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Glioma, a malignant and infiltrative neoplasm of the central nervous system, poses a significant threat due to its high mortality rates. Branched-chain amino acid transaminase 1 (BCAT1), a key enzyme in branched-chain amino acid (BCAA) catabolism, exhibits elevated expression in gliomas and correlates strongly with poor prognosis. Nonetheless, the regulatory mechanisms underlying this increased BCAT1 expression remains incompletely understood. In this study, we reveal that ubiquitination at Lys360 facilitates BCAT1 degradation, with low ubiquitination levels contributing to high BCAT1 expression in glioma cells. The Carboxyl terminus of Hsc70-interacting protein (CHIP), an E3 ubiquitin ligase, interacts with BCAT1 via its coiled-coil (CC) domain, promoting its K48-linkage ubiquitin degradation through proteasomal pathway. Moreover, CHIP-mediated BCAT1 degradation induces metabolic reprogramming, and impedes glioma cell proliferation and tumor growth both in vitro and in vivo. Furthermore, a positive correlation is observed between low CHIP expression, elevated BCAT1 levels, and unfavorable prognosis among glioma patients. Additionally, we show that the CHIP/BCAT1 axis enhances glioma sensitivity to temozolomide by reducing glutathione (GSH) synthesis and increasing oxidative stress. These findings underscore the critical role of CHIP/BCAT1 axis in glioma cell proliferation and temozolomide sensitivity, highlighting its potential as a diagnostic marker and therapeutic target in glioma treatment.
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Prolifération cellulaire , Gliome , Témozolomide , Transaminases , Ubiquitin-protein ligases , Ubiquitination , Humains , Témozolomide/pharmacologie , Témozolomide/usage thérapeutique , Ubiquitin-protein ligases/métabolisme , Ubiquitin-protein ligases/génétique , Prolifération cellulaire/effets des médicaments et des substances chimiques , Gliome/métabolisme , Gliome/anatomopathologie , Gliome/génétique , Gliome/traitement médicamenteux , Animaux , Lignée cellulaire tumorale , Transaminases/métabolisme , Transaminases/génétique , Souris , Souris nude , Ubiquitine/métabolisme , Tumeurs du cerveau/métabolisme , Tumeurs du cerveau/anatomopathologie , Tumeurs du cerveau/génétique , Tumeurs du cerveau/traitement médicamenteux , Protéolyse/effets des médicaments et des substances chimiques , Mâle , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , FemelleRÉSUMÉ
OBJECTIVE: Although blood urea nitrogen (BUN) has a crucial impact on many diseases, its effect on outcomes in patients with hyperlipidemia remains unknown. The study aimed to investigate the relationships between BUN levels and all-cause and cardiovascular disease (CVD) mortality in individuals with hyperlipidemia. METHODS: This analysis comprised 28,122 subjects with hyperlipidemia from the National Health and Nutrition Examination Survey (NHANES) spanning 1999 to 2018. The risk of BUN on mortality was evaluated using weighted Cox regression models. Additionally, to illustrate the dose-response association, the restricted cubic spline (RCS) was used. RESULTS: During the observation period, 4276 participant deaths were recorded, of which 1206 were due to CVD. Compared to patients with hyperlipidemia in the third BUN quintile, the hazard ratios (HRs) for all-cause mortality were 1.26 (95% CIs: 1.09, 1.45) and 1.22 (95% CIs: 1.09, 1.37) for patients in the first and fifth quintiles of BUN, respectively. The HRs for CVD mortality among patients in the fifth quintile of BUN were 1.48 (95% CIs: 1.14, 1.93). BUN levels were found to have a U-shaped association with all-cause mortality and a linear association with CVD mortality using restricted triple spline analysis. CONCLUSIONS: This study revealed that both low and high BUN levels in patients with hyperlipidemia are associated with heightened all-cause mortality. Furthermore, elevated BUN levels are also associated with increased CVD mortality. The findings indicate that patients with hyperlipidemia may face an elevated risk of death if they have abnormal BUN levels.
