End stage heart failure(ESHF) is the terminal stage of heart failure in patients with heart failure, or refractory heart failure. heart transplantation(HT) and mechanical circulatory assistance represented by ventricular assist device(VAD) are the main treatments for circulatory support in patients with ESHF. However, the serious shortage of donors has restricted the extensive development of HT. VAD technology, represented by left ventricular assist device(LVAD), has developed rapidly, and the 2-year survival rate after surgery has approached of HT. Although LVAD support can directly alleviate symptoms of left heart failure, it only partially relieves symptoms of right heart failure, resulting in high readmission rates.Therefore, more precise monitoring and regulation of right heart function in LVAD recipients is key to improving long-term prognosis. This article aims to provide an overview of strategies for the regulation of right heart function in patients after LVAD implantation.

OBJECTIVE: To explore the mechanisms that mediate the anti-inflammatory activity of Eurycoma longifolia. METHODS: Kunming mouse models of xylene-induced ear swelling and lipopolysaccharide (LPS)-induced acute pneumonia were used to compare the anti- inflammatory activities of aqueous and ethanol extracts of Eurycoma longifolia. UPLC-Q-TOF-MS/MS was used to identify the chemical composition in the ethanol extract of Eurycoma longifolia, based on which the potential antiinflammatory targets of Eurycoma longifolia were screened using the databases including SwissADME, SwissTargetPrediction, and Genecards. The String database was used to generate the protein-protein interaction (PPI) network, and Cytoscape was used for network topology analysis and screening the core targets. The enrichment of the core targets was analyzed using Metascape database, the core components and targets were docked with Autodock software, and the docking results were visualized using Pymol software. In a RAW264.7 cell model of LPS-induced inflammation, the Griess reagent was used to measure NO level, and Western blotting was performed to detect the expression levels of MAPK1, JAK2, and STAT3 proteins to verify the anti- inflammatory mechanism of Eurycoma longifolia. RESULTS: The ethanol extract (75%) of Eurycoma longifolia (ELE) was the active site, which contained a total of 37 chemical components. These chemical compounds and diseases had 541 targets, involving the JAK/STAT3, cAMP and other signaling pathways. Twelve indicator components were identified, which all showed good results of molecular docking with two core targets involved in the signaling pathways. In the cell validation experiment, treatment of the cells with low-, medium-, and high-dose ELE significantly reduced NO release in the cells, and ELE at the medium dose significantly decreased the cellular expressions of JAK2 and STAT3. CONCLUSION The anti-inflammatory activity of Eurycoma longifolia is attributed primarily to its active ingredients bitter lignin and alkaloids, which may regulate the JAK/STAT3 signaling pathway by targeting JAK2 and STAT3.
Animals ; Mice ; Network Pharmacology ; Eurycoma ; Lipopolysaccharides ; Molecular Docking Simulation ; Tandem Mass Spectrometry ; Anti-Inflammatory Agents/pharmacology* ; Ethanol ; Plant Extracts/pharmacology*

OBJECTIVE: To investigate the effect of dihydromyricetin (DHM) on cardiac insufficiency in diabetic rats and explore the underlying mechanism. METHOD: Twenty-four male SD rats were randomized equally into normal control group, type 2 diabetes (T2DM) group fed on a high-glucose and high-fat diet for 6 weeks with low-dose streptozotocin (STZ) injection, metformin (MET) group with daily intragastric administration of MET (150 mg/kg) for 8 weeks after T2DM modeling, and dihydromyricetin (DHM) group with daily intragastric administration of DHM (250 mg/kg) for 8 weeks after modeling. The levels of fasting blood glucose, low density lipoprotein (LDL-C), triglyceride (TG), total cholesterol (TC), high density lipoprotein (HDL-C) and glycosylated hemoglobin (HbA1c) of the rats were measured, and plasma levels of insulin and high mobility group protein-1 (HMGB1) were detected with ELISA. The cardiac function of the rats was assessed using color echocardiography, ECG was measured using a biological signal acquisition system, and myocardial pathology was observed with HE staining. The protein expressions of HMGB1, nuclear factor-κB (NF-κB) p65 and phospho-NF-κB p65 (p-NF-κB p65) in the myocardial tissue were detected using Western blotting. RESULTS: Compared with the control group, the rats in T2DM group showed significant anomalies in cardiac function after modeling with significantly increased plasma HMGB1 level and expressions of HMGB1, NF-κB p65 and p-NF-κB p65 proteins in the myocardial tissue (P < 0.05 or 0.01). Treatment with DHM significantly improved the indexes of cardiac function of the diabetic rats (P < 0.05 or 0.01), decreased plasma HMGB1 level and down-regulated the protein expressions of HMGB1 and p-NF-κB p65 in the myocardial tissue (P < 0.05 or 0.01). CONCLUSION DHM treatment can improve cardiac function in diabetic rats possibly by down-regulation of HMGB1 and phospho-NF-κB p65 expressions in the myocardium.
Animals ; Diabetes Mellitus, Experimental/metabolism* ; Diabetes Mellitus, Type 2/metabolism* ; Flavonols ; HMGB1 Protein ; Heart Failure ; Male ; Metformin/therapeutic use* ; NF-kappa B/metabolism* ; Rats ; Rats, Sprague-Dawley

