RÉSUMÉ
The blood-brain barrier (BBB) continues to be one of the main clinical obstacles in the treatment of glioma. Current chemotherapies always bring many different side effects, some even permanent. To date, nanomaterial-based vehicles have shown great potential in treating glioma. Herein, we developed a dual targeting liposomal delivery vector loaded with the anticancer drug doxorubicin (DOX) to treat glioma. SS31, a small peptide, has shown dual targeting effects of penetrating the BBB and specifically targeting mitochondria. In this study, a new liposomal delivery system, LS-DOX, was prepared by modifying DOX-loaded liposomes with SS31 for the treatment of in situ glioma. The liposomes demonstrated a high drug encapsulation rate and drug-loading capacity, satisfactory biocompatibility, high glioma accumulation ability, and good stability in vitro. Experimental results showed that the liposomes could effectively cross the BBB and target gliomas, and mitochondria-targeting of SS31 enhances cell uptake. In addition, the liposomes showed a good therapeutic effect on nude mice with glioma in situ with no obvious toxicity and side effects. Therefore, the present research will provide a novel alternative and reference for the effective treatment of glioma.
Sujet(s)
Tumeurs du cerveau , Gliome , Souris , Animaux , Liposomes/pharmacologie , Systèmes de délivrance de médicaments/méthodes , Tumeurs du cerveau/traitement médicamenteux , Souris nude , Lignée cellulaire tumorale , Gliome/traitement médicamenteux , Doxorubicine/pharmacologie , Doxorubicine/usage thérapeutique , Barrière hémato-encéphaliqueRÉSUMÉ
The soluble crude polysaccharides from Dioscorea opposita (DOP1 and DOP2) were prepared and characterized. DOP1 and DOP2 obtained carbohydrate (65.71% and 70.18%, respectively), uronic acid (63.71% and 24.84%, respectively) and protein (8.09% and 9.51%, respectively) with molecular weight of 49.24 kDa and 21.62 kDa, respectively. DOP samples were mainly composed of mannose, glucose, galacturonic acid, galactose, and glucuronic acid. The digestibility in vitro, antioxidant activity and intestinal peristalsis effect were then investigated. DOP1 and DOP2 were degraded with decreased molecular weights (39.58 kDa and 18.56 kDa respectively), increased reducing sugar contents (from 16.95% to 19.27%; 12.45% to 15.50% respectively) and free monosaccharides (from 0.89% to 1.42%; 0.90% to 1.14% respectively) after gastric digestion. Both DOP1 and DOP2 were resistant to intestinal digestion, suggesting that DOP samples can be considered as a dietary fiber. Additionally, DOP1 and DOP2 exhibited antioxidant activities positively correlated with the concentration and remained the activities after gastrointestinal digestion in vitro. Furthermore, DOP reduced the fluorescence intensity significantly, indicating DOP can promote the intestinal peristalsis of zebrafish larvae (5 pdf) at 500 µg/mL. Therefore, DOP1 and DOP2 have a better functionality as dietary fibers, including antioxidant activity and intestinal peristalsis promotion, which can be developed as functional foods.
Sujet(s)
Antioxydants , Dioscorea , Animaux , Antioxydants/pharmacologie , Danio zébré/métabolisme , Dioscorea/métabolisme , Péristaltisme , Polyosides/pharmacologie , Polyosides/métabolisme , Fibre alimentaireRÉSUMÉ
Changes in the cerebral microenvironment caused by acute ischemic stroke-reperfusion are the main obstacle to the recovery of neurological function and an important cause of stroke recurrence after thrombolytic therapy. The intracerebral microenvironment after ischemia-reperfusion reduces the neuroplasticity of the penumbra and ultimately leads to permanent neurological damage. To overcome this challenge, we developed a triple-targeted self-assembled nanodelivery system, which combines the neuroprotective drug rutin with hyaluronic acid through esterification to form a conjugate, and then connected SS-31, a small peptide that can penetrate the blood brain barrier and target mitochondria. Brain targeting, CD44-mediated endocytosis, hyaluronidase 1-mediated degradation, and the acidic environment synergistically promoted the enrichment of nanoparticles and drug release in the injured area. Results demonstrate that rutin has a high affinity for ACE2 receptors on the cell membrane and can directly activate ACE2/Ang1-7 signaling, maintain neuroinflammation, and promote penumbra angiogenesis and normal neovascularization. Importantly, this delivery system enhanced the overall plasticity of the injured area and significantly reduced neurological damage after stroke. The relevant mechanism was expounded from the aspects of behavior, histology, and molecular cytology. All results suggest that our delivery system may be an effective and safe strategy for the treatment of acute ischemic stroke-reperfusion injury.
