ischemic stroke. We explore the intricate interplay between post-stroke neuroinflammation and the modulatory effects of SalA on pro-inflammatory cytokines, inflammatory signaling pathways, the peripheral immune cell infiltration through blood-brain barrier disruption, and endothelial cell function. The pharmacokinetic profiles of SalA in the context of stroke, characterized by enhanced cerebral penetration post-ischemia, makes it particularly suitable as a therapeutic agent. Preliminary clinical findings have demonstrated that salvianolic acids (SA) has a positive impact on cerebral perfusion and neurological deficits in stroke patients, warranting further investigation. This review emphasizes SalA as a potential anti-inflammatory agent for the advancement of innovative therapeutic approaches in the treatment of ischemic stroke.
Assuntos
Anti-Inflamatórios , Ácidos Cafeicos , Doenças Neuroinflamatórias , Acidente Vascular Cerebral , Humanos , Animais , Ácidos Cafeicos/uso terapêutico , Ácidos Cafeicos/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/etiologia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Lactatos/uso terapêutico , Lactatos/farmacologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacosRESUMO
OBJECTIVES: Reflecting the need for an effective support for the daily oral hygiene routine of patients experiencing (symptoms of) gum inflammation, a new mouthwash has been developed containing an amine + zinc lactate + fluoride system. The in vitro efficacy of this product was assessed using traditional laboratory methods, as well as novel experimentation. MATERIALS AND METHODS: This mouthwash has been evaluated in a series of laboratory tests including two short interval kill tests (SIKTs), a 12-h (longer term) biofilm regrowth assay, a plaque glycolysis assay, and an aerobic, repeated exposure biofilm model, as well as tests for soft tissue uptake and LPS neutralization. RESULTS: Several laboratory studies demonstrate that a mouthwash containing an amine + zinc lactate + fluoride system provides short-term and long-term antibacterial activity. While the immediate efficacy of this formula has been shown to be driven by the presence of the amine, zinc lactate provides a long-term antibacterial effect, as well as is able to inhibit bacterial metabolism. CONCLUSIONS: This research provides the basis for understanding the mode of action of this new mouthwash formulation and explains the previously observed clinical efficacy of this formula against plaque and gingivitis.
Assuntos
Antibacterianos , Biofilmes , Placa Dentária , Fluoretos , Antissépticos Bucais , Antissépticos Bucais/farmacologia , Biofilmes/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/administração & dosagem , Humanos , Fluoretos/farmacologia , Placa Dentária/microbiologia , Placa Dentária/tratamento farmacológico , Lactatos/farmacologia , Aminas/farmacologia , Aminas/química , Gengivite/tratamento farmacológico , Gengivite/microbiologia , Gengivite/prevenção & controle , Compostos de Zinco/farmacologiaRESUMO
Non-alcoholic fatty liver disease (NAFLD) affects approximately a quarter of the population and, to date, there is no approved drug therapy for this condition. Individuals with type 2 diabetes mellitus (T2DM) are at a significantly elevated risk of developing NAFLD, underscoring the urgency of identifying effective NAFLD treatments for T2DM patients. Salvianolic acid A (SAA) is a naturally occurring phenolic acid that is an important component of the water-soluble constituents isolated from the roots of Salvia miltiorrhiza Bunge. SAA has been demonstrated to possess anti-inflammatory and antioxidant stress properties. Nevertheless, its potential in ameliorating diabetes-associated NAFLD has not yet been fully elucidated. In this study, diabetic ApoE-/- mice were employed to establish a NAFLD model via a Western diet. Following this, they were treated with different doses of SAA (10 mg/kg, 20 mg/kg) via gavage. The study demonstrated a marked improvement in liver injury, lipid accumulation, inflammation, and the pro-fibrotic phenotype after the administration of SAA. Additionally, RNA-seq analysis indicated that the primary pathway by which SAA alleviates diabetes-induced NAFLD involves the cascade pathways of lipid metabolism. Furthermore, SAA was found to be effective in the inhibition of lipid accumulation, mitochondrial dysfunction and ferroptosis. A functional enrichment analysis of RNA-seq data revealed that SAA treatment modulates the AMPK pathway and IGFBP-1. Further experimental results demonstrated that SAA is capable of inhibiting lipid accumulation through the activation of the AMPK pathway and IGFBP-1.
