Emerging role of PES1 in disease: A promising therapeutic target?

Pescadillo ribosomal biogenesis factor 1 (PES1), a nucleolar protein initially identified in zebrafish, plays an important role in embryonic development and ribosomal biogenesis. Notably, PES1 has been found to be overexpressed in a number of cancer types, where it contributes to tumorigenesis and cancer progression by promoting cell proliferation, suppressing cellular senescence, modulating the tumor microenvironment (TME) and promoting drug resistance in cancer cells. Moreover, recent emerging evidence suggests that PES1 expression is significantly elevated in the livers of Type 2 diabetes mellitus (T2DM) and obese patients, indicating its involvement in the pathogenesis of metabolic diseases through lipid metabolism regulation. In this review, we present the structural characteristics and biological functions of PES1, as well as complexes in which PES1 participates. Furthermore, we comprehensively summarize the multifaceted role of PES1 in various diseases and the latest insights into its underlying molecular mechanisms. Finally, we discuss the potential clinical translational perspectives of targeting PES1, highlighting its promising as a therapeutic intervention and treatment target.

Huanglian-Jiedu decoction promotes adipose thermogenesis in obese mice by suppressing the expression of HDAC3.

ETHNOPHARMACOLOGICAL RELEVANCE: Huanglian Jiedu Decoction (HLJDD) is an ancient formula of traditional Chinese medicine that is commonly utilized in a range of disorders, and it has been shown to have pharmacological effects on glucose and lipid metabolism. However, the specific mechanism of HLJDD for the treatment of obesity and related metabolic disorders remains to be further investigated. AIM OF THE STUDY: It has been thought that encouraging adipose thermogenesis to raise the body's energy expenditure is a useful tactic for improving metabolic abnormalities and losing weight. In this study, we investigated the ability and underlying mechanisms of HLJDD to regulate fat cell thermogenesis to improve energy expenditure in obesity. METHODS: The obese mouse model was established on a high-fat diet for 12 weeks. All mice were divided into NC, HFD, HFD with HLJDD of a low dose (2.25 g/kg/d), and HFD with HLJDD of a high dose (4.5 g/kg/d) groups and kept for 4 weeks. In vitro experiments were conducted to evaluate the effects of 5% and 10% HLJDD-containing serum on differentiated 3T3-L1 cells and HDAC3-knocking-down 3T3-L1 cells. RESULTS: The results showed that HLJDD treatment significantly improved glucose and insulin tolerance and decreased the adipocyte radius of WATs, as well as increased energy consumption in obese mice. Besides, HLJDD treatment dramatically increased the levels of thermogenic genes UCP-1 and PGC-1α while suppressing HDAC3 levels in WATs and 3T3-L1 adipocytes. Importantly, the effects of HLJDD on PGC-1α and UCP-1 were blocked in HDAC3 knockdown adipocytes. CONCLUSIONS: Therefore, these results suggest that HLJDD enhanced adipose thermogenesis and improved energy expenditure by inhibiting HDAC3, thereby increasing UCP-1 and PGC-1α expression. These findings amplified the mechanisms of HLJDD and its potential to treat obesity and related metabolic disorders.

The macroscale routing mechanism of structural brain connectivity related to body mass index.

Understanding the brain's mechanisms in individuals with obesity is important for managing body weight. Prior neuroimaging studies extensively investigated alterations in brain structure and function related to body mass index (BMI). However, how the network communication among the large-scale brain networks differs across BMI is underinvestigated. This study used diffusion magnetic resonance imaging of 290 young adults to identify links between BMI and brain network mechanisms. Navigation efficiency, a measure of network routing, was calculated from the structural connectivity computed using diffusion tractography. The sensory and frontoparietal networks indicated positive associations between navigation efficiency and BMI. The neurotransmitter association analysis identified that serotonergic and dopaminergic receptors, as well as opioid and norepinephrine systems, were related to BMI-related alterations in navigation efficiency. The transcriptomic analysis found that genes associated with network routing across BMI overlapped with genes enriched in excitatory and inhibitory neurons, specifically, gene enrichments related to synaptic transmission and neuron projection. Our findings suggest a valuable insight into understanding BMI-related alterations in brain network routing mechanisms and the potential underlying cellular biology, which might be used as a foundation for BMI-based weight management.

