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RATIONALE AND OBJECTIVES: The tumor-tropic properties of mesenchymal stem cells (MSCs) enable them to serve as appealing cellular vehicles for delivering therapeutic agents to treat malignant glioma. However, the exact engraftment status of MSCs in glioma via different administration routes remains unclear due to the lack of quantitative analysis. This study aimed to quantify the engraftment of MSCs in glioma after administration via different routes using non-invasive dual-modality magnetic resonance imaging (MRI) and bioluminescence imaging (BLI). MATERIALS AND METHODS: MSCs were transduced with a lentivirus overexpressing ferritin heavy chain (FTH) and firefly luciferase (FLUC) reporter genes to yield FTH- and FLUC-overexpressed MSCs (FTH-FLUC-MSCs). Wistar rats bearing intracranial C6 glioma received peritumoral, intratumoral, intra-arterial, and intravenous injection of FTH-FLUC-MSCs, respectively. MRI and BLI were performed to monitor FTH-FLUC-MSCs in vivo. RESULTS: FTH-FLUC-MSCs administered via peritumoral, intratumoral and intra-arterial routes migrated specially toward the intracranial glioma in vivo, as detected by MRI and BLI. As quantified by the BLI signal intensity, the percentages of FTH-FLUC-MSCs in the glioma were significantly higher with peritumoral injection (61%) and intratumoral injection (71%) compared to intra-arterial injection (30%) and intravenous injection (0%). Peritumorally injected FTH-FLUC-MSCs showed a gradual decline, with approximately 6% of FTH-FLUC-MSCs still retained within the tumor up to 11 days after injection. Meanwhile, the number of FTH-FLUC-MSCs injected via other routes dropped quickly, and none were detectable by day 11 post-injection. CONCLUSION: Peritumoral delivery of FTH-FLUC-MSCs offers robust engraftment and could be used as the optimal delivery route for treating malignant glioma.
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Atherosclerosis (AS) is a common cause of coronary heart disease and stroke. The delivery of exogenous H2S and in situ production of O2 within atherosclerotic plaques can help suppress inflammatory cell infiltration and alleviate disease progression. However, the uncontrolled release of gas donors hinders achieving effective drug concentrations and causes toxic effects. Herein, diallyl trisulfide (DATS)-loaded metal-organic cage (MOC)-68-doped MnO2 nanoparticles are developed as a microenvironment-responsive nanodrug with the capacity for the in situ co-delivery of H2S and O2 to inflammatory cells within plaques. This nanomedicine exhibited excellent monodispersity and stability and protected DATS from degradation in the circulation. In vitro studies showed that the nanomedicine reduced macrophage polarization toward an inflammatory phenotype and inhibited the formation of foam cells, while suppressing the expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and interleukin-1ß. In a mouse model of ApoE-/- genotype, the nanomedicine reduces the plaque burden, inflammatory infiltration, and hypoxic conditions within the plaques. Furthermore, the treatment process and therapeutic effects can be monitored by magnetic resonance image (MRI), in real time upon Mn2+ release from the acidic- and H2O2- microenvironment-responsive MnO2 nanoparticles. The DATS-loaded MOC-68-doped MnO2-based nanodrug holds great promise as a novel theranostic platform for AS.
