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Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) is a widely used organophosphate ester that can adversely affect animal or human health. The intestinal microbiota is critical to human health. High-dose exposure to TDCIPP can markedly affect the intestinal ecosystem of mice, but the effects of long-term exposure to lower concentrations of TDCIPP on the intestinal flora and body metabolism remain unclear. In this study, TDCIPP was administered to Sprague-Dawley rats by gavage at a dose of 13.3â¯mg/kg bw/day for 90 days. TDCIPP increased the relative weight of the kidneys (P = 0.017), but had no effect on the relative weight of the heart, liver, spleen, lungs, testes, and ovaries (P > 0.05). 16â¯S rRNA gene sequencing revealed that long-term TDCIPP exposure affected the diversity, relative abundance, and functions of rat gut microbes. The serum metabolomics of the rats showed that TDCIPP can disrupt the serum metabolic profiles, result in the up-regulation of 26 metabolites and down-regulation of 3 metabolites, and affect multiple metabolic pathways in rat sera. In addition, the disturbed genera and metabolites were correlated. The functions of some disturbed gut microbes were consistent with the affected metabolic pathways in the sera, and these metabolic pathways were all associated with kidney disease, suggesting that TDCIPP may cause kidney injury in rats by affecting the intestinal flora and serum metabolism.
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Microbioma Gastrointestinal , Ratas Sprague-Dawley , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Ratas , Masculino , Femenino , Riñón/efectos de los fármacos , ARN Ribosómico 16S , Compuestos OrganofosforadosRESUMEN
BACKGROUND: Observational studies have indicated that peripheral blood eosinophil count is elevated in individuals diagnosed with ulcerative colitis (UC) and correlates with the disease activity of UC. However, this conclusion contradicts with findings from other studies. Therefore, we employed Mendelian randomization (MR) method to assess the genetic link between eosinophil count and UC. METHOD: This MR study utilized summary data from genome-wide association studies (GWAS) on eosinophil count and UC. The main approach used for conducting MR analysis was the inverse variance weighted (IVW) method. Meta-analysis of the IVW results was performed alongside multiple sensitivity analyses to confirm the robustness of the MR analysis results. RESULTS: The IVW method unveiled a causal relationship between eosinophil count and UC (OR = 1.18, 95% CI: 1.04-1.33, p = .01) in the discovery cohort. This finding was further corroborated by the replication cohorts (OR = 1.16, 95% CI: 1.04-1.29, p = .01; OR = 1.12, 95% CI: 1.01-1.24, p = .03). The meta-analysis indicated that the overall odds ratio (OR) for all studies was 1.15 (common effect model, 95% CI: 1.08-1.23, p < .01). Sensitivity analysis suggested the absence of heterogeneity and horizontal pleiotropy in all MR analyses. CONCLUSION: Based on bidirectional two-sample MR analysis, there is an indication that elevated eosinophil count may increase the risk of UC. However, potential confounding factors cannot be ruled out, and further research is necessary to explore how eosinophils contribute to the onset and progression of UC.
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Aqueous Zn-metal battery (AZMB) is a promising candidate for future large-scale energy storage with commendable capacity, exceptional safety characteristics, and low cost. Acetonitrile (AN) has been widely used as an effective electrolyte constituent to improve AZMBs' performance. However, its functioning mechanisms remain unclear. In this study, we unveiled the critical roles of AN in AZMBs via comparative in situ electrochemical, gaseous, and morphological analyses. Despite its limited ability to solvate Zn ions, AN-modulated Zn-ion solvation sheath with increased anions and decreased water achieves a weakly-solvating electrolyte. As a result, the Zn||Zn cell with AN addition exhibited 63â times longer cycle life than cell without AN and achieved a 4â Ah cm-2 accumulated capacity with no H2 generation. In V2O5||Zn cells, for the first time, AN suppressing CO2 generation, elevating CO2-initiation voltage from 2â2.44â V (H2: 2.43â2.55â V) was discovered. AN-impeded transit and Zn-side deposition of dissolved vanadium ions, known as "crosstalk," ameliorated inhomogeneous Zn deposition and dendritic Zn growth. At last, we demonstrated an AN-enabled high-areal-capacity AZMB (3.3â mAh cm-2) using high-mass-loading V2O5 cathode (26â mg cm-2). This study shed light on the strategy of constructing fast-desolvation electrolytes and offered insights for future electrolyte accommodation for high-voltage AZMB cathodes.
