DEC1 is involved in circadian rhythm disruption-exacerbated pulmonary fibrosis.

BACKGROUND: The alveolar epithelial type II cell (AT2) and its senescence play a pivotal role in alveolar damage and pulmonary fibrosis. Cell circadian rhythm is strongly associated with cell senescence. Differentiated embryonic chondrocyte expressed gene 1 (DEC1) is a very important circadian clock gene. However, the role of DEC1 in AT2 senescence and pulmonary fibrosis was still unclear. RESULTS: In this study, a circadian disruption model of light intervention was used. It was found that circadian disruption exacerbated pulmonary fibrosis in mice. To understand the underlying mechanism, DEC1 levels were investigated. Results showed that DEC1 levels increased in lung tissues of IPF patients and in bleomycin-induced mouse fibrotic lungs. In vitro study revealed that bleomycin and TGF-ß1 increased the expressions of DEC1, collagen-I, and fibronectin in AT2 cells. Inhibition of DEC1 mitigated bleomycin-induced fibrotic changes in vitro and in vivo. After that, cell senescence was observed in bleomycin-treated AT2 cells and mouse models, but these were prevented by DEC1 inhibition. At last, p21 was confirmed having circadian rhythm followed DEC1 in normal conditions. But bleomycin disrupted the circadian rhythm and increased DEC1 which promoted p21 expression, increased p21 mediated AT2 senescence and pulmonary fibrosis. CONCLUSIONS: Taken together, circadian clock protein DEC1 mediated pulmonary fibrosis via p21 and cell senescence in alveolar epithelial type II cells.

BMAL1/p53 mediating bronchial epithelial cell autophagy contributes to PM2.5-aggravated asthma.

BACKGROUND: Fine particulate matter (PM2.5) is associated with increased incidence and severity of asthma. PM2.5 exposure disrupts airway epithelial cells, which elicits and sustains PM2.5-induced airway inflammation and remodeling. However, the mechanisms underlying development and exacerbation of PM2.5-induced asthma were still poorly understood. The aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1) is a major circadian clock transcriptional activator that is also extensively expressed in peripheral tissues and plays a crucial role in organ and tissue metabolism. RESULTS: In this study, we found PM2.5 aggravated airway remodeling in mouse chronic asthma, and exacerbated asthma manifestation in mouse acute asthma. Next, low BMAL1 expression was found to be crucial for airway remodeling in PM2.5-challenged asthmatic mice. Subsequently, we confirmed that BMAL1 could bind and promote ubiquitination of p53, which can regulate p53 degradation and block its increase under normal conditions. However, PM2.5-induced BMAL1 inhibition resulted in up-regulation of p53 protein in bronchial epithelial cells, then increased-p53 promoted autophagy. Autophagy in bronchial epithelial cells mediated collagen-I synthesis as well as airway remodeling in asthma. CONCLUSIONS: Taken together, our results suggest that BMAL1/p53-mediated bronchial epithelial cell autophagy contributes to PM2.5-aggravated asthma. This study highlights the functional importance of BMAL1-dependent p53 regulation during asthma, and provides a novel mechanistic insight into the therapeutic mechanisms of BMAL1. Video Abstract.

Effects of Ginsenoside Rb1 on Expressions of Phosphorylation Akt/Phosphorylation mTOR/Phosphorylation PTEN in Artificial Abnormal Hippocampal Microenvironment in Rats.

