Objectives
(1) To evaluate clinical and molecular cardiovascular disease (CVD) signs and their relationship with psoriatic arthritis (PsA) features and (2) to identify a clinical patient profile ...susceptible to benefit from methotrexate (MTX) and/or apremilast regarding CVD risk.
Methods
This cross‐sectional study included 100 patients with PsA and 100 age‐matched healthy donors. In addition, an exploratory cohort of 45 biologically naïve patients treated for 6 months with apremilast, MTX or combined therapy according to routine clinical practice was recruited. Extensive clinical and metabolic profiles were obtained. Ninety‐nine surrogate CVD‐related molecules were analysed in plasma and peripheral blood mononuclear cells (PBMCs). Hard cluster analysis was performed to identify the clinical and molecular phenotypes. Mechanistic studies were performed on adipocytes.
Results
Cardiometabolic comorbidities were associated with disease activity and long‐term inflammatory status. Thirty‐five CVD‐related proteins were altered in the plasma and PBMCs of PsA patients and were associated with the key clinical features of the disease. Plasma levels of some of the CVD‐related molecules might distinguish insulin‐resistant patients (MMP‐3, CD163, FABP‐4), high disease activity (GAL‐3 and FABP‐4) and poor therapy outcomes (CD‐163, LTBR and CNTN‐1). Hard cluster analysis identified two phenotypes of patients according to the rates of cardiometabolic comorbidities with distinctive clinical and molecular responses to each treatment.
Conclusions
(1) Novel CVD‐related proteins associated with clinical features could be emerging therapeutic targets in the context of PsA and (2) the pleiotropic action of apremilast could make it an excellent choice for the management of PsA patients with high CVD risk, targeting metabolic alterations and CVD‐related molecules.
1) To characterize the inflammatory proteome of synovial fluid (SF) from patients with Psoriatic Arthritis (PsA) using a high-quality throughput proteomic platform, and 2) to evaluate its potential ...to stratify patients according to clinical features.
Inflammatory proteome profile of SF from thirteen PsA patients with active knee arthritis were analyzed using proximity extension assay (PEA) technology (Olink Target 96 Inflammation panel). Four patients with OA were included as control group.
Seventy-nine inflammation-related proteins were detected in SF from PsA patients (SF-PsA). Unsupervised analyzes of the molecular proteome profile in SF-PsA identified two specific phenotypes characterized by higher or lower levels of inflammation-related proteins. Clinically, SF-PsA with higher levels of inflammatory proteins also showed increased systemic inflammation and altered glucose and lipid metabolisms. Besides, SF from PsA patients showed 39 out of 79 proteins significantly altered compared to SF-OA specifically related to cell migration and inflammatory response. Among these, molecules such as TNFα, IL-17A, IL-6, IL-10, IL-8, ENRAGE, CCL20, TNFSF-14, OSM, IFNγ, MCP-3, CXCL-11, MCP4, CASP-8, CXCL-6, CD-6, ADA, CXCL-10, TNFβ and IL-7 showed the most significantly change.
This is the first study that characterizes the inflammatory landscape of synovial fluid of PsA patients by analyzing a panel of 92 inflammatory proteins using PEA technology. Novel SF proteins have been described as potential pathogenic molecules involved in the pathogenesis of PsA. Despite the flare, inflammatory proteome could distinguish two different phenotypes related to systemic inflammation and lipid and glucose alterations.
Mitogen-activated protein kinases (MAPK) such as p38 and the c-Jun N-terminal kinases (JNKs) are activated during the cellular response to stress signals. Their activity is regulated by the ...MAPK-phosphatase 1 (DUSP1), a key component of the anti-inflammatory response. Stress kinases are well-described elements of the response to otic injury and the otoprotective potential of JNK inhibitors is being tested in clinical trials. By contrast, there are no studies exploring the role of DUSP1 in hearing and hearing loss. Here we show that
expression is age-regulated in the mouse cochlea.
gene knock-out caused premature progressive hearing loss, as confirmed by auditory evoked responses in
mice. Hearing loss correlated with cell death in hair cells, degeneration of spiral neurons and increased macrophage infiltration.
mouse cochleae showed imbalanced redox status and dysregulated expression of cytokines. These data suggest that DUSP1 is essential for cochlear homeostasis in the response to stress during ageing.
Unfortunately, cisplatin has multiple adverse effects and causes irreversible hearing loss (HL) in a large proportion of patients, which severely impacts their quality of life.1 Here, we confirm that ...treatment with LPT99, a small molecule inhibitor of the apoptosome, preserves hearing levels in a rat model of cisplatin-induced HL and prevents apoptosis in cisplatin-exposed HEI-OC1 cells. ...more effective agents are urgently needed, preferably formulated for local (intratympanic) administration to avoid interfering with the antineoplastic activity of cisplatin. LPT99-co-treated cochleae also showed less dilatation of strial microvasculature, particularly in the middle turn and exhibited higher levels of Kir4.1, a marker of intermediate cells (Figure 4I and O). Because the stria vascularis is the entry point of cisplatin into the cochlea and a long-term accumulation site, it has emerged as an important target to prevent cisplatin ototoxicity.2 Further studies are needed to demonstrate a direct effect of LPT99 on strial cells.
RA patients are at higher risk of cardiovascular disease, influenced by therapies. Studying their cardiovascular and cardiometabolic proteome can unveil biomarkers and insights into related ...biological pathways.
This study included two cohorts of RA patients: newly diagnosed individuals (n=25) and those with established RA (disease duration >25 years, n=25). Both cohorts were age and sex-matched with a control group (n=25). Additionally, a longitudinal investigation was conducted on a cohort of 25 RA patients treated with methotrexate and another cohort of 25 RA patients treated with tofacitinib for 6 months. Clinical and analytical variables were recorded, and serum profiling of 184 proteins was performed using the Olink technology platform.
RA patients exhibited elevated levels of 75 proteins that might be associated with cardiovascular disease. In addition, 24 proteins were increased in RA patients with established disease. Twenty proteins were commonly altered in both cohorts of RA patients. Among these, elevated levels of CTSL1, SORT1, SAA4, TNFRSF10A, ST6GAL1 and CCL18 discriminated RA patients and HDs with high specificity and sensitivity. Methotrexate treatment significantly reduced the levels of 13 proteins, while tofacitinib therapy modulated the expression of 10 proteins. These reductions were associated with a decrease in DAS28. Baseline levels of SAA4 and high levels of BNP were associated to the non-response to methotrexate. Changes in IL6 levels were specifically linked to the response to methotrexate. Regarding tofacitinib, differences in baseline levels of LOX1 and CNDP1 were noted between non-responder and responder RA patients. In addition, response to tofacitinib correlated with changes in SAA4 and TIMD4 levels.
In summary, this study pinpoints molecular changes linked to cardiovascular disease in RA and proposes candidate protein biomarkers for distinguishing RA patients from healthy individuals. It also highlights how methotrexate and tofacitinib impact these proteins, with distinct alterations corresponding to each drug's response, identifying potential candidates, as SAA4, for the response to these therapies.
OmpR, is one of the best characterized response regulators families, which includes transcriptional regulators with a variety of physiological roles including the control of symbiotic nitrogen ...fixation (SNF). The
Rhizobium etli
CE3 genome encodes 18 OmpR-type regulators; the function of the majority of these regulators during the SNF in common bean, remains elusive. In this work, we demonstrated that a
R. etli
mutant strain lacking the OmpR-type regulator RetPC57 (ΔRetPC57), formed less nodules when used as inoculum for common bean. Furthermore, we observed reduced expression level of bacterial genes involved in Nod Factors production (
nodA
and
nodB
) and of plant early-nodulation genes (
NSP2
,
NIN
,
NF-YA
and
ENOD40
), in plants inoculated with ΔRetPC57. RetPC57 also contributes to the appropriate expression of genes which products are part of the multidrug efflux pumps family (MDR). Interestingly, nodules elicited by ΔRetPC57 showed increased expression of genes relevant for Carbon/Nitrogen nodule metabolism (
PEPC
and
GOGAT
) and ΔRetPC57 bacteroids showed higher nitrogen fixation activity as well as increased expression of key genes directly involved in SNF (
hfixL, fixKf, fnrN, fixN, nifA
and
nifH
). Taken together, our data show that the previously uncharacterized regulator RetPC57 is a key player in the development of the
R. etli
-
P. vulgaris
symbiosis.
El oxígeno se ha identificado como una de las principales causas que conducen a daños por desecación, mientras que el tiempo que el microorganismo está expuesto a condiciones ambiente puede ...contribuir a su degradación. En el Centro de Ingeniería Genética y Biotecnología de Camagüey, se desarrolló un producto ecológico de formulación sólida con probada acción bionematicida llamado HeberNem-S®, cuyo ingrediente activo es la bacteria Gram positiva Brevibacterium celere C-924. En el presente trabajo se realizó un estudio de estabilidad del ingrediente activo del producto HeberNem-SÒ a las temperaturas de 16, 28 y 37 ºC sin vacío. Como resultado del estudio se obtuvo un modelo matemático que simula la degradación que ocurre en el rango de temperaturas evaluadas y sin vacío. El modelo matemático logarítmico-exponencial obtenido permite estimar el grado de supervivencia ante modificaciones ambientales asociadas a los parámetros estudiados, sin necesidad de realizar evaluaciones experimentales de determinación de la viabilidad.
Oxygen has been identified as one of the main causes leading to desiccation damage, while the time that the microorganism is exposed to ambient conditions can contribute to its degradation. At the Center of Genetic Engineering and Biotechnology of Camagüey, an ecological product with a solid formulation with proven bionematicidal action called HeberNem-S® was developed, whose active ingredient is the Gram-positive bacterium Brevibacterium celere C-924. In the present work, a stability study of the active ingredient of the HeberNem-SÒ product was carried out at temperatures of 16, 28 and 37 ºC without vacuum. As a result of the study, a mathematical model was obtained that simulates the degradation that occurs in the range of temperatures evaluated and without vacuum. The logarithmic-exponential mathematical model obtained makes it possible to estimate the degree of survival in the face of environmental modifications associated with the parameters studied, without the need to carry out experimental evaluations to determine viability.
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