PD-1/PD-L1 axis: implications in immune regulation, cancer progression, and translational applications.

The PD-1/PD-L1 axis is a complex signaling pathway that has an important role in the immune system cells. Programmed cell death protein 1 (PD-1) acts as an immune checkpoint on the T lymphocytes, B lymphocytes, natural killer (NK), macrophages, dendritic cells (DCs), monocytes, and myeloid cells. Its ligand, the programmed cell death 1 ligand (PD-L1), is expressed in the surface of the antigen-presenting cells (APCs). The binding of both promotes the downregulation of the T cell response to ensure the activation to prevent the onset of chronic immune inflammation. This axis in the tumor microenvironment (TME) performs a crucial role in the tumor progression and the escape of the tumor by neutralizing the immune system, the engagement of PD-L1 with PD-1 in the T cell causes dysfunctions, neutralization, and exhaustion, providing the tumor mass production. This review will provide a comprehensive overview of the functions of the PD-1/PD-L1 system in immune function, cancer, and the potential therapeutic implications of the PD-1/PD-L1 pathway for cancer management.

Bioceramic versus traditional biomaterials for endodontic sealers according to the ideal properties.

Odontology, as a scientific discipline, continuously collaborates with biomaterials engineering to enhance treatment characteristics and patients' satisfaction. Endodontics, a specialized field of dentistry, focuses on the study, diagnosis, prevention, and treatment of dental disorders affecting the dental pulp, root, and surrounding tissues. A critical aspect of endodontic treatment involves the careful selection of an appropriate endodontic sealer for clinical use, as it significantly influences treatment outcomes. Traditional sealers, such as zinc oxide-eugenol, fatty acid, salicylate, epoxy resin, silicone, and methacrylate resin systems, have been extensively used for decades. However, advancements in endodontics have given rise to bioceramic-based sealers, offering improved properties and addressing new challenges in endodontic therapy. In this review, a classification of these materials and their ideal properties are presented to provide evidence-based guidance to clinicians. Physicochemical properties, including sealing ability, stability over time and space, as well as biological properties such as biocompatibility and antibacterial characteristics, along with cost-effectiveness, are essential factors influencing clinicians' decisions based on individual patient evaluations.

Emerging histological and serological biomarkers in oral squamous cell carcinoma: Applications in diagnosis, prognosis evaluation and personalized therapeutics (Review).

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity and accounts for >90% of all oral cancers. Despite advances in diagnostic procedures and therapeutic interventions, overall survival has not improved significantly in recent decades, primarily due to late diagnosis, locoregional recurrence and treatment resistance. Identifying reliable biomarkers for early detection, prognosis evaluation and treatment response prediction is critical for improving clinical outcomes in patients with OSCC. In the present review, the prognostic and predictive utility of circulating biomarkers, such as circulating tumour cells, serological biomarkers and histological and genetic biomarkers, were explored in the context of OSCC. In addition, the potential role of immune checkpoints in the treatment of OSCC was highlighted and the rapidly evolving field of liquid biopsy and its potential to revolutionize diagnosis, prognosis evaluation and treatment were examined. The existing evidence for the clinical utility of these biomarkers was critically evaluated and the challenges and limitations associated with their introduction into routine clinical practice were addressed. In conclusion, the present review highlights the promising role of biomarkers in improving the current understanding of the pathogenesis of OSCC and offers potential avenues for improving patient care through personalized medicine approaches.

AIF1: Function and Connection with Inflammatory Diseases.

Macrophages are a type of immune cell distributed throughout all tissues of an organism. Allograft inflammatory factor 1 (AIF1) is a calcium-binding protein linked to the activation of macrophages. AIF1 is a key intracellular signaling molecule that participates in phagocytosis, membrane ruffling and F-actin polymerization. Moreover, it has several cell type-specific functions. AIF1 plays important roles in the development of several diseases: kidney disease, rheumatoid arthritis, cancer, cardiovascular diseases, metabolic diseases and neurological disorders, and in transplants. In this review, we present a comprehensive review of the known structure, functions and role of AIF1 in inflammatory diseases.

Adverse effects, pharmacological interactions, and cardiovascular drugs in COVID-19 treatment.