Assuntos
Proteínas Quinases Ativadas por AMP , Ácidos Cafeicos , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina , Lactatos , Hepatopatia Gordurosa não Alcoólica , Transdução de Sinais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Camundongos , Lactatos/farmacologia , Lactatos/uso terapêutico , Lactatos/química , Proteínas Quinases Ativadas por AMP/metabolismo , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/química , Ácidos Cafeicos/uso terapêutico , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Masculino , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos KnockoutRESUMO
BACKGROUND: This study investigated the impact of salvianolic acids, derived from Danshen, on melanoma cell growth. Specifically, we assessed the ability of salvianolic acid A (Sal A) to modulate melanoma cell proliferation. METHODS: We used human melanoma A2058 and A375 cell lines to investigate the effects of Sal A on cell proliferation and death by measuring bromodeoxyuridine incorporation and lactate dehydrogenase release. We assessed cell viability and cycle progression using water soluble tetrazolium salt-1 (WST-1) mitochondrial staining and propidium iodide. Additionally, we used a phospho-kinase array to investigate intracellular kinase phosphorylation, specifically measuring the influence of Sal A on checkpoint kinase-2 (Chk-2) via western blot analysis. RESULTS: Sal A inhibited the growth of A2058 and A375 cells dose-responsively and induced cell cycle arrest at the G2/M phase. Notably, Sal A selectively induces Chk-2 phosphorylation without affecting Chk-1, thereby degrading Chk-2-regulated genes Cdc25A and Cdc2. However, Sal A does not affect the Chk1-Cdc25C pathway. CONCLUSIONS: Salvianolic acids, especially Sal A, effectively hinder melanoma cell growth by inducing Chk-2 phosphorylation and disrupting G2/M checkpoint regulation.
Assuntos
Ácidos Cafeicos , Proliferação de Células , Quinase do Ponto de Checagem 2 , Lactatos , Melanoma , Fosfatases cdc25 , Humanos , Quinase do Ponto de Checagem 2/metabolismo , Quinase do Ponto de Checagem 2/genética , Fosfatases cdc25/metabolismo , Fosfatases cdc25/genética , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Melanoma/genética , Melanoma/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Lactatos/farmacologia , Lactatos/metabolismo , Ácidos Cafeicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacosRESUMO
Danshensu, also known as salvianic acid A, is a primary active compound extracted from a traditional Chinese herb Danshen (Salvia miltiorrhiza). While its antioxidative and neuroprotective effects are well-documented, the underlying mechanisms are poorly understood. In this study, we sought out to investigate if and how Danshensu modulates neuronal excitability and voltage-gated ionic currents in the central nervous system. We prepared brain slices of the mouse brainstem and performed patch-clamp recording in bushy cells in the anteroventral cochlear nucleus, with or without Danshensu incubation for 1â h. QX-314 was used internally to block Na+ current, while tetraethylammonium and 4-aminopyridine were used to isolate different subtypes of K+ current. We found that Danshensu of 100â µm decreased the input resistance of bushy cells by approximately 60% and shifted the voltage threshold of spiking positively by approximately 7â mV, resulting in significantly reduced excitability. Furthermore, we found this reduced excitability by Danshensu was caused by enhanced voltage-gated K+ currents in these neurons, including both low voltage-activated IK,A, by approximately 100%, and high voltage-activated IK,dr, by approximately 30%. Lastly, we found that the effect of Danshensu on K+ currents was dose-dependent in that no enhancement was found for Danshensu of 50â µm and Danshensu of 200 µm failed to cause significantly more enhancement on K+ currents when compared to that of 100â µm. We found that Danshensu reduced neuronal excitability in the central nervous system by enhancing voltage-gated K+ currents, providing mechanistic support for its neuroprotective effect widely seen in vivo.