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Lithium-rich manganese-based layered cathode materials are considered to be one of the best options for next-generation lithium-ion batteries, owing to their ultra-high specific capacity (>250 mAh·g−1) and platform voltage. However, their poor cycling stability, caused by the release of lattice oxygen as well as the electrode/electrolyte side reactions accompanying complex phase transformation, makes it difficult to use this material in practical applications. In this work, we suggest a molybdenum surface modification strategy to improve the electrochemical performance of Li1.2Mn0.54Ni0.13Co0.13O2. The Mo-modified Li1.2Mn0.54Ni0.13Co0.13O2 material exhibits an enhanced discharge specific capacity of up to 290.5 mAh·g−1 (20 mA·g−1) and a capacity retention rate of 82% (300 cycles at 200 mA·g−1), compared with 261.2 mAh·g−1 and a 70% retention rate for the material without Mo modification. The significantly enhanced performance of the modified material can be ascribed to the formation of a Mo-compound-involved nanolayer on the surface of the materials, which effectively lessens the electrolyte corrosion of the cathode, as well as the activation of Mo6+ towards Ni2+/Ni4+ redox couples and the pre-activation of a Mo compound. This study offers a facile and effective strategy to address the poor cyclability of lithium-rich manganese-based layered cathode materials.
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The CCN proteins are a family of extracellular matrix- (ECM-) associated proteins which currently consist of six secreted proteins (CCN1-6). CCN3 protein, also known as nephroblastoma overexpressed protein (NOV), is a member of the CCN family with multiple biological functions, implicated in major cellular processes such as cell growth, migration, and differentiation. Recently, CCN3 has emerged as a critical regulator in a variety of diseases, including immune-related diseases, including rheumatology arthritis, osteoarthritis, and systemic sclerosis. In this review, we will briefly introduce the structure and function of the CCN3 protein and summarize the roles of CCN3 in immune-related diseases, which is essential to understand the functions of the CCN3 in immune-related diseases.
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Sistema Inmunológico/fisiopatología , Proteína Hiperexpresada del Nefroblastoma/fisiología , Animales , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Diferenciación Celular , Movimiento Celular , Proliferación Celular , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliales/metabolismo , Matriz Extracelular/metabolismo , Fibrosis , Glomerulonefritis/inmunología , Glomerulonefritis/metabolismo , Humanos , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Neoplasias/inmunología , Neoplasias/metabolismo , Osteoartritis/inmunología , Osteoartritis/metabolismo , Esclerodermia Sistémica/inmunología , Esclerodermia Sistémica/metabolismoRESUMEN
Background: Changes in circulating endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs) are considered as a new perspective reflection of the endothelial injury and repair status. Our previous studies have demonstrated that berberine improved endothelial function and arterial stiffness in healthy subjects. In this study, we further investigated the effects of berberine on regulating the circulating EMPs and EPCs, and preventing endothelial dysfunction and arterial stiffness in spontaneously hypertensive rats (SHRs). Methods: Twenty male SHRs were randomly divided into two groups: Berberine-treated SHR group and vehicle-treated SHR group. The SHR rats were intragastrically treated with physiologic saline, berberine 50 mg/kg.d or vehicle for 4 weeks, respectively. Ten male Wistar-Kyoto (WKY) rats treated with vehicle served as normotensive controls. Tail systolic blood pressure was monitored every 2 weeks. At the end of the study, aortic pulse wave velocity (aPWV) was measured in vivo, and aorta were collected for measurement of endothelium-dependent vasodilation and immunohistological staining of elastic fiber. Peripheral blood was collected for circulating EMP detection and EPC culture. Results: Compared to normotensive rats, hypertensive rats displayed significantly higher circulating CD31+/CD42- MPs, lower number and colony-forming units (CFUs) of EPCs, worse endothelium-dependent vasodilation, and faster aPWV. Berberine treatment in SHRs partly reduced the blood pressure and circulating EMPs, and augmented EPC numbers and CFUs. In addition, berberine preserved arterial elasticity by lowering aPWV and increasing the content of arterial media elastin fiber, and improved endothelial function by maintaining better endothelium-dependent vasodilation. Robust relationship was observed among circulating CD31+/CD42- MPs, EPC numbers and aPWV. Conclusions: Abnormal changes of circulating EMPs and EPCs in SHRs are associated with endothelial dysfunction and arterial stiffness. Berberine may be a novel therapeutic option for the hypertension-related vascular injury in SHRs.
