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Video-based remote photoplethysmography (rPPG) has emerged as a promising technology for non-contact vital sign monitoring, especially under controlled conditions. However, the accurate measurement of vital signs in real-world scenarios faces several challenges, including artifacts induced by videocodecs, low-light noise, degradation, low dynamic range, occlusions, and hardware and network constraints. In this article, a systematic and comprehensive investigation of these issues is conducted, measuring their detrimental effects on the quality of rPPG measurements. Additionally, practical strategies are proposed for mitigating these challenges to improve the dependability and resilience of video-based rPPG systems. Methods for effective biosignal recovery in the presence of network limitations are detailed, along with denoising and inpainting techniques aimed at preserving video frame integrity. Compared to previous studies, this paper addresses a broader range of variables and demonstrates improved accuracy across various rPPG methods, emphasizing generalizability for practical applications in diverse scenarios with varying data quality. Extensive evaluations and direct comparisons demonstrate the effectiveness of these approaches in enhancing rPPG measurements under challenging environments, contributing to the development of more reliable and effective remote vital sign monitoring technologies.
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Artefactos , Fotopletismografía , Grabación en Video , Humanos , Fotopletismografía/métodos , Procesamiento de Señales Asistido por Computador , Masculino , Femenino , Adulto , Monitoreo Fisiológico/métodosRESUMEN
BACKGROUND: The burden of chronic liver disease (CLD) deaths attributable to the hepatitis B virus (HBV) and hepatitis C virus (HCV) remains unknown. Further research is required to elucidate the extent of this burden in the eventual elimination of these diseases. METHODS: Data on liver cancer, cirrhosis, and other CLD among 204 countries and territories between 1990 and 2019 was extracted from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) published in 2019. The Bayesian age-period-cohort model was used to analyze the temporal trend and predict the disease burden by 2030. RESULTS: The number of HCV-related CLD deaths surpassed that of CLD deaths caused by HBV in 2019 (536833 deaths versus 523003 deaths) and is expected to be maintained until 2030 (689124 deaths versus 628824 deaths). East Asia had the highest burden of chronic HBV and HCV infections during the study period. In 2019, the largest age-standardized death rates (ASDR) of CLD deaths caused by HBV and HCV were mainly observed in Western Sub-Saharan Africa (18.75%) and Eastern Sub-Saharan Africa (16.42%), respectively. South Asia and East Asia are predicted to have the highest number of CLD deaths related to HCV and HBV by 2030. Eastern Europe and South Asia show the largest expected increase in disease burden caused by HCV or HBV between 2019 and 2030. No GBD region is projected to achieve the WHO target of a 65% reduction in mortality from chronic HBV and HCV infections by 2030. CONCLUSIONS: Although the mortality of CLD caused by HBV and HCV decreased in the last three decades (from 1990 to 2019), the number of deaths will continue to increase until 2030. Therefore, governments and international organizations need to strengthen the effectiveness of vaccines, screening, and treatment, especially in potential emerging hotspot regions.
