In our previous studies, we reported that myeloid differentiation protein 1 (MD1) serves as a negative regulator in several cardiovascular diseases. However, the role of MD1 in heart failure with ...preserved ejection fraction (HFpEF) and the underlying mechanisms of its action remain unclear. Eight‐week‐old MD1‐knockout (MD1‐KO) and wild‐type (WT) mice served as models of HFpEF induced by uninephrectomy, continuous saline or d‐aldosterone infusion and a 1.0% sodium chloride treatment in drinking water for 4 weeks to investigate the effect of MD1 on HFpEF in vivo. H9C2 cells were treated with aldosterone to evaluate the role of MD1 KO in vitro. MD1 expression was down‐regulated in the HFpEF mice; HFpEF significantly increased the levels of intracellular reactive oxygen species (ROS) and promoted autophagy; and in the MD1‐KO mice, the HFpEF‐induced intracellular ROS and autophagy effects were significantly exacerbated. Moreover, MD1 loss activated the p38‐MAPK pathway both in vivo and in vitro. Aldosterone‐mediated cardiomyocyte autophagy was significantly inhibited in cells pre‐treated with the ROS scavenger N‐acetylcysteine (NAC) or p38 inhibitor SB203580. Furthermore, inhibition with the autophagy inhibitor 3‐methyladenine (3‐MA) offset the aggravating effect of aldosterone‐induced autophagy in the MD1‐KO mice and cells both in vivo and in vitro. Our results validate a critical role of MD1 in the pathogenesis of HFpEF. MD1 deletion exaggerates cardiomyocyte autophagy in HFpEF via the activation of the ROS‐mediated MAPK signalling pathway.
A comprehensive mechanistic study conducted on the formation mechanism of five-fold twinned copper nanowires by heating copper(I) chloride with oleylamine at 170 °C is presented. Electron microscopy ...and UV–visible absorption spectra are used to analyze the growth mechanism of copper nanowires. High-resolution transmission electron microscopy and selected-area electron diffraction are used to investigate the detailed structure of copper nanowires and nanoparticles, and a five-twinned structure is shown to exist in the copper nanowires and nanoparticles. Additionally, experiments have been performed to indirectly confirm that oleylamine preferentially adsorbs on the {100} facets of growing crystals. On the basis of the above results, the self-seeded growth of copper nanowires is confirmed. In the initial stage of reactions, copper nanoparticles with two distinctive sizes are formed. As the reaction proceeds, larger five-twinned copper nanoparticles serve as seeds for anisotropic crystal growth. Further, copper atoms generated from an Ostwald ripening process or reduction reactions of a copper(I) chloride–oleylamine complex continue to deposit and crystallize on the twin boundaries. Once the {110} planes are generated, oleylamine preferentially adsorbs on the newly formed {100} facets and then guides the formation of nanowires. The electrical resistivity of a single copper nanowire is measured to be 41.25 nΩ-m, which is of the same order of magnitude as the value of bulk copper (16.78 nΩ-m). Finally, an effective surface-enhanced Raman spectroscopy active substrate made of copper nanowire is used to detect the 4-mercaptobenzoic acid molecules.