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Berberina/farmacología , Micropartículas Derivadas de Células/metabolismo , Endotelio Vascular , Hipertensión , Rigidez Vascular/efectos de los fármacos , Alcaloides/farmacología , Animales , Arterias/patología , Arterias/fisiopatología , Elasticidad , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Hipertensión/fisiopatología , Masculino , Análisis de la Onda del Pulso/métodos , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
Senescence-accelerated mouse strains have proved to be an accelerated-aging model, which mimics numerous features with Alzheimer's disease (AD). Three, six, and nine-month senescence-accelerated resistant 1 and senescence-accelerated prone 8 (SAMP8) mice were used in the current study, to unravel potential mechanisms for dementia and explore new diagnostic approaches for AD. The amyloid-ß (Aß40) and Aß42 levels were elevated in hippocampi and platelets from SAMP8, along with a reduced α-secretase expression and an enhanced ß-secretase expression extent with age, compared to control mice. Furthermore, hippocampal Aß40 and Aß42 of SAMP8 were positively correlated with platelet of these mice with aging progression. In addition, ß-γ-secretase-modulated proteolytic proceeding of amyloid precursor protein in platelet might work through the PI3K/Akt/GSK3ß pathway. These results indicate that platelet could be a potential early marker in the periphery to study the age-correlative aggregation of the amyloid-ß peptide in patients with AD, while still requiring the considerable study.
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Enfermedad de Alzheimer/sangre , Péptidos beta-Amiloides/sangre , Plaquetas/metabolismo , Fragmentos de Péptidos/sangre , Adenosina Trifosfato/sangre , Factores de Edad , Enfermedad de Alzheimer/genética , Secretasas de la Proteína Precursora del Amiloide/sangre , Animales , Modelos Animales de Enfermedad , Glucógeno Sintasa Quinasa 3 beta/sangre , Hipocampo/metabolismo , Masculino , Ratones , Fosfatidilinositol 3-Quinasa/sangre , Proteolisis , Proteínas Proto-Oncogénicas c-akt/sangre , Transducción de SeñalRESUMEN
BACKGROUND: Hypertension and dyslipidemia are major risk factors for cardiovascular disease (CVD). In 2012, over 270 million patients (25.2%) in China were hypertensive and 40.4% was dyslipidemic. The majority of these patients rely on statins for the prevention of cardiovascular disease. However, certain types of statins (e.g., atorvastatin), compared to others (e.g., pitavastatin), may be associated with unfavorable effects on glucose metabolism. This leads to concerns when prescribing statins to patients who also have a predisposition to glucose metabolic disorders (i.e., prediabetes). Thus, this study aims to investigate the effect of pitavastatin, compared to atorvastatin, on glucose metabolism, as measured by hemoglobin A1c (HbA1c), in Chinese prediabetics with hypertension and dyslipidemias. METHODS: The China hemoglobin A1c Metabolism Protection Union Study (CAMPUS) is a multi-center, prospective, open-label, 12-month, two-arm parallel group, and non-inferiority randomized controlled trial (RCT). A total of 396 prediabetics with hypertension and dyslipidemias will be randomly assigned 1:1 to either pitavastatin 2 mg/day or atorvastatin 20 mg/day, and followed for 12 months (follow-up visits at 1, 3, 6, and 12 months) for HbA1c levels, as well as other measures of glucose metabolism, serum lipid levels, blood pressure control, measures of inflammation, vascular endothelial function, carotid atherosclerosis, and hypertension-related left ventricular hypertrophy. If the results of low-density lipoprotein cholesterol (LDL-C) levels in month 3 after treatment initiation do not meet individual target, drug dose for the participant would be doubled. DISCUSSION: CAMPUS will be the first RCT to investigate the effect of pitavastatin, compared to atorvastatin, on glucose metabolism in Chinese prediabetics with hypertension and dyslipidemias. Further, this study might eventually provide information to design a clinical strategy, and facilitate the improvement of primary prevention in patients at risk for diabetes and CVD. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT03532620. Registered 22 May 2018.
