ABSTRACT
Nasopharyngeal carcinoma (NPC) is a malignant tumor of epithelial origin in head and neck with high incidence rate in South China, Southeast Asia and North Africa. The intervention of tumor-associated macrophages (Mφs) (TAMs)-mediated immunosuppression is a potential therapeutic strategy against tumor metastasis, but the exact mechanisms of TAM-mediated immunosuppression in nasopharyngeal carcinoma are unclear. Furthermore, how TAM affects the occurrence and development of nasopharyngeal carcinoma through metabolism is rarely involved. In this work, we revealed that NPC cells promoted M2-type Mφ polarization and elevated itaconic acid (ITA) release. Also, TAMs facilitated NPC cell proliferation, migration, and invasion through immune response gene 1 (IRG1)-catalyzed ITA production. Then, IRG1-mediated ITA production in TAMs repressed the killing of CD8+ T cells, induced M2-type polarization of TAMs, and reduced the phagocytosis of TAMs. Moreover, we demonstrated ITA played a tumor immunosuppressive role by binding and dampening ten-eleven translocation-2 (TET2) expression. Finally, we proved that ITA promotes NPC growth by facilitating immune escape in CD34+ hematopoietic stem cell humanized mice. In Conclusion, TAM-derived ITA facilitated NPC progression by enhancing immune escape through targeting TET2, highlighting that interfering with the metabolic pathway of ITA may be a potential strategy for NPC treatment.
Subject(s)
DNA-Binding Proteins , Dioxygenases , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Proto-Oncogene Proteins , Succinates , Tumor Escape , Tumor-Associated Macrophages , Nasopharyngeal Carcinoma/pathology , Nasopharyngeal Carcinoma/immunology , Tumor-Associated Macrophages/immunology , Tumor-Associated Macrophages/metabolism , Humans , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Animals , Mice , Succinates/pharmacology , Nasopharyngeal Neoplasms/pathology , Nasopharyngeal Neoplasms/immunology , Nasopharyngeal Neoplasms/metabolism , Cell Line, Tumor , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins/genetics , Disease Progression , Cell Proliferation , Cell Movement/drug effects , CD8-Positive T-Lymphocytes/immunology , Carboxy-LyasesABSTRACT
OBJECTIVE: The aim of this study is to evaluate the impact of methylprednisolone (MP) on scar composition following spinal cord injury (SCI). DESIGN: A total of 40 adult Sprague Dawley rats underwent right hemisection injuries to the spinal cord. INTERVENTIONS: The rats were randomly divided into two groups: the vehicle group and the MP group. In the MP group, rats received intraperitoneal injections of MP at a dose of 30 mg/kg for 7 consecutive days, while the vehicle group received intraperitoneal injections of saline as a control. Weekly assessments of hindlimb performance in the rat models were conducted using the Basso-Beattie-Bresnahan test (BBB) score and the horizontal ladder-walking test. Changes in scar components were identified through immunofluorescence staining, and an axonal regeneration assay was employed to evaluate regrowth under inhibitory conditions. RESULTS: The administration of MP led to a significant improvement in BBB scores compared to the control group at 7 days post-injury, although this improvement was not consistent. Furthermore, rats in the MP group did not demonstrate progressive improvement in horizontal ladder walking. Notably, there were no significant changes in the content of scar components in the injured area following MP treatment, and the axon length of neurons treated with MP did not exhibit significant extension compared to the vehicle group. CONCLUSIONS: Our findings indicate that the administration of MP does not effectively enhance hindlimb motor function or promote neuronal axon growth within a scarred environment after SCI.
