RÉSUMÉ
Theoretically determining the lowest-energy structure of a cluster has been a persistent challenge due to the inherent difficulty in accurate description of its potential energy surface (PES) and the exponentially increasing number of local minima on the PES with the cluster size. In this work, density-functional theory (DFT) calculations of Co clusters were performed to construct a dataset for training deep neural networks to deduce a deep potential (DP) model with near-DFT accuracy while significantly reducing computational consumption comparable to classic empirical potentials. Leveraging the DP model, a high-efficiency hybrid differential evolution (HDE) algorithm was employed to search for the lowest-energy structures of CoN (N = 11-50) clusters. Our results revealed 38 of these clusters superior to those recorded in the Cambridge Cluster Database and identified diverse architectures of the clusters, evolving from layered structures for N = 11-27 to Marks decahedron-like structures for N = 28-42 and to icosahedron-like structures for N = 43-50. Subsequent analyses of the atomic arrangement, structural similarity, and growth pattern further verified their hierarchical structures. Meanwhile, several highly stable clusters, i.e., Co13, Co19, Co22, Co39, and Co43, were discovered by the energetic analyses. Furthermore, the magnetic stability of the clusters was verified, and a competition between the coordination number and bond length in affecting the magnetic moment was observed. Our study provides high-accuracy and high-efficiency prediction of the optimal structures of clusters and sheds light on the growth trend of Co clusters containing tens of atoms, contributing to advancing the global optimization algorithms for effective determination of cluster structures.
RÉSUMÉ
Six ionone glycosides (1-3 and 5-7), including three new ones, named capitsesqsides A-C (1-3), together with an eudesmane sesquiterpenoid glycoside (4) and three known triterpenoid saponins (8-10) were isolated from Rhododendron capitatum. The structures of these compounds were determined by extensive spectroscopic techniques (MS, UV, 1D-NMR, and 2D-NMR) and comparison with data reported in the literature. The absolute configurations were determined by comparison of the experimental and theoretically calculated ECD curves and LC-MS analyses after acid hydrolysis and derivatization. The anti-inflammatory activities of these compounds were evaluated in the LPS-induced RAW264.7 cells. Molecular docking demonstrated that 2 has a favorable affinity for NLRP3 and iNOS.
Sujet(s)
Hétérosides , Rhododendron , Rhododendron/composition chimique , Souris , Hétérosides/composition chimique , Hétérosides/pharmacologie , Hétérosides/isolement et purification , Cellules RAW 264.7 , Animaux , Simulation de docking moléculaire , Anti-inflammatoires/pharmacologie , Anti-inflammatoires/composition chimique , Anti-inflammatoires/isolement et purification , Norisoprénoïdes/composition chimique , Norisoprénoïdes/pharmacologie , Norisoprénoïdes/isolement et purification , Structure moléculaire , Nitric oxide synthase type II/métabolisme , Nitric oxide synthase type II/antagonistes et inhibiteurs , Lipopolysaccharides/pharmacologie , Extraits de plantes/composition chimique , Extraits de plantes/pharmacologieRÉSUMÉ
BACKGROUND: Elizabethkingia spp. are emerging as nosocomial pathogens causing various infections. These pathogens express resistance to a broad range of antibiotics, thus requiring antimicrobial combinations for coverage. However, possible antagonistic interactions between antibiotics have not been thoroughly explored. This study aimed to evaluate the effectiveness of antimicrobial combinations against Elizabethkingia infections, focusing on their impact on pathogenicity, including biofilm production and cell adhesion. METHODS: Double-disc diffusion, time-kill, and chequerboard assays were used for evaluating the combination effects of antibiotics against Elizabethkingia spp. We further examined the antagonistic effects of antibiotic combinations on biofilm formation and adherence to A549 human respiratory epithelial cells. Further validation of the antibiotic interactions and their implications was performed using ex vivo hamster precision-cut lung sections (PCLSs) to mimic in vivo conditions. RESULTS: Antagonistic effects were observed between cefoxitin, imipenem and amoxicillin/clavulanic acid in combination with vancomycin. The antagonism of imipenem toward vancomycin was specific to its effects on the genus Elizabethkingia. Imipenem further hampered the bactericidal effect of vancomycin and impaired its inhibition of biofilm formation and the adhesion of Elizabethkingia meningoseptica ATCC 13253 to human cells. In the ex vivo PCLS model, vancomycin exhibited dose-dependent bactericidal effects; however, the addition of imipenem also reduced the effect of vancomycin. CONCLUSIONS: Imipenem reduced the bactericidal efficacy of vancomycin against Elizabethkingia spp. and compromised its capacity to inhibit biofilm formation, thereby enhancing bacterial adhesion. Clinicians should be aware of the potential issues with the use of these antibiotic combinations when treating Elizabethkingia infections.
