RESUMEN
Alzheimer's disease (AD, also known as dementia) has become a serious global health problem along with population aging, and neuroinflammation is the underlying cause of cognitive impairment in the brain. Nowadays, the development of multitarget anti-AD drugs is considered to be one effective approach. Imidazolylacetophenone oxime ethers or esters (IOEs) were multifunctional agents with neuroinflammation inhibition, metal chelation, antioxidant and neuroprotection properties against Alzheimer's disease. In this study, IOEs derivatives 1-8 were obtained by structural modifications of the oxime and imidazole groups, and the SARs showed that (Z)-oxime ether (derivative 2) had stronger anti-neuroinflammatory and neuroprotective ability than (E)-congener. Then, IOEs derivatives 9-30 were synthesized based on target-directed ligands and activity-based groups hybridization strategy. In vitro anti-AD activity screening revealed that some derivatives exhibited potentially multifunctional effects, among which derivative 28 exhibited the strongest inhibitory activity on NO production with EC50 value of 0.49 µM, and had neuroprotective effects on 6-OHDA-induced cell damage and RSL3-induced ferroptosis. The anti-neuroinflammatory mechanism showed that 28 could inhibit the release of pro-inflammatory factors PGE2 and TNF-α, down-regulate the expression of iNOS and COX-2 proteins, and promote the polarization of BV-2 cells from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. In addition, 28 can dose-dependently inhibit acetylcholinesterase (AChE) and Aß42 aggregation. Moreover, the selected nuclide [18F]-labeled 28 was synthesized to explore its biodistribution by micro-PET/CT, of which 28 can penetrate the blood-brain barrier (BBB). These results shed light on the potential of 28 as a new multifunctional candidate for AD treatment.
Asunto(s)
Acetofenonas , Enfermedad de Alzheimer , Diseño de Fármacos , Imidazoles , Fármacos Neuroprotectores , Oximas , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Oximas/química , Oximas/farmacología , Oximas/síntesis química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/síntesis química , Animales , Relación Estructura-Actividad , Imidazoles/farmacología , Imidazoles/química , Imidazoles/síntesis química , Acetofenonas/química , Acetofenonas/farmacología , Acetofenonas/síntesis química , Estructura Molecular , Humanos , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Acetilcolinesterasa/metabolismo , Relación Dosis-Respuesta a Droga , Ratas , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/químicaRESUMEN
BACKGROUND: Depression and anxiety are common in patients with decompensated hepatitis B virus (HBV) cirrhosis. This study aimed to evaluate the relieving effects of the jiao-tune of 5-element music on negative emotions in patients with decompensated HBV cirrhosis. METHODS: The patients were randomly allocated into the control group (standard nursing care) and the jiao-tune group (standard nursing care plus a 2-month course of music therapy with the jiao-tune of 5-element music). The negative emotions of patients were assessed before intervention treatment and at the end of the 2-month follow-up using the Zung Self-Rating Depression Scale (SDS) and Zung Self-Rating Anxiety Scale (SAS). RESULTS: The analysis included 209 patients, with 102 in the control group and 107 in the jiao-tune group, all of whom returned their completed questionnaires. Baseline clinical characteristics and length of hospital stay were comparable between 2 groups. Before intervention treatment, there were no significant differences in SAS score (55.78â ±â 5.64 vs 56.47â ±â 3.28) and SDS score (65.13â ±â 3.12 vs 64.48â ±â 4.47) between the jiao-tune group and control group. After 2-month follow-up, the jiao-tune group had a significantly lower SAS score (53.17â ±â 5.61) and SDS score (61.28â ±â 1.52) compared with the control group (55.49â ±â 3.37 and 63.08â ±â 2.76), there were significant differences between 2 groups (Pâ <â .001). CONCLUSIONS: The jiao-tune of 5-element music can relieve the negative emotions in patients with decompensated HBV cirrhosis.
