RESUMO
Arsenic, a naturally occurring toxic element, manifests in various chemical forms and is widespread in the environment. Exposure to arsenic is a well-established risk factor for an elevated incidence of various cancers and chronic diseases. The crux of arsenic-mediated toxicity lies in its ability to induce oxidative stress, characterized by an unsettling imbalance between oxidants and antioxidants, accompanied by the rampant generation of reactive oxygen species and free radicals. In response to this oxidative turmoil, cells deploy their defense mechanisms, prominently featuring the redox-sensitive transcription factor known as nuclear factor erythroid 2-related factor 2 (NRF2). NRF2 stands as a primary guardian against the oxidative harm wrought by arsenic. When oxidative stress activates NRF2, it orchestrates a symphony of downstream antioxidant genes, leading to the activation of pivotal antioxidant enzymes like glutathione-S-transferase, heme oxygenase-1, and NAD(P)H: quinone oxidoreductase 1. This comprehensive review embarks on the intricate and diverse ways by which various arsenicals influence the NRF2 antioxidant pathway and its downstream targets, shedding light on their roles in defending against arsenic exposure toxic effects. It offers valuable insights into targeting NRF2 as a strategy for safeguarding against or treating the harmful and carcinogenic consequences of arsenic exposure.
Assuntos
Arsênio , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Fator 2 Relacionado a NF-E2/metabolismo , Arsênio/toxicidade , Humanos , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Thyroid cancer is increasing globally, with anaplastic thyroid carcinoma (ATC) being the most aggressive type and having a poor prognosis. Current clinical treatments for thyroid cancer present numerous challenges, including invasiveness and the necessity of lifelong medication. Furthermore, a significant portion of patients with ATC experience cancer recurrence and metastasis. To overcome this dilemma, we developed a pH-responsive biomimetic nanocarrier (CLP@HP-A) through the incorporation of Chlorin e6 (Ce6) and Lenvatinib (Len) within hollow polydopamine nanoparticles (HP) that were further modified with platinum nanoparticles (Pt), enabling synergistic chemotherapy and sonodynamic therapy. The CLP@HP-A nanocarriers exhibited specific binding with galectin-3 receptors, facilitating their internalization through receptor-mediated endocytosis for targeted drug delivery. Upon exposure to ultrasound (US) irradiation, Ce6 rapidly generated reactive oxygen species (ROS) to induce significant oxidative stress and trigger apoptosis in tumor cells. Additionally, Pt not only alleviated tumor hypoxia by catalyzing the conversion of H2O2 to oxygen (O2) but also augmented intracellular ROS levels through the production of hydroxyl radicals (â¢OH), thereby enhancing the efficacy of sonodynamic therapy. Moreover, Len demonstrated a potent cytotoxic effect on thyroid cancer cells through the induction of apoptosis. Transcriptomics analysis findings additionally corroborated that CLP@HP-A effectively triggered cancer cell apoptosis, thereby serving as a crucial mechanism for its cytotoxic effects. In conclusion, the integration of sonodynamic/chemo combination therapy with targeted drug delivery systems offers a novel approach to the management of malignant tumors.
Assuntos
Clorofilídeos , Indóis , Platina , Polímeros , Porfirinas , Neoplasias da Glândula Tireoide , Microambiente Tumoral , Terapia por Ultrassom , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/terapia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/metabolismo , Humanos , Linhagem Celular Tumoral , Microambiente Tumoral/efeitos dos fármacos , Indóis/química , Terapia por Ultrassom/métodos , Porfirinas/química , Porfirinas/farmacologia , Polímeros/química , Animais , Platina/química , Platina/uso terapêutico , Platina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Apoptose/efeitos dos fármacos , Nanopartículas/química , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Camundongos , Quinolinas/farmacologia , Quinolinas/química , Camundongos Nus , Portadores de Fármacos/químicaRESUMO
The accumulation of photosensitizers (PSs) in lesion sites but not in other organs is an important challenge for efficient image guiding in photodynamic therapy. Cancer cells are known to express a significant number of albumin-binding proteins that take up albumin as a nutrient source. Here, we converted albumin to a novel BODIPY-like PS by generating a tetrahedral boron environment via a flick reaction. The formed albumin PS has almost the same 3-dimensional structural feature as free albumin because binding occurs at Sudlow Site 1, which is located in the interior space of albumin. An i.v. injection experiment in tumor-bearing mice demonstrated that the human serum albumin PS effectively accumulated in cancer tissue and, more surprisingly, albumin PS accumulated much more in the cancer tissue than in the liver and kidneys. The albumin PS was effective at killing tumor cells through the generation of reactive oxygen species under light irradiation. The crystal structure of the albumin PS was fully elucidated by X-ray crystallography; thus, further tuning of the structure will lead to novel physicochemical properties of the albumin PS, suggesting its potential in biological and clinical applications.