RÉSUMÉ
Herein, a multi-bioresponsive self-assembled nano-drug delivery system (HSSG) was constructed by conjugating the anticancer drug Geraniol (GER) to hyaluronic acid (HA) via a disulfide bond. The HSSG NPs displayed a uniform spherical shape with an average diameter of â¼110 nm, maintained high stability, and realized controlled drug release in the tumor microenvironment (pH/glutathione/hyaluronidase). Results of fluorescence microscopy and flow cytometry verified that HSSG NPs were selectively uptaken by human hepatocellular carcinoma cell lines HepG2 and Huh7 via CD44 receptor-mediated internalization. Studies on H22 tumor-bearing mice demonstrate that HSSG NPs could effectively accumulate at the tumor site for a long period. In vitro and in vivo studies show that HSSG NPs significantly promoted the death of cancer cells while reducing the toxicity as compared to GER. Therefore, the HSSG NPs have great potential in the treatment of tumors.
Sujet(s)
Tumeurs du foie , Nanoparticules , Souris , Humains , Animaux , Système d'administration de médicaments à base de nanoparticules , Acide hyaluronique/composition chimique , Nanoparticules/composition chimique , Tumeurs du foie/traitement médicamenteux , Lignée cellulaire tumorale , Systèmes de délivrance de médicaments/méthodes , Libération de médicament , Microenvironnement tumoralRÉSUMÉ
Hepatocellular carcinoma (HCC) is a disease with high morbidity, high mortality, and low cure rate. Hyaluronic acid (HA) is widely adopted in tissue engineering and drug delivery. 5-(4-Hydroxyphenyl)-3H-1, 2-dithiol-3-thione (ADT-OH) is one of commonly used H2S donors. In our previous study, HA-ADT was designed and synthesized via coupling of HA and ADT-OH. In this study, compared with sodium hydrosulfide (NaHS, a fast H2S-releasing donor) and morpholin-4-ium (4-methoxyphenyl)-morpholin-4-ylsulfanylidenesulfido-λ5-phosphane (GYY4137, a slow H2S-releasing donor), HA-ADT showed stronger inhibitory effect on the proliferation, migration, invasion, and cell cycle of human HCC cells. HA-ADT promoted apoptosis by suppressing the expressions of phospho (p)-protein kinase B (PKB/AKT), p-glycogen synthase kinase-3ß (GSK-3ß), p-ß-catenin, and also inhibited autophagy via the downregulation of the protein levels of p-Smad2, p-Smad3, and transforming growth factor-ß (TGF-ß) in human HCC cells. Moreover, HA-ADT inhibited HCC xenograft tumor growth more effectively than both NaHS and GYY4137. Therefore, HA-ADT can suppress the growth of HCC cells by blocking the AKT/GSK-3ß/ß-catenin and TGF-ß/Smad2/3 signaling pathways. HA-ADT and its derivatives may be developed as promising antitumor drugs.
