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The differentiation and specificity of human CD4+ T follicular helper cells (TFH cells) after influenza vaccination have been poorly defined. Here we profiled blood and draining lymph node (LN) samples from human volunteers for over 2 years after two influenza vaccines were administered 1 year apart to define the evolution of the CD4+ TFH cell response. The first vaccination induced an increase in the frequency of circulating TFH (cTFH) and LN TFH cells at week 1 postvaccination. This increase was transient for cTFH cells, whereas the LN TFH cells further expanded during week 2 and remained elevated in frequency for at least 3 months. We observed several distinct subsets of TFH cells in the LN, including pre-TFH cells, memory TFH cells, germinal center (GC) TFH cells and interleukin-10+ TFH cell subsets beginning at baseline and at all time points postvaccination. The shift toward a GC TFH cell phenotype occurred with faster kinetics after the second vaccine compared to the first vaccine. We identified several influenza-specific TFH cell clonal lineages, including multiple responses targeting internal influenza virus proteins, and found that each TFH cell state was attainable within a clonal lineage. Thus, human TFH cells form a durable and dynamic multitissue network.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and mRNA vaccination induce robust CD4+ T cell responses. Using single-cell transcriptomics, here, we evaluated CD4+ T cells specific for the SARS-CoV-2 spike protein in the blood and draining lymph nodes (dLNs) of individuals 3 months and 6 months after vaccination with the BNT162b2 mRNA vaccine. We analyzed 1,277 spike-specific CD4+ T cells, including 238 defined using Trex, a deep learning-based reverse epitope mapping method to predict antigen specificity. Human dLN spike-specific CD4+ follicular helper T (TFH) cells exhibited heterogeneous phenotypes, including germinal center CD4+ TFH cells and CD4+IL-10+ TFH cells. Analysis of an independent cohort of SARS-CoV-2-infected individuals 3 months and 6 months after infection found spike-specific CD4+ T cell profiles in blood that were distinct from those detected in blood 3 months and 6 months after BNT162b2 vaccination. Our findings provide an atlas of human spike-specific CD4+ T cell transcriptional phenotypes in the dLNs and blood following SARS-CoV-2 vaccination or infection.
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Current seasonal influenza vaccines, which mainly target hemagglutinin (HA), require annual updates due to the continuous antigenic drift of the influenza virus. Developing an influenza vaccine with increased breadth of protection will have significant public health benefits. The recent discovery of broadly protective antibodies to neuraminidase (NA) has provided important insights into developing a universal influenza vaccine, either by improving seasonal influenza vaccines or designing novel immunogens. However, further in-depth molecular characterizations of NA antibody responses are warranted to fully leverage broadly protective NA antibodies for influenza vaccine designs. Overall, we posit that focusing on NA for influenza vaccine development is synergistic with existing efforts targeting HA, and may represent a cost-effective approach to generating a broadly protective influenza vaccine.
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Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza , Influenza Humana , Infecções por Orthomyxoviridae , Humanos , Infecções por Orthomyxoviridae/prevenção & controle , Neuraminidase , Anticorpos Antivirais , Influenza Humana/prevenção & controleRESUMO
Steatotic liver disease (SLD) is a highly prevalent chronic liver disease with significant challenges for global health. The pathophysiology of SLD involves an interplay among genetic, endocrine, and metabolic factors. Successful management of SLD entails accurate diagnosis and disease monitoring through noninvasive methods such as advanced imaging techniques and biomarkers. Many emerging pharmacotherapies for SLD are now in the pipeline, which target different pathways like collagen turnover, fibrogenesis, inflammation, and metabolism. The recent approval of resmetirom for noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) has been a milestone in addressing the unmet medical need for an efficacious SLD treatment. Finally, the potential of personalized medicine approaches and interdisciplinary cooperation in improving patient outcomes and reducing disease burden should be strongly pursued. SIGNIFICANCE STATEMENT: The healthcare burden due to steatotic liver disease (SLD) is enormous. This perspective sheds light on the recent advances in understanding the pathophysiology and diagnosis of SLD as well as promising drug development approaches.