Assuntos
Compostos de Boro , Fotoquimioterapia , Fármacos Fotossensibilizantes , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fotoquimioterapia/métodos , Animais , Compostos de Boro/química , Humanos , Camundongos , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C , Espécies Reativas de Oxigênio/metabolismo , Camundongos Nus , Albuminas/química , Albuminas/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/metabolismoRESUMO
Bacteria-infected wounds pose challenges to healing due to persistent infection and associated damage to nerves and vessels. Although sonodynamic therapy can help kill bacteria, it is limited by the residual oxidative stress, resulting in prolonged inflammation. To tackle these barriers, novel 4 octyl itaconate-coated Li-doped ZnO/PLLA piezoelectric composite microfibers are developed, offering a whole-course "targeted" treatment under ultrasound therapy. The inclusion of Li atoms causes the ZnO lattice distortion and increases the band gap, enhancing the piezoelectric and sonocatalytic properties of the composite microfibers, collaborated by an aligned PLLA conformation design. During the infection and inflammation stages, the piezoelectric microfibers exhibit spatiotemporal-dependent therapeutic effects, swiftly eliminating over 94.2 % of S. aureus within 15 min under sonodynamic therapy. Following this phase, the microfibers capture reactive oxygen species and aid macrophage reprogramming, restoring mitochondrial function, achieving homeostasis, and shortening inflammation cycles. As the wound progresses through the healing stages, bioactive Zn2+ and Li + ions are continuously released, improving cell recruitment, and the piezoelectrical stimulation enhances wound recovery with neuro-vascularization. Compared to commercially available dressings, our microfibers accelerate the closure of rat wounds (Φ = 15 mm) without scarring in 12 days. Overall, this "one stone, four birds" wound management strategy presents a promising avenue for infected wound therapy.
Assuntos
Terapia por Ultrassom , Cicatrização , Animais , Cicatrização/efeitos dos fármacos , Terapia por Ultrassom/métodos , Ratos Sprague-Dawley , Ratos , Staphylococcus aureus/efeitos dos fármacos , Óxido de Zinco/química , Camundongos , Estimulação Elétrica , Masculino , Infecções Estafilocócicas/terapia , Poliésteres/química , Espécies Reativas de Oxigênio/metabolismo , Terapia por Estimulação Elétrica/métodos , Neovascularização Fisiológica/efeitos dos fármacosRESUMO
Biofilm-associated infections (BAIs) continue to pose a major challenge in the medical field. Nanomedicine, in particular, promises significant advances in combating BAIs through the introduction of a variety of nanomaterials and nano-antimicrobial strategies. However, studies to date have primarily focused on the removal of the bacterial biofilm and neglect the subsequent post-biofilm therapeutic measures for BAIs, rendering pure anti-biofilm strategies insufficient for the holistic recovery of affected patients. Herein, we construct an emerging dual-functional composite nanosheet (SiHx@Ga) that responds to pHs fluctuation in the biofilm microenvironment to enable a sequential therapy of BAIs. In the acidic environment of biofilm, SiHx@Ga employs the self-sensitized photothermal Trojan horse strategy to effectively impair the reactive oxygen species (ROS) defense system while triggering oxidative stress and lipid peroxidation of bacteria, engendering potent antibacterial and anti-biofilm effects. Surprisingly, in the post-treatment phase, SiHx@Ga adsorbs free pathogenic nucleic acids released after biofilm destruction, generates hydrogen with ROS-scavenging and promotes macrophage polarization to the M2 type, effectively mitigating damaging inflammatory burst and promoting tissue healing. This well-orchestrated strategy provides a sequential therapy of BAIs by utilizing microenvironmental variations, offering a conceptual paradigm shift in the field of nanomedicine anti-infectives.
