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Disruption of mitochondrial function is observed in multiple drug-induced liver injuries (DILIs), a significant global health threat. However, how the mitochondrial dysfunction occurs and whether maintain mitochondrial homeostasis is beneficial for DILIs remains unclear. Here, we show that defective mitophagy by OPTN (optineurin) ablation causes disrupted mitochondrial homeostasis and aggravates hepatocytes necrosis in DILIs, while OPTN overexpression protects against DILI depending on its mitophagic function. Notably, mass spectrometry analysis identifies a new mitochondrial substrate, GCDH (glutaryl-CoA dehydrogenase), which can be selectively recruited by OPTN for mitophagic degradation, and a new cofactor, VCP (valosin containing protein) that interacts with OPTN to stabilize BECN1 during phagophore assembly, thus boosting OPTN-mediated mitophagy initiation to clear damaged mitochondria and preserve mitochondrial homeostasis in DILIs. Then, the accumulation of OPTN in different DILIs is further validated with a protective effect, and pyridoxine is screened and established to alleviate DILIs by inducing OPTN-mediated mitophagy. Collectively, our findings uncover a dual role of OPTN in mitophagy initiation and implicate the preservation of mitochondrial homeostasis via inducing OPTN-mediated mitophagy as a potential therapeutic approach for DILIs.Abbreviation: AILI: acetaminophen-induced liver injury; ALS: amyotrophic lateral sclerosis; APAP: acetaminophen; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CHX: cycloheximide; Co-IP: co-immunoprecipitation; DILI: drug-induced liver injury; FL: full length; GCDH: glutaryl-CoA dehydrogenase; GOT1/AST: glutamic-oxaloacetic transaminase 1; GO: gene ontology; GSEA: gene set enrichment analysis; GPT/ALT: glutamic - pyruvic transaminase; INH: isoniazid; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MMP: mitochondrial membrane potential; MST: microscale thermophoresis; MT-CO2/COX-II: mitochondrially encoded cytochrome c oxidase II; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; TSN: toosendanin; VCP: valosin containing protein, WIPI2: WD repeat domain, phosphoinositide interacting 2.
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Huanglian Jiedu Decoction (HJD) is a well-known Traditional Chinese Medicine formula that has been used for liver protection in thousands of years. However, the therapeutic effects and mechanisms of HJD in treating drug-induced liver injury (DILI) remain unknown. In this study, a total of 26 genes related to both HJD and DILI were identified, which are corresponding to a total of 41 potential active compounds in HJD. KEGG analysis revealed that Tryptophan metabolism pathway is particularly important. The overlapped genes from KEGG and GO analysis indicated the significance of CYP1A1, CYP1A2, and CYP1B1. Experimental results confirmed that HJD has a protective effect on DILI through Tryptophan metabolism pathway. In addition, the active ingredients Corymbosin, and Moslosooflavone were found to have relative strong intensity in UPLC-Q-TOF-MS/MS analysis, showing interactions with CYP1A1, CYP1A2, and CYP1B1 through molecule docking. These findings could provide insights into the treatment effects of HJD on DILI.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Medicamentos Herbarios Chinos , Simulación del Acoplamiento Molecular , Farmacología en Red , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Humanos , Animales , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP1A2/efectos de los fármacosRESUMEN
BACKGROUND: Sepsis is a disease characterized by infection-induced multiorgan dysfunction, which can progress to septic shock if not promptly treated. Early identification of sepsis is crucial for its treatment. However, there are currently limited specific biomarkers for sepsis or septic shock. This study aims to identify potential biomarkers for sepsis and septic shock. METHODS: We analyzed single-cell transcriptomic data of peripheral blood mononuclear cells (PBMCs) from healthy individuals, sepsis and septic shock patients, identified differences in gene expression and cell-cell communication between different cell types during disease progression. Moreover, our analyses were further validated with flow cytometry and bulk RNA-seq data. RESULTS: Our study elucidates the alterations in cellular proportions and cell-cell communication among healthy controls, sepsis, and septic shock patients. We identified a specific augmentation in the Resistin signaling within sepsis monocytes, mediated via RETN-CAP1 ligand-receptor pairs. Additionally, we observed enhanced IL16 signaling within monocytes from septic shock patients, mediated through IL16-CD4 ligand-receptor pairs. Subsequently, we confirmed our findings by validating the increase in CAP-1+ monocytes in sepsis and IL16+ monocytes in septic shock in mouse models. And a significant upregulation of CAP-1 and IL16 was also observed in the bulk RNA-seq data from patients with sepsis and septic shock. Furthermore, we identified four distinct clusters of CD14+ monocytes, highlighting the heterogeneity of monocytes in the progress of sepsis. CONCLUSIONS: In summary, our work demonstrates changes in cell-cell communication of healthy controls, sepsis and septic shock, confirming that the molecules CAP-1 and IL16 on monocytes may serve as potential diagnostic markers for sepsis and septic shock, respectively. These findings provide new insights for early diagnosis and stratified treatment of the disease.
