Succinate is a signaling metabolite sensed extracellularly by succinate receptor 1 (SUNCR1). The accumulation of succinate in macrophages is known to activate a pro-inflammatory program; however, the ...contribution of SUCNR1 to macrophage phenotype and function has remained unclear. Here we found that activation of SUCNR1 had a critical role in the anti-inflammatory responses in macrophages. Myeloid-specific deficiency in SUCNR1 promoted a local pro-inflammatory phenotype, disrupted glucose homeostasis in mice fed a normal chow diet, exacerbated the metabolic consequences of diet-induced obesity and impaired adipose-tissue browning in response to cold exposure. Activation of SUCNR1 promoted an anti-inflammatory phenotype in macrophages and boosted the response of these cells to type 2 cytokines, including interleukin-4. Succinate decreased the expression of inflammatory markers in adipose tissue from lean human subjects but not that from obese subjects, who had lower expression of SUCNR1 in adipose-tissue-resident macrophages. Our findings highlight the importance of succinate-SUCNR1 signaling in determining macrophage polarization and assign a role to succinate in limiting inflammation.
Current demand of consumers for healthy and sustainable food products has led the industry to search for different sources of plant protein isolates and concentrates. Legumes represent an excellent ...nonanimal protein source with high‐protein content. Legume species are distributed in a wide range of ecological conditions, including regions with drought conditions, making them a sustainable crop in a context of global warming. However, their use as human food is limited by the presence of antinutritional factors, such as protease inhibitors, lectins, phytates, and alkaloids, which have adverse nutritional effects. Antitechnological factors, such as fiber, tannins, and lipids, can affect the purity and protein extraction yield. Although most are removed or reduced during alkaline solubilization and isoelectric precipitation processes, some remain in the resulting protein isolates. Selection of appropriate legume genotypes and different emerging and sustainable facilitating technologies, such as high‐power ultrasound, pulsed electric fields, high hydrostatic pressure, microwave, and supercritical fluids, can be applied to increase the removal of unwanted compounds. Some technologies can be used to increase protein yield. The technologies can also modify protein structure to improve digestibility, reduce allergenicity, and tune technological properties. This review summarizes recent findings regarding the use of emerging technologies to obtain high‐purity protein isolates and the effects on techno‐functional properties and health.
Olfactomedins (OLFMs) are a family of glycoproteins that play a relevant role in embryonic development and in some pathological processes. Although OLFM2 is involved in the regulation of the energy ...metabolism and OLFM4 is an important player in inflammation, innate immunity and cancer, the role of OLFMs in NAFLD-related intestinal dysbiosis remains unknown. In this study, we analysed the hepatic mRNA expression of
and the jejunal expression of
in a well-established cohort of women with morbid obesity (MO), classified according to their hepatic histology into normal liver (
= 27), simple steatosis (
= 26) and nonalcoholic steatohepatitis (NASH,
= 16). Our results showed that
hepatic mRNA was higher in NASH, in advanced degrees of steatosis and in the presence of lobular inflammation. Additionally, we obtained positive correlations between hepatic
and glucose, cholesterol, trimethylamine N-oxide and deoxycholic acid levels and hepatic fatty acid synthase, and negative associations with weight and jejunal Toll-like receptors (
) and
expression. Regarding jejunal
, we observed positive correlations with circulating interleukin (IL)-8, IL-10, IL-17 and jejunal
. In conclusion, OLFM2 in the liver seems to play a relevant role in NAFLD progression, while OLFM4 in the jejunum could be involved in gut dysbiosis-related inflammatory events.
