Tumor microenvironment-responsive size-changeable and biodegradable HA-CuS/MnO2 nanosheets for MR imaging and synergistic chemodynamic therapy/phototherapy.

Tumor microenvironment (TME)-responsive size-changeable and biodegradable nanoplatforms for multimodal therapy possess huge advantages in anti-tumor therapy. Hence, we developed a hyaluronic acid (HA) modified CuS/MnO2 nanosheets (HCMNs) as a multifunctional nanoplatform for synergistic chemodynamic therapy (CDT)/photothermal therapy (PTT)/photodynamic therapy (PDT). The prepared HCMNs exhibited significant NIR light absorption and photothermal conversion efficiency because of the densely deposited ultra-small sized CuS nanoparticles on the surface of MnO2 nanosheet. They could precisely target the tumor cells and rapidly decomposed into small sized nanostructures in the TME, and then efficiently promote intracellular ROS generation through a series of cascade reactions. Moreover, the local temperature elevation induced by photothermal effect also promote the PDT based on CuS nanoparticles and the Fenton-like reaction of Mn2+, thereby enhancing the therapeutic efficiency. Furthermore, the T1-weighted magnetic resonance (MR) imaging was significantly enhanced by the abundant Mn2+ ions from the decomposition process of HCMNs. In addition, the CDT/PTT/PDT synergistic therapy using a single NIR light source exhibited considerable anti-tumor effect via in vitro cell test. Therefore, the developed HCMNs will provide great potential for MR imaging and multimodal synergistic cancer therapy.

Salidroside Regulates Mitochondrial Homeostasis After Polarization of RAW264.7 Macrophages.

ABSTRACT: Salidroside has anti-inflammatory and antiatherosclerotic effects, and mitochondrial homeostasis imbalance is closely related to cardiovascular disease. The aim of this study was to investigate the effect of salidroside on mitochondrial homeostasis after macrophage polarization and elucidate its possible mechanism against atherosclerosis. RAW264.7 cells were stimulated with 1 µg·mL -1 Lipopolysaccharide and 50 ng·mL -1 IFN-γ establish M1 polarization and were also pretreated with 400 µM salidroside. The relative expression of proinflammatory genes was detected by RT-PCR whereas that of mitochondrial homeostasis-related proteins and nuclear factor kappa-B (NF-κB) was detected by WB. Levels of intracellular reactive oxygen species (ROS), mitochondrial membrane potential, and mass were measured by chemifluorescence whereas that of NF-κB nuclear translocation was detected by immunofluorescence. Compared with the Mφ group, the M1 group demonstrated increased mRNA expression of interleukin-1ß , inductible nitric oxide synthase (iNOS), and tumor necrosis factor-α ; increased protein expression of iNOS, NOD-like receptor protein 3, putative kinase 1 , and NF-κB p65 but decreased protein expression of MFN2, Tom20, and PGC-1α; decreased mitochondrial membrane potential and mass; and increased ROS levels and NF-κB p65 nuclear translocation. Salidroside intervention decreased mRNA expression of interleukin-1ß and tumor necrosis factor-α compared with the M1 group but did not affect that of iNOS. Furthermore, salidroside intervention prevented the changes in protein expression, mitochondrial membrane potential and mass, ROS levels, and NF-κB p65 nuclear translocation observed in the M1 group. In summary, salidroside ultimately inhibits M1 macrophage polarization and maintains mitochondrial homeostasis after macrophage polarization by increasing mitochondrial membrane potential, decreasing ROS levels, inhibiting NF-κB activation, and in turn regulating the expression of proinflammatory factors and mitochondrial homeostasis-associated proteins.

Long non-coding RNAs: Modulators of phenotypic transformation in vascular smooth muscle cells.

Long non-coding RNA (lncRNAs) are longer than 200 nucleotides and cannot encode proteins but can regulate the expression of genes through epigenetic, transcriptional, and post-transcriptional modifications. The pathophysiology of smooth muscle cells can lead to many vascular diseases, and studies have shown that lncRNAs can regulate the phenotypic conversion of smooth muscle cells so that smooth muscle cells proliferate, migrate, and undergo apoptosis, thereby affecting the development and prognosis of vascular diseases. This review discusses the molecular mechanisms of lncRNA as a signal, bait, stent, guide, and other functions to regulate the phenotypic conversion of vascular smooth muscle cells, and summarizes the role of lncRNAs in regulating vascular smooth muscle cells in atherosclerosis, hypertension, aortic dissection, vascular restenosis, and aneurysms, providing new ideas for the diagnosis and treatment of vascular diseases.

