REVIEW | doi:10.20944/preprints202207.0423.v1
Subject: Life Sciences, Cell & Developmental Biology Keywords: Aging; cellular senescence; fibroblast; osteoarthritis; remodeling-associated secretory phenotype (RASP); remodeling activation
Online: 27 July 2022 (13:38:36 CEST)
One of the most striking findings in biogerontology in the 2010s was the demonstration that elimination of senescent cells delays many late-life diseases and extends lifespan in mice. This implied that accumulation of senescent cells promotes late-life diseases, particularly through action of senescent cell secretions (the senescence-associated secretory phenotype or SASP). But what exactly is a senescent cell? Subsequent to the initial characterization of cellular senescence it became clear that, prior to aging, this phenomenon is in fact adaptive. It supports tissue remodeling functions in a variety of contexts, including embryogenesis, parturition and acute inflammatory processes that restore normal tissue architecture and function, such as wound healing, tissue repair after infection, and amphibian limb regeneration. In these contexts such cells are normal and healthy, and not in any way senescent in the true sense of the word, as originally meant by Hayflick. Thus, it is misleading to refer to them as “senescent”. Similarly, the common assertion that senescent cells accumulate with age due to stress and DNA damage is no longer safe, particularly given their role in inflammation - a process that becomes persistent in later life. We therefore suggest that it would be useful to update some terminology, to bring it into line with contemporary understanding, and to avoid future confusion. To open a discussion of this issue, we propose replacing the term cellular senescence with remodeling activation, and SASP with RASP (remodeling-associated secretory phenotype).
COMMUNICATION | doi:10.20944/preprints202104.0579.v1
Online: 21 April 2021 (12:30:38 CEST)
Poly(dA:dT) tracts cause nucleosome depletion in many species, e.g., at promoters and replication origins. Their intrinsic biophysical sequence properties make them stiff and unfavorable for nucleosome assembly, as probed by in vitro nucleosome reconstitution. The mere correlation between nucleosome depletion over poly(dA:dT) tracts in vitro and in vivo inspired an intrinsic nucleosome exclusion mechanism in vivo. However, we compile here published and new evidence that this correlation does not reflect mechanistic causation. 1) Nucleosome depletion over poly(dA:dT) in vivo is not universal, e.g., very weak in S. pombe. 2) The energy penalty for incorporating poly(dA:dT) tracts into nucleosomes is modest (<10%) relative to ATP hydrolysis energy abundantly invested by chromatin remodelers. 3) Nucleosome depletion over poly(dA:dT) is much stronger in vivo than in vitro if monitored without MNase and 4) actively maintained in vivo. 5) S. cerevisiae promoters evolved a biased poly(dA) versus poly(dT) distribution. 6) Nucleosome depletion over poly(dA) is directional in vivo. 7) The ATP dependent chromatin remodeler RSC preferentially and directionally displaces nucleosomes towards 5’ of poly(dA). Especially bias and directionality would not be expected for an intrinsic mechanism. Together, this argues for a mechanism where active and species-specific read out of intrinsic sequence properties, e.g., by remodelers, shapes nucleosome occupancy.
ARTICLE | doi:10.20944/preprints202110.0276.v1
Subject: Life Sciences, Biotechnology Keywords: Mesenchymal stem cells; collagen type I; remodeling; oxidation
Online: 19 October 2021 (12:19:16 CEST)
Abstract: The effect of collagen type 1 (Col I) oxidation on Adipose Tissue-Derived Mesenchymal Stem Cells (ADMSCs) remodeling is described as a model for acute oxidative stress. Morphologically, remodeling was presented by a mechanical rearrangement of adsorbed FITC-Col I and a trend for its organization in a fibril-like pattern - a process strongly abrogated in oxidized samples, but without visible changes in cell morphology. The cellular proteolytic activity was quantified in multiple samples utilizing fluorescence de-quenching (FRET effect). In the presence of ADMSCs a significant increase of native FITC-Col I fluorescence was observed, almost absent in the oxidized samples. Parallel studies in cell-free systems confirmed the enzymatic de-quenching of native FITC-Col I by Clostridial collagenase, again showing significant inhibition in oxidized samples. The structural changes in the oxidized Col I was further studied by Differential Scanning Calorimetry: an additional endotherm at 33.6°C along with the typical for native Col I at 40.5°C with sustained enthalpy (∆H) was observed in oxidized samples. Collectively, it has been evidenced that remodeling of Col I by ADMSCs is altered upon oxidation due to the intrinsic changes in the protein structure, thus presenting a novel mechanism for the control of stem cells' behavior toward collagen.