RÉSUMÉ
The existing treatments for ischemic stroke cannot meet the clinical needs so far. Quercetin (QT) is an effective apoptosis inhibitor and antioxidant flavonoid, but its water solubility is poor and has no targeting. In this study, QT is modified with hyaluronic acid (HA) to form a water-soluble conjugate HA-QT, which can specifically bind to CD44 receptors and response to hyaluronidase. Next, a novel delivery system SS31-HA-QT is prepared by further modification with SS31, a polypeptide capable of penetrating the blood-brain barrier (BBB) and indiscriminately targeting mitochondria. Meanwhile, IR780, a near-infrared dye, is conjugated onto HA-QT and SS31-HA-QT to form diagnosis tools to trace HA-QT and SS31-HA-QT. In vitro and in vivo results shows that SS31 can four-fold increase the drug penetration into BBB without any toxicity. The highly expressed CD44 and hyaluronidase in ischemic area ensured the targeted delivery of QT to the ischemic region. Importantly, the mitochondrial targeting of damaged neurons is also achieved by SS31. Further studies confirmed that SS31-HA-QT exerted neuron-protection by activating mitophagy, and its mechanism involved Akt/mTOR related TFEB and HIF-1α activation. Hence, SS31-HA-QT shall be a promising neuroprotective drug due to its high water-solubility, superior triple-targeted neuroprotective ability, low toxicity, and high efficiency.
Sujet(s)
Encéphalopathie ischémique , Quercétine , Humains , Quercétine/pharmacologie , Mitophagie , Eau , Hyaluronoglucosaminidase , Neurones , Encéphalopathie ischémique/traitement médicamenteux , Acide hyaluronique/pharmacologieRÉSUMÉ
Endometrial damage is an important factor leading to infertility and traditional conventional treatments have limited efficacy. As an emerging technology in recent years, stem cell therapy has provided new hope for the treatment of this disease. By comparing the advantages of stem cells from different sources, it is believed that menstrual blood endometrial stem cells have a good application prospect as a new source of stem cells. However, the clinical utility of stem cells is still limited by issues such as colonization rates, long-term efficacy, tumor formation, and storage and transportation. This paper summarizes the mechanism by which stem cells repair endometrial damage and clarifies the material basis of their effects from four aspects: replacement of damaged sites, paracrine effects, interaction with growth factors, and other new targets. According to the pathological characteristics and treatment requirements of intrauterine adhesion (IUA), the research work to solve the above problems from the aspects of functional bioscaffold preparation and multi-functional platform construction is also summarized. From the perspective of scaffold materials and component functions, this review will provide a reference for comprehensively optimizing the clinical application of stem cells.
RÉSUMÉ
The mechanisms underlining pathogenesis of polycystic ovary syndrome (PCOS) remain largely unknown. Dysfunction of ovarian granulosa cells plays an important role. The present study performed the lncRNA and mRNA profiling by whole genome transcriptomic sequencing of ovary granulosa cells from women with PCOS and investigated the potential role of differentially expressed gens (DEGs) in the pathomechanism of PCOS. In total, 1,936 DEGs (30 upregulated and 1,906 downregulated mRNAs and lncRNAs) were identified in the ovary granulosa cells between control and PCOS group. Functional enrichment analysis showed that DEGs were mainly associated with cytokine-cytokine receptor interaction, neuroactive ligand-receptor interaction, and olfactory transduction. qRT-PCR validated the upregulation of DLGAP5 mRNA in ovary from PCOS group when compared to control group. Immunostaining and TUNEL assays showed that DLGAP5 protein level was increased while apoptosis was decreased in follicles of ovary in PCOS group. In vitro functional assays showed that DLGPA5 knockdown repressed viability and proliferation, but enhanced apoptosis and disrupted cell cycle in granulosa cells; while DLGAP5 overexpression had the opposite effects in granulosa cells. In conclusion, the study showed differentially expressed lncRNA and mRNA profile in the granulosa cells in ovaries of PCOS. Functional results demonstrated that DLGAP5 is a dysregulated candidate gene in the pathogenesis of PCOS, especially granulosa cell apoptosis and proliferation.