In severe coronavirus disease (COVID)-19 patients, an extraordinary systemic inflammatory response is seen. It could impact in multiple organ disorders, specially a severe myocardial injury, an acute myocarditis results in focal or global myocardial inflammation and necrosis. Those events can be present in healthy subjects or cardiovascular (CV) patients. It is clinically associated with ventricular dysfunction exacerbation or worsening and tachyarrhythmias. It is also related to a poor outcome for CV patients with ischemic heart disease, hypertensión, and heart failure. COVID-19 patients require multiple and complex treatment that alleviates symptoms, the vast variety of agents interacts with diseases and CV drugs. Our purpose is to correlate in guidance synopsis: Adverse effects, pharmacological interactions, and CV drugs in COVID-19 treatment.

En pacientes con COVID-19 grave se ha observado una extraordinaria respuesta inflamatoria sistémica. Este impacto se traduce en múltiples trastornos de órganos, especialmente cardíacos, por lesión miocárdica grave, miocarditis aguda que resulta en inflamación focal o miocárdica global, necrosis cardiaca. Estos tremendos eventos son observados en sujetos sanos como pacientes cardiovasculares. Clínicamente asociados con nueva presentación o empeoramiento de la disfunción ventricular y taquiarritmias. Relacionado a un predictor principal de malos resultado en pacientes cardiovasculares (CV), especialmente en aquellos con cardiopatía isquémica, hipertensión e insuficiencia cardíaca. Los enfermos con COVID-19 requieren múltiples y complejos tratamientos que alivien los síntomas, esta gran variedad de agentes interactúa con enfermedades y medicamentos CV. Nuestro propósito es correlacionar, en una guía sinóptica: efectos adversos, interacciones farmacológicas y fármacos cardiovasculares en el tratamiento del COVID-19.

Clinimetric analysis of heart failure in Mexican patients.

Heart failure (HF) is a syndrome characterized basically by a circulatory deficit to cover the metabolic and energetic demands of the body. This condition has a broad spectrum in its clinical presentation, affects the quality of life significantly, impacts the family/social environment, and generates a great demand for health services. The purpose of this research is to report the situational diagnose of patients with HF in Mexico. We evaluated 292 patients, 70.2% were men. Average age was 56.7 ± 14.3 years. Ischemic heart disease is the main etiology (98 patients, 33.9%) followed by hypertensive (22.6%) and idiopathic (23.3%) heart disease. The associated clinical background was obesity (31.1%), systemic hypertension (36.7%), myocardial infarction (26.4%), and dyslipidemia (15.1%). The most common symptom was stress dyspnea (41.4%) and jugular vein engorgement at physical examination (32.5%). Anemia was observed in 1% of patients. The average left ventricular ejection fraction was 29.2 ± 10.6%. Sinus rhythm was the most frequently detected in 84.9%. 19.9% of patients had an implantable cardioverter-defibrillator or cardiac resynchronization therapy. 13.7% of patients with QRS > 130 ms. In our population, the meta-analysis global group in chronic heart failure risk score calculated was 16.8 ± 5.7 and for EMPHASIS 3.3 ± 1.5. We observed that age at presentation in HF in this analysis is at least 10 years younger than in other reports. The grade of obesity takes relevance in our group. The association of anemia and HF in Mexico is rare.

La insuficiencia cardiaca es un síndrome caracterizado fundamentalmente por un déficit circulatorio para cubrir las demandas metabólicas y energéticas del organismo. Esta entidad tiene un amplio espectro en su presentación clínica, afecta de manera significativa la calidad de vida, impacta en el entorno familiar/social y genera una gran demanda de los servicios de salud. El propósito de esta investigación es reportar el diagnóstico situacional de pacientes con insuficiencia cardiaca (IC) en México. Evaluamos 292 enfermos, 70.2% eran hombres. Con edad promedio 56.7 ± 14.3 años. La principal etiología es la cardiopatía isquémica (33.9%), seguida de la hipertensiva (22.6%) e idiopática (23.3%). Los antecedentes clínicos asociados fueron: obesidad (31.1%), hipertensión arterial sistémica (36.7%), infarto al miocardio (26.4%) y dislipidemia (15.1%). El síntoma con mayor presentación fue la disnea de esfuerzos (41.4%) y a la exploración física la ingurgitación yugular (32.5%). Se observó anemia en 1% de los enfermos. La fracción de expulsión del ventrículo izquierdo (FEVI) promedio fue de 29.2 + 10.6%. El ritmo sinusal fue el más frecuentemente detectado en 84.9%. El 19.9% de los pacientes tenían instalado un desfibrilador automático implantable (DAI) o tratamiento de resincronización cardiaca (TRC). El 13.7% de los enfermos con QRS mayor de 130 ms. El riesgo (MAGGIC) calculado en nuestro grupo poblacional fue de 16.8 ± 5.7 y para EMPHASIS 3.3 ± 1.5. Observamos que la edad de presentación de la IC en el presente análisis es menor por 10 años en comparación con otros reportes. El grado de obesidad toma relevancia en nuestro grupo. La asociación de anemia e IC en México es poco frecuente.

