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With the increasing prevalence of age-related chronic diseases burdening healthcare systems, there is a pressing need for innovative management strategies. Our study focuses on the gut microbiota, essential for metabolic, nutritional, and immune functions, which undergoes significant changes with aging. These changes can impair intestinal function, leading to altered microbial diversity and composition that potentially influence health outcomes and disease progression. Using advanced metagenomic sequencing, we explore the potential of personalized probiotic supplements in 297 older adults by analyzing their gut microbiota. We identified distinctive Lactobacillus and Bifidobacterium signatures in the gut microbiota of older adults, revealing probiotic patterns associated with various population characteristics, microbial compositions, cognitive functions, and neuroimaging results. These insights suggest that tailored probiotic supplements, designed to match individual probiotic profile, could offer an innovative method for addressing age-related diseases and functional declines. Our findings enhance the existing evidence base for probiotic use among older adults, highlighting the opportunity to create more targeted and effective probiotic strategies. However, additional research is required to validate our results and further assess the impact of precision probiotics on aging populations. Future studies should employ longitudinal designs and larger cohorts to conclusively demonstrate the benefits of tailored probiotic treatments.
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Envelhecimento , Suplementos Nutricionais , Microbioma Gastrointestinal , Probióticos , Probióticos/uso terapêutico , Probióticos/administração & dosagem , Humanos , Idoso , Feminino , Masculino , Idoso de 80 Anos ou mais , Pessoa de Meia-Idade , Lactobacillus/genética , Metagenômica/métodos , BifidobacteriumRESUMO
Lymphoproliferative disorders (LPD) comprise a heterogeneous group and are originally classified into the "Disease of immune dysregulation" category. Of 96 Taiwanese patients during 2003-2022, 31 (median 66, range 0.03-675 months) developed LPD, mainly including palpable lymphadenopathy (in 10 patients), intestinal lymphadenopathy associated with refractory inflammatory bowel disease (IBD in 8) and hepatosplenomegaly (in 7) during long-term follow-up (median 144, range 3-252 months). They distributed in the categories of antibody deficiency (2 CVID, 2 TTC37, PIK3CD, PIK3R1 and AICDA each), phagocyte (4 CYBB, 1 STAT1 and 1 IFNRG1), immune dysregulation (2 FOXP3, 2 XIAP and 2 HLH), combined immunodeficiencies (2 IL2RG; CD40L, ZAP70 and unknown each), syndromic features (2 STAT3-LOF, 1 WAS and 1 ATM) and three with anti-IFN-γ autoantibodies. An increased senescent (CD8 + CD57+) and CD21-low, disturbed transitional B (CD38 + IgM++), plasmablast B (CD38++IgM-), memory B (CD19 + CD27+) and TEMRA (CD27-IgD-) components were often observed in cross-sectional immunophenotyping and trended to develop LPD.
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Imunofenotipagem , Transtornos Linfoproliferativos , Humanos , Transtornos Linfoproliferativos/imunologia , Masculino , Feminino , Criança , Pré-Escolar , Adolescente , Lactente , Adulto , Adulto Jovem , Pessoa de Meia-Idade , Síndromes de Imunodeficiência/imunologia , Linfócitos/imunologiaRESUMO
PURPOSE: Heterozygous STAT1 Gain-of-Function (GOF) mutations are the most common cause of chronic mucocutaneous candidiasis (CMC) among Inborn Errors of Immunity. Clinically, these mutations manifest as a broad spectrum of immune dysregulation, including autoimmune diseases, vascular disorders, and malignancies. The pathogenic mechanisms of immune dysregulation and its impact on immune cells are not yet fully understood. In treatment, JAK inhibitors have shown therapeutic effectiveness in some patients. METHODS: We analyzed clinical presentations, cellular phenotypes, and functional impacts in five Taiwanese patients with STAT1 GOF. RESULTS: We identified two novel GOF mutations in 5 patients from 2 Taiwanese families, presenting with symptoms of CMC, late-onset rosacea, and autoimmunity. The enhanced phosphorylation and delayed dephosphorylation were displayed by the patients' cells. There are alterations in both innate and adaptive immune cells, including expansion of CD38+HLADR +CD8+ T cells, a skewed activated Tfh cells toward Th1, reduction of memory, marginal zone and anergic B cells, all main functional dendritic cell lineages, and a reduction in classical monocyte. Baricitinib showed therapeutic effectiveness without side effects. CONCLUSION: Our study provides the first comprehensive clinical and molecular characteristics in STAT1 GOF patient in Taiwan and highlights the dysregulated T and B cells subsets which may hinge the autoimmunity in STAT1 GOF patients. It also demonstrated the therapeutic safety and efficacy of baricitinib in pediatric patient. Further research is needed to delineate how the aberrant STAT1 signaling lead to the changes in cellular populations as well as to better link to the clinical manifestations of the disease.
