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Purpose To assess adherence to the US Liver Imaging Reporting and Data System (LI-RADS) recommendations for hepatocellular carcinoma (HCC) surveillance and associated patient-level factors in a vulnerable, diverse patient sample. Materials and Methods The radiology report database was queried retrospectively for patients who underwent US LI-RADS-based surveillance examinations at a single institution between June 1, 2020, and February 28, 2021. Initial US and follow-up liver imaging were included. Sociodemographic and clinical data were captured from electronic medical records. Adherence to radiologist recommendation was defined as imaging (US, CT, or MRI) follow-up in 5-7 months for US-1, imaging follow-up in 3-6 months for US-2, and CT or MRI follow-up in 2 months for US-3. Descriptive analysis and multivariable modeling that adjusted for age, sex, race, and time since COVID-19 pandemic onset were performed. Results Among 936 patients, the mean age was 59.1 years; 531 patients (56.7%) were male and 544 (58.1%) were Asian or Pacific Islander, 91 (9.7%) were Black, 129 (13.8%) were Hispanic, 147 (15.7%) were White, and 25 (2.7%) self-reported as other race. The overall adherence rate was 38.8% (95% CI: 35.7, 41.9). The most common liver disease etiology was hepatitis B (60.6% [657 of 936 patients]); 19.7% of patients (183 of 936) had current or past substance use disorder, and 44.8% (416 of 936) smoked. At adjusted multivariable analysis, older age (odds ratio [OR], 1.20; P = .02), male sex (OR, 1.62; P = .003), hepatology clinic attendance (OR, 3.81; P < .001), and recent prior US examination (OR, 2.44; P < .001) were associated with full adherence, while current smoking (OR, 0.39; P < .001) was negatively associated. Conclusion Adherence to HCC imaging surveillance was suboptimal, despite US LI-RADS implementation. Keywords: Liver, Ultrasound, Screening, Abdomen/GI, Cirrhosis, Metabolic Disorders, Socioeconomic Issues Supplemental material is available for this article. © RSNA, 2024.

Dipeptidyl peptidase 4 (DPP-4) is a promising biomarker for cancer and metabolic diseases. We demonstrate the design of novel fluorescent DPP-4 probes based on the protease's native substrates using a thioamide as a quencher for measuring in vitro kinetics, inhibition with sitagliptin, and DPP-4 activity in saliva samples. [ABSTRACT FROM AUTHOR]

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a ubiquitous neurotrophic factor that exhibits a variety of physiological functions and plays a critical role in the exploitation of therapeutic potential across a range of diseases, including cardiovascular disorders, nervous system diseases, metabolic imbalances, and cancers. In the context of cardiac diseases, MANF significantly promotes cardiomyocyte survival and improves cardiac functionality. Furthermore, MANF not only provides neuroprotection by shielding neurons from damage and promoting nerve regeneration in neurological disorders, but also involves in insulin resistance, lipid metabolism disturbances and fat-containing liver lesions. However, the oncogenic or tumor suppressive function of MANF in cancer remains unclear, requiring further investigation to elucidate its precise role in the process of cancer initiation and progression. This review aims to summarize the latest advancements in understanding the molecular pathways, intricate mechanisms, and therapeutic potential of MANF in the prevention and treatment of various diseases, emphasizing its multifaceted contributions to health and disease management. [ABSTRACT FROM AUTHOR]

Resistant dextrin (RD) is a kind of glucan extracted and processed from starch. It has been approved as a Generally Recognized as Safe food which has a promising future. However, there is less comprehensive basic and applied information about RD. Therefore, this paper presents the progress of research on the preparation and purification methods, physicochemical properties, physiological activities and applications of RD, with a focus on highlighting its physiological activities and potential mechanisms of action. The aim is to provide theoretical references for the comprehensive development and utilization of RD in the fields of functional foods and medicinal foods, so that RD can be better applied in the treatment of chronic metabolic diseases. [ABSTRACT FROM AUTHOR]

Background and Purpose: Antipsychotics such as olanzapine are associated with significant metabolic dysfunction, attributed to gut microbiome dysbiosis. A recent notion that most psychotropics are detrimental to the gut microbiome has arisen from consistent findings of metabolic adverse effects. However, unlike olanzapine, the metabolic effects of lurasidone are conflicting. Thus, this study investigates the contrasting effects of olanzapine and lurasidone on the gut microbiome to explore the hypothesis of 'gut neutrality' for lurasidone exposure. Experimental Approach: Using Sprague–Dawley rats, the effects of olanzapine and lurasidone on the gut microbiome were explored. Faecal and blood samples were collected weekly over a 21‐day period to analyse changes to the gut microbiome and related metabolic markers. Key Results: Lurasidone triggered no significant weight gain or metabolic alterations, instead positively modulating the gut microbiome through increases in mean operational taxonomical units (OTUs) and alpha diversity. This novel finding suggests an underlying mechanism for lurasidone's metabolic inertia. In contrast, olanzapine triggered a statistically significant decrease in mean OTUs, substantial compositional variation and a depletion in short‐chain fatty acid abundance. Microbiome depletion correlated with metabolic dysfunction, producing a 30% increase in weight gain, increased pro‐inflammatory cytokine expression, and increased blood glycaemic and triglyceride levels. Conclusion and Implications: Our results challenge the notion that all antipsychotics disrupt the gut microbiome similarly and highlights the potential benefits of gut‐neutral antipsychotics, such as lurasidone, in managing metabolic side effects. Further research is warranted to validate these findings in humans to guide personalised pharmacological treatment regimens for schizophrenia. [ABSTRACT FROM AUTHOR]

The human gut microbiota plays numerous roles in regulating host growth, the immune system, and metabolism. Age-related changes in the gut environment lead to chronic inflammation, metabolic dysfunction, and illness, which in turn affect aging and increase the risk of neurodegenerative disorders. Local immunity is also affected by changes in the gut environment. Polyamines are crucial for cell development, proliferation, and tissue regeneration. They regulate enzyme activity, bind to and stabilize DNA and RNA, have antioxidative properties, and are necessary for the control of translation. All living organisms contain the natural polyamine spermidine, which has anti-inflammatory and antioxidant properties. It can regulate protein expression, prolong life, and improve mitochondrial metabolic activity and respiration. Spermidine levels experience an age-related decrease, and the development of age-related diseases is correlated with decreased endogenous spermidine concentrations. As more than just a consequence, this review explores the connection between polyamine metabolism and aging and identifies advantageous bacteria for anti-aging and metabolites they produce. Further research is being conducted on probiotics and prebiotics that support the uptake and ingestion of spermidine from food extracts or stimulate the production of polyamines by gut microbiota. This provides a successful strategy to increase spermidine levels. [ABSTRACT FROM AUTHOR]

Chronic kidney disease-mineral and bone disorder (CKD-MBD) are recognized as a systemic disease affecting the prognosis of patients with CKD. Proper management of CKD-MBD is important to improve the prognosis of patients with CKD. Although proteinuria is recognized as a poor prognostic factor in these patients, few reports have examined its association with CKD-MBD. We examined the association between proteinuria and CKD-MBD using data from the Japan Chronic Kidney Disease Database Extension (J-CKD-DB-Ex). Among the patients registered in the J-CKD-DB-Ex, 30,977 with CKD stages G2–G5 who had serum creatinine, albumin, calcium, and phosphate concentrations measured at least once and urinalysis performed were included. The patients were divided into four groups (negative, 1+, 2+, and 3+) according to the degree of proteinuria. The association between proteinuria and CKD-MBD was examined by a logistic regression analysis. In a model adjusted for age, sex, diabetes, and the estimated glomerular filtration rate (eGFR), the odds ratio of the 3 + group compared with the negative group significantly increased to 2.67 (95% confidence interval, 2.29–3.13) for hyperphosphatemia, 2.68 (1.94–3.71) for hypocalcemia, and 1.56 (1.24–1.98) for hypomagnesemia. Proteinuria is associated with hyperphosphatemia, hypocalcemia, and hypomagnesemia in patients with CKD independently of eGFR. [ABSTRACT FROM AUTHOR]