Assuntos
Núcleo Coclear , Lactatos , Neurônios , Animais , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Lactatos/farmacologia , Núcleo Coclear/efeitos dos fármacos , Núcleo Coclear/fisiologia , Técnicas de Patch-Clamp , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Masculino , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/metabolismo , Camundongos Endogâmicos C57BLRESUMO
The primary inhibitory targets of phenyllactic acid (PLA, including D-PLA and L-PLA) on Mucor were investigated using Mucor racemosus LD3.0026 isolated from naturally spoiled cherry, as an indicator fungi. The results demonstrated that the minimum inhibitory concentration (MIC) of PLA against Mucor was 12.5 mmol·L-1. Results showed that the growing cells at the tip of the Mucor were not visibly deformed, and there was no damage to the cell wall following PLA treatment; however, PLA damaged the cell membrane and internal structure. The results of isobaric tags for relative and absolute quantification (iTRAQ) indicated that the Mucor mitochondrial respiratory chain may be the target of PLA, potentially inhibiting the energy supply of Mucor. These results indicate that the antifungal mechanism of PLA against mold is independent of its molecular configuration. The growth of Mucor is suppressed by PLA, which destroys the organelle structure in the mycelium and inhibits energy metabolism.
Assuntos
Antifúngicos , Mucor , Proteômica , Mucor/metabolismo , Mucor/crescimento & desenvolvimento , Mucor/química , Mucor/efeitos dos fármacos , Antifúngicos/farmacologia , Antifúngicos/química , Testes de Sensibilidade Microbiana , Lactatos/farmacologia , Lactatos/metabolismo , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/químicaRESUMO
Phenyllactic acid (PLA) as a natural phenolic acid exhibits antibacterial activity against non-spore-forming bacteria, while the inhibitory effect against bacterial spore remained unknown. Herein, this study investigated the inactivation effect of PLA against Bacillus cereus spores. The results revealed that the minimum inhibitory concentration of PLA was 1.25 mg/mL. PLA inhibited the outgrowth of germinated spores into vegetative cells rather than germination of spores. PLA disrupted the spore coat, and damaged the permeability and integrity of inner membrane. Moreover, PLA disturbed the establishment of membrane potential due to the inhibition of oxidative metabolism. SEM observations further visualized the morphological changes and structural disruption caused by PLA. Besides, PLA caused the degradation of DNA of germinated spores. Finally, PLA was applied in milk beverage, and showed promising inhibitory effect against B. cereus spores. This finding could provide scientific basis for the application of PLA against spore-forming bacteria in food industry.
Assuntos
Antibacterianos , Bacillus cereus , Leite , Esporos Bacterianos , Bacillus cereus/crescimento & desenvolvimento , Bacillus cereus/efeitos dos fármacos , Bacillus cereus/metabolismo , Esporos Bacterianos/efeitos dos fármacos , Esporos Bacterianos/crescimento & desenvolvimento , Esporos Bacterianos/metabolismo , Leite/química , Leite/microbiologia , Antibacterianos/farmacologia , Antibacterianos/química , Animais , Bebidas/análise , Bebidas/microbiologia , Testes de Sensibilidade Microbiana , Lactatos/farmacologia , Lactatos/química , Lactatos/metabolismoRESUMO
Oxidative stress induced endothelial dysfunction plays a particularly important role in promoting the development of cardiovascular diseases (CVDs). Salvianolic acid A (SalA) is a water-soluble component of traditional Chinese medicine Salvia miltiorrhiza Bunge with anti-oxidant potency. This study aims to explore the regulatory effect of SalA on oxidative injury using an in vitro model of H2O2-induced injury in human umbilical vein endothelial cells (HUVECs). In the study, we determined cell viability, the activities of Lactate dehydrogenase (LDH) and Superoxide dismutase (SOD), cell proliferation rate and intracellular reactive oxygen species (ROS). Flow cytometry was used to detect cell apoptosis. Western-blotting was used to evaluate the expression of cell senescence, apoptosis, autophagy and pyroptosis protein factors. The expression level of miRNA was determined by qRT-PCR. Compared with H2O2-induced HUVECs, SalA promoted cell viability and cell proliferation rate; decreased LDH and ROS levels; and increased SOD activity. SalA also significantly attenuated endothelial senescence, inhibited cell apoptosis, reversed the increase of LC3 II/I ratio and NLRP3 accumulation. Furthermore, miR-204-5p was regulated by SalA. Importantly, miR-204-5p inhibitor had similar effect to that of SalA on H2O2-induced HUVECs. Our results indicated that SalA could alleviate H2O2-induced oxidative injury by downregulating miR-204-5p in HUVECs.