ARTICLE | doi:10.20944/preprints201809.0431.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: hesperidin; L-NAME; cardiovascular remodeling; oxidative stress; inflammation
Online: 21 September 2018 (08:15:47 CEST)
Hesperidin is a major flavonoid isolated from citrus fruits that exhibits several biological activities. This study aims to evaluate the effect of hesperidin on cardiovascular remodeling induced by N-nitro L-arginine methyl ester (L-NAME) in rats. Male Sprague-Dawley rats were treated with L-NAME (40 mg/kg); L-NAME plus hesperidin (15 mg/kg), or hesperidin (30 mg/kg), or captopril (2.5 mg/kg) for five weeks (n = 8/group). Hesperidin or captopril significantly prevented the development of hypertension in L-NAME rats. Moreover, hesperidin or captopril alleviated L-NAME-induced cardiac remodeling; increases in wall thickness, cross sectional area (CSA) and fibrosis of left ventricular (LV), and vascular remodeling; increases in wall thickness, CSA, vascular smooth muscle cells and collagen deposition in the aorta. These were associated with reduced oxidative stress markers, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta 1 (TGF-β1) and enhancing plasma nitric oxide metabolite (NOx) in L-NAME treated groups. Furthermore, up-regulation of tumor necrosis factor receptor type 1 (TNF-R1) and TGF-β1 protein expression and the over-expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) were suppressed in L-NAME rats treated with hesperidin or captopril. These data suggested that hesperidin had cardioprotective effects in L-NAME hypertensive rats. The possible mechanism may involve its antioxidant and anti-inflammatory effects.
ARTICLE | doi:10.20944/preprints202010.0428.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Injured tissue; Tissue remodeling; Treatment resistance; Radioisotope; Cancer stroma
Online: 21 October 2020 (10:36:25 CEST)
Background: In treatment-refractory cancers, tumor tissues damaged by therapy initiate the repair response; therefore, tumor tissues must be exposed to an additional burden before successful repair. We hypothesized that an agent recognizing a molecule that responds to anticancer treatment–induced tissue injury could deliver an additional antitumor agent including a radionuclide to damaged cancer tissues during repair. We selected the extracellular matrix glycoprotein tenascin-C (TNC) as such a molecule, and three antibodies recognizing human and murine TNC were employed to evaluate X-irradiation–induced changes in TNC uptake by subcutaneous tumors. Methods: TNC expression was assessed by immunohistochemical staining of BxPC-3 tumors treated with or without X-irradiation (30 Gy) for 7 days. Antibodies against TNC (3-6, 12-2-7, TDEAR) and a control antibody were radiolabeled with 111In and injected into nude mice having BxPC-3 tumors 7 days after X-irradiation, and temporal uptake was monitored for an additional 4 days by biodistribution and single-photon emission computed tomography with computed tomography (SPECT/CT) studies. Intratumoral distribution was analyzed by autoradiography. Results: The immunohistochemical signal for TNC expression was faint in nontreated tumors but increased and expanded with time until day 7 after X-irradiation. Biodistribution studies revealed increased tumor uptake of all three 111In-labeled antibodies and the control antibody. However, a statistically significant increase in uptake was evident only for 111In-labeled 3-6 (35%ID/g for 30 Gy vs. 15%ID/g for 0 Gy at day 1, P < 0.01; ID, injected dose), whereas limited changes in 111In-labeled TDEAR2, 12-2-27, and control antibody were observed (several %ID/g for 0 and 30 Gy). Serial SPECT/CT imaging with 111In-labeled 3-6 or control antibody provided consistent results. Autoradiography revealed noticeably stronger signals in irradiated tumors injected with 111In-labeled 3-6 compared with each of nonirradiated tumors and the control antibody. The signals were observed in TNC-expressing stroma. Conclusion: Markedly increased uptake of 111In-labeled 3-6 in irradiated tumors supports our concept that an agent, such as an antibody, that recognizes a molecule, such as TNC, involved in tissue-injury repair could enhance drug delivery to therapy-experienced tumor tissues. The combination of antibody 3-6 coupled to a tumoricidal drug and conventional therapy has the potential to achieve better outcomes for patients with refractory cancer.