Artificial abnormal microenvironment caused by microperfusion of L-glutamate (Glu) and Ca2+ in the hippocampus results in neuron damage, which is closely related to cerebral ischemia. Ginsenoside Rb1, a compound from Panax notoginseng, was previously used to counter the artificial abnormal hippocampal environment in a microperfusion model. In addition, while the Akt/mTOR/PTEN signaling pathway has been shown to mediate neuronprotection in cerebral ischemia, whether this pathway is involved in the neuroprotection of ginsenoside Rb1 is unknown. Here SH-SY5Y cells exposed to OGD/R injury in treated with LY294002, ginsenoside Rb1, ginsenoside Rb1+ LY294002. Expressions of phosphorylation (P-)Akt/P-mTOR/P-PTEN (24 h after OGD/R) were detected by Western blotting. Effects were examined via the memory function of rats (by Morris water maze test), morphological changes in pyramidal cell (by histology), and mRNA expression (by qRT-PCR) and phosphorylation (P-) (by Western blotting and immunohistochemical staining) of Akt, P-mTOR, and P-PTEN in the hippocampus. The memory deficit of rats and pyramidal cellular necrosis and apoptosis in the CA1 region of hippocampus after microperfusion of Glu and Ca2+ were dose dependently alleviated by ginsenoside Rb1.Moreover,Western blot showed that ginsenoside Rb1 increased the expressions of P-Akt, P-mTOR and reduced P-PTEN in vivo and vitro. Thus, the potent neuroprotection of ginsenoside Rb1 in artificial abnormal microenvironment is, at least partially, related to the activation of P-AKT/P-mTOR signaling pathway and inhibition of P-PTEN protein.

Appearance and Frequency of Gas Interface Artifacts Involving Small Bowel on Rapid-Voltage-Switching Dual-Energy CT Iodine-Density Images.

OBJECTIVE: The purpose of this study is to describe the appearance and frequency of gas interface artifacts in the jejunum that may mimic severe bowel disease on iodine-density images generated from rapid-voltage-switching dual-energy CT (DECT) scans. MATERIALS AND METHODS: Two readers retrospectively reviewed 108 consecutive abdominal rapid-voltage-switching DECT scans to record the presence of image artifacts in jejunal segments with different degrees of gaseous luminal filling, classified as full, partial, or absent. Readers viewed iodine-density images and corresponding 140-kVp and 65-keV virtual monochromatic images and classified the jejunal artifacts on iodine-density images as pseudostratified appearance of the bowel wall, pseudopneumatosis, pseudohyperenhancement, or pseudohypoenhancement. We correlated the presence of the artifacts with clinical features suggesting bowel disease. RESULTS: Image artifacts were found in 91 of 108 scans (84.3%), appeared in 148 of 265 jejunal segments (55.8%), and included each type except for pseudohypoenhancement. Artifacts occurred exclusively when gas was present in the bowel lumen and were seen in 59 of 59 (100%) fully gas-distended segments, 89 of 98 (90.8%) partially gas-distended segments, and none of 108 gas-absent segments (p < 0.0001). In fully and partially gas-distended jejunal segments (n = 157), 148 (94.3%) segments had two or more artifacts. None of the patients was found to have clinical bowel-related injury on follow-up of medical records. CONCLUSION: Pseudostratified appearance, pseudopneumatosis, and pseudohyperenhancement, but not pseudohypoenhancement, artifacts are common in gas-filled jejunal segments on iodine-density images generated from rapid-voltage-switching DECT scans and are not seen in the corresponding 140-kVp or 65-keV images. Knowledge of the appearance of such iodine-density image artifacts will avoid potential examination interpretation pitfalls.

UBTD1 induces cellular senescence through an UBTD1-Mdm2/p53 positive feedback loop.

The tumour suppressor p53 plays an important role in tumourigenesis. Besides inducing apoptosis, it regulates cellular senescence, which constitutes an important barrier to tumourigenesis. The mechanism of regulation of cellular senescence by p53 and its downstream pathway are poorly understood. Here, we report that the ubiquitin domain-containing 1 (UBTD1) gene, a new downstream target of p53, induces cellular senescence and acts as a novel tumour suppressor by a mechanism that depends on p53. Expression of UBTD1 increased upon cellular senescence induced by serial passageing of cultures, as well as by exposure to DNA-damageing drugs that induce premature senescence. Over-expression of UBTD1 induces senescence in human fibroblasts and cancer cells and attenuation of the transformed phenotype in cancer cells. UBTD1 is down-regulated in gastric and colorectal cancer tissues, and its lower expression correlates with a more aggressive phenotype and worse prognosis. Multivariate analysis revealed that UBTD1 expression was an independent prognostic factor for gastric cancer patients. Furthermore, UBTD1 increased the stability of p53 protein, by promoting the degradation of Mdm2 protein. Importantly, UBTD1 and p53 function mutually depend on each other in regulating cellular senescence and proliferation. Thus, our data suggest that, upon DNA damage, p53 induction by UBTD1 creates a positive feedback mechanism to further increase p53 expression. Our results establish UBTD1 as a regulator of cellular senescence that mediates p53 function, and provide insights into the mechanism of Mdm2 inhibition that impacts p53 dynamics during cellular senescence and tumourigenesis.

