Aerobic Exercise Attenuates Pressure Overload-Induced Myocardial Remodeling and Myocardial Inflammation via Upregulating miR-574-3p in Mice.

BACKGROUND: Exercise training can promote cardiac rehabilitation, thereby reducing cardiovascular disease mortality and hospitalization rates. MicroRNAs (miRs) are closely related to heart disease, among which miR-574-3p plays an important role in myocardial remodeling, but its role in exercise-mediated cardioprotection is still unclear. METHODS: A mouse myocardial hypertrophy model was established by transverse aortic coarctation, and a 4-week swimming exercise training was performed 1 week after the operation. After swimming training, echocardiography was used to evaluate cardiac function in mice, and histopathologic staining was used to detect cardiac hypertrophy, myocardial fibrosis, and cardiac inflammation. Quantitative real-time polymerase chain reaction was used to detect the expression levels of miR-574-3p and cardiac hypertrophy markers. Western blotting detected the IL-6 (interleukin-6)/JAK/STAT inflammatory signaling pathway. RESULTS: Echocardiography and histochemical staining found that aerobic exercise significantly improved pressure overload-induced myocardial hypertrophy (n=6), myocardial interstitial fibrosis (n=6), and cardiac inflammation (n=6). Quantitative real-time polymerase chain reaction detection showed that aerobic exercise upregulated the expression level of miR-574-3p (n=6). After specific knockdown of miR-574-3p in mouse hearts with adeno-associated virus 9 using cardiac troponin T promoter, we found that the protective effect of exercise training on the heart was significantly reversed. Echocardiography and histopathologic staining showed that inhibiting the expression of miR-574-3p could partially block the effects of aerobic exercise on cardiac function (n=6), cardiomyocyte cross-sectional area (n=6), and myocardial fibrosis (n=6). Western blotting and immunohistochemical staining showed that the inhibitory effects of aerobic exercise on the IL-6/JAK/STAT pathway and cardiac inflammation were partially abolished after miR-574-3p knockdown. Furthermore, we also found that miR-574-3p exerts cardioprotective effects in cardiomyocytes by targeting IL-6 (n=3). CONCLUSIONS: Aerobic exercise protects cardiac hypertrophy and inflammation induced by pressure overload by upregulating miR-574-3p and inhibiting the IL-6/JAK/STAT pathway.

Loss of USP22 alleviates cardiac hypertrophy induced by pressure overload through HiF1-α-TAK1 signaling pathway.

Ubiquitin-specific protease 22 (USP22) is a member of the ubiquitin specific protease family (ubiquitin-specific protease, USPs), the largest subfamily of deubiquitinating enzymes, and plays an important role in the treatment of tumors. USP22 is also expressed in the heart. However, the role of USP22 in heart disease remains unclear. In this study, we found that USP22 was elevated in hypertrophic mouse hearts and in angiotensin II (Ang II)-induced cardiomyocytes. The inhibition of USP22 expression with adenovirus significantly rescued hypertrophic phenotype and cardiac dysfunction induced by pressure overloaded. Consistent with in vivo study, silencing by USP22 shRNA expression in vitro had similar results. Molecular analysis revealed that transforming growth factor-ß-activating protein 1 (TAK1)-(JNK1/2)/P38 signaling pathway and HIF-1α was activated in the Ang II-induced hypertrophic cardiomyocytes, whereas HIF-1α expression was decreased after the inhibition of USP22. Inhibition of HIF-1α expression reduces TAK1 expression. Co-immunoprecipitation and ubiquitination studies revealed the regulatory mechanism between USP22 and HIF1α.Under hypertrophic stress conditions, USP22 enhances the stability of HIF-1α through its deubiquitination activity, which further activates the TAK1-(JNK1/2)/P38 signaling pathway to lead to cardiac hypertrophy. Inhibition of HIF-1α expression further potentiates the in vivo pathological effects caused by USP22 deficiency. In summary, this study suggests that USP22, through HIF-1α-TAK1-(JNK1/2)/P38 signaling pathway, may be potential targets for inhibiting pathological cardiac hypertrophy induced by pressure overload.

