Aerobic exercise-induced HIF-1α upregulation in heart failure: exploring potential impacts on MCT1 and MPC1 regulation.

BACKGROUND: The terminal stage of ischemic heart disease develops into heart failure (HF), which is characterized by hypoxia and metabolic disturbances in cardiomyocytes. The hypoxic failing heart triggers hypoxia-inducible factor-1α (HIF-1α) actions in the cells sensitized to hypoxia and induces metabolic adaptation by accumulating HIF-1α. Furthermore, soluble monocarboxylic acid transporter protein 1 (MCT1) and mitochondrial pyruvate carrier 1 (MPC1), as key nodes of metabolic adaptation, affect metabolic homeostasis in the failing rat heart. Aerobic exercise training has been reported to retard the progression of HF due to enhancing HIF-1α levels as well as MCT1 expressions, whereas the effects of exercise on MCT1 and MPC1 in HF (hypoxia) remain elusive. This research aimed to investigate the action of exercise associated with MCT1 and MPC1 on HF under hypoxia. METHODS: The experimental rat models are composed of four study groups: sham stented (SHAM), HF sedentary (HF), HF short-term exercise trained (HF-E1), HF long-term exercise trained (HF-E2). HF was initiated via left anterior descending coronary artery ligation, the effects of exercise on the progression of HF were analyzed by ventricular ultrasound (ejection fraction, fractional shortening) and histological staining. The regulatory effects of HIF-1α on cell growth, MCT1 and MPC1 protein expression in hypoxic H9c2 cells were evaluated by HIF-1α activatort/inhibitor treatment and plasmid transfection. RESULTS: Our results indicate the presence of severe pathological remodelling (as evidenced by deep myocardial fibrosis, increased infarct size and abnormal hypertrophy of the myocardium, etc.) and reduced cardiac function in the failing hearts of rats in the HF group compared to the SHAM group. Treadmill exercise training ameliorated myocardial infarction (MI)-induced cardiac pathological remodelling and enhanced cardiac function in HF exercise group rats, and significantly increased the expression of HIF-1α (p < 0.05), MCT1 (p < 0.01) and MPC1 (p < 0.05) proteins compared to HF group rats. Moreover, pharmacological inhibition of HIF-1α in hypoxic H9c2 cells dramatically downregulated MCT1 and MPC1 protein expression. This phenomenon is consistent with knockdown of HIF-1α at the gene level. CONCLUSION: The findings propose that long-term aerobic exercise training, as a non- pharmacological treatment, is efficient enough to debilitate the disease process, improve the pathological phenotype, and reinstate cardiac function in HF rats. This benefit is most likely due to activation of myocardial HIF-1α and upregulation of MCT1 and MPC1.

Wnt10b knockdown regulates the relative balance of adipose tissue-resident T cells and inhibits white fat deposition.

BACKGROUND: Wnt10b is one of critical Wnt family members that being involved in networks controlling stemness, pluripotency and cell fate decisions. However, its role in adipose-resident T lymphocytes and further in fat metabolism yet remains largely unknown. METHODS AND RESULTS: In the present study, we demonstrated a distinctive effect for Wnt10b on the relative balance of T lymphocytes in adipose tissue by using a Wnt10b knockdown mouse model. Wnt10b knockdown led to a reduction of adipose-resident CD4+ T cells and an elevation of Foxp3+/CD4+ Treg cells. Wnt10b-knockdown mice fed with standard diet showed less white fat deposition owing to the suppressed adipogenic process. Moreover, under high fat diet conditions, Wnt10b knockdown resulted in an alleviated obesity symptoms, as well as an improvement of glucose homeostasis and hepatic steatosis. CONCLUSIONS: Collectively, we reveal an unexpected and novel function for Wnt10b in mediating the frequency of adipose-resident T cell subsets, that when knockdown skewing toward a Treg-dominated phenotype and further improving fat metabolism.

Inhibition of high sulfur on functional microorganisms and genes in slightly contaminated soil by cadmium and chromium.