ARTICLE | doi:10.20944/preprints202007.0532.v1
Subject: Biology, Other Keywords: Phosphatidylinositol; actin remodeling; phagocytosis; dietary fatty acids; Alzheimer’s disease
Online: 22 July 2020 (14:15:35 CEST)
Alzheimer’s disease is one of the neurodegenerative diseases, characterized by the accumulation of abnormal protein deposits, which disrupt the signal transduction in neurons and other glia cells. The pathological protein Tau and amyloid-β contributes to the disrupted microglial signaling pathways, actin cytoskeleton, and cellular receptor expression. The important secondary messenger lipids i.e., phosphatidylinositols are largely affected by protein deposits of amyloid-beta in Alzheimer’s disease. Phosphatidylinositols are the product of different phosphatidylinositol kinases and the state of phosphorylation at D3, D4, and D5 positions of inositol ring. PI 3, 4, 5-P3 involves in phagocytic cup formation and relates actin remodeling whereas PI 4, 5-P2-mediates the process of phagosomes formation and further fusion with early endosome. The necessary activation of actin-binding proteins such as Rac, WAVE complex, and ARP2/3 complex for the actin polymerization in the process of phagocytosis, migration is regulated and maintained by PI 3, 4, 5-P3 and PI 4, 5-P2. Dietary fatty acids depending on their ratio and types of intake influence secondary lipid messenger along with the cellular content of phaphatidylcholine and phosphatidylethanolamine. The deposited Aβ deposits and extracellular Tau seed disrupt levels of phosphatidylinositol and actin cytoskeletal changes that hamper microglia signaling pathways in AD. We hypothesize that being a lipid species intracellular levels of phosphatidylinositol would be regulated by dietary fatty acids. We keen to understand different types of phosphatidylinositol species levels in signaling events such as phagocytosis and actin remodeling owing to the exposure of various types of dietary fatty acids.
REVIEW | doi:10.20944/preprints201807.0334.v1
Subject: Medicine & Pharmacology, Cardiology Keywords: cardiopulmonary lesions, endocrine disruptors, ID3, vascular dysfunction, vascular remodeling
Online: 19 July 2018 (12:57:32 CEST)
Cardiopulmonary lesions, which manifest from various types of diseases such as pulmonary arterial hypertension, atherosclerosis, pulmonary arteriovenous malformations, lymphangioleiomyomatosis, and peripheral arterial disease, pose a public health problem. Vascular remodeling, which refers to alternations to the structure of the vessel is an important pathophysiological feature of these diseases. The Inhibitor of DNA-binding/Differentiation-3 (ID3), which is part of the ID family of transcriptional regulators, has been demonstrated to contribute to an essential role in the vasculature and therefore may influence the alterations of these lesions. This review will cover the existing understanding of how ID3 may contribute to cardiopulmonary lesion perturbations via involvement in vascular remodeling. Furthermore, based on the accumulative quantity of reports that indicate oxidative stress plays a essential function in the pathophysiology of vascular remodeling, we will also consider the impact of exposure to estrogenic endocrine disruptors (EEDs) such as polychlorinated biphenyls (PCBs) and bisphenol A (BPA) on ID3 & cardiopulmonary disease. Improved understanding of how ID3 pathways contributes to these molecular mechanisms in the lesion will prospectively deliver beneficial information in the mediation of vascular remodeling associated with ID3 & EED exposure, which may play an essential role in cardiopulmonary disease prevalence.