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Biomarcadores , Comunicación Celular , Sepsis , Choque Séptico , Análisis de la Célula Individual , Humanos , Choque Séptico/sangre , Choque Séptico/inmunología , Animales , Sepsis/inmunología , Sepsis/diagnóstico , Sepsis/genética , Ratones , Masculino , Monocitos/inmunología , Monocitos/metabolismo , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/inmunología , Análisis de Secuencia de ARN , Femenino , Ratones Endogámicos C57BL , Persona de Mediana EdadRESUMEN
Colorectal cancer (CRC) is the third most common malignant disease worldwide, and its incidence is increasing, but the molecular mechanisms of this disease are highly heterogeneous and still far from being fully understood. Increasing evidence suggests that fibrosis mediated by abnormal activation of fibroblasts based in the microenvironment is associated with a poor prognosis. However, the function and pathogenic mechanisms of fibroblasts in CRC remain unclear. Here, combining scrna-seq and clinical specimen data, DAZ Interacting Protein 1 (DZIP1) was found to be expressed on fibroblasts and cancer cells and positively correlated with stromal deposition. Importantly, pseudotime-series analysis showed that DZIP1 levels were up-regulated in malignant transformation of fibroblasts and experimentally confirmed that DZIP1 modulates activation of fibroblasts and promotes epithelial-mesenchymal transition (EMT) in tumor cells. Further studies showed that DZIP1 expressed by tumor cells also has a driving effect on EMT and contributes to the recruitment of more fibroblasts. A similar phenomenon was observed in xenografted nude mice. And it was confirmed in xenograft mice that downregulation of DZIP1 expression significantly delayed tumor formation and reduced tumor size in CRC cells. Taken together, our findings suggested that DZIP1 was a regulator of the CRC mesenchymal phenotype. The revelation of targeting DZIP1 provides a new avenue for CRC therapy.
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Erectile Dysfunction (ED) is considered a physical and mental illness. A variety of potential associations between gut microbiota and health or disease have been found. By comparing the gut microbiota of healthy controls and ED patients, our study investigated the relationship between ED and gut microbiota. The results revealed that the ED group exhibited a significantly higher relative abundance of Bacteroides, Fusobacterium, Lachnoclostridium, Escherichia-Shigella and Megamonas, while showing a significantly lower relative abundance of Bifidobacterium compared to the control group. The dysbiosis of gut microbiota played a role in the onset and progression of ED by influencing the gut barrier, cardiovascular system and mental health, which provided a novel perspective on understanding the pathophysiology of ED. What is more, we had identified several key gut microbiota. By combining 16S rRNA sequencing with machine learning techniques, we were able to uncover the significant value and impact of gut microbiota in the early detection of ED.