Sujet(s)
Syndrome des ovaires polykystiques , Femelle , Gènes régulateurs , Cellules de la granulosa/métabolisme , Humains , Protéines tumorales/génétique , Syndrome des ovaires polykystiques/génétique , Syndrome des ovaires polykystiques/métabolisme , Transcriptome , Régulation positiveRÉSUMÉ
Particulate matter with 10⯵m or less in diameter (PM10) exposure is a major threat to health and environment around the world. Even though a number of clinical and experimental studies have focused on the cardiopulmonary effects of PM10, its impact on neurovascular development and the underlying toxicity is relatively less studied. The present study is therefore undertaken to evaluate the potential toxic effects of PM10 on neurodevelopment and the associated gene expression profiles in the zebrafish embryo/larvae. During 2017-2018, PM10 samples (24â¯h sampling, 180 sampling days) were collected in an urban downtown site of Jinan, Shandong province, China. To delineate the potential toxic effects of PM10 during neurodevelopment, zebrafish embryos/larvae were exposed to different concentrations viz., 25, 50, 100, 200, and 400⯵g/mL of PM10 solution for 24-120â¯h post-fertilization (hpf) and the effects on the mortality, morphology, swimming behavior, electroencephalogram discharges, growth of dopaminergic neurons, neurovasculature development and gene expression profiles of dopaminergic and neurodevelopment-related genes using qRT-PCR were studied. A significant increase in the mortality rate and morphological abnormalities were observed in 200⯵g/mL of the PM10 treated group at 120â¯hpf. High concentrations (≥100⯵g/mL) of PM10 exposure reduced locomotor behavior, caused abnormal electroencephalogram discharges, degeneration of dopaminergic neurons, inhibition of neurovascular development, cerebral hemorrhage, and significant changes in the expression pattern of genes involved in dopaminergic pathway and neurodevelopment such as (th1, dat, drd1, drd2a, drd3, drd4b, syn2a, gap43, α1-tubulin, gfap, map2, elavl3, eno2, neurog1, sox2, shha, and mbp). Taken together, all these parameters collectively imply developmental neurotoxicity and dysfunction of the dopaminergic neurons which provides the first evidence of PM10-induced neurodevelopmental toxicity in the zebrafish embryo/larvae.
Sujet(s)
Encéphale/effets des médicaments et des substances chimiques , Neurones dopaminergiques/effets des médicaments et des substances chimiques , Développement embryonnaire/effets des médicaments et des substances chimiques , Matière particulaire/toxicité , Animaux , Encéphale/embryologie , Encéphale/croissance et développement , Relation dose-effet des médicaments , Électroencéphalographie , Embryon non mammalien/effets des médicaments et des substances chimiques , Larve/effets des médicaments et des substances chimiques , Larve/croissance et développement , Locomotion/effets des médicaments et des substances chimiques , Polluants de l'eau , Polluants chimiques de l'eau/toxicité , Danio zébré/embryologieRÉSUMÉ
Neuroinflammation is considered as an important mechanism of vascular dementia (VaD). Our primary study showed that the bisindole analogue (2-(2-(bis(5-chloro-1H-indol-3-yl)methyl)phenoxy)aniline, compound 4ae) had great anti-inflammation in zebrafish. Rat model of permanent occlusion of the bilateral common carotid arteries (2-vessel occlusion, 2VO) was utilized to evaluate the neuroprotective effect of 4ae. Our results showed that 4ae treatment effectively reduced Iba-1 positive microglia cells in cerebral cortex and hippocampus after cerebral ischemia. Compared with the model group, neuroinflammation characterized by Interleukin (IL)-6 and tumor necrosis factor (TNF)-α, oxidative stress characterized by reactive oxygen species (ROS) and superoxide dismutase (SOD) were both improved significantly after treatment with 4ae. Moreover, 4ae treatment significantly reversed ischemia-induced ACE enhancement, while notably increased the level of ACE2. To further elucidate the role of 4ae on neuroinflammation, we investigated the effects of 4ae on lipopolysaccharide (LPS)-induced inflammation in BV2 microglia cells, a kind of innate immune cells in central nervous system. The results demonstrated that the expressions of CD11b, TNFα and IL-6 and the level of ROS were up-regulated after treatment with LPS. More importantly, 4ae was able to block the activation of BV2 by reducing ROS production and the expression of inflammatory cytokines. In addition, our results suggested that 4ae inhibited the inflammatory response mediated by microglia cells by inhibiting NF-κB. This anti-inflammatory effect on microglia may be a potential mechanism for the neuroprotective effect of 4ae in VaD.