Assuntos
Antibacterianos , Biofilmes , Gálio , Espécies Reativas de Oxigênio , Biofilmes/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Gálio/química , Gálio/farmacologia , Camundongos , Portadores de Fármacos/química , Células RAW 264.7 , Humanos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologiaRESUMO
Radiotherapy as a mainstay of in-depth cervical cancer (CC) treatment suffers from its radioresistance. Radiodynamic therapy (RDT) effectively reverses radio-resistance by generating reactive oxygen species (ROS) with deep tissue penetration. However, the photosensitizers stimulated by X-ray have high toxicity and energy attenuation. Therefore, X-ray responsive diselenide-bridged mesoporous silica nanoparticles (DMSNs) are designed, loading X-ray-activated photosensitizer acridine orange (AO) for spot blasting RDT like Trojan-horse against radio-resistance cervical cancer (R-CC). DMSNs can encapsulate a large amount of AO, in the tumor microenvironment (TME), which has a high concentration of hydrogen peroxide, X-ray radiation triggers the cleavage of diselenide bonds, leading to the degradation of DMSNs and the consequent release of AO directly at the tumor site. On the one hand, it solves the problems of rapid drug clearance, adverse distribution, and side effects caused by simple AO treatment. On the other hand, it fully utilizes the advantages of highly penetrating X-ray responsive RDT to enhance radiotherapy sensitivity. This approach results in ROS-induced mitochondria damage, inhibition of DNA damage repair, cell cycle arrest and promotion of cancer cell apoptosis in R-CC. The X-ray responsive DMSNs@AO hold considerable potential in overcoming obstacles for advanced RDT in the treatment of R-CC.
Assuntos
Nanopartículas , Dióxido de Silício , Humanos , Animais , Raios X , Nanopartículas/química , Feminino , Dióxido de Silício/química , Camundongos , Neoplasias do Colo do Útero/terapia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Espécies Reativas de Oxigênio/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Tolerância a Radiação/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Camundongos Nus , Células HeLa , Camundongos Endogâmicos BALB C , Apoptose/efeitos dos fármacos , Linhagem Celular TumoralRESUMO
Accurate and early detection of atherosclerosis (AS) is imperative for their effective treatment. However, fluorescence probes for efficient diagnosis of AS often encounter insufficient deep tissue penetration, which hinders the reliable assessment of plaque vulnerability. In this work, a reactive oxygen species (ROS) activated near-infrared (NIR) fluorescence and photoacoustic (FL/PA) dual model probe TPA-QO-B is developed by conjugating two chromophores (TPA-QI and O-OH) and ROS-specific group phenylboronic acid ester. The incorporation of ROS-specific group not only induces blue shift in absorbance, but also inhibits the ICT process of TPA-QO-OH, resulting an ignorable initial FL/PA signal. ROS triggers the convertion of TPA-QO-B to TPA-QO-OH, resulting in the concurrent amplification of FL/PA signal. The exceptional selectivity of TPA-QO-B towards ROS makes it effectively distinguish AS mice from the healthy. The NIR emission can achieve a tissue penetration imaging depth of 0.3 cm. Moreover, its PA775 signal possesses the capability to penetrate tissues up to a thickness of 0.8 cm, ensuring deep in vivo imaging of AS model mice in early stage. The ROS-triggered FL/PA dual signal amplification strategy improves the accuracy and addresses the deep tissue penetration problem simultaneously, providing a promising tool for in vivo tracking biomarkers in life science and preclinical applications.
Assuntos
Corantes Fluorescentes , Técnicas Fotoacústicas , Placa Aterosclerótica , Espécies Reativas de Oxigênio , Animais , Espécies Reativas de Oxigênio/metabolismo , Técnicas Fotoacústicas/métodos , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/metabolismo , Corantes Fluorescentes/química , Camundongos , Imagem Óptica/métodos , Camundongos Endogâmicos C57BL , Humanos , MasculinoRESUMO
The development of artificial Antigen Presenting Cells (aAPCs) has led to improvements in adoptive T cell therapy (ACT), an immunotherapy, for cancer treatment. aAPCs help to streamline the consistent production and expansion of T cells, thus reducing the time and costs associated with ACT. However, several issues still exist with ACT, such as insufficient T cell potency, which diminishes the translational potential for ACT. While aAPCs have been used primarily to increase production efficiency of T cells for ACT, the intrinsic properties of a biomaterial-based aAPC may affect T cell phenotype and function. In CD8+ T cells, reactive oxygen species (ROS) and oxidative stress accumulation can activate Forkhead box protein O1 (FOXO1) to transcribe antioxidants which reduce ROS and improve memory formation. Alginate, a biocompatible and antioxidant rich biomaterial, is promising for incorporation into an aAPC formulation to modulate T cell phenotype. To investigate its utility, a novel alginate-based aAPC platform was developed that preferentially expanded CD8+ T cells with memory related features. Alginate-based aAPCs allowed for greater control of CD8+ T cell qualities, including, significantly improved in vivo persistence and augmented in vivo anti-tumor T cell responses.
