The p53/p21/p16 and PI3K/Akt signaling pathways are involved in the ameliorative effects of maltol on D-galactose-induced liver and kidney aging and injury.

Successive evidence has established that maltol, a flavor-enhancing agent, could provide resistance to oxidative stress-induced tissue injury in various animal models though its benefits for aging-induced liver and kidney injuries are still undetermined. In the present work, for demonstrating maltol's ameliorative effect and probable mechanism against aging-induced liver and kidney injuries, D-galactose (D-Gal)-induced animal in vivo and HEK293 cells in vitro models were established and results demonstrated that long-term D-Gal treatment increases the accumulation of advanced glycation end products (AGEs) in liver and kidney tissues, mitigates cell viability, and arrests the cycle. Interestingly, 4-weeks maltol treatment at 50 and 100 mg/kg activated aging-associated proteins including p53, p21, and p16 followed by inhibiting malondialdehyde (MDA)'s over-production and increasing the levels of antioxidant enzymes. Therefore, decreases in cytochrome P450 E1 (CYP2E1) and 4-hydroxydecene (4-HNE)'s immunofluorescence expression levels are confirmed. Furthermore, maltol improved oxidative stress injury by activating the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. In conclusion, the purpose of the present study was to estimate the mechanistic insights into maltol's role as an antioxidant in liver and kidney cell senescence and injury, which will reflect potential of therapeutic strategy for antiaging and aging-related disease treatment.

Efficient CRISPR/Cas9-mediated gene editing in Guangdong small-ear spotted pig cells using an optimized electrotransfection method.

OBJECTIVES: Guangdong Small-ear Spotted (GDSS) pigs are a pig breed native to China that possesses unfortunate disadvantages, such as slow growth rate, low lean-meat percentage, and reduced feed utilization. In contrast to traditional genetic breeding methods with long cycle time and high cost, CRISPR/Cas9-mediated gene editing for the modification of the pig genome can quickly improve production traits, and therefore this technique exhibits important potential in the genetic improvement and resource development of GDSS pigs. In the present study, we aimed to establish an efficient CRISPR/Cas9-mediated gene-editing system for GDSS pig cells by optimizing the electrotransfection parameters, and to realize efficient CRISPR/Cas9-mediated gene editing of GDSS pig cells. RESULTS: After optimization of electrotransfection parameters for the transfection of GDSS pig cells, we demonstrated that a voltage of 150 V and a single pulse with a pulse duration of 20 ms were the optimal electrotransfection parameters for gene editing in these cells. In addition, our study generated GDSS pig single-cell colonies with biallelic mutations in the myostatin (MSTN) gene and insulin-like growth factor 2 (IGF2) intron-3 locus, which play an important role in pig muscle growth and muscle development. The single-cell colonies showed no foreign gene integration or off-target effects, and maintained normal cell morphology and viability. These gene-edited, single-cell colonies can in the future be used as donor cells to generate MSTN- and IGF2-edited GDSS pigs using somatic cell nuclear transfer (SCNT). CONCLUSIONS: This study establishes the foundation for genetic improvement and resource development of GDSS pigs using CRISPR/Cas9-mediated gene editing combined with SCNT.

Ultrabright and Stable Luminescent Labels for Correlative Cathodoluminescence Electron Microscopy Bioimaging.

The mechanistic understanding of structure-function relationships in biological systems heavily relies on imaging. While fluorescence microscopy allows the study of specific proteins following their labeling with fluorophores, electron microscopy enables holistic ultrastructural analysis based on differences in electron density. To identify specific proteins in electron microscopy, immunogold labeling has become the method of choice. However, the distinction of immunogold-based protein labels from naturally occurring electron dense granules and the identification of several different proteins in the same sample remain challenging. Correlative cathodoluminescence electron microscopy (CCLEM) bioimaging has recently been suggested to provide an attractive alternative based on labels emitting characteristic light. While luminescence excitation by an electron beam enables subdiffraction imaging, structural damage to the sample by high-energy electrons has been identified as a potential obstacle. Here, we investigate the feasibility of various commonly used luminescent labels for CCLEM bioimaging. We demonstrate that organic fluorophores and semiconductor quantum dots suffer from a considerable loss of emission intensity, even when using moderate beam voltages (2 kV) and currents (0.4 nA). Rare-earth element-doped nanocrystals, in particular Y2O3:Tb3+ and YVO4:Bi3+,Eu3+ nanoparticles with green and orange-red emission, respectively, feature remarkably high brightness and stability in the CCLEM bioimaging setting. We further illustrate how these nanocrystals can be readily differentiated from morphologically similar naturally occurring dense granules based on optical emission, making them attractive nanoparticle core materials for molecular labeling and (multi)color CCLEM.