Clinimetric analysis of heart failure in Mexican patients / Análisis clinimétrico de la insuficiencia cardiaca en pacientes mexicanos

Abstract Heart failure (HF) is a syndrome characterized basically by a circulatory deficit to cover the metabolic and energetic demands of the body. This condition has a broad spectrum in its clinical presentation, affects the quality of life significantly, impacts the family/social environment, and generates a great demand for health services. The purpose of this research is to report the situational diagnose of patients with HF in Mexico. We evaluated 292 patients, 70.2% were men. Average age was 56.7 +- 14.3 years. Ischemic heart disease is the main etiology (98 patients, 33.9%) followed by hypertensive (22.6%) and idiopathic (23.3%) heart disease. The associated clinical background was obesity (31.1%), systemic hypertension (36.7%), myocardial infarction (26.4%), and dyslipidemia (15.1%). The most common symptom was stress dyspnea (41.4%) and jugular vein engorgement at physical examination (32.5%). Anemia was observed in 1% of patients. The average left ventricular ejection fraction was 29.2 +- 10.6%. Sinus rhythm was the most frequently detected in 84.9%. 19.9% of patients had an implantable cardioverter-defibrillator or cardiac resynchronization therapy. 13.7% of patients with QRS > 130 ms. In our population, the meta-analysis global group in chronic heart failure risk score calculated was 16.8 +- 5.7 and for EMPHASIS 3.3 +- 1.5. We observed that age at presentation in HF in this analysis is at least 10 years younger than in other reports. The grade of obesity takes relevance in our group. The association of anemia and HF in Mexico is rare.

Resumen La insuficiencia cardiaca es un síndrome caracterizado fundamentalmente por un déficit circulatorio para cubrir las demandas metabólicas y energéticas del organismo. Esta entidad tiene un amplio espectro en su presentación clínica, afecta de manera significativa la calidad de vida, impacta en el entorno familiar/social y genera una gran demanda de los servicios de salud. El propósito de esta investigación es reportar el diagnóstico situacional de pacientes con insuficiencia cardiaca (IC) en México. Evaluamos 292 enfermos, 70.2% eran hombres. Con edad promedio 56.7 +- 14.3 años. La principal etiología es la cardiopatía isquémica (33.9%), seguida de la hipertensiva (22.6%) e idiopática (23.3%). Los antecedentes clínicos asociados fueron: obesidad (31.1%), hipertensión arterial sistémica (36.7%), infarto al miocardio (26.4%) y dislipidemia (15.1%). El síntoma con mayor presentación fue la disnea de esfuerzos (41.4%) y a la exploración física la ingurgitación yugular (32.5%). Se observó anemia en 1% de los enfermos. La fracción de expulsión del ventrículo izquierdo (FEVI) promedio fue de 29.2 + 10.6%. El ritmo sinusal fue el más frecuentemente detectado en 84.9%. El 19.9% de los pacientes tenían instalado un desfibrilador automático implantable (DAI) o tratamiento de resincronización cardiaca (TRC). El 13.7% de los enfermos con QRS mayor de 130 ms. El riesgo (MAGGIC) calculado en nuestro grupo poblacional fue de 16.8 +- 5.7 y para EMPHASIS 3.3 +- 1.5. Observamos que la edad de presentación de la IC en el presente análisis es menor por 10 años en comparación con otros reportes. El grado de obesidad toma relevancia en nuestro grupo. La asociación de anemia e IC en México es poco frecuente.

IAOx induces the SUR phenotype and differential signalling from IAA under different types of nitrogen nutrition in Medicago truncatula roots.