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Candidíase Mucocutânea Crônica , Mutação com Ganho de Função , Imunofenotipagem , Pirazóis , Fator de Transcrição STAT1 , Humanos , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/diagnóstico , Candidíase Mucocutânea Crônica/terapia , Masculino , Feminino , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Azetidinas/uso terapêutico , Purinas/uso terapêutico , Criança , Adolescente , Taiwan , AdultoRESUMO
An electrochemical and selective decarboxylation and dehydration using α-keto acids with amines is accomplished, which leads to the easy accessibility of amides and α-ketoamides, which are not only ubiquitous and valuable structure motifs found in pharmaceuticals, but also versatile building blocks in synthetic chemistry. Notably, for this efficient and green protocol, neither metal catalysts nor external oxidants are required. The process exhibits a broad scope and functional group tolerance to deliver various amides and α-ketoamides. Moreover, these two reactions have also been applied to late-stage derivatization and can be safely conducted on gram scale.
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In this present study, we developed a reliable and simple ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay for the simultaneous quantification of paeoniflorin, albiflorin, oxypaeoniflorin, benzoylpaeoniflorin and isomaltopaeoniflorin in beagle dog plasma. We also analyzed the pharmacokinetics of those components after oral administration of fried Radix Paeoniae Alba (FRPA) in beagle dogs. Plasma samples were processed by protein precipitation with methanol. Chromatographic separation was performed with a Waters HSS-T3 C18 column (100 × 2.1 mm, 1.8 µm, kept at 40°C) using multiple reaction monitoring mode. A gradient elution procedure was used with solvent A (0.02% formic acid-water) and solvent B (0.02% formic acid-acetonitrile) as mobile phases. Method validation was performed as US Food and Drug Administration guidelines, and the results met the acceptance criteria. The method we establish in this experiment was successfully applied to the pharmacokinetic study after oral administration of FRPA extract to beagle dogs.
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Medicamentos de Ervas Chinesas , Formiatos , Espectrometria de Massas em Tandem , Cães , Animais , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/farmacocinética , SolventesRESUMO
This study established a convenient, rapid, and sensitive ultra-performance liquid chromatography tandem mass spectrometry(UPLC-MS/MS) method for simultaneous determination of magnoflorine,(R)-coclaurine, vicenin â ¡, isospinosin, spinosin, swertisin, N-nornuciferine, 6î-feruloylspinosin, and jujuboside B in beagle dog plasma after oral administration of fried Ziziphi Spinosae Semen(FZSS) extract. The Waters HSS-T3 C_(18) column(2.1 mm×100 mm, 1.8 µm) was used. The methanol-aqueous solution(containing 0.01% formic acid) was adopted as the mobile phase for gradient elution. The nine components and two internal standards were completely separated within 8 min. The mass spectrometry detection was performed in multiple reaction monitoring(MRM) mode by positive and negative ion switching of electrospray ionization. The analytical method was validated in terms of specificity, selectivity, linear range, accuracy, precision, recovery, matrix effect, and stability. It could meet the requirement of pharmacokinetic research after oral administration of FZSS extract to beagle dogs. The results showed that the time to reach the peak concentration(T_(max)) of magnoflorine,(R)-coclaurine, vicenin â ¡, isospinosin, spinosin, 6î-feruloylspinosin, and jujuboside B was 2.40-3.20 h, and the elimination halflife(t_(1/2)) was 2.08-6.79 h after a single-dose oral administration of FZSS to beagle dogs. The exposure of magnoflorine and spinosin was high, with a peak concentration(C_(max)) of 76.7 and 31.5 ng·mL~(-1) and an area under the curve(AUC_(0-∞)) of 581 and 315 ng·h·mL~(-1), respectively. The exposure of the remaining five compounds was lower, with a C_(max) of 0.81-13.0 ng·mL~(-1) and an AUC_(0-∞) of 6.00-106 ng·h·mL~(-1). This study provides a reference for the follow-up research of FZSS.