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Atorvastatina/uso terapéutico , Glucemia/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Dislipidemias/tratamiento farmacológico , Hemoglobina Glucada/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipertensión/fisiopatología , Estado Prediabético/sangre , Quinolinas/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Atorvastatina/efectos adversos , Biomarcadores/sangre , Glucemia/metabolismo , China , Dislipidemias/sangre , Dislipidemias/complicaciones , Dislipidemias/diagnóstico , Estudios de Equivalencia como Asunto , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Hipertensión/complicaciones , Hipertensión/diagnóstico , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Estado Prediabético/complicaciones , Estado Prediabético/diagnóstico , Estudios Prospectivos , Quinolinas/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: An association between primary biliary cholangitis (PBC) and connective tissue diseases (CTDs) [rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), systemic sclerosis (SSc)] has been found in observational studies. However, the direction causality is unclear. The aim of this study was to assess the causality between PBC and CTDs and to promote early screening, pre-emptive therapy, and accurate stratification. METHODS: A two-sample Mendelian randomization (MR) analysis was performed to assess the causal relationship between PBC [Genome-Wide Association Study (GWAS) meta-analysis, 8021 cases/16498 controls], and SLE (GWAS meta-analysis, 8021 cases/16489 controls), RA(FinnGen, 6236 cases/14727 controls), SS(FinnGen, 2495 cases/365533 controls), SSc (FinnGen, 302 cases/213145 controls). Inverse variance weighting (IVW) was used as the primary analysis method, supplemented by four sensitivity analyses to assess the robustness of the results. RESULTS: The IVW revealed that genetically predicted PBC increased the risk of SLE [odd's ratio (OR) = 1.43, 95% confidence interval (CI) 1.30-1.58, P < 0.001]), RA (OR = 1.09, 95%CI1.04-1.14, P<0.001), and SS (OR = 1.18, 95%CI1.12-1.24, P<0.001), but not that of SSc. In addition, no association was observed between CTDs as an exposure and PBC. Sensitivity analyses did not reveal horizontal pleiotropy. CONCLUSIONS: Our study provided new genetic evidence for a causal relationship between PBC and CTDs. PBC increased the risk of SLE, RA, and SS. Our findings highlighted the importance of active screening and intervention for CTDs in patients with PBC.
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Artritis Reumatoide , Enfermedades del Tejido Conjuntivo , Cirrosis Hepática Biliar , Lupus Eritematoso Sistémico , Esclerodermia Sistémica , Síndrome de Sjögren , Humanos , Estudio de Asociación del Genoma Completo , Cirrosis Hepática Biliar/genética , Análisis de la Aleatorización Mendeliana , Lupus Eritematoso Sistémico/genética , Síndrome de Sjögren/epidemiología , Síndrome de Sjögren/genética , Esclerodermia Sistémica/genéticaRESUMEN
Background: Epidermal growth factor receptor (EGFR) mutations have been identified as promising therapeutic targets for non-small cell lung cancer. Osimertinib, a third-generation EGFR-tyrosine kinase inhibitor-targeting drug, has good anti-tumor ability and excellent intracranial effects. However, management of osimertinib resistance is a clinical challenge. The clinical benefit of osimertinib combined with the antiangiogenic drug, bevacizumab, remains to be determined. Case presentation: A 40-year-old female with right lung adenocarcinoma (cT2aN3M1c, IVb) was confirmed positive for EGFR exon 19 deletion mutation (c.2235_2249del, 1.3%). After receiving 5 months of osimertinib (80 mg, qd) therapy, the patient's disease progressed and she subsequently accepted treatment with osimertinib (80 mg, qd) plus bevacizumab (15 mg/kg, q21d) and achieved notable clinical remission for 23 months until renal impairment occurred, after which bevacizumab was discontinued. The patient had 6 months of remission before progression, after which bevacizumab was added again. To date, the disease has been under control. The brain lesion showed partial response again, and the side effects of bevacizumab were tolerable. The overall survival time exceeded 4 years. Conclusion: This case report describes a treatment strategy for osimertinib-resistant patients with EGFR exon 19 deletion mutations. Metronomic treatment with osimertinib plus bevacizumab was achieved for more than 4 years.
