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Parkinson's disease (PD) exhibits heterogeneity in terms of symptoms and prognosis, likely due to diverse neuroanatomical alterations. This study employs a contrastive deep learning approach to analyze Magnetic Resonance Imaging (MRI) data from 932 PD patients and 366 controls, aiming to disentangle PD-specific neuroanatomical alterations. The results reveal that these neuroanatomical alterations in PD are correlated with individual differences in dopamine transporter binding deficit, neurodegeneration biomarkers, and clinical severity and progression. The correlation with clinical severity is verified in an external cohort. Notably, certain proteins in the cerebrospinal fluid are strongly associated with PD-specific features, particularly those involved in the immune function. The most notable neuroanatomical alterations are observed in both subcortical and temporal regions. Our findings provide deeper insights into the patterns of brain atrophy in PD and potential underlying molecular mechanisms, paving the way for earlier patient stratification and the development of treatments to slow down neurodegeneration.
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Progressão da Doença , Aprendizado de Máquina , Imageamento por Ressonância Magnética , Doença de Parkinson , Índice de Gravidade de Doença , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/líquido cefalorraquidiano , Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/metabolismo , Biomarcadores/líquido cefalorraquidiano , Aprendizado ProfundoRESUMO
The relationship between maternal peripheral blood mitochondrial DNA and adverse pregnancy outcomes, specifically preterm birth (PTB), remains uncertain. To investigate the effects of preconception mitochondrial DNA copy number (mtDNAcn) on the association between prenatal air pollutants exposure and PTB risk, a total of 1871 expectant mothers from six regions in Henan Province were recruited. Information regarding air pollutants was obtained from 151 environmental monitoring sites, and relative mtDNAcn was evaluated using real-time PCR analysis. After adjusting for potential confounding variables, it was determined that the risk of PTB increased with elevated levels of inhalable particulate matter (PM10), fine particulate matter (PM2.5), sulfur dioxide (SO2), carbon monoxide (CO) and ozone (O3) exposure (P < 0.05) but decreased with higher nitrogen dioxide (NO2) exposure (0.05 < P < 0.10) during the entire pregnancy. Additionally, the preconception relative mtDNAcn was lower in the PTB group (0.82 ± 0.23) compared to the term group (0.92 ± 0.29). Furthermore, for each 0.1-unit increase in preconception mtDNAcn, the risk of PTB decreased by 14.8%. Stratified analyses revealed that the risk of PTB rose with increasing O3 concentrations, regardless of the relative mtDNAcn. Moreover, the study found a significant association between PTB risk and prenatal exposure to elevated PM10, PM2.5, SO2, and CO, particularly in mothers with low mtDNAcn (≤0.88) (P < 0.05). Conversely, a decrease in the PTB risk was observed with elevated NO2 exposure in mothers with high mtDNAcn (>0.88). Interaction analysis revealed that exposure to PM10, PM2.5, SO2, NO2, and CO interacted with mtDNAcn, respectively, affecting PTB risk (P-interaction<0.05). These findings indicate a noteworthy association between PTB risk and prenatal air pollutants exposure, which is influenced by the preconception mtDNAcn.
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Non-ST-segment elevation acute myocardial infarction (NSTEMI) is a life-threatening clinical emergency with a poor prognosis. However, there are no individualized nomogram models to identify patients at high risk of NSTEMI who may undergo death. The aim of this study was to develop a nomogram for in-hospital mortality in patients with NSTEMI to facilitate rapid risk stratification of patients. A total of 774 non-diabetic patients with NSTEMI were included in this study. Least Absolute Shrinkage and Selection Operator regression was used to initially screen potential predictors. Univariate and multivariate logistic regression (backward stepwise selection) analyses were performed to identify the optimal predictors for the prediction model. The corresponding nomogram was constructed based on those predictors. The receiver operating characteristic curve, GiViTI calibration plot, and decision curve analysis (DCA) were used to evaluate the performance of the nomogram. The nomogram model consisting of six predictors: age (OR = 1.10; 95% CI: 1.05-1.15), blood urea nitrogen (OR = 1.06; 95% CI: 1.00-1.12), albumin (OR = 0.93; 95% CI: 0.87-1.00), triglyceride (OR = 1.41; 95% CI: 1.09-2.00), D-dimer (OR = 1.39; 95% CI: 1.06-1.80), and aspirin (OR = 0.16; 95% CI: 0.06-0.42). The nomogram had good discrimination (area under the curve (AUC) = 0.89, 95% CI: 0.84-0.94), calibration, and clinical usefulness. In this study, we developed a nomogram model to predict in-hospital mortality in patients with NSTEMI based on common clinical indicators. The proposed nomogram has good performance, allowing rapid risk stratification of patients with NSTEMI.