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Medicamentos de Ervas Chinesas , Espectrometria de Massas em Tandem , Ziziphus , Animais , Cães , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/administração & dosagem , Ziziphus/química , Masculino , Espectrometria de Massa com Cromatografia LíquidaRESUMO
PURPOSE: The presence of anti-interferon-γ autoantibodies (AutoAbs-IFN-γ) is not rare in patients suffering from persistent non-tuberculous mycobacterial (NTM) infections that are characteristic of adult-onset immunodeficiency syndrome. The immune disturbances in this distinct disorder remain to be elucidated. METHODS: Patients with NTM infections but without effective response over 3 months' treatment were referred to our institute to quantify their level of AutoAbs-IFN-γ after excluding defective IL12/23-IFN-γ circuit and reactive oxygen species production. The AutoAbs-IFN-γ and percentage of lymphocyte subpopulations most relevant to T and B cell pools were assessed and compared with age-matched healthy controls. RESULTS: A total of 31 patients were enrolled during the 15-year study period (2008-2022), 20 patients with > 50% suppression of IFN-γ detection at 1:100 serum dilution were classified into the Auto-NTM group. The remaining 11 with negligible suppression were assigned to the No Auto-NTM group. Mycobacterium chimaera-intracellulare group (MAC), M. kansasii, and M. abscessus were the most common pathogens. Pneumonia (19 vs 7), lymphadenitis (11 vs 5), Salmonella sepsis (6 vs 2), osteomyelitis (5 vs 1), and cutaneous herpes zoster (4 vs 4) were the main manifestations in both the Auto-NTM and No Auto-NTM groups who had similar onset-age (55.3 vs 53.6 years; p = 0.73) and follow-up duration (71.9 vs 54.6 months; p = 0.45). The Auto-NTM group had significantly higher transitional (IgM + + CD38 + +), CD19 + CD21-low, and plasmablast (IgM-CD38 + +) in the B cell pool, with higher effector memory (CD4 + /CD8 + CD45RO + CCR7 -), senescent CD8 + CD57 + , and Th17 cells, but lower naïve (CD4 + /CD8 + CD45RO - CCR7 +) and Treg cells in the T cell pool when compared to the No Auto-NTM and healthy groups. NTM patients with/without AutoAbs-IFN-γ had lower Th1-like Tfh (CD4 + CXCR5 + CXCR3 + CCR6 -) cells. All Auto-NTM patients still had non-remitted mycobacterial infections and higher AutoAbs-IFN-γ despite anti-CD20 therapy in 3 patients. CONCLUSION: In patients with suspected adult-onset immunodeficiency syndrome, two thirds (20/31) were recognized as having significantly inhibitory AutoAbs-IFN-γ with higher antibody-enhancing transitional, CD19 + CD21-low and plasmablast B cells; as well as higher effector memory, senescent CD8 + CD57 + and Th17 cells, but lower naïve T and Treg cells in contrast to those with negligible AutoAbs-IFN-γ. Such immunophenotyping disturbances might correlate with the presence of AutoAbs-IFN-γ. However, the mutual mechanisms need to be further clarified.