SUMMARY Peroxisomes house diverse metabolic pathways that are essential for plant and animal survival, including enzymes that produce or inactivate toxic byproducts. Despite the importance of peroxisomes and their collaborations with other organelles, the mechanisms that trigger or prevent peroxisome turnover and the cellular impacts of impaired peroxisomes are incompletely understood. When Arabidopsis thaliana LON2, a peroxisomal protein with chaperone and protease capacity, is disrupted, metabolic dysfunction and protein instability in peroxisomes ensue. Paradoxically, preventing autophagy in lon2 mutants appears to normalize peroxisomal metabolism and stabilize peroxisomal proteins—hinting at a role for autophagy in causing the peroxisomal defects observed in lon2 seedlings. Using a combination of transcriptomics, proteomics, and in silico investigations, we compared wild type to lon2 and autophagy null mutants and double mutants. Through this analysis, we found that impeding autophagy via an atg2 null mutation alleviated several of the global defects observed when LON2 is absent. Moreover, we revealed processes influenced by LON2 that are independent of autophagy, including impacts on lipid droplet and chloroplast protein levels. Finally, we identified and classified potential LON2 substrates, which include proteins that might provide signal(s) for pexophagy. [ABSTRACT FROM AUTHOR]

Congenital disorders of glycosylation (CDG) are a family of rare inherited metabolic disorders. This study aimed to examine the carbohydrate-deficient transferrin (CDT) screening results of 1,328 patients with suspected CDG by using transferrin- high pressure liquid chromatography (Tf- HPLC) method and to evaluate the performance of the method as a reference diagnostic tool.Relative CDT levels (CDT concentrations expressed as percent of total transferrin) were determined in serum samples by HPLC. The method sensitivity, specificity and positive predictive value (PPV) were further calculated.Abnormal transferrin isoform profile consistent with CDG Type-I and CDG Type-II were determined in 50 cases; in 44 cases asiolo-Tf (7.63 ± 5.44 %) and disialo-Tf (36.29 ± 9.04 %), in six cases monosialo-Tf (3.95 ± 0.95 %) and trisialo-Tf (25.05 ± 4.46 %) were determined and decreased tetrasialo-Tf (49.75 ± 11.59 %) was identified in all cases. Two cases having abnormal CDT pattern were molecularly diagnosed with hereditary fructose intolerance and galactosemia and 11 cases diagnosed with CDG based on clinical and molecular analysis showed a normal pattern. The sensitivity, specificity and positive predictive values of Tf-HPLC method were 81.96 %, 99% and 96 %, respectively.Tf-HPLC is a useful, highly sensitive, cost-advantageous and reliable method for the detection and preliminary diagnosis of CDG for laboratories working with large sample series. [ABSTRACT FROM AUTHOR]

Background: G1, a specific agonist targeting the G protein–coupled receptor 30 (GPR30), has demonstrated significant involvement in combating obesity and regulating glucose homeostasis. Nevertheless, the beneficial effects of G1 treatment have solely been investigated in animal models under normal feeding conditions, leaving its therapeutic potential in high‐fat feeding scenarios unexplored. Material and Methods: To address this gap, our study employed an ovariectomized high‐fat diet mouse model to assess the therapeutic effects of G1 in combating obesity and metabolic dysfunction. Results: The findings revealed that G1 treatment resulted in weight loss, but concurrently led to increased blood glucose levels and insulin resistance. Treatment with G1 resulted in an amplification of fat mobilization and an enhancement of pyruvate carboxylase activity in mice fed a high‐fat diet. Moreover, the combined impact of G1 treatment and a high‐fat diet on pyruvate metabolism, as well as the regulation of crucial gluconeogenesis enzymes such as pyruvate dehydrogenase kinase 4 (PDK4), phosphoenolpyruvate carboxykinase (PEPCK), and glucose transporter 2 (GLUT2), expedites the elevation of blood glucose and the progression of insulin resistance. Conclusions: These findings indicate that G1 treatment is influenced by a high‐fat diet, potentially disrupting glucolipid metabolism and promoting insulin resistance alongside its antiobesity effects. Consequently, further investigation is imperative to thoroughly explore this potential toxic side effect of G1 therapy. [ABSTRACT FROM AUTHOR]

Background: Obesity is associated with an increased risk of reflux esophagitis (RE). Metabolic abnormalities have been implicated in the pathogenesis of RE. However, the role of metabolic status in the risk of RE among individuals with varying degrees of obesity remains unclear. Therefore, our study aimed to assess the association between metabolic obesity phenotypes and the risk of RE. Methods: This study included a cohort of 24,368 participants aged 18 years and older who underwent upper gastrointestinal endoscopy at the First Affiliated Hospital of Dalian Medical University during health checkups between January 1, 2008, and December 31, 2021. Among these participants, a total of 9,947 individuals were classified into four groups based on their obesity phenotype: metabolically healthy normal weight (MHNW), metabolically healthy obesity (MHO), metabolically unhealthy normal weight (MUNW), and metabolically unhealthy obesity (MUO). To account for potential confounding factors, multivariate logistic regression analysis was applied to examine the association between metabolic obesity phenotypes and the risk of RE, with stratification by sex and age. Results: Among all participants, the MUNW, MHO, and MUO groups demonstrated a higher risk of RE when compared to the MHNW group. After controlling for all confounding factors, the MUO group exhibited the highest risk, with an odds ratio (OR) of 3.723 (95% CI: 2.751–5.040) in males and 5.482 (95% CI: 4.080–7.367) in females. The prevalence of RE increased in proportion to the number of metabolic risk factors. Subgroup analyses, which accounted for all confounders, revealed that the MHO, MUNW, and MUO phenotypes were associated with an elevated risk of RE in individuals under 60 years old as well as those over 60 years old. Interestingly, a more comprehensive analysis indicated that obesity may have a greater effect on the risk of RE than metabolic disorders. Conclusions: Both metabolic disorders and obesity were associated with an increased risk of RE. The effect of obesity on RE prevalence may be stronger than that of metabolic disorders, emphasizing the significance of obesity regardless of metabolic health status. Clinical interventions should address not only obesity but also metabolic disorders in order to reduce the risk of RE. [ABSTRACT FROM AUTHOR]

Modern lifestyle changes, especially the consumption of a diet high in salt, sugar, and fat, have contributed to the increasing incidence and prevalence of chronic metabolic diseases such as diabetes, obesity, and gout. Changing lifestyles continuously shape the gut microbiota which is closely related to the occurrence and development of metabolic diseases due to its specificity of composition and structural diversity. A large number of pathogenic bacteria such as Yersinia, Salmonella, Shigella, and pathogenic E. coli in the gut utilize the type III secretion system (T3SS) to help them resist host defenses and cause disease. Although the T3SS is critical for the virulence of many important human pathogens, its relationship with metabolic diseases remains unknown. This article reviews the structure and function of the T3SS, the disruption of intestinal barrier integrity by the T3SS, the changes in intestinal flora containing the T3SS in metabolic diseases, the possible mechanisms of the T3SS affecting metabolic diseases, and the application of the T3SS in the treatment of metabolic diseases. The aim is to provide insights into metabolic diseases targeting the T3SS, thereby serving as a valuable reference for future research on disease diagnosis, prevention, and treatment. [ABSTRACT FROM AUTHOR]

Practical Application Hyperlipidemia is a metabolic disorder resulted from unhealthy dietary and lifestyle habits. Its pathogenesis is possibly linked to gut microbiota dysbiosis. This study investigates the preventive effects of chitosan self‐assembled coconut residue dietary fiber (CRFSC) on hyperlipidemia induced by a high‐fat diet (HFD) and gut microbiota. CRFSC resulted in a significant weight loss of 7.9% in HFD rats and had a preventive effect on all four lipid parameter abnormalities. HFD supplemented with oat group resulted in a weight loss of 3.8% in HFD rats and had no preventive effect on low‐density lipoprotein cholesterol (LDL‐C) abnormalities. Prevention was achieved not only through the modulation of gut microbiota composition and the increase of short‐chain fatty acids (SCFAs) levels, but also through the activation of superoxide dismutase enzyme and the inhibition of malondialdehyde accumulation, all of which are the factors leading to the controlling of lipid abnormalities and oxidative damage. The prevention of lipid parameters by chitosan self‐assembled coconut residue dietary fiber (CRFSC) may be attributed to its richness in chitosan and insoluble dietary fiber, as well as its ability to enrich beneficial bacteria such as Akkermansia, Roseburia, and Ruminococcus. Correlation analysis demonstrated that key bacterial species producing SCFAs, which are rich in the CRFSC diet, had a positive impact on controlling hyperlipidemia. Hence, consumption of a CRFSC diet could serve as an effective strategy for preventing and controlling the development of hyperlipidemia due to its potential ability to regulate gut microbiota and SCFAs.This study showed that dietary fiber from coconut residue after chitosan self‐assembly had preventive effects on overweight, dyslipidemia, and oxidative damage in rats. In addition, CRFSC also increased the content of short‐chain fatty acids in the gut. And improve gut health by affecting gut microbiota. This finding suggests that CRFSC can be used as a dietary strategy to prevent hyperlipidemia and has practical significance in developing new healthy foods. [ABSTRACT FROM AUTHOR]