Sujet(s)
Antibactériens , Biofilms , Infections à Flavobacteriaceae , Imipénem , Tests de sensibilité microbienne , Vancomycine , Animaux , Imipénem/pharmacologie , Antibactériens/pharmacologie , Biofilms/effets des médicaments et des substances chimiques , Humains , Vancomycine/pharmacologie , Infections à Flavobacteriaceae/microbiologie , Infections à Flavobacteriaceae/traitement médicamenteux , Flavobacteriaceae/effets des médicaments et des substances chimiques , Adhérence bactérienne/effets des médicaments et des substances chimiques , Cellules A549 , Cricetinae , Interactions médicamenteuses , Poumon/microbiologieRÉSUMÉ
OBJECTIVE: To describe patient characteristics, etiology, treatment outcomes and complications of caudoventral hip luxation (CvHL) in a large cohort of dogs and investigate factors associated with nonsurgical treatment outcomes. STUDY DESIGN: Multicenter retrospective case series. ANIMAL POPULATION: A total of 160 client-owned dogs (170 limbs). METHODS: Medical records from 2003 to 2023 were reviewed for signalment, history, treatment outcomes and complications. Logistic regression was performed to investigate factors associated with nonsurgical treatment outcome. RESULTS: Low-trauma accidents accounted for 82.9% of cases. Over-represented breeds included poodles (38.1%) and poodle crosses (11.3%). On a per-treatment basis, success rates of closed reduction alone, closed reduction/Ehmer sling, closed reduction/hobbles were 9.1%, 15.2% and 48.8%, respectively. When accounting for repeated attempts using closed reduction alone, Ehmer sling, or hobbles, eventual success rate increased to 10.3%, 18.5% and 61.8%, respectively. Success rate for toggle rod stabilization was 88.2%. Complication rate of hobbles was 31.9% versus 60.6% for Ehmer slings. Use of hobbles (OR:7.62, p = .001, CI:2.23-26.05), treatment by specialist surgeons (OR:2.68, p = .047, CI: 1.01-7.08) and increasing age (OR:1.15, p < .005, CI: 1.08-1.23) were associated with successful nonsurgical treatments. CONCLUSION: Low-trauma etiology, and poodles and their crosses were over-represented in cases of CvHL. Success rate of nonsurgical treatments was lower than previously reported. Hobbles were 7.6 times more likely to be successful when compared to dogs treated without hobbles and remains a viable noninvasive first-line treatment. CLINICAL SIGNIFICANCE/IMPACT: Hobbles are recommended as a low-morbidity first-line treatment for CvHL. An Ehmer sling is not recommended. Toggle rod stabilization is an effective surgical treatment for CvHL.
