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Development of single-component organic phosphor attracts increasing interest due to its wide applications in optoelectronic technologies. Theoretically, activating efficient intersystem crossing (ISC) via 1(π, π*) to 3(π, π*) transitions, rather than 1(n, π*) â 3(π, π*) transitions, is an alternative access to purely organic phosphors but remains challenging. Herein, we designed and successfully synthesized the sila-8-membered ring fused biaryl benzoskeleton by transition metal catalysis, which served as a new organic phosphor with efficient 1(π, π*) to 3(π, π*) ISC. We first found that such a compound exhibits a record-long phosphorescence lifetime of 6.5 s at low temperature for single-component organic systems. Then, we developed two strategies to tune their decay channels to evolve such nonemissive molecules into bright phosphors with elongated lifetimes at room temperature: 1) Physic-based design, where quantitative analyses of electron-phonon coupling led us to reveal and hinder the major nonradiative channels, thus lighted up room temperature phosphorescence (RTP) with a lifetime of 480 ms at 298 K; 2) chemical geometry-driven molecular engineering, where a geometry-based descriptor ΔΘT1-S0/ΘS0 was developed for rational screening RTP candidates and further improved the RTP lifetime to 794 ms. This study clearly shows the power of interdiscipline among synthetic methodology, physics-based rational design, and computational modeling, which represents a paradigm for the development of an organic emitter.
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Reusable point-of-care biosensors offer a cost-effective solution for serial biomarker monitoring, addressing the critical demand for tumour treatments and recurrence diagnosis. However, their realization has been limited by the contradictory requirements of robust reusability and high sensing capability to multiple interactions among transducer surface, sensing probes and target analytes. Here we propose a drug-mediated organic electrochemical transistor as a robust, reusable epidermal growth factor receptor sensor with striking sensitivity and selectivity. By electrostatically adsorbing protonated gefitinib onto poly(3,4-ethylenedioxythiophene):polystyrene sulfonate and leveraging its strong binding to the epidermal growth factor receptor target, the device operates with a unique refresh-in-sensing mechanism. It not only yields an ultralow limit-of-detection concentration down to 5.74 fg ml-1 for epidermal growth factor receptor but, more importantly, also produces an unprecedented regeneration cycle exceeding 200. We further validate the potential of our devices for easy-to-use biomedical applications by creating an 8 × 12 diagnostic drug-mediated organic electrochemical transistor array with excellent uniformity to clinical blood samples.
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American Indians (AI) demonstrate the highest rates of both suicidal behaviors (SB) and alcohol use disorders (AUD) among all ethnic groups in the US. Rates of suicide and AUD vary substantially between tribal groups and across different geographical regions, underscoring a need to delineate more specific risk and resilience factors. Using data from over 740 AI living within eight contiguous reservations, we assessed genetic risk factors for SB by investigating: (1) possible genetic overlap with AUD, and (2) impacts of rare and low-frequency genomic variants. Suicidal behaviors included lifetime history of suicidal thoughts and acts, including verified suicide deaths, scored using a ranking variable for the SB phenotype (range 0-4). We identified five loci significantly associated with SB and AUD, two of which are intergenic and three intronic on genes AACSP1, ANK1, and FBXO11. Nonsynonymous rare and low-frequency mutations in four genes including SERPINF1 (PEDF), ZNF30, CD34, and SLC5A9, and non-intronic rare and low-frequency mutations in genes OPRD1, HSD17B3 and one lincRNA were significantly associated with SB. One identified pathway related to hypoxia-inducible factor (HIF) regulation, whose 83 nonsynonymous rare and low-frequency variants on 10 genes were significantly linked to SB as well. Four additional genes, and two pathways related to vasopressin-regulated water metabolism and cellular hexose transport, also were strongly associated with SB. This study represents the first investigation of genetic factors for SB in an American Indian population that has high risk for suicide. Our study suggests that bivariate association analysis between comorbid disorders can increase statistical power; and rare and low-frequency variant analysis in a high-risk population enabled by whole-genome sequencing has the potential to identify novel genetic factors. Although such findings may be population specific, rare functional mutations relating to PEDF and HIF regulation align with past reports and suggest a biological mechanism for suicide risk and a potential therapeutic target for intervention.
