Treatment Of Cardiometabolic Diseases Research Articles

Can Daily Dietary Choices Have a Cardioprotective Effect? Food Compounds in the Prevention and Treatment of Cardiometabolic Diseases

Cardiovascular diseases accompanying metabolic syndrome comprise one of the leading causes of death worldwide. The medical community undertakes attempts to improve treatment options and minimize cardiovascular diseases’ numerous consequences and exacerbations. In parallel with pharmacotherapies provided by physicians, nutritionists are developing strategies for diet therapy and prevention based on lifestyle changes, with high success rates. Consumption of specified food compounds included in various products with proven protective properties can be helpful in this regard. Due to the wide possibilities of diet in metabolic health promotion, it seems necessary to systematize information about the metabolically protective and cardioprotective properties of fiber, probiotic bacteria, plant sterols, folic acid, vitamins B12, C, and E, PUFAs, lycopene, polyphenols, arginine, CoQ10, and allicin. The aim of this review was to present the food compounds with potential use in cardiometabolic prevention and diet therapy based on the latest available literature.

Ninerafaxstat in the Treatment of Cardiometabolic Disease: Shifting Metabolic Paradigms.

Cardiovascular disease (CVD) refers to a wide array of conditions that damage the heart muscle and impede its ability to effectively circulate blood throughout the body. In damaged or pathological states, the heart muscle might not function as effectively as it would have had there been no insult to it. Understanding this, certain CVDs can put the heart in a "metabolic disadvantage"-a state in which it cannot synthesize energy stores, in the form of adenosine triphosphate (ATP), as efficiently as it was once able to do. While the heart typically uses fatty acids for its ATP synthesis, the metabolic processes required to do so consume more oxygen per mole than the processes required to convert glucose (or carbohydrates) to ATP. In conditions when oxygen demand outweighs supply-such as angina, heart failure, and certain inherited CVDs-the myocardium can more efficiently run via glucose oxidation. Despite this knowledge, there are no currently approved therapeutics or interventions that encourage this "metabolic shift" in the myocardial cells. Currently in phase II clinical trials, however, is a novel medication called ninerafaxstat. This novel drug is a partial inhibitor of fatty acid oxidation and thus pushes the heart to convert glucose (instead of fatty acids) to ATP-ultimately cutting down on oxygen supply. While still completing clinical trials, ninerafaxstat must undergo further safety and efficacy evaluation before it can be used as a standard of care. If, however, the drug makes it to market, it might offer a unique way to improve both the symptoms and quality of life of the millions of Americans who suffer from CVDs.

Gender differences in the association between changes in the atherogenic index of plasma and cardiometabolic diseases: a cohort study

ObjectiveThe relationship between changes in Atherogenic Index of Plasma (AIP) and cardiometabolic diseases (CMD) in middle-aged and elderly individuals remains unclear. This study aims to explore the association between changes in AIP and CMD.MethodsThis study included 3,791 individuals aged over 45 years from CHARLS. Participants were divided into four groups using the K-Means clustering method. Cumulative AIP was used as a quantitative indicator reflecting changes in AIP. Differences in baseline data and CMD incidence rates among these four groups were compared. Multifactorial logistic regression models were used to assess the relationship between changes in AIP and CMD, and subgroup analysis and interaction tests were conducted to evaluate potential relationships between changes in AIP and CMD across different subgroups. Restricted cubic splines (RCS) were used to assess the dose-response relationship between cumulative AIP and CMD.ResultsChanges in AIP were independently and positively associated with CMD. In males, the risk significantly increased in class4 compared to class1 (OR 1.75, 95%CI 1.12-2.73). In females, changes in AIP were not significantly associated with CMD. Cumulative AIP was positively correlated with CMD (OR 1.15, 95%CI 1.01-1.30), with significant gender differences in males (OR 1.29, 95%CI 1.07-1.55) and females (OR 1.03, 95%CI 0.87-1.23) (p for interaction = 0.042). In addition, a linear relationship was observed between cumulative AIP and CMD in male.ConclusionSubstantial changes in AIP may increase the risk of CMD in middle-aged and elderly Chinese males. Dynamic monitoring of AIP is of significant importance for the prevention and treatment of CMD.