OBJECTIVE: To investigate the role of Numb in regulating mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling pathway. METHODS: Male BALB/C mouse models of acute kidney injury (AKI) were subjected to intravenous injections of Numb-siRNA or NC-siRNA with or without intraperitoneal cisplatin injections. After the treatments, the expressions and distribution of Numb and megalin in the renal tissues of the mice were detected with immunohistochemistry, and the renal expressions of Numb, S6, p-S6, S6K1, p-S6K1, 4EBP1 and p-4EBP1 were examined with Western blotting. The proximal renal tubular epithelial cells were isolated from the mice transfected with Numb-siRNA for in vitro culture. In NRK-52E cells, the effects of amino acid stimulation, Numb knockdown, and V1G1 overexpression, alone or in combination, on expressions of Numb, S6 and p-S6 were detected with Western blotting; the expressions of AMPK and p-AMPK were also detected in transfected NRK-52E cells, mouse kidneys and cultured mouse renal tubular epithelial cells. RESULTS: In BALB/C mice, injection of Numb-siRNA caused significant reductions of Numb and p-S6 expressions without affecting megalin expression in the renal proximal tubules (P < 0.05). Cisplatin treatment obviously upregulated p-S6K1 and p-4EBP1 expressions in the kidneys of the mice (P < 0.05), and this effect was significantly inhibited by treatment with Numb-siRNA (P < 0.05). In NRK-52E cells, amino acid stimulation significantly upregulated the expression of p-S6 (P < 0.05), which was strongly suppressed by transfection with Numb-siRNA (P < 0.05). Numb knockdown inhibited AMPK activation in NRK-52E cells, mouse kidneys and primary proximal tubular epithelial cells (P < 0.05). Numb knockdown significantly downregulated V1G1 expression in NRK-52E cells (P < 0.05), and V1G1 overexpression obviously reversed the inhibitory effect of Numb-siRNA on S6 phosphorylation (P < 0.05). CONCLUSION Numb promotes the activation of mTORC1 signaling in proximal tubular epithelial cells by upregulating V1G1 expression.
Animals ; Male ; Mice ; Amino Acids/pharmacology* ; AMP-Activated Protein Kinases/metabolism* ; Cisplatin/pharmacology* ; Epithelial Cells ; Low Density Lipoprotein Receptor-Related Protein-2/metabolism* ; Mammals/metabolism* ; Mechanistic Target of Rapamycin Complex 1/metabolism* ; Membrane Proteins/metabolism* ; Mice, Inbred BALB C ; Nerve Tissue Proteins/metabolism* ; RNA, Small Interfering/metabolism* ; Signal Transduction ; Vacuolar Proton-Translocating ATPases/metabolism*