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Alcoholismo , Indígenas Norteamericanos , Suicidio , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Alcoholismo/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Indígenas Norteamericanos/genética , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Ideación Suicida , Intento de Suicidio , Estados Unidos/epidemiologíaRESUMEN
Microbial remediation of heavy metal polluted environment is ecofriendly and cost effective. Therefore, in the present study, Shewanella putrefaciens stain 4H was previously isolated by our group from the activated sludge of secondary sedimentation tank in a dyeing wastewater treatment plant. The bacterium was able to reduce chromate effectively. The strains showed significant ability to reduce Cr(VI) in the pH range of 8.0 to 10.0 (optimum pH 9.0) and 25-42 â (optimum 30 â) and were able to reduce 300 mg/L of Cr(VI) in 72 h under parthenogenetic anaerobic conditions. In this paper, the complete genome sequence was obtained by Nanopore sequencing technology and analyzed chromium metabolism-related genes by comparative genomics The genomic sequence of S. putrefaciens 4H has a length of 4,631,110 bp with a G + C content of 44.66% and contains 4015 protein-coding genes and 3223, 2414, 2343 genes were correspondingly annotated into the COG, KEGG, and GO databases. The qRT-PCR analysis showed that the expression of chrA, mtrC, and undA genes was up-regulated under Cr(VI) stress. This study explores the Chromium Metabolism-Related Genes of S. putrefaciens 4H and will help to deepen our understanding of the mechanisms of Cr(VI) tolerance and reduction in this strain, thus contributing to the better application of S. putrefaciens 4H in the field of remediation of chromium-contaminated environments.
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Shewanella putrefaciens , Shewanella putrefaciens/genética , Shewanella putrefaciens/metabolismo , Oxidación-Reducción , Cromo/toxicidad , Cromo/metabolismo , Bacterias/metabolismoRESUMEN
Creating a perfect catalyst to operate enzyme-like chiral recognition has been a long-sought aim. A challenging example in this context is constructing acyclic all-carbon quaternary stereogenic centers by transition metal-catalyzed enantioselective C-H activation. We now report highly enantioselective iridium-catalyzed primary C-H borylation of α-all-carbon substituted 2,2-dimethyl amides enabled by a tailor-made chiral bidentate boryl ligand (CBL). The success of the current transformation is attributed to the CBL/iridium catalyst, which has a confined chiral pocket. This protocol provides a diverse array of acyclic all-carbon quaternary stereocenters with excellent enantiocontrol and distinct structural features. Computational study reveals that steric hindrance of CBL could regulate the type of dominant orbital interaction between the catalyst and substrate, which is crucial to conferring high chiral induction.
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Monosubstituted tetrazines are important bioorthogonal reactive tools due to their rapid ligation with trans-cyclooctene. However, their application is limited by the reactivity-stability paradox in biological environments. In this study, we demonstrated that steric effects are crucial in resolving this paradox through theoretical methods and developed a simple synthetic route to validate our computational findings, leading to the discovery of 1,3-azole-4-yl and 1,2-azole-3-yl monosubstituted tetrazines as superior bioorthogonal tools. These new tetrazines surpass previous tetrazines in terms of high reactivities and elevated stabilities. The most stable tetrazine exhibits a reasonable stability (71% remaining after 24 h incubation in cell culture medium) and an exceptionally high reactivity (k2 > 104 M-1 s-1 toward trans-cyclooctene). Due to its good stability in biological systems, a noncanonical amino acid containing such a tetrazine side chain was genetically encoded into proteins site-specifically via an expanded genetic code. The encoded protein can be efficiently labeled using cyclopropane-fused trans-cyclooctene dyes in living mammalian cells with an ultrafast reaction rate exceeding 107 M-1 s-1, making it one of the fastest protein labeling reactions reported to date. Additionally, we showed its superiority through in vivo reactions in living mice, achieving an efficient local anchoring of proteins. These tetrazines are expected to be optimal bioorthogonal reactive tools within living systems.