Indole-3-acetaldoxime (IAOx) is a particularly relevant molecule as an intermediate in the pathway for tryptophan-dependent auxin biosynthesis. The role of IAOx in growth-signalling and root phenotype is poorly studied in cruciferous plants and mostly unknown in non-cruciferous plants. We synthesized IAOx and applied it to M. truncatula plants grown axenically with NO3-, NH4+ or urea as the sole nitrogen source. During 14 days of growth, we demonstrated that IAOx induced an increase in the number of lateral roots, especially under NH4+ nutrition, while elongation of the main root was inhibited. This phenotype is similar to the phenotype known as "superroot" previously described in SUR1- and SUR2-defective Arabidopsis mutants. The effect of IAOx, IAA or the combination of both on the root phenotype was different and dependent on the type of N-nutrition. Our results also showed the endogenous importance of IAOx in a legume plant in relation to IAA metabolism, and suggested IAOx long-distance transport depending on the nitrogen source provided. Finally, our results point out to CYP71A as the major responsible enzymes for IAA synthesis from IAOx, while they exclude indole-3-acetaldehyde oxidases.

Pretreatment and enzymatic hydrolysis for the efficient production of glucose and furfural from wheat straw, pine and poplar chips.

A flexible approach to a two-step Biorefinery for the production of glucose and furfural from three different feedstocks is presented. Pretreatment conditions were selected to drive the production towards the generation of glucose or furfural. Harsh pretreatment conditions produced solids with highly accessible glycan contents for the enzymatic hydrolysis with 100% glucose yields when wheat straw or poplar chips were used as feedstock. Mild conditions afforded xylan-rich hydrolysates that could be efficiently transformed to furfural, either under conventional or microwave heating in biphasic media. Yields for the transformation of xylan from feedstocks ranged between 45% and 90% depending on the feedstock, the thermal pretreatment and the cyclodehydration conditions. Up to 12.6 kg of glucose and materials and 2.5 kg of furfural can be produced starting from 50 kg of biomass. A new analytical methodology based on 13C NMR that provided good quality analytical results is also presented.

Clinical usefulness of abdominal bioimpedance (ViScan) in the determination of visceral fat and its application in the diagnosis and management of obesity and its comorbidities.

BACKGROUND & AIMS: Visceral adipose tissue (VAT) has been shown to be profoundly responsible of most of the obesity-associated metabolic derangements. The measurement of VAT usually implies the use of imaging techniques such as magnetic resonance imaging or computed tomography (CT). Our aim was to evaluate the accuracy of the determination of VAT by means of abdominal bioimpedance (BIA) with the ViScan device in comparison with CT and its clinical usefulness in the management of obesity. METHODS: We studied a sample of 140 subjects (73 males/67 females) with BMI ranging from 17.7 to 50.4 kg/m2 to evaluate the accuracy of the ViScan in comparison to CT to determine VAT. To further analyze ViScan's clinical usefulness we studied a separate cohort (n = 2849) analyzing cardiometabolic risk factors. Furthermore, we studied the ability of the ViScan to detect changes in VAT after weight gain (n = 107) or weight loss (n = 335). The study was performed from October 2009 through June 2015. RESULTS: ViScan determines VAT with a good accuracy in individuals with a CT-VAT up to 200 cm2, and then with lower precision with increasing body mass, exhibiting a moderate-high correlation with CT-VAT (r = 0.75, P < 0.001). Importantly, VAT determination with the ViScan exhibits better correlations with several cardiometabolic risk factors such as glucose, triglycerides, HDL-cholesterol and markers of fatty liver than anthropometric measurements such as BMI or waist circumference. ViScan is able to detect VAT variations after body weight changes. CONCLUSIONS: Since the possibility of measuring VAT by imaging techniques is not always available, abdominal BIA represents a good alternative to estimate VAT, allowing the identification of patients with increased VAT-related cardiometabolic risk and a better management of obese patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01055626 and NCT01572090.

The Role and Potential Therapeutic Implications of the Fibroblast Growth Factors in Energy Balance and Type 2 Diabetes.