Subject: Life Sciences, Microbiology Keywords: membrane remodeling; membrane biosynthesis; membrane curvature; phospholipids; inner membrane; lipid biosynthesis
Online: 25 August 2020 (10:03:25 CEST)
Membrane remodeling and phospholipid biosynthesis are normally tightly regulated to maintain the shape and function of cells. Indeed, different physiological mechanisms ensure a precise coordination between de novo phospholipid biosynthesis and modulation of membrane morphology. Interestingly, the overproduction of certain membrane proteins hijack these regulation networks, leading to the formation of impressive intracellular membrane structures in both prokaryotic and eukaryotic cells. The proteins triggering an abnormal accumulation of membrane structures inside the cells (or membrane proliferation) share two major common features: 1) they promote the formation of highly curved membrane domains and 2) they lead to an enrichment in anionic, cone-shaped phospholipids (cardiolipin or phosphatidic acid) in the newly formed membranes. Taking into account the available examples of membrane proliferation upon protein overproduction, together with the latest biochemical, biophysical and structural data, we explore the relationship between protein synthesis and membrane biogenesis. We propose a mechanism for the formation of these non-physiological intracellular membranes that shares similarities with natural inner membrane structures found in α-proteobacteria, mitochondria and some viruses-infected cells, pointing towards a conserved feature through evolution. We hope that the information discussed in this review will give a better grasp of the biophysical mechanisms behind physiological and induced intracellular membrane proliferation, and inspire new applications, either for academia (high-yield membrane protein production and nanovesicle production) or industry (biofuel production and vaccine preparation).
ARTICLE | doi:10.20944/preprints202208.0298.v1
Subject: Medicine & Pharmacology, Other Keywords: Adipose tissue-derived mesenchymal stem cell; collagen type I; EGCG; oxidation; remodeling
Online: 17 August 2022 (04:11:29 CEST)
Mesenchymal stem cells (MSCs) are involved in the process of extracellular matrix (ECM) remodeling where collagens play a pivotal role. We recently demonstrated that the remodeling of adsorbed collagen type I might be disordered upon oxidation following its fate in the presence of human adipose-derived MSC (ADMSCs). With the present study, we intended to learn more about the effect of polyphenolic antioxidant Epigallocatechin gallate (EGCG) attempting to mimic the conditions of oxidative stress in vivo and its putative prevention by antioxidants. Collagen Type I was isolated from mouse tail tendon (MTC) and labeled with FITC before oxidizing according to Fe2+/H2O2 protocol. FITC-collagen remodeling by ADMSC was assessed morphologically before and after EGCG pretreatment and confirmed via detailed morphometry analysis measuring the anisotropy index (AI) and fluorescence intensity (FI) in selected regions of interest (ROI), namely: outside the cells; over the cells and central (nuclear perinuclear) region, whereas the pericellular proteolytic activity was measured by de-quenching of fluorescent collagen probes (FRET effect). Here we provide morphological evidence that MTC undergoes significant reorganization by the adhering ADMSC along with the substantial activation of pericellular proteolysis, and further confirm that both processes are suppressed upon collagen oxidation. An important observation was that this abrogated remodeling cannot be prevented by the EGCG pretreatment. Conversely, the detailed morphometry analysis showed that oxidized FITC-collagen rather tends to accumulate beneath the cells and around the cell’s nuclei suggesting the activation of alternative routes for its removal, such as internalization and/or transcytosis. Morphometry analysis also revealed that both processes are supported by EGCG pretreatment.