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It's challenging work to identify disease-causing genes from the next-generation sequencing (NGS) data of patients with Mendelian disorders. To improve this situation, researchers have developed many phenotype-driven gene prioritization methods using a patient's genotype and phenotype information, or phenotype information only as input to rank the candidate's pathogenic genes. Evaluations of these ranking methods provide practitioners with convenience for choosing an appropriate tool for their workflows, but retrospective benchmarks are underpowered to provide statistically significant results in their attempt to differentiate. In this research, the performance of ten recognized causal-gene prioritization methods was benchmarked using 305 cases from the Deciphering Developmental Disorders (DDD) project and 209 in-house cases via a relatively unbiased methodology. The evaluation results show that methods using Human Phenotype Ontology (HPO) terms and Variant Call Format (VCF) files as input achieved better overall performance than those using phenotypic data alone. Besides, LIRICAL and AMELIE, two of the best methods in our benchmark experiments, complement each other in cases with the causal genes ranked highly, suggesting a possible integrative approach to further enhance the diagnostic efficiency. Our benchmarking provides valuable reference information to the computer-assisted rapid diagnosis in Mendelian diseases and sheds some light on the potential direction of future improvement on disease-causing gene prioritization methods.
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Biología Computacional , Secuenciación de Nucleótidos de Alto Rendimiento , Biología Computacional/métodos , Genotipo , Humanos , Fenotipo , Estudios RetrospectivosRESUMEN
ß-Carotene is one kind of the most important carotenoids. The major functions of ß-carotene include the antioxidant and anti-cardiovascular properties, which make it a growing market. Recently, the use of metabolic engineering to construct microbial cell factories to synthesize ß-carotene has become the latest model for its industrial production. Among these cell factories, yeasts including Saccharomyces cerevisiae and Yarrowia lipolytica have attracted the most attention because of the: security, mature genetic manipulation tools, high flux toward carotenoids using the native mevalonate pathway and robustness for large-scale fermentation. In this review, the latest strategies for ß-carotene biosynthesis, including protein engineering, promoters engineering and morphological engineering are summarized in detail. Finally, perspectives for future engineering approaches are proposed to improve ß-carotene production.
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Ingeniería Metabólica , Yarrowia , beta Caroteno/genética , beta Caroteno/metabolismo , Yarrowia/genética , Yarrowia/metabolismo , Saccharomyces cerevisiae/genética , Regiones Promotoras GenéticasRESUMEN
Factors that determine nonresponse to immune checkpoint inhibitor (ICI) remain unclear. The protumor activities of cancer-associated fibroblasts (CAFs) suggest that they are potential therapeutic targets for cancer treatment. There is, however, a lack of CAF-related signature in predicting response to immunotherapy in gastric cancer (GC). Single-cell RNA sequencing (scRNA-seq) and RNA sequencing (RNA-seq) data of GC immunotherapy were downloaded from the Gene Expression Omnibus database. Bulk RNA-seq data were obtained from The Cancer Genome Atlas. The R package 'Seurat' was used for scRNA-seq data processing. Cellular infiltration, receptor-ligand interactions, and evolutionary trajectory analysis were further explored. Differentially expressed genes affecting overall survival were obtained using the limma package. Weighted Gene Correlation Network Analysis was used to identify key modules of immunotherapy nonresponder. Prognostic model was constructed by univariate Cox and least absolute contraction and selection operator analysis using the intersection of activated fibroblast genes (AFGs) with key module genes. The differences in clinicopathological features, immune microenvironment, immunotherapy prediction, and sensitivity to small molecule agents between the high- and low-risk groups were further investigated. Based on scRNA-seq, we finally identified 20 AFGs associations with the prognosis of GC patients. AFGs' high expression levels were correlated with both poor prognosis and tumor progression. Three genes (FRZB, SPARC, and FKBP10) were identified as immunotherapy nonresponse-related fibroblast genes and used to construct the prognostic signature. This signature is an independent significant risk factor affecting the clinical outcomes of GC patients. Remarkably, there were more CD4 memory T cells, resting mast cells, and M2 macrophages infiltrating in the high-risk group, which was characterized by higher tumor immune exclusion. Moreover, patients with higher risk scores were more prone to not respond to immunotherapy but were more sensitive to various small molecule agents, such as memantine. In conclusion, this study constructed a fibroblast-associated ICI nonresponse gene signature, which could predict the response to immunotherapy. This study potentially revealed a novel way to overcome immune resistance in GC.
