Microplastics Distribution within Western Arctic Seawater and Sea Ice.

Microplastic pollution has emerged as a global environmental concern, exhibiting wide distribution within marine ecosystems, including the Arctic Ocean. Limited Arctic microplastic data exist from beached plastics, seabed sediments, floating plastics, and sea ice. However, no studies have examined microplastics in the sea ice of the Canadian Arctic Archipelago and Tallurutiup Imanga National Marine Conservation Area, and few have explored Arctic marginal seas' water column. The majority of the microplastic data originates from the Eurasian Arctic, with limited data available from other regions of the Arctic Ocean. This study presents data from two distinct campaigns in the Canadian Arctic Archipelago and Western Arctic marginal seas in 2019 and 2020. These campaigns involved sampling from different regions and matrices, making direct comparisons inappropriate. The study's primary objective is to provide insights into the spatial and vertical distribution of microplastics. The results reveal elevated microplastic concentrations within the upper 50 m of the water column and significant accumulation in the sea ice, providing evidence to support the designation of sea ice as a microplastic sink. Surface seawater exhibits a gradient of microplastic counts, decreasing from the Chukchi Sea towards the Beaufort Sea. Polyvinyl chloride polymer (~60%) dominated microplastic composition in both sea ice and seawater. This study highlights the need for further investigations in this region to enhance our understanding of microplastic sources, distribution, and transport.

Generation of site-distinct N-glycan variants for in vitro bioactivity testing.

Glycosylation, a critical product quality attribute, may affect the efficacy and safety of therapeutic proteins in vivo. Chinese hamster ovary fed-batch cell culture batches yielded consistent glycoprofiles of a Fc-fusion antibody comprizing three different N-glycosylation sites. By adding media supplements at specific concentrations in cell culture and applying enzymatic glycoengineering, a diverse N-glycan variant population was generated, including high mannose, afucosylated, fucosylated, agalactosylated, galactosylated, asialylated, and sialylated forms. Site-specific glycosylation profiles were elucidated by glycopeptide mapping and the effect of the glycosylation variants on the FcγRIIIa receptor binding affinity and the biological activity (cell-based and surface plasmon resonance) was assessed. The two fusion body glycosylation sites were characterized by a high degree of sialic acid, more complex N-glycan structures, a higher degree of antennarity, and a site-specific behavior in the presence of a media supplement. On the other hand, the media supplements affected the Fc-site glycosylation heterogeneity similarly to the various studies described in the literature with classical monoclonal antibodies. Enzymatic glycoengineering solely managed to generate high levels of galactosylation at the fusion body sites. Variants with low core fucosylation, and to a lower extent, high mannose glycans exhibited increased FcγRIIIa receptor binding affinity. All N-glycan variants exhibited weak effects on the biological activity of the fusion body. Both media supplementation and enzymatic glycoengineering are suitable to generate sufficient diversity to assess the effect of glycostructures on the biological activity.

A novel micro-photogrammetric instrument for visualizing in 3D small objects applied to the quantitative study of the dissolution behavior of a pharmaceutical dosage form.

The work presented here proposes an innovative approach to 3D chemical mapping of solid formulations by microphotogrammetry. We present details of a novel microphotogrammetry apparatus and the first results for the application of photogrammetry to the dissolution analysis of solid pharmaceutical dosage forms. Unlike other forms of optical imaging, microphotogrammetry allows a true 3D model to be constructed that includes direct observation of the sides of the sample rather than only top-down topographic imaging. Volume and structural changes are assessed quantitatively and related to chemical analysis by high performance liquid chromatography. The recently introduced method of chemical identification by dissolution analysis, or chemical imaging by dissolution analysis, is employed for the first time to obtain tomographic images of the dissolution process.

Ambulatory Arterial Stiffness Index (AASI) is Unable to Estimate Arterial Stiffness of Hypertensive Subjects: Role of Nocturnal Dipping of Blood Pressure.