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Fígado Gorduroso , Animais , Humanos , Desenvolvimento de Medicamentos , Fígado Gorduroso/terapia , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Medicina de PrecisãoRESUMO
G-protein coupled receptors (GPCRs) transduce a wide range of extracellular signals. They are key players in the majority of biologic functions including vision, olfaction, chemotaxis, and immunity. However, as essential as most of them are to body function and homeostasis, overactivation of GPCRs has been implicated in many pathologic diseases such as cancer, asthma, and heart failure (HF). Therefore, an important feature of G protein signaling systems is the ability to control GPCR responsiveness, and one key process to control overstimulation involves initiating receptor desensitization. A number of steps are appreciated in the desensitization process, including cell surface receptor phosphorylation, internalization, and downregulation. Rapid or short-term desensitization occurs within minutes and involves receptor phosphorylation via the action of intracellular protein kinases, the binding of ß-arrestins, and the consequent uncoupling of GPCRs from their cognate heterotrimeric G proteins. On the other hand, long-term desensitization occurs over hours to days and involves receptor downregulation or a decrease in cell surface receptor protein level. Of the proteins involved in this biologic phenomenon, ß-arrestins play a particularly significant role in both short- and long-term desensitization mechanisms. In addition, ß-arrestins are involved in the phenomenon of biased agonism, where the biased ligand preferentially activates one of several downstream signaling pathways, leading to altered cellular responses. In this context, this review discusses the different patterns of desensitization of the α 1-, α 2- and the ß adrenoceptors and highlights the role of ß-arrestins in regulating physiologic responsiveness through desensitization and biased agonism. SIGNIFICANCE STATEMENT: A sophisticated network of proteins orchestrates the molecular regulation of GPCR activity. Adrenoceptors are GPCRs that play vast roles in many physiological processes. Without tightly controlled desensitization of these receptors, homeostatic imbalance may ensue, thus precipitating various diseases. Here, we critically appraise the mechanisms implicated in adrenoceptor desensitization. A better understanding of these mechanisms helps identify new druggable targets within the GPCR desensitization machinery and opens exciting therapeutic fronts in the treatment of several pathologies.
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Transdução de Sinais , Humanos , Animais , Receptores Adrenérgicos/metabolismo , Receptores Adrenérgicos/fisiologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/fisiologia , beta-Arrestinas/metabolismoRESUMO
The development of the human central nervous system initiates in the early embryonic period until long after delivery. It has been shown that several neurological and neuropsychiatric diseases originate from prenatal incidents. Mathematical models offer a direct way to understand neurodevelopmental processes better. Mathematical modelling of neurodevelopment during the embryonic period is challenging in terms of how to 'Approach', how to initiate modelling and how to propose the appropriate equations that fit the underlying dynamics of neurodevelopment during the embryonic period while including the variety of elements that are built-in naturally during the process of neurodevelopment. It is imperative to answer where and how to start modelling; in other words, what is the appropriate 'Approach'? Therefore, one objective of this study was to tackle the mathematical issue broadly from different aspects and approaches. The approaches were divided into three embryonic categories: cell division, neural tube growth and neural plate growth. We concluded that the neural plate growth approach provides a suitable platform for simulation of brain formation/neurodevelopment compared to cell division and neural tube growth. We devised a novel equation and designed algorithms that include geometrical and topological algorithms that could fit most of the necessary elements of the neurodevelopmental process during the embryonic period. Hence, the proposed equations and defined mathematical structure would be a platform to generate an artificial neural network that autonomously grows and develops.
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Modelos Biológicos , Tubo Neural , Animais , Humanos , Algoritmos , Divisão Celular , Desenvolvimento Embrionário , Modelos Neurológicos , Redes Neurais de Computação , Placa Neural/citologia , Placa Neural/embriologia , Tubo Neural/embriologia , Neurogênese , Neurônios/citologiaRESUMO
Vascular smooth muscle cells (VSMCs) play a critical role in regulating vasotone, and their phenotypic plasticity is a key contributor to the pathogenesis of various vascular diseases. Two main VSMC phenotypes have been well described: contractile and synthetic. Contractile VSMCs are typically found in the tunica media of the vessel wall, and are responsible for regulating vascular tone and diameter. Synthetic VSMCs, on the other hand, are typically found in the tunica intima and adventitia, and are involved in vascular repair and remodeling. Switching between contractile and synthetic phenotypes occurs in response to various insults and stimuli, such as injury or inflammation, and this allows VSMCs to adapt to changing environmental cues and regulate vascular tone, growth, and repair. Furthermore, VSMCs can also switch to osteoblast-like and chondrocyte-like cell phenotypes, which may contribute to vascular calcification and other pathological processes like the formation of atherosclerotic plaques. This provides discusses the mechanisms that regulate VSMC phenotypic switching and its role in the development of vascular diseases. A better understanding of these processes is essential for the development of effective diagnostic and therapeutic strategies.