Proteomics-based evaluation of the mechanism underlying vascular injury via DNA interstrand crosslinks, glutathione perturbation, mitogen-activated protein kinase, and Wnt and ErbB signaling pathways induced by crotonaldehyde.

Crotonaldehyde (CRA)-one of the major environmental pollutants from tobacco smoke and industrial pollution-is associated with vascular injury (VI). We used proteomics to systematically characterize the presently unclear molecular mechanism of VI and to identify new related targets or signaling pathways after exposure to CRA. Cell survival assays were used to assess DNA damage, whereas oxidative stress was determined using colorimetric assays and by quantitative fluorescence study; additionally, cyclooxygenase-2, mitogen-activated protein kinase pathways, Wnt3a, ß-catenin, phospho-ErbB2, and phospho-ErbB4 were assessed using ELISA. Proteins were quantitated via tandem mass tag-based liquid chromatography-mass spectrometry and bioinformatics analyses, and 34 differentially expressed proteins were confirmed using parallel reaction monitoring, which were defined as new indicators related to the mechanism underlying DNA damage; glutathione perturbation; mitogen-activated protein kinase; and the Wnt and ErbB signaling pathways in VI based on Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein-protein interaction network analyses. Parallel reaction monitoring confirmed significant (p < 0.05) upregulation (> 1.5-fold change) of 23 proteins and downregulation (< 0.667-fold change) of 11. The mechanisms of DNA interstrand crosslinks; glutathione perturbation; mitogen-activated protein kinase; cyclooxygenase-2; and the Wnt and ErbB signaling pathways may contribute to VI through their roles in DNA damage, oxidative stress, inflammation, vascular dysfunction, endothelial dysfunction, vascular remodeling, coagulation cascade, and the newly determined signaling pathways. Moreover, the Wnt and ErbB signaling pathways were identified as new disease pathways involved in VI. Taken together, the elucidated underlying mechanisms may help broaden existing understanding of the molecular mechanisms of VI induced by CRA.

Transplantation of Gut Microbiota From High-Fat-Diet-Tolerant Cynomolgus Monkeys Alleviates Hyperlipidemia and Hepatic Steatosis in Rats.

Emerging evidence has been reported to support the involvement of the gut microbiota in the host's blood lipid and hyperlipidemia (HLP). However, there remains unexplained variation in the host's blood lipid phenotype. Herein a nonhuman primate HLP model was established in cynomolgus monkeys fed a high-fat diet (HFD) for 19 months. At month 19%, 60% (3/5) of the HFD monkeys developed HLP, but surprisingly 40% of them (2/5) exhibited strong tolerance to the HFD (HFD-T) with their blood lipid profiles returning to normal levels. Metagenomic analysis was used to investigate the compositional changes in the gut microbiota in these monkeys. Furthermore, the relative abundance of Megasphaera remarkably increased and became the dominant gut microbe in HFD-T monkeys. A validation experiment showed that transplantation of fecal microbiota from HFD-T monkeys reduced the blood lipid levels and hepatic steatosis in HLP rats. Furthermore, the relative abundance of Megasphaera significantly increased in rats receiving transplantation, confirming the successful colonization of the microbe in the host and its correlation with the change of the host's blood lipid profiles. Our results thus suggested a potentially pivotal lipid-lowering role of Megasphaera in the gut microbiota, which could contribute to the variation in the host's blood lipid phenotype.

Characterization of Changes and Driver Microbes in Gut Microbiota During Healthy Aging Using A Captive Monkey Model.