Sujet(s)
Démence vasculaire , Microglie , Animaux , RatsRÉSUMÉ
In this paper, a curcumin derivative Cur20 was synthesized for better hydrolytic stability, which showed a higher angiogenic effect on zebrafish model than curcumin. In order to reveal the potential effects on neuroprotection, a mouse model of vascular dementia (VaD) induced by permanent right common carotid artery occlusion (rUCCAO) was established. After two weeks of curcumin administration, the cognitive function of mice was detected by Morris water maze and Y maze. The alteration on oxidative injuries and morphological damage were also analyzed by reactive oxygen species, superoxide dismutase, GSH, malondialdehyde tests, and Nissl stain on cortex/hippocampus. The angiogenesis and related signal factors were evaluated as well. The results showed that Cur20 significantly attenuated the cognitive dysfunction and histopathological changes of the VaD mice with enhanced antioxidant system and angiogenesis. In addition, primary rat brain microvessel endothelial cells (rBMECs) with oxygen glucose deprivation (OGD) were applied to further verify the possible mechanisms of Cur20-induced angiogenesis. The results demonstrated that the proliferation effect and the activation of pro-angiogenesis factors such as HIF-1α, VEGF, and TFEB might contribute to the protection of ischemic injury. Based on the above, our conclusion is that Cur20 can be considered as a promising therapeutic strategy for VaD.
RÉSUMÉ
Thyroid associated ophthalmopathy (TAO) is an organ-specific autoimmune disease occurring in patients with thyroid disease. Patients with TAO-related proptosis is largely due to excessive orbital adipose tissue Adipocyte phospholipase A2 (AdPLA) is one of the most important regulatory factors in adipocyte lipolysis, which may be associated with TAO-related proptosis. Thus, silencing AdPLA by RNA interference may be beneficial for the treatment of TAO. In this study, we sought to evaluate the efficiency of two types of microneedles to deliver siRNAs for silencing AdPLA. Our results showed that AdPLA mRNA was up-regulated in the orbit adipose tissues from TAO patients. Silence of AdPLA by siRNA can reduce lipid accumulation in both human and mouse adipocyte cell lines. Moreover, silence effects of silicon microneedle array patch-based and injectable microneedle device-based siRNA administration were examined at the belly site of the mice, and injectable microneedle device showed higher knockdown efficiency than silicon microneedle array patch. This study sets the stage not only for future treatment of TAO-related proptosis using AdPLA siRNA, but also provides the foundation for targeted siRNA delivery by using microneedles.
Sujet(s)
Adipocytes/métabolisme , Ophtalmopathie basedowienne/génétique , Phospholipases A2/métabolisme , Petit ARN interférent/métabolisme , Maladies de la thyroïde/complications , Administration par voie cutanée , Adulte , Exophtalmie , Femelle , Ophtalmopathie basedowienne/anatomopathologie , Humains , Mâle , TransfectionRÉSUMÉ
P-glycoprotein (P-gp) is located on the luminal surface of brain vascular endothelium and its status may determine the delivery of the agents into the brain tissues. Previous study showed that upregulation of P-gp at the blood-brain barrier (BBB) after ischemic stroke were mediated by nuclear factor-B (NF-kB) and tumour necrosis factor-α (TNF-α). Based on middle cerebral artery occlusion (MCAO) rats and oxygen-glucose deprivation (OGD) in co-culture of rat brain microvessel endothelial cells (rBMECs) and astrocytes system, the present data indicated that potentiated P-gp expression and activity in brain microvessels or rBMECs were associated with the increase in high-mobility group box 1 (HMGB1), Toll-like receptor 4 (TLR4) and activation of NF-kB and that HMGB1 can release from nucleus to the cytoplasm in activated astrocytes, then into the medium. Moreover, changes in TLR4, TIR domain-containing adaptor protein (TIRAP), NF-kB and P-gp in rBMECs were attenuated by addition of 1 mM ethyl pyruvate (EP), 10 µM TAK-242 and 10 µM pyrrolidine dithiocarbamate (PDTC), respectively. These results demonstrated that HMGB1 promoted P-gp at the BBB after cerebral ischemia via TLR4/NF-κB signaling pathway.