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Disfunción Eréctil , Microbioma Gastrointestinal , Masculino , Humanos , Microbioma Gastrointestinal/fisiología , ARN Ribosómico 16S/genética , Disbiosis/microbiología , BifidobacteriumRESUMEN
INTRODUCTION: Diabetes mellitus is one of the major chronic diseases, which enhances the risk of erectile dysfunction. However, the central pathological mechanisms of erectile dysfunction in diabetes mellitus patients are still unclear. METHODS: Resting-state functional magnetic resonance imaging data were acquired in 30 type-2 diabetes mellitus, 31 type-2 diabetes mellitus with erectile dysfunction patients, and 31 healthy controls. The measure of fractional amplitude of low-frequency fluctuation was calculated and compared among groups. RESULTS: Differences of fractional amplitude of low-frequency fluctuation values were found in the left superior frontal gyrus (medial) and middle temporal gyrus among three groups. Compared with healthy controls group, type-2 diabetes mellitus group exhibited lower fractional amplitude of low-frequency fluctuation values in the left superior frontal gyrus (dorsolateral), anterior cingulate gyrus, calcarine fissure, and increased fractional amplitude of low-frequency fluctuation values in the left post-central gyrus. Compared with healthy controls group, erectile dysfunction with type-2 diabetes mellitus group exhibited lower fractional amplitude of low-frequency fluctuation values in the left superior frontal gyrus (medial), middle temporal gyrus, temporal middle (pole), and increased fractional amplitude of low-frequency fluctuation values in the right post-central gyrus. Compared with type-2 diabetes mellitus group, erectile dysfunction with type-2 diabetes mellitus group exhibited increased fractional amplitude of low-frequency fluctuation values in the right median cingulum gyrus and left calcarine fissure. CONCLUSION: Erectile dysfunction with type-2 diabetes mellitus patients showed functional changes in brain regions that were closely correlated with sexual dysfunction, which suggested that altered regional brain activity might be related to the pathophysiology of erectile dysfunction with type-2 diabetes mellitus.
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Diabetes Mellitus Tipo 2 , Disfunción Eréctil , Masculino , Humanos , Imagen por Resonancia Magnética , Encéfalo/diagnóstico por imagen , Diabetes Mellitus Tipo 2/complicaciones , Red NerviosaRESUMEN
The triboelectrification effect caused by dynamic contact between particles is an issue for explosions caused by electrostatic discharging (ESD) in the triboelectric nanogenerators (TENGs) for powering the flexible and wearable sensors. The electrostatic strength of dielectric particles (surface charge density, surface potential, electric field, etc.) is essential to evaluate the level of ESD risk. Those differential electrostatic characteristics concerned with unhomogenized swarmed particles cannot be offered via in-current employed-joint COMSOL 6.1 simulation, in which the discrete charged dielectric particles are mistakenly regarded as continuous ones. In this paper, the hybrid discrete element method (EDEM tool) associated with programming in COMSOL Multiphysics 6.1 with MATLAB R2023a was employed to obtain the electrostatic information of the triboelectric dielectric particle swarm. We revealed that the high-accuracy strengths of electric potential and electric field inside particle warm are crucial to evaluating ESD risk. The calculated electrostatic characteristics differ from the grid method and continuous method in the surface potential and electric field. This EDEM-based simulation method is significant for microcosmic understanding and the assessment of the ESD risk in TENGs.