ROS-triggered and macrophage-targeted micelles modulate mitochondria function and polarization in obesity.

Inflammation involving adipose macrophages is an important inducer of obesity. Regulating macrophages polarization and improving the inflammatory microenvironment of adipose tissue is a new strategy for the treatment of obesity. An amphiphilic chondroitin sulfate phenylborate derivative (CS-PBE) was obtained by modifying the main chain of chondroitin sulfate with the hydrophobic small molecule phenylborate. Using CS-PBE self-assembly, macrophage targeting, reactive oxygen species (ROS) release and celastrol (CLT) encapsulation were achieved. The cytotoxicity, cellular uptake, internalization pathways and transmembrane transport efficiency of CS-PBE micelles were studied in Caco-2 and RAW264.7 cells. Hemolysis and organotoxicity tests were performed to assess the safety of the platform, while its therapeutic efficacy was investigated in high-fat diet-induced obese mice. Multifunctional micelles with macrophage targeting and ROS clearance capabilities were developed to improve the efficacy of CLT in treating obesity.In vitrostudies indicated that CS-PBE micelles had better ability to target M1 macrophages, better protective effects on mitochondrial function, better ability to reduce the number of LPS-stimulated M1 macrophages, better ability to reduce the number of M2 macrophages, and better ability to scavenge ROS in inflammatory macrophages.In vivostudies have shown that CS-PBE micelles improve inflammation and significantly reduce toxicity of CLT in the treatment of obesity. In summary, CS-PBE micelles could significantly improve the ability to target inflammatory macrophages and scavenge ROS in adipose tissue to alleviate inflammation, suggesting that CS-PBE micelles are a highly promising approach for the treatment of obesity.

Preparation, pharmacokinetics and anti-obesity effects on dogs of nuciferine liposomes.

BACKGROUND: Nuciferine (NUC), a natural compound extracted from lotus leaves, has been proven to have anti-obesity effects. However, the development and application of NUC as an anti-obesity drug in dogs are hindered due to its poor water solubility and low bioavailability. OBJECTIVE: To promote the development of NUC-related products for anti-obesity in dogs, this study prepared NUC into a liposome formulation and evaluated its characteristics, pharmacokinetics in dogs, and anti-obesity effects on high-fat diet dogs. METHODS: NUC liposomes were prepared by the ethanol injection method, using NUC, egg lecithin, and ß-sitosterol as raw materials. The characteristics and release rate in vitro of liposomes were evaluated by particle size analyser and dialysis method, respectively. The pharmacokinetics in dogs after oral administration of NUC-liposomes was carried out by the high-performance liquid chromatography (HPLC) method. Moreover, we investigated the anti-obesity effect of NUC-liposomes on obese dogs fed with a high-fat diet. RESULTS: NUC-liposome was successfully prepared, with an EE of (79.31 ± 1.06)%, a particle size of (81.25 ± 3.14) nm, a zeta potential of (-18.75 ± 0.23) mV, and a PDI of 0.175 ± 0.031. The cumulative release rate in vitro of NUC from NUC-liposomes was slower than that of NUC. The T1/2 and relative bioavailability of NUC-liposomes in dogs increased, and CL reduced compared with NUC. In addition, the preventive effect of NUC-liposomes on obesity in high-fat diet dogs is stronger than that of NUC. CONCLUSIONS: The liposome formulation of NUC was conducive to improve its relative bioavailability and anti-obesity effect in dogs.

Association between the weight-adjusted-waist index and circadian syndrome in findings from a nationwide study.

Weight-adjusted-waist index (WWI) is an emerging parameter for evaluating obesity. We sought to ascertain the link between WWI and circadian syndrome (CircS). The study population consisted of 8275 eligible subjects who were included in the ultimate analysis from the NHANES 2011-2018. By using multivariable regression models, the association of WWI and CircS was analyzed. In subgroup analysis, we explored the relationship in different groups and tested the stability of the intergroup connection using interaction testing. To investigate whether WWI and CircS had a potential non-linear relationship, smooth curve fittings, and threshold effects tests were also constructed. In a multivariate linear regression model, WWI is significantly positively related to CircS (OR = 1.77, 95% CI 1.50-2.08). Through subgroup analysis and interaction testing, the stability of this positive association was also validated. It was further found that there was an inverted U-shaped association, with a turning point of 11.84, between WWI and CircS. Our findings supported a strong association between WWI values and CircS. Central obesity management is pivotal for preventing or alleviating CircS.

Update on the epidemiology of obstructive sleep apnea syndrome in Central Eastern Tunisia over 11 years.

Introduction: obstructive sleep apnea syndrome (OSAS) is the most common sleep-related breathing disorder. Knowledge about OSAS incidence trends could be extremely useful in assessing health needs and implementing preventive measures accordingly. This study aimed at the epidemiological and clinical specificities of OSAS and to give an update on its current chronological trends. Methods: we conducted a retrospective study including all cases of OSAS diagnosed over 11 years, from January 1, 2012, to December 31, 2022, at the Sleep Unit of the Neurophysiology Department of the Sahloul University Hospital, Tunisia. Results: overall, 848 new cases of OSAS were diagnosed. The mean annual number of OSAS cases was 74.8/year. The crude incidence rate (CIR) was 12.3/100000 inhabitants/year, it was significantly increasing over the years (rho=0.7; p=0.01). The median age was 56 (IQR= [48-64]) years, it increased significantly during the study period from 54 years (IQR= [43-63]) in 2012 to 58 years (IQR= [50.5-65]) in 2022 (rho=0.7; p=0.015). The median BMI was 35.5 (IQR= [31.3-40.3]) kg/m2. The median BMI of patients diagnosed with OSAS increased significantly from 34.6 kg/m2 to 38.3 kg/m2 (rho=0.75; p=0.008). This equated to an annual increase in median BMI of 0.41 kg/m2. The median AHI showed a significant upward trend for all patients, rising from 26.30 events/h in 2012 to 34.07 events/h in 2022 (rho=0.68; p=0.02). Conclusion: the CIR of OSAS is related to BMI and age. Thus, we assume that it will continue to increase in the coming years with the rise in obesity and the aging of the population.

Drug Development Failure: How GLP-1 Development Was Abandoned in 1990.

Many factors determine whether and when a class of therapeutic agents will be successfully developed and brought to market, and historians of science, entrepreneurs, drug developers, and clinicians should be interested in accounts of both successes and failures. Successes induce many participants and observers to document them, whereas failed efforts are often lost to history, in part because involved parties are typically unmotivated to document their failures. The GLP-1 class of drugs for diabetes and obesity have emerged over the past decade as clinical and financial blockbusters, perhaps soon becoming the highest single source of revenue for the pharmaceutical industry (Berk 2023). In that context, it is instructive to tell the story of the first commercial effort to develop this class of drugs for metabolic disease, and how, despite remarkable early success, the work was abandoned in 1990. Told by a key participant in the effort, this story documents history that would otherwise be lost and suggests a number of lessons about drug development that remain relevant today.

MicroRNAs in metabolic dysfunction-associated diseases: Pathogenesis and therapeutic opportunities.

Metabolic dysfunction-associated diseases often refer to various diseases caused by metabolic problems such as glucose and lipid metabolism disorders. With the improvement of living standards, the increasing prevalence of metabolic diseases has become a severe public health problem, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), diabetes and obesity. These diseases are both independent and interdependent, with complex and diverse molecular mechanisms. Therefore, it is urgent to explore the molecular mechanisms and find effective therapeutic targets of these diseases. MicroRNAs (miRNAs) have emerged as key regulators of metabolic homoeostasis due to their multitargets and network regulatory properties within the past few decades. In this review, we discussed the latest progress in the roles of miRNA-mediated regulatory networks in the development and progression of MASLD, ALD, diabetes and obesity.