Background: Green synthesized nanoparticles have recently gained significant medicinal applications and oftentimes outperform their green sources. Selenium is of fundamental importance to human health, stemming from its distinctive physicochemical properties, such as antioxidant activity, inhibition of Lipid peroxidation, stabilization of membrane proteins, maintenance of membrane fluidity and modulation of cell signaling. Though reports have shown some therapeutic potential of Ackee plant parts such as antioxidant, anti-inflammatory, antimicrobial, neuroprotective, very few scientific proofs still exist in support of these effects. Methods: This study synthesized selenium nanoparticles (Se-NPs) from crude methanolic extracts of Ackee leaves (AKL) and Ackee arils (AKA), examined the photo-physical characteristics of the Se-NPs and determined the in-vitro antioxidant, antidiabetic, and anti-inflammatory potentials of AKL, AKA, and their Se-NPs using established protocols. Results: In both leaves and arils Se-NPs: UV spectroscopy revealed a qualitative absorbance at 310 nm; FTIR indicated multiple vibrations around 4000 cm−1- 400 cm−1; SEM images of 5 µm principally showed consistent size distribution of amorphous and granular shape at a magnification of 10,000X; while EDS spectra strongly confirm the presence of atomic Se compound at 30 kV. Various antioxidant activities assays carried out showed a range of approximately 4 to 60 times higher activities of the AKL, AKA, and Se-NPs than Ascorbic acid—the standard drug used. Furthermore, appreciable activities of more than 50% were obtained for alpha-amylase and alpha-glucosidase inhibitory activities, along with highly significant activities of haemoglobin glycosylation, glucose uptake, membrane stabilization, anti-arthritic, anti-haemolysis activities, when AKL, AKA, and Se-NPs were compared with standard drugs. Conclusion: Encouraging the development and utilization of AKL, AKA, and Se-NPs will provide tremendous therapeutic efficacy and bioavailability approaches towards the management of diabetes, inflammation, and other oxidative stress-related diseases. [ABSTRACT FROM AUTHOR]

Introduction: Podophyllotoxin (PPT) is a high-content and high-activity compound extracted from the traditional Chinese medicinal plant Dysosma versipellis (DV) which exhibits various biological activities. However, its severe toxicity limits its use. In clinical settings, patients with DV poisoning often experience adverse reactions when taking large doses in a short period. The heart is an important toxic target organ, so it is necessary to conduct 24-h acute cardiac toxicity studies on PPT to understand its underlying toxicity mechanism. Methods: Based on the concept of the toxicological evidence chain (TEC), we utilized targeted metabolomic and transcriptomic analyses to reveal the mechanism of the acute cardiotoxicity of PPT. The manifestation of toxicity in Sprague-Dawley rats, including changes in weight and behavior, served as Injury Phenotype Evidence (IPE). To determine Adverse Outcomes Evidence (AOE), the hearts of the rats were evaluated through histopathological examination and by measuring myocardial enzyme and cardiac injury markers levels. Additionally, transcriptome analysis, metabolome analysis, myocardial enzymes, and cardiac injury markers were integrated to obtain Toxic Event Evidence (TEE) using correlation analysis. Results: The experiment showed significant epistaxis, hypokinesia, and hunched posture in PPT group rats within 24 h after exposure to 120 mg/kg PPT. It is found that PPT induced cardiac injury in rats within 24 h, as evidenced by increased serum myocardial enzyme levels, elevated concentrations of cardiac injury biomarkers, and altered cardiac cell morphology, all indicating some degree of cardiac toxicity. Transcriptome analysis revealed that primary altered metabolic pathway was arachidonic acid metabolism after PPT exposure. Cyp2e1, Aldob were positively correlated with differential metabolites, while DHA showed positive correlation with differential genes Fmo2 and Timd2, as well as with heart injury markers BNP and Mb. Conclusion: This study comprehensively evaluated cardiac toxicity of PPT and initially revealed the mechanism of PPT-induced acute cardiotoxicity, which involved oxidative stress, apoptosis, inflammatory response, and energy metabolism disorder. [ABSTRACT FROM AUTHOR]

In recent years, there has been considerable interest in using amino acids like tryptophan (Trp) and tyrosine (Tyr) as biomarkers for various diseases, including type 2 diabetes mellitus (T2D). In diseases like T2D, the metabolism of Trp and Tyr is altered. The activity of enzymes involved in Trp metabolism increases, leading to a decrease in its serum level. On the other hand, the serum level of Tyr increases due to the suppressed activity of its metabolizing enzymes. These observations suggest that Trp and Tyr metabolism may play a crucial role in the pathophysiology of type 2 diabetes. Our study highlights the potential utility of Trp and Tyr as biomarkers for the early detection, prognosis, and monitoring of this metabolic disorder. Given these observations, we aimed to develop a high-performance thin-layer chromatographic (HPTLC) method that is sensitive, selective, rapid, and environmentally friendly for estimating the concentrations of Trp and Tyr in biological fluids, particularly serum samples. To evaluate the method, we performed analysis using serum samples from controlled and streptozotocin-induced diabetic rats. Our main objective was to develop a method that is sensitive and selective for precisely determining Trp and Tyr serum levels, which could serve as potential biomarkers for T2D. Fluorescence and absorption modes were employed for densitometry scanning. We assessed the precision and high separation efficiency of the chromatographic system by calculating parameters such as separation and resolution factors, number of theoretical plates, and height equivalent to theoretical plates. To evaluate the environmental impact of our proposed method, we employed the AGREE (Analytical GREEnness metric) and GAPI (Green Analytical Procedure Index) greenness assessment tools. The results confirmed that our method is environmentally friendly and exhibits superior eco-friendliness and greenness compared to other reported methods. [ABSTRACT FROM AUTHOR]

Objective: To explore the association between the Oxidative Balance Score (OBS), which represents the balance of multiple oxidative stress-related dietary and lifestyle exposures, and the risk of metabolic syndrome (MetS). Methods: A population-based cross-sectional study design was adopted and 16,850 participants in NHANES database were included in the statistics analysis stage. The OBS was constructed by combining information from 20 a priori selected pro- and antioxidant factors. Weighted logistic regression and restricted cubic splines (RCS) were used to estimate the association between OBS and MetS. Results: Participants in the highest OBS quartile, indicating low oxidative stress (OS) levels, exhibited a significantly lower risk of MetS (odds Ratio [OR] = 0.55, 95% confidence Interval [CI]: 0.47–0.64) compared to the lowest quartile. Specifically, higher OBS was inversely associated with abdominal obesity (OR = 0.61, 95% CI: 0.54–0.69), hypertension (OR = 0.69, 95% CI: 0.58–0.83), elevated triglycerides (OR = 0.68, 95% CI: 0.57–0.82), low high-density lipoprotein cholesterol (HDL-C) levels (OR = 0.60, 95% CI: 0.50–0.70) and fasting blood glucose (FBG) levels (OR = 0.74, 95% CI: 0.62–0.88). The observed inverse association between OBS and hypertension or FBG levels appeared to primarily influenced by BMI. The association between dietary OBS intervals and elevated FBG levels was not statistically significant in men, whereas the risk was lower by 25% in women. Conclusions: A higher OBS, representing a balance of multiple oxidative stress-related dietary and lifestyle exposures, is associated with a lower risk of MetS. Therefore, adhering to an antioxidant diet and lifestyle may help prevent the occurrence of metabolic disorders. [ABSTRACT FROM AUTHOR]

Metabolic diseases are caused by a complex interplay between genetics and the environment, yet many basic studies guiding our understanding of metabolism are confined to single genetic backgrounds, like the C57BL/6 J mouse. Recent studies across different genetic backgrounds have revealed profound phenotypic diversity, questioning the robustness and utility of observations derived from isolated strains. Those embracing genetic diversity will likely discover novel and penetrant mechanisms underlying metabolic dysregulation and disease, and findings may even benefit from increased translatability to humans. The purpose of this commentary is to equip researchers with a practical guide to performing studies across genetically diverse mice, and to highlight some of the important challenges such studies present. As part of EMBO Journal's 2024 metabolism methods series, this commentary revisits the impact of genetics on metabolic studies, enabling dissection of novel mechanisms and phenotypes. [ABSTRACT FROM AUTHOR]

Metabolic syndrome (MetS) is a cluster of conditions that increase the risk of cardiovascular disease and diabetes. This study aimed to investigate the association between Neutrophil-Percentage-to-Albumin Ratio (NPAR) and MetS in a large, nationally representative US population. We analyzed data from 28,178 participants in the National Health and Nutrition Examination Survey (NHANES) 2005–2018. Logistic regression models were used to evaluate the association between NPAR and MetS. Restricted cubic spline (RCS) models were employed to assess the dose-response relationship. Mediation analyses were conducted to explore potential mediating effects of serum uric acid and triglyceride-glucose (TyG) index. After adjusting for confounders, participants in the highest NPAR quartile had a 14% higher risk of MetS compared to those in the lowest quartile (OR 1.14, 95%CI 1.03–1.27, P = 0.010). RCS models revealed a monotonic increasing trend between NPAR and MetS risk (P for overall association = 0.002). Mediation analyses showed that serum uric acid and TyG index mediated 14.93% and 29.45% of the total effect of NPAR on MetS, respectively. Subgroup analyses indicated that the positive association between NPAR and MetS was more pronounced in Mexican Americans, individuals aged 20–65 years, those with lower income, males, current smokers, and moderate drinkers. Higher NPAR is associated with increased risk of MetS in the US adult population. This association is partially mediated by serum uric acid and TyG index. These findings suggest that NPAR may serve as a novel biomarker for MetS risk assessment and provide insights into potential mechanisms linking inflammation and metabolic disorders. [ABSTRACT FROM AUTHOR]

Recent considerations of natural sources as potential anticancer agents have arisen due to the origins of numerous drugs commonly used in chemotherapy. Plant‐based drugs, in particular, have attracted attention for offering the advantage of low adverse effects. Among these, the black mulberry plant (Morus nigra L.) stands out as a natural source of polyphenols, widely used to treat metabolic dysfunctions and confer benefits on human health. This study explores the potential of this plant as an anticancer agent, examining its effectiveness based on the type of application of the plant extracts or isolated substances, extraction methods, and its potential biological effects on cancer cells. Consequently, this study contributes to a better understanding of the distribution of phytochemicals in M. nigra and their applications in the context of cancer field. Among the compounds found in black mulberry are flavonoids, chlorogenic acid, cryptochlorogenic acid, and protocatechuic acid, along with cyanidin‐3‐O‐glucoside as the main anthocyanin on the fruit. The phytochemicals derived from M. nigra exhibit antinociceptive and antimicrobial activities, while also showing protective effects, such as antioxidant properties that underline their potential as anticancer agents. The black mulberry's roots, stem bark, pulp, and leaves are particularly rich sources of anti‐inflammatory compounds. Ethanol and methanol extraction methods appear to be the most effective in cancer management, offering compounds that facilitate the integration of apoptosis induction, cell growth inhibition, and cytotoxicity modulation. These results collectively represent the salient biological attributes that positioned black mulberry as a promising anticancer agent. Therefore, these findings highlight the multifaceted potential of M. nigra as an anticancer agent, making a compelling case for further research to advance prospects in the medical field. [ABSTRACT FROM AUTHOR]

Dietary lipid absorption is facilitated by bile acids. In the Zucker rat (ZR) model of obesity, bile acid absorption, mediated by the apical sodium bile acid transporter (ASBT), was increased in villus cells from the distal ileum. However, whether ASBT may be de novo expressed more proximally in the small intestine during obesity to facilitate additional bile acid absorption is not known. For this, starting from the end of the ileum to the mid jejunum, caudal-orally, five intestinal segments of equal length (S1–S5) were separated from lean and obese ZRs (LZR and OZR). Intestinal mucosa obtained from these segments were used for total RNA extraction, RT-qPCR and 3H-TCA uptake. The results showed that bile acid absorption along with the mRNA expression of ASBT and FXR progressively decreased caudal-orally in both LZRs and OZRs but was significantly higher in all small intestinal segments in OZRs. The expression of GATA4 was absent in the distal ileum (S1) in both LZRs and OZRs, but steadily increased along the proximal length in both. However, this steady increase was significantly reduced in the comparative obese proximal intestinal segments S2, S3, S4 and S5. The expressions of bile acid-activated G-protein-coupled bile acid receptor TGR5 and S1PR2 were unaltered in segments S1–S4 but were significantly increased in OZR S5. The paradigm changing observation of this study is that ASBT is expressed more proximally in the small intestine in obesity. This likely increases overall bile acid absorption and thereby lipid absorption in the proximal small intestine in obesity. [ABSTRACT FROM AUTHOR]

Background/Objectives: The relationship between BMI, inflammation, and mental health is complex. A high BMI, especially obesity, is associated with chronic inflammation, which can lead to mental disorders such as depression. Inflammatory cytokines affect neurotransmitters and the stress axis, worsening mental health. Obesity and mental disorders can mutually reinforce each other. New findings show that inflammation can lead to neurobiological changes, and the gut microbiota may play a key role. Obesity has been implicated as a factor in the high mortality and duration of influenza-like illnesses, even in people who do not have other chronic diseases that may increase the risk of complications. The aim of this study was to determine the associations between BMI and chronic inflammation, metabolic disorders, depression, and anxiety in patients hospitalized with COVID-19 up to 12 months after hospitalization. Methods: The study included 248 participants previously hospitalized for SARS-CoV-2 infection up to 12 months after hospitalization. The study was conducted in a multistage design using a diagnostic survey, anthropometric measurements, and laboratory methods. Results: A statistically significantly higher BDI-II score was observed among women. Statistical analysis showed a statistically significant higher GAD-7 score among women and those over 75 years of age. Conclusions: Higher BMI among subjects is often associated with elevated values of inflammatory markers and immune cells, such as WBC, neutrophils, monocytes, and CRP, as well as higher blood glucose levels. These associations may be related to the chronic inflammation and metabolic disorders that often accompany obesity. Lymphocytes and eosinophils may show more varied relationships depending on individual factors and specific health conditions. It is therefore important to continue research in this area. [ABSTRACT FROM AUTHOR]

Viruses are intracellular parasites that utilize organelles, signaling pathways, and the bioenergetics machinery of the cell to replicate the genome and synthesize proteins to build up new viral particles. Mitochondria are key to supporting the virus life cycle by sustaining energy production, metabolism, and synthesis of macromolecules. Mitochondria also contribute to the antiviral innate immune response. Here, we describe the different mechanisms involved in virus–mitochondria interactions. We analyze the effects of viral infections on the metabolism of glucose in the Warburg phenotype, glutamine, and fatty acids. We also describe how viruses directly regulate mitochondrial function through modulation of the activity of the electron transport chain, the generation of reactive oxygen species, the balance between fission and fusion, and the regulation of voltage-dependent anion channels. In addition, we discuss the evasion strategies used to avoid mitochondrial-associated mechanisms that inhibit viral replication. Overall, this review aims to provide a comprehensive view of how viruses modulate mitochondrial function to maintain their replicative capabilities. [ABSTRACT FROM AUTHOR]

Objective: Olanzapine (OLZ) is used by some patients with bipolar disorder and schizophrenia. Some of its side effects include weight gain and metabolic syndrome. Zeaxanthin (Zx), a yellow pigment found in egg yolk as well as some yellow and orange plants and fruits, is an anti-obesity factor that aids in the treatment of metabolic disorders. The effects of Zx on metabolic disorders caused by OLZ were investigated in this study. Materials and Methods: Female Wistar rats were randomly divided into seven groups (n=6): 1. control (vehicle); 2. OLZ (5 mg/kg, 14 days, intraperitoneal (i.p.)); 3-5. OLZ + Zx (12.5, 25, and 50 mg/kg, 14 days, gavage); 6. OLZ+ metformin (100 mg/kg, 14 days, i.p.); and 7. Zx (50 mg/kg, 14 days). Weight changes were checked every 3 days and food intake was monitored every day. Systolic blood pressure, insulin, blood sugar, triglyceride, cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and leptin levels were evaluated on the last day of the study. Results: OLZ caused an increase in weight (84.5% increase on day 15), food intake, blood pressure, triglyceride, LDL, insulin, blood sugar, and leptin compared to the control group (p<0.01 and p<0.001). The use of different doses of Zx (12.5, 25, and 50 mg/kg) and metformin decreased weight (the percentages of weigh reduction on day 15 were 91.92% for Zx (50 mg/kg) and 59.39% for metformin), food intake, systolic blood pressure, triglyceride, LDL, insulin, blood sugar, and leptin compared to the OLZ group. The amounts of cholesterol and HDL were not different in different groups. Conclusion: Zx alleviates metabolic abnormalities including hypertension, hyperglycemia, and dyslipidemia in rats. [ABSTRACT FROM AUTHOR]

Overconsumption of food, especially dietary fat, leads to metabolic disorders such as obesity and type 2 diabetes. Long‐chain fatty acids, such as palmitoleate are recognized as the risk factors for these disorders owing to their high‐energy content and lipotoxicity. In contrast, medium‐chain fatty acids (MCFAs) metabolic benefits; however, their underlying molecular mechanisms remain unclear. GPR84 is an MCFA receptor, particularly for C10:0. Although evidence from in vitro experiments and oral administration of C10:0 in mice suggests that GPR84 is related to the metabolic benefits of MCFAs via glucose metabolism, its precise roles in vivo remain unclear. Therefore, the present study investigated whether GPR84 affects glucose metabolism and metabolic function using Gpr84‐deficient mice. Although Gpr84‐deficient mice were lean and had increased endogenous MCFAs under high‐fat diet feeding conditions, they exhibited hyperglycemia and hyperlipidemia along with lower plasma insulin and glucagon‐like peptide‐1 (GLP‐1) levels compared with wild‐type mice. Medium‐chain triglyceride (C10:0) intake suppressed obesity, and improved plasma glucose and lipid levels, and increased plasma GLP‐1 levels in wild‐type mice; however, these effects were partially attenuated in Gpr84‐deficient mice. Our results indicate that long‐term MCFA‐mediated GPR84 activation improves the dysfunction of glucose and lipid homeostasis. Our findings may be instrumental for future studies on drug development with GPR84 as a potential target, thereby offering new avenues for the treatment of metabolic disorders like obesity and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Epigenetic alterations play a pivotal role in conditions influenced by environmental factors such as overweight and obesity. Many of these changes are tissue-specific, which entails a problem in its study since obtaining human tissue is a complex and invasive practice. While blood is widely used as a surrogate biomarker, it cannot directly extrapolate the evidence found in blood to tissue. Moreover, the intricacies of metabolic diseases add a new layer of complexity, as obesity leads to significant alterations in adipose tissue, potentially causing associated pathologies that can disrupt existing correlations seen in healthy individuals. Here, our objective was to determine which epigenetic markers exhibit correlations between blood and adipose tissue, regardless of the metabolic status. We collected paired blood and adipose tissue samples from 64 patients with morbidity obesity and non-obese and employed the MethylationEPIC 850 K array for analysis. We found that only a small fraction, specifically 4.3% (corresponding to 34,825 CpG sites), of the sites showed statistically significant correlations (R ≥ 0.6) between blood and adipose tissue. Within this subset, 5327 CpG sites exhibited a strong correlation (R ≥ 0.8) between blood and adipose tissue. Our findings suggest that the majority of epigenetic markers in peripheral blood do not reliably reflect changes occurring in visceral adipose tissues. However, it is important to note that there exists a distinct set of epigenetic markers that can indeed mirror changes in adipose tissue within blood samples. Key messages: More than 8% of methylation sites exhibit similarity between blood and adipose tissues, regardless of BMI The correlation percentage between blood and adipose tissue is strongly influenced by gender The principal genes implicated in this correlation are related to metabolism or the immunological system [ABSTRACT FROM AUTHOR]

Background: Artificial intelligence models such as ChatGPT (Open AI) have performed well on the exams of various medical and surgical fields. It is not yet known how ChatGPT performs on similar metabolic and bariatric surgery (MBS) questions. Objective: Assess the performance of ChatGPT on Focused Practice Designation in Metabolic and Bariatric Surgery board-style questions. Setting: United States. Methods: Questions obtained from the largest commercially available bank of FPD-MBS practice questions were entered into ChatGPT-4, as is, without prior training. We assessed the overall percentage correct as well as the percentage correct within each of the five American Board of Surgery (ABS) question categories. One-way ANOVA was used to determine if the frequency of correct answers differed between categories. Results: Out of 255 questions, ChatGPT-4 correctly answered 189 (74.1%). Between the five question categories there was no difference between the frequency of correct answers (p = 0.22). It did not matter if questions were entered individually or in groups of up to 10. Conclusion: Without prior training, ChatGPT-4 scored highly when evaluated on the largest practice question bank for the FPD-MBS exam. [ABSTRACT FROM AUTHOR]

Background and methods: Our study sought to evaluate if an association exists between Helicobacter pylori (H. pylori), metabolic dysfunction- associated steatotic liver disease (MASLD), and liver fibrosis in patients with severe obesity (BMI > 35). Our retrospective study included 584 patients over the age of 18 years with severe obesity, who underwent preoperative liver transient elastography (VCTE), upper endoscopy, blood work, and intra-operative liver biopsy concurrent with bariatric surgery at a single institution from July 2020 to September 2021. Liver fibrosis scores including FIB-4, APRI, NAFLD fibrosis score, BARD score, AST: ALT ratio, and NAFLD activity score (NAS) were calculated from the laboratory results and liver biopsy findings. The presence or absence of H. pylori was determined based on gastric biopsies obtained during upper endoscopy. Other variables collected included age, gender, mean preoperative weight, BMI, and the presence or absence of comorbidities. Student's t-test and non-parametric testing were used for the analysis of continuous variables and Chi-square analysis was used for categorical data. Results: Of the 584 patients, 14.7% were H. pylori positive and 85.3% were negative. Liver fibrosis scores including FIB-4, APRI, and NAFLD fibrosis scores were significantly higher in the positive group (p < 0.05), but there was no difference in AST: ALT ratio and BARD score. A significantly higher VCTE steatosis and fibrosis scores were noted in the H. pylori-positive group (p < 0.05). Similarly, a significantly higher NAS (NAFLD activity score) on liver biopsies was noted in the positive group, with all the individual components of NAS (steatosis, lobular inflammation, and hepatocyte ballooning) being significantly higher in the positive group (p < 0.05). A significantly higher incidence of fibrosis on liver biopsies was noted in the positive group overall and across all stages of fibrosis (p < 0.05). There were no significant differences between the groups in relation to gender, mean weight, BMI, presence of comorbidities including Diabetes Mellitus, and laboratory values. Conclusion: Our study demonstrates that H. pylori colonization or infection is associated with a higher risk of development of MASLD and progression to fibrosis. Further, population-based studies are needed to corroborate our findings. [ABSTRACT FROM AUTHOR]

Background and aims: The association between metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM) is unclear. This study aimed to investigate the impact of spectrum of SLD on the risk of heart failure and cardiovascular (CV) mortality in patients with T2DM. Methods: In a nationwide cohort study, 2,745,689 adults with T2DM were followed from 2009 to 2012 until 2018. Participants were categorized into no steatotic liver disease (no SLD) and SLD groups. The SLD group was stratified based on metabolic risk factors, alcohol consumption and viral hepatitis. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for heart failure (HF) and CV mortality risk. Results: The prevalence of MASLD, metabolic alcohol-associated liver disease (MetALD), alcohol-associated liver disease with metabolic dysfunction (ALD with MD) and MASLD with viral hepatitis (VH) was 49.6%, 7.2%, 2.3%, and 2.0%. Individuals with MASLD (adjusted HR [aHR], 1.11), MetALD (aHR, 1.14), ALD with MD (aHR, 1.32) and MASLD with VH (aHR, 1.12) had a higher risk of developing HF compared with the no SLD group. The risk of CV mortality was also increased in those with SLD groups compared to those with no SLD. The risk of new-onset HF and CV mortality showed a J-shaped association with alcohol consumption regardless of SLD status. Conclusion: SLD is independent risk factor of new-onset HF and CV mortality in persons with T2DM, and alcohol consumption has a J-shaped association with risk of HF and CV mortality, regardless of SLD status. [ABSTRACT FROM AUTHOR]

• The retardation of digestive enzymes α-amylase and α-glucosidase is an important approach targeted at reducing the post-prandial surge in blood glucose levels. • Syzygium cordatum is very rich in terpenoid and phenolic compounds. • The study suggests that the hypoglycaemic activity of S. cordatum may be due to the synergistic or individual action of its constituents. Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic dysfunction characterized by hyperglycemia. T2DM is a growing global epidemic with diffuse complications, including a high mortality rate. High blood sugar can be lowered by impeding the activities of pancreatic α-amylase and intestinal α-glucosidase enzymes. Although there are a number of orthodox medications used in the management of hyperglycemia, medicinal plants remain a veritable option in many cultures of the world owing to their overall efficacy and affordability. This study was designed to investigate the hypoglycemic potential of Syzygium cordatum leaf extract fractions in the retardation of pancreatic α-amylase and intestinal α-glucosidase enzymes in vitro. The bioactive components of the active fractions were identified using the Gas Chromatography-Mass Spectrometry (GC-MS) and their potential hypoglycemic properties were assessed using the molecular in silico modelling approach. The in vitro α-amylase and α-glucosidase inhibitory activities of S. cordatum revealed that the organic solvent fractions retarded the digestive enzymes considerably although the standard drug (acarbose) had the least half-maximal inhibitory concentration (IC 50) value. Analytical and computational analysis identified the potential of cubenol, to interact with important residues of α-glucosidase and α-amylase emphasizing its hypoglycemic potential. The result of this study revealed that S. cordatum is a rich source of pharmacologically important bioactive compounds with a remarkable capacity to retard α-amylase and α-glucosidase enzymes. Cubenol was identified as an efficient and safe hypoglycemic agent of S. cordatum. [ABSTRACT FROM AUTHOR]

Clinical pathway recommendations (CPR) are based on existing guidelines and deliver a short overview on how to deal with a specific diagnosis, resulting therapy and follow-up. In this paper we propose a methodology for developing CPRs for Pompe disease, a metabolic myopathy caused by deficiency of lysosomal acid alpha-glucosidase. The CPR document was developed within the activities of the MetabERN, a non-profit European Reference Network for Metabolic Diseases established by the European Union. A working group was selected among members of the MetabERN lysosomal storage disease subnetwork, with specific expertise in the care of Pompe disease, and patient support group representatives. The working strategy was based on a systematic literature search to develop a database, followed by quality assessment of the studies selected from the literature, and by the development of the CPR document according to a matrix provided by MetabERN. Quality assessment of the literature and collection of citations was conducted according to the AGREE II criteria and Grading of Recommendations, Assessment, Development and Evaluation methodology. General aspects were addressed in the document, including pathophysiology, genetics, frequency, classification, manifestations and clinical approach, laboratory diagnosis and multidisciplinary evaluation, therapy and supportive measures, follow-up, monitoring, and pregnancy. The CPR document that was developed was intended to be a concise and easy-to-use tool for standardization of care for patients among the healthcare providers that are members of the network or are involved in the care for Pompe disease patients. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a globally prevalent metabolic disorder, and cardiovascular disease (CVD) is a significant cause of mortality and morbidity in diabetic individuals. In addition to hyperglycemia, lipid abnormalities associated with T2DM play a crucial role in the development of CVD complications. Diabetic dyslipidemia is characterized by elevated levels of triglyceride (TG)-rich lipoproteins and small dense low-density lipoprotein (LDL) particles, reduced high-density lipoprotein (HDL) cholesterol, and impaired HDL function. Angiopoietin protein-like 3 (ANGPTL3) is a liver-derived protein that plays a crucial role in regulating plasma lipoprotein metabolism by inhibiting lipoprotein lipase and influencing lipid levels. Inhibiting ANGPTL3 has shown promising effects in promoting HDL-mediated cholesterol reverse transport and reducing the levels of TG-rich lipoproteins and LDL cholesterol. Here, we explore the potential of ANGPTL3 as a therapeutic target for lipid management in T2DM patients. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder exacerbated by obesity. Single Anastomosis Sleeve-Ileal Bypass (SASI) has emerged as a promising metabolic bariatric procedure that combines sleeve gastrectomy and ileal bypass, facilitating substantial weight loss and T2DM remission through restrictive and malabsorptive mechanisms. This study aims to evaluate the effects of SASI on T2DM remission, weight loss, and safety in one year follow-up. A retrospective cohort study analyzed 31 patients with obesity and T2DM who underwent SASI. Data collected included demographic characteristics, preoperative and postoperative BMI, HbA1c levels, and bariatric outcomes, including %TWL and T2DM changes. The mean age was 45 years, with a mean preoperative BMI of 40.7 kg/m². One year postoperatively, the mean %EWL was 85.6% and %TWL was 31.7%. T2DM remission was achieved in 24 (77.4%) patients, improvement in 4 (12.9%), and no change in 3 (9.7%). Hypertension improved in 21 (87.5%) patients, with 12 (50%) achieving remission. Significant reductions in BMI and HbA1c levels were observed (p < 0.001). Responders (R) and non-responders (NR) groups showed significant differences in postoperative BMI and %EWL (p = 0.007, p = 0.023). One patient experienced a Clavien-Dindo Grade III complication; no deaths occurred. SASI is an effective and safe procedure for treating T2DM, resulting in significant weight loss and metabolic improvements over a one-year follow-up. SASI seems to be a favorable option for T2DM management in metabolic bariatric surgery. [ABSTRACT FROM AUTHOR]

The therapeutic effects of polypeptides isolated from sea cucumber Acaudina molpadioides (AP) on the intestinal flora and glycolipid metabolic disturbance in high-fat diet/STZ-induced T2DM rats were investigated. The results showed that AP intervention notably ameliorated blood glucose, lipid levels, and pancreas injuries in T2DM rats. The diversity of intestinal microbial communities in T2DM rats was also enhanced by AP. Moreover, microbially derived short-chain fatty acids concentrations markedly improved in the feces of diabetic rats after AP treatment. These results suggest that AP played a protective role in T2DM rats by regulating glucose, lipid metabolism, and altering intestinal microbial. [ABSTRACT FROM AUTHOR]

Objective(s): Gestational diabetes mellitus (GDM), one of the most common metabolic disorders in pregnancy, impacts maternal and fetal health. This study was designed to assess the effects of mild GDM on the histology, ultrastructure, and morphometry of fetal liver tissue. Materials and Methods: In this experimental study, twenty pregnant rats were randomly allocated into control and streptozotocin (STZ)-induced diabetic groups. Mild hyperglycemia was induced by intraperitoneal injection of STZ (40 mg/kg/bw) on the 5th day of gestation. At day 19 of gestation, fetal livers were separated and subjected to histological, transmission electron microscopic, and quantitative morphometric examinations. Results: In the GDM group, PAS staining was positive, revealing scattered eosinophilic inclusions in some hepatocytes. Masson trichrome staining was also positive and showed some fibrous tissue as fine fibers in the portal spaces that extended to the central vein. Reticulin staining in the GDM group was focally positive in the areas of fibrosis and the portal spaces. Ultrastructural examination showed pyknotic nuclei, karyolysis, degranulation and vesiculation of the rough endoplasmic reticulum, and degeneration of mitochondria in the GDM group. The morphometric examination demonstrated that the mean area of hepatocytes was significantly lower in the GDM group than in the control group (P<0.05). Moreover, the mean diameter of the central vein and the density of megakaryocytes were significantly higher in the GDM group than in the control group (P<0.05). Conclusion: Uncontrolled mild GDM induced the histological, ultrastructural and morphometric alterations in the fetal liver. [ABSTRACT FROM AUTHOR]

Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants previously associated with elevated liver enzymes in human cohorts and steatotic liver disease in animal models. We aimed to evaluate the associations between PFAS exposures, and liver enzymes and vibration controlled transient elastography (VCTE) biomarkers of metabolic dysfunction associated steatotic liver disease (MASLD) in adult National Health and Nutrition Examination Survey (NHANES) 2017 to 2018. VCTE was determined by FibroScan. Serum PFAS (n  = 14), measured by mass spectrometry, were analyzed individually and by principal component (PC). Univariate and multivariable associations were determined between PFAS exposures and liver disease outcome variables: alanine aminotransferase (ALT), controlled attenuation parameter (CAP), liver stiffness measurement (LSM), FibroScan-based Score (FAST), using R. About 1,400 participants including 50% women with a mean age of 48 ± 19 years and a mean BMI of 29 ± 7 kg/m2 were analyzed. Four PFAS clustered to PC1, whereas 3 PFAS clustered to PC2. PC1 was significantly associated with ALT (β = 0.028), CAP (β = 0.041), LSM (β = 0.025), and FAST (β = 0.198) in univariate analysis. Individual PFAS exposures were oftentimes inversely associated with these measurements in multivariate analysis. In adult NHANES 2017–2018, PFAS may not be a significant burden for MASLD, because of the inconsistent associations between the environmental PFAS exposures and biomarkers of liver steatosis, inflammation, and fibrosis. More data are required to better understand the relationships between PFAS exposures and liver disease. [ABSTRACT FROM AUTHOR]

Lipid-associated macrophages (LAMs) occur in a broad range of diseased structures and lesions in tissues important for metabolic homeostasis. LAMs can be distinguished from other tissue-resident macrophages by their lipid-handling capacity and expression of specific marker genes (e.g., Trem2 , Gpnmb , and CD36). LAMs exhibit a functional spectrum (with respect to inflammation, lipid handling, and efferocytosis) that can vary depending on metabolic and disease state, location, and microenvironmental needs. LAM pools emerge largely from monocyte-derived precursors, but may also increase in abundance through (re-)polarization and self-renewal. Evidence for the importance of LAMs in metabolic disease justifies ventures into therapeutics that manipulate LAM abundance and phenotypes. Lipid-associated macrophages (LAMs) are phagocytic cells with lipid-handling capacity identified in various metabolic derangements. During disease development, they locate to atherosclerotic plaques, adipose tissue (AT) of individuals with obesity, liver lesions in steatosis and steatohepatitis, and the intestinal lamina propria. LAMs can also emerge in the metabolically demanding microenvironment of certain tumors. In this review, we discuss major questions regarding LAM recruitment, differentiation, and self-renewal, and, ultimately, their acute and chronic functional impact on the development of metabolic diseases. Further studies need to clarify whether and under which circumstances LAMs drive disease progression or resolution and how their phenotype can be modulated to ameliorate metabolic disorders. [ABSTRACT FROM AUTHOR]

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]

Background: People experiencing psychosis are at greater risk of physical health conditions and premature mortality. It is likely that Indigenous Māori youth, who experience additional systemic inequities caused by settler-colonisation, face even greater physical health and mortality risks following a diagnosis of first-episode psychosis. Objective: Compare Māori and non-Māori for risk of hospitalisation and mortality for up to 15 years following first-episode psychosis diagnosis. Methods: A cohort (N = 14,122) of young people (16–24 years) with first-episode psychosis diagnosis between 2001 and 2019 were identified. Using crude Kaplan–Meier and adjusted Cox proportional hazards models, Māori (n = 5211) and non-Māori (n = 8911) were compared on hospitalisation and mortality outcomes for up to 15 years. Results: In the 15 years following first-episode psychosis diagnosis, Māori had higher adjusted risk of all-cause mortality (hazard ratio = 1.21, 95% confidence interval = [1.01, 1.45]), hospitalisation with diabetes (hazard ratio = 1.44, 95% confidence interval = [1.15, 1.79]), injury/poisoning (hazard ratio = 1.11, 95% confidence interval = [1.05, 1.16]), general physical health conditions (hazard ratio = 1.07, 95% confidence interval = [1.02, 1.13]) and also appeared to be at greater risk of cardiovascular hospitalisations (hazard ratio = 1.34, 95% confidence interval = [0.97, 1.86]). Kaplan–Meier plots show hospitalisation and mortality inequities emerging approximately 4–7 years following first-episode psychosis diagnosis. Conclusions: Māori are at greater risk for hospitalisation and premature mortality outcomes following first-episode psychosis. Early screening and intervention, facilitated by culturally safe health service delivery, is needed to target these inequities early. [ABSTRACT FROM AUTHOR]

Importance: The recent change in terminology from nonalcoholic fatty liver disease (NAFLD) to metabolic dysfunction‐associated fatty liver disease (MAFLD) and metabolic dysfunction‐associated steatotic liver disease (MASLD) highlights the link between hepatic steatosis and metabolic dysfunction, taking out the stigmata of alcohol. Objective: We compared the effects of NAFLD and MAFLD definitions on the risk of overall and cardiovascular (CV) mortality, liver‐related events (LRE), nonfatal CV events (CVE), chronic kidney disease (CKD), and extra‐hepatic cancers (EHC). Data Sources and Study Selection: We systematically searched four large electronic databases for cohort studies (published through August 2023) that simultaneously used NAFLD and MAFLD definitions for examining the risk of mortality and adverse CV, renal, or oncological outcomes associated with both definitions. In total, 21 eligible cohort studies were identified. Meta‐analysis was performed using random‐effects modelling. Results: Compared with those with NAFLD, individuals with MAFLD had significantly higher rates of overall mortality (random‐effect OR 1.12, 95% CI 1.04–1.21, p =.004) and CV mortality (random‐effect OR 1.15, 95% CI 1.04–1.26, p =.004), and a marginal trend towards higher rates of developing CKD (random‐effect OR 1.06, 95% CI 1.00–1.12, p =.058) and EHC events (random‐effect OR 1.11, 95% CI 1.00–1.23, p =.052). We found no significant differences in the risk LREs and nonfatal CVE between MAFLD and NAFLD. Meta‐regression analyses identified male sex and metabolic comorbidities as the strongest risk factors related to the risk of adverse clinical outcomes in MAFLD compared to NAFLD. Conclusions and Relevance: Individuals with MAFLD have higher rates of overall and CV mortality and higher rates of developing CKD and EHC events than those with NAFLD, possibly due to the dysmetabolic risk profile related to MAFLD. [ABSTRACT FROM AUTHOR]

[Display omitted] • Selective autophagy is characterized by its ability to specifically degrade a certain substrate, rather than causing widespread cell autophagy. • The mechanisms underlying selective autophagy can be broadly dispersed in three steps: designation, targeting and sequestration, and degradation. • Numerous human diseases and their progression are closely linked to aberrant selective autophagy. • Deciphering the molecular mechanisms underlying selective autophagy provides a theoretical framework for treating relevant clinical disorders. • Regulation of selective autophagy by discovering and developing small-molecule agents has great clinical application prospects for the treatment of related diseases. Autophagy is an evolutionarily conserved turnover process for intracellular substances in eukaryotes, relying on lysosomal (in animals) or vacuolar (in yeast and plants) mechanisms. In the past two decades, emerging evidence suggests that, under specific conditions, autophagy can target particular macromolecules or organelles for degradation, a process termed selective autophagy. Recently, accumulating studies have demonstrated that the abnormality of selective autophagy is closely associated with the occurrence and progression of many human diseases, including neurodegenerative diseases, cancers, metabolic diseases, and cardiovascular diseases. This review aims at systematically and comprehensively introducing selective autophagy and its role in various diseases, while unravelling the molecular mechanisms of selective autophagy. By providing a theoretical basis for the development of related small-molecule drugs as well as treating related human diseases, this review seeks to contribute to the understanding of selective autophagy and its therapeutic potential. In this review, we systematically introduce and dissect the major categories of selective autophagy that have been discovered. We also focus on recent advances in understanding the molecular mechanisms underlying both classical and non-classical selective autophagy. Moreover, the current situation of small-molecule drugs targeting different types of selective autophagy is further summarized, providing valuable insights into the discovery of more candidate small-molecule drugs targeting selective autophagy in the future. On the other hand, we also reveal clinically relevant implementations that are potentially related to selective autophagy, such as predictive approaches and treatments tailored to individual patients. [ABSTRACT FROM AUTHOR]

Survodutide is a glucagon/glucagon-like peptide-1 receptor dual agonist in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). We investigated the pharmacokinetic and safety profile of survodutide in people with cirrhosis. This multinational, non-randomized, open-label, phase I clinical trial initially evaluated a single subcutaneous dose of survodutide 0.3 mg in people with Child-Pugh class A, B or C cirrhosis and healthy individuals with or without overweight/obesity matched for age, sex, and weight; the primary endpoints were the area under the plasma concentration-time curve from 0 to infinity (AUC 0-∞) and maximal plasma concentration (C max). Subsequently, people with overweight/obesity with or without cirrhosis (Child-Pugh class A or B) received once-weekly subcutaneous doses escalated from 0.3 mg to 6.0 mg over 24 weeks then maintained for 4 weeks; the primary endpoint was drug-related treatment-emergent adverse events, with MASH/cirrhosis-related endpoints explored. In the single-dose cohorts (n = 41), mean AUC 0-∞ and C max were similar in those with cirrhosis compared with healthy individuals (90% CIs for adjusted geometric mean ratios spanned 1). Drug-related adverse events occurred in 25.0% of healthy individuals and ≤25.0% of those with cirrhosis after single doses, and 82.4% and 87.5%, respectively, of the multiple-dose cohorts (n = 41) over 28 weeks. Liver fat content, liver stiffness, liver volume, body weight, and other hepatic and metabolic disease markers were generally reduced after 28 weeks of survodutide treatment. Survodutide is generally tolerable in people with compensated or decompensated cirrhosis, does not require pharmacokinetic-related dose adjustment, and may improve liver-related non-invasive tests, supporting its investigation for MASH-related cirrhosis. Survodutide is a glucagon receptor/glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH), which causes cirrhosis in ∼20% of cases. This trial delineates the pharmacokinetic and safety profile of survodutide in people with compensated or decompensated cirrhosis, and revealed associated reductions in liver fat content, markers of liver fibrosis and body weight. These findings have potential relevance for people with MASH—including those with decompensated cirrhosis, who are usually excluded from clinical trials of investigational drugs. Based on this study, further investigation of survodutide for MASH-related cirrhosis is warranted. NCT05296733. [Display omitted] • Survodutide is a glucagon/glucagon-like peptide-1 receptor dual agonist under investigation for MASH. • This multinational phase I trial of survodutide included people with compensated or decompensated cirrhosis. • The pharmacokinetics of survodutide were not affected by cirrhosis. • Survodutide was generally tolerable and was associated with improvements in liver-related non-invasive tests. • These are the first safety and efficacy data for a dual agonist in people with decompensated cirrhosis. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus is a prevalent metabolic disease, posing a considerable threat to public health. Oligonucleotide drugs have proven to be a promising field of therapy for the diseases. In this study, we reported that a herbal small RNA (sRNA), JGL‐sRNA‐h7 (B34735529, F1439.L002444.A11), could exhibit potent hypoglycemic effects by targeting glucose‐6‐phosphatase. Oral administration of sphingosine (d18:1)‐JGL‐sRNA‐h7 bencaosomes ameliorated hyperglycemia and diabetic kidney injury better than metformin in db/db mice. Furthermore, glucose tolerance was also improved in sphingosine (d18:1)‐JGL‐sRNA‐h7 bencaosomes‐treated beagle dogs. Our study indicates that JGL‐sRNA‐h7 could be a promising hypoglycemic oligonucleotide drug. [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]