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Mortalidade Hospitalar , Nomogramas , Infarto do Miocárdio sem Supradesnível do Segmento ST , Humanos , Feminino , Masculino , Infarto do Miocárdio sem Supradesnível do Segmento ST/mortalidade , Infarto do Miocárdio sem Supradesnível do Segmento ST/sangue , Idoso , Pessoa de Meia-Idade , Medição de Risco/métodos , PrognósticoRESUMO
We report an efficient perfluoroalkoxylation reaction of alkyl halides catalyzed by copper(I) iodide (CuI), which facilitates the simultaneous activation of both perfluoroalkoxide and alkyl halides. This methodology is tolerant of a wide range of functional groups and eliminates the need for costly metal reagents. The reaction is conducted in a single step under mildly practical conditions.
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Recent advances in spatial transcriptomics (ST) techniques provide valuable insights into cellular interactions within the tumor microenvironment (TME). However, most analytical tools lack consideration of histological features and rely on matched single-cell RNA sequencing data, limiting their effectiveness in TME studies. To address this, we introduce the Morphology-Enhanced Spatial Transcriptome Analysis Integrator (METI), an end-to-end framework that maps cancer cells and TME components, stratifies cell types and states, and analyzes cell co-localization. By integrating spatial transcriptomics, cell morphology, and curated gene signatures, METI enhances our understanding of the molecular landscape and cellular interactions within the tissue. We evaluate the performance of METI on ST data generated from various tumor tissues, including gastric, lung, and bladder cancers, as well as premalignant tissues. We also conduct a quantitative comparison of METI with existing clustering and cell deconvolution tools, demonstrating METI's robust and consistent performance.
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Perfilação da Expressão Gênica , Neoplasias , Transcriptoma , Microambiente Tumoral , Humanos , Microambiente Tumoral/genética , Perfilação da Expressão Gênica/métodos , Neoplasias/genética , Neoplasias/patologia , Neoplasias/metabolismo , Análise de Célula Única/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/metabolismo , Análise por ConglomeradosRESUMO
BACKGROUND: Cholestasis is a common yet severe complication that occurs during the advancement of liver metastasis. However, how cholestasis impacts the development, treatment, and tumor microenvironment (TME) of liver metastasis remains to be elucidated. METHODS: Extrahepatic and intrahepatic cholestatic mouse models with liver metastasis were established to detect the differential expression levels of genes, infiltration of immune cells and change in bile acid-associated metabolites by using RNA-Sequencing, flowcytometry, and liquid chromatography and mass spectrometry. Western blot was applied to neutrophils under the stimulation of primary bile acids (BAs) in vitro to study the mechanism of phenotypic alteration. In vitro coculture of BA-treated neutrophils with CD8+ T cells were performed to study the immune-suppressive effect of phenotypic-altered neutrophils. Clinical samples collected from colorectal cancer patients with liver metastasis and cholestasis were applied to RNA-Seq. RESULTS: Compared to non-cholestatic mice, the progression of liver metastasis of cholestatic mice was significantly accelerated, which was associated with increased neutrophil infiltration and T-cell exclusion. Both neutrophils and T cells expressed higher immunosuppressive markers in the cholestatic mouse model, further indicating that an immunosuppressive tumor microenvironment was induced during cholestasis. Although neutrophils deletion via anti-Ly6G antibody partially hindered liver metastasis progression, it reduced the overall survival of mice. Tauro-ß-muricholic acid (Tß-MCA) and Glycocholic acid (GCA), the two most abundant cholestasis-associated primary BAs, remarkably promoted the expression of Arg1 and iNOS on neutrophils via p38 MAPK signaling pathway. In addition, BAs-pretreated neutrophils significantly suppressed the activation and cytotoxic effects of CD8+ T cells, indicating that the immunosuppressive phenotype of neutrophils was directly induced by BAs. Importantly, targeting BA anabolism with Obeticholic acid (OCA) under cholestasis effectively suppressed liver metastasis progression, enhanced the efficacy of immune checkpoint blockade, and prolonged survival of mice. CONCLUSIONS: Our study reveals the TME of cholestasis-associated liver metastasis and proposes a new strategy for such patients by targeting bile acid anabolism.
