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1.
Heliyon ; 10(13): e33449, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-39071562

RESUMEN

Climate change still adversely affects agriculture in the sub-Saharan Africa. There is need to strengthen early action to bolster livelihoods and food security. Most governments use pre- and post-harvest field surveys to capture statistics for National Food Balance Sheets (NFBS) key in food policy and economic planning. These surveys, though accurate, are costly, time consuming, and may not offer rapid yield estimates to support governments, emergency organizations, and related stakeholders to take advanced strategic decisions in the face of climate change. To help governments in Kenya (KEN), Zambia (ZMB), and Malawi (MWI) adopt digitally advanced maize yield forecasts, we developed a hybrid model based on the Regional Hydrologic Extremes Assessment System (RHEAS) and machine learning. The framework is set-up to use weather data (precipitation, temperature, and wind), simulations from RHEAS model (soil total moisture, soil temperature, solar radiation, surface temperature, net transpiration from vegetation, net evapotranspiration, and root zone soil moisture), simulations from DSSAT (leaf area index and water stress), and MODIS vegetation indices. Random Forest (RF) machine learning model emerged as the best hybrid setup for unit maize yield forecasts per administrative boundary scoring the lowest unbiased Root Mean Square Error (RMSE) of 0.16 MT/ha, 0.18 MT/ha, and 0.20 MT/ha in Malawi's Karonga district, Kenya's Homa Bay county, and Zambia's Senanga district respectively. According to relative RMSE, RF outperformed other hybrid models attaining the lowest score in all countries (ZMB: 25.96%, MWI: 28.97%, and KEN: 27.54%) followed by support vector machines (ZMB: 26.92%, MWI: 31.14%, and KEN: 29.50%), and linear regression (ZMB: 29.44%, MWI: 31.76%, and KEN: 47.00%). Lastly, the integration of VI and RHEAS information using hybrid models improved yield prediction. This information is useful for NFBS bulletins forecasts, design and certification of maize insurance contracts, and estimation of loss and damage in the advent of climate justice.

2.
Environ Monit Assess ; 196(7): 608, 2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38861164

RESUMEN

Satellite-based precipitation estimates are a critical source of information for understanding and predicting hydrological processes at regional or global scales. Given the potential variability in the accuracy and reliability of these estimates, comprehensive performance assessments are essential before their application in specific hydrological contexts. In this study, six satellite-based precipitation products (SPPs), namely, CHIRPS, CMORPH, GSMaP, IMERG, MSWEP, and PERSIANN, were evaluated for their utility in hydrological modeling, specifically in simulating streamflow using the Variable Infiltration Capacity (VIC) model. The performance of the VIC model under varying flow conditions and timescales was assessed using statistical indicators, viz., R2, KGE, PBias, RMSE, and RSR. The findings of the study demonstrate the effectiveness of VIC model in simulating hydrological components and its applicability in evaluating the accuracy and reliability of SPPs. The SPPs were shown to be valuable for streamflow simulation at monthly and daily timescales, as confirmed by various performance measures. Moreover, the performance of SPPs for simulating extreme flow events (streamflow above 75%, 90%, and 95%) using the VIC model was assessed and a significant decrease in the performance was observed for high-flow events. Comparative analysis revealed the superiority of IMERG and CMORPH for streamflow simulation at daily timescale and high-flow conditions. In contrast, the performances of CHIRPS and PERSIANN were found to be poor. This study highlights the importance of thoroughly assessing the SPPs in modeling diverse flow conditions.


