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Osteoporosis is a metabolic bone disorder for which treatment options include antiresorptive therapies (e.g., bisphosphonates, denosumab); anabolics (e.g., teriparatide, abaloparatide); and dual mechanisms (e.g., romosozumab). Management of osteoporosis with concurrent antiresorptive and anabolic agents may be superior to monotherapy, as demonstrated in the DATA trial with the combination of denosumab and teriparatide. However, there is limited experience with the combination of denosumab and romosozumab, which may be an alternative antiresorptive/anabolic regimen for individuals who are not candidates for PTH receptor agonists. In this case, we present a young man with glucocorticoid-induced osteoporosis who could not tolerate a daily injectable anabolic and who experienced improvement in bone mineral density with concurrent denosumab and off-label romosozumab administration. [ABSTRACT FROM AUTHOR]

Neonatal diabetes mellitus is a rare disorder of glucose metabolism with onset within the first 6 months of life. The initial treatment is based on insulin infusion. The technologies for diabetes treatment can be very helpful, even if guidelines are still lacking. The current study aimed to provide a comprehensive review of the literature about the safety and efficacy of insulin treatment with technology for diabetes to support clinicians in the management of infants with neonatal diabetes mellitus. A total of 22 papers were included, most of them case reports or case series. The first infants with neonatal diabetes mellitus treated with insulin pumps were described nearly two decades ago. Over the years, continuous glucose monitoring systems were added to treat these individuals, allowing for a better customization of insulin administration. Insulin was diluted in some cases to further minimize the doses. Improvement in technology for diabetes prompted clinicians to use new devices and algorithms for insulin delivery in infants with neonatal diabetes as well. These systems are safe and effective, may shorten hospital stay, and help clinicians weaning insulin during the remission phase in the transient forms or switching from insulin to sulfonylurea when suggested by the molecular diagnosis. New technologies for insulin delivery in infants with neonatal diabetes can be used safely and closed-loop algorithms can work properly in these situations, optimizing blood glucose control. [ABSTRACT FROM AUTHOR]

Remnant cholesterol (RC), a key indicator of dyslipidemia, has been validated as a contributing factor to metabolic and cardiovascular diseases, both of which are closely associated with kidney stones (KS). This study aimed to investigate the association between RC and the risk of KS in Chinese adults. A total of 8,576 KS cases (mean age 55.87, 69.37% male) and 137,523 controls (mean age 54.57, 51.62% male) were included in this case-control study. RC was calculated using the formula: RC = TC-HDL-LDL. KS was ascertained with ultrasound by well-trained physicians. Multivariable logistic and restricted cubic spline (RCS) were applied to investigate the relationship between RC and KS. A total of 146,099 subjects (weighted mean age 54.64 years and 52.66% male) were included with mean RC = 0.8 for controls and RC = 0.72 for KS cases (P < 0.001). The multivariable-adjusted OR for KS occurrence across consecutive quartiles was 1.00 (reference), 1.05 (0.98–1.12), 1.15 (1.07–1.22), and 1.44 (1.35–1.53), respectively. Moreover, each standard deviation increment of RC was associated with a 15% (OR:1.15, 95% CI: 1.12–1.19) higher risk of KS occurrence. RCS showed significant and linear dose-response relationships between RC and KS occurrence (P-overall < 0.001, P-nonlinear = 0.270). The positive associations between RC and KS risk persisted in sensitivity analyses, suggesting the robustness of the results. In this case-control study of Chinese adults, elevated RC was associated with the occurrence of KS. [ABSTRACT FROM AUTHOR]

Obesity is a global health issue that is intricately linked to the development and progression of chronic liver disease (CLD). This bidirectional connection, coupled with the obesity paradox (OP), presents a management dilemma. The established influence of obesity on the development and progression of chronic liver disease (CLD) is surpassed by the liver's impact on the onset and advancement of obesity. Patients with CLD always experience increased energy expenditure, reduced appetite, and low protein synthesis, all of which might lead to weight loss. However, metabolic disturbances, hormonal imbalances, inflammatory signaling, immobility, drugs, and alterations in nutrient metabolism can contribute to the development and exacerbation of obesity. Despite the propagation of the OP concept, none of the guidelines has changed, recommending being overweight. Research bias and confounders might be the lifebuoy explanation. Additionally, overlooking the lethal morbidities of obesity for survival benefits full of suffering seems to be an illogical idea. Therefore, rather than endorsing an overweight status, emphasis should be placed on improving cardiorespiratory fitness and preventing sarcopenia to achieve better outcomes in patients with CLD. Accordingly, the complex interplay between obesity, CLD, and the concept of OP requires a sophisticated individualized management approach. Maximizing cardiorespiratory fitness and mitigating sarcopenia should be considered essential strategies for attaining the most favourable outcomes in patients with chronic liver disease (CLD). [ABSTRACT FROM AUTHOR]

This study aimed to address the diagnostic challenges in distinguishing between alcohol-related liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD). We utilized whole-slide imaging technology to conduct a comprehensive digital analysis of liver specimens collected from patients undergoing transplantation. This study included 36 and 17 patients with ALD and MASLD cirrhosis, respectively, who underwent transplantation at our institution. Digital slides were analyzed for fibrosis patterns using FibroNest™. Patient background characteristics were comparable between ALD (n = 36) and MASLD (n = 17) groups, except for sex. The ALD group exhibited thicker collagen per strand, longer and more flexural fibrosis, and a more heterogeneous distribution than the MASLD group. In patients with ALD and concomitant metabolic dysfunction, fiber distribution became relatively uniform, resembling MASLD. Application of the phenotypic fibrosis composite score achieved 100% sensitivity and specificity for ALD/MASLD diagnosis. Digital pathological analysis of the fibrosis patterns showed morphological differences between ALD and MASLD. This approach holds promise for histological differentiation, providing valuable insights beyond the current definitions based solely on alcohol intake. This study emphasizes the potential of digital pathology in refining the diagnostic criteria for hepatic disorders. [ABSTRACT FROM AUTHOR]

Active vitamin D, known for its role in promoting osteoporosis, has immunomodulatory effects according to the latest evidence. Eldecalcitol (ED-71) is a representative of the third-generation novel active vitamin D analogs, and its specific immunological mechanisms in ameliorating diabetic osteoporosis remain unclear. We herein evaluated the therapeutic effects of ED-71 in the context of type 2 diabetes mellitus (T2DM), delving into its underlying mechanisms. In a T2DM mouse model, ED-71 attenuated bone loss and marrow adiposity. Simultaneously, it rectified imbalanced glucose homeostasis and dyslipidemia, ameliorated pancreatic β-cell damage and hepatic glycolipid metabolism disorder. Subsequently, in mice injected with the Treg cell-depleting agent CD25, we observed that the beneficial effects of ED-71 mentioned earlier were partially contingent on the Treg subsets ratio. Mechanistically, ED-71 promoted the differentiation of CD4+ T cells into Treg subsets, facilitating Ca2+ influx and the expression of ORAI1 and STIM1, pivotal proteins in store-operated Ca2+ entry (SOCE). The SOCE inhibitor, 2-APB, partially attenuated the positive effects of ED-71 observed in the above results. Overall, ED-71 regulates SOCE-mediated Treg cell differentiation, accomplishing the dual purpose of simultaneously ameliorating diabetic osteoporosis and glucolipid metabolic disorders, showcasing its potential in osteoimmunity therapy and interventions for diseases involving SOCE. [ABSTRACT FROM AUTHOR]

