Metabolic syndrome and cardiovascular disease among adult cancer patients: results from NHANES 2007-2018.

BACKGROUND: Metabolic syndrome (MetS) is a risk factor for cardiovascular disease (CVD), and CVD is a major challenge for cancer patients. This study aimed to investigate the prevalence and association of MetS and CVD among adult cancer patients. METHODS: This cross-sectional study included cancer patients aged > 18 years from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018. The prevalence of MetS and CVD was calculated using weighted analysis. Multivariable logistic regression was used to assess the association between MetS and CVD. RESULTS: The study included 2658 adult cancer patients, of whom 1260 exhibited MetS and 636 had CVD. The weighted prevalence of MetS and CVD in cancer patients was 45.44%, and 19.23%, respectively. Multivariable logistic regression showed a 79% increased risk in higher CVD prevalence in cancer patients with MetS, with the OR (95% CI) of 1.79 (1.31, 2.44). Notably, obesity, elevated blood pressure (BP), high glucose, and low high density lipoprotein cholesterol (HDL-C) in the MetS components were significantly associated with higher CVD prevalence after adjusting for covariates. Moreover, the risk of CVD prevalence in cancer patients increased with more MetS components. Notably, MetS was more strongly linked to CVD in patients aged < 65 and women. CONCLUSIONS: Among adult cancer patients, over two-fifths (45.44%) were estimated to have MetS, while about one-fifth (19.23%) were considered to have CVD. Notably, obesity, elevated BP, high glucose, low HDL-C, and higher number of MetS components were found to be significantly associated with higher CVD prevalence among cancer adults. Cancer patients under 65 and women with MetS may be at increased risk of CVD.

The roles and regulatory mechanisms of cigarette smoke constituents in vascular remodeling.

Vascular remodeling is a dynamic process involving cellular and molecular changes, including cell proliferation, migration, apoptosis and extracellular matrix (ECM) synthesis or degradation, which disrupt the homeostasis of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). Cigarette smoke exposure (CSE) is thought to promote vascular remodeling, but the components are complex and the mechanisms are unclear. In this review, we overview the progression of major components of cigarette smoke (CS), such as nicotine and acrolein, involved in vascular remodeling in terms of ECs injury, VSMCs proliferation, migration, apoptosis, and ECM disruption. The aim was to elucidate the effects of different components of CS on different cells of the vascular system, to discover the relevance of their actions, and to provide new references for future studies.

LDHA contributes to nicotine induced cardiac fibrosis through autophagy flux impairment.

Cardiac fibrosis is a typical feature of cardiac pathological remodeling, which is associated with adverse clinical outcomes and has no effective therapy. Nicotine is an important risk factor for cardiac fibrosis, yet its underlying molecular mechanism remains poorly understood. This study aimed to identify its potential molecular mechanism in nicotine-induced cardiac fibrosis. Our results showed nicotine exposure led to the proliferation and transformation of cardiac fibroblasts (CFs) into myofibroblasts (MFs) by impairing autophagy flux. Through the use of drug affinity responsive target stability (DARTS) assay, cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR) technology, it was discovered that nicotine directly increased the stability and protein levels of lactate dehydrogenase A (LDHA) by binding to it. Nicotine treatment impaired autophagy flux by regulating the AMPK/mTOR signaling pathway, impeding the nuclear translocation of transcription factor EB (TFEB), and reducing the activity of cathepsin B (CTSB). In vivo, nicotine treatment exacerbated cardiac fibrosis induced in spontaneously hypertensive rats (SHR) and worsened cardiac function. Interestingly, the absence of LDHA reversed these effects both in vitro and in vivo. Our study identified LDHA as a novel nicotine-binding protein that plays a crucial role in mediating cardiac fibrosis by blocking autophagy flux. The findings suggest that LDHA could potentially serve as a promising target for the treatment of cardiac fibrosis.