PURPOSE OF REVIEW: Obesity and its associated metabolic diseases have reached epidemic proportions worldwide, reducing life expectancy and quality of life. Several drugs have been tested to treat these diseases but many of them have damaging side effects. Consequently, there is an urgent need to develop more effective therapies. Recently, endocrine fibroblast growth factors (FGFs) have become attractive targets in the treatment of metabolic diseases. This review summarizes their most important functions as well as FGF-based therapies for the treatment of obesity and type 2 diabetes (T2D). RECENT FINDINGS: Recent studies demonstrate that circulating levels of FGF19 are reduced in obesity. In fact, exogenous FGF19 administration is associated with a reduction in food intake as well as with improvements in glycaemia. In contrast, FGF21 levels are elevated in subjects with abdominal obesity, insulin resistance and T2D, probably representing a compensatory response. Additionally, elevated levels of circulating FGF23 in individuals with obesity and T2D are reported in most clinical studies. Finally, increased FGF1 levels in obese patients associated with adipogenesis have been described. FGFs constitute important molecules in the treatment of metabolic diseases due to their beneficial effects on glucose and lipid metabolism. Among all members, FGF19 and FGF21 have demonstrated the ability to improve glucose, lipid and energy homeostasis, along with FGF1, which was recently discovered to have beneficial effects on metabolic homeostasis. Additionally, FGF23 may also play a role in insulin resistance or energy homeostasis beyond mineral metabolism control. These results highlight the relevant use of FGFs as potential biomarkers for the early diagnosis of metabolic diseases. In this regard, notable progress has been made in the development of FGF-based therapies and different approaches are being tested in different clinical trials. However, further studies are needed to determine their potential therapeutic use in the treatment of obesity and obesity-related comorbidities.

Altered Concentrations in Dyslipidemia Evidence a Role for ANGPTL8/Betatrophin in Lipid Metabolism in Humans.

CONTEXT: Angiopoietin-like protein 8 (ANGPTL8)/betatrophin is a secreted protein initially involved in ß-cell replication. Recent data in humans and mice models suggest that ANGPTL8/betatrophin is more related to lipid metabolism. OBJECTIVE: The aim of the present study was to compare the circulating concentrations of ANGPTL8/betatrophin in individuals with dyslipidemia defined as having high or low levels of high-density lipoprotein (HDL)-cholesterol or triglycerides, respectively. DESIGN, SETTING, AND PARTICIPANTS: Serum concentrations of ANGPTL8/betatrophin were measured by an ELISA in 177 subjects. We studied two different selected case-control dyslipidemic cohorts including individuals with high (n = 43) or low (n = 46) circulating concentrations of HDL-cholesterol or with low (n = 48) or high (n = 40) levels of triglycerides. RESULTS: Circulating concentrations of ANGPTL8/betatrophin were significantly lower in individuals with dyslipidemia (P < .001) in both males (controls 27.8 ± 15.2 vs dyslipidemic 17.0 ± 11.2 ng/mL) and females (controls 50.0 ± 22.2 vs dyslipidemic 27.0 ± 16.5 ng/mL). The magnitude of the differences was higher in dyslipidemic patients with low HDL-cholesterol than in those with high triglyceride concentrations. ANGPTL8/betatrophin levels were lower in subjects with type 2 diabetes (P < .001), but the impact of type 2 diabetes vanished (P = .257) when the effect of dyslipidemia was included in the analysis. CONCLUSIONS: We conclude that serum ANGPTL8/betatrophin concentrations are altered in human dyslipidemia. ANGPTL8/betatrophin emerges as a potential player in dyslipidemia with a strong association with HDL-cholesterol and a potential therapeutic tool for the treatment of dyslipidemia.

Factors related to increased resting energy expenditure in men with liver cirrhosis.

OBJECTIVE: Hypermetabolism in cirrhosis is associated with a high risk of complications and mortality. However, studies about underlying mechanisms are usually focussed on isolated potential determinants and specific etiologies, with contradictory results. We aimed at investigating differences in nutrition, metabolic hormones, and hepatic function between hypermetabolic and nonhypermetabolic men with cirrhosis of the liver. PATIENTS AND METHODS: We prospectively enrolled 48 male cirrhotic inpatients. We evaluated their resting energy expenditure (REE) and substrate utilization by indirect calorimetry, body composition by dual-energy X-ray absorptiometry, liver function, and levels of major hormones involved in energy metabolism by serum sample tests. Patients with ascites, specific metabolic disturbances, and hepatocellular carcinoma were excluded. RESULTS: REE and REE adjusted per fat-free mass (FFM) were significantly increased in cirrhotic patients. Overall, 58.3% of cirrhotic patients were classified as hypermetabolic. Groups did not differ significantly in age, etiology of cirrhosis, liver function, presence of ascites, use of diuretics, ß-blockers, or presence of transjugular intrahepatic portosystemic shunts. Hypermetabolic cirrhotic patients had lower weight, BMI (P<0.05), nonprotein respiratory quotient (P<0.01), leptin (P<0.05), and leptin adjusted per fat mass (FM) (P<0.05), but higher FFM% (P<0.05) and insulin resistance [homeostatic model assessment-insulin resistance (HOMA-IR)] (P<0.05). Only HOMA-IR, leptin/FM, and FFM% were independently related to the presence of hypermetabolism. CONCLUSION: Hypermetabolic cirrhotic men are characterized by lower weight, higher FFM%, insulin resistance, and lower leptin/FM when compared with nonhypermetabolic men. HOMA-IR, FFM%, and leptin/FM were independently associated with hypermetabolism, and may serve as easily detectable markers of this condition in daily clinical practice.