Assuntos
Alginatos , Células Apresentadoras de Antígenos , Linfócitos T CD8-Positivos , Memória Imunológica , Imunoterapia Adotiva , Alginatos/química , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Animais , Imunoterapia Adotiva/métodos , Células Apresentadoras de Antígenos/imunologia , Memória Imunológica/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Humanos , Proliferação de Células/efeitos dos fármacosRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Sea buckthorn (Hippophae rhamnoides), a traditional Tibetan medicinal herb, exhibits protective effects against cardiovascular and respiratory diseases. Although Sea buckthorn extract (SBE) has been confirmed to alleviate airway inflammation in mice, its therapeutic effect and underlying mechanism on chronic obstructive pulmonary disease (COPD) requires further clarification. AIM OF THE STUDY: To elucidate the alleviative effect and molecular mechanism of SBE on lipopolysaccharides (LPS)/porcine pancreatic elastase (PPE)-induced COPD by blocking ferroptosis. METHODS: The anti-ferroptotic effects of SBE were evaluated in human BEAS-2B bronchial epithelial cells using CCK8, RT-qPCR, western blotting, and transmission electron microscopy. Transwell was employed to detect chemotaxis of neutrophils. COPD model was induced by intranasally administration of LPS/PPE in mice and measured by alterations of histopathology, inflammation, and ferroptosis. RNA-sequencing, western blotting, antioxidant examination, flow cytometry, DARTS, CETSA, and molecular docking were then used to investigate its anti-ferroptotic mechanisms. RESULTS: In vitro, SBE not only suppressed erastin- or RSL3-induced ferroptosis by suppressing lipid peroxides (LPOs) production and glutathione (GSH) depletion, but also suppressed ferroptosis-induced chemotactic migration of neutrophils via reducing mRNA expression of chemokines. In vivo, SBE ameliorated LPS/PPE-induced COPD phenotypes, and inhibited the generation of LPOs, cytokines, and chemokines. RNA-sequencing showed that p53 pathway and mitogen-activated protein kinases (MAPK) pathway were implicated in SBE-mediated anti-ferroptotic action. SBE repressed erastin- or LPS/PPE-induced overactivation of p53 and MAPK pathway, thereby decreasing expression of diamine acetyltransferase 1 (SAT1) and arachidonate 15-lipoxygenase (ALOX15), and increasing expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). Mechanistically, erastin-induced elevation of reactive oxygen species (ROS) was reduced by SBE through directly scavenging free radicals, thereby contributing to its inhibition of p53 and MAPK pathways. CETSA, DARTS, and molecular docking further showed that ROS-generating enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) may be the target of SBE. Overexpression of NOX4 partially impaired the anti-ferroptotic activity of SBE. CONCLUSION: Our results demonstrated that SBE mitigated COPD by suppressing p53 and MAPK pro-ferroptosis pathways via directly scavenging ROS and blocking NOX4. These findings also supported the clinical application of Sea buckthorn in COPD therapy.
Assuntos
Ferroptose , Hippophae , Extratos Vegetais , Doença Pulmonar Obstrutiva Crônica , Espécies Reativas de Oxigênio , Proteína Supressora de Tumor p53 , Ferroptose/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Humanos , Espécies Reativas de Oxigênio/metabolismo , Hippophae/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Camundongos , Masculino , Camundongos Endogâmicos C57BL , Linhagem Celular , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Modelos Animais de Doenças , Simulação de Acoplamento MolecularRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Mountain-cultivated Panax ginseng C.A.Mey. (MCG) with high market price and various properties was valuable special local product in Northeast of Asia. MCG has been historically used to mitigate heart failure (HF) for thousand years, HF is a clinical manifestation of deficiency of "heart-qi" in traditional Chinese medicine. However, there was little report focus on the activities of extracted residue of MCG. AIM OF THE STUDY: A novel glycopeptide (APMCG-1) was isolated from step ethanol precipitations of alkaline protease-assisted extract from MCG residue. MATERIALS AND METHODS: The molecular weight and subunit structure of APMCG-1 were determined by FT-IR, HPLC and GPC technologies, as well as the H9c2 cells, Tg (kdrl:EGFP) zebrafish were performed to evaluated the protective effect of APMCG-1. RESULTS: APMCG-1 was identified as a glycopeptide containing seven monosaccharides and seven amino acids via O-lined bonds. Further, in vitro, APMCG-1 significantly decreased reactive oxygen species production and lactate dehydrogenase contents in palmitic acid (PA)-induced H9c2 cells. APMCG-1 also attenuated endoplasmic reticulum stress and mitochondria-mediated apoptosis in H9c2 cells via the PI3K/AKT signaling pathway. More importantly, APMCG-1 reduced the blood glucose, lipid contents, the levels of heart injury, oxidative stress and inflammation of 5 days post fertilization Tg (kdrl:EGFP) zebrafish with type 2 diabetic symptoms in vivo. CONCLUSIONS: APMCG-1 protects PA-induced H9c2 cells while reducing cardiac dysfunction in zebrafish with type 2 diabetic symptoms. The present study provides a new insight into the development of natural glycopeptides as heart-related drug therapies.