Adipose-derived mesenchymal stem cells (ASCs) are a promising option for the treatment of obesity and its metabolic co-morbidities. Despite the recent identification of brown adipose tissue (BAT) as ...a potential target in the management of obesity, the use of ASCs isolated from BAT as a therapy for patients with obesity has not yet been explored. Metabolic activation of BAT has been shown to have not only thermogenic effects, but it also triggers the secretion of factors that confer protection against obesity. Herein, we isolated and characterized ASCs from the visceral adipose tissue surrounding a pheochromocytoma (IB-hASCs), a model of inducible BAT in humans. We then compared the anti-obesity properties of IB-hASCs and human ASCs isolated from visceral white adipose tissue (W-hASCs) in a murine model of diet-induced obesity. We found that both ASC therapies mitigated the metabolic abnormalities of obesity to a similar extent, including reducing weight gain and improving glucose tolerance. However, infusion of IB-hASCs was superior to W-hASCs in suppressing lipogenic and inflammatory markers, as well as preserving insulin secretion. Our findings provide evidence for the metabolic benefits of visceral ASC infusion and support further studies on IB-hASCs as a therapeutic option for obesity-related comorbidities.
There is a clear association between the molecular profile of colorectal cancer liver metastases (CRCLM) and the degree to which aggressive progression of the disease impacts patient survival. ...However, much of our knowledge of the molecular behaviour of colorectal cancer cells comes from experimental studies with, as yet, limited application in clinical practice. In this article, we review the current advances in the understanding of the molecular behaviour of CRCLM and present possible future therapeutic applications. This review focuses on three important steps in CRCLM development, progression and treatment: (1) the dissemination of malignant cells from primary tumours and the seeding to metastatic sites; (2) the response to modern regimens of chemotherapy; and (3) the possibility of predicting early progression and recurrence patterns by molecular analysis in liquid biopsy.
Background
Concomitant gallstones and common bile duct stones (CBDS) is a relatively frequent presentation. The optimal treatment remains controversial and the debate persists between two strategies. ...The
one-stage approach
: laparoscopic cholecystectomy with laparoscopic common bile duct exploration (LCBDE) has been shown to be equally safe and more cost-effective than the more traditional
two-stage approach
: endoscopic retrograde cholangiography followed by laparoscopic cholecystectomy (ERCP + LC). However, many surgeons worldwide still prefer the two-stage procedure. This survey evaluated contemporary management of CBDS in Spain and assessed the impact of surgeon and hospital factors on provision of LCBDE.
Methods
A 25-item, web-based anonymous survey was sent to general surgeons members of the Spanish Surgeons Association. Descriptive statistics were applied to summarize results.
Results
Responses from 305 surgeons across 173 Spanish hospitals were analyzed. ERCP is the initial approach for preoperatively suspected CBDS for 86% of surgeons. LCBDE is the preferred method for only 11% of surgeons and only 11% treat more than 10 cases per year. For CBDS discovered intraoperatively, 59% of respondents attempt extraction while 32% defer to a postoperative ERCP. The main reasons cited for not performing LCBDE were lack of equipment, training and timely availability of an ERCP proceduralist. Despite these barriers, most surgeons (84%) responded that LCBDE should be implemented in their departments.
Conclusions
ERCP was the preferred approach for CBDS for the majority of respondents. There remains limited use of LCBDE despite many surgeons indicating it should be implemented. Focused planning and resourcing of both training and operational demands are required to facilitate adoption of LCBDE as option for patients.
Pancreatic ductal adenocarcinoma contributes significantly to global cancer-related deaths, featuring only a 10% survival rate over five years. The quest for novel tumor markers is critical to ...facilitate early diagnosis and tailor treatment strategies for this disease, which is key to improving patient outcomes. In pancreatic ductal adenocarcinoma, these markers have been demonstrated to play a crucial role in early identification, continuous monitoring, and prediction of its prognosis and have led to better patient outcomes. Nowadays, biopsy specimens serve to ascertain diagnosis and determine tumor type. However, liquid biopsies present distinct advantages over conventional biopsy techniques. They offer a noninvasive, easily administered procedure, delivering insights into the tumor's status and facilitating real-time monitoring. Liquid biopsies encompass a variety of elements, such as circulating tumor cells, circulating tumor DNA, extracellular vesicles, microRNAs, circulating RNA, tumor platelets, and tumor endothelial cells. This review aims to provide an overview of the clinical applications of liquid biopsy as a technique in the management of pancreatic cancer.