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BACKGROUND: Depression is a hidden burden, yet it is a leading cause of disability worldwide. Despite the adverse effects of depression, fewer than one-third of patients receive care. Internet-based cognitive behavioral therapy (i-CBT) is an effective treatment for depression, and combining i-CBT with supervised care could make the therapy scalable and effective. A stepped care model is a framework for beginning treatment with an effective and low-intensity intervention while adapting care based on the patient's needs. OBJECTIVE: This study investigated the efficacy of a stepped care i-CBT model for depression based on changes in self-reported depressive symptoms. METHODS: In this single-blinded, randomized controlled trial, participants were allocated to either the i-CBT-only group (28/56, 50%) or the i-CBT with stepped care group (28/56, 50%). Both groups received a 13-week i-CBT program tailored for depression. The i-CBT program was provided through a secure, online mental health clinic called the Online Psychotherapy Tool. Participants read through the sessions and completed the assignments related to each session. Participants in the stepped care group received additional interventions from their care provider based on standard questionnaire scores (ie, Patient Health Questionnaire-9 [PHQ-9], Quick Inventory of Depressive Symptomatology [QIDS], and Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form) and their assignment responses. From lowest to highest intensity, the additional interventions included SMS text messages, phone calls, video calls, or a video call with a psychiatrist. RESULTS: For this study, 56 participants were recruited to complete an i-CBT program (n=28, 50%; mean age 37.9; SD 13.08 y; 7/28, 27% were men) or an i-CBT with stepped care program (n=28, 50%; mean age 40.6; SD 14.28 y; 11/28, 42% were men). The results of this study indicate that the i-CBT program was effective in significantly reducing depressive symptoms, as measured by the PHQ-9 (F4,80=9.95; P<.001) and QIDS (F2,28=5.73; P=.008); however, there were no significant differences in the reduction of depressive symptoms between the 2 groups (PHQ-9: F4,80=0.43; P=.78; QIDS: F2,28=3.05; P=.06). The stepped care group was not significantly better in reducing depressive symptoms than the i-CBT group (PHQ-9, P=.79; QIDS, P=.06). Although there were no significant differences observed between the number of participants who completed the program between the groups (χ21=2.6; P=.10), participants in the stepped care group, on average, participated in more sessions than those who prematurely terminated participation in the i-CBT group (t55=-2; P=.03; 95% CI -4.83 to -0.002). CONCLUSIONS: Implementing a stepped care approach in i-CBT is an effective treatment for depression, and the stepped care model can assist patients to complete more sessions in their treatment. TRIAL REGISTRATION: Clinicaltrials.gov NCT04747873; https://clinicaltrials.gov/study/NCT04747873.
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Terapia Cognitivo-Conductual , Depresión , Masculino , Humanos , Adulto , Femenino , Depresión/terapia , Calidad de Vida , Terapia Cognitivo-Conductual/métodos , Psicoterapia/métodos , InternetRESUMEN
Nickel (Ni)-rich cathodes are among the most promising cathode materials of lithium batteries, ascribed to their high-power density, cost-effectiveness, and eco-friendliness, having extensive applications from portable electronics to electric vehicles and national grids. They can boost the wide implementation of renewable energies and thereby contribute to carbon neutrality and achieving sustainable prosperity in the modern society. Nevertheless, these cathodes suffer from significant technical challenges, leading to poor cycling performance and safety risks. The underlying mechanisms are residual lithium compounds, uncontrolled lithium/nickel cation mixing, severe interface reactions, irreversible phase transition, anisotropic internal stress, and microcracking. Notably, they have become more serious with increasing Ni content and have been impeding the widespread commercial applications of Ni-rich cathodes. Various strategies have been developed to tackle these issues, such as elemental doping, adding electrolyte additives, and surface coating. Surface coating has been a facile and effective route and has been investigated widely among them. Of numerous surface coating materials, have recently emerged as highly attractive options due to their high lithium-ion conductivity. In this review, a thorough and comprehensive review of lithium-ion conductive coatings (LCCs) are made, aimed at probing their underlying mechanisms for improved cell performance and stimulating new research efforts.