Assuntos
Diabetes Mellitus Tipo 2 , Glicopeptídeos , Insuficiência Cardíaca , Panax , Peixe-Zebra , Animais , Panax/química , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ratos , Linhagem Celular , Glicopeptídeos/farmacologia , Glicopeptídeos/química , Apoptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Cardiotônicos/farmacologia , Cardiotônicos/química , Cardiotônicos/isolamento & purificação , Cardiotônicos/uso terapêutico , Miócitos Cardíacos/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacosRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Melastoma dodecandrum Lour. (MD), a traditional Chinese medicine used by the She ethnic group, has been used to treat cerebral ischemia-reperfusion (CIR) injury due to its efficacy in promoting blood circulation and removing blood stasiss; however, the therapeutic effects and mechanisms of MD in treating CIR injury remain unclear. AIM: To investigate the protective effects of MD on CIR injury, in addition to its impact on oxidative stress, endoplasmic reticulum (ER) stress, and cell apoptosis. MATERIALS AND METHODS: The research was conducted using both cell experiments and animal experiments. The CCK-8 method, immunofluorescence staining, and flow cytometry were used to analyze the effects of MD-containing serum on oxygen-glucose deprivation/reperfusion (OGD/R)-induced PC12 cell viability, reactive oxygen species (ROS) clearance, anti-inflammatory, neuroprotection and inhibition of apoptosis. Furthermore, 2,3,5-Triphenyl tetrazolium chloride staining, hematoxylin and eosin staining, Nissl staining, and immunohistochemistry were used to detect infarct size, pathological changes, Nissl corpuscula and neuronal protein expression in middle cerebral artery occlusion (MCAO) rats. Polymerase chain reaction and Western Blotting were conducted in cell and animal experiments to detect the expression levels of ER stress-related genes and proteins. RESULTS: The MD extract enhanced the viability of PC12 cells under OGD/R modeling, reduced ROS and IL-6 levels, increased MBP levels, and inhibited cell apoptosis. Furthermore, MD improved the infarct area in MCAO rats, increased the number of Nissl bodies, and regulated neuronal protein levels including Microtubule-Associated Protein 2 (MAP-2), Myelin Basic Protein (MBP), Glial Fibrillary Acidic Protein (GFAP), and Neurofilament 200 (NF200). Additionally, MD could regulate the expression levels of oxidative stress proteins malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and catalase (CAT). Both cell and animal experiments demonstrated that MD could inhibit ER stress-related proteins (GRP78, ATF4, ATF6, CHOP) and reduce cell apoptosis. CONCLUSION: This study confirmed that the therapeutic mechanism of the MD extract on CIR injury was via the inhibition of oxidative stress and the ER stress pathway, in addition to the inhibition of apoptosis.
Assuntos
Apoptose , Estresse do Retículo Endoplasmático , Fármacos Neuroprotetores , Estresse Oxidativo , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Animais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Ratos , Células PC12 , Masculino , Fármacos Neuroprotetores/farmacologia , Apoptose/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêuticoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Tubeimoside-I (TBM) promotes various cancer cell death by increasing the reactive oxygen species (ROS) production. However, the specific molecular mechanisms of TBM and its impact on oxaliplatin-mediated anti-CRC activity are not yet fully understood. AIM OF THE STUDY: To elucidate the therapeutic effect and underlying molecular mechanism of TBM on oxaliplatin-mediated anti-CRC activity. MATERIALS AND METHODS: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing assays and flow cytometry were conducted to investigate the changes in cell phenotypes and ROS generation. Real-time quantitative PCR (qRT-PCR) and western blotting were performed to detect the expressions of related mRNA and proteins. Finally, mouse xenograft models demonstrated that synergistic anti-tumor effects of combined treatment with TBM and oxaliplatin. RESULTS: The synergistic enhancement of the anti-tumor effects of oxaliplatin in colon cancer cells by TBM involved in the regulation of ROS-mediated endoplasmic reticulum (ER) stress, C-jun-amino-terminal kinase (JNK), and p38 MAPK signaling pathways. Mechanistically, TBM increased ROS generation in colon cancer cells by inhibiting heat shock protein 60 (HSPD1) expression. Knocking down HSPD1 increased TBM-induced antitumor activity and ROS generation in colon cancer cells. The mouse xenograft tumor models further validated that the combination therapy exhibited stronger anti-tumor effects than monotherapy alone. CONCLUSIONS: Combined therapy with TBM and oxaliplatin might be an effective therapeutic strategy for some CRC patients.