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AIM: To investigate the trajectory patterns and influencing factors of supportive care needs in stroke patients. DESIGN: A longitudinal study. METHODS: In total, 207 stroke patients who received treatment at the Department of Neurology in a hospital in Xuzhou between July 2022 and July 2023 were recruited using convenience sampling. Questionnaires including supportive care needs, hospital anxiety and depression scale, and the Barthel index were investigated at baseline and at 1, 3, and 6 months. A latent class growth model was applied to identify the supportive care needs trajectories. Multiple logistic regression was used to determine the predictors for membership. This study adheres to STROBE reporting guidelines. RESULTS: Three patterns of supportive care needs trajectories were identified: A high needs slow decline group (20.8%), a medium needs stable group (56.5%) and a medium needs rapid decline group (22.7%). Based on further analysis, the findings indicated that age, education level, monthly income, comorbidity, activities of daily living, anxiety and depression were associated with the trajectory categories of supportive care needs with stroke patients. CONCLUSION: This study demonstrates heterogeneity in changes in supportive care needs among stroke patients. Healthcare providers need to consider these different categories of needs and develop individualized care measures based on the characteristics of different patients. IMPACT: Healthcare providers should be aware of the fluctuations in care needs of stroke patients at various stages. Additionally, the study aimed to identify patients' specific needs based on their circumstances, monitor the rehabilitation process and establish a more personalized and optimized care plan through multidisciplinary collaboration. The ultimate goal was to alleviate symptomatic distress and address the long-term care needs of patients. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.
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Taking the green credit policy in 2012 as a quasi-natural experiment, this paper uses the difference-in-differences method to explore the impact of green credit policy on enterprises' financial asset allocation and the moderating effect of government subsidy. We find that green credit policy significantly promotes the financial asset allocation of heavy-polluting enterprises, which is mainly reflected in short-term liquid financial investment, thus supporting the precautionary motivation of holding financial assets. The mechanism analysis shows that green credit policy promotes the financial asset allocation of heavy-polluting enterprises by reducing the scale of debt financing and increasing the financing cost. Government subsidy can significantly weaken the promoting effect of green credit policy on enterprises' financial asset allocation, and there is heterogeneity due to the regional environmental regulation intensity and financial development level. Further analysis shows that the negative moderating effect of government subsidy on green credit policy and enterprises' financial asset allocation significantly promotes the "shifting form virtual to real" of heavy polluting enterprises by reducing financial asset allocation. This paper discusses the impact of green credit policy on financial asset allocation of heavy-polluting enterprises in China and further clarifies the significant role of government subsidy in the process, so as to provide suggestions for government to control the "shifting from real to virtual" of enterprises. The results also provide an important reference for countries, especially developing countries, to implement green credit policy and government subsidy to achieve sustainable economic development.
Subject(s)
Economic Development , Government , China , Policy , Financing, GovernmentABSTRACT
PURPOSE: Zinc oxide nanoparticles (ZnO NPs) are widely used in sunscreen, cosmetics, and topical drugs. Most previous studies have confirmed the safety of ZnO NPs applied to normal skin; however, little is known about the safety and potential toxicity of ZnO NPs applied to inflamed skin. This study aimed to evaluate the exposure risk of ZnO NPs in the treatment of inflammatory skin diseases. METHODS: Normal human and tumor necrosis factor-α (TNF-α)-induced inflammatory keratinocytes were incubated with ZnO NPs to assess their toxic effects on cell viability and autophagy signaling pathway. Tandem mass tag (TMT)-based proteomics analysis was used to identify differentially expressed proteins following incubation of inflammatory keratinocytes with ZnO NPs. Protein expression was assessed by Western blot, and double fluorescent labeling and siRNA-knockdown further elucidated the role of the TRIM16-NRF2-p62 pathway in mediating the effects of ZnO NP. RESULTS: In TNF-α-induced inflammatory keratinocytes, ZnO NPs activated cytoprotective autophagy and mediated p62-related autophagic flux block, thereby reducing the viability of inflammatory keratinocytes. Additionally, TRIM16-NRF2 was essential in ZnO NP-mediated autophagy flux block and cell viability reduction in inflammatory keratinocytes. Inhibition of the TRIM16-NRF2 pathway reduced p62 levels, alleviated autophagy flux blockade, and slightly restored the viability of inflammatory keratinocytes. CONCLUSION: ZnO NPs activated protective cell autophagy. Blockade of autophagy flux mediated by the TRIM16-NRF2-p62 pathway led to decreased cell viability. This study provided a deeper understanding of the toxicity mechanism of ZnO NPs in inflammatory keratinocytes.