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The gut microbial metabolite trimethylamine N-oxide (TMAO) is regarded as a novel risk factor for hypertension. Berberine (BBR) exerts cardiovascular protective effects by regulating the gut microbiota-metabolite production pathway. However, whether and how BBR alleviates TMAO-induced vascular dysfunction in hypertension remains unclear. In the present study, we observed that plasma TMAO and related bacterial abundance were significantly elevated and negatively correlated with vascular function in 86 hypertensive patients compared with 46 normotensive controls. TMAO activated endoplasmic reticulum stress (ERS) signaling pathway to promote endothelial cell dysfunction and apoptosis in vitro. BBR (100, 200â¯mg⯷â¯kg-1 ·d-1) for 4 weeks ameliorates TMAO-induced vascular dysfunction and ERS activation in a choline-angiotensin II hypertensive mouse model. We found that plasma TMAO levels in 15 hypertensive patients treated with BBR (0.4â¯g, tid) were reduced by 8.8â¯% and 16.7â¯% at months 1 and 3, respectively, compared with pretreatment baseline. The oral BBR treatment also improved vascular function and lowered blood pressure. Faecal 16â¯S rDNA showed that BBR altered the gut bacterial composition and reduced the abundance of CutC/D bacteria in hypertensive mice and patients. In vitro bacterial cultures and enzyme reaction systems indicated that BBR inhibited the biosynthesis of TMAO precursor in the gut microbiota by binding to and inhibiting the activity of CutC/D enzyme. Our results indicate that BBR improve vascular dysfunction at least partially by decreasing TMAO via regulation of the gut microbiota in hypertension.
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Berberina , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico , Microbioma Gastrointestinal , Hipertensión , Metilaminas , Berberina/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Animales , Metilaminas/metabolismo , Humanos , Hipertensión/tratamiento farmacológico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ratones , Masculino , Persona de Mediana Edad , Femenino , Bacterias/clasificación , Bacterias/efectos de los fármacos , Bacterias/genética , Bacterias/aislamiento & purificación , Bacterias/metabolismo , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos C57BL , Regulación hacia Abajo/efectos de los fármacos , Anciano , Presión Sanguínea/efectos de los fármacos , Apoptosis/efectos de los fármacos , Heces/microbiología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismoRESUMEN
Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide. Recently, accumulating evidence has revealed hepatic mediators, termed as liver-derived secretory factors (LDSFs), play an important role in regulating CVDs such as atherosclerosis, coronary artery disease, thrombosis, myocardial infarction, heart failure, metabolic cardiomyopathy, arterial hypertension, and pulmonary hypertension. LDSFs presented here consisted of microbial metabolite, extracellular vesicles, proteins, and microRNA, they are primarily or exclusively synthesized and released by the liver, and have been shown to exert pleiotropic actions on cardiovascular system. LDSFs mainly target vascular endothelial cell, vascular smooth muscle cells, cardiomyocytes, fibroblasts, macrophages and platelets, and further modulate endothelial nitric oxide synthase/nitric oxide, endothelial function, energy metabolism, inflammation, oxidative stress, and dystrophic calcification. Although some LDSFs are known to be detrimental/beneficial, controversial findings were also reported for many. Therefore, more studies are required to further explore the causal relationships between LDSFs and CVDs and uncover the exact mechanisms, which is expected to extend our understanding of the crosstalk between the liver and cardiovascular system and identify potential therapeutic targets. Furthermore, in the case of patients with liver disease, awareness should be given to the implications of these abnormalities in the cardiovascular system. These studies also underline the importance of early recognition and intervention of liver abnormalities in the practice of cardiovascular care, and a multidisciplinary approach combining hepatologists and cardiologists would be more preferable for such patients.
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There is a growing body of evidence supporting the significant impact of microbiota on heart development. Alternative polyadenylation (APA) is a crucial mechanism for gene expression regulation and has been implicated in postnatal heart development. Nonetheless, whether microbiota can influence postnatal heart development through the regulation of APA remains unclear. Therefore, we conducted APA sequencing on heart tissues collected from specific pathogen-free (SPF) mice and germ-free (GF) mice at three different developmental stages: within the first 24 h after birth (P1), 7-day-old SPF mice, and 7-day-old GF mice. This approach allowed us to obtain a comprehensive genome-wide profile of APA sites in the heart tissue samples. In this study, we made a significant observation that GF mice exhibited noticeably longer 3' untranslated region (3' UTR) lengths. Furthermore, we confirmed significant alterations in the 3' UTR lengths of mitochondria-related genes, namely Rala, Timm13, and Uqcc3. Interestingly, the GF condition resulted in a marked decrease in mitochondrial cristae density and a reduction in the level of Tomm20 in postnatal hearts. Moreover, we discovered a connection between Rala and Src, which further implicated their association with other differentially expressed genes (DEGs). Notably, most of the DEGs were significantly downregulated in GF mice, with the exceptions being Thbs1 and Egr1. Importantly, the GF condition demonstrated a correlation with a lower infiltration of immune cells, whereby the levels of resting NK cells, Th17 cells, immature dendritic cells, and plasma cells in GF mice were comparable to those observed in P1 mice. Furthermore, we established significant correlations between these immune cells and Rala as well as the related DEGs. Our findings clearly indicated that microbiota plays a vital role in postnatal heart development by affecting APA switching, mitochondria and immune cell infiltrations.