Cardiometabolic Profile Related to Body Adiposity Identifies Patients Eligible for Bariatric Surgery More Accurately than BMI.

BACKGROUND: Eligibility criteria for bariatric surgery (BS) are based on BMI and the presence of major comorbidities. Our aim was to analyze the usefulness of body adiposity determination in establishing the indication for BS. METHODS: In order to analyze the cardiometabolic risk according to eligibility criteria for BS, four groups were studied. Morbidly obese patients with BMI ≥ 40 kg/m(2) (n = 360), and obese subjects with BMI ≥ 35 kg/m(2) and at least one comorbidity (n = 431), represented two groups of patients meeting original NIH criteria for BS. A third group included two cohorts of patients with a high body fat (BF)% that do not meet the original NIH eligibility criteria for BS: patients with either a BMI <35 kg/m(2) or a BMI ≥ 35 kg/m(2) without comorbidities (n = 266, NEHF). Lean subjects by BMI were the reference group (n = 140). BMI, BF% and markers of insulin sensitivity, lipid profile, and cardiovascular risk were measured. RESULTS: Individuals from the NEHF group exhibited increased HbA1c (P < 0.05) and decreased insulin sensitivity evidenced by a significant reduction in QUICKI (P < 0.001). Triglyceride concentrations were similarly increased (P < 0.05) in the three groups of obese patients. Uric acid concentrations were significantly elevated (P < 0.01) to a similar extent in the obese groups. Levels of the inflammatory marker CRP and hepatic enzymes were significantly increased in the three obese groups. CONCLUSION: The present study provides evidence for the existence of an adverse cardiometabolic profile in subjects currently considered to be outside traditional NIH guidelines but exhibiting a highly increased adiposity. It is concluded that body composition analysis yields valuable information to be incorporated into indication criteria for BS and that adiposity may be an independent indicator for BS.

Expression of syntaxin 8 in visceral adipose tissue is increased in obese patients with type 2 diabetes and related to markers of insulin resistance and inflammation.

BACKGROUND AND AIMS: Obesity is associated with increased adipose tissue inflammation as well as with the development of type 2 diabetes (T2D). Syntaxin 8 (STX8) is a protein required for the transport of endosomes. In this study we analyzed the relationship of STX8 with the presence of T2D in the context of obesity. METHODS: With this purpose, 21 subjects (seven lean [LN], eight obese normoglycemic [OB-NG] and six obese with type 2 diabetes [OB-T2D]) were included in the study. Gene and protein expression levels of STX8 and GLUT4 were analyzed in visceral adipose tissue (VAT). RESULTS: mRNA (p = 0.008) and protein (p <0.001) expression levels of STX8 were significantly increased in VAT of OB-T2D patients. Moreover, gene expression levels of SLC2A4 (GLUT4) were downregulated (p = 0.002) in VAT of obese patients. We found that STX8 was positively correlated (p <0.05) with fasting glucose concentrations, plasma glucose 2 h after an OGTT and C-reactive protein. Interestingly, the expression of STX8 was negatively correlated (p <0.05) with the expression of SLC2A4 in VAT. CONCLUSIONS: Increased STX8 expression in VAT appears to be associated with the presence of T2D in obese patients through a mechanism that may involve GLUT4.

Circulating betatrophin concentrations are decreased in human obesity and type 2 diabetes.