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Iodoacetic acid (IAA) is a halogenated disinfection by-product of growing concern due to its high cytotoxicity, genotoxicity, endocrine disruptor effects, and potential carcinogenicity. However, the data on distribution and excretion of IAA after ingestion by mammals are still scarce. Here, we developed a reliable and validated method for detecting IAA in biological specimens (plasma, urine, feces, liver, kidney, and tissues) based on modified QuEChERS sample preparation combined with gas chromatography-tandem triple quadrupole mass spectrometry (GC-MS/MS). The detection method for IAA exhibited satisfactory recovery rates (62.6-108.0%) with low relative standard deviations (RSD < 12.3%) and a low detection limit for all biological matrices ranging from 0.007 to 0.032 ng/g. The study showed that the proposed method was reliable and reproducible for analyzing IAA in biological specimens. It was successfully used to detect IAA levels in biological samples from rats given gavage administration. The results indicated that IAA was found in various tissues and organs, including plasma, thyroid, the liver, the kidney, the spleen, gastrointestinal tract, and others, 6 h after exposure. This study provides the first data on the in vivo distribution in and excretion of IAA by mammals following oral exposure.
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Cromatografía de Gases y Espectrometría de Masas , Ácido Yodoacético , Límite de Detección , Espectrometría de Masas en Tándem , Animales , Cromatografía de Gases y Espectrometría de Masas/métodos , Espectrometría de Masas en Tándem/métodos , Ratas , Masculino , Distribución Tisular , Reproducibilidad de los Resultados , Ratas Sprague-Dawley , Riñón/química , Riñón/metabolismo , Heces/química , Hígado/química , Hígado/metabolismoRESUMEN
The host matrix is an important means to tune emission color and improve luminescence efficiency of near-infrared (NIR) thermally activated delay fluorescence (TADF) light-emitting diodes. However, the mechanism of NIR TADF of the guest-host systems is still unclear. Namely, there is a controversy on whether the formation of J-aggregation, solid-state solvent effect, molecular polarization or intermolecular charge transfer (CT) is responsible for the NIR TADF. Here, the morphologies, geometrical and electronic structures, and photophysical properties are explored by combining molecular dynamics simulation, density functional theory and thermal vibration correlation function theory for the guest-host (TPAAP: TPBi) films with different concentrations. It is found that the red TADF is generated largely by the solid-state solvent effect in the low 1 wt% doped film while the NIR TADF is attributed to the synergistic effect of solid-state solvent and guest-guest intermolecular CT in the high 20 wt% film. These findings provide a deeper understanding of the mechanism of NIR-TADF of the guest-host systems.
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External pressure can regulate the photophysical property and charge transport performance of organic semiconductors, however, the underlying mechanism at the microscopic level is still elusive. Using thermal vibrational correlation function coupled quantum mechanics/molecular mechanics and full quantum charge transfer rate theory, we systematically explore the influence of pressure on fluorescence emission and charge transport behaviours of representative cyclooctatetrathiophene (COTh). It is found that, upon pressurization, the intramolecular configurations of COTh became more twisted, leading to the blue-shifted emission. The fluorescence quantum efficiency (FQE) of COTh crystals decreases monotonically in a wide pressure range of 0-4.38 GPa, because the increase of intermolecular electronic energy transfer rate constant (keet) is larger than the decrease of internal conversion rate constant (kic), and the variation of keet is dominant. The decrease in kic is attributed to the decreasing reorganization energy, reflecting the suppression of the low-frequency flipping vibrations of four thiophene rings and the high-frequency stretching vibrations of central cyclooctatetraene, while the keet increase is due to the simultaneous increase in exciton coupling and spectra overlap. Moreover, we predicted that the hole mobility of COTh increases monotonically by nearly an order of magnitude from 0.39 to 3.00 cm2 V-1 s-1 upon compression, because of the increase in transfer integral and the decrease of charged reorganization energy. Furthermore, its hole mobility exhibits obvious anisotropy. Our work systematically builds the external pressure, molecular packing, luminescence and transport properties relationships of organic semiconductors and provides theoretical guidance for the rational design of pressure responsive organic semiconductors with excellent photoelectric performance.
