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1.
Sci Total Environ ; 782: 146785, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-33838376

RESUMO

In this research, the organelle damage, apoptosis and necrosis induced by PM2.5, BC and Kaolin were studied using human bronchial epithelial (16HBE) cells. PM2.5, BC and Kaolin all induce cell death, LDH release and excess intracellular ROS generation. For the organelle injuries, Kaolin and high-dose PM2.5 (240 µg/mL) cause lysosomal acidification, but BC causes lysosomal alkalization (lysosomal membrane permeabilization, LMP). BC and Kaolin cause the loss of mitochondrial membrane potential (MMP), while PM2.5 does not. For the cell death mode, PM2.5 causes both apoptosis and necrosis. However only necrosis has been detected in the BC and Kaolin treated groups, indicating the more severe cellular insult. Excess ROS generation is involved in the organelle damage and cell death. ROS contributes to the BC-induced LMP and necrosis, but does not significantly affect the Kaolin-induced MMP loss and necrosis. Therefore, the BC component in PM2.5 may cause cytotoxicity via ROS-dependent pathways, the Kaolin component may damage cells via ROS-independent mechanisms such as strong interaction. The PM2.5-induced apoptosis and necrosis can be partially mitigated after the removal of ROS, indicating the existence of both the ROS-dependent and ROS-independent mechanisms due to the complicated PM2.5 components. BC represents the anthropogenic source component in PM2.5, while Kaolin represents the natural source component. Our results provide knowledge on the toxic mechanisms of typical PM2.5 components at the cellular and subcellular levels.


Assuntos
Apoptose , Material Particulado , Linhagem Celular , Humanos , Necrose/induzido quimicamente , Material Particulado/toxicidade , Espécies Reativas de Oxigênio
2.
Pestic Biochem Physiol ; 173: 104801, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33771250

RESUMO

Rotenone, a selective inhibitor of mitochondrial complex I, has been extensively studied on kinds of neuron and neuroblast in Parkinson's disease. However, little is known about the potential mechanism of this promising botanical insecticide upon insect cells. In the article, cell proliferation of two Lepidoptera cell lines, Spodoptera litura SL-1 cells and Spodoptera frugiperda Sf9 cells, were all inhibited by rotenone in a time- and dose-dependent manner. Typical necrotic characteristics of cell morphology and ultrastructure, such as plasma membrane collapses and organelle lyses, were all observed by transmission electron microscope and scanning electron microscope. Moreover, irregular DNA degradation was also detected by DNA gel electrophoresis and Hoechst 33258 staining, while the typical apoptotic feature, DNA ladder, hadn't been observed. Flow cytometric analysis showed that rotenone-induced cell death of Sf9 and SL-1 cells accompanied with the plasma membrane potential depolarization and mitochondrial membrane potential reduction. Furthermore, the activity of Na+-K+-ATPase was detected in our study. In conclusion, rotenone could cause necrosis but not apoptosis in insect cells through a mitochondrial- and plasmic membrane-dependent pattern, which shed a light on the rotenone-induced cytotoxicity on insects.


Assuntos
Apoptose , Rotenona , Animais , Membrana Celular , Potencial da Membrana Mitocondrial , Mitocôndrias/metabolismo , Necrose/induzido quimicamente , Rotenona/toxicidade
3.
Spec Care Dentist ; 41(3): 431-436, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33606289

RESUMO

AIMS: Methamphetamine (meth) is a powerful, highly addictive stimulant that affects the central nervous system, and its side effects may result in severe self-mutilation. This report describes a case of a meth user with severe oral injury that demonstrates the necessity for prompt treatment when severe tongue biting occurs. METHODS AND RESULTS: A 43-year-old meth-using man with severe tongue biting was left untreated for more than 24 hours, resulting in extensive ischemic changes in the tongue and eventual extensive tissue necrosis. After debridement and deep suture repair in several layers, the wound healed. However, tongue dysfunction and a speech disorder remained because of tongue shortening. CONCLUSION: Meth may induce or aggravate severe oral self-mutilation. Tongue biting with severe tissue damage may occur as oral self-mutilation in meth users; however, among self-mutilation behaviors, tongue biting is especially difficult to prevent. A withdrawal from meth and a behavioral approach may be necessary for fundamental prevention, but it is often difficult in high dependence users. When severe tongue biting occurs, prompt suture reconstruction must be performed before ischemic change occurs to prevent tissue necrosis.