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Infecções por HIV , Síndromes de Imunodeficiência , Infecções por Mycobacterium não Tuberculosas , Humanos , Pessoa de Meia-Idade , Autoanticorpos , Imunoglobulina M , Síndromes de Imunodeficiência/diagnóstico , Imunofenotipagem , Interferon gama , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Micobactérias não Tuberculosas , Receptores CCR7RESUMO
PURPOSE: Diarrhea lasting longer than 14 days which fails to respond to conventional management is defined as severe and protracted diarrhea and might overlap with inflammatory bowel disease (IBD). METHODS: The prevalence, associated pathogens, and prognosis of severe and protracted diarrhea without IBD (SD) and with monogenetic IBD (mono-IBD) in primary immunodeficiency patients (PID) were investigated in Taiwan. RESULTS: A total of 301 patients were enrolled between 2003 and 2022, with predominantly pediatric-onset PID. Of these, 24 PID patients developed the SD phenotype before prophylactic treatment, including Btk (six), IL2RG (four), WASP, CD40L, gp91 (three each), gp47, RAG1 (one each), CVID (two), and SCID (one) without identified mutations. The most detectable pathogens were pseudomonas and salmonella (six each), and all patients improved after approximately 2 weeks of antibiotic and/or IVIG treatments. Six (25.0%) mortalities without HSCT implementation were due to respiratory failure from interstitial pneumonia (3 SCID and 1 CGD), intracranial hemorrhage (WAS), and lymphoma (HIGM). In the mono-IBD group, seventeen patients with mutant TTC7A (2), FOXP3 (2), NEMO (2), XIAP (2), LRBA (1), TTC37 (3), IL10RA (1), STAT1 (1), ZAP70 (1), PIK3CD (1), and PIK3R1 (1) genes failed to respond to aggressive treatments. Nine mono-IBD patients with TTC7A (2), FOXP3 (2), NEMO (2), XIAP (2), and LRBA (1) mutations were fatal in the absence of HSCT. The mono-IBD group had a significantly earlier age of diarrhea onset (1.7 vs 33.3 months, p = 0.0056), a longer TPN duration (34.2 vs 7.0 months, p < 0.0001), a shorter follow-up period (41.6 vs 132.6 months, p = 0.007), and a higher mortality rate (58.9 vs 25.0%, p = 0.012) compared with the SD group. CONCLUSION: When compared to those with the SD phenotype, the mono-IBD patients had significant early-onset and poor responses to empiric antibiotics, IVIG, and steroids. Anti-inflammatory biologics and suitable HSCT still have the potential to control or even cure the mono-IBD phenotype.
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Imunoglobulinas Intravenosas , Doenças Inflamatórias Intestinais , Humanos , Doenças Inflamatórias Intestinais/genética , Diarreia/epidemiologia , Fenótipo , Fatores de Transcrição Forkhead/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas/genéticaRESUMO
The COVID-19 pandemic has had a profound impact on the mental health of healthcare workers (HCWs). We aimed to identify the factors associated with depression among HCWs during the pandemic. We conducted literature search using eight electronic databases up to July 27 2022. Observational studies with more than 200 participants investigating correlates of depression in HCWs after COVID-19 outbreak were included. We used fixed- and random-effects models to pool odds ratios (ORs) across studies, and Cochran's chi-squared test and I 2 statistics to assess study heterogeneity. Publication bias was evaluated by funnel plots. Thirty-five studies involving 44,362 HCWs met the inclusion criteria. Female (OR=1.50, 95% CI [1.23,1.84]), single (OR=1.36, 95% CI [1.21,1.54]), nurse (OR=1.69, 95% CI [1.28,2.25]), history of mental diseases (OR=2.53, 95% CI [1.78,3.58]), frontline (OR=1.79, 95% CI [1.38,2.32]), health anxiety due to COVID-19 (OR=1.88, 95% CI [1.29,2.76]), working in isolation wards (OR=1.98, 95% CI [1.38,2.84]), and insufficient personal protective equipment (OR=1.49, 95% CI [1.33,1.67]) were associated with increased risk of depression. Instead, HCWs with a positive professional prospect (OR=0.34, 95% CI [0.24,0.49]) were less likely to be depressed. This meta-analysis provides up-to-date evidence on the factors linked to depression among HCWs during the COVID-19 pandemic. Given the persistent threats posed by COVID-19, early screening is crucial for the intervention and prevention of depression in HCWs.