Sujet(s)
Luxation de la hanche , Animaux , Chiens/traumatismes , Études rétrospectives , Femelle , Mâle , Luxation de la hanche/médecine vétérinaire , Résultat thérapeutique , Maladies des chiens/thérapieRÉSUMÉ
rRNAs are prevalent in living organisms. They are produced in nucleolus and mitochondria and play essential cellular functions. In addition to the primary biofunction in protein synthesis, rRNAs have been recognized as the emerging signaling molecule and drug target for studies on nucleolus morphology, mitochondrial autophagy, and tumor cell malignancy. Currently, only a few rRNA-selective probes have been developed, and most of them encounter the drawbacks of low water solubility, poor nuclear membrane permeability, short emission wavelength, low stability against photobleaching, and high cytotoxicity. These unfavorable properties of rRNA probes limit their potential applications. In the present study, we reported a new rRNA-selective and near-infrared fluorescent turn-on probe, 4MPS-TO, capable of tracking rRNA in live human cancer cells. The real-time monitoring performance in nucleolus morphology and mitochondrial autophagy is demonstrated in HeLa cells. The probe shows great application potential for being used as a rRNA-selective, sensitive, and photostable imaging tool in chemical biology study and drug screening.
Sujet(s)
Mitophagie , Tumeurs , Humains , Cellules HeLa , Colorants fluorescents/composition chimique , Imagerie optique/méthodes , AutophagieRÉSUMÉ
This study examined the cognitive-linguistic and literacy-related correlates of dyslexia in three Chinese cities and the English word reading and mathematics performances of Chinese children with dyslexia. Chinese children with/without dyslexia were measured with an equivalent test battery of literacy and mathematics in Beijing, Hong Kong, and Taipei. Univariate analysis results suggested that phonological sensitivity distinguished those with and without dyslexia across all three cities in group comparisons. In Taipei and Hong Kong, morphological awareness, delayed copying, and spelling also distinguished the groups. Logistic regression analyses demonstrated that Chinese character reading, as directly compared to Chinese word reading, also distinguished the groups particularly well. In addition, in Beijing and Hong Kong, children with dyslexia performed significantly less well in English word reading than those without dyslexia. In Hong Kong and Taipei, children with dyslexia also had difficulties in mathematics performance. Findings highlight the fundamental importance of some cognitive-linguistic skills for explaining Chinese dyslexia across cultures, the utility of recognizing the individual Chinese character as a foundational unit of analysis in Chinese across cultures, and the generalizability of the comorbidity of both English as a second language (L2) and mathematics with dyslexia in Chinese children in both Beijing and Hong Kong.
Sujet(s)
Dyslexie , Humains , Hong Kong , Mâle , Enfant , Femelle , Dyslexie/physiopathologie , Taïwan , Lecture , Pékin/épidémiologie , Comparaison interculturelle , Performance scolaire/statistiques et données numériques , Cognition/physiologie , Asiatiques , Lettrisme/statistiques et données numériques , Multilinguisme , Chine/épidémiologieRÉSUMÉ
Al 6082 aluminum alloy has excellent corrosion resistance, strength, and formability. However, owing to the recrystallization effect of a hot working process, coarse grains form easily in this material, which reduces its strength and service life. The novel continuous casting direct rolling (CCDR) method can prevent the deterioration of this material. Thus, we used CCDR Al 6082 aluminum alloy as the research material in this study. By subjecting a CCDR Al 6082 aluminum alloy to heat treatment (T4 and T6) and cold rolling, the influence of recrystallization effect on its mechanical properties and on impact failure resistance were explored. The results demonstrated that the specimen subjected to T4 heat treatment had a higher elongation and that the specimen subjected to T6 heat treatment had a higher strength. After cold rolling, the hardness and strength of the specimens subjected to different heat treatments (coded T4R4 and T6R4) increased because of the work's hardening effect. Moreover, the elongations of both specimens decreased, but they were higher than the industrial standard (>10%). The strength of specimen T6R4 was higher (up to 400 MPa) than specimen T4R4. Moreover, relative to specimen T4R4, specimen T6R4 had greater tensile and Charpy impact failure toughness.