ARTICLE | doi:10.20944/preprints202108.0019.v1
Subject: Medicine & Pharmacology, Allergology Keywords: leptin; JAK/STAT pathway; myocardial infarction; hemodynamics; arrhythmias; dyslipidaemia; inflammation; cardiac remodeling
Online: 2 August 2021 (11:24:57 CEST)
Hyperleptinemia potentiates the effects of many atherogenic factors, such as inflammation, platelet aggregation, migration, hypertrophy, proliferation of vascular smooth muscle cells, and endothelial cell dysfunction. The present study analysed the eﬀects of long-term hyperleptinemia in an in vivo myocardial ischemia-reperfusion model to demonstrate whether the in vivo deleterious effect also affects cardiac structure and function. Rats by were subcutaneously administered leptin for 8 days to estimate the involvement of the JAK/STAT pathway. Data from 58 male Wistar rats were included in the final analysis. Myocardial infarction (MI) was modelled by the 30-minute ligation of the main left coronary artery followed by 120-minute reperfusion. Hemodynamic measurements, electrocardiography monitoring, echocardiography, myocardial infarct size and area at risk, blood biochemical parameters, leptin, IL-6, TNF-alpha, FGF-21, and cardiomyocyte morphology were measured. Statistical analyses were performed using IBM SPSS Statistics v.26. Seven-day hyperleptinemia in rats led to increased an blood pressure and heart rate, myocardial hypertrophy, impaired LV function, an increased frequency of ischemic arrhythmias, dyslipidaemia, systemic inflammation, and an increased size of induced myocardial infarction. The blockade of the JAK/STAT signalling pathway effectively reversed the negative effects of leptin, including increased blood pressure and total cholesterol.
ARTICLE | doi:10.20944/preprints202201.0041.v1
Subject: Engineering, Civil Engineering Keywords: building remodeling; concentrated loads; FRP reinforcement; FRP strips; shear capacity, vertical concrete cantilever
Online: 5 January 2022 (13:01:16 CET)
Renovation, restoration, remodeling, refurbishment, and retrofitting of build-ings often imply modifying the behavior of the structural system. Modification sometimes includes applying forces (i.e., concentrated loads) to beams that before were subjected to distributed loads only. For a reinforced concrete structure, the new condition causes a beam to bear a concentrated load with the crack pattern that was produced by the distributed loads that acted in the past. If the concentrated load is applied at or near the beam’s midspan, the new shear demand reaches the maximum around the midspan. But around the midspan, the cracks are vertical or quasi-vertical, and no inclined bar is present. So, the actual shear capacity around the midspan not only is low, but also can be substantially lower than the new demand. In order to bring the beam capacity up to the demand, fiber-reinforced-polymer composites can be used. This paper presents a design method to increase the concentrated load-carrying capacity of reinforced concrete beams whose load distribution has to be changed from distributed to concentrated, and an analytical model to pre-dict the concentrated load-carrying capacity of a beam in the strengthened state.