Recent population studies have significantly advanced our understanding of how age shapes the gut microbiota. However, the actual role of age could be inevitably confounded due to the complex and variable environmental factors in human populations. A well-controlled environment is thus necessary to reduce undesirable confounding effects, and recapitulate age-dependent changes in the gut microbiota of healthy primates. Herein we performed 16S rRNA gene sequencing, characterized the age-associated gut microbial profiles from infant to elderly crab-eating macaques reared in captivity, and systemically revealed the lifelong dynamic changes of the primate gut microbiota. While the most significant age-associated taxa were mainly found as commensals such as Faecalibacterium, the abundance of a group of suspicious pathogens such as Helicobacter was exclusively increased in infants, underlining their potential role in host development. Importantly, topology analysis indicated that the network connectivity of gut microbiota was even more age-dependent than taxonomic diversity, and its tremendous decline with age could probably be linked to healthy aging. Moreover, we identified key driver microbes responsible for such age-dependent network changes, which were further linked to altered metabolic functions of lipids, carbohydrates, and amino acids, as well as phenotypes in the microbial community. The current study thus demonstrates the lifelong age-dependent changes and their driver microbes in the primate gut microbiota, and provides new insights into their roles in the development and healthy aging of their hosts.

Glyoxal damages human aortic endothelial cells by perturbing the glutathione, mitochondrial membrane potential, and mitogen-activated protein kinase pathways.

BACKGROUND: Exposure to glyoxal, the smallest dialdehyde, is associated with several diseases; humans are routinely exposed to glyoxal because of its ubiquitous presence in foods and the environment. The aim of this study was to examine the damage caused by glyoxal in human aortic endothelial cells. METHODS: Cell survival assays and quantitative fluorescence assays were performed to measure DNA damage; oxidative stress was detected by colorimetric assays and quantitative fluorescence, and the mitogen-activated protein kinase pathways were assessed using western blotting. RESULTS: Exposure to glyoxal was found to be linked to abnormal glutathione activity, the collapse of mitochondrial membrane potential, and the activation of mitogen-activated protein kinase pathways. However, DNA damage and thioredoxin oxidation were not induced by dialdehydes. CONCLUSIONS: Intracellular glutathione, members of the mitogen-activated protein kinase pathways, and the mitochondrial membrane potential are all critical targets of glyoxal. These findings provide novel insights into the molecular mechanisms perturbed by glyoxal, and may facilitate the development of new therapeutics and diagnostic markers for cardiovascular diseases.

Upregulated Tripartite Motif 47 Could Facilitate Glioma Cell Proliferation and Metastasis as a Tumorigenesis Promoter.

INTRODUCTION: Tripartite motif 47 (TRIM47) belongs to a category of the TRIM family. It takes part in cancer tumorigenesis, thus demonstrating important functions across numerous carcinomas. Unfortunately, it is still elusive towards TRIM47 expression, characteristic, and biological function in brain gliomas. METHODS: Public database analysis was applied to analyze TRIM47 expression, and quantitative real-time PCR (qRT-PCR) was applied to detect the expression of TRIM47 in 9 paired tissues of glioma. The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases were applied to evaluate the overall survival (OS). Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were applied to analyze differentially expressed gene (DEG) functions. In vitro experiments were performed to validate TRIM47-mediated effects on glioma cell proliferation, migration, and invasion. RESULTS: Compared to that in normal tissues, TRIM47 expression was greatly higher in glioma tissues, and its expression level was associated with different grades of glioma. Our data indicated that highly expressed TRIM47 displayed an association with the poor prognosis of glioma patients. Ablating TRIM47 obviously impeded glioma cell invasion and migration. CONCLUSION: TRIM47 could modulate glioma cell proliferation, invasion, and migration. Highly expressed TRIM47 exhibited a correlation with poor prognosis. All data imply that TRIM47 is a probable biomarker for glioma and has the potentiality to become a newly generated target for glioma treatment.

Fasting Plasma Glucose and Coronary Heart Disease in a Rural Population of North Henan, China.

Even in individuals without diabetes, the incidence of coronary heart disease (CHD) increases with the rise in fasting plasma glucose (FPG); however, the threshold of FPG for CHD in rural areas of China is unclear. We retrospectively examined 2,987 people. Coronary angiography records were used to determine the presence of CHD as well as its severity. Risk factors for CHD and the relationship between different levels of FPG and CHD were analyzed. After adjusting for age, hypertension, dyslipidemia, smoking, drinking, chronic kidney disease, and previous ischemic stroke, the incidence of CHD in nondiabetic women began to increase when FPG exceeded 5.2 mmol/L (odds ratio (OR) = 1.438, 95% confidence interval (CI) = 1.099-1.880, p=0.008), and the degree of coronary artery lesions also became more severe (OR = 1.406, 95% CI = 1.107-1.788, p=0.005). However, no such correlations were found in nondiabetic men. In conclusion, among the nondiabetic women in rural areas of northern Henan, both the incidence of CHD and the severity of lesions increased when FPG levels were greater than 5.2 mmol/L, while no significant correlation between FPG and CHD was observed in diabetes-free men.

