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Background Increased acid sphingomyelinase (ASMase) activity is associated with insulin resistance and cardiac dysfunction. However, the effects of ASMase on diabetic cardiomyopathy (DCM) and the molecular mechanism(s) underlying remain to be elucidated. We here investigated whether ASMase caused DCM through NADPH oxidase 4-mediated apoptosis. Methods and results We used pharmacological and genetic approaches coupled with study of murine and cell line samples to reveal the mechanisms initiated by ASMase in diabetic hearts. The protein expression and activity of ASMase were upregulated, meanwhile ceramide accumulation was increased in the myocardium of HFD mice. Inhibition of ASMase with imipramine (20 mg Kg−1 d−1) or siRNA reduced cardiomyocyte apoptosis, fibrosis, and mitigated cardiac hypertrophy and cardiac dysfunction in HFD mice. The similar effects were observed in cardiomyocytes treated with high glucose (HG, 30 mmol L−1) + palmitic acid (PA, 100 μmol L−1) or C16 ceramide (CER, 20 μmol L−1). Interestingly, the cardioprotective effect of ASMase inhibition was not accompanied by reduced ceramide accumulation, indicating a ceramide-independent manner. The mechanism may involve activated NADPH oxidase 4 (NOX4), increased ROS generation and triggered apoptosis. Suppression of NOX4 with apocynin prevented HG + PA and CER incubation induced Nppb and Myh7 pro-hypertrophic gene expression, ROS production and apoptosis in H9c2 cells. Furthermore, cardiomyocyte-specific ASMase knockout (ASMaseMyh6KO) restored HFD-induced cardiac dysfunction, remodeling, and apoptosis, whereas NOX4 protein expression was downregulated. Conclusions These results demonstrated that HFD-mediated activation of cardiomyocyte ASMase could increase NOX4 expression, which may stimulate oxidative stress, apoptosis, and then cause metabolic cardiomyopathy.

Background Suppressed mitochondrial biosynthesis has been reported to be the early signal of mitochondrial dysfunction which contributes to diabetic cardiomyopathy, but the mechanism of mitochondrial biosynthesis suppression is unclear. Nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) is closely related to diabetic cardiovascular complications. This study was to determine whether endogenous ADMA accumulation was involved in the suppression of myocardial mitochondrial biogenesis in diabetic rats and to elucidate the potential mechanism in rat cardiomyocytes. Methods Type 2 diabetic rat model was induced by high-fat feeding plus single intraperitoneal injection of small dose streptozotocin (35 mg/kg). The copy number ratio of mitochondrial gene to nuclear gene was measured to reflect mitochondrial biogenesis. The promoter activity of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and its post-translational modifications were detected by dual-luciferase reporter assay and immunoprecipitation. Results Myocardial ADMA content was enhanced and associated with suppressions of myocardial mitochondrial biogenesis and cardiac function in parallel with PGC-1α downregulation and uncoupling protein 2 (UCP2) upregulation in the myocardium of diabetic rats compared with control rats. Similarly, ADMA and its homolog could inhibit myocardial mitochondrial biogenesis and PGC-1α expression, increase UCP2 expression and oxidative stress in vitro and in vivo. Moreover, ADMA also suppressed the promoter activity and PGC-1α expression but boosting its protein acetylation and phosphorylation in rat cardiomyocytes. Conclusions These results indicate that endogenous ADMA accumulation contributes to suppression of myocardial mitochondrial biogenesis in type 2 diabetic rats. The underlying mechanisms may be associated with reducing PGC-1α promoter activity and expression but boosting its protein acetylation and phosphorylation.