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BACKGROUND: Patients with stroke frequently experience pulmonary dysfunction. AIM: To explore the effects of information-motivation-behavioral (IMB) skills model-based nursing care on pulmonary function, blood gas indices, complication rates, and quality of life (QoL) in stroke patients with pulmonary dysfunction. METHODS: We conducted a controlled study involving 120 stroke patients with pulmonary dysfunction. The control group received routine care, whereas the intervention group received IMB-model-based nursing care. Various parameters including pulmonary function, blood gas indices, complication rates, and QoL were assessed before and after the intervention. RESULTS: Baseline data of the control and intervention groups were comparable. Post-intervention, the IMB model-based care group showed significant improvements in pulmonary function indicators, forced expiratory volume in 1 sec, forced vital capacity, and peak expiratory flow compared with the control group. Blood gas indices, such as arterial oxygen pressure and arterial oxygen saturation, increased significantly, and arterial carbon dioxide partial. pressure decreased significantly in the IMB model-based care group compared with the control group. The intervention group also had a lower complication rate (6.67% vs 23.33%) and higher QoL scores across all domains than the control group. CONCLUSION: IMB model-based nursing care significantly enhanced pulmonary function, improved blood gas indices, reduced complication rates, and improved the QoL of stroke patients with pulmonary dysfunction. Further research is needed to validate these results and to assess the long-term efficacy and broader applicability of the model.
ABSTRACT
The development of necroptosis inhibitors has emerged as a promising strategy to effectively mitigate necroptosis-related inflammatory diseases, neurodegenerative diseases, and cancers. In this paper, we reported a series of 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole derivatives as potent necroptosis inhibitors. The representative compound 26 displayed potent anti-necroptotic activity in both human and mouse cellular assays and exhibited potent inhibitory activity against receptor-interacting protein kinase 1 (RIPK1). In vivo pharmacokinetic studies were performed to determine the oral exposure of compound 26. Finally, molecular docking elucidated that compound 26 could effectively bind to the allosteric pocket of RIPK1 and serve as a type III inhibitor. Taken together, our findings highlighted that compound 26 represented a promising lead compound for future necroptosis inhibitor development.
ABSTRACT
Mitogen-activated protein kinase-activated protein kinase 2 (MK2) emerges as a pivotal target in developing anti-cancer therapies. The limitations of ATP-competitive inhibitors, due to insufficient potency and selectivity, underscore the urgent need for a covalent irreversible MK2 inhibitor. Our initial analyses of The Cancer Genome Atlas database revealed MK2's overexpression across various cancer types, especially those characterized by inflammation, linking it to poor prognosis and highlighting its significance. Investigating MK2's kinase domain led to the identification of a unique cysteine residue, enabling the creation of targeted covalent inhibitors. Compound 11 was developed, demonstrating robust MK2 inhibition (IC50 = 2.3 nM) and high selectivity. It binds irreversibly to MK2, achieving prolonged signal suppression and reducing pathological inflammatory cytokines in macrophages. Furthermore, compound 11 or MK2 knockdown can inhibit the tumor-promoting macrophage M2 phenotype in vitro and in vivo. In macrophage-rich tumor model, compound 11 notably slowed growth in a dose-dependent manner. These findings support MK2 as a promising anticancer target, especially relevant in cancers fueled by inflammation or dominated by macrophages, and provide compound 11 serving as an invaluable chemical tool for exploring MK2's functions.