Approximately 30% of patients with Epstein-Barr virus (EBV)-positive advanced nasopharyngeal carcinoma (NPC) display chemoresistance to cisplatin-based regimens, but the underlying mechanisms are ...unclear. The Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1), a functional homologue of the tumor necrosis factor receptor family, contributes substantially to the oncogenic potential of EBV through the activation of multiple signaling pathways, and it is closely associated with a poorer prognosis for NPC. Recent studies show that EBV infection can induce the expression of many cellular miRNAs, including microRNA-21, a biomarker for chemoresistance. However, neither a link between LMP1 expression and miR-21 upregulation nor their cross talk in affecting chemoresistance to cisplatin have been reported. Here, we observed that stable LMP1-transformed NPC cells were less sensitive to cisplatin treatment based on their proliferation, colony formation, the IC50 value of cisplatin and the apoptosis index. Higher levels of miR-21 were found in EBV-carrying and LMP1-positive cell lines, suggesting that LMP1 may be linked to miR-21 upregulation. These data were confirmed by our results that exogenous LMP1 increased miR-21 in both transiently and stably LMP1-transfected cells, and the knock down of miR-21 substantially reversed the resistance of the NPC cells to cisplatin treatment. Moreover, the proapoptotic factors programmed cell death 4 (PDCD4) and Fas ligand (Fas-L), which were negatively regulated by miR-21, were found to play an important role in the program of LMP1-dependent cisplatin resistance. Finally, we demonstrated that LMP1 induced miR-21 expression primarily by modulating the PI3K/AKT/FOXO3a signaling pathway. Taken together, we revealed for the first time that viral LMP1 triggers the PI3K/Akt/FOXO3a pathway to induce human miR-21 expression, which subsequently decreases the expression of PDCD4 and Fas-L, and results in chemoresistance in NPC cells.
In comparison to the well-characterized bottom-up synthesis of Au and Ag nanomaterials, the synthesis of Cu nanocrystals with well-defined and controllable shapes is still in need of improvement. ...Among the many shapes, a cube covered by six {100} facets can be regarded as a standard model to study the surface properties of {100} facets. Herein, we have prepared monodisperse Cu nanoparticles having a slightly truncated cubic shape with an average edge length of 75.7 nm and a standard deviation of 3.87% by using CuCl as the precursor, oleylamine as the reaction solvent, and trioctylphosphine and octadecylamine as shape control agents. The as-prepared Cu nanocubes tend to self-assemble on transmission electron microscopy grids or silicon substrates. Electron microscopy and small-angle X-ray scattering reveal that the Cu nanocubes prefer to self-assemble into 2D or 3D rhombohedral structures (RS). Large-area dense-packed films (1.5 cm × 2.5 cm) composed of monodisperse Cu nanocubes were fabricated by immersing a Si substrate in a dispersion of dodecanethiol-capped Cu nanocubes in toluene and evaporating the toluene at a controlled rate while holding the substrate at an angle. The electrical properties of the Cu films with various thickness and annealing temperatures were studied.
New Findings
What is the central question of this study?
In this study, we investigated whether MD1 interacted with the sympathetic nerves in ventricular arrhythmia (VA) during heart failure with ...preserved ejection fraction (HFpEF).
What is the main finding and its importance?
Mice with HFpEF showed increased susceptibility to VA, adverse electrical remodelling, impaired heart rate variability, enhanced sympathetic hyperactivity, activation of the NLRP3 inflammasome and increased interleukin‐1β release. These changes induced by HFpEF were exacerbated by MD1 deficiency.
Sympathetic hyperactivity can promote malignant ventricular arrhythmia (VA), and myeloid differentiation 1 (MD1) has been reported to play an important role in obesity‐induced VA. However, it is not known whether an interaction of MD1 with sympathetic hyperactivity contributes to the VA induced by heart failure with preserved ejection fraction (HFpEF). The aim of this study was to investigate the potential interaction between MD1 and sympathetic hyperactivity in HFpEF‐induced VA and the underlying mechanism. Eight‐week‐old MD1‐knockout (MD1‐KO) and wild‐type (WT) mice were subjected to a model of HFpEF induced by uninephrectomy, a continuous saline or d‐aldosterone infusion and provision of drinking water containing 1.0% sodium chloride for 4 weeks. Echocardiography and haemodynamics were used to verify the model of HFpEF. An isolated electrophysiological study was performed to assess the susceptibility to VA. Four weeks later, the mice with HFpEF showed an increased heart weight to tibia length ratio, decreased left ventricular minimum rates of pressure rise (dP/dtmin), increased τ, lung weight to tibia length ratio and preserved left ventricular ejection fraction compared with WT mice. The mice with HFpEF exhibited increased susceptibility to VA, as shown by the shortened effective refractory period, prolonged action potential duration (APD), increased APD alternans threshold and higher incidence of VA. Moreover, we also found that mice with HFpEF showed impaired heart rate variability, sympathetic hyperactivity, activation of the NLRP3 inflammasome and increased interleukin‐1β release. These changes induced by HFpEF were exacerbated by MD1 deficiency. We conclude that MD1‐KO contributes to sympathetic hyperactivity and facilitates VA in HFpEF via activation of the NLRP3 inflammasome. Treatment targeting MD1 and NLRP3 might decrease the risk of HFpEF‐induced VA.