Sujet(s)
Azote uréique sanguin , Maladies cardiovasculaires , Hyperlipidémies , Enquêtes nutritionnelles , Humains , Hyperlipidémies/sang , Hyperlipidémies/mortalité , Mâle , Femelle , Adulte d'âge moyen , Maladies cardiovasculaires/mortalité , Maladies cardiovasculaires/sang , Modèles des risques proportionnels , Sujet âgé , Adulte , Facteurs de risqueRÉSUMÉ
The human eye is susceptible to various disorders that affect its structure or function, including glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy (DR). Mitochondrial dysfunction has been identified as a critical factor in the pathogenesis and progression of eye disorders, making it a potential therapeutic target in the clinic. Natural products have been used in traditional medicine for centuries and continue to play a significant role in modern drug development and clinical therapeutics. Recently, there has been a surge in research exploring the efficacy of natural products in treating eye disorders and their underlying physiological mechanisms. This review aims to discuss the involvement of mitochondrial dysfunction in eye disorders and summarize the recent advances in the application of natural products targeting mitochondria. In addition, we describe the future perspective and challenges in the development of mitochondria-targeting natural products.
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Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly, which is primarily attributed to oxidative stress-induced damage to the retinal pigment epithelium (RPE). Human amniotic mesenchymal stem cells (hAMSC) were considered to be one of the most promising stem cells for clinical application due to their low immunogenicity, tissue repair ability, pluripotent potential and potent paracrine effects. The conditional medium (hAMSC-CM) and exosomes (hAMSC-exo) derived from hAMSC, as mediators of intercellular communication, play an important role in the treatment of retinal diseases, but their effect and mechanism on oxidative stress-induced retinal degeneration are not explored. Here, we reported that hAMSC-CM alleviated H2O2-induced ARPE-19 cell death through inhibiting mitochondrial-mediated apoptosis pathway in vitro. The overproduction of reactive oxygen species (ROS), alteration in mitochondrial morphology, loss of mitochondrial membrane potential and elevation of Bax/Bcl2 ratio in ARPE-19 cells under oxidative stress were efficiently reversed by hAMSC-CM. Moreover, it was found that hAMSC-CM protected cells against oxidative injury via PI3K/Akt/FoxO3 signaling. Intriguingly, exosome inhibitor GW4869 alleviated the inhibitory effect of hAMSC-CM on H2O2-induced decrease in cell viability of ARPE-19 cells. We further demonstrated that hAMSC-exo exerted the similar protective effect on ARPE-19 cells against oxidative damage as hAMSC-CM. Additionally, both hAMSC-CM and hAMSC-exo ameliorated sodium iodate-induced deterioration of RPE and retinal damage in vivo. These results first indicate that hAMSC-CM and hAMSC-exo protect RPE cells from oxidative damage by regulating PI3K/Akt/FoxO3 pathway, suggesting hAMSC-CM and hAMSC-exo will be a promising cell-free therapy for the treatment of AMD in the future.
Sujet(s)
Amnios , Exosomes , Protéine O3 à motif en tête de fourche , Cellules souches mésenchymateuses , Stress oxydatif , Phosphatidylinositol 3-kinases , Protéines proto-oncogènes c-akt , Dégénérescence de la rétine , Épithélium pigmentaire de la rétine , Transduction du signal , Humains , Cellules souches mésenchymateuses/métabolisme , Exosomes/métabolisme , Amnios/cytologie , Milieux de culture conditionnés/pharmacologie , Phosphatidylinositol 3-kinases/métabolisme , Protéines proto-oncogènes c-akt/métabolisme , Dégénérescence de la rétine/métabolisme , Dégénérescence de la rétine/anatomopathologie , Dégénérescence de la rétine/étiologie , Protéine O3 à motif en tête de fourche/métabolisme , Épithélium pigmentaire de la rétine/métabolisme , Épithélium pigmentaire de la rétine/anatomopathologie , Apoptose , Cellules cultivées , Espèces réactives de l'oxygène/métabolisme , Potentiel de membrane mitochondriale , Technique de Western , Animaux , Survie cellulaire , Peroxyde d'hydrogène/toxicitéRÉSUMÉ
Liver fibrosis, characterized by the overproduction of extracellular matrix proteins within liver tissue, poses a rising global health concern. However, no approved antifibrotic drugs are currently available, highlighting the critical need for understanding the molecular mechanisms of liver fibrosis. This knowledge could not only aid in developing therapies but also enable early intervention, enhance disease prediction, and improve our understanding of the interaction between various underlying conditions and the liver. Notably, natural products used in traditional medicine systems worldwide and demonstrating diverse biochemical and pharmacological activities are increasingly recognized for their potential in treating liver fibrosis. This review aims to comprehensively understand liver fibrosis, emphasizing the molecular mechanisms and advancements in exploring natural products' antifibrotic potential over the past five years. It also acknowledges the challenges in their development and seeks to underscore their potency in enhancing patient prognosis and reducing the global burden of liver disease.