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Colestase , Neoplasias Colorretais , Neoplasias Hepáticas , Neutrófilos , Animais , Neutrófilos/imunologia , Camundongos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/imunologia , Colestase/imunologia , Colestase/metabolismo , Microambiente Tumoral , Masculino , Camundongos Endogâmicos C57BL , Humanos , Modelos Animais de DoençasRESUMO
BACKGROUND: Patients with myocardial infarction (MI) frequently experience a heightened incidence of depression, thereby increasing the risk of adverse cardiovascular events. Consequently, early detection and intervention in depressive symptoms among patients with MI are imperative. Shexiang Baoxin Pills (SBP), a Chinese patent medicine employed for the treatment of MI, exhibits diverse mechanisms targeting this condition. Nevertheless, its therapeutic efficacy on postmyocardial infarction depressive symptoms remains unclear. The aim of this study is to investigate the effectiveness and mechanism of SBP in managing depression during acute myocardial infarction (AMI). METHODS: A rat model combining MI and depression was established, and the rats were randomly divided into four groups: the model (MOD) group, SBP group, Fluoxetine (FLX) group, and Sham group. After 28 days of drug intervention, cardiac function was assessed using echocardiography while behavior was evaluated through sucrose preference test (SPT), forced swimming test (FST), and open-field test (OFT). Additionally, levels of inflammatory factors in serum and hippocampus were measured along with NLRP3 inflammasome-related protein expression via Western blotting and immunofluorescence. RESULTS: SBP can enhance cardiac function in rats with AMI and depression, while significantly ameliorating depressive-like behavior. Compared to the Sham group, levels of IL-1ß, IL-18, TNF-α, and other inflammatory factors were markedly elevated in the MOD group. However, expressions of these inflammatory factors were reduced to varying degrees following treatment with SBP or FLX. Analysis of NLRP3 inflammasome-related proteins in the hippocampus revealed a significant upregulation of IL-1ß, IL-18, NLRP3, ASC, caspase-1, and GSDMD in the MOD group; conversely, these measures were significantly attenuated after SBP intervention. CONCLUSION: We have observed a significant amelioration in depression-like behavior upon SBP administration during the treatment of AMI, suggesting that this effect may be attributed to the inhibition of NLRP3-mediated pyroptosis. (The main findings are summarized in the graphical abstract in the supplementary file.).
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Antidepressivos , Depressão , Medicamentos de Ervas Chinesas , Inflamassomos , Infarto do Miocárdio , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos Sprague-Dawley , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/complicações , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/administração & dosagem , Ratos , Depressão/tratamento farmacológico , Depressão/etiologia , Antidepressivos/farmacologia , Antidepressivos/administração & dosagem , Masculino , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Modelos Animais de Doenças , Transdução de Sinais/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacosRESUMO
The drug development process is poised for significant transformation due to the rapid advancement of modern biological and information technologies, such as artificial intelligence (AI). As these new technologies and concepts infiltrate every stage of drug development, the efficiency and success rate of research and development are expected to improve substantially. Traditional Chinese medicine (TCM), a time-honored therapeutic system encompassing herbal medicine, acupuncture, and qigong, will also be profoundly impacted by these advancements. Over the next decade, Traditional Chinese medicine research will encounter both opportunities and challenges as it integrates with modern technologies and concepts. By 2035, TCM is anticipated to merge with modern medicine through a more contemporary and open research and development model, providing substantial support for treating a broader spectrum of diseases.
