RESUMEN
BACKGROUND: Mycoplasma pneumoniae (M. pneumoniae) is a significant contributor to community-acquired pneumonia among children. Since 1968, when a strain of M. pneumoniae resistant to macrolide antibiotics was initially reported in Japan, macrolide-resistant M. pneumoniae (MRMP) has been documented in many countries worldwide, with varying incidence rates. MRMP infections lead to a poor response to macrolide antibiotics, frequently resulting in prolonged fever, extended antibiotic treatment, increased hospitalization, intensive care unit admissions, and a significantly higher proportion of patients receiving glucocorticoids or second-line antibiotics. Since 2000, the global incidence of MRMP has gradually increased, especially in East Asia, which has posed a serious challenge to the treatment of M. pneumoniae infections in children and attracted widespread attention from pediatricians. However, there is still no global consensus on the diagnosis and treatment of MRMP in children. METHODS: We organized 29 Chinese experts majoring in pediatric pulmonology and epidemiology to write the world's first consensus on the diagnosis and treatment of pediatric MRMP pneumonia, based on evidence collection. The evidence searches and reviews were conducted using electronic databases, including PubMed, Embase, Web of Science, CNKI, Medline, and the Cochrane Library. We used variations in terms for "macrolide-resistant", "Mycoplasma pneumoniae", "MP", "M. pneumoniae", "pneumonia", "MRMP", "lower respiratory tract infection", "Mycoplasma pneumoniae infection", "children", and "pediatric". RESULTS: Epidemiology, pathogenesis, clinical manifestations, early identification, laboratory examination, principles of antibiotic use, application of glucocorticoids and intravenous immunoglobulin, and precautions for bronchoscopy are highlighted. Early and rapid identification of gene mutations associated with MRMP is now available by polymerase chain reaction and fluorescent probe techniques in respiratory specimens. Although the resistance rate to macrolide remains high, it is fortunate that M. pneumoniae still maintains good in vitro sensitivity to second-line antibiotics such as tetracyclines and quinolones, making them an effective treatment option for patients with initial treatment failure caused by macrolide antibiotics. CONCLUSIONS: This consensus, based on international and national scientific evidence, provides scientific guidance for the diagnosis and treatment of MRMP in children. Further studies on tetracycline and quinolone drugs in children are urgently needed to evaluate their effects on the growth and development. Additionally, developing an antibiotic rotation treatment strategy is necessary to reduce the prevalence of MRMP strains.
RESUMEN
Interest in the use of proteolysis-targeting chimeras (PROTACs) in cancer therapy has increased in recent years. Targeting bromodomain and extra terminal domain (BET) proteins, especially bromodomain-containing protein 4 (BRD4), has shown inhibitory effects on basal-like breast cancer (BLBC). However, the bioavailability of BRD4 PROTACs is restricted by their non-selective biodegradability and low tumor-targeting ability. We demonstrated that 6b (BRD4 PROTAC) suppresses BLBC cell growth by targeting BRD4, but not BRD2 and BRD3, for cereblon (CRBN)-mediated ubiquitination and proteasomal degradation. Compound 6b also inhibited expression of Krüppel-like factor 5 (KLF5) transcription factor, a key oncoprotein in BLBC, controlled by BRD4-mediated super-enhancers. Moreover, 6b inhibited HCC1806 tumor growth in a xenograft mouse model. The combination of 6b and KLF5 inhibitors showed additive effects on BLBC. These results suggest that BRD4-specific PROTAC can effectively inhibit BLBC by downregulating KLF5, and that 6b has potential as a novel therapeutic drug for BLBC.
RESUMEN
Recent studies have hinted at a potential link between Alzheimer's Disease (AD) and cancer. Thus, our study focused on finding genes common to AD and Liver Hepatocellular Carcinoma (LIHC), assessing their promise as diagnostic indicators and guiding future treatment approaches for both conditions. Our research utilized a broad methodology, including differential gene expression analysis, Weighted Gene Co-expression Network Analysis (WGCNA), gene enrichment analysis, Receiver Operating Characteristic (ROC) curves, and Kaplan-Meier plots, supplemented with immunohistochemistry data from the Human Protein Atlas (HPA) and machine learning techniques, to identify critical genes and significant pathways shared between AD and LIHC. Through differential gene expression analysis, WGCNA, and machine learning methods, we identified nine key genes associated with AD, which served as entry points for LIHC analysis. Subsequent analyses revealed IKBKE and HSPA1A as shared pivotal genes in patients with AD and LIHC, suggesting these genes as potential targets for intervention in both conditions. Our study indicates that IKBKE and HSPA1A could influence the onset and progression of AD and LIHC by modulating the infiltration levels of immune cells. This lays a foundation for future research into targeted therapies based on their shared mechanisms.