Assuntos
Apoptose , Sobrevivência Celular , Células Endoteliais da Veia Umbilical Humana , Peróxido de Hidrogênio , Lactatos , MicroRNAs , Estresse Oxidativo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Peróxido de Hidrogênio/toxicidade , Peróxido de Hidrogênio/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Lactatos/farmacologia , Lactatos/metabolismo , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ácidos Cafeicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Autofagia/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Antioxidantes/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genéticaRESUMO
Intracerebral hemorrhage (ICH) is a common cerebral vascular disease with high incidence, disability, and mortality. Ferroptosis is a regulated type of iron-dependent, non-apoptotic programmed cell death. There is increasing evidence that ferroptosis may lead to neuronal damage mediated by hemorrhagic stroke mediated neuronal damage. Salvianolic acid A (SAA) is a natural bioactive polyphenol compound extracted from salvia miltiorrhiza, which has anti-inflammatory, antioxidant, and antifibrosis activities. SAA is reported to be an iron chelator that inhibits lipid peroxidation and provides neuroprotective effects. However, whether SAA improves neuronal ferroptosis mediated by hemorrhagic stroke remains unclear. The study aims to evaluate the therapeutic effect of SAA on Ferroptosis mediated by Intracerebral hemorrhage and explore its potential mechanisms. We constructed in vivo and in vitro models of intracerebral hemorrhage in rats. Multiple methods were used to analyze the inhibitory effect of SAA on ferroptosis in both in vivo and in vitro models of intracerebral hemorrhage in rats. Then, network pharmacology is used to identify potential targets and mechanisms for SAA treatment of ICH. The SAA target ICH network combines SAA and ICH targets with protein-protein interactions (PPIs). Find the specific mechanism of SAA acting on ferroptosis through molecular docking and functional enrichment analysis. In rats, SAA (10 mg/kg in vivo and 50 µM in vitro, p < 0.05) alleviated dyskinesia and brain injury in the ICH model by inhibiting ferroptosis (p < 0.05). The molecular docking results and functional enrichment analyses suggested that AKT (V-akt murine thymoma viral oncogene homolog) could mediate the effect of SAA. NRF2 (Nuclear factor erythroid 2-related factor 2) was a potential target of SAA. Our further experiments showed that salvianolic acid A enhanced the Akt /GSK-3ß/Nrf2 signaling pathway activation in vivo and in vitro. At the same time, SAA significantly expanded the expression of GPX4, XCT proteins, and the nuclear expression of Nrf2, while the AKT inhibitor SH-6 and the Nrf2 inhibitor ML385 could reduce them to some extent. Therefore, SAA effectively ameliorated ICH-mediated neuronal ferroptosis. Meanwhile, one of the critical mechanisms of SAA inhibiting ferroptosis was activating the Akt/GSK-3ß/Nrf2 signaling pathway.
Assuntos
Ácidos Cafeicos , Hemorragia Cerebral , Ferroptose , Lactatos , Fármacos Neuroprotetores , Animais , Ferroptose/efeitos dos fármacos , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/química , Ratos , Lactatos/farmacologia , Lactatos/química , Lactatos/uso terapêutico , Masculino , Fármacos Neuroprotetores/farmacologia , Ratos Sprague-Dawley , Fator 2 Relacionado a NF-E2/metabolismo , Simulação de Acoplamento Molecular , Modelos Animais de Doenças , Transdução de Sinais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
ABSTRACT: Cardiac fibrosis, characterized by excessive collagen accumulation in heart tissues, poses a significant clinical challenge in various heart diseases and complications. Although salvianolic acid A (Sal A) from Danshen ( Salvia miltiorrhiza ) has shown promise in the treatment of ischemic heart disease, myocardial infarction, and atherosclerosis, its effects on cardiac fibrosis remain unexplored. Our study investigated the efficacy of Sal A in reducing cardiac fibrosis and elucidated its underlying molecular mechanisms. We observed that Sal A demonstrated significant cardioprotective effects against Angiotensin II (Ang II)-induced cardiac remodeling and fibrosis, showing a dose-dependent reduction in fibrosis in mice and suppression of cardiac fibroblast proliferation and fibrotic protein expression in vitro . RNA sequencing revealed that Sal A counteracted Ang II-induced upregulation of Txnip, and subsequent experiments indicated that it acts through the inflammasome and ROS pathways. These findings establish the antifibrotic effects of Sal A, notably attenuated by Txnip overexpression, and highlight its significant role in modulating inflammation and oxidative stress pathways. This underscores the importance of further research on Sal A and similar compounds, especially regarding their effects on inflammation and oxidative stress, which are key factors in various cardiovascular diseases.