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Currently, platinum (Pt)/carbon support composite materials have tremendous application prospects in the hydrogen evolution reaction (HER). However, one of the primary challenges for boosting their performance is designing a substrate with the desired microstructure. Herein, the intact hollow carbon spheres (HCSs) were prepared via template method. Based on the morphology variation of the as-prepared HCSs-x, we conjectured that the polydopamine (PDA) core was generated first and then slowly grew into a complete overburden (SiO2@PDA). Afterward, Pt atomic clusters were anchored on the outer shells of HCSs-4 to construct composite electrocatalysts (Pty/HCSs-4) by a chemical reduction method. Due to the low charge-transfer resistance, the HCSs have a large electrochemical surface area and provide a continuous electron transport pathway, boosting the atom utilization efficiency during hydrogen production and release. The synthesized Pt2.5/HCSs-4 electrocatalysts exhibit excellent HER activity in acidic media, which can be ascribed to the compositional modulation and delicate structural design. Specifically, when the overpotential is 10 A g-1, the overpotential can achieve 92 mV. This work opens a new route to fabricate Pt-based electrocatalysts and brings a new understanding of the formation mechanism of HCSs.
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OBJECTIVE: To analyze the efficacy and adverse effects of anti-PD-1 immune checkpoint inhibitors aimed at nasopharyngeal carcinoma (NPC). METHODS: During the first stage of the study, using 40 patients with stage III/IVa NPC treated with anti-PD-1 immune checkpoint inhibitors in combination with chemoradiotherapy as a first-line treatment (observation group) and 70 patients with NPC treated with chemoradiotherapy alone (control group). In the second stage of the study, 88 patients with NPC treated with immune checkpoint inhibitors were grouped according to the number of lines of immunotherapy, the number of times, and the types of application. RESULTS: Observation of the short-term effects in the first stage indicated that the objective response rate (ORR) of the observation group and the control group against primary foci of NPC was 75.0% versus 40.0%; the mortality rate of the observation group was much lower than that of the control group. The overall first-line treatment evaluation of the observation vs. control groups were as follows: ORR (67.5% vs. 38.6%); median PFS (17.52 vs. 17.21 months); and median OS (18.68 vs. 18.14 months), respectively (p < 0.05). The second stage of the study had an ORR of 53.4%, and the efficacy of immunotherapy was related to staging, timing, and frequency. CONCLUSION: Anti-PD-1 immune checkpoint inhibitors combined with chemoradiotherapy as the first-line treatment for nasopharyngeal carcinoma may improve patient outcomes significantly. Timing, frequency, and the type of immunotherapy exerted an effect on the efficacy of immunotherapy. Adverse effects that occurred during treatment were tolerable and controllable.
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Quimiorradioterapia , Inibidores de Checkpoint Imunológico , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Receptor de Morte Celular Programada 1 , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/mortalidade , Adulto , Idoso , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Estadiamento de Neoplasias , Resultado do Tratamento , Adulto JovemRESUMO
This editorial provides insights from a case report by Sun et al published in the World Journal of Clinical Cases. The case report focuses on a case where a multilocular thymic cyst (MTC) was misdiagnosed as a thymic tumor, resulting in an unnecessary surgical procedure. Both MTCs and thymic tumors are rare conditions that heavily rely on radiological imaging for accurate diagnosis. However, the similarity in their imaging presentations can lead to misinterpretation, resulting in unnecessary surgical procedures. Due to the ongoing lack of comprehensive knowledge about MTCs and thymic tumors, we offer a summary of diagnostic techniques documented in recent literature and examine potential causes of misdiagnosis. When computer tomography (CT) values surpass 20 Hounsfield units and display comparable morphology, there is a risk of misdiagnosing MTCs as thymic tumors. Employing various differential diagnostic methods like biopsy, molecular biology, multi-slice CT, CT functional imaging, positron emission tomography/CT molecular functional imaging, magnetic resonance imaging and radiomics, proves advantageous in reducing clinical misdiagnosis. A deeper understanding of these conditions requires increased attention and exploration by healthcare providers. Moreover, the continued advancement and utilization of various diagnostic methods are expected to enhance precise diagnoses, provide appropriate treatment options, and improve the quality of life for patients with thymic tumors and MTCs in the future.