Association of rs712 polymorphism in Kras gene 3'-luntranslated region and cancer risk: a meta-analysis.

PURPOSE: Mutation and polymorphism of Kras oncogene are considered as candidate risk factor and drug response predictor for cancer. However, the conclusions of accumulating reports related to the relationship of rs712 of Kras gene and risk of cancer remain nuclear. METHODS: We performed a meta-analysis including 6 eligible studies containing 1661 cases and 2139 controls to explore the role of rs712 in the risk of cancer development. RESULTS: Meta-analysis results showed that rs712 allele T (P(H)=0.08, odds ratio/OR=1.35, 95% confidence interval/ CI=1.17-1.55) and genotype TT (P(H)=0.174, OR=2.32, 95% CI=1.60-3.37), and allele T carrier genotype (GT/TT) (P(H)=0.14, OR=1.30, 95% CI=1.10-1.55) were strongly associated with cancer in Chinese population. No evidence of association was observed between rs712 and risk of cancer in overall population. CONCLUSION: The findings suggested that allele T, genotype TT and allele T carrier (GT/TT) of rs712 may increase susceptibility to cancer risk in Chinese population, and can be used as a genetic factor for evaluating risk of cancer.

The Impact of Nursing Interventions on the Treatment Outcomes of Renal Cell Carcinoma with Postoperative Interleukin-2 and Recombinant Human Interferon.

Objective: This study investigates the impact of nursing interventions on treatment outcomes and adverse reaction rates in renal cell carcinoma (RCC) patients treated postoperatively with Interleukin-2 and recombinant human Interferon. Methods: In a retrospective analysis of 90 RCC patients, 43 received standard care (control group), while 47 received additional nursing interventions (intervention group), including psychological care, vital signs monitoring, dietary care, adverse reaction management, and post-discharge care. Patients with concurrent major diseases or other malignancies were excluded. Key assessments included clinical symptom improvement, treatment efficacy, and postoperative adverse reactions. Results: Among the 90 participants, no significant demographic differences were found between the two groups. The intervention group showed significant improvements in fever resolution, leukocyte normalization, and shorter hospital stays. The overall treatment effectiveness was similar in both groups (90.7% in the intervention group vs 91.5% in the control group). However, the intervention group experienced significantly fewer postoperative adverse reactions, including fever, gastrointestinal symptoms, bone marrow suppression, and neurological abnormalities (6.3% vs 23.2%). Conclusion: The study suggests that nursing interventions can improve treatment outcomes by reducing postoperative adverse reactions in RCC patients receiving postoperative Interleukin-2 and recombinant human Interferon. The overall effectiveness of treatment and care was comparable between the groups. Further extensive studies are needed to confirm these findings and fully understand the impact of nursing interventions on RCC patient outcomes.

LncRNA SNHG26 promotes gastric cancer progression and metastasis by inducing c-Myc protein translation and an energy metabolism positive feedback loop.

Metastasis is a bottleneck in cancer treatment. Studies have shown the pivotal roles of long noncoding RNAs (lncRNAs) in regulating cancer metastasis; however, our understanding of lncRNAs in gastric cancer (GC) remains limited. RNA-seq was performed on metastasis-inclined GC tissues to uncover metastasis-associated lncRNAs, revealing upregulated small nucleolar RNA host gene 26 (SNHG26) expression, which predicted poor GC patient prognosis. Functional experiments revealed that SNHG26 promoted cellular epithelial-mesenchymal transition and proliferation in vitro and in vivo. Mechanistically, SNHG26 was found to interact with nucleolin (NCL), thereby modulating c-Myc expression by increasing its translation, and in turn promoting energy metabolism via hexokinase 2 (HK2), which facilitates GC malignancy. The increase in energy metabolism supplies sufficient energy to promote c-Myc translation and expression, forming a positive feedback loop. In addition, metabolic and translation inhibitors can block this loop, thus inhibiting cell proliferation and mobility, indicating potential therapeutic prospects in GC.

