Comparison of the effectiveness of physical training and extract of soursop leaf to histopathology of abdominal aorta foam cells in hipercolesterolemia-diabetes rat

Phthalate promotes atherosclerosis through interacting with long-non coding RNA and induces macrophage foam cell formation and vascular smooth muscle damage

Tofacitinib ameliorates atherosclerosis and reduces foam cell formation in apoE deficient mice

The mechanisms of increased expression of toll-like receptor 4 (TLR-4) during the formation of foam cells were explored. Low density lipoprotein (LDL) was prepared by density gradient ultracentrifugation and oxidized by incubation with CuCl2. The human monocytic leukemia cell line (THP-1) was cultured in RPMI1640. The differentiation of THP-1 cells into macrophages (MPs) was induced by using myristate acetate (PMA) for 48 h. The macrophages were then incubated with oxidized LDL (ox-LDL) to generate foam cells (FCs). The mRNA and protein expression levels of human TLR-4 were detected by immunocytochemistry, Western blotting and reverse transcription polymerase chain reaction (RT-PCR). The results showed that the TLR-4 mRNA and the protein expression levels were significantly increased during the differentiation of monocytes into macrophages (P < 0.05) as well as during the formation of lipid-laden foam cells (P < 0.05). It was concluded that the upregulation of human TLR-4 gene expression during the differentiation of monocytes into macrophages and the differentiation of macrophages into foam cells could increase TLR-4 protein synthesis dramatically, which may enhance the ability of foam cells inflammation reaction in atherosclerosis.

What is the central question of this study? Clinical studies suggest that obesity 'protects' against osteoporosis. However, these studies used only bone densitometry and assessed only one bone site, which is insufficient to enable conclusions to be drawn about the response of the whole skeleton. Furthermore, the effects of exercise on bone responses in obesity have not been explored previously. What is the main finding and what is its importance? We show that obesity causes osteopetrosis. Therefore, the classical perspective of 'protective effects of obesity' needs to be reviewed, and exercise is an important tool to avoid these alterations and to maintain the homeostasis of bone. A sedentary lifestyle and obesity induce systemic inflammatory responses. Although the effects of physical inactivity on osseous tissue have been well established, the effects of obesity on bone tissue remain controversial. Furthermore, the effects of physical training on bone tissue responses in the presence of diet-induced obesity are unknown. Our aim was to investigate the effects of obesity and physical training at multiple bone sites in rats. Female Wistar rats were divided into the following four groups: (i) control diet, non-trained (C-NT); (ii) high-refined carbohydrate-containing diet, non-trained (HC-NT); (iii) control diet, trained (C-T); and (iv) high-refined carbohydrate-containing diet, trained (HC-T). At 5 months of age, the rats were submitted to daily exercise for 30 min day(-1). After 13 weeks, blood samples, adipose and skeletal tissues were harvested. Two-way ANOVA was applied to detect differences (significance accepted when P ≤ 0.05). The HC-NT group exhibited increased body mass, adiposity, serum leptin, serum insulin, insulin resistance index and concentrations of tumour necrosis factor-α and interleukin-6. Obese rats (HC-NT) exhibited thickening of nasal bones, trabecular bones in the lumbar vertebrae and long bones in a site-dependent manner. The HC-T group exhibited similar adiposity and inflammatory results. Morphological analysis of the lumbar vertebrae in rats fed the HC diet revealed characteristics of osteopetrosis that were inhibited by exercise. In conclusion, the HC diet induced obesity and inflammatory/hormonal alterations and increased the trabecular bone in a site-dependent manner. However, obesity caused osteopetrosis in the lumbar vertebrae, which could be inhibited by physical training. Although exercise inhibited the development of bone alterations, physical training did not inhibit the HC diet-induced obesity responses.

The present study investigated the effects of moderate physical training on some of the parameters in the GH-IGF axis in experimental diabetic rats. Male Wistar rats were allocated into the following groups: sedentary control, trained control, sedentary diabetic, trained diabetic. Diabetes was induced by alloxan (32 mg/kg, b.w. iv). The physical training protocol consisted of 1 h swimming session/day, 5 days/week for 8 weeks supporting a load corresponding to 90% of maximal lactate steady state. After the experimental period, blood was collected to measure serum glucose, insulin, triglycerides, albumin, insulin-like growth factors-I (IGF-I), and growth hormone (GH). Pituitary gland was removed for GH quantification. Diabetes increased blood glucose and triglycerides and decreased insulin, IGF-I, serum and pituitary GH. Physical training decreased glucose and triglycerides, and also counteracted the reduction of serum IGF-I in diabetic rats. In conclusion, physical training recovered serum IGF-I showing no alteration of serum or pituitary GH levels.