Preservation of Muscle during Treatment for Obesity in Adults with Intellectual Disabilities.

OBJECTIVES: Adults with intellectual disabilities will frequently experience sedentary behavior and excessive weight, which may cause or exacerbate a multitude of medical and behavioral problems. This study examined a program to encourage increased activity and weight loss in an outpatient service for adults with intellectual disabilities. METHODS: Behavioral methods were used to treat obesity in 33 male and 21 female adults with intellectual disabilities for a mean of 9 months. They were retrospectively analyzed to determine the effects of treatment on muscle and adiposity using body composition analysis. RESULTS: The 54 participants of the original 122 (44.3%) who did not drop out were divided into three groups: weight loss ≥3 kg/3% (n = 20, 37%), weight loss <3 kg/3% (n = 17, 31.5%), and no weight loss or weight gain (n = 17, 31.5%). Only men and women who lost ≥3 kg/3%, demonstrated significant gain of relative muscle mass. Those who gained weight lost muscle mass. CONCLUSIONS: If motivation remains high and follow-up is reasonably long, then a multicomponent obesity treatment program can lead to significant weight loss with preservation of muscle in adults with intellectual disabilities.

Gut microbiota derived short-chain fatty acids in physiology and pathology: An update.

Short-chain fatty acids (SCFAs) are essential molecules produced by gut bacteria that fuel intestinal cells and may also influence overall health. An imbalance of SCFAs can result in various acute and chronic diseases, including diabetes, obesity and colorectal cancer (CRC). This review delves into the multifaceted roles of SCFAs, including a brief discussion on their source and various gut-residing bacteria. Primary techniques used for detection of SCFAs, including gas chromatography, high-performance gas chromatography, nuclear magnetic resonance and capillary electrophoresis are also discussed through this article. This review study also compiles various synthesis pathways of SCFAs from diverse substrates such as sugar, acetone, ethanol and amino acids. The different pathways through which SCFAs enter cells for immune response regulation are also highlighted. A major emphasis is the discussion on diseases associated with SCFA dysregulation, such as anaemia, brain development, CRC, depression, obesity and diabetes. This includes exploring the relationship between SCFA levels across ethnicities and their connection with blood pressure and CRC. In conclusion, this review highlights the critical role of SCFAs in maintaining gut health and their implications in various diseases, emphasizing the need for further research on SCFA detection, synthesis and their potential as diagnostic biomarkers. Future studies of SCFAs will pave the way for the development of novel diagnostic tools and therapeutic strategies for optimizing gut health and preventing diseases associated with SCFA dysregulation.

NUTRITION AND PHYSICAL ACTIVITY OF PREGNANT WOMEN INCLUDING BARIATRIC SURGERY.

A healthy, balanced diet of a pregnant woman is an integral part for the full development of the fetus, mainly pregnant women receive the mentioned recommendations from gynecologists, because consulting a nutritionist is less mandatory at this stage still in our country. Since obesity is highly prevalent paralleling the globe, especially among the European population but nevertheless it's a preventable risk factor which is associated with negative outcomes for both mother and fetus. That's where bariatric surgery plays an important role, that has increased among women for an achievable pregnancy but being overweight prevents it. I have created a general medical booklet that would be useful to them as well, easy to understand and will bring positive results. This book shows the amount of calories to be consumed by pregnant mothers each trimester, kind of food to go for or should be avoided and type and duration of physical activity. That's where bariatric surgery plays an important role, that has increased among women for an achievable pregnancy, but being overweight prevents it. The crucial part to focus is how many months later the pregnancy occurred and how her nutrition was going. Being a pediatrician and nutritionist it's foremost important to observe mother and baby after the mentioned operation. Because monitoring the diet properly leads to better health in both mother and newborn since this topic is still lagging in research areas especially in European countries and data about obesity among pregnant women is lacking, so future studies would be beneficial among obese pregnant women for the betterment of their health.

Study of obesity research using machine learning methods: A bibliometric and visualization analysis from 2004 to 2023.