ARTICLE | doi:10.20944/preprints202107.0563.v1
Subject: Materials Science, Biomaterials Keywords: sandblasted implants; acid-etched implants; taper connection; marginal bone remodeling; marginal bone loss
Online: 26 July 2021 (10:25:54 CEST)
Aim: the purpose of the present prospective, case series study were to report implant survival rate and marginal bone remodeling expected five years after loading using dental implants placed in in the daily practice. Material and Methods: this research was designed as an open-cohort, prospective case series study. Any completely or partially edentulous patients scheduled to receive at least one bone leve were considered eligible for this study. Primary outcomes were: cumulative implant (ISR) and prosthetic (PSR) survival rates, and any complications experienced up the five years follow-up. Secondary outcomes were: marginal bone remodeling, implant insertion torque, implant stability quotient (ISQ), and thickness of gingival biotype. Results: ninety consecutive patients (34 males and 56 females; mean age 53.2±15.4 years; range of 24–81 years), 243 implants were placed and followed for at least five years after loading (mean of 65.4±3.1 months; range of 60–72 months). The mean implant insertion torque was 42.9±4.8 Ncm (range from 15 to 45 Ncm). Overall, 83.5% of the implants (n=203) were placed with an insertion torque between 35 and 45 Ncm. At the one year follow-up, no drop-outs were recorded, but 17 patients (18.9%) with 18 restorations (12.6%) delivered on 34 implants (14%) were lost at the five years examination. At the five-year examination, six implants failed in six patients, resulting in a cumulative ISR of 97.5%. At the five-year follow-up, four prostheses failed (2.8%) resulting in a cumulative PSR of 97.2%. At the five-year examination, five complications were reported by five different patients, resulting in a prosthetic success rate of 96.5%, measured at patient level. Five years after loading, mean MBL was 0.41 ± 0.30 mm (95% CI: 0.26–0.34). Difference from the one year data was 0.04 ± 0.19 mm (95% CI: 0.01–0.07). The mean ISQ value at implant placement was 71.6 ± 5.5 (range of 45–88). Six months later, the mean ISQ was 76.7 ± 4.4 (range of 66–89). The difference was statistically significant (P=0.0001). Statistically significant higher MBL was found for smokers, and patient with thin gingival biotype. Conclusions: High implant survival and success rates could be expected with stable marginal bone remodeling up to five years after loading. Smoking and thin tissue biotype were the most important variabilities associated with higher MBL. Further research are needed to confirm these results.
REVIEW | doi:10.20944/preprints201907.0188.v1
Subject: Life Sciences, Other Keywords: polybrominated diphenyl ethers; PBDE; neurodevelopment; epigenetics; DNA methylation; chromatin remodeling; environmental toxins; toxicity
Online: 16 July 2019 (07:25:37 CEST)
Disruption of epigenetic regulation by environmental toxins is an emerging point of focus for understanding the latter’s impact on human health. Polybrominated diphenyl ethers (PBDEs), one such toxin, are an environmentally pervasive class of brominated flame retardants that have been extensively used as coatings on a wide range of consumer products. Their environmental stability, propensity for bioaccumulation, and known links to adverse health effects have evoked extensive research to characterize underlying biological mechanisms of toxicity. Of particular concern is the growing body of evidence correlating human exposure levels to behavioral deficits related to neurodevelopmental disorders. The developing nervous system is particularly sensitive to influence by environmental signals, including dysregulation by toxins. Several major modes of actions have been identified, but a clear understanding of how observed effects relate to negative impacts on human health has not been established. Here we review the growing body of evidence for epigenetic disruptions induced by PBDEs, including DNA methylation, chromatin dynamics, and non-coding RNA expression while discussing potential relationship between PBDEs and neurodevelopmental disorders.