Asunto(s)
Depresión , Cirrosis Hepática , Musicoterapia , Humanos , Musicoterapia/métodos , Masculino , Femenino , Persona de Mediana Edad , Cirrosis Hepática/psicología , Cirrosis Hepática/terapia , Cirrosis Hepática/complicaciones , Depresión/terapia , Depresión/etiología , Adulto , Ansiedad/etiología , Ansiedad/terapia , Emociones , Hepatitis B/psicología , Hepatitis B/tratamiento farmacológicoRESUMEN
As one of the main pathmechanisms of Alzheimer's disease (AD), amyloid-ß (Aß) is widely considered to be the prime target for the development of AD therapy. Recently, imidazolylacetophenone oxime ethers or esters (IOEs) have shown neuroprotective effects against neuronal cells damage, suggesting their potential use in the prevention and treatment of AD. Thirty IOEs compounds from our lab in-house library were constructed and screened for the inhibitory effects on Aß42-induced cytotoxicity. Among them, TJ1, as a new IOEs hit, preliminarily showed the effect on inhibiting Aß42-induced cytotoxicity. Furthermore, the inhibitory effects of TJ1 on Aß42 aggregation were tested by ThT assays and TEM. The neuroprotective effects of TJ1 were evaluated in Aß42-stimulated SH-SY5Y cells, LPS-stimulated BV-2 cells, and H2O2- and RSL3-stimulated PC12 cells. The cognitive improvement of TJ1 was assessed in 5xFAD (C57BL/6J) transgenic mouse. These results showed that TJ1 had strong neuroprotective effects and high blood-brain barrier (BBB) permeability without obvious cytotoxicity. TJ1 impeded the self-accumulation process of Aß42 by acting on Aß oligomerization and fibrilization. Besides, TJ1 reversed Aß-, H2O2- and RSL3-induced neuronal cell damage and decreased neuroinflammation. In 5xFAD mice, TJ1 improved cognitive impairment, increased GSH level, reduced the level of Aß42 and Aß plaques, and attenuated the glia reactivation and inflammatory response in the brain,. Taken together, our results demonstrate that TJ1 improves cognitive impairments as a new neuroprotective candidate via targeting amyloidogenesis, which suggests the potential of TJ1 as a treatment for AD.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Barrera Hematoencefálica , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Ratones Transgénicos , Fármacos Neuroprotectores , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Humanos , Ratones , Ratas , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Fragmentos de Péptidos/metabolismo , Células PC12 , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Oximas/farmacología , Oximas/uso terapéutico , Línea Celular Tumoral , MasculinoRESUMEN
Intensive agricultural activities could cause lead (Pb) bioaccumulation, threatening human health. Although the enzyme-induced carbonate precipitation (EICP) technology has been applied to tackle the aforesaid problem, the urease may denature or even lose its activity when subjected to a significant Pb2+ toxicity effect. To this end, the nano-hydroxyapatite (nHAP)-assisted EICP was proposed to reduce the mobility of Pb2+. Results indicated that a below 30% immobilization efficiency at 60 mM Pb2+ was attained under EICP. nHAP adsorbed the majority of Pb2+, preventing Pb2+ attachment to urease. Further, hydroxylphosphohedyphane or hydroxylpyromorphite was formed at 60 mM Pb2+, followed by the formation of cerussite, allowing hydroxylphosphohedyphane or hydroxylpyromorphite to be wrapped by cerussite. By contrast, carbonate-bearing hydroxylpyromorphite of higher stability (Pb10(PO4)6CO3) was developed at 20 mM Pb2+ as CO3 2- substituted the hydroxyl group in hydroxylpyromorphite. Moreover, nHAP helped EICP to form nucleated minerals. As a result, the EICP-nHAP technology raised the immobilization efficiency at 60 mM Pb2+ up to 70%. The findings highlight the potential of applying the EICP-nHAP technology to Pb-containing water bodies remediation.