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Background: The neutrophil-to-lymphocyte ratio (NLR) and lactate dehydrogenase (LDH) level are inflammatory markers related to tumor growth and metabolism. This study investigated the value of preoperative NLR, LDH and the combination of NLR and LDH (NLR-LDH) for predicting colorectal cancer liver metastasis (CRLM) and tumor prognosis in the early stages of colorectal cancer (CRC). Materials and methods: Three hundred patients undergoing CRC resection were included. Logistic regression analysis was used to estimate the correlation between CRLM time and inflammatory markers, and Kaplan-Meier survival and Cox regression analyses were used to estimate overall survival (OS). Forest plots were prepared based on the multivariate Cox analysis model and evaluated by receiver operating characteristic (ROC) curve analysis. Results: The NLR cut-off value was 2.071 according to the ROC curve. The multivariate analysis showed that the elevated LDH level and a high NLR-LDH level were independent predictors of synchronous CRLM and OS (p < 0.05). The combination of a high NLR and elevated LDH and NLR-LDH levels suggested a poor prognosis and a significantly shorter median survival time than a low NLR and low levels of LDH and NLR-LDH. The ROC curve analysis results illustrated that the predictive value of the NLR-LDH score for synchronous CRLM [area under the curve (AUC) = 0.623, p < 0.001] and OS (AUC = 0.614, p = 0.001) was superior to that of the NLR or LDH score used alone. Conclusion: LDH and NLR-LDH are reliable, easy-to-use, independent biomarkers for predicting synchronous or metachronous CRLM and OS in CRC patients. The NLR is an important monitoring index for CRLM. Preoperative NLR, LDH and NLR-LDH may help to guide the use of therapeutic strategies and cancer surveillance.
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With the complexity and diversification of thermoelectric (TE) application scenarios, it becomes increasingly difficult for single-component thermoelectric materials to satisfy practical demands. Therefore, recent researches have largely focused on the development of the multi-component nanocomposites, which are probably a good solution for the TE application of some materials that are not eligible when used alone. In this work, a seires of single-walled carbon nanotube (SWCNT)/polypyrrole (PPy)/tellurium (Te)/lead telluride (PbTe) multi-layer flexible composite films were fabricated via the successive electrodeposition of the flexible PPy layer with a low thermal conductivity, the ultra-thin Te induction layer, and the brittle PbTe layer with a large Seebeck coefficient over the pre-fabricated SWCNT membrane electrode with a high electrical conductivity. Through the complementary advantages between different components and the multiple synergies of the interface engineering, the SWCNT/PPy/Te/PbTe composites harvested the excellent TE performance with a maximum power factor (PF) of 929.8 ± 35.4 µW m-1 K-2 at room temperature, outperforming those of most of the electrochemically-prepared organic/inorganic TE composites reported previously. This work evidenced that the electrochemical multi-layer assembly is a feasible tactic for constructing special thermoelectric materials to meet customized requirements, which could also be applied to other material platforms.
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Age-related macular degeneration is a common cause of blindless among the aged, which can mainly be attributed to oxidative stress and dysregulated autophagy in retinal pigment epithelium cells. Lactate was reported to act as a signaling molecule and exerted beneficial effect against oxidative stress. This study aims to investigate the protective effect of lactate against oxidative stress-induced retinal degeneration. Here, H2O2-induced oxidative stress cell model and sodium iodate-induced mice retinal degeneration model were established. It was found that H2O2 inhibited cell viability in ARPE-19 cells and sodium iodate induced deterioration of retinal pigment epithelium as well as apoptosis in retina. Pretreatment with lactate alleviated oxidative stress-induced cell death and retinal degeneration. Molecularly, lactate activated autophagy by up-regulating the ratio of LC3II/I, increased formation of LC3 puncta and autophagic vacuole. Further, lactate prevented H2O2-induced mitochondrial fission and maintained mitochondrial function by alleviating H2O2-induced mitochondrial membrane potential disruption and intracellular ROS generation. In contrast, application of 3-methyladenine, an inhibitor of autophagy, effectively weakened the protective effect of lactate against oxidative stress in vivo and in vitro. Taken together, all data in this study indicate that lactate protects against oxidative stress-induced retinal degeneration and preserves mitochondrial function by activating autophagy.