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BACKGROUND: Catheter-associated urinary tract infection (CAUTI) ranks second among nosocomial infections in elderly patients after lung infections. Improper treatment can lead to death. This study analysed the risk factors, pathogen distribution, clinical characteristics and outcomes of CAUTI in elderly inpatients with a large sample size to provide evidence for clinical prevention and control. METHODS: Based on the HIS and LIS, a caseâcontrol study was conducted on all hospitalized patients with indwelling urinary catheters ≥ 60 years old from January 1, 2019, to December 31, 2022, and the patients were divided into the CAUTI group and the non-CAUTI group. RESULTS: CAUTI occurred in 182 of 7295 patients, and the infection rate was 3.4/per 1000 catheter days. Urine pH ≥ 6.5, moderate dependence or severe dependence in the classification of self-care ability, age ≥ 74 years, male sex, hospitalization ≥ 14 days, indwelling urinary catheter ≥ 10 days, diabetes and malnutrition were independent risk factors for CAUTI (P < 0.05). A total of 276 strains of pathogenic bacteria were detected in urine samples of 182 CAUTI patients at different times during hospitalization. The main pathogens were gram-negative bacteria (n = 132, 47.83%), followed by gram-positive bacteria (n = 91, 32.97%) and fungi (n = 53, 19.20%). Fever, abnormal procalcitonin, positive urinary nitrite and abnormal urination function were the clinical characteristics of elderly CAUTI patients (P < 0.001). Once CAUTI occurred in elderly patients, the hospitalization days were increased by 18 days, the total hospitalization cost increased by ¥18,000, and discharge all-cause mortality increased by 2.314 times (P<0.001). CONCLUSION: The situation of CAUTI in the elderly is not optimistic, it is easy to have a one-person multi-pathogen infection, and the proportion of fungi infection is not low. Urine pH ≥ 6.5, moderate or severe dependence on others and malnutrition were rare risk factors for elderly CAUTI in previous studies. Our study analysed the clinical characteristics of CAUTI in the elderly through a large sample size, which provided a reliable basis for its diagnosis and identified the adverse outcome of CAUTI.
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Infecciones Relacionadas con Catéteres , Infección Hospitalaria , Desnutrición , Infecciones Urinarias , Humanos , Masculino , Anciano , Persona de Mediana Edad , Cateterismo Urinario/efectos adversos , Infecciones Relacionadas con Catéteres/prevención & control , Estudios de Casos y Controles , Infecciones Urinarias/etiología , Infecciones Urinarias/microbiología , Infección Hospitalaria/etiología , Infección Hospitalaria/microbiología , Catéteres de Permanencia/microbiología , Catéteres Urinarios/efectos adversos , Desnutrición/complicacionesRESUMEN
Background: Chronic kidney disease (CKD) and non-alcoholic fatty liver disease (NAFLD) are closely related to immune and inflammatory pathways. This study aimed to explore the diagnostic markers for CKD patients with NAFLD. Methods: CKD and NAFLD microarray data sets were screened from the GEO database and analyzed the differentially expressed genes (DEGs) in GSE10495 of CKD date set. Weighted Gene Co-Expression Network Analysis (WGCNA) method was used to construct gene coexpression networks and identify functional modules of NAFLD in GSE89632 date set. Then obtaining NAFLD-related share genes by intersecting DEGs of CKD and modular genes of NAFLD. Then functional enrichment analysis of NAFLD-related share genes was performed. The NAFLD-related hub genes come from intersection of cytoscape software and machine learning. ROC curves were used to examine the diagnostic value of NAFLD related hub genes in the CKD data sets and GSE89632 date set of NAFLD. CIBERSORTx was also used to explore the immune landscape in GSE104954, and the correlation between immune infiltration and hub genes expression was investigated. Results: A total of 45 NAFLD-related share genes were obtained, and 4 were NAFLD-related hub genes. Enrichment analysis showed that the NAFLD-related share genes were significantly enriched in immune-related pathways, programmed cell death, and inflammatory response. ROC curve confirmed 4 NAFLD-related hub genes in CKD training set GSE104954 and other validation sets. Then they were used as diagnostic markers for CKD. Interestingly, these 4 diagnostic markers of CKD also showed good diagnostic value in the NAFLD date set GSE89632, so these genes may be important targets of NAFLD in the development of CKD. The expression levels of the 4 diagnostic markers for CKD were significantly correlated with the infiltration of immune cells. Conclusion: 4 NAFLD-related genes (DUSP1, NR4A1, FOSB, ZFP36) were identified as diagnostic markers in CKD patients with NAFLD. Our study may provide diagnostic markers and therapeutic targets for CKD patients with NAFLD.
