Valorization applications of pineapple and papaya byproducts in food industry.

The recent increase in the harvesting and industrial processing of tropical fruits such as pineapple and papaya is leading to unavoidable amounts of byproducts rich in valuable compounds. Given the significance of the chemical composition of these byproducts, new research avenues are opening up to exploit them in the food industry. In this sense, the revalorization of pineapple and papaya byproducts is an emerging trend that is encouraging the full harnessing of these tropical fruits, offering the opportunity for developing innovative value-added products. Therefore, the main aim of this review is to provide an overview of the state of the art of the current valorization applications of pineapple and papaya byproducts in the field of food industry. For that proposal, comprehensive research of valorization applications developed in the last years has been conducted using scientific databases, databases, digital libraries, and scientific search engines. The latest valorization applications of pineapple and papaya byproducts in the food industry have been systematically revised and gathered with the objective of synthesizing and critically analyzing existing scientific literature in order to contribute to the advancement of knowledge in the field of tropical byproduct revalorization providing a solid foundation for further research and highlighting scientific gaps and new challenges that should be addressed in the future.

Inhibition of hepatic p63 ameliorates steatohepatitis with fibrosis in mice.

OBJECTIVE: p63 is a transcription factor involved in multiple biological functions. In the liver, the TAp63 isoform induces lipid accumulation in hepatocytes. However, the role of liver TAp63 in the progression of metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis is unknown. METHODS: We evaluated the hepatic p63 levels in different mouse models of steatohepatitis with fibrosis induced by diet. Next, we used virogenetic approaches to manipulate the expression of TAp63 in adult mice under diet-induced steatohepatitis with fibrosis and characterized the disease condition. Finally, we performed proteomics analysis in mice with overexpression and knockdown of hepatic TAp63. RESULTS: Levels of TAp63, but not of ΔN isoform, are increased in the liver of mice with diet-induced steatohepatitis with fibrosis. Both preventive and interventional strategies for the knockdown of hepatic TAp63 significantly ameliorated diet-induced steatohepatitis with fibrosis in mice fed a methionine- and choline-deficient diet (MCDD) and choline deficient and high fat diet (CDHFD). The overexpression of hepatic TAp63 in mice aggravated the liver condition in mice fed a CDHFD. Proteomic analysis in the liver of these mice revealed alteration in multiple proteins and pathways, such as oxidative phosphorylation, antioxidant activity, peroxisome function and LDL clearance. CONCLUSIONS: These results indicate that liver TAp63 plays a critical role in the progression of diet-induced steatohepatitis with fibrosis, and its inhibition ameliorates the disease.

Tinea Capitis Kerion Type in Three Siblings Caused by Nannizzia Gypsea.

This case report describes a rare occurrence of tinea capitis kerion type caused by Nannizzia gypsea in three siblings. The clinical presentation included pseudo-alopecic plaques with a dirty appearance, erythema, and honey-like crusts. A direct examination revealed ecto-endothrix parasitization in the hair shaft. Shared use of a comb among the siblings was suspected as the mode of transmission. Treatment with oral terbinafine resulted in a complete resolution. Systematic epidemiological surveys on N. gypsea tinea infections are scarce, and preliminary data from our center indicated a higher prevalence. The literature review identified five reported cases of N. gypsea-induced tinea capitis.

Ulcerative Unilateral Tinea Manuum Caused by Nannizzia gypsea.

Dermatophytes, fungi specialized in keratin degradation, are key agents in skin infections, commonly referred to as tineas. Tinea manuum, affecting the hands, typically presents in noninflammatory or inflammatory forms, with ulcerative manifestations rarely reported. Nannizzia gypsea, a relatively uncommon cause of tineas, exhibits variable prevalence influenced by geographic factors. This study investigates a case of Ulcerative Unilateral Tinea Manuum caused by N. gypsea, aiming to explore the differential diagnosis, pathogenesis, and management. A 23-year-old female from the Yucatan Peninsula presented with an ulcerated lesion on her left hand. Initially suspected as Leishmaniasis, subsequent examination revealed tinea manuum. The study discusses differential diagnoses, highlighting the rarity of ulcerative presentations in dermatophytosis, and explores potential pathogenic mechanisms. This case underscores the importance of considering dermatophytes in ulcerative skin lesions and suggests a comprehensive diagnostic approach, particularly in endemic regions.

Association between endocrine and neuropsychological endophenotypes and gambling disorder severity.