Sujet(s)
Dégénérescence de la rétine , Souris , Animaux , Dégénérescence de la rétine/induit chimiquement , Dégénérescence de la rétine/traitement médicamenteux , Dégénérescence de la rétine/prévention et contrôle , Espèces réactives de l'oxygène/métabolisme , Acide lactique/métabolisme , Acide lactique/pharmacologie , Peroxyde d'hydrogène/métabolisme , Stress oxydatif , Épithélium pigmentaire de la rétine/métabolisme , AutophagieRÉSUMÉ
Nonalcoholic fatty liver disease (NAFLD) is a prevalent hepatic disease in the world. Disorders of branched chain amino acid (BCAA) metabolism is involved in various diseases. In this study, we aim to explore the role of BCAA metabolism in the development of NAFLD and the protective effect of BCATc Inhibitor 2, an inhibitor of cytosolic branched chain amino acid transaminase, against NAFLD as well as its underlying mechanism. It was found that oleic acid induced lipid accumulation and apoptosis in HepG2 and LO2 cells. Supplementation of BCAAs further aggravated oleic acid-induced lipid accumulation and apoptosis. In contrast, treatment of BCATc Inhibitor 2 ameliorated oleic acid-induced lipid accumulation and apoptosis. Molecularly, supplementation of BCAAs or treatment of BCATc Inhibitor 2 up-regulated or down-regulated the expression of SREBP1 and lipogenesis-related genes without affecting lipolysis-related genes. BCATc Inhibitor 2 maintained mitochondrial function by ameliorating oleic acid-induced mitochondrial ROS generation and mitochondrial membrane potential disruption. In addition, BCATc Inhibitor 2 treatment alleviated oleic acid-induced activation of JNK and AKT signaling pathway and Bcl2/Bax/Caspase axis. In conclusion, our results indicate BCAA metabolism is involved in NAFLD and BCATc Inhibitor 2 protects against oleic acid-induced lipid accumulation and apoptosis. These findings suggest that BCATc Inhibitor 2 is a promising candidate drug for the treatment of NAFLD.
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Gastric cancer (GC) is one of the most common tumors worldwide, and cisplatin is a standard chemotherapeutic reagent for GC treatment. However, chemoresistance is an inherent challenge which limits its application and effectiveness in clinic. This study aims to investigate the mechanism of metformin-induced cisplatin resistance in GC. Intriguingly, the upregulation of mitophagy markers, mitochondrial fission, autophagy and mitophagosome were observed in SGC-7901/DDP cells compared to those in the SGC-7901 cells. Treatment with metformin significantly increased mitochondrial fission and mitophagy in both AGS and SGC-7901 cells, resulting in decreased ATP production, which unexpectedly protected GC cells against the cytotoxicity of cisplatin. In contrast, application of Chloroquine and 3-methyladenine, two inhibitors of autophagy, significantly alleviated the protective effect of metformin on SGC-7901 and AGS cells against cytotoxicity of cisplatin. Moreover, metformin also stimulated the phosphorylation of AMPK (Thr172) and increased the expression of mitophagy markers including Parkin and PINK1 in the AMPK signaling-dependent manner. Consistently, the cell viability and cell apoptosis assay showed that metformin-induced cisplatin resistance was prevented by knockdown of AMPKα1. Taken together, all data in this study indicate that metformin induced AMPK activation and PINK1/Parkin dependent mitophagy, which may contribute to the progression of cisplatin resistance in GC.
