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Frontiers in Endocrinology 2024Ectopic ACTH syndrome (EAS) remains one of the most demanding diagnostic and therapeutic challenges for endocrinologists. Thymic neuroendocrine tumors account for 5%-10%...
Ectopic ACTH syndrome (EAS) remains one of the most demanding diagnostic and therapeutic challenges for endocrinologists. Thymic neuroendocrine tumors account for 5%-10% of all EAS cases. We report a unique case of a 31-year-old woman with severe EAS caused by primary metastatic combined large-cell neuroendocrine carcinoma and atypical carcinoid of the thymus. The patient presented with severe hypercortisolemia, which was successfully controlled with continuous etomidate infusion. Complex imaging initially failed to detect thymic lesion; however, it revealed a large, inhomogeneous, metabolically active left adrenal mass infiltrating the diaphragm, suspected of primary disease origin. The patient underwent unilateral adrenalectomy, which resulted in hypercortisolemia resolve. The pathology report showed an adenoma with adrenal infarction and necrosis. The thymic tumor was eventually revealed a few weeks later on follow-up imaging studies. Due to local invasion and rapid progression, only partial resection of the thymic tumor was possible, and the patient was started on radio- and chemotherapy.
PubMed: 38948516
DOI: 10.3389/fendo.2024.1399930 -
Frontiers in Endocrinology 2024Analyzing bacterial microbiomes consistently using next-generation sequencing (NGS) is challenging due to the diversity of synthetic platforms for 16S rRNA genes and...
Comparative analysis of gut microbiota in children with obstructive sleep apnea: assessing the efficacy of 16S rRNA gene sequencing in metabolic function prediction based on weight status.
BACKGROUND
Analyzing bacterial microbiomes consistently using next-generation sequencing (NGS) is challenging due to the diversity of synthetic platforms for 16S rRNA genes and their analytical pipelines. This study compares the efficacy of full-length (V1-V9 hypervariable regions) and partial-length (V3-V4 hypervariable regions) sequencing of synthetic 16S rRNA genes from human gut microbiomes, with a focus on childhood obesity.
METHODS
In this observational and comparative study, we explored the differences between these two sequencing methods in taxonomic categorization and weight status prediction among twelve children with obstructive sleep apnea.
RESULTS
The full-length NGS method by Pacbio identified 118 genera and 248 species in the V1-V9 regions, all with a 0% unclassified rate. In contrast, the partial-length NGS method by Illumina detected 142 genera (with a 39% unclassified rate) and 6 species (with a 99% unclassified rate) in the V3-V4 regions. These approaches showed marked differences in gut microbiome composition and functional predictions. The full-length method distinguished between obese and non-obese children using the / ratio, a known obesity marker ( = 0.046), whereas the partial-length method was less conclusive ( = 0.075). Additionally, out of 73 metabolic pathways identified through full-length sequencing, 35 (48%) were associated with level 1 metabolism, compared to 28 of 61 pathways (46%) identified through the partial-length method. The full-length NGS also highlighted complex associations between body mass index z-score, three bacterial species (, , and ATCC 15912), and 17 metabolic pathways. Both sequencing techniques revealed relationships between gut microbiota composition and OSA-related parameters, with full-length sequencing offering more comprehensive insights into associated metabolic pathways than the V3-V4 technique.
CONCLUSION
These findings highlight disparities in NGS-based assessments, emphasizing the value of full-length NGS with amplicon sequence variant analysis for clinical gut microbiome research. They underscore the importance of considering methodological differences in future meta-analyses.
PubMed: 38948515
DOI: 10.3389/fendo.2024.1344152 -
Frontiers in Endocrinology 2024Obesity impairs bone marrow (BM) glucose metabolism. Adult BM constitutes mostly of adipocytes that respond to changes in energy metabolism by modulating their...
OBJECTIVES
Obesity impairs bone marrow (BM) glucose metabolism. Adult BM constitutes mostly of adipocytes that respond to changes in energy metabolism by modulating their morphology and number. Here we evaluated whether diet or exercise intervention could improve the high-fat diet (HFD) associated impairment in BM glucose uptake (BMGU) and whether this associates with the morphology of BM adipocytes (BMAds) in rats.