Vaginal Epithelial Cell Membrane-Based Phototherapeutic Decoy Confers a "Three-in-One" Strategy to Treat against Intravaginal Infection of Candida albicans.

Phototherapy is an effective strategy to control Candida albicans (C. albicans) infection without raising the concern of drug resistance. Despite its effectiveness, a higher dose of phototherapeutic power is required for C. albicans elimination compared to bacteria that have to be used, which is readily accompanied by off-target heat and toxic singlet oxygen to damage normal cells, thus limiting its usefulness for antifungal applications. Here to overcome this, we develop a "three-in-one" biomimetic nanoplatform consisting of an oxygen-dissolved perfluorocarbon camouflaged by a photosensitizer-loaded vaginal epithelial cell membrane. With a cell membrane coating, the nanoplatform is capable of specifically binding with C. albicans at the superficial or deep vaginal epithelium, thereby centering the phototherapeutic agents on C. albicans. Meanwhile, the cell membrane coating endows the nanoplatform to competitively protect healthy cells from candidalysin-medicated cytotoxicity. Upon candidalysin sequestration, pore-forming on the surface of the nanoplatform accelerates release of the preloaded photosensitizer and oxygen, resulting in enhanced phototherapeutic power for improved anti-C. albicans efficacy under near-infrared irradiation. In an intravaginal C. albicans-infected murine model, treatment with the nanoplatform leads to a significantly decreased C. albicans burden, particularly when leveraging candidalysin for further elevated phototherapy and C. albicans inhibition. Also, the same trends hold true when using the nanoplatform to treat the clinical C. albicans isolates. Overall, this biomimetic nanoplatform can target and bind with C. albicans and simultaneously neutralize the candidalysin and then transform such toxins that are always considered a positive part in driving C. albicans infection with the power of enhancing phototherapy for improved anti-C. albicans efficacy.

Notoginsenoside R1 protects against myocardial ischemia/reperfusion injury in mice via suppressing TAK1-JNK/p38 signaling.

Previous studies show that notoginsenoside R1 (NG-R1), a novel saponin isolated from Panax notoginseng, protects kidney, intestine, lung, brain and heart from ischemia-reperfusion injury. In this study we investigated the cardioprotective mechanisms of NG-R1 in myocardial ischemia/reperfusion (MI/R) injury in vivo and in vitro. MI/R injury was induced in mice by occluding the left anterior descending coronary artery for 30 min followed by 4 h reperfusion. The mice were treated with NG-R1 (25 mg/kg, i.p.) every 2 h for 3 times starting 30 min prior to ischemic surgery. We showed that NG-R1 administration significantly decreased the myocardial infarction area, alleviated myocardial cell damage and improved cardiac function in MI/R mice. In murine neonatal cardiomyocytes (CMs) subjected to hypoxia/reoxygenation (H/R) in vitro, pretreatment with NG-R1 (25 µM) significantly inhibited apoptosis. We revealed that NG-R1 suppressed the phosphorylation of transforming growth factor ß-activated protein kinase 1 (TAK1), JNK and p38 in vivo and in vitro. Pretreatment with JNK agonist anisomycin or p38 agonist P79350 partially abolished the protective effects of NG-R1 in vivo and in vitro. Knockdown of TAK1 greatly ameliorated H/R-induced apoptosis of CMs, and NG-R1 pretreatment did not provide further protection in TAK1-silenced CMs under H/R injury. Overexpression of TAK1 abolished the anti-apoptotic effect of NG-R1 and diminished the inhibition of NG-R1 on JNK/p38 signaling in MI/R mice as well as in H/R-treated CMs. Collectively, NG-R1 alleviates MI/R injury by suppressing the activity of TAK1, subsequently inhibiting JNK/p38 signaling and attenuating cardiomyocyte apoptosis.

Cardiac-Specific Overexpression of Caveolin-1 in Rats With Ischemic Cardiomyopathy Improves Arrhythmogenicity and Cardiac Remodelling.