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Photochromic molecules with aggregation-induced emission (AIE) effects are of great value and prospective in various practical applications. To explore its inherent mechanism, the open isomer ap-BBTE and the closed isomer c-BBTE were chosen to perform the theoretical calculation using the quantum mechanics/molecular mechanics model combined with thermal vibration correlation function formalism. The calculations show that the photocyclization (PC) reaction from ap-BBTE to c-BBTE facilitates an improvement in the AIE effect. It is found that the fluorescence quantum yield (ΦF) enhancement of ap-BBTE is attributed to the restriction of the low-frequency rotational motion of the benzothiophene moiety and the high-frequency stretching vibrations of the C-C bond between the benzothiophene and benzylbis(thiadiazole) vinyl groups after aggregation. For c-BBTE, the increase in ΦF upon aggregation is mainly due to the suppression of the high-frequency stretching vibration of the C-C bond between the benzothiophene and the benzobis(thiadiazole) vinyl groups. In addition, the AIE effect was also enhanced from ap-BBTE to c-BBTE, which is consistent with the experimental phenomenon. The corresponding emission spectrum red-shifted from ap-BBTE to c-BBTE in both dilute solution and the crystalline state due to the improved intramolecular conjugation of c-BBTE. Moreover, the PC reaction from ap-BBTE to c-BBTE easily occurs in an excited state with a low energy barrier transition state by forming a C-C bond between benzothiophene groups effectively in dilute solution. Our calculations provide theoretical guidance for the further rational design of efficient AIE luminogens.
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PURPOSE: Quality-adjusted life-year (QALY) is a dominant measurement of health gain in economic evaluations for pricing drugs. However, end-of-life (EoL) patients' preference for QALY gains in life expectancy (LE) and quality of life (QoL) during different disease stages remains unknown and is seldom involved in decision-making. This study aims to measure preferences and willingness-to-pay (WTP) towards different types of QALY gain among EoL cancer patients. METHODS: We attributed QALY gain to four types, gain in LE and QoL, respectively, and during both progression-free survival (PFS) and post-progression survival (PPS). A discrete choice experiment including five attributes (the four QALY attributes and one cost attribute) with three levels each was developed and conducted with 85 Chinese advanced non-small cell lung cancer patients in 2022. All levels were set with QALY gain/cost synthesised from research on anti-lung cancer drugs recently listed by Chinese National Healthcare Security Administration. Each respondent answered six choice tasks in a face-to-face interview. The data were analysed using mixed logit models. RESULTS: Patients valued LE-related QALY gain in PFS most, with a relative importance of 81.8% and a WTP of $43,160 [95% CI 26,751 ~ 59,569] per QALY gain. Respondents consistently preferred LE-related to QoL-related QALY gain regardless of disease stage. Patients with higher income or lower education levels tended to pay more for QoL-related QALY gain. CONCLUSION: Our findings suggest a prioritised resource allocation to EoL-prolonging health technologies. Given the small sample size and large individual heterogeneity, a full-scale study is needed to provide more robust results.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Calidad de Vida/psicología , Proyectos Piloto , Años de Vida Ajustados por Calidad de Vida , Muerte , Conducta de Elección , Prioridad del Paciente , Encuestas y CuestionariosRESUMEN
This study aims to examine the clinical characteristics and outcomes of clinical myocarditis in pediatric patients in China. This is a multicenter retrospective study. Children diagnosed with clinical myocarditis from 20 hospitals in China and admitted between January 1, 2015, and December 30, 2021, were enrolled. The clinical myocarditis was diagnosed based on the "Diagnostic Recommendation for Myocarditis in Children (Version 2018)". The clinical data were collected from their medical records. A total of 1210 patients were finally enrolled in this study. Among them, 45.6% had a history of respiratory tract infection. An abnormal electrocardiogram was observed in 74.2% of patients. Echocardiography