At present, the optimal treatment for posterior cruciate ligament tibial avulsion fracture (PCLTAF) combined with concomitant ipsilateral lower limb fractures remains unclear. The present study aimed ...to assess the preliminary outcomes of treatment for PCLTAF with concomitant ipsilateral lower limb fractures by open reduction and internal fixation (ORIF).
The medical records of patients who sustained PCLTAF with concomitant ipsilateral lower limb fractures between March 2015 and February 2019 and underwent treatment at a single institution were retrospectively reviewed. Imaging examinations performed at the time of injury were applied to identify concomitant ipsilateral lower limb fractures. We used 1:2 matching between patients with PCLTAF combined with concomitant ipsilateral lower limb fractures (combined group; n = 11) and those with isolated PCLTAF (isolated group; n = 22). Outcome data were collected, including the range of motion (ROM) and visual analogue scale (VAS), Tegner, Lysholm, and International Knee Documentation Committee (IKDC) scores. At the final follow-up, the clinical outcomes were compared between the combined and isolated groups and between patients who underwent early-stage surgery and those who underwent delayed treatment for PCLTAF.
Thirty-three patients (26 males, 7 females) were included in this study, with eleven patients having PCLTAF and concomitant ipsilateral lower limb fractures and a follow-up of 3.1 to 7.4 years (average, 4.8 years). Compared to patients in the isolated group, patients in the combined group demonstrated significantly worse Lysholm scores (85.7 ± 5.8 vs. 91.5 ± 3.9, p = 0.040), Tegner scores (4.4 ± 0.9 vs. 5.4 ± 0.8, p = 0.006), and IKDC scores (83.6 ± 9.3 vs. 90.5 ± 3.0, p = 0.008). Inferior outcomes were found in patients with delayed treatment.
Inferior results were found in patients with concomitant ipsilateral lower limb fractures, while better outcomes were obtained in patients with PCLTAF through early-stage ORIF using the posteromedial approach. The present findings may help determine the prognoses of patients with PCLTAF combined with concomitant ipsilateral lower limb fractures treated through early-stage ORIF.
The abnormal fibrillation of human islet amyloid polypeptide (hIAPP) is associated with development of type II diabetes mellitus (T2DM). (-)-Epigallocatechin gallate (EGCG) can bind amyloid proteins ...to inhibit the fibrillation of these proteins. However, the mechanic detail of EGCG inhibiting amyloid formation is still unclear at the molecular level. In the present work, we sought to investigate the effect of EGCG on amidated hIAPP (hIAPP-NH
) fibrillation and aggregation by using spectroscopic and microscopic techniques, and also sought to gain insights into the interaction of EGCG and hIAPP
by using spectroscopic experiments and quantum chemical calculations. ThT fluorescence, real-time NMR, and TEM studies demonstrated that EGCG inhibits the formation of hIAPP-NH
fibrils, while promoting the formation of hIAPP-NH
amorphous aggregates. Phenylalanine intrinsic fluorescence and NMR studies of the EGCG/hIAPP
complex revealed three important binding sites including the A ring of EGCG, residue Phe23, and residue Ile26. DFT calculations identified the dominant binding structures of EGCG/Phe23 and EGCG/Ile26 complexes, named structure I and structure II, respectively. Our study demonstrates the inhibitory mechanism of EGCG on fibrillation and aggregation of hIAPP-NH
in which EGCG interacts with hIAPP-NH
through hydrogen bonding and π-π interactions between the A ring and residue Phe23 as well as hydrophobic interactions between the A ring and residue Ile26, which can thus inhibit the interpeptide interaction between hIAPP-NH
monomers and finally inhibit fibrillation of hIAPP-NH
. This study agrees with and reinforces previous studies and offers an intuitive explanation at both the atomic and molecular levels. Our findings may provide an invaluable reference for the future development of new drugs in the management of diabetes.
