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The TNNI3 p.R186Q mutation is responsible for hypertrophic cardiomyopathy via promoting FASN-stimulated abnormal fatty acid metabolism
No full textIntroduction: The TNNI3 gene encodes the protein of cardiac troponin I (cTnI), which is an inhibitory subunit of sarcomeres. Mutations in this gene account for 3% of hypertrophic cardiomyopathy (HCM) and the molecular mechanism is complex. Recently, lipid metabolism has been revealed to be involved in HCM. Aim: The purpose of this work is to identify whether the pathological mechanism of the hotspot mutation TNNI3 p.R186Q in HCM is related to abnormal lipid metabolism.Methods and Results: A knock-in (KI) mouse model carrying the Tnni3 p.R186Q homozygous mutation (Tnni3R186Q/R186Q) was novelty generated by CRISPR/Cas9 technology and successfully constructed a typical phenotype of cardiac-myopathy. Likewise, neonatal rat cardiomyocytes (NRCMs) transfected with a mutant plasmid with the TNNI3 p.R186Q mutation showed the same phenomenon. In-depth experiments on related functions and molecular mechanisms were conducted, and Tnni3R186Q/R186Q mice exhibited abnormal fatty acid metabolism, which was induced by the activation of epidermal growth factor receptor (EGFR)-dependent high expression of fatty acid synthase (FASN) in vivo and in vitro. Specifically, the direct binding of EGFR and cTnI was destroyed by TNNI3 p.R186Q mutation, as observed through bioinformatics, Co-IP and GST-pull down analysis.Conclusion: In the present study, we successfully engineered Tnni3R186Q/R186Q mice with the typical phenotype of myocardial hypertrophy. We demonstrated that the TNNI3 p.R186Q mutation could induce HCM by the dissociation of EGFR and cTnI, which further led to EGFR-dependent increased expression of FASN and abnormal lipid metabolism
Long COVID-19 and diabetes mellitus: a short review
No full textThe persistence of Covid-19 infection for more than four weeks after the acute phase is defined as the long Covid-19 syndrome. This condition, otherwise defined by the persistence of signs and symptoms for more than 12 weeks, shares several features with diabetes mellitus: diabetes mellitus and Covid-19 infections have a pandemic dimension, are characterized by an inflammatory milieu, and show a bidirectional relationship. Diabetic patients appear more likely to develop long Covid-19 syndrome than non-diabetic individuals. The chronicity of Covid-19 favors the development of new cases of diabetes. In this short review, we discuss the evidence supporting the link between Covid-19 and diabetes mellitus, focusing on the epidemiological and pathophysiological aspects of this dangerous relationship.Highlights● Patients affected by diabetes both type 1 and type 2 seem more likely to develop a long Covid-19 syndrome compared to non-diabetic subjects;● Long Covid-19 syndrome is associated with new-onset cases of diabetes, both type 1 and type 2 higher than expected;● Presence of other comorbidities prior to acute Covid-19 infection favors the development of long Covid-19 syndrome;● Most frequent symptoms of long Covid-19 in diabetic patients are fatigue, shortness of breath, neurocognitive and neurological manifestations, and cardiovascular sequelae;● Long Covid-19 can exacerbate microvascular dysfunction in patients with diabetes
Linking processing parameters with melt pool properties of multiple nickel-based superalloys via high-dimensional Gaussian process regression
No full textA physics-based model is used to predict the melt pool properties in the laser-directed energy deposition of several nickel-based superalloys for different process parameters. The input space is high-dimensional, consisting of a common 19-dimensional composition space for each alloy and the process parameters (laser power and scan velocity). Gaussian Process-based regression frameworks are developed by training surrogates on data generated by a validated analytical model. These surrogates are thereafter used to predict and define relationships between the composition, resultant thermophysical properties, process parameters, and the subsequent melt pool property. The probabilistic predictions are augmented by uncertainty quantification and sensitivity analysis to substantiate the findings further
An insight into the fate of Cu2+ and zero-valent iron during removal of Cu2+ by nanoscale zero-valent iron
No full textAim: The transformation of zero-valent iron (Fe0) and Cu2+ during Cu2+ removal by nanoscale zero-valent iron (nZVI) has not been properly investigated using modern analytical techniques, despite its importance in environmental toxicology and surface chemistry associated with wastewater treatment/groundwater remediation. This study critically examines the phenomenon using a variety of modern instruments that characterize the physical and chemical properties of materials and provides extensive comprehension of the subject. Methods: As-prepared nZVI was used to remove Cu2+ in 5 mmol/L CuSO4. The morphological and structural characteristics of the Cu2+ and nZVI after removal were investigated with the aid of scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD) and X-ray photoelectron spectrometry (XPS). Results: Complete removal of Cu2+ by the nZVI was achieved within 60 min and remained constant till 120 min. The Cu2+ got