The ability to form spheroids under non‐adherent conditions is a well‐known property of human mesenchymal stem cells (hMSCs), in addition to stemness and multilineage differentiation features. In the ...present study, we tested the ability of hMSCs isolated from the vascular wall (hVW‐MSCs) to grow as spheres, and provide a characterization of this 3D model. hVW‐MSCs were isolated from femoral arteries through enzymatic digestion. Spheres were obtained using ultra‐low attachment and hanging drop methods. Immunophenotype and pluripotent genes (SOX‐2, OCT‐4, NANOG) were analyzed by immunocytochemistry and real‐time PCR, respectively. Spheres histological and ultrastructural architecture were examined. Cell viability and proliferative capacity were measured using LIVE/DEATH assay and ki‐67 proliferation marker. Metabolomic profile was obtained with liquid chromatography–mass spectrometry. In 2D, hVW‐MSCs were spindle‐shaped, expressed mesenchymal antigens, and displayed mesengenic potential. 3D cultures of hVW‐MSCs were CD44+, CD105low, CD90low, exhibited a low propensity to enter the cell cycle as indicated by low percentage of ki‐67 expression and accumulated intermediate metabolites pointing to slowed metabolism. The 3D model of hVW‐MSCs exhibits stemness, dormancy and slow metabolism, typically observed in stem cell niches. This culture strategy can represent an accurate model to investigate hMSCs features for future clinical applications in the vascular field.
hVW‐MSCs are able to form spheres, characterized by high NANOG and CD44 expression, low ki‐67 levels and slow metabolism. hVW‐MSC spheres represent an in vitro model of stem cell niche, suitable for investigating MSCs in the vascular field.
Since the beginning of the COVID-19 pandemic and until September 2021, Spain suffered five waves of infection, the latter being related to the expansion of the Delta variant and with a high ...incidence. A vaccination campaign began in December 2020 and by the end of the fifth wave 77.3% of people had been fully vaccinated. Examining the changing dynamics of COVID-19 pandemic and its impact on outcomes among those hospitalized is essential. Our objective was to ascertain any differences in the characteristics and outcomes of hospitalized patients during that period compared to previous waves. We prospectively enrolled 200 consecutively admitted hospital patients from each wave and collected their clinical and demographic data from the medical records, including symptoms, comorbidities, deaths and whether they needed to be admitted to the Intensive Care Unit to receive assisted ventilation. We found that patients in the fifth wave were considerably younger than before, and the mortality rate fell from 22.5 to 2.0%. Admissions to the Intensive Care Unit decreased from 10 to 2%. Patients in the fifth wave had fewer comorbidities, and the age of the patients who died was higher than those who survived. Our results show a marked improvement in patient outcomes in the fifth wave, suggesting success of the vaccination campaign despite the explosion in cases due to the Delta variant.
Obesity is not necessarily a predisposing factor for disease. It is the handling of fat and/or excessive energy intake that encompasses the linkage of inflammation, oxidation, and metabolism to the ...deleterious effects associated with the continuous excess of food ingestion. The roles of cytokines and insulin resistance in excessive energy intake have been studied extensively. Tobacco use and obesity accompanied by an unhealthy diet and physical inactivity are the main factors that underlie noncommunicable diseases. The implication is that the management of energy or food intake, which is the main role of mitochondria, is involved in the most common diseases. In this study, we highlight the importance of mitochondrial dysfunction in the mutual relationships between causative conditions. Mitochondria are highly dynamic organelles that fuse and divide in response to environmental stimuli, developmental status, and energy requirements. These organelles act to supply the cell with ATP and to synthesise key molecules in the processes of inflammation, oxidation, and metabolism. Therefore, energy sensors and management effectors are determinants in the course and development of diseases. Regulating mitochondrial function may require a multifaceted approach that includes drugs and plant-derived phenolic compounds with antioxidant and anti-inflammatory activities that improve mitochondrial biogenesis and act to modulate the AMPK/mTOR pathway.