Assuntos
Angiotensina II , Proteínas de Transporte , Fibrose , Lactatos , Transdução de Sinais , Tiorredoxinas , Animais , Camundongos , Transdução de Sinais/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Masculino , Lactatos/farmacologia , Lactatos/uso terapêutico , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/uso terapêutico , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , Proteínas de Ciclo Celular/metabolismoRESUMO
Regulating metabolic disorders has become a promising focus in treating intervertebral disc degeneration (IDD). A few drugs regulating metabolism, such as atorvastatin, metformin, and melatonin, show positive effects in treating IDD. Glutamine participates in multiple metabolic processes, including glutaminolysis and glycolysis; however, its impact on IDD is unclear. The current study reveals that glutamine levels are decreased in severely degenerated human nucleus pulposus (NP) tissues and aging Sprague-Dawley (SD) rat nucleus pulposus tissues, while lactate accumulation and lactylation are increased. Supplementary glutamine suppresses glycolysis and reduces lactate production, which downregulates adenosine-5'-monophosphate-activated protein kinase α (AMPKα) lactylation and upregulates AMPKα phosphorylation. Moreover, glutamine treatment reduces NP cell senescence and enhances autophagy and matrix synthesis via inhibition of glycolysis and AMPK lactylation, and glycolysis inhibition suppresses lactylation. Our results indicate that glutamine could prevent IDD by glycolysis inhibition-decreased AMPKα lactylation, which promotes autophagy and suppresses NP cell senescence.
Assuntos
Degeneração do Disco Intervertebral , Ratos , Animais , Humanos , Degeneração do Disco Intervertebral/tratamento farmacológico , Degeneração do Disco Intervertebral/metabolismo , Ratos Sprague-Dawley , Glutamina , Proteínas Quinases Ativadas por AMP , Autofagia , Lactatos/farmacologia , Lactatos/uso terapêuticoRESUMO
The necroptotic effector molecule MLKL accumulates in neurons over the lifespan of mice, and its downregulation has the potential to improve cognition through neuroinflammation, and changes in the abundance of synaptic proteins and enzymes in the central nervous system. Notwithstanding, direct evidence of cell-autonomous effects of MLKL expression on neuronal physiology and metabolism are lacking. Here, we tested whether the overexpression of MLKL in the absence of cell death in the neuronal cell line Neuro-2a recapitulates some of the hallmarks of aging at the cellular level. Using genetically-encoded fluorescent biosensors, we monitored the cytosolic and mitochondrial Ca2+ levels, along with the cytosolic concentrations of several metabolites involved in energy metabolism (lactate, glucose, ATP) and oxidative stress (oxidized/reduced glutathione). We found that MLKL overexpression marginally decreased cell viability, however, it led to reduced cytosolic and mitochondrial Ca2+ elevations in response to Ca2+ influx from the extracellular space. On the contrary, Ca2+ signals were elevated after mobilizing Ca2+ from the endoplasmic reticulum. Transient elevations in cytosolic Ca2+, mimicking neuronal stimulation, lead to higher lactate levels and lower glucose concentrations in Neuro-2a cells when overexpressing MLKL, which suggest enhanced neuronal glycolysis. Despite these alterations, energy levels and glutathione redox state in the cell bodies remained largely preserved after inducing MLKL overexpression for 24-48 h. Taken together, our proof-of-concept experiments are consistent with the hypothesis that MLKL overexpression in the absence of cell death contributes to both Ca2+ and metabolic dyshomeostasis, which are cellular hallmarks of brain aging.