Background
Coronavirus-19 (COVID-19) disease is driven by an unchecked immune response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus which alters host ...mitochondrial-associated mechanisms. Compromised mitochondrial health results in abnormal reprogramming of glucose metabolism, which can disrupt extracellular signalling. We hypothesized that examining mitochondrial energy-related signalling metabolites implicated in host immune response to SARS-CoV-2 infection would provide potential biomarkers for predicting the risk of severe COVID-19 illness.
Methods
We used a semi-targeted serum metabolomics approach in 273 patients with different severity grades of COVID-19 recruited at the acute phase of the infection to determine the relative abundance of tricarboxylic acid (Krebs) cycle-related metabolites with known extracellular signaling properties (pyruvate, lactate, succinate and α-ketoglutarate). Abundance levels of energy-related metabolites were evaluated in a validation cohort (n=398) using quantitative fluorimetric assays.
Results
Increased levels of four energy-related metabolites (pyruvate, lactate, a-ketoglutarate and succinate) were found in critically ill COVID-19 patients using semi-targeted and targeted approaches (p<0.05). The combined strategy proposed herein enabled us to establish that circulating pyruvate levels (p<0.001) together with body mass index (p=0.025), C-reactive protein (p=0.039), D-Dimer (p<0.001) and creatinine (p=0.043) levels, are independent predictors of critical COVID-19. Furthermore, classification and regression tree (CART) analysis provided a cut-off value of pyruvate in serum (24.54 µM; p<0.001) as an early criterion to accurately classify patients with critical outcomes.
Conclusion
Our findings support the link between COVID-19 pathogenesis and immunometabolic dysregulation, and show that fluorometric quantification of circulating pyruvate is a cost-effective clinical decision support tool to improve patient stratification and prognosis prediction.
Nuclear magnetic resonance (NMR)-based advanced lipoprotein tests have demonstrated that LDL and HDL particle numbers (LDL-P and HDL-P) are more powerful cardiovascular (CV) risk biomarkers than ...conventional cholesterol markers. Of interest, in people living with HIV (PLHIV), predictors of preclinical atherosclerosis and vascular dysfunction may be associated with impaired immune function. We previously stated that immunological non-responders (INR) were at higher CV risk than immunological responders (IR) before starting antiretroviral therapy (ART). Using Liposcale® tests, we characterized the lipoprotein profile from the same cohort of PLHIV at month 12 and month 36 after starting ART, intending to explore what happened with these indicators of CV risk during viral suppression. ART initiation dissipates the differences in lipoprotein-based CV risk markers between INR and IR, and only an increase in the number of HDL-P was found in INR + IR when compared to controls (p = 0.047). Interestingly, CD4+ T-cell counts negatively correlated with medium HDL-P concentrations at month 12 in all individuals (ρ = −0.335, p = 0.003). Longitudinal analyses showed an important increase in LDL-P and HDL-P at month 36 when compared to baseline values in both IR and INR. A proper balance between a proatherogenic and atherogenic environment may be related to the reconstitution of CD4+ T-cell count in PLHIV.
Sepsis of biliary origin is increasing worldwide and has become one of the leading causes of emergency department admissions. The presence of multi-resistant bacteria (MRB) is increasing, and ...mortality rates may reach 20%. This review focuses on the changes induced by the Tokyo guidelines and new concepts related to the early treatment of severe biliary disease. If cholecystitis or cholangitis is suspected, ultrasound is the imaging test of choice. Appropriate empirical antibiotic treatment should be initiated promptly, and selection should be performed while bearing in mind the severity and risk factors for MRB. In acute cholecystitis, laparoscopic cholecystectomy is the main therapeutic intervention. In patients not suitable for surgery, percutaneous cholecystostomy is a valid alternative for controlling the infection. Treatment of severe acute cholangitis is based on endoscopic or transhepatic bile duct drainage and antibiotic therapy. Endoscopic ultrasound and other new endoscopic techniques have been added to the arsenal as novel alternatives in high-risk patients. However, biliary infections remain serious conditions that can lead to sepsis and death. The introduction of internationally accepted guidelines, based on clinical presentation, laboratory tests, and imaging, provides a framework for their rapid diagnosis and treatment. Prompt assessment of patient severity, timely initiation of antimicrobials, and early control of the source of infection are essential to reduce morbidity and mortality rates.
PDF