Asunto(s)
Enfermedad de Alzheimer , Carcinoma Hepatocelular , Biología Computacional , Proteínas HSP70 de Choque Térmico , Neoplasias Hepáticas , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Biología Computacional/métodos , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Aprendizaje AutomáticoRESUMEN
Lithium supply risk is increasing and driving rapid progress in lithium recovery schemes from spent lithium-ion batteries (LIBs). In this study, a facile recycling process consisting mainly of reduction roasting and NaHCO3 leaching was adopted to improve lithium recovery. The Li of spent LiNixCoyMn1-x-yO2 powder were converted to Li2CO3 and LiAlO2 with the reduction effect of C and residual Al in the roasting process. NaHCO3 leaching was utilized to selectively dissolve lithium from Li2CO3 and water-insoluble LiAlO2. The activation energy of NaHCO3 leaching was 9.31 kJâmol-1 and the leaching of lithium was a diffusion control reaction. More than 95.19 % lithium was leached and recovered as a Li2CO3 product with a purity of 99.80 %. Thus, this approach provides a green path to selective recovery of lithium with good economics.
Asunto(s)
Suministros de Energía Eléctrica , Litio , Reciclaje , Litio/química , Reciclaje/métodos , Bicarbonato de Sodio/químicaRESUMEN
Ferroptosis is an emerging target in rheumatoid arthritis (RA). We previously reported that transient receptor potential melastatin 7 (TRPM7) expression is correlated with RA cartilage destruction and demonstrated that TRPM7 mediates ferroptosis in chondrocytes. Here, we further determined the role and mechanism of (R)-N-(Benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphthylamine (NS8593), a TRPM7 inhibitor, in chondrocyte ferroptosis of RA. We established in vitro models of ferroptosis in human chondrocytes (C28/I2 cells) by using ferroptosis inducer Erastin. The results showed that NS8593 could protect C28/I2 cells from ferroptosis by inhibiting TRPM7 channel, which was manifested by restoring cell viability, reducing cytotoxicity, affecting the expression of ferroptosis marker protein, and restoring redox balance to alleviate Erastin-induced oxidative stress injury. Mechanistically, the Heme oxygenase-1 (HO-1) axis responded to Erastin stimulation, which resulted in TRPM7-mediated chondrocyte ferroptosis, NS8593 could reduce the expression of HO-1 by inhibiting TRPM7 channel. Moreover, NS8593 alleviated articular cartilage destruction and inhibited chondrocyte ferroptosis in AA rats. In conclusion, NS8593 mitigated articular cartilage damage and chondrocyte ferroptosis through the TRPM7/HO-1 pathway, suggesting that NS8593 may be a potential novel drug for the treatment of RA.
Asunto(s)
Artritis Experimental , Condrocitos , Ferroptosis , Canales Catiónicos TRPM , Animales , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Condrocitos/patología , Ferroptosis/efectos de los fármacos , Canales Catiónicos TRPM/metabolismo , Canales Catiónicos TRPM/antagonistas & inhibidores , Canales Catiónicos TRPM/genética , Ratas , Artritis Experimental/patología , Artritis Experimental/metabolismo , Artritis Experimental/tratamiento farmacológico , Humanos , Masculino , Ratas Sprague-Dawley , Hemo-Oxigenasa 1/metabolismo , Transducción de Señal/efectos de los fármacos , 1-Naftilamina/análogos & derivados , 1-Naftilamina/farmacología , Estrés Oxidativo/efectos de los fármacos , Hemo Oxigenasa (Desciclizante)RESUMEN
The incidence and mortality rates of gastric cancer (GC) remain alarmingly high worldwide, imposing a substantial healthcare burden. In this study, we utilized data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A 4-gene prognostic model was developed to predict patient prognosis, and its accuracy was validated across multiple datasets. Patients with a low-risk score exhibited improved prognosis, elevated tumor mutation burden, heightened sensitivity to both immunotherapy and conventional chemotherapy. Notably, our investigation revealed that the key gene RGS5 positively modulates the expression of mismatch repair proteins via c-Myc. Furthermore, co-immunoprecipitation (COIP) assays demonstrated the interaction between RGS5 and c-Myc. Additionally, we confirmed that RGS5 regulates c-Myc through the ubiquitin-proteasome pathway. Moreover, RGS5 was identified as a positive regulator of PD-L1 expression and exhibited a negative correlation with the majority of immune cells. These findings underscore the potential of RGS5 as a novel biomarker and therapeutic target in the context of GC.