Summary: Interleukin‐18 (IL‐18), a potent and multifunctional pro‐inflammatory cytokine, plays a critical role in regulating β‐cell failure, β‐cell death, insulin resistance, and various complications of diabetes mellitus (DM). It exerts its effects by triggering various signaling pathways, enhancing the production of pro‐inflammatory cytokines and nitric oxide (NO), as well as promoting immune cells infiltration and β‐cells death. Abnormal alterations in IL‐18 levels have been revealed to be strongly associated with the onset and development of DM and its complications. Targeting IL‐18 may present a novel and promising approach for DM therapy. An increasing number of IL‐18 inhibitors, including chemical and natural inhibitors, have been developed and have been shown to protect against DM and diabetic complications. This review provides a comprehensive understanding of the production, biological functions, action mode, and activated signaling pathways of IL‐18. Next, we shed light on how IL‐18 contributes to the pathogenesis of DM and its associated complications with links to its roles in the modulation of β‐cell failure and death, insulin resistance in various tissues, and pancreatitis. Furthermore, the therapeutic potential of targeting IL‐18 for the diagnosis and treatment of DM is also highlighted. We hope that this review will help us better understand the functions of IL‐18 in the pathogenesis of DM and its complications, providing novel strategies for DM diagnosis and treatment. DM is one of the most common chronic metabolic diseases caused by β‐cells β‐cell dysfunction and insulin resistance. IL‐18 contributes to the progression of DM and its complications by inducing β‐cells failure and death, insulin resistance, and pancreatitis. IL‐18 orchestrates β‐cell failure and death, insulin resistance, and pancreatitis through modulation of IL‐18‐related signaling pathway, inflammatory responses, NO production, and immune cells infiltration. [ABSTRACT FROM AUTHOR]

Summary: Childhood obesity represents a significant public health concern, imposing a substantial burden on the healthcare system. Furthermore, weight‐loss programs often exhibit reduced effectiveness in adults who have a history of childhood obesity. Therefore, early intervention against childhood obesity is imperative. Presently, the primary method for diagnosing childhood obesity relies on body mass index (BMI), yet this approach has inherent limitations. Leptin, a satiety hormone produced by adipocytes, holds promise as a superior tool for predicting both childhood and subsequent adulthood obesity. In this review, we elucidate the tools employed for assessing obesity in children, delve into the biological functions of leptin, and examine the factors governing its expression. Additionally, we discuss maternal and infantile leptin levels as predictors of childhood obesity. By exploring the relationship between leptin levels and weight loss, we present leptin as a potential indicator of the effectiveness of obesity interventions. [ABSTRACT FROM AUTHOR]

Aim: To assess the disease burden of familial partial lipodystrophy (FPLD) caused by LMNA (FPLD2) and PPARG (FPLD3) variants to augment the knowledge of these rare disorders characterized by selective fat loss and metabolic complications. Materials and Methods: An observational longitudinal study, including 157 patients (FPLD2: 139 patients, mean age 46 ± 17 years, 70% women; FPLD3: 18 patients, mean age: 44 ± 17 years, 78% women) from 66 independent families in two countries (83 from Turkey and 74 from Spain), was conducted. Results: Patients were diagnosed at a mean age of 39 ± 19 years, 20 ± 16 years after the first clinical signs appeared. Men reported symptoms later than women. Symptom onset was earlier in FPLD2. Fat loss was less prominent in FPLD3. In total, 92 subjects (59%) had diabetes (age at diagnosis: 34 ± 1 years). Retinopathy was more commonly detected in FPLD3 (P <.05). Severe hypertriglyceridaemia was more frequent among patients with FPLD3 (44% vs. 17%, P =.01). Hepatic steatosis was detected in 100 subjects (66%) (age at diagnosis: 36 ± 2 years). Coronary artery disease developed in 26 patients (17%) and 17 (11%) suffered from a myocardial infarction. Turkish patients had a lower body mass index, a higher prevalence of hepatic steatosis, greater triglyceride levels and a tendency towards a higher prevalence of coronary artery disease. A total of 17 patients died, with a mean time to death of 75 ± 3 years, which was shorter in the Turkish cohort (68 ± 2 vs. 83 ± 4 years, P =.01). Cardiovascular events were a major cause of death. Conclusions: Our analysis highlights severe organ complications in patients with FPLD, showing differences between genotypes and Mediterranean countries. FPLD3 presents a milder phenotype than FPLD2, but with comparable or even greater severity of metabolic disturbances. [ABSTRACT FROM AUTHOR]

Abnormal glucose metabolism is a common disease of the endocrine system. The effects of drugs on glucose metabolism have been reported frequently in recent years, and since abnormal glucose metabolism increases the risk of microvascular and macrovascular complications, metabolic disorders, and infection, clinicians need to pay close attention to these effects. A variety of common drugs can affect glucose metabolism and have different mechanisms of action. Hypertension is a common chronic cardiovascular disease that requires long‐term medication. Studies have shown that various antihypertensive drugs also have an impact on glucose metabolism. Among them, α‐receptor blockers, angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers can improve insulin resistance, while β‐receptor blockers, thiazides and loop diuretics can impair glucose metabolism. The aim of this review was to discuss the mechanisms underlying the effects of various antihypertensive drugs on glucose metabolism in order to provide reference information for rational clinical drug use. [ABSTRACT FROM AUTHOR]

Increasing evidence indicates that disturbance of the clock genes, which leads to systemic endocrine perturbation, plays a crucial role in the pathogenesis of metabolic and liver diseases. Fluorene-9-bisphenol (BHPF) is utilized in the manufacturing of plastic materials but its biological effects on liver homeostasis remain unknown. The impacts and involved mechanisms of BHPF on the liver diseases, metabolism, and circadian clock were comprehensively studied by zebrafish and mouse models. The therapeutic effect of melatonin (MT) was also verified. Zebrafish and mouse models with either acute exposure (0.5 and 1 µmol/L, 1-4 days post-fertilization) or chronic oral exposure (0.5 and 50 mg/(kg·2 days), 30 days) were established with various BHPF concentrations. Herein, we identified a crucial role for estrogenic regulation in liver development and circadian locomotor rhythms damaged by BHPF in a zebrafish model. BHPF mice showed chaos in circadian activity through the imbalance of circadian clock component Brain and Muscle Aryl hydrocarbon receptor nuclear translocator-like 1 in the liver and brain. The liver sexual dimorphic alteration along with reduced growth hormone and estrogens played a critical role in damaged glucose metabolism, hepatic inflammation, and fibrosis induced by BHPF. Besides, sleep improvement by exogenous MT alleviated BHPF‐related glucose metabolism and liver injury in mice. We proposed the pathogenesis of metabolic and liver disease resulting from BHPF and promising targeted therapy for liver metabolism disorders associated with endocrine perturbation chemicals. These results might play a warning role in the administration of endocrine-disrupting chemicals in everyday life and various industry applications. [Display omitted] [ABSTRACT FROM AUTHOR]

The 2022 American Society of Metabolic and Bariatric Surgery (ASMBS) and International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) updated the indications for Metabolic and Bariatric Surgery (MBS), replacing the previous guidelines established by the NIH over 30 years ago. The evidence supporting these updated guidelines has been strengthened to assist metabolic and bariatric surgeons, nutritionists, and other members of multidisciplinary teams, as well as patients. This study aims to assess the level of evidence and the strength of recommendations compared to the previously published criteria. [ABSTRACT FROM AUTHOR]