RESUMEN
BACKGROUND: Fusarium graminearum is a devastating fungal pathogen that poses a significant threat to global wheat production and quality. Control of this toxin-producing pathogen remains a major challenge. This study aimed to isolate strains with antagonistic activity against F. graminearum and at the same time to analyze the synthesis of deoxynivalenol (DON), in order to provide a new basis for the biological control of FHB. RESULTS: Total of 69 microorganisms were isolated from the soil of a wheat-corn crop rotation field, and an antagonistic bacterial strain F12 was identified as Burkholderia pyrrocinia by molecular biology and carbon source utilization. F. graminearum control by strain F12 showed excellent biological activities under laboratory conditions (95.8%) and field testing (63.09%). Meanwhile, the DON content of field-treated wheat grains was detected the results showed that F12 have significantly inhibited of DON, which was further verified by qPCR that F12 produces secondary metabolites that inhibit the expression of DON and pigment-related genes. In addition, the sterile fermentation broth of F12 not only inhibited mycelial growth and spore germination, but also prevented mycelia from producing spores. CONCLUSION: In this study B. pyrrocinia was reported to have good control of FHB and inhibition of DON synthesis. This novel B. pyrrocinia F12 is a promising biological inoculant, providing possibilities for controlling FHB, and a theoretical basis for the development of potential biocontrol agents and biofertilizers for agricultural use. © 2024 Society of Chemical Industry.
RESUMEN
OBJECTIVE: To explore the effects of positional care combined with doula delivery during childbirth in the correction of abnormal fetal position. METHODS: In this retrospective study, a total 108 pregnant women with abnormal fetal orientation were included from February 2018 to February 2021 in the Jinan City People's Hospital. Among them, 54 patients who received positional care combined with doula delivery were included in the intervention group (IG), while the other 54 patients who received routine nursing were included in the control group (CG). The data of the fetal orientation correction, delivery method and the pain score of puerpera of two groups were collected. The length of delivery, delivery fear score, the degree of neonatal asphyxia and nursing satisfaction were observed as the secondary outcomes. RESULTS: Compared with the CG, puerpera in the IG had more occipital anterior position, less occipital transverse and posterior position, higher eutocia rate, lower pain and fear scores and shorter length of delivery; the Apgar score and nursing satisfaction were higher in the IG (all P<0.05). CONCLUSION: Positional care combined with doula delivery can effectively correct abnormal fetal orientation, improve the rate of eutocia, reduce puerpera's pain and fear, shorten the length of delivery, and improve the quality of neonatal outcome and patients' satisfaction.
RESUMEN
Liver Stagnation and Spleen Deficiency (LSSD) is a Chinese Medicine (CM) pattern commonly observed in gastrointestinal (GI) diseases, yet its biological nature remains unknown. This limits the global use of CM medications for treating GI diseases. Recent studies emphasize the role of gut microbiota and their metabolites in the pathogenesis and treatment of LSSD-associated GI diseases. There is increasing evidence supporting that an altered gut microbiome in LSSD patients or animals contributes to GI and extra-intestinal symptoms and affects the effectiveness of CM therapies. The gut microbiota is considered to be an essential component of the biological basis of LSSD. This study aims to provide an overview of existing research findings and gaps for the pathophysiological study of LSSD from the gut microbiota perspective in order to understand the relationship between the CM pattern and disease progression and to optimize CM-based diagnosis, prevention, and therapy.
Asunto(s)
Enfermedades Gastrointestinales , Microbioma Gastrointestinal , Animales , Humanos , Medicina Tradicional ChinaRESUMEN
Obesity, a global health challenge, is a major risk factor for multiple life-threatening diseases, including diabetes, fatty liver, and cancer. There is an ongoing need to identify safe and tolerable therapeutics for obesity management. Herein, we show that treatment with artesunate, an artemisinin derivative approved by the FDA for the treatment of severe malaria, effectively reduces body weight and improves metabolic profiles in preclinical models of obesity, including male mice with overnutrition-induced obesity and male cynomolgus macaques with spontaneous obesity, without inducing nausea and malaise. Artesunate promotes weight loss and reduces food intake in obese mice and cynomolgus macaques by increasing circulating levels of Growth Differentiation Factor 15 (GDF15), an appetite-regulating hormone with a brainstem-restricted receptor, the GDNF family receptor α-like (GFRAL). Mechanistically, artesunate induces the expression of GDF15 in multiple organs, especially the liver, in mice through a C/EBP homologous protein (CHOP)-directed integrated stress response. Inhibition of GDF15/GFRAL signalling by genetic ablation of GFRAL or tissue-specific knockdown of GDF15 abrogates the anti-obesity effect of artesunate in mice with diet-induced obesity, suggesting that artesunate controls bodyweight and appetite in a GDF15/GFRAL signalling-dependent manner. These data highlight the therapeutic benefits of artesunate in the treatment of obesity and related comorbidities.