Assuntos
Neoplasias Colorretais , Sinergismo Farmacológico , Estresse do Retículo Endoplasmático , Oxaliplatina , Espécies Reativas de Oxigênio , Saponinas , Triterpenos , Animais , Humanos , Masculino , Camundongos , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células HCT116 , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oxaliplatina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Saponinas/farmacologia , Triterpenos/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Fully restoring the lost population of cardiomyocytes and heart function remains the greatest challenge in cardiac repair post myocardial infarction. In this study, a pioneered highly ROS-eliminating hydrogel was designed to enhance miR-19a/b induced cardiomyocyte proliferation by lowering the oxidative stress and continuously releasing miR-19a/b in infarcted myocardium in situ. In vivo lineage tracing revealed that â¼20.47 % of adult cardiomyocytes at the injected sites underwent cell division in MI mice. In MI pig the infarcted size was significantly reduced from 40 % to 18 %, and thereby marked improvement of cardiac function and increased muscle mass. Most importantly, our treatment solved the challenge of animal death--all the treated pigs managed to live until their hearts were harvested at day 50. Therefore, our strategy provides clinical conversion advantages and safety for healing damaged hearts and restoring heart function post MI, which will be a powerful tool to battle cardiovascular diseases in patients.
Assuntos
Proliferação de Células , MicroRNAs , Infarto do Miocárdio , Miócitos Cardíacos , Estresse Oxidativo , Animais , MicroRNAs/metabolismo , MicroRNAs/genética , Miócitos Cardíacos/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Camundongos , Suínos , Hidrogéis/química , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismoRESUMO
The notorious tumor microenvironment (TME) usually becomes more deteriorative during phototherapeutic progress that hampers the antitumor efficacy. To overcome this issue, we herein report the ameliorative and adaptive nanoparticles (TPASIC-PFH@PLGA NPs) that simultaneously reverse hypoxia TME and switch photoactivities from photothermal-dominated state to photodynamic-dominated state to maximize phototherapeutic effect. TPASIC-PFH@PLGA NPs are designed by incorporating oxygen-rich liquid perfluorohexane (PFH) into the intraparticle microenvironment to regulate the intramolecular motions of AIE photosensitizer TPASIC. TPASIC exhibits a unique aggregation-enhanced reactive oxygen species (ROS) generation feature. PFH incorporation affords TPASIC the initially dispersed state, thus promoting active intramolecular motions and photothermal conversion efficiency. While PFH volatilization leads to nanoparticle collapse and the formation of tight TPASIC aggregates with largely enhanced ROS generation efficiency. As a consequence, PFH incorporation not only currently promotes both photothermal and photodynamic efficacies of TPASIC and increases the intratumoral oxygen level, but also enables the smart photothermal-to-photodynamic switch to maximize the phototherapeutic performance. The integration of PFH and AIE photosensitizer eventually delivers more excellent antitumor effect over conventional phototherapeutic agents with fixed photothermal and photodynamic efficacies. This study proposes a new nanoengineering strategy to ameliorate TME and adapt the treatment modality to fit the changed TME for advanced antitumor applications.
Assuntos
Fluorocarbonos , Nanopartículas , Fotoquimioterapia , Fármacos Fotossensibilizantes , Espécies Reativas de Oxigênio , Microambiente Tumoral , Nanopartículas/química , Microambiente Tumoral/efeitos dos fármacos , Animais , Fotoquimioterapia/métodos , Espécies Reativas de Oxigênio/metabolismo , Fluorocarbonos/química , Fluorocarbonos/farmacologia , Linhagem Celular Tumoral , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Humanos , Camundongos , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Camundongos Endogâmicos BALB C , Terapia Fototérmica/métodos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Fototerapia/métodos , FemininoRESUMO
Microbial oxidation and the mechanism of Sb(III) are key governing elements in biogeochemical cycling. A novel Sb oxidizing bacterium, Klebsiella aerogenes HC10, was attracted early and revealed that extracellular metabolites were the main fractions driving Sb oxidation. However, linkages between the extracellular metabolite driven Sb oxidation process and mechanism remain elusive. Here, model phenolic and quinone compounds, i.e., anthraquinone-2,6-disulfonate (AQDS) and hydroquinone (HYD), representing extracellular oxidants secreted by K. aerogenes HC10, were chosen to further study the Sb(III) oxidation mechanism. N2 purging and free radical quenching showed that oxygen-induced oxidation accounted for 36.78% of Sb(III) in the metabolite reaction system, while hydroxyl free radicals (·OH) accounted for 15.52%. ·OH and H2O2 are the main driving factors for Sb oxidation. Radical quenching, methanol purification and electron paramagnetic resonance (EPR) analysis revealed that ·OH, superoxide radical (O2â¢-) and semiquinone (SQ-â¢) were reactive intermediates of the phenolic induced oxidation process. Phenolic-induced ROS are one of the main oxidants in metabolites. Cyclic voltammetry (CV) showed that electron transfer of quinone also mediated Sb(III) oxidation. Part of Sb(V) was scavenged by the formation of the secondary Sb(V)-bearing mineral mopungite [NaSb(OH)6] in the incubation system. Our study demonstrates the microbial role of oxidation detoxification and mineralization of Sb and provides scientific references for the biochemical remediation of Sb-contaminated soil.