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Salud Global , Hepatitis B Crónica , Hepatitis C Crónica , Humanos , Salud Global/estadística & datos numéricos , Hepatitis C Crónica/mortalidad , Hepatitis C Crónica/epidemiología , Hepatitis B Crónica/mortalidad , Hepatitis B Crónica/epidemiología , Hepatitis B Crónica/complicaciones , Masculino , Femenino , Factores de Riesgo , Persona de Mediana Edad , Adulto , Hepatitis B/mortalidad , Hepatitis B/epidemiología , Carga Global de Enfermedades , Hepatopatías/mortalidad , Hepatopatías/epidemiología , Enfermedad Crónica/epidemiología , Hepatitis C/mortalidad , Hepatitis C/epidemiología , Teorema de Bayes , AncianoRESUMEN
Mutations in p53 and KRAS are seen in most cases of colon cancer. The impact of these mutations on signaling pathways related to cancer growth has been studied in depth, but relatively less is known on their effects on amino acid transporters in cancer cells. This represents a significant knowledge gap because amino acid nutrition in cancer cells profoundly influences macropinocytosis and ferroptosis, two processes with opposing effects on tumor growth. Here, we used isogenic colon cancer cell lines to investigate the effects of p53 deletion and KRAS activation on two amino acid transporters relevant to macropinocytosis (SLC38A5) and ferroptosis (SLC7A11). Our studies show that the predominant effect of p53 deletion is to induce SLC7A11 with the resultant potentiation of antioxidant machinery and protection of cancer cells from ferroptosis, whereas KRAS activation induces not only SLC7A11 but also SLC38A5, thus offering protection from ferroptosis as well as improving amino acid nutrition in cancer cells via accelerated macropinocytosis. Niclosamide, an FDA-approved anti-helminthic, blocks the functions of SLC7A11 and SLC38A5, thus inducing ferroptosis and suppressing macropinocytosis, with the resultant effective reversal of tumor-promoting actions of oncogenic changes in p53 and KRAS. These findings underscore the potential of this drug in colon cancer treatment.
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Neoplasias del Colon , Ferroptosis , Niclosamida , Pinocitosis , Proteínas Proto-Oncogénicas p21(ras) , Proteína p53 Supresora de Tumor , Humanos , Ferroptosis/efectos de los fármacos , Ferroptosis/genética , Pinocitosis/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Neoplasias del Colon/metabolismo , Neoplasias del Colon/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Línea Celular Tumoral , Niclosamida/farmacología , Niclosamida/uso terapéutico , Antineoplásicos/farmacología , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Mutación/genéticaRESUMEN
BACKGROUND: Histologic and serologic studies suggest the induction of local and systemic Treponema pallidum-specific CD4+ T-cell responses to T. pallidum infection. We hypothesized that T. pallidum-specific CD4+ T cells are detectable in blood and in the skin rash of secondary syphilis and persist in both compartments after treatment. METHODS: Peripheral blood mononuclear cells collected from 67 participants were screened by interferon-γ (IFN-γ) ELISPOT response to T. pallidum sonicate. T. pallidum-reactive T-cell lines from blood and skin were probed for responses to 89 recombinant T. pallidum antigens. Peptide epitopes and HLA class II restriction were defined for selected antigens. RESULTS: We detected CD4+ T-cell responses to T. pallidum sonicate ex vivo. Using T. pallidum-reactive T-cell lines we observed recognition of 14 discrete proteins, 13 of which localize to bacterial membranes or the periplasmic space. After therapy, T. pallidum-specific T cells persisted for at least 6 months in skin and 10 years in blood. CONCLUSIONS: T. pallidum infection elicits an antigen-specific CD4+ T-cell response in blood and skin. T. pallidum-specific CD4+ T cells persist as memory in both compartments long after curative therapy. The T. pallidum antigenic targets we identified may be high-priority vaccine candidates.