ABSTRACT
BACKGROUND: Preserving laryngeal function after partial laryngectomy for laryngeal cancer is an important consideration. Therefore, we examined the use of thyroid flaps for this purpose. METHODS: We analyzed 21 patients who underwent thyroid flap reconstruction after partial laryngectomy for laryngeal cancer in the Department of Otorhinolaryngology Head and Neck Surgery, the Second Xiangya Hospital of Central South University from January 2010 to January 2020. All patients were male and aged 51-64 years. Seventeen patients underwent modified tracheocricohyoidoepiglottopexy, and the remaining four patients underwent modified cricohyoidopexy. The thyroid flap was pedicled from the superior thyroid blood vessels. In the modified tracheocricohyoidoepiglottopexy, the flap was turned to cover the area between the tracheal ring and epiglottis to reconstruct the anterior wall of the cricoid cartilage, whereas in the modified cricohyoidopexy, it was turned over between the cricoid cartilage and tongue root to reduce anastomotic tension. A total of seven patients underwent radiotherapy and chemotherapy after surgery. RESULTS: Thyroid flap reconstruction was successfully performed in all patients. The postoperative hospitalization time was 9-21 days, the postoperative nasal feeding time was 18-47 days, and the tracheotomy tube was removed 30-160 days after surgery. No laryngeal stenosis, flap necrosis, bleeding complication, or dysfunction of the thyroid and parathyroid glands was observed after surgery. Two patients experienced wound infections about 1 week after discharge and were admitted again for antibiotic treatment. After dressing and compressing the neck wound, the patients were discharged. Three patients experienced local tumor recurrence after surgery, two of whom did not receive radiotherapy and chemotherapy after modified tracheocricohyoidoepiglottopexy. No patients had distant metastasis after surgery. CONCLUSIONS: Thyroid flaps have significant application value in the reconstruction of the laryngeal cavity after partial laryngectomy for laryngeal cancer. It has high safety and feasibility, convenient surgical procedure, and satisfactory postoperative outcomes.
ABSTRACT
Necroptosis is a form of regulated necrotic cell death and has been confirmed to play pivotal roles in the pathogenesis of multiple autoimmune diseases such as rheumatoid arthritis (RA) and psoriasis. The development of necroptosis inhibitors may offer a promising therapeutic strategy for the treatment of these autoimmune diseases. Herein, starting from the in-house hit compound 1, we systematically performed structural optimization to discover potent necroptosis inhibitors with good pharmacokinetic profiles. The resulting compound 33 was a potent necroptosis inhibitor for both human I2.1 cells (IC50 < 0.2 nM) and murine Hepa1-6 cells (IC50 < 5 nM). Further target identification revealed that compound 33 was an inhibitor of receptor interacting protein kinase 1 (RIPK1) with favorable selectivity. In addition, compound 33 also exhibited favorable pharmacokinetic profiles (T1/2 = 1.32 h, AUC = 1157 ng·h/mL) in Sprague-Dawley rats. Molecular docking and molecular dynamics simulations confirmed that compound 33 could bind to RIPK1 with high affinity. In silico ADMET analysis demonstrated that compound 33 possesses good drug-likeness profiles. Collectively, compound 33 is a promising candidate for antinecroptotic drug discovery.
ABSTRACT
Seven new 13,14-seco withaphysalins including two new skeletons (1 and 9) were isolated from the whole plants of Physalis minima, together with three known analogues (6-8). Among them, compound 1 was an extremely rare steroid with a 6, 8-cyclo ring. Their structures were established by extensive analysis of spectroscopic data, experimental electronic circular dichroism measurements, and single-crystal X-ray crystallographic analysis. In Raw264.7 cells, compounds 1-3, 5, 6, and 8 demonstrated potent ability to reduce the NLRP3-dependent caspase-1 activation. Among these compounds, 1 and 2 showed a superior potential, consistently concentration-dependent downregulating NLRP3-dependent proinflammatory cytokine IL-1ß production in macrophage. Mechanistically, compounds 1 and 2 reduced the cleavage of caspase-1 and GSDMD, and exhibited no obvious impact both on the NF-κB activation and the expression of NLRP3 and IL-1ß, suggesting that the compounds target the activation of the NLRP3 pathway mainly by inhibiting the NLRP3 inflammasome activation step rather than the priming step.