RÉSUMÉ
Contamination by pathogens, such as bacteria, can irritate a wound and prevent its healing, which may affect the physical fitness of the infected person. As such, the development of more novel nano-biomaterials able to cope with the inflammatory reaction to bacterial infection during the wound healing process to accelerate wound healing is required. Herein, a halofuginonesilver nano thermosensitive hydrogel (HTPM&AgNPs-gel) was prepared via a physical swelling method. HTPM&AgNPs-gel was characterized based on thermogravimetric analysis, differential scanning calorimetry, morphology, injectability, and rheological mechanics that reflected its exemplary nature. Moreover, HTPM&AgNPs-gel was further tested for its ability to facilitate healing of skin fibroblasts and exert antibacterial activity. Finally, HTPM&AgNPs-gel was tested for its capacity to accelerate general wound healing and treat bacterially induced wound damage. HTPM&AgNPs-gel appeared spherical under a transmission electron microscope and showed a grid structure under a scanning electron microscope. Additionally, HTPM&AgNPs-gel demonstrated excellent properties, including injectability, temperature-dependent swelling behavior, low loss at high temperatures, and appropriate rheological properties. Further, HTPM&AgNPs-gel was found to effectively promote healing of skin fibroblasts and inhibit the proliferation of Escherichia coli and Staphylococcus aureus. An evaluation of the wound healing efficacy demonstrated that HTPM&AgNPs-gel had a more pronounced ability to facilitate wound repair and antibacterial effects than HTPM-gel or AgNPs-gel alone, and exhibited ideal biocompatibility. Notably, HTPM&AgNPs-gel also inhibited inflammatory responses in the healing process. HTPM&AgNPs-gel exhibited antibacterial, anti-inflammatory, and scar repair features, which remarkably promoted wound healing. These findings indicated that HTPM&AgNPs-gel holds great clinical potential as a promising and valuable wound healing treatment.
Sujet(s)
Nanoparticules métalliques , Pipéridines , Quinazolinones , Argent , Humains , Argent/pharmacologie , Argent/composition chimique , Staphylococcus aureus , Cicatrisation de plaie , Nanoparticules métalliques/composition chimique , Antibactériens/pharmacologie , Hydrogels/composition chimique , Anti-inflammatoires/pharmacologieSujet(s)
Infections à Flavobacteriaceae , Humains , Association de pipéracilline et de tazobactam/pharmacologie , Antibactériens/pharmacologie , Pipéracilline/pharmacologie , Acide pénicillanique/pharmacologie , Tests de sensibilité microbienne , Association de médicaments , Inhibiteurs des bêta-lactamasesRÉSUMÉ
SUMMARY: Lying-ear deformity refers to an auricle that bends backward excessively, is excessively folded against the head, and has a very prominent antihelix. It usually requires experienced surgeons to perform surgical treatment and a prolonged postoperative recovery process. This article proposes a simple and effective hyaluronic acid injection technique that significantly improves the shape of the outer ear and enhances perceived facial aesthetics. Twenty patients underwent treatment with multiple injections. Measure-related parameters were used to evaluate the postoperative effect, and the results were graded using a visual analog scale. Interrater reliability among graders was evaluated using intraclass correlation coefficients. After treatment, no serious complications, such as infection or embolism, occurred. Six months after the procedure, the average auriculocephalic angle increased from 25.11 ± 9.46 to 32.72 ± 8.29 degrees, the average conchoscaphal angle increased from 87.69 ± 9.06 to 95.94 ± 7.11 degrees, and patients' average visual analog scale score increased from 4.40 ± 1.14 to 8.57 ± 0.68. Interrater reliability was fair to good for visual analog scale before injection and 6 months after injection (intraclass correlation coefficients, 0.49 and 0.45, respectively; both P < 0.001). The patients were satisfied with the injection process and results. This injection protocol improved the shape of the outer ear, resulting in excellent postoperative outcomes.