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Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/genética , Biomarcadores , Aprendizaje Automático , Apoptosis , Biología ComputacionalRESUMEN
Context: With the rapidly aging population globally, osteoporosis (OP) has become a major public health problem, and fracture is a common complication of OP. Older adults, especially postmenopausal women, have a higher incidence of OP. Objective: The study intended to analyze the clinical information, epidemiological characteristics, treatments, and follow-up results of patients with osteoporotic fractures (OPFs) in adults over 65 years old, to provide data support for the prevention, treatment, and use of OPF focus groups in clinical practice. Design: The research team performed a retrospective analysis using electronic medical records and related imaging data of patients. Setting: The study took place at Hebei General Hospital in Hebei, China. Participants: Participants were 387 patients over 65 years old with osteoporotic fractures who had been admitted to the hospital between July 2012 and July 2018. Outcome Measures: The research team recorded participants' ages, genders, fracture causes, and fracture sites. The team performed a follow-up analysis on refractures, treatment with anti-osteoporotic drugs, exercise, and survival status within the 3 years after surgery. Results: The study's male-to-female ratio was 1:3.1, and the rate of osteoporotic fracture for females was significantly higher than that of males. The mean age of participants with fractures was 75.6 ± 8.5 years, and most fractures occurred in participants 78 to 85 years old. Of the 387 participants, 169 participants had hip fractures (43.67%); 98 had vertebral compression fractures (25.32%); 51 had distal radius and ulna fractures (13.18%); 42 had proximal humerus fractures (10.85%); and 27 had other fractures (6.98%). The number of women with fractures at each site was greater than the number of men, but the differences weren't statistically significant (P > .05). The main causes of injury were falls (71.58%), and the main place of the occurrence of injury was at home (65.6%). Of the 387 participants, 346 had surgical treatment (89.41%), and the effective rate of surgical treatment was 99.42%. Three years after surgery, the research team followed up with 235 participants, for a follow-up rate of 60.72%. Within the 3 years of the follow-up period, 61 participants had refractures (25.63%), 29 received treatment with regular anti-osteoporotic drugs (12.34%), 36 exercised twice or more a week (15.32%), and 32 had died for various reasons (13.62%). Conclusions: The study preliminarily described the epidemiological characteristics of 387 osteoporotic fractures in adults over 65 years old. More women had fractures than men; the hip was the most common fracture site, and falls were the main cause of injury. Most of the fractures occurred in the place of residence, and the refracture rate was 25.96% at three years after surgery.
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Fracturas por Compresión , Osteoporosis , Fracturas Osteoporóticas , Fracturas de la Columna Vertebral , Femenino , Humanos , Masculino , Anciano , Anciano de 80 o más Años , Fracturas Osteoporóticas/epidemiología , Fracturas Osteoporóticas/cirugía , Estudios Retrospectivos , Osteoporosis/complicaciones , Osteoporosis/epidemiología , Osteoporosis/tratamiento farmacológicoRESUMEN
Curcumol, a natural product isolated from the traditional Chinese medicine Rhizoma curcumae, possesses various potential therapeutic values in many diseases. However, evidence of its toxicological profile is currently lacking. In this study, a repeated toxicity study of curcumol was conducted for the first time. SD rats were exposed to doses of 250, 500, 1000 mg/kg in a selected dose formulation for 28 days through oral administration. The potential toxic effects of curcumol on the blood system were observed and further validated in vivo and in vitro. Moreover, other hematology and biochemistry parameters as well as the weight of organs were altered, but no related histopathological signs were observed, indicating these changes were not regarded as toxicologically relevant. Our current findings provide a complete understanding of the safety profile of curcumol, which may contribute to its further study of investigational new drug application.