Candesartan inhibits LPS-induced expression increase of toll-like receptor 4 and downstream inflammatory factors likely via angiotensin II type 1 receptor independent pathway in human renal tubular epithelial cells.

The present study was to determine whether candesartan, an angiotensin II type 1 receptor blocker (ARB), exerts anti-inflammatory effects through inhibiting the toll-like receptor 4 (TLR4) pathway in human renal tubular epithelial cells (HKCs). The experiments were carried on cultured HKCs. By means of flow cytometry, Western blot, RT-PCR and ELISA techniques, the TLR4 protein, angiotensin II type 1 receptor (AT1R) and phosphorylated nuclear factor-kappa B (NF-κB) p65 protein level, mRNA levels of macrophage chemoattractant protein-1 (MCP-1) and regulated upon expression normal T cell expressed and secreted (RANTES), as well as MCP-1 and RANTES protein concentrations in conditioned media were measured. The results showed that lipopolysaccharide (LPS) upregulated the TLR4 protein level in cultured HKCs. Application of LPS increased NF-κB activation and induced release of its downstream inflammatory factors including MCP-1 and RANTES. Candesartan reversed LPS-induced upregulation of TLR4 expression, inhibited NF-κB activation, and reduced MCP-1 and RANTES release. However, knockdown on AT1R by siRNA did not change those previous effects of candesartan. These results suggest that candesartan-induced anti-inflammatory effect may be through a novel pathway, independent of AT1R.

Herbal combinations against COVID-19: A network pharmacology, molecular docking and dynamics study.

OBJECTIVE: The aim of this study is to identify molecules from traditional Chinese medicine (TCM) with potential activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants. METHODS: We applied the Apriori algorithm to identify important combinations of herbs in the TCM prescriptions for the treatment of coronavirus disease 2019 (COVID-19). Then, we explored the active components and core targets using network pharmacology. In addition, the molecular docking approach was performed to investigate the interaction of these components with the main structural and non-structural proteins, as well as the mutants. Furthermore, their stability in the binding pockets was further evaluated with the molecular dynamics approach. RESULTS: A combination of Amygdalus Communis Vas., Ephedra Herba and Scutellaria baicalensis Georgi was selected as the important herbal combination, and 11 main components and 20 core targets against COVID-19 were obtained. These components, including luteolin, naringenin, stigmasterol, baicalein, and so on, were the potentially active compounds against COVID-19. The binding affinity of these compounds with the potential targets was as high as the positive controls. Among them, baicalein could interfere with multiple targets simultaneously, and it also interfered with the interaction between spike protein and angiotensin-converting enzyme 2 receptor. Additionally, almost all the systems reached stability during dynamics simulation. CONCLUSION: The combination of A. communis, Ephedra Herba and S. baicalensis was the most important herbal combination for the treatment of COVID-19. Baicalein may be a potential candidate against SARS-CoV-2 and its variants. Please cite this article as: Song JB, Zhao LQ, Wen HP, Li YP. Herbal combinations against COVID-19: A network pharmacology, molecular docking and dynamics study. J Integr Med. 2023;21(6):593-604.

Neuroprotection of Oral Edaravone on Middle Cerebral Artery Occlusion in Rats.

Edaravone has been widely used in the treatment of acute ischemic stroke. However, there has been no oral preparation of edaravone in the clinic. In this study, we assessed the effect and possible mechanisms of oral edaravone on the middle cerebral artery occlusion (MCAO) model in rats. Highly bioavailable form of novel edaravone formulation developed using self-nanomicellizing solid dispersion strategy which showed up to 16.1-fold improved oral bioavailability was considered oral edaravone. The male rats (n = 84) were randomly divided into sham; model; oral edaravone in low dose (10 mg/kg), medium dose (20 mg/kg), and high dose (30 mg/kg); and edaravone by intraperitoneal administration group (IP group, 10 mg/kg). Rats were treated with different drugs 5 h after the operation, twice a day for 7 days. The behavioral data were dose-dependently improved by oral edaravone and sensorimotor functions of the high dose group were similar to those of the edaravone by IP route group. Furthermore, oral edaravone significantly reduced cerebral infarction area and downregulated the levels of caspase-3, GFAP, Iba1, 3-NT, and 4-HNE, whereas upregulated those of Vamp-2 and Map-2 in a dose-dependent manner. Especially effect of the high dose on these molecules was equal to that of edaravone by IP administration. Taken together, our data suggest that the improvement of sensorimotor deficits by oral edaravone in high doses after ischemia is similar to that in edaravone by IP administration. Neuroprotection of oral edaravone is at least partial by minimizing oxidative stress, the overactivation of glial cells, and the levels of the apoptosis-associated proteins, and alleviating synaptic damage in a dose-dependent manner.