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Oxidative stress plays a crucial role in the damage of retinal neuronal cells. Curcumin, the phytocompound, has anti-inflammatory and antioxidative properties. It was shown that curcumin exerted a beneficial effect on retinal neuronal cell survival. However, the role of mitochondrial dynamics in curcumin-mediated protective effect on retinal neuronal cells remains to be elucidated. Here, H2O2 was used to mimic the oxidative stress in retinal neuronal R28 cells. Drp1 and Mfn2 are key regulators of mitochondrial fission and fusion. 100 µM of H2O2 significantly increased the cleavage of caspase-3 and Drp1 expression, but downregulated the expression of Mfn2. Pretreatment with 5 µM curcumin effectively alleviated H2O2-induced alterations in the expression of Drp1 and Mfn2 and mitochondrial fission in R28 cells. In addition, curcumin and Drp1 knockdown prevented H2O2-induced intracellular ROS increment and mitochondrial membrane potential disruption. On the contrary, knockdown of Mfn2 diminished curcumin-mediated protection against ROS increment and mitochondrial membrane potential disruption after H2O2. Moreover, curcumin protected R28 cells against H2O2-induced PINK1 expression, mitophagy, caspase-3 cleavage and apoptosis. Knockdown of Mfn2 significantly alleviated the protective effect of curcumin on R28 cells after H2O2. Taken together, our data indicate that curcumin protects against oxidative stress-induced injury in retinal neuronal cells by promoting mitochondrial fusion.
Sujet(s)
Curcumine , Dynamique mitochondriale , Curcumine/pharmacologie , Caspase-3/métabolisme , Espèces réactives de l'oxygène/métabolisme , Peroxyde d'hydrogène/toxicité , Stress oxydatif , Apoptose , Protein kinases/métabolisme , Protein kinases/pharmacologieRÉSUMÉ
Sloanea hemsleyana is a potential commercial and oil tree species. This study is the first to report and analyze complete chloroplast genome sequences of S. hemsleyana as a genomic resource for conservation purposes. The chloroplast genome is 158,085 bp in length and consisted of a large single-copy (LSC) region (88,446 bp), and a small single-copy (SSC) region (17,659 bp), separated by a pair of inverted repeats (IR) regions (25,990 bp). It contains 108 genes, with 74 protein-coding genes, 30 tRNA genes, and 4 rRNA genes. Phylogenetic analysis revealed that S. hemsleyana was most closely related to S. sinensis.
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BACKGROUND AND AIMS: Cholecystectomy is performed for most gallbladder polyps (GPs). However, cholecystectomy results concerning complications in some patients. For benign GPs, adoption of gallbladder-preserving surgery is worth to recommend. We describe our experiences performing gallbladder-preserving polypectomy for GPs by embryonic-natural orifice transumbilical endoscopic surgery (E-NOTES) with a gastric endoscopy. METHODS: This is a retrospective study of patients with GPs who underwent gallbladder-preserving polypectomy by E-NOTES with a gastric endoscopy from April 2018 to September 2019 in our hospital. The operative time, intraoperative hemorrhage, intraoperative and postoperative complications, gallbladder emptying function were obtained and analyzed. RESULTS: The procedure was performed successfully in all 12 patients with 5 cases of single polyp and 7 cases of multiple polyps. The range of GPs size was 2 mm to 15 mm. The mean operation time was (95.33 ± 23.08) minutes (55-135 min). There were no adverse events including heavy bleeding, mortality and conversion to open surgery during operation. All patients were discharged in 4-5 days after surgery without postoperative complications such as delayed bleeding, fever, peritonitis, intra-abdominal abscess and abdominal wall incisional hernia. All patients were followed up at 1, 3, 6, and 12 months postoperation who had almost no visible incision on the umbilical region, no recurrent GPs. The gallbladder emptying function decreased one month after surgery, and gradually improved 3, 6 and 12 months after surgery. CONCLUSION: E-NOTES gallbladder-preserving polypectomy is a safe and effective option for patients with GPs and is close to scar-free surgery which can be performed in routine clinical practice.