Assuntos
Estimulantes do Sistema Nervoso Central , Metanfetamina , Doenças da Língua , Adulto , Estimulantes do Sistema Nervoso Central/efeitos adversos , Humanos , Masculino , Metanfetamina/efeitos adversos , Necrose/induzido quimicamente , Língua , Doenças da Língua/induzido quimicamente
4.
Dermatol Surg ; 47(2): 227-234, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33565776

RESUMO

BACKGROUND: As the use of injectable skin fillers increase in popularity, an increase in the reported adverse events is expected. OBJECTIVE: This systematic review supports the development of American Society for Dermatologic Surgery practice guideline on the management of adverse events of skin fillers. METHODS AND MATERIALS: Several databases for studies on risk factors or treatments of injection-related visual compromise (IRVC), skin necrosis, inflammatory events, and nodules were searched. Meta-analysis was conducted when feasible. RESULTS: The review included 182 studies. However, IRVC was very rare (1-2/1,000,000 patients) but had poor prognosis with improvement in 19% of cases. Skin necrosis was more common (approximately 5/1,000) with better prognosis (up to 77% of cases showing improvement). Treatments of IRVC and skin necrosis primarily depend on hyaluronidase injections. Risk of skin necrosis, inflammatory events, and nodules may be lower with certain fillers, brands, injection techniques, and volume. Treatment of inflammatory events and nodules with antibiotics, corticosteroids, 5-FU, and hyaluronidase was associated with high response rate (75%-80%). Most of the studies were small and noncomparative, making the evidence certainty very low. CONCLUSION: Practitioners must have adequate knowledge of anatomy, elicit history of skin filler use, and establish preemptive protocols that prepare the clinical practice to manage complications.


Assuntos
Técnicas Cosméticas/efeitos adversos , Preenchedores Dérmicos/efeitos adversos , Reação no Local da Injeção/terapia , Guias de Prática Clínica como Assunto , Comitês Consultivos/normas , Tomada de Decisão Clínica , Preenchedores Dérmicos/administração & dosagem , Dermatologia/normas , Estética , Medicina Baseada em Evidências/normas , Face/anatomia & histologia , Humanos , Reação no Local da Injeção/etiologia , Comunicação Interdisciplinar , Necrose/induzido quimicamente , Necrose/terapia , Pele/irrigação sanguínea , Pele/efeitos dos fármacos , Pele/inervação , Pele/patologia , Sociedades Médicas/normas , Especialidades Cirúrgicas/normas , Estados Unidos
5.
Environ Pollut ; 274: 116497, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33540250

RESUMO

Cadmium (Cd) pollution in the environment could cause toxic damage to animals and humans. MAPK pathways could regulate their downstream inflammatory factors, and plays a crucial role in necrosis. Since the swine kidney tissue is an important accumulation site of Cd and target organ of its toxic damage, but the damage form of Cd to swine kidney and the role of MAPK pathways in it are still not clear, we selected six week old weaned piglets as the research object, and fed a diet supplemented CdCl2 (20 mg/kg) to establish the model of liver injury induced by Cd. The expressions and phosphorylation of MAPK pathways (ERK, JNK, p38), expression levels of inflammatory factors (TNF-α, NF-κB, iNOS, COX-2 and PTGE) and necrosis related genes (MLKL, RIPK1, RIPK3 and FADD) and heat shock proteins (HSPs) were detected by RT-PCR and Western blot. H.E. staining was used to determine the damage of kidney caused by Cd exposure. The results showed that Cd exposure could activate p38 and JNK pathway phosphorylation, rather than ERK 1/2, up regulated the expressions of inflammatory factors, finally induced programmed necrosis (increasing the expressions of MLKL, RIPK1, RIPK3 and FADD) in swine kidney. Our study elucidated the mechanism of Cd-damage to swine kidney and the relationship among MAPK pathways, inflammatory factors and programmed necrosis in swine.


Assuntos
Cádmio , NF-kappa B , Animais , Cádmio/toxicidade , Rim , Necrose/induzido quimicamente , Suínos , Fator de Necrose Tumoral alfa
6.
Eur J Med Chem ; 215: 113251, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33611187

RESUMO

Development of the drug with high therapeutic efficacy and low toxicity is crucial to cancer ablation. In this study, we have demonstrated a red light-responsive prodrug BDP-TK-CPT by connecting the chemotherapeutic agent camptothecin with a boron dipyrromethene (BDP)-based photosensitizer via a reactive oxygen species (ROS)-labile thioketal chain. Since camptothecin is modified by a BDP-based macrocycle at the active site, the formed prodrug displays an extremely low toxicity in dark. However, upon illumination by red light, it can efficiently generate ROS leading to cell death by photodynamic therapy. Meanwhile, the ROS generated can destroy thioketal group to release free camptothecin which further results in local cell death by chemotherapy. The combined antitumor effects of the prodrug have been verified in HepG2, EC109, and HeLa cancer cells and mice bearing H22 tumors. This study may provide an alternative strategy for stimuli-responsive combination treatment of tumors by conjugation of ROS-activatable prodrugs with photosensitizing agents.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Pró-Fármacos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/efeitos da radiação , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Terapia Combinada , Tratamento Farmacológico , Feminino , Humanos , Luz , Camundongos , Necrose/induzido quimicamente , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/efeitos da radiação , Pró-Fármacos/síntese química , Pró-Fármacos/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo
7.
Am J Case Rep ; 22: e929002, 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33493142

