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INTRODUCTION: Patients with clinically significant portal hypertension (CSPH) are recommended to be treated with non-selective beta-blockers (ie, carvedilol) to prevent the first hepatic decompensation event by the renewing Baveno VII consensus. CSPH is defined by hepatic venous pressure gradient (HVPG)≥10 mm Hg; however, the HVPG measurement is not widely adopted due to its invasiveness. Liver stiffness (LS)≥25 kPa can be used as a surrogate of HVPG≥10 mm Hg to rule in CSPH with 90% of the positive predicting value in majority aetiologies of patients. A compelling argument is existing for using LS≥25 kPa to diagnose CSPH and then to initiate carvedilol in patients with compensated cirrhosis, and about 5%-6% of patients under this diagnosis criteria may not be benefited from carvedilol and are at risk of lower heart rate and mean arterial pressure. Randomised controlled trial on the use of carvedilol to prevent liver decompensation in CSPH diagnosed by LS remains to elucidate. Therefore, we aimed to investigate if compensated cirrhosis patients with LS≥25 kPa may benefit from carvedilol therapy. METHODS AND ANALYSIS: This study is a randomised, double-blind, placebo-controlled, multicentre trial. We will randomly assign 446 adult compensated cirrhosis patients with LS≥25 kPa and without any previous decompensated event and without high-risk gastro-oesophageal varices. Patients are randomly divided into two groups, with 223 subjects in group A and 223 subjects in group B. Group A is a carvedilol intervention group, while group B is a placebo group. All patients in both groups will receive aetiology therapies and are followed up at an interval of 6 months. The 3-year incidences of decompensated events of cirrhosis-related and liver-related death are the primary outcome. The secondary outcomes include development of each complication of portal hypertension individually (ascites, variceal bleeding or overt hepatic encephalopathy), development of spontaneous bacterial peritonitis and other bacterial infections, development of new varices, growth of small varices to large varices, delta changes in LS and spleen stiffness, change in hepatic dysfunction assessed by Child-Pugh and model for end-stage liver disease score, change in platelet count, development of hepatocellular carcinoma, development of portal vein thrombosis and adverse events with a 3-year follow-up. A predefined interim analysis will be performed to ensure that the calculation is reasonable. ETHICS AND DISSEMINATION: The study protocol has been approved by the ethics committees of the Sixth People's Hospital of Shenyang (2023-05-003-01) and independent ethics committee for clinical research of Zhongda Hospital, affiliated to Southeast University (2023ZDSYLL433-P01). The results from this trial will be submitted for publication in peer-reviewed journals and will be presented at international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300073864.
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Carvedilol , Hipertensão Portal , Cirrose Hepática , Carvedilol/uso terapêutico , Carvedilol/farmacologia , Humanos , Hipertensão Portal/tratamento farmacológico , Hipertensão Portal/etiologia , Cirrose Hepática/complicações , Método Duplo-Cego , China/epidemiologia , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Antagonistas Adrenérgicos beta/uso terapêutico , Feminino , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Pressão na Veia Porta/efeitos dos fármacos , Varizes Esofágicas e Gástricas/etiologia , Varizes Esofágicas e Gástricas/prevenção & controle , Técnicas de Imagem por Elasticidade , Adulto , MasculinoRESUMO
BACKGROUND: Our previous study has shown that intrahepatic necroinflammation favors the eliminations of HBV integration and clonal hepatocytes. Here, the effect of inflammation on host DNA damage eliminations in liver biopsy tissues from patients with chronic hepatitis B (CHB) was further investigated. METHODS: DNA damage markers, histone γ-H2AX and phosphorylated heterochromatin protein 1γ (p-HP1γ), and senescent marker p21 were detected using immunohistochemical and immunofluorescent assays in liver biopsy samples from 69 CHB patients and 12 liver cirrhosis (LC) patients. Twenty paired hepatocellular carcinoma (HCC) surgical samples were used as controls. RESULTS: Both γ-H2AX and p-HP1γ were sensitively detected in nuclear and cytoplasmic/nuclear patterns. Nuclear γ-H2AX was superior as a DNA damage marker in hepatocytes. The level of nuclear γ-H2AX in CHB, comparable to those in LC and HCC, was correlated with liver fibrosis and coexisted with the senescent marker p21. However, hepatocytes carried an alleviated level of DNA damages, which was associated with the level of cytoplasmic γ-H2AX. Cytoplasmic γ-H2AX chiefly occurred in hepatocytes near necroinflammatory foci, was correlated with liver inflammation and usually indicated the decrease or disappearance of nuclear γ-H2AX. The lack of cytoplasmic γ-H2AX together with the high level of nuclear γ-H2AX was associated with the progression from large cell changes/dysplasia to small cell changes/dysplasia. CONCLUSIONS: Hepatocytes in CHB already carry massive DNA damages and undergo cellular senescence. The DNA damages in those senescent hepatocytes are histopathologically demonstrated to be amended by a novel cytoplasmic γ-H2AX-indicated and inflammation-driven rescue repair mechanism, which may be involved in hepatocarcinogenesis if it works improperly.