Fucoxanthin alleviates lipopolysaccharide-induced intestinal barrier injury in mice.

The aim of this study was to evaluate the preventive role and underlying mechanisms of fucoxanthin (Fx) on lipopolysaccharide (LPS)-induced intestinal barrier injury in mice. Our results demonstrated that the oral administration of Fx (50 and 200 mg per kg body weight per day) for consecutive 7 days significantly alleviated the severity of LPS-induced intestinal barrier injury in mice, as evidenced by attenuating body weight loss, improving intestinal permeability, and ameliorating intestinal morphological damage such as reduction in the ratio of the villus length to the crypt depth (V/C), intestinal epithelium distortion, goblet cell depletion, and low mucin 2 (MUC2) expression. Fx also significantly mitigated LPS-induced excessive apoptosis of intestinal epithelial cells (IECs) and curbed the decrease of tight junction proteins including claudin-1, occludin, and zonula occludens-1 in the ileum and colon. Additionally, Fx effectively alleviated LPS-induced extensive infiltration of macrophages and neutrophils into the intestinal mucosa, the overproduction of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin 1beta (IL-1ß) and IL-6, and gasdermin D (GSDMD)-mediated pyroptosis of IECs. The underlying mechanisms might be associated with inhibiting the activation of nuclear factor-kappa B (NF-κB), mitogen-activated protein kinases (MAPKs) and nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signaling pathways. Moreover, Fx also notably restrained intestinal reactive oxygen species (ROS), malondialdehyde and protein carbonylation levels in LPS-treated mice, and it might be mediated by activating the nuclear factor-erythroid 2 related factor 2 (Nrf2) signaling pathway. Overall, these findings indicated that Fx might be developed as a potential effective dietary supplement to prevent intestinal barrier injury.

Association of Chronic Kidney Disease with Cardiovascular Disease in Cancer Patients: A Cross-Sectional Study.

INTRODUCTION: Due to the cardiotoxicity of cancer treatment and traditional risk factors for cardiovascular disease (CVD) such as obesity, diabetes, dyslipidemia, and hypertension, cancer patients are at higher risk of developing CVD. However, limited research exists on the correlation between chronic kidney disease (CKD) and CVD risk in cancer patients. METHODS: This cross-sectional study selected cancer patients aged ≥20 years from the National Health and Nutrition Examination Survey (NHANES) conducted from 2015 to 2020. Multivariable logistic regression was used to assess the association between CKD and CVD in cancer patients. Additionally, subgroup analyses were conducted to investigate the association among different groups of cancer patients. RESULTS: We included 1,700 adult cancer patients (52.53% were females). After multivariable adjustment for covariates including traditional CVD factors, CKD was significantly associated with CVD, with an odds ratio (95% confidence interval) and p value of 1.61 (1.18, 2.19) and 0.004. Subgroup analyses after multivariable adjustment showed a significant correlation between CKD and increased CVD risk in the following cancer patients: age ≥60 years, males, white ethnicity, and individuals with or without traditional CVD factors (obesity, diabetes, dyslipidemia, and hypertension). CONCLUSIONS: CKD remains a significant factor in the higher risk of CVD among adult cancer patients in the United States, even after adjustment for traditional CVD risk factors. Therefore, to reduce the risk of CVD in cancer patients, it is important to treat CKD as a non-traditional risk factor for CVD and actively manage it.

Krill oil prevents lipopolysaccharide-evoked acute liver injury in mice through inhibition of oxidative stress and inflammation.

Acute liver injury is a life-threatening syndrome that often results from the actions of viruses, drugs and toxins. Herein, the protective effect and potential mechanism of krill oil (KO), a novel natural product rich in long-chain n-3 polyunsaturated fatty acids bound to phospholipids and astaxanthin, on lipopolysaccharide (LPS)-evoked acute liver injury in mice were investigated. Male C57BL/6J mice were administered intragastrically with 400 mg kg-1 KO or fish oil (FO) once per day for 28 consecutive days prior to LPS exposure (10 mg kg-1, intraperitoneally injected). The results revealed that KO pretreatment significantly ameliorated LPS-evoked hepatic dysfunction indicated by reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and attenuated hepatic histopathological damage. KO pretreatment also mitigated LPS-induced hepatic oxidative stress, as evidenced by decreased malondialdehyde (MDA) contents, elevated glutathione (GSH) levels, and elevated catalase (CAT) and superoxide dismutase (SOD) activities. Additionally, LPS-evoked overproduction of pro-inflammatory mediators in serum and the liver was inhibited by KO pretreatment. Furthermore, KO pretreatment suppressed LPS-induced activation of the hepatic toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB)/NOD-like receptor family pyrin domain containing 3 (NLRP3) signaling pathway. Interestingly, the hepatoprotective effect of KO was superior to that of FO. Collectively, the current findings suggest that KO protects against LPS-evoked acute liver injury via inhibition of oxidative stress and inflammation.

Nicotine Causes Mitochondrial Dynamics Imbalance and Apoptosis Through ROS Mediated Mitophagy Impairment in Cardiomyocytes.

Nicotine contained in traditional cigarettes, hookahs, and e-cigarettes is an important risk factor for cardiovascular disease. Our previous study showed that macroautophagic flux impairment occurred under nicotine stimulation. However, whether nicotine influences mitochondrial dynamics in neonatal rat ventricular myocytes (NRVMs) is unclear. The purpose of this study was to explore the effects and potential mechanism of nicotine on mitophagy, mitochondrial dynamics, apoptosis, and the relationship between these processes in NRVMs. Our results showed that nicotine exposure increased mitochondria-derived superoxide production, decreased mitochondrial membrane potential, and impaired PINK1/Parkin-mediated mitophagic flux in NRVMs. Interestingly, nicotine significantly promoted dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and suppressed mitofusin (MFN)-mediated fusion, which was also observed in the bafilomycin A1-treated group. These results suggest that mitophagic flux impairment may contribute to Drp-1-mediated mitochondrial fission. Finally, nicotine caused excessive mitochondrial fission and contributed to apoptosis, which could be alleviated by mdivi-1, an inhibitor of Drp1. In addition to CTSB, as we previously reported, the enzyme activity of cathepsin L (CTSL) was also decreased in lysosomes after stimulation with nicotine, which may be the main cause of the hindered mitophagic flux induced by nicotine in NRVMs. Pretreatment with Torin 1, which is an inhibitor of mTOR, activated CTSL and ameliorated nicotine-induced mTOR activation and mitophagy impairment, decreased mitochondria-derived superoxide production, and blunted mitochondrial fission and apoptosis. Pretreatment with the ROS scavenger N-acetyl-cysteine (NAC) or inhibitors of p38 and JNK, which could also alleviate mitophagy impairment, exhibited similar effects as Torin1 on mitochondria. Taken together, our study demonstrated that nicotine treatment may lead to an increase in Drp1-mediated mitochondrial fission by blocking mitophagic flux by weakening the enzyme activity of CTSL and activating the ROS/p38/JNK signaling pathway. Excessive mitochondrial fission induced by nicotine ultimately leads to apoptosis. Torin1 restored the decreased CTSL enzyme activity by removing excessive ROS and alleviated the effects of nicotine on mitophagic flux, mitochondrial dynamics, and apoptosis. These results may provide new evidence on the relationship between mitophagic flux and mitochondrial dynamics and new perspectives on nicotine's effects on mitochondrial dynamics in cardiomyocytes.

Cilostazol alleviate nicotine induced cardiomyocytes hypertrophy through modulation of autophagy by CTSB/ROS/p38MAPK/JNK feedback loop.

Nicotine is proved to be an important factor for cardiac hypertrophy. Autophagy is important cell recycling system involved in the regulation of cardiac hypertrophy. Cilostazol, which is often used in the management of peripheral vascular disease. However, the effects of cilostazol on nicotine induced autophagy and cardiac hypertrophy are unclear. Here, we aim to determine the role and molecular mechanism of cilostazol in alleviating nicotine-induced cardiomyocytes hypertrophy through modulating autophagy and the underlying mechanisms. Our results clarified that nicotine stimulation caused cardiomyocytes hypertrophy and autophagy flux impairment significantly in neonatal rat ventricular myocytes (NRVMs), which were evidenced by augments of LC3-II and p62 levels, and impaired autophagosomes clearance. Interestingly, cathepsin B (CTSB) activity decreased dramatically after stimulation with nicotine in NRVMs, which was crucial for substrate degradation in the late stage of autophagy process, and cilostazol could reverse this effect dramatically. Intracellular ROS levels were increased significantly after nicotine exposure. Meanwhile, p38MAPK and JNK were activated after nicotine treatment. By using ROS scavenger N-acetyl-cysteine (NAC) could reverse the effects of nicotine by down-regulation the phosphorylation of p38MAPK and JNK pathways, and pretreatment of specific inhibitors of p38MAPK and JNK could restore the autophagy impairment and cardiomyocytes hypertrophy induced by nicotine. Moreover, CTSB activity of lysosome regained after the treatment with cilostazol. Cilostazol also inhibited the ROS accumulation and the activation of p38MAPK and JNK, which providing novel connection between lysosome CTSB and ROS/p38MAPK/JNK related oxidative stress pathway. This is the first demonstration that cilostazol could alleviate nicotine induced cardiomyocytes hypertrophy through restoration of autophagy flux by activation of CTSB and inhibiting ROS/p38/JNK pathway, exhibiting a feedback loop on regulation of autophagy and cardiomyocytes hypertrophy.

Aspirin alleviates cardiac fibrosis in mice by inhibiting autophagy.

Aspirin (ASA) is a cardioprotective drug with anti-cardiac fibrosis action in vivo. This study was aimed to clarify the anti-cardiac fibrosis action of ASA and the underlying mechanisms. Two heart injury models (injection of isoproterenol and ligation of the left anterior descending branch) were used in mice to induce cardiac fibrosis. The animals were treated with ASA (10 mg·kg-1·d-1, ig) for 21 and 14 d, respectively. ASA administration significantly improved cardiac function, and ameliorated heart damage and fibrosis in the mice. The mechanisms underlying ASA's anti-fibrotic effect were further analyzed in neonatal cardiac fibroblasts (CFs) exposed to hypoxia in vitro. ASA (0.5-5 mmol/L) dose-dependently inhibited the proliferation and Akt phosphorylation in the CFs. In addition, ASA significantly inhibited CF apoptosis, and decreased the levels of apoptosis markers (cleaved caspase 3 and Parp1), which might serve as a side effect of anti-fibrotic effect of ASA. Furthermore, ASA dose-dependently inhibited the autophagy in the CFs, as evidenced by the reduced levels of autophagy marker LC3-II. The autophagy inhibitor Pepstatin A (PepA) promoted the inhibitory effect of ASA on CF proliferation, whereas the autophagy inducer rapamycin rescued ASA-caused inhibition of CF proliferation, suggesting an autophagy-dependent anti-proliferative effect of ASA. Both p38 inhibitor SB203580 and ROS scavenger N-acetyl-cysteine (NAC) significantly decreased Akt phosphorylation in CFs in the basal and hypoxic situations, but they both significantly increased LC3-II levels in the CFs. Our results suggest that an autophagy- and p38/ROS-dependent pathway mediates the anti-cardiac fibrosis effect of ASA in CFs. As PepA and SB203580 did not affect ASA-caused inhibition of CF apoptosis, the drug combination will enhance ASA's therapeutic effects.

Efficacy and safety of proprotein convertase subtilisin/kexin type 9 monoclonal antibody in adults with familial hypercholesterolemia.