Esculetin, a natural derivative from the traditional and widely-used Chinese medicinal herb Cortex Fraxini, has a variety of pharmacological effects, especially in anti-inflammation. However, it is not clear whether esculetin has a therapeutic effect on sepsis. This study aimed to investigate the anti-inflammatory and protective effects of esculetin on early sepsis. The results showed that the lung injury was significantly relieved with the treatment of esculetin, accompanied with the restrained production of inflammatory factors including IL-1β, IL-6, TNF-α, CCL2 and iNOS during the early phase of E.coli-induced sepsis. Of note, activation of NF-κB and STAT1/STAT3 signals, the main upstream signals of many inflammatory factors, were attenuated by esculetin in both lung tissues from septic mice and LPS-stimulated macrophage. These findings suggested that the protection of esculetin against early sepsis should be related to its anti-inflammatory effect, which was at least partly due to its inhibition on NF-κB and STAT1/STAT3 signaling pathway in macrophage. Thus, esculetin could serve as a potential therapeutic agent by rebalancing innate immune response in macrophage for the treatment of early sepsis.

In the original publication, Figure 4G was incorrectly published. The correct version of Figure 4G is presented in this correction. This correction does not affect the conclusions of the paper.

The present study was designed to examine the therapeutic effects of Botulinum neurotoxin A (BoNT/A) on depression-like behaviors in mice and to explore the potential mechanisms. These results revealed that a single facial injection of BoNT/A induced a rapid and prolonged improvement of depression-like behaviors in naïve and space-restriction-stressed (SRS) mice, reflected by a decreased duration of immobility in behavioral despair tests. BoNT/A significantly increased the 5-hydroxytryptamine (5-HT) levels in several brain regions, including the hippocampus and hypothalamus, in SRS mice. BoNT/A increased the expression of the N-methyl-D-aspartate receptor subunits NR1 and NR2B in the hippocampus, which were significantly decreased in SRS mice. Furthermore, BoNT/A significantly increased the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus, hypothalamus, prefrontal cortex, and amygdala, which were decreased in SRS mice. Finally, BoNT/A transiently increased the levels of phosphorylated extracellular signal-regulated kinase (p-ERK) and cAMP-response element binding protein (p-CREB), which were suppressed in the hippocampus of SRS mice. Collectively, these results demonstrated that BoNT/A treatment has anti-depressant-like activity in mice, and this is associated with increased 5-HT levels and the activation of BDNF/ERK/CREB pathways in the hippocampus, supporting further investigation of BoNT/A therapy in depression.

Objective To investigate the expression of LncRNA TCONS_00003757 in papillary thyroid carcinoma ( PTC) , and to explore the effect of LncRNA TCONS_00003757 on the proliferation, migration, and invasion in TPC-1 cells. Methods Sixty cases of papillary thyroid carcinoma specimens and paired normal tissues were collected after surgery from October 2017 to March 2018 in the Tangshan Workers Hospital. Real-time PCR analysis was used to examine the expression level of LncRNA TCONS_00003757 in PTC tissues, and the association of LncRNA TCONS_00003757 expression levels with the clinicopathological data of patients was analyzed. The effects of LncRNA TCONS_00003757 and ST3GAL5 silencing on the proliferation, migration, and invasion in TPC-1 cells were assessed by MTT, scratch test, and transwell assay. Protein expression of ST3GAL5 was detected by Western blot after LncRNA TCONS_00003757 silencing. Results LncRNA TCONS_00003757 expression was increased in PTC tissues compared with that in normal tissues ( P<0. 05 ) , which was correlated with capsule invasion and lymph node metastasis( P<0.05) . LncRNA TCONS_00003757 expression in TPC-1 cells was higher than that in normal thyroid follicular epithelial Nthy-ori 3-1 cells(P<0.05). LncRNA TCONS_00003757 and ST3GAL5 silencing inhibited the proliferation, migration, and invasion of thyroid cancer TPC-1 cells, and ST3GAL5 expression was decreased after LncRNA TCONS_00003757 silencing (P<0.05). Conclusion LncRNA TCONS_00003757 expression in PTC is significantly increased and correlated with its occurrence and development. Silencing LncRNA TCONS_00003757 may inhibit the proliferation, migration, and invasion of thyroid papillary cancer cells via decreasing ST3GAL5 expression.

