Current Progress in Cancer Treatment Using Nanomaterials.

The pathological processes of cancer are complex. Current methods used for chemotherapy have various limitations, such as cytotoxicity, multi-drug resistance, stem-like cells growth, and lack of specificity. Several types of nanomaterials are used for cancer treatment. Nanomaterials 1-100 nm in size have special optical, magnetic, and electrical characteristics. Nanomaterials have been fabricated for cancer treatments to overcome cytotoxicity and low specificity, and improve drug capacity and bioavailability. Despite the increasing number of related studies, few nanodrugs have been approved for clinical use. To improve translation of these materials, studies of targeted drug delivery using nanocarriers are needed. Cytotoxicity, enhanced permeability and retention effects, and the protective role of the protein corona remain to be addressed. This mini-review summarizes new nanomaterials manufactured in studies and in clinical use, analyses current barriers preventing their translation to clinical use, and describes the effective application of nanomaterials in cancer treatment.

Effects of IL-38 on Macrophages and Myocardial Ischemic Injury.

Macrophages play an important role in clearing necrotic myocardial tissues, myocardial ischemia-reperfusion injury, and ventricular remodeling after myocardial infarction. M1 macrophages not only participate in the inflammatory response in myocardial tissues after infarction, which causes heart damage, but also exert a protective effect on the heart during ischemia. In contrast, M2 macrophages exhibit anti-inflammatory and tissue repair properties by inducing the production of high levels of anti-inflammatory cytokines and fibro-progenitor cells. Interleukin (IL)-38, a new member of the IL-1 family, has been reported to modulate the IL-36 signaling pathway by playing a role similar to that of the IL-36 receptor antagonist, which also affects the production and secretion of macrophage-related inflammatory factors that play an anti-inflammatory role. IL-38 can relieve myocardial ischemia-reperfusion injury by promoting the differentiation of M1 macrophages into M2 macrophages, inhibit the activation of NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome, and increase the secretion of anti-inflammatory cytokines, such as IL-10 and transforming growth factor-ß. The intact recombinant IL-38 can also bind to interleukin 1 receptor accessory protein-like 1 (IL-1RAPL1) to activate the c-jun N-terminal kinase/activator protein 1 (JNK/AP1) pathway and increase the production of IL-6. In addition, IL-38 regulates dendritic cell-induced cardiac regulatory T cells, thereby regulating macrophage polarization and improving ventricular remodeling after myocardial infarction. Accordingly, we speculated that IL-38 and macrophage regulation may be therapeutic targets for ameliorating myocardial ischemic injury and ventricular remodeling after myocardial infarction. However, the specific mechanism of the IL-38 action warrants further investigation.

Laser solid-phase synthesis of single-atom catalysts.

Single-atom catalysts (SACs) with atomically dispersed catalytic sites have shown outstanding catalytic performance in a variety of reactions. However, the development of facile and high-yield techniques for the fabrication of SACs remains challenging. In this paper, we report a laser-induced solid-phase strategy for the synthesis of Pt SACs on graphene support. Simply by rapid laser scanning/irradiation of a freeze-dried electrochemical graphene oxide (EGO) film loaded with chloroplatinic acid (H2PtCl6), we enabled simultaneous pyrolysis of H2PtCl6 into SACs and reduction/graphitization of EGO into graphene. The rapid freezing of EGO hydrogel film infused with H2PtCl6 solution in liquid nitrogen and the subsequent ice sublimation by freeze-drying were essential to achieve the atomically dispersed Pt. Nanosecond pulsed infrared (IR; 1064 nm) and picosecond pulsed ultraviolet (UV; 355 nm) lasers were used to investigate the effects of laser wavelength and pulse duration on the SACs formation mechanism. The atomically dispersed Pt on graphene support exhibited a small overpotential of -42.3 mV at -10 mA cm-2 for hydrogen evolution reaction and a mass activity tenfold higher than that of the commercial Pt/C catalyst. This method is simple, fast and potentially versatile, and scalable for the mass production of SACs.

GARP and GARP-Treated tDC Prevented the Formation of Atherosclerotic Plaques in ApoE-/- Mice.