Spring Meeting of the Young Researchers of SID, SIIA, SIMI, SIPREC, SISA

The IX Spring Meeting of Young Researchers of the Italian Society of Diabetology (SID), the Italian Society of Arterial Hypertension (SIIA), the Italian Society of Internal Medicine (SIMI), the Italian Society of Cardiovascular Prevention (SIPREC) and the Italian Society for the Study of Atherosclerosis (SISA), entitled “Research drives us crazy”, was held in Rimini on February 25-27, 2024. The Congress was organized by young researchers from the aforementioned scientific societies working in the cardiometabolic field. The Congress hosted five sessions promoted by the five societies, addressing hot topics in the prevention and treatment of cardiometabolic diseases. More than one hundred young researchers had the opportunity to discuss their scientific work in dedicated oral and poster sessions. In this conference report, we offer an overview of the key topics covered in the presentations at the meeting.

Bile salt signaling and bile salt-based therapies in cardiometabolic disease.

Bile salts have an established role in the emulsification and intestinal absorption of dietary lipids, and their homeostasis is tightly controlled by various transporters and regulators in the enterohepatic circulation. Notably, emerging evidence points toward bile salts as major modulators of cardiometabolic disease (CMD), an umbrella disease of disorders affecting the heart and blood vessels that is caused by systemic metabolic diseases such as Type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD), the latter encompassing also metabolic dysfunction-associated steatohepatitis (MASH). The underlying mechanisms of protective effects of bile salts are their hormonal properties, enabling them to exert versatile metabolic effects by activating various bile salt-responsive signaling receptors with the nuclear farnesoid X receptor (FXR) and the Takeda G-protein-coupled receptor 5 (TGR5) as most extensively investigated. Activation of FXR and TGR5 is involved in the regulation of glucose, lipid and energy metabolism, and inflammation. Bile salt-based therapies directly targeting FXR and TGR5 signaling have been evaluated for their therapeutic potential in CMD. More recently, therapeutics targeting bile salt transporters thereby modulating bile salt localization, dynamics, and signaling, have been developed and evaluated in CMD. Here, we discuss the current knowledge on the contribution of bile salt signaling in the pathogenesis of CMD and the potential of bile salt-based therapies for the treatment of CMD.

Transcription factor EB: A potential integrated network regulator in metabolic-associated cardiac injury.

With the worldwide pandemic of metabolic diseases, such as obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD), cardiometabolic disease (CMD) has become a significant cause of death in humans. However, the pathophysiology of metabolic-associated cardiac injury is complex and not completely clear, and it is important to explore new strategies and targets for the treatment of CMD. A series of pathophysiological disturbances caused by metabolic disorders, such as insulin resistance (IR), hyperglycemia, hyperlipidemia, mitochondrial dysfunction, oxidative stress, inflammation, endoplasmic reticulum stress (ERS), autophagy dysfunction, calcium homeostasis imbalance, and endothelial dysfunction, may be related to the incidence and development of CMD. Transcription Factor EB (TFEB), as a transcription factor, has been extensively studied for its role in regulating lysosomal biogenesis and autophagy. Recently, the regulatory role of TFEB in other biological processes, including the regulation of glucose homeostasis, lipid metabolism, etc. has been gradually revealed. In this review, we will focus on the relationship between TFEB and IR, lipid metabolism, endothelial dysfunction, oxidative stress, inflammation, ERS, calcium homeostasis, autophagy, and mitochondrial quality control (MQC) and the potential regulatory mechanisms among them, to provide a comprehensive summary for TFEB as a potential new therapeutic target for CMD.