A New Predictive Model for the Prognosis of MDA5+ DM-ILD.

Purpose: The purpose of this study is to analyze clinical information and combine significant parameters to generate a predictive model and achieve a better prognosis prediction of dermatomyositis-associated interstitial lung disease with positive melanoma differentiation-associated gene 5 antibody (MDA5+ DM-ILD) and stratify patients according to prognostic risk factors appropriately. Methods: We retrospectively reviewed 63 patients MDA5+ DM-ILD who were treated in our hospital from January 2018 to January 2021. Our study incorporated most clinical characteristics in clinical practice to explore the associations and predictive functions of clinical characteristics and prognosis. Student's t-test, Mann-Whitney U-test, chi-squared test, Pearson correlation analysis, Cox regression analysis, R, receiver operating characteristic curves (ROC curves), and Kaplan-Meier survival curves were performed to identify independent predictors for the prognosis of MDA5+DM-ILD. Results: In all the 63 patients with MDA5+DM-ILD, 44 improved but 19 did not. Poor prognosis was found more frequently in patients who were older, clinically amyopathic variant of dermatomyositis (CADM), and/or with short duration, short interval of DM and ILD, long length of stay, fever, dyspnea, non-arthralgia, pulmonary infection, pleural effusion (PE), high total computed tomography scores (TCTs), ground-glass opacity (GGO), consolidation score, reticular score and fibrosis score, decreased forced vital capacity (FVC), forced expiratory volume in 1s (FEV1), albumin, A/G, glomerular filtration rate (GFR) and tumor necrosis factor α (TNFα), high titer of anti-MDA5, proteinuria, high levels of monocyte, lactate dehydrogenase (LDH), ferritin (FER), neuron specific enolase (NSE) and glucocorticoid, antibiotic, antiviral, and non-invasive positive pressure ventilation (NPPV). The multivariate Cox regression analysis demonstrated that duration, fever, PE, TCTs and aspartate transaminase (AST) were independent predictors of poor prognosis in patients with MDA5+DM-ILD. The nomogram model quantified the risk of 400-day death as: duration ≤ 4 months (5 points), fever (88 points), PE (21 points), TCTs ≥10 points (22 points), and AST ≥200 U/L (100 points) with high predictive accuracy and convenience. The ROC curves possessed good discriminative ability for combination of fever, PE, TCTs, and AST, as reflected by the area under curve (AUC) being.954, 95% CI 0.902-1.000, and sensitivity and specificity being 84.2 and 94.6%, respectively. Conclusion: We demonstrated that duration, fever, PE, TCTs, and AST could be integrated together to be independent predictors of poor prognosis in MDA5+ DM-ILD with highly predictive accuracy.