PURPOSE: This study aims to clarify the specific mechanism by which GARP affects the atherosclerotic plaques in ApoE-/- mice and the effect of GARP-tDC on atherosclerosis. METHODS: The mice were randomly divided into three groups: the control group, the GARP-overexpressed group and the GARP-inhibited group. After 12 weeks, all the mice were euthanized, and the specimens were collected. In vitro, experiments were conducted to observe the effect of GARP on DC phenotype and the changes of the proportion of CD4+CD25+Foxp3+ Treg cells when GARP-tDCs were co-cultured with CD4+ T cells. Furthermore, adoptive transmission of GARP-tDCs was used to observe the effect on atherosclerotic plaque in mice. RESULTS: The GARP-overexpressed group enhanced the biological activity of Foxp3+ CD4+CD25+ Tregs and resulted in increased expression of LAP in T cells. In addition, the GARP-overexpressed group significantly suppressed the function of Th1 and Th17, and decreased the secretion of INF-γ and IL-17A. Thus, GARP had a protective effect on atherosclerosis. In vitro, we found that GARP-tDC had a tolerance-inducing phenotype, and GARP-tDC also had the ability to induce tolerance when co-cultured with CD4+ T cells. More importantly, adoptive transmission of GARP-tDCs reduced the size of atherosclerotic plaques. CONCLUSION: GARP and the GARP-tDC play protective roles in atherosclerosis. The protective effect of GARP on atherosclerosis is achieved by increasing CD4+CD25+Foxp3+ Treg cells and inhibiting the production of IFN-γ and IL-17A.

Modulation of Charge Transport at Grain Boundaries in SrTiO3: Toward a High Thermoelectric Power Factor at Room Temperature.

Modulation of the grain boundary properties in thermoelectric materials that have thermally activated electrical conductivity is crucial in order to achieve high performance at low temperatures. In this work, we show directly that the modulation of the potential barrier at the grain boundaries in perovskite SrTiO3 changes the low-temperature dependency of the bulk material's electrical conductivity. By sintering samples in a reducing environment of increasing strength, we produced La0.08Sr0.9TiO3 (LSTO) ceramics that gradually change their electrical conductivity behavior from thermally activated to single-crystal-like, with only minor variations in the Seebeck coefficient. Imaging of the surface potential by Kelvin probe force microscopy found lower potential barriers at the grain boundaries in the LSTO samples that had been processed in the more reducing environments. A theoretical model using the band offset at the grain boundary to represent the potential barrier agreed well with the measured grain boundary potential dependency of conductivity. The present work showed an order of magnitude enhancement in electrical conductivity (from 85 to 1287 S cm-1) and power factor (from 143 to 1745 µW m-1 K-2) at 330 K by this modulation of charge transport at grain boundaries. This significant reduction in the impact of grain boundaries on charge transport in SrTiO3 provides an opportunity to achieve the ultimate "phonon glass electron crystal" by appropriate experimental design and processing.

Phosphorylcholine-Primed Dendritic Cells Aggravate the Development of Atherosclerosis in ApoE-/- Mice.

Background: Atherosclerosis is an inflammatory disease involving activation of adaptive and innate immune responses to antigens, including oxidized low-density lipoprotein (oxLDL) and phosphorylcholine (PC). Dendritic cells (DCs), which are antigen-presenting cells that activate T cells, are present in atherosclerotic lesions and are activated in immune organs. However, the mechanism by which PC promotes atherosclerosis is unclear. Methods and Results: To evaluate whether PC promotes atherosclerosis via DCs, 2×105 DCs activated by PC-keyhole limpet hemocyanin (DCs+PC-KLH) were injected into ApoE-/- mice and the features of the plaques and the effects of the DCs on cellular and humoral immunity against PC-KLH were determined. Mice injected with DCs+PC-KLH had significantly larger atherosclerotic lesions than controls, with increased inflammation in the lesions and plaque instability. Furthermore, DCs+PC-KLH were characterized using flow cytometry after coculture of bone marrow-derived DCs and naïve T cells. DCs+PC-KLH showed an inflammatory phenotype, with increased CD86, CD40, and major histocompatibility complex Class II molecules (MHC-II), which promoted PC-specific T helper (Th) 1 and Th17 cell differentiation in vivo and in vitro. Moreover, 2 weeks after the administration of DCs+PC-KLH to mice, these mice produced PC- and oxLDL-specific IgG2a, compared with no production in the controls. Conclusions: These findings suggest that DCs presenting PC promote specific immunity to PC, increase lesion inflammation, and accelerate atherosclerosis, which may explain how PC promotes atherosclerosis.

Clinical Characteristics and Prognosis of 244 Cardiovascular Patients Suffering From Coronavirus Disease in Wuhan, China.

Background The coronavirus disease 2019 (COVID-19) has developed into a global outbreak. Patients with cardiovascular disease (CVD) with COVID-19 have different clinical characteristics and prognostic outcomes. This study aimed to summarize the clinical characteristics and laboratory indicators of patients with COVID-19 with CVD, especially the critically ill patients. Methods and Results This study included 244 patients diagnosed with COVID-19 and CVD (hypertension, coronary heart disease, or heart failure). The patients were categorized into critical (n=36) and noncritical (n=208) groups according to the interim guidance of China's National Health Commission. Clinical, laboratory, and outcome data were collected from the patients' medical records and compared between the 2 groups. The average body mass index of patients was significantly higher in the critical group than in the noncritical group. Neutrophil/lymphocyte ratio, and C-reactive protein, procalcitonin, and fibrinogen, and d-dimer levels at admission were significantly increased in the critical group. The all-cause mortality rate among cases of COVID-19 combined with CVD was 19.26%; the proportion of coronary heart disease and heart failure was significantly higher in deceased patients than in recovered patients. High body mass index, previous history of coronary heart disease, lactic acid accumulation, and a decrease in the partial pressure of oxygen were associated with death. Conclusions All-cause mortality in patients with COVID-19 with CVD in hospitals is high. The high neutrophil/lymphocyte ratio may be a predictor of critical patients. Overweight/obesity combined with coronary heart disease, severe hypoxia, and lactic acid accumulation resulting from respiratory failure are related to poor outcomes. Registration URL: https://www.chictr.org.cn; Unique identifier: ChiCTR2000029865.

Unravelling the Mechanism of Rechargeable Aqueous Zn-MnO2 Batteries: Implementation of Charging Process by Electrodeposition of MnO2.

Poor cycling stability and mechanistic controversies have hindered the wider application of rechargeable aqueous Zn-MnO2 batteries. Herein, direct evidence was provided of the importance of Mn2+ in this type of battery by using a bespoke cell. Without pre-addition of Mn2+ , the cell exhibited an abnormal discharge-charge profile, meaning it functioned as a primary battery. By adjusting the Mn2+ content in the electrolyte, the cell recovered its charging ability through electrodeposition of MnO2 . Additionally, a dynamic pH variation was observed during the discharge-charge process, with a precipitation of Zn4 (OH)6 (SO4 )⋅5H2 O buffering the pH of the electrolyte. Contrary to the conventional Zn2+ intercalation mechanism, MnO2 was first converted into MnOOH, which reverted to MnO2 through disproportionation, resulting in the dissolution of Mn2+ . The charging process occurred by the electrodeposition of MnO2 , thus improving the reversibility through the availability of Mn2+ ions in the solution.

The Long Noncoding RNA Hotair Regulates Oxidative Stress and Cardiac Myocyte Apoptosis during Ischemia-Reperfusion Injury.

Oxidative stress and subsequent cardiac myocyte apoptosis play central roles in the initiation and progression of myocardial ischemia-reperfusion (I/R) injury. Homeobox transcript antisense intergenic RNA (Hotair) was previously implicated in various heart diseases, yet its role in myocardial I/R injury has not been clearly demonstrated. Mice with cardiac-restricted knockdown or overexpression of Hotair were exposed to I/R surgery. H9c2 cells were cultured and subjected to hypoxia/reoxygenation (H/R) stimulation to further verify the role and underlying mechanisms of Hotair in vitro. Histological examination, molecular detection, and functional parameters were determined in vivo and in vitro. In response to I/R or H/R treatment, Hotair expression was increased in a bromodomain-containing protein 4-dependent manner. Cardiac-restricted knockdown of Hotair exacerbated, whereas Hotair overexpression prevented I/R-induced oxidative stress, cardiac myocyte apoptosis, and cardiac dysfunction. Mechanistically, we observed that Hotair exerted its beneficial effects via activating AMP-activated protein kinase alpha (AMPKα). Further detection revealed that Hotair activated AMPKα through regulating the enhancer of zeste homolog 2/microRNA-451/calcium-binding protein 39 (EZH2/miR-451/Cab39) axis. We provide the evidence that endogenous lncRNA Hotair is an essential negative regulator for oxidative stress and cardiac myocyte apoptosis in myocardial I/R injury, which is dependent on AMPKα activation via the EZH2/miR-451/Cab39 axis.

Knockdown of TRIM28 inhibits PDGF-BB-induced vascular smooth muscle cell proliferation and migration.

