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.

Insights into the Dermal Absorption, Deposition, and Elimination of Poly- and Perfluoroalkyl Substances in Rats: The Importance of Skin Exposure.

Humans are frequently exposed to poly- and perfluoroalkyl substances (PFASs) via direct skin contact with personal care and consumer products containing them. Here, we used a rat model to estimate the dermal penetration efficiency of 15 representative PFASs. After 144 h post-dosing, 4.1-18.0 and 5.3-15.1% of the applied PFASs in the low (L) and high (H) groups, respectively, were absorbed into the rats. PFAS absorption and permeation were parabolically associated with the perfluorinated carbon chain length (CF), peaking for perfluoroheptanoic acid (PFHpA). The lipid-rich stratum corneum of the skin barrier substantially suppressed the penetration of less hydrophobic short-chain PFASs, whereas the water-rich viable epidermis and dermis served as obstacles to hydrophobic long-chain PFAS permeation. However, the renal clearance (CLrenal) of the target PFAS decreased with increasing CF, suggesting that urinary excretion is crucial to eliminate less hydrophobic short-chain PFASs. Notably, the peak times of PFASs in the systemic circulation of rats (8-72 h) were remarkably longer than those after oral administration (1-24 h). These results suggest that dermal penetration can be long-lasting and contribute considerably to the body burden of PFASs, especially for those with moderate hydrophobicity due to their favorable skin permeation and unfavorable urinary excretion.

Dapagliflozin attenuates pressure overload-induced myocardial remodeling in mice via activating SIRT1 and inhibiting endoplasmic reticulum stress.

Endoplasmic reticulum stress-mediated apoptosis plays a vital role in the occurrence and development of heart failure. Dapagliflozin (DAPA), a new type of sodium-glucose cotransporter 2 (SGLT2) inhibitor, is an oral hypoglycemic drug that reduces glucose reabsorption by the kidneys and increases glucose excretion in the urine. Studies have shown that DAPA may have the potential to treat heart failure in addition to controlling blood sugar. This study explored the effect of DAPA on endoplasmic reticulum stress-related apoptosis caused by heart failure. In vitro, we found that DAPA inhibited the expression of cleaved caspase 3, Bax, C/EBP homologous protein (CHOP), and glucose-regulated protein78 (GRP78) and upregulated the cardiomyoprotective protein Bcl-2 in angiotensin II (Ang II)-treated cardiomyocytes. In addition, DAPA promoted the expression of silent information regulator factor 2-related enzyme 1 (SIRT1) and suppressed the expression of activating transcription factor 4 (ATF4) and the ratios p-PERK/PERK and p-eIF2α/eIF2α. Notably, the therapeutic effect of DAPA was weakened by pretreatment with the SIRT1 inhibitor EX527 (10 µM). Simultaneous administration of DAPA inhibited the Ang II-induced transformation of fibroblasts into myofibroblasts and inhibited fibroblast migration. In summary, our present findings first indicate that DAPA could inhibit the PERK-eIF2α-CHOP axis of the ER stress response through the activation of SIRT1 in Ang II-treated cardiomyocytes and ameliorate heart failure development in vivo.

Halogenated Organic Pollutant Residuals in Human Bared and Clothing-Covered Skin Areas: Source Differentiation and Comprehensive Health Risk Assessment.

To comprehensively clarify human exposure to halogenated flame retardants (HFRs) and polychlorinated biphenyls (PCBs) through dermal uptake and hand-to-mouth intake, skin wipe samples from four typical skin locations from 30 volunteers were collected. The total concentration of the target chemicals (24 HFRs and 16 PCBs) ranged from 203 to 4470 ng/m2. BDE-209 and DBDPE accounted for about 37 and 40% of ∑24HFRs, respectively, and PCB-41 and PCB-110 were the dominant PCB congeners, with proportion of 24 and 10%, respectively. Although exhibiting relatively lower concentrations of contaminants than bared skin locations, clothing-covered skin areas were also detected with considerable levels of HFRs and PCBs, indicating clothing to be a potentially significant exposure source. Significant differences in HFR and PCB levels and profiles were also observed between males and females, with more lower-volatility chemicals in male-bared skin locations and more higher-volatility compounds in clothing-covered skin locations of female participants. The mean estimated whole-body dermal absorption doses of ∑8HFRs and ∑16PCBs (2.9 × 10-4 and 6.7 × 10-6 mg/kg·d) were 1-2 orders of magnitude higher than ingestion doses via hand-to-mouth contact (6.6 × 10-7 and 3.1 × 10-7 mg/kg·d). The total noncarcinogenic health risk resulted from whole-body dermal absorption and oral ingestion to ∑7HFRs and ∑16PCBs were 5.2 and 0.35, respectively.

Contamination characteristics of trace metals in dust from different levels of roads of a heavily air-polluted city in north China.