RESUMO

BACKGROUND Apixaban is one of the newer direct oral anticoagulants (DOACs) being used to manage venous thrombosis. Skin toxicities are recognized adverse effects of the new DOACs, but are rare and usually associated with vasculitis. This report is of a 78-year-old man admitted to the hospital with pulmonary thromboembolism, who developed severe and extensive skin necrosis of both forearms 7 days after treatment with apixaban. CASE REPORT A 78-year-old man was admitted for pulmonary embolism and congestive heart failure exacerbation. He was started on therapeutic enoxaparin and diuresis. Later on, enoxaparin was substituted with apixaban. Seven days after starting apixaban, he suddenly developed skin changes that developed into skin necrosis on both forearms and the abdominal wall. A skin biopsy was not performed due to the high risk of bleeding. Skin necrosis was diagnosed based on clinical findings. A review of clinical data and the patient's medication profile did not reveal any other possible etiology or culprit medication. Clinical presentation and lab values were not consistent with infections or autoimmune etiologies. Apixaban was discontinued as it was perceived to be the likely cause of skin necrosis. The skin changes gradually improved within 1 week with supportive wound care, and the patient did not require a skin graft. The patient was discharged safely with subcutaneous low-molecular-weight heparin therapy. CONCLUSIONS This report shows that skin toxicity can be associated with apixaban and that with the increasing use of these newer DOACs, clinicians should be aware of these potential adverse effects.


Assuntos
Embolia Pulmonar , Tromboembolia Venosa , Idoso , Anticoagulantes/efeitos adversos , Inibidores do Fator Xa/efeitos adversos , Humanos , Masculino , Necrose/induzido quimicamente , Embolia Pulmonar/induzido quimicamente , Embolia Pulmonar/tratamento farmacológico , Pirazóis , Piridonas/efeitos adversos
8.
Chem Biol Interact ; 330: 109227, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32818478

RESUMO

The use of 3D models in various scientific applications is becoming more popular to replace traditional monolayers models. In this work, we used a three-dimensional in-house model of epidermis using HaCaT immortalized cells to evaluate the dermal toxicity induced by Basic Blue 99 and Basic Red 51, both present in commercial hair dye formulations. Our data show that cells cultured in the 3D model respond differently to those cultured in monolayer. Basic Red 51 dye induces apoptosis an DNA breaks in both models, however, these effects is more pronounced in cells cultured in monolayer. The toxic mode of action of Basic Blue 99 seems to be the induction of cell death, without genotoxic effects, but while the necrotic pathway is observed in HaCaT monolayer cell culture, was apoptosis seen in the Equivalent Human Epidermis (EHE) model. We could also confirm that cells in EHE model, an environment that could better mimic human effects, react differently to chemical stressors than the cells cultivated in 2D.


Assuntos
Técnicas de Cultura de Células/métodos , Epiderme/efeitos dos fármacos , Tinturas para Cabelo/toxicidade , Apoptose/efeitos dos fármacos , Compostos Azo/toxicidade , Técnicas de Cultura de Células/normas , Linhagem Celular , Dano ao DNA/efeitos dos fármacos , Tinturas para Cabelo/análise , Humanos , Naftoquinonas/toxicidade , Necrose/induzido quimicamente , Compostos de Amônio Quaternário/toxicidade
9.
Leg Med (Tokyo) ; 47: 101740, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32634765