Asunto(s)
Biomarcadores de Tumor , Regulación Neoplásica de la Expresión Génica , Proteínas Proto-Oncogénicas c-myc , Proteínas RGS , Neoplasias Gástricas , Humanos , Proteínas RGS/genética , Proteínas RGS/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Pronóstico , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Reparación de la Incompatibilidad de ADN , Complejo de la Endopetidasa Proteasomal/metabolismo , Complejo de la Endopetidasa Proteasomal/genéticaRESUMEN
BACKGROUND: Few studies have explored the impact of preoperative frailty on infectious complications in patients with a diagnosis of colorectal cancer (CRC). Therefore, this study aimed to investigate the effect of preoperative frailty on postoperative infectious complications and prognosis in patients with CRC using propensity score matching (PSM). METHODS: This prospective single-centre observational cohort study included 245 patients who underwent CRC surgery at the Department of Gastrointestinal Surgery, The Affiliated Lianyungang Hospital of Xuzhou Medical University between August 2021 to May 2023. Patients were categorised into two groups: frail and non-frail. They were matched for confounders and 1:1 closest matching was performed using PSM. Rates of infectious complications, intensive care unit (ICU) admission, 30-day mortality, and 90-day mortality, as well as postoperative length of hospital stay, total length of hospital stay, and hospital costs, were compared between the two groups. Binary logistic regression using data following PSM to explore independent factors for relevant outcome measures. RESULTS: After PSM, each confounding factor was evenly distributed between groups, and 75 pairs of patients were successfully matched. The incidence of intra-abdominal infectious complications was significantly higher in the frail group than in the non-frail group (10.7% vs. 1.3%, P < 0.05). There were no significant differences in ICU admission rate, postoperative length of hospital stay, total length of hospital stay, hospital costs, 30-day mortality rate, or 90-day mortality rate between the two groups (P > 0.05). Our logistic regression analysis result showed that preoperative frailty (OR = 12.014; 95% CI: 1.334-108.197; P = 0.027) was an independent factor for intra-abdominal infection. CONCLUSIONS: The presence of preoperative frailty elevated the risk of postoperative intra-abdominal infectious complications in patients undergoing CRC surgery. Therefore, medical staff should assess preoperative frailty in patients with CRC early and provide targeted prehabilitation interventions.
Asunto(s)
Neoplasias Colorrectales , Fragilidad , Complicaciones Posoperatorias , Puntaje de Propensión , Humanos , Masculino , Femenino , Neoplasias Colorrectales/cirugía , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/mortalidad , Estudios Prospectivos , Pronóstico , Anciano , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Persona de Mediana Edad , Fragilidad/complicaciones , Fragilidad/epidemiología , Estudios de Seguimiento , Tiempo de Internación/estadística & datos numéricos , Factores de Riesgo , Tasa de Supervivencia , Infección de la Herida Quirúrgica/epidemiología , Infección de la Herida Quirúrgica/etiología , IncidenciaRESUMEN
BACKGROUND: Nipple-areola complex (NAC) necrosis is a major complication for breast reconstruction after nipple-sparing mastectomy. Although intraoperative indocyanine green angiography helps to assess the viability of tissue, the imaging could be conservative which may lead to aggressive resection. The plastic surgeons are eager to know the perfusion changes of NAC throughout the perioperative period. METHODS: In this prospective cohort study, the authors enrolled patients who underwent NSM and immediate direct-to-implant breast reconstruction. All patients underwent laser speckle contrast imaging before surgery, immediately after mastectomy, after implant placement, and 24 h and 72 h after surgery. RESULTS: A total of 94 breasts were analyzed, including 64 breasts healed with viable NAC and 30 breasts with NAC necrosis. In viable NACs, the average blood supply decreased to 56% after NSM and 42% after reconstruction, then recovered to 68% and 80% at 24-h and 72-h post-operation. In necrotic NACs, the average blood supply decreased to 33% after NSM and 24% after reconstruction, and partial perfusion recovery was also recorded at 24-h (31%) and 72-h (37%) post-operation. The cutoff value for predicting NAC viability is 40% after NSM and 25% after implant placement. CONCLUSIONS: The study quantified the NAC perfusion changes during the perioperative period. NAC perfusion decreased significantly after NSM and would be the lowest after the end of breast reconstruction. Viable NACs displayed more perfusion during the operation and showed significant nipple revascularization after breast reconstruction. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. 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 .