reduced into cuprite (Cu2O) and copper metal (Cu0) (the crystals of both transformation products were cubic), while the Fe0 nanoparticles transformed into lath-like lepidocrocite (γ-FeOOH) and twin-rod goethite (α-FeOOH). The mechanism of Fe0 transformation was that the Fe2+ produced by Fe0 corrosion and oxidation by Cu2+ was hydrolyzed and oxidized to form hydropyrite, which was later converted into lepidocrocite and goethite with the assistance of Fe2+. The transformation of Cu2+ was due to the strong reduction property of Fe0. The toxicity and bioavailability of the transformed products were lower than those of Cu2+ and Fe0 nanoparticles.Conclusion: The findings are critical in understanding the fate of Fe0 nanoparticles and Cu2+ during Cu2+ removal by nZVI and can provide guidance for the application of nZVI technology
Effects of spirulina (Arthrospira maxima) on teratogenicity and diclofenac-induced oxidative damage in Xenopus laevis
No full textDiclofenac (DCF) is a medication that is highly consumed and eliminated worldwide; it is constantly detected in the environment (primarily in water) and resists conventional degradation processes. It was included in the European Union watch list for the water framework. There are no regulations for this compound in Mexico. Therefore, this study evaluated the protective effect antioxidant activity of spirulina (Arthrospira maxima) against DCF-induced toxicity in Xenopus laevis at early life stages. X. laevis oocytes were exposed at the medium blastula stage for 96 h to three different mixtures: DCF+S 2 (149 µg L-1 DCF plus 2 mg L-1 spirulina), DCF+S 4 (149 µg L-1 DCF plus 4 mg L-1 spirulina), DCF+S 10 (149 µg L-1 DCF plus 10 mg L-1 spirulina). Other groups of oocytes were also exposed to DCF 149 µg L-1 and a control group. The mortality and malformation rate, growth, lipid peroxidation, and antioxidant enzymatic activity (superoxide dismutase and catalase) were determined. Spirulina at 4 and 10 mg L-1 reduced DCF-induced mortality by 80% and reduced malformations in severity and frequency. The abnormalities were malformations of the eye, tail, notochord, intestine, and rectum. All spirulina exposure groups showed an increase in total body size compared to those exposed to DCF. Regarding oxidative damage, the groups exposed to the mixture with spirulina decreased lipid peroxidation levels and diminished antioxidant activity. Spirulina reduced DCF-induced damage in X. laevis at early life stages and decreased mortality, frequency, and severity of abnormalities, growth inhibition, and oxidative damage. Further research is needed to evaluate the effects of spirulina against toxicity induced by xenobiotics in the early stages of development
New perspectives on epigenetic modifications and PARP inhibitor resistance in HR-deficient cancers
No full textThe clinical treatment of DNA-repair defective tumours has been revolutionised by the use of poly(ADP) ribose polymerase (PARP) inhibitors. However, the efficacy of these compounds is hampered by resistance, which is attributed to numerous mechanisms including rewiring of the DNA damage response to favour pathways that repair PARP inhibitor-mediated damage. Here, we comment on recent findings by our group identifying the lysine methyltransferase SETD1A as a novel factor that conveys PARPi resistance. We discuss the implications, with a particular focus on epigenetic modifications and H3K4 methylation. We also deliberate on the mechanisms responsible, the consequences for the refinement of PARP inhibitor use in the clinic, and future possibilities to circumvent drug resistance in DNA-repair deficient cancers
Concomitant medications and circulating tumor cells: friends or foes?
No full textThe use of concomitant medications by patients with cancer is observed almost globally; however, little attention has been paid to this topic in the medical literature. Most clinical studies do not describe the type and duration of drugs used at the time of inclusion and during treatment or how these drugs may affect the experimental and/or standard therapy. Even less information has been published on the potential interaction between concomitant medications and tumor biomarkers. However, we do know that concomitant drugs can complicate cancer clinical trials and biomarker development, thus contributing to their interaction, leading to side effects, and resulting in suboptimal adherence to anticancer treatment. On the basis of these premises and moving from the study by Jurisova et al., which reported the effect of commonly used drugs on the prognosis of women with breast cancer and the detection of circulating tumor cells (CTCs), we comment on the role of CTCs as an emerging diagnostic and prognostic tool for breast cancer. We also report the known and hypothesized mechanisms of CTC interplay with other tumor and blood components, possibly modulated by widespread drugs, including over-the-counter compounds, and discuss the possible implications of commonly used concomitant medications on CTC detection and clearance. After considering all these points, it is conceivable that concomitant drugs are not necessarily a problem, but on the contrary, their virtuous mechanisms can be exploited to reduce tumor spread and enhance the effect of anticancer therapies
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