RESUMO

Hepatotoxicity from paracetamol/acetaminophen has occasionally been reported at lower than expected doses. As herbal preparations may interact with pharmaceutical drugs the following in vitro study was undertaken to determine whether the toxic effects of paracetamol on liver cell growth in culture would be exacerbated by the addition of psoralen, a furanocoumarin compound that is present in Psoralea corylifolia, a common Chinese herb. The following study utilising a liver carcinoma cell line (HepG2) showed that Psoralea corylifolia was significantly toxic from 0.3 mg/ml to 5 mg/ml (p < 0.05), whereas paracetamol was not toxic below 50 mM (p = 0.0026). Interactions between previously non-toxic levels of 0.1 mg/ml of Psoralea corylifolia and increasing concentrations of paracetamol (0-50 mM), however, were observed, with a significant increase in toxicity compared to paracetamol alone (30% cell death vs. 72% cell death with Psoralea corylifolia). A significant synergistic interaction was observed at 40 mM paracetamol with 0.1 mg/ml of Psoralea (p = 0.038). This study has, therefore, shown significantly increased hepatotoxicity in cell cultures exposed to paracetamol when herbal compounds containing furanocoumarins were added. Fulminant acute liver failure occurring after the ingestion of low doses of paracetamol may not, therefore, always be due to an occult idiosyncratic response to paracetamol, but instead possibly to the combined effects of paracetamol and herbal preparations. Given the widespread use of both paracetamol and herbal preparations this possibility should be considered in cases of unexplained hepatic necrosis and liver failure that present for medicolegal investigation.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Ficusina/toxicidade , Fígado/patologia , Morte Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Sinergismo Farmacológico , Ficusina/isolamento & purificação , Células Hep G2 , Humanos , Falência Hepática/induzido quimicamente , Necrose/induzido quimicamente , Psoralea/química
10.
Bone Joint J ; 102-B(6): 795-803, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32475245

RESUMO

AIMS: To assess the correlation between the histological response to preoperative chemotherapy and event-free survival (EFS) or overall survival (OS) in patients with high-grade localized osteosarcoma. METHODS: Out of 625 patients aged ≤ 40 years treated for primary high-grade osteosarcoma between 1997 and 2016, 232 patients without clinically detectable metastases at the time of diagnosis and treated with preoperative high-dose methotrexate, adriamycin and cisplatin (MAP) chemotherapy and surgery were included. Associations of chemotherapy-induced necrosis in the resected specimen and EFS or OS were assessed using Cox model and the Pearson's correlation coefficients (r). Time-dependent receiver operating characteristic analysis was applied to determine the optimal cut-off value of chemotherapy-induced necrosis for EFS and OS. RESULTS: OS was 74% (95% confidence interval (CI) 67 to 79) at five years. Median chemotherapy-induced necrosis was 85% (interquartile range (IQR) 50% to 97%). In multivariate Cox model, chemotherapy-induced necrosis was significantly associated with EFS and OS (hazard ratio (HR) = 0.99 (95% CI 0.98 to 0.99); p < 0.001 and HR = 0.98 (95% CI 0.97 to 0.99); p < 0.001, respectively). Positive correlation was observed between chemotherapy-induced necrosis and five-year EFS and five-year OS (r = 0.91; p < 0.001, and r = 0.85; p < 0.001, respectively). The optimal cut-off value of chemotherapy-induced necrosis for five-year EFS and five-year OS was 85% and 72%, respectively. CONCLUSION: Chemotherapy-induced necrosis in the resected specimen showed positive correlation with EFS and OS in patients with high-grade localized osteosarcoma after MAP chemotherapy. In our analysis, optimal cut-off values of MAP chemotherapy-induced necrosis in EFS and OS were lower than the commonly used 90%, suggesting the need for re-evaluation of the optimal cut-off value through larger, international collaborative research. Cite this article: Bone Joint J 2020;102-B(6):795-803.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/cirurgia , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Metotrexato/administração & dosagem , Osteossarcoma/tratamento farmacológico , Osteossarcoma/cirurgia , Adolescente , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Criança , Correlação de Dados , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Necrose/induzido quimicamente , Terapia Neoadjuvante , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Período Pré-Operatório , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
11.
Chemosphere ; 258: 127341, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32563067

RESUMO

Cadmium (Cd) is a primary environmental pollutant which causes the immune dysfunction of aquatic animals. MicroRNAs (miRNAs) play a key role in programmed necrosis and apoptosis of immune organs. Selenium (Se), known as an important element, can antagonize Cd toxicity in birds, but the impact of Se on common carps (Cyprinus carpio) has not been reported. To investigate the Cd-induced immunotoxicity mechanism mediated by miR-216a in splenic lymphocytes of common carp and antagonized by Se, we extracted lymphocytes from the spleen and divided them into control group, Se group (10-6 mol/L of Na2SeO3), Se + Cd group and Cd group (4 × 10-5 mol/L of CdCl2). After 6 h of incubation, AO/EB staining, Flow cytometry, qPCR and Western blot were performed. The results showed that Cd exposure caused the apoptosis (BAX, Bcl-2, Caspase 3, Caspase 9) and programmed necrosis (RIP, RIP3, MLKL) in lymphocytes, increased the expression of CYP enzymes, glycometabolism-related enzymes and production of ROS, while irritated the oxidative stress (MDA, SOD, CAT and GSH-PX), upregulated the expression of miR-216a which attenuated the levels of PI3K. However, those variations were apparently mitigated in the Se + Cd group. In short, we have proven that Cd activates oxidative stress and miR-216a-PI3K/AKT axis disorder, thus promoting apoptosis and necrosis in lymphocytes. Moreover, Se can antagonize Cd-triggered apoptosis and necrosis in lymphocytes.