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This study reports a carbonylative acetylation for the synthesis of N-phenyl-N-(pyridin-2-yl)acetamides using N,N-dimethylformamide (DMF) as a methyl source and CO as a carbonyl source. Interestingly, dimethyl sulfoxide (DMSO) can be also used as a methyl source when using only DMSO as the solvent. Mechanistic studies using DMSO-d6 revealed that the methyl group was derived from the methyl group of DMF instead of DMSO when using DMF and DMSO as a mixed solvent. These results indicated that DMF was a preferential methyl source.
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Despite the widespread applications of sulfoximines, green and efficient access to functionalized sulfoximines remains a challenge. By employing an electrochemical strategy, we describe an approach for the construction of N-aroylsulfoximines, which features a broad substrate scope, mild reaction conditions, safety on a gram scale, and no need for an external oxidant and transition metal catalysts.
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BACKGROUND: Tetanops sintenisi is a pest that mainly damages the root of quinoa (Chenopodium quinoa) and it is first discovered in China in 2018. METHODS AND RESULTS: Here, the complete mitochondrial genome (mitogenome) of T. sintenisi was sequenced and compared with the mitogenomes of other Diptera species. The results revealed that the mitogenome of T. sintenisi is 15,763 bp in length (GenBank accession number: MT795181) and is comprised of 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA) genes, 2 ribosomal RNA genes, and a non-coding A + T-rich region (959 bp). The highly conserved gene arrangement of the mitogenome of T. sintenisi was identical to that of other Diptera insects. Twelve PCGs contained the typical insect start codon ATN, while cox1 had CGA as the start codon. The genes cox2, nad4, and nad1 contained an incomplete termination codon T; nad3, nad5, and cob contained the complete termination codon TAG; and the remaining seven PCGs contained the termination codon TAA. All tRNA genes were predicted to fold into the typical cloverleaf secondary structure. Phylogenetic analysis of 48 species based on the mitogenome sequence revealed that T. sintenisi clustered with the Tephritidae family, indicating that T. sintenisi and Tephritidae have a close phylogenetic relationship. CONCLUSIONS: The phylogenetic relationship of T. sintenisi based on the mitogenome is consistent with the traditional morphological taxonomy, according to which T. sintenisi belongs to the family Otitidae, which is closely related to the family Muscidae.
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Genoma Mitocondrial , Tephritidae , Animais , Filogenia , Genoma Mitocondrial/genética , Códon de Terminação , Códon de Iniciação , RNA de Transferência/genética , RNA de Transferência/química , Tephritidae/genéticaRESUMO
Sodium-rich anti-perovskites have unique advantages in terms of composition tuning and electrochemical stability when used as solid-state electrolytes in sodium-ion batteries. However, their Na+ transport mechanism is not clear and Na+ conductivity needs to be improved. In this paper, we investigate the stability, elastic properties and Na+ transport mechanisms of both the double anti-perovskite Na3S0.5O0.5I and anti-perovskite Na3OI. The results indicate that the NaI Schottky defect is the most favorable intrinsic defect for Na+ transport and due to the substitution of S2- for O2-, Na3S0.5O0.5I has stronger ductility and higher Na+ conductivity compared to Na3OI, despite the electrochemical window being slightly narrower. Divalent alkaline earth metal dopants can increase the Na+ vacancy concentration, while impeding Na+ migration. Among the dopants, Sr2+ and Ca2+ are the optimal dopants for Na3S0.5O0.5I and Na3OI, respectively. Notably, the Na+ conductivity of the non-stoichiometric Na3S0.5O0.5I at room temperature is 1.2 × 10-3 S cm-1, indicating its great potential as a solid-state electrolyte. Moreover, strain effect calculations show that biaxial tensile strain is beneficial for Na+ transport. Our work reveals the sodium-ion transport mechanism and elastic properties of double anti-perovskites, which is of great significance for the development of solid-state electrolytes.