Proprotein convertase-subtilisin/kexin type 9 (PCSK9) monoclonal antibody is a new therapy to reduce low-density lipoprotein cholesterol (LDL-C) level in patients with familial hypercholesterolemia (FH). This pooled analysis aimed to estimate the efficacy and safety of PCSK9 antibody therapy in FH. Reports of randomized controlled trials (RCTs) comparing PCSK9 antibody to placebo were retrieved by a search of MEDLINE via PubMed, EMBASE, the Cochrane Library databases, ClinicalTrials.gov and Clinical Trial Results (up to November 30, 2015) with no language restriction. Data were abstracted by a standardized protocol. We found eight RCTs (1,879 patients with FH) for the pooled analysis. As compared with placebo, PCSK9 antibody therapy remarkably reduced LDL-C level (mean reduction: -48.54 %, 95 % CI: -53.19 to -43.88), total cholesterol (mean reduction: -31.08%, 95 % CI: -35.20 to -26.95), lipoprotein (a) (mean reduction: -20.44%, 95 % CI: -25.21 to -15.66), and apolipoprotein B (mean reduction: -36.32%, 95 % CI: -40.75 to -31.90) and elevated the level of high-density lipoprotein cholesterol (mean change: 6.29 %, 95 % CI: 5.12 to 7.46) and apolipoprotein A1(mean change: 4.86%, 95 % CI: 3.77 to 5.95). Therapy with and without PCSK9 antibodies did not differ in rate of adverse events (pooled rate: 50.86 % vs. 48.63%; RR: 1.03; 95 % CI: 0.92 to 1.15; P = 0.64; heterogeneity P = 0.13; I2= 40%) or serious adverse events (pooled rate: 7.14% vs. 6.74%; RR: 1.05; 95 % CI: 0.70 to 1.58; P = 0.80; heterogeneity P = 0.69; I2= 0%). PCSK9 antibody may be an effective and safe treatment for FH.

Patchouli alcohol attenuates experimental atherosclerosis via inhibiting macrophage infiltration and its inflammatory responses.

Patchouli alcohol (PA) is a tricyclic sesquiterpene extracted from a traditional Chinese herb pogostemonis herba. Literatures have proven that PA could inhibit inflammatory responses in various inflammatory disease models. However, whether PA could protect against atherosclerosis, a chronic vascular inflammation, is unknown. In this study, we sought to explore this issue in atherosclerosis-prone apolipoprotein E knockout mice fed an atherogenic diet, with or without daily PA intragastrical administration (40mg/kg). Our results showed that PA administration did not change plasma lipids metabolism, however, it significantly attenuated atherosclerotic plaque burdens in both the aorta and the aortic root. The lesional macrophage content, shown as Mac2 positive areas, was reduced, while the lesional smooth muscle cell and collagen content, shown as α-SMA positive areas and by Sirius red staining, respectively, was not affected in PA-treated mice, compared with non-treated controls. Aortic mRNA expression of macrophage inflammatory cytokines, including MCP-1, iNOS, IL-1ß, IL-6, CXCL9 and CXCL11, was also reduced in PA-treated mice. Therefore, we demonstrated that PA could attenuate atherosclerosis, possibly by inhibiting macrophage infiltration and its inflammatory responses.

MicroRNA-7a/b protects against cardiac myocyte injury in ischemia/reperfusion by targeting poly(ADP-ribose) polymerase.