Assuntos
Apoptose/efeitos dos fármacos , Cádmio/toxicidade , Carpas/metabolismo , Linfócitos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Selênio/farmacologia , Animais , MicroRNAs/metabolismo , Necrose/induzido quimicamente , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Selênio/metabolismo , Baço/citologia
12.
An Acad Bras Cienc ; 92(1): e20181120, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32321020

RESUMO

the focus ofthis study was to testthe hypothesisthatthere would be no difference betweenthe biocompatibility of silicon dioxide nanofilms used as antimicrobial agents. Sixty male Wistar rats were divided into 4 groups (n=15): Group C (Control,Polyethylene), Group AR (Acrylic Resin), Group NP (Acrylic Resin coated with NP-Liquid), Group BG (Acrylic Resin coated with Bacterlon).the animals were sacrificed with 7,15 and 30 days and tissues analyzed as regardsthe events of inflammatory infiltrate, edema, necrosis, granulation tissue, mutinucleated giant cells, fibroblasts and collagen. Kruskal-Wallis and Dunn tests was used (P<0.05). Intense inflammatory infiltrate was shown mainly in Groups BG and AR, with significant difference from Control Group inthe time interval of 7days (P=0.004). Necrosis demonstrated significant difference between Group BG and Control Group (P<0.05) inthe time intervals of 7 days. For collagen fibers,there was significant difference betweenthe Control Group and Groups AR and BG inthe time interval of 7 days (P=0.006), and between BG and Control Groups inthe time intervals of 15 days (P=0.010).the hypothesis was rejected. Bacterlon demonstratedthe lowest level, and NP-Liquid Glassthe highest level of tissue compatibility, and best cell repair.the coating with NP-Liquid Glass was demonstrated to be highly promising for clinical use.


Assuntos
Resinas Acrílicas/farmacologia , Materiais Biocompatíveis/farmacologia , Edema/induzido quimicamente , Necrose/induzido quimicamente , Dióxido de Silício/farmacologia , Tela Subcutânea/patologia , Resinas Acrílicas/química , Animais , Materiais Biocompatíveis/química , Edema/patologia , Masculino , Teste de Materiais , Modelos Animais , Necrose/patologia , Ratos , Ratos Wistar , Dióxido de Silício/química , Tela Subcutânea/efeitos dos fármacos
13.
Proc Natl Acad Sci U S A ; 117(11): 6014-6022, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123065

RESUMO

Fungal predatory behavior on nematodes has evolved independently in all major fungal lineages. The basidiomycete oyster mushroom Pleurotus ostreatus is a carnivorous fungus that preys on nematodes to supplement its nitrogen intake under nutrient-limiting conditions. Its hyphae can paralyze nematodes within a few minutes of contact, but the mechanism had remained unclear. We demonstrate that the predator-prey relationship is highly conserved between multiple Pleurotus species and a diversity of nematodes. To further investigate the cellular and molecular mechanisms underlying rapid nematode paralysis, we conducted genetic screens in Caenorhabditis elegans and isolated mutants that became resistant to P. ostreatus We found that paralysis-resistant mutants all harbored loss-of-function mutations in genes required for ciliogenesis, demonstrating that the fungus induced paralysis via the cilia of nematode sensory neurons. Furthermore, we observed that P. ostreatus caused excess calcium influx and hypercontraction of the head and pharyngeal muscle cells, ultimately resulting in rapid necrosis of the entire nervous system and muscle cells throughout the entire organism. This cilia-dependent predatory mechanism is evolutionarily conserved in Pristionchus pacificus, a nematode species estimated to have diverged from C. elegans 280 to 430 million y ago. Thus, P. ostreatus exploits a nematode-killing mechanism that is distinct from widely used anthelmintic drugs such as ivermectin, levamisole, and aldicarb, representing a potential route for targeting parasitic nematodes in plants, animals, and humans.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Micotoxinas/toxicidade , Pleurotus/fisiologia , Animais , Caenorhabditis elegans/citologia , Caenorhabditis elegans/fisiologia , Cálcio/metabolismo , Cílios/fisiologia , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/inervação , Necrose/induzido quimicamente
14.
Sci Rep ; 10(1): 4190, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144343