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Dissecção Aórtica , Aterosclerose , Hipertensão , Músculo Liso Vascular , Humanos , Dissecção Aórtica/patologia , Aterosclerose/patologia , Proliferação de Células , Células Cultivadas , Hipertensão/patologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , FenótipoRESUMO
C-peptide, a byproduct of insulin synthesis believed to be biologically inert, is emerging as a multifunctional molecule. C-peptide serves an anti-inflammatory and anti-atherogenic role in type 1 diabetes mellitus (T1DM) and early T2DM. C-peptide protects endothelial cells by activating AMP-activated protein kinase α, thus suppressing the activity of NAD(P)H oxidase activity and reducing reactive oxygen species (ROS) generation. It also prevents apoptosis by regulating hyperglycemia-induced p53 upregulation and mitochondrial adaptor p66shc overactivation, as well as reducing caspase-3 activity and promoting expression of B-cell lymphoma-2. Additionally, C-peptide suppresses platelet-derived growth factor (PDGF)-beta receptor and p44/p42 mitogen-activated protein (MAP) kinase phosphorylation to inhibit vascular smooth muscle cells (VSMC) proliferation. It also diminishes leukocyte adhesion by virtue of its capacity to abolish nuclear factor kappa B (NF-kB) signaling, a major pro-inflammatory cascade. Consequently, it is envisaged that supplementation of C-peptide in T1DM might ameliorate or even prevent end-organ damage. In marked contrast, C-peptide increases monocyte recruitment and migration through phosphoinositide 3-kinase (PI-3 kinase)-mediated pathways, induces lipid accumulation via peroxisome proliferator-activated receptor γ upregulation, and stimulates VSMC proliferation and CD4+ lymphocyte migration through Src-kinase and PI-3K dependent pathways. Thus, it promotes atherosclerosis and microvascular damage in late T2DM. Indeed, C-peptide is now contemplated as a potential biomarker for insulin resistance in T2DM and linked to increased coronary artery disease risk. This shift in the understanding of the pathophysiology of diabetes from being a single hormone deficiency to a dual hormone disorder warrants a careful consideration of the role of C-peptide as a unique molecule with promising diagnostic, prognostic, and therapeutic applications.
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Peptídeo C , Humanos , Peptídeo C/metabolismo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Transdução de SinaisRESUMO
Cardiovascular disorders are still challenging and are among the deadly diseases. As a major risk factor for atherosclerotic cardiovascular disease, dyslipidemia, and high low-density lipoprotein cholesterol in particular, can be prevented primary and secondary by lipid-lowering medications. Therefore, insights are still needed into designing new drugs with minimal side effects. Proprotein convertase subtilisin/kexin 9 (PCSK9) enzyme catalyses protein-protein interactions with low-density lipoprotein, making it a critical target for designing promising inhibitors compared to statins. Therefore, we screened for potential compounds using a redesigned PCSK9 conformational behaviour to search for a significantly extensive chemical library and investigated the inhibitory mechanisms of the final compounds using integrated computational methods, from ligand essential functional group screening to all-atoms MD simulations and MMGBSA-based binding free energy. The inhibitory mechanisms of the screened compounds compared with the standard inhibitor. K31 and K34 molecules showed stronger interactions for PCSK9, having binding energy (kcal/mol) of -33.39 and -63.51, respectively, against -27.97 of control. The final molecules showed suitable drug-likeness, non-mutagenesis, permeability, and high solubility values. The C-α atoms root mean square deviation and root mean square fluctuation of the bound-PCSK9 complexes showed stable and lower fluctuations compared to apo PCSK9. The findings present a model that unravels the mechanism by which the final molecules proposedly inhibit the PCSK9 function and could further improve the design of novel drugs against cardiovascular diseases.