Sujet(s)
Glycoprotéine P/métabolisme , Barrière hémato-encéphalique/métabolisme , Protéine HMGB1/métabolisme , Infarctus du territoire de l'artère cérébrale moyenne/métabolisme , Facteur de transcription NF-kappa B/métabolisme , Récepteur de type Toll-4/métabolisme , Animaux , Astrocytes/métabolisme , Cellules cultivées , Techniques de coculture , Cellules endothéliales/métabolisme , Mâle , Rat Sprague-Dawley , Transduction du signalRÉSUMÉ
AIM: This study was aimed at investigating the effects and molecular mechanisms of physical activity intervention on Parkinson's disease (PD) and providing theoretical guidance for the prevention and treatment of PD. METHODS: Four electronic databases up to December 2019 were searched (PubMed, Springer, Elsevier, and Wiley database), 176 articles were selected. Literature data were analyzed by the logic analysis method. RESULTS: (1) Risk factors of PD include dairy products, pesticides, traumatic brain injury, and obesity. Protective factors include alcohol, tobacco, coffee, black tea, and physical activity. (2) Physical activity can reduce the risk and improve symptoms of PD and the beneficial forms of physical activity, including running, dancing, traditional Chinese martial arts, yoga, and weight training. (3) Different forms of physical activity alleviate the symptoms of PD through different mechanisms, including reducing the accumulation of α-syn protein, inflammation, and oxidative stress, while enhancing BDNF activity, nerve regeneration, and mitochondrial function. CONCLUSION: Physical activity has a positive impact on the prevention and treatment of PD. Illustrating the molecular mechanism of physical activity-induced protective effect on PD is an urgent need for improving the efficacy of PD therapy regimens in the future.
Sujet(s)
Exercice physique/physiologie , Maladie de Parkinson/prévention et contrôle , Maladie de Parkinson/thérapie , Facteur neurotrophique dérivé du cerveau/métabolisme , Traitement par les exercices physiques , Humains , Inflammation/prévention et contrôle , Mitochondries/physiologie , Stress oxydatif/physiologie , Maladie de Parkinson/épidémiologie , Maladie de Parkinson/physiopathologie , Facteurs de risque , alpha-Synucléine/métabolismeRÉSUMÉ
Particulate matter (PM10) is one of the most important indicators of the pollution that characterizes air quality. Epidemiological studies have shown that PM10 can cause cardiovascular-related diseases in the population. And, we studied the developmental toxicity of PM10 and the underlying mechanism of its effects on the cardiovascular system of zebrafish embryo/larva. Changes in cardiac morphology, sinus venosus and bulbus arteriosus (SV-BA) distance, heart rate, vascular subintestinalis, blood flow, returned blood volume, and reactive oxygen species (ROS) level were measured, and changes in the expression levels of certain genes were assessed via RT-PCR. The results showed that PM10 caused a significant increase in pericardial sac area and SV-BA distance, a decrease in heart rate, inhibition of vascular subintestinalis growth, blood flow obstruction, reduced venous return, and other cardiovascular toxicities. PM10 induced an increase in the ROS level and significant increases in the expression levels of ERS signalling pathway factors and Nrf2 signalling pathway factors. The expression levels of the Wnt pathway-related genes also showed significant changes. Furthermore, ROS inhibitor N-Acetyl-l-cysteine (NAC) could ameliorate the cardiovascular toxicity of PM10 in zebrafish larvae. It is speculated that PM10 may result in cardiovascular toxicity by inducing higher ROS levels in the body, which could then induce ERS and lead to defects in the expression of genes related to the Wnt signalling pathway. The Nrf2 signalling pathway was activated as a stress compensatory mechanism during the early stage of PM10-induced cardiovascular injury. However, it was insufficient to counteract the PM10-induced cardiovascular toxicity.