Asunto(s)
Músculo Liso , Historia del Siglo XX , Músculo Liso/fisiología , Humanos , Fisiología/historia , Historia del Siglo XXI , AnimalesRESUMEN
Itching is an aversive somatosensation that triggers the desire to scratch. Transient receptor potential (TRP) channel proteins are key players in acute and chronic itch. However, whether the modulatory effect of fibroblast growth factor 13 (FGF13) on acute and chronic itch is associated with TRP channel proteins is unclear. Here, we demonstrated that conditional knockout of Fgf13 in dorsal root ganglion neurons induced significant impairment in scratching behaviors in response to acute histamine-dependent and chronic dry skin itch models. Furthermore, FGF13 selectively regulated the function of the TRPV1, but not the TRPA1 channel on Ca2+ imaging and electrophysiological recordings, as demonstrated by a significant reduction in neuronal excitability and current density induced by TRPV1 channel activation, whereas TRPA1 channel activation had no effect. Changes in channel currents were also verified in HEK cell lines. Subsequently, we observed that selective modulation of TRPV1 by FGF13 required its microtubule-stabilizing effect. Furthermore, in FGF13 knockout mice, only the overexpression of FGF13 with a tubulin-binding domain could rescue TRP channel function and the impaired itch behavior. Our findings reveal a novel mechanism by which FGF13 is involved in TRPV1-dependent itch transduction and provide valuable clues for alleviating pathological itch syndrome.
Asunto(s)
Factores de Crecimiento de Fibroblastos , Ratones Noqueados , Microtúbulos , Prurito , Canales Catiónicos TRPV , Animales , Humanos , Masculino , Ratones , Factores de Crecimiento de Fibroblastos/metabolismo , Factores de Crecimiento de Fibroblastos/genética , Ganglios Espinales/metabolismo , Células HEK293 , Ratones Endogámicos C57BL , Microtúbulos/metabolismo , Prurito/metabolismo , Prurito/genética , Canal Catiónico TRPA1/metabolismo , Canal Catiónico TRPA1/genética , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/genéticaRESUMEN
Reliable nitrogen (N) fertilizer management indicators are essential for improving crop yields and minimizing environmental impacts for sustainable production. The objectives of this study were to assess the importance of major N management indicators (NMIs) for higher yield with low risks of environmental pollution in an intensive potato system under drip irrigation. Six drip-irrigated field experiments with no N application (Control), farmer practice (FP), and optimized N management (OM) based on N-balance, soil mineral N (Nmin), and target yield were conducted from 2018 to 2020 in Inner Mongolia, China. The response of NMIs to potato yield and yield-based environment impact indices (EIY) was evaluated by the random forest algorithm. The N input, N losses from N leaching, ammonia (NH3) volatilization, nitrous oxide (N2O) emission, N use efficiency (NUE), N surplus, and soil residual N after harvest were obtained to identify the best NMIs for high yield and minimal ecological impact. The N management practices in field experimental sites affected the importance of the order of NMIs on potato yield and EIY. The NUE and N leaching were identified as the highest importance scores and the most essential controlling variables to potato yield and EIY, respectively. The integrated NUE and N leaching indicator played a vital role in improving potato yield and reducing ecological impact. The OM treatment achieved 46.0%, 63.6%, and 64.6% lower in N application rate, N surplus, and reactive N loss, and 62.4% higher in NUE than the FP treatment while achieving equal potato yields, respectively. Those key NMIs can guide farmers in understanding their practice short comes to achieve both high productivity and environmental sustainability in intensive potato production systems under drip irrigation.