Subject(s)
Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Physalis , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Mice , Animals , Physalis/chemistry , Inflammasomes/metabolism , Inflammasomes/antagonists & inhibitors , RAW 264.7 Cells , Molecular Structure , Structure-Activity Relationship , Dose-Response Relationship, Drug , Interleukin-1beta/metabolism , Interleukin-1beta/antagonists & inhibitorsABSTRACT
Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon compound that is generated during combustion processes, and is present in various substances such as foods, tobacco smoke, and burning emissions. BaP is extensively acknowledged as a highly carcinogenic substance to induce multiple forms of cancer, such as lung cancer, skin cancer, and stomach cancer. Recently it is shown to adversely affect the reproductive system. Nevertheless, the potential toxicity of BaP on oocyte quality remains unclear. In this study, we established a BaP exposure model via mouse oral gavage and found that BaP exposure resulted in a notable decrease in the ovarian weight, number of GV oocytes in ovarian, and oocyte maturation competence. BaP exposure caused ribosomal dysfunction, characterized by a decrease in the expression of RPS3 and HPG in oocytes. BaP exposure also caused abnormal distribution of the endoplasmic reticulum (ER) and induced ER stress, as indicated by increased expression of GRP78. Besides, the Golgi apparatus exhibited an abnormal localization pattern, which was confirmed by the GM130 localization. Disruption of vesicle transport processes was observed by the abnormal expression and localization of Rab10. Additionally, an enhanced lysosome and LC3 fluorescence intensity indicated the occurrence of protein degradation in oocytes. In summary, our results suggested that BaP exposure disrupted the distribution and functioning of organelles, consequently affecting the developmental competence of mouse oocytes.
Subject(s)
Benzo(a)pyrene , Endoplasmic Reticulum Chaperone BiP , Oocytes , Animals , Benzo(a)pyrene/toxicity , Oocytes/drug effects , Female , Mice , Endoplasmic Reticulum Stress/drug effects , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/metabolism , Golgi Apparatus/drug effects , Golgi Apparatus/metabolism , Organelles/drug effects , Mice, Inbred ICRABSTRACT
The primary purpose of genetic improvement in lean pig breeds is to enhance production performance. Owing to their similar breeding directions, Duroc and Pietrain pigs are ideal models for investigating the phenotypic convergence underlying artificial selection. However, most important economic traits are controlled by a polygenic basis, so traditional strategies for detecting selection signatures may not fully reveal the genetic basis of complex traits. The pathway-based gene network analysis method utilizes each pathway as a unit, overcoming the limitations of traditional strategies for detecting selection signatures by revealing the selection of complex biological processes. Here, we utilized 13 122 398 high-quality SNPs from whole-genome sequencing data of 48 Pietrain pigs, 156 Duroc pigs and 36 European wild boars to detect selective signatures. After calculating FST and iHS scores, we integrated the pathway information and utilized the r/bioconductor graphite and signet packages to construct gene networks, identify subnets and uncover candidate genes underlying selection. Using the traditional strategy, a total of 47 genomic regions exhibiting parallel selection were identified. The enriched genes, including INO80, FZR1, LEPR and FAF1, may be associated with reproduction, fat deposition and skeletal development. Using the pathway-based selection signatures detection method, we identified two significant biological pathways and eight potential candidate genes underlying parallel selection, such as VTN, FN1 and ITGAV. This study presents a novel strategy for investigating the genetic basis of complex traits and elucidating the phenotypic convergence underlying artificial selection, by integrating traditional selection signature methods with pathway-based gene network analysis.