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Aterosclerose , Simulação de Dinâmica Molecular , Inibidores de PCSK9 , Pró-Proteína Convertase 9 , Humanos , Pró-Proteína Convertase 9/metabolismo , Pró-Proteína Convertase 9/química , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Desenho de Fármacos , Doenças Cardiovasculares/tratamento farmacológico , FarmacóforoRESUMO
We synthesized two isoreticular furan-based metal-organic frameworks (MOFs), MOF-LA2-1(furan) and MOF-LA2-2(furan) with rod-like secondary building units (SBUs) featuring 1D channels, as sorbents for atmospheric water harvesting (LA = long arm). These aluminum-based MOFs demonstrated a combination of high water uptake and stability, exhibiting working capacities of 0.41 and 0.48 gwater/gMOF (under isobaric conditions of 1.70 kPa), respectively. Remarkably, both MOFs showed a negligible loss in water uptake after 165 adsorption-desorption cycles. These working capacities rival that of MOF-LA2-1(pyrazole), which has a working capacity of 0.55 gwater/gMOF. The current MOFs stand out for their high water stability, as evidenced by 165 cycles of water uptake and release. MOF-LA2-2(furan) is the first aluminum MOF to employ a double 'long arm' extension strategy, which is confirmed through single-crystal X-ray diffraction (SCXRD). The MOFs were synthesized by using a straightforward synthesis route. This study offers valuable insights into the design of durable, water-stable MOFs and underscores their potential for efficient water harvesting.
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We have developed two series of amine-functionalized zirconium (Zr) metal-organic framework-808 (MOF-808), which were produced by postsynthetic modifications to have either amino acids coordinated to Zr ions (MOF-808-AAs) or polyamines covalently bound to the chloro-functionalized structure (MOF-808-PAs). These MOF variants were comprehensively characterized by liquid-state 1H nuclear magnetic resonance (NMR) measurements and potentiometric acid-base titration to determine the amounts of amines, energy-dispersive X-ray spectroscopy to assess the extent of covalent substitution by polyamines, powder X-ray diffraction analysis to verify the maintenance of the MOF crystallinity and structure after postsynthetic modifications, nitrogen sorption isotherm measurements to confirm retention of the porosity, and water sorption isotherm measurements to find the water uptake in the pores of each member of the series. Evaluation and testing of these compounds in direct air capture (DAC) of CO2 showed improved CO2 capture performance for the functionalized forms, especially under humid conditions: In dry conditions, the l-lysine- and tris(3-aminopropyl)amine-functionalized variants, termed as MOF-808-Lys and MOF-808-TAPA, exhibited the highest CO2 uptakes at 400 ppm, measuring 0.612 and 0.498 mmol g-1, and further capacity enhancement was achieved by introducing 50% relative humidity, resulting in remarkable uptakes of 1.205 and 0.872 mmol g-1 corresponding to 97 and 75% increase compared to the dry uptakes, respectively. The mechanism underlying the enhanced uptake efficiency was revealed by 13C solid-state NMR and temperature-programmed desorption measurements, indicating the formation of bicarbonate species, and therefore a stoichiometry of 1:1 CO2 to each amine site.
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Escherichia coli is a major cause of serious infections, with antibiotic resistance rendering many treatments ineffective. Hence, novel strategies to combat this pathogen are needed. Anti-virulence therapy is a promising new approach for the subsequent era. Recent research has examined the impact of sub-inhibitory doses of ascorbic acid and paracetamol on Escherichia coli virulence factors. This study evaluated biofilm formation, protease production, motility behavior, serum resistance, expression of virulence-regulating genes (using RT-PCR), and survival rates in a mouse model. Ascorbic acid significantly reduced biofilm formation, protease production, motility, and serum resistance from 100% in untreated isolates to 22-89%, 10-89%, 2-57%, and 31-35% in treated isolates, respectively. Paracetamol also reduced these factors from 100% in untreated isolates to 16-76%, 1-43%, 16-38%, and 31-35%, respectively. Both drugs significantly down-regulated virulence-regulating genes papC, fimH, ompT_m, stcE, fliC, and kpsMTII. Mice treated with these drugs had a 100% survival rate compared with 60% in the positive control group control inoculated with untreated bacteria. This study highlights the potential of ascorbic acid and paracetamol as anti-virulence agents, suggesting their use as adjunct therapies alongside conventional antimicrobials or as alternative treatments for resistant Escherichia coli infections.