Assuntos
Lactatos , Neurônios , Camundongos , Animais , Neurônios/metabolismo , Linhagem Celular , Morte Celular , Lactatos/metabolismo , Lactatos/farmacologia , Glucose/metabolismo , Proteínas Quinases/metabolismoRESUMO
The antiglycation mechanisms of three structurally different salvianolic acids (Sals) including salvianolic acid A (Sal-A), salvianolic acid B (Sal-B) and salvianolic acid C (Sal-C) were investigated using the bovine serum albumin (BSA)-fructose model. The results showed that the three compounds could inhibit the formation of glycation products, maintain protein structural stability, mitigate the development of amyloid fibrils and scavenge radicals. Notably, Sal-A possessed the highest anti-glycated activity compared with Sal-B and Sal-C. This may be related to the fact that Sal-A contained the most molecules of caffeic acid (Sal-A, Sal-B, and Sal-C possessing two, one, and zero caffeic acid units, respectively), and caffeic acid played a leading role in the antiglycation properties relative to Danshensu. Moreover, these compounds quenched the intrinsic fluorescence intensity of BSA in a static mode, with the binding constants in the order of Sal-A > Sal-B > Sal-C. Obviously, Sal-A possessed the strongest binding affinity among these compounds, which may be one of the reasons why it exhibited the optimal antiglycation capability. Furthermore, molecular docking demonstrated that the three Sals exerted protective effects on BSA by preventing glycation modification of lysine and arginine residues. These findings would provide valuable insights into the potential application of Sals for alleviating non-enzymatic glycation of protein.
Assuntos
Benzofuranos , Ácidos Cafeicos , Lactatos , Polifenóis , Soroalbumina Bovina , Soroalbumina Bovina/química , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/química , Glicosilação/efeitos dos fármacos , Polifenóis/farmacologia , Polifenóis/química , Benzofuranos/farmacologia , Benzofuranos/química , Lactatos/farmacologia , Lactatos/química , Alcenos/farmacologia , Alcenos/química , Animais , Produtos Finais de Glicação Avançada/química , Produtos Finais de Glicação Avançada/metabolismo , Bovinos , Simulação de Acoplamento Molecular , DepsídeosRESUMO
Triple-negative breast cancer (TNBC) is a deadly breast cancer with a poor prognosis. Pyruvate kinase M2 (PKM2), a key rate-limiting enzyme in glycolysis, is abnormally highly expressed in TNBC. Overexpressed PKM2 amplifies glucose uptake, enhances lactate production, and suppresses autophagy, thereby expediting the progression of oncogenic processes. A high mortality rate demands novel chemotherapeutic regimens at once. Herein, we report the rational development of an imidazopyridine-based thiazole derivative 7d as an anticancer agent inhibiting PKM2. Nanomolar range PKM2 inhibitors with favorable drug-like properties emerged through enzyme assays. Experiments on two-dimensional (2D)/three-dimensional (3D) cell cultures, lactate release assay, surface plasmon resonance (SPR), and quantitative real-time polymerase chain reaction (qRT-PCR) validated 7d preclinically. In vivo, 7d outperformed lapatinib in tumor regression. This investigation introduces a lead-based approach characterized by its clear-cut chemistry and robust efficacy in designing an exceptionally potent inhibitor targeting PKM2, with a focus on combating TNBC.
Assuntos
Antineoplásicos , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Piruvato Quinase , Lapatinib/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Lactatos/farmacologia , Linhagem Celular Tumoral , Glicólise , Proliferação de CélulasRESUMO
Serum renin increases in response to sympathetic nerve activation and hypotension. Recent studies have reported the association of serum renin levels with adverse clinical outcomes in acute care settings. This scoping review aimed to systematically review the available literature on renin as a prognostic marker in intensive care and perioperative patients. We searched for studies published since inception until March 31, 2023, which assessed the association between serum renin levels and clinical outcomes or the effect of synthetic angiotensin II administration on serum renin levels in critically ill and perioperative patients in PubMed, Embase, and the Cochrane Library. The primary outcome was mortality at the longest follow-up; the secondary outcomes were adverse renal outcomes (ie, acute kidney injury, the need for renal replacement therapy, and major adverse kidney events), hemodynamic instability, outcomes to angiotensin II administration, and prognostic performance for mortality when compared with lactate. Among the 2081 studies identified, we included 16 studies with 1573 patients (7 studies on shock, 5 on