Subject(s)
Phenotype , Polymorphism, Single Nucleotide , Selection, Genetic , Sus scrofa , Animals , Sus scrofa/genetics , Male , Breeding , Gene Regulatory NetworksABSTRACT
Background: Fat overload syndrome is a rare and severe adverse reaction triggered by the infusion of a single source of lipid emulsion, resulting in elevated blood triacylglycerol (TG) levels. The majority of literature reports focus on cases of fat overload syndrome in patients with mild symptoms. This case is significant because it demonstrates the diagnostic and therapeutic experience and provide valuable insights for the management for severe fat overload syndrome. Case Presentation: We present a case report of a female patient who developed fat overload syndrome following prolonged and excessive infusion of lipid emulsion after colon resection surgery. In the setting of compromised immune function and malnutrition, the patient's pulmonary infection and respiratory distress symptoms have further exacerbated. Hence, in addition to severe pancreatitis, the patient has also contracted severe pneumonia. Upon admission, tracheal intubation, plasma exchange and blood perfusion were performed. Subsequently, comprehensive treatment was provided, including anti-infection, antispasmodic, acid suppression, enzyme inhibition, as well as targeted supportive measures to stabilize electrolytes and nutritional status. After treatment, there was a progressive reduction in blood lipid levels. After assessing the relevant risks, it was deemed necessary to perform an emergency computed tomography (CT)-guided percutaneous drainage tube placement procedure targeting the necrotic area of the pancreas while the patient was still intubated. Finally, the patient was discharged from the hospital. Conclusion: The case highlights the association between fat overload syndrome and pancreatitis as well as the use of lipid emulsions and suggests the treatment strategies for severe fat overload syndrome.
ABSTRACT
Monitoring urban structure and development requires high-quality data at high spatio-temporal resolution. While traditional censuses have provided foundational insights into demographic and socio-economic aspects of urban life, their pace may not always align with the pace of urban development. To complement these traditional methods, we explore the potential of analysing alternative big-data sources, such as human mobility data. However, these often noisy and unstructured big data pose new challenges. Here, we propose a method to extract meaningful explanatory variables and classifications from such data. Using movement data from Beijing, which are produced as a by-product of mobile communication, we show that meaningful features can be extracted, revealing, for example, the emergence and absorption of subcentres. This method allows the analysis of urban dynamics at a high-spatial resolution (here 500 m) and near real-time frequency, and high computational efficiency, which is especially suitable for tracing event-driven mobility changes and their impact on urban structures.
Subject(s)
Censuses , Humans , Beijing , Urban Renewal , Urban Population , Population DynamicsABSTRACT
The forefront of micro- and nanorobot research involves the development of smart swimming micromachines emulating the complexity of natural systems, such as the swarming and collective behaviors typically observed in animals and microorganisms, for efficient task execution. This study introduces magnetically controlled microrobots that possess polymeric sequestrant "hands" decorating a magnetic core. Under the influence of external magnetic fields, the functionalized magnetic beads dynamically self-assemble from individual microparticles into well-defined rotating planes of diverse dimensions, allowing modulation of their propulsion speed, and exhibiting a collective motion. These mobile microrobotic swarms can actively capture free-swimming bacteria and dispersed microplastics "on-the-fly", thereby cleaning aquatic environments. Unlike conventional methods, these microrobots can be collected from the complex media and can release the captured contaminants in a second vessel in a controllable manner, that is, using ultrasound, offering a sustainable solution for repeated use in decontamination processes. Additionally, the residual water is subjected to UV irradiation to eliminate any remaining bacteria, providing a comprehensive cleaning solution. In summary, this study shows a swarming microrobot design for water decontamination processes.