Atherosclerosis is a common type of cardiovascular disease (CVD), remaining one of the leading causes of global death. Tripartite motif-containing 28 (TRIM28) is a member of TRIM family that has been found to be involved in atherosclerosis. However, the role of TRIM28 in atherosclerosis remains unknown. This study aimed to investigate the effects of TRIM28 on the phenotypic switching of human aortic smooth muscle cells (HASMCs), which is considered as a fundamental event during the development of atherosclerosis. The results showed that TRIM28 was highly expressed in human atherosclerotic tissues, as well in cultured HASMCs stimulated by platelet-derived growth factor subunit B homodimer (PDGF-BB). Knockdown of TRIM28 by transfection with siRNA targeting TRIM28 (si-TRIM28) significantly suppressed the PDGF-BB-induced cell proliferation and migration of HASMCs. Besides, knockdown of TRIM28 inhibited the expressions of matrix metalloproteinase (MMP)-2 and MMP-9. The VSMC markers including α-smooth muscle actin (α-SMA), calponin and SM22α were upregulated in TRIM28 knocked down HASMCs. Furthermore, knockdown of TRIM28 blocked PDGF-BB-induced NF-κB activation in HASMCs. Collectively, knockdown of TRIM28 prevented PDGF-BB-induced phenotypic switching of HASMCs, which might be mediated by the regulation of NF-κB signaling pathway.

Decreased Helios Expression in Regulatory T Cells in Acute Coronary Syndrome.

Regulatory T cells (Tregs) play an essential role in acute coronary syndrome (ACS). However, there is debate about which Treg subsets are truly critical to ACS. Helios, a transcription factor, was recently reported to be a bona fide marker for natural Tregs or activated Tregs with a suppression function, but little is known about its role in ACS. We therefore examined Helios+ Tregs in patients with ACS, patients with stable angina, and control subjects. 73 patients with ACS, 30 patients with stable angina, and 48 control subjects were enrolled. The frequencies and estimated absolute numbers of different Treg subsets in peripheral blood were measured by flow cytometry. Plasma cytokine level was measured by ELISA. The mRNA expression of Foxp3 and Helios in purified CD4+ T cells was determined by RT-PCR. Helios+ Tregs was decreased significantly in patients with ACS. The frequency and estimated absolute numbers of CD4+Foxp3+Helios+ Tregs were negatively correlated with IL-6 and positively correlated with circulating level of TGF-beta1 and HDL-C. The mRNA expression of Foxp3 and Helios was decreased in CD4+ T cells from patients with ACS. In summary, Helios+ Tregs was downregulated in patients with ACS and may play a role in ACS.

Thymic stromal lymphopoietin-induced HOTAIR activation promotes endothelial cell proliferation and migration in atherosclerosis.

Endothelial cells' (EC) injury is a major step for the pathological progression of atherosclerosis. Recent study demonstrated that thymic stromal lymphopoietin (TSLP) exerts a protective role in atherosclerosis. However, the effect of TSLP and the exact molecular mechanism involved in EC remains unknown. In the present study, we found that long noncoding RNA (lncRNA) HOTAIR was much lower in EC from atherosclerotic plaque. Functional assays showed that HOTAIR facilitated cell proliferation and migration, and suppressed apoptosis in EC. Moreover, we demonstrated that TSLP functions upstream of HOTAIR. We found that serum level of TSLP was decreased in atherosclerosis patients and serum TSLP level positively correlated with HOTAIR expression in EC. Further investigation demonstrated that TSLP activated HOTAIR transcription through PI3K/AKT-IRF1 pathway and then regulates the EC proliferation and migration. TSLP-HOTAIR axis also plays a protective role in low-density lipoprotein (ox-LDL)-induced EC injury. Taken together, TSLP-HOTAIR may be a potential therapy for EC dysfunction in atherosclerosis.

Meta-analysis of serum non-high-density lipoprotein cholesterol and risk of coronary heart disease in the general population.