Concentrations of eight trace metals (TMs) in road dust (RD) (particles < 25 µm) from urban areas of Xinxiang, China, were determined by inductively coupled plasma mass spectrometry. The geometric mean concentrations of Zn, Mn, Pb, As, Cu, Cr, Ni and Cd were 489, 350, 114, 101, 60.0, 39.7, 31.6, and 5.1 mg kg-1, respectively. When compared with TM levels in background soil, the samples generally display elevated TM concentrations, except for Cr and Mn, and for Cd the enrichment value was 69.6. Spatial variations indicated TMs in RD from park path would have similar sources with main roads, collector streets and bypasses. Average daily exposure doses of the studied TMs were about three orders of magnitude higher for hand-to-mouth ingestion than dermal contact, and the exposure doses for children were 9.33 times higher than that for adults. The decreasing trend of calculated hazard indexes (HI) for the eight elements was As > Pb > Cr > Mn > Cd > Zn > Ni > Cu for both children and adults.

Penetration pathways, influencing factors and predictive models for dermal absorption of exobiotic molecules: A critical review.

This review provides a comprehensive summary of the skin penetration pathways of xenobiotics, including metals, organic pollutants, and nanoparticles (NPs), with a particular focus on the methodologies employed to elucidate these penetration routes. The impacts of the physicochemical properties of exogenous substances and the properties of solvent carriers on the penetration efficiencies were discussed. Furthermore, the review outlines the steady-state and transient models for predicting the skin permeability of xenobiotics, emphasizing the models which enable realistic visualization of pharmaco-kinetic phenomena via detailed geometric representations of the skin microstructure, such as stratum corneum (SC) (bricks and mortar) and skin appendages (hair follicles and sebaceous gland units). Limitations of published research, gaps in current knowledge, and recommendations for future research are highlighted, providing insight for a better understanding of the skin penetration behavior of xenobiotics and associated health risks in practical application contexts.

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.

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.

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.

Identification and characterization of a novel 6'-N-aminoglycoside acetyltransferase AAC(6')-Va from a clinical isolate of Aeromonas hydrophila.

Background: Aeromonas species have been identified as agents responsible for various diseases in both humans and animals. Multidrug-resistant Aeromonas strains pose a significant public health threat due to their emergence and spread in clinical settings and the environment. The aim of this study was to determine a novel resistance mechanism against aminoglycoside antimicrobials in a clinical isolate. Methods: The function of aac(6')-Va was verified by gene cloning and antibiotic susceptibility tests. To explore the in vivo activity of the enzyme, recombinant proteins were expressed, and enzyme kinetics were tested. To determine the molecular background and mechanism of aac(6')-Va, whole-genome sequencing and bioinformatic analysis were performed. Results: The novel aminoglycoside N-acetyltransferase gene aac(6')-Va confers resistance to several aminoglycosides. Among the antimicrobials tested, ribostamycin showed the highest increase (128-fold) in the minimum inhibitory concentration (MIC) compared with the control strains. According to the MIC results of the cloned aac(6')-Va, AAC(6')-Va also showed the highest catalytic efficiency for ribostamycin [kcat/Km ratio = (3.35 ± 0.17) × 104 M-1 s-1]. Sharing the highest amino acid identity of 54.68% with AAC(6')-VaIc, the novel aminoglycoside N-acetyltransferase constituted a new branch of the AAC(6') family due to its different resistance profiles. The gene context of aac(6')-Va and its close relatives was conserved in the genomes of species of the genus Aeromonas. Conclusion: The novel resistance gene aac(6')-Va confers resistance to several aminoglycosides, especially ribostamycin. Our finding of a novel resistance gene in clinical A. hydrophila will help us develop more effective treatments for this pathogen's infections.

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.

Effects of Danhong injection combined with tirofiban on cardiac function, myocardial enzyme spectrum and lipoprotein-associated phospholipase A2 level in patients with acute myocardial infarction.

OBJECTIVE: To determine the effect of Danhong injection combined with tirofiban on cardiac function, myocardial enzyme spectrum and lipoprotein-associated phospholipase A2 (Lp-PLA2) level in patients with acute myocardial infarction (AMI). METHODS: The clinical data of 124 AMI patients who were treated in the Second Affiliated Hospital of Wenzhou Medical University from August 2019 to April 2021 were collected and analyzed retrospectively. Among them, 58 patients treated with routine thrombolysis combined with tirofiban were assigned to the control group, and the other 66 patients treated with Danhong injection on the basis of treatment to the control group were assigned to the observation group. Treatment efficacy, cardiac function, myocardial enzyme spectrum, and Lp-PLA2 level before and after treatment, and adverse cardiovascular events during treatment were compared between the two groups. The patients were further grouped into an occurrence group and a non-occurrence group in the light of the occurrence of adverse cardiovascular events after treatment, and then the risk factors of adverse cardiovascular events were analyzed by logistic regression. RESULTS: The control group showed a notably lower total effective rate than the observation group (P=0.015). After treatment, the observation group showed a higher left ventricular ejection fraction (LVEF) level and a lower left ventricular end-diastolic dimension (LVEDD) than the control group (both P < 0.05). In addition, the observation group showed lower levels of CK, CK-MB and Lp-PLA2 than the control group (all P < 0.05). A significantly higher incidence of adverse cardiovascular events was found in the control group than that in the observation group (P=0.039), and Logistic regression analysis showed that NYHA grade, LVEF, LVEDD, CK-MB and Lp-PLA2 were independent risk factors (P < 0.05). The prediction model =-86.255 + (4.645*NYHA grade) + (-0.581*LVEF) + (1.058*LVEDD) + (0.263*CK-MB) + (0.121*Lp-PLA2). According to the ROC curve analysis, the area under the curve of the model in predicting adverse cardiovascular events among patients was 0.970. CONCLUSION: Danhong injection combined with tirofiban can improve the cardiac function, myocardial enzyme spectrum and Lp-PLA2 level in AMI patients.

Identifying dermal exposure as the dominant pathway of children's exposure to flame retardants in kindergartens.

Exploration of multiple sources of brominated (BFRs) and organophosphate flame retardants (OPFRs) for children promotes the understanding of exposure pathways and health risk. 10 BFRs and 9 OPFRs were measured in skin wipes from hands, forehead, and arms of 30 children, and surface wipe samples from sills, toys, desks and floors, and indoor air samples of kindergartens from Xinxiang, China. Higher ∑9OPFRs concentrations were observed in the forehead (1840 ng/m2), followed by hand (1420 ng/m2) and arm wipes (1130 ng/m2), and the ∑8BFRs concentrations in forehead, hand and arm wipes were 116, 315 and 165 ng/m2, respectively. The total concentration of OPFRs and BFRs in floor wipes (66.1 and 24.5 ng/m2) were lower than those in toy (205 and 535 ng/m2), sill (227 and 30.1 ng/m2) and desk (84.4 and 139 ng/m2) wipes. Concentrations of FRs in forehead wipes were significantly correlated with those in gaseous air (p < 0.05), moderate correlations were found between the hand wipes and surface wipes (p = 0.054). We estimated the daily average dosages (DADs) of children exposure to FRs via multiple pathways. Compared to DADs via inhalation and hand-to-mouth transfer, dermal exposure was determined to be the predominant exposure pathway to ∑9OPFRs and ∑8BFRs.

[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.

Study on non-bioparticles and Staphylococcus aureus by dielectrophoresis.

This article demonstrated a chip device with alternating current (AC) dielectrophoresis (DEP) for separation of non-biological micro-particle and bacteria mixtures. The DEP separation was achieved by a pair of metal electrodes with the shape of radal-interdigital to generate a localized non-uniform AC electric field. The electric field and DEP force were firstly investigated by finite element methods (FEM). The mixed microparticles such as different scaled polystyrene (PS) beads, PS beads with inorganic micro-particles (e.g., ZnO and silica beads) and non-bioparticles with bacterial Staphylococcus aureus (S. aureus) were successfully separated at DEP-on-a-chip by an AC electric field of 20 kHz, 10 kHz and 1 MHz, respectively. The results indicated that DEP trapping can be considered as a potential candidate method for investigating the separation of biological mixtures, and may well prove to have a great impact on in situ monitoring of environmental and/or biological samples by DEP-on-a-chip.

The CD4+CD25 bright regulatory T cells and CTLA-4 expression in peripheral and decidual lymphocytes are down-regulated in human miscarriage.

The present study was undertaken to analyze the changes in the proportion of CD4(+)CD25(bright) regulatory T (Treg) cells and the expression of costimulatory molecules, CTLA-4 and CD28, in the peripheral blood and deciduas in the setting of non-pregnancy, normal early pregnancy and miscarriage. In this study, we showed that CD4(+)CD25(bright) T cells significantly increased in the peripheral of normal pregnancy compared to that of non-pregnancy. The proportions of CD4(+)CD25(bright) T cells in both peripheral blood and deciduas were significantly lower in miscarriage than that of normal pregnancy. CD4(+)CD25(bright) T cells were characterized by high-level FoxP3 expression and low-level CD69 expression. An increase in the CD28 mRNA expression was accompanied by a decrease in the CTLA-4 mRNA expression in decidual tissues from human miscarriage. The ratios of CTLA-4(+)/CD28(+) in miscarriage were significantly lower than that of the normal pregnancy both in the peripheral and in deciduas. The ratio of CTLA-4(+)/CD28(+) in CD4(+)CD25(bright) T cells was significantly higher than that of the CD4(+)CD25(dim) T cells both in normal pregnancy and in miscarriage. The decidual T cells in the miscarriage appeared higher in responsiveness and IL-2 and IFN-gamma production in comparison with the decidual T cells in the early pregnancy. These results above suggest that CD4(+)CD25(bright) Treg cells might play a role in the maintenance of pregnancy via up-regulation of CTLA-4 expression. The down-regulation of Treg cells and their functions, and the imbalance of positive and negative regulators of costimulatory signals might lead to an abnormal immune milieu, which confer susceptibility to pregnancy loss.