BACKGROUND: Ischemic cardiomyopathy (ICM) is associated with electrical and structural remodelling, leading to arrhythmias. Caveolin-1 (Cav1) is a membrane protein involved in the pathogenesis of ischemic injury. Cav1 deficiency has been associated with arrhythmogenicity. The current study aimed to determine how Cav1 overexpression inhibits arrhythmias and cardiac remodelling in ICM. METHODS: ICM was modelled using left anterior descending (LAD) artery ligation for 4 weeks. Cardiac-specific Cav1 overexpression in ICM on arrhythmias, excitation-contraction coupling, and cardiac remodelling were investigated using the intramyocardial injection of an adeno-associated virus serotype 9 (AAV-9) system, carrying a specific sequence expressing Cav1 (AAVCav1) under the cardiac troponin T (cTnT) promoter. RESULTS: Cav1 overexpression decreased susceptibility to arrhythmias by upregulating gap junction connexin 43 (CX43) and reducing spontaneous irregular proarrhythmogenic Ca2+ waves in ventricular cardiomyocytes. It also alleviated ischemic injury-induced contractility weakness by improving Ca2+ cycling through normalizing Ca2+-handling protein levels and improving Ca2+ homeostasis. Masson stain and immunoblotting revealed that the deposition of excessive fibrosis was attenuated by Cav1 overexpression, inhibiting the transforming growth factor-ß (TGF-ß)/Smad2 signalling pathway. Coimmunoprecipitation assays demonstrated that the interaction between Cav1 and cSrc modulated CX43 expression and Ca2+-handling protein levels. CONCLUSIONS: Cardiac-specific overexpression of Cav1 attenuated ventricular arrhythmia, improved Ca2+ cycling, and attenuated cardiac remodelling. These effects were attributed to modulation of CX43, normalized Ca2+-handling protein levels, improved Ca2+ homeostasis, and attenuated cardiac fibrosis.

[Effects of a novel spermine oxidase inhibitor SI-4650 on proliferation and EMT of human ovarian cancer SKVO-3 cells].

Objective: To investigate the effects of SI-4650, a novel small molecule inhibitor of spermine oxidase (SMO), on the proliferation and epithelial mesenchymal transformation (EMT) of human ovarian cancer SKVO-3 cells as well as its underlying molecular mechanisms. Methods: SKVO-3 cells treated with 0 µmol/L SI-4650 were used as control group, SKVO-3 cells treated with 30, 60 µmol/L SI-4650 were used as experimental group. The effects of SI-4650 on the activity of SMO, the polyamine contents and the cellular reactive oxygen species (ROS) were detected. Cell proliferation, cell cycle and mitochondrial membrane potential change of SKVO-3 cells were tested. The effects of SI-4650 on apoptosis, migration and invasion were investigated. The effects of SI-4650 on Bax, Bcl-2, Caspase3, E-cadherin, N-cadherin, Vimentin, matrix metalloproteinase 2 ( MMP2) and MMP 9 expression levels in SKVO-3 cells were detected. Results: Comparison between blank control group and experimental groups,SI-4650 could improve the content of SI-4650 in SKVO-3 cells. SI-4650 could inhibit the activity of SMO (P＜0.01), reduce the ROS (P＜0.01)and polyamine content in SKVO-3 cells (P＜0.01). Treatment of SKVO-3 cells with SI-4650 inhibited the proliferation (the inhibition rate was 32.27% and 47.31% in experimental groups), caused S-phase cell cycle arrest (P＜0.01) and induced apoptosis (P＜0.01). The expressions of Bax and c-Caspase3 in SKVO-3 cells were increased (P＜0.01),the content of Bcl-2 was decreased (P＜0.01), and the mitochondrial membrane potential was decreased (P＜0.01), and the number of apoptotic cells was increased(31.41% and 43.51% in experimental groups). At the same time, SI-4650 could change the expression levels of EMT-related factors, increased the expression level of E-cad , decreased the expression levels of N-cad, Vimentin, MMP-2 and MMP-9, and inhibited the migration and invasion of SKVO-3 cells. Conclusion: SI-4650 can effectively inhibit proliferation, invasion and metastasis of human ovarian cancer SKVO-3 cells, and the mechanism may be related to its ability to depress the activity of SMO, interfere polyamine metabolism and induce cell cycle arrest, mitochondrial apoptosis and inhibit EMT. This study reveals potential application of SI-4650 in the treatment of ovarian cancer.