Infectious and many non-infectious diseases share common molecular mechanisms. Among them, oxidative stress and the subsequent inflammatory reaction are of particular note. Metabolic disorders ...induced by external agents, be they bacterial or viral pathogens, excessive calorie intake, poor-quality nutrients, or environmental factors produce an imbalance between the production of free radicals and endogenous antioxidant systems; the consequence being the oxidation of lipids, proteins, and nucleic acids. Oxidation and inflammation are closely related, and whether oxidative stress and inflammation represent the causes or consequences of cellular pathology, both produce metabolic alterations that influence the pathogenesis of the disease. In this review, we highlight two key molecules in the regulation of these processes: Paraoxonase-1 (PON1) and chemokine (C-C motif) ligand 2 (CCL2). PON1 is an enzyme bound to high-density lipoproteins. It breaks down lipid peroxides in lipoproteins and cells, participates in the protection conferred by HDL against different infectious agents, and is considered part of the innate immune system. With PON1 deficiency, CCL2 production increases, inducing migration and infiltration of immune cells in target tissues and disturbing normal metabolic function. This disruption involves pathways controlling cellular homeostasis as well as metabolically-driven chronic inflammatory states. Hence, an understanding of these relationships would help improve treatments and, as well, identify new therapeutic targets.
Abstract
Patients with morbid obesity frequently present non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) associated with pro-atherogenic alterations. Laparoscopic sleeve ...gastrectomy (LSG) is an effective treatment for weight reduction, and for the remission of hepatic alterations. Using
1
H-nuclear magnetic resonance (
1
H-NMR), we investigated the effects of LSG on lipoprotein and glycoprotein profile in patients with morbid obesity and liver disease. We included 154 patients with morbid obesity (49 non-NASH, 54 uncertain NASH, 51 definite NASH). A blood sample was obtained before surgery and, in patients with definite NASH, one year after surgery. Patients with NASH had increased concentrations of medium and small VLDL particles, VLDL and IDL cholesterol concentrations, IDL, LDL, and HDL triglyceride concentrations, and elevated glycoprotein levels. These changes were more marked in patients with type 2 diabetes mellitus. LSG produced significant decreases in the concentration of VLDL particles, VLDL cholesterol and triglycerides, an increase in the concentration LDL particles and LDL cholesterol concentrations, and a decrease in protein glycation. We conclude that patients with obesity and NASH had significant alterations in circulating levels of lipoproteins and glycoproteins that were associated with the severity of the disease. Most of these changes were reversed post-LSG.
Metabolic vulnerability is associated with age-related diseases and concomitant co-morbidities, which include obesity, diabetes, atherosclerosis and cancer. Most of the health problems we face today ...come from excessive intake of nutrients and drugs mimicking dietary effects and dietary restriction are the most successful manipulations targeting age-related pathways. Phenotypic heterogeneity and individual response to metabolic stressors are closely related food intake. Understanding the complexity of the relationship between dietary provision and metabolic consequences in the long term might provide clinical strategies to improve healthspan. New aspects of metformin activity provide a link to many of the overlapping factors, especially the way in which organismal bioenergetics remodel one-carbon metabolism. Metformin not only inhibits mitochondrial complex 1, modulating the metabolic response to nutrient intake, but also alters one-carbon metabolic pathways. Here, we discuss findings on the mechanism(s) of action of metformin with the potential for therapeutic interpretations.
Hepatic biopsy is the gold standard for staging nonalcoholic fatty liver disease (NAFLD). Unfortunately, accessing the liver is invasive, requires a multidisciplinary team and is too expensive to be ...conducted on large segments of the population. NAFLD starts quietly and can progress until liver damage is irreversible. Given this complex situation, the search for noninvasive alternatives is clinically important. A hallmark of NAFLD progression is the dysregulation in lipid metabolism. In this context, recent advances in the area of machine learning have increased the interest in evaluating whether multi-omics data analysis performed on peripheral blood can enhance human interpretation. In the present review, we show how the use of machine learning can identify sets of lipids as predictive biomarkers of NAFLD progression. This approach could potentially help clinicians to improve the diagnosis accuracy and predict the future risk of the disease. While NAFLD has no effective treatment yet, the key to slowing the progression of the disease may lie in predictive robust biomarkers. Hence, to detect this disease as soon as possible, the use of computational science can help us to make a more accurate and reliable diagnosis. We aimed to provide a general overview for all readers interested in implementing these methods.