Asunto(s)
Factor 15 de Diferenciación de Crecimiento , Obesidad , Ratones , Masculino , Animales , Artesunato/farmacología , Artesunato/uso terapéutico , Factor 15 de Diferenciación de Crecimiento/genética , Factor 15 de Diferenciación de Crecimiento/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Primates , Macaca/metabolismoRESUMEN
Indigo naturalis (IN) is a dried powder derived from plants such as Baphicacanthus cusia (Neeks) Bremek., Polygonum tinctorium Ait. and Isatis indigotica Fork. It has a historical application as a dye in ancient India, Egypt, Africa and China. Over time, it has been introduced to China and Japan for treatment of various ailments including hemoptysis, epistaxis, chest discomfort, and aphtha. Clinical and pre-clinical studies have widely demonstrated its promising effects on autoimmune diseases like psoriasis and Ulcerative colitis (UC). Despite the documented efficacy of IN in UC patients, concerns have been raised on the development of adverse effects with long term consumption, prompting a closer examination of its safety and tolerability in these contexts. This review aims to comprehensively assess the efficacy of IN in both clinical and pre-clinical settings, with a detailed exploration of the mechanisms of action involved. Additionally, it summarizes the observed potential toxicity of IN in animal and human settings was summarized. This review will deepen our understanding on the beneficial and detrimental effects of IN in UC, providing valuable insights for its future application in patients with this condition.
Asunto(s)
Colitis Ulcerosa , Medicamentos Herbarios Chinos , Psoriasis , Animales , Humanos , Carmin de Índigo/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Psoriasis/inducido químicamente , ChinaRESUMEN
OBJECTIVE: Functional constipation (FC) is a common intestinal disease worldwide. Despite the presence of criteria such as Roman IV, there is no standardized diagnosis and treatment algorithm in Hong Kong that combines both Western and Chinese medicine approaches. This study integrates current effective and safe diagnosis and treatment methods for FC and provides a clear and scientific pathway for clinical professionals and patients. METHODS: A systematic search of the PubMed, Cochrane Library, and China National Knowledge Infrastructure databases was performed from their inception to June 30th, 2022, collecting the current evidence about the efficacious integrative management for FC. We organized a meeting of professionals in fields relevant to treatment and management of FC to develop a consensus agreement on clinical pathway process. RESULTS: We developed a clinical pathway for the treatment of FC based on the most recent published guidelines and consultation with experts. This pathway includes a hierarchy of recommendations for every step of the clinical process, including clinical intake, diagnostic examination, recommended labs, diagnostic flowchart, and guidance for selection of therapeutic drugs. CONCLUSION: This pathway establishes clinical standards for the diagnosis and treatment of FC using Chinese medicine and Western medicine; it will help to provide high-quality medical services in Hong Kong for patients with FC. Please cite this article as: Wei DJ, Li HJ, Lyu ZP, Lyu AP, Bian ZX, Zhong LL. A clinical pathway for integrative medicine in the treatment of functional constipation in Hong Kong, China. J Integr Med. 2023; 21(6): 550-560.