Asunto(s)
Monitoreo del Ambiente , Hidrología , Lluvia , Ríos , India , Ríos/química , Monitoreo del Ambiente/métodos , Modelos Teóricos , Movimientos del Agua , Imágenes Satelitales , Clima Tropical
3.
Int J Mol Sci ; 25(9)2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38732224

RESUMEN

In this report we present seven lines of bioinformatic evidence supporting the conclusion that the Pentameric Ligand-gated Ion Channel (pLIC) Family is a member of the Voltage-gated Ion Channel (VIC) Superfamily. In our approach, we used the Transporter Classification Database (TCDB) as a reference and applied a series of bioinformatic methods to search for similarities between the pLIC family and members of the VIC superfamily. These include: (1) sequence similarity, (2) compatibility of topology and hydropathy profiles, (3) shared domains, (4) conserved motifs, (5) similarity of Hidden Markov Model profiles between families, (6) common 3D structural folds, and (7) clustering analysis of all families. Furthermore, sequence and structural comparisons as well as the identification of a 3-TMS repeat unit in the VIC superfamily suggests that the sixth transmembrane segment evolved into a re-entrant loop. This evidence suggests that the voltage-sensor domain and the channel domain have a common origin. The classification of the pLIC family within the VIC superfamily sheds light onto the topological origins of this family and its evolution, which will facilitate experimental verification and further research into this superfamily by the scientific community.


Asunto(s)
Canales Iónicos Activados por Ligandos , Canales Iónicos Activados por Ligandos/metabolismo , Canales Iónicos Activados por Ligandos/química , Canales Iónicos Activados por Ligandos/genética , Humanos , Secuencia de Aminoácidos , Biología Computacional/métodos , Modelos Moleculares , Familia de Multigenes , Animales , Dominios Proteicos , Filogenia , Cadenas de Markov
4.
Cancers (Basel) ; 15(20)2023 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-37894278

RESUMEN

Ewing sarcoma (EWS) is an aggressive pediatric malignancy of the bone and soft tissues in need of novel therapeutic options. To identify potential therapeutic targets, we focused on essential biological pathways that are upregulated by EWS-FLI1, the primary oncogenic driver of EWS, including mitotic proteins such as Aurora kinase A (AURKA) and kinesin family member 15 (KIF15) and its binding partner, targeting protein for Xklp2 (TPX2). KIF15/TPX2 cooperates with KIF11, a key mitotic kinesin essential for mitotic spindle orientation. Given the lack of clinical-grade KIF15/TPX2 inhibitors, we chose to target KIF11 (using SB-743921) in combination with AURKA (using VIC-1911) given that phosphorylation of KIF15S1169 by Aurora A is required for its targeting to the spindle. In vitro, the drug combination demonstrated strong synergy (Bliss score ≥ 10) at nanomolar doses. Colony formation assay revealed significant reduction in plating efficiency (1-3%) and increased percentage accumulation of cells in the G2/M phase with the combination treatment (45-52%) upon cell cycle analysis, indicating mitotic arrest. In vivo studies in EWS xenograft mouse models showed significant tumor reduction and overall effectiveness: drug combination vs. vehicle control (p ≤ 0.01), SB-743921 (p ≤ 0.01) and VIC-1911 (p ≤ 0.05). Kaplan-Meier curves demonstrated superior overall survival with the combination compared to vehicle or monotherapy arms (p ≤ 0.0001).