BACKGROUND: Neurobiological characteristics have been identified regarding the severity of gambling disorder (GD). The aims of this study were: (1) to examine, through a path analysis, whether there was a relationship between neuroendocrine features, potentially mediational GD variables, and GD severity, and (2) to associate neuroendocrine variables, with GD severity-related variables according to gambling preferences. METHODS: The sample included 297 outpatients with GD. We analyzed endocrine concentrations of different appetite-related hormones (ghrelin, liver antimicrobial peptide 2 [LEAP-2], leptin, adiponectin), and neuropsychological performance (working memory, cognitive flexibility, inhibition, decision making, premorbid intelligence). Path analysis assessed mechanisms between neuroendocrine features and GD severity, including mediational GD variables (impulsivity traits and gambling-related cognitive distortions). Partial correlations evaluated the associations between neuroendocrine variables, including impulsivity traits, and variables related to GD severity (DSM-5, South Oaks Gambling Screen, illness duration, and gambling-related cognitive distortions). RESULTS: Lower adiponectin concentrations predicted greater GD severity, while higher LEAP-2 concentrations predicted more gambling-related cognitive distortions. Likewise, better neuropsychological performance directly predicted GD severity, but worse neuropsychological performance was associated with GD severity through the mediational variables of impulsivity traits and gambling-related cognitive distortions. Also, in non-strategic individuals with GD, poor working memory was associated with gambling expectancies and predictive control. In strategic individuals with GD, poor cognitive flexibility was associated with illusion of control, predictive control, and inability to stop gambling. CONCLUSIONS: These results provide updated information about the comprehension of the interaction between neuroendocrine features, clinical variables, and severity of GD. Thus, neurobiological functions seem to be strongly related to GD severity.

p63 controls metabolic activation of hepatic stellate cells and fibrosis via an HER2-ACC1 pathway.

The p63 protein has pleiotropic functions and, in the liver, participates in the progression of nonalcoholic fatty liver disease (NAFLD). However, its functions in hepatic stellate cells (HSCs) have not yet been explored. TAp63 is induced in HSCs from animal models and patients with liver fibrosis and its levels positively correlate with NAFLD activity score and fibrosis stage. In mice, genetic depletion of TAp63 in HSCs reduces the diet-induced liver fibrosis. In vitro silencing of p63 blunts TGF-ß1-induced HSCs activation by reducing mitochondrial respiration and glycolysis, as well as decreasing acetyl CoA carboxylase 1 (ACC1). Ectopic expression of TAp63 induces the activation of HSCs and increases the expression and activity of ACC1 by promoting the transcriptional activity of HER2. Genetic inhibition of both HER2 and ACC1 blunt TAp63-induced activation of HSCs. Thus, TAp63 induces HSC activation by stimulating the HER2-ACC1 axis and participates in the development of liver fibrosis.

Hypothalamic free fatty acid receptor-1 regulates whole-body energy balance.

OBJECTIVE: Free fatty acid receptor-1 (FFAR1) is a medium- and long-chain fatty acid sensing G protein-coupled receptor that is highly expressed in the hypothalamus. Here, we investigated the central role of FFAR1 on energy balance. METHODS: Central FFAR1 agonism and virogenic knockdown were performed in mice. Energy balance studies, infrared thermographic analysis of brown adipose tissue (BAT) and molecular analysis of the hypothalamus, BAT, white adipose tissue (WAT) and liver were carried out. RESULTS: Pharmacological stimulation of FFAR1, using central administration of its agonist TUG-905 in diet-induced obese mice, decreases body weight and is associated with increased energy expenditure, BAT thermogenesis and browning of subcutaneous WAT (sWAT), as well as reduced AMP-activated protein kinase (AMPK) levels, reduced inflammation, and decreased endoplasmic reticulum (ER) stress in the hypothalamus. As FFAR1 is expressed in distinct hypothalamic neuronal subpopulations, we used an AAV vector expressing a shRNA to specifically knockdown Ffar1 in proopiomelanocortin (POMC) neurons of the arcuate nucleus of the hypothalamus (ARC) of obese mice. Our data showed that knockdown of Ffar1 in POMC neurons promoted hyperphagia and body weight gain. In parallel, these mice developed hepatic insulin resistance and steatosis. CONCLUSIONS: FFAR1 emerges as a new hypothalamic nutrient sensor regulating whole body energy balance. Moreover, pharmacological activation of FFAR1 could provide a therapeutic advance in the management of obesity and its associated metabolic disorders.

Cluster analysis in gambling disorder based on sociodemographic, neuropsychological, and neuroendocrine features regulating energy homeostasis.