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While the combination of liquid chromatography (LC) and mass spectrometry (MS) serves as a robust approach for oligosaccharide analysis, it has difficulty distinguishing the smallest differences between isomers. The integration of infrared (IR) spectroscopy within a mass spectrometer as an additional analytical dimension can effectively address this limitation by providing a molecular fingerprint that is unique to each isomer. However, the direct interfacing of LC-MS with IR spectroscopy presents a technical challenge arising from the mismatch in the operational time scale of each method. In previous studies, this temporal incompatibility was mitigated by employing strategies designed to slow down or broaden the LC elution peaks of interest, but this workaround is applicable only for a few species at a time, necessitating multiple LC runs for comprehensive analysis. In the current work, we directly couple LC with cryogenic IR spectroscopy by acquiring a spectrum in as little as 10 s. This allows us to generate an orthogonal data dimension for molecular identification in the same amount of time that it normally takes for LC analysis. We successfully demonstrate this approach on a commercially available human milk oligosaccharide product, acquiring spectral information on the eluting peaks in real time and using it to identify both the specified constituents and nonspecified product impurities.
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Oligossacarídeos , Humanos , Cromatografia Líquida , Espectrometria de Massas/métodos , Isomerismo , Espectrofotometria Infravermelho , Oligossacarídeos/químicaRESUMO
Peritoneal carcinomatosis (PC) is a complex manifestation of abdominal cancers, with a poor prognosis and limited treatment options. Recent work identifying high concentrations of the cytokine interleukin-6 (IL-6) and its soluble receptor (sIL-6-Rα) in the peritoneal cavity of patients with PC has highlighted this pathway as an emerging potential therapeutic target. This review article provides a comprehensive overview of the current understanding of the potential role of IL-6 in the development and progression of PC. We discuss mechansims by which the IL-6 pathway may contribute to peritoneal tumor dissemination, mesothelial adhesion and invasion, stromal invasion and proliferation, and immune response modulation. Finally, we review the prospects for targeting the IL-6 pathway in the treatment of PC, focusing on common sites of origin, including ovarian, gastric, pancreatic, colorectal and appendiceal cancer, and mesothelioma.
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Interleucina-6 , Neoplasias Peritoneais , Humanos , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/secundário , Interleucina-6/metabolismo , Interleucina-6/antagonistas & inibidores , Animais , Terapia de Alvo Molecular , Transdução de SinaisRESUMO
This study evaluated the potential for antibody-dependent enhancement (ADE) in serum samples from patients exposed to Middle East respiratory syndrome coronavirus (MERS-CoV). Furthermore, we evaluated the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination on ADE in individuals with a MERS infection history. We performed ADE assay in sera from MERS recovered and SARS-CoV-2-vaccinated individuals using BHK cells expressing FcgRIIa, SARS-CoV-2, and MERS-CoV pseudoviruses (PVs). Further, we analyzed the association of ADE to serum IgG levels and neutralization. Out of 16 MERS patients, nine demonstrated ADE against SARS-CoV-2 PV, however, none of the samples demonstrated ADE against MERS-CoV PV. Furthermore, out of the seven patients exposed to SARS-CoV-2 vaccination after MERS-CoV infection, only one patient (acutely infected with MERS-CoV) showed ADE for SARS-CoV-2 PV. Further analysis indicated that IgG1, IgG2, and IgG3 against SARS-CoV-2 S1 and RBD subunits, IgG1 and IgG2 against the MERS-CoV S1 subunit, and serum neutralizing activity were low in ADE-positive samples. In summary, samples from MERS-CoV-infected patients exhibited ADE against SARS-CoV-2 and was significantly associated with low levels of neutralizing antibodies. Subsequent exposure to SARS-CoV-2 vaccination resulted in diminished ADE activity while the PV neutralization assay demonstrated a broadly reactive antibody response in some patient samples.