nonspecific critical illness, 2 on cardiac surgery, 1 on noncardiac surgery, and 1 on coronavirus disease 2019). A significant association between serum renin levels and poor outcomes was identified in 14 studies, with 10 studies demonstrating an association with mortality. One post hoc analysis found that angiotensin II administration reduced mortality in patients with markedly elevated renin values. Two studies showed that renin was superior to lactate as a prognostic marker of mortality. Our scoping review showed that elevated serum renin levels may be associated with clinically relevant outcomes among various perioperative and intensive care populations. Increased serum renin levels may identify patients in which synthetic angiotensin II administration improves clinical outcomes and may outperform serum lactate in predicting mortality.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Renina , Humanos , Renina/farmacologia , Prognóstico , Angiotensina II , Cuidados Críticos , Lactatos/farmacologia , Sistema Renina-AngiotensinaRESUMO
The chemo-regulation abilities of chemotherapeutic medications are appealing to address the low immunogenicity, immunosuppressive lactate microenvironment, and adaptive immune resistance of colorectal cancer. In this work, the proteolysis targeting chimera (PROTAC) of BRD4 (dBET57) is found to downregulate colorectal cancer glycolysis through the transcription inhibition of c-Myc, which also inhibits the expression of programmed death ligand 1 (PD-L1) to reverse immune evasion and avoid adaptive immune resistance. Based on this, self-delivery nano-PROTACs (designated as DdLD NPs) are further fabricated by the self-assembly of doxorubicin (DOX) and dBET57 with the assistance of DSPE-PEG2000. DdLD NPs can improve the stability, intracellular delivery, and tumor targeting accumulation of DOX and dBET57. Meanwhile, the chemotherapeutic effect of DdLD NPs can efficiently destroy colorectal cancer cells to trigger a robust immunogenic cell death (ICD). More importantly, the chemo-regulation effects of DdLD NPs can inhibit colorectal cancer glycolysis to reduce the lactate production, and downregulate the PD-L1 expression through BRD4 degradation. Taking advantages of the chemotherapy and chemo-regulation ability, DdLD NPs systemically activated the antitumor immunity to suppress the primary and metastatic colorectal cancer progression without inducing any systemic side effects. Such self-delivery nano-PROTACs may provide a new insight for chemotherapy-enabled tumor immunotherapy.
Assuntos
Antígeno B7-H1 , Neoplasias Colorretais , Humanos , Quimera de Direcionamento de Proteólise , Proteínas Nucleares , Linhagem Celular Tumoral , Fatores de Transcrição , Doxorrubicina/uso terapêutico , Doxorrubicina/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Imunoterapia , Lactatos/farmacologia , Microambiente Tumoral , Proteínas que Contêm Bromodomínio , Proteínas de Ciclo CelularRESUMO
Metabolic heterogeneity is one of the characteristics of tumour cells. In order to adapt to the tumour microenvironment of hypoxia, acidity and nutritional deficiency, tumour cells have undergone extensive metabolic reprogramming. Metabolites involved in tumour cell metabolism are also very different from normal cells, such as a large number of lactate and adenosine. Metabolites play an important role in regulating the whole tumour microenvironment. Taking metabolites as the target, it aims to change the metabolic pattern of tumour cells again, destroy the energy balance it maintains, activate the immune system, and finally kill tumour cells. In this paper, the regulatory effects of metabolites such as lactate, glutamine, arginine, tryptophan, fatty acids and adenosine were reviewed, and the related targeting strategies of nano-medicines were summarised, and the future therapeutic strategies of nano-drugs were discussed. The abnormality of tumour metabolites caused by tumour metabolic remodelling not only changes the energy and material supply of tumour, but also participates in the regulation of tumour-related signal pathways, which plays an important role in the survival, proliferation, invasion and metastasis of tumour cells. Regulating the availability of local metabolites is a new aspect that affects tumour progress. (The graphical abstract is by Figdraw).
Metabolic heterogeneity is one of the important characteristics of tumour cells, and the metabolites of tumour cells are very different from those of normal cells.Lactate, fatty acids, glutamine, arginine, tryptophan and adenosine are all important metabolites in tumour metabolism.Nano-medicines are used to regulate tumour metabolites, affecting the energy and material supply of tumour cells, thus achieving therapeutic effects.