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Cholécystectomie laparoscopique , Maladies de la vésicule biliaire , Polypes , Cholécystectomie laparoscopique/méthodes , Endoscopie gastrointestinale , Maladies de la vésicule biliaire/chirurgie , Humains , Polypes/chirurgie , Complications postopératoires/étiologie , Complications postopératoires/chirurgie , Études rétrospectives , Résultat thérapeutique , Ombilic/chirurgieRÉSUMÉ
BACKGROUND: Hepatitis E virus (HEV) infection is a leading cause of acute hepatitis worldwide, and results in high morbidity and mortality rates among elderly people in China. The hepatitis E vaccine, Hecolin®, has been shown to be safe and highly efficacious among healthy adults aged 16-65â¯years old. However, there is no data about Hecolin® vaccination in elderly people older than 65â¯years (y). METHODS: An open-labeled, controlled trial was conducted to evaluate the safety and immunogenicity of Hecolin® among the elderly aged >65 y. A total of 601 eligible participants were enrolled. Among them, 200 elderly people aged >65 y and 201 adults aged 18-65 y were assigned to the Hecolin® groups and vaccinated at day 0, month 1 and month 6. Serum samples were collected for anti-HEV IgG determination at day 0 prior to immunization and at month 7. The remaining 200 elderly people aged >65 y were assigned to the safety control group and received no intervention but were instructed to report any adverse events that occurred during the whole study period in the same way as those in the Hecolin® groups. RESULTS: After receiving 3 doses of Hecolin® with the standard schedule, most (96.7%) of the vaccinated elderly people aged >65 y seroconverted at one month after the final dose (month 7). At month 7, the geometric mean concentrations of anti-HEV IgG were 5.36 (95% CI, 3.88-7.41) and 19.65 (95% CI, 16.81-22.98) among the baseline seronegative and seropositive elderly, respectively. Of the vaccinated elderly, 97.3% (177/182) had anti-HEV IgG levels higher than 1.0 WU/ml at month 7. Hecolin® was very well tolerated in this population. No vaccine-related SAEs were reported. CONCLUSIONS: Hecolin® is immunogenic and well tolerated in elderly people aged greater than 65â¯years.
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Virus de l'hépatite E/immunologie , Hépatite E/immunologie , Immunogénicité des vaccins/immunologie , Vaccins synthétiques/immunologie , Vaccins contre les hépatites virales/immunologie , Vaccins antiviraux/immunologie , Adulte , Sujet âgé , Chine , Femelle , Anticorps de l'hépatite/immunologie , Humains , Immunoglobuline G/immunologie , Mâle , Vaccination/méthodesRÉSUMÉ
The fragile X premutation (PM) allele contains a CGG expansion of 55-200 repeats in the FMR1 gene's promoter. Male PM carriers have an elevated risk of developing neurological and psychiatric changes, including an approximately 50% risk of the fragile X-associated tremor/ataxia syndrome (FXTAS). The aim of this study was to assess the relationships of regional white matter hyperintensities (wmhs) semi-quantitative scores, clinical status, motor (UPDRS, ICARS, Tremor) scales, and cognitive impairments, with FMR1-specific genetic changes, in a sample of 32 unselected male PM carriers aged 39-81 years. Half of these individuals were affected with FXTAS, while the non-FXTAS group comprised subcategories of non-affected individuals and individuals affected with non-syndromic changes. The dynamics of pathological processes at the cellular level relevant to the clinical status of PM carriers was investigated using the enzyme AMP-activated protein kinase (AMPK), which is a highly sensitive cellular stress-sensing alarm protein. This enzyme, as well as genetic markers - CGG repeat number and the levels of the FMR1 mRNA - were assessed in blood lymphoblasts. The results showed that the repeat distribution for FXTAS individuals peaked at 85-90 CGGs; non-FXTAS carriers were distributed within the lowest end of the PM repeat range, and non-syndromic carriers assumed an intermediate position. The size of the CGG expansion was significantly correlated, across all three categories, with infratentorial and total wmhs and with all motor scores, and the FMR1 mRNA levels with all the wmh scores, whilst AMPK activity showed considerable elevation in the non-FXTAS combined group, decreasing in the FXTAS group, proportionally to increasing severity of the wmhs and tremor/ataxia. We conclude that the size of the CGG expansion relates to the risk for FXTAS, to severity of infratentorial wmhs lesions, and to all three motor scale scores. FMR1 mRNA shows a strong association with the extent of wmhs, which is the most sensitive marker of the pathological process. However, the AMPK activity findings - suggestive of a role of this enzyme in the risk of FXTAS - need to be verified and expanded in future studies using larger samples and longitudinal assessment.