revealed that 32.3% of patients had a left ventricular ejection fraction of less than 50%. Cardiac MRI was performed in 4.9% of children with clinical myocarditis, of which 61% showed localized or diffuse hypersignal on T2-weighted images. Serum levels of cardiac troponin I (cTnI), creatine kinase-MB (CK-MB), and N-terminal B-type natriuretic peptide (NT-proBNP) were higher in patients with fulminant myocarditis than in patients with myocarditis, making them potential risk factors for fulminant myocarditis. Following active treatment, 12.1% of patients were cured, and 79.1% were discharged with improvement. CONCLUSION: Clinical myocarditis in children often presents with symptoms outside the cardiovascular system. CK-MB, cTnI, and NT-proBNP are important indicators for assessing clinical myocarditis. The electrocardiogram and echocardiogram findings in children with clinical myocarditis exhibit significant variability but lack specificity. Cardiac MRI can be a useful tool for screening clinical myocarditis. Most children with clinical myocarditis have a favorable prognosis. WHAT IS KNOWN: ⢠Pediatric myocarditis presents complex clinical manifestations and exhibits varying degrees of severity. Children with mild myocarditis generally have a favorable prognosis, while a small number of children with critically ill myocarditis experience sudden onset, hemodynamic disorders, and fatal arrhythmias. Therefore, early diagnosis and timely treatment of myocarditis are imperative. WHAT IS NEW: ⢠To the best of our knowledge, this multicenter retrospective study is the largest ever reported in China, aiming to reveal the clinical characteristics and outcomes of pediatric clinical myocarditis in China. We provided an extensive analysis of the clinical characteristics, diagnosis, treatment, prognosis, and factors impacting disease severity in pediatric clinical myocarditis in China, which provides insights into the epidemiological characteristics of pediatric clinical myocarditis.
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Miocarditis , Niño , Humanos , Miocarditis/diagnóstico , Miocarditis/terapia , Estudios Retrospectivos , Volumen Sistólico , Función Ventricular Izquierda , Forma MB de la Creatina-Quinasa , Arritmias Cardíacas , China/epidemiologíaRESUMEN
Cannabis use disorder (CUD) is common and has in part a genetic basis. The risk factors underlying its development likely involve multiple genes that are polygenetic and interact with each other and the environment to ultimately lead to the disorder. Co-morbidity and genetic correlations have been identified between CUD and other disorders and traits in select populations primarily of European descent. If two or more traits, such as CUD and another disorder, are affected by the same genetic locus, they are said to be pleiotropic. The present study aimed to identify specific pleiotropic loci for the severity level of CUD in three high-risk population cohorts: American Indians (AI), Mexican Americans (MA), and European Americans (EA). Using a previously developed computational method based on a machine learning technique, we leveraged the entire GWAS catalog and identified 114, 119, and 165 potentially pleiotropic variants for CUD severity in AI, MA, and EA respectively. Ten pleiotropic loci were shared between the cohorts although the exact variants from each cohort differed. While majority of the pleiotropic genes were distinct in each cohort, they converged on numerous enriched biological pathways. The gene ontology terms associated with the pleiotropic genes were predominately related to synaptic functions and neurodevelopment. Notable pathways included Wnt/ß-catenin signaling, lipoprotein assembly, response to UV radiation, and components of the complement system. The pleiotropic genes were the most significantly differentially expressed in frontal cortex and coronary artery, up-regulated in adipose tissue, and down-regulated in testis, prostate, and ovary. They were significantly up-regulated in most brain tissues but were down-regulated in the cerebellum and hypothalamus. Our study is the first to attempt a large-scale pleiotropy detection scan for CUD severity. Our findings suggest that the different population cohorts may have distinct genetic factors for CUD, however they share pleiotropic genes from underlying pathways related to Alzheimer's disease, neuroplasticity, immune response, and reproductive endocrine systems.