Identifying and tracing potential energy surfaces of electronic excitations with specific character via their transition origins: application to oxirane.

We show that the transition origins of electronic excitations identified by quantified natural transition orbital (QNTO) analysis can be employed to connect potential energy surfaces (PESs) according to their character across a wide range of molecular geometries. This is achieved by locating the switching of transition origins of adiabatic potential surfaces as the geometry changes. The transition vectors for analysing transition origins are provided by linear response time-dependent density functional theory (TDDFT) calculations under the Tamm-Dancoff approximation. We study the photochemical CO ring opening of oxirane as an example and show that the results corroborate the traditional Gomer-Noyes mechanism derived experimentally. The knowledge of specific states for the reaction also agrees well with that given by previous theoretical work using TDDFT surface-hopping dynamics that was validated by high-quality quantum Monte Carlo calculations. We also show that QNTO can be useful for considerably larger and more complex systems: by projecting the excitations to those of a reference oxirane molecule, the approach is able to identify and analyse specific excitations of a trans-2,3-diphenyloxirane molecule.

Significant role of the DNA backbone in mediating the transition origin of electronic excitations of B-DNA--implication from long range corrected TDDFT and quantified NTO analysis.

We systematically investigate the possible complex transition origin of electronic excitations of giant molecular systems by using the recently proposed QNTO analysis [J.-H. Li, J.-D. Chai, G. Y. Guo and M. Hayashi, Chem. Phys. Lett., 2011, 514, 362.] combined with long-range corrected TDDFT calculations. Thymine (Thy) related excitations of a B-DNA biomolecule are then studied as examples, where the model systems have been constructed by extracting from the perfect or an X-ray crystal (PDB code 3BSE) B-DNA structure with at least one Thy included. In the first part, we consider the systems composed of a core molecular segment (e.g. Thy, or di-Thy) and a surrounding physical/chemical environment of interest (e.g. backbone, adjacent stacking nucleobases) in gas phase and examine how the excitation properties of the core vary in response to the environment. We find that the orbitals contributed by the DNA backbone and surrounding nucleobases often participate in a transition of Thy-related excitations affecting their composition, absorption energy, and oscillator strength. A vast number of strongly backbone-orbital involved excitations are also found at an absorption wavelength below ∼180 nm predicted by TD-ωB97X. In the second part, we take into account geometrically induced variation of the excitation properties of various B-DNA segments, e.g. di-Thy, dTpdT etc., obtained from different sources (ideal and 3BSE). It is found that the transition origin of several Thy-related excitations of these segments is sensitive to slight conformational variations, suggesting that DNA with thermal motions may from time to time exhibit very different photo-induced physical and/or chemical processes.

[Sensitivity of spring phenology to elevation in Qinling Mountains, China]. / 秦岭山区植被春季物候的海拔敏感性.

Vegetation phenology, a regular and periodic phenomenon in nature, is an important indicator for natural environment, especially climate change. The study of spatiotemporal variations of vegetation phenology is of great significance for monitoring the changes of terrestrial vegetation. In this study, the Savitzky-Golay (S-G) filtering method was used to reconstruct time-series MODIS enhanced vegetation index (EVI) data in the Qinling Mountains from 2001 to 2018. The dynamic threshold method was used to extract the spring phenological parameter (start of growth season, SOS). The correlation between multi-year mean SOS and interannual variation with altitude and slope was analyzed. The results showed that SOS was delayed by 1.82 d with every 100 m increase in altitude in the Qinling Mountains. The interannual change trends of SOS mainly concentrated in 0-5 d·(10 a)-1. The pixels with delaying trend were mainly distributed in low-altitude regions, with the delaying degree being gradually decreased with the elevation. The interannual change trend of SOS in high-altitude regions was more complex than that in lower-altitude regions. The multi-year average SOS in the northern slope was approximately 2.9 d earlier than that of the southern slope, whereas the southern slope had a more significant advancing trend. The interannual change trends of SOS in both north and south slopes showed a delaying trend in low-altitude, with little difference between north and south slopes. The advancing trend in middle and high altitude was significantly different.

Pharmacotherapy for Behçet's Disease and the Risk of Malignancy.