Sujet(s)
Auricule de l'oreille , , Humains , Reproductibilité des résultats , Oreille externe/chirurgie , Auricule de l'oreille/chirurgie , Transplantation de peau , Résultat thérapeutiqueRÉSUMÉ
Objective:To analyze the clinical and epidemiological characteristics of adult carotid body tumors (CBTs) in Northwest China to provide references for early diagnosis and treatment of CBTs.Methods:A multicenter, retrospective, non-intervention epidemiological investigation was conducted on adult CBTs patients who were hospitalized from January 1, 2011 to June 30, 2023 in 7 Class A tertiary hospitals in Northwest China (Departments of Neurosurgery, First Affiliated Hospital of Air Force Medical University, Second Affiliated Hospital of Lanzhou University, People's Hospital of Gansu Province, 940 th Hospital of PLA Joint Logistic Support Force, People's Hospital of Qinghai Province, General Hospital of Ningxia Medical University, People's Hospital of Ningxia Hui Autonomous Region). Medical records were collected in these patients, and they were divided into 2 groups according to their average altitude residence: high altitude group (≥1 500 m) and low altitude group (<1 500 m); meanwhile, these patients were divided into Shamblin type I, type II and type III groups according to Shamblin classification criteria; differences in general data and clinical features among patients from different altitude groups or Shamblin subgroups were compared. Independent influencing factors for Shamblin type III CBTs were analyzed by multivariate ordered Logistic regression. Results:(1) A total of 359 patients were enrolled in the study, including 276 females and 83 males, aged (48.80±12.07) years; 211 patients were into the high altitude group and 148 into the low altitude group; 165 patients were into Shamblin type I group, 146 into Shamblin type II group, and 48 into Shamblin type III group. (2) Compared with those in the low altitude group, patients in the high altitude group had higher proportion of females, older age, lower proportion of Han nationality, higher proportion of Shamblin type I, smaller tumor volume, lower platelet count, higher red blood cell count, hematocrit, hemoglobin level, platelet distribution width and mean platelet volume, and higher large platelet percentage, with significant differences ( P<0.05). (3) Compared with those in the Shamblin type I group, patients in the Shamblin type III group had younger age, lower resident altitude, larger tumor volume, longer time interval from onset to diagnosis, higher proportion of unintentional tumor discovery, larger volume of intraoperative blood loss, lower hemoglobin level, hematocrit, mean erythrocyte volume, and mean hemoglobin concentration, decreased erythrocyte distribution width variable coefficient, and increased platelet count, with significant differences ( P<0.05). Compared with those in the Shamblin type II group, patients in Shamblin type III group had younger age, larger tumor volume, longer time interval from onset to diagnosis, larger volume of intraoperative blood loss, lower hemoglobin, hematocrit and mean erythrocyte volume, higher erythrocyte distribution width variable coefficient and platelet count, with significant differences ( P<0.05). (4) Age ( OR=0.960, 95% CI: 0.942-0.977, P<0.001), residence altitude ( OR=0.992, 95% CI: 0.990-0.999, P=0.020) and time interval from onset to diagnosis ( OR=1.009, 95% CI: 1.005-1.014, P<0.001) were independent influencing factors for Shamblin type III CBTs. Conclusions:More females than males are noted in patients with adult CBTs in Northwest China, and more CBTs patients live at high altitude, with Shamblin type I enjoying the highest proportion. More female and old patients lived at high altitude is noted than those lived at low altitude; patients with Shamblin type III have the youngest age, lowest altitude, and longest time interval from onset to diagnosis. CBTs patients with young age, low residence altitude, and long time interval from onset to diagnosis are more likely to develop Shamblin type III.
RÉSUMÉ
Objective Based on the global burden of disease (GBD) study data, to analyze the current situation and changing trend of refractive disorders in China by comparing Japan, India, the United States, the United Kingdom and the world. Methods The prevalence, years lived with disability (YLD) rate of refractive disorders from 1990 to 2019 were obtained from the global health exchange (GHDx)database. The disease burden and change trend of refractive disorders were analyzed using Joinpoint and other software. Results In 2019, the number of refractive disorders in China exceeded 27 million, with the prevalence and YLD rate were 19.18‰ and 89.40/100,000 respectively. From 1990 to 2019, the prevalence and YLD rate of refractive disorders showed an increasing trend globally (except India), with the largest increase in China (up by 53.21% and 53.96% respectively). The age standardized YLD rates in China, Japan, the United States, and the United Kingdom were all lower than the global average level, but China's age standardized YLD rates were higher than the developed countries (Japan, the United States, and the United Kingdom). Conclusion From 1990 to 2019, there was a certain gap between China and developed countries in the control of refractive disorders. Therefore, it is necessary to understand the disease status from a global perspective in order to better prevent and control refractive disorders in the future.