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Due to high ion conductivity, low cost, and adjustable composition, antiperovskite has attracted much attention as a potentially useful material in solid-state batteries. Compared with simple antiperovskite, Ruddlesden-Popper (R-P) antiperovskite is an updated material, which is not only more stable but also reported to significantly enhance conductivity when added to simple antiperovskite. However, systematic theoretical research on R-P antiperovskite is scarce, hindering its further development. In this study, the recently reported easily synthesized R-P antiperovskite LiBr(Li2OHBr)2 is calculated for the first time. Comparative calculations were conducted on the transport performance, thermodynamic properties, and mechanical properties of H-rich LiBr(Li2OHBr)2 and H-free LiBr(Li3OBr)2. Our results indicate that due to the presence of protons, LiBr(Li2OHBr)2 is more prone to defects, and synthesizing more LiBr Schottky defects can improve its Li-ion conductivity. Young's modulus of the LiBr(Li2OHBr)2 is as low as 30.61 GPa, which is beneficial for its application as a sintering aid. However, the calculated Pugh's ratio (B/G) of 1.28 and 1.50, respectively, indicates that R-P antiperovskites LiBr(Li2OHBr)2 and LiBr(Li3OBr)2 exhibit mechanical brittleness, which is not conducive to its application as solid electrolytes. Through quasi-harmonic approximation, we found that the linear thermal expansion coefficient of LiBr(Li2OHBr)2 is 2.07 × 10-5 K-1, which is more advantageous in matching electrodes than LiBr(Li3OBr)2 and even simple antiperovskites. Overall, our research provides comprehensive insights into the practical application of R-P antiperovskite in solid-state batteries.
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Calcium signals are initiated in immune cells by the process of store-operated calcium entry (SOCE), where receptor activation triggers transient calcium release from the endoplasmic reticulum, followed by opening of plasma-membrane calcium-release activated calcium (CRAC) channels. ORAI1, ORAI2, and ORAI3 are known to comprise the CRAC channel; however, the contributions of individual isoforms to neutrophil function are not well understood. Here, we show that loss of ORAI1 partially decreases calcium influx, while loss of both ORAI1 and ORAI2 completely abolishes SOCE. In other immune-cell types, loss of ORAI2 enhances SOCE. In contrast, we find that ORAI2-deficient neutrophils display decreased calcium influx, which is correlated with measurable differences in the regulation of neutrophil membrane potential via KCa3.1. Decreased SOCE in ORAI1-, ORAI2-, and ORAI1/2-deficient neutrophils impairs multiple neutrophil functions, including phagocytosis, degranulation, leukotriene, and reactive oxygen species (ROS) production, rendering ORAI1/2-deficient mice highly susceptible to staphylococcal infection. This study demonstrates that ORAI1 and ORAI2 are the primary components of the neutrophil CRAC channel and identifies subpopulations of neutrophils where cell-membrane potential functions as a rheostat to modulate the SOCE response. These findings have implications for mechanisms that modulate neutrophil function during infection, acute and chronic inflammatory conditions, and cancer.