It is generally accepted that sulfur can passivate the bioavailability of heavy metals in soil, but it is not clear whether high sulfur in cadmium (Cd) and chromium (Cr) contaminated soil has negative effect on soil microbial community and ecological function. In this study, total sulfur (TS) inhibited the Chao 1, Shannon, Phylogenetic diversity (Pd) of bacterial and Pd of fungi in slightly contaminated soil by Cd and Cr around pyrite. TS, total potassium, pH, total chromium, total cadmium, total nitrogen, soil organic matter were the predominant factors for soil microbial community; the contribution of TS in shaping bacterial and fungal communities ranked at first and fifth, respectively. Compared with the low sulfur group, the abundance of sulfur sensitive microorganisms Gemmatimonas, Pseudolabrys, MND1, and Schizothecium were decreased by 68.79-97.22% (p < 0.01) at high sulfur one; the carbon fixation, nitrogen cycling, phosphorus cycling and resistance genes abundance were significantly lower (p < 0.01) at the latter. Such variations were strongly and closely correlated to the suppression of energy metabolism (M00009, M00011, M00086) and carbon fixation (M00173, M00376) functional module genes abundance in the high sulfur group. Collectively, high sulfur significantly suppressed the abundances of functional microorganisms and functional genes in slightly contaminated soil with Cd and Cr, possibly through inhibition of energy metabolism and carbon fixation of functional microorganisms. This study provided new insights into the environmental behavior of sulfur in slightly contaminated soil with Cd and Cr.

PGC-1α regulates critical period onset/closure, mediating cortical plasticity.

Peroxisome proliferator-activated receptor PPARγ coactivator-α (PGC-1α) is concentrated in inhibitory interneurons and plays a vital role in neuropsychiatric diseases. We previously reported some characteristic features of schizophrenia (SZ) in GABAergic neuron-specific Pgc-1alpha knockout (KO) mice (Dlx5/6-Cre: Pgc-1alphaf/f). However, there is a fundamental gap in the molecular mechanism by which the Pgc-1alpha gene is involved in the neurobehavioral abnormalities of SZ. The loss of critical period (CP) triggers-maturations of parvalbumin interneurons (PVIs) and brakes-and the formation of perineuronal nets (PNNs) implicates mistimed trajectories during adult brain development. In this study, using the Pgc-1alpha KO mouse line, we investigated the association of Pgc-1alpha gene deletion with SZ-like behavioral deficits, PVI maturation, PNN integrity and synaptic ultrastructure. These findings suggest that Pgc-1alpha gene deletion resulted in a failure of CP onset and closure, thereby prolonging cortical plasticity timing. To determine whether the manipulation of the PNN structure is a potential method of altering neuronal plasticity, GM6001, a broad-spectrum matrix metalloproteinase (MMP)-inhibitor was applied. Here we confirmed that the treatment could effectively correct the CP plasticity window and ameliorate the synaptic ultrastructure in the Pgc-1alpha KO brain. Moreover, the intervention effect on neuronal plasticity was followed by the rescue of short-term habituation deficits and the mitigation of aberrant salience, which are some characteristic features of SZ. Taken collectively, these findings suggest that the role of PGC-1α in regulating cortical plasticity is mediated, at least partially, through the regulation of CP onset/closure. Strategically introduced reinforcement of molecular brakes may be a novel preventive therapy for psychiatric disorders associated with PGC-1α dysregulation.

Wnt10b knockdown promotes UCP1 expression in brown adipose tissue in mice.

The effect of Wnt10b overexpression on adipose tissue development has been reported. However, the impact of Wnt10b knockdown on the function of brown adipose tissue (BAT) is yet largely unknown. Here, we used the CRISPR/Cas9 technique to generate Wnt10b-knockdown (Wnt10b+/- ) mice. We compared the development and thermogenic gene expression of interscapular BAT (iBAT) between Wnt10b+/- and Wnt10b+/+ mice under a chow diet, high-fat diet (HFD), and cold exposure conditions. Moreover, the effect of Wnt10b knockdown on brown adipocyte function was tested via in vitro experiments. Results indicated that Wnt10b knockdown decreased the iBAT mass and the brown adipocyte size and enhanced thermogenic gene expression, including UCP1, under chow diet conditions. In addition, Wnt10b+/- mice appeared to be able to maintain their body temperature better than the control in a cold environment, accompanied by higher UCP1 protein expression. Intriguingly, even under HFD conditions, Wnt10b+/- mice still showed higher UCP1 expression, which was associated with an alleviated obesity phenotype. In vitro studies further evidenced the Wnt10b knockdown stimulation of UCP1 expression and suppression of the adipogenic program. This study indicates that Wnt10b knockdown enhances UCP1 expression and inhibits the adipogenic differentiation of brown adipocytes, providing a novel option for therapeutic interventions in adiposity.