RÉSUMÉ
PURPOSE: The aim of this study was to elucidate the factors associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that may initiate cytokine cascades and correlate the clinical characteristics of patients with coronavirus disease 2019 (COVID-19) with their serum cytokine profiles. METHODS: Recombinant baculoviruses displaying SARS-CoV-2 spike or nucleocapsid protein were constructed and transfected into A549 cells and THP-1-derived macrophages, to determine which protein initiate cytokine release. SARS-CoV-2-specific antibody titers and cytokine profiles of patients with COVID-19 were determined, and the results were associated with their clinical characteristics, such as development of pneumonia or length of hospital stay. RESULTS: The SARS-CoV-2 nucleocapsid protein, rather than the spike protein, triggers lung epithelial A549 cells to express IP-10, RANTES, IL-16, MIP-1α, basic FGF, eotaxin, IL-15, PDGF-BB, TRAIL, VEGF-A, and IL-5. Additionally, serum CTACK, basic FGF, GRO-α, IL-1α, IL-1RA, IL-2Rα, IL-9, IL-15, IL-16, IL-18, IP-10, M-CSF, MIF, MIG, RANTES, SCGF-ß, SDF-1α, TNF-α, TNF-ß, VEGF, PDGF-BB, TRAIL, ß-NGF, eotaxin, GM-CSF, IFN-α2, INF-γ, and MCP-1 levels were considerably increased in patients with COVID-19. Among them, patients with pneumonia had higher serum IP-10 and M-CSF levels than patients without. Patients requiring less than 3 weeks to show negative COVID-19 tests after contracting COVID-19 had higher serum IP-10 levels than the remaining patients. CONCLUSION: Our study revealed that nucleocapsid protein, lung epithelial cells, and IP-10 may be potential targets for the development of new strategies to prevent, or control, severe COVID-19.
Sujet(s)
COVID-19 , Protéines de la nucléocapside des coronavirus , Cytokines , Cellules épithéliales , SARS-CoV-2 , Glycoprotéine de spicule des coronavirus , Humains , COVID-19/immunologie , COVID-19/sang , Glycoprotéine de spicule des coronavirus/immunologie , SARS-CoV-2/immunologie , Cytokines/sang , Femelle , Mâle , Adulte d'âge moyen , Cellules épithéliales/virologie , Cellules épithéliales/immunologie , Protéines de la nucléocapside des coronavirus/immunologie , Sujet âgé , Cellules A549 , Poumon/anatomopathologie , Poumon/immunologie , Syndrome de libération de cytokines/immunologie , Syndrome de libération de cytokines/sang , Adulte , Anticorps antiviraux/sang , PhosphoprotéinesRÉSUMÉ
The incidence of zoonotic diseases, such as coronavirus disease 2019 and Ebola virus disease, is increasing worldwide. However, drug and vaccine development for zoonotic diseases has been hampered because the experiments involving live viruses are limited to high-containment laboratories. The Ebola virus minigenome system enables researchers to study the Ebola virus under BSL-2 conditions. Here, we found that the addition of the nucleocapsid protein of human coronaviruses, such as severe acute respiratory syndrome coronavirus 2, can increase the ratio of green fluorescent protein-positive cells by 1.5-2 folds in the Ebola virus minigenome system. Further analysis showed that the nucleocapsid protein acts as an activator of the Ebola virus minigenome system. Here, we developed an EBOV MiniG Plus system based on the Ebola virus minigenome system by adding the SARS-CoV-2 nucleocapsid protein. By evaluating the antiviral effect of remdesivir and rupintrivir, we demonstrated that compared to that of the traditional Ebola virus minigenome system, significant concentration-dependent activity was observed in the EBOV MiniG Plus system. Taken together, these results demonstrate the utility of adding nucleocapsid protein to the Ebola virus minigenome system to create a powerful platform for screening antiviral drugs against the Ebola virus.