RESUMO

Epidemiological studies link long term exposure to xenoestrogen Bisphenol-A to adverse cardiovascular effects. Our previous results show that BPA induces hypertension by a mechanism involving CamKII activation and increased redox stress caused by eNOS uncoupling. Recently, CamKII sustained activation has been recognized as a central mediator of programmed cell death in cardiovascular diseases, including necroptosis. However, the role of necroptosis in cardiac response to BPA had not yet been explored. Mice exposed to BPA for 16 weeks showed altered heart function, electrical conduction, and increased blood pressure. Besides, a stress test showed ST-segment depression, indicative of cardiac ischemia. The hearts exhibited cardiac hypertrophy and reduced vascularization, interstitial edema, and large hemorrhagic foci accompanied by fibrinogen deposits. BPA initiated a cardiac inflammatory response, up-regulation of M1 macrophage polarization, and increased oxidative stress, coinciding with the increased expression of CamKII and the necroptotic effector RIP3. In addition, cell death was especially evident in coronary endothelial cells within hemorrhagic areas, and Evans blue extravasation indicated a vascular leak in response to Bisphenol-A. Consistent with the in vivo findings, BPA increased the necroptosis/apoptosis ratio, the expression of RIP3, and CamKII activation in endothelial cells. Necrostatin-1, an inhibitor of necroptosis, alleviated BPA induced cardiac dysfunction and prevented the inflammatory and hemorrhagic response in mice. Mechanistically, silencing of RIP3 reversed BPA-induced necroptosis and CamKII activation in endothelial cells, while inhibition of CamKII activation by KN-93 had no effect on RIP3 expression but decreased necroptotic cell death suggesting that BPA induced necroptosis is mediated by a RIP 3/CamKII dependent pathway. Our results reveal a novel pathogenic role of BPA on the coronary circulation. BPA induces endothelial cell necroptosis, promotes the weakening of coronary vascular wall, which caused internal ventricular hemorrhages, delaying the reparative process and ultimately leading to cardiac dysfunction.


Assuntos
Compostos Benzidrílicos/toxicidade , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Necrose/induzido quimicamente , Fenóis/toxicidade , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Apoptose/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Linhagem Celular , Células Cultivadas , Ecocardiografia , Eletrocardiografia , Feminino , Imuno-Histoquímica , Masculino , Camundongos , Microscopia Confocal , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Necroptose/efeitos dos fármacos , RNA Mensageiro/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de Sinais/efeitos dos fármacos
15.
Food Chem Toxicol ; 138: 111240, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32145352

RESUMO

Acetaminophen (APAP) is a widely used analgesic drug, which can cause severe liver injury after an overdose. The intracellular signaling mechanisms of APAP-induced cell death such as reactive metabolite formation, mitochondrial dysfunction and nuclear DNA fragmentation have been extensively studied. Hepatocyte necrosis releases damage-associated molecular patterns (DAMPs) which activate cytokine and chemokine formation in macrophages. These signals activate and recruit neutrophils, monocytes and other leukocytes into the liver. While this sterile inflammatory response removes necrotic cell debris and promotes tissue repair, the capability of leukocytes to also cause tissue injury makes this a controversial topic. This review summarizes the literature on the role of various DAMPs, cytokines and chemokines, and the pathophysiological function of Kupffer cells, neutrophils, monocytes and monocyte-derived macrophages, and NK and NKT cells during APAP hepatotoxicity. Careful evaluation of results and experimental designs of studies dealing with the inflammatory response after APAP toxicity provide very limited evidence for aggravation of liver injury but support of the hypothesis that these leukocytes promote tissue repair. In addition, many cytokines and chemokines modulate tissue injury by affecting the intracellular signaling events of cell death rather than toxicity of leukocytes. Reasons for the controversial results in this area are also discussed.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/fisiopatologia , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Animais , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Imunidade Inata , Inflamação/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Fígado/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Necrose/induzido quimicamente , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia
16.
Plast Reconstr Surg ; 145(4): 957-964, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32221213

RESUMO

BACKGROUND: Soft-tissue necrosis caused by vascular compromise is a frequent and troublesome complication of hyaluronic acid filler injection. Hyaluronidase has been proposed as a treatment for this condition. This study aimed to determine the effective dose and administration interval of hyaluronidase injection in a skin necrosis animal model. METHODS: New Zealand rabbits were used to simulate the hyaluronic acid-associated vascular occlusion model. Hyaluronic acid filler (0.1 ml) was injected into the central auricular artery to create an occlusion. Three rabbit auricular flaps were injected with 500 IU of hyaluronidase once (group A) and three flaps each were injected at 15-minute intervals with 250 IU of hyaluronidase twice (group B), 125 IU of hyaluronidase four times (group C), 100 IU of hyaluronidase five times (group D), and 75 IU of hyaluronidase seven times (group E), all at 24 hours after occlusion. No intervention was administered after occlusion in the control group. Flap fluorescence angiography was performed immediately after hyaluronidase injection and on postoperative days 2, 4, and 7. Flap necrotic areas were analyzed. RESULTS: All control and experimental flaps demonstrated total occlusion after hyaluronic acid injection. The average total survival rate (positive area/total area ×100 percent) of control flaps was 37.61 percent. For experimental groups, the average total survival rates were 74.83 percent, 81.49 percent, 88.26 percent, 56.48 percent, and 60.69 percent in groups A through E, respectively. CONCLUSION: A better prognosis can be obtained by administering repeated doses rather than a single high dose of hyaluronidase.