OBJECTIVES: MicroRNA-7 (miR-7) is highly connected to cancerous cell proliferation and metastasis. It is also involved in myocardial ischemia-reperfusion (I/R) injury and is upregulated in cardiomyocyte under simulated I/R (SI/R). We aimed to investigate the role of miR-7 during myocardial I/R injury in vitro and in vivo and a possible gene target. METHODS AND RESULTS: Real-time PCR revealed that miR-7a/b expression was upregulated in H9c2 cells after SI/R. Flow cytometry showed SI/R-induced cell apoptosis was decreased with miR-7a/b mimic transfection but increased with miR-7a/b inhibitor in H9c2 cells. In a rat cardiac I/R injury model, infarct size determination and TUNEL assay revealed that miR-7a/b mimic decreased but miR-7a/b inhibitor increased cardiac infarct size and cardiomyocyte apoptosis as compared with controls. We previously identified an important gene connected with cell apoptosis--poly(ADP-ribose) polymerase (PARP)--as a candidate target for miR-7a/b and verified the target by luciferase reporter activity assay and western blot analysis. CONCLUSIONS: miR-7a/b is sensitive to I/R injury and protects myocardial cells against I/R-induced apoptosis by negatively regulating PARP expression in vivo and in vitro. miR-7a/b may provide a new therapeutic approach for treatment of myocardial I/R injury. Poly(ADP-ribose) polymerase.

[A study on K469E polymorphism of ICAM1 gene and ICAM1 plasma level in patients with coronary heart disease].

OBJECTIVE: To study the linkage between K469E polymorphism of intercellular adhesion molecule 1(ICAM1) gene with ICAM1 plasma level and coronary heart disease (CHD) in Han population of China. METHODS: One hundred and sixty-four controls without CHD and 160 patients with CHD were enrolled in our study. By nested PCR with allele-specific oligonucleotide primers, all patients and controls were genotyped for the ICAM1 polymorphism. And the ICAM1 plasma level was measured by ELISA. RESULTS: In the patients with CHD, both K allele frequency and the plasma level of ICAM1 were higher than those in control (P<0.05). The individual with K allele had higher plasma level of ICAM1 than that without K allele (344.34+/-128.59 microg/L vs 303.54+/-108.74 microg/L, P=0.008). K allele enhanced the risk of CHD (P<0.01, OR=2.158, 95%CI: 1.250-3.727). There was the K allele cooperation with smoking in influencing the risk of CHD. CONCLUSION: There is the polymorphism of ICAM1 K469E gene in Han population of China, and the K allele may be a genetic factor influencing the risk of CHD.

[Effect of shenfu injection on brain natriuretic polypeptide and aminoterminal peptide of precollagen type III in patients with acute myocardial infarction during intervention treatment].

OBJECTIVE: To investigate the effect of Shenfu injection (SFI) on indexes of heart function and myocardial fibrosis in patients with acute myocardial infarction (AMI) treated by percutaneous coronary intervention (PCI). METHODS: Ninety-three AMI patients treated by PCI were randomly divided into two groups, 47 in the treatment group (treated by PCI plus 40 ml SFI intravenous injection, once a day for 7 days) and 46 in the control group (treated by PCI only). Levels of brain natriuretic poly peptide (BNP) and aminoterminal peptide of precollagen type III (NP III) were measured at different time points, i.e. immediately after admission (T1), and at 24th hour (T2) and 7th day (T3) after AMI onset in the two groups. RESULTS: The proportion of TIMI 3 grade of front blood flow in AMI related vessels after PCI was insignificantly different in the two groups. The concentration of BNP of T2 was significantly higher than that of T1 in the two groups (P < 0.01), and it was higher in the control group than that in the treatment group (P < 0.01), while at T3, it was insignificantly different in the treatment group to that of T1 (P > 0.05), but in the control group, it was still significantly higher than that in the treatment group and that of T1 (P < 0.01). The levels of NP III the two groups were similar at T1 and T2 (P > 0.05). At T3, it showed an increase in the treatment group, but with no significant difference (P > 0.05) as compared with that at T1, but in the control group did markedly increase and showed significant difference as compared with that of T1 and that in the treatment group at T3 (P < 0.05). CONCLUSION: Early applying of SFI can protect myocardium from ischemia/reperfusion injury after AMI, ameliorate the degree of injury, improve heart function of patients and prevent myocardial fibrosis.