Asunto(s)
Riego Agrícola , Producción de Cultivos , Fertilizantes , Nitrógeno , Suelo , Solanum tuberosum , Solanum tuberosum/crecimiento & desarrollo , Riego Agrícola/métodos , Producción de Cultivos/métodos , Suelo/química , China , Agricultura/métodos , Productos Agrícolas/crecimiento & desarrolloRESUMEN
Rapidly identifying and quantifying Gram-positive bacteria are crucial to diagnosing and treating bacterial lower respiratory tract infections (LRTIs). This work presents a field-deployable biosensor for detecting Gram-positive bacteria from exhaled breath condensates (EBCs) based on peptidoglycan recognition using an aptamer. Dielectrophoretic force is employed to enrich the bacteria in 10 s without additional equipment or steps. Concurrently, the measurement of the sensor's interfacial capacitance is coupled to quantify the bacteria during the enrichment process. By incorporation of a semiconductor condenser, the whole detection process, including EBC collection, takes about 3 min. This biosensor has a detection limit of 10 CFU/mL, a linear range of up to 105 CFU/mL and a selectivity of 1479:1. It is cost-effective and disposable due to its low cost. The sensor provides a nonstaining, culture-free and PCR-independent solution for noninvasive and real-time diagnosis of Gram-positive bacterial LRTIs.
Asunto(s)
Técnicas Biosensibles , Pruebas Respiratorias , Bacterias Grampositivas , Peptidoglicano , Peptidoglicano/análisis , Peptidoglicano/química , Pruebas Respiratorias/métodos , Bacterias Grampositivas/aislamiento & purificación , Humanos , Límite de Detección , Aptámeros de Nucleótidos/químicaRESUMEN
Apelin-13, a type of active peptide, can alleviate lipopolysaccharide (LPS)-induced acute lung injury (ALI). However, the specific mechanism is unclear. Cell cycle checkpoint kinase 1 (Chk1) plays an important role in DNA damage. Here, we investigated the regulatory effect of Apelin on Chk1 in ALI. Chk1-knockout and -overexpression mice were used to explore the role of Chk1 in LPS-induced ALI mice treated with or without Apelin-13. In addition, A549 cells were also treated with LPS to establish a cell model. Chk1 knockdown inhibited the destruction of alveolar structure, the damage of lung epithelial barrier function, and DNA damage in the ALI mouse model. Conversely, Chk1 overexpression had the opposite effect. Furthermore, Apelin-13 reduced Chk1 expression and DNA damage to improve the impaired lung epithelial barrier function in the ALI model. However, the high expression of Chk1 attenuated the protective effect of Apelin-13 on ALI. Notably, Apelin-13 promoted Chk1 degradation through autophagy to regulate DNA damage in LPS-treated A549 cells. In summary, Apelin-13 regulates the expression of Chk1 by promoting autophagy, thereby inhibiting epithelial DNA damage and repairing epithelial barrier function.
Asunto(s)
Lesión Pulmonar Aguda , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Daño del ADN , Lipopolisacáridos , Ratones Endogámicos C57BL , Ratones Noqueados , Animales , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Lipopolisacáridos/toxicidad , Ratones , Daño del ADN/efectos de los fármacos , Daño del ADN/fisiología , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/genética , Humanos , Células A549 , Masculino , Modelos Animales de Enfermedad , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Péptidos y Proteínas de Señalización Intercelular/genética , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/efectos de los fármacosRESUMEN
BACKGROUND: The oral cavity is home to various ecological niches, each with its own unique microbial composition. Understanding the microbial communities and gene composition in different ecological niches within the oral cavity of oral cancer (OC) patients is crucial for determining how these microbial populations contribute to disease progression. METHODS: In this study, saliva and dental plaque samples were collected from patients with OC. Metagenomic sequencing was employed to analyze the microbial community classification and functional composition of the different sample groups. RESULTS: The results of the study revealed significant differences in both the function and classification of microbial communities between saliva and dental plaque samples. The diversity of microbial species in saliva was found to be higher compared to that in plaque samples. Notably, Actinobacteria were enriched in the dental plaque of OC patients. Furthermore, the study identified several inter-group differential marker species, including Prevotella intermedia, Haemophilus parahaemolyticus, Actinomyces radius, Corynebacterium matruchitii, and Veillonella atypica. Additionally, 1,353 differential genes were annotated into 23 functional pathways. Interestingly, a significant correlation was observed between differentially labeled species and Herpes simplex virus 1 (HSV-1) infection, which may be related to the occurrence and development of cancer. CONCLUSIONS: Significant differences in the microbial and genetic composition of saliva and dental plaque samples were observed in OC patients. Furthermore, pathogenic bacteria associated with oral diseases were predominantly enriched in saliva. The identification of inter-group differential biomarkers and pathways provide insights into the relationship between oral microbiota and the occurrence and development of OC.