Subject(s)
Nanoparticles , Zinc Oxide , Humans , Zinc Oxide/toxicity , Oxidative Stress , Reactive Oxygen Species/metabolism , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Tumor Necrosis Factor-alpha/metabolism , Cell Survival , Keratinocytes , Nanoparticles/toxicity , Autophagy , Tripartite Motif Proteins/metabolism , Tripartite Motif Proteins/pharmacology , Ubiquitin-Protein Ligases/metabolismABSTRACT
BACKGROUND: Due to the chronic progressive disease characteristics of primary biliary cholangitis (PBC), patients with advanced PBC should not be ignored. Most prognostic score studies have focused on early stage PBC. AIM: To compare the prognostic value of various risk scores in advanced PBC to help PBC patients obtain more monitoring and assessment. METHODS: This study considered patients diagnosed with PBC during hospitalization between 2015 and 2021. The clinical stage was primarily middle and late, and patients usually took ursodeoxycholic acid (UDCA) after diagnosis. The discriminatory performance of the scores was assessed with concordance statistics at baseline and after 1 year of UDCA treatment. Telephone follow-up was conducted to analyze the course and disease-associated outcomes. The follow-up deadline was December 31, 2021. We compared the risk score indexes between those patients who reached a composite end point of death or liver transplantation (LT) and those who remained alive at the deadline. The combined performance of prognostic scores in estimating the risk of death or LT after 1 year of UDCA treatment was assessed using Cox regression analyses. Predictive accuracy was evaluated by comparing predicted and actual survival through Kaplan-Meier analyses. RESULTS: We included 397 patients who were first diagnosed with PBC during hospitalization and received UDCA treatment; most disease stages were advanced. After an average of 6.4 ± 1.4 years of follow-up, 82 patients had died, and 4 patients had undergone LT. After receiving UDCA treatment for 1 year, the score with the best discrimination performance was the Mayo, with a concordance statistic of 0.740 (95% confidence interval: 0.690-0.791). The albumin-bilirubin, GLOBE, and Mayo scores tended to overestimate transplant-free survival. Comparing 7 years of calibration results showed that the Mayo score was the best model. CONCLUSION: The Mayo, GLOBE, UK-PBC, and ALBI scores demonstrated comparable discriminating performance for advanced stage PBC. The Mayo score showed optimal discriminatory performance and excellent predictive accuracy.
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The locus coeruleus (LC) is the site where tau accumulation is preferentially observed pathologically in Alzheimer's disease (AD) patients, but the changes in gray matter co-alteration patterns between the LC and the whole brain in the predementia phase of AD remain unclear. In this study, we estimated and compared the gray matter volume of the LC and its structural covariance (SC) with the whole brain among 161 normal healthy controls (HCs), 99 individuals with significant memory concern (SMC) and 131 patients with mild cognitive impairment (MCI). We found that SC decreased in MCI groups, which mainly involved the salience network and default mode network. These results imply that seeding from LC, the gray matter network disruption and disconnection appears early in the MCI group. The altered SC network seeding from the LC can serve as an imaging biomarker for discriminating the patients in the potential predementia phase of AD from the normal subjects.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Humans , Locus Coeruleus/diagnostic imaging , Magnetic Resonance Imaging , Brain , Cognitive Dysfunction/diagnostic imaging , Gray Matter/diagnostic imaging , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/psychologyABSTRACT
Parabacteroides distasonis (P. distasonis) plays an important role in human health, including diabetes, colorectal cancer and inflammatory bowel disease. Here, we show that P. distasonis is decreased in patients with hepatic fibrosis, and that administration of P. distasonis to male mice improves thioacetamide (TAA)- and methionine and choline-deficient (MCD) diet-induced hepatic fibrosis. Administration of P. distasonis also leads to increased bile salt hydrolase (BSH) activity, inhibition of intestinal farnesoid X receptor (FXR) signaling and decreased taurochenodeoxycholic acid (TCDCA) levels in liver. TCDCA produces toxicity in mouse primary hepatic cells (HSCs) and induces mitochondrial permeability transition (MPT) and Caspase-11 pyroptosis in mice. The decrease of TCDCA by P. distasonis improves activation of HSCs through decreasing MPT-Caspase-11 pyroptosis in hepatocytes. Celastrol, a compound reported to increase P. distasonis abundance in mice, promotes the growth of P. distasonis with concomitant enhancement of bile acid excretion and improvement of hepatic fibrosis in male mice. These data suggest that supplementation of P. distasonis may be a promising means to ameliorate hepatic fibrosis.