Xanthine oxidase catalyzes the oxidation of xanthine to uric acid. This process generates excessive reactive oxygen species (ROS) that play an important role in atherogenesis. Recent studies show that LRR and PYD domains-containing protein 3 (NLRP3), a component of the inflammasome, may be involved in the formation of foam cells, a hallmark of atherosclerosis. This study was designed to study the role of various scavenger receptors and NLRP3 inflammasome in xanthine oxidase and uric acid-induced foam cell formation. Human vascular smooth muscle cells (VSMCs) and THP-1 macrophages were treated with xanthine oxidase or uric acid. Xanthine oxidase treatment (of both VSMCs and THP-1 cells) resulted in foam cell formation in concert with generation of ROS and expression of cluster of differentiation 36 (CD36) and oxidized low density lipoprotein (lectin-like) receptor 1 (LOX-1), but not of scavenger receptor A (SRA). Uric acid treatment resulted in foam cell formation, ROS generation and expression of CD36, but not of LOX-1 or SRA. Further, treatment of cells with xanthine oxidase, but not uric acid, activated NLRP3 and its downstream pro-inflammatory signals- caspase-1, interleukin (IL)-1β and IL-18. Blockade of LOX-1 or NLRP3 inflammasome with specific siRNAs reduced xanthine oxidase-induced foam cell formation, ROS generation and activation of NLRP3 and downstream signals. Xanthine oxidase induces foam cell formation in large part through activation of LOX-1 - NLRP3 pathway in both VSMCs and THP-1 cells, but uric acid-induced foam cell formation is exclusively through CD36 pathway. Further, LOX-1 activation is upstream of NLRP3 activation. Graphical Abstract Steps in the formation of foam cells in response to xanthine oxidase and uric acid. Xanthine oxidase stimulates LOX-1 expression on the cell membrane of macrophages and vascular smooth muscle cells (VSMCs) and increases generation of ROS, which activate NLRP3 inflammasome and downstream pro-inflammatory mediators such as Caspase-1, IL-1β and IL-18. Xanthine oxidase also induces CD36 expression. Activation of both LOX-1 and CD36 (LOX-1>>CD36) participates in the transformation of macrophages and VSMCs into foam cells. Uric acid formed from xanthine-xanthine oxidase interaction stimulates CD36 expression and triggers foam cell formation independent of NLRP3 activation.

Monocyte recruitment and foam cell formation in atherosclerosis

In order to solve the problem of observing the effect of rehabilitation physical training on basketball player injury, a kind of observation study on the effect of rehabilitation physical training on basketball player injury based on memory ultrasound examination was proposed. This study makes a comprehensive analysis of physical fitness training factors such as physical fitness test plan, training arrangement, training method, training monitoring, and effect evaluation. Through the experiment, it is found that there are still gaps in physical training, diagnostic standards, training plans and requirements, load monitoring, standardization of operation, nutrition, and recovery in the training organization. There are only 23.81% of full-time physical coaches and 25.40% of professional team doctors at all levels of sports teams. There were only 23.81% of full-time physical fitness coaches and 25.40% of professional team doctors in all levels of sports teams. Basketball players in the basketball injury survey had 67 sports injuries throughout the year, with a rate of 3.35 injuries per person and 2.48 injuries per 1000 hours. The location of chronic injuries is usually the lower back, knee joint, and ankle. The main injuries are due to the physical component, with injuries occurring most frequently throughout the training season in July, August, and September. Experiments show that good and professional physical training can reduce the risk of injury to a greater extent than strengthening the specific skills of athletes.

BackgroundTo investigate the role and underlying mechanism of cyclin G2 (G2-type cyclin) in the formation of vascular smooth muscle cells (VSMCs) derived foam cells.MethodsThe levels of α-SMA (alpha-SM-actin), p-NF-κB (phosphorylation nuclear transcription factors kappa B), and LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1) were measured by immunohistochemistry and western blotting. The mouse aortic root smooth muscle cell line MOVAS was transfected to over-express cyclin G2, which were then stimulated with 80 µg/mL ox-LDL (oxidized low-density lipoprotein) to induce foam cell formation. DT-061 an activator of PP2A (protein phosphatase 2A) agonist was used to verify the role of PP2A in the process.ResultsKnocking out the Ccng2 gene in Apoe-/- mice alleviated aortic lipid plaque, foam cell formulation, ameliorative body weight, and LDL-cholesterol. We observed that the number of α-SMA positive cells was significantly decreased in Apoe-/-Ccng2-/- mice compared to Apoe-/- mice. Also, the protein levels of p-NF-κB and LOX-1 were markedly reduced in the aortic root of Apoe-/-Ccng2-/- mice. Upon stimulation with ox-LDL, upregulated cyclin G2 increased the intracellular lipid accumulation in MOVAS cells. Also, it suppressed the activity of PP2A but up-regulated LOX-1. Additionally, the cell nuclear translocation of p-NF-κB was increased. Interestingly, DT-061 intervention, re-activating the activity of PP2A, reduced the levels of nuclear p-NF-κB and LOX-1. This led to decreased lipid endocytosis reducing the formation of VSMCs- derived foam cells.ConclusionsCyclin G2 increases the nuclear translocation of p-NF-κB by reducing the enzymatic activity of PP2A and upregulating LOX-1, thereby promotes the formation of VSMCs -derived foam cells in atherosclerosis.

Background:Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-laden foam cells and plaques within the arterial wall. Dysfunctional vascular smooth muscle cells (VSMCs), fibroblasts, endothelial cells (ECs), and macrophages contribute to disease progression. Here, we report that macrophage-specific expression of epsins, highly conserved endocytic adaptor proteins involved in clathrin-mediated endocytosis, accelerates atherosclerosis in Western diet (WD)-fed mice.Methods:Apoe-deficient (WT/Apoe−/−) mice and littermates with a myeloid-specific deletion of epsin 1/2 on an Apoe−/− background (LysM-DKO/Apoe−/−) were generated and fed a WD for 16 weeks. Single-cell RNA sequencing (scRNA-seq) was conducted to investigate the cellular and molecular mechanisms regulated by macrophage epsins during atherosclerosis. Findings from scRNA-seq were validated through metabolic profiling, qRT-PCR, immunostaining, and co-culture experiments to assess associated phenotypic changes.Results:LysM-DKO/Apoe−/− mice exhibited significantly reduced atherosclerotic foam cell formation compared to WT/Apoe−/− controls. scRNA-seq analysis identified 19 major cell types, including six VSMC and five macrophage subpopulations. Modulated VSMC1 and VSMC2 subtypes were associated with inflammation, migration, and VSMC-to-macrophage transition. These populations, along with foamy-Trem2 and inflammatory macrophages, were markedly reduced in LysM-DKO/Apoe−/− mice. Transition of modulated VSMC2 subtype into macrophages was significantly inhibited, as confirmed by both computational analysis and experimental validation. Additionally, macrophage epsin deletion reversed endothelial dysfunction, suppressed cholesterol- and glucose-mediated signaling, and reduced expression of pro-inflammatory ligands IL-1β and TNF-α.Conclusion:Macrophage epsin deletion limits foam cell formation and preserves VSMC and endothelial cell phenotypes and functions. These findings reveal a potential therapeutic strategy targeting macrophage epsins to combat atherosclerosis.

Grier, TL, Canham-Chervak, M, Anderson, MK, Bushman, TT, and Jones, BH. Effects of physical training and fitness on running injuries in physically active young men. J Strength Cond Res 31(1): 207-216, 2017-The purpose of this investigation was to determine the effects of physical training (PT) and fitness on risks for running-related injuries (RRIs) in physically active young men. Personal characteristics, PT, Army Physical Fitness Test scores, and injury data were obtained by survey. Army Physical Fitness Test variables (push-ups, sit-ups, and 2-mile run) were converted into quartiles (Q), where Q1 = lowest performance and Q4 = highest performance. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using multivariate logistic regression. Over 4,000 (n = 4,236) soldiers were surveyed. Running injury incidence was 14%. A greater risk of an RRI was associated with older age (OR31+/<22 years = 1.62, 95% CI, 1.21-2.18), higher BMI ((Equation is included in full-text article.)), and total distance ran per week during unit PT (OR16.1+/1-5 miles = 1.66, 95% CI, 1.15-2.41). A lower risk of an RRI was associated with total distance run per week during personal PT (OR5.1-10/1-5 miles = 0.70, 95% CI, 0.53-0.91, OR10.1-16 +/1-5 miles = 0.58, 95% CI, 0.35-0.97, OR16.1+/1-5 miles = 0.54, 95% CI, 0.30-0.98), higher aerobic endurance as measured by 2-mile run performance (ORQ4/Q1 = 0.50, 95% CI, 0.35-0.72), and unit resistance training ≥3 times a week (OR≥3 times per week/none = 0.46, 95% CI, 0.29-0.73). Greater personal PT running mileage decreased injuries in this population suggesting that the increased protective effect of higher aerobic fitness outweighed the injurious effect of running more miles during personal PT. Countermeasures to prevent RRIs could entail enhancing aerobic endurance, providing opportunities for personal aerobic training, monitoring for excessive unit PT running mileage and encouraging unit resistance training ≥3 times per week.

Atherosclerosis is a chronic immunoinflammatory disease associated with blood lipid disorders. Previous studies in mice have demonstrated that liver X receptor (LXR)‑ATP‑binding cassette (ABC)A1/ABCG1/C‑C chemokine receptor type 7 (CCR7)and nuclear factorκB (NF‑κB) signaling pathways are important for atherosclerotic plaque formation. In addition, Sirtuin1 (SIRT1) has been reported as a key regulator in the protection from risk of atherosclerosis. However, the exact mechanism by which SIRT1 prevents atherosclerosis remains largely unknown. To explore the possible mechanisms, the expression of SIRT1 and the association between SIRT1, LXR and NF‑κB in the process of foam cell formation was investigated in an invitro human mononuclear U937 cell line. Monocyte‑derived foam cells were induced by palmitate and Ox‑LDL treatment. Oil RedO staining revealed an accumulation of a large number of lipid droplets in foam cells. Results of reverse transcription polymerase chain reaction (RT-PCR) revealed that SIRT1 expression was downregulated during foam cell formation. In addition, the expression of LXRα and its targets, ABCA1, ABCG1 and CCR7, were downregulated. However, NF‑κB and its targets, tumor necrosis factorα (TNFα) and interleukin (IL)‑1β, were upregulated in foam cells. Following activation of SIRT1 by SRT1720, the expression of LXRα and its targets increased, whereas expression of NF‑κB and its targets decreased. Furthermore, the formation of foam cells was blocked. The SIRT1 inhibitor, nicotinamide, was found to eliminate the effects of SRT1720. Results of the present study indicate that SIRT1 may prevent the formation and progression of atherosclerosis by enhancing the LXR‑ABCA1/ABCG1/CCR7 and inhibiting the NF‑κB pathways.

Robust empirical evidence supports the effectiveness of physical and cognitive training in preventing and delaying cognitive decline. Emerging research suggests distinct neurobiological mechanisms underpin the effects of these different training modalities. An unresolved question is whether the mechanisms through which these training modalitiesimpart their effect interact synergistically to improve cognitive outcomes, rather than exerting additive effects, differ. In addition, past research has been inconsistent in adequately controlling for or documenting the dosage of physical and/or cognitive training. Consequently, the aim of this study is to assess the relative effectiveness of physical and cognitive training conducted in isolation or concurrently, whilst rigorously controlling and documenting the treatment parameters. This study is a three-arm randomised controlled trial conducted over a 3-month period, comparing cognitive training, physical activity, and a combination of both interventions. Older cognitively healthy participants (n = 126) aged 60-75years will be recruited from the community. The physical only training will require participants to cycle on a cycle ergometer at above 60% of their age-predicted heart rate maximum for 50min with a 3-min warm-up and cool-down period. The cognitive only training will require participants to complete up to five different cognitive tasks selected from a set of eight on the BrainHQ platform during each 50-min training session. The concurrent cognitive and physical training will require participants to undertake both treatments at the same time. Primary outcomes, assessed pre- and post- intervention, will include speed of processing and episodic memory assessed with the NIH Toolbox, as well as general driving skills assessed on a driving simulator. Findings will inform the design of interventions and population health advice aimed at mitigating cognitive decline. If a substantial synergetic effect is detected, it may lead to the use of more widespread concurrent physical and cognitive training and the potential development of methods to make concurrent training practical. Findings will also provide important clarification as to the relative benefit of the two modes of training. Prospective registration with Australia and New Zealand Clinical Trial Registry (ACTRN12624001088538) on 10th September 2024 and World Health Organisation International Clinical Trials Registry (U1111-1280-3851).