BACKGROUND: Obesity, a multifactorial and complex health condition, has emerged as a significant global public health concern. Integrating machine learning techniques into obesity research offers great promise as an interdisciplinary field, particularly in the screening, diagnosis, and analysis of obesity. Nevertheless, the publications on using machine learning methods in obesity research have not been systematically evaluated. Hence, this study aimed to quantitatively examine, visualize, and analyze the publications concerning the use of machine learning methods in obesity research by means of bibliometrics. METHODS: The Web of Science core collection was the primary database source for this study, which collected publications on obesity research using machine learning methods over the last 20 years from January 1, 2004, to December 31, 2023. Only articles and reviews that fit the criteria were selected for bibliometric analysis, and in terms of language, only English was accepted. VOSviewer, CiteSpace, and Excel were the primary software utilized. RESULTS: Between 2004 and 2023, the number of publications on obesity research using machine learning methods increased exponentially. Eventually, 3286 publications that met the eligibility criteria were searched. According to the collaborative network analysis, the United States has the greatest volume of publications, indicating a significant influence on this research. coauthor's analysis showed the authoritative one in this field is Leo Breiman. Scientific Reports is the most widely published journal. The most referenced publication is "R: a language and environment for statistical computing." An analysis of keywords shows that deep learning, support vector machines, predictive models, gut microbiota, energy expenditure, and genome are hot topics in this field. Future research directions may include the relationship between obesity and its consequences, such as diabetic retinopathy, as well as the interaction between obesity and epidemiology, such as COVID-19. CONCLUSION: Utilizing bibliometrics as a research tool and methodology, this study, for the first time, reveals the intrinsic relationship and developmental pattern among obesity research using machine learning methods, which provides academic references for clinicians and researchers in understanding the hotspots and cutting-edge issues as well as the developmental trend in this field to detect patients' obesity problems early and develop personalized treatment plans.

Exploring the importance of family socio-economic position on the association between parental BMI and offspring BMI trajectories.

PURPOSE: We aimed to investigate the associations between parental BMI and offspring BMI trajectories and to explore whether the parent-offspring BMI growth trajectory association differed according to family SEP or social mobility. METHODS: We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Children's weight and height were collected from 1 to 18 years. Parents' height and weight were reported pre-pregnancy. We assessed family SEP by measuring parents' and grandparents' educational attainment, social class, and social mobility by changes in education attainment across generations. Multilevel models were used to develop trajectories and assess patterns of change in offspring BMI, to associate parental BMI with these trajectories, and explore whether these associations differed by family SEP and social mobility. RESULTS: 13,612 children were included in the analyses. The average BMI of offspring whose parents were overweight or obese was higher throughout childhood and adolescence, compared to those with parents of normal BMI. Parental and grandparental low SEP were associated with higher child BMI, but there was little evidence of modification of parent-offspring associations. For example, at age 15 years the predicted mean BMI difference between children of overweight or obese mothers versus normal-weight mothers was 12.5 % (95 %CI: 10.1 % to 14.7 %) and 12.2 % (95 %CI: 10.3 % to 13.7 %) for high and low grandparental SEP, respectively. DISCUSSION: These findings strengthen the evidence that higher parental BMI and lower family SEP were associated with higher offspring BMI, but we did not observe strong evidence that family SEP modifies the parental-offspring BMI association.

Swimming training prevents obesity installation and normalizes hypothalamic expressions of GLP1 and leptin receptors in adult offspring born in small litters.