Assuntos
Antimônio , Oxirredução , Espécies Reativas de Oxigênio , Transporte de Elétrons , Antimônio/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
4-Nitrophenol (4-NP), as a toxic and refractory pollutant, has generated significant concern due to its adverse effects. However, the potential toxic effects and mechanism remained unclear. In this study, the reproduction, development, locomotion and reactive oxygen species (ROS) production of Caenorhabditis elegans were investigated to evaluate the 4-NP toxicity. We used metabolomics to assess the potential damage mechanisms. The role of metabolites in mediating the relationship between 4-NP and phenotypes was examined by correlation and mediation analysis. 4-NP (8 ng/L and 8 µg/L) caused significant reduction of brood size, ovulation rate, total germ cells numbers, head thrashes and body bends, and an increase in ROS. However, the oosperm numbers in uterus, body length and body width were decreased in 8 µg/L. Moreover, 36 differential metabolites were enriched in the significant metabolic pathways, including lysine biosynthesis, ß-alanine metabolism, tryptophan metabolism, pentose phosphate pathway, pentose and glucuronate interconversions, amino sugar and nucleotide sugar metabolism, starch and sucrose metabolism, galactose metabolism, propanoate metabolism, glycerolipid metabolism, and estrogen signaling pathway. The mechanism of 4-NP toxicity was that oxidative stress caused by the perturbation of amino acid, which had effects on energy metabolism through disturbing carbohydrate and lipid metabolism, and finally affected the estrogen signaling pathway to exert toxic effects. Moreover, correlation and mediation analysis showed glycerol-3P, glucosamine-6P, glucosamine-1P, UDP-galactose, L-aspartic acid, and uracil were potential markers for the reproduction and glucose-1,6P2 for developmental toxicity. The results provided insight into the pathways involved in the toxic effects caused by 4-NP and developed potential biomarkers to evaluate 4-NP toxicity.
Assuntos
Caenorhabditis elegans , Estrogênios , Nitrofenóis , Reprodução , Transdução de Sinais , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/fisiologia , Reprodução/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Nitrofenóis/toxicidade , Estrogênios/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Estresse Oxidativo/efeitos dos fármacosRESUMO
Innately designed to induce physiological changes, pharmaceuticals are foreknowingly hazardous to the ecosystem. Advanced oxidation processes (AOPs) are recognized as a set of contemporary and highly efficient methods being used as a contrivance for the removal of pharmaceutical residues. Since reactive oxygen species (ROS) are formed in these processes to interact and contribute directly toward the oxidation of target contaminant(s), a profound insight regarding the mechanisms of ROS leading to the degradation of pharmaceuticals is fundamentally significant. The conceptualization of some specific reaction mechanisms allows the design of an effective and safe degradation process that can empirically reduce the environmental impact of the micropollutants. This review mainly deliberates the mechanistic reaction pathways for ROS-mediated degradation of pharmaceuticals often leading to complete mineralization, with a focus on acetaminophen as a drug waste model.
Assuntos
Acetaminofen , Espécies Reativas de Oxigênio , Acetaminofen/química , Espécies Reativas de Oxigênio/metabolismo , Poluentes Químicos da Água/química , Oxirredução , Preparações Farmacêuticas/metabolismoRESUMO
Bisphenol A (BPA) is an industrial pollutant that can cause immune impairment. Selenium acts as an antioxidant, as selenium deficiency often accompanies oxidative stress, resulting in organ damage. This study is the first to demonstrate that BPA and/or selenium deficiency induce pyroptosis and ferroptosis-mediated thymic injury in chicken and chicken lymphoma cell (MDCC-MSB-1) via oxidative stress-induced endoplasmic reticulum (ER) stress. We established a broiler chicken model of BPA and/or selenium deficiency exposure and collected thymus samples as research subjects after 42 days. The results demonstrated that BPA or selenium deficiency led to a decrease in antioxidant enzyme activities (T-AOC, CAT, and GSH-Px), accumulation of peroxides (H2O2 and MDA), significant upregulation of ER stress-related markers (GRP78, IER 1, PERK, EIF-2α, ATF4, and CHOP), a significant increase in iron ion levels, significant upregulation of pyroptosis-related gene (NLRP3, ASC, Caspase1, GSDMD, IL-18 and IL-1ß), significantly increase ferroptosis-related genes (TFRC, COX2) and downregulate GPX4, HO-1, FTH, NADPH. In vitro experiments conducted in MDCC-MSB-1 cells confirmed the results, demonstrating that the addition of antioxidant (NAC), ER stress inhibitor (TUDCA) and pyroptosis inhibitor (Vx765) alleviated oxidative stress, endoplasmic reticulum stress, pyroptosis, and ferroptosis. Overall, this study concludes that the combined effects of oxidative stress and ER stress mediate pyroptosis and ferroptosis in chicken thymus induced by BPA exposure and selenium deficiency.