Association between cardiometabolic diseases and quality of life and the mediation effect of perceived stress

Objective: To explore the association between cardiometabolic diseases (CMD) and quality of life, the association between CMD and perceived stress, and the mediation effect of perceived stress on the association between CMD and quality of life, and to provide evidence for the prevention and treatment of CMD and the improvement of quality of life in these patients. Methods: This is a cross-sectional study. Data were collected by the employees' physical examination of a company in Xi'an in 2021. Multiple linear regression models were used to analyze the association between the status of CMD (divided into three categories: no CMD, presence of one kind of CMD, and with≥2 kinds of CMD (≥2 kinds of CMD were defined as cardiometabolic multimorbidity (CMM)), quality of life, and perceived stress. Mediation analysis with a multi-categorical independent variable was conducted to determine the mediation effect of perceived stress on the association between CMD and quality of life. Results: Among all 4 272 participants, 1 457 (34.1%) participants had one kind of CMD and 677 (15.8%) participants had CMM. The average scores for quality of life and perceived stress were (57.5±15.7) and (16.9±7.9), respectively. Compared with participants without CMD, after adjusting for demographic and lifestyle factors, no statistically significant associations were observed between one kind of CMD and perceived stress or quality of life (both P>0.05). Perceived stress did not mediate the association between one kind of CMD and quality of life. However, participants with CMM had lower quality of life and higher perceived stress than participants without CMD. The relative total effect coefficient c (95%CI) and the relative direct effect coefficient c' (95%CI) between CMM and quality of life were -3.71 (-5.04--2.37) and -2.52 (-3.81--1.24) (both P<0.05), respectively. The relative indirect effect coefficient a2b (95%CI) of perceived stress on the association between CMM and quality of life was -1.18 (-1.62--0.77) (P<0.05). The mediation effect size was 31.8%. Conclusions: CMM is negatively associated with quality of life and positively associated with perceived stress. Perceived stress partially mediates the association between CMM and quality of life. Our results suggest that, in addition to preventing and treating CMM actively, efforts should be taken to relieve the perceived stress of people with CMM to improve their quality of life.

Physical performance during energy deficiency in humans: An evolutionary perspective

Energy deficiency profoundly disrupts normal endocrinology, metabolism, and physiology, resulting in an orchestrated response for energy preservation. As such, despite energy deficit is typically thought as positive for weight-loss and treatment of cardiometabolic diseases during the current obesity pandemic, in the context of contemporary sports and exercise nutrition, chronic energy deficiency is associated to negative health and athletic performance consequences. However, the evidence of energy deficit negatively affecting physical capacity and sports performance is unclear. While severe energy deficiency can negatively affect physical capacity, humans can also improve aerobic fitness and strength while facing significant energy deficit. Many athletes, also, compete at an elite and world-class level despite showing clear signs of energy deficiency. Maintenance of high physical capacity despite the suppression of energetically demanding physiological traits seems paradoxical when an evolutionary viewpoint is not considered. Humans have evolved facing intermittent periods of food scarcity in their natural habitat and are able to thrive in it. In the current perspective it is argued that when facing limited energy availability, maintenance of locomotion and physical capacity are of high priority given that they are essential for food procurement for survival in the habitat where humans evolved. When energetic resources are limited, energy may be allocated to tasks essential for survival (e.g. locomotion) while minimising energy allocation to traits that are not (e.g. growth and reproduction). The current perspective provides a model of energy allocation during energy scarcity supported by observation of physiological and metabolic responses that are congruent with this paradigm.

Murine Fecal Isolation and Microbiota Transplantation.

Gut microbiota dysbiosis plays a role in the pathophysiology of cardiovascular and metabolic disorders, but the mechanisms are not well understood. Fecal microbiota transplantation (FMT) is a valuable approach to delineating a direct role of the total microbiota or isolated species in disease pathophysiology. It is a safe treatment option for patients with recurrent Clostridium difficile infection. Preclinical studies demonstrate that manipulating the gut microbiota is a useful tool to study the mechanistic link between dysbiosis and disease. Fecal microbiota transplantation may help elucidate novel gut microbiota-targeted therapeutics for the management and treatment of cardiometabolic disease. Despite a high success rate in rodents, there remains translational changes associated with the transplantation. The goal here is to provide guidance in studying the effects of gut microbiome in experimental cardiovascular disease. In this study, a detailed protocol for the collection, handling, processing, and transplantation of fecal microbiota in murine studies is described. The collection and processing steps are described for both human and rodent donors. Lastly, we describe using a combination of the Swiss-rolling and immunostaining techniques to assess gut-specific morphology and integrity changes in cardiovascular disease and related gut microbiota mechanisms.