Subject(s)
Microplastics , Robotics , Microplastics/chemistry , Robotics/instrumentation , Polymers/chemistry , Bacteria/isolation & purification , Water/chemistry , Magnetic Fields , Escherichia coli/isolation & purification , Particle SizeABSTRACT
Both epidemiological and animal studies suggest that adverse environment during pregnancy can change the offspring development programming, but it is difficult to achieve prenatal early warning. In this study we investigated the impact of prenatal dexamethasone exposure (PDE) on sperm quality and function of blood-testis barrier (BTB) in adult offspring and the underlying mechanisms. Pregnant rats were injected with dexamethasone (0.1, 0.2 and 0.4 mg·kg-1·d-1, s.c.) from GD9 to GD20. After weaning (PW4), the pups were fed with lab chow. At PW12 and PW28, the male offspring were euthanized to collect blood and testes samples. We showed that PDE significantly decreased sperm quality (including quantity and motility) in male offspring, which was associated with impaired BTB and decreased CX43/E-cadherin expression in the testis. We demonstrated that PDE induced morphological abnormalities of fetal testicle and Sertoli cell development originated from intrauterine. By tracing to fetal testicular Sertoli cells, we found that PDE dose-dependently increased expression of histone lysine demethylases (KDM1B), decreasing histone 3 lysine 9 dimethylation (H3K9me2) levels of follistatin-like-3 (FSTL3) promoter region and increased FSTL3 expression, and inhibited TGFß signaling and CX43/E-cadherin expression in offspring before and after birth. These results were validated in TM4 Sertoli cells following dexamethasone treatment. Meanwhile, the H3K9me2 levels of FSTL3 promoter in maternal peripheral blood mononuclear cell (PBMC) and placenta were decreased and its expression increased, which was positively correlated with the changes in offspring testis. Based on analysis of human samples, we found that the H3K9me2 levels of FSTL3 promoter in maternal blood PBMC and placenta were positively correlated with fetal blood testosterone levels after prenatal dexamethasone exposure. We conclude that PDE can reduce sperm quality in adult offspring rats, which is related to the damage of testis BTB via epigenetic modification and change of FSTL3 expression in Sertoli cells. The H3K9me2 levels of the FSTL3 promoter and its expression in the maternal blood PBMC can be used as a prenatal warning marker for fetal testicular dysplasia.
Subject(s)
Blood-Testis Barrier , Dexamethasone , Prenatal Exposure Delayed Effects , Signal Transduction , Animals , Male , Female , Pregnancy , Dexamethasone/toxicity , Prenatal Exposure Delayed Effects/chemically induced , Blood-Testis Barrier/drug effects , Blood-Testis Barrier/metabolism , Signal Transduction/drug effects , Rats , Spermatozoa/drug effects , Spermatozoa/metabolism , Transforming Growth Factor beta/metabolism , Rats, Sprague-Dawley , Sertoli Cells/drug effects , Sertoli Cells/metabolism , Testis/drug effects , Testis/metabolism , Testis/pathologyABSTRACT
OBJECTIVE: The aim of this study was to explore the laboratory results in severe as asthma patients with omalizumab therapy and provide evidence for estimating omalizumab efficacy. METHODS: Retrospective study of 18 patients with severe asthma received omalizumab therapy in Shanghai General Hospital from 2020 to 2022 was performed. The basic data of patients were collected. The absolute number and the percentage of basophil and eosinophil in peripheral blood, total IgE level in serum, and as pulmonary function were detected at the beginning of treatment and 4 months after treatment. Differences between two groups were analyzed using Paired T test. RESULTS: The most common allergens collected from patients with moderate to severe asthma were dust mite (positive ratio 55.56%), mixed mold (16.67%), cat and dog dander, and Aspergillus fumigatus (11.11%). There was no significant difference in eosinophil and basophil counts in peripheral blood between the two groups. However, serum total IgE levels increased from (437.55±279.35) KU/L to (1071.42±721.28) KU/L (P=0.004), and FEV1/FVC ratio increased from (65.53±14.15)% to (73.91±13.63)% (P=0.005) after 4 months of treatment. CONCLUSIONS: The existing laboratory indicators for evaluation of omalizumab efficacy are still very limited, and new biomarkers need to be further developed. Elevated serum IgE levels at four weeks of treatment and FEV1/FVC may be potential indicators for omalizumab monitoring.