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OBJECTIVE: The specific breast milk-derived metabolites that mediate host-microbiota interactions and contribute to the onset of atopic dermatitis (AD) remain unknown and require further investigation. DESIGN: We enrolled 250 mother-infant pairs and collected 978 longitudinal faecal samples from infants from birth to 6 months of age, along with 243 maternal faecal samples for metagenomics. Concurrently, 239 corresponding breast milk samples were analysed for metabolomics. Animal and cellular experiments were conducted to validate the bioinformatics findings. RESULTS: The clinical findings suggested that a decrease in daily breastfeeding duration was associated with a reduced incidence of AD. This observation inspired us to investigate the effects of breast milk-derived fatty acids. We found that high concentrations of arachidonic acid (AA), but not eicosapentaenoic acid (EPA) or docosahexaenoic acid, induced gut dysbiosis in infants. Further investigation revealed that four specific bacteria degraded mannan into mannose, consequently enhancing the mannan-dependent biosynthesis of O-antigen and lipopolysaccharide. Correlation analysis confirmed that in infants with AD, the abundance of Escherichia coli under high AA concentrations was positively correlated with some microbial pathways (eg, 'GDP-mannose-derived O-antigen and lipopolysaccharide biosynthesis'). These findings are consistent with those of the animal studies. Additionally, AA, but not EPA, disrupted the ratio of CD4/CD8 cells, increased skin lesion area and enhanced the proportion of peripheral Th2 cells. It also promoted IgE secretion and the biosynthesis of prostaglandins and leukotrienes in BALB/c mice fed AA following ovalbumin immunostimulation. Moreover, AA significantly increased IL-4 secretion in HaCaT cells costimulated with TNF-α and INF-γ. CONCLUSIONS: This study demonstrates that AA is intimately linked to the onset of AD via gut dysbiosis.
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Chronic obstructive pulmonary disease (COPD) is a common disease with high global morbidity and mortality. Macrophages release IL-1ß and orchestrate airway inflammation in COPD. Previously, we explored the role of a new lncRNA, LincR-PPP2R5C, in regulating Th2 cells in asthma. Here, we established a murine model of COPD and explored the roles and mechanisms by which LincR-PPP2R5C regulates IL-1ß in macrophages. LincR-PPP2R5C was highly expressed in pulmonary macrophages from COPD-like mice. LincR-PPP2R5C deficiency ameliorated emphysema and pulmonary inflammation, as characterized by reduced IL-1ß in macrophages. Unexpectedly, in both lung tissues and macrophages, LincR-PPP2R5C deficiency decreased the expression of the IL-1ß protein but not the IL-1ß mRNA. Furthermore, we found that LincR-PPP2R5C deficiency increased the level of ubiquitinated IL-1ß in macrophages, which was mediated by PP2A activity. Targeting PP2A with FTY720 decreased IL-1ß and improved COPD. In conclusion, LincR-PPP2R5C regulates IL-1ß ubiquitination by affecting PP2A activity in macrophages, contributing to the airway inflammation and emphysema in a murine model of COPD. PP2A and IL-1ß ubiquitination in macrophages might be new therapeutic avenues for COPD therapy.