Purpose: Surgical stress is a phenomenon not completely understood from the biochemical point of view, although it produces alterations in the oxidative balance and inflammatory status. The present ...study aimed to investigate the alterations of the circulating levels of paraoxonase-1 (PON1)-related variables and markers of inflammation in hospitalized patients who underwent surgery. Methods: We recruited 285 hospitalized patients. Of those, 115 were hospitalized due to a surgical intervention and 170 for reasons other than surgery. The control group consisted of 128 healthy volunteers. A blood sample was obtained for the measurement of serum PON1-related variables, and C-reactive protein (CRP), chemokine (C-C motif) ligand 2 (CCL2), and procalcitonin concentrations. Results: Hospitalized patients had lower serum PON1 activities paraoxonase: 215.6 (168.6 - 277.8) vs. 298.7 (229.7 - 382.6) U/L, p < 0.001; lactonase: 3.0 (2.3 - 3.7) vs. 5.7 (4.6 - 6.5) U/L, p < 0.001, and higher CCL2, CRP and procalcitonin concentrations than the healthy individuals. The days elapsed following surgery and the duration of the procedure itself inversely correlated with PON1-related variables, and directly correlated with CRP concentrations. Patients that were operated on by laparotomy had higher PON1 activity than patients operated on by laparoscopy. Local and regional anesthesia was associated with higher PON1 activities and lower CRP concentrations. Conclusion: These results show a decrease in PON1 activities and an increase in acute phase response in hospitalized patients undergoing surgery and support the hypothesis that these phenomena are related to post-surgical metabolic alterations.
Many countries have seen a two-wave pattern in reported cases of coronavirus disease-19 during the 2020 pandemic, with a first wave during spring followed by the current second wave in late summer ...and autumn. Empirical data show that the characteristics of the effects of the virus do vary between the two periods. Differences in age range and severity of the disease have been reported, although the comparative characteristics of the two waves still remain largely unknown. Those characteristics are compared in this study using data from two equal periods of 3 and a half months. The first period, between 15th March and 30th June, corresponding to the entire first wave, and the second, between 1st July and 15th October, corresponding to part of the second wave, still present at the time of writing this article. Two hundred and four patients were hospitalized during the first period, and 264 during the second period. Patients in the second wave were younger and the duration of hospitalization and case fatality rate were lower than those in the first wave. In the second wave, there were more children, and pregnant and post-partum women. The most frequent signs and symptoms in both waves were fever, dyspnea, pneumonia, and cough, and the most relevant comorbidities were cardiovascular diseases, type 2 diabetes mellitus, and chronic neurological diseases. Patients from the second wave more frequently presented renal and gastrointestinal symptoms, were more often treated with non-invasive mechanical ventilation and corticoids, and less often with invasive mechanical ventilation, conventional oxygen therapy and anticoagulants. Several differences in mortality risk factors were also observed. These results might help to understand the characteristics of the second wave and the behaviour and danger of SARS-CoV-2 in the Mediterranean area and in Western Europe. Further studies are needed to confirm our findings.
Abstract Objective A significant residual cardiovascular risk is consistently observed in patients treated with statins. A combined treatment with fibrates reduces cardiovascular events in very ...high-risk patients. Because this is apparently unconnected to an improvement in lipid-related outcomes we hypothesized that the cardioprotective effects of fibrates might be associated with an improvement in paraoxonase-1 (PON1) status. Method The search for existing evidence, using the Medline, Scopus and Cochrane databases, was systematic and followed the PRISMA statement without restrictions on publication date. We excluded non-clinical and observational studies and we extracted data on baseline and post-treatment values of serum PON1 activity and other measurements of PON1 status. Results Nine studies (including 12 treatment arms) in patients with hyperlipidemia, diabetes or metabolic syndrome treated with fibrates, alone or in combination with statins, were included to synthesize results. A meta-analysis of the data using a random-effects model revealed a significant increase in serum PON1 activity following fibrate therapy (WMD: 15.64 U/L, 95% CI: 6.94, 24.34, p < 0.001), an effect that was robust and not sensitive to any particular study. Subgroup analysis indicated differences in the effect size among types of fibrates and that PON1 alterations were associated with high-density lipoprotein cholesterol changes following fibrate therapy. Conclusions Results indicate a significant PON1-enhancing effect of fibrates. Whether this effect is associated with a clinical benefit, although likely, remains to be further investigated.
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