CONTEXT: Betatrophin is a secreted protein recently involved in ß-cell replication with a potential role in type 2 diabetes mellitus (T2D). OBJECTIVE: The aim of the present study was to compare the circulating concentrations of betatrophin in human obesity and T2D. DESIGN, SETTING, AND PARTICIPANTS: Serum concentrations of betatrophin were measured by ELISA in 153 subjects: 75 obese normoglycemic subjects (OB-NG), 30 obese subjects with impaired glucose tolerance (OB-IGT), and 15 obese subjects with T2D (OB-T2D) matched by sex, age, and body adiposity, in comparison with 33 lean normoglycemic individuals (LN-NG). RESULTS: Circulating levels of betatrophin were significantly decreased in obese individuals and further diminished in IGT and T2D participants (LN-NG, 45.1 ± 24.4 ng/mL; OB-NG, 26.9 ± 15.4 ng/mL; OB-IGT, 18.3 ± 10.7 ng/mL; OB-T2D, 13.5 ± 8.8 ng/mL; P < .001). A marked sexual dimorphism was found, with betatrophin levels being significantly higher in women than in men (males, 21.1 ± 16.0 ng/mL; females, 34.1 ± 20.1 ng/mL; P < .001). Interestingly, betatrophin levels were positively correlated with the quantitative insulin sensitivity check index (r = 0.46; P < .001) and with high-density lipoprotein-cholesterol concentrations (r = 0.51; P < .001). CONCLUSIONS: We conclude that serum betatrophin is decreased in human obesity, being further reduced in obesity-associated insulin resistance. Betatrophin levels are closely related to obesity-associated cardiometabolic risk factors, emerging as a potential biomarker of insulin resistance and T2D.

Increased cardiometabolic risk factors and inflammation in adipose tissue in obese subjects classified as metabolically healthy.

OBJECTIVE: It has been suggested that individuals with the condition known as metabolically healthy obesity (MHO) may not have the same increased risk for the development of metabolic abnormalities as their non-metabolically healthy counterparts. However, the validity of this concept has recently been challenged, since it may not translate into lower morbidity and mortality. The aim of the current study was to compare the cardiometabolic/inflammatory profile and the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes (T2D) in patients categorized as having MHO or metabolically abnormal obesity (MAO). RESEARCH DESIGN AND METHODS: We performed a cross-sectional analysis to compare the cardiometabolic/inflammatory profile of 222 MHO and 222 MAO patients (62% women) matched by age, including 255 lean subjects as reference (cohort 1). In a second cohort, we analyzed the adipokine profile and the expression of genes involved in inflammation and extracellular matrix remodeling in visceral adipose tissue (VAT; n = 82) and liver (n = 55). RESULTS: The cardiometabolic and inflammatory profiles (CRP, fibrinogen, uric acid, leukocyte count, and hepatic enzymes) were similarly increased in MHO and MAO in both cohorts. Moreover, above 30%of patients classified as MHO according to fasting plasma glucose exhibited IGT or T2D [corrected]. The profile of classic (leptin, adiponectin, resistin) as well as novel (serum amyloid A and matrix metallopeptidase 9) adipokines was almost identical in MHO and MAO groups in cohort 2. Expression of genes involved in inflammation and tissue remodeling in VAT and liver showed a similar alteration pattern in MHO and MAO individuals. CONCLUSIONS: The current study provides evidence for the existence of a comparable adverse cardiometabolic profile in MHO and MAO patients; thus the MHO concept should be applied with caution. A better identification of the obesity phenotypes and a more precise diagnosis are needed for improving the management of obese individuals.

Comparative effects of gastric bypass and sleeve gastrectomy on plasma osteopontin concentrations in humans.