Supplemental material, sj-docx-1-eji-10.1177_20587392211000890 for The risk factors for severe patients with COVID-19 in China: A systematic review and meta-analysis by Xie Yue-liang, Wang Jiang-lin, Yang Hui-qin, Zhou Ge, Deng Hongyu, Fang Wei-jin and Zuo Xiao-cong in European Journal of Inflammation

Supplemental material, sj-pdf-5-eji-10.1177_20587392211000890 for The risk factors for severe patients with COVID-19 in China: A systematic review and meta-analysis by Xie Yue-liang, Wang Jiang-lin, Yang Hui-qin, Zhou Ge, Deng Hongyu, Fang Wei-jin and Zuo Xiao-cong in European Journal of Inflammation

Supplemental material, sj-docx-2-eji-10.1177_20587392211000890 for The risk factors for severe patients with COVID-19 in China: A systematic review and meta-analysis by Xie Yue-liang, Wang Jiang-lin, Yang Hui-qin, Zhou Ge, Deng Hongyu, Fang Wei-jin and Zuo Xiao-cong in European Journal of Inflammation

Supplemental material, sj-docx-4-eji-10.1177_20587392211000890 for The risk factors for severe patients with COVID-19 in China: A systematic review and meta-analysis by Xie Yue-liang, Wang Jiang-lin, Yang Hui-qin, Zhou Ge, Deng Hongyu, Fang Wei-jin and Zuo Xiao-cong in European Journal of Inflammation

The cardiac protection of resveratrol may due to improvement of mitochondrial function through SIRT1 activation and PGC-1α deacetylation. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases, is associated with diabetic cardiovascular complications and reported to have cross-talk with lysine acetylation in cells. This study was to determine the role of ADMA in the pathogenesis of diabetic cardiomyopathy, whether resveratrol could revise ADMA-induced pathological changes and elucidate the underlying mechanisms in rat model of type 2 diabetes mellitus (T2DM). Resveratrol was orally administered (50mg/kg/d) to T2DM rats for 16w. Echocardiography was performed to detect cardiac function. Contents of myocardial ATP and mitochondrial DNA were measured to evaluate mitochondrial function and biogenesis. Elevated endogenous ADMA content and its signal disorders were associated with cardiac and mitochondrial dysfunction in the myocardium of T2DM rats compared with control rats. Treatment with resveratrol significantly attenuated endogenous ADMA accumulation and cardiac dysfunction, increased myocardial mitochondrial DNA and ATP contents, as well as upregulated PGC-1α expression in the myocardium of resveratrol-treated diabetic rats compared with untreated diabetic rats. A positive feedback was observed in vitro that elevated ADMA return promoting its synthetic enzyme PRMT1 expression, reducing its metabolic enzymes DDAH2 expression, reproducing myocardial hypertrophy and mitochondrial dysfunction. Resveratrol treatment could reverse these pathological changes. More importantly, ADMA could enhance PGC-1α acetylation and reduced SIRT1 expressions, all of which were antagonized by resveratrol in cardiomyocytes. These results suggest that ADMA-induced PGC-1α hyperacetylation may serve as potential therapeutic targets for resveratrol to improve diabetic cardiomyopathy. Disclosure Y. Xiong: None. W. Fang: None. Z. He: None. Funding National Natural Science Research Foundation of China (81570751); Natural Science Foundation of Guangdong Province (2016A030311050)

Deficiency of primary cilia formation by knockout kinesin family member 3A (Kif3a) in mature osteoblasts led to osteopenia and enhanced adipogenesis. Adipogenesis plays an important role in adipose tissue expansion by High-fat-diet (HFD) induced obesity. Whether primary cilia participate in high-fat-diet induced adiposity remains unclear. In this study, we found that the number and length of primary cilia and expression levels of KIF3A and intraflagellar transport 88 homolog (IFT88) mRNA and proteins reached peak on the day 3 of adipogenesis, followed by a decrease to reach low basal expression levels at day 9 when differentiated to lipid accumulating adipocytes in VAT-SVFs derived from lean mice. The number of primary cilia was reduced by shRNA and chemical methods, leading to elevated transcripts of Pparγ, Cebp-α, Srebp-1, and Fasn and protein levels of PPARγ and FASN. Similar to the proadipogenic effect by the inhibition of primary cilia formation in control VAT-SVFs, HFD caused severe reduction of primary cilia formation and enhancement of adipogenesis in VAT-SVFs cultures. Flow cytometry analysis revealed percentage of G2/M phase cells and the protein expression of Cyclin A2 and CDK2 increased in control VAT-SVFs by knockdown of primary cilia with shRNA or chemical methods and HFD induced obese VAT-SVFs. In conclusion, the expression of primary cilia was in reverse correlation with adipogenic differentiation. HFD caused severe defects of primary cilia in VAT-SVFs, leading to adipose tissue expansion by enhancement of adipogenesis through promoting cell cycle re-entry at the early stage of adipogenesis.