5.
Molecules ; 28(17)2023 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-37687172

RESUMEN

Baicalein (BE), the major component of Scutellaria Baicalensis, exhibited potently antifungal activity against drug-resistant Candida albicans, and strong inhibition on biofilm formation. Therefore, a series of baicalein-core derivatives were designed and synthesized to find more potent compounds and investigate structure-activity relationship (SAR) and mode of action (MoA). Results demonstrate that A4 and B5 exert a more potent antifungal effect (MIC80 = 0.125 µg/mL) than BE (MIC80 = 4 µg/mL) when used in combination with fluconazole (FLC), while the MIC80 of FLC dropped from 128 µg/mL to 1 µg/mL. SAR analysis indicates that the presence of 5-OH is crucial for synergistic antifungal activities, while o-dihydroxyls and vic-trihydroxyls are an essential pharmacophore, whether they are located on the A ring or the B ring of flavonoids. The MoA demonstrated that these compounds exhibited potent antifungal effects by inhibiting hypha formation of C. albicans. However, sterol composition assay and enzymatic assay conducted in vitro indicated minimal impact of these compounds on sterol biosynthesis and Eno1. These findings were further confirmed by the results of the in-silico assay, which assessed the stability of the complexes. Moreover, the inhibition of hypha of this kind of compound could be attributed to their effect on the catalytic subunit of 1,3-ß-d-glucan synthase, 1,3-ß-d-glucan-UDP glucosyltransferase and glycosyl-phosphatidylinositol protein, rather than inhibiting ergosterol biosynthesis and Eno1 activity by Induced-Fit Docking and Molecular Dynamics Simulations. This study presents potential antifungal agents with synergistic effects that can effectively inhibit hypha formation. It also provides new insights into the MoA.


Asunto(s)
Antifúngicos , Flavanonas , Antifúngicos/farmacología , Flavanonas/farmacología , Flavonoides , Bioensayo , Candida albicans
6.
Eur J Surg Oncol ; 49(11): 106981, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37455182

RESUMEN

BACKGROUND: BRAF V600E mutant-metastatic colorectal cancer (mCRC) is characterized by its short survival time. Treatment approaches vary depending on whether or not the metastases are initially resectable. The benefit of metastasectomy remains unclear, and the optimal first-line treatment is controversial. This study aimed to describe the prognosis of BRAF V600E mutant-mCRC, analyze the recurrence pattern in resectable patients, and explore the optimal first-line treatment for unresectable patients. METHODS: Patients diagnosed with BRAF V600E mutant-mCRC between February 2014 and January 2022 in five hospitals were enrolled. Date on clinical and pathological characteristics, treatment features, and survival outcomes were collected. RESULTS: Of the 220 included patients, 64 initially resectable patients had a significantly longer overall survival (OS) (37.07 vs. 20.20 months, P < 0.001) than initially unresectable patients. Of 156 unresectable patients, 54 received doublet (FOLFOX, XELOX or FOLFIRI) or triplet (FOLFOXIRI) chemotherapies (Chemo), 55 received Chemo plus Bevacizumab (Chemo+Bev), and 33 received vemurafenib plus cetuximab and irinotecan (VIC). The VIC regimen had a better progression-free survival (PFS) (12.70 months) than the Chemo (6.70 months, P < 0.001) and Chemo+Bev (8.8 months, P = 0.044) regimens. Patients treated with VIC had the best overall response rate (60.16%, P < 0.001), disease control rate (93.94%, P < 0.001) and conversional resection rate (24.24%, P = 0.003). CONCLUSIONS: Metastasectomy is beneficial to the survival of patients with BRAF V600E mutant-mCRC. For initially unresectable patients, VIC as first-line therapy is associated with a better prognosis and efficacy than doublet and triplet chemotherapy with or without bevacizumab.


Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Bevacizumab/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/tratamiento farmacológico , Irinotecán , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , Cetuximab/uso terapéutico , Vemurafenib/uso terapéutico , Mutación , Protocolos de Quimioterapia Combinada Antineoplásica , Fluorouracilo , Leucovorina
7.
Expert Opin Biol Ther ; 23(6): 553-564, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37171790

RESUMEN

INTRODUCTION: Heart valve disease is a growing burden on the healthcare system. Current solutions are insufficient for young patients and do not offer relief from reintervention. Tissue engineered heart valves (TEHVs) offer a solution that grows and responds to the native environment in a similar way to a healthy valve. Stem cells hold potential to populate these valves as a malleable source that can adapt to environmental cues. AREAS COVERED: This review covers current methods of recapitulating features of native heart valves with tissue engineering through use of stem cell populations with in situ and in vitro methods. EXPERT OPINION: In the field of TEHVs, we see a variety of approaches in cell source, biomaterial, and maturation methods. Choosing appropriate cell populations may be very patient specific; consistency and predictability will be key to long-term success. In situ methods are closer to translation but struggle with consistent cellularization. In vitro culture requires specialized methods but may recapitulate native valve cell populations with higher fidelity. Understanding how cell populations react to valve conditions and immune response is vital for success. Detrimental valve pathologies have proven to be difficult to avoid in early translation attempts.