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Sinalização do Cálcio , Cálcio/imunologia , Neutrófilos/imunologia , Proteína ORAI1/imunologia , Proteína ORAI2/imunologia , Animais , Feminino , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína ORAI1/genética , Proteína ORAI2/genéticaRESUMO
BACKGROUND: Hyperlipidemia is a common complication after liver transplantation (LT) and develops mostly in the early posttransplant period. Recently, some studies have reported a positive correlation between hyperlipidemia and favorable prognosis in patients with hepatocellular carcinoma (HCC) undergoing hepatectomy. This study aimed to evaluate the possibility of predicting prognosis in HCC patients receiving LT by early posttransplant dyslipidemia. METHODS: From January 2015 to December 2017, a total of 806 HCC patients from China Liver Transplant Registry database were retrospectively enrolled. The prognostic relevance of early posttransplant hypertriglyceridemia or hypercholesterolemia was examined using survival analysis, and subgroup analysis was implemented based on LT criteria. RESULTS: Early posttransplant hypercholesterolemia (EPHC) was independently inversely associated with the risk of recurrence [hazard ratio (HR) = 0.630; P = 0.022], but was not significantly correlated with the mortality. However, early posttransplant hypertriglyceridemia was not related to prognosis. Intriguingly, with further classification, we found that borderline EPHC (B-EPHC), instead of significant EPHC, was a predictor of lower risk for both recurrence (HR = 0.504; P = 0.006) and mortality (HR = 0.511; P = 0.023). Compared with non-EPHC patients, B-EPHC patients achieved significantly superior 1-year and 3-year tumor-free survival (89.6% and 83.7% vs. 83.8% and 72.7% respectively; P = 0.023), and 1-year and 3-year overall survival (95.8% and 84.8% vs. 94.6% and 77.6% respectively; P = 0.039). In the subgroup analysis, B-EPHC remained an independent predictor of better prognosis in patients beyond Milan criteria and those within Hangzhou criteria; whereas there was no significant relationship between B-EPHC and prognosis in patients within Milan criteria and those beyond Hangzhou criteria. More interestingly, patients beyond Milan criteria but within Hangzhou criteria were identified as the crucial subpopulation who benefited from B-EPHC (recurrence HR = 0.306, P = 0.011; mortality HR = 0.325, P = 0.031). CONCLUSIONS: B-EPHC could assist transplant teams in dynamically evaluating prognosis after LT for HCC as a postoperative non-oncological biomarker, especially in patients beyond Milan criteria but within Hangzhou criteria.
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Carcinoma Hepatocelular , Hipercolesterolemia , Hiperlipidemias , Neoplasias Hepáticas , Transplante de Fígado , Humanos , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/cirurgia , Prognóstico , Transplante de Fígado/efeitos adversos , Neoplasias Hepáticas/patologia , Estudos Retrospectivos , Hipercolesterolemia/complicações , Hipercolesterolemia/diagnóstico , Recidiva Local de Neoplasia/patologiaRESUMO
An efficient and direct carbonylation of aminoquinoline benzamides has been developed using abundant and inexpensive Ni(OAc)2·4H2O as the catalyst and carbon monoxide as a cost-efficient C1 building block. This process features good functional-group tolerance and can be conducted on gram scale. The directing group can be easily removed under mild conditions.
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BACKGROUND: Effective-component compatibility of Bufei Yishen formula III (ECC-BYF III) demonstrates positive effects on stable chronic obstructive pulmonary disease (COPD). PURPOSE: To investigate the mechanisms of ECC-BYF III on COPD rats from the aspect of airway epithelial cell senescence. METHODS: COPD model rats (Sprague-Dawley rat) were treated with ECC-BYF III for 8 weeks, and the efficacy was evaluated. Cigarette smoke extract (CSE)-induced senescence model of airway epithelial cells was treated with ECC-BYF III, and related enzymes and proteins involved in oxidative stress and mitophagy were detected. RESULTS: ECC-BYF III markedly rescued pulmonary function and histopathological changes, which might be associated with the amelioration of lung senescence, including the reduction of malondialdehyde (MDA) and tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and matrix metalloproteinase (MMP)-9 levels, increase of the level in total superoxide dismutase (T-SOD), and decease in the p21 level in the airways. Furthermore, ECC-BYF III suppressed p16 and p21 expressions and senescence-associated ß-galactosidase (SA-ß-Gal) in CSE-induced airway epithelial cells. Moreover, ECC-BYF III upregulated mitophagy-related proteins, including the co-localizations of TOM20 and LC3B, PINK1 and PARK2, and improved mitochondrial function by upregulating mitochondrial mitofusin (MFN)2 and reducing dynamin-related protein 1 (DRP1) expression. ECC-BYF III enhanced the activities of T-SOD and GSH-PX by up-regulating NRF2, thus inhibiting oxidative stress. After intervention with NRF2 inhibitor, the regulation effects of ECC-BYF III on oxidative stress, mitophagy and senescence in airway epithelial cells were significantly suppressed. CONCLUSIONS: ECC-BYF III exerts beneficial effects on COPD rats by ameliorating airway epithelial cell senescence, which is mediated by inhibiting oxidative stress and subsequently enhancing mitophagy through the activation of NRF2 signaling.