Brain metabolism in Alzheimer's disease: biological mechanisms of exercise.

Alzheimer's disease (AD) is a major subtype of neurodegenerative dementia caused by long-term interactions and accumulation of multiple adverse factors, accompanied by dysregulation of numerous intracellular signaling and molecular pathways in the brain. At the cellular and molecular levels, the neuronal cellular milieu of the AD brain exhibits metabolic abnormalities, compromised bioenergetics, impaired lipid metabolism, and reduced overall metabolic capacity, which lead to abnormal neural network activity and impaired neuroplasticity, thus accelerating the formation of extracellular senile plaques and intracellular neurofibrillary tangles. The current absence of effective pharmacological therapies for AD points to the urgent need to investigate the benefits of non-pharmacological approaches such as physical exercise. Despite the evidence that regular physical activity can improve metabolic dysfunction in the AD state, inhibit different pathophysiological molecular pathways associated with AD, influence the pathological process of AD, and exert a protective effect, there is no clear consensus on the specific biological and molecular mechanisms underlying the advantages of physical exercise. Here, we review how physical exercise improves crucial molecular pathways and biological processes associated with metabolic disorders in AD, including glucose metabolism, lipid metabolism, Aß metabolism and transport, iron metabolism and tau pathology. How metabolic states influence brain health is also presented. A better knowledge on the neurophysiological mechanisms by which exercise improves AD metabolism can contribute to the development of novel drugs and improvement of non-pharmacological interventions.

Treadmill exercise promotes E3 ubiquitin ligase to remove amyloid ß and P-tau and improve cognitive ability in APP/PS1 transgenic mice.

BACKGROUND: Moderate physical exercise is conducive to the brains of healthy humans and AD patients. Previous reports have suggested that treadmill exercise plays an anti-AD role and improves cognitive ability by promoting amyloid clearance, inhibiting neuronal apoptosis, reducing oxidative stress level, alleviating brain inflammation, and promoting autophagy-lysosome pathway in AD mice. However, few studies have explored the relationships between the ubiquitin-proteasome system and proper exercise in AD. The current study was intended to investigate the mechanism by which the exercise-regulated E3 ubiquitin ligase improves AD. METHODS: Both wild type and APP/PS1 transgenic mice were divided into sedentary (WTC and ADC) and exercise (WTE and ADE) groups (n = 12 for each group). WTE and ADE mice were subjected to treadmill exercise of 12 weeks in order to assess the effect of treadmill running on learning and memory ability, Aß plaque burden, hyperphosphorylated Tau protein and E3 ubiquitin ligase. RESULTS: The results indicated that exercise restored learning and memory ability, reduced Aß plaque areas, inhibited the hyperphosphorylation of Tau protein activated PI3K/Akt/Hsp70 signaling pathway, and improved the function of the ubiquitin-proteasome system (increased UCHL-1 and CHIP levels, decreased BACE1 levels) in APP/PS1 transgenic mice. CONCLUSIONS: These findings suggest that exercise may promote the E3 ubiquitin ligase to clear ß-amyloid and hyperphosphorylated Tau by activating the PI3K/Akt signaling pathway in the hippocampus of AD mice, which is efficient in ameliorating pathological phenotypes and improving learning and memory ability.

[Construction and evaluation of a gradient stress model of PC12 cells induced by corticosterone].

Objective: A gradient stress model of PC12 cells induced by corticosterone was established to provide a basis for the evaluation and regulation of cell stress. Methods: The effect of corticosterone on cell viability was observed by measuring PC12 cell viability at different concentrations of corticosterone (0~1 000 µmol/L) after different intervention times (8~48 h) to screen the cell models for optimal intervention conditions. Key stress indicators (MDA, SOD, NADH, LDH) were measured spectrophotometrically and microscopically to evaluate the models. Results: When the concentration of corticosterone was below 200 µmol/L and the intervention time was 12 h, the cell viability was below half inactivation rate, which could reduce the confounding factors due to the decrease of cell viability in each group. Compared with the blank control group, corticosterone increased the levels of MDA, NADH and LDH,and decreased the levels of SOD in the model group in a concentration-dependent manner (P＜0.01), which was consistent with the construction of the gradient stress model. Conclusion: A gradient stress injury model of PC12 cells was successfully established, with intervention concentrations of 0 µmol/L, 25 µmol/L, 50 µmol/L, 100 µmol/L, 150 µmol/L and 200 µmol/L corticosterone at an intervention time of 12 h. The degree of stress injury of the cell model was increased gradually, which could be used as a basis and object for conducting cell stress injury assessment and regulation experiments.