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Anticorpos Neutralizantes , Anticorpos Antivirais , Anticorpos Facilitadores , COVID-19 , Imunoglobulina G , Coronavírus da Síndrome Respiratória do Oriente Médio , SARS-CoV-2 , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Anticorpos Antivirais/sangue , SARS-CoV-2/imunologia , Imunoglobulina G/sangue , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , COVID-19/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Pessoa de Meia-Idade , Masculino , Feminino , Testes de Neutralização , Adulto , Vacinas contra COVID-19/imunologia , Antígenos Virais/imunologia , Animais , Idoso , Glicoproteína da Espícula de Coronavírus/imunologia , VacinaçãoRESUMO
The cardiovascular and renovascular complications of metabolic deterioration are associated with localized adipose tissue dysfunction. We have previously demonstrated that metabolic impairment delineated the heightened vulnerability of both the perivascular (PVAT) and perirenal adipose tissue (PRAT) depots to hypoxia and inflammation, predisposing to cardioautonomic, vascular and renal deterioration. Interventions either addressing underlying metabolic disturbances or halting adipose tissue dysfunction rescued the observed pathological and functional manifestations. Several lines of evidence implicate adipose tissue thromboinflammation, which entails the activation of the proinflammatory properties of the blood clotting cascade, in the pathogenesis of metabolic and cardiovascular diseases. Despite offering valuable tools to interrupt the thromboinflammatory cycle, there exists a significant knowledge gap regarding the potential pleiotropic effects of anticoagulant drugs on adipose inflammation and cardiovascular function. As such, a systemic investigation of the consequences of PVAT and PRAT thromboinflammation and its interruption in the context of metabolic disease has not been attempted. Here, using an established prediabetic rat model, we demonstrate that metabolic disturbances are associated with PVAT and PRAT thromboinflammation in addition to cardioautonomic, vascular and renal functional decline. Administration of rivaroxaban, a FXa inhibitor, reduced PVAT and PRAT thromboinflammation and ameliorated the cardioautonomic, vascular and renal deterioration associated with prediabetes. Our present work outlines the involvement of PVAT and PRAT thromboinflammation during early metabolic derangement and offers novel perspectives into targeting adipose tissue thrombo-inflammatory pathways for the management its complications in future translational efforts.
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Estado Pré-Diabético , Trombose , Doenças Vasculares , Ratos , Animais , Tromboinflamação , Inflamação/patologia , Trombose/metabolismo , Doenças Vasculares/metabolismo , Tecido Adiposo/metabolismoRESUMO
Hypertension is a major harbinger of cardiovascular morbidity and mortality. It predisposes to higher rates of myocardial infarction, chronic kidney failure, stroke, and heart failure than most other risk factors. By 2025, the prevalence of hypertension is projected to reach 1.5 billion people. The pathophysiology of this disease is multifaceted, as it involves nitric oxide and endothelin dysregulation, reactive oxygen species, vascular smooth muscle proliferation, and vessel wall calcification, among others. With the advent of new biomolecular techniques, various studies have elucidated a gaping hole in the etiology and mechanisms of hypertension. Indeed, epigenetics, DNA methylation, histone modification, and microRNA-mediated translational silencing appear to play crucial roles in altering the molecular phenotype into a hypertensive profile. Here, we critically review the experimentally determined associations between microRNA (miRNA) molecules and hypertension pharmacotherapy. Particular attention is given to the epigenetic mechanisms underlying the physiological responses to antihypertensive drugs like candesartan, and other relevant drugs like clopidogrel, aspirin, and statins among others. Furthermore, how miRNA affects the pharmaco-epigenetics of hypertension is especially highlighted.
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Heart failure with reduced ejection fraction (HFrEF) is a clinical syndrome characterized by volume overload, impaired exercise capacity, and recurrent hospital admissions. A major contributor to the pathophysiology and clinical presentation of heart failure is the activation of the renin-angiotensin-aldosterone system (RAAS). Normally, RAAS is responsible for the homeostatic regulation of blood pressure, extracellular fluid volume, and serum sodium concentration. In HFrEF, RAAS gets chronically activated in response to decreased cardiac output, further aggravating the congestion and cardiotoxic effects. Hence, inhibition of RAAS is a major approach in the pharmacologic treatment of those patients. The most recently introduced RAAS antagonizing medication class is angiotensin receptor blocker/ neprilysin inhibitor (ARNI). In this paper, we discuss ARNIs' superiority over traditional RAAS antagonizing agents in reducing heart failure hospitalization and mortality. We also tease out the evidence that shows ARNIs' renoprotective functions in heart failure patients including those with chronic or end stage kidney disease. We also discuss the evidence showing the added benefit resulting from combining ARNIs with a sodium-glucose cotransporter-2 (SGLT-2) inhibitor. Moreover, how ARNIs decrease the risk of arrhythmias and reverse cardiac remodeling, ultimately lowering the risk of cardiovascular death, is also discussed. We then present the positive outcome of ARNIs' use in patients with diabetes mellitus and those recovering from acute decompensated heart failure. ARNIs' side effects are also appreciated and discussed. Taken together, the provided insight and critical appraisal of the evidence justifies and supports the implementation of ARNIs in the guidelines for the treatment of HFrEF.