Advances in Research on the circRNA-miRNA-mRNA Network in Coronary Heart Disease Treated with Traditional Chinese Medicine.

There has been an increase in morbidity and mortality related to coronary heart disease (CHD) in China in recent years. Numerous clinical experiences and studies have shown that traditional Chinese medicine (TCM) plays an important role in the prevention, treatment, and prognosis of CHD. However, the mechanism of TCM in the treatment of CHD has not yet been elucidated. The circRNA-miRNA-mRNA network consists of miRNA that is competitively bound by circRNA, and miRNA regulates the transcription level of mRNA. Through literature review, we found that the circRNA-miRNA-mRNA network acts to contribute to certain effects to CHD such as myocardial hypertrophy, myocardial fibrosis, and heart failure. TCM contains constituents that act against CHD by antiatherosclerosis and apoptosis inhibition action, cardiac and cardiomyocyte protection, and these components also promote cell growth and protection of the vascular system by regulating miRNAs. Therefore, we consider that the circRNA-miRNA-mRNA network may be a new regulatory mechanism for the effective treatment of CHD by TCM.

Birth month associates with risk of coronary artery disease and its complications: A propensity score matched analysis / El mes de nacimiento se asocia con el riesgo de padecer una arteriopatía coronaria y sus complicaciones: análisis mediante propensity score

Objective: Birth month and climate affect lifetime disease risk, while the underlying mechanisms remain largely elusive. It is vital to investigate the risks of coronary artery disease (CAD) and its complications in patients born in different months. Methods: A total of 12,263 patient medical records were reviewed from the BioBank of First Affiliated Hospital of Xinxiang Medical University, with 4729 records from patients with CAD (CAD group) and 7534 records from control patients without CAD (control group). Two groups of patients were matched by the propensity score matched method. Birth months were compared between two groups of patients. The relationships between birth month and the numbers of CAD and its complications were also investigated. Interestingly, we also explore the relationship between the birth seasons and the numbers of CAD and its complications. Results: Compared to control, CAD group had greater CAD risks for patients born in November (OR 1.390, 95% CI 1.090-1.772), December (OR 1.358, 95% CI 1.067-1.730), and February (OR 1.332, 95% CI 1.043-1.700) compared to those born in May. Compared to patients born in December, patients born in January to March and May to September had greater risk of heart failure (P<0.05). There was no difference in the incidence of myocardial infarction, conduction block, and atrial fibrillation across birth months (P>0.05). In terms of birth season, patients born in winter have greater CAD risk than those born in spring (OR 1.247, 95% CI 1.075-1.447). And there was no difference in the incidence of CAD complications across with birth seasons (P>0.05). Conclusions: There was a correlation between birth month and CAD. People born in November, December, and February had greater CAD risk, and people born in winter had greater CAD risk. Among CAD patients, those born in January to March and May to September had the greater risk of heart failure

Objetivo: El mes de nacimiento y el clima están relacionados con el riesgo de padecer una enfermedad crónica, aunque siguen desconociéndose en gran medida los mecanismos subyacentes. Resulta fundamental investigar los riesgos de padecer una arteriopatía coronaria (AC) y sus complicaciones en pacientes nacidos en distintos meses. Métodos: Se revisaron un total de 12.263 historias clínicas de pacientes extraídas del Biobanco del primer hospital afiliado de la Universidad Médica de Xinxiang, de las cuales 4.729 correspondían a pacientes con una AC (grupo con AC) y 7.534 correspondían a pacientes control sin una AC (grupo comparativo). Se emparejaron a 2 grupos de pacientes siguiendo el método de pareamiento por puntaje de propensión, y se compararon los meses de nacimiento de los pacientes de ambos grupos. También se investigó la relación existente entre el mes de nacimiento y el número de casos de AC y sus complicaciones. Resulta interesante destacar que también exploramos la relación existente entre las estaciones de nacimiento y el número de casos de AC y sus complicaciones. Resultados: En comparación con los pacientes del grupo comparativo, los pacientes del grupo con AC nacidos en noviembre (razón de posibilidades odds ratio [OR]: 1,390; intervalo de confianza [IC] del 95%: 1,090-1,772), diciembre (OR: 1,358; IC 95%: 1,067-1,730) y febrero (OR: 1,332; IC 95%: 1,043-1,700) presentaban un mayor riesgo de padecer una AC en comparación con los nacidos en mayo. En comparación con los pacientes nacidos en diciembre, los pacientes nacidos entre enero y marzo, y entre mayo y septiembre, presentaron un mayor riesgo de padecer una insuficiencia cardíaca (P<0,05). No se observaron diferencias en la incidencia de infarto de miocardio, bloqueo de la conducción y fibrilación auricular entre los distintos meses de nacimiento (P>0,05). En cuanto a la temporada de nacimiento, los pacientes nacidos en invierno presentaron un mayor riesgo de desarrollar una AC que los nacidos en primavera (OR: 1,247; IC 95%: 1,075-1,447). No se observaron diferencias en la incidencia de complicaciones de la AC entre las distintas temporadas de nacimiento (P>0,05). Conclusiones: Se observó una correlación entre el mes de nacimiento y la AC. Tanto las personas nacidas en los meses de noviembre, diciembre y febrero, como las nacidas en la temporada de invierno presentaron un mayor riesgo de padecer una AC. Entre los pacientes con AC, los nacidos entre enero y marzo, y entre mayo y septiembre, presentaron un mayor riesgo de padecer una insuficiencia cardíaca

Birth month associates with risk of coronary artery disease and its complications: A propensity score matched analysis.

OBJECTIVE: Birth month and climate affect lifetime disease risk, while the underlying mechanisms remain largely elusive. It is vital to investigate the risks of coronary artery disease (CAD) and its complications in patients born in different months. METHODS: A total of 12,263 patient medical records were reviewed from the BioBank of First Affiliated Hospital of Xinxiang Medical University, with 4729 records from patients with CAD (CAD group) and 7534 records from control patients without CAD (control group). Two groups of patients were matched by the propensity score matched method. Birth months were compared between two groups of patients. The relationships between birth month and the numbers of CAD and its complications were also investigated. Interestingly, we also explore the relationship between the birth seasons and the numbers of CAD and its complications. RESULTS: Compared to control, CAD group had greater CAD risks for patients born in November (OR 1.390, 95% CI 1.090-1.772), December (OR 1.358, 95% CI 1.067-1.730), and February (OR 1.332, 95% CI 1.043-1.700) compared to those born in May. Compared to patients born in December, patients born in January to March and May to September had greater risk of heart failure (P<0.05). There was no difference in the incidence of myocardial infarction, conduction block, and atrial fibrillation across birth months (P>0.05). In terms of birth season, patients born in winter have greater CAD risk than those born in spring (OR 1.247, 95% CI 1.075-1.447). And there was no difference in the incidence of CAD complications across with birth seasons (P>0.05). CONCLUSIONS: There was a correlation between birth month and CAD. People born in November, December, and February had greater CAD risk, and people born in winter had greater CAD risk. Among CAD patients, those born in January to March and May to September had the greater risk of heart failure.

[Explore molecular mechanism of Chinese herbs with promoting blood circulation and resolving phlegm effects on myocardial ischemia reperfusion injury based on correlation between microRNA and mtDNA].

A large number of basic and clinical studies have shown that the Chinese herbs with promoting blood circulation and resolving phlegm effects could prevent and treat myocardial ischemia-reperfusion injury(MIRI) by regulating lipid metabolism. But its mechanism is not yet clear. The studies show that mitochondrial DNA (mtDNA), microRNAs and lipid metabolism participate in the whole process of MIRI and affect the prognosis. mtDNA mutation is the primary factor to cause myocardial ischemia and reperfusion myocardial cell damage. microRNAs aggravate or reduce MIRI injury by down-regulating or up-regulating related genes expression, while miR-33, as a key regulator of cholesterol transport, regulates lipid metabolism through CROT, PGC-1α, AMPK and other genes located in the mitochondria. There are less studies on correlation between miR-33 and mtDNA, microRNAs. Therefore, further studies on the correlation between miR-33 and mtDNA, microRNAs, as well as the discussions on whether the traditional Chinese medicine (TCM) with promoting blood circulation and resolving phlegm effects could target miR-33 to regulate lipid metabolism and inducemt DNA mutations or deletions, would have important significance for the prevention and treatment of MIRI.