Diabetic cardiomyopathy is a major cause of morbidity and mortality among diabetic patients. Endoplasmic reticulum (ER) stress has been involved in diabetic cardiomyopathy. Accumulation of endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) is associated with diabetic cardiovascular complications. This study was to determine whether ADMA accumulation contributes to diabetic cardiomyopathy and whether its mechanism is related to ER stress in streptozotocin-induced diabetic rats and cultured rat cardiomyocytes. Cardiac function was measured by M-echocardiography. ER stress was reflected by transcription of glucose-regulated protein78, phosphorylation of eukaryotic initiation factor 2α kinase, splicing of X box-binding protein-1 mRNA and expression of C/EBP homologues protein. Changes of ADMA signal pathway were evaluated by ADMA and nitric oxide contents, NOS and dimethylarginine dimethylaminohydrolase activities, as well as their protein expression. The levels of ADMA in serum and myocardium were significantly elevated in diabetic rats compared to control rats. This elevation was associated with left ventricular diastolic and systolic dysfunction of diabetic rats in comparison with control rats. Furthermore, ADMA accumulation was not only coupled with the disorder of ADMA signal pathway, but also tied to ER stress and oxidative stress in myocardium of diabetic rats. Treatment of diabetic rats with antioxidant N-acetylcysteine could reduce oxidative stress and ER stress, but also ameliorate cardiac dysfunction of diabetic rats. Similar results to diabetic rats were observed in the exogenous NOS inhibitor-treated normal rats and ADMA-incubated cardiomyocytes. These results indicate that endogenous ADMA accumulation plays a pivotal role in the development of diabetic cardiomyopathy, and the underlying mechanism is close related to ER stress and oxidative stress. Disclosure Y. Xiong: None. Y. He: None. W. Fang: None. Y. Lei: None. Y. Lin: None. Z. He: None.

Background and Aim. Aberrant activation of the TGF-β1/Smad pathway contributes to the activation of hepatic stellate cells (HSCs). MicroRNA-195 has been shown to regulate the activation of HSCs. The aim of this study was to investigate the role of miRNA-195 in HSCs activation. Methods. A liver fibrotic rat model induced by diethylnitrosamine was established. Dual luciferase reporter assays were performed to verify that Smad7 was the target of miRNA-195. The expression levels of miR-195, Smad7, and α-SMA in HSC-T6 transfected, respectively, with miR-195 mimic, inhibitor, or control were measured by qRT-PCR. The protein expression of Smad7 was detected by Western blot analysis. Results. Enhanced miR-195 and decreased Smad7 were observed in diethylnitrosamine-induced liver fibrotic rats (P<0.05). Dual luciferase reporter assays showed that the miR-195 mimic significantly suppressed the luciferase activity of a reporter plasmid carrying the binding site of miR-195 on the 3′UTR of Smad7 (P<0.05). The miR-195 mimics activated HSCs, further elevated miR-195 and α-SMA (P<0.01), and reduced the Smad7 level (P<0.05). The miR-195 inhibitors blocked the activation of HSCs, reduced the expression of miR-195 and α-SMA (P<0.01), and upregulated the expression of Smad7 (P<0.05). Conclusion. Collectively, we demonstrated that miRNA-195 activated HSCs by targeting Smad7.

This work proposes a full-duplex 60-GHz Radio-over-Fiber Orthogonal-Frequency-Division-Multiplexing (ROF-OFDM) system employing a frequency quintupling optical up-conversion scheme. To avoid the subcarrier signal beat interference (SSBI) due to dispersion-induced fading, a modified single sideband modulation scheme is proposed for the 10-Gbps QPSK-OFDM down-link signal. The power penalty of less than 2-dB was observed after a 50-km single mode fiber (SMF) and 4 m wireless transmission. Wavelength reuse with a 1.25-Gbps OOK for up-link transmission is also demonstrated with a receiver penalty of less than 0.5-dB following 50-km SMF transmission.