Blockade of phosphotyrosine pathways suggesting SH2 superbinder as a novel therapy for pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrotic disease with high mortality. Currently, pirfenidone and nintedanib are the only approved drugs for IPF by the U.S. Food and Drug Administration (FDA), but their efficacy is limited. The activation of multiple phosphotyrosine (pY) mediated signaling pathways underlying the pathological mechanism of IPF has been explored. A Src homology-2 (SH2) superbinder, which contains mutations of three amino acids (AAs) of natural SH2 domain has been shown to be able to block phosphotyrosine (pY) pathway. Therefore, we aimed to introduce SH2 superbinder into the treatment of IPF. Methods: We analyzed the database of IPF patients and examined pY levels in lung tissues from IPF patients. In primary lung fibroblasts obtained from IPF patient as well as bleomycin (BLM) treated mice, the cell proliferation, migration and differentiation associated with pY were investigated and the anti-fibrotic effect of SH2 superbinder was also tested. In vivo, we further verified the safety and effectiveness of SH2 superbinder in multiple BLM mice models. We also compared the anti-fibrotic effect and side-effect of SH2 superbinder and nintedanib in vivo. Results: The data showed that the cytokines and growth factors pathways which directly correlated to pY levels were significantly enriched in IPF. High pY levels were found to induce abnormal proliferation, migration and differentiation of lung fibroblasts. SH2 superbinder blocked pY-mediated signaling pathways and suppress pulmonary fibrosis by targeting high pY levels in fibroblasts. SH2 superbinder had better therapeutic effect and less side-effect compare to nintedanib in vivo. Conclusions: SH2 superbinder had significant anti-fibrotic effects both in vitro and in vivo, which could be used as a promising therapy for IPF.

Enriched environment mitigates depressive behavior by changing the inflammatory activation phenotype of microglia in the hippocampus of depression model rats.

BACKGROUND: Inflammation mediated by microglia has been shown to be involved in the pathogenesis of depression. The enriched environment (EE) can improve depression-like behaviors and reduce inflammatory reactions, but it is unclear whether this is by changing the inflammatory activation phenotype of microglia. METHOD: A depression rat model was established using chronic unpredictable stress (CUS) for four weeks. The rats were then treated with EE or fluoxetine administration during the following three weeks. Behavior tests including sucrose preference, forced swimming and open field were applied to evaluate the depression-like behaviors of rats at the baseline period prior to CUS, the end of fourth week and at the end of the seventh week. Microglial activation and hippocampal neuro-inflammation were detected on postmortem using immunofluorescence, western blotting, and real-time polymerase reaction (PCR). RESULT: The results showed that severe depressive-like behavior was induced by four weeks of CUS. Changes in peripheral blood inflammatory cytokines were detected by ELISA. Immunofluorescent staining showed the IBA-1 of microglia activation marker level significantly increased in affected rats. The hippocampal microglial activation state was determined by measuring the increased levels of iNOS an M1 marker and the decreased levels of CD206, an M2 marker. The activation of NF-κB upregulation of inflammatory cytokines in the hippocampus and factors such as IL-10 were decreased. This study showed that EE and chronic fluoxetine treatment alleviated the depressive-like behavior induced by chronic stress and significantly inhibited microglial activation, activated NF-κB inflammasome and increased pro-inflammatory cytokines. CONCLUSION: EE can alleviate depression-like behavior by modulating the phenotype of microglia, inhibiting pro-inflammatory genes, and promoting anti-inflammatory genes. Furthermore, EE can effectively reduce the phosphorylation and expression levels of NF-κB.

3',7',7'-Trimethyl-1'-phenyl-5',6',7',8'-tetra-hydro-spiro-[indoline-3,4'-(1H,4H-pyrazolo-[3,4-b]chromene)]-2,5'-dione.

The title spiro-oxindole compound, C(26)H(23)N(3)O(3), was prepared by the reaction of isatin, 3-methyl-1-phenyl-2-pyrazolin-5-one and 5,5-dimethyl-cyclo-hexane-1,3-dione in an ethanol solution. The fused cyclo-hexene ring adopts an envelope conformation. The dihedral angle between the aromatic and pyrazoline rings is 23.70 (8)°. An intra-molecular C-H⋯O inter-action occurs. The crystal structure is stabilized by N-H⋯N hydrogen-bonding inter-actions, leading to a zigzag chain along the b axis.

SCFAs-Induced GLP-1 Secretion Links the Regulation of Gut Microbiome on Hepatic Lipogenesis in Chickens.