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Dano ao DNA , Hepatite B Crônica , Hepatócitos , Histonas , Humanos , Hepatócitos/patologia , Hepatócitos/metabolismo , Hepatite B Crônica/patologia , Histonas/metabolismo , Masculino , Pessoa de Meia-Idade , Adulto , Feminino , Inflamação/patologia , Inflamação/metabolismo , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Cirrose Hepática/metabolismo , Homólogo 5 da Proteína Cromobox , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Neoplasias Hepáticas/metabolismo , Reparo do DNA , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Carcinoma Hepatocelular/metabolismo , Proteínas Cromossômicas não Histona/metabolismoRESUMO
BACKGROUND: Vertical sleeve gastrectomy (SGx) is a type of bariatric surgery to treat morbid obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular mechanisms of SGx to improve MASLD are unclear, but increased bile acids (BAs) and FGF19 (mouse FGF15) were observed. FGF15/19 is expressed in the ileum in response to BAs and is critical in not only suppressing BA synthesis in the liver but also promoting energy expenditure. We hypothesized the reduction of obesity and resolution of MASLD by SGx may be mediated by FGF15/19. METHODS: First, we conducted hepatic gene expression analysis in obese patients undergoing SGx, with the results showing increased expression of FGF19 in obese patients' livers. Next, we used wild-type and intestine-specific Fgf15 knockout mice (Fgf15ile-/-) to determine the effects of FGF15 deficiency on improving the metabolic effects. RESULTS: SGx improved metabolic endpoints in both genotypes, evidenced by decreased obesity, improved glucose tolerance, and reduced MASLD progression. However, Fgf15ile-/- mice showed better improvement compared to wild-type mice after SGx, suggesting that other mediators than FGF15 are also responsible for the beneficial effects of FGF15 deficiency. Further gene expression analysis in brown adipose tissue suggests increased thermogenesis. CONCLUSIONS: FGF15 deficiency, the larger BA pool and higher levels of secondary BAs may increase energy expenditure in extrahepatic tissues, which may be responsible for improved metabolic functions following SGx.