OBJECTIVE: Glucagon-like peptide-1 (GLP1) and leptin (Lep) are afferent signals that regulate energy metabolism. Lactational hypernutrition results in hyperphagia and adiposity in adult life, and these events can be prevented by exercise. We evaluated the effects of swimming training on hypothalamic (GLP1-R) and Lep receptor (Lep-R) gene expressions in lactational hypernutrition-induced obesity. METHODS: On the 3rd postnatal day, the litter sizes of lactating dams were adjusted to small litters (SL; 3 pups/dams) or normal litters (NL; 9 pups/dams). After weaning (21 days), NL and SL male rats were randomly distributed to sedentary (Sed) and exercised (Exe) groups. Exercised mice swam (30 min/3 times/week) for 68 days. Food intake and body weight gain were registered. At 92 days, intraperitoneal glucose and insulin tolerance tests were performed and rats were euthanized at 93 days; adipose tissue depots were weighed, and blood counts and plasma biochemical analyses performed. Hypothalamus were isolated to evaluate Lep-R and GLP1-R gene expressions. RESULTS: Small litters sedentary rats presented increased body weight gain, adiposity, insulin sensibility and higher fasting values of glucose and triglycerides, besides higher hypothalamic gene expressions of Lep-R and GLP1-R, compared to NLSed animals. SLExe rats did not develop obesity or metabolic abnormalities and Lep-R and GLP1-R hypothalamic gene expressions were normalized. CONCLUSION: Lactational hypernutrition induces obesity and metabolic dysfunction in adult life, in association with higher hypothalamic expressions of the Lep-R and GLP1-R genes. Exercise prevented obesity and improved metabolic state in SL overnourished rats, and normalized their hypothalamic Lep-R and GLP1-R gene expressions.

Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials.

BACKGROUND: Heart failure with mildly reduced or preserved ejection fraction (hereafter referred to as HFpEF) is the most common type of heart failure and is associated with a high risk of hospitalisation and death, especially in patients with overweight, obesity, or type 2 diabetes. In the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide improved heart failure-related symptoms and physical limitations in participants with HFpEF. Whether semaglutide also reduces clinical heart failure events in this group remains to be established. METHODS: We conducted a post-hoc pooled, participant-level analysis of four randomised, placebo-controlled trials (SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM) to examine the effects of once-weekly subcutaneous semaglutide (2·4 mg in SELECT, STEP-HFpEF, and STEP-HFpEF DM; 1·0 mg in FLOW) on heart failure events. The STEP-HFpEF and STEP-HFpF DM trials enrolled participants with obesity-related HFpEF, the SELECT trial enrolled participants with atherosclerotic cardiovascular disease and overweight or obesity, and the FLOW trial enrolled participants with type 2 diabetes and chronic kidney disease. Hence, for this analysis, we include all participants from the STEP-HFpEF trials and those with an investigator-reported history of HFpEF from SELECT and FLOW. The main outcomes for this analysis were the composite endpoint of time to cardiovascular death or first worsening heart failure event (defined as hospitalisation or urgent visit due to heart failure), time to first worsening heart failure event, and time to cardiovascular death. Efficacy and safety endpoints were analysed with the full analysis set (ie, all participants randomly assigned to treatment, according to the intention-to-treat principle). The SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM trials are registered at ClinicalTrials.gov, NCT03574597, NCT03819153, NCT04788511, and NCT04916470, respectively, and all are complete. FINDINGS: Across the four trials, 3743 (16·8%) of 22 282 participants had a history of HFpEF (1914 assigned to semaglutide and 1829 assigned to placebo). In this group of participants with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or heart failure events (103 [5·4%] of 1914 in the semaglutide group had events vs 138 [7·5%] of 1829 in the placebo group; hazard ratio [HR] 0·69 [95% CI 0·53-0·89]; p=0·0045). Semaglutide also reduced the risk of worsening heart failure events (54 [2·8%] vs 86 [4·7%]; HR 0·59 [0·41-0·82]; p=0·0019). No significant effect on cardiovascular death alone was seen (59 [3·1%] vs 67 [3·7%]; HR 0·82 [0·57-1·16]; p=0·25). A lower proportion of patients treated with semaglutide had serious adverse events than did those who were treated with placebo (572 [29·9%] vs 708 [38·7%]). INTERPRETATION: In patients with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or worsening heart failure events, and worsening heart failure events alone, whereas its effect on cardiovascular death alone was not significant. These data support the use of semaglutide as an efficacious therapy to reduce the risk of clinical heart failure events in patients with HFpEF, for whom few treatment options are currently available. FUNDING: Novo Nordisk.