Asunto(s)
Placa Dental , Neoplasias de la Boca , Humanos , Saliva/microbiología , Placa Dental/microbiología , Bacterias/genética , ARN Ribosómico 16S/genéticaRESUMEN
The Hippo pathway is a key regulator of tissue growth, organ size, and tumorigenesis. Activating the Hippo pathway by gene editing or pharmaceutical intervention has been proven to be a new therapeutic strategy for treatment of the Hippo pathway-dependent cancers. To now, a number of compounds that directly target the downstream effector proteins of Hippo pathway, including YAP and TEADs, have been disclosed, but very few Hippo pathway activators are reported. Here, we discovered a new class of Hippo pathway activator, YL-602, which inhibited CTGF expression in cells irrespective of cell density and the presence of serum. Mechanistically, YL-602 activates the Hippo pathway via MST1/2, which is different from known activators of Hippo pathway. In vitro, YL-602 significantly induced tumor cell apoptosis and inhibited colony formation of tumor cells. In vivo, oral administration of YL-602 substantially suppressed the growth of cancer cells by activation of Hippo pathway. Overall, YL-602 could be a promising lead compound, and deserves further investigation for its mechanism of action and therapeutic applications.
Asunto(s)
Antineoplásicos , Vía de Señalización Hippo , Proteínas Serina-Treonina Quinasas , Transducción de Señal , Humanos , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Antineoplásicos/farmacología , Ratones , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Ratones Desnudos , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Factor de Crecimiento del Tejido Conjuntivo/genética , Ratones Endogámicos BALB C , Apoptosis/efectos de los fármacos , FemeninoRESUMEN
The transmembrane channel-like (TMC) protein family comprises eight members, with TMC1 and TMC2 being extensively studied. This study demonstrates substantial co-expression of TMC7 with the mechanosensitive channel Piezo2 in somatosensory neurons. Genetic deletion of TMC7 in primary sensory ganglia neurons in vivo enhances sensitivity in both physiological and pathological mechanosensory transduction. This deletion leads to an increase in proportion of rapidly adapting (RA) currents conducted by Piezo2 in dorsal root ganglion (DRG) neurons and accelerates RA deactivation kinetics. In HEK293 cells expressing both proteins, TMC7 significantly suppresses the current amplitudes of co-expressed Piezo2. Our findings reveal that TMC7 and Piezo2 exhibit physical interactions, and both proteins also physically interact with cytoskeletal ß-actin. We hypothesize that TMC7 functions as an inhibitory modulator of Piezo2 in DRG neurons, either through direct inhibition or by disrupting the transmission of mechanical forces from the cytoskeleton to the channel.
Asunto(s)
Ganglios Espinales , Canales Iónicos , Mecanotransducción Celular , Células Receptoras Sensoriales , Humanos , Células Receptoras Sensoriales/metabolismo , Animales , Canales Iónicos/metabolismo , Canales Iónicos/genética , Ganglios Espinales/metabolismo , Células HEK293 , Ratones , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Ratones Endogámicos C57BL , Actinas/metabolismoRESUMEN
Introduction: The transmembrane channel-like (TMC) protein family contains eight members, TMC1-TMC8. Among these members, only TMC1 and TMC2 have been intensively studied. They are expressed in cochlear hair cells and are crucial for auditory sensations. TMC6 and TMC8 contribute to epidermodysplasia verruciformis, and predispose individuals to human papilloma virus. However, the impact of TMC on peripheral sensation pain has not been previously investigated. Methods: RNAscope was employed to detect the distribution of TMC6 mRNA in DRG neurons. Electrophysiological recordings were conducted to investigate the effects of TMC6 on neuronal characteristics and M channel activity. Zn2+ indicators were utilized to detect the zinc concentration in DRG tissues and dissociated neurons. A series of behavioural tests were performed to assess thermal and mechanical sensation in mice under both physiological and pathological conditions. Results and Discussion: We demonstrated that TMC6 is mainly expressed in small and medium dorsal root ganglion (DRG) neurons and is involved in peripheral heat nociception. Deletion of TMC6 in DRG neurons hyperpolarizes the resting membrane potential and inhibits neuronal excitability. Additionally, the function of the M channel is enhanced in TMC6 deletion DRG neurons owing to the increased quantity of free zinc in neurons. Indeed, heat and mechanical hyperalgesia in chronic pain are alleviated in TMC6 knockout mice, particularly in the case of heat hyperalgesia. This suggests that TMC6 in the small and medium DRG neurons may be a potential target for chronic pain treatment.