Asunto(s)
Prótesis Valvulares Cardíacas , Ingeniería de Tejidos , Humanos , Válvulas Cardíacas , Células Madre , Materiales Biocompatibles
8.
ISA Trans ; 138: 534-545, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-36898910

RESUMEN

The biggest challenge associated with a renewable energy source (RES) based microgrids is to maintain their frequency stability. In solving this challenge, virtual inertia control (VIC) could be viewed as an unavoidable part of alternating current (AC) microgrids. For VIC, a phase-locked loop (PLL) is essential for obtaining information regarding the changes in the frequency of the microgrid. However, implementation of PLL might cause greater oscillation in frequency because of its system dynamics. Such type of issues can be resolved by using a multistage proportional integral derivative (PID) controller which restricts the undesirable frequency measurement and thus helps in improving the stability of the microgrid. In this paper, a novel Sine augmented scaled arithmetic optimization algorithm is proposed in purpose to tune the parameters of the aforementioned controller. The effectiveness of the proposed methodology is validated through contrastive simulation results, and the impact of a few standard strategies such as a change in system boundaries and various steps of RESs penetration are also demonstrated.

9.
Front Cardiovasc Med ; 9: 942430, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36386326

RESUMEN

Diabetes and its major key determinants insulin resistance and hyperglycemia are known risk factors for calcific aortic valve disease (CAVD). The processes leading to molecular and structural alterations of the aortic valve are yet not fully understood. In previous studies, we could show that valvular interstitial cells (VIC) display canonical elements of classical insulin signaling and develop insulin resistance upon hyperinsulinemia and hyperglycemia accompanied by impaired glucose metabolism. Analyses of cultured VIC and aortic valve tissue revealed extracellular matrix remodeling and degenerative processes. Since PI3K signaling through mammalian target of rapamycin (mTOR) is involved in fibrotic processes of the heart, we aim at further functional investigation of this particular Akt-downstream signaling pathway in the context of diabetes-induced CAVD. Primary cultures of VIC were treated with hyperinsulinemia and hyperglycemia. Phosphorylation of mTOR(Ser2448) was determined by Western blot analysis after acute insulin stimulus. Inhibition of mTOR phosphorylation was performed by rapamycin. Phosphorylation of mTOR complex 1 (MTORC1) downstream substrates 4E-BP1(Thr37/46) and P70S6K(Thr389), and MTORC2 downstream substrate Akt(Ser473) as well as the PDK1-dependent phosphorylation of Akt(Thr308) was investigated. Markers for extracellular matrix remodeling, cell differentiation and degenerative changes were analyzed by Western blot analysis, semi-quantitative real-time PCR and colorimetric assays. Hyperinsulinemia and hyperglycemia lead to alterations of VIC activation, differentiation and matrix remodeling as well as to an abrogation of mTOR phosphorylation. Inhibition of mTOR signaling by rapamycin leads to a general downregulation of matrix molecules, but to an upregulation of α-smooth muscle actin expression and alkaline phosphatase activity. Comparison of expression patterns upon diabetic conditions and rapamycin treatment reveal a possible regulation of particular matrix components and key degeneration markers by MTORC1 downstream signaling. The present findings broaden the understanding of mitogenic signaling pathways in VIC triggered by hyperinsulinemia and hyperglycemia, supporting the quest for developing strategies of prevention and tailored treatment of CAVD in diabetic patients.