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Linfocitos T CD4-Positivos , Piel , Sífilis , Treponema pallidum , Humanos , Treponema pallidum/inmunología , Linfocitos T CD4-Positivos/inmunología , Sífilis/inmunología , Piel/inmunología , Piel/microbiología , Adulto , Masculino , Femenino , Proteínas de la Membrana/inmunología , Antígenos Bacterianos/inmunología , Persona de Mediana Edad , Interferón gamma/metabolismo , Proteínas Bacterianas/inmunología , Ensayo de Immunospot Ligado a Enzimas , Leucocitos Mononucleares/inmunología , Adulto JovenRESUMEN
Subclinical vascular impairment can be exacerbated in individuals who experience sustained inflammation after COVID-19 infection. Our study explores the prevalence and impact of autoantibodies on vascular dysfunction in healthy COVID-19 survivors, an area that remains inadequately investigated. Focusing on autoantibodies against the atypical chemokine receptor 1 (ACKR1), COVID-19 survivors demonstrated significantly elevated anti-ACKR1 autoantibodies, correlating with systemic cytokines, circulating damaged endothelial cells, and endothelial dysfunction. An independent cohort linked these autoantibodies to increased vascular disease outcomes during a median 6.7-yr follow-up. We analyzed a single-cell transcriptome atlas of endothelial cells from diverse mouse tissues, identifying enriched Ackr1 expressions in venous regions of the brain and soleus muscle vasculatures, which holds intriguing implications for tissue-specific venous thromboembolism manifestations reported in COVID-19. Functionally, purified immunoglobulin G (IgG) extracted from patient plasma did not trigger cell apoptosis or increase barrier permeability in human vein endothelial cells. Instead, plasma IgG enhanced antibody-dependent cellular cytotoxicity mediated by patient PBMCs, a phenomenon alleviated by blocking peptide or liposome ACKR1 recombinant protein. The blocking peptide uncovered that purified IgG from COVID-19 survivors possessed potential epitopes in the N-terminal extracellular domain of ACKR1, which effectively averted antibody-dependent cellular cytotoxicity. Our findings offer insights into therapeutic development to mitigate autoantibody reactivity in blood vessels in chronic inflammation.
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Autoanticuerpos , COVID-19 , SARS-CoV-2 , Humanos , Autoanticuerpos/inmunología , COVID-19/inmunología , Animales , Ratones , Femenino , Masculino , SARS-CoV-2/inmunología , Inflamación/inmunología , Persona de Mediana Edad , Endotelio Vascular/metabolismo , Endotelio Vascular/inmunología , Inmunoglobulina G/inmunología , Inmunoglobulina G/sangre , Células Endoteliales/metabolismo , Células Endoteliales/inmunología , Adulto , AncianoRESUMEN
Aeromonas spp. are commonly found in the aquatic environment and have been responsible for motile Aeromonas septicemia (MAS) in striped catfish, resulting in significant economic loss. These organisms also cause a range of opportunistic infections in humans with compromised immune systems. Here, we conducted a genomic investigation of 87 Aeromonas isolates derived from diseased catfish, healthy catfish and environmental water in catfish farms affected by MAS outbreaks in eight provinces in Mekong Delta (years: 2012-2022), together with 25 isolates from humans with bloodstream infections (years: 2010-2020). Genomics-based typing method precisely delineated Aeromonas species while traditional methods such as aerA PCR and MALDI-TOF were unable identify A. dhakensis. A. dhakensis was found to be more prevalent than A. hydrophila in both diseased catfish and human infections. A. dhakensis sequence type (ST) 656 followed by A. hydrophila ST251 were the predominant virulent species-lineages in diseased catfish (43.7 and 20.7â%, respectively), while diverse STs were found in humans with bloodstream infections. There was evidence of widespread transmission of ST656 and ST251 on striped catfish in the Mekong Delta region. ST656 and ST251 isolates carried a significantly higher number of acquired antimicrobial resistance (AMR) genes and virulence factors in comparison to other STs. They, however, exhibited several distinctions in key virulence factors (i.e. lack of type IV pili and enterotoxin ast in A. dhakensis), AMR genes (i.e. presence of imiH carbapenemase in A. dhakensis), and accessory gene content. To uncover potential conserved proteins of Aeromonas spp. for vaccine development, pangenome analysis has unveiled 2202 core genes between ST656 and ST251, of which 78 proteins were in either outer membrane or extracellular proteins. Our study represents one of the first genomic investigations of the species distribution, genetic landscape, and epidemiology of Aeromonas in diseased catfish and human infections in Vietnam. The emergence of antimicrobial resistant and virulent A. dhakensis strains underscores the needs of enhanced genomic surveillance and strengthening vaccine research and development in preventing Aeromonas diseases in catfish and humans, and the search for potential vaccine candidates could focus on Aeromonas core genes encoded for membrane and secreted proteins.
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Aeromonas , Bagres , Enfermedades de los Peces , Infecciones por Bacterias Gramnegativas , Sepsis , Animales , Bagres/microbiología , Vietnam/epidemiología , Aeromonas/genética , Aeromonas/aislamiento & purificación , Aeromonas/clasificación , Aeromonas/patogenicidad , Infecciones por Bacterias Gramnegativas/microbiología , Infecciones por Bacterias Gramnegativas/veterinaria , Infecciones por Bacterias Gramnegativas/epidemiología , Humanos , Sepsis/microbiología , Sepsis/veterinaria , Sepsis/epidemiología , Enfermedades de los Peces/microbiología , Filogenia , Genómica , Genoma Bacteriano , Factores de Virulencia/genética , Antibacterianos/farmacologíaRESUMEN
Objectives This study aimed to determine which method to triage intensive care patients using chronic comorbidity in a pandemic was perceived to be the fairest by the general public. Secondary objectives were to determine whether the public perceived it fair to provide preferential intensive care triage to vulnerable or disadvantaged people, and frontline healthcare workers. Methods A postal survey of 2000 registered voters randomly selected from the Australian Electoral Commission electoral roll was performed. The main outcome measures were respondents' fairness rating of four hypothetical intensive care triage methods that assess comorbidity (chronic medical conditions, long-term survival, function and frailty); and respondents' fairness rating of providing preferential triage to vulnerable or disadvantaged people, and frontline healthcare workers. Results The proportion of respondents who considered it fair to triage based on chronic medical conditions, long-term survival, function and frailty, was 52.1, 56.1, 65.0 and 62.4%, respectively. The proportion of respondents who considered it unfair to triage based on these four comorbidities was 31.9, 30.9, 23.8 and 23.2%, respectively. More respondents considered it unfair to preferentially triage vulnerable or disadvantaged people, than fair (41.8% versus 21.2%). More respondents considered it fair to preferentially triage frontline healthcare workers, than unfair (44.2% versus 30.0%). Conclusion Respondents in this survey perceived all four hypothetical methods to triage intensive care patients based on comorbidity in a pandemic disaster to be fair. However, the sizable minority who consider this to be unfair indicates that these triage methods could encounter significant opposition if they were to be enacted in health policy.
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COVID-19 , Comorbilidad , Opinión Pública , Triaje , Humanos , Triaje/métodos , Australia , Femenino , Masculino , COVID-19/epidemiología , Adulto , Persona de Mediana Edad , Pandemias , Cuidados Críticos/estadística & datos numéricos , Anciano , Encuestas y Cuestionarios , SARS-CoV-2 , Adulto JovenRESUMEN
In a 7-year 11-wave study of low-SES adolescents (N = 856, age = 15.98), we compared multiple well-established transdiagnostic risk factors as predictors of first incidence of significant depressive, anxiety, and substance abuse symptoms across the transition from adolescence to adulthood. Risk factors included negative emotionality, emotion regulation ability, social support, gender, history of trauma, parental histories of substance abuse, parental mental health, and socioeconomic status. Machine learning models revealed that negative emotionality was the most important predictor of both depression and anxiety, and emotion regulation ability was the most important predictor of future significant substance abuse. These findings highlight the critical role that dysregulated emotion may play in the development of some of the most prevalent forms of mental illness.
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In the original publication [...].
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BACKGROUND: Pathology testing is a very common investigation in the intensive care unit (ICU). Many tests are ordered on a routine basis rather than for a specific clinical indication, resulting in potential patient harm and unnecessary financial and environmental costs. OBJECTIVE: The objective of this study was to determine whether a multifaceted intervention based on the principles of education, audit, and feedback can result in a decrease in unnecessary pathology tests without a commensurate increase in adverse patient outcomes and to measure this decrease in terms of the associated reduction in environmental and financial costs. METHODS: A before and after quality improvement project was conducted between 2017 and 2019 across four ICUs in three 12-month phases, divided according to baseline, intervention implementation, and follow-up. Local clinician champions from each site partnered with the project coordinating centre to develop and implement a range of interventions based on the principles of education, audit, and feedback. Data were collected for the number of pathology tests performed and the clinical characteristics of patients admitted to a participating ICU across the three phases. RESULTS: A total of 196 323 arterial blood gases and 460 258 other tests across eight categories were performed on the 22 210 patients admitted to participating ICUs during the project. A decrease in testing was observed across all but one category, with the greatest reduction seen in arterial blood gases (31.2% reduction in tests per bed-day). Across all categories, this equated to a mean reduction of 1.8 tCO2e (tonnes of carbon dioxide equivalent), a potential estimated total saving of Australian dollar $918 497.50. No increase in adverse clinical outcomes was observed. CONCLUSION: A multifaceted intervention based on the principles of education, audit, and feedback can produce a significant decrease in the number of unnecessary pathology tests performed. This reduction translates to substantial environmental and financial savings without any associated increase in adverse patient outcomes.
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Unidades de Cuidados Intensivos , Mejoramiento de la Calidad , Humanos , Femenino , Masculino , Procedimientos Innecesarios/estadística & datos numéricos , Persona de Mediana Edad , Pruebas Hematológicas , Adulto , Anciano , AustraliaRESUMEN
Background: Citrus reticulata Blanco essential oil (CBEO) has attracted increasing attention as a potential treatment for depression and anxiety in recent years. However, there is limited evidence regarding the active compounds responsible for its therapeutic effects. In addition, substantial amounts of CBEO and prolonged therapy are often required. This study aims to investigate the rapid acting antidepressant and anxiolytic effects of CBEO, identify the underlying composition as well as optimize its dosage and duration. Methods: CBEO composition was determined using gas chromatography-mass spectrometry (GC-MS), and the corresponding targets were obtained from the SwissTargetPrediction database. Depression-related targets were collected from DisGeNET, GeneCards, Therapeutic Target Database, and Online Mendelian Inheritance in Man. Subsequently, the overlap between CBEO and depression targets was utilized to build a network diagram depicting the relationship between the active ingredients and targets using Cytoscape software. The STRING database facilitated the construction of a protein-protein interaction network, and the Ma'ayan Laboratory Enrichment tool was employed for Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Wiki pathway analyses. Molecular docking was conducted using AutoDock Vina and Discovery Studio Visualizer. Topological analysis predicted the main antidepressant active ingredients in CBEO. A mixture of these compounds was prepared based on their relative GC-MS ratios. Tail suspension test, elevated plus maze, corticosterone-induced PC12 cells, and lipopolysaccharide (LPS)-induced BV2 cells were used to validate the antidepressant and anxiolytic potential of CBEO and CBEO's main bioactive constituents. Results: CBEO contains 18 components that target 121 proteins. We identified 595 targets associated with depression; among them, 29 targets were located between essential oils and depression. Topological results revealed that linalool, p-cymene, α-terpinene, terpinen-4-ol, and α-terpineol were the major active compounds of CBEO in the management of depression. GO analysis identified G protein-coupled opioid receptor activity, phospholipase C-activating G protein-coupled receptor, and neuron projections that were mostly related to molecular functions, cellular components, and biological processes. Neuroactive ligand-receptor interactions, chemical carcinogenesis, and calcium signaling pathways were the major pathways identified in KEGG analysis. Molecular docking showed that the main bioactive ingredients of CBEO had favorable binding affinities for Protein-Protein Interaction's hub proteins, including OPRM1, PTGS2, ESR1, SLC6A4, DRD2, and NR3C1. These five compounds were then mixed at 0.8:5:0.6:2:1 (w/w) ratio to form a CBEO antidepressant active compound mixture. An acute intranasal treatment of CBEO (25 mg/kg) only demonstrated an antidepressant effect, whereas the main bioactive compounds combination (12.5 mg/kg) illustrated both antidepressant and anxiolytic effects in mice. Linalool, p-cymene, and terpinene-4-ol exhibited neuroprotective and anti-neuroinflammation in the in vitro study, while these effects were not observed for α-terpinene and α-terpineol. Conclusion: Linalool, p-cymene, α-terpinene, terpinen-4-ol, and α-terpineol cymene might be mainly contributing to CBEO's antidepressant effect by regulating neuroactive ligand-receptor interaction, neuron projection, and receptor signaling pathway. A mixture of these compounds showed rapid antidepressant potential via intranasal administration, which was comparable to that of CBEO. The mixture also exhibited an anxiolytic effect while not seen in CBEO.