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Acute kidney injury (AKI) caused by anti-tumor drugs, such as cisplatin, is a severe complication with no effective treatment currently, leading to the reduction or discontinuation of chemotherapy. Natural products or herbal medicines are gradually considered as promising agents against cisplatin-induced AKI with the advantages of multi-targeting, multi-effects, and less resistance. In this study, we investigated the effects of kaempferide, a natural flavonoid extracted from the rhizome of Kaempferia galanga, in experimental AKI models in vitro and in vivo. We first conducted pharmacokinetic study in mice and found a relative stable state of kaempferide with a small amount of conversion into kaempferol. We showed that both kaempferide (10 µM) and kaempferol (10 µM) significantly inhibited cisplatin-caused injuries in immortalized proximal tubule epithelial cell line HK-2. In AKI mice induced by injection of a single dose of cisplatin (15 mg/kg), oral administration of kaempferide (50 mg/kg) either before or after cisplatin injection markedly improved renal function, and ameliorated renal tissue damage. We demonstrated that kaempferide inhibited oxidative stress and induced autophagy in cisplatin-treated mice and HK-2 cells, thus increasing tubular cell viability and decreasing immune responses to attenuate the disease progression. In addition, treatment with kaempferide significantly ameliorated ischemia-reperfusion-induced renal injury in vitro and in vivo. We conclude that kaempferide is a promising natural product for treating various AKI. This study has great implications for promotion of its use in healthcare products, and help to break through the limited use of cisplatin in the clinic.
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Lesión Renal Aguda , Cisplatino , Ratones , Animales , Cisplatino/farmacología , Quempferoles/farmacología , Quempferoles/uso terapéutico , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/patología , Estrés Oxidativo , Autofagia , Apoptosis , Ratones Endogámicos C57BLRESUMEN
Objective: Curcumol is one of the major active ingredients isolated from the traditional Chinese medicine Curcumae Rhizoma and is reported to exhibit various bioactivities, such as anti-tumor and anti-liver fibrosis effects. However, studies of curcumol pharmacokinetics and tissue distribution are currently lacking. This study aims to characterize the pharmacokinetics, tissue distribution, and protein binding rate of curcumol. Methods: Pharmacokinetics properties of curcumol were investigated afte doses of 10, 40, and 80 mg/kg of curcumol for rats and a single dose of 2.0 mg/kg curcumol was given to rats via intravenous administration to investigate bioavailability. Tissue distribution was investigated after a single dose of 40 mg/kg of orally administered curcumol. Plasma protein binding of curcumol was studied in vitro via the rapid equilibrium dialysis system. Bound and unbound curcumol in rat plasma were analyzed to calculate the plasma protein binding rate. A UHPLC-MS/MS method was developed and validated to determine curcumol in rat plasma and tissues and applied to study the pharmacokinetics, tissue distribution, and plasma protein binding in rats. Results: After oral administration of 10, 40, and 80 mg/kg curcumol, results indicated a rapid absorption and quick elimination of curcumol in rats. The bioavailability ranging from 9.2% to 13.1% was calculated based on the area under the curves (AUC) of oral and intravenous administration of curcumol. During tissue distribution, most organs observed a maximum concentration of curcumol within 0.5-1.0 h. A high accumulation of curcumol was found in the small intestine, colon, liver, and kidney. Moreover, high protein binding rates ranging from 85.6% to 93.4% of curcumol were observed in rat plasma. Conclusion: This study characterized the pharmacokinetics, tissue distribution, and protein binding rates of curcumol in rats for the first time, which can provide a solid foundation for research into the mechanisms of curcumol's biological function and clinical application.
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Chronic liver disease (CLD) is an extremely common clinical condition accompanied by sustained inflammatory response leading to tissue damage. Transforming growth factor-ß1 (TGF-ß1) is known as a master immune regulator in CLDs, but the association between TGF-ß1 polymorphisms and CLD risk is controversial and inconclusive, and the genetic dominance of CLDs remains unknown. In this study, the relationship between TGF-ß1 polymorphisms and CLD susceptibility is systematically analyzed based on 35 eligible studies. Individuals with the TGF-ß1-509 allele (TT or CT) or codon 10 allele (Pro/Pro) show an increased risk of CLDs. Subgroup analyses indicate TGF-ß1-509C/T has a significant correlation with cirrhosis and chronic hepatitis C, codon 10 is associated with chronic hepatitis B occurrence, and codon 25 exhibits a relationship with autoimmune hepatitis risk. Missense mutations in G29E, A105S, D191N, and F321L of TGF-ß1 are the genetic factors of HCC susceptibility. Furthermore, the TGF-ß1 gene expression is significantly elevated in CLD patients, and the TGF-ß1 codon 263 is located close to the region where the TGF-ß1 dimerization interacts, indicating the TGF-ß1 codon 263 variant may affect the secretion of TGF-ß1 by altering its dimerization. Together, our findings provide new insights into the immune regulator gene TGF-ß1 polymorphisms as susceptibility factors for CLD occurrence and regulators for TGF-ß1 expression, which have implications for the regulation of immune factors during CLD development.