The impact of gut microbiota and its metabolites on fat metabolism have been widely reported in human and animals. However, the critical mediators and the signal transductions are not well demonstrated. As ovipara, chicken represents a specific case in lipid metabolism that liver is the main site of lipid synthesis. The aim of this study is to elucidate the linkage of gut microbiota and fat synthesis in broiler chickens. The broilers were subjected to dietary treatments of combined probiotics (Animal bifidobacterium: 4 × 108 cfu/kg; Lactobacillus plantarum: 2 × 108 cfu/kg; Enterococcus faecalis: 2 × 108 cfu/kg; Clostridium butyrate: 2 × 108 cfu/kg, PB) and guar gum (1 g/kg, GG), respectively. Results showed that dietary supplementation of PB and GG changed the cecal microbiota diversity, altered short chain fatty acids (SCFAs) contents, and suppressed lipogenesis. In intestinal epithelial cells (IECs), SCFAs (acetate, propionate, and butyrate) up-regulated the expression of glucagon-like peptide-1 (GLP-1) via mitogen-activated protein kinase (MAPK) pathways, mainly via the phospho - extracellular regulated protein kinase (ERK) and phospho-p38 mitogen activated protein kinase (p38 MAPK) pathways. GLP-1 suppressed lipid accumulation in primary hepatocytes with the involvement of (AMP)-activated protein kinase/Acetyl CoA carboxylase (AMPK/ACC) signaling. In conclusion, the result suggests that SCFAs-induced GLP-1 secretion via MAPK pathway, which links the regulation of gut microbiota on hepatic lipogenesis in chickens.

Computed tomography perfusion in evaluating the therapeutic effect of transarterial chemoembolization for hepatocellular carcinoma.

AIM: To prospectively assess the changes in parameters of computed tomography (CT) perfusion pre- and post-transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) in different treatment response groups, and to correlate the changes with various responses of HCC to TACE. METHODS: Thirty-nine HCC patients underwent CT perfusion examinations pre-(1 d before TACE) and post-treatment (4 wk after TACE). The response evaluation criteria for solid tumors (RECIST) were referred to when treatment responses were distributed. Wilcoxon-signed ranks test was used to compare the differences in CT perfusion parameters pre- and post-TACE for different response groups. RESULTS: Only one case had treatment response to CR and the CT perfusion maps of post-treatment lesion displayed complete absence of signals. In the PR treatment response group, hepatic artery perfusion (HAP), hepatic arterial fracture (HAF) and hepatic blood volume (HBV) of viable tumors post-TACE were reduced compared with pre-TACE (P = 0.001, 0.030 and 0.001, respectively). In the SD group, all CT perfusion parameters were not significantly different pre- and post-TACE. In the PD group, HAP, HAF, portal vein perfusion (PVP) and hepatic blood flow (HBF) of viable tumors post-TACE were significantly increased compared with pre-TACE (P = 0.005, 0.012, 0.035 and 0.005, respectively). CONCLUSION: Changes in CT perfusion parameters of viable tumors are correlated with different responses of HCC to TACE. Therefore, CT perfusion imaging is a feasible technique for monitoring response of HCC to TACE.

CBX7 regulates stem cell-like properties of gastric cancer cells via p16 and AKT-NF-κB-miR-21 pathways.

BACKGROUND: Chromobox protein homolog 7 (CBX7), a member of the polycomb group (PcG) family of proteins, is involved in the regulation of cell proliferation and cancer progression. PcG family members, such as BMI, Mel-18, and EZH2, are integral constituents of the polycomb repressive complexes (PRCs) and have been known to regulate cancer stem cell (CSC) phenotype. However, the role of other PRCs' constituents such as CBX7 in the regulation of CSC phenotype remains largely elusive. This study was to investigate the role of CBX7 in regulating stem cell-like properties of gastric cancer and the underlying mechanisms. METHODS: Firstly, the role of CBX7 in regulating stem cell-like properties of gastric cancer was investigated using sphere formation, Western blot, and xenograft tumor assays. Next, RNA interference and ectopic CBX7 expression were employed to determine the impact of CBX7 on the expression of CSC marker proteins and CSC characteristics. The expression of CBX7, its downstream targets, and stem cell markers were analyzed in gastric stem cell spheres, common cancer cells, and gastric cancer tissues. Finally, the pathways by which CBX7 regulates stem cell-like properties of gastric cancer were explored. RESULTS: We found that CBX7, a constituent of the polycomb repressive complex 1 (PRC1), plays an important role in maintaining stem cell-like characteristics of gastric cancer cells via the activation of AKT pathway and the downregulation of p16. Spearman rank correlation analysis showed positive correlations among the expression of CBX7 and phospho-AKT (pAKT), stem cell markers OCT-4, and CD133 in gastric cancer tissues. In addition, CBX7 was found to upregulate microRNA-21 (miR-21) via the activation of AKT-NF-κB pathway, and miR-21 contributes to CBX7-mediated CSC characteristics. CONCLUSIONS: CBX7 positively regulates stem cell-like characteristics of gastric cancer cells by inhibiting p16 and activating AKT-NF-κB-miR-21 pathway.