BackgroundNutritional control of gene regulation guides the transformation of smooth muscle cells (SMC) into foam cells in atherosclerosis. Oxidative stress has been reported in areas of lipid accumulation, activating proliferation genes. Suppression of oxidative stress by antioxidant administration reduces this activation and the progression of lesions. We hypothesized that fish oil consumption may protect against atherosclerotic vascular disease. The study objective was to determine the effects of dietary cholesterol and fish-oil intake on the apoptotic pathways induced by 25-hydroxycholesterol (25-HC) in SMC cultures.MethodsAn in vivo/in vitro cell model was used, culturing SMC isolated from chicks exposed to an atherogenic cholesterol-rich diet with 5% of cholesterol (SMC-Ch) alone or followed by an anti-atherogenic fish oil-rich diet with 10% of menhaden oil (SMC-Ch-FO) and from chicks on standard diet (SMC-C). Cells were exposed to 25-HC, studying apoptosis levels by flow cytometry (Annexin V) and expressions of caspase-3, c-myc, and p53 genes by quantitative real-time reverse transcriptase-polymerase chain reaction. Results: Exposure to 25-HC produced apoptosis in all three SMC cultures, which was mediated by increases in caspase-3, c-myc, and p53 gene expression. Changes were more marked in SMC-Ch than in SMC-C, indicating that dietary cholesterol makes SMC more susceptible to 25-HC-mediated apoptosis. Expression of p53 gene was elevated in SMC-Ch-FO. This supports the proposition that endogenous levels of p53 protect SMC against apoptosis and possibly against the development of atherosclerosis. Fish oil attenuated the increase in c-myc levels observed in SMC-C and SMC-Ch, possibly through its influence on the expression of antioxidant genes.ConclusionReplacement of a cholesterol-rich diet with a fish oil-rich diet produces some reversal of the cholesterol-induced changes, increasing the resistance of SMC to apoptosis.

BackgroundAutophagy is an essential process for breaking down macromolecules and aged/damaged cellular organelles to maintain cellular energy balance and cellular nutritional status. The idea that autophagy regulates lipid metabolism is an emerging concept with important implications for atherosclerosis. However, the potential role of autophagy and its relationship with lipid metabolism in foam cell formation remains unclear. In this study, we found that autophagy was involved in the lipopolysaccharide (LPS)-induced the formation of foam cells and was at least partially dependent on adipose differentiation-related protein (ADRP).MethodFoam cell formation was evaluated by Oil red O staining. Autophagic activity was determined by immunofluorescence and Western blotting. ADRP gene expression of ADRP was examined by real-time PCR (RT-PCR). The protein expression of ADRP and LC3 was measured using Western blotting analysis. Intracellular cholesterol and triglyceride levels in foam cells were quantitatively measured by enzymatic colorimetric assays.ResultsLPS promoted foam cell formation by inducing lipid accumulation in macrophages. The activation of autophagy with rapamycin (Rap) decreased intracellular cholesterol and triglyceride levels, whereas the inhibition of autophagy with 3-methyladenine (3MA) enhanced the accumulation of lipid droplets. Overexpression of ADRP alone increased the formation of foam cells and consequently autophagic activity. In contrast, the inhibitory effects of ADRP activity with siRNA suppressed the activation of autophagy. Taken together, we propose a novel role for ADRP in the regulation of macrophage autophagy during LPS stimulation.ConclusionWe defined a new molecular pathway in which LPS-induced foam cell formation is regulated through autophagy. These findings facilitate the understanding of the role of autophagy in the development of atherosclerosis.