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Carcinoma Hepatocelular , Hepatitis Autoinmune , Neoplasias Hepáticas , Humanos , Factor de Crecimiento Transformador beta1/genética , Neoplasias Hepáticas/genética , Polimorfismo GenéticoRESUMEN
Pyrroloquinoline quinone (PQQ) is a powerful antioxidant coenzyme existing in diet, benefiting growth, development, cognition function, and the repair of damaged organs. However, a method for detecting PQQ in vivo was rarely described, limiting the research on the bioanalysis and metabolic properties of PQQ. In this study, a novel, simple, and efficient ultra-high performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to quantify the concentration of PQQ in rat plasma. Detection through mass spectrometry was operated by multiple reaction monitoring (MRM) in negative electrospray ionization mode with ion transitions m/z 328.99â197.05 for PQQ and m/z 280.04â195.04 for the internal standard. The calibration curves were linear up to 10,000 ng/mL, with a lower limit of quantitation of 10 ng/mL. Inter-run and intra-run precision ranged from 1.79% to 10.73% and accuracy ranged from -7.73% to 7.30%. The method was successfully applied to a toxicokinetic study in Sprague-Dawley rats after the oral administration of PQQ disodium salt at doses of 250 mg/kg, 500 mg/kg, and 1000 mg/kg. The toxicokinetic parameters were subsequently analyzed, which may provide valuable references for the toxicokinetic properties and safety evaluation of PQQ.
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Cofactor PQQ , Espectrometría de Masas en Tándem , Ratas , Animales , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas en Tándem/métodos , Cromatografía Liquida , Toxicocinética , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Ventilator-associated pneumonia (VAP) is one of the most common intensive care unit (ICU)-acquired infections, which can cause multiple adverse events. Due to bacterial mutation and overuse of antimicrobial drugs, multidrug-resistant organisms (MDRO) has become one of the major causes of postoperative VAP infections in cardiac patients. Therefore, this study aims to explore the risk factors for VAP with MDRO following cardiac surgery in adults. METHODS: The clinical data of adult VAP patients following cardiac surgery in the hospital from Jan 2017 to May 2021 were analyzed retrospectively, and the patients were divided into the MDRO VAP group and the non-MDRO VAP group. Univariable and multivariable logistic regression analyses were performed on risk factors in patients with MDRO VAP. The species and drug sensitivity of pathogens isolated from the VAP patients were also analyzed. RESULTS: A total of 61 VAP cases were involved in this study, with 34 cases in the MDRO VAP group (55.7%) and 27 cases in the non-MDRO VAP group (44.3%). Multivariable logistic regression analysis showed that independent risk factors for MDRO VAP included preoperative creatinine clearance rate (CCR) ≥ 86.6ml, intraoperative cardiopulmonary bypass (CPB) time ≥ 151 min, postoperative acute kidney injury (AKI) and nasal feeding. Gram-negative bacilli were the main pathogens in VAP patients (n = 54, 90.0%), with the highest rate of Acinetobacter baumannii (n = 24, 40.0%). Additionally, patients with MDRO VAP had a significantly longer postoperative intensive care unit (ICU) duration and higher hospitalization costs than non-MDRO VAP patients, but there was no notable difference in the 28-day mortality rate between the two groups. CONCLUSION: Based on implementing measures to prevent VAP, clinicians should pay more attention to patients with kidney disease, longer intraoperative CPB time, and postoperative nasal feeding to avoid MDRO infections.