Subject(s)
Liver Cirrhosis , Pyroptosis , Humans , Mice , Male , Animals , Liver Cirrhosis/metabolism , Liver/metabolism , Hepatocytes/metabolism , Bile Acids and Salts/metabolism , Caspases/metabolism , Mice, Inbred C57BLABSTRACT
OBJECTIVE: To study the effect and mechanism of the Clostridium metabolite p-Cresol sulfate (PCS) in primary biliary cholangitis (PBC). METHODS: Gas chromatography-mass spectrometry (GC-MS) was used to detect differences in tyrosine, phenylalanine, tryptophan, PCS, and p-Cresyl glucuronide (PCG) between the serum of PBC patients and healthy controls. In vivo experiments, mice were divided into the normal control, PBC group, and PBC tyrosine group. GC-MS was used to detect PCS and PCG. Serum and liver inflammatory factors were compared between groups along with the polarization of liver Kupffer cells. Additionally, PCS was cultured with normal bile duct epithelial cells and Kupffer cells, respectively. PCS-stimulated Kupffer cells were co-cultured with lipopolysaccharide-injured bile duct epithelial cells to detect changes in inflammatory factors. RESULTS: Levels of tyrosine and phenylalanine were increased, but PCS level was reduced in PBC patients, with PCG showing a lower concentration distribution in both groups. PCS in PBC mice was also lower than those in normal control mice. After oral administration of tyrosine feed to PBC mice, PCS increased, liver inflammatory factors were decreased, and anti-inflammatory factors were increased. Furthermore, Kupffer cells in the liver polarized form M1 transitioned to M2. PCS can damage normal bile duct epithelial cells and suppress the immune response of Kupffer cells. But PCS protects bile duct epithelial cells damaged by LPS through Kupffer cells. CONCLUSIONS: PCS produced by Clostridium-metabolized tyrosine reduced PBC inflammation, suggesting that intervention by food, or supplementation with PCS might represent an effective clinical strategy for treating PBC.
Subject(s)
Liver Cirrhosis, Biliary , Mice , Animals , Liver Cirrhosis, Biliary/drug therapy , Liver Cirrhosis, Biliary/metabolism , Kupffer Cells/metabolism , Sulfates , Inflammation , Lipopolysaccharides/pharmacology , Tyrosine , Clostridium , PhenylalanineABSTRACT
OBJECTIVE: The purpose of this systematic review was to assess the suitability of health-related quality of life (HRQOL) questionnaires in patients with primary biliary cholangitis. METHODS: Relevant studies were compiled from a search of five electronic databases. The properties under investigation included the validity of the translated questionnaires, floor and ceiling effects, internal consistency and test-retest reliability. RESULTS: Forty-four studies were included, from which fifteen HRQOL questionnaires were identified. The most frequently used instruments were the PBC-40 (n = 22), the SF-36 (n = 19), the PBC-27 (n = 4), the CLDQ (n = 3) and the NIDDK-QA (n = 2). The remaining instruments were used only once. Twenty-six studies used a translated HRQOL questionnaire, but only six reported or referenced validating the translated questionnaire. CONCLUSIONS: PBC-specific HRQOL questionnaires generally have good psychometric properties. However, many studies have directly applied HRQOL tools without verifying their validity and reliability in PBC patients. There was no clear indication that one HRQOL tool was superior to another, although the PBC-40 is the most well-studied. Thus, more robust psychometric studies are needed to investigate the measurement properties of HRQOL questionnaires.