Objective To investigate the mRNA level of glucocorticoid receptor α (GRα) and heat shock protein 90 (HSP90) in peripheral blood mononuclear cells (PBMCs) and the plasma protein level of macrophage migration inhibitory factor (MIF) in patients with systemic lupus erythematosus (SLE) and to analyze their association with glucocorticoid (GC) resistance.Methods One hundred and six patients with SLE and thirty-eight healthy controls were enrolled in this study.Transcription levels of GRα and HSP90 were determined by real-time polymerase chain reaction.Enzyme-linked immunosorbent assay was used to detect the protein level of plasma MIF.The association between these parameters and GC resistance was analyzed by Spearman correlation analysis.The multivariate logistic regression model was used to analyze the risk factors for GC resistance.Results The mRNA level of GRα and HSP90 in GC resistance group was significantly lower than that in GC sensitive group [10.18(3.12,17.20) vs 16.83(12.01,24.18), P =0.001;18.46(14.77,26.45) vs 25.84 (17.97,35.90), P =0.005].MIF protein level in GC resistance group was significantly higher than that in GC sensitive group [(23.21 ±7.98) μg/L vs (18.34 ±6.29)μg/L;P =0.013].The mRNA level of HSP90 in the high MIF group was significantly lower than that in the low MIF group [23.67 (13.84,28.32) vs 26.64 (23.61,47.16);P =0.001], as well as HSP90/GRαratio(P =0.008).Additionally, the plasma protein level of MIF was negatively correlated with HSP90 (r =-0.275, P =0.004) and HSP90/GRα ratio(r =-0.341, P ＜ 0.001).SLE activity index score in GC resistance group was significantly higher than that in GC sensitive group [(12.23 ±2.86) μg./L vs (9.63 ± 3.48) μg/L;P =0.003].Logistic regression model indicated that disease activity was an independent risk factor for GC resistance (OR =17.481, 95％ CI 1.747-174.903, P =0.015).Conclusions Our preliminary findings suggest that low mRNA level of GRα and HSP90 and high protein level of MIF are associated with GC resistance.Elevated MIF level in SLE patients may play an important role in the development of GC resistance through down-regulating HSP90 and destabilizing the balance of HSP90/ Grα.Disease activity is the risk factor for GC resistance, which might be the viable evidence of therapy response.

Objective To explore the anti-apoptotic mechanism of Roux-en-Y gastric bypass (RYGB) through exam?ine the postoperative change of adiponectin levels and expressions of pancreatic islets relative apoptotic protein. Methods Sixty SD rats were randomly allocated to RYGB group (n=20), type 2 diabetes mellitus group (T2DM, n=20) and normal con?trol group (NC, n=20). Rats in the NC group were fed with normal diet. In order to make type 2 diabetic rat models, the rats in the T2DM and RYGB groups were fed with high fat diet (22.19 kJ/g) combined with administration of intraperitoneal strep?tozotocin injection (STZ, 30 mg/kg) on the 13th day of high fat diet. RYGB operation were performed in RYGB group and sham-operation were performed in the T2DM and NC groups when diabetic model was contructed. Rats were weight preoper?atively and at the 7th, 14th, 21st days after operations. Fasting plasma glucose and adiponectin (ELISA) were measured preoper?atively and at 21st day postoperatively. Protein expressions of Bcl-2,Caspase 8 and Caspase 9 in pancreatic islets were ex?amined by immunohistochemistry at the 21st day postoperatively. Results Body weights do not vary significantly among three groups preoperatively. Compared to rats in the NC group, fast plasma glucose level was higher but adiponectin was low?er in rats in RYGB and T2DM groups. Body weights of rats in RYGB group decreased significantly compared to those of rats in NC and T2DM groups postoperatively. Compared to rats in T2DM group, fasting glucose level was lower while adiponectin concentrations was higher in rats in RYGB group but no differences of these parameters were seen in rats in NC group at the 21st day postoperatively. Expression of Bcl-2 in RYGB group was significantly elevated while expressions of Caspase 8 and Caspase 9 were significantly decreased compared to those in T2DM group postoperatively. Conclusion Adiponectin levelswas elevated;expressions of Bcl-2 was increased;expressions of Caspase 8, Caspase 9 were decreased upon RYGB opera?tion in T2DM model. RYGB might reduce pancreatic islets apoptosis through mitochondrial pathway.