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Modelos Animais de Doenças , Interleucina-1beta , Camundongos Endogâmicos C57BL , Doença Pulmonar Obstrutiva Crônica , RNA Longo não Codificante , Ubiquitinação , Animais , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Interleucina-1beta/metabolismo , Camundongos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteína Fosfatase 2/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Humanos , Masculino , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/imunologia , Enfisema Pulmonar/patologia , Enfisema Pulmonar/genética , Pulmão/patologia , Pulmão/imunologia , Camundongos KnockoutRESUMO
We explored physiological effects of the sodium-glucose co-transporter-2 inhibitor empagliflozin on intact experimentally hypertrophic murine hearts following transverse aortic constriction (TAC). Postoperative drug (2-6 weeks) challenge resulted in reduced late Na+ currents, and increased phosphorylated (p-)CaMK-II and Nav1.5 but not total (t)-CaMK-II, and Na+/Ca2+ exchanger expression, confirming previous cardiomyocyte-level reports. It rescued TAC-induced reductions in echocardiographic ejection fraction and fractional shortening, and diastolic anterior and posterior wall thickening. Dual voltage- and Ca2+-optical mapping of Langendorff-perfused hearts demonstrated that empagliflozin rescued TAC-induced increases in action potential durations at 80% recovery (APD80), Ca2+ transient peak signals and durations at 80% recovery (CaTD80), times to peak Ca2+ (TTP100) and Ca2+ decay constants (Decay30-90) during regular 10-Hz stimulation, and Ca2+ transient alternans with shortening cycle length. Isoproterenol shortened APD80 in sham-operated and TAC-only hearts, shortening CaTD80 and Decay30-90 but sparing TTP100 and Ca2+ transient alternans in all groups. All groups showed similar APD80, and TAC-only hearts showed greater CaTD80, heterogeneities following isoproterenol challenge. Empagliflozin abolished or reduced ventricular tachycardia and premature ventricular contractions and associated re-entrant conduction patterns, in isoproterenol-challenged TAC-operated hearts following successive burst pacing episodes. Empagliflozin thus rescues TAC-induced ventricular hypertrophy and systolic functional, Ca2+ homeostatic, and pro-arrhythmogenic changes in intact hearts.
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Compostos Benzidrílicos , Cálcio , Glucosídeos , Homeostase , Animais , Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Camundongos , Cálcio/metabolismo , Homeostase/efeitos dos fármacos , Masculino , Potenciais de Ação/efeitos dos fármacos , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/cirurgia , Camundongos Endogâmicos C57BL , Isoproterenol/farmacologia , Modelos Animais de DoençasRESUMO
Current clinically used electronic implants, including cardiac pacing leads for epicardial monitoring and stimulation of the heart, rely on surgical suturing or direct insertion of electrodes to the heart tissue. These approaches can cause tissue trauma during the implantation and retrieval of the pacing leads, with the potential for bleeding, tissue damage, and device failure. Here, we report a bioadhesive pacing lead that can directly interface with cardiac tissue through physical and covalent interactions to support minimally invasive adhesive implantation and gentle on-demand removal of the device with a detachment solution. We developed 3D-printable bioadhesive materials for customized fabrication of the device by graft-polymerizing polyacrylic acid on hydrophilic polyurethane and mixing with poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) to obtain electrical conductivity. The bioadhesive construct exhibited mechanical properties similar to cardiac tissue and strong tissue adhesion, supporting stable electrical interfacing. Infusion of a detachment solution to cleave physical and covalent cross-links between the adhesive interface and the tissue allowed retrieval of the bioadhesive pacing leads in rat and porcine models without apparent tissue damage. Continuous and reliable cardiac monitoring and pacing of rodent and porcine hearts were demonstrated for 2 weeks with consistent capture threshold and sensing amplitude, in contrast to a commercially available alternative. Pacing and continuous telemetric monitoring were achieved in a porcine model. These findings may offer a promising platform for adhesive bioelectronic devices for cardiac monitoring and treatment.
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Marca-Passo Artificial , Animais , Suínos , Ratos , Monitorização Fisiológica/métodos , Ratos Sprague-Dawley , Eletrodos Implantados , Adesivos , Impressão Tridimensional , Modelos AnimaisRESUMO
BACKGROUND: Ultrapluse CO2 fractional laser technology has emerged as an effective treatment for scar management. However, one drawback of this modality is the pain caused during the procedure. This study aims to explore the efficacy and safety of dezocine (DZC) as preemptive analgesia for reduction of pain induced by ultrapulse CO2 fractional laser treatment for acne scars. METHODS: The study cohort included 78 outpatients with acne scars between February and April 2023. Patients were randomly assigned into three groups with intravenous injection (iv) of DZC prior to laser treatment: (1) control, iv of saline; (2) DZC group 1 (DZC_1), iv of DZC at 0.15 mg/kg; and (3) DZC_2, iv of DZC at 0.20 mg/kg. After 30 min, one session of ultrapulse CO2 fractional laser treatment on acne scars was performed. Hemodynamics, visual analogue scale (VAS), and anxiety visual analog test (AVAT) were monitored prior to, during, and after the procedure. RESULTS: Operative success rates for patients in the control, DZC_1, and DZC_2 groups were 34.6%, 84.6%, and 100%, respectively. DZC administered with either dosage significantly reduced the VAS and AVAT scores of patients in treatment groups as compared with the subjects in the control group during the course of ultrapulse CO2 fractional laser treatment. Patients in DZC_1 and DZC_2 groups did not show any significant difference in hemodynamic parameters, VAS, and AVAT scores. Temporary adverse effects such as nausea and dizziness were observed in some subjects after treatment; the symptoms were quickly dissolved after a rest in supine position. CONCLUSIONS: DZC as preemptive analgesia could effectively reduce pain and anxiety induced by ultrapulse CO2 fractional laser treatment in patients. This study provided an option of preemptive anesthesia to minimize the pain and discomforts associated with laser treatments in clinical practices.