Subject(s)
Liver Cirrhosis, Biliary , Quality of Life , Humans , Psychometrics , Reproducibility of Results , Surveys and QuestionnairesABSTRACT
Purpose: Zinc oxide nanoparticles (ZnO-NPs) have exerted antimicrobial properties. However, there is insufficient evaluation regarding the in vivo antifungal activity of ZnO-NPs. This study aimed to investigate the efficacy and mechanism of ZnO-NPs in controlling Candida albicans in the invertebrate Galleria mellonella. Methods: Galleria mellonella larvae were injected with different doses of ZnO-NPs to determine their in vivo toxicity. Non-toxic doses of ZnO-NPs were chosen for prophylactic injection in G. mellonella followed by C. albicans infection. Then the direct in vitro antifungal effect of ZnO-NPs against C. albicans was evaluated. In addition, the mode of action of ZnO-NPs was assessed in larvae through different assays: quantification of hemocyte density, morphology observation of hemocytes, characterization of hemocyte aggregation and phagocytosis, and measurement of hemolymph phenoloxidase (PO) activity. Results: Zinc oxide nanoparticles were non-toxic to the larvae at relatively low concentrations (≤20 mg/kg). ZnO-NP pretreatment significantly prolonged the survival of C. albicans-infected larvae and decreased the fungal dissemination and burden in the C. albicans-infected larvae. This observation was more related to the activation of host defense rather than their fungicidal capacities. Specifically, ZnO-NP treatment increased hemocyte density, promoted hemocyte aggregation, enhanced hemocyte phagocytosis, and activated PO activity in larvae. Conclusion: Prophylactic treatment with lower concentrations of ZnO-NPs protects G. mellonella from C. albicans infection. The innate immune response primed by ZnO-NPs may be part of the reason for the protective effects. This study provides new evidence of the capacity of ZnO-NPs in enhancing host immunity and predicts that ZnO-NPs will be attractive for further anti-infection applications.
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Internal and external factors cause various types of wounds on the skin. Infections, nonhealing chronic wounds, and aesthetic and functional recovery all cause challenges for clinicians. The development of nanotechnology in biomedicine has brought many new materials, methods and therapeutic targets for the treatment of wounds, which are believed to have great prospects. In this work, the nanomaterials applied in different stages to promote wound healing and systematically expounded their mechanisms were reviewed. Then, the difficulties and defects of the present research and suggested methods for improvement were pointed out. Moreover, based on the current application status of nanomaterials in wound treatment, some new ideas for subsequent studies were proposed and the feasibility of intelligent healing by real-time monitoring, precision regulation, and signal transmission between electronic signals and human nerve signals in the future were discussed. This review will provide valuable directions and spark new thoughts for researchers.
Subject(s)
Biocompatible Materials , Nanostructures , Humans , Nanotechnology , Skin , Wound HealingABSTRACT
Tim-3, which is expressed on a variety of innate immune cells including NK cells, plays a key role in many autoimmune diseases. However, the immunomodulatory actions of Tim-3 on NK cells in primary biliary cholangitis (PBC) remain uncertain. Using a murine model of PBC we evaluated the expression of Tim-3 and its ligand Gal-9 in peripheral blood, liver, and spleen. Additionally, we studied Tim-3 regulation of chemokine receptors (CXCR1 and CXCR3) in vitro. Flow cytometric analysis indicated large numbers of infiltrating NK cells in the liver which exhibited high expression of Tim-3 and CXCR3. Moreover, we found overexpression of CXCR1 in liver tissue and liver-derived NK cells in PBC mice. We also observed lower levels of soluble Tim-3 in the serum of PBC mice. In vitro experiments with liver-derived NK cells from PBC mice indicated that CXCR3 was up-regulated by treatment with recombinant mouse TIM-3 Fc (rmTim-3 Fc) to activate the Tim-3 pathway. Furthermore, stimulating normal mouse spleen NK cells with poly I:C resulted in elevated expression of CXCR1 and interferon-γ release. Nonetheless, adding rmTim-3 Fc or rmGal-9 significantly down-regulated CXCR1 expression and IFN-γ release in NK cells activated by poly I:C, proposing a means to exploit the Tim-3 pathway to reverse responses in NK cells. In conclusion, our data demonstrate that dysregulation of Tim-3/Gal-9 is involved in modulating the local immune microenvironment in PBC mice. Our findings highlight the potential of Tim-3 pathway to modulate chemokine responses in NK cells during autoimmunity.