ARTICLE | doi:10.20944/preprints202105.0383.v1
Subject: Medicine & Pharmacology, Allergology Keywords: CDC2; CDK1; FOXM1; PLK1; smooth muscle cells; pulmonary arterial hypertension; cell cycle; vascular remodeling
Online: 17 May 2021 (11:08:44 CEST)
A key feature of pulmonary arterial hypertension (PAH) is the hyperplastic proliferation exhibited by the vascular smooth muscle cells from patients (HPASMC). The growth inducers FOXM1 and PLK1 are highly upregulated in these cells. The mechanism by which these two proteins direct aberrant growth in these cells is not clear. Herein we identify cyclin dependent kinase 1 (CDK1) also termed cell division cycle protein 2 (CDC2), as having a primary role in promoting progress of the cell cycle leading to proliferation in HPASMC. HPASMC obtained from PAH patients and pulmonary arteries from Sugen/hypoxia rats were investigated for their expression of CDC2. Protein levels of CDC2 were much higher in PAH than in cells from normal donors. Knocking down FOXM1 or PLK1 protein expression with siRNA or pharmacological inhibitors lowered the cellular expression of CDC2 considerably. However, knockdown of CDC2 with siRNA or inhibiting its activity with RO-3306 did not reduce the protein expression of FOXM1 or PLK1. Expression of CDC2 and FOXM1 reached its maximum at G1/S, while PLK1 reached its maximum at G2/M phase of the cell cycle. The expression of other CDKs such as CDK2, CDK4, CDK6, CDK7 and CDK9 did not change in PAH HPASMC. Moreover, inhibition via Wee1 inhibitor adavosertib or siRNAs targeting Wee1, Myt1, CDC25A, CDC25B, or CDC25C led to dramatic decreases in CDC2 protein expression. Lastly, we found CDC2 expression at the RNA and protein level to be upregulated in pulmonary arteries during disease progression Sugen/hypoxia rats. In sum, our present results illustrate that the increased expression of FOXM1 and PLK1 in PAH leads directly to increased expression of CDC2 resulting in a potentiated growth hyperactivity of PASMC from patients with pulmonary hypertension. Our results further suggest that the regulation of CDC2, or associated regulatory proteins, will prove beneficial in the treatment of this disease.
ARTICLE | doi:10.20944/preprints201911.0039.v1
Subject: Medicine & Pharmacology, Cardiology Keywords: heart failure; Sacubitril/valsartan; Neprilysin inhibition; reduced ejection fraction; echocardiography; Nt-Pro-BNP; hemodynamic; remodeling
Online: 4 November 2019 (11:20:22 CET)
Background: Sacubitril/valsartan has been shown to be superior to enalapril in reducing the risks of death and hospitalization for heart failure (HF). However the effect on cardiac performance remains unknown. We sought to evaluate the effects of sacubitril/valsartan on clinical, bioumoral and echocardiographic parameters in patients with HFrEF. Methods: Sacubitril/valsartan was administered to 205 HFrEF patients. Results: Among 230 patients (mean age 59 ± 10 years, 46% with ischemic heart disease) 205 (89%) completed the study. After a follow–up of 10.49 (2.93±18.44) months, the percentage of patients in NYHA class III changed from 40% to 17% (p<0.001). Median N–Type natriuretic peptide (Nt-proBNP) decreased from 1865 ± 2318 to 1514 ± 2205 pg/mL, (p=0.01). Furosemide dose reduced from 131.3 ± 154.5 to 120 ± 142.5 (p=0.047). Ejection fraction (from 27± 5.9% to 30 ± 7.7% (p<0.001) and E/A ratio (from 1.67 ± 1.21 to 1.42 ± 1.12 (p=0.002)) improved. Moderate to severe mitral regurgitation (from 30.1% to 17.4%; p=0.002) and tricuspid velocity decreased from 2.8 ± 0.55 m/sec to 2.64 ± 0.59 m/sec (p<0.014). CONCLUSIONS: Sacubitril/valsartan induce “hemodynamic reverse remodeling” and in association with Nt-proBNP concentrations lowering improve NYHA class despite a diuretic dose reduction.