RÉSUMÉ
This study focuses on the additive manufacturing technique of selective laser melting (SLM) to produce Ti-6Al-4V-Zn titanium alloy. The addition of zinc at 0.3 wt.% was investigated to improve the strength and ductility of SLM Ti-6Al-4V alloys. The microstructure and mechanical properties were analyzed using different vacuum heat treatment processes, with the 800-4-FC specimen exhibiting the most favorable overall mechanical properties. Additionally, zinc serves as a stabilizing element for the ß phase, enhancing the resistance to particle erosion and corrosion impedance of Ti-6Al-4V-Zn alloy. Furthermore, the incorporation of trace amounts of Zn imparts improved impact toughness and stabilized high-temperature tensile mechanical properties to SLM Ti-6Al-4V-Zn alloy. The data obtained serve as valuable references for the application of SLM-64Ti.
RÉSUMÉ
OBJECTIVE: To study the efficacy and mechanism of three phenylethanoid glycosides (PhGs) (verbascoside, echinacoside, and crenatoside) on altitude-induced fatigue in rats. METHODS: Altitude-induced fatigue model rats were established in a large hypobaric chamber. Swimming time, energy storage substances, metabolic enzymes, and metabolites were used to evaluate the anti-fatigue activities and mechanism of three PhGs (verbascoside, echinacoside, and crenatoside) (150 mg/kg, intragastric administration) in the hypoxic environment. RESULTS: The three PhGs, especially verbascoside, could prolong the swimming time of rats, ameliorate the edema and inflammatory infiltration of liver and skeletal muscle, increase the level of energy storage substances, reduce the decomposition of proteins, and exhibit positive effects on the metabolism-related enzyme activity and metabolites. CONCLUSIONS: The PhGs, especially verbascoside, are very potential with anti-fatigue activity in hypoxia. The mechanism may be explained with regulation of energy metabolism and reduction of oxidative stress.
Sujet(s)
Altitude , Hétérosides , Animaux , Rats , Hétérosides/usage thérapeutique , Hypoxie/traitement médicamenteux , Phénols/usage thérapeutiqueRÉSUMÉ
Chondrosarcoma, a treatment-resistant cancer with limited therapeutic options, lacks significant advancements in treatment methods. However, PR-619, a novel inhibitor of deubiquitinating enzymes, has demonstrated anti-tumor effects in various malignancies. This study aimed to investigate the impact of PR-619 on chondrosarcoma both in vitro and in vivo. Two human chondrosarcoma cell lines, SW11353 and JJ012, were utilized. Cell viability was assessed using an MTT assay, while flow cytometry enabled the detection of apoptosis and cell cycle progression. Western blotting analyses were conducted to evaluate apoptosis, cell stress, and endoplasmic reticulum (ER) stress. Furthermore, the in vivo anti-tumor effects of PR-619 were examined using a xenograft mouse model. The results revealed that PR-619 induced cytotoxicity, apoptosis, and cell cycle arrest at the G0/G1 stage by activating caspases, PARP cleavage, and p21. Moreover, PR-619 increased the accumulation of polyubiquitinated proteins and ER stress by activating IRE1, GRP78, caspase-4, CHOP, and other cellular stress responses, including JNK activation. In vivo analysis demonstrated that PR-619 effectively inhibited tumor growth with minimal toxicity in the xenograft mouse model. These findings provide evidence of the anti-tumor effects and induction of cellular and ER stress by PR-619 in human chondrosarcoma, suggesting its potential as a novel therapeutic strategy for in human chondrosarcoma.