Subject(s)
Hepatitis A Virus Cellular Receptor 2/metabolism , Killer Cells, Natural/immunology , Liver Cirrhosis, Biliary/pathology , Receptors, CXCR3/biosynthesis , Receptors, Interleukin-8A/biosynthesis , Animals , Autoimmunity/immunology , Cells, Cultured , Cellular Microenvironment/immunology , Disease Models, Animal , Female , Galectins/metabolism , Gene Expression Regulation/genetics , Hepatitis A Virus Cellular Receptor 2/blood , Interferon-gamma/biosynthesis , Liver/metabolism , Mice , Mice, Inbred C57BL , Spleen/metabolismABSTRACT
BACKGROUND/AIMS: Previous studies have found that the injection of rat bone marrow mesenchymal stem cells (rBMSCs) in a mouse model of acute hepatic failure significantly relieves intestinal damage and endotoxemia. However, the mechanism of this process remains unknown. This study demonstrated the differentiation of rBMSCs into enterocyte-like cells and possible molecular mechanisms for this with the aim of finding a new treatment for intestinal epithelial injury and endotoxemia during liver failure. MATERIALS AND METHODS: rBMSCs were isolated from rat femurs and tibias. Differentiation was induced by co-culturing rBMSCs with rat intestinal epithelial cells (mIEC-6) using Transwell plates; after three, seven, and ten days of induction, expression of specific differentiation molecules were quantified. To inhibit the activity of the Mitogen-activated protein kinase 1/2 (ERK1/2) signaling pathway, an inhibitor of Mitogen-activated protein kinase kinase 1/2 (MEK1/2) was added to the co-culture medium, and western blot analysis was performed after 36 or 72 h to evaluate the expression of ERK1/2 signaling pathway markers (p-MEK1/2 and p-ERK1/2). RESULTS: The rBMSCs differentiated into enterocyte-like cells when co-cultured with mIEC-6 cells. Inhibition of ERK1/2 signaling abrogated the activity of MEK1/2, but MEK increased after 72 h, and the epithelioid differentiation of rBMSCs was consistent with the change in MEK expression. CONCLUSION: rBMSCs differentiate into intestinal epithelium after co-culture with mIEC-6 by regulation of the ERK1/2 signaling pathway. Further research is needed to elucidate the network of mechanisms.
Subject(s)
Cell Differentiation/physiology , Epithelioid Cells/physiology , Intestinal Mucosa/cytology , MAP Kinase Signaling System/physiology , Mesenchymal Stem Cells/physiology , Animals , Cells, Cultured , RatsABSTRACT
BACKGROUND Kupffer cells and natural killer (NK) cells has been identified as contributing factors in the pathogenesis of hepatitis, but the detailed mechanism of these cell types in the pathogenesis of primary biliary cholangitis (PBC) is poorly understood. MATERIAL AND METHODS In this study, polyinosinic: polycytidylic acid (poly I: C), 2-octynoic acid-bovine serum albumin (2OA-BSA) and Freund's adjuvant (FA) were injected to establish a murine PBC model, from which NK cells and Kupffer cells were extracted and isolated. The cells were then co-cultivated in a designed culture system, and then NK group 2, member D (NKG2D), retinoic acid early inducible-1 (RAE-1), F4/80, and cytokine expression levels were detected. RESULTS The results showed close crosstalk between Kupffer cells and NK cells. PBC mice showed increased surface RAE-1 protein expression and Kupffer cell cytokine secretion, which subsequently activated NK cell-mediated target cell killing via NKG2D/RAE-1 recognition, and increased inflammation. NK cell-derived interferon-γ (IFN-γ) and Kupffer cell-derived tumor necrosis factor alpha (TNF-alpha) were found to synergistically regulate inflammation. Moreover, interleukin (IL)-12 and IL-10 improved the crosstalk between NK cells and Kupffer cells. CONCLUSIONS Our ï¬ndings in mice are the first to suggest the involvement of the NKG2D/RAE-1 interaction and cytokines in the synergistic effects of NK and Kupffer cells in PBC.