BACKGROUND: Non-high-density lipoprotein cholesterol (non-HDL-C) has been proposed an independent risk factor for coronary heart disease (CHD). However, the magnitude of this association in the general population varied considerably. OBJECTIVE: To investigate the association of baseline non-HDL-C level with CHD risk in the general population by conducting a meta-analysis. METHODS: A comprehensive literature search was performed in the Pubmed and Embase until January 2017. Prospective observational studies that investigated the association between baseline non-HDL-C level and CHD risk in the general population were included. Pooled hazard ratio (HR) and corresponding 95% confidence interval (CI) were calculated for the highest vs. the lowest non-HDL-C category. RESULTS: Seven articles with 9 independent prospective studies involving 448,732 individuals were included. Meta-analysis showed that individuals with the highest non-HDL-C level at baseline were associated with greater risk of CHD (RR 1.79; 95% CI 1.68-1.91) than those in the lowest non-HDL-C level category. Subgroup analysis suggested that the risk of CHD seemed more pronounced among men (HR 1.98; 95% CI 1.70-2.30) than among women (HR 1.63; 95% CI 1.35-1.96). CONCLUSIONS: Higher baseline non-HDL-C level is associated with increased risk of CHD in the general population. This risk seems more pronounced in men than in women. However, gender difference in non-HDL-C level associated with CHD risk should be verified by more well-designed prospective studies.

Cardioprotective Effects of Malvidin Against Isoproterenol-Induced Myocardial Infarction in Rats: A Mechanistic Study.

BACKGROUND Malvidin (alvidin-3-glucoside) is a polyphenol that belongs to the class of natural anthocyanin, which is abundantly found in red wines, colored fruits, and the skin of red grapes. Therefore, the current investigation was intended to evaluate the effect of malvidin against myocardial infarction induced by isoproterenol in the rats. MATERIAL AND METHODS The cardioprotective effects was assessed by determining the effect of malvidin on the activities of endogenous antioxidants - catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH) - and on the levels of lipid peroxidation and serum marker enzymes. The serum levels of IL-6 and TNF-α were also determined using an enzyme-linked immunosorbent assay (ELISA) kit. RESULTS The present study demonstrated a significant cardioprotective effect of malvidin by restoring the defensive activities of endogenous antioxidants - catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH) - and by reducing the levels of lipid peroxidation and serum marker enzymes lactate dehydrogenase (LD) and creatine kinase (CK). Malvidin significantly ameliorated the histopathological changes and impaired mitochondria in the cardiac necrosis stimulated with isoproterenol. Additionally, the results also demonstrated that nuclear translocation of Nrf-2 and subsequent HO-1 expression might be associated with nuclear factor kappa B (NF-κB) pathway activation. CONCLUSIONS Our findings suggest that malvidin exerts cardioprotective effects that might be due to possible strong antioxidant and anti-inflammatory activities. Therefore, this study provides the basis for the development of malvidin as a safe and effective treatment of myocardial infarction.

Genome-Wide Analysis of DNA Methylation and Acute Coronary Syndrome.

RATIONALE: Acute coronary syndrome (ACS) is a leading cause of death worldwide. Immune functions play a vital role in ACS development; however, whether epigenetic modulation contributes to the regulation of blood immune cells in this disease has not been investigated. OBJECTIVE: We conducted an epigenome-wide analysis with circulating immune cells to identify differentially methylated genes in ACS. METHODS AND RESULTS: We examined genome-wide methylation of whole blood in 102 ACS patients and 101 controls using HumanMethylation450 array, and externally replicated significant discoveries in 100 patients and 102 controls. For the replicated loci, we further analyzed their association with ACS in 6 purified leukocyte subsets, their correlation with the expressions of annotated genes, and their association with cardiovascular traits/risk factors. We found novel and reproducible association of ACS with blood methylation at 47 cytosine-phosphoguanine sites (discovery: false discovery rate <0.005; replication: Bonferroni corrected P<0.05). The association of methylation levels at these cytosine-phosphoguanine sites with ACS was further validated in at least 1 of the 6 leukocyte subsets, with predominant contributions from CD8+ T cells, CD4+ T cells, and B cells. Blood methylation of 26 replicated cytosine-phosphoguanine sites showed significant correlation with expressions of annotated genes (including IL6R, FASLG, and CCL18; P<5.9×10-4), and differential gene expression in case versus controls corroborated the observed differential methylation. The replicated loci suggested a role in ACS-relevant functions including chemotaxis, coronary thrombosis, and T-cell-mediated cytotoxicity. Functional analysis using the top ACS-associated methylation loci in purified T and B cells revealed vital pathways related to atherogenic signaling and adaptive immune response. Furthermore, we observed a significant enrichment of the replicated cytosine-phosphoguanine sites associated with smoking and low-density lipoprotein cholesterol (Penrichment≤1×10-5). CONCLUSIONS: Our study identified novel blood methylation alterations associated with ACS and provided potential clinical biomarkers and therapeutic targets. Our results may suggest that immune signaling and cellular functions might be regulated at an epigenetic level in ACS.