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Abuso de Marihuana , Masculino , Femenino , Humanos , Abuso de Marihuana/diagnóstico , Abuso de Marihuana/epidemiología , Factores de Riesgo , FenotipoRESUMEN
Deoxynivalenol (DON), commonly known as vomitoxin, is a mycotoxin produced by fungi and is frequently found as a contaminant in various cereal-based food worldwide. While the harmful effects of DON have been extensively studied in different tissues, its specific impact on the proliferation of skeletal muscle cells remains unclear. In this study, we utilized murine C2C12 myoblasts as a model to explore the influence of DON on their proliferation. Our observations indicated that DON exhibits dose-dependent toxicity, significantly inhibiting the proliferation of C2C12 cells. Through the application of RNA-seq analysis combined with gene set enrichment analysis, we identified a noteworthy downregulation of genes linked to the extracellular matrix (ECM) and condensed chromosome. Concurrently with the reduced expression of ECM genes, immunostaining analysis revealed notable changes in the distribution of fibronectin, a vital ECM component, condensing into clusters and punctate formations. Remarkably, the exposure to DON induced the formation of multipolar spindles, leading to the disruption of the normal cell cycle. This, in turn, activated the p53-p21 signaling pathway and ultimately resulted in apoptosis. These findings contribute significant insights into the mechanisms through which DON induces toxicity within skeletal muscle cells.
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Apoptosis , Mioblastos , Tricotecenos , Animales , Tricotecenos/toxicidad , Apoptosis/efectos de los fármacos , Ratones , Mioblastos/efectos de los fármacos , Línea Celular , Mitosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Matriz Extracelular/efectos de los fármacosRESUMEN
Photodynamic therapy (PDT) has been a topic of interest since the first report in 1900 but has yet to become a 'mainstream' treatment protocol in the medical field. There are clear indications for which PDT might be the 'method of choice', but it is unlikely that there will be protocols for the treatment of systemic disease. This report discusses recent developments for promoting PDT efficacy, in the context of what is already known. Factors that can limit the scope of these applications are also indicated. Among the more interesting of these developments is the use of formulation techniques to target specific organelles for photodamage. This can enhance responses to PDT and circumvent situations where an impaired death pathway interferes with PDT efficacy.
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Fotoquimioterapia , Fármacos Fotosensibilizantes , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéuticoRESUMEN
Hypertension is the most common chronic disease in clinics and has become the most common risk factor for cardiovascular diseases. Because of its high incidence rate, disability rate, and mortality, it has attracted worldwide attention. Despite continuous progress in modern medicine in the treatment of hypertension with new antihypertensive drugs such as Zilebesiran, a nucleic acid drug that acts on microRNA, direct renin inhibitors, and renal sympathetic blockade, the control rate is still not ideal. How to effectively prevent and control hypertension has become one of the urgent clinical challenges to be solved. Traditional Chinese medicine(TCM) has a long record of treating hypertension and has accumulated rich experience, including theoretical understanding, effective single medicine, compound medicine, traditional Chinese patent medicines, and classic famous prescriptions. In TCM, hypertension belongs to the categories of diseases such as dizziness and headache. Previous literature and clinical studies have found that hypertension has key pathogenesis such as fire syndrome, fluid syndrome, deficiency syndrome, and blood stasis syndrome. Among them, the hyperactivity of liver Yang is closely related to blood pressure fluctuations, blood pressure variability, inflammation, and sympathetic activity stimulation. Internal obstruction by blood stasis is closely related to the damage of target organs such as the heart, brain, and kidneys in hypertension. Therefore, the two key pathogenesis of liver yang hyperactivity and internal obstruction by blood stasis run through the entire process of hypertension. Previous studies have found that the effective empirical formula Tianxiong Granules, based on the principles of suppressing Yang and promoting blood circulation, originated from the classic formula Xiongqiong Tianma Pills in Yu Yao Yuan Fang. It is composed of Gastrodiae Rhizoma, Chuanxiong Rhizoma, Puerariae Lobatae Radix, Achyranthis Bidentatae Radix, and Cyathulae Radix and has significant therapeutic effects in the treatment of hypertension. The clinical indications include headache, dizziness, bloating, strong neck, and weak waist and legs. At the same time, it may be accompanied by poor speech, thirst, normal or loose stools, soreness in the waist and legs, lower limb pain, muscle and pulse spasm, menstrual and abdominal pain, dark red tongue, strong pulse strings, or straight and long pulse strings that pass through the mouth of an inch. In the combination rule, it can be used according to the different pathogenesis stages of hypertension patients. In the fire syndrome stage, it is often combined with Tianma Gouteng Decoction and Chaihu Jia Longgu Muli Decoction. In the fluid syndrome stage, it is often combined with Banxia Baizhu Tianma Decoction. In the deficiency syndrome stage, it is often combined with Liuwei Dihuang Pills and Shenqi Pills. In terms of dosage, it is important to focus on the main symptoms and adjust the dosage of key drugs based on blood pressure values. Some drugs can be used in sufficient quantities. By analyzing the compatibility of Tianxiong Granules, clinical application indications, combined formula experience, and dosage application experience, we provide effective treatment methods and more options for TCM to treat hypertension with Yang hyperactivity and blood stasis syndrome.