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Acute myeloid leukemia (AML) is a hematological malignancy that is characterized by an expansion of immature myeloid precursors. Despite therapeutic advances, the prognosis of AML patients remains poor and there is a need for the evaluation of promising therapeutic candidates to treat the disease. The objective of this study was to evaluate the efficacy of duocarmycin Stable A (DSA) in AML cells in vitro. We hypothesized that DSA would induce DNA damage in the form of DNA double-strand breaks (DSBs) and exert cytotoxic effects on AML cells within the picomolar range. Human AML cell lines Molm-14 and HL-60 were used to perform 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT), DNA DSBs, cell cycle, 5-ethynyl-2-deoxyuridine (EdU), colony formation unit (CFU), Annexin V, RNA sequencing and other assays described in this study. Our results showed that DSA induced DNA DSBs, induced cell cycle arrest at the G2M phase, reduced proliferation and increased apoptosis in AML cells. Additionally, RNA sequencing results showed that DSA regulates genes that are associated with cellular processes such as DNA repair, G2M checkpoint and apoptosis. These results suggest that DSA is efficacious in AML cells and is therefore a promising potential therapeutic candidate that can be further evaluated for the treatment of AML.
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Apoptosis , Proliferación Celular , Duocarmicinas , Leucemia Mieloide Aguda , Humanos , Apoptosis/efectos de los fármacos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/metabolismo , Proliferación Celular/efectos de los fármacos , Duocarmicinas/farmacología , Línea Celular Tumoral , Roturas del ADN de Doble Cadena/efectos de los fármacos , Células HL-60 , Antineoplásicos/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacosRESUMEN
BACKGROUND: Intranasal administration has been adopted in traditional medicine to facilitate access to the bloodstream and central nervous system (CNS). In modern medicine, nasal drug delivery systems are valuable for disease treatment because of their noninvasiveness, good absorption, and fast-acting effects. OBJECTIVE: This study aimed to systematically organize preclinical and clinical studies on intranasal herbal medicines to highlight their potential in drug development. METHODS: A comprehensive search for literature until February 2023 was conducted on PubMed and the Web of Science. From the selected publications, we extracted key information, including the types of herbal materials, target diseases, intranasal conditions, methods of toxicity evaluation, main outcomes, and mechanisms of action, and performed quality assessments for each study. RESULTS: Of the 45 studies, 13 were clinical and 32 were preclinical; 28 studies used herbal extracts, 9 used prescriptions, and 8 used natural compounds. The target diseases were rhinosinusitis, influenza, fever, stroke, migraine, insomnia, depression, memory disorders, and lung cancer. The common intranasal volumes were 8-50 µl in mice, 20-100 µl in rats, and 100-500 µl in rabbits. Peppermint oil, Ribes nigrum folium, Melia azedarach L., Elaeocarpus sylvestris, Radix Bupleuri, Da Chuan Xiong Fang, Xingnaojing microemulsion, and Ginsenoside Rb1 emerged as potential candidates for rapid intranasal therapy. The in vivo toxicity assessments were based on mortality, body weight, behavioral changes, mucociliary activity, histopathology, and blood tests. Most intranasal treatments were safe, except for Cyclamen europaeum, Jasminum sambac, Punica granatum L., and violet oil, which caused mild adverse effects. At lower doses, intranasal herbal treatments often show greater effects than oral administration. The actions of intranasal herbal medicine mainly involve regulating inflammation and neurotransmission, with the olfactory bulb and anterior cingulate cortex to be relevant brain regions. CONCLUSION: Intranasal delivery of herbal materials holds promise for enhancing drug delivery efficacy and reducing treatment duration, offering a potential future perspective for developing intranasal therapies for various diseases.