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Hypoaconitine (HA), a major secondary metabolite of aconite (a plant-derived rodenticide), is a highly toxic di-ester alkaloidal constituent. The toxicity of HA is intense with a low LD50. However, studies on its toxicity mechanism have mainly focused on cardiotoxicity, with few reports on the mechanism of hepatotoxicity. In this study, we combined metabolomics and network toxicology to investigate the effects of HA on the liver and analyzed the mechanisms by which it causes hepatotoxicity. The results of metabolomics studies indicated diethylphosphate, sphingosine-1-phosphate, glycerophosphorylcholine, 2,8-quinolinediol, guanidinosuccinic acid, and D-proline as differential metabolites after HA exposure. These metabolites are involved in eight metabolic pathways including arginine and proline metabolism, ether lipid metabolism, ß-alanine metabolism, sphingolipid metabolism, glutathione metabolism, and glycerophospholipid metabolism. Network toxicology analysis of HA may affect the HIF-1 signaling pathway, IL-17 signaling pathway, PI3K-Akt signaling pathway, MAPK signaling pathway, and so on by regulating the targets of ALB, HSP90AA1, MMP9, CASP3, and so on. Integrating the results of metabolomics and network toxicology, it was concluded that HA may induce hepatotoxicity by triggering physiological processes such as oxidative stress, inflammatory response, and inducing apoptosis in hepatocytes.
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Aconitina , Fígado , Metabolômica , Animais , Camundongos , Masculino , Aconitina/análogos & derivados , Aconitina/toxicidade , Fígado/metabolismo , Fígado/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: L-theanine is a unique non-protein amino acid in tea that is widely used as a safe food additive. We investigated the cardioprotective effects and mechanisms of L-theanine in myocardial ischemia-reperfusion injury (MIRI). METHODS: The cardioprotective effects and mechanisms of L-theanine and the role of Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling were investigated in MIRI mice using measures of cardiac function, oxidative stress, and apoptosis. RESULTS: Administration of L-theanine (10 mg/kg, once daily) suppressed the MIRI-induced increase in infarct size and serum creatine kinase and lactate dehydrogenase levels, as well as MIRI-induced cardiac apoptosis, as evidenced by an increase in Bcl-2 expression and a decrease in Bax/caspase-3 expression. Administration of L-theanine also decreased the levels of parameters reflecting oxidative stress, such as dihydroethidium, malondialdehyde, and nitric oxide, and increased the levels of parameters reflecting anti-oxidation, such as total antioxidant capacity (T-AOC), glutathione (GSH), and superoxide dismutase (SOD) in ischemic heart tissue. Further analysis showed that L-theanine administration suppressed the MIRI-induced decrease of phospho-JAK2 and phospho-STAT3 in ischemic heart tissue. Inhibition of JAK2 by AG490 (5 mg/kg, once daily) abolished the cardioprotective effect of L-theanine, suggesting that the JAK2/STAT3 signaling pathway may play an essential role in mediating the anti-I/R effect of L-theanine. CONCLUSIONS: L-theanine administration suppresses cellular apoptosis and oxidative stress in part via the JAK2/STAT3 signaling pathway, thereby attenuating MIRI-induced cardiac injury. L-theanine could be developed as a potential drug to alleviate cardiac damage in MIRI.