BACKGROUND: Ambulatory Arterial Stiffness Index (AASI) has been proposed as an indirect and simpler method to estimate the Arterial Stiffness (AS). AASI, calculated from a set of data collected during a 24-hours ambulatory blood pressure monitoring (ABPM), is defined as 1 minus the regression slope of diastolic on systolic blood pressure (BP) values. For a given increase in diastolic BP, the increase in systolic BP is smaller in a compliant compared to a stiff artery; the stiffer the arterial tree, the closer AASI is to 1. AASI was demonstrated to predict cardiovascular mortality, cerebrovascular events and to be associated with target organ damage. Taking into account the almost complete absence of data regarding the ability of AASI to predict the different degree of AS when hypertensives are divided into four classes of dipping in relation to the extent of the nocturnal reduction of BP (extreme dippers, dippers, mild dippers and reverse dippers) aim to clarify the ability of AASI to estimate the different degree of AS of hypertensive subjects with different nocturnal BP profile and resulting in different extent of organ damage. MATERIALS AND METHODS: We enrolled 816 subjects (403 men and 413 women) with essential hypertension, referred to the U.O.C of Medicina Interna e Cardioangiologia of the University of Palermo; 173 subjects (71 men and 102 women, mean age 44.4 ± 14.6 years) without a history of hypertension were enrolled as controls. RESULTS: The analysis of data was performed by dividing the population into four categories in relation to the extent of the nocturnal decline of BP: 124 extreme dipper (mean age 54,8 ± 12,4 years, men 46.8 %); 287 dipper (mean age 55,9 ± 14,2 years, men 54,0 %); 271 mild dipper (mean age 61,5 ± 14,7 years, men 52,0 %); 134 reverse dipper (mean age 61,5 ± 14,7 years, men 33.6 %). The mean value of AASI was significantly higher for mild and reverse dippers versus control patients and versus the other categories of dipping. The multiple regression analysis with AASI as the dependent variable confirmed the significant association between AASI and nocturnal dip (p: 0.015). The Multinomial Logistic Regression Analysis, in which AASI values were adjusted for the main confounders (age, sex, Body Mass Index, 24h SBP, 24h DBP) showed that the association between AASI and dipping is maintained only for dipper and extreme dipper hypertensives, missing the significance for mild and reverse subjects. CONCLUSION: 1) AASI levels are associated with night-to-day BP ratio; 2) Lower levels of AASI are significantly associated to extreme dipper and dipper BP nocturnal profile when compared to healthy controls. 3) After correction for the major confounding factors, the association between AASI and the high-damaged class of hypertensive subjects with lower or no nocturnal fall of BP is lost. Our findings support the hypothesis that AASI is unable to estimate AS of older hypertensive subjects with a high burden of organ and vascular damage and several comorbidities, probably because the nocturnal reduction of BP is the main determinant of AASI, being more powerful than AS itself.

Are the Myokines the Mediators of Physical Activity-Induced Health Benefits?

BACKGROUND: The concept of the muscle as a secretory organ, developed during the last decades, partially answers to the issue of how the crosstalk between skeletal muscle and distant tissues happens. The beneficial effects of exercise transcend the simple improved skeletal muscle functionality: systemic responses to exercise have been observed in distal organs like heart, kidney, brain and liver. Increasing data have accumulated regarding the synthesis, the kinetics of release and the biological roles of muscular cytokines, now called myokines. The most recent techniques have meaningfully improved the identification of the muscle cell secretome, but several issues regarding the extent of secretion from the muscle as well as the actions of the myokines remain unexplained. METHODS: The goal of this review is to provide an update about the secretory properties of skeletal muscle during and after an acute bout of exercise and after exercise training, showing the main experimental evidences, but also speculate about the possible therapeutic use of the physical training-induced circulating factors, especially in some categories of patients in which the baseline conditions are heavily damaged by one or more pathological conditions. RESULTS: studies on myokines are relatively recent, and to date most of the evidence available in humans has focused on the biological role of Il-6 during muscle contraction. Regarding to the myokines more recently identified, for example myostatin, fibroblast growth factor 21 (FGF21), secreted protein acidic and rich in cysteine (SPARC) or follistatin-like 1 some of these seem to be promising therapeutic agents, but our awareness about their potential benefits towards human health is only at the beginning. CONCLUSION: for many of the myokines identified to date, the information available is limited and not enough to characterize precise functions and activities carried out by those in man. Several issues need to be addressed by future studies, tailored to ascertain accurately and surely the biological role and the therapeutic potential of some myokines.

Synthesis, in vitro evaluation, and molecular modeling investigation of benzenesulfonimide peroxisome proliferator-activated receptors α antagonists.

Recent evidences suggest a moderate activation of Peroxisome Proliferator-Activated Receptors (PPARs) could be favorable in metabolic diseases, reducing side effects given from full agonists. PPAR partial agonists and antagonists represent, to date, interesting tools to better elucidate biological processes modulated by these receptors. In this work are reported new benzenesulfonimide compounds able to block PPARα, synthesized and tested by transactivation assays and gene expression analysis. Some of these compounds showed a dose-dependent antagonistic behavior on PPARα, submicromolar potency, different profiles of selectivity versus PPARγ, and a repressive effect on CPT1A expression. Dockings and molecular dynamics on properly selected benzenesulfonimide derivatives furnished fresh insights into the molecular determinant most likely responsible for PPARα antagonism.

MMPs and angiogenesis affect the metastatic potential of a human vulvar leiomyosarcoma cell line.

Gynaecological leiomyosarcoma (gLMS) represent a heterogeneous group of soft tissue sarcoma, characterized by rare incidence, high aggressiveness and propensity to infiltrate secondary organs, poor prognosis and lethality, because of the lack of biological mechanisms that underlying their progression and effective pharmaceutical treatments. This study was focused on some of the aspects of progression and dissemination of a subtype of gLMS namely vulvar LMS (vLMS). We therefore used a vulvar LMS-derived cell line namely SK-LMS-1, coupled with in vitro and in vivo assays. We observed that SK-LMS-1 cells have a strong invasive capacity in vitro, through the activity of matrix metalloproteinases 2 and 9, while in vivo these cells induce a strong angiogenic response and disseminate to the chick embryo liver. Therefore, we postulate that metalloproteinases are involved in the spreading behaviour of SK-LMS-1. Further investigations are necessary to better understand the molecular and cellular machinery involved in the progression of this malignancy.

Reversed-phase high-performance liquid chromatography method with fluorescence detection to screen nitric oxide synthases inhibitors.

Nitric oxide synthase (NOS) inhibitors are potential drug candidates due to the critical role of an excessive production of nitric oxide in a range of diseases. At present, the radiometric detection of L-[(3)H]-citrulline produced from L-[(3)H]-arginine during the enzymatic reaction is one of the most accepted methods to assess the in vitro activity of NOS inhibitors. Here we report a fast, easy, and cheap reversed-phase high-performance liquid chromatography method with fluorescence detection, based on the precolumn derivatization of L-citrulline with o-phthaldialdehyde/N-acetyl cysteine, for the in vitro screening of NOS inhibitors. To evaluate enzyme inhibition by the developed method, N-[3-(aminomethyl)benzyl]acetamidine, a potent and selective inhibitor of inducible NOS, was used as a test compound. The half maximal inhibitory concentration obtained was comparable to that derived by the well-established radiometric assay.

Effect of stilbene and chalcone scaffolds incorporation in clofibric acid on PPARα agonistic activity.

In an effort to develop safe and efficacious compounds for the treatment of metabolic disorders, new compounds based on a combination of clofibric acid, the active metabolite of clofibrate, and trans-stilbene, chalcone, and other lipophilic groups were synthesized. They were evaluated for PPARα transactivation activity; all branched derivatives showed an increase of the transcriptional activity of receptor compared to the linear ones. Noteworthy, stilbene and benzophenone branched derivatives activated the PPARα better than clofibric acid.

Fibrate-derived N-(methylsulfonyl)amides with antagonistic properties on PPARα.

The identification of novel PPAR ligands represents an attractive research to fully understand the complex biological pathways regulated by these receptors. Selective PPAR modulators, inverse agonists and antagonists of three PPAR isoforms could help to clarify biological effects on lipid and glucose homeostasis. Here we describe the identification of a group of N-(methylsulfonyl)amides, derived from PPARα agonist carboxylic acids. Transactivation and FRET assay confirmed an antagonist behaviour on PPARα for some of these compounds, with submicromolar IC(50). A preliminary analysis on selectivity α/γ revealed different profiles of inhibition or activation.

Synthesis and structure-activity relationships of fibrate-based analogues inside PPARs.

In an effort to develop safe and efficacious compounds for the treatment of metabolic disorders, new compounds based on a combination of clofibric acid, the active metabolite of clofibrate, and lipophilic groups derived from natural products chalcone and stilbene were synthesised. Some of them were found to be active at micromolar concentrations only on PPARα or PPARγ, while others were identified as dual agonists PPARα/γ.

Discovery of gemfibrozil analogues that activate PPARα and enhance the expression of gene CPT1A involved in fatty acids catabolism.

A new series of gemfibrozil analogues conjugated with α-asarone, trans-stilbene, chalcone, and their bioisosteric modifications were synthesized and evaluated to develop PPARα agonists. In this attempt, we have removed the methyls on the phenyl ring of gemfibrozil and introduced the above scaffolds in para position synthesizing two series of derivatives, keeping the dimethylpentanoic skeleton of gemfibrozil unaltered or demethylated. Four compounds exhibited good activation of the PPARα receptor and were also screened for their activity on PPARα-regulated gene CPT1A.

Relação entre a prática de exercício físico e risco de doenças cardiovasculares / Relationship between the practice of physical exercise and risk of cardiovascular diseases

The aim of the present study was to evaluate, in adults, the nutritional statusand risk factors for cardiovascular disease and correlate them with exercise. We evaluated 77 employees , both male and female, aged an average 31.5 years. Body weight, height, waist circumference (WC), hip circumference (HC) and body fat percent (BF%) were measured. Cardiovascular risk was assessed by waist-to-hip ratio (WHR) and conicity index (CI). Weanalyzed blood pressure, total cholesterol, triglycerides and glucose. Alcohol consumption and physical exercise were also evaluated. According to BMI, 77.8% were eutrophic, 20.8% overweight and 1.3% underweight in the total sample. As for BF%, 44.2% were above the average and 41.6% below it. The variables serum cholesterol and exercise showed significant correlation (p = 0.001), and all individuals who had borderline cholesterol levels did not exercise regularly. Through the comparison of numerical variables between physical activity and triglyceride values, higher values of serum triglycerides were found for those who did not do physical exercise (p = 0.037). The remaining variables showed no significant differences. Only 1.3% of men had metabolic syndrome and this classification was not relatedto physical exercise. Although this is a population with a high prevalence of sedentarism, elevated triglycerides and overweight, it can be inferred that the study population showed a low prevalence of cardiovascular disease risk.

El objetivo de este estudio fue evaluar, en adultos, el estado nutricional y factores de riesgo de enfermedad cardiovascular y larelación con la práctica de ejercicio físico. Se estudiaron 77 empleados de ambos sexos,con un promedio de 31,5 años. Se midieron: peso, talla, circunferencia de cintura (CC), circunferencia de cadera (HC) y porcentaje de grasa corporal (% GC). El riesgo cardiovascular fue estimado por medio de la relación cinturacadera (RCC) y el índice de conicidad (IC). Sedeterminaron: presión arterial, colesterol total, triglicéridos y glucosa, consumo de alcoholy ejercicio físico. De acuerdo con el IMC del grupo de estudio, 77,8% eran eutróficos; 20,8%presentaban sobrepeso y 1,3% estaban con bajopeso. Con respecto a G%, 44,2% estaban sobrela media y 41,6% bajo la media. El riesgo para enfermedades cardiovasculares por el IC fue de13%. El colesterol sérico mostró una correlación positiva significativa (p=0,001) con la prácticade actividad física y todas las personas que portaban índice de colesterol elevado o limítrofe no practicaban ejercicio con regularidad. La comparación de variables numéricas entre actividad física y niveles de triglicéridos mostraba estos últimos más elevados en los individuos que no practicaban ejercicio físico (p = 0,037). Las otras variables estudiadas nomostraron diferencias significativas. Solamente el 1,3% de los hombres presentaba SM que no se relacionaba con la práctica de ejercicio físico. Apesar de ser una población con alta prevalencia de sedentarismo, portadora de triglicéridos elevados y sobrepeso, presenta baja prevalenciade ECV.

O objetivo do presente estudo foi avaliar, em adultos, o estado nutricional e fatores de risco para doenças cardiovasculares e correlacioná-los com a prática de exercício físico. Foram avaliados 77 funcionários, de ambos os gêneros, com média de 31,5 anos. Foram mensurados: peso, estatura, circunferência da cintura (CC), do quadril (CQ) e percentual de gordura (%G). O risco cardiovascular foi avaliado pela relação cintura-quadril (RCQ) e pelo índice de conicidade (IC). Analisou-se pressão arterial, colesterol total, triglicérides e glicemia; consumo de bebida alcoólica e prática de exercícios físicos. De acordo com o IMC, observou-se eutrofia em 77,8%, 20,8% com sobrepeso e 1,3% baixo peso na amostra total. Quanto ao %G, 44,2% encontravam-se acima da média e 41,6% abaixo da média. O risco para doenças cardiovasculares pelo IC foi de 13%. As variáveis colesterol total sérico e prática de exercícios apresentaram correlação positiva significante (p=0,001), sendo que todos os indivíduos que apresentaram taxa de colesterol limítrofe não praticavam exercícios físicos de modo regular. Por meio da comparação das variáveis numéricas entre prática de exercício físico e triglicérides foram encontrados valores maiores de triglicérides séricos nos que não praticavam exercício físico (p=0,037). As demais variáveis não apresentaram diferenças significativas. Apenas 1,3% dos indivíduos do gênero masculino apresentaram SM e esta classificação não apresentou relação com a prática de exercício físico. Apesar de se tratar de uma população com altas prevalências de sedentarismo, triglicérides elevados, sobrepeso, pode-se inferir que a população de estudo apresentou baixa prevalência de risco para DCV.

Benzothiazole-based N-(phenylsulfonyl)amides as a novel family of PPARα antagonists.

The discovery of PPAR antagonists is emerging as an useful tool for elucidating the biological role of the receptor. Here we report the identification of N-(phenylsulfonyl)amides containing the benzothiazole scaffold, a novel class of potent PPARα antagonists obtained from chemical modification of carboxylic acid agonists. In this work, a group of phenylsulfonamides were synthesized and in vitro evaluated against the agonistic effect of GW7647; they showed an inhibitory effect on PPARα activation, with best compounds revealing a dose-dependent antagonistic profile. Some of these antagonists showed also an inhibitory effect on CPT1A pattern expression.