Assuntos
Neoplasias , Humanos , Neoplasias/metabolismo , Metabolismo Energético , Redes e Vias Metabólicas , Lactatos/farmacologia , Lactatos/uso terapêutico , Adenosina , Microambiente TumoralRESUMO
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. Up to now, no treatment can stop the progression of IPF. Vitamin D3 (VD) reduces experimental lung fibrosis in murine models and depletion of vitamin D3 might be associated with the reduced survival of patients with IPF. In this context, we determined if VD can prevent the pro-fibrotic functions of human lung fibroblasts (HLFs) isolated from patients with IPF. IPF and control HLFs were derived from surgical lung biopsies collected from patients with IPF or with primary lung cancer, respectively. VD (3-100 nM) markedly reduced the basal and PDGF-induced proliferation of HLFs. VD also altered cell cycle by increasing the percentage of IPF HLFs arrested in the G0/G1 phase, and by downregulating the expression of various cell cycle regulatory proteins. In addition, VD barely prevented the TGF-ß1-induced differentiation in HLFs. At 100 nM, VD slightly reduced the expression of the pro-fibrotic marker α-smooth muscle actin, and had no effect on fibronectin and collagen-1 expression. In contrast, 100 nM VD strongly inhibited the aerobic glycolytic metabolism induced by TGF- ß1. Finally, VD reduced both the secretion of lactate, the levels of lactate deshydrogenase mRNA and the activity of intracellular LDH in IPF HLFs. In conclusion, our study shows that VD reduced pro-fibrotic functions of HLFs. These findings suggest that it might be interesting to assess the potential clinical benefits of vitamin D supplementation in patients with IPF, especially on lung function decline.
Assuntos
Fibrose Pulmonar Idiopática , Pulmão , Humanos , Animais , Camundongos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Fibroblastos/metabolismo , Diferenciação Celular , Lactatos/farmacologiaRESUMO
Objective: To investigate the effect of the kinase inhibitor AT9283 on Burkitt lymphoma (BL) cells and elucidate the underlying mechanisms. Methods: The effect of AT9283 on the proliferation of BL cell lines was tested using the MTT assay. Apoptosis and cell cycle were measured by flow cytometry. The proteins associated with the cell cycle, apoptosis, and the Warburg effect were detected using Western blotting. Alterations in glycolytic metabolism in terms of glucose intake and lactate concentrations were determined by glucose and lactate assays. Results: The current study utilized the GEPIA, the Human Protein Atlas (HAP) database and immunohistochemistry to conduct analyses, which revealed a high expression of Aurora kinases and Warburg effect-related proteins in malignant B-cell lymphoma tissues. AT9283 significantly inhibited the cell proliferation of BL cells and induced G2/M arrest. Additionally, AT9283 induced apoptosis in BL cells and reversed the Warburg effect by increasing glucose uptake and reducing lactate production. Moreover, the protein expression of hexokinase 2, pyruvate kinase M2, and lactate dehydrogenase A was significantly suppressed by AT9283, possibly through the inhibition of c-Myc and HIF-1α protein expression. Conclusion: The reversal of the Warburg effect in BL cells and the subsequent inhibition of cell proliferation and induction of apoptosis were observed by targeting Aurora A and Aurora B with AT9283. This finding may present new therapeutic options and targets for BL.
Assuntos
Linfoma de Burkitt , Humanos , Linfoma de Burkitt/tratamento farmacológico , Apoptose , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo Celular , Inibidores de Proteínas Quinases/farmacologia , Lactatos/farmacologia , Glucose/farmacologiaRESUMO
Cancer cells prefer to utilizing aerobic glycolysis to generate energy and anabolic metabolic intermediates for cell growth. However, whether the activities of glycolytic enzymes can be regulated by specific posttranslational modifications, such as SUMOylation, in response to oncogenic signallings, thereby promoting the Warburg effect, remain largely unclear. Here, we demonstrate that phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key glycolytic enzyme, interacts with SUMO-conjugating enzyme UBC9 and is SUMOylated at K302 in glioblastoma cells. Expression of UBC9, which competitively prevents the binding of ubiquitin E3 ligase APC/C to PFKFB3 and subsequent PFKFB3 polyubiquitination, increases PFKFB3 stability and expression. Importantly, EGFR activation increases the interaction between UBC9 and PFKFB3, leading to increased SUMOylation and expression of PFKFB3. This increase is blocked by inhibition of EGFR-induced AKT activation whereas expression of activate AKT by itself was sufficient to recapitulate EGF-induced effect. Knockout of PFKFB3 expression decreases EGF-enhanced lactate production and GBM cell proliferation and this decrease was fully rescued by reconstituted expression of WT PFKFB3 whereas PFKFB3 K302R mutant expression abrogates EGF- and UBC9-regulated lactate production and GBM cell proliferation. These findings reveal a previously unknown mechanism underlying the regulation of the Warburg effect through the EGFR activation-induced and UBC9-mediated SUMOylation and stabilization of PFKFB3.