BACKGROUND: Bariatric surgery (BS) has proven to be an effective treatment for morbid obesity. Osteopontin (OPN) is a proinflammatory cytokine involved in the development of obesity. The aim of our study was to determine the effect of weight loss following BS on circulating levels of OPN in humans. METHODS: Body composition and circulating concentrations of OPN and markers of bone metabolism were determined in obese patients who underwent Roux-en-Y gastric bypass (RYGB; n = 40) or sleeve gastrectomy (SG; n = 11). RESULTS: Patients who underwent RYGB or SG showed decreased body weight (P < 0.001) and body fat percentage (P < 0.001) as well as lower insulin resistance. However, plasma OPN levels were significantly increased after RYGB (P < 0.001) but remained unchanged following SG (P = 0.152). Patients who underwent RYGB also showed significantly increased C-terminal telopeptide of type-I collagen (ICTP) (P < 0.01) and osteocalcin (P < 0.001) while bone mineral density tended to decrease (P = 0.086). Moreover, OPN concentrations were positively correlated with the bone resorption marker ICTP after surgery. On the other hand, patients who underwent SG showed significantly increased ICTP levels (P < 0.05), and the change in OPN was positively correlated with the change in ICTP and negatively with the change in vitamin D after surgery (P < 0.05). CONCLUSIONS: RYGB increased circulating OPN levels, while they remained unaltered after SG. The increase in OPN levels after RYGB could be related to the increased bone resorption in relation to its well-known effects on bone of this malabsorptive procedure in comparison to the merely restrictive SG.

Increased levels of chemerin and its receptor, chemokine-like receptor-1, in obesity are related to inflammation: tumor necrosis factor-α stimulates mRNA levels of chemerin in visceral adipocytes from obese patients.

BACKGROUND: Chemerin is a novel adipokine that regulates adipocyte development and metabolic function and glucose metabolism. Our aim was to determine the effect of chemerin and its receptor, chemokine-like receptor-1, in obesity-associated low-grade chronic inflammation, exploring its circulating and gene expression levels in obesity and the effect of weight loss and to analyze the effect of the stimulation with tumor necrosis factor-α in human visceral adipocytes at a University hospital. METHODS: We included 52 women (16 lean and 36 obese) in the present study. The plasma concentrations of chemerin and the expression levels of chemerin and its receptor in visceral adipose tissue were analyzed. The chemerin concentrations were also measured before and after weight loss achieved by Roux-en-Y gastric bypass (n = 26). RESULTS: The circulating concentrations and visceral adipose tissue expression of chemerin were increased in obese patients (P < .01) and were associated with well-established markers of inflammation (P < .001). Gene expression levels of chemokine-like receptor-1 followed the same trend and were upregulated (P < .05) in human obesity. Elevated chemerin levels in obese patients did not change after Roux-en-Y gastric bypass weight loss. Tumor necrosis factor-α treatment significantly enhanced (P < .05) the mRNA levels of chemerin in human visceral adipocytes, but the gene expression levels of chemokine-like receptor-1 were not affected. CONCLUSION: The increased levels of chemerin in obesity and its positive association with inflammation suggest a role for this chemoattractant protein in the changes that take place in visceral adipose tissue in the presence of energy surplus, establishing a link between inflammation and the greater risk of the development of metabolic disease.

Six-transmembrane epithelial antigen of prostate 4 and neutrophil gelatinase-associated lipocalin expression in visceral adipose tissue is related to iron status and inflammation in human obesity.

PURPOSE: Six-transmembrane epithelial antigen of prostate (STEAP)-4 and neutrophil gelatinase-associated lipocalin (NGAL) are novel adipokines related to iron homeostasis with potential roles in insulin resistance and inflammation. The aim of the present work was to evaluate the effect of obesity and iron status on gene expression levels of STEAP-4 and NGAL in visceral adipose tissue (VAT) and its implication in inflammation. METHODS: VAT biopsies obtained from 53 subjects were used in the study. Real-time PCR and Western-blot were performed to quantify the levels of STEAP4 and NGAL in VAT as well as the association with other genes implicated in inflammatory pathways. Circulating ferritin and free iron concentrations were also determined. RESULTS: Obese patients exhibited significantly increased STEAP4 and NGAL mRNA expression levels (P < 0.001) compared to lean subjects. Protein expression levels of NGAL (P < 0.05) and STEAP4 were also higher in the visceral fat depot of obese patients, although protein levels of STEAP4 did not reach statistical significance. A negative correlation (P < 0.05) between free iron concentrations and gene expression levels of both STEAP4 and NGAL was found, while circulating ferritin concentrations were positively correlated (P < 0.05) with NGAL mRNA after body fat (BF) adjustment. Furthermore, a significant positive association between STEAP4 and NGAL gene expression levels with inflammatory markers was also detected (P < 0.01). CONCLUSION: These findings represent the first observation that STEAP4 and NGAL mRNA and protein levels in human VAT are related to iron status. Moreover, STEAP4 and NGAL are associated with pro-inflammatory markers suggesting their potential involvement in the low-grade chronic inflammation accompanying obesity.