Assuntos
Hialuronoglucosaminidase/farmacologia , Pele/patologia , Animais , Constrição Patológica/induzido quimicamente , Constrição Patológica/tratamento farmacológico , Preenchedores Dérmicos/administração & dosagem , Preenchedores Dérmicos/efeitos adversos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Orelha Externa/irrigação sanguínea , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/efeitos adversos , Hialuronoglucosaminidase/administração & dosagem , Injeções Intra-Arteriais , Necrose/induzido quimicamente , Necrose/tratamento farmacológico , Coelhos , Distribuição Aleatória , Retalhos Cirúrgicos/irrigação sanguínea
17.
Sci Rep ; 10(1): 5557, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32221312

RESUMO

Extracellular release of HMGB1 contributes to acetaminophen-induced liver injury. HMGB1 acts as a danger-associated molecular patterns during this toxic process but the mechanisms of action and targeted cells are incompletely defined. Here we studied, in vitro, the role of HMGB1 in amplifying the acetaminophen-induced hepatocyte necrosis process. Using cultured HepaRG cells, primary human hepatocytes and selective chemical inhibitors we evaluated acetaminophen-induced toxicity. We confirmed that addition of acetaminophen induced HepaRG cell death and HMGB1 release. We showed that inhibition of HMGB1 decreased acetaminophen-induced HepaRG cell death, suggesting a feedforward effect. We provide the first evidence that exposure of HepaRG cells to recombinant human HMGB1 (rhHMGB1) also resulted in cell death. Moreover, we found that both acetaminophen and rhHMGB1 induced programmed HepaRG cell necrosis through a RIPK3-dependent mechanism. By using TLR4 blocking antibody, we demonstrated the reduction of the HepaRG cell death induced by acetaminophen and rhHMGB1. Furthermore, inhibition of TRIF, known to induce a RIPK3-dependent cell death, reduced rhHMGB1-induced HepaRG cell death. Our data support that released HMGB1 from acetaminophen-stressed hepatocytes induced necrosis of neighboring hepatocytes by TLR4-TRIF-RIPK3- pathway. This in vitro study gives new insights in the role of HMGB1 in the amplification of acetaminophen-induced toxicity.


Assuntos
Acetaminofen/efeitos adversos , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Proteína HMGB1/metabolismo , Hepatócitos/metabolismo , Necrose/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Receptor 4 Toll-Like/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Hepatócitos/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Necrose/induzido quimicamente
18.
Inorg Chem ; 59(6): 3919-3933, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32096986

RESUMO

We report the synthesis and photochemical and biological characterization of Ru(II) complexes containing π-expansive ligands derived from dimethylbenzo[i]dipyrido[3,2-a:2',3'-c]phenazine (Me2dppn) adorned with flanking aryl substituents. Late-stage Suzuki couplings produced Me2dppn ligands substituted at the 10 and 15 positions with phenyl (5), 2,4-dimethylphenyl (6), and 2,4-dimethoxyphenyl (7) groups. Complexes of the general formula [Ru(tpy)(L)(py)](PF6)2 (8-10), where L = 4-7, were characterized and shown to have dual photochemotherapeutic (PCT) and photodynamic therapy (PDT) behavior. Quantum yields for photodissociation of monodentate pyridines from 8-10 were about 3 times higher than that of parent complex [Ru(tpy)(Me2dppn)(py)](PF6)2 (1), whereas quantum yields for singlet oxygen (1O2) production were ∼10% lower than that of 1. Transient absorption spectroscopy indicates that 8-10 possess long excited state lifetimes (τ = 46-50 µs), consistent with efficient 1O2 production through population and subsequent decay of ligand-centered 3ππ* excited states. Complexes 8-10 displayed greater lipophilicity relative to 1 and association to DNA but do not intercalate between the duplex base pairs. Complexes 1 and 8-10 showed photoactivated toxicity in breast and prostate cancer cell lines with phototherapeutic indexes, PIs, as high as >56, where the majority of cell death was achieved 4 h after treatment with Ru(II) complexes and light. Flow cytometric data and rescue experiments were consistent with necrotic cell death mediated by the production of reactive oxygen species, especially 1O2. Collectively, this study confirms that DNA intercalation by Ru(II) complexes with π-expansive ligands is not required to achieve photoactivated cell death.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/efeitos da radiação , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Complexos de Coordenação/efeitos da radiação , DNA/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Radical Hidroxila/metabolismo , Ligantes , Luz , Necrose/induzido quimicamente , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/efeitos da radiação , Rutênio/química , Oxigênio Singlete/metabolismo
19.
Biomed Res Int ; 2020: 2934315, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32047807