Generation of αGal-enhanced bifunctional tumor vaccine.

Hepatocellular carcinoma (HCC) is a common malignant tumor with poor prognosis and high mortality. In this study, we demonstrated a novel vaccine targeting HCC and tumor neovascular endothelial cells by fusing recombinant MHCC97H cells expressing porcine α-1,3-galactose epitopes (αGal) and endorphin extracellular domains (END) with dendritic cells (DCs) from healthy volunteers. END+/Gal+-MHCC97H/DC fusion cells induced cytotoxic T lymphocytes (CTLs) and secretion of interferon-gamma (IFN-γ). CTLs targeted cells expressing αGal and END and tumor angiogenesis. The fused cell vaccine can effectively inhibit tumor growth and prolong the survival time of human hepatoma mice, indicating the high clinical potential of this new cell based vaccine.

Platelets for cancer treatment and drug delivery.

Extensive research is currently being conducted into a variety of bio-inspired biomimetic nanoparticles (NPs) with new cell simulation functions across the fields of materials science, chemistry, biology, physics, and engineering. Cells such as erythrocytes, platelets, and stem cells have been engineered as new drug carriers. The platelet-derived drug delivery system, which is a new targeted drug delivery system (TDDS), can effectively navigate the blood circulatory system and interact with the complex tumor microenvironment; it appears to outperform traditional anticancer drugs; hence, it has attracted considerable research interest. In this review, we describe innovative studies and outline the latest progress regarding the use of platelets as tumor targeting and drug delivery vehicles; we also highlight opportunities and challenges relevant to the manufacture of tumor-related platelet TDDSs.

Prospects of TIM-3 as a Promising Diagnostic and Prognostic Biomarker for Cancer Patients.

T cell immunoglobulin mucin-3 (TIM-3) is expressed on the surface of most immune cells and is involved in anti-tumor immunity. In recent years, diagnoses and therapies based on the TIM-3 target have advanced substantially in clinical trials. In this review, we summarized the progress of TIM-3 as a biomarker in the field of diagnosis and prognosis of cancer. In the peripheral blood of cancer patients, the expression level of TIM-3 on T cells is significantly higher than that of control samples, which can be a physiological indicator of cancer. Moreover, in the cancer tissue of patients, the high expression level of TIM-3 on tumor-infiltrating T cells is negatively correlated with relapse-free survival time, which can act as a promising prognostic marker. In conclusion, the TIM-3 is a promising biomarker for the diagnosis and prognosis of cancer.

Application of Molecular Nanoprobes in the Analysis of Differentially Expressed Genes and Prognostic Models of Primary Hepatocellular Carcinoma.

Analyzing hub genes related to tumorigenesis based on biological big data has recently become a hotspot in biomedicine. Nanoprobes, nanobodies and theranostic molecules targeting hub genes delivered by nanocarriers have been widely applied in tumor theranostics. Hepatocellular carcinoma (HCC) is one of the most common cancers, with a poor prognosis and high mortality. Identifying hub genes according to the gene expression levels and constructing prognostic signatures related to the onset and outcome of HCC will be of great significance. In this study, the expression profiles of HCC and normal tissue were obtained from the GEO database and analyzed by GEO2R to identify DEGs. GO terms and KEGG pathways were enriched in DAVID software. The STRING database was consulted to find protein-protein interactions between proteins encoded by the DEGs, which were visualized by Cytoscape. Then, overall survival associated with the hub genes was calculated by the Kaplan-Meier plotter online tool, and verification of the results was carried out on TCGA samples and their corresponding clinical information. A total of 603 DEGs were obtained, of which 479 were upregulated and 124 were downregulated. PPI networks including 603 DEGs and 18 clusters were constructed, of which 7 clusters with MCODE score ≥3 and nodes ≥5 were selected. The 5 genes with the highest degrees of connectivity were identified as hub genes, and a prognostic model was constructed. The expression and prognostic potential of this model was validated on TCGA clinical data. In conclusion, a five-gene signature (TOP2A, PCNA, AURKA, CDC20, CCNB2) overexpressed inHCC was identified, and a prognostic model was constructed. This gene signature may act as a prognostic model for HCC and provide potential targets of nanotechnology.