Pore Structure and Fractal Characteristics of Deep Shale: A Case Study from Permian Shanxi Formation Shale, from the Ordos Basin.

Pore structure has certain significance for the preservation and enrichment of shale gas. However, less attention is paid to deep shale (>3000 m) which has unique pore characteristics that distinguish it from the shallow and medium layers. In order to study the pore structure characteristics of deep shale, 10 samples of the Shanxi Formation are collected from well YP-1 within the depth of 3550-3610 m in the Fuxian block of the Ordos Basin. The pore structure characteristics of shale samples are quantitatively studied by scanning electron microscopy (SEM), low-temperature nitrogen adsorption-desorption, and high-pressure mercury injection experiments. The pore surface area (SA) and pore volume (PV) of the deep shale of Shanxi formation are low, with average values of 4.282 m2/g and 0.0126 mL/g, respectively. The content of total organic carbon (TOC) is high, which is in the high over mature stage, with undeveloped organic pores and developed microfractures. The main mineral components are clay (51.6%∼89.1%) and quartz (8%∼41.7%). By establishing the relationship between SA, PV, and TOC for quartz and clay minerals, it is found that these three parameters have little contribution to SA and PV. The pore diameter is mainly mesoporous, 2.5-4 nm and 8-11 nm. The complexity of pore structure is discussed through the fractal dimension calculated by the fractal Frenkel-Halsey-Hill (FHH) model. The pore fractal dimension D 2 (2.6240) is greater than D 1 (2.5608), and the complexity of the pore structure is greater than that of the pore surface. The fractal dimension of deep shale in Shanxi is negatively correlated with TOC content and weakly correlated with quartz and clay minerals. It shows that the mineral composition of deep shale in Shanxi Formation in the study area has little effect on pore development, and the development of microfractures is the main contribution of SA and PV.

Controls on the Organic Matter Accumulation of the Marine-Continental Transitional Shanxi Formation Shale in the Southeastern Ordos Basin.

The marine-continental transitional shale with favorable geological conditions for shale gas accumulation and broad resource prospects is widely distributed in China, which is also well developed in the Ordos Basin. The reservoir characteristic and gas-bearing properties of the transitional Shanxi Formation shale have been studied in previous studies. However, the factors influencing the organic matter (OM) accumulation have not been well studied, which restricts shale gas exploration and development of the Shanxi Formation in the Ordos Basin. According to analyses of organic geochemistry, mineral compositions, and major and trace elements, this paper has studied the paleoenvironment characteristic and its influence on the OM accumulation of the Shanxi Formation shale. The results indicate that the OM is characterized by the high mature stage and type III kerogen while the total organic content (TOC) of Member 1 is higher than that of Member 2. From Member 1 to Member 2, the paleowater depth gradually decreases, along with a gradually relative cold and dry climate, decreasing the terrestrial influx intensity and paleoproductivity and increasing the oxygen content in the water column. For Member 1, the OM accumulation is mainly controlled by the terrestrial influx intensity and paleowater depth, and other paleoenvironment factors have an unobvious contribution to the OM accumulation. For Member 2, the OM accumulation is commonly controlled by the weak terrestrial influx, low paleoproductivity, and oxic water column, resulting in the low TOC of Member 2. This study reveals the paleoenvironment characteristic and controls on the OM accumulation of the Shanxi Formation shale, which is beneficial to the reservoir selection of the Shanxi Formation in the southeastern Ordos Basin and the understanding of the OM accumulation in other transitional shales.

An NADH-selective and sensitive fluorescence probe to evaluate living cell hypoxic stress.

Cellular disease and senescence are often accompanied by an imbalance in the local oxygen supply. Under hypoxia, mitochondrial NADH and FADH2 cannot be oxidized by the mitochondrial electron transport chain, which leads to the accumulation of reducing equivalents and subsequent reduction stress. Detecting changes in intracellular NADH levels is expected to allow an assessment of stress. We synthesized a red fluorescent probe, DPMQL1, with high selectivity and sensitivity for detecting NADH in living cells. The probe DPMQL1 has strong anti-interference abilities toward various potential biological interferences, such as metal ions, anions, redox species, and other biomolecules. In addition, its detection limit can reach the nanomolar level, meaning it can display small changes in NADH levels in living cells, so as to realize the evaluation of cell-based hypoxic stress.

A New Approach to Explore the Surface Profile of Clay Soil Using White Light Interferometry.

In order to have a better understanding of the real contact area of granular materials, the white light interference method is applied to explore the real surface morphology of clay soils under high stress. Analysis of the surface profile indicates that there exists a support point height z0 with the highest distribution frequency. A concept of a real contact region (from z0 to z0 + d90; d90 represents the particle size corresponding to 90% of the volume fraction) is proposed by combining a surface profile with the particle size distribution of clay soil. It was found that under the compressive stress of 106 MPa-529 MPa, the actual contact area ratio of clay soil varies between 0.375 and 0.431. This demonstrates an increasing trend with the rise of stress. On the contrary, the apparent porosity decreases with an increasing stress, varying between 0.554 and 0.525. In addition, as the compressive stress increases, the cumulative frequency of apparent profile height (from z0 - d90 to z0 + d90) has a concentrated tendency with a limited value of 0.9.

Novel frequency stability measurement method with whole sample time range.

A method to measure the frequency stabilities with a nearly whole range of sample time is presented. Precision as high as 10-5/100 ns has been obtained by it when measuring transient stability with 100 ns sample time, 10-12/s has been obtained toward short-term stability with 1 s sample time, and 10-16/day has been obtained with regard to long-term stability with 1 day sample time. In addition, because the frequency stabilities in a wider range of sample time can correspond to the phase noise index more accurately, the phenomena which are difficult to be observed in a phase noise curve can be detected through this measurement.

Measurement and control from frequency to phase based on virtual signal reconstruction.

A virtual reconstruction method of directly capturing phase information between different nominal frequency signals, without frequency transformation, is proposed in this paper, building a virtual standard frequency signal whose frequency equals the measured nominal frequency and then making continuous comparison in the measuring gate which is synchronous with multiple periods between the measured signal and the reference frequency signal. Phase variations of the measured signal in every continuous gate are determined, and continuous phase-measuring is implemented. The experimental result verifies this special method for directly processing the phase difference between different nominal frequency signals and realizes a comparison precision of 10-17/day in a wide range.

Excited State Intramolecular Proton Transfer in Ethynyl-Extended Regioisomers of 2-(2'-Hydroxyphenyl)benzothiazole: Effects of the Position and Electronic Nature of Substituent Groups.

Although the organic dyes based on excited state intramolecular proton transfer (ESIPT) mechanism have attracted significant attention, the structure-property relationship of ESIPT dyes needs to be further exploited. In this paper, three series of ethynyl-extended regioisomers of 2-(2'-hydroxyphenyl)benzothiazole (HBT), at the 3'-, 4'- and 6-positions, respectively, have been synthesized. Changes in the absorption and emission spectra were correlated with the position and electronic nature of the substituent groups. Although 4'- and 6-substituted HBT derivatives exhibited absorption bands at longer wavelengths, the keto-emission of 3'-substituted HBT derivatives was found at a substantially longer wavelength. The gradual red-shifted fluorescence emission was found for 3'-substituted HBT derivatives where the electron-donating nature of substituent group increased, which was opposite to what was observed for 4'- and 6-substituted HBT derivatives. The results derived from the theoretical calculations were in conformity with the experimental observations. Our study could potentially provide experimental and theoretical basis for designing novel ESIPT dyes that possess unique fluorescent properties.

[Spectral investigation of atmospheric pressure plasma column].

Atmospheric pressure plasma column has many important applications in plasma stealth for aircraft. In the present paper, a plasma column with a length of 65 cm was generated in argon at atmospheric pressure by using dielectric barrier discharge device with water electrodes in coaxial configurations. The discharge mechanism of the plasma column was studied by optical method and the result indicates that a moving layer of light emission propagates in the upstream region. The propagation velocity of the plasma bullet is about 0.6 x 10(5) m x s(-1) through optical measurement. Spectral intensity ratios as functions of the applied voltage and driving frequency were also investigated by spectroscopic method. The variation in spectral intensity ratio implies a change in the averaged electron energy. Results show that the averaged electron energy increases with the increase in the applied voltage and the driving frequency. These results have significant values for industrial applications of the atmospheric pressure discharge and have extensive application potentials in stealth for military aircraft.