RESUMO

This study aimed to compare the quality of human spermatozoa vitrified by direct plunging into liquid nitrogen vs. liquid air. Spermatozoa were divided into three groups: fresh spermatozoa (Group F) were used as a control. Spermatozoa suspension (20 µl) was vitrified in open granules by direct dropping into liquid nitrogen (Group LN) or clean liquid air (Group LA). After warming at 37°C, the progressive motility rate of Group F was reduced from 65.9 ± 2.5% to 34.0 ± 1.9% (Group LN) and 38.1 ± 2.3% (Group LA), respectively (P1-2,3 < 0.05). The reductions in viability were 65.6 ± 2.2%, 29.0 ± 1.8%, and 36.6 ± 2.6% for Groups F, LN, and LA, respectively (P1-2,3 < 0.05). Comparing spermatozoa vitrified in liquid nitrogen vs. liquid air, no significant differences were detected in motility (34.0 ± 1.9% vs. 38.1 ± 2.3%), viability (29.0 ± 1.8% vs. 36.6 ± 2.6%), early apoptosis (13.8 ± 1.5% vs. 14.3 ± 1.8%), late apoptosis (45.5 ± 1.8% vs. 43.7 ± 2.2%), and necrosis (19.5 ± 2.0% vs. 15.0 ± 1.8%; p > 0.01 for all respective differences). There was a statistical tendency for increasing rates of "progressive motility" and "viability" and decreasing rates of "apoptosis" and "necrosis" when comparing spermatozoa vitrified in liquid air vs. liquid nitrogen. It is concluded that cryoprotectant-free vitrification by the direct dropping of human spermatozoa in a clean cooling agent (liquid air) is a good alternative to the use of nonsterile liquid nitrogen and can be used to cool cells while minimising the risk of microbial contamination.


Assuntos
Apoptose/fisiologia , Criopreservação/métodos , Preservação do Sêmen/métodos , Motilidade Espermática/fisiologia , Espermatozoides/fisiologia , Vitrificação , Ar , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Crioprotetores/efeitos adversos , Fertilidade/efeitos dos fármacos , Humanos , Masculino , Necrose/induzido quimicamente , Nitrogênio , Preservação do Sêmen/instrumentação , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos
20.
PLoS Negl Trop Dis ; 14(2): e0008054, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32032357

RESUMO

Naja atra envenomation is one of the most significant clinical snakebite concerns in Taiwan. Taiwanese freeze-dried neurotoxic antivenom (FNAV) is currently used clinically for the treatment of cobra snakebite, and has been shown to limit the mortality of cobra envenomation to less than 1%. However, more than half of victims (60%) require surgery because of local tissue necrosis, a major problem in patients with cobra envenomation. Although the importance of evaluating the neutralizing effect of FNAV on this pathology is recognized, whether FNAV is able to prevent the local necrosis extension induced by N. atra venom has not been investigated in detail. Cytotoxins (CTXs) are considered as the major components of N. atra venom that cause necrosis. In the current study, we isolated CTXs from whole cobra venom and used both whole venom and purified CTXs to develop animal models for assessing the neutralization potential of FNAV against venom necrotizing activity. Local necrotic lesions were successfully produced in mice using CTXs in place of whole N. atra venom. FNAV was able to rescue mice from a subcutaneously injected lethal dose of cobra venom; however, it was unable to prevent CTX-induced dermo-necrosis. Furthermore, using the minimal necrosis dose (MND) of CTXs and venom proteome data, we found a dose of whole N. atra venom suitable for FNAV and developed a workable protocol for inducing local necrosis in rodent models that successfully imitated the clinical circumstance of cobra envenoming. This information provides a more comprehensive understanding of the pathophysiology of N. atra envenomation, and serves as a guide for improving current antivenom strategies and advancing clinical snakebite management in Taiwan.


Assuntos
Antivenenos/uso terapêutico , Venenos Elapídicos/toxicidade , Naja naja , Necrose/induzido quimicamente , Animais , Citotoxinas/química , Citotoxinas/toxicidade , Venenos Elapídicos/química , Camundongos , Camundongos Endogâmicos ICR , Taiwan
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