Higher health risk resulted from dermal exposure to PCBs than HFRs and the influence of haze.

To investigate the influence of haze on human dermal exposure to a series of halogenated flame retardants (HFRs) and polychlorinated biphenyls (PCBs), paired forehead wipes were collected from 46 volunteers (23 males, 23 females) using gauze pads soaked in isopropyl alcohol under heavy and light haze pollution levels. The median levels of ∑27HFRs and ∑27PCBs in all 92 samples were 672 and 1300ng/m2, respectively. Decabromodiphenyl ether (BDE-209) (171ng/m2) and decabromodiphenylethane (DBDPE) (134ng/m2) were the dominant components of HFRs, indicating that dermal exposure may also be the significant pathway for non-volatile compounds. PCB-37 contributed the most to ∑27PCBs, with a median concentration of 194ng/m2, followed by PCB-60 (141ng/m2). Generally, PBDE, PCB and DD (dehalogenated derivatives of DPs) levels on the foreheads of female participants (291, 1340, 0.92ng/m2) were higher (p=0.037, 0.001, and 0.031, respectively) than those of male participants (226, 989, and 0.45ng/m2). A significant difference (p=0.001) in PCBs was found between light (1690ng/m2) and heavy (996ng/m2) haze pollution conditions. Nevertheless, HFR levels under heavy (median=595ng/m2, ranging from 295 to 1490ng/m2) and light haze pollution conditions (ranging from 205 to 1220ng/m2 with a median of 689ng/m2) did not show significant differences (p=0.269). The non-carcinogenic health risk resulting from dermal exposure to ∑8HFRs and ∑27PCBs was 8.72×10-5 and 1.63×10-2, respectively, raising more concern about populations' exposure to PCBs than HFRs.

The non-negligible environmental risk of recycling halogenated flame retardants associated with plastic regeneration in China.

To investigate halogenated flame retardant (HFR) contents in recycled plastic materials, 23 recycled plastic samples manufactured in five Chinese provinces were randomly purchased online, and the ∑12HFR concentrations of these samples (including 8 polybrominated diphenyl ethers (PBDEs, BDE 28, 47, 99, 100, 154, 153, 183 and 209), decabromodiphenylethane (DBDPE), 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), and 2 dechlorane plus isomers (DP, syn-DP and anti-DP)) varied from ND to 169,000 ng g-1 (mean ±â€¯SD, 46,900 ±â€¯44,700 ng g-1). BDE 209 and DBDPE were the dominant components and their concentration ranges were from ND to 106,000 ng g-1 and ND to 81,900 ng g-1, respectively. Generally, the HFR content and plastic variety closely correlate, and the ∑HFR concentrations in the polyvinyl chloride (PVC, N = 5), polypropylene (PP, N = 9), acrylonitrile butadiene styrene (ABS, N = 5), polystyrene (PS, N = 1) and polyethylene (PE, N = 3) samples were 65,300 ±â€¯42,400, 36,700 ±â€¯56,000, 30,000 ±â€¯25,200, 24,300 and 4330 ±â€¯7500 ng g-1, respectively. The HFR abundance in plastic from Guangdong (76,000 ±â€¯56,400 ng g-1, N = 7) and Hebei (37,500 ±â€¯11,500 ng g-1, N = 4) was much higher than that for other provinces/cities.

Spatial, seasonal and particle size dependent variations of PAH contamination in indoor dust and the corresponding human health risk.

To investigate the particle size distribution, spatial variation, and corresponding health risks of polycyclic aromatic hydrocarbons (PAHs) in indoor environments, composite settled dust samples were collected from four types of microenvironments (offices, hotels, dormitories and kindergartens) in Beijing, and each pooled dust sample was homogenized and fractionated into 9 fractions (F1 (900-2000 µm), F2 (500-900 µm), F3 (400-500 µm), F4 (300-400 µm), F5 (200-300 µm), F6 (100-200 µm), F7 (74-100 µm), F8 (50-74 µm), and F9 (<50 µm)). The total concentrations of 15 PAHs varied from 388 ng g-1 (kindergarten dust, F1) to 8140 ng g-1 (hotel dust, F7) in the 31 size-segregated samples. Particle size distribution patterns of PAHs were found to vary for the different types of dust samples. The seasonality of PAH contamination in indoor dust was discussed within 36 samples collected weekly and biweekly from two offices of one building in Beijing. Generally, the seasonal trends of PAHs in dust from these two offices were consistent, showing that PAH levels in cold seasons were higher than those in warm seasons. Diagnostic ratios and principal component analysis (PCA) indicated the important contribution of fuel combustion to PAHs in the indoor dust samples. The estimated incremental lifetime cancer risk (ILCR) values ranged from 10-6 to 10-5 for all relevant populations corresponding to the four types of microenvironments.

Preliminary assessment on exposure of four typical populations to potentially toxic metals by means of skin wipes under the influence of haze pollution.

To investigate the exposure risk of human beings to nine potentially toxic metals (PTMs), namely, Cu, Cr, Zn, As, Cd, Pb, Ni, Mn, and Co, skin wipe samples were collected from four types of populations, namely, children, undergraduates, security guards, and professional drivers, under different haze pollution levels in Xinxiang, China by using Ghost wipes. The Ghost wipes were quantitatively analyzed by inductively coupled plasma mass spectrometry (ICP-MS) after microwave digestion. Generally, Zn (ND-1350µg/m2 for undergraduates, ND-2660µg/m2 for security guards, ND-2460µg/m2 for children, and ND-2530µg/m2 for professional drivers) showed the highest concentration among the four populations, followed by Cu (0.02-83.4µg/m2 for undergraduates, ND-70.2µg/m2 for security guards, 23.2-487µg/m2 for children, and ND-116µg/m2 for professional drivers). As (ND-5.7µg/m2 for undergraduates, ND-2.3µg/m2 for security guards, ND-21.1µg/m2 for children, and ND-11.0µg/m2 for professional drivers) and Co (ND-6.0µg/m2 for undergraduates, ND-7.9µg/m2 for security guards, ND-13.4µg/m2 for children, and ND-2.1µg/m2 for professional drivers) showed the lowest concentrations in all populations. Remarkable differences were found among the four populations and PTM levels decreased in the following order: children, professional drivers, security guards, and undergraduates. Gender variation was discovered for undergraduates and children. Generally, PTM contamination in skin wipes collected during a light haze pollution level was generally higher than that during a heavy haze pollution level, but PTM contamination was comparable between the two haze pollution levels for children. Non-carcinogenic exposure risks to As, Cd, and Pb for all populations were higher than those for the other six elements but all of them were within the acceptable safety threshold, indicating no apparent non-carcinogenic risk.

Vehicles as outdoor BFR sources: Evidence from an investigation of BFR occurrence in road dust.

The distribution of brominated flame retardants (BFRs) including ∑8PBDEs, DBDPE, BTBPE, EH-TBB, BEH-TEBP and PBEB in road dust (RD) collected in Xinxiang, China was characterized. Analysis of RD samples indicated that the BFR abundance declined as traffic density decreased, with total mean levels of 292, 184, 163, 104 and 70 ng g-1 dust at sites from traffic intersections, main roads, collector streets, bypasses and parks, respectively. A possible explanation for this phenomenon is that the majority of BFRs may be emitted from the interior of vehicles via their ventilation systems. Of the 13 analyzed substances, BDE-209 and BEH-TEBP were the most abundant components in RD from Xinxiang. Similar amounts of ∑BDEs excluding BDE-209 were found at different types of sampling sites, and thus, atmospheric deposition is also a probable source of BFRs in RD which can be subject to air transportation. The main PBDE sources were traced to commercial products including DE-71, Bromkal 79-8DE, Saytex 201E and Bromkal 82 DE mixtures. Our results confirm that the use of deca-BDE commercial mixture is a major source of PBDE contamination in RD. Risk assessment indicated the concentrations of BFRs in RD in this study do not constitute a non-cancer or cancer risk to humans through ingestion. Annual emission fluxes of the commonly detected BFRs via RD in China were estimated to be up to 4980 kg year-1.