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Fígado Gorduroso , Fatores de Crescimento de Fibroblastos , Gastrectomia , Camundongos Knockout , Obesidade Mórbida , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Animais , Gastrectomia/métodos , Camundongos , Obesidade Mórbida/cirurgia , Obesidade Mórbida/genética , Obesidade Mórbida/metabolismo , Humanos , Masculino , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Feminino , Ácidos e Sais Biliares/metabolismo , Fígado/metabolismo , Adulto , Pessoa de Meia-Idade , Cirurgia Bariátrica , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Lipocalin 13 (LCN13) is a member of the lipocalin family that consists of numerous secretory proteins. LCN13 high-expression has been reported to possess anti-obesity and anti-diabetic effects. Although metabolic dysfunction-associated steatotic liver diseases (MASLD) including metabolic dysfunction-associated steatohepatitis (MASH) are frequently associated with obesity and insulin resistance, the functional role of endogenous LCN13 and the therapeutic effect of LCN13 in MASH and related metabolic deterioration have not been evaluated. METHODS: We employed a methionine-choline deficient diet model and MASH cell models to investigate the role of LCN13 in MASH development. We sought to explore the effects of LCN13 on lipid metabolism and inflammation in hepatocytes under PA/OA exposure using Western blotting, real-time RT-PCR, enzyme-linked immunosorbent assay, hematoxylin and eosin staining, oil red O staining. Using RNA sequencing, chromatin immunoprecipitation assay, and luciferase reporter assays to elucidate whether farnesoid X receptor (FXR) regulates human LCN13 transcription as a transcription factor. RESULTS: Our study found that LCN13 was down-regulated in MASH patients, MASH mouse and cell models. LCN13 overexpression in hepatocyte cells significantly inhibited lipid accumulation and inflammation in vitro. Conversely, LCN13 downregulation significantly exacerbated lipid accumulation and inflammatory responses in vivo and in vitro. Mechanistically, we provided the first evidence that LCN13 was transcriptionally activated by FXR, representing a novel direct target gene of FXR. And the key promoter region of LCN13 binds to FXR was also elucidated. We further revealed that LCN13 overexpression via FXR activation ameliorates hepatocellular lipid accumulation and inflammation in vivo and in vitro. Furthermore, LCN13-down-regulated mice exhibited aggravated MASH phenotypes, including increased hepatic lipid accumulation and inflammation. CONCLUSION: Our findings provide new insight regarding the protective role of LCN13 in MASH development and suggest an innovative therapeutic strategy for treating MASH or related metabolic disorders.
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Carcinoma Hepatocelular , Fígado Gorduroso , Neoplasias Hepáticas , Animais , Humanos , Camundongos , Carcinoma Hepatocelular/metabolismo , Fígado Gorduroso/metabolismo , Inflamação/metabolismo , Lipídeos , Lipocalinas/metabolismo , Fígado , Neoplasias Hepáticas/metabolismo , Camundongos Endogâmicos C57BL , Obesidade/metabolismoRESUMO
This experiment was conducted to investigate whether low-dose zinc-loaded montmorillonite (Zn-MMT) could be used as a potential alternative for high-dose conventional ZnO in preventing diarrhea in weaned piglets. In total, 180 piglets were randomly divided to receive either of the three treatments, with six replicates per treatment and 10 piglets per replicate. The treatments were the control group (CT), the Zn-MMT group (ZM), and the ZnO group (ZO). Compared with the CT group, the ZM and ZO groups exhibited increased ADG at 14-28 days and during the whole period (p < 0.05), and a significantly decreased diarrhea rate during the whole period (p < 0.01). The activities of T-AOC and SOD were significantly increased (p < 0.05), whereas the MDA level decreased (p < 0.05) in the serum and colonic mucosa of Zn-MMT- and ZnO-fed piglets. Dietary supplementation with Zn-MMT and ZnO decreased the contents of IFN-γ, TNF-α, IL-1ß, IL-6, DAO, and LPS in the serum and colonic mucosa (p < 0.01), and increased the IL-10 level (p < 0.01). The relative mRNA expressions of TLR-4, claudin 2, Pbd1, and MUC2 were elevated in the colonic mucosa of the Zn-MMT and ZnO groups (p < 0.05). 16S rRNA gene sequencing analysis revealed that the abundances of Proteobacteria and Actinobacteria in the ileum and the populations of Ruminnococcus and Faecalibacterium in the cecum were higher in the CT group than in the other two groups. Collectively, dietary addition of Zn from Zn-MMT was comparable to Zn from ZnO for increasing growth performance, alleviating diarrhea, as well as improving mucosal barrier integrity, and regulating the gut microbiota of weaned piglets.
