Receptor signaling relays on intracellular events amplified by secondary and tertiary messenger molecules. In cardiomyocytes and smooth muscle cells, cyclic AMP (cAMP) and subsequent calcium (Ca
) ...fluxes are the best characterized receptor-regulated signaling events. However, most of receptors able to modify contractility and other intracellular responses signal through a variety of other messengers, and whether these signaling events are interconnected has long remained unclear. For example, the PI3K (phosphoinositide 3-kinase) pathway connected to the production of the lipid second messenger PIP3/PtdIns(3,4,5)P3 (phosphatidylinositol (3,4,5)-trisphosphate) is potentially involved in metabolic regulation, activation of hypertrophy, and survival pathways. Recent studies, highlighted in this review, started to interconnect PI3K pathway activation to Ca
signaling. This interdependency, by balancing contractility with metabolic control, is crucial for cells of the cardiovascular system and is emerging to play key roles in disease development. Better understanding of the interplay between Ca
and PI3K signaling is, thus, expected to provide new ground for therapeutic intervention. This review explores the emerging molecular mechanisms linking Ca
and PI3K signaling in health and disease.
We report the first dark matter search results using the commissioning data from PandaX-4T. Using a time projection chamber with 3.7 tonne of liquid xenon target and an exposure of 0.63 tonne·year, ...1058 candidate events are identified within an approximate nuclear recoil energy window between 5 and 100 keV. No significant excess over background is observed. Our data set a stringent limit to the dark matter-nucleon spin-independent interactions, with a lowest excluded cross section (90% C.L.) of 3.8×10^{-47} cm^{2} at a dark matter mass of 40 GeV/c^{2}.
Anthracyclines, such as doxorubicin, represent one group of chemotherapy drugs with the most cardiotoxicity. Despite that anthracyclines are capable of treating assorted solid tumors and ...hematological malignancies, the side effect of inducing cardiac dysfunction has hampered their clinical use. Currently, the mechanism underlying anthracycline cardiotoxicity remains obscure. Increasing evidence points to mitochondria, the energy factory of cardiomyocytes, as a major target of anthracyclines. In this review, we will summarize recent findings about mitochondrial mechanism during anthracycline cardiotoxicity. In particular, we will focus on the following aspects: 1) the traditional view about anthracycline-induced reactive oxygen species (ROS), which is produced by mitochondria, but in turn causes mitochondrial injury. 2) Mitochondrial iron-overload and ferroptosis during anthracycline cardiotoxicity. 3) Autophagy, mitophagy and mitochondrial dynamics during anthracycline cardiotoxicity. 4) Anthracycline-induced disruption of cardiac metabolism.
We report a novel search for the cosmic-ray boosted dark matter using the 100 tonne·day full dataset of the PandaX-II detector located at the China Jinping Underground Laboratory. With the extra ...energy gained from the cosmic rays, sub-GeV dark matter particles can produce visible recoil signals in the detector. The diurnal modulations in rate and energy spectrum are utilized to further enhance the signal sensitivity. Our result excludes the dark matter-nucleon elastic scattering cross section between 10^{-31} and 10^{-28} cm^{2} for dark matter masses from 0.1 MeV/c^{2} to 0.1 GeV/c^{2}, with a large parameter space previously unexplored by experimental collaborations.
Aims
Butyric acid (BUT), a short chain fatty acid produced daily by the gut microbiota, has proven beneficial in models of cardiovascular diseases. With advancements in cancer survival, an increasing ...number of patients are at risk of anticancer drug cardiotoxicity. Here we assess whether the novel BUT derivative phenylalanine‐butyramide (FBA) protects from doxorubicin (DOXO) cardiotoxicity, by decreasing oxidative stress and improving mitochondrial function.
Methods and results
In C57BL6 mice, DOXO produced left ventricular dilatation assessed by echocardiography. FBA prevented left ventricular dilatation, fibrosis and cardiomyocyte apoptosis when co‐administered with DOXO. DOXO increased atrial natriuretic peptide, brain natriuretic peptide, connective tissue growth factor, and matrix metalloproteinase‐2 mRNAs, which were not elevated on co‐treatment with FBA. DOXO, but not FBA + DOXO mice, also showed higher nitrotyrosine levels, and increased inducible nitric oxide synthase expression. Accordingly, DOXO hearts showed lower levels of intracellular catalase vs. sham, while pre‐treatment with FBA prevented this decrease. We then assessed for reactive oxygen species (ROS) emission: DOXO induced increased activity of mitochondrial superoxide dismutase and higher production of H2O2, which were blunted by FBA pre‐treatment. FBA also ameliorated mitochondrial state 3 and state 4 respiration rates that were compromised by DOXO. Furthermore, in DOXO animals, the mitochondrial degree of coupling was significantly increased vs. sham, while FBA was able to prevent such increase, contributing to limit ROS production, Finally, FBA reduced DOXO damage in human cellular models, and increased the tumour‐killing action of DOXO.