Background: Behçet's disease (BD) is associated with an increased risk of cancer. Few reports have been published on the relationship between drug exposure and the risk of cancer in patients with BD. Herein, we explored the relationship between pharmacologic interventions for BD and the risk of cancer. Methods: we carried out a retrospective nested case-control study in a cohort of BD patients from attending our institution. Among 1,148 patients, 22 cancer patients were individually 1:2 matched to 44 cancer-free controls. The following biochemical indicators were evaluated: routine blood analysis, liver and kidney function tests, inflammatory indexes, blood gas analysis, blood electrolyte and previous pharmacologic interventions to manage BD including systemic glucocorticoids, methotrexate, cyclosporine-A, azathioprine, cyclophosphamide (CYC), and thalidomide, which are considered the primary medicines used for the management of BD. Results: Among the 22 BD patients with cancers, myelodysplastic syndrome (MDS) (22.72%) was the most common type. Furthermore, CYC administration was significantly higher in BD patients with cancer compared with the cancer-free matched control group. Further, we observed that complement 4 (C4) (odds ratio [OR] = 0.0001, 95% confidence interval [CI]: 0.001-0.065) and hemoglobin (Hb) (OR = 0.891, 95% CI: 0.795-0.998) levels were independent protective factors for predicting cancer risk in BD patients on multivariate analyses. Conclusion: Our study revealed that CYC was associated with a high risk of cancer in BD patients. Furthermore, C4 and Hb are independent protective factors for oncogenesis in BD patients. These findings may provide references and suggestions for clinicians to select appropriate treatments and for the early recognition of high-risk patients to reduce cancer incidence in BD patients.

Multiscale Analysis of Metal Oxide Nanoparticles in Tissue: Insights into Biodistribution and Biotransformation.

Metal oxide nanoparticles have emerged as exceptionally potent biomedical sensors and actuators due to their unique physicochemical features. Despite fascinating achievements, the current limited understanding of the molecular interplay between nanoparticles and the surrounding tissue remains a major obstacle in the rationalized development of nanomedicines, which is reflected in their poor clinical approval rate. This work reports on the nanoscopic characterization of inorganic nanoparticles in tissue by the example of complex metal oxide nanoparticle hybrids consisting of crystalline cerium oxide and the biodegradable ceramic bioglass. A validated analytical method based on semiquantitative X-ray fluorescence and inductively coupled plasma spectrometry is used to assess nanoparticle biodistribution following intravenous and topical application. Then, a correlative multiscale analytical cascade based on a combination of microscopy and spectroscopy techniques shows that the topically applied hybrid nanoparticles remain at the initial site and are preferentially taken up into macrophages, form apatite on their surface, and lead to increased accumulation of lipids in their surroundings. Taken together, this work displays how modern analytical techniques can be harnessed to gain unprecedented insights into the biodistribution and biotransformation of complex inorganic nanoparticles. Such nanoscopic characterization is imperative for the rationalized engineering of safe and efficacious nanoparticle-based systems.

The multiscale hierarchical structure of Heloderma suspectum osteoderms and their mechanical properties.

Osteoderms are hard tissues embedded in the dermis of vertebrates and have been suggested to be formed from several different mineralized regions. However, their nano architecture and micro mechanical properties had not been fully characterized. Here, using electron microscopy, µ-CT, atomic force microscopy and finite element simulation, an in-depth characterization of osteoderms from the lizard Heloderma suspectum, is presented. Results show that osteoderms are made of three different mineralized regions: a dense apex, a fibre-enforced region comprising the majority of the osteoderm, and a bone-like region surrounding the vasculature. The dense apex is stiff, the fibre-enforced region is flexible and the mechanical properties of the bone-like region fall somewhere between the other two regions. Our finite element analyses suggest that when combined into the osteoderm structure, the distinct tissue regions are able to shield the body of the animal by bearing the external forces. These findings reveal the structure-function relationship of the Heloderma suspectum osteoderm in unprecedented detail. STATEMENT OF SIGNIFICANCE: The structures of bone and teeth have been thoroughly investigated. They provide a basis not only for understanding the mechanical properties and functions of these hard tissues, but also for the de novo design of composite materials. Osteoderms, however, are hard tissues that must possess mechanical properties distinct from teeth and bone to function as a protective armour. Here we provide a detailed analysis of the nanostructure of vertebrate osteoderms from Heloderma suspectum, and show that their mechanical properties are determined by their multiscale hierarchical tissue. We believe this study contributes to advance the current knowledge of the structure-function relationship of the hierarchical structures in the Heloderma suspectum osteoderm. This knowledge might in turn provide a source of inspiration for the design of bioinspired and biomimetic materials.

Maltol (3-Hydroxy-2-methyl-4-pyrone) Slows d-Galactose-Induced Brain Aging Process by Damping the Nrf2/HO-1-Mediated Oxidative Stress in Mice.