10.
J Pers Med ; 12(10)2022 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-36294829

RESUMEN

In the paper, using the video image correlation method, a study of the micro-movement pattern of the dental implant and of a normal was performed. It is revealed that there are great differences between these two situations. The linear displacement type of the dental implant refers to the linear elastic modulus of bone tissue in the case of normal bite forces. It seems that the major influencing factor regarding the type and value of implant micro-movement is defined by the underlying bone tissue. It is to be considered that masticator force transmission inside a more stiff and dense bone could be attenuated by the antagonist teeth parodontium, dental implant and abutment connection type, and the elastic modulus of material of the dental crown. Because of the elasticity of the periodontal ligament system, during the loading of the dental implant, the natural tooth has been displaced slightly more, leaving the dental implant in an unfavorable position, having to bear the full amount of loading forces. When comparing the relative displacements in the case of the loaded tooth, it is shown that the dental implant has been moving almost symmetrically with the tooth. This could mean that large amounts of forces are transmitted towards the periimplant bone tissue, but in a more optimal, parabolic manner due to the action of the periodontal ligaments surrounding the natural tooth.

11.
J Agric Food Chem ; 70(40): 12946-12952, 2022 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-36191081

RESUMEN

Ciguatera poisoning can occur following the consumption of fish contaminated with trace levels of ciguatoxins (CTXs). These trace levels represent an analytical challenge for confirmation by LC-MS due to matrix interferences and the high instrument sensitivity required. Sample preparation procedures are laborious and require extensive cleanup procedures to address these issues. The application of a selective isolation technique employing boronate affinity polymers was therefore investigated for the capture of vic-diol-containing Caribbean and Pacific CTXs from fish extracts. A dispersive SPE procedure was developed where nearly complete binding of CTXs in fish extracts occurred with boric acid gel in less than 1 h. Release of the bound CTXs resulted in >95% recovery of C-CTX1/2, C-CTX3/4, CTX1B, 54-deoxyCTX1B, and 52-epi-54-deoxyCTX1B from the extracts. This selective extraction tool has the potential to greatly simplify both analytical sample preparation and preparative extraction and isolation of CTXs for structure elucidation and production of standards.


Asunto(s)
Intoxicación por Ciguatera , Ciguatoxinas , Animales , Región del Caribe , Cromatografía Liquida , Ciguatoxinas/análisis , Ciguatoxinas/química , Peces , Polímeros
12.
Curr Res Food Sci ; 5: 1266-1275, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36061408

RESUMEN

This study evaluated the viability of encapsulated Lactobacillus delbrueckii subsp. bulgaricus in chocolate during storage and in-vitro gastrointestinal transit. Flavonoid contents and short chain fatty acids (SCFAs) production during gastrointestinal transit were also assessed. Encapsulated L. delbrueckii subsp. bulgaricus survived well in chocolates >7 logs both after 120 days of storage at 4 °C and 25 °C, and during in-vitro gastrointestinal transit. The release of SCFAs through in-vitro gastrointestinal digestion and colonic fermentation revealed that probiotic-chocolates could be an excellent source of nutrients for the gut microbiota. Encapsulated probiotic in chocolates with 70% cocoa produced significantly (P < 0.05) more acetic, propionic, isobutyric, butyric and isovaleric acids than that with 45% cocoa. The bioconversion results of a specific polyphenol by L. delbrueckii subsp. bulgaricus exhibited that chocolate polyphenols could be utilized by probiotics for their metabolism. These findings confirmed that chocolate could be successfully fortified with L. delbrueckii subsp. bulgaricus encapsulation to improve health promoting properties of chocolates.

13.
JACC Basic Transl Sci ; 7(7): 697-712, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35958694

RESUMEN

There are currently no pharmacological therapies for calcific aortic valve disease (CAVD). Here, we evaluated the role of protein tyrosine phosphatase 1B (PTP1B) inhibition in CAVD. Up-regulation of PTP1B was critically involved in calcified human aortic valve, and PTP1B inhibition had beneficial effects in preventing fibrocalcific response in valvular interstitial cells and LDLR-/- mice. In addition, we reported a novel function of PTP1B in regulating mitochondrial homeostasis by interacting with the OPA1 isoform transition in valvular interstitial cell osteogenesis. Thus, these findings have identified PTP1B as a potential target for preventing aortic valve calcification in patients with CAVD.