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Coxsackievirus A16 (CA16) is one of the major pathogens associated with human hand, foot, and mouth disease (HFMD) in the Asia-pacific region. Although CA16 infections are generally mild, severe neurological manifestations or even death has been reported. Studies on CA16 pathogenesis and vaccine development are severely hampered because the small animal models that are currently available show major limitations. In this study, gerbils (Meriones unguiculatus) were investigated for their suitability as an animal model to study CA16 pathogenesis and vaccine development. Our results showed that gerbils up to the age of 21 days were fully susceptible to CA16 and all died within five days post-infection. CA16 showed a tropism towards the skeletal muscle, spinal cord and brainstem of gerbils, and severe lesions, including necrosis, were observed. In addition, an inactivated CA16 whole-virus vaccine administrated to gerbils was able to provide full protection to the gerbils against lethal doses of CA16 strains. These results demonstrate that gerbils are a suitable animal model to study CA16 infection and vaccine development.
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In combination with studies of post-mortem Parkinson's disease (PD) brains, pharmacological and genetic models of PD have suggested that two fundamental interacting cellular processes are impaired - proteostasis and mitochondrial respiration. We have re-examined the role of mitochondrial dysfunction in lymphoblasts isolated from individuals with idiopathic PD and an age-matched control group. As previously reported for various PD cell types, the production of reactive oxygen species (ROS) by PD lymphoblasts was significantly elevated. However, this was not due to an impairment of mitochondrial respiration, as is often assumed. Instead, basal mitochondrial respiration and ATP synthesis are dramatically elevated in PD lymphoblasts. The mitochondrial mass, genome copy number and membrane potential were unaltered, but the expression of indicative respiratory complex proteins was also elevated. This explains the increased oxygen consumption rates by each of the respiratory complexes in experimentally uncoupled mitochondria of iPD cells. However, it was not attributable to increased activity of the stress- and energy-sensing protein kinase AMPK, a regulator of mitochondrial biogenesis and activity. The respiratory differences between iPD and control cells were sufficiently dramatic as to provide a potentially sensitive and reliable biomarker of the disease state, unaffected by disease duration (time since diagnosis) or clinical severity. Lymphoblasts from control and PD individuals thus occupy two distinct, quasi-stable steady states; a 'normal' and a 'hyperactive' state characterized by two different metabolic rates. The apparent stability of the 'hyperactive' state in patient-derived lymphoblasts in the face of patient ageing, ongoing disease and mounting disease severity suggests an early, permanent switch to an alternative metabolic steady state. With its associated, elevated ROS production, the 'hyperactive' state might not cause pathology to cells that are rapidly turned over, but brain cells might accumulate long-term damage leading ultimately to neurodegeneration and the loss of mitochondrial function observed post-mortem. Whether the 'hyperactive' state in lymphoblasts is a biomarker specifically of PD or more generally of neurodegenerative disease remains to be determined.
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Lymphocytes/métabolisme , Lymphocytes/anatomopathologie , Mitochondries/métabolisme , Maladie de Parkinson/métabolisme , Maladie de Parkinson/anatomopathologie , AMP-Activated Protein Kinases/métabolisme , Adénosine triphosphate/métabolisme , Adulte , Facteurs âges , Lignée de cellules transformées , Respiration cellulaire , Dosage génique , Génome , Humains , Potentiel de membrane mitochondriale , Phosphorylation oxydative , Consommation d'oxygène , Maladie de Parkinson/sang , Maladie de Parkinson/diagnostic , ARN messager/génétique , ARN messager/métabolisme , Courbe ROC , Espèces réactives de l'oxygène/métabolisme , Analyse de régression , Indice de gravité de la maladieRÉSUMÉ
AIM OF STUDY: The aim was to explore the structure and functions of new target spot c-Myc target from laryngeal cancer cell. (MTLC) of c-Myc gene. METHODS: This study adopted bioinformatic methods to analyze the physicochemical property, secondary structure, hydrophobic region, a transmembrane region, and prediction of functions. RESULTS: The results showed that the whole length of the open reading frames was 708 bp, coding was 235 amino acids. This protein was a basic protein possessed two transmembrane structures and weight was about 26592.5 Da. The main elements of secondary structure were alpha-helix and random coil. MTLC was a membrane constitutive protein that possessed signal transduction and regulation may locate on karyotheca as results of subcellular localization and function prediction. CONCLUSION: This study has provided the theoretical basis for the further discussion of the effect and mechanism of action of MTLC in the occurrence of laryngeal cancer.