Enriched environment combined with fluoxetine ameliorates depression-like behaviors and hippocampal SYP expression in a rat CUS model.

Effects of enriched environment (EE) combined with fluoxetine in a chronic unpredictable stress (CUS) rat model were examined in our study. Thirty male Sprague-Dawley rats were randomly divided into control group, CUS group, CUS+EE group, CUS+fluoxetine group, and CUS+EE+fluoxetine group (n=six per group). Rats in the CUS group were bred under conditions of CUS and separation for 6 weeks; Control group animals were bred in group cages (three rats per cage) under standard laboratory conditions for 6 weeks; Rats in CUS+EE group, CUS+fluoxetine group, and CUS+EE+fluoxetine groups were bred under the conditions of CUS and separation for 6 weeks and had an intervention of EE, an oral gavage of fluoxetine, and an intervention of EE+oral gavage of fluoxetine, respectively, every day for the final 3 weeks. Every rat underwent a behavioral assessment at the beginning of the 1st week, at the end of the 3rd week and at the end of the 6th week. Behavioral assessments included sucrose water consumption, weight measurement, and an open field test (measuring horizontal moving distance, rearing behavior, and defecation). Finally, the level of synaptophysin expressed in the hippocampus was measured with immunohistochemistry. We found that EE, fluoxetine, and EE+fluoxetine all reversed the depression-like behaviors of CUS rats. The effect of EE+fluoxetine appeared to be superior to EE or fluoxetine alone; the expression level of synaptophysin in CA1, CA3, and DG of the hippocampus was decreased in CUS rats, however, exposure to EE, fluoxetine, and EE+fluoxetine all reversed this decrease.

Comparison of hepatocellular carcinoma conspicuity on hepatobiliary phase images with gadoxetate disodium vs. delayed phase images with extracellular cellular contrast agent.

OBJECTIVE: To compare the conspicuity of hepatocellular carcinoma (HCC) on hepatobiliary phase of gadoxetate disodium-enhanced vs. delayed phase of gadodiamide-enhanced MR images, relative to liver function. METHODS AND MATERIALS: We retrospectively identified 86 patients with newly diagnosed HCC between 2010 and 2013 and recorded the severity of liver disease by Child-Pugh class (CPC). 38 patients had gadodiamide-enhanced 5-min delayed and 48 had gadoxetate disodium-enhanced 20-min delayed hepatobiliary MR images. The conspicuity of 86 HCCs (mean size, 2.7 cm) was graded visually on a 3-point scale and quantified by liver-to-tumor contrast ratios (LTC). The relative liver parenchymal enhancement (RPE) was measured. For different CPCs, we compared the conspicuity of HCC and RPE between gadodiamide and gadoxetate. RESULTS: In patients with CPC A, the visual conspicuity and LTC of the 27 HCCs imaged with gadodiamide were significantly lower than those of the 38 HCCs with gadoxetate (P < 0.01, <0.01, respectively). RPE was lower in gadodiamide scans than gadoxetate scans (P < 0.01). Conversely, in patients with CPC B and C, HCCs appeared more frequently as definite hypointensity when imaged with gadodiamide (72.7%, 8/11) than gadoxetate (20%, 2/10, P = 0.03). LTC (mean 18.1 vs. 7.5, P = 0.04) and RPE (mean 75.5 vs. 45.4, P = 0.04) was significantly higher in the gadodiamide than gadoxetate scans. CONCLUSION: In patients with compromised liver function, hypointensity of HCC is more conspicuous in the gadodiamide delayed phase than the gadoxetate hepatobiliary phase. This likely reflects the high extracellular accumulation of gadodiamide and poor hepatocyte uptake of gadoxetate in patients with compromised liver function.