RESUMEN
BACKGROUND AND OBJECTIVE: Rumination, a common factor of chronic insomnia disorder (CID) caused by cognitive-emotional arousal, is associated with an increased amount of rapid eye movement (REM) sleep. However, the specific subtypes, such as phasic REM and tonic REM, that contribute to the increased REM sleep have not been reported. This study aimed to determine the association between rumination and different REM sleep subtypes in patients with CID. METHODS: This study enrolled 35 patients with CID and 27 age- and sex-matched healthy controls. The Immersion-Rumination Questionnaire evaluated participants' rumination, and the Insomnia Severity Index was used to assess insomnia severity. Finally, polysomnography was used to monitor objective sleep quality and quantification of different types of REM. RESULTS: The CID patients had higher rumination scores than the healthy controls. They had a shorter REM sleep duration, less phasic REM, a lower percentage of phasic REM time, and a higher percentage of tonic REM time. Spectral analysis revealed that the patients affected by insomnia had higher ß power during REM sleep, higher ß and σ power during phasic REM sleep, and higher ß, and γ power during tonic REM sleep. Partial correlation analysis showed that rumination in the CID patients correlated negatively with the duration of phasic REM sleep. Additionally, rumination correlated negatively with δ power in REM sleep and positively with ß power in REM sleep, tonic REM sleep, phasic REM sleep, N3and N2 sleep in the patients with CID. CONCLUSION: The CID patients had stronger rumination, reduced total and phasic REM sleep, and the stronger rumination was, the shorter phasic REM was and the higher fast (ß) wave power in REM sleep.
Asunto(s)
Trastorno de la Conducta del Sueño REM , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Sueño REM , Trastornos del Inicio y del Mantenimiento del Sueño/complicaciones , Polisomnografía , Nivel de Alerta , Trastorno de la Conducta del Sueño REM/complicacionesRESUMEN
Objective: Previous studies from outside China showed that the knowledge, attitudes, and practice (KAP) of chronic refractory cough (CRC) was moderate among physicians. This study examined the KAP toward CRC in Chinese healthcare providers. Methods: This single-center cross-sectional study was conducted at The Sixth Affiliated Hospital of Nantong University, Yancheng Third People's Hospital, from July 2022 to January 2023 and enrolled healthcare providers. The demographic characteristics and KAP scores were collected using a questionnaire (Cronbach's α = 0.934) developed based on CRC guidelines. Results: The study included 539 healthcare providers. The mean knowledge score was 8.27 ± 2.37 (maximum of 14, 59.07%), indicating poor knowledge. The highest rates of inaccuracies pertained to knowledge about the definition of chronic cough, empirical treatment methods, and potential risks of different treatments, suggesting a need for unified training in all aspects of CRC for medical staff. The mean attitude score was 49.74 ± 63.63 (maximum of 60, 82.90%), indicating favorable attitudes. Most healthcare providers believed that CRC affects normal work and life and that it would be necessary to provide more help to patients from the perspectives of drug treatment and psychological counseling. The mean practice score was 23.20 ± 6.28 (maximum of 35, 66.29%), indicating poor practice. Conclusion: This study suggests that healthcare providers in Yancheng have poor knowledge, favorable attitudes, and poor practice of CRC. This study provides points that should be targeted in future training and continuing education activities.
RESUMEN
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are serious lung injuries caused by various factors, leading to increased permeability of the alveolar-capillary barrier, reduced stability of the alveoli, inflammatory response, and hypoxemia. Despite several decades of research since ARDS was first formally described in 1967, reliable clinical treatment options are still lacking. Currently, supportive therapy and mechanical ventilation are prioritized, and there is no medication that can be completely effective in clinical treatment. In recent years, nanomedicine has developed rapidly and has exciting preclinical treatment capabilities. Using a drug delivery system based on nanobiotechnology, local drugs can be continuously released in lung tissue at therapeutic levels, reducing the frequency of administration and improving patient compliance. Furthermore, this novel drug delivery system can target specific sites and reduce systemic side effects. Currently, many nanomedicine treatment options for ARDS have demonstrated efficacy. This review briefly introduces the pathophysiology of ARDS, discusses various research progress on using nanomedicine to treat ARDS, and anticipates future developments in related fields.