14.
JACC Basic Transl Sci ; 7(7): 642-655, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35958695

RESUMEN

We hypothesized that excess endothelial-associated von Willebrand factor (vWF) and secondary platelet adhesion contribute to aortic valve stenosis (AS). We studied hyperlipidemic mice lacking ADAMTS13 (LDLR -/- AD13 -/- ), which cleaves endothelial-associated vWF multimers. On echocardiography and molecular imaging, LDLR -/- AD13 -/- compared with control strains had increased aortic endothelial vWF and platelet adhesion and developed hemodynamically significant AS, arterial stiffening, high valvulo-aortic impedance, and secondary load-dependent reduction in LV systolic function. Histology revealed leaflet thickening and calcification with valve interstitial cell myofibroblastic and osteogenic transformation, and evidence for TGFß1 pathway activation. We conclude that valve leaflet endothelial vWF-platelet interactions promote AS through juxtacrine platelet signaling.

15.
JACC Basic Transl Sci ; 7(4): 333-345, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35540096

RESUMEN

Expression of a neuropilin-like protein, DCBLD2, is reduced in human calcific aortic valve disease (CAVD). DCBLD2-deficient mice develop bicuspid aortic valve (BAV) and CAVD, which is more severe in BAV mice compared with tricuspid littermates. In vivo and in vitro studies link this observation to up-regulated bone morphogenic protein (BMP)2 expression in the presence of DCBLD2 down-regulation, and enhanced BMP2 signaling in BAV, indicating that a combination of genetics and BAV promotes aortic valve calcification and stenosis. This pathway may be a therapeutic target to prevent CAVD progression in BAV.

16.
Sci Total Environ ; 838(Pt 2): 155845, 2022 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-35561902

RESUMEN

Recent drought events in the Mekong River Basin (MRB) have resulted in devastating environmental and economic losses, and climate change and human-induced alterations have exacerbated drought conditions. Using hydrologic models and multiple climate change scenarios, this study quantified the future climate change impacts on conventional and flash drought conditions in the MRB. The Soil and Water Assessment Tool (SWAT) and Variable Infiltration Capacity (VIC) models were applied to estimate long-term drought indices for conventional and flash drought conditions over historical and future periods (1966-2099), using two emission scenarios (RCP 4.5 and RCP8.5), and four climate models from the Coupled Model Intercomparison Project Phase 5 (CMIP5). For the conventional drought assessment, monthly scale drought indices were estimated, and pentad-scale (5 days) drought indices were computed for the flash drought evaluations. There were overall increases in droughts from the SWAT model for the conventional drought conditions and overall decreases from the VIC model. For the flash drought conditions, the SWAT-driven drought indices showed overall increases in drought occurrences (up to 165%). On the contrary, the VIC-driven drought indices presented decreases in drought occurrences (up to -44%). The conventional and flash drought evaluations differ between these models as they partition the water budget, specifically soil moisture differently. We conclude that the proposed framework, which includes hydrologic models, various emission scenarios, and projections, allows us to assess the various perspectives on drought conditions. Basin countries have differential impacts, so targeted future adaptation strategy is required.