Sujet(s)
Système cardiovasculaire/effets des médicaments et des substances chimiques , Embryon non mammalien/effets des médicaments et des substances chimiques , Larve/effets des médicaments et des substances chimiques , Matière particulaire/toxicité , Animaux , Larve/métabolisme , Facteur-2 apparenté à NF-E2/effets des médicaments et des substances chimiques , Facteur-2 apparenté à NF-E2/métabolisme , Organogenèse , Espèces réactives de l'oxygène/métabolisme , Voie de signalisation Wnt/effets des médicaments et des substances chimiques , Danio zébré/métabolisme , Protéines de poisson-zèbre/génétiqueRÉSUMÉ
Isoniazid (INH) is a first-line anti-tuberculosis drug. INH has been detected in surface waters which may create a risk to aquatic organisms. In this study, the hepatotoxicity of INH was elucidated using zebrafish. The liver morphology, transaminase level, redox-related enzyme activity, reactive oxygen species (ROS) content and mRNA levels of liver injury-related genes were measured. The results showed that INH (4, 6â¯mM) significantly caused liver atrophy and increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in zebrafish. INH (6â¯mM) led to decreased catalase (CAT) activity, glutathione peroxidase (GPx) activity and glutathione (GSH) content but increased ROS and malondialdehyde (MDA) levels. Moreover, INH (6â¯mM) decreased expression levels of miR-122 and pparα but increased mRNA levels of ap-1 and c-jun. Furthermore, mRNA levels of factors related to endoplasmic reticulum stress (ERS) (grp78, atf6, perk, ire1, xbp1s and chop), apoptosis (bax, cyt, caspase-3, caspase-8 and caspase-9) and the Nrf2 signalling pathway (nrf2, ho-1, nqo1, gclm and gclc) were significantly upregulated. INH may act on hepatotoxicity in zebrafish by increasing ROS content, which weakens the antioxidant capacity, leading to ERS, cell apoptosis and liver injury. In addition, the Nrf2 signalling pathway is activated as a stress compensation mechanism during INH-induced liver injury, but it is not sufficient to counteract INH-induced hepatotoxicity.
Sujet(s)
Lésions hépatiques dues aux substances/étiologie , Stress du réticulum endoplasmique/effets des médicaments et des substances chimiques , Isoniazide/toxicité , Larve/métabolisme , Espèces réactives de l'oxygène , Danio zébré/métabolisme , Animaux , Antioxydants/métabolisme , Antituberculeux/toxicité , Lésions hépatiques dues aux substances/génétique , Lésions hépatiques dues aux substances/anatomopathologie , Stress du réticulum endoplasmique/génétique , Régulation de l'expression des gènes , Larve/effets des médicaments et des substances chimiques , Facteur-2 apparenté à NF-E2/métabolisme , Stress oxydatif/physiologie , Espèces réactives de l'oxygène/effets indésirables , Transduction du signal , Protéines de poisson-zèbre/génétique , Protéines de poisson-zèbre/métabolismeRÉSUMÉ
Isoniazid (INH) is a first-line antituberculosis drug. The incidence of adverse reactions accompanied by inflammation in the liver during drug administration to tuberculosis patients is high and severely affects clinical treatment. To better understand the mechanism of hepatotoxicity induced by INH under the inflammatory state, we compared the differences in levels of hepatotoxicity from INH between normal zebrafish and zebrafish in an inflammatory state to elucidate the hepatotoxic mechanism using different endpoints such as mortality, malformation, inflammatory effects, liver morphology, histological changes, transaminase analysis, and expression levels of certain genes. The results showed that the toxic effect of INH in zebrafish in an inflammatory state was more obvious than that in normal zebrafish, that liver size was significantly decreased as measured by liver fatty acid binding protein (LFABP) reporter fluorescence and intensity, and that alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were significantly increased. Hematoxylin and eosin (HE) staining and electron microscopy showed that hepatocyte injury was more obvious in the inflammatory state. In the inflammatory state, INH significantly increased the expression levels of endoplasmic reticulum stress (ERS)-related factors (GRP78, ATF6, PERK, IRE1, XBP1s, GRP94, and CHOP), autophagy-related factors (beclin 1, LC3, Atg3, and Atg12), and apoptosis-related factors (caspase-3, caspase-8, caspase-9, Bax, p53, and Cyt) in larvae. Correlational analyses indicated that the transcription levels of the inflammatory factors interleukin-1b (IL-1b), tumor necrosis factor beta (TNF-ß), cyclooxygenase 2 (COX-2), and TNF-É were strongly positively correlated with ALT and AST. Furthermore, the ERS inhibitor sodium 4-phenylbutyrate (4-PBA) could ameliorate the hepatotoxicity of INH-lipopolysaccharide (LPS) in zebrafish larvae. These results indicated that INH hepatotoxicity was enhanced in the inflammatory state. ERS and its mediated autophagy and apoptosis pathways might be involved in INH-induced liver injury promoted by inflammation.