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Enterovirus A71 (EV-A71) is a highly contagious virus that poses a major threat to global health, representing the primary etiological agent for hand-foot and mouth disease (HFMD) and neurological complications. It has been established that interferon signaling is critical to establishing a robust antiviral state in host cells, mainly mediated through the antiviral effects of numerous interferon-stimulated genes (ISGs). The host restriction factor SHFL is a novel ISG with broad antiviral activity against various viruses through diverse underlying molecular mechanisms. Although SHFL is widely acknowledged for its broad-spectrum antiviral activity, it remains elusive whether SHFL inhibits EV-A71. In this work, we validated that EV-A71 triggers the upregulation of SHFL both in cell lines and in a mouse model. Knockdown and overexpression of SHFL in EVA71-infected cells suggested that this factor could markedly suppress EV-A71 replication. Our findings further revealed an intriguing mechanism of SHFL that it could interact with the nonstructural proteins 3Dpol of EV-A71 and promoted the degradation of 3Dpol through the ubiquitin-proteasome pathway. Furthermore, the zinc-finger domain and the 36 amino acids (164-199) of SHFL were crucial to the interaction between SHFL and EV-A71 3Dpol . Overall, these findings broadened our understanding of the pivotal roles of SHFL in the interaction between the host and EV-A71.
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Enterovirus Humano A , Infecções por Enterovirus , Enterovirus , Doença de Mão, Pé e Boca , Animais , Camundongos , Enterovirus Humano A/genética , Complexo de Endopeptidases do Proteassoma , Produtos do Gene pol , Antígenos Virais/genética , Antivirais , Interferons , UbiquitinasRESUMO
Whether hypervariable region 1 (HVR1)-targeting antibodies elicited during natural hepatitis C virus (HCV) infection contribute to virus clearance and what is the mechanism underlying remain unclear. Here, we demonstrated that treatment of HCV-infected hepatoma Huh7.5 cells with the IgGs purified from 2 of 28 (7.1%) chronic hepatitis C (CHC) patients efficiently controlled the infection, for which genotype 1b HVR1 (1bHVR1)-binding antibody was critical. Moreover, we found that 1bHVR1 peptide was superior to 2aHVR1 in rabbit immunization to elicit antibodies neutralizing genotypes 1a, 2a, 3a, and 4a. The neutralization effect of 1bHVR1 IgG could be augmented by HH-1, an antibody constructed from CHC memory B cells but without binding to HVR1 peptide. Mechanistic studies showed that 1bHVR1 antisera and IgGs disrupted the interaction of E2-SR-B1 receptor. This study highlights the neutralizing activity of HVR1 antibody elicited by CHC patients and generated by HVR1-immunization against the established infections of multiple HCV genotypes.
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Platelet-derived growth factor receptor ß (PDGFRß) has been demonstrated to be an effective biomarker for a variety of malignant cancers, and affibody-based PDGFRß molecules have potential as positron emission tomography (PET) tracers for the diagnosis of cancers. Based on previous pharmacokinetics studies, short-lived positron emission radionuclides, such as fluorine-18 and gallium-68, would be more suitable for affibody-based PET imaging. Thus, in the present study, we prepared a gallium-68-labeled PDGFRß-targeting dimeric affibody conjugate and evaluated its capability for visualizing malignant tumors by micro-PET/computed tomography (CT) imaging. The PDGFRß-targeting ZPDGFRß affibody was conjugated with the p-NCS-Bn-DOTA macrocyclic ligand and radiolabeled with gallium-68 to generate the 68Ga-DOTA-ZPDGFRß PET probe . Then, several types of malignant carcinoma cells (U-87 MG, LS 174T, A549, H1688, and H446) were used to evaluate the targeted cellular binding capability of the PET probe through in vitro/in vivo cellular assays and whole-body imaging by micro-PET/CT. The 68Ga-DOTA-ZPDGFRß was successfully prepared with a radiochemical yield of 93% and exhibited ideal stability for up to 4 h at room temperature in vitro. This radioactive conjugate demonstrated specific binding ability with PDGFRß-expressing U-87 MG cells, which was suppressed by PDGFRß ligands. The biodistribution of 68Ga-DOTA-ZPDGFRß indicated fast liver clearance and a kidney-bladder excretion route. The U-87 MG xenografted tumor was clearly visualized with 68Ga-DOTA-ZPDGFRß at 1 h postinjection using micro-PET/CT imaging. 68Ga-DOTA-ZPDGFRß is a potential radiopharmaceutical for the diagnosis of PDGFRß-expressing tumors.
