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The efficacy of functional lipids with antioxidant properties in reducing cardiovascular risk has not been consistent. Randomized controlled trials (RCTs) reporting estimates for the effects of antioxidant functional lipid supplementations on cardiometabolic risk factors were searched up to 1 May 2024. Overall, antioxidant lipid supplementations, compared with placebo, had favorable effects on systolic blood pressure (lycopene: −1.95 [−3.54, −0.36] mmHg), low-density lipoprotein cholesterol (n6 fatty acid: −0.39 [−0.71, −0.06] mmol/L; astaxanthin: −0.11 [−0.21, −0.01] mmol/L), high-density lipoprotein cholesterol (n3 fatty acid: 0.20 [0.13, 0.27] mmol/L; n6 fatty acid: 0.08 [0.01, 0.14] mmol/L; astaxanthin: 0.13 [0.05, 0.21] mmol/L), total cholesterol (n6 fatty acid: −0.24 [−0.37, −0.11] mmol/L; astaxanthin: −0.22 [−0.32, −0.12] mmol/L; beta-carotene: −0.13 [−0.23, −0.04] mmol/L), triglyceride (n3 fatty acid: −0.37 [−0.47, −0.28] mmol/L; astaxanthin: −0.46 [−0.83, −0.10] mmol/L), and fasting blood insulin (astaxanthin: −2.66 [−3.98, −1.34] pmol/L). The benefits of antioxidant lipid supplementations appeared to be most evident in blood pressure and blood lipids in participants with different cardiometabolic health statuses. Notably, n9 fatty acid increased triglyceride and hemoglobin A1C in the total population, which increases CVD risk. Antioxidant lipid supplementations ameliorate cardiometabolic risk factors, while their effect may depend on type and cardiometabolic health status. Long-term RCTs are needed to corroborate risk–benefit ratios across different antioxidant functional lipid supplementation settings. [ABSTRACT FROM AUTHOR]

Background: Sarcopenia is an age-related condition characterized by progressive loss of muscle mass, strength, and function. The occurrence of sarcopenia has a huge impact on physical, psychological, and social health. Therefore, the prevention and treatment of sarcopenia is becoming an important public health issue. Method: 35 six-week-old male C57BL/6 mice were randomly divided into five groups, one of which served as a control group, while the rest of the groups were constructed as a model of sarcopenia by intraperitoneal injection of D-galactose. The intervention with lactoferrin, creatine, and their mixtures, respectively, was carried out through gavage for 8 weeks. Muscle function was assessed based on their endurance, hanging time, and grip strength. The muscle tissues were weighed to assess the changes in mass, and the muscle RNA was extracted for myogenic factor expression and transcriptome sequencing to speculate on the potential mechanism of action by GO and KEGG enrichment analysis. Result: The muscle mass (lean mass, GAS index), and muscle function (endurance, hanging time, and grip strength) decreased, and the size and structure of myofiber was smaller in the model group compared to the control group. The intervention with lactoferrin and creatine, either alone or combination, improved muscle mass and function, restored muscle tissue, and increased the expression of myogenic regulators. The combined group demonstrated the most significant improvement in these indexes. The RNA-seq results revealed enrichment in the longevity-regulated pathway, MAPK pathway, focal adhesion, and ECM–receptor interaction pathway in the intervention group. The intervention group may influence muscle function by affecting the proliferation, differentiation, senescence of skeletal muscle cell, and contraction of muscle fiber. The combined group also enriched the mTOR-S6K/4E-BPs signaling pathway, PI3K-Akt signaling pathway, and energy metabolism-related pathways, including Apelin signaling, insulin resistance pathway, and adipocytokine signaling pathway, which affect energy metabolism in muscle. Conclusions: Lactoferrin and creatine, either alone or in combination, were found to inhibit the progression of sarcopenia by influencing the number and cross-sectional area of muscle fibers and muscle protein synthesis. The combined intervention appears to exert a more significant effect on energy metabolism. [ABSTRACT FROM AUTHOR]

Background: The discovery of traditional plants' medicinal and nutritional properties has opened up new avenues for developing pharmaceutical and dietary strategies to prevent atherosclerosis. However, the effect of the antioxidant Dendrobium officinale polysaccharide (DOP) on atherosclerosis is still not elucidated. Purpose: This study aims to investigate the inhibitory effect and the potential mechanism of DOP on high-fat diet-induced atherosclerosis in Apolipoprotein E knockout (ApoE−/−) mice. Study design and methods: The identification of DOP was measured by high-performance gel permeation chromatography (HPLC) and Fourier transform infrared spectroscopy (FTIR). We used high-fat diet (HFD)-induced atherosclerosis in ApoE−/− mice as an animal model. In the DOP intervention stage, the DOP group was treated by gavage with 200 μL of 200 mg/kg DOP at regular times each day and continued for eight weeks. We detected changes in serum lipid profiles, inflammatory factors, anti-inflammatory factors, and antioxidant capacity to investigate the effect of the DOP on host metabolism. We also determined microbial composition using 16S rRNA gene sequencing to investigate whether the DOP could improve the structure of the gut microbiota in atherosclerotic mice. Results: DOP effectively inhibited histopathological deterioration in atherosclerotic mice and significantly reduced serum lipid levels, inflammatory factors, and malondialdehyde (F/B) production. Additionally, the levels of anti-inflammatory factors and the activity of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), were significantly increased after DOP intervention. Furthermore, we found that DOP restructures the gut microbiota composition by decreasing the Firmicutes/Bacteroidota (F/B) ratio. The Spearman's correlation analysis indicated that serum lipid profiles, antioxidant activity, and pro-/anti-inflammatory factors were associated with Firmicutes, Bacteroidota, Allobaculum, and Coriobacteriaceae_UCG-002. Conclusions: This study suggests that DOP has the potential to be developed as a food prebiotic for the treatment of atherosclerosis in the future. [ABSTRACT FROM AUTHOR]