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Administración Intranasal , Extractos Vegetales , Animales , Encéfalo , Fiebre/tratamiento farmacológico , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , HumanosRESUMEN
The amino acid transporters SLC38A5 and SLC7A11 are upregulated in triple-negative breast cancer (TNBC). SLC38A5 transports glutamine, methionine, glycine and serine, and therefore activates mTOR signaling and induces epigenetic modifications. SLC7A11 transports cystine and increases the cellular levels of glutathione, which protects against oxidative stress and lipid peroxidation via glutathione peroxidase, a seleno (Se)-enzyme. The primary source of Se is dietary Se-methionine (Se-Met). Since SLC38A5 transports methionine, we examined its role in Se-Met uptake in TNBC cells. We found that SLC38A5 interacts with methionine and Se-Met with comparable affinity. We also examined the influence of Se-Met on Nrf2 in TNBC cells. Se-Met activated Nrf2 and induced the expression of Nrf2-target genes, including SLC7A11. Our previous work discovered niclosamide, an antiparasitic drug, as a potent inhibitor of SLC38A5. Here, we found SLC7A11 to be inhibited by niclosamide with an IC50 value in the range of 0.1-0.2 µM. In addition to the direct inhibition of SLC38A5 and SLC7A11, the pretreatment of TNBC cells with niclosamide reduced the expression of both transporters. Niclosamide decreased the glutathione levels, inhibited proliferation, suppressed GPX4 expression, increased lipid peroxidation, and induced ferroptosis in TNBC cells. It also significantly reduced the growth of the TNBC cell line MB231 in mouse xenografts.
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Background: Histologic and serologic studies suggest the induction of local and systemic Treponema pallidum ( Tp )-specific CD4+ T cell responses to Tp infection. We hypothesized that Tp -specific CD4+ T cells are detectable in blood and in the skin rash of secondary syphilis and persist in both compartments after treatment. Methods: PBMC collected from 67 participants were screened by IFNγ ELISPOT response to Tp sonicate. Tp -reactive T cell lines from blood and skin were probed for responses to 88 recombinant Tp antigens. Peptide epitopes and HLA class II restriction were defined for selected antigens. Results: We detected CD4+ T cell responses to Tp sonicate ex vivo. Using Tp -reactive T cell lines we observed recognition of 14 discrete proteins, 13 of which localize to bacterial membranes or the periplasmic space. After therapy, Tp -specific T cells persisted for at least 6 months in skin and 10 years in blood. Conclusions: Tp infection elicits an antigen-specific CD4+ T cell response in blood and skin. Tp -specific CD4+ T cells persist as memory in both compartments long after curative therapy. The Tp antigenic targets we identified may be high priority vaccine candidates.