BACKGROUND: The heterogeneity of gambling disorder (GD) has led to the identification of different subtypes, mostly including phenotypic features, with distinctive implications on the GD severity and treatment outcome. However, clustering analyses based on potential endophenotypic features, such as neuropsychological and neuroendocrine factors, are scarce so far. AIMS: This study firstly aimed to identify empirical clusters in individuals with GD based on sociodemographic (i.e., age and sex), neuropsychological (i.e., cognitive flexibility, inhibitory control, decision making, working memory, attention, and set-shifting), and neuroendocrine factors regulating energy homeostasis (i.e., leptin, ghrelin, adiponectin, and liver-expressed antimicrobial peptide 2, LEAP-2). The second objective was to compare the profiles between clusters, considering the variables used for the clustering procedure and other different sociodemographic, clinical, and psychological features. METHODS: 297 seeking-treatment adult outpatients with GD (93.6% males, mean age of 39.58 years old) were evaluated through a semi-structured clinical interview, self-reported psychometric assessments, and a protocolized neuropsychological battery. Plasma concentrations of neuroendocrine factors were assessed in peripheral blood after an overnight fast. Agglomerative hierarchical clustering was applied using sociodemographic, neuropsychological, and neuroendocrine variables as indicators for the grouping procedure. Comparisons between the empirical groups were performed using Chi-square tests (χ2) for categorical variables, and analysis of variance (ANOVA) for quantitative measures. RESULTS: Three-mutually-exclusive groups were obtained, being neuropsychological features those with the greatest weight in differentiating groups. The largest cluster (Cluster 1, 65.3%) was composed by younger males with strategic and online gambling preferences, scoring higher on self-reported impulsivity traits, but with a lower cognitive impairment. Cluster 2 (18.2%) and 3 (16.5%) were characterized by a significantly higher proportion of females and older patients with non-strategic gambling preferences and a worse neuropsychological performance. Particularly, Cluster 3 had the poorest neuropsychological performance, especially in cognitive flexibility, while Cluster 2 reported the poorest inhibitory control. This latter cluster was also distinguished by a poorer self-reported emotion regulation, the highest prevalence of food addiction, as well as a metabolic profile characterized by the highest mean concentrations of leptin, adiponectin, and LEAP-2. CONCLUSIONS: To the best of our knowledge, this is the first study to identify well-differentiated GD clusters using neuropsychological and neuroendocrine features. Our findings reinforce the heterogeneous nature of the disorder and emphasize a role of potential endophenotypic features in GD subtyping. This more comprehensive characterization of GD profiles could contribute to optimize therapeutic interventions based on a medicine of precision.

Plasma concentration of leptin is related to food addiction in gambling disorder: Clinical and neuropsychological implications.

Background: Data implicate overlaps in neurobiological pathways involved in appetite regulation and addictive disorders. Despite different neuroendocrine measures having been associated with both gambling disorder (GD) and food addiction (FA), how appetite-regulating hormones may relate to the co-occurrence of both entities remain incompletely understood. Aims: To compare plasma concentrations of ghrelin, leptin, adiponectin, and liver-expressed antimicrobial peptide 2 (LEAP-2) between patients with GD, with and without FA, and to explore the association between circulating hormonal concentrations and neuropsychological and clinical features in individuals with GD and FA. Methods: The sample included 297 patients diagnosed with GD (93.6% males). None of the patients with GD had lifetime diagnosis of an eating disorder. FA was evaluated with the Yale Food Addiction Scale 2.0. All patients were assessed through a semi-structured clinical interview and a psychometric battery including neuropsychological tasks. Blood samples to measure hormonal variables and anthropometric variables were also collected. Results: From the total sample, FA was observed in 23 participants (FA+) (7.7% of the sample, 87% males). When compared participants with and without FA, those with FA+ presented both higher body mass index (BMI) (p < 0.001) and leptin concentrations, after adjusting for BMI (p = 0.013). In patients with FA, leptin concentrations positively correlated with impulsivity, poorer cognitive flexibility, and poorer inhibitory control. Other endocrine measures did not differ between groups. Discussion and conclusions: The present study implicates leptin in co-occurring GD and FA. Among these patients, leptin concentration has been associated with clinical and neuropsychological features, such as impulsivity and cognitive performance in certain domains.

Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism.