Asunto(s)
Cambio Climático , Ríos , Sequías , Humanos , Suelo , Agua
17.
Front Cardiovasc Med ; 9: 783543, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35355968

RESUMEN

Calcific aortic valve disease (CAVD) is a common acquired valvulopathy, which carries a high burden of mortality. Chronic inflammation has been postulated as the predominant pathophysiological process underlying CAVD. So far, no effective medical therapies exist to halt the progression of CAVD. This review aims to outline the known pathways of inflammation and calcification in CAVD, focussing on the critical roles of mechanical stress and mechanosensing in the perpetuation of valvular inflammation. Following initiation of valvular inflammation, dysregulation of proinflammatory and osteoregulatory signalling pathways stimulates endothelial-mesenchymal transition of valvular endothelial cells (VECs) and differentiation of valvular interstitial cells (VICs) into active myofibroblastic and osteoblastic phenotypes, which in turn mediate valvular extracellular matrix remodelling and calcification. Mechanosensitive signalling pathways convert mechanical forces experienced by valve leaflets and circulating cells into biochemical signals and may provide the positive feedback loop that promotes acceleration of disease progression in the advanced stages of CAVD. Mechanosensing is implicated in multiple aspects of CAVD pathophysiology. The mechanosensitive RhoA/ROCK and YAP/TAZ systems are implicated in aortic valve leaflet mineralisation in response to increased substrate stiffness. Exposure of aortic valve leaflets, endothelial cells and platelets to high shear stress results in increased expression of mediators of VIC differentiation. Upregulation of the Piezo1 mechanoreceptor has been demonstrated to promote inflammation in CAVD, which normalises following transcatheter valve replacement. Genetic variants and inhibition of Notch signalling accentuate VIC responses to altered mechanical stresses. The study of mechanosensing pathways has revealed promising insights into the mechanisms that perpetuate inflammation and calcification in CAVD. Mechanotransduction of altered mechanical stresses may provide the sought-after coupling link that drives a vicious cycle of chronic inflammation in CAVD. Mechanosensing pathways may yield promising targets for therapeutic interventions and prognostic biomarkers with the potential to improve the management of CAVD.

18.
Chem Biodivers ; 19(3): e202100768, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35170204

RESUMEN

In this work, novel vic-dioxime ligand (LH2 ) containing bound to the N4 -oxime core moiety and its complexes with Cu(II), Ni(II), Ti(IV), VO(IV), and Zn(II) salts have been studied. The structure of the ligand and its complexes were successfully synthesized and characterized using NMR (1 H and 13 C), LC/MS/MS spectrometer, FT-IR and UV/VIS spectroscopy, melting point, and magnetic susceptibility measurements. Vic-dioxime ligand (LH2 ) (1) and its metal complexes ([Cu(LH)2 ] (2), [Ni(LH)2 ] (3), [Ti(LH)2 ]Cl2 (4), [VO(LH)2 ] (5), and [Zn(LH)2 ] (6), respectively) were tested for them in-vitro antibacterial and antioxidant activities. According to the metal chelating results of the study, it was determined that compounds (1), (2), (3), and (6) showed very good activity, and especially compound (2), had a stronger metal chelating capacity due to ligand dissociation from the synthesized metal complexes, which then would chelate Fe(II) in the experimental setting. When microorganisms were evaluated in terms of the % viability effect, it was observed that all compounds had activity against C. Albicans and S. Cerevisiae at rates similar to antibiotics.


Asunto(s)
Complejos de Coordinación , Antibacterianos/farmacología , Antioxidantes/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Cobre/química , Ligandos , Pruebas de Sensibilidad Microbiana , Saccharomyces cerevisiae , Bases de Schiff/química , Espectroscopía Infrarroja por Transformada de Fourier , Espectrometría de Masas en Tándem , Titanio , Zinc/química
19.
Int J Cardiol ; 352: 104-114, 2022 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-35074490