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Tumeurs du larynx/métabolisme , Larynx/composition chimique , Protéines nucléaires/composition chimique , Protéines proto-oncogènes c-myc/composition chimique , Biologie informatique , Humains , Interactions hydrophobes et hydrophiles , Tumeurs du larynx/anatomopathologie , Larynx/métabolisme , Larynx/anatomopathologie , Protéines nucléaires/métabolisme , Structure secondaire des protéines , Protéines proto-oncogènes c-myc/métabolismeRÉSUMÉ
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with an increasing incidence worldwide. Apolipoprotein M (apoM) is a novel apolipoprotein that is mainly expressed in liver and kidney tissues. However, the anti-tumor properties of apoM remain largely unknown. We evaluated the anti-tumor activities and mechanisms of apoM in HCC both in vivo and in vitro. Bioinformatic analysis and luciferase reporter assay results showed that apoM was a potential target of hsa-miR-573 and was downregulated after transfection with hsa-miR-573 mimics. Overexpression of apoM suppressed migration, invasion, and proliferation of hepatoma cells in vitro. Overexpression of hsa-miR-573 in hepatoma cells reduced apoM expression, leading to promotion of the invasion, migration, and proliferation of hepatoma cells in vitro. In addition, hsa-miR-573 markedly promoted growth of xenograft tumors in nude mice with an accompanying reduction in cell apoptosis. ApoM markedly inhibited growth of xenograft tumors in nude mice and promoted cell apoptosis. Moreover, Bcl2A1 mRNA and protein levels were inhibited by apoM overexpression and an increase in apoptosis rate by apoM was markedly compensated by Bcl2A1 overexpression in HepG2 cells. These results provide evidence that hsa-miR-573 promoted tumor growth by inhibition of hepatocyte apoptosis and this pro-tumor effect might be mediated through Bcl2A1 in an apoM-dependent manner. Therefore, our findings may be useful to improve understanding of the critical effects of hsa-miR-573 and apoM in HCC pathogenesis.
Sujet(s)
Apoptose , Carcinogenèse/métabolisme , Hépatocytes/métabolisme , microARN/métabolisme , Transduction du signal , Régions 3' non traduites , Animaux , Apolipoprotéines/métabolisme , Apolipoprotéines M , Lignée cellulaire tumorale , Mouvement cellulaire , Prolifération cellulaire , Hépatocytes/anatomopathologie , Hétérogreffes , Humains , Lipocalines/métabolisme , Mâle , Souris , Souris de lignée BALB C , Souris nude , Antigènes mineurs d'histocompatibilité , Invasion tumorale , Transplantation tumorale , Protéines proto-oncogènes c-bcl-2/métabolismeRÉSUMÉ
Neurogenic pulmonary edema caused by severe brainstem encephalitis is the leading cause of death in young children infected by Enterovirus 71 (EV71). However, no pulmonary lesions have been found in EV71-infected transgenic or non-transgenic mouse models. Development of a suitable animal model is important for studying EV71 pathogenesis and assessing effect of therapeutic approaches. We had found neurological disorders in EV71-induced young gerbils previously. Here, we report severe pulmonary lesions characterized with pulmonary congestion and hemorrhage in a gerbil model for EV71 infection. In the EV71-infected gerbils, six 21-day-old or younger gerbils presented with a sudden onset of symptoms and rapid illness progression after inoculation with 1×105.5 TCID50 of EV71 via intraperitoneal (IP) or intramuscular (IM) route. Respiratory symptoms were observed along with interstitial pneumonia, pulmonary congestion and extensive lung hemorrhage could be detected in the lung tissues by histopathological examination. EV71 viral titer was found to be peak at late stages of infection. EV71-induced pulmonary lesions, together with severe neurological disorders were also observed in gerbils, accurately mimicking the disease process in EV71-infected patients. Passive transfer with immune sera from EV71 infected adult gerbils with a neutralizing antibody (GMT=89) prevented severe pulmonary lesion formation after lethal EV71 challenge. These results establish this gerbil model as a useful platform for studying the pathogenesis of EV71-induced pulmonary lesions, immunotherapy and antiviral drugs.