Neddylation is a post-translational mechanism that adds a ubiquitin-like protein, namely neural precursor cell expressed developmentally downregulated protein 8 (NEDD8). Here, we show that neddylation in mouse liver is modulated by nutrient availability. Inhibition of neddylation in mouse liver reduces gluconeogenic capacity and the hyperglycemic actions of counter-regulatory hormones. Furthermore, people with type 2 diabetes display elevated hepatic neddylation levels. Mechanistically, fasting or caloric restriction of mice leads to neddylation of phosphoenolpyruvate carboxykinase 1 (PCK1) at three lysine residues-K278, K342, and K387. We find that mutating the three PCK1 lysines that are neddylated reduces their gluconeogenic activity rate. Molecular dynamics simulations show that neddylation of PCK1 could re-position two loops surrounding the catalytic center into an open configuration, rendering the catalytic center more accessible. Our study reveals that neddylation of PCK1 provides a finely tuned mechanism of controlling glucose metabolism by linking whole nutrient availability to metabolic homeostasis.

Downregulated Adipose Tissue Expression of Browning Genes With Increased Environmental Temperatures.

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.

Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function.

OBJECTIVE: O-GlcNAcylation is a post-translational modification that directly couples the processes of nutrient sensing, metabolism, and signal transduction, affecting protein function and localization, since the O-linked N-acetylglucosamine moiety comes directly from the metabolism of glucose, lipids, and amino acids. The addition and removal of O-GlcNAc of target proteins are mediated by two highly conserved enzymes: O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) and O-GlcNAcase (OGA), respectively. Deregulation of O-GlcNAcylation has been reported to be associated with various human diseases such as cancer, diabetes, and cardiovascular diseases. The contribution of deregulated O-GlcNAcylation to the progression and pathogenesis of NAFLD remains intriguing, and a better understanding of its roles in this pathophysiological context is required to uncover novel avenues for therapeutic intervention. By using a translational approach, our aim is to describe the role of OGT and O-GlcNAcylation in the pathogenesis of NAFLD. METHODS: We used primary mouse hepatocytes, human hepatic cell lines and in vivo mouse models of steatohepatitis to manipulate O-GlcNAc transferase (OGT). We also studied OGT and O-GlcNAcylation in liver samples from different cohorts of people with NAFLD. RESULTS: O-GlcNAcylation was upregulated in the liver of people and animal models with steatohepatitis. Downregulation of OGT in NAFLD-hepatocytes improved diet-induced liver injury in both in vivo and in vitro models. Proteomics studies revealed that mitochondrial proteins were hyper-O-GlcNAcylated in the liver of mice with steatohepatitis. Inhibition of OGT is able to restore mitochondrial oxidation and decrease hepatic lipid content in in vitro and in vivo models of NAFLD. CONCLUSIONS: These results demonstrate that deregulated hyper-O-GlcNAcylation favors NAFLD progression by reducing mitochondrial oxidation and promoting hepatic lipid accumulation.

Obesity wars: hypothalamic sEVs a new hope.

There are currently several pharmacological therapies available for the treatment of obesity, targeting both the central nervous system (CNS) and peripheral tissues. In recent years, small extracellular vesicles (sEVs) have been shown to be involved in many pathophysiological conditions. Because of their special nanosized structure and contents, sEVs can activate receptors and trigger intracellular pathways in recipient cells. Notably, in addition to transferring molecules between cells, sEVs can also alter their phenotypic characteristics. The purpose of this review is to discuss how sEVs can be used as a CNS-targeted strategy for treating obesity. Furthermore, we will evaluate current findings, such as the sEV-mediated targeting of hypothalamic AMP-activated protein kinase (AMPK), and discuss how they can be translated into clinical application.

A longitudinal study of free leptin index in pre-eclamptic pregnancies.

The ratio between circulating levels of leptin and soluble leptin receptor (sOB-R), the free leptin index (FLI), is used as a marker of leptin resistance. Therefore, the aim of our study was to investigate the FLI in mild pre-eclamptic pregnancies in a nested case-control study within a prospective observational study. Circulating levels of leptin and sOB-R levels rise significantly during pregnancy in healthy (p < 0.05) (n = 46) and pre-eclamptic pregnancies (p < 0.05) (n = 20). Serum levels of leptin were significantly higher in pre-eclamptic compared to healthy pregnancies at second and third trimesters of pregnancy (p < 0.05). Additionally, serum levels of sOB-R were significantly lower in pre-eclamptic pregnancies during the second and third trimesters of pregnancy compared to healthy pregnancies (p < 0.05). Moreover, we found that FLI did not vary significantly during pregnancy in healthy women (p > 0.05), while it increases in pre-eclamptic pregnancies (p < 0.05). Indeed, FLI was significantly higher at second and third trimesters of pregnancy in pre-eclamptic compared to healthy pregnancies (p < 0.05). In addition, FLI was significantly higher in the luteal phase compared with the follicular phase of the menstrual cycle in eumenorrheic women (p < 0.05). Receiver operating characteristic (ROC) curve analysis revealed the ability of leptin (AUC = 0.72) and FLI (AUC = 0.67) as a reliable predictor for mild pre-eclampsia during the second trimester of pregnancy. In conclusion, our findings show that FLI were significantly increased in mild pre-eclamptic pregnancies and allowed us to hypothesize that this rise might alter leptin bioavailability and bioactivity which might lead to the sympathetic hyperactivity and the hypertensive disorders during pregnancy.