M1 macrophages induce protective immunity against infection, but also contribute to metabolic and inflammatory diseases. Here we show that the E3 ubiquitin ligase, MDM2, promotes the glycolytic and inflammatory activities of M1 macrophage by increasing the production of IL-1β, MCP-1 and nitric oxide (NO). Mechanistically, MDM2 triggers the ubiquitination and degradation of E3 ligase, SPSB2, to stabilize iNOS and increases production of NO, which s-nitrosylates and activates HIF-1α for triggering the glycolytic and pro-inflammatory programs in M1 macrophages. Myeloid-specific haplodeletion of MDM2 in mice not only blunts LPS-induced endotoxemia and NO production, but also alleviates obesity-induced adipose tissue-resident macrophage inflammation. By contrast, MDM2 haplodeletion induces higher mortality, tissue damage and bacterial burden, and also suppresses M1 macrophage response, in the cecal ligation and puncture-induced sepsis mouse model. Our findings thus identify MDM2 as an activator of glycolytic and inflammatory responses in M1 macrophages by connecting the iNOS-NO and HIF-1α pathways. Proinflammatory macrophages mediate protective immunity but also contribute to inflammatory diseases. Here the authors show that the E3 ligase, MDM2, induces nitric oxide from macrophage, potentially triggering the s-nitrosylation and activation of HIF-1α for the production of inflammatory cytokines, to protect mice from sepsis but aggravate obesity-induced inflammation. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the independent and joint associations of vitamin B12 and methylmalonic acid (MMA) with all-cause, cardiovascular disease (CVD), and cancer mortality in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: We included 6797 individuals with MASLD from the U.S. National Health and Nutrition Examination Survey. Serum MMA was measured using gas/liquid chromatography-mass spectrometry. Serum vitamin B12 was measured using commercial kits. The separate and joint associations of dietary intake and serum vitamin B12 (cutoff: 400 pg/mL) and MMA (cutoff: 250 nmol/L) levels with mortality were assessed by Cox proportional hazards regression. Results: During a median follow-up of 9.3 years, 1604 deaths were documented, including 438 from CVD and 365 from cancer. In MASLD patients, dietary intake and serum vitamin B12 did not associate with mortality, while MMA was associated with a 1.35-fold increased risk of all-cause mortality (P-trend < 0.001). The adjusted hazard ratios for the joint association of vitamin B12 and MMA with all-cause and CVD mortality were 1 in the B12lowMMAlow group (reference), 1.02 (0.87–1.20) and 1.15 (0.90–1.47) in the B12highMMAlow group, 1.55 (1.29–1.86) and 1.84 (1.28–2.65) in the B12lowMMAhigh group, and 1.82 (1.49–2.21) and 2.28 (1.40–3.71) in the B12highMMAhigh group, respectively. The joint association was modified by serum folate (P-interaction = 0.001). Conclusions: In MASLD patients, MMA rather than dietary and serum vitamin B12 was positively associated with all-cause mortality. The joint effect of high levels of MMA and vitamin B12 showed the strongest associations with all-cause and CVD mortality, with a significant interaction with serum folate. [ABSTRACT FROM AUTHOR]

Obesity is an important healthcare issue caused by abnormally increased adipose tissue because of energy-intake overcoming energy expenditure. Disturbances in the physiological function of adipose tissue mediate the development of diabetes. It is a metabolic disease that results from decreased insulin-levels and/or changes in the insulin action mechanism. Tumor Necrosis Factor-Associated Apoptosis-Inducing Ligand(TRAIL), which is a member of the Tumor Necrosis Factor(TNF)-family with an important role in adipose tissue biology, is included in many studies with its ability to induce apoptosis in cancer cells, but the number of human-studies conducted on the gene related to its protective-role against diabetes and obesity at this level is insufficient. Our study was carried out as a case and control and included three groups (80 diabetic obese, 80 non-diabetic obese, and 80 healthy individuals as the control group). The Real-Time-PZR(RT-qPZR), and DNA Sanger-Sequencing Methods were used for gene expression and gene squences. As a result of the analyses, TRAIL gene expression level was found to be higher in the controls than in the diabetic-obese and non-diabetic-obese group. This change in TRAIL gene expression suggests that TRAIL maybe a protective factor against diabetes. The presence of rs781673405, rs143353036, rs1244378045, rs767450259, rs759369504, rs750556128, and rs369143448 mutations, which was determined with the Sequencing-Method, was shown for the first time in the present study. In addition, it is the first study in which human TRAIL gene-expression and sequencing were performed together. We believe that these data will make an important contribution to the literature. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is strongly associated with type 2 diabetes mellitus (T2DM). The kynurenine and serotonin pathways, as well as chronic low-grade inflammation, are being considered potential links between them. MDD associated with T2DM is less responsive to treatment than that without T2DM; however, the underlying mechanism remains unknown. We aimed to investigate the effects of inflammatory cytokines on the kynurenine and serotonin pathways in patients with comorbid MDD and T2DM and those with only MDD. We recruited 13 patients with comorbid MDD and T2DM and 27 patients with only MDD. We measured interleukin-6 and tumor necrosis factor-α (TNF-α) levels as inflammatory cytokines and metabolites of the kynurenine pathway and examined the relationship between the two. TNF-α levels were significantly higher in patients with comorbid MDD and T2DM than in those with only MDD in univariate (p = 0.044) and multivariate (adjusted p = 0.036) analyses. TNF-α showed a statistically significant effect modification (interaction) with quinolinic acid/tryptophan and serotonin in patients from both groups (β = 1.029, adjusted p < 0.001; β = − 1.444, adjusted p = 0.047, respectively). Limitations attributed to the study design and number of samples may be present. All patients were Japanese with mild to moderate MDD; therefore, the generalizability of our findings may be limited. MDD with T2DM has more inflammatory depression components and activations of the kynurenine pathway by inflammatory cytokines than MDD without T2DM. Hence, administering antidepressants and anti-inflammatory drugs in combination may be more effective in patients with comorbid MDD and T2DM. [ABSTRACT FROM AUTHOR]

Introduction: The human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection presents significant challenges due to the complex interplay between these diseases, leading to exacerbated metabolic disturbances. Understanding these metabolic profiles is crucial for improving diagnostic and therapeutic approaches. Objective: This study aimed to characterise the urinary acylcarnitine and amino acid profiles, including 5-hydroxyindoleacetic acid (5-HIAA), in patients co-infected with HIV and TB using targeted liquid chromatography mass spectrometry (LC–MS) metabolomics. Methods: Urine samples, categorised into HIV, TB, HIV/TB co-infected, and healthy controls, were analysed using HPLC–MS/MS. Statistical analyses included one-way ANOVA and a Kruskal-Wallis test to determine significant differences in the acylcarnitine and amino acid profiles between groups. Results: The study revealed significant metabolic alterations, especially in TB and co-infected groups. Elevated levels of medium-chain acylcarnitines indicated increased fatty acid oxidation, commonly associated with cachexia in TB. Altered amino acid profiles suggested disruptions in protein and glucose metabolism, indicating a shift towards diabetes-like metabolic states. Notably, TB was identified as a primary driver of these changes, affecting protein turnover, and impacting energy metabolism in co-infected patients. Conclusion: The metabolic profiling of HIV/TB co-infection highlights the profound impact of TB on metabolic pathways, which may exacerbate the clinical complexities of co-infection. Understanding these metabolic disruptions can guide the development of targeted treatments and improve management strategies, ultimately enhancing the clinical outcomes for these patients. Further research is required to validate these findings and explore their implications in larger, diverse populations. [ABSTRACT FROM AUTHOR]

Crocin, a natural bioactive compound derived from saffron (Crocus sativus) and other Crocus genera, has gained significant attention recently due to its potential therapeutic properties. The multifaceted nature of crocin's biological effects has piqued the interest of researchers and health enthusiasts, prompting further investigations into its mechanisms of action and therapeutic applications. This review article comprehensively explores the emerging evidence supporting crocin's role as a promising ally in protecting against metabolic disorders. The review covers the molecular mechanisms underlying crocin's beneficial effects and highlights its potential applications in preventing and treating diverse pathological conditions. Understanding the mechanisms through which crocin exerts its protective effects could advance scientific knowledge and offer potential avenues for developing novel therapeutic interventions. As we uncover the potential of crocin as a valuable ally in the fight against disorders, it becomes evident that nature's palette holds remarkable solutions for enhancing our health. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has introduced the medical community to the phenomenon of long COVID, a condition characterized by persistent symptoms following the resolution of the acute phase of infection. Among the myriad of symptoms reported by long COVID sufferers, chronic fatigue, cognitive disturbances, and exercise intolerance are predominant, suggesting systemic alterations beyond the initial viral pathology. Emerging evidence has pointed to mitochondrial dysfunction as a potential underpinning mechanism contributing to the persistence and diversity of long COVID symptoms. This review aims to synthesize current findings related to mitochondrial dysfunction in long COVID, exploring its implications for cellular energy deficits, oxidative stress, immune dysregulation, metabolic disturbances, and endothelial dysfunction. Through a comprehensive analysis of the literature, we highlight the significance of mitochondrial health in the pathophysiology of long COVID, drawing parallels with similar clinical syndromes linked to post-infectious states in other diseases where mitochondrial impairment has been implicated. We discuss potential therapeutic strategies targeting mitochondrial function, including pharmacological interventions, lifestyle modifications, exercise, and dietary approaches, and emphasize the need for further research and collaborative efforts to advance our understanding and management of long COVID. This review underscores the critical role of mitochondrial dysfunction in long COVID and calls for a multidisciplinary approach to address the gaps in our knowledge and treatment options for those affected by this condition. [ABSTRACT FROM AUTHOR]

Currently, accumulating evidence has indicated that overnutrition-associated obesity may result in not only metabolic dysregulations, but also cognitive impairments. This study aimed to investigate the protective effects of Diosmetin, a bioflavonoid compound with multiple biological functions, on cognitive deficits induced by a high fat diet (HFD) and the potential mechanisms. In the present study, oral administration of Diosmetin (25, 50 and 100 mg/kg) for 12 weeks significantly reduced the body weight, restored glucose tolerance and normalized lipid profiles in the serum and liver in HFD-induced obese rats. Diosmetin also significantly ameliorated depression-like behaviors and impaired spatial memory in multiple behavioral tests, including the open field test, elevated plus-maze and Morris water maze, which was in accordance with the decreased pathological changes and neuronal damage in different regions of hippocampus as suggested by H&E and Nissl staining. Notably, our results also indicated that Diosmetin could significantly improve mitochondrial dysfunction induced by HFD through upregulating genes involved in mitochondrial biogenesis and dynamics, increasing mitochondrial ATP levels and inhibiting oxidative stress. Moreover, the levels of key enzymes involved in the TCA cycle were also significantly increased upon Diosmetin treatment. Meanwhile, Diosmetin inhibited HFD-induced microglial overactivation and down-regulated inflammatory cytokines both in the serum and hippocampus. In conclusion, these results indicated that Diosmetin might be a novel nutritional intervention to prevent the occurrence and development of obesity-associated cognitive dysfunction via metabolic regulation and anti-inflammation. [ABSTRACT FROM AUTHOR]

Purpose: Gestational obesity (GO) presents a multifaceted challenge to maternal and fetal health, with an escalating prevalence and far-reaching consequences extending beyond pregnancy. This perspective statement by the Italian Society of Obesity (SIO) provides current insights into the diagnosis, maternal and fetal impacts, and treatment strategies for managing this pressing condition. Methods: This article provides a comprehensive review of the maternal and fetal effects of GO and provides suggestions on strategies for management. Comprehensive review was carried out using the MEDLINE/PubMed, CINAHL, EMBASE, and Cochrane Library databases. Results: The diagnosis of GO primarily relies on pre-pregnancy body mass index (BMI), although standardized criteria remain contentious. Anthropometric measures and body composition assessments offer valuable insights into the metabolic implications of GO. Women with GO are predisposed to several health complications, which are attributed to mechanisms such as inflammation and insulin resistance. Offspring of women with GO face heightened risks of perinatal complications and long-term metabolic disorders, indicating intergenerational transmission of obesity-related effects. While nutritional interventions are a cornerstone of management, their efficacy in mitigating complications warrants further investigation. Additionally, while pharmacological interventions have been explored in other contexts, evidence on their safety and efficacy specifically for GO remains lacking, necessitating further investigation. Conclusion: GO significantly impacts maternal and fetal health, contributing to both immediate and long-term complications. Effective management requires a multifaceted approach, including precise diagnostic criteria, personalized nutritional interventions, and potential pharmacological treatments. These findings underscore the need for individualized care strategies and further research to optimize outcomes for mothers and their offspring are needed. Enhanced understanding and management of GO can help mitigate its intergenerational effects, improving public health outcomes. Level of evidence: Level V narrative review. [ABSTRACT FROM AUTHOR]

Background: Metabolic dysfunction-associated steatotic liver (MASLD) disease is the commonest hepatic cause of liver fibrosis and cirrhosis after the introduction of the direct acting antivirals and eradication of hepatitis C. MASLD is usually associated with metabolic syndrome and elevated inflammatory markers. Magnetic resonance spectroscopy (MRS) offers a non-invasive diagnostic, alternative to liver biopsy. This is a case–control diagnostic-accuracy study conducted on 40 patients in the Hepato-gastroenterology Unit in the Internal Medicine Department, Ain Shams University Hospitals, to study the role of MRI spectroscopy as a new diagnostic model for assessment of liver steatosis in non-diabetic MASLD patients compared to the standard ultrasound and clinical criteria. MASLD was diagnosed by a combination of a validated ultrasound hepatic steatosis score grading system and hepatic steatosis index using clinical and laboratory parameters. MRS was performed in all patients and fat peak, water peak, and fat fraction % were measured, and diagnostic accuracy of different MRS is compared to the US scoring and different laboratory and clinical parameters. To our knowledge this is the first study conducted on MRS in our region and Egypt. Results: This study revealed no statistically significant difference between the two groups regarding HbA1C, creatinine, while there was highly statistically significant difference regarding fasting blood sugar, 2 h post-prandial glucose level, urine albumin, and low-density lipoprotein levels. Hepatic steatosis score grading by abdominal ultrasound on the 20 controls showed no fatty changes with grade 0 (50%), and on the 20 MASLD patients showed that 2 cases were grade 1 steatosis (5%), 9 cases were grade 2 steatosis (22.5%), and 9 cases were grade 3 steatosis (22.5%). The diagnostic accuracy of predicting hepatic steatosis using different MRS parameters: fat peak, water peak, and fat fraction had area under the curve of 99.9%, 88.6%, and 100%, respectively. The sensitivity and specificity of fat fraction in detecting hepatic steatosis were 100%. The sensitivity and specificity of the fat peak in detecting hepatic steatosis were 100% and 95%, respectively. Moreover, the sensitivity and specificity of the water peak in detecting the hepatic steatosis were 88.6% and 85%, respectively. There is a statistically significant correlation between the three MRS parameters and the abdominal ultrasound hepatic steatosis score grades. Conclusion: MRS parameters: fat fraction, fat peak, and water peak, have high diagnostic accuracy for predicting the liver steatosis. Moreover, MRS has the added advantage of being a non-invasive and a tool with low radiation risk. MRS also shows the metabolic changes in the liver and could be an eligible outcome in therapeutic clinical trials. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction associated fatty liver disease (MAFLD) is a common cause of liver disease in children and adolescents. The relationship between insulin resistance (IR) and MAFLD in children with short stature remains largely unknown. The present study was to investigate the relationship between the triglyceride–glucose (TyG) index and alanine aminotransferase (ALT) levels in children with short stature. A total of 1754 children with short stature were enrolled. Anthropometric, biochemical and hormonal indexes were collected through physical measurement examinations and laboratory tests. A nonlinear association was found between the TyG index and ALT. The inflection point of the curve was at a TyG index of 8.24. In multivariate piecewise linear regression, only when the TyG index was greater than 8.24 was there a significant positive association between the TyG index and ALT (β 5.75, 95% CI 3.30, 8.19; P < 0.001). However, when the TyG index was less than 8.24, there was no significant association between the TyG index and ALT (β −0.57, 95% CI −1.84, 0.71; P = 0.382). This study demonstrated a nonlinear relationship between TyG index and ALT in children with short stature. This finding suggests that a high TyG index is associated with elevated ALT in children with short stature. [ABSTRACT FROM AUTHOR]

Thoracic cancers comprise non-small cell lung cancers (NSCLCs), small cell lung cancers (SCLCs) and malignant pleural mesotheliomas (MPM). Collectively, they account for the highest rate of death from malignancy worldwide. Genomic instability is a universal feature of cancer, which fuels mutations and tumour evolution. Deficiencies in DNA damage response (DDR) genes amplify genomic instability. Homologous recombination deficiency (HRD), resulting from BRCA1/BRCA2 inactivation, is exploited for therapeutic synthetic lethality with poly-ADP ribose polymerase (PARP) inhibitors in breast and ovarian cancers, as well as in prostate and pancreatic cancers. However, DDR deficiency and its therapeutic implications are less well established in thoracic cancers. Emerging evidence suggests that a subset of thoracic cancers may harbour DDR deficiency and may, thus, be effectively targeted with DDR agents. Here, we review the current evidence surrounding DDR in thoracic cancers and discuss the challenges and promise for achieving clinical benefit with such therapeutics. [ABSTRACT FROM AUTHOR]

Understanding the biological mechanisms behind multimorbidity patterns in adolescence is important as they may act as intermediary risk factor for long-term health. We aimed to explore relationship between prenatal exposures and adolescent's psycho-cardiometabolic intermediary traits mediated through epigenetic biomarkers, using structural equation modeling (SEM). We used data from mother–child dyads from pregnancy and adolescents at 16–17 years from two prospective cohorts: Northern Finland Birth Cohort 1986 (NFBC1986) and Raine Study from Australia. Factor analysis was applied to generate two different latent factor structures: (a) prenatal exposures and (b) adolescence psycho-cardiometabolic intermediary traits. Furthermore, three types of epigenetic biomarkers were included: (1) DNA methylation score for maternal smoking during pregnancy (DNAmMSS), (2) DNAm age estimate PhenoAge and (3) DNAm estimate for telomere length (DNAmTL). Similar factor structure was observed between both cohorts yielding three prenatal factors, namely BMI (Body Mass Index), SOP (Socio-Obstetric-Profile), and Lifestyle, and four adolescent factors: Anthropometric, Insulin-Triglycerides, Blood Pressure, and Mental health. In the SEM pathways, stronger direct effects of F1prenatal-BMI (NFBC1986 = β: 0.27; Raine = β: 0.39) and F2prenatal-SOP (β: −0.11) factors were observed on adolescent psycho-cardiometabolic multimorbidity. We observed an indirect effect of prenatal latent factors through epigenetic markers on a psycho-cardiometabolic multimorbidity factor in Raine study (P < 0.05). The present study exemplifies an evidence-based approach in two different birth cohorts to demonstrate similar composite structure of prenatal exposures and psycho-cardiometabolic traits (despite cultural, social, and genetic differences) and a common plausible pathway between them through underlying epigenetic markers. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) is the most common metabolic disorder among women of reproductive age. Many factors are involved in the development of PCOS, among which genetic predisposition is probably the main contributor that is also influenced by lifestyle and environmental factors. This study aims to determine the prevalence of PCOS in different continents based on Rotterdam, AES and NIH diagnostic criteria. Methods: We conducted a systematic review and meta-analysis to evaluate the prevalence of polycystic ovary syndrome in women according to (Preferred Reporting Items for Systematic Review and Meta-Analysis) PRISMA guidelines. PubMed, Scopus, Science Direct, Web of Science and Google Scholar databases were comprehensively searched until February 2021 for relevant articles. Heterogeneity between the studies was assessed using the I2 index. Begg and Mazumdar's test was used to evaluate publication bias. Results: A total of 35 studies with 12,365,646 subjects were retrieved. The mean age ranged from 10–45 years. Global prevalence of PCOS was 9.2% (95% CI: 6.8–12.5%) based on meta-analysis, our results showed that the global prevalence of PCOS was 5.5% (95% CI: 3.9–7.7%) based on NIH criteria, 11.5 (95% CI: 6.6–19.4) based on Rotterdam criteria, and 7.1% (95% CI: 2.3–20.2%) based on AES criteria. According to self-report subgroup analysis, the prevalence of PCOS was found to be 11% (95% CI: 5.2–21.8%). Conclusion: Based on the results of the present study, the prevalence of PCOS in the world was 9.2% (95% CI: 6.8–12.5%). According to the results of the present study and the high prevalence of PCOS, especially in the Africa continent, it is necessary for health systems to implement measures to timely prevent and treat this syndrome. [ABSTRACT FROM AUTHOR]

Obesity has a pivotal and multifaceted role in pain associated with osteoarthritis (OA), extending beyond the mechanistic influence of BMI. It exerts its effects both directly and indirectly through various modifiable risk factors associated with OA-related pain. Adipose tissue dysfunction is highly involved in OA-related pain through local and systemic inflammation, immune dysfunction, and the production of pro-inflammatory cytokines and adipokines. Adipose tissue dysfunction is intricately connected with metabolic syndrome, which independently exerts specific effects on OA-related pain, distinct from its association with BMI. The interplay among obesity, adipose tissue dysfunction and metabolic syndrome influences OA-related pain through diverse pain mechanisms, including nociceptive pain, peripheral sensitization and central sensitization. These complex interactions contribute to the heightened pain experience observed in individuals with OA and obesity. In addition, pain management strategies are less efficient in individuals with obesity. Importantly, therapeutic interventions targeting obesity and metabolic syndrome hold promise in managing OA-related pain. A deeper understanding of the intricate relationship between obesity, metabolic syndrome and OA-related pain is crucial and could have important implications for improving pain management and developing innovative therapeutic options in OA. In this Review, the authors explore the complex interactions between osteoarthritis-related pain and obesity, adipose tissue dysfunction and metabolic syndrome, and discuss how knowledge of these relationships could help improve pain management and identify new therapeutic options. Key points: Obesity serves as an important risk factor for pain in osteoarthritis (OA) and is associated with all modifiable risk factors related to OA-related pain. Adipose tissue dysfunction has a specific role in OA-related pain independently of BMI. Serum and synovial fluid levels of leptin are closely associated with OA-related pain after adjustment for BMI, whereas the role of adiponectin in OA pain is controversial. Metabolic syndrome is associated with OA-related pain independently of BMI. Obesity modulates nociceptive, neuropathic-like and nociplastic pain through neuromodulators and both peripheral and central sensitization. Therapeutics used in the treatment of obesity and metabolic syndrome could also hold promise for the management of OA-related pain, particularly GLP1R agonists. [ABSTRACT FROM AUTHOR]

Thrombin inhibition suppresses adiposity, WAT inflammation and metabolic dysfunction in mice. Protease-activated receptor (PAR)1 does not account for thrombin-driven obesity, so we explored the culprit role of PAR4 in this context. Male WT and PAR-4-/- mice received a high fat diet (HFD) for 8 weeks, WT controls received standard chow. Body fat was quantified by NMR. Epididymal WAT was assessed by histology, immunohistochemistry, qPCR and lipase activity assay. 3T3-L1 preadipocytes were differentiated ± thrombin, acutely stimulated ± PAR4 activating peptide (AP) and assessed by immunoblot, qPCR and U937 monocyte adhesion. Epicardial adipose tissue (EAT) from obese and lean patients was assessed by immunoblot. PAR4 was upregulated in mouse WAT under HFD. PAR4-/- mice developed less visceral adiposity and glucose intolerance under HFD, featuring smaller adipocytes, fewer macrophages and lower expression of adipogenic (leptin, PPARγ) and pro-inflammatory genes (CCL2, IL-1β) in WAT. HFD-modified activity and expression of lipases or perilipin were unaffected by PAR4 deletion. 3T3-L1 adipocytes differentiated with thrombin retained Ki67 expression, further upregulated IL-1β and CCL2 and were more adhesive for monocytes. In mature adipocytes, PAR4-AP increased phosphorylated ERK1/2 and AKT, upregulated Ki67, CCl2, IL-β and hyaluronan synthase 1 but not TNF-α mRNA, and augmented hyaluronidase-sensitive monocyte adhesion. Obese human EAT expressed more PAR4, CD68 and CD54 than lean EAT. PAR4 upregulated in obesity supports adipocyte hypertrophy, WAT expansion and thrombo-inflammation. The emerging PAR4 antagonists provide a therapeutic perspective in this context beyond their canonical antiplatelet action. [ABSTRACT FROM AUTHOR]

Purpose: Sleeve gastrectomy (SG) is the most performed metabolic and bariatric surgery (MBS). However, with the increase of SG in different regions, recurrent weight gain after SG is challenging for bariatric surgeons. We introduce a modified operation with a long, narrow pouch in RYGB (LN-RYGB) for weight regain after SG which enhanced the restrictive function in RYGB. Methods and Results: The LN-RYGB has a longer and narrow gastric pouch for 10 cm. The length of small Roux and biliopancreatic are the same as RYGB. As a revisional surgery, the post-1 year excess weight loss percentage (%EWL) was 63.1% and total weight loss percentage (%TWL) was 29.1% in 5 cases. Conclusion: LN-RYGB is an optional treatment for recurrent weight gain after SG; a randomized control trial is needed to verify the long-term effect of LN-RYGB. [ABSTRACT FROM AUTHOR]

Congenital portosystemic shunts (CPSS) are rare congenital vascular anomalies characterized by abnormal connections between the portal vein and systemic circulation, bypassing the liver. They can lead to complications such as recurrent encephalopathy, liver nodules, portopulmonary hypertension, and neurocognitive issues due to hyperammonemia and rarely kidney involvement. Hepatic hemodynamic changes can lead to liver nodules and hepatocellular carcinoma, particularly in extrahepatic shunts. We describe here an 11-year-old girl with type 1 intrahepatic portosystemic shunt with focal nodular hyperplasia in the liver, presenting with nephrotic syndrome that was diagnosed as membranoproliferative glomerulonephritis on kidney biopsy and that responded partially to therapy with immunosuppressants. [ABSTRACT FROM AUTHOR]

Our study aims to investigate whether Macleaya cordata extracts (MCE) could alleviate the adverse reactions caused by a high-fat (HF) diet in Marsupenaeus japonicus. Three experimental treatments including a control group (CG, 8.06% lipid), HF group (14.76% lipid), and HF group supplemented with 1200 mg/kg Macleaya cordata extract (HFG + MCE) were designed. The results showed that growth performance was not influenced (P > 0.05) by different diet treatments after a 42-day feeding trial. Compared with the control group, the HF group significantly decreased (P < 0.05) the activities of antioxidant enzymes in the serum and hepatopancreas. Expression of antioxidant-related genes was synchronously decreased (P < 0.05), while hsp70 gene expression was increased (P < 0.05) in the hepatopancreas. Hepatopancreatic glycolipid metabolism was upregulated (P < 0.05), which could be identified by lipid/glycogen content and gene expression. Compared with the HC group, the HC + MCE group significantly alleviated HC-induced oxidative stress, which was identified by the increased (P < 0.05) antioxidant enzyme activities and gene expression. Meanwhile, hepatopancreatic glycolipid metabolism was downregulated (P < 0.05). In conclusion, dietary supplementation with MCE could alleviate HF-induced damage of antioxidant capacity and immune function and alleviate the disorder of glycolipid metabolism in M. japonicus. [ABSTRACT FROM AUTHOR]

Background: Cervical cancer is a prevalent malignancy and an important health concern worldwide. Recent research has highlighted the potential impact of metabolic factors, such as hyperlipidemia and diabetes, on cancer progression, increased mortality, and patient outcomes. However, insufficient data have been reported regarding their relationship with cervical cancer. This study aimed to investigate the relationships between metabolic disorders, including dyslipidemia, dysglycemia, and metabolic syndrome, and survival in patients with cervical cancer. Methods: We retrospectively analyzed demographic information, clinical characteristics, and metabolic health indicators of patients with cervical cancer. Patients were categorized into groups based on specific metabolic conditions: high triglyceride, high low-density lipoprotein, high cholesterol, and diabetes groups. Additionally, the presence of metabolic syndrome and other metabolic comorbidities was recorded. The log-rank test was used to compare survival rates between different patient groups and identify associated risk factors. Survival curves generated via the Cox proportional hazards model were used to evaluate the associations between metabolic parameters and survival. Results: The Cox proportional hazards model was used to analyze data from 840 patients with cervical cancer between 28 and 72 years old who underwent surgery. The hazard ratio (HR) of mortality was 1.804 (95% CI 1.394–2.333, p < 0.001) in the high-density lipoprotein group, 0.758 (95% CI 0.558 to 1.030, p < 0.001) in the high-triglyceride group, 1.794 (95% CI 1.304–2.470, p < 0.001) in the high low-density lipoprotein group, and 0.011 (95% CI 0.005–0.025, p < 0.001) in the diabetes group. These factors were significantly associated with reduced survival in patients with cervical cancer, and these associations persisted after adjusting for age, cancer stage, treatment type, and the presence of metabolic syndrome or other comorbidities. Conclusion: This study highlights the importance of metabolic health and the significance of controlling metabolic disorders, including hyperlipidemia, diabetes, and metabolic syndrome, to improve survival outcomes in patients with cervical cancer. Future research should explore the impact of managing multiple metabolic conditions on the prognosis of these patients. [ABSTRACT FROM AUTHOR]

Background: With the fast pace of modern life, people have less time for meals, but few studies have examined the association between the habit of fast eating and metabolic diseases. Objective: Combining the results of the current study and the prior ones, we aimed to investigate the possible relationship between fast eating and the risk of metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: This is a sub-analysis of a multicenter cross-sectional study of 1965 participants investigated the association between fast eating and MASLD in Chinese. Fast eating was defined as meal time less than five minutes and participants were divided into three categories based on their self-reported frequency of fast eating: ≤1 time/month, ≤1 time/week and ≥2 times/week. We further conducted a literature search for available studies published before November, 2023 as well as a meta-analysis to investigate the association between fast eating and MASLD. Results: The proportion of MASLD was 59.3%, 50.5%, and 46.2% in participants with fast eating ≥2 times/week, ≤1 time/week and ≤1 time/month, respectively (P for trend <0.001). The frequency of fast eating was independently associated with risk of MASLD after multiple adjustment for sex, age, demographics, smoking and drinking status, BMI and clinical metabolic parameters (OR, 1.29; 95%CI, 1.09–1.53). Participants who ate fast frequently (≥2 times/week) had 81% higher risk of MASLD (P = 0.011). A meta-analysis of five eligible studies confirmed that frequent fast eating was associated with increased risk of MASLD (pooled OR, 1.22; 95%CI, 1.07–1.39). Conclusions: Frequent fast eating was associated with an increased risk of MASLD. [ABSTRACT FROM AUTHOR]

Advanced glycation end-products (AGEs) formation increases with metabolic disorders, leading to higher serum AGE levels in patients with progressive vascular complications. Measuring AGE levels in biological samples requires multiple pre-analytical processing steps, rendering analysis of multiple samples challenging. This study evaluated the progression of diabetic complications by analyzing AGE levels using a pre-analytical processing strategy based on a fully automated solid phase-extraction system. Serum samples from patients with diabetes, with or without macrovascular complications (Mac or non-Mac) or microvascular complications (Mic or non-Mic), were processed with the established methods. Free and total AGE levels in sera were measured using liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS). In patients with diabetes, both free and total AGE levels were elevated in those with complications compared to those without complications. In Mac and Mic groups, free and total AGE levels and z-scores (the sum of normalized AGE levels) also increased. AGE z-scores were markedly higher than those of single AGE levels in distinguishing each complication. Our study demonstrated that the free AGE z-score, measured using a new analytical method without hydrolysis, correlated with the presence of vascular complications and may serve as a marker of disease complications. [ABSTRACT FROM AUTHOR]

Fecal microbial transplantation (FMT) offers promise for treating ulcerative colitis (UC), though the mechanisms underlying treatment failure are unknown. This study harnessed longitudinally collected colonic biopsies (n = 38) and fecal samples (n = 179) from 19 adults with mild-to-moderate UC undergoing serial FMT in which antimicrobial pre-treatment and delivery mode (capsules versus enema) were assessed for clinical response (≥ 3 points decrease from the pre-treatment Mayo score). Colonic biopsies underwent dual RNA-Seq; fecal samples underwent parallel 16S rRNA and shotgun metagenomic sequencing as well as untargeted metabolomic analyses. Pre-FMT, the colonic mucosa of non-responsive (NR) patients harbored an increased burden of bacteria, including Bacteroides, that expressed more antimicrobial resistance genes compared to responsive (R) patients. NR patients also exhibited muted mucosal expression of innate immune antimicrobial response genes. Post-FMT, NR and R fecal microbiomes and metabolomes exhibited significant divergence. NR metabolomes had elevated concentrations of immunostimulatory compounds including sphingomyelins, lysophospholipids and taurine. NR fecal microbiomes were enriched for Bacteroides fragilis and Bacteroides salyersiae strains that encoded genes capable of taurine production. These findings suggest that both effective mucosal microbial clearance and reintroduction of bacteria that reshape luminal metabolism associate with FMT success and that persistent mucosal and fecal colonization by antimicrobial-resistant Bacteroides species may contribute to FMT failure. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a chronic disorder of glucose metabolism that threatens several organs, including the submandibular (SMG) salivary glands. Antox (ANX) is a strong multivitamin with significant antioxidant benefits. The goal of this study was to demonstrate the beneficial roles of ANX supplementation in combination with insulin in alleviating diabetic SMG changes. For four weeks, 30 rats were divided into equal five groups (n = 6): (1) control group; (2) diabetic group (DM), with DM induced by streptozotocin (STZ) injection (50 mg/kg i.p.); (3) DM + ANX group: ANX was administrated (10 mg/kg/day/once daily/orally); (4) DM + insulin group: insulin was administrated 1U once/day/s.c.; and (5) DM + insulin + ANX group: co-administrated insulin. The addition of ANX to insulin in diabetic rats alleviated hyposalivation and histopathological alterations associated with diabetic rats. Remarkably, combined ANX and insulin exerted significant antioxidant effects, suppressing inflammatory and apoptotic pathways associated with increased salivary advanced glycation end-product (AGE) production and receptor for advanced glycation end-product expression (RAGE) activation in diabetic SMG tissues. Combined ANX and insulin administration in diabetic rats was more effective in alleviating SMG changes (functions and structures) than administration of insulin alone, exerting suppressive effects on AGE production and frustrating RAGE downstream pathways. [ABSTRACT FROM AUTHOR]

The level of ROS (fluorescent probe 2',7'-dichlorodihydrofluorescein diacetate) and lipid content (fluorescent lipophilic dye Nile Red) in the peripheral blood monocyte fraction from patients with type 1 diabetes mellitus and healthy volunteers were assessed by flow cytofluorimetry. The number of CD36+ monocytes was assessed using specific antibodies. In patients with type 1 diabetes mellitus, the levels of ROS and intracellular lipids in monocytes and the number of cells expressing CD36 fatty acid translocase were elevated. These results indicate metabolic changes in the peripheral blood cells of patients with carbohydrate metabolism disorders and can be considered as possible prognostic markers for the development of type 1 diabetes mellitus complications. [ABSTRACT FROM AUTHOR]

Purpose: Maternal high-fat diet (HF) programs obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), hypertriglyceridemia, and hyperglycemia associated with increased endocannabinoid system (ECS) in the liver of adult male rat offspring. We hypothesized that maternal HF would induce sex specific ECS changes in the liver of newborn rats, prior to obesity onset, and maternal fish oil (FO) supplementation would reprogram the ECS and lipid metabolism markers preventing liver triglycerides (TG) accumulation. Methods: Female rats received a control (CT) (10.9% fat) or HF (28.7% fat) diet 8 weeks prior to mating and during pregnancy. A subgroup of HF dams received 3% FO supplementation in the HF diet (35.4% fat) during pregnancy (HFFO). Serum hormones and liver TG, ECS, lipid metabolism, oxidative stress and autophagy markers were assessed in male and female newborn offspring. Results: Maternal HF diet increased liver cannabinoid receptor 1 (CB1) in males and decreased CB2 in females, with no effect on liver TG. Maternal FO supplementation reduced liver CB1 regardless of the offspring sex, but reduced TG liver content only in females. FO reduced the liver content of the endocannabinoid anandamide in males, and the content of 2-arachidonoylglycerol in both sexes. Maternal HF increased lipogenic and decreased lipid oxidation markers, and FO induced the opposite regulation in the liver of offspring. Conclusion: Prenatal HF and FO differentially modulate liver ECS in the offspring before obesity and MASLD development. These results suggest that maternal nutrition at critical stages of development can modulate the offspring's ECS, predisposing or preventing the onset of metabolic diseases. [ABSTRACT FROM AUTHOR]

Uniparental disomy (UPD) is the inheritance of both homologues of a chromosome from only one parent. The detection of UPDs in sequencing data is not well established and a common gap in genetic diagnostics. We applied our in-house UPD detection pipeline to evaluate a cohort of 9212 samples, including multigene panels as well as exome sequencing data in a single, duo or trio constellation. We used the results to inform the design of our publicly available web app altAFplotter. UPDs categorized as heterodisomy, whole chromosome or segmental isodisomy were identified and validated with microsatellites, multiplex ligation-dependent probe amplification as well as Sanger sequencing. We detected 14 previously undiagnosed UPDs including nine isodisomies, four segmental isodisomies as well as one heterodisomy on chromosome 22. We characterized eight findings as potentially causative through homozygous pathogenic variants or imprinting disorders. Overall, our study demonstrates the utility of our UPD detection pipeline with our web app, altAFplotter, to reliably identify UPDs. This not only increases the diagnostic yield of cases with growth and metabolic disturbances, as well as developmental delay, but also enhances the understanding of UPDs that may be relevant for recurrence risks and genetic counseling. [ABSTRACT FROM AUTHOR]

Purpose of Review: The recent surge in inflammatory bowel disease (IBD) cases has paralleled a significant rise in obesity and metabolic comorbidities rates. In this article, we explore the potential influence of obesity and associated metabolic comorbidities on disease progression, complications, treatment response, surgical outcomes, health economics, and the potential impact of obesity treatment on the course of IBD. Findings: Contrary to visceral adiposity, obesity does not consistently result in an increased risk of IBD-related complications. Patients with IBD have a higher risk of acute arterial events, likely linked to systemic inflammation. Substantial evidence suggests that obesity has a negative impact on the response to IBD treatment, with this effect being most thoroughly studied in biologics and immunomodulators. The rates of overall complications and post-operative infections are higher in patients who are obese. There are limited but promising data regarding the impact of weight loss techniques, including exercise, medications, and bariatric interventions, on the outcomes in IBD. Both obesity and diabetes have adverse effects on the overall quality of life and place an increased financial burden on the IBD population. Summary: A growing body of evidence indicates a connection between obesity and associated metabolic comorbidities and negative outcomes in IBD, yet further efforts are required to fully understand this relationship. [ABSTRACT FROM AUTHOR]

Obesity is associated with changes in the gut microbiota, as well as with increased permeability of the intestinal wall. In 130 non-obese volunteers, 57 patients with metabolically healthy obesity (MHO), and 76 patients with metabolically unhealthy obesity (MUHO), bacterial DNA was isolated from stool samples, and the 16S rRNA gene was sequenced. The metabolic profile of the microbiota predicted by PICRUSt2 (https://huttenhower.sph.harvard.edu/picrust/) was more altered in patients with MUHO than MHO. Obesity, especially MUHO, was accompanied by an increase in the ability of the gut microbiota to degrade energy substrates, produce energy through oxidative phosphorylation, synthesize water-soluble vitamins (B1, B6, B7), nucleotides, heme, aromatic amino acids, and protective structural components of cells. Such changes may be a consequence of the microbiota adaptation to the MUHO-specific conditions. Thus, a vicious circle is formed, when MUHO promotes the depletion of the gut microbiome, and further degeneration of the latter contributes to the pathogenesis of metabolic disorders. The concentration of the trefoil factor family (TFF) in the serum of the participants was also determined. In MHO and MUHO patients, the TFF2 and TFF3 levels were increased, but we did not find significant associations of these changes with the metabolic profile of the gut microbiota. [ABSTRACT FROM AUTHOR]

Diabetes is a metabolic disease that seriously endangers human health, and monitoring glucose levels is one of the main diagnostic methods for its prevention and treatment. In this paper, we propose a high-performance glucose sensor based on the Sagnac interferometer (SI) utilizing photonic crystal fiber (PCF) with micro-holes. By setting two columns of micro-holes in the center of the PCF, the high birefringence effect is obtained to improve the detection sensitivity. All air holes are assumed to fill with the glucose solution, and the sensing characteristics of the PCF sensor are theoretically studied by the finite element method (FEM). The results show that the sensitivity and resolution of the PCF glucose sensor can reach 4.14 nm/(g/L) and 0.48 mg/dL within the concentration range of 0–120 g/L, respectively. In addition, the effects of the partial-filling methods and PCF structural parameters on the sensing performance are also analyzed to achieve optimal performance. The proposed glucose sensor possesses high sensitivity and simple structure, which exhibits good application prospects in the field of medical monitoring. [ABSTRACT FROM AUTHOR]

Functional genetics has identified drug targets for metabolic disorders. Opioid use impacts metabolic homeostasis, although mechanisms remain elusive. Here, we explore the OPRD1 gene (encoding delta opioid receptor, DOP) to understand its impact on type 2 diabetes. Large-scale sequencing of OPRD1 and in vitro analysis reveal that loss-of-function variants are associated with higher adiposity and lower hyperglycemia risk, whereas gain-of-function variants are associated with lower adiposity and higher type 2 diabetes risk. These findings align with studies of opium addicts. OPRD1 is expressed in human islets and beta cells, with decreased expression under type 2 diabetes conditions. DOP inhibition by an antagonist enhances insulin secretion from human beta cells and islets. RNA-sequencing identifies pathways regulated by DOP antagonism, including nerve growth factor, circadian clock, and nuclear receptor pathways. Our study highlights DOP as a key player between opioids and metabolic homeostasis, suggesting its potential as a therapeutic target for type 2 diabetes. Opioid use impacts metabolic homeostasis, although the mechanisms remain elusive. Here, the authors explore the OPRD1 gene (encoding the delta opioid receptor, DOP) to understand its impact on type 2 diabetes and highlight DOP as a key player between opioids and metabolic homeostasis. [ABSTRACT FROM AUTHOR]

The transition to adult health care (HCT, Health Care Transition), is the purposeful, planned movement of patients from paediatric to adult services. For the adolescent living with obesity (ALwO), the HCT represents a crucial window for effective intervention that can help improve body weight, adiposopathy, and metabolic complications. Nevertheless, no transition guidelines, models, and tools have been developed for these patients. The present statement of the Italian Society of Obesity examines the critical transition of ALwO from paediatric to adult healthcare. It synthesises current knowledge and identifies gaps in HCT of ALwO. Drawing on successful practices and evidence-based interventions worldwide, the paper explores challenges, including disparities and barriers, while advocating for patient and family involvement. Additionally, it discusses barriers and perspectives within the Italian health care scenario. The need for specialised training for healthcare providers and the impact of transition on healthcare policies are also addressed. The conclusions underscore the significance of well-managed transitions. The SIO recognises that without proper support during this transition, ALwOs risk facing a gap in healthcare delivery, exacerbating their condition, and increasing the likelihood of complications. Addressing this gap requires concerted efforts to develop effective transition models, enhance healthcare provider awareness, and ensure equitable access to care for all individuals affected by obesity. The document concludes by outlining avenues for future research and improvement. [ABSTRACT FROM AUTHOR]

The World Health Organization recently declared 2021–2030 the decade of healthy aging. Such emphasis on healthy aging requires an understanding of the biologic challenges aging populations face. Physical frailty is a syndrome of vulnerability that puts a subset of older adults at high risk for adverse health outcomes including functional and cognitive decline, falls, hospitalization, and mortality. The physiology driving physical frailty is complex with age-related biological changes, dysregulated stress response systems, chronic inflammatory pathway activation, and altered energy metabolism all likely contributing. Indeed, a series of recent studies suggests circulating metabolomic distinctions can be made between frail and non-frail older adults. For example, marked restrictions on glycolytic and mitochondrial energy production have been independently observed in frail older adults and collectively appear to yield a reliance on the highly fatigable ATP-phosphocreatine (PCr) energy system. Further, there is evidence that age-associated impairments in the primary ATP generating systems (glycolysis, TCA cycle, electron transport) yield cumulative deficits and fail to adequately support the ATP-PCr system. This in turn may acutely contribute to several major components of the physical frailty phenotype including muscular fatigue, weakness, slow walking speed and, over time, result in low physical activity and accelerate reductions in lean body mass. This review describes specific age-associated metabolic declines and how they can collectively lead to metabolic inflexibility, ATP-PCr reliance, and the development of physical frailty. Further investigation remains necessary to understand the etiology of age-associated metabolic deficits and develop targeted preventive strategies that maintain robust metabolic health in older adults. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction associated-steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH) is the liver manifestation of metabolic syndrome, which is characterized by insulin resistance, hyperglycemia, hypertension, dyslipidemia, and/or obesity. Environmental pollutant exposure has been recently identified as a risk factor for developing MASH. Heterocyclic amines (HCAs) are mutagens generated when cooking meat at high temperatures or until well-done. Recent epidemiological studies reported that dietary HCA exposure may be linked to insulin resistance and type II diabetes, and we recently reported that HCAs induce insulin resistance and glucose production in human hepatocytes. However, no previous studies have examined the effects of HCAs on hepatic lipid homeostasis. In the present study, we assessed the effects of two common HCAs, MeIQx (2-amino-3, 8-dimethylimidazo [4, 5-f] quinoxaline) and PhIP (2-amino-1-methyl-6-phenylimidazo[4, 5-b] pyridine), on lipid homeostasis in cryopreserved human hepatocytes. Exposure to a single concentration of 25 μM MeIQx or PhIP in human hepatocytes led to dysregulation of lipid homeostasis, typified by significant increases in lipid droplets and triglycerides. PhIP significantly increased expression of lipid droplet-associated genes, PNPLA3 and HSD17B13, and both HCAs significantly increased PLIN2. Exposure to MeIQx or PhIP also significantly increased expression of several key genes involved in lipid synthesis, transport and metabolism, including FASN, DGAT2, CPT1A, SCD, and CD36. Furthermore, both MeIQx and PhIP significantly increased intracellular cholesterol and decreased expression of PON1 which is involved in cholesterol efflux. Taken together, these results suggest that HCAs dysregulate lipid production, metabolism, and storage. The current study demonstrates, for the first time, that HCA exposure may lead to fat accumulation in hepatocytes, which may contribute to hepatic insulin resistance and MASH. [ABSTRACT FROM AUTHOR]

The lack of an appropriate preclinical model of metabolic dysfunction-associated steatotic liver disease (MASLD) that recapitulates the whole disease spectrum impedes exploration of disease pathophysiology and the development of effective treatment strategies. Here, we develop a mouse model (Streptozotocin with high-fat diet, STZ + HFD) that gradually develops fatty liver, metabolic dysfunction-associated steatohepatitis (MASH), hepatic fibrosis, and hepatocellular carcinoma (HCC) in the context of metabolic dysfunction. The hepatic transcriptomic features of STZ + HFD mice closely reflect those of patients with obesity accompanying type 2 diabetes mellitus, MASH, and MASLD-related HCC. Dietary changes and tirzepatide administration alleviate MASH, hepatic fibrosis, and hepatic tumorigenesis in STZ + HFD mice. In conclusion, a murine model recapitulating the main histopathologic, transcriptomic, and metabolic alterations observed in MASLD patients is successfully established. Metabolic dysfunction-associated steatotic liver disease (MASLD) characterizes a spectrum of liver disorders initiated by hepatic lipid accumulation associated with metabolic syndrome. Here, the authors generate a mouse model that recapitulates the main histopathologic, transcriptomics, and metabolic alterations observed in MASLD patients. [ABSTRACT FROM AUTHOR]

Background: The gut microbiota (GM) and their metabolites have garnered significant attention for their roles in metabolic syndrome (MetS) and associated conditions. MetS, characterized by a cluster of metabolic abnormalities, significantly increases the risk of cardiovascular disease (CVD), obesity, insulin resistance, and type 2 diabetes mellitus (T2DM). The dysbiosis of gut microbiota, marked by changes in microbial composition and function, has been implicated in the pathogenesis of MetS. Main body: This review synthesizes recent findings elucidating the influence of GM composition and microbiota-derived metabolites on MetS pathogenesis and progression. Notably, alterations in GM composition and dysregulation of metabolites such as short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), polyamines, amino acids, and indole derivatives have been implicated in MetS development. These metabolites play crucial roles in metabolic processes, and their imbalance can trigger or exacerbate metabolic disturbances associated with MetS. Various therapeutic approaches, including dietary interventions, probiotics, prebiotics, and precision medicine targeting specific metabolites, offer promising strategies for managing MetS. These interventions aim to restore a healthy GM balance and regulate the production of beneficial metabolites. Conclusion: The complexity of GM interactions and their systemic effects necessitate more standardized research methodologies. Future investigations focusing on personalized therapeutic interventions and non-invasive diagnostic tools are warranted to address the complexities of MetS management. Advancing our understanding of the GM-metabolite-MetS axis will be crucial for developing effective, targeted treatments and improving patient outcomes in MetS. [ABSTRACT FROM AUTHOR]

Mentha haplocalyx essential oil (MEO) has demonstrated inhibitory effects on Fusarium oxysporum. Despite its environmentally friendly properties as a natural product, the limited water solubility of MEO restricts its practical application in the field. The use of nanoemulsion can improve bioavailability and provide an eco-friendly approach to prevent and control Panax notoginseng root rot. In this study, Tween 80 and anhydrous ethanol (at a mass ratio of 3) were selected as carriers, and the ultrasonic method was utilized to produce a nanoemulsion of MEO (MNEO) with an average particle size of 26.07 nm. Compared to MTEO (MEO dissolved in an aqueous solution of 2% DMSO and 0.1% Tween 80), MNEO exhibited superior inhibition against F. oxysporum in terms of spore germination and hyphal growth. Transcriptomics and metabolomics results revealed that after MNEO treatment, the expression levels of certain genes related to glycolysis/gluconeogenesis, starch and sucrose metabolism were significantly suppressed along with the accumulation of metabolites, leading to energy metabolism disorder and growth stagnation in F. oxysporum. In contrast, the inhibitory effect from MTEO treatment was less pronounced. Furthermore, MNEO also demonstrated inhibition on meiosis, ribosome function, and ribosome biogenesis in F. oxysporum growth process. These findings suggest that MNEO possesses enhanced stability and antifungal activity, which effectively hinders F. oxysporum through inducing energy metabolism disorder, meiotic stagnation, as well as ribosome dysfunction, thus indicating its potential for development as a green pesticide for prevention and control P. notoginseng root rot caused by F.oxyosporum. [ABSTRACT FROM AUTHOR]

Risk prediction for subsequent cardiovascular events remains an unmet clinical issue in patients with coronary artery disease. We aimed to investigate prognostic metabolic biomarkers by considering both shared and distinct metabolic disturbance associated with the composite and individual cardiovascular events. Here, we conducted an untargeted metabolomics analysis for 333 incident cardiovascular events and 333 matched controls. The cardiovascular events were designated as cardiovascular death, myocardial infarction/stroke and heart failure. A total of 23 shared differential metabolites were associated with the composite of cardiovascular events. The majority were middle and long chain acylcarnitines. Distinct metabolic patterns for individual events were revealed, and glycerophospholipids alteration was specific to heart failure. Notably, the addition of metabolites to clinical markers significantly improved heart failure risk prediction. This study highlights the potential significance of plasma metabolites on tailed risk assessment of cardiovascular events, and strengthens the understanding of the heterogenic mechanisms across different events. Investigating metabolic disturbances in coronary artery disease (CAD) may allow the identifications of new prognostic biomarkers. Here the authors perform a metabolomics study to highlight the shared and distinct metabolites characterizing risks of several cardiovascular events in CAD patients. [ABSTRACT FROM AUTHOR]