Conclusions
Phenylalanine‐butyramide protects against experimental doxorubicin cardiotoxicity. Such protection is accompanied by reduction in oxidative stress and amelioration of mitochondrial function.
Background Basement membrane (BM) is an important component of the extracellular matrix, which plays an important role in the growth and metastasis of tumor cells. However, few biomarkers based on BM ...have been developed for prognostic assessment and prediction of immunotherapy in bladder cancer (BLCA). Methods In this study, we used the BLCA public database to explore the relationship between BM-related genes (BMRGs) and prognosis. A novel molecular typing of BLCA was performed using consensus clustering. LASSO regression was used to construct a signature based on BMRGs, and its relationship with prognosis was explored using survival analysis. The pivotal BMRGs were further analyzed to assess its clinical characteristics and immune landscape. Finally, immunohistochemistry was used to detect the expression of the hub gene in BLCA patients who underwent surgery or received immune checkpoint inhibitor (ICI) immunotherapy in our hospital. Results We comprehensively analyzed the relationship between BMRGs and BLCA, and established a prognostic-related signature which was an independent influence on the prognostic prediction of BLCA. We further screened and validated the pivotal gene-MMP14 in public database. In addition, we found that MMP14 expression in muscle invasive bladder cancer (MIBC) was significantly higher and high MMP14 expression had a poorer response to ICI treatment in our cohort. Conclusions Our findings highlighted the satisfactory value of BMRGs and suggested that MMP14 may be a potential biomarker in predicting prognosis and response to immunotherapy in BLCA. Keywords: Bladder cancer, Basement membrane, MMP14, Immunohistochemistry, Immunotherapy
Community-based ecotourism (CBET) has become a popular strategy to alleviate the contradiction between ecological protection and community development. As the stakeholders of CBET, the community’s ...participation in the planning process is of great importance to in order to realize the sustainability of CBET. Taking a community in Wolong Nature Reserve as a case study, in this study we developed a decision-making participation mechanism based on the participatory scenario method. Through this mechanism, community stakeholders can effectively reach consensus with other stakeholders on the planning of CBET in the future. The results showed that community participation in the planning process can mean decisions are more likely to reflect their interests. They unanimously proposed that future CBET must adhere to the basic principle of protecting biodiversity and must maximize the welfare of the community. Moreover, achieving the sustainability of CBET in protected areas requires the cooperation of all stakeholders.
Three Ni-Cr-Si coatings were synthesized on the surface of copper by laser cladding. The microstructures of the coatings were characterized by optical microscopy (OM), X-ray diffraction (XRD), and ...scanning electron microscopy (SEM) with an energy dispersive spectrometer (EDS). According to the analysis results of phase compositions, Gibbs free energy change and microstructures, the phases of three coatings appeared were Cr₃Si+γ-Ni+Cu
(Coating 1, Ni-26Cr-29Si), Cr₆Ni
Si₇+Ni₂Si+Cu
(Coating 2, Ni-10Cr-30Si) and Cr₃Ni₅Si₂+Cr₂Ni₃+Cu
(Coating 3, Ni-29Cr-16Si). The crystal growth in the solidification process was analyzed with a modified model, which is a combination of Kurz-Giovanola-Trivedi (KGT) and Lipton-Kurz-Trivedi (LKT) models. The dendrite tip undercooling in Coating 2 was higher than those of Coating 1 and Coating 3. Well-developed dendrites were found in Coating 2. A modification of Hunt's model was adopted to describe the morphological differences in the three coatings. The results show that Coating 1 was in the equiaxed dendrite region, while Coatings 2 and 3 were in the columnar dendrite region. The average friction coefficients of the three coatings were 0.45, 0.5 and 0.4, respectively. Obvious plastic deformation could be found in the subsurface zone of Coatings 2 and 3.
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