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Objective: The increased prevalence of major depressive disorder (MDD) amid the COVID-19 pandemic has resulted in substantial growth in online mental health care delivery. Compared to its in-person counterpart, online cognitive behavioral therapy (e-CBT) is a time-flexible and cost-effective method of improving MDD symptoms. However, how its efficacy compares to in-person CBT is yet to be explored. Therefore, the current study compared the efficacy of a therapist-supported, electronically delivered e-CBT program to in-person therapy in individuals diagnosed with MDD. Methods: Participants (n = 108) diagnosed with MDD selected either a 12 week in-person CBT or an asynchronous therapist-supported e-CBT program. E-CBT participants (n = 55) completed weekly interactive online modules delivered through a secure cloud-based online platform (Online Psychotherapy Tool; OPTT). These modules were followed by homework in which participants received personalized feedback from a trained therapist. Participants in the in-person CBT group (n = 53) discussed sessions and homework with their therapists during one-hour weekly meetings. Program efficacy was evaluated using clinically validated symptomatology and quality of life questionnaires. Results: Both treatments yielded significant improvements in depressive symptoms and quality of life from baseline to post-treatment. Participants who opted for in-person therapy presented significantly higher baseline symptomatology scores than the e-CBT group. However, both treatments demonstrated comparable significant improvements in depressive symptoms and quality of life from baseline to post-treatment. e-CBT seems to afford higher participant compliance as dropouts in the e-CBT group completed more sessions on average than those in the in-person CBT group. Conclusion: The findings support e-CBT with therapist guidance as a suitable option to treat MDD. Future studies should investigate how treatment accessibility is related to program completion rates in the e-CBT vs. in-person group. Clinical Trial Registration: ClinicalTrials.Gov Protocol Registration and Results System (NCT04478058); clinicaltrials.gov/ct2/show/NCT04478058.
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Background: Generalized anxiety disorder (GAD) is a debilitating mental health disorder with first-line treatments include cognitive behavioral therapy (CBT) and pharmacotherapy. CBT is costly, time-consuming, and inaccessible. Electronic delivery (e-CBT) is a promising solution to address these barriers. However, due to the novelty of this intervention, more research testing the e-CBT efficacy independently and in conjunction with other treatments is needed. Objective: This study investigated the efficacy of e-CBT compared to and in conjunction with pharmacotherapy for GAD. Methods: This study employed a quasi-experimental design where patients selected their preferred treatment modality. Patients with GAD were enrolled in either e-CBT, medication, or combination arms. The 12-week e-CBT program was delivered through a digital platform. The medications followed clinical guidelines. The efficacy of each arm was evaluated using questionnaires measuring depression, anxiety, and stress severity, as well as quality of life. Results: There were no significant differences between arms (N e-CBT = 41; N Medication = 41; N Combination = 33) in the number of weeks completed or baseline scores. All arms showed improvements in anxiety scores after treatment. The medication and combination arms improved depression scores. The e-CBT and Combination arms improved quality of life, and the combination arm improved stress scores. There were no differences between the groups in depression, anxiety, or stress scores post-treatment. However, the combination arm had a significantly larger improvement in quality of life. Gender and treatment arm were not predictors of dropout, whereas younger age was. Conclusion: Incorporating e-CBT on its own or in combination with pharmaceutical interventions is a viable option for treating GAD. Treating GAD with e-CBT or medication appears to offer significant improvements in symptoms, with no meaningful difference between the two. Combining the treatments also offer significant improvements, while not necessarily superior to either independently. The findings suggest that all options are viable. Taking the patient's preferred treatment route based on their lifestyle, personality, and beliefs into account when deciding on treatment should be a priority for care providers.