Asunto(s)
Medicina Integrativa , Humanos , Hong Kong , Vías Clínicas , China , Estreñimiento/diagnóstico , Estreñimiento/terapiaRESUMEN
The incidence of metabolic syndrome is significantly higher in patients with irritable bowel syndrome (IBS), but the mechanisms involved remain unclear. Gut microbiota is causatively linked with the development of both metabolic dysfunctions and gastrointestinal disorders, thus gut dysbiosis in IBS may contribute to the development of metabolic syndrome. Here, we show that human gut bacterium Ruminococcus gnavus-derived tryptamine and phenethylamine play a pathogenic role in gut dysbiosis-induced insulin resistance in type 2 diabetes (T2D) and IBS. We show levels of R. gnavus, tryptamine, and phenethylamine are positively associated with insulin resistance in T2D patients and IBS patients. Monoassociation of R. gnavus impairs insulin sensitivity and glucose control in germ-free mice. Mechanistically, treatment of R. gnavus-derived metabolites tryptamine and phenethylamine directly impair insulin signaling in major metabolic tissues of healthy mice and monkeys and this effect is mediated by the trace amine-associated receptor 1 (TAAR1)-extracellular signal-regulated kinase (ERK) signaling axis. Our findings suggest a causal role for tryptamine/phenethylamine-producers in the development of insulin resistance, provide molecular mechanisms for the increased prevalence of metabolic syndrome in IBS, and highlight the TAAR1 signaling axis as a potential therapeutic target for the management of metabolic syndrome induced by gut dysbiosis.
Asunto(s)
Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Resistencia a la Insulina , Síndrome del Colon Irritable , Síndrome Metabólico , Humanos , Animales , Ratones , Disbiosis , Fenetilaminas/farmacología , Triptaminas/farmacologíaRESUMEN
A series of novel trienomycin A (TA)-mimetic compounds (5a-p) have been designed, synthesized, and evaluated for their in vitro anti-neuroinflammatory and neuroprotective activities. Among them, compounds 5h, 5n, and 5o exhibits relatively strong NO inhibitory activity in LPS-activated BV-2 cells with the EC50 values of 12.4, 17.3, and 8.9 µM, respectively. Moreover, 5h showed evidently neuroprotective effect against H2O2-induced PC-12 cells without cytotoxicity at 20 µM. Overall, these compounds can provide a better understanding of the structure-activity relationship of TA and furnish research ideas for anti-neuroinflammatory and neuroprotective agents.
Asunto(s)
Peróxido de Hidrógeno , Fármacos Neuroprotectores , Ratas , Animales , Peróxido de Hidrógeno/farmacología , Relación Estructura-Actividad , Células PC12 , Alanina , Fármacos Neuroprotectores/farmacologíaRESUMEN
INTRODUCTION: Hepatocellular carcinoma (HCC) is one of the most common malignant tumours in the world and has a high mortality rate. However, the pathogenesis of HCC remains unclear. This study aimed to investigate the potential biomarkers of HCC. METHODS: ONCOMINE, HCCDB and THE HUMAN PROTEIN ATLAS were used to identify myelin expression factor 2 (MYEF2) as a potential biomarker for HCC. The Cancer Genome Atlas database was used to further validate and analyse the value of MYEF2. Kaplan-Meier Plotter was used for the prognostic analysis. The COX regression model and Kaplan-Meier method were used to investigate the clinical value of MYEF2 in the prognosis of HCC by reviewing the survival status of patients. Fluorescent quantitative polymerase chain reaction (qPCR) and immunohistochemistry were used to detect the expressions of the MYEF2 mRNA and protein in HCC tissues and cell lines. qPCR and Western blotting were used to validate the efficiency of MYEF2 knockout and overexpression in HCC cells. The invasion and migration abilities regulated by MYEF2 were detected by performing transwell and wound healing assays. RESULTS: MYEF2 is significantly upregulated in HCC and is mainly located in the nucleus of HCC cells. MYEF2 expression is significantly associated with the tumour stage, histological grade and TNM stage. High MYEF2 expression is an independent prognostic factor for patients with HCC. Functionally, elevated MYEF2 facilitated cell migration and invasion in vitro. In contrast, decreased MYEF2 inhibited cell migration and invasion. CONCLUSIONS: MYEF2 may be a novel biomarker with potential diagnosis and prognosis values and as a potential therapeutic target for HCC.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteínas del Tejido Nervioso , Proteínas Represoras , Humanos , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/patología , Pronóstico , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismoRESUMEN
Diarrhea-predominant irritable bowel syndrome (IBS-D), a globally prevalent functional gastrointestinal (GI) disorder, is associated with elevated serotonin that increases gut motility. While anecdotal evidence suggests that the gut microbiota contributes to serotonin biosynthesis, mechanistic insights are limited. We determined that the bacterium Ruminococcus gnavus plays a pathogenic role in IBS-D. Monocolonization of germ-free mice with R. gnavus induced IBS-D-like symptoms, including increased GI transit and colonic secretion, by stimulating the production of peripheral serotonin. R. gnavus-mediated catabolism of dietary phenylalanine and tryptophan generated phenethylamine and tryptamine that directly stimulated serotonin biosynthesis in intestinal enterochromaffin cells via a mechanism involving activation of trace amine-associated receptor 1 (TAAR1). This R. gnavus-driven increase in serotonin levels elevated GI transit and colonic secretion but was abrogated upon TAAR1 inhibition. Collectively, our study provides molecular and pathogenetic insights into how gut microbial metabolites derived from dietary essential amino acids affect serotonin-dependent control of gut motility.
Asunto(s)
Síndrome del Colon Irritable , Animales , Ratones , Serotonina/metabolismo , Diarrea/metabolismoRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Angiotensin-converting enzyme 2 (ACE2) is an entry receptor for SARS-CoV-2. The full-length membrane form of ACE2 (memACE2) undergoes ectodomain shedding to generate a shed soluble form (solACE2) that mediates SARS-CoV-2 entry via receptor-mediated endocytosis. Currently, it is not known how the physiological regulation of ACE2 shedding contributes to the etiology of COVID-19 in vivo. The present study identifies Membrane-type 1 Matrix Metalloproteinase (MT1-MMP) as a critical host protease for solACE2-mediated SARS-CoV-2 infection. SARS-CoV-2 infection leads to increased activation of MT1-MMP that is colocalized with ACE2 in human lung epithelium. Mechanistically, MT1-MMP directly cleaves memACE2 at M706-S to release solACE218-706 that binds to the SARS-CoV-2 spike proteins (S), thus facilitating cell entry of SARS-CoV-2. Human solACE218-706 enables SARS-CoV-2 infection in both non-permissive cells and naturally insusceptible C57BL/6 mice. Inhibition of MT1-MMP activities suppresses solACE2-directed entry of SARS-CoV-2 in human organoids and aged mice. Both solACE2 and circulating MT1-MMP are positively correlated in plasma of aged mice and humans. Our findings provide in vivo evidence demonstrating the contribution of ACE2 shedding to the etiology of COVID-19.
Asunto(s)
Enzima Convertidora de Angiotensina 2 , COVID-19 , Interacciones Huésped-Patógeno , Metaloproteinasa 14 de la Matriz , SARS-CoV-2 , Animales , Humanos , Ratones , Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/metabolismo , COVID-19/virología , Ratones Endogámicos C57BL , Peptidil-Dipeptidasa A/metabolismo , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismoRESUMEN
INTRODUCTION: Sepsis is a primary cause of death in critically ill patients and is characterized by multiple organ dysfunction, including sepsis-induced acute kidney injury (AKI), which contributes to high mortality in sepsis. However, its pathophysiological mechanisms remain unclear. The kidney has one of the richest and most diversified endothelial cell populations in the body. This study was designed to investigate the effects of endothelial dysfunction in sepsis-induced AKI and explore possible intervention measures to offer new insight into the pathogenesis and treatment of sepsis-induced AKI. METHODS: The circulating levels of endothelial adhesion molecules were detected in patients with sepsis and healthy controls to observe the role of endothelial damage in sepsis and sepsis-induced AKI. A murine sepsis model induced by cecal ligation and perforation was pretreated with a phosphoinositide 3-kinase gamma (PI3Kγ) inhibitor (CZC24832), and survival, kidney damage, and renal endothelial injury were assessed by pathological examination, immunohistochemistry, quantitative polymerase chain reaction, and Western blotting. Lipopolysaccharides and CZC24832 were administered to human umbilical vein endothelial cells in vitro, and endothelial cell function and the expression of adhesion molecules were evaluated. RESULTS: Endothelial damage was more serious in sepsis-induced AKI than that in non-AKI, and the inhibition of PI3Kγ alleviates renal endothelial injury in a murine sepsis model, protecting endothelial cell function and repairing endothelial cell injury through the Akt signaling pathway. CONCLUSIONS: In this study, endothelial cell dysfunction plays an important role in sepsis-induced AKI, and the inhibition of PI3Kγ alleviates endothelial cell injury in sepsis-induced AKI through the PI3Kγ/Akt pathway, providing novel targets for treating sepsis and related kidney injury.