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Antagonistas de Receptores de Angiotensina , Insuficiência Cardíaca , Neprilisina , Volume Sistólico , Humanos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Neprilisina/antagonistas & inibidores , Volume Sistólico/efeitos dos fármacos , Animais , Antagonistas de Receptores de Angiotensina/uso terapêutico , Antagonistas de Receptores de Angiotensina/efeitos adversos , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
This research explores the synthesis, characterization, and application of Vanadium Pentoxide nanoparticles (V2O5 NPs), focusing on their efficacy in the photocatalytic degradation of organic dyes under visible light. Utilizing a co-precipitation method, we synthesized V2O5 NPs characterized by an orthorhombic crystal structure with a consistent average particle size of 28 nm. The optical properties of V2O5 NPs, including their band gap, were thoroughly investigated to understand their light absorption capabilities, which are crucial for photocatalytic activity. In our study, Methyl Violet (MV) dye was employed as a model organic pollutant to assess the photocatalytic performance of the nanoparticles. Under visible light irradiation, the V2O5 nanoparticles demonstrated an exceptional photocatalytic degradation efficiency, achieving up to 85% degradation of the MV dye within 100 min. This high level of efficiency is attributed to the nanoparticles' ability to effectively absorb visible light and generate electron-hole pairs, thereby facilitating a robust degradation process. Further analysis revealed that the photocatalytic activity led to the generation of reactive oxygen species (ROS) such as superoxide and hydroxyl radicals, which are integral to the dye degradation mechanism. These ROS play a critical role in breaking down the dye molecules, significantly contributing to the overall effectiveness of the photocatalytic process. The results of this study highlight the potential of V2O5 nanoparticles as a sustainable and effective photocatalytic material for environmental remediation applications, particularly in the treatment of wastewater containing organic dyes. This research not only advances our understanding of the photocatalytic properties of V2O5 nanoparticles but also demonstrates their practical application in addressing environmental pollution through innovative and efficient degradation of hazardous substances.
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BACKGROUND: Interleukin (IL)-38, the latest member of the IL-1 cytokine family, is proposed to have a pathogenic role in rheumatoid arthritis (RA). It is encoded by the IL1F10 gene, which harbors single nucleotide polymorphisms (SNPs) that may predict the risk of autoimmune diseases. Among them are 5' untranslated region (UTR) SNPs, which play a key role in post-transcriptional control, but have not been studied in Iraqi RA patients. METHODS: Two novel IL1F10 5'UTR SNPs (rs3811050 C/T and rs3811051 T/G) were explored in RA and control women (n = 120 and 110, respectively). SNPs were genotyped using TaqMan assay. An ELISA kit was used to measure serum IL-38 concentrations. RESULTS: A reduced risk of RA was associated with rs3811050 T allele and CT genotype (corrected probability [pc] = 0.01 and < 0.001, respectively), while there was no significant association with rs3811051. Haplotype analysis demonstrated that C-T haplotype was associated with a 1.65-fold greater risk of RA, whereas a reduced risk was linked to T-G haplotype. IL-38 concentrations were higher in patients than in controls (p < 0.001). In addition, IL-38 showed acceptable performance in distinguishing between RA and control women (p < 0.001). When IL-38 concentrations were stratified according to SNP genotypes, no significant differences were found. CONCLUSIONS: The rs3811050 variant was more likely to affect RA susceptibility in Iraqi women, and the T allele may play a role in reducing disease risk. IL-38 concentrations were elevated in RA patients, but were not affected by the rs3811050 and rs3811051 genotypes.