METHODS
Eight-week-old male Sprague-Dawley rats were fed either HFD or chow diet for 24 weeks. Additionally after 12 weeks, HFD-fed rats switched either to chow diet, voluntary intermittent running exercise, or both for another 12 weeks. BMAd morphology was assessed by perilipin-1 immunofluorescence staining in formalin-fixed paraffin-embedded tibial sections. Insulin-stimulated sternal and humeral BMGU were measured using [F]FDG-PET/CT. Tibial microarchitecture and mineral density were measured with microCT.
RESULTS
HFD rats had significantly higher whole-body fat percentage compared to the chow group (17% vs 13%, respectively; = 0.004) and larger median size of BMAds in the proximal tibia (815 µm vs 592 µm, respectively; = 0.03) but not in the distal tibia. Switch to chow diet combined with running exercise normalized whole-body fat percentage ( < 0.001) but not the BMAd size. At 32 weeks of age, there was no significant difference in insulin-stimulated BMGU between the study groups. However, BMGU was significantly higher in sternum compared to humerus ( < 0.001) and higher in 8-week-old compared to 32-week-old rats ( < 0.001). BMAd size in proximal tibia correlated positively with whole-body fat percentage (r = 0.48, = 0.005) and negatively with humeral BMGU (r = -0.63, = 0.02). HFD significantly reduced trabecular number ( < 0.001) compared to the chow group. Switch to chow diet reversed this as the trabecular number was significantly higher ( = 0.008) than in the HFD group.
CONCLUSION
In this study we showed that insulin-stimulated BMGU is age- and site-dependent. BMGU was not affected by the study interventions. HFD increased whole-body fat percentage and the size of BMAds in proximal tibia. Switching from HFD to a chow diet and running exercise improved glucose homeostasis and normalized the HFD-induced increase in body fat but not the hypertrophy of BMAds.
PubMed: 38948514
DOI: 10.3389/fendo.2024.1422869 -
Frontiers in Pharmacology 2024Schizophrenia significantly impacts cognitive and behavioral functions and is primarily treated with second-generation antipsychotics (SGAs) such as olanzapine. Despite...
Schizophrenia significantly impacts cognitive and behavioral functions and is primarily treated with second-generation antipsychotics (SGAs) such as olanzapine. Despite their efficacy, these drugs are linked to serious metabolic side effects which can diminish patient compliance, worsen psychiatric symptoms and increase cardiovascular disease risk. This study explores the hypothesis that SGAs affect the molecular determinants of synaptic plasticity and brain activity, particularly focusing on the lateral septum (LS) and its interactions within hypothalamic circuits that regulate feeding and energy expenditure. Utilizing functional ultrasound imaging, RNA sequencing, and weighted gene co-expression network analysis, we identified significant alterations in the functional connection between the hypothalamus and LS, along with changes in gene expression in the LS of mice following prolonged olanzapine exposure. Our analysis revealed a module closely linked to increases in body weight and adiposity, featuring genes primarily involved in lipid metabolism pathways, notably , , and . These findings suggest that olanzapine may influence body weight and adiposity through its impact on lipid metabolism-related genes in the LS. Therefore, the neural circuits connecting the LS and LH, along with the accompanying alterations in lipid metabolism, are likely crucial factors contributing to the weight gain and metabolic side effects associated with olanzapine treatment.
PubMed: 38948475
DOI: 10.3389/fphar.2024.1419098 -
Frontiers in Pharmacology 2024Heart failure and cognitive impairment emerge as public health problems that need to be addressed due to the aging global population. The conditions that often coexist... (Review)
Review
Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, anti-diabetic drugs in heart failure and cognitive impairment: potential mechanisms of the protective effects.
Heart failure and cognitive impairment emerge as public health problems that need to be addressed due to the aging global population. The conditions that often coexist are strongly related to advancing age and multimorbidity. Epidemiological evidence indicates that cardiovascular disease and neurodegenerative processes shares similar aspects, in term of prevalence, age distribution, and mortality. Type 2 diabetes increasingly represents a risk factor associated not only to cardiometabolic pathologies but also to neurological conditions. The pathophysiological features of type 2 diabetes and its metabolic complications (hyperglycemia, hyperinsulinemia, and insulin resistance) play a crucial role in the development and progression of both heart failure and cognitive dysfunction. This connection has opened to a potential new strategy, in which new classes of anti-diabetic medications, such as glucagon-like peptide-1 receptor (GLP-1R) agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, are able to reduce the overall risk of cardiovascular events and neuronal damage, showing additional protective effects beyond glycemic control. The pleiotropic effects of GLP-1R agonists and SGLT2 inhibitors have been extensively investigated. They exert direct and indirect cardioprotective and neuroprotective actions, by reducing inflammation, oxidative stress, ions overload, and restoring insulin signaling. Nonetheless, the specificity of pathways and their contribution has not been fully elucidated, and this underlines the urgency for more comprehensive research.
PubMed: 38948473
DOI: 10.3389/fphar.2024.1422740 -
Frontiers in Pharmacology 2024Amdizalisib, also named HMPL-689, a novel selective and potent PI3Kδ inhibitor, is currently under Phase II clinical development in China for treating hematological...
Amdizalisib, also named HMPL-689, a novel selective and potent PI3Kδ inhibitor, is currently under Phase II clinical development in China for treating hematological malignancies. The preclinical pharmacokinetics (PK) of amdizalisib were extensively characterized and to support the further development of amdizalisib. We characterized the plasma protein binding, blood-to-plasma partition ratio, cell permeability, hepatic microsomal metabolic stability, and drug-drug interaction potential of amdizalisib using experiments. PK assessment was undertaken in mice, rats, dogs, and monkeys following a single intravenous or oral administration of amdizalisib. The tissue distribution and excretion of amdizalisib were evaluated in rats. The PK parameters (CL and V) of amdizalisib in preclinical species (mice, rats, dogs, and monkeys) were utilized for the human PK projection using the allometric scaling (AS) approach. Amdizalisib was well absorbed and showed low-to-moderate clearance in mice, rats, dogs, and monkeys. It had high cell permeability without P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) substrate liability. Plasma protein binding of amdizalisib was high (approximately 90%). It was extensively distributed but with a low brain-to-plasma exposure ratio in rats. Amdizalisib was extensively metabolized , and the recovery rate of the prototype drug was low in the excreta. Amdizalisib and/or its metabolites were primarily excreted via the bile and urine in rats. Amdizalisib showed inhibition potential on P-gp but not on BCRP and was observed to inhibit CYP2C8 and CYP2C9 with IC values of 30.4 and 10.7 μM, respectively. It exhibited induction potential on CYP1A2, CYP2B6, CYP3A4, and CYP2C9. The preclinical data from these ADME studies demonstrate a favorable pharmacokinetic profile for amdizalisib, which is expected to support the future clinical development of amdizalisib as a promising anti-cancer agent.
PubMed: 38948472
DOI: 10.3389/fphar.2024.1392209 -
World Journal of Hepatology Jun 2024Nonalcoholic fatty liver disease (NAFLD) is a liver condition that is prevalent worldwide and associated with significant health risks and economic burdens. As it has...
BACKGROUND
Nonalcoholic fatty liver disease (NAFLD) is a liver condition that is prevalent worldwide and associated with significant health risks and economic burdens. As it has been linked to insulin resistance (IR), this study aimed to perform a bibliometric analysis and visually represent the scientific literature on IR and NAFLD.
AIM
To map the research landscape to underscore critical areas of focus, influential studies, and future directions of NAFLD and IR.
METHODS
This study conducted a bibliometric analysis of the literature on IR and NAFLD indexed in the SciVerse Scopus database from 1999 to 2022. The search strategy used terms from the literature and medical subject headings, focusing on terms related to IR and NAFLD. VOSviewer software was used to visualize research trends, collaborations, and key thematic areas. The analysis examined publication type, annual research output, contributing countries and institutions, funding agencies, journal impact factors, citation patterns, and highly cited references.
RESULTS
This analysis identified 23124 documents on NAFLD, revealing a significant increase in the number of publications between 1999 and 2022. The search retrieved 715 papers on IR and NAFLD, including 573 (80.14%) articles and 88 (12.31%) reviews. The most productive countries were China ( = 134; 18.74%), the United States ( = 122; 17.06%), Italy ( = 97; 13.57%), and Japan ( = 41; 5.73%). The leading institutions included the Università degli Studi di Torino, Italy ( = 29; 4.06%), and the Consiglio Nazionale delle Ricerche, Italy ( = 19; 2.66%). The top funding agencies were the National Institute of Diabetes and Digestive and Kidney Diseases in the United States ( = 48; 6.71%), and the National Natural Science Foundation of China ( = 37; 5.17%). The most active journals in this field were (27 publications), the (17 publications), and the and (13 publications). The main research hotspots were "therapeutic approaches for IR and NAFLD" and "inflammatory and high-fat diet impacts on NAFLD".
CONCLUSION
This is the first bibliometric analysis to examine the relationship between IR and NAFLD. In response to the escalating global health challenge of NAFLD, this research highlights an urgent need for a better understanding of this condition and for the development of intervention strategies. Policymakers need to prioritize and address the increasing prevalence of NAFLD.
PubMed: 38948442
DOI: 10.4254/wjh.v16.i6.951 -
World Journal of Hepatology Jun 2024Non-alcoholic fatty liver disease (NAFLD) was the term first used to describe hepatic steatosis in patients with the metabolic syndrome who did not consume excess...
Non-alcoholic fatty liver disease (NAFLD) was the term first used to describe hepatic steatosis in patients with the metabolic syndrome who did not consume excess amounts of alcohol. Alcoholic liver disease (ALD) has many similarities to NAFLD in both pathogenesis and histology. This entity is now the most prevalent chronic liver disease worldwide as a consequence of the epidemic of obesity. Attempts to incorporate the importance of the metabolic syndrome in the development of steatosis resulted in the renaming of NAFLD as metabolic-associated fatty liver disease. This new term, however, has the disadvantage of the use of terms that may be perceived as derogatory. The terms fatty and non-alcoholic have negative connotations in many cultures. In addition, non-alcoholic is not usually a term applicable to pediatric cases of hepatic steatosis. Recently, an international collaborative effort, with participants from 56 countries, after a global consultation process, recommended to change the nomenclature to steatotic liver disease -including metabolic dysfunction- associated steatotic liver disease, metabolic-associated steatohepatitis and metabolic dysfunction-associated ALD. The new terminology is consistent with most of the previously published epidemiological studies and will have a major impact on research into diagnosis, prognosis and treatment.
PubMed: 38948440
DOI: 10.4254/wjh.v16.i6.863 -
World Journal of Hepatology Jun 2024Sarcopenia and metabolic dysfunction associated steatotic liver disease (MASLD) are closely intertwined. Sarcopenia, traditionally a disease of the older adult and...
Sarcopenia and metabolic dysfunction associated steatotic liver disease (MASLD) are closely intertwined. Sarcopenia, traditionally a disease of the older adult and chronic disease population, has been closely studied as one of the pathophysiologic conditions at play in the development of MASLD. They share similar risk factors of insulin resistance and physical inactivity. Given similar pathophysiology along the liver-muscle axis, sarcopenia has been studied as a risk factor for MASLD, and vice versa. Current research suggests a bidirectional relationship. Given the chronicity of MASLD as a chronic inflammatory liver disease, it can break down muscle mass and lead to sarcopenia, while sarcopenia promotes intramuscular lipid accumulation that releases cytokines that can aggravate inflammation in the liver. However, for the longest time, a lack of consensus definition for MASLD and sarcopenia made it difficult to study their relationship and outcomes. A recent nomenclature update to diagnosing MASLD has made it easier for researchers to identify cohorts for study. However, no gold standard technique to measure muscle mass or consensus sarcopenia definition has been identified yet. Future studies are needed to reach a consensus and reduce diagnostic variation. With similar pathophysiology and shared risk factors between the two diseases, future research may also identify potential therapeutic targets along the liver-muscle axis that would benefit both sarcopenia and MASLD in order to maximize their outcomes.
PubMed: 38948439
DOI: 10.4254/wjh.v16.i6.871 -
World Journal of Hepatology Jun 2024The gut microbiota is of growing interest to clinicians and researchers. This is because there is a growing understanding that the gut microbiota performs many different...
The gut microbiota is of growing interest to clinicians and researchers. This is because there is a growing understanding that the gut microbiota performs many different functions, including involvement in metabolic and immune processes that are systemic in nature. The liver, with its important role in detoxifying and metabolizing products from the gut, is at the forefront of interactions with the gut microbiota. Many details of these interactions are not yet known to clinicians and researchers, but there is growing evidence that normal gut microbiota function is important for liver health. At the same time, factors affecting the gut microbiota, including nutrition or medications, may also have an effect through the gut-liver axis.
PubMed: 38948437
DOI: 10.4254/wjh.v16.i6.878