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Mitofagia , Doença Pulmonar Obstrutiva Crônica , Ratos , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Ratos Sprague-Dawley , Senescência Celular , Células Epiteliais/metabolismo , Proteínas Quinases/metabolismo , Proteínas Quinases/farmacologia , Superóxido Dismutase/metabolismoRESUMO
Astragalus Membranaceus (AM) is widely applied in Chinese herbal compound formulas for treating various kinds of diseases. However, relative pharmacokinetics data on AM in nonrodents is still lacking. Here, an UPLC-MS/MS method for determining the six main compounds of AM was developed. The chromatographic separation was carried out by a Waters Acquity UPLC HSS T3 column (100 × 2.1 mm, 1.8 µm) with gradient elution of water-formic acid (99.98:0.02, v/v) and acetonitrile-formic acid (99.98:0.02, v/v) at a flow rate of 0.3 ml/min within 11 min. Analyses of all compounds were conducted in multiple reaction monitoring mode with a positive/negative ion-switching mode of an electrospray ionization source in a single run. The analytical method was validated in terms of specificity, linearity, accuracy, precision, stability, etc. The method showed excellent linearity (r > 0.999) over certain concentration ranges. The intra-day and inter-day precisions were evaluated, and the RSD values were <12.4%. Furthermore, the validated method was successfully applied to determine the six components in plasma after oral administration of AM aqueous extract to beagle dogs and the pharmacokinetic parameters were obtained. Together, this study provides a reference for medication in the clinical practice of AM.
Assuntos
Astragalus propinquus , Espectrometria de Massas em Tandem , Cães , Animais , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Administração Oral , Água , Reprodutibilidade dos TestesRESUMO
PURPOSE: Female carriers with X-linked chronic granulomatous disease (XL-CGD) who have < 10% reactive oxygen species (ROS) production due to profound X-chromosome inactivation (XCI or lyonization) are more susceptible to infections. We assessed ROS production in Taiwanese female carriers with XL-CGD to investigate whether the level of ROS correlated to their clinical features of infection, autoimmunity, and autoinflammation. METHODS: Clinical course, ROS production, flavocytochrome b558 (Cyto b558) expression, and genetic analysis in carriers were investigated after identifying their index cases between 2004 and 2019. RESULTS: A total of 19 mothers (median 27 years; range 25-60 years) and three of four girls (range 4-6 years) relative to 22 male index XL-CGD cases from 19 unrelated families were enrolled. Approximately half (8/19, 42%) of the mothers had novel one-allele mutations. Twenty-two of the 23 females were carriers. One carrier with de novo [Arg290X]CYBB who suffered from refractory salmonella sepsis and chorioretinitis as an XL-CGD phenotype had extreme XCI, absent Cyto b558 expression, and only 8% ROS production. The remaining carriers had bimodal patterns of Cyto b558 expressions (median 40.2%, 26.8-52.4%) and ROS production (38.3%, range 28.2-54.2%) sufficient to prevent significant infections, although neck lymphadenitis recurred in one mother and sister who had ROS expressions of 28.2% and 38.0%, respectively. However, none of the carriers had manifestations of autoimmunity or autoinflammation (e.g., photosensitivity, aphthous stomatitis, or joint disorders), of which each was seen in approximately one-third of XL-CGD carriers from the Western world. CONCLUSION: One carrier had undetectable Cyto b558 expression and an extremely low ROS production, and consequently presented with an XL-CGD phenotype. One mother and her daughter experienced recurrent neck lymphadenitis despite having sufficient ROS production. Significant autoimmunity/autoinflammation did not develop in any of the carriers. Studies with a longer follow-up period are needed to validate our findings.