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Radioisótopos de Gálio , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Distribuição Tecidual , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Receptores do Fator de Crescimento Derivado de Plaquetas , Linhagem Celular TumoralRESUMO
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a new coronavirus causing Coronavirus Disease 2019 (COVID-19), is a major topic of global human health concern. The Delta and Omicron variants have caused alarming responses worldwide due to their high transmission rates and a number of mutations. During a one-year follow-up (from June 2020 to June 2021), we included 114 patients with SARS-CoV-2 infection to study the long-term dynamics and the correlative factors of neutralizing antibodies (NAbs) in convalescent patients. The blood samples were collected at two detection time points (at 6 and 12 months after discharge). We evaluated the NAbs response of discharged patients by performing a micro-neutralization assay using a SARS-CoV-2 wild type. In addition, a total of 62 serum samples from discharged COVID-19 patients with Alpha, Beta, Delta, and Omicron variants of infection were enrolled to perform cross-neutralization tests using the original SARS-CoV-2 strain and VOCs variants (including Alpha, Beta, Gamma, Delta, and Omicron variants) and to assess the ability of NAbs against the SARS-CoV-2 variants. NAbs seroconversion occurred in 91.46% of patients (n = 82) in the first timepoint and in 89.29% of patients (n = 84) in the second detection point, and three kinds of NAbs kinetics curves were perceived. The NAbs levels in young patients had higher values than those in elder patients. The kinetics of disease duration was accompanied by an opposite trend in NAbs levels. Despite a declining NAbs response, NAbs activity was still detectable in a substantial proportion of recovered patients one year after discharge. Compared to the wild strain, the Omicron strain could lead to a 23.44-, 3.42-, 8.03-, and 2.57-fold reduction in neutralization capacity in "SAlpha", "SBeta", "SDelta", and "SOmicron", respectively, and the NAbs levels against the Omicron strain were significantly lower than those of the Beta and Delta variants. Remarkably, the NAbs activity of convalescent serum with Omicron strain infection was most obviously detectable against six SARS-CoV-2 strains in our study. The role of the vaccination history in NAbs levels further confirmed the previous study that reported vaccine-induced NAbs as the convincing protection mechanism against SARS-CoV-2. In conclusion, our findings highlighted the dynamics of the long-term immune responses after the disappearance of symptoms and revealed that NAbs levels varied among all types of convalescent patients with COVID-19 and that NAbs remained detectable for one year, which is reassuring in terms of protection against reinfection. Moreover, a moderate correlation between the duration of disease and Nabs titers was observed, whereas age was negatively correlated with Nabs titers. On the other hand, compared with other VOCs, the Omicron variant was able to escape the defenses of the immune system more significantly, and the convalescent serum infected with the Omicron variant played a critical part in protection against different SARS-CoV-2 variants. Recovery serum from individuals vaccinated with inactivated vaccine preceding infection with the Omicron strain had a high efficacy against the original strain and the VOCs variants, whereas the convalescent serum of persons vaccinated by inactivated vaccine prior to infection with the Delta variant was only potent against the wild-type strain.
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Tumor-associated macrophages (TAMs) are known to promote cancer development and metastasis. In this study, a TAMs-targeting peptide named M2pep was selected to investigate the feasibility of [68Ga]Ga-labeled M2pep as a noninvasive probe in targeted TAMs imaging. The peptide M2pep was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with 68Ga. The cellular uptake and binding assay were assessed in M2 macrophages and in the B16F10 cell line. Micro-PET imaging and a biodistribution study were performed on B16F10 tumor-bearing mice. High radiochemical purity [68Ga]Ga-DOTA-M2pep (>95%) was prepared and was stabilized in saline and bovine serum at 37 °C for 2 h. In vitro studies demonstrated high uptake of [68Ga]Ga-DOTA-M2pep in M2 macrophages, which was effectively blocked by the "cold" M2pep (free peptide). The micro-PET imaging and biodistribution study revealed that [68Ga]Ga-DOTA-M2pep reached the tumor site rapidly and showed high accumulation in the tumor at 1 h post-injection. In addition, the probe was rapidly cleared from the blood and mainly excreted via the kidneys, resulting in a high tumor/background ratio. Preclinical studies have shown that [68Ga]Ga-DOTA-M2pep specifically targets TAMs and might be a promising molecular probe for the noninvasive visualization of TAMs expression.