Red cell distribution width (RDW) has been associated with heart failure (HF) hospitalization in the general population, but the correlation to HF hospitalization in patients with hypertrophic ...cardiomyopathy (HCM) is unclear.Ninety-eight HCM patients without a history of HF were enrolled and RDW was assessed as a predictor.During a 16.8 ± 9.0 month follow-up period, 17 subjects were hospitalized due to HF. HF hospitalization patients had higher RDW than non-HF patients (14.7 ± 1.4% versus 13.0 ± 0.9%, P < 0.001). The cut-off value of RDW for predicting HF hospitalization was 14% with a sensitivity of 83.2% and a specificity of 82.7%. Multivariate analysis demonstrated that brain natriuretic protein (BNP) (HR 1.028, 95% CI 1.011-1.045, P = 0.001) and RDW (HR 1.711, 95% CI 1.042-2.809, P = 0.034) were predictors of HF hospitalization.High RDW is an independent predictor of HF hospitalization and might be useful for predicting the prognosis in HCM patients.
Danhong injection (DHI) is a traditional Chinese medicine injection that promotes blood circulation and removes blood stasis and has been widely used in the treatment of stroke. Many studies have ...focused on the mechanism of DHI in acute ischemic stroke (IS); however, few studies have thoroughly explored its role during recovery. In this study, we aimed to determine the effect of DHI on long-term neurological function recovery after cerebral ischemia and explored the related mechanisms. Middle cerebral artery occlusion (MCAO) was used to establish an IS model in rats. The efficacy of DHI was assessed using neurological severity scores, behaviors, cerebral infarction volume and histopathology. Immunofluorescence staining was performed to assess hippocampal neurogenesis. An in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) cell model was constructed and western-blot analyses were performed to verify the underlying mechanisms. Our results showed that DHI treatment greatly reduced the infarct volume, promoted neurological recovery and reversed brain pathological changes. Furthermore, DHI promoted neurogenesis by increasing the migration and proliferation of neural stem cells, and enhancing synaptic plasticity. Moreover, we found that the pro-neurogenic effects of DHI were related to an increase in brain-derived neurotrophic factor (BDNF) expression and the activation of AKT/CREB, which were attenuated by ANA-12 and LY294002, the inhibitors of the BDNF receptor and PI3K. These results suggest that DHI improves neurological function by enhancing neurogenesis and activating the BDNF/AKT/CREB signaling pathways.
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•We focus on the effects of DHI on long-term neurological function after stroke.•DHI improves neurological functional rehabilitation by enhancing neurogenesis.•DHI promotes neurogenesis by activating BDNF/AKT/CREB signaling pathway.
Graphene oxide (GO) is a nanomaterial with burgeoning bioapplications, while autophagy is implicated in cancer therapy. Although induction of autophagy by nanomaterials is reported, the underlying ...signaling mechanism in cancer cells and how this implicates the potential of GO in cancer therapy remain obscure. Here, it is shown that GO itself can induce the toll-like receptors (TLRs) responses and autophagy in cancer cells and confer antitumor effects in mice. GO can be phagocytosed by CT26 colon cancer cells, simultaneously triggering autophagy as well as TLR-4 and TLR-9 signaling cascades. By dissecting the crosstalk between the TLRs and autophagy pathways, it is uncovered that the GO-activated autophagy is regulated through the myeloid differentiation primary response gene 88 (MyD88)- and TNF receptor-associated factor 6 (TRAF6)-associated TLR-4/9 signaling pathways. Injection of GO alone into immunocompetent mice bearing the CT26 colon tumors not only suppresses the tumor progression but also enhances cell death, autophagy, and immune responses within the tumor bed. These data altogether implicate the potential of GO as an effective nanomaterial for autophagy induction and cancer therapy.
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