Subject(s)
Killer Cells, Natural/metabolism , Kupffer Cells/metabolism , Liver Cirrhosis, Biliary/metabolism , Animals , Cytokines/metabolism , Disease Models, Animal , Female , Interferon-gamma/metabolism , Interleukin-12/metabolism , Killer Cells, Natural/pathology , Kupffer Cells/pathology , Liver Cirrhosis, Biliary/physiopathology , Mice , Mice, Inbred C57BL , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Nuclear Matrix-Associated Proteins/metabolism , Nucleocytoplasmic Transport Proteins/metabolismABSTRACT
Triptolide (TP), one of the main active ingredients in Tripterygium wilfordii Hook F, is clinically used to treat immune diseases but is known to cause liver injury. The aim of this study was to investigate the biomarkers for TP-induced hepatotoxicity in mice and to determine potential mechanisms of its liver injury. LC/MS-based metabolomics was used to determine the metabolites that were changed in TP-induced liver injury. The accumulation of long-chain acylcarnitines in serum indicated that TP exposure disrupted endogenous peroxisome proliferator-activated receptor α (PPARα) signaling. Triptolide-induced liver injury could be alleviated by treatment of mice with the PPARα agonist fenofibrate, whereas the PPARα antagonist GW6471 increased hepatotoxicity. Furthermore, fenofibrate did not protect Ppara-/- mice from TP-induced liver injury, suggesting an essential role for the PPARα in the protective effect of fenofibrate. Elevated long-chain acylcarnitines may protect TP-induced liver injury through activation of the NOTCH-NRF2 pathway as revealed in primary mouse hepatocytes and in vivo. In agreement with these observations in mice, the increase in long-chain acylcarnitines was observed in the serum of patients with cholestatic liver injury compared with healthy volunteers. These data demonstrated the role of PPARα and long-chain acylcarnitines in TP-induced hepatotoxicity, and suggested that modulation of PPARα may protect against drug-induced liver injury.
ABSTRACT
Celastrol, derived from the roots of the Tripterygium Wilfordi, shows a striking effect on obesity. In the present study, the role of celastrol in cholestasis was investigated using metabolomics and transcriptomics. Celastrol treatment significantly alleviated cholestatic liver injury in mice induced by α-naphthyl isothiocyanate (ANIT) and thioacetamide (TAA). Celastrol was found to activate sirtuin 1 (SIRT1), increase farnesoid X receptor (FXR) signaling and inhibit nuclear factor-kappa B and P53 signaling. The protective role of celastrol in cholestatic liver injury was diminished in mice on co-administration of SIRT1 inhibitors. Further, the effects of celastrol on cholestatic liver injury were dramatically decreased in Fxr-null mice, suggesting that the SIRT1-FXR signaling pathway mediates the protective effects of celastrol. These observations demonstrated a novel role for celastrol in protecting against cholestatic liver injury through modulation of the SIRT1 and FXR.