ABSTRACT
The excessive usage of veterinary antibiotics has raised significant concerns regarding their environmental hazard and agricultural impact when entering surface water and soil. Animal waste serves as a primary source of organic fertilizer for intensive large-scale agricultural cultivation, including the widely utilized medicinal and edible plant, Polygonatum cyrtonem. In this study, we employed a novel plant stress tissue culture technology to investigate the toxic effects of tetracycline hydrochloride (TCH) and sulfadiazine (SDZ) on P. cyrtonema. TCH and SDZ exhibited varying degrees of influence on plant growth, photosynthesis, and the reactive oxygen species (ROS) scavenging system. Flavonoid levels increased following exposure to TCH and SDZ. The biosynthesis and signaling pathways of the growth hormones auxin and gibberellic acid were suppressed by both antibiotics, while the salicylic acid-mediated plant stress response was specifically induced in the case of SDZ. Overall, the study unveiled both common and unique responses at physiological, biochemical, and molecular levels in P. cyrtonema following exposure to two distinct types of antibiotics, providing a foundational framework for comprehensively elucidating the precise toxic effects of antibiotics and the versatile adaptive mechanisms in plants.
Subject(s)
Anti-Bacterial Agents , Polygonatum , Anti-Bacterial Agents/toxicity , Photosynthesis , Plant Growth Regulators , Polygonatum/chemistry , Sulfadiazine , Tetracycline , TranscriptomeABSTRACT
Tropomyosin receptor kinase (TRK) fusion, an oncogenic form of kinase with pan-tumor occurrence, is a clinically validated important antitumor target. In this study, we screened our in-house kinase inhibitor library against TRK and identified a promising hit compound 4 with a novel pyridin-2(1H)-one scaffold. Through a combination of structure-based drug design and structure-activity relationship (SAR) study, compound 14q was identified as a potent TRK inhibitor with good kinase selectivity. It also blocked cellular TRK signaling, thereby inhibiting TRK-dependent cell viability. Additionally, 14q displayed acceptable pharmacokinetic properties with 37.8% oral bioavailability in mice. Strong in vivo tumor growth inhibition of 14q was observed in subcutaneous M091 and KM12 tumor xenograft models with TRK fusion, causing significant tumor inhibition or even complete tumor regression.
Subject(s)
Antineoplastic Agents , Neoplasms , Animals , Humans , Mice , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Neoplasms/pathology , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacokinetics , Receptor, trkA , Signal Transduction , Structure-Activity Relationship , Pyridones/chemistry , Pyridones/pharmacologyABSTRACT
Exposure to organic ultraviolet (UV) filters has raised concerns due to their potential adverse effects on environments. However, their toxic mechanisms on plants remain elusive. In this study, using integrative physiological and transcriptomic approaches we investigated the physiological and molecular responses to three representative UV filters, namely oxybenzone (OBZ), avobenzone (AVB), and octinoxate (OMC), in an agricultural model plant tobacco. The exposure to UV filters disrupts the functionality of photosystem reaction centers and the light-harvesting apparatus. Concurrently, UV filters exert a suppressive effect on the expression of genes encoding Rubisco and Calvin-Benson cycle enzymes, resulting in a decreased efficiency of the Calvin-Benson cycle and consequently hampering the process of photosynthesis. Exposure to UV filters leads to significant generation of reactive oxygen species within tobacco leaves and downregulation of oxidoreductase activities. Moreover, UV filters promote abscisic acid (ABA) accumulation by inducing the expression of ABA biosynthesis genes whereas repress indole-3-acetic acid (IAA) biosynthesis gene expression, which induce leaf yellowing and slow plant growth. In summary, the organic UV filters exert toxic effects on tobacco growth by inhibiting chlorophyll synthesis, photosynthesis, and the Calvin-Benson cycle, while generating excessive reactive oxygen species. This study sheds light on the toxic and tolerance mechanisms of UV filters in agricultural crops.