Mutations of the FBN1 gene lead to Marfan syndrome (MFS), which is an autosomal dominant connective tissue disorder featured by thoracic aortic aneurysm risk. There is currently no effective treatment for MFS. Here, we studied the role of mitochondrial dysfunction in the phenotypic transformation of human smooth muscle cells (SMCs) and whether a mitochondrial boosting strategy can be a potential treatment. We knocked down FBN1 in SMCs to create an MFS cell model and used rotenone to induce mitochondrial dysfunction. Furthermore, we incubated the shFBN1 SMCs with Coenzyme Q10 (CoQ10) to assess whether restoring mitochondrial function can reverse the phenotypic transformation. The results showed that shFBN1 SMCs had decreased TFAM (mitochondrial transcription factor A), mtDNA levels and mitochondrial mass, lost their contractile capacity and had increased synthetic phenotype markers. Inhibiting the mitochondrial function of SMCs can decrease the expression of contractile markers and increase the expression of synthetic genes. Imposing mitochondrial stress causes a double-hit effect on the TFAM level, oxidative phosphorylation and phenotypic transformation of FBN1-knockdown SMCs while restoring mitochondrial metabolism with CoQ10 can rapidly reverse the synthetic phenotype. Our results suggest that mitochondria function is a potential therapeutic target for the phenotypic transformation of SMCs in MFS. [ABSTRACT FROM AUTHOR]

Inconsistent findings exist regarding the relationship between heme iron intake and type 2 diabetes (T2D) among Western and Eastern populations. Easterners tend to consume a plant-based diet which is abundant in antioxidant minerals. To examine the hypothesis that antioxidant mineral may modify the relationship between iron and T2D, we performed a case–control study by measuring the serum mineral levels in 2198 Chinese subjects. A total of 2113 T2D patients and 2458 controls were invited; 502 T2D patients and 1696 controls were finally analyzed. In the total population, high serum iron showed a positive association with T2D odds (odds ratio [OR] = 1.27 [1.04, 1.55]); high magnesium (OR = 0.18 [0.14, 0.22]), copper (OR = 0.27 [0.21, 0.33]), zinc (OR = 0.37 [0.30, 0.46]), chromium (OR = 0.61 [0.50, 0.74]), or selenium concentrations (OR = 0.39 [0.31, 0.48]) were inversely associated with T2D odds. In contrast, in individuals with higher magnesium (>2673.2 µg/dL), zinc (>136.7 µg/dL), copper (>132.1 µg/dL), chromium (>14.0 µg/dL), or selenium concentrations (>16.8 µg/dL), serum iron displayed no association with T2D (p > 0.05). Serum copper and magnesium were significant modifiers of the association between iron and T2D in individuals with different physiological status (p < 0.05). Our findings support the idea that consuming a diet rich in antioxidant minerals is an effective approach for preventing T2D. [ABSTRACT FROM AUTHOR]

Background and Aims Stanford type A aortic dissection (AD) is a degenerative aortic remodelling disease marked by an exceedingly high mortality without effective pharmacologic therapies. Smooth muscle cells (SMCs) lining tunica media adopt a range of states, and their transformation from contractile to synthetic phenotypes fundamentally triggers AD. However, the underlying pathomechanisms governing this population shift and subsequent AD, particularly at distinct disease temporal stages, remain elusive. Methods Ascending aortas from nine patients undergoing ascending aorta replacement and five individuals undergoing heart transplantation were subjected to single-cell RNA sequencing. The pathogenic targets governing the phenotypic switch of SMCs were identified by trajectory inference, functional scoring, single-cell regulatory network inference and clustering, regulon, and interactome analyses and confirmed using human ascending aortas, primary SMCs, and a β-aminopropionitrile monofumarate–induced AD model. Results The transcriptional profiles of 93 397 cells revealed a dynamic temporal-specific phenotypic transition and marked elevation of the activator protein-1 (AP-1) complex, actively enabling synthetic SMC expansion. Mechanistically, tumour necrosis factor signalling enhanced AP-1 transcriptional activity by dampening mitochondrial oxidative phosphorylation (OXPHOS). Targeting this axis with the OXPHOS enhancer coenzyme Q10 or AP-1-specific inhibitor T-5224 impedes phenotypic transition and aortic degeneration while improving survival by 42.88% (58.3%–83.3% for coenzyme Q10 treatment), 150.15% (33.3%–83.3% for 2-week T-5224), and 175.38% (33.3%–91.7% for 3-week T-5224) in the β-aminopropionitrile monofumarate–induced AD model. Conclusions This cross-sectional compendium of cellular atlas of human ascending aortas during AD progression provides previously unappreciated insights into a transcriptional programme permitting aortic degeneration, highlighting a translational proof of concept for an anti-remodelling intervention as an attractive strategy to manage temporal-specific AD by modulating the tumour necrosis factor–OXPHOS–AP-1 axis. [ABSTRACT FROM AUTHOR]