Asunto(s)
Lesión Renal Aguda , Sepsis , Humanos , Ratones , Animales , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasa , Lesión Renal Aguda/patología , Sepsis/complicaciones , Sepsis/patología , Transducción de Señal , Riñón/patología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patologíaRESUMEN
BACKGROUND: Intradural anesthesia caused by anesthetic drug leakage during percutaneous vertebroplasty (PVP) has rarely been reported. We here report a 71-year-old woman who suffered this rare and life-threatening complication during PVP. CASE SUMMARY: A 71-year-old woman, who suffered from 2 wk of severe back pain with a visual analog score of 8, came to our outpatient clinic. She was later diagnosed with a newly compressed L1 fracture and was then admitted in our department. PVP was initially attempted again under local anesthesia. However, serendipitous intradural anesthesia leading to total spinal anesthesia happened. Fortunately, after successful resuscitation of the patient, PVP was safely and smoothly performed. Great pain relief was achieved postoperatively, and she was safely discharged on postoperative day 4. The patient recovered normally at 3-mo follow-up. CONCLUSION: Total spinal anesthesia secondary to PVP by anesthetic drug leakage rarely occurs. In cases of inadvertent wrong puncture leading to drug leakage when performing it under local anesthesia, surgeons should be highly vigilant during the whole procedure. Electrocardiogram monitoring, oxygen inhalation, intravenous cannula set prior to surgery, regular checking of motor activity and a meticulous imaging monitoring with slower pushing of anesthetic drugs, etc. should be highly recommended.
RESUMEN
BACKGROUND: Liver failure (LF) is a life-threatening clinical syndrome characterized by intense systemic inflammation and organ failure(s), leading to a high mortality rate. The pathogenesis of LF is multifactorial, immune response, and gut bacterial translocation are thought to be major contributing factors. Mucosal-associated invariant T (MAIT) cells play a critical role in immune response and gut bacterial translocation. We aimed to investigate changes of the MAIT cell ratio in patients with LF and to explore the predictive value for long-term prognosis in patients with LF. MATERIAL AND METHOD: We recruited 75 patients with LF from Nantong Third People's Hospital, isolated peripheral blood mononuclear cells, and detected the proportion of circulating MAIT cells by flow cytometry. Statistical analyses were performed using the GraphPad Prism software. RESULTS: Our data showed that the proportion of MAIT cells alterations was independent of the cause of viral infection in patients with LF. Kaplan-Meier survival analysis showed that LF patients with low level of MAIT cells had poor long-term prognosis. The area under the receiver operating characteristic curve of the MAIT cell proportion was larger than that of the Model for End-Stage Liver Disease (MELD) score. More importantly, the combination of MAIT cell proportion and MELD score had a better effect in predicting long-term prognosis of LF patients than any single index (AUC = 0.91, 95% CI:0.84-0.97), and multivariate logistic regression analysis indicated that the circulating MAIT cell proportion was an independent risk factor for LF. CONCLUSION: The proportion of MAIT cells in PBMC is an outstanding predictor for the long-term prognosis in patients with LF.