Subject(s)
Nicotiana , Ultraviolet Rays , Reactive Oxygen Species/metabolism , Photosynthesis , Abscisic AcidABSTRACT
Pancreatic cancer is among the most malignant cancers, and thus early intervention is the key to better survival outcomes. However, no methods have been derived that can reliably identify early precursors of development into malignancy. Therefore, it is urgent to discover early molecular changes during pancreatic tumorigenesis. As aberrant glycosylation is closely associated with cancer progression, numerous efforts have been made to mine glycosylation changes as biomarkers for diagnosis; however, detailed glycoproteomic information, especially site-specific N-glycosylation changes in pancreatic cancer with and without drug treatment, needs to be further explored. Herein, we used comprehensive solid-phase chemoenzymatic glycoproteomics to analyze glycans, glycosites, and intact glycopeptides in pancreatic cancer cells and patient sera. The profiling of N-glycans in cancer cells revealed an increase in the secreted glycoproteins from the primary tumor of MIA PaCa-2 cells, whereas human sera, which contain many secreted glycoproteins, had significant changes of glycans at their specific glycosites. These results indicated the potential role for tumor-specific glycosylation as disease biomarkers. We also found that AMG-510, a small molecule inhibitor against Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C mutation, profoundly reduced the glycosylation level in MIA PaCa-2 cells, suggesting that KRAS plays a role in the cellular glycosylation process, and thus glycosylation inhibition contributes to the anti-tumor effect of AMG-510.
Subject(s)
Humans , Glycosylation , Pancreatic Neoplasms/pathology , Adenocarcinoma , Proto-Oncogene Proteins p21(ras)/metabolism , Glycoproteins , Mass Spectrometry , Biomarkers/metabolism , PolysaccharidesABSTRACT
Objective:To compare esketamine versus dexmedetomidine in improving the adverse mood after cesarean section.Methods:One hundred and fourteen pregnant women undergoing elective cesarean section, aged 20-45 yr, with body mass index≤33 kg/m 2, of American Society of Anesthesiologists Physical Status classification Ⅱ or Ⅲ, were divided into 3 groups ( n=38 each) by the random number table method: esketamine group (group S), dexmedetomidine group (group D) and control group (group C). After delivery, esketamine was intravenously injected as a bolus of 0.3 mg/kg, followed by an infusion of 0.3 mg·kg -1·h -1 throughout the surgery in group S, dexmedetomidine was intravenously injected as a bolus of 0.6 μg/kg, followed by an infusion of 0.6 μg·kg -1·h -1 throughout the surgery in group D, while the equal volume of normal saline was given instead, followed by an infusion of 14 ml/h throughout the surgery in group C. Patient-controlled intravenous analgesia was performed after the end of surgery. Esketamine 50 mg, sufentanil 50 μg and ondansetron 8 mg were given in group S, dexmedetomidine 200 μg, sufentanil 50 μg and ondansetron 8 mg were given in group D, while sufentanil 50 μg and ondansetron 8 mg were given in group C. When the visual analog scale score ≥4 within 48 h after operation, flurbiprofen axidate was intravenously injected as a rescue analgesic. Self-rating Anxiety Scale (SAS) scores and Edinburgh Postnatal Depression Scale (EPDS) scores were assessed at 1 day before surgery and 2 and 7 days after surgery. Serum levels of brain-derived neurotrophic factor (BDNF) were measured by enzyme-linked immunosorbent assay at 1 day before surgery and 2 days after surgery. The effective pressing times of patient-controlled analgesia (PCA) and requirement for rescue analgesia after operation were recorded. The occurrence of adverse reactions during operation and within 48 h after operation was also recorded. Results:Compared with group C, SAS scores and EPDS scores were significantly decreased at 2 and 7 days after surgery, serum BDNF concentrations were increased at 2 days after surgery, the effective pressing times of PCA were reduced, the requirement for rescue analgesia was decreased, and the incidence of intraoperative nausea and vomiting was reduced in S and D groups ( P<0.05). Compared with group D, SAS scores and EPDS scores were significantly decreased at 7 days after surgery, the effective pressing times of PCA were reduced ( P<0.05), and no significant change was found in serum BDNF concentrations at 2 days after surgery and requirement for rescue analgesia in group S ( P>0.05). The incidence of dreaminess was significantly higher in group S than in group C and group D ( P<0.05). Conclusions:Esketamine is better than dexmedetomidine in improving the adverse mood after cesarean section.