Dandelion (Taraxacum officinale), a member of the Asteraceae (Compositae) family, is well known as the traditional medical plant. Dandelion polysaccharides, a natural active ingredient extracted from the dandelion, possess immune regulation, anti-inflammatory, antioxidant, and anti-aggregation properties. These properties suggest that dandelion polysaccharides might alleviate atherosclerosis. Using an ApoE−/− atherosclerotic mice model fed a high-fat diet, we investigated the impact and potential mechanism of dandelion polysaccharides on atherosclerosis. We observed that dandelion polysaccharides significantly reduced the levels of triglyceride, total cholesterol, and low-density lipoprotein-cholesterol in serum, while elevated the high-density lipoprotein-cholesterol level. Concomitantly, dandelion polysaccharides reduced the area of atherosclerotic lesions and necrotic core of the aortic sinus, and increased the collagen content. Mechanistic studies showed that dandelion polysaccharides were effective in reducing serum malondialdehyde levels while elevating the enzymatic activities of superoxide dismutase and glutathione peroxidase. Furthermore, dandelion polysaccharides reduced the expression of chemotactic factor Mcp-1 and pro-inflammatory cytokines (Tnf-α, Il-1β, and Il-6) in atherosclerotic lesions. Overall, these results indicated that dandelion polysaccharides may take an important part in the attenuation of atherosclerosis via its antioxidant and anti-inflammatory properties. [ABSTRACT FROM AUTHOR]

Vascular inflammation triggers the development of thoracic aortic dissection (TAD). Zinc deficiency could dampen tissue inflammation. However, the role of zinc as a nutritional intervention in the progression of TAD remains elusive. In this study, we employed a classical β-aminopropionitrile monofumarate (BAPN)-induced TAD model in mice treated with low zinc and observed that the TAD progression was greatly ameliorated under low zinc conditions. Our results showed that low zinc could significantly improve aortic dissection and rupture (BAPN + low zinc vs. BAPN, 36% vs. 100%) and reduce mortality (BAPN + low zinc vs. BAPN, 22% vs. 57%). Mechanically, low zinc attenuated the infiltration of macrophages and inhibited the expression of inflammatory cytokines, suppressed the phenotype switch of vascular smooth muscle cells from contractile to synthetic types, and eventually alleviated the development of TAD. In conclusion, this study suggested that low zinc may serve as a potential nutritional intervention approach for TAD prevention. [ABSTRACT FROM AUTHOR]

An editorial focuses on the impact of proteins and polysaccharides on health and disease prevention. It emphasize their role in reducing inflammation, oxidative stress, and improving overall health. It is further reported that this research provides a foundation for considering these nutrients in dietary guidance for disease management.

Vascular remodeling is a common pathological hallmark of many cardiovascular diseases. Vascular smooth muscle cells (VSMCs) are the predominant cell type lining the tunica media and play a crucial role in maintaining aortic morphology, integrity, contraction and elasticity. Their abnormal proliferation, migration, apoptosis and other activities are tightly associated with a spectrum of structural and functional alterations in blood vessels. Emerging evidence suggests that mitochondria, the energy center of VSMCs, participate in vascular remodeling through multiple mechanisms. For example, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)-mediated mitochondrial biogenesis prevents VSMCs from proliferation and senescence. The imbalance between mitochondrial fusion and fission controls the abnormal proliferation, migration and phenotypic transformation of VSMCs. Guanosine triphosphate-hydrolyzing enzymes, including mitofusin 1 (MFN1), mitofusin 2 (MFN2), optic atrophy protein 1 (OPA1) and dynamin-related protein 1 (DRP1), are crucial for mitochondrial fusion and fission. In addition, abnormal mitophagy accelerates the senescence and apoptosis of VSMCs. PINK/Parkin and NIX/BINP3 pathways alleviate vascular remodeling by awakening mitophagy in VSMCs. Mitochondrial DNA (mtDNA) damage destroys the respiratory chain of VSMCs, resulting in excessive ROS production and decreased ATP levels, which are related to the proliferation, migration and apoptosis of VSMCs. Thus, maintaining mitochondrial homeostasis in VSMCs is a possible way to relieve pathologic vascular remodeling. This review aims to provide an overview of the role of mitochondria homeostasis in VSMCs during vascular remodeling and potential mitochondria-targeted therapies. [ABSTRACT FROM AUTHOR]