Sujet(s)
Antituberculeux/effets indésirables , Stress du réticulum endoplasmique/effets des médicaments et des substances chimiques , Isoniazide/effets indésirables , Lipopolysaccharides/toxicité , Alanine transaminase/métabolisme , Animaux , Apoptose/effets des médicaments et des substances chimiques , Aspartate aminotransferases/métabolisme , Femelle , Foie/effets des médicaments et des substances chimiques , Foie/enzymologie , Mâle , Stress oxydatif/effets des médicaments et des substances chimiques , Espèces réactives de l'oxygène/métabolisme , Danio zébréRÉSUMÉ
Previous research showed N1-(quinolin-2-ylmethy) butane-1, 4-diamine (QMA), a polyamine analogue, was efficacious in the prevention of oxidative injury in models of cerebral ischemia. The present study manifested that pretreatment with QMA attenuated ischemic damage accompanying up regulation of Nuclear factor erythroid 2related factor (Nrf2), Heme oxygenase1 (HO1), p-ERK and p-Akt in cerebral cortex tissues of middle cerebral artery occlusion (MCAO) rats and oxygen-glucose deprivation (OGD)-treated PC12 cells. Further more, treatment with LY294002 (specific PI3K inhibitor), PD98059 (specific ERK inhibitor), brusatol (specific Nrf2 inhibitor) and SnPP (specific HO-1 inhibitor) deprived almost all the effects of QMA in MCAO rats and OGD-treated PC12 cells. These data suggested that the protective actions of QMA on the cerebral ischemia may be related to activation of endogenous cytoprotective mechanism via ERK and Akt activated Nrf2/HO-1 signaling pathway.
Sujet(s)
Extracellular Signal-Regulated MAP Kinases/métabolisme , Heme oxygenase (decyclizing)/métabolisme , Infarctus du territoire de l'artère cérébrale moyenne/traitement médicamenteux , Facteur-2 apparenté à NF-E2/métabolisme , Neuroprotecteurs/usage thérapeutique , Polyamines/usage thérapeutique , Protéines proto-oncogènes c-akt/métabolisme , Quinoléines/usage thérapeutique , Lésion d'ischémie-reperfusion/traitement médicamenteux , Animaux , Infarctus du territoire de l'artère cérébrale moyenne/métabolisme , Mâle , Neuroprotecteurs/pharmacologie , Cellules PC12 , Polyamines/pharmacologie , Quinoléines/pharmacologie , Rats , Lésion d'ischémie-reperfusion/métabolisme , Transduction du signal/effets des médicaments et des substances chimiquesRÉSUMÉ
Accumulated evidence displayed that transplantation of stem cells may be a promising approach for the treatment of neurological disorders. However, the underlying mechanisms remain to be well elucidated. Moreover, some investigators cannot reproduce similar results as the previous. The present results showed that transplantation of fresh human umbilical cord blood mononuclear cells (cbMNCs) attenuated ischemic damage in middle cerebral artery occlusion (MCAO) rats, accompanied with improvement of neurologic deficits, learning and memory function. The increase in neovascularization and related molecules such as vascular endothelial growth factor (VEGF), Angiopoietin-1 (Ang-1) and endothelium-specific receptor tyrosine kinase 2 (Tie-2) in the injured brain was observed in cbMNCs-treated rats. Moreover, nuclear factor-κB (NF-κB) activation and nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome were also inhibited by the cells graft, resulting in reduction in cleaved caspase-1 and mature interleukin-1ß (IL-1ß) content. These results suggested that the protective actions of the cells on the cerebral ischemia may be related to inhibition of NF-κB pathway and NLRP3 inflammasome.