Subject(s)
Cholestasis, Intrahepatic/drug therapy , Receptors, Cytoplasmic and Nuclear/metabolism , Sirtuin 1/metabolism , Triterpenes/administration & dosage , 1-Naphthylisothiocyanate/adverse effects , Adult , Animals , Cholestasis, Intrahepatic/blood , Cholestasis, Intrahepatic/chemically induced , Cholestasis, Intrahepatic/genetics , Disease Models, Animal , Female , Gene Expression Profiling/methods , Humans , Male , Metabolomics/methods , Mice , Middle Aged , Pentacyclic Triterpenes , Signal Transduction/drug effects , Thioacetamide/adverse effects , Treatment Outcome , Triterpenes/pharmacologyABSTRACT
Transjugular intrahepatic portosystemic shunting (TIPS) is an effective treatment modality for refractory variceal bleeding and ascites in patients with cirrhotic portal hypertension (CPH). Variceal rebleeding and shunt dysfunction are major post-TIPS morbidities. This study aimed to retrospectively evaluate the effectiveness and safety of use of concomitant variceal embolization and prophylactic antiplatelet/anticoagulative in patients with CPH undergoing TIPS. Between October 2006 and October 2011, 182 patients with CPH were retrospectively and consecutively hospitalized for elective TIPS with Fluency stenting. Concomitant variceal embolization was given after establishing the shunt. Subcutaneous heparin was given after TIPS and replaced by oral clopidogrel, aspirin, or warfarin for at least 6 months. Main outcome measures included shunt patency rate, recurrence of CPH (rebleeding and/or refractory ascites), hepatic encephalopathy (HE) frequency, and post-TIPS survival. The cumulative primary patency rate was 96%, 94%, 90%, 88%, and 88% at 6, 12, 24, 36, and 48 months, respectively. Shunt stenosis occurred in 16 (9%) patients, gastrointestinal (GI) rebleeding in 32 (17.5%) patients, recurrence of refractory ascites 44 (48%) patients, HE in 42 (23%) patients, and death in 36 (20%) patients during the follow-up period. Use of concomitant variceal embolization and prophylactic antiplatelet/anticoagulative was associated with a favorable shunt patency and a low risk of GI rebleeding.
Subject(s)
Embolization, Therapeutic/methods , Esophageal and Gastric Varices/therapy , Gastrointestinal Hemorrhage/prevention & control , Platelet Aggregation Inhibitors/therapeutic use , Portasystemic Shunt, Transjugular Intrahepatic/methods , Combined Modality Therapy , Esophageal and Gastric Varices/complications , Female , Gastrointestinal Hemorrhage/etiology , Humans , Hypertension, Portal/complications , Hypertension, Portal/surgery , Liver Cirrhosis/etiology , Liver Cirrhosis/surgery , Male , Middle Aged , Retrospective Studies , Treatment OutcomeABSTRACT
The incidence of small (≤2 cm), non-functioning pancreatic neuroendocrine tumors (NF-pNETs) increased in the last decades. Before making appropriate strategy for patients with NF-pNETs ≤2 cm, pathological confirmation is vital. Incidentally diagnosed, sporadic small NF-pNETs may bring aggressive behavior and poor prognosis, such as extrapancreatic extension, lymph nodal metastasis, distant metastasis and recurrence, even causing disease-related death. Understanding and formulating an appropriate strategy for the patients with sporadic small, non-functioning pancreatic neuroendocrine tumors have been controversial for some time. Although several studies have reported that patients with NF-pNETs ≤2 cm had less rate of malignant behavior compared with larger ones (>2 cm); and the surgery approach may leading to surgery-related pancreatic complications; but there is still a lack of level I evidence to convince surgeons to abandon all cases with sporadic small NF-pNETs. Based on an updated literature search and review, the members of the Chinese Study Group for Neuroendocrine Tumors (CSNET) from high-volume centers have reached a consensus on the issue of the management strategy for the sporadic small NF-pNETs. We recommend that, except for some selected patients with NF-pNETs <1 cm, incidentally discovered and unacceptable surgical risks, all others with NF-pNETs ≤2 cm should undergo tumor resection with lymph node dissection or at least lymph node sampling and careful postoperative surveillance.