Autophagy is a multi-step catabolic process that delivers cellular components to lysosomes for degradation and recycling. The dysregulation of this precisely controlled process disrupts cellular homeostasis and leads to many pathophysiological conditions. The mechanistic target of rapamycin (mTOR) is a central nutrient sensor that integrates growth signals with anabolism to fulfil biosynthetic and bioenergetic requirements. mTOR nucleates two distinct evolutionarily conserved complexes (mTORC1 and mTORC2). However, only mTORC1 is acutely inhibited by rapamycin. Consequently, mTORC1 is a well characterized regulator of autophagy. While less is known about mTORC2, the availability of acute small molecule inhibitors and multiple genetic models has led to increased understanding about the role of mTORC2 in autophagy. Emerging evidence suggests that the regulation of mTORC2 in autophagy is mainly through its downstream effector proteins, and is variable under different conditions and cellular contexts. Here, we review recent advances that describe a role for mTORC2 in this catabolic process, and propose that mTORC2 could be a potential clinical target for the treatment of autophagy-related diseases. 9Lt7sUyeer2rpHK_6kHuux Video abstract [ABSTRACT FROM AUTHOR]

Antioxidant minerals including zinc, copper and selenium play critical roles in the maintenance of the redox balance in the body. However, their influences on type 2 diabetes mellitus (T2DM) are still inconclusive in Chinese populations. To elucidate the relationship between antioxidant minerals and T2DM, serum zinc, copper and selenium concentrations were measured in 1443 Chinese urban residents using a 1:2 matched case-control study. Conditional logistic regression models (CLR) were used to obtain the odds ratios (ORs) and 95% confidence intervals (CIs), and restricted cubic splines (RCS) were used to examine their dose–response associations. Serum zinc (OR = 0.52 [0.35, 0.77]) and copper concentrations (OR = 0.25 [0.17, 0.37]) were negatively associated with T2DM in a fully adjusted model. An L-shaped zinc-T2DM association (Poverall association = 0.003, and Pnonlinearity = 0.005) and a negative linear copper-T2DM association (Poverall association < 0.0001, and Pnonlinearity = 0.395) were observed. No association was found between serum selenium and T2DM in fully adjusted CLR or RCS models. In addition, joint associations with T2DM were identified between serum zinc and copper and between serum selenium and copper. In conclusion, our study emphasizes the importance of an adequate intake of antioxidant minerals for T2DM prevention in the Chinese population. [ABSTRACT FROM AUTHOR]

High mortality rates due to cardiovascular diseases (CVDs) have attracted worldwide attention. It has been reported that mitochondrial dysfunction is one of the most important mechanisms affecting the pathogenesis of CVDs. Mitochondrial DNA (mtDNA) mutations may result in impaired oxidative phosphorylation (OXPHOS), abnormal respiratory chains, and ATP production. In dysfunctional mitochondria, the electron transport chain (ETC) is uncoupled and the energy supply is reduced, while reactive oxygen species (ROS) production is increased. Here, we discussed and analyzed the relationship between mtDNA mutations, impaired mitophagy, decreased OXPHOS, elevated ROS, and CVDs from the perspective of mitochondrial dysfunction. Furthermore, we explored current potential therapeutic strategies for CVDs by eliminating mtDNA mutations (e.g., mtDNA editing and mitochondrial replacement), enhancing mitophagy, improving OXPHOS capacity (e.g., supplement with NAD+, nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and nano-drug delivery), and reducing ROS (e.g., supplement with Coenzyme Q10 and other antioxidants), and dissected their respective advantages and limitations. In fact, some therapeutic strategies are still a long way from achieving safe and effective clinical treatment. Although establishing effective and safe therapeutic strategies for CVDs remains challenging, starting from a mitochondrial perspective holds bright prospects. [ABSTRACT FROM AUTHOR]

The elderly proportion of the population is gradually increasing, which poses a great burden to society, the economy, and the medical field. Aging is a physiological process involving multiple organs and numerous reactions, and therefore it is not easily explained or defined. At present, a growing number of studies are focused on the mechanisms of aging and potential strategies to delay aging. Some clinical drugs have been demonstrated to have anti-aging effects; however, many still have deficits with respect to safety and long-term use. Polysaccharides are natural and efficient biological macromolecules that act as antioxidants, anti-inflammatories, and immune regulators. Not surprisingly, these molecules have recently gained attention for their potential use in anti-aging therapies. In fact, multiple polysaccharides have been found to have excellent anti-aging effects in different animal models including Caenorhabditis elegans, Drosophila melanogaster, and mice. The anti-aging qualities of polysaccharides have been linked to several mechanisms, such as improved antioxidant capacity, regulation of age-related gene expression, and improved immune function. Here, we summarize the current findings from research related to anti-aging polysaccharides based on various models, with a focus on the main anti-aging mechanisms of oxidative damage, age-related genes and pathways, immune modulation, and telomere attrition. This review aims to provide a reference for further research on anti-aging polysaccharides. [ABSTRACT FROM AUTHOR]

Casein hydrolysate has various biological functional activities, especially prominent are angiotensin I-converting enzyme inhibitory activities. Increasing evidence has reported the prominent hypotensive effect of casein hydrolysate. However, the effects of casein hydrolysate on cardiovascular risk factors remain unclear and require more comprehensive and detailed studies. Here, we conducted a systematic review and meta-analysis on eligible randomized controlled trials (RCTs) to summarize the effects of casein hydrolysate supplementation on blood pressure, blood lipids, and blood glucose. In the pooled analyses, casein hydrolysate significantly reduced systolic blood pressure by 3.20 mmHg (−4.53 to −1.87 mmHg) and diastolic blood pressure by 1.50 mmHg (−2.31 to −0.69 mmHg). Supplementation of casein hydrolysate displayed no effect on total cholesterol (−0.07 mmol/L; −0.17 to 0.03 mmol/L), low-density lipoprotein cholesterol (−0.04 mmol/L; −0.15 to 0.08 mmol/L), high-density lipoprotein cholesterol (−0.01 mmol/L; −0.06 to 0.03 mmol/L), triglycerides (−0.05 mmol/L, −0.14 to 0.05 mmol/L), or fasting blood glucose (−0.01 mmol/L; −0.10 to 0.09 mmol/L) compared with the placebo diets. Collectively, this study indicated that supplementation of casein hydrolysate displayed decreasing effect on blood pressure without affecting blood lipids or glycemic status. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOXO) is a potent chemotherapeutic drug widely used to treat various cancers. However, its clinical application is limited due to serious adverse effects on dose-dependent cardiotoxicity. Although the underlying mechanism has not been fully clarified, DOXO-induced cardiotoxicity has been mainly attributed to the accumulation of reactive oxygen species (ROS) in cardiomyocytes. Fucoidan, as a kind of sulphated polysaccharide existing in numerous brown seaweed, has potent anti-oxidant, immune-regulatory, anti-tumor, anti-coagulate and anti-viral activities. Here, we explore the potential protective role and mechanism of fucoidan in DOXO-induced cardiotoxicity in mice. Our results show that oral fucoidan supplement exerts potent protective effects against DOXO-induced cardiotoxicity by reducing oxidative stress and preventing mitochondrial function injury. The improved effect of fucoidan on DOXO-induced cardiotoxicity was evaluated by echocardiography, cardiac myocytes size and cardiac fibrosis analysis, and the expression of genes related to cardiac dysfunction and remodeling. Fucoidan reduced the ROS content and the MDA levels but enhanced the activity of antioxidant enzymes GSH-PX and SOD in the mouse serum in a DOXO-induced cardiotoxicity model. In addition, fucoidan also increased the ATP production capacity and restored the levels of a mitochondrial respiratory chain complex in heart tissue. Collectively, this study highlights fucoidan as a potential polysaccharide for protecting against DOXO-induced cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Mitochondria, as the main site of cellular energy metabolism and the generation of oxygen free radicals, are the key switch for mitochondria-mediated endogenous apoptosis. Ca2+ is not only an important messenger for cell proliferation, but it is also an indispensable signal for cell death. Ca2+ participates in and plays a crucial role in the energy metabolism, physiology, and pathology of mitochondria. Mitochondria control the uptake and release of Ca2+ through channels/transporters, such as the mitochondrial calcium uniporter (MCU), and influence the concentration of Ca2+ in both mitochondria and cytoplasm, thereby regulating cellular Ca2+ homeostasis. Mitochondrial Ca2+ transport-related processes are involved in important biological processes of tumor cells including proliferation, metabolism, and apoptosis. In particular, MCU and its regulatory proteins represent a new era in the study of MCU-mediated mitochondrial Ca2+ homeostasis in tumors. Through an in-depth analysis of the close correlation between mitochondrial Ca2+ and energy metabolism, autophagy, and apoptosis of tumor cells, we can provide a valuable reference for further understanding of how mitochondrial Ca2+ regulation helps diagnosis and therapy. [ABSTRACT FROM AUTHOR]

Background The iron-chelating activities of polyphenols raise concern whether there is a risk of iron deficiency or anemia induced by polyphenol supplementation. Results from clinical trials regarding the effects of polyphenol supplementation on iron status and erythropoiesis are inconclusive. Objective We performed a systematic review and meta-analysis of randomized controlled trials to determine the effects of polyphenol supplementation on iron status and erythropoiesis. Methods Published articles were searched between May 1988 and 7 December, 2020. Finally, we identified 34 randomized controlled trials. Random-effects meta-analyses were performed to obtain the weighted mean difference of serum iron (SI), transferrin saturation (TS), ferritin, and hemoglobin concentration. Funnel plots and Egger's test were used to determine the risk of bias. The robustness of the effect sizes was examined by sensitivity analysis. Results Polyphenol supplementation had an inhibitory effect on the SI concentration (–13.72 μg/dL; 95% CI: –20.74, –6.71) and TS (–3.10%; 95% CI: –4.93, –1.27), with no effect on ferritin (–9.34 ng/mL; 95% CI: –28.55, 9.87). Polyphenols increased the hemoglobin concentration (8.53 g/L; 95% CI: 3.33, 13.73). In healthy participants, polyphenol reduced the TS (–3.83%; 95% CI: –7.47, –0.19) and increased the hemoglobin concentration (12.87 g/L; 95% CI: 1.61, 24.14). Similarly, polyphenol reduced the SI concentration (–8.60 μg/dL; 95% CI: –16.10, –1.10) and increased the hemoglobin concentration (8.50 g/L; 95% CI: 0.86, 16.15) in patients with metabolic diseases. In patients with β-thalassemia, polyphenol decreased the SI concentration (–23.19 μg/dL; 95% CI: –35.84, –10.55), TS (–3.23%; 95% CI: –5.54, –0.91), and ferritin concentration (–223.62 ng/mL; 95% CI: –359.32, –87.91), but had no effect on the hemoglobin concentration. Conclusion Healthy individuals and patients with metabolic diseases may benefit from the positive impact of polyphenols on erythropoiesis. Patients with β-thalassemia may benefit from the effect of polyphenols on reducing SI. This trial was registered at PROSPERO (International prospective register of systematic reviews) as CRD42020161983. [ABSTRACT FROM AUTHOR]

Obesity and its related complications pose an increasing threat to human health; however, targetable obesity‐related membrane receptors are not yet elucidated. Here, the membrane receptor CD146 is demonstrated to play an essential role in obesity. In particular, CD146 acts as a new adipose receptor for angiopoietin‐like protein 2 (ANGPTL2), which is thought to act on endothelial cells to activate adipose inflammation. ANGPTL2 binds to CD146 to activate cAMP response element‐binding protein (CREB), which then upregulates CD146 during adipogenesis and adipose inflammation. CD146 is present in preadipocytes and mature adipocytes, where it is mediated by its ligands ANGPTL2 and galectin‐1. In preadipocytes, CD146 ablation suppresses adipogenesis, whereas the loss of CD146 in mature adipocytes suppresses lipid accumulation and enhances energy expenditure. Moreover, anti‐CD146 antibodies inhibit obesity by disrupting the interactions between CD146 and its ligands. Together, these findings demonstrate that ANGPTL2 directly affects adipocytes via CD146 to promote obesity, suggesting that CD146 can be a potential target for treating obesity. [ABSTRACT FROM AUTHOR]

Obesity and its related complications pose an increasing threat to human health; however, targetable obesity‐related membrane receptors are not yet elucidated. Here, the membrane receptor CD146 is demonstrated to play an essential role in obesity. In particular, CD146 acts as a new adipose receptor for angiopoietin‐like protein 2 (ANGPTL2), which is thought to act on endothelial cells to activate adipose inflammation. ANGPTL2 binds to CD146 to activate cAMP response element‐binding protein (CREB), which then upregulates CD146 during adipogenesis and adipose inflammation. CD146 is present in preadipocytes and mature adipocytes, where it is mediated by its ligands ANGPTL2 and galectin‐1. In preadipocytes, CD146 ablation suppresses adipogenesis, whereas the loss of CD146 in mature adipocytes suppresses lipid accumulation and enhances energy expenditure. Moreover, anti‐CD146 antibodies inhibit obesity by disrupting the interactions between CD146 and its ligands. Together, these findings demonstrate that ANGPTL2 directly affects adipocytes via CD146 to promote obesity, suggesting that CD146 can be a potential target for treating obesity. [ABSTRACT FROM AUTHOR]

The Hippo–YAP signaling pathway plays an essential role in epithelial cells during intestinal regeneration and tumorigenesis. However, the molecular mechanism linking stromal signals to YAP‐mediated intestinal regeneration and tumorigenesis is poorly defined. Here, we report a stroma–epithelium ISLR–YAP signaling axis essential for stromal cells to modulate epithelial cell growth during intestinal regeneration and tumorigenesis. Specifically, upon inflammation and in cancer, an oncogenic transcription factor ETS1 in stromal cells induces expression of a secreted protein ISLR that can inhibit Hippo signaling and activate YAP in epithelial cells. Deletion of Islr in stromal cells in mice markedly impaired intestinal regeneration and suppressed tumorigenesis in the colon. Moreover, the expression of stromal cell‐specific ISLR and ETS1 significantly increased in inflamed mucosa of human IBD patients and in human colorectal adenocarcinoma, accounting for the epithelial YAP hyperactivation. Collectively, our findings provide new insights into the signaling crosstalk between stroma and epithelium during tissue regeneration and tumorigenesis. Synopsis: YAP activation in the intestinal epithelium is linked to intestinal regeneration and tumorigenesis. Here, the mesenchyme‐derived extracellular protein ISLR is shown to mediate stroma‐epithelium crosstalk in the intestine to activate YAP both during regeneration and cancer formation. Stromal ISLR levels are increased in inflamed intestinal mucosa of human patients with inflammatory bowel disease and colorectal adenocarcinoma.Transcription factor ETS1 directly induces ISLR expression in stromal cells.In mice, deletion of Islr in stromal cells impairs intestinal regeneration and suppresses tumorigenesis in the colon.Stromal ISLR suppresses Hippo signaling in epithelial cells.Context‐dependent YAP activation via ISLR promotes either intestinal regeneration or tumorigenesis. [ABSTRACT FROM AUTHOR]

Isoenzyme c of horseradish peroxidase (HRP-C) is widely used in enzyme immunoassay combined with chemiluminescence (CL) detection. For this application, HRP-C activity measurement is usually based on luminol oxidation in the presence of hydrogen peroxide (H2O2). However, this catalysis reaction was enhancer dependent. In this study, we demonstrated that Jatropha curcas peroxidase (JcGP1) showed high efficiency in catalyzing luminol oxidation in the presence of H2O2. Compared with HRP-C, the JcGP1-induced reaction was enhancer independent, which made the enzyme-linked immunosorbent assay (ELISA) simpler. In addition, the JcGP1 catalyzed reaction showed a long-term stable CL signal. We optimized the conditions for JcGP1 catalysis and determined the favorable conditions as follows: 50 mM Tris buffer (pH 8.2) containing 10 mM H2O2, 14 mM luminol and 0.75 M NaCl. The optimum catalysis temperature was 30°C. The detection limit of JcGP1 under optimum condition was 0.2 pM. Long-term stable CL signal combined with enhancer-independent property indicated that JcGP1 might be a valuable candidate peroxidase for clinical diagnosis and enzyme immunoassay with CL detection. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Angiogenesis, a process that newly-formed blood vessels sprout from pre-existing ones, is vital for vertebrate development and adult homeostasis. Previous studies have demonstrated that the neuronal guidance molecule netrin-1 participates in angiogenesis and morphogenesis of the vascular system. Netrin-1 exhibits dual activities in angiogenesis: either promoting or inhibiting angiogenesis. The anti-angiogenic activity of netrin-1 is mediated by UNC5B receptor. However, how netrin-1 promotes angiogenesis remained unclear. Here we report that CD146, an endothelial transmembrane protein of the immunoglobulin superfamily, is a receptor for netrin-1. Netrin-1 binds to CD146 with high affinity, inducing endothelial cell activation and downstream signaling in a CD146-dependent manner. Conditional knockout of the cd146 gene in the murine endothelium or disruption of netrin-CD146 interaction by a specific anti-CD146 antibody blocks or reduces netrin-1-induced angiogenesis. In zebrafish embryos, downregulating either netrin-1a or CD146 results in vascular defects with striking similarity. Moreover, knocking down CD146 blocks ectopic vascular sprouting induced by netrin-1 overexpression. Together, our data uncover CD146 as a previously unknown receptor for netrin-1 and also reveal a functional ligand for CD146 in angiogenesis, demonstrating the involvement of netrin-CD146 signaling in angiogenesis during vertebrate development. [ABSTRACT FROM AUTHOR]

CD146 is a newly identified endothelial biomarker that has been implicated in angiogenesis. Though in vitro angiogenic function of CD146 has been extensively reported, in vivo evidence is still lacking. To address this issue, we generated endothelial-specific CD146 knockout (CD146) mice using the Tg(Tek-cre) system. Surprisingly, these mice did not exhibit any apparent morphological defects in the development of normal retinal vasculature. To evaluate the role of CD146 in pathological angiogenesis, a xenograft tumor model was used. We found that both tumor volume and vascular density were significantly lower in CD146 mice when compared to WT littermates. Additionally, the ability for sprouting, migration and tube formation in response to VEGF treatment was impaired in endothelial cells (ECs) of CD146 mice. Mechanistic studies further confirmed that VEGF-induced VEGFR-2 phosphorylation and AKT/p38 MAPKs/NF-κB activation were inhibited in these CD146-null ECs, which might present the underlying cause for the observed inhibition of tumor angiogenesis in CD146 mice. These results suggest that CD146 plays a redundant role in physiological angiogenic processes, but becomes essential during pathological angiogenesis as observed in tumorigenesis. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOXO) can be used to treat a variety of human tumors, but its clinical application is limited due to severe cardiotoxic side effect. Here, we explore the role of β-glucan in DOXO-induced cardiotoxicity in mice and study its underlying mechanism. When co-administered with DOXO, β-glucan was observed to prevent left ventricular dilation and fibrosis. In fact, DOXO reduces the activity of mitochondrial respiratory chain complex and enhances oxidative stress, which in turn impairs heart function. DOXO decreases the ATP production capacity of the heart and increases the ROS content, while β-glucan can restore the heart capacity and reduce oxidative stress. β-glucan also increases the activity of antioxidant enzymes GSH-PX and SOD, and reduces the level of MDA in the serum. In addition, the mRNAs of cardiac dysfunction marker genes ANP, BNP and Myh7 were significantly increased after DOXO induction, however, they did not increase when combined with β-glucan administration. In conclusion, our results indicate that β-glucan can improve the antioxidant capacity of the heart, thereby serving as a potential therapeutic strategy to prevent DOXO-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Ferrous sulfate is a commonly used iron supplement for the correction of iron-deficiency anemia but with frequent gastrointestinal side effects. Milk-derived iron-binding glycoprotein lactoferrin possesses well gastrointestinal tolerance and fewer side effects caused by the intake of high-dose iron. However, the underlying mechanism of the iron-enhancing effect of lactoferrin remains unclear. In addition, the comparative efficacies between lactoferrin and ferrous sulfate are also remained to be determined. We conducted a systematic review and meta-analysis on published intervention studies to investigate how lactoferrin modulate iron metabolism and evaluate the comparative effects between lactoferrin and ferrous sulfate supplementation on iron absorption, iron storage, erythropoiesis and inflammation. Lactoferrin supplementation had better effects on serum iron (WMD: 41.44 ug/dL; p < 0.00001), ferritin (WMD: 13.60 ng/mL; p = 0.003) and hemoglobin concentration (11.80 g/dL; p < 0.00001), but a reducing effect on fractional iron absorption (WMD: −2.08%; p = 0.02) and IL-6 levels (WMD: −45.59 pg/mL; p < 0.00001) compared with ferrous sulfate. In conclusion, this study supports lactoferrin as a superior supplement to ferrous sulfate regarding the improvement in serum iron parameters and hemoglobin levels. Considering the weak influence of lactoferrin on iron absorption, the anti-inflammation effect of lactoferrin may be the potential mechanism to explain its efficacy on iron status and erythropoiesis. [ABSTRACT FROM AUTHOR]