Asunto(s)
Medicamentos Herbarios Chinos , Hipertensión , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/uso terapéutico , Circulación Sanguínea/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Medicina Tradicional China , Antihipertensivos/farmacologíaRESUMEN
Coronary heart disease is a common cardiovascular disease, attacking about 11.4 million patients in China. With increasing prevalence and mortality year by year, coronary heart disease has become a major factor threatening human health and public health. Although primary and secondary prevention, intervention, coronary artery bypass grafting and other interventions have reduced the death rate, there are drug(aspirin) resistance, secondary nitroglycerin failure, post-intervention fatigue, chest tightness, and an-xiety, and complication with a high risk of bleeding, which have become the key clinical and scientific issues needed to be resolved. Coronary heart disease belongs to the category of chest impediment and heart pain in traditional Chinese medicine(TCM). The TCM etiology of this disease includes external contraction of cold, emotional disorders, constitutional insufficiency, physical weakness, and labor injury, which are closely related to sympathetic nerve activity, state of cardiac and psychological diseases, family history, and cardiovascular metabolic disorders in modern medicine. The TCM causes of coronary heart disease include Qi depression, phlegm turbidity, blood stasis, fire-heat, cold congealing, and healthy Qi deficiency, which are associated with emotional factors such as anxiety and depression, abnormal lipid metabolism, abnormalities in blood circulation and coagulation, inflammatory responses, hyperactive immune responses, and heart failure, chronic wasting disease, or aging, respectively. Accordingly, the patients with Qi depression should be treated with Chaihu Longgu Muli Decoction, and those with phlegm turbidity should be treated with Wendan Decoction and Gualou Xiebai Banxia Decoction. Xuefu Zhuyu Decoction and Guizhi Fuling Pills are recommended for blood stasis, Xiaoxianxiong Decoction and Sanhuang Xiexin Decoction for fire-heat, Zhishi Xiebai Guizhi Decoction for cold congealing, and Renshen Decoction for healthy Qi deficiency. Due to the changes in the spectrum of diseases from ancient to modern times as well as the differences in physical constitution, the key cause of coronary heart disease has evolved from the chest Yang deficiency and cold congealing to Qi depression, phlegm turbidity, phlegm combined with stasis, and fire-heat, showing a shift from cold to heat and from deficiency to excess. The combination of classic formulas presents a pattern. That is, the core formula-syndrome correspondence of a disease often fixedly appears with other formula-syndrome correspondence, which may be related to the development of the pathophysiological mechanism of the disease. In the clinical application of modern pharmacological results, the research team has formulated the clinical principle of pathogenesis corresponding to pathological changes and medicinal nature corresponding pharmacological effects. The modern pharmacological research on classic formulas is conducive to targeted treatment. Moreover, classic formulas help to ameliorate aspirin resistance, clopidogrel resistance, post-intervention anxiety, and high risk of bleeding and address the lack of effective blockade of critical lesions in the coronary artery and the progression of post-infarction heart failure. The innovative understanding of the etiology and pathogenesis of co-ronary heart disease helps to improve the clinical efficacy of TCM and the clinical system for treating coronary heart disease with classic formulas.