Maltol, a maillard reaction product from ginseng (Panax ginseng C. A. Meyer), has been confirmed to inhibit oxidative stress in several animal models. Its beneficial effect on oxidative stress related brain aging is still unclear. In this study, the mouse model of d-galactose (d-Gal)-induced brain aging was employed to investigate the therapeutic effects and potential mechanisms of maltol. Maltol treatment significantly restored memory impairment in mice as determined by the Morris water maze tests. Long-term d-Gal treatment reduced expression of cholinergic regulators, i.e., the cholineacetyltransferase (ChAT) (0.456 ± 0.10 vs 0.211 ± 0.03 U/mg prot), the acetylcholinesterase (AChE) (36.4 ± 5.21 vs 66.5 ± 9.96 U/g). Maltol treatment prevented the reduction of ChAT and AChE in the hippocampus. Maltol decreased oxidative stress levels by reducing levels of reactive oxygen species (ROS) and malondialdehyde (MDA) production in the brain and by elevating antioxidative enzymes. Furthermore, maltol treatment minimized oxidative stress by increasing the phosphorylation levels of phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt), nuclear factor-erythroid 2-related factor 2 (Nrf2), and hemeoxygenase-1 (HO-1). The above results clearly indicate that supplementation of maltol diminishes d-Gal-induced behavioral dysfunction and neurological deficits via activation of the PI3K/Akt-mediated Nrf2/HO-1 signaling pathway in brain. Maltol might become a potential drug to slow the brain aging process and stimulate endogenous antioxidant defense capacity. This study provides the novel evidence that maltol may slow age-associated brain aging.

Enhancing the power conversion efficiency of dye-sensitized solar cells via molecular plasmon-like excitations.

We introduce a tactic for employing molecular plasmon-like excitations to enhance solar-to-electric power conversion efficiency of dye-sensitized solar cells. We offer general design principles of dimeric dyes, in which a strong plasmonic interaction between two π-conjugated moieties is promoted. The π-stacked conformations of these dimeric dyes result in a desirable broadened absorption and a longer absorption onset wavelength.

Clinical significance of costimulatory molecules CD40/CD40L and CD134/CD134L in coronary heart disease: A case-control study.

The aim of the study was to evaluate the potential role of CD40/CD40 ligand (CD40L) and CD134/CD134 ligand (CD134L) in the development of coronary heart disease (CHD) via the performance of a case-control study.The research objects were 234 cases of CHD patients and 120 cases of well-matched normal controls. Following the separation of peripheral blood mononuclear cells (PBMCs), real-time quantitative PCR (qRT-PCR), Western blot, immunohistochemistry, and flow cytometry were applied for the detection of mRNA levels and expression levels of CD40/CD40L and CD134/CD134L; meanwhile, intercellular adhesion molecule-1 (ICAM-1) and Fas protein mRNA levels were detected using qRT-PCR.There was no statistical difference in the comparison of baseline characteristics between groups, indicating comparability between groups. qRT-PCR and Western blot analysis indicated that CD40/CD40L and CD134/CD134L mRNA and protein expression levels were all increased in the CHD group than those in the control group. Flow cytometry further confirmed the similar tendency. Meanwhile, ICAM-1 and Fas protein mRNA levels were elevated in the CHD group and positively correlated with the above parameters. Furthermore, CD40/CD40L expression rates were negatively correlated with gender and different types of CHD. Meanwhile, CD134/CD134L expressions were also higher in male patients, in patients with family history, previous history of hypertension, diabetes, and cerebrovascular diseases.CD40/CD40L and CD134/CD134L are increased and may have potential correlation with clinical pathological features of patients with CHD. Further in-depth exploration of costimulatory molecules for CHD guidance as well as intrinsic mechanisms are needed combined with in vivo and in vitro experiments.

The value of diffusion tensor imaging in differentiating high-grade gliomas from brain metastases: a systematic review and meta-analysis.

PURPOSE: Differentiation of high-grade gliomas and solitary brain metastases is an important clinical issue because the treatment strategies differ greatly. Our study aimed to investigate the potential value of diffusion tensor imaging (DTI) in differentiating high-grade gliomas from brain metastases using a meta-analytic approach. MATERIALS AND METHODS: We searched Pubmed, Embase and the Cochrane Library for relevant articles published in English. Studies that both investigated high-grade gliomas and brain metastases using DTI were included. Random effect model was used to compare fractional anisotropy (FA) and mean diffusivity (MD) values in the two tumor entities. RESULTS: Nine studies were included into the meta-analysis. In the peritumoral region, compared with brain metastases, high-grade gliomas had a significant increase of FA (SMD  = 0.47; 95% CI, 0.22-0.71; P<0.01) and a significant decrease of MD (SMD  = -1.49; 95% CI, -1.91 to -1.06; P<0.01). However, in the intratumoral area, no significant change in FA (SMD  = 0.16; 95% CI, -0.49 to 0.82; P = 0.73) or MD (SMD  = 0.34; 95% CI, -0.91 to 1.60; P = 0.59) was detected between gliomas and metastases. CONCLUSIONS: High-grade gliomas may be distinguished from brain metastases by comparing the peritumoral FA and MD values. DTI appears to be a promising tool in diagnosing solitary intracranial lesions.

Noninvasive assessment of the carotid and cerebrovascular atherosclerotic plaques by multidetector CT in type-2 diabetes mellitus patients with transient ischemic attack or stroke.

BACKGROUND: The cerebrovasuclar artery disease as a common complication of type-2 diabetes mellitus (T2DM) caused huge economic burden and lives threatening to patients. We evaluated the prevalence and morphology of carotid and cerebrovascular atherosclerotic plaques in T2DM patients with transient ischemic attack (TIA) or stroke using multidetector CT (MDCT). METHODS: 64-MDCT and dual-source CT (DSCT) angiographies were performed in 195 T2DM patients with TIA or stroke (mean age 65.7+/-12.8 years; 118 men) between January 2009 to August 2011. During the process, plaque type, its distribution, extensive and obstructive natures were determined for each segment derived from the patients. RESULTS: Atherosclerotic plaques were detected in 183 (93.8%) patients. A total of 1056 segments with plaque were identified, of which 450 (42.6%) were non-calcified, 192 (18.2%) were mixed and 414 (39.2%) calcified ones. Among them, 562 (53.2%) resulted in mild stenosis, 291 (27.6%) moderate stenosis, 170 (16.1%) severe stenosis and 33 (3.1%) occlusion. Non-calcified plaques contributed 91.8% to non-obstructive lumen narrowing, while mixed and calcified plaques contributed 89.0% and 65.0% respectively. CONCLUSIONS: MDCT angiography detected a high prevalence of plaques in T2DM patients with TIA or stroke. A relatively high proportion of plaques were non-calcified, as well as with non-obstructive stenosis. MDCT angiography might further enhance the detection and management of carotid and cerebrovascular atherosclerosis in T2DM patients with TIA and stroke.

Minocycline inhibits 5-lipoxygenase expression and accelerates functional recovery in chronic phase of focal cerebral ischemia in rats.

AIMS: We previously reported that minocycline attenuates acute brain injury and inflammation after focal cerebral ischemia, and this is partly mediated by inhibition of 5-lipoxygenase (5-LOX) expression. Here, we determined the protective effect of minocycline on chronic ischemic brain injury and its relation with the inhibition of 5-LOX expression after focal cerebral ischemia. MAIN METHODS: Focal cerebral ischemia was induced by 90 min of middle cerebral artery occlusion followed by reperfusion for 36 days. Minocycline (45 mg/kg) was administered intraperitoneally 2h and 12h after ischemia and then every 12h for 5 days. Sensorimotor function was evaluated 1-28 days after ischemia and cognitive function was determined 30-35 days after ischemia. Thereafter, infarct volume, neuron density, astrogliosis, and 5-LOX expression in the brain were determined. KEY FINDINGS: Minocycline accelerated the recovery of sensorimotor and cognitive functions, attenuated the loss of neuron density, and inhibited astrogliosis in the boundary zone around the ischemic core, but did not affect infarct volume. Minocycline significantly inhibited the increased 5-LOX expression in the proliferated astrocytes in the boundary zone, and in the macrophages/microglia in the ischemic core. SIGNIFICANCE: Minocycline accelerates functional recovery in the chronic phase of focal cerebral ischemia, which may be partly associated with the reduction of 5-LOX expression.

[Effects of partial revascularization in elderly patients over 80 years old with coronary artery diseases].

OBJECTIVE: To observe the clinical effects of partial revascularization on elderly patients with coronary artery diseases(CAD) METHODS: Percutaneous coronary interventions (PCI) of the most likely culprit vessels were performed in 37 patients over 80 years old with multivessel coronary artery diseases (CAD). RESULTS: The success rate of PCI was 100% in these elderly patients without serious complications. The in-hospital mortality rate was 2.7%, and all the other patients recovered and were discharged. CONCLUSION: Partial revascularization for elderly CAD patients can achieve satisfactory clinical results, and close attention should be given to the heart and kidney function of these patients.