Cell adhesion molecules (CAMs) are crucial effectors for the development and maintenance of the nervous system. Mutations in human CAM genes are linked to brain disorders and psychological diseases, and CAM knockout mice always exhibit similar behavioral abnormalities. CD146 is a CAM of the immunoglobulin superfamily that interacts with Neurite Outgrowth Factor and involved in neurite extension in vitro. However, little is known about its in vivo function in the nervous system. In this study, we used a murine CD146 nervous system knockout (CD146ns-ko) model. We found that the brains of some CD146ns-ko mice were malformed with small olfactory bulbs. CD146ns-ko mice exhibited lower body weights and smaller food intake when compared with wild type littermates. Importantly, behavior tests revealed that CD146ns-ko mice exhibited significant decreased locomotor activity and impaired capacity for spatial learning and memory. Our results demonstrate that CD146 is important for mammalian nervous system development and proper behavior patterns. [ABSTRACT FROM AUTHOR]

Mitochondria are vital to life and provide biological energy for other organelles and cell physiological processes. On the mitochondrial double layer membrane, there are a variety of channels and transporters to transport different metal ions, such as Ca2+, K+, Na+, Mg2+, Zn2+ and Fe2+/Fe3+. Emerging evidence in recent years has shown that the metal ion transport is essential for mitochondrial function and cellular metabolism, including oxidative phosphorylation (OXPHOS), ATP production, mitochondrial integrity, mitochondrial volume, enzyme activity, signal transduction, proliferation and apoptosis. The homeostasis of mitochondrial metal ions plays an important role in maintaining mitochondria and cell functions and regulating multiple diseases. In particular, channels and transporters for transporting mitochondrial metal ions are very critical, which can be used as potential targets to treat neurodegeneration, cardiovascular diseases, cancer, diabetes and other metabolic diseases. This review summarizes the current research on several types of mitochondrial metal ion channels/transporters and their functions in cell metabolism and diseases, providing strong evidence and therapeutic strategies for further insights into related diseases. [ABSTRACT FROM AUTHOR]

The mechanistic target of rapamycin complex 2 (mTORC2) coordinates cell proliferation, survival, and metabolism with environmental inputs, yet how extracellular stimuli such as growth factors (GFs) activate mTORC2 remains enigmatic. Here we demonstrate that in human endothelial cells, activation of mTORC2 signaling by GFs is mediated by transmembrane cell adhesion protein CD146. Upon GF stimulation, the cytoplasmic tail of CD146 is phosphorylated, which permits its positively charged, juxtamembrane KKGK motif to interact with Rictor, the defining subunit of mTORC2. The formation of the CD146-Rictor/mTORC2 complex protects Rictor from ubiquitin-proteasome-mediated degradation, thereby specifically upregulating mTORC2 activity with no intervention of the PI3K and mTORC1 pathways. This CD146-mediated mTORC2 activation in response to GF stimulation promotes cell proliferation and survival. Therefore, our findings identify a molecular mechanism by which extracellular stimuli regulate mTORC2 activity, linking environmental cues with mTORC2 regulation. • CD146 deficiency reduces Rictor expression and mTORC2 activity in human cells • CD146 stabilizes Rictor from UPS degradation by interaction via its KKGK motif • Rictor-CD146 interaction depends on the growth factor (GF) activation of RTK • mTORC2 activation by GFs can be regulated by Rictor stability via CD146 Xu et al. demonstrate that the transmembrane adhesion molecule CD146 interacts with and stabilizes the mTORC2 core subunit Rictor in response to growth factor stimulation, thereby acting as an upstream regulator for mTORC2 activation. Therefore, this study identifies a molecular mechanism integrating environmental cues with mTORC2 activity. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a vascular remodeling disease of cardiopulmonary units. No cure is currently available due to an incomplete understanding of vascular remodeling. Here we identify CD146-hypoxia-inducible transcription factor 1 alpha (HIF-1α) cross-regulation as a key determinant in vascular remodeling and PAH pathogenesis. CD146 is markedly upregulated in pulmonary artery smooth muscle cells (PASMCs/SMCs) and in proportion to disease severity. CD146 expression and HIF-1α transcriptional program reinforce each other to physiologically enable PASMCs to adopt a more synthetic phenotype. Disruption of CD146-HIF-1α cross-talk by genetic ablation of Cd146 in SMCs mitigates pulmonary vascular remodeling in chronic hypoxic mice. Strikingly, targeting of this axis with anti-CD146 antibodies alleviates established pulmonary hypertension (PH) and enhances cardiac function in two rodent models. This study provides mechanistic insights into hypoxic reprogramming that permits vascular remodeling, and thus provides proof of concept for anti-remodeling therapy for PAH through direct modulation of CD146-HIF-1α cross-regulation. Vascular remodelling contributes to the development of pulmonary hypertension (PH). Here Luo and colleagues find that increases in CD146 levels drive vascular remodelling in PH through a cross-talk with hypoxia inducible factor (HIF) signalling, and show that inhibition of CD146 can attenuate disease progression. [ABSTRACT FROM AUTHOR]