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Emerging infectious diseases have brought a huge impact on human society in recent years. The outbreak of Zika virus (ZIKV) in the Americas resulted in a large number of babies born with microcephaly. More seriously, the Coronavirus Disease 2019 (COVID-19) was globally spread and caused immeasurable damages. Thus, the monitoring of highly pathogenic viruses is important to prevent and control emerging infectious diseases. Herein, a dendritic polymer probe-amplified ECL-scan imaging system was constructed to realize trace analysis of viral emerging infectious diseases. A dendritic polymer probe was employed as the efficient signal emitter component that could generate an amplified ECL signal on the integrated chip, and the signal was detected by a single-photon level charge coupled device-based ECL-scan imaging system. With this strategy, the ZIKV in a complex system of blood, urine, and saliva was detected. The results indicated that a high sensitivity of 50 copies and superior specificity were achieved. Furthermore, this strategy realized highly sensitive detection (10 copies) of the S and N protein gene sequence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov2) and spiked pseudovirus samples. Thus, the dendritic polymer probe-amplified ECL-scan imaging system suitably met the strict clinical requirements for trace analysis of an emerging virus, and thus has the potential to serve as a paradigm for monitoring emerging infectious diseases.
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Zika virus (ZIKV) is a re-emerging flavivirus that leads to devastating consequences for fetal development. It is crucial to visualize the pathogenicity activities of ZIKV ranging from infection pathways to immunity processes, but the accurate labeling of ZIKV remains challenging due to the lack of a reliable labeling technique. We introduce the photo-activated bio-orthogonal cycloaddition to construct a fluorogenic probe for the labeling and visualizing of ZIKV. Via a simple UV photoirradiation, the fluorogenic probes could be effectively labeled on the ZIKV. We demonstrated that it can be used for investigating the interaction between ZIKV and diverse cells and avoiding the autofluorescence phenomenon in traditional immunofluorescence assay. Thus, this bioorthogonal-enabled labeling strategy can serve as a promising approach to monitor and understand the interaction between the ZIKV and host cells.
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PURPOSE: Sigma-1 receptor (Sig-1R), a chaperone that resides at the mitochondrion-associated endoplasmic reticulum (ER) membrane, is an ER stress biomarker. It is thought that ER stress plays a critical role in the progression of metabolic-associated fatty liver disease (MAFLD). The aim of this study was to evaluate a positron emission tomography (PET) tracer [18F]F-TZ3108 targeting Sig-1R for MAFLD. PROCEDURES: The mouse model of MAFLD was established by feeding high-fat diet (HFD) for 12 weeks. Dynamic (0-60 min) PET/CT scans were performed after intravenous injection of 2-deoxy-2[18F]fluoro-D-glucose ([18F]-FDG) and [18F]F-TZ3108. Tracer kinetic modeling was performed for quantification of the PET/CT imaging of the liver. Post-PET biodistribution, the liver tissue western blotting (WB), and immunofluorescence (IF) were performed to compare the expression of Sig-1R levels in the organs harvested from both MAFLD and age-matched control mice. RESULTS: The micro PET/CT imaging revealed a significantly decreased uptake of [18F]F-TZ3108 in the livers of the MAFLD group compared to the healthy controls, while the uptake of [18F]-FDG in the livers was not significantly different between the two groups. Based on the tracer kinetic modeling, the binding disassociate rate (k4) for [18F]F-TZ3108 was significantly increased in MAFLD group compared to healthy controls. The volume distribution (VT), and the non-displacement binding potential (BPND) revealed significantly decrease in MAFLD compared to healthy controls respectively. The post-PET biodistribution (%ID/g) of [18F]F-TZ3108 in the livers of MAFLD mice was significantly reduced nearly twofold than that in the livers of control mice. WB and IF experiments further confirmed the reduction of Sig-1R expression in the MAFLD group. CONCLUSIONS: The expression of Sig-1R in the liver, measured by the PET tracer, [18F]F-TZ3108, was significantly decreased in mouse model of MAFLD. The [18F]F-TZ3108 PET/CT imaging may provide a novel means of visualization for ER stress in MAFLD or other diseases in vivo.