RÉSUMÉ
BACKGROUND: Modifications of lipid metabolism were closely associated with the manifestations and prognosis of coronavirus disease of 2019 (COVID-19). Pre-existing metabolic conditions exacerbated the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection while modulations of aberrant lipid metabolisms alleviated the manifestations. To elucidate the underlying mechanisms, an experimental platform that reproduces human respiratory physiology is required. METHODS: Here we generated induced pluripotent stem cell-derived airway organoids (iPSC-AOs) that resemble the human native airway. Single-cell sequencing (ScRNAseq) and microscopic examination verified the cellular heterogeneity and microstructures of iPSC-AOs, respectively. We subjected iPSC-AOs to SARS-CoV-2 infection and investigated the treatment effect of lipid modifiers statin drugs on viral pathogenesis, gene expression, and the intracellular trafficking of the SARS-CoV-2 entry receptor angiotensin-converting enzyme-2 (ACE-2). RESULTS: In SARS-CoV-2-infected iPSC-AOs, immunofluorescence staining detected the SARS-CoV-2 spike (S) and nucleocapsid (N) proteins and bioinformatics analysis further showed the aberrant enrichment of lipid-associated pathways. In addition, SARS-CoV-2 hijacked the host RNA replication machinery and generated the new isoforms of a high-density lipoprotein constituent apolipoprotein A1 (APOA1) and the virus-scavenging protein deleted in malignant brain tumors 1 (DMBT1). Manipulating lipid homeostasis using cholesterol-lowering drugs (e.g. Statins) relocated the viral entry receptor angiotensin-converting enzyme-2 (ACE-2) and decreased N protein expression, leading to the reduction of SARS-CoV-2 entry and replication. The same lipid modifications suppressed the entry of luciferase-expressing SARS-CoV-2 pseudoviruses containing the S proteins derived from different SARS-CoV-2 variants, i.e. wild-type, alpha, delta, and omicron. CONCLUSIONS: Together, our data demonstrated that modifications of lipid pathways restrict SARS-CoV-2 propagation in the iPSC-AOs, which the inhibition is speculated through the translocation of ACE2 from the cell membrane to the cytosol. Considering the highly frequent mutation and generation of SARS-CoV-2 variants, targeting host metabolisms of cholesterol or other lipids may represent an alternative approach against SARS-CoV-2 infection.
RÉSUMÉ
BACKGROUND: Cryopreserved fat has limited clinical applications due to its rapid absorption, high degree of fibrosis, and risk of complications after grafting. Many studies have verified that Adipose-derived mesenchymal stem cell-derived exosomes (ADSC-Exos) can improve fresh fat graft survival. This study assessed whether ADSC-Exos could improve the survival of cryopreserved fat grafts. METHODS: Exosomes were isolated from human ADSCs were subcutaneously engrafted with adipose tissues stored under different conditions (fresh; cryopreserved for 1 month) into the backs of BALB/c nude mice (n = 24), and exosomes or PBS were administered weekly. Grafts were harvested at 1, 2, 4, and 8 weeks, and fat retention rate, histologic, and immunohistochemical analyses were conducted. RESULTS: At 1, 2, and 4 weeks after the transfer, cryopreserved fat grafts in groups of exosome-treated showed better fat integrity, fewer oil cysts, and reduced fibrosis. Further investigations of macrophage infiltration and neovascularization revealed that those exosomes increased the number of M2 macrophages at 2 and 4 weeks (p<0.05), but had limited impact on vascularization (p>0.05). It's important to note that no significant differences (p>0.05) were observed between the two groups in both histological and immunohistochemical evaluations at 8 weeks post-transplantation. CONCLUSIONS: This study suggests that ADSC-Exos could improve the survival of cryopreserved fat grafts in the short term (within 4 weeks), but the overall improvement was poor (after 8 weeks). This suggests that the utility of using ADSC-Exos to treat cryopreserved adipose tissue grafts is limited. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .