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BACKGROUND: The molecular mediators responsible for the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) to steatohepatitis (MASH) have not yet been completely disentangled. We sought to analyze whether FNDC4, an hepatokine and adipokine with anti-inflammatory properties, is involved in TNF-α-induced inflammatory cell death in patients with MASLD. METHODS: Plasma FNDC4 (n = 168) and hepatic FNDC4 and inflammatory cell death (n = 65) were measured in samples from patients with severe obesity with available liver biopsy-proven MASLD diagnosis. The effect of FNDC4 on TNF-α-induced pyroptosis, apoptosis and necroptosis (PANoptosis) and mitochondrial dysfunction was studied in vitro using human HepG2 hepatocytes. RESULTS: Compared with individuals with normal liver, patients with type 2 diabetes and MASLD exhibited decreased hepatic FNDC4 mRNA and protein levels, which were related to liver inflammation. An overexpression of TNF-α, its receptor TNF-R1 and factors involved in inflammatory cell death was also found in the liver of these patients. FNDC4-knockdown in HepG2 hepatocytes increased apoptotic cell death, while FNDC4 treatment blunted NLRP3 inflammasome-induced pyroptosis, apoptosis and necroptosis in TNF-α-stimulated hepatocytes. Moreover, FNDC4 improved TNF-α-induced hepatocyte mitochondrial dysfunction by enhancing mitochondrial DNA (mtDNA) copy number and OXPHOS complex subunits I, II, III and V protein expression. Mechanistically, AMP-activated protein kinase α (AMPKα) was required for the FNDC4-mediated inhibition of cell death and increase in mtDNA content. CONCLUSIONS: FNDC4 acts as a hepatocyte survival factor favouring mitochondrial homeostasis and decreasing inflammatory cell death via AMPKα. Collectively, our study identifies FNDC4 as an attractive target to prevent hepatocellular damage in patients with MASLD.
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BACKGROUND: The estimation of obesity-associated cardiometabolic risk does not usually take into account body composition or the distribution of adiposity. The aim of the present study was to assess the clinical usefulness of a novel obesity phenotyping system based on the combination of actual body fat percentage (BF%) and waist circumference (WC) according to the cardiometabolic risk estimation. METHODS: A classification matrix combining BF% and WC as measures of both amount and distribution of adiposity establishing nine body phenotypes (3 BF% x 3 WC) was developed. Individuals were grouped in five different cardiometabolic risk phenotypes. We conducted a validation study in a large cohort of White subjects from both genders representing a wide range of ages and adiposity (n = 12,754; 65 % females, aged 18-88 years). RESULTS: The five risk groups using the matrix combination of BF% and WC exhibited a robust linear distribution regarding cardiometabolic risk, estimated by the Metabolic Syndrome Severity Score, showing a continuous increase between groups with significant differences (P < 0.001) among them, as well as in other cardiometabolic risk factors. An additional 24 % of patients at very high risk was detected with the new classification system proposed (P < 0.001) as compared to an equivalent matrix using BMI and WC instead of BF% and WC. CONCLUSIONS: A more detailed phenotyping should be a priority in the diagnosis and management of patients with obesity. Our classification system allows to gradually estimate the cardiometabolic risk according to BF% and WC, thus representing a novel and useful tool for both research and clinical practice.
Subject(s)
Adiposity , Cardiometabolic Risk Factors , Metabolic Syndrome , Obesity , Phenotype , Waist Circumference , Humans , Female , Male , Aged , Middle Aged , Adult , Aged, 80 and over , Adolescent , Young Adult , Metabolic Syndrome/diagnosis , Risk Assessment/methods , Body Mass Index , Cardiovascular Diseases/etiologyABSTRACT
BACKGROUND: Obesity-associated dysfunctional intestinal permeability contributes to systemic chronic inflammation leading to the development of metabolic diseases. The inflammasomes constitute essential components in the regulation of intestinal homeostasis. We aimed to determine the impact of the inflammasomes in the regulation of gut barrier dysfunction and metabolic inflammation in the context of obesity and type 2 diabetes (T2D). METHODS: Blood samples obtained from 80 volunteers (n = 20 normal weight, n = 21 OB without T2D, n = 39 OB with T2D) and a subgroup of jejunum samples were used in a case-control study. Circulating levels of intestinal damage markers and expression levels of inflammasomes as well as their main effectors (IL-1ß and IL-18) and key inflammation-related genes were analyzed. The impact of inflammation-related factors, different metabolites and Akkermansia muciniphila in the regulation of inflammasomes and intestinal integrity genes was evaluated. The effect of blocking NLRP6 by using siRNA in inflammation was also studied. RESULTS: Increased circulating levels (P < 0.01) of the intestinal damage markers endotoxin, LBP, and zonulin in patients with obesity decreased (P < 0.05) after weight loss. Patients with obesity and T2D exhibited decreased (P < 0.05) jejunum gene expression levels of NLRP6 and its main effector IL18 together with increased (P < 0.05) mRNA levels of inflammatory markers. We further showed that while NLRP6 was primarily localized in goblet cells, NLRP3 was localized in the intestinal epithelial cells. Additionally, decreased (P < 0.05) mRNA levels of Nlrp1, Nlrp3 and Nlrp6 in the small intestinal tract obtained from rats with diet-induced obesity were found. NLRP6 expression was regulated by taurine, parthenolide and A. muciniphila in the human enterocyte cell line CCL-241. Finally, a significant decrease (P < 0.01) in the expression and release of MUC2 after the knockdown of NLRP6 was observed. CONCLUSIONS: The increased levels of intestinal damage markers together with the downregulation of NLRP6 and IL18 in the jejunum in obesity-associated T2D suggest a defective inflammasome sensing, driving to an impaired epithelial intestinal barrier that may regulate the progression of multiple obesity-associated comorbidities.
Subject(s)
Diabetes Mellitus, Type 2 , Inflammasomes , Humans , Rats , Animals , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Interleukin-18/genetics , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/genetics , Intestinal Barrier Function , Case-Control Studies , Inflammation , Obesity/complications , RNA, Messenger/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Receptors, Angiotensin/metabolism , Receptors, Vasopressin/metabolismABSTRACT
Unhealthy dietary habits and sedentarism coexist with a rising incidence of excess weight and associated comorbidities. We aimed to analyze the dietary and drinking patterns of patients with excess weight, their main characteristics, plausible gender differences and impact on cardiometabolic risk factors, with a particular focus on the potential contribution of beer consumption. Data from 200 consecutive volunteers (38 ± 12 years; 72% females) living with overweight or class I obesity attending the obesity unit to lose weight were studied. Food frequency questionnaires and 24 h recalls were used. Reduced-rank regression (RRR) analysis was applied to identify dietary patterns (DPs). Anthropometry, total and visceral fat, indirect calorimetry, physical activity level, comorbidities and circulating cardiometabolic risk factors were assessed. Study participants showed high waist circumference, adiposity, insulin resistance, dyslipidemia, pro-inflammatory adipokines and low anti-inflammatory factors like adiponectin and interleukin-4. A low-fiber, high-fat, energy-dense DP was observed. BMI showed a statistically significant (p < 0.05) correlation with energy density (r = 0.80) as well as percentage of energy derived from fat (r = 0.61). Excess weight was associated with a DP low in vegetables, legumes and whole grains at the same time as being high in sweets, sugar-sweetened beverages, fat spreads, and processed meats. RRR analysis identified a DP characterized by high energy density and saturated fat exhibiting negative loadings (>-0.30) for green leafy vegetables, legumes, and fruits at the same time as showing positive factor loadings (>0.30) for processed foods, fat spreads, sugar-sweetened beverages, and sweets. Interestingly, for both women and men, wine represented globally the main source of total alcohol intake (p < 0.05) as compared to beer and distillates. Beer consumption cannot be blamed as the main culprit of excess weight. Capturing the DP provides more clinically relevant and useful information. The focus on consumption of single nutrients does not resemble real-world intake behaviors.
Subject(s)
Cardiometabolic Risk Factors , Diet , Male , Humans , Female , Diet/adverse effects , Obesity/epidemiology , Obesity/etiology , Feeding Behavior , Weight Gain , Vegetables , Diet, Fat-Restricted , Alcohol Drinking/epidemiology , Risk FactorsABSTRACT
OBJECTIVE: To assess how inaccurately the body mass index (BMI) is used to diagnose obesity compared to body fat percentage (BF%) measurement and to compare the cardiometabolic risk in children and adolescents with or without obesity according to BMI but with a similar BF%. METHODS: A retrospective cross-sectional investigation was conducted including 553 (378 females/175 males) white children and adolescents aged 6-17 years, 197 with normal weight (NW), 144 with overweight (OW) and 212 with obesity (OB) according to BMI. In addition to BMI, BF% measured by air displacement plethysmography, as well as markers of cardiometabolic risk had been determined in the existing cohort. RESULTS: We found that 7% of subjects considered as NW and 62% of children and adolescents classified as OW according to BMI presented a BF% within the obesity range. Children and adolescents without obesity by the BMI criterion but with obesity by BF% exhibited higher blood pressure and C-reactive protein (CRP) in boys, and higher blood pressure, glucose, uric acid, CRP and white blood cells count, as well as reduced HDL-cholesterol, in girls, similar to those with obesity by BMI and BF%. Importantly, both groups of subjects with obesity by BF% showed a similarly altered glucose homeostasis after an OGTT as compared to their NW counterparts. CONCLUSIONS: Results from the present study suggest increased cardiometabolic risk factors in children and adolescents without obesity according to BMI but with obesity based on BF%. Being aware of the difficulty in determining body composition in everyday clinical practice, our data show that its inclusion could yield clinically useful information both for the diagnosis and treatment of overweight and obesity.
Subject(s)
Adiposity , Hypertension , Male , Female , Humans , Adolescent , Child , Body Mass Index , Overweight , Cross-Sectional Studies , Retrospective Studies , Obesity/diagnosis , Obesity/epidemiology , C-Reactive Protein , GlucoseABSTRACT
CONTEXT: Climate change and global warming have been hypothesized to influence the increased prevalence of obesity worldwide. However, the evidence is scarce. OBJECTIVE: We aimed to investigate how outside temperature might affect adipose tissue physiology and metabolic traits. METHODS: The expression of genes involved in thermogenesis/browning and adipogenesis were evaluated (through quantitative polymerase chain reaction) in the subcutaneous adipose tissue (SAT) from 1083 individuals recruited in 5 different regions of Spain (3 in the North and 2 in the South). Plasma biochemical variables and adiponectin (enzyme-linked immunosorbent assay) were collected through standardized protocols. Mean environmental outdoor temperatures were obtained from the National Agency of Meteorology. Univariate, multivariate, and artificial intelligence analyses (Boruta algorithm) were performed. RESULTS: The SAT expression of genes associated with browning (UCP1, PRDM16, and CIDEA) and ADIPOQ were significantly and negatively associated with minimum, average, and maximum temperatures. The latter temperatures were also negatively associated with the expression of genes involved in adipogenesis (FASN, SLC2A4, and PLIN1). Decreased SAT expression of UCP1 and ADIPOQ messenger RNA and circulating adiponectin were observed with increasing temperatures in all individuals as a whole and within participants with obesity in univariate, multivariate, and artificial intelligence analyses. The differences remained statistically significant in individuals without type 2 diabetes and in samples collected during winter. CONCLUSION: Decreased adipose tissue expression of genes involved in browning and adiponectin with increased environmental temperatures were observed. Given the North-South gradient of obesity prevalence in these same regions, the present observations could have implications for the relationship of the obesity pandemic with global warming.
Subject(s)
Adiponectin , Diabetes Mellitus, Type 2 , Humans , Temperature , Adiponectin/metabolism , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/complications , Artificial Intelligence , Adipose Tissue/metabolism , Obesity/epidemiology , Obesity/genetics , Obesity/complications , Adipose Tissue, White/metabolism , Adipose Tissue, Brown/metabolism , Thermogenesis/geneticsABSTRACT
BACKGROUND: Lysosomal diseases (LDs) are progressive life-threatening disorders that are usually asymptomatic at birth. Specific treatments are available for several LDs, and early intervention improves patient's outcomes. Thus, these diseases benefit from newborn screening (NBS). We have performed a pilot study for six LDs in Brazil by tandem mass spectrometry. METHODS: Dried blood spot (DBS) samples of unselected newborns were analyzed by the Neo-LSD™ kit (Perkin-Elmer) by MS/MS. Samples with low enzyme activity were submitted to the evaluation of specific biomarkers by ultra-performance liquid chromatography tandem-mass spectrometry as the second-tier, and were analyzed by a next-generation sequencing (NGS) multi-gene panel as the third-tier. All tests were performed in the same DBS sample. RESULTS: In 20,066 newborns analyzed, 15 samples showed activity of one enzyme below the cutoff. Two newborns had biochemical and molecular results compatible with Fabry disease, and five newborns had biochemical results and pathogenic variants or variants of unknown significance (VUS) in GAA. CONCLUSIONS: This study indicates that the use of enzyme assay as the first-tier test gives an acceptably low number of positive results that requires second/third tier testing. The possibility to run all tests in a DBS sample makes this protocol applicable to large-scale NBS programs.
Subject(s)
Fabry Disease , Neonatal Screening , Humans , Infant, Newborn , Neonatal Screening/methods , Pilot Projects , Tandem Mass Spectrometry/methods , Brazil/epidemiology , Fabry Disease/diagnosisABSTRACT
BACKGROUND: The biological mediators supporting the resolution of liver steatosis, inflammation and fibrosis after bariatric surgery in patients with obesity and NAFLD remain unclear. We sought to analyze whether uroguanylin and guanylin, two gut hormones involved in the regulation of satiety, food preference and adiposity, are involved in the amelioration of obesity-associated NAFLD after bariatric surgery. METHODS: Proguanylin (GUCA2A) and prouroguanylin (GUCA2B) were measured in 214 participants undergoing bariatric surgery with biopsy-proven NAFLD diagnosis. Pathways involved in lipid metabolism, mitochondrial network and fibrogenesis were evaluated in liver biopsies (n = 137). The effect of guanylin and uroguanylin on these metabolic functions was assessed in HepG2 hepatocytes and LX-2 hepatic stellate cells (HSC) under lipotoxic and profibrogenic conditions. RESULTS: Plasma and hepatic expression of GUCA2B were decreased in obesity-associated NAFLD. Both GUCA2A and GUCA2B levels were increased after sleeve gastrectomy and Roux-en-Y gastric bypass in parallel to the improved liver function. The liver of patients with type 2 diabetes showed impaired mitochondrial ß-oxidation, biogenesis, dynamics as well as increased fibrosis. Uroguanylin diminished the lipotoxicity in palmitate-treated HepG2 hepatocytes, evidenced by decresased steatosis and lipogenic factors, as well as increased mitochondrial network expression, AMPK-induced ß-oxidation and oxygen consumption rate. Additionally, uroguanylin, but not guanylin, reversed HSC myofibroblast transdifferentiation as well as fibrogenesis after TGF-ß1 stimulation. CONCLUSIONS: Uroguanylin constitutes a protective factor against lipotoxicity, mitochondrial dysfunction and fibrosis. Increased GUCA2B levels might contribute to improve liver injury in patients with obesity-associated NAFLD after bariatric surgery.
Subject(s)
Bariatric Surgery , Diabetes Mellitus, Type 2 , Non-alcoholic Fatty Liver Disease , Obesity, Morbid , Humans , Non-alcoholic Fatty Liver Disease/pathology , Obesity, Morbid/surgery , Diabetes Mellitus, Type 2/metabolism , Obesity/complications , Obesity/surgery , Obesity/metabolism , Liver/metabolism , Fibrosis , Mitochondria/metabolismABSTRACT
BACKGROUND: Growing evidence suggests the key role of ghrelin in the onset and progression of nonalcoholic fatty liver disease (NAFLD). The potential participation of ghrelin and the ghrelin receptor antagonist, LEAP-2, in the onset of liver fibrosis in patients with severe obesity and NAFLD through the regulation of TGF-ß1-induced hepatic stellate cell (HSC) activation was investigated. METHODS: Circulating (n = 179) and hepatic expression (n = 95) of ghrelin and LEAP-2 were measured in patients with severe obesity and available liver pathology analysis undergoing Roux-en-Y gastric bypass (RYGB). The effect of ghrelin isoforms and LEAP-2 on TGF-ß1-induced HSC activation, fibrogenic response, and contractile properties was evaluated in vitro in human LX-2 cells. RESULTS: Plasma and hepatic ghrelin were negatively associated, while LEAP-2 exhibited a positive association with liver fibrosis in patients with obesity and NAFLD. Six months after RYGB, hepatic function was improved and, although acylated ghrelin and LEAP-2 concentrations remained unchanged, both hormones were inversely related to post-surgical levels of profibrogenic factors TGF-ß1 and TIMP-1. Acylated ghrelin treatment reversed TGF-ß1-induced myofibroblast-like phenotype, collagen contractile properties, and the upregulation of factors involved in HSC activation and fibrogenesis via PI3K/Akt/mTOR pathway. Moreover, acylated ghrelin inhibited the mild HSC activation induced by LEAP-2. CONCLUSIONS: Ghrelin is an anti-fibrogenic factor blocking HSC activation induced by the most potent fibrogenic cytokine, TGF-ß1, and LEAP-2. The imbalance between acylated ghrelin and ghrelin receptor antagonist LEAP-2 might contribute to maintain liver fibrosis in patients with obesity and NAFLD.
Subject(s)
Non-alcoholic Fatty Liver Disease , Obesity, Morbid , Humans , Non-alcoholic Fatty Liver Disease/metabolism , Transforming Growth Factor beta1/adverse effects , Transforming Growth Factor beta1/metabolism , Hepatic Stellate Cells/metabolism , Hepatic Stellate Cells/pathology , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol 3-Kinases/pharmacology , Ghrelin/adverse effects , Receptors, Ghrelin , Liver Cirrhosis/etiology , Liver/metabolismABSTRACT
The black-faced ibis, Theristicus melanopis, is considered a useful bird species for agricultural activity because it preys upon various invertebrate and vertebrate pests. Although it is a common species in Chile, limited information is available regarding its parasites. The main objective of this study was to recover the diversity of ectoparasites and gastrointestinal helminths in black-faced ibises living in the communes of Valdivia and Panguipulli, Los Ríos region. A total of 74 specimens were received for examination from the Centro de Rehabilitación de Fauna Silvestre at the Universidad Austral de Chile (CEREFAS-UACh), Valdivia, in 2011-2015. Black-faced ibises were externally inspected for ectoparasites by direct examining of the plumage, and necropsies were performed to examine digestive and respiratory organs in search of endoparasites. For each taxon, prevalence, mean intensity, mean abundance, and range of parasites per bird were estimated. Five species of ectoparasites and six species of helminths were identified. A total of 298 lice (Insecta: Phthiraptera) belonging to four species were collected: Ardeicola melanopis (13.51%), Colpocephalum trispinum (20.27%), Ibidoecus fissisignatus (4.05%), and Plegadiphilus mamillatus (9.46%). In addition, one feather mite species, Diodochaetus melanopis (Acari: Pterolichoidea) (17.56%), was isolated. In 48 black-faced ibis (64.86%), a total of 1229 gastrointestinal helminths were found: two nematodes, Porrocaecum heteropterum (55.41%) and Baruscapillaria obsignata (24.32%); one tapeworm Eugonodaeum nasuta (20.27%); two digeneans, Echinoparyphium recurvatum (1.35%) and Strigea bulbosa (6.76%); and the acanthocephalan Sphaerirostris sp. (1.35%). The findings of the following parasites present new host-parasite associations: P. mamillatus, D. melanopis, B. obsignata, E. recurvatum, S. bulbosa, and Sphaerirostris sp. Additionally, the louse P. mamillatus, feather mite D. melanopis, platyhelminths E. nasuta, E. recurvatum and S. bulbosa, and the acanthocephalan Sphaerirostris sp. are new records for the fauna of Chile.
Subject(s)
Anoplura , Helminths , Intestinal Diseases, Parasitic , Mites , Parasites , Animals , Chile/epidemiology , Birds/parasitology , Intestinal Diseases, Parasitic/epidemiology , Intestinal Diseases, Parasitic/veterinaryABSTRACT
[This corrects the article DOI: 10.1016/j.ymgmr.2022.100888.].
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[This corrects the article DOI: 10.3389/fimmu.2022.832185.].
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Netrin (NTN)-1, an extracellular matrix protein with a crucial role in inflammation, is dysregulated during obesity (OB) and influences colon cancer (CC) progression. To decipher the mechanisms underlying CC development during obesity, we examined the expression of NTN1 and its receptors in the visceral adipose tissue (VAT) of 74 (25 normal weight (NW)) (16 with CC) and 49 patients with OB (12 with CC). We also evaluated the effect of caloric restriction (CR) on the gene expression levels of Ntn1 and its receptors in the colon from a rat model fed a normal diet. The impact of adipocyte-conditioned media (ACM) from patients with OB and NTN-1 was assessed on the expression levels of neogenin 1(NEO1), deleted in colorectal carcinomas (DCC) and uncoordinated-5 homolog B (UNC5B) in Caco-2 and HT-29 human colorectal cell lines, as well as on Caco-2 cell migration. Increased NTN1 and NEO1 mRNA levels in VAT were due to OB (p < 0.05) and CC (p < 0.001). In addition, an upregulation in the expression levels of DCC and UNC5B in patients with CC (p < 0.01 and p < 0.05, respectively) was observed. Decreased (p < 0.01) Ntn1 levels in the colon from rats submitted to CR were found. In vitro experiments showed that ACM increased DCC (p < 0.05) and NEO1 (p < 0.01) mRNA levels in HT-29 and Caco-2 cell lines, respectively, while UNC5B decreased (p < 0.01) in HT-29. The treatment with NTN-1 increased (p < 0.05) NEO1 mRNA levels in HT-29 cells and DCC (p < 0.05) in both cell lines. Finally, we revealed a potent migratory effect of ACM and NTN-1 on Caco-2 cells. Collectively, these findings point to increased NTN-1 during OB and CC fuelling cancer progression and exerting a strong migratory effect on colon cancer cells.
ABSTRACT
BACKGROUND: Acid sphingomyelinase deficiency (ASMD) is a lysosomal disorder caused by deficiency of acid sphingomyelinase (ASM) leading to the accumulation of sphingomyelin (SM) in a variety of cell types. Lysosphingomyelin (LysoSM) is the de-acetylated form of SM and it has been shown as a biomarker for ASMD in tissues, plasma, and dried blood spots (DBS) and lysosphingomyelin-509 (LysoSM509) is the carboxylated analogue of LysoSM. High levels of Lysosphingomyelin 509 (LysoSM509) have also been shown in ASMD patients. In this study, we report the utility of the quantification of LysoSM and LysoSM509 in DBS of patients from Latin America with ASMD by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). RESULTS: DBS samples from 14 ASMD patients were compared with 15 controls, and 44 general newborns. All patients had their diagnosis confirmed by the quantification of ASM and the measurement of the activity of chitotriosidase. All patients had significantly higher levels of lysoSM and lysoSM509 compared to controls and general newborns. CONCLUSIONS: The quantification of lysosphingolipids in DBS is a valuable tool for the diagnosis of ASMD patients and lysoSM can be useful in the differential diagnosis with NPC. This method is also valuable in the ASMD newborn screening process.
Subject(s)
Niemann-Pick Disease, Type A , Niemann-Pick Diseases , Infant, Newborn , Humans , Chromatography, Liquid/methods , Tandem Mass Spectrometry/methods , Sphingomyelin PhosphodiesteraseABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has affected the entire world, causing the coronavirus disease 2019 (COVID-19) pandemic since it was first discovered in Wuhan, China in December 2019. Among the clinical presentation of the disease, in addition to fever, fatigue, cough, dyspnea, diarrhea, nausea, vomiting, and abdominal pain, infected patients may also experience neurological and psychiatric repercussions during the course of the disease and as a post-COVID-19 sequelae. Thus, headache, dizziness, olfactory and gustatory dysfunction, cerebrovascular disorders, neuromuscular abnormalities, anxiety, depression, and post-traumatic stress disorder can occur both from the infection itself and from social distancing and quarantine. According to current evidence about this infection, the virus has the ability to infect the central nervous system (CNS) via angiotensin-converting enzyme 2 (ACE2) receptors on host cells. Several studies have shown the presence of ACE2 in nerve cells and nasal mucosa, as well as transmembrane serine protease 2, key points for interaction with the viral Spike glycoprotein and entry into the CNS, being olfactory tract and blood-brain barrier, through hematogenous dissemination, potential pathways. Thus, the presence of SARS-CoV-2 in the CNS supports the development of neuropsychiatric symptoms. The management of these manifestations seems more complex, given that the dense parenchyma and impermeability of brain tissue, despite protecting the brain from the infectious process, may hinder virus elimination. Still, some alternatives used in non-COVID-19 situations may lead to worse prognosis of acute respiratory syndrome, requiring caution. Therefore, the aim of this review is to bring more current points related to this infection in the CNS, as well as the repercussions of the isolation involved by the pandemic and to present perspectives on interventions in this scenario.
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Netrin (NTN)-1 exhibits pro- and anti-inflammatory roles in different settings, playing important roles in the obesity-associated low-grade chronic inflammation. We aimed to determine the impact of NTN-1 on obesity and obesity-associated type 2 diabetes, as well as its role in visceral adipose tissue (VAT) inflammation. A total of 91 subjects were enrolled in this case-control study. Circulating levels of NTN-1 and its receptor neogenin (NEO)-1 were determined before and after weight loss achieved by caloric restriction and bariatric surgery. mRNA levels of NTN1 and NEO1 were assessed in human VAT, liver, and peripheral blood mononuclear cells. In vitro studies in human visceral adipocytes and human monocytic leukemia cells (THP-1)-derived macrophages were performed to analyze the impact of inflammation-related mediators on the gene expression levels of NTN1 and its receptor NEO1 as well as the effect of NTN-1 on inflammation. Increased (p < 0.001) circulating concentrations of NTN-1 in obesity decreased (p < 0.05) after diet-induced weight loss being also associated with a reduction in glucose (p < 0.01) and insulin levels (p < 0.05). Gene expression levels of NTN1 and NEO1 were upregulated (p < 0.05) in the VAT from patients with obesity with the highest expression in the stromovascular fraction cells compared with mature adipocytes (p < 0.01). NTN1 expression levels were enhanced (p < 0.01) under hypoxia and by inflammatory factors in both adipocytes and macrophages. Adipocyte-conditioned media strongly upregulated (p < 0.001) the mRNA levels of NTN1 in macrophages. The treatment of adipocytes with NTN-1 promoted the upregulation (p < 0.05) of pro-inflammatory and chemotactic molecules as well as its receptor NEO1. Collectively, these findings suggest that NTN-1 regulates VAT chronic inflammation and insulin resistance in obesity.
Subject(s)
Diabetes Mellitus, Type 2 , Insulin Resistance , Insulins , Netrin-1 , Obesity , Humans , Adipose Tissue/metabolism , Case-Control Studies , Culture Media, Conditioned , Glucose/metabolism , Inflammation/metabolism , Insulins/metabolism , Intra-Abdominal Fat/metabolism , Leukocytes, Mononuclear/metabolism , Netrin-1/metabolism , Obesity/metabolism , RNA, Messenger/genetics , Weight LossABSTRACT
Recent research has demonstrated that critically ill patients with coronavirus disease 2019 (COVID-19) show significant immune system dysregulation. Due to that, some nutrients that influence immunomodulation have been suggested as a form of treatment against the infection. This review collected the information on the impact of vitamins on the prognosis of COVID-19, with the intention of facilitating treatment and prevention of the disease risk status in patients. The collected information was obtained using the PubMed electronic database by searching for articles that relate COVID-19 and the mechanisms/effects of the nutrients: Proteins, glucose, lipids, vitamin B12, vitamin D, calcium, iron, copper, zinc, and magnesium, including prospective, retrospective, and support articles. The findings reveal an optimal response related mainly to omega-3, eicosapentaenoic acid, docosahexaenoic acid, calcium, and iron that might represent benefits in the treatment of critically ill patients. However, nutrient supplementation should be done with caution due to the limited availability of randomized controlled studies.
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Dysfunctional adipose tissue (AT) in the context of obesity leads to chronic inflammation together with an altered extracellular matrix (ECM) remodelling, favouring cancer development and progression. Recently, the influence of dermatopontin (DPT) in AT remodelling and inflammation has been proposed. We aimed to evaluate the role of DPT in the development of obesity-associated colon cancer (CC). Samples obtained from 73 subjects [26 lean (LN) and 47 with obesity (OB)] were used in a case-control study. Enrolled subjects were further subclassified according to the established diagnostic protocol for CC (42 without CC and 31 with CC). In vitro studies in the adenocarcinoma HT-29 cell line were performed to analyse the impact of pro- and anti-inflammatory mediators on the transcript levels of DPT as well as the effect of DPT on ECM remodelling and inflammation. Although obesity increased (p < 0.05) the circulating levels of DPT, its concentrations were significantly decreased (p < 0.05) in patients with CC. Gene expression levels of DPT in the colon from patients with CC were downregulated and, oppositely, a tendency towards increased mRNA levels in visceral AT was found. We further showed that DPT expression levels in HT-29 cells were enhanced (p < 0.05) by inflammatory factors (LPS, TNF-α and TGF-ß), whereas the anti-inflammatory IL-4 decreased (p < 0.05) its expression levels. We also demonstrated that DPT upregulated (p < 0.05) the mRNA of key molecules involved in ECM remodelling (COL1A1, COL5A3, TNC and VEGFA) whereas decorin (DCN) expression was downregulated (p < 0.05) in HT-29 cells. Finally, we revealed that the adipocyte-conditioned medium obtained from volunteers with OB enhanced (p < 0.01) the expression of DPT in HT-29 and Caco-2 cells. The decreased circulating and expression levels of DPT in the colon together with the tendency towards increased levels in visceral AT in patients with CC and its influence on the expression of ECM proteins suggest a possible role of DPT in the OB-associated CC.
Subject(s)
Colonic Neoplasms , Extracellular Matrix Proteins , Caco-2 Cells , Case-Control Studies , Colonic Neoplasms/genetics , Colonic Neoplasms/metabolism , Extracellular Matrix/metabolism , Extracellular Matrix Proteins/genetics , Extracellular Matrix Proteins/metabolism , Humans , Inflammation/metabolism , Obesity/complications , Obesity/metabolism , RNA, Messenger/metabolismABSTRACT
Niemann-Pick disease type C (NPC) is a lysosomal disorder caused by impaired cholesterol metabolism. Levels of lysosphingomyelin 509 (LysoSM509) have been shown elevated in dried blood spots (DBS) of NPC and acid sphingomyelinase deficiency patients. In this study, we report our experience using a two-tier approach (1st tier is the quantification of lysoSM509 by ultra-performance liquid chromatography tandem mass spectrometry followed by the 2nd tier with next-generation sequencing of the NPC1 and NPC2 genes). DBS samples from 450 suspected patients were received by the NPC Brazil network. Of these, 33 samples had elevated levels of lysoSM509, and in 25 of them, variants classified as pathogenic, likely pathogenic, or of unknown significance were identified in the NPC1 or NPC2 genes by next-generation sequencing. The quantification of lysoSM509 in DBS as a first-tier test for the diagnosis of NPC followed by molecular analysis of the NPC1 and NPC2 genes almost doubled the detection rate when compared to the performance of chitotriosidase activity as a first-tier biomarker, and it could likely be increased with the addition of a third tier with MLPA of the two genes involved. This strategy seems suitable for the neonatal screening (NBS) of NPC if this disease is eventually adopted by NBS programs.
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Many studies have demonstrated that malnutrition has a negative impact on quality of life and mortality in patients with cancer. During the SARS-CoV-2 lockdown, dietary intake changes were detected in the Spanish population, reflecting an increase in the consumption of fruit, bread, flours, and eggs. The present study analyzed the nutritional status of 728 patients with cancer admitted once the SARS-CoV-2 lockdown finished, comparing it with the previous year as well as with mortality rates. The Malnutrition Universal Screening Tool (MUST) was applied in the first 24 h after admission. Age, gender, days of stay, circulating concentrations of albumin, cholesterol, C-reactive protein (CRP), lymphocytes, prealbumin, and mortality data were analyzed. Patients with cancer admitted between June and December of 2020 exhibited no statistical differences in BMI, age, or gender as compared to patients admitted in 2019. Statistically significant differences in nutritional status (p < 0.05), albumin (p < 0.001), and CRP (p = 0.005) levels regarding lockdown were observed in relation with a small non-significant reduction in mortality. In conclusion, following the SARS-CoV-2 lockdown, an improved nutritional status in cancer patients at admission was observed with a decrease in the percentage of weight loss and CRP levels together with an increase in albumin levels compared to oncological patients admitted the previous year.