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Fluordesoxiglucose F18 , Hepatopatias , Animais , Camundongos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Distribuição Tecidual , Tomografia por Emissão de Pósitrons/métodosRESUMO
ABSTRACT: Nasal-type extranodal natural killer/T-cell lymphoma (ENKTL) rarely involves the vocal cord. Herein, we present a case of an ENKTL patient with vocal cord involvement revealed by FDG PET/CT. Nasopharyngoscopy showed a neoplasm in the larynx, which was eventually confirmed as ENKTL by immunohistochemical results. PET/CT was subsequently performed for staging, and intense FDG uptake in the left side of vocal cord suggested ENKTL involvement.
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Linfoma Extranodal de Células T-NK , Linfoma de Células T Periférico , Fluordesoxiglucose F18 , Humanos , Linfoma Extranodal de Células T-NK/diagnóstico por imagem , Linfoma Extranodal de Células T-NK/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons/métodos , Estudos Retrospectivos , Prega Vocal/diagnóstico por imagemRESUMO
This study was conducted to determine relative bioavailability (RBV) of basic zinc chloride (BZC) compared to zinc sulfate monohydrate (ZSM) for broilers. A randomized design involving a 2 × 3 factorial arrangement of the different treatment regimens plus one negative control was set up for this study. A total of 630 newly hatched male AA broiler chicks were randomly allocated to 42 different pens (15 chickens/pen) and assigned to 7 dietary treatments in a completely randomized design. The diet was supplemented with 0, 20, 40, or 80 mg of Zn mg/kg of feed in the form of ZSM or BZC. The results showed that zinc supplementation altered average daily gain (ADG) and feed conversion ratio (FCR) (P < 0.05) for both zinc sources. It was observed that the weight gain increased linearly (P < 0.01) and FCR decreased linearly as dietary BZC and ZSM concentration increased. Moreover, compared with chickens fed with ZSM, chickens fed with BZC had higher ADG and lower FCR from days 0 to 14 (P < 0.05), and higher activity of plasma alkaline phosphatase (ALP) (P < 0.05), total superoxide dismutase (T-SOD), and CuZn superoxide dismutase (CuZn-SOD) (P < 0.01) in the plasma of chickens fed with BZC at zinc level 80 mg/kg at day 14. The pancreas divalent metal-ion transporter-1 (DMT1) mRNA expression of chickens fed with BZC was found to be significantly enhanced at day 28, and the pancreas metallothionein (MT) mRNA expression for BZC fed group was also markedly increased at Zn levels of 20 and 40 mg/kg respectively. The relative bioavailability (RBV) of BZC (Zn sulfate 100%) based on ADG in the starter phase was 110.82%, whereas the tibia zinc content, as well as the activities of plasma ALP and CuZn-SOD, and the pancreas MT mRNA level were in the range between 108 and 119%. It was thus concluded that BZC was more efficacious than Zn sulfate and could serve as a potentially novel zinc source in the broilers.