RESUMEN

OBJECTIVE: To explore the mechanism of CircANKRD36 regulating cell heterogeneity and endothelial mesenchymal transition in aortic valve stromal cells by regulating miR-599 and TGF-ß signaling pathway. METHODS: Human tissue specimens were divided into Control group (n = 25) and CAVD group (n = 25). The mRNA expressions of CircANKRD36 and miR-599 in tissue samples were analyzed by qRT-PCR. Western blot was used to analyze the protein expression of osteogenic differentiation related factors induced by OM.The expressions of ALP, osteocalcin, osteopontin, Runx2 and Cadherin11 were detected by Western blot. RESULTS: The expression of CircANKRD36mRNA in CAVD tissue was lower than that in Control tissue (P < 0.05), and the expression of miR-599mRNA in CAVD tissue was higher than that in Control tissue (P < 0.05). CircANKRD36 was negatively correlated with ALP, osteocalcin, osteopontin, Runx2, Cadherin11 expression level after OM induced osteogenic differentiation. The expression level of miR-599 was positively correlated with ALP, osteocalcin, osteopontin, Runx2 and Cadherin11 after OM induced osteogenic differentiation.The expression of ALP, osteocalcin, osteopontin, Runx2 and Cadherin11 protein in circ+miR-599 group was lower than that in circ+miR-NC group (P < 0.05). Compared with Vector+miR-NC group, the protein expressions of TGF-ß1, TGF-ß2 and SMAD4 in circ+miR-NC group decreased (P < 0.05), while the protein expressions of TGF-ß1, TGF-ß2 and SMAD4 in circ+miR-599 group increased (P < 0.05). CONCLUSION: CircANKRD36 can inhibit the expression of miR-599 and the activation of TGF-ß signaling pathway, thus inhibiting the expression of differentiation-related factors of VIC osteogenesis and the formation of calcified nodules. Therefore, circANKRD36-miR-599-TGF-ß axis can be a new theoretical basis for treating CAVD.


Asunto(s)
MicroARNs , Proteínas Nucleares , Osteogénesis , Células del Estroma , Enfermedades de la Aorta , Válvula Aórtica/citología , Válvula Aórtica/metabolismo , Calcinosis , Diferenciación Celular , Células Cultivadas , Humanos , Proteínas Nucleares/genética , Osteogénesis/genética , ARN Circular , Transducción de Señal/genética , Células del Estroma/citología , Células del Estroma/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo
20.
Artículo en Inglés | MEDLINE | ID: mdl-34856502

RESUMEN

Gambierdiscus spp. are epi-benthic dinoflagellates that have been associated with ciguatera poisoning. These microalgae can have complex secondary metabolite profiles including ciguatoxins, maitotoxins, and gambierones, with varying compositions and toxicities across species and strains. Given this chemical diversity there is a need to develop selective and sensitive methods for secondary metabolite profiling. In this study, we used a cultured Caribbean strain of Gambierdiscus silvae to develop sample preparation and analysis strategies for characterizing vic-diol containing secondary metabolites. A pooled cellular extract was first screened by liquid chromatography-high-resolution mass spectrometry (LC-HRMS) for ciguatoxin-related compounds, which resulted in the confirmation of gambierone (1) and a novel isomer of 44-methylgambierone (3). Treatment of the extract with periodate confirmed that the gambierones each contained one reactive vic-diol, which was exploited for the development of a selective extraction procedure using m-aminophenylboronic acid gel and the non-aqueous binding solvent chloroform. Using this non-traditional boronate affinity procedure, LC-HRMS also revealed the presence of additional sulfated polycyclic ethers in the gambierone-containing vic-diol fraction, while pigments and other contaminants were removed. The developed tools could be applied to screen collections of Gambierdiscus and other benthic algae to provide additional chemical characterization of gambierone-related compounds. The selective extraction procedure may also prove useful as a step in the isolation of these sulfated polyethers for structural, toxicological and biotransformation studies.


Asunto(s)
Cromatografía Liquida/métodos , Dinoflagelados , Éteres , Espectrometría de Masas/métodos , Ácidos Borónicos/química , Dinoflagelados/química , Dinoflagelados/metabolismo , Éteres/análisis , Éteres/química , Éteres/aislamiento & purificación , Éteres/metabolismo , Sefarosa/química
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