Small extracellular vesicle targeting of hypothalamic AMPKα1 promotes weight loss in leptin receptor deficient mice.

BACKGROUND AND AIMS: Leptin receptor (LEPR) deficiency promotes severe obesity and metabolic disorders. However, the current therapeutic options against this syndrome are scarce. METHODS: db/db mice and their wildtypes were systemically treated with neuronal-targeted small extracellular vesicles (sEVs) harboring a plasmid encoding a dominant negative mutant of AMP-activated protein kinase alpha 1 (AMPKα1-DN) driven by steroidogenic factor 1 (SF1) promoter; this approach allowed to modulate AMPK activity, specifically in SF1 cells of the ventromedial nucleus of the hypothalamus (VMH). Animals were metabolically phenotyped. RESULTS: db/db mice intravenously injected with SF1-AMPKα1-DN loaded sEVs showed a marked feeding-independent weight loss and decreased adiposity, associated with increased sympathetic tone, brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT). CONCLUSION: Overall, this evidence indicates that specific modulation of hypothalamic AMPK using a sEV-based technology may be a suitable strategy against genetic forms of obesity, such as LEPR deficiency.

Hepatic p63 regulates glucose metabolism by repressing SIRT1.

OBJECTIVE: p63 is a transcription factor within the p53 protein family that has key roles in development, differentiation and prevention of senescence, but its metabolic actions remain largely unknown. Herein, we investigated the physiological role of p63 in glucose metabolism. DESIGN: We used cell lines and mouse models to genetically manipulate p63 in hepatocytes. We also measured p63 in the liver of patients with obesity with or without type 2 diabetes (T2D). RESULTS: We show that hepatic p63 expression is reduced on fasting. Mice lacking the specific isoform TAp63 in the liver (p63LKO) display higher postprandial and pyruvate-induced glucose excursions. These mice have elevated SIRT1 levels, while SIRT1 knockdown in p63LKO mice normalises glycaemia. Overexpression of TAp63 in wild-type mice reduces postprandial, pyruvate-induced blood glucose and SIRT1 levels. Studies carried out in hepatocyte cell lines show that TAp63 regulates SIRT1 promoter by repressing its transcriptional activation. TAp63 also mediates the inhibitory effect of insulin on hepatic glucose production, as silencing TAp63 impairs insulin sensitivity. Finally, protein levels of TAp63 are reduced in obese persons with T2D and are negatively correlated with fasting glucose and homeostasis model assessment index. CONCLUSIONS: These results demonstrate that p63 physiologically regulates glucose homeostasis.

Atypical Mycobacteriosis Due to Mycobacterium abscessus subsp. massiliense: Our Experince.

BACKGROUND: Members of Micobacterium. abscessus complex comprises three subspecies (M. abscessus subsp. Abscessus, M. abscessus subsp. Bolletii, and M. abscessus subsp. Massiliense) and are a rapid-growing nontuberculous mycobacteria present in different aquatic habitats and soil. It often causes a wide spectrum of infections involving pulmonary infections, surgical wound infections, and infections related to mesotherapy, catheters, hemodialysis devices, endocarditis, and disseminated infections in immunocompromised individuals. METHODS: In this article we comment on the most relevant aspects of nine patients with skin lesions caused by M. abscessus subsp. massiliense infection. Clinical characteristics, histopathology, and molecular identification were performed. RESULTS: The patients in the clinical cases presented a history of trauma, tattoos, and physical therapy techniques. The most common treatments were minocycline and clindamycin, doxycycline, ceftriaxone, cephalexin, moxifloxacin, rifampicin, and trimethoprim-sulfamethoxazole. The evolution of the treated patients was acceptable, except for one patient, who showed a partial improvement. M. massiliense were identified in all clinical cases using a species-specific PCR. CONCLUSION: Our series consisted of nine cases of skin biopsies recorded in different years; for this reason, we do not have all the data necessary for a complete description, in particular in four cases, causing limitations in the manuscript, especially in the therapy used and the evolution of patients due to lack of follow-up.