Subject: Medicine & Pharmacology, Gastroenterology Keywords: liver failure; microRNAs (miRNAs); placenta-derived mesenchymal stem cells (PD-MSCs); phosphatase of regenerating liver-1 (PRL-1); regenerative medicine; stem cells homing; vascular remodeling
Online: 1 July 2019 (17:00:18 CEST)
Placenta-derived mesenchymal stem cells (PD-MSCs) have been highlighted as therapeutic sources in several degenerative diseases. Recently, microRNAs (miRNAs) were mediated one of the therapeutic mechanisms of PD-MSCs in regenerative medicine. To enhance the therapeutic effects of PD-MSCs, we established functionally enhanced PD-MSCs with phosphatase of regenerating liver-1 overexpression (PRL-1(+)). However, the profile and functions of miRNAs induced by PRL-1(+) PD-MSCs in a rat model with hepatic failure prepared by bile duct ligation (BDL) remained unclear. Hence, the objectives of the present study were to analyze the expression of miRNAs and investigate their therapeutic mechanisms for hepatic regeneration via PRL-1(+) in a rat model with BDL. We selected candidate miRNAs based on microarray analysis. Under hypoxic conditions, compared with invaded naïve PD-MSCs, invaded PRL-1(+) PD-MSCs showed improved integrin-dependent migration ability through RHO family-targeted miRNA expression (e.g., hsa-miR-30a-5p, 340-5p, and 146a-3p). Moreover, rno-miR-30a-5p and 340-5p regulated engraftment into injured rat liver by transplanted PRL-1(+) PD-MSCs through the integrin family. Additionally, an increase in PDGFRA by suppressing rno-miR-27a-3p improved vascular structure in rat liver tissues after PRL-1(+) PD-MSCs transplantation. Furthermore, decreased rno-miR-122-5p was significantly correlated with increased proliferation of hepatocytes in liver tissues by PRL-1(+) PD-MSCs by activating IL-6 signaling pathway through the repression of rno-miR-21-5p. Taken together, these findings improve the understanding of therapeutic mechanisms based on miRNA-mediated stem cell therapy in liver diseases.
REVIEW | doi:10.20944/preprints201811.0389.v1
Subject: Medicine & Pharmacology, Cardiology Keywords: adverse remodeling; aldosterone; cardiac myocyte; crosstalk; G protein-coupled receptor (GPCR); GPCR-kinase (GRK); heart failure; inflammation; mineralocorticoid receptor; myocardial infarction; oxidative stress; signal transduction
Online: 16 November 2018 (07:54:04 CET)
The mineralocorticoid hormone aldosterone regulates sodium and potassium homeostasis but also adversely modulates the maladaptive process of cardiac adverse remodeling post-myocardial infarction. Through activation of its mineralocorticoid receptor (MR), a classic steroid hormone receptor/transcription factor, aldosterone promotes inflammation and fibrosis of the heart, the vasculature, and the kidneys. This is why MR antagonists reduce morbidity and mortality of heart disease patients and are part of the mainstay pharmacotherapy of advanced human heart failure. A plethora of animal studies using cell type–specific targeting of the MR gene have established the importance of MR signaling and function in cardiac myocytes, vascular endothelial and smooth muscle cells, renal cells, and macrophages. In terms of its signaling properties, the MR is distinct from nuclear receptors in that it has, in reality, two physiological hormonal agonists: not only aldosterone but also cortisol. In fact, in several tissues, including in the myocardium, cortisol is the primary hormone activating the MR. There is a considerable amount of evidence indicating that the effects of the MR in each tissue expressing it depend on tissue- and ligand-specific engagement of molecular co-regulators that either activate or suppress its transcriptional activity. Identification of these co-regulators for every ligand that interacts with the MR in the heart (and in other tissues) is of utmost importance therapeutically, since it can not only help elucidate fully the pathophysiological ramifications of the cardiac MR`s actions but also help design and develop novel better MR antagonist drugs for heart disease therapy. Among the various proteins the MR interacts with are molecules involved in cardiac G protein-coupled receptor (GPCR) signaling. This results in a significant amount of crosstalk between GPCRs and the MR, which can affect the latter`s activity dramatically in the heart and in other cardiovascular tissues. This review summarizes the current experimental evidence for this GPCR-MR crosstalk in the heart and discusses its pathophysiological implications for cardiac adverse remodeling as well as for heart disease therapy. Novel findings revealing non-conventional roles of GPCR signaling molecules, specifically of GPCR-kinase (GRK)-5, in cardiac MR regulation are also highlighted.