Abstract 159: Palmitic Acid Alters Enhancers And Super Enhancers Near Inflammatory And Efferocytosis-associated Genes In Human Monocytes

Background: Elevated free fatty acids (FFA) like palmitic acid (PA) are associated with inflammatory cardiometabolic disorders like diabetes and atherosclerosis. FFA induced dysregulated gene expression in monocytes plays important roles in inflammation, but the epigenetic mechanisms involved are unclear. Here we examined PA induced alterations in enhancer and super-enhancer (E/SE) repertoires to elucidate epigenetic mechanisms of inflammatory gene regulation in monocyte dysfunction. Methods: Human CD14 + monocytes from healthy volunteers were treated with PA (200 μM, 24 h) or vehicle (0.2% BSA). ChIP-seq with histone-H3K27ac was performed to identify Es/SEs and RNA-seq to analyze gene expression genome-wide. Publicly available Genomic Regions Enrichment of Annotations Tool, and datasets from promoter capture Hi-C (PCHiC) and GWAS on diabetes, obesity and BMI were used to analyze functions/disease relevance of Es/SEs. ChIP/RT-qPCRs were used to validate ChIP-/RNA-seq results. Functions of SEs were determined using JQ1 (SE/BET bromodomain inhibitor). Results: ChIP-seq results showed PA extensively dysregulated Es/SEs in CD14 + monocytes vs. vehicle control. PA-regulated Es/SEs showed enrichment of immune system related processes, differentiation, and cytokine production. RNA-seq showed significant correlations between dysregulated enhancers and differential expression of nearby genes. These genes were also altered in adipose tissue macrophages from high fat fed mice, and bone marrow derived macrophages from type2 diabetic db/db mice and Apoe -/- mice with accelerated atherosclerosis. Differentially regulated Es/SEs harbored SNPs associated with diabetes, obesity, and BMI. PCHiC revealed interactions between Es/SEs and promoters of key genes associated with efferocytosis ( MERTK ), metabolism ( OSBPL8 ) and inflammation ( IRAK2, CSF2 and RIPK2 ). Changes in gene expression and H3K27ac at Es/SEs were validated. Treatment with JQ1 reversed PA-induced inflammatory genes in monocytes. Conclusions: PA treatment dysregulated Es/SEs involved in key monocyte functions including efferocytosis, inflammation and metabolism. Targeting such epigenetic mechanisms could be beneficial in the treatment of cardiometabolic diseases.

The The multifaceted functions of mineralocorticoid receptor in cardiometabolic disease

Cardiometabolic diseases (CMDs), which cause 31% of all global deaths, are one of the greatest public health challenges. Mineralocorticoid receptor (MR), as a key nuclear transcription factor, is an important drug target for the treatment of CMDs. It is known that MR is expressed in almost all tissues and organs involved in cardiovascular homeostasis, including immune tissue, adipose tissue, brain, heart, kidney, and blood vessels. In the pathophysiology of CMDs, MR exerts different functions in different tissues and cells. This review summarizes the roles of MR in various cell types and discusses the molecular mechanisms through which MR exerts it functions in CMDs.

A nutritional supplement based on a synbiotic combination of Bacillus subtilis DSM 32315 and L-alanyl-L-glutamine improves glucose metabolism in healthy prediabetic subjects - A real-life post-marketing study.

Impaired glucose homeostasis is a significant risk factor for cardiometabolic diseases, whereas the efficacy of available standard therapies is limited, mainly because of poor adherence. This post-marketing study assessed the glucose-lowering potential of a synbiotic-based formulation. One hundred ninety-two participants were enrolled in a digital nutrition program with continuous glucose monitoring (CGM) and received a study product comprising Bacillus subtilis DSM 32315 and L-alanyl-L-glutamine. Participants underwent a first sensor phase without supplementation, followed by a 14-day supplementation phase without sensor, and completed by a second sensor phase while continuing supplementation. Fasting glucose levels were determined before and after supplementation by CGM. In addition, the postprandial glycemic response to an oral glucose challenge, body weight, HbA1c concentrations, and BMI was analyzed. Subgroup analyses of subjects with elevated glucose and HbA1c levels vs. normoglycemic subjects were performed. Supplementation with the study product resulted in significant improvements in glucose parameters (delta values: fasting glucose -2,13% ± 8.86; iAUC0-120 -4.91% ± 78.87; HbA1c: -1.20% ± 4.72) accompanied by a significant weight reduction (-1.07 kg ± 2.30) in the study population. Subgroup analyses revealed that the improvements were mainly attributed to a prediabetic subgroup with elevated fasting glucose and HbA1c values before supplementation (delta values: fasting glucose -6.10% 4± 7.89; iAUC0-120 -6.28% ± 115.85; HbA1c -3.31% ± 4.36; weight: -1.47 kg ± 2.82). This study indicates that the synbiotic composition is an effective and convenient approach to counteract hyperglycemia. Further placebo-controlled studies are warranted to test its efficacy in the treatment of cardiometabolic diseases.

Oral Bioavailability-Enhancing and Anti-obesity Effects of Hydroxysafflor Yellow A in Natural Deep Eutectic Solvent.

Hydroxysafflor yellow A (HSYA), a primary active component in Carthami Flos, has been extensively applied in the treatment of cardiometabolic diseases. In this study, a natural deep eutectic solvent composed of glucose and choline chloride with 10% (v/v) of water (90% GCH) was evaluated to enhance the oral absorption of HSYA. Compared with HSYA in water, the relative oral bioavailability of HSYA in 90% GCH was increased to 326.08%. Furthermore, 90% GCH was demonstrated to decrease the mucus viscosity and increase the absorption rate constant of HSYA in the jejunum by 2.95 times. A pharmacodynamic study revealed that HSYA in 90% GCH was more effective in reducing body weight and correcting steatohepatitis and dyslipidemia in high-fat diet-induced obese rats. Serum metabolomics results showed that the correction of serum aromatic amino acid disorder may contribute to the anti-obesity effect of HSYA in 90% GCH. In conclusion, 90% GCH could be a delivery carrier for HSYA against obesity.

Curcumin - The Nutraceutical With Pleiotropic Effects? Which Cardiometabolic Subjects Might Benefit the Most?

Despite continuous advances in pharmacotherapy, atherosclerotic cardiovascular disease remains the world's leading killer. Atherosclerosis relates not only to an increased level of cholesterol, but involves the development of atherosclerotic plaques, which are formed as a result of processes including inflammation and oxidative stress. Therefore, in addition to the classical risk factors for ASCVD (such as type 2 diabetes, overweight, obesity, hypertension and metabolic syndrome), residual risk factors such as inflammation and oxidative stress should also be reduced. The most important intervention in ASCVD is prevention, which includes promoting a healthy diet based on products of natural origin. Curcumin, which is often present in the diet, has been demonstrate to confer several benefits to health. It has been shown in numerous clinical trials that curcumin exhibited anti-diabetic, lipid-lowering, antihypertensive, antioxidant and anti-inflammatory effects, as well as promoting weight loss. All this means that curcumin has a comprehensive impact on the most important risk factors of ASCVD and may be a beneficial support in the treatment of these diseases. Recently, it has also been shown that curcumin may have a beneficial effect on the course of SARS-CoV-2 infection and might be helpful in the prevention of long-COVID complications. The aim of this review is to summarize the current knowledge regarding the safety and efficacy of curcumin in the prevention and treatment of cardiometabolic diseases.

Emerging Roles and Mechanism of m6A Methylation in Cardiometabolic Diseases

Cardiometabolic diseases (CMDs) are currently the leading cause of death and disability worldwide, and their underlying regulatory mechanisms remain largely unknown. N6-methyladenosine (m6A) methylation, the most common and abundant epigenetic modification of eukaryotic mRNA, is regulated by m6A methyltransferase, demethylase, and the m6A binding protein, which affect the transcription, cleavage, translation, and degradation of target mRNA. m6A methylation plays a vital role in the physiological and pathological processes of CMDs. In this review, we summarize the role played by m6A methylation in CMDs, including obesity, hypertension, pulmonary hypertension, ischemic heart disease, myocardial hypertrophy, heart failure, and atherosclerosis. We also describe mechanisms that potentially involve the participation of m6A methylation, such as those driving calcium homeostasis, circadian rhythm, lipid metabolism, autophagy, macrophage response, and inflammation. m6A methylation and its regulators are expected to be targets for the treatment of CMDs.

Beneficial effects of psyllium on the prevention and treatment of cardiometabolic diseases

Cardiometabolic diseases are reaching epidemic proportions worldwide. Dietary fiber intake can improve the risk factors associated with CMD. Psyllium, especially its husk, is one of the most widely used dietary fiber supplements, which is often used to enrich cereals and other food products. Numerous pharmacological studies have investigated the active ingredients and therapeutic effects of psyllium and its extracts, including antioxidant, anti-tumor, antidiabetic, hypotensive, anti-inflammation, neuroprotection, antidiarrheal, and antiviral activities. In this review, we will summarize the available studies on the therapeutic potential and possible mechanisms of psyllium in treating CMDs, such as hyperlipidemia, diabetes mellitus, and its complications, hypertension, hyperuricemia and obesity, and its applications in food systems.

Quality Matters as Much as Quantity of Skeletal Muscle: Clinical Implications of Myosteatosis in Cardiometabolic Health.

Although age-related changes in skeletal muscles are closely associated with decreases in muscle strength and functional decline, their associations with cardiometabolic diseases in the literature are inconsistent. Such inconsistency could be explained by the fact that muscle quality—which is closely associated with fatty infiltration of the muscle (i.e., myosteatosis)—is as important as muscle quantity in cardiometabolic health. However, muscle quality has been less explored compared with muscle mass. Moreover, the standard definition of myosteatosis and its assessment methods have not been established yet. Recently, some techniques using single axial computed tomography (CT) images have been introduced and utilized in many studies, as the mass and quality of abdominal muscles could be measured opportunistically on abdominal CT scans obtained during routine clinical care. Yet, the mechanisms by which myosteatosis affect metabolic and cardiovascular health remain largely unknown. In this review, we explore the recent advances in the assessment of myosteatosis and its changes associated with aging. We also review the recent literature on the clinical implication of myosteatosis by focusing on metabolic and cardiovascular diseases. Finally, we discuss the challenges and unanswered questions that need addressing to set myosteatosis as a therapeutic target for the prevention or treatment of cardiometabolic diseases.

Exercise, Physical Activity, and Cardiometabolic Health: Insights into the Prevention and Treatment of Cardiometabolic Diseases.

Physical activity (PA) and exercise are widely recognized as essential components of primary and secondary cardiovascular disease (CVD) prevention efforts and are emphasized in the health promotion guidelines of numerous professional societies and committees. The protean benefits of PA and exercise extend across the spectrum of CVD, and include the improvement and reduction of risk factors and events for atherosclerotic CVD (ASCVD), cardiometabolic disease, heart failure, and atrial fibrillation (AF), respectively. Here, we highlight recent insights into the salutary effects of PA and exercise on the primary and secondary prevention of ASCVD, including their beneficial effects on both traditional and nontraditional risk mediators; exercise "prescriptions" for ASCVD; the role of PA regular exercise in the prevention and treatment of heart failure; and the relationships between, PA, exercise, and AF. While our understanding of the relationship between exercise and CVD has evolved considerably, several key questions remain including the association between extreme volumes of exercise and subclinical ASCVD and its risk; high-intensity exercise and resistance (strength) training as complementary modalities to continuous aerobic exercise; and dose- and intensity-dependent associations between exercise and AF. Recent advances in molecular profiling technologies (ie, genomics, transcriptomics, proteomics, and metabolomics) have begun to shed light on interindividual variation in cardiometabolic responses to PA and exercise and may provide new opportunities for clinical prediction in addition to mechanistic insights.

Abstract P158: Hepatic Trib1 Induces Proteosome-dependent Degradation Of C/ebpα In A Cop1- And Stk40- Dependent Manner

The gene tribbles pseudokinase 1 ( TRIB1 ) has been repeatedly linked to multiple human cardiometabolic traits through genome-wide association studies, including coronary artery disease, plasma cholesterol and triglycerides, and circulating liver transaminases, signaling that TRIB1 is a key regulator of liver metabolism and health. Studies in liver specific Trib1 KO mice have shown that hepatic TRIB1 regulates de novo lipogenesis and steatosis through the regulation of protein levels of the transcription factor C/EBPα, yet the mechanism governing this relationship in hepatocytes has not been investigated. We demonstrate here that human TRIB1 promotes the degradation of C/EBPα in both a COP1- and proteasome-dependent manner in human hepatoma cells. We also observe rapid degradation of TRIB1 protein in hepatoma cells, and find that this is also COP1- and proteasome-dependent. To identify hepatocyte-specific interacting partners of TRIB1 that regulate these processes, we performed tandem-affinity purification of TRIB1 in Huh7 cells and subsequent mass-spec analysis, and identified multiple novel TRIB1 binding partners including the pseudokinases serine/threonine kinase 38 (STK38) and 40 (STK40). We confirmed these interactions in vitro and found that STK40, but not STK38, is required for TRIB1-mediated proteasomal degradation of C/EBPα. Together, our results reveal that TRIB1 induces proteasomal degradation of CEBP/α in a COP1- and proteasome-dependent manner in human hepatocytes. Further, we identify the pseudokinase STK40 as a novel regulator of hepatic TRIB1 function, and ongoing work aims to investigate the role of STK40 in hepatic lipid metabolism. Finally, we show that TRIB1 is itself degraded by the proteosome in a COP1-dependent manner. As increased hepatic Trib1 confers a beneficial metabolic profile in mice, these findings could provide a novel avenue for therapeutic targeting of TRIB1 in the treatment of cardiometabolic disease. Overall, our findings add greater detail to the molecular mechanisms governing the regulation of metabolism by hepatic TRIB1, a gene which human genetics highlights as a crucial regulator of cardiometabolic traits in humans.

Current Knowledge on Functionality and Potential Therapeutic Uses of Donkey Milk.

Simple SummaryThis paper examines scientific evidence on the positive effects of donkey milk consumption on human health and its possible therapeutic applications. The most investigated clinical use of donkey milk is in feeding infants with food allergies, in whom donkey milk is well tolerated in the 82.6–98.5% of cases. Donkey milk has shown several beneficial properties, including immunomodulatory activity, antioxidant and detoxifying effects, modulation of the intestinal microbiota, and lowering of blood sugar and triglycerides, which have been tested almost exclusively in experimental animals. Inhibitory actions on microorganisms have been also observed in vitro studies. This literature review highlights the need for new clinical trials to collect stronger evidence about the positive effects observed in experimental models which could lead to new therapeutic applications of donkey milk in humans.The increase of knowledge on the composition of donkey milk has revealed marked similarities to human milk, which led to a growing number of investigations focused on testing the potential effects of donkey milk in vitro and in vivo. This paper examines the scientific evidence regarding the beneficial effects of donkey milk on human health. Most clinical studies report a tolerability of donkey milk in 82.6–98.5% of infants with cow milk protein allergies. The average protein content of donkey milk is about 18 g/L. Caseins, which are main allergenic components of milk, are less represented compared to cow milk (56% of the total protein in donkey vs. 80% in cow milk). Donkey milk is well accepted by children due to its high concentration of lactose (about 60 g/L). Immunomodulatory properties have been reported in one study in humans and in several animal models. Donkey milk also seems to modulate the intestinal microbiota, enhance antioxidant defense mechanisms and detoxifying enzymes activities, reduce hyperglycemia and normalize dyslipidemia. Donkey milk has lower calorie and fat content compared with other milks used in human nutrition (fat ranges from 0.20% to 1.7%) and a more favourable fatty acid profile, being low in saturated fatty acids (3.02 g/L) and high in alpha-linolenic acid (about 7.25 g/100 g of fat). Until now, the beneficial properties of donkey milk have been mostly related to whey proteins, among which β-lactoglobulin is the most represented (6.06 g/L), followed by α-lactalbumin (about 2 g/L) and lysozyme (1.07 g/L). So far, the health functionality of donkey milk has been tested almost exclusively on animal models. Furthermore, in vitro studies have described inhibitory action against bacteria, viruses, and fungi. From the literature review emerges the need for new randomized clinical trials on humans to provide stronger evidence of the potential beneficial health effects of donkey milk, which could lead to new applications as an adjuvant in the treatment of cardiometabolic diseases, malnutrition, and aging.