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Procedimientos Quirúrgicos Cardíacos , Neumonía Asociada al Ventilador , Adulto , Humanos , Neumonía Asociada al Ventilador/diagnóstico , Neumonía Asociada al Ventilador/epidemiología , Neumonía Asociada al Ventilador/etiología , Estudios Retrospectivos , Unidades de Cuidados Intensivos , Factores de Riesgo , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Antibacterianos/uso terapéuticoRESUMEN
Objectives: Medial patellofemoral ligament (MPFL) reconstruction is an important surgical therapy for recurrent patellar dislocation. However, few studies have focused on exercise therapy after MPFL reconstruction. Therefore, the first purpose was to compare the active and traditional postoperative exercise therapies on the recovery of knee joint function and reduction of muscle atrophy after MPFL reconstruction, and the second purpose was to compare the active and traditional postoperative exercise therapies on the patellar stability after MPFL reconstruction. Methods: The cases of 31 patients with recurrent patellar dislocation treated with patella double semi-tunnel anatomical MPFL reconstruction from February 2016 and February 2019 were retrospectively reviewed. The clinical outcomes, including the patellar tilt angle (PTA), lateral patellofemoral angle (LPFA), thigh circumference reduction, Kujala score, and Lysholm score, were compared between two groups (i.e., active exercise and traditional exercise groups) preoperatively, 3 months postoperatively, 6 months postoperatively, 12 months postoperatively, and 24 months postoperatively. Results: The Kujala score was significantly higher in the active exercise group than traditional exercise group 3 months postoperatively (80.06 vs. 74.80, P < 0.01), 6 months postoperatively (89.19 vs. 82.07, P < 0.01), 12 months postoperatively (91.43 vs. 86.60, P < 0.01), and 24 months postoperatively (92.50 vs. 90.27, P = 0.02). Similarly, there was a higher Lysholm score in the active exercise group compared with traditional exercise group 3 months postoperatively (81.25 vs. 76.53, P < 0.01), 6 months postoperatively (89.81 vs. 84.80, P < 0.01), 12 months postoperatively (93.25 vs. 88.40, P < 0.01), and 24 months postoperatively (93.69 vs. 90.67, P < 0.01). Significantly lower thigh circumference reduction was reported in the active exercise group compared with that in the traditional exercise group 3 months postoperatively (1.90 ± 0.57 vs. 2.45 ± 0.45, P < 0.01) and 6 months postoperatively (1.50 ± 0.31 vs. 1.83 ± 0.32, P < 0.01). No statistical difference was observed between the two groups in terms of PTA (P > 0.05) or LPFA postoperatively (P > 0.05). Conclusions: Our results suggested that active exercise therapy might benefit the early recovery of knee joint function and reduction of muscle atrophy in patients with recurrent patellar dislocation after MPFL reconstruction.
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Selective glucocorticoid receptor modulators (SGRMs), which can dissociate the transactivation from the transrepression of the glucocorticoid receptor (GR), are regarded as very promising therapeutics for inflammatory and autoimmune diseases. We previously discovered a SGRM HP-19 based on the passive antagonistic conformation of GR and bioassays. In this study, we further analyzed the dynamic changes of the passive antagonistic state upon the binding of HP-19 and designed and synthesized 62 N-acyl-6-sulfonamide-tetrahydroquinoline derivatives by structural optimization of HP-19. Therein, compound B53 exhibits the best transrepression activity (IC50 NF-κB = 0.009 ± 0.001 µM) comparable with dexamethasone (IC50 NF-κB = 0.005 ± 0.001 µM) and no transactivation activity. B53 can efficiently reduce the expression of inflammatory factors IL-6, IL-1ß, TNF-α, and so on and makes a milder adverse effect and is highly specific to GR. Furthermore, B53 is able to significantly relieve dermatitis on a mouse model via oral drug intervention.