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BACKGROUND: Tetrahexydecyl ascorbate (THDA) is a lipophilic precursor to ascorbic acid that may be stabilized by acetyl zingerone (AZ). Studies have shown that the topical application of THDA may have photoprotective effects. Similarly, AZ has been shown to mitigate oxidative and inflammatory stress, thereby improving the appearance of photoaging. AIMS: To examine the effects of THDA and AZ (THDA-AZ) on skin photoaging compared to THDA alone. PATIENTS/METHODS: In this double-blind, randomized controlled trial, healthy individuals aged 30 to 65 were included and 44 participants were randomized to receive either THDA-AZ (THDA 5% + AZ 1%) or THDA only (THDA 5%) for 8 weeks. Facial photographs were taken at 0, 4, and 8 weeks to analyze wrinkle severity, pigment intensity, and redness intensity. A skin colorimeter was used to assess infraorbital pigmentation and erythema. Self-perception of skin and tolerability were assessed through questionnaires. RESULTS: Average wrinkle severity was significantly decreased in the THDA-AZ group at Weeks 4 and 8 by 0.75% (p = 0.023) and 3.72% (p = 0.048), respectively, compared to the THDA group where wrinkle severity at Weeks 4 and 8 was increased by 7.88% and 4.48%, respectively. Facial pigment intensity was significantly decreased in the THDA-AZ group by 4.10% (p = 0.0002) at Week 8 compared to a 0.69% decrease in the THDA group. Facial redness intensity was decreased in the THDA-AZ group at Weeks 4 and 8 by 3.73% (p = 0.0162) and 14.25% (p = 0.045), respectively, compared to the THDA group where at Weeks 4 and 8 erythema increased by 27.5% and 8.34%, respectively. There were no significant differences in either group for infraorbital pigmentation or erythema. CONCLUSIONS: Daily use of combined THDA and AZ may improve facial wrinkle severity, pigment intensity, and erythema to a greater extent than THDA. While THDA alone increases facial wrinkle severity and erythema, the addition of AZ reduces both.
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Ácido Ascórbico , Cara , Envejecimiento de la Piel , Humanos , Método Doble Ciego , Envejecimiento de la Piel/efectos de los fármacos , Persona de Mediana Edad , Femenino , Adulto , Ácido Ascórbico/administración & dosificación , Ácido Ascórbico/efectos adversos , Ácido Ascórbico/farmacología , Masculino , Estudios Prospectivos , Administración Cutánea , Guayacol/análogos & derivados , Guayacol/administración & dosificación , Guayacol/farmacología , Guayacol/efectos adversos , Anciano , Pigmentación de la Piel/efectos de los fármacos , Pigmentación de la Piel/efectos de la radiación , Resultado del Tratamiento , Antioxidantes/administración & dosificación , Antioxidantes/efectos adversos , Eritema/etiologíaRESUMEN
Aerobic glycolysis in cancer cells, originally observed by Warburg 100 years ago, which involves the production of lactate as the end product of glucose breakdown even in the presence of adequate oxygen, is the foundation for the current interest in the cancer-cell-specific reprograming of metabolic pathways. The renewed interest in cancer cell metabolism has now gone well beyond the original Warburg effect related to glycolysis to other metabolic pathways that include amino acid metabolism, one-carbon metabolism, the pentose phosphate pathway, nucleotide synthesis, antioxidant machinery, etc. Since glucose and amino acids constitute the primary nutrients that fuel the altered metabolic pathways in cancer cells, the transporters that mediate the transfer of these nutrients and their metabolites not only across the plasma membrane but also across the mitochondrial and lysosomal membranes have become an integral component of the expansion of the Warburg effect. In this review, we focus on the interplay between these transporters and metabolic pathways that facilitates metabolic reprogramming, which has become a hallmark of cancer cells. The beneficial outcome of this recent understanding of the unique metabolic signature surrounding the Warburg effect is the identification of novel drug targets for the development of a new generation of therapeutics to treat cancer.
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A novel class of o-carboranyl luminophores, 2CB-BuDABNA (1) and 3CB-BuDABNA (2) is reported, in which o-carborane moieties are incorporated at the periphery of the B,N-doped multi-resonance thermally activated delayed fluorescence (MR-TADF) core. Both compounds maintain the inherent local emission characteristics of their MR-emitting core, exhibiting intense MR-TADF with high photoluminescence quantum yields in toluene and rigid states. In contrast, the presence of the dark lowest-energy charge transfer state, induced by cage rotation in THF, is suggested to be responsible for emission quenching in a polar solvent. Despite the different arrangement of the cage on the DABNA core, both 1 and 2 show red-shifted emissions compared to the parent compound BuDABNA (3). By utilizing 1 as the emitter, high-efficiency blue organic light-emitting diodes (OLEDs) are achieved with a remarkable maximum external quantum efficiency of 25%, representing the highest reported efficiency for OLEDs employing an o-carboranyl luminophore as the emitter.