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Egg consumption is one of the many inconsistencies in evidence linking dietary cholesterol to cardiovascular disease (CVD). In addition, the gut microbiota and its metabolite, trimethylamine-N-oxide (TMAO), have been shown to play a crucial role in the development of CVD. The fact that egg is rich in choline suggests that excessive egg consumption may increase TMAO production by altering the gut microbiota. However, the effects of egg consumption on vascular function and gut microbiota remain unclear. Here, the diet of nine young male subjects was supplemented with two boiled eggs daily for 2 weeks. Changes in vascular function, inflammation, metabolism, oxidative stress, and gut microbiota were examined. We found that egg consumption increased flow-mediated dilation and decreased brachial-ankle pulse wave velocity. Furthermore, egg consumption positively modulated the gut microbiota function but had no effects on the levels of C-reactive protein, glucose, lipid profile, malondialdehyde, superoxide dismutase, or TMAO. The current study provides evidence that egg consumption improves vascular function, which may be related to the alterations seen in the gut microbiota. Therefore, moderate egg consumption may help to improve vascular and intestinal function in individuals at low risk of developing CVD and other metabolic disorders.
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Background: Gut microbiota plays an important role in cardiovascular health and disease, including congenital heart disease (CHD). Tetralogy of Fallot (TOF) is the most common form of cyanotic CHD characterized by systemic chronic hypoxia and sustained pressure overload of the right ventricle. It is well-known that hypoxia and pressure overload can affect gut microbiota. However, the effects of TOF on the gut microbiota remain little understood. This study explored the profile of the gut microbiota in children with unrepaired TOF. Methods: A total of 12 pediatric patients diagnosed with TOF and 9 healthy age- and gender-matched children were enrolled in this study. Fecal samples were collected from every participant and subjected to 16S rDNA gene sequencing. The raw sequencing data were processed using the Quantitative Insights Into Microbial Ecology pipeline. Results: A comparison of the gut microbiota revealed that pediatric patients with TOF had developed dysbiosis as reflected by the altered taxonomic composition and impaired functional profile. A total of 14 indicative bacterial genera were identified as differential biomarkers capable of distinguishing between healthy children and TOF patients. Furthermore, functional annotations revealed that the gut microbiota in TOF patients was characterized by increased levels of inflammatory, oxidative, and immune responses, and decreased activities of adaptation, synthesis, and metabolism. Conclusions: Pediatric patients with unrepaired TOF have intestinal dysbacteriosis that is characterized by altered taxonomic composition and impaired functional profile. These findings suggested that the interplay between gut microbiota and the host may be dysregulated in patients with TOF.
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Claudin 6 (CLDN6) is an important component of tight junctions. Through the PDZ binding motif, CLDN6 binds to a variety of signaling proteins that contain the PDZ domain to regulate different signaling pathways, and plays an important role in the occurrence and development of tumors. Our previous work showed that CLDN6 was expressed at low levels in breast cancer cells, and overexpression of CLDN6 inhibited breast cancer cell proliferation, migration and invasion. However, the mechanism of how CLDN6 works remains unclear. In this study, we aimed to explore the mechanism by which CLDN6 inhibits breast cancer cell malignant behavior. As a result, overexpression of CLDN6 inhibited the proliferation of breast cancer cells along with the downregulation of cyclin D1, which plays an important role in regulating cell proliferation. After overexpression of Sp1 in CLDN6-overexpressing cells, the expression of cyclin D1 was upregulated. On the other hand, CLDN6 inhibited breast cancer cell migration and invasion along with the downregulation of IL-8, CXCR2 and FAK. When treated with IL-8, the migration and invasion ability were promoted along with the upregulation of CXCR2 and p-FAK, and the cytoskeleton was rearranged in CLDN6-overexpressing cells. Furthermore, when treated with the ERK signaling activator PMA, the proliferation, migration and invasion abilities were promoted along with the upregulation of Sp1, cyclin D1 and IL-8 in CLDN6-overexpressin cells. In conclusion, CLDN6 suppressed ERK/Sp1/cyclin D1 and ERK/IL-8 signaling to inhibit proliferation, migration and invasion in breast cancer cells. The mechanism may provide experimental evidence for the treatment of breast cancer targeting CLDN6.