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Galinhas , Zinco , Animais , Masculino , Ração Animal/análise , Disponibilidade Biológica , Galinhas/metabolismo , Dieta/veterinária , Suplementos Nutricionais , Metalotioneína/genética , Metalotioneína/metabolismo , RNA Mensageiro/genética , Glycine max , Sulfatos/metabolismo , Superóxido Dismutase/metabolismo , Zea mays/metabolismo , Zinco/metabolismo , Sulfato de ZincoRESUMO
Background: Venomous arthropods have substances in their venom with antiproliferative potential for neoplastic cells. Objectives: To identify a polypeptide from Myrmeleon bore (antlion) with antiproliferative activity against neoplastic cells, and to elucidate the molecular mechanism of the activity. Methods: We used gel filtration and ion exchange chromatography to purify a polypeptide with antiproliferative activity against MG-63 human osteosarcoma cells from a proteinaceous extract of antlion. The polypeptide was sequenced and the stability of its antiproliferative activity was tested under a range of conditions in vitro. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine the antiproliferative activity of the polypeptide against the MG-63 osteosarcoma cells and MC3T3-E1 mouse calvarial osteoblasts, which were used as a non-neoplastic control. We used western blotting to compare the levels of expression of heat shock transcription factor 1 (HSF1), heat shock protein 90 (HSP90), cyclin-dependent kinase 4 (CDK4), and protein kinase B alpha (ATK1) in MG-63 osteosarcoma cells and their mouse homologs in MC3T3-E1 osteoblasts after their treatment with the antlion antiproliferative polypeptide (ALAPP). Results: The 85-amino-acid ALAPP has a 56% sequence identity with the human heat shock factor binding protein 1 (HSBP1). The antiproliferative activity of the polypeptide is relatively insensitive to temperature, pH, and metal ions. ALAPP has a strong concentration-dependent antiproliferative activity against MG-63 osteosarcoma cells compared with its effect on MC3T3-E1 osteoblasts. ALAPP significantly upregulates the expression of HSF1 in MC3T3-EL osteoblasts, but not in MG-63 osteosarcoma. ALAPP significantly downregulated the expression of HSP90, CDK4, and AKT1 expression in MG-63 osteosarcoma, but not in the osteoblasts. Conclusions: ALAPP has significant antiproliferative activity against MG-63 osteosarcoma cells, but not nonneoplastic MC3T3-E1 osteoblasts. We speculate that non-neoplastic cells may evade the antiproliferative effect of ALAPP by upregulating HSF1 to maintain their HSP90, CDK4, and AKT1 expression at a relatively constant level.
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BACKGROUND: Diagnosing the biochemical recurrence (BCR) of prostate cancer (PCa) is a clinical challenge, and early detection of BCR can help patients receive optimal treatment. We conducted a meta-analysis to define the diagnostic accuracy of PET/CT using 18F-labeled choline, fluciclovine, and prostate-specific membrane antigen (PSMA) in patients with BCR. METHODS: Multiple databases were searched until March 30, 2021. We included studies investigating the diagnostic accuracy of 18F-choline, 18F-fluciclovine, and 18F-PSMA PET/CT in patients with BCR. The pooled sensitivity, specificity, and detection rate of 18F-labeled tracers were calculated with a random-effects model. RESULTS: A total of 46 studies met the included criteria; 17, 16, and 13 studies focused on 18F-choline, fluciclovine, and PSMA, respectively. The pooled sensitivities of 18F-choline and 18F-fluciclovine were 0.93 (95% CI, 0.85-0.98) and 0.80 (95% CI, 0.65-0.897), and the specificities were 0.91 (95% CI, 0.73-0.97) and 0.66 (95% CI, 0.50-0.79), respectively. The pooled detection rates of 18F-labeled choline, fluciclovine and PSMA were 66, 74, and 83%, respectively. Moreover, the detection rates of 18F-labeled choline, fluciclovine, and PSMA were 35, 23, and 58% for a PSA level less than 0.5 ng/ml; 41, 46, and 75% for a PSA level of 0.5-0.99 ng/ml; 62, 57, and 86% for a PSA level of 1.0-1.99 ng/ml; 80, 92, and 94% for a PSA level more than 2.0 ng/ml. CONCLUSION: These three 18F-labeled tracers are promising for detecting BCR in prostate cancer patients, with 18F-choline showing superior diagnostic accuracy. In addition, the much higher detection rates of 18F-PSMA showed its superiority over other tracers, particularly in low PSA levels. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, identifier CRD42020212531.