Brown and brown-like adipose tissues have attracted significant attention for their role in metabolism and therapeutic potential in diabetes and obesity. Despite compelling evidence of an interplay between adipocytes and lymphocytes, the involvement of these tissues in immune responses remains largely unexplored. This study explicates a newfound connection between neuroinflammation and brown- and bone marrow adipose tissue. Leveraging the use of [18F]F-AraG, a mitochondrial metabolic tracer capable of tracking activated lymphocytes and adipocytes simultaneously, we demonstrate, in models of glioblastoma and multiple sclerosis, the correlation between intracerebral immune infiltration and changes in brown- and bone marrow adipose tissue. Significantly, we show initial evidence that a neuroinflammation-adipose tissue link may also exist in humans. This study proposes the concept of an intricate immuno-neuro-adipose circuit, and highlights brown- and bone marrow adipose tissue as an intermediary in the communication between the immune and nervous systems. Understanding the interconnectedness within this circuitry may lead to advancements in the treatment and management of various conditions, including cancer, neurodegenerative diseases and metabolic disorders. A mitochondrial PET tracer, [18F]FAraG, enabled visualization of a cooccurrence of neuroinflammation and metabolic changes in brown- and bone marrow adipose tissue in glioblastoma and multiple sclerosis models, as well as in post-acute COVID subjects. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to explore the relationship between oral contraceptive use and blood pressure values and in a national cohort of women adolescents and to investigate the level of coexistence of the high blood pressure levels, dyslipidemia or insulin resistance. Methods: This is a retrospective cohort study that evaluated data form 14,299 adolescents aged 14 to 17 years. Crude and race-and age-adjusted analyses were performed using Poisson regression to estimate the prevalence ratios. Data clustering analysis was performed using machine learning approaches supported by an unsupervised neural network of self-organizing maps. Results: We found that 14.5% (n = 2076) of the women adolescents use oral contraceptives. Moreover, an increased prevalence of high blood pressure, dyslipidemia, and insulin resistance (all P < 0.001) was observed among adolescents who use oral contraceptives as compared to those who do not. Our analysis also showed that 2.3% of adolescents using oral contraceptives had both high blood pressure levels and dyslipidemia, whereas 3.2% had high blood pressure levels combined with insulin resistance (all P < 0.001). The algorithmic investigative approach demonstrated that total cholesterol, LDLc, HDLc, insulin, and HOMA-IR were the most predicted variables to assist classificatory association in the context of oral contraceptive use among women adolescents with high blood pressure. Conclusions: These findings suggest that oral contraceptives were associated with an increased prevalence of high blood pressure, dyslipidemia, and insulin resistance among women adolescents. Although the indication of this therapy is adequate to avoid unintended pregnancies, their use must be based on rigorous individual evaluation and under constant control of the cardiometabolic risk factors. [ABSTRACT FROM AUTHOR]

Prolonged adaptation of ancestors of indigenous peoples of the Far North of Asia and America to extreme natural and climatic conditions of the Arctic has resulted in changes in genes controlling various metabolic processes. However, most genetic variability observed in the Eskimo and Paleoasians (the Chukchi and Koryaks) is related to adaptation to the traditional Arctic diet, which is rich in lipids and proteins but extremely poor in plant carbohydrates. The results of population genetic studies have demonstrated that specific polymorphic variants in genes related to lipid metabolism (CPT1A, FADS1, FADS2, and CYB5R2) and carbohydrate metabolism (AMY1, AMY2A, and SI) are prevalent in the Eskimo and Paleoasian peoples. When individuals deviate from their traditional dietary patterns, the aforementioned variants of genetic polymorphism can lead to the development of metabolic disorders. American Eskimo-specific variants in genes related to glucose metabolism (TBC1D and ADCY) significantly increase the risk of developing type 2 diabetes. These circumstances indicate the necessity for a large-scale genetic testing of indigenous population of the Far North and the need to study the biochemical and physiological consequences of genetically determined changes in the activity of enzymes of lipid and carbohydrate metabolism. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are a heterogeneous population of membrane-bound nanoparticles (< 1 µm in size) secreted by various cell types. Most of EVs circulating in human blood are derived from platelets, leukocytes, erythrocytes, and endotheliocytes. The composition of circulating adipocyte-derived EVs under various pathological conditions has been virtually unknown. Small EVs were isolated by ultrafiltration and double ultracentrifugation from blood plasma of patients with colorectal cancer (CRC) and colonic polyps with obesity or metabolic syndrome. The composition of adipocyte-derived EVs was analyzed by immunoprecipitation combined with Western blotting and flow cytometry. EVs fractions (FABP4- and CD11b-immunoprecipitated EVs, as well as EVs contained in the supernatant after removal of CD11b-positive EVs) contained a complex of adipocyte markers (FABP4, PPAR-γ, perilipin 1). In CRC patients without obesity, monocyte/macrophage-derived EVs precipitated on CD11b-coated particles were characterized by a combined overexpression of FABP4 and perilipin 1, while such an overexpression was not typical for CRC patients with metabolic syndrome or obesity. The fraction of true adipocyte-derived EVs (supernatant after removal of CD11b-positive EVs) was characterized by the presence of a complex of adipocyte markers with a predominant expression of FABP4 in all patients both with metabolic syndrome/metabolically healthy obesity and without metabolic disorders. To correctly characterize circulating EVs in patients without obesity, it is necessary first to remove the fraction of CD11b-positive monocyte/macrophage-derived EVs from EV preparations by immunoprecipitation or similar methods, and then, after removal/sorption of precipitated EVs, to analyze the composition of adipocyte-derived EVs in the supernatant using a set of above-mentioned adipocyte markers. Moreover, in patients with metabolic disorders, given the insignificant FABP4 expression in CD11b-immunoprecipitated EVs, the pre-depletion of EV preparations does not appear to be that necessary. [ABSTRACT FROM AUTHOR]

Background: Children's urinary system stones may develop from environmental, metabolic, anatomical, and other causes. Our objective is to determine the recurrence and prognosis, demographic, clinical, and etiological characteristics of children with urolithiasis. Methods: Medical records of patients were evaluated retrospectively. Patients' demographic data and medical history, serum/urine biochemical and metabolic analysis, blood gas analysis, stone analysis, imaging findings, and medical/surgical treatments were recorded. Results: The study included 364 patients (male 187). Median age at diagnosis was 2.83 (IQR 0.83–8.08) years. The most common complaints were urinary tract infection (23%) and urine discoloration (12%). Sixty-two percent had a family history of stone disease. At least one metabolic disorder was found in 120 (88%) of 137 patients having all metabolic analyses: hypercalciuria was found in 45%, hypocitraturia in 39%, and hyperoxaluria in 37%. Anatomical abnormalities were detected in 18% of patients. Of 58 stones analyzed, 65.5% were calcium and 20.6% were cystine stones. Stone recurrence rate was 15% (55/364). Older age (> 5 years), family history of stone disease, stone size (≥ 5 mm), and urinary system anatomical abnormalities were significantly associated with stone recurrence (p = 0.027, p = 0.031, p < 0.001, and p < 0.001, respectively). In adjusted logistic regression analysis, stone size ≥ 5 mm (OR 4.85, 95% CI 2.53–9.3), presence of urinary system anatomical abnormalities (OR 2.89, 95% CI 1.44–5.78), and family history of stone disease (OR 2.41, 95% CI 1.19–4.86) had increased recurrence rate. Conclusions: All children with urolithiasis should be evaluated for factors affecting stone recurrence. Children at higher risk of recurrence need to be followed carefully. [ABSTRACT FROM AUTHOR]

Epidemiological data demonstrate strong associations between psoriasis and metabolic comorbidities, including obesity, hypertension, diabetes mellitus, dyslipidemia, and non-alcoholic fatty liver disease. The presence of metabolic comorbidities significantly influences the selection and effectiveness of pharmacological treatments. Some drugs should be prescribed with caution in patients with metabolic comorbidities because of an increased risk of adverse events, while others could have a reduced effectiveness. The aim of this narrative review is to highlight the challenges that healthcare professionals may face regarding the management of psoriasis in patients with metabolic comorbidities. In the first part of the article, the epidemiological association between psoriasis and metabolic comorbidities and their pathogenetic mechanisms is summarized. The second part describes the efficacy and safety profile of conventional and biologic drugs in patients with selected metabolic comorbidities including obesity, non-alcoholic fatty liver disease/hepatic steatosis, and diabetes. Finally, the role of pharmacological and non-pharmacological interventions, such as diet, alcohol abstinence, physical activity, and smoking avoidance is discussed. In conclusion, the choice of the best approach to manage patients with psoriasis with metabolic comorbidities should encompass both tailored pharmacological and individualized non-pharmacological interventions. [ABSTRACT FROM AUTHOR]