Assuntos
Compostos Benzidrílicos , Galinhas , Estresse do Retículo Endoplasmático , Ferroptose , Fenóis , Piroptose , Espécies Reativas de Oxigênio , Selênio , Animais , Compostos Benzidrílicos/toxicidade , Ferroptose/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Selênio/deficiência , Fenóis/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Timo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
Photodynamic therapy (PDT) is an appealing modality for cancer treatments. However, the limited tissue penetration depth of external-excitation light makes PDT impossible in treating deep-seated tumors. Meanwhile, tumor hypoxia and intracellular reductive microenvironment restrain the generation of reactive oxygen species (ROS). To overcome these limitations, a tumor-targeted self-illuminating supramolecular nanoparticle T-NPCe6-L-N is proposed by integrating photosensitizer Ce6 with luminol and nitric oxide (NO) for chemiluminescence resonance energy transfer (CRET)-activated PDT. The high H2O2 level in tumor can trigger chemiluminescence of luminol to realize CRET-activated PDT without exposure of external light. Meanwhile, the released NO significantly relieves tumor hypoxia via vascular normalization and reduces intracellular reductive GSH level, further enhancing ROS abundance. Importantly, due to the different ROS levels between cancer cells and normal cells, T-NPCe6-L-N can selectively trigger PDT in cancer cells while sparing normal cells, which ensured low side effect. The combination of CRET-based photosensitizer-activation and tumor microenvironment modulation overcomes the innate challenges of conventional PDT, demonstrating efficient inhibition of orthotopic and metastatic tumors on mice. It also provoked potent immunogenic cell death to ensure long-term suppression effects. The proof-of-concept research proved as a new strategy to solve the dilemma of PDT in treatment of deep-seated tumors.
Assuntos
Nanopartículas , Fotoquimioterapia , Fármacos Fotossensibilizantes , Microambiente Tumoral , Fotoquimioterapia/métodos , Microambiente Tumoral/efeitos dos fármacos , Animais , Nanopartículas/química , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Humanos , Camundongos , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Transferência de Energia , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Camundongos Endogâmicos BALB C , Luz , Camundongos Nus , Óxido Nítrico/metabolismoRESUMO
The prevalence of Alzheimer's disease (AD) is increasing globally due to population aging. However, effective clinical treatment strategies for AD still remain elusive. The mechanisms underlying AD onset and the interplay between its pathological factors have so far been unclear. Evidence indicates that AD progression is ultimately driven by neuronal loss, which in turn is caused by neuroapoptosis and neuroinflammation. Therefore, the inhibition of neuroapoptosis and neuroinflammation could be a useful anti-AD strategy. Nonetheless, the delivery of active drug agents into the brain parenchyma is hindered by the blood-brain barrier (BBB). To address this challenge, we fabricated a black phosphorus nanosheet (BP)-based methylene blue (MB) delivery system (BP-MB) for AD therapy. After confirming the successful preparation of BP-MB, we proved that its BBB-crossing ability was enhanced under near-infrared light irradiation. In vitro pharmacodynamics analysis revealed that BP and MB could synergistically scavenge excessive reactive oxygen species (ROS) in okadaic acid (OA)-treated PC12 cells and lipopolysaccharide (LPS)-treated BV2 cells, thus efficiently reversing neuroapoptosis and neuroinflammation. To study in vivo pharmacodynamics, we established a mouse model of AD mice, and behavioral tests confirmed that BP-MB treatment could successfully improve cognitive function in these animals. Notably, the results of pathological evaluation were consistent with those of the in vitro assays. The findings demonstrated that BP-MB could scavenge excessive ROS and inhibit Tau hyperphosphorylation, thereby alleviating downstream neuroapoptosis and regulating the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Overall, this study highlights the therapeutic potential of a smart nanomedicine with the capability of reversing neuroapoptosis and neuroinflammation for AD treatment.