A novel full duplex cost-effective hybrid radio-over-fibre passive-optical-network based on external modulation of a distributed feedback laser diode and dual-drive Mach–Zehnder modulator with multi-wavelength output characteristic is proposed and experimentally demonstrated. Baseband non-return-to-zero (BB-NRZ) signals, radio-frequency NRZ (RF-NRZ) signals, as well as RF orthogonal frequency division multiplexing (RF-OFDM) signals are successfully transmitted simultaneously. After transmission over 50 km of a single-mode fibre, low-bit-error rate and clear eye diagram are achieved for BB-NRZ and RF-NRZ transmission system. The power penalties for BB-NRZ, RF-NRZ and RF-OFDM downstream signals are less than 1 dB. The frequency of local oscillator signal is reduced because of frequency quadrupling scheme. Compared with recent schemes, the cost of the proposed system is largely reduced.

In this article, we propose and demonstrate an orthogonal frequency division multiplexing-radio over fiber (OFDM-ROF) system based on three channels sextupling-frequency scheme using an external modulation of a distributed feedback laser diode (DFB-LD) and dual drive Mach–Zehnder modulator (DD-MZM) for carrying 100 GHz W-band frequency multiple-input multiple-output (MIMO)-OFDM signals with 90 Gbps downstream. MIMO-OFDM algorithms effectively compensate for impairments in the wireless link. Without using costly W-band components, a transmission system with 50 km single mode fiber (SMF) and 4 m wireless transmission operation at 100 GHz is experimentally validated. The power penalties for MIMO-OFDM signals of base stations are less than 3 dBm. For the upstream transmission, wavelength reuse with 30 Gbps 4QAM upstream signals is experimentally demonstrated. The minimum optical spectral gap between residue downstream OFDM band and upstream OFDM band that guarantees a tolerable amount of optical interference has been determined through experiment. The frequency of local oscillator is reduced due to frequency sextupling scheme. The cost of the proposed system is largely reduced. © 2012 Wiley Periodicals, Inc. Microwave Opt Technol Lett 55:93–99, 2013; View this article online at wileyonlinelibrary.com. DOI 10.1002/mop.27251

Recent studies indicate that histone deacetylases (HDACs) activity is associated with the development and progression of cardiac hypertrophy. In this study, we investigated the effects of a HDACs inhibitor, valproic acid sodium (VPA), on cardiac remodeling and the differential expression of HDACs in left ventricles (LVs) of renovascular hypertensive rats. Renovascular hypertension was induced in rats by the two-kidney two-clip (2K2C) method. Cardiac remodeling, heart function and the differential expression of HDACs were examined at different weeks after 2K2C operation. The effects of VPA on cardiac remodeling, the expressions of HDACs, transforming growth factor-beta 1 (TGF-β1) and connective tissue growth factor (CTGF) in LV were investigated. The expressions of atrial natriuretic factor, β-myosin heavy chain, HDAC2 and HDAC8 increased in LV of 2K2C rats at 4, 8, 12 weeks after operation. Cardiac dysfunction, cardiac hypertrophy and fibrosis were markedly attenuated by VPA treatment in 2K2C rats. Further studies revealed that VPA inhibited the expressions of HDAC2, HDAC8, TGF-β1 and CTGF in LV of 2K2C rats. In summary, these data indicate that HDAC2 and HDAC8 play a key role in cardiac remodeling in renovascular hypertensive rats and that VPA attenuates hypertension and cardiac remodeling. The effect of VPA is possibly exerted via decreasing HDAC2, HDAC8, TGF-β1 and CTGF expressions in LV of 2K2C rats.

To observe the effect of Cornus officinalis fruit core extract on cardiac hypertrophy induced by two kidney two clip (2K2C) and its mechanism.Male Sprague-Dawley rats were randomly divided into 4 groups: sham-operated group, model group and treatment groups (300, 600 mg/kg). Rats were intragastric administered medicine for 4 weeks from the fourth week after surgery. Sham-operated and 2K2C rats were given vehicle for 4 weeks. Blood pressure and hemodynamic parameters were measured. Left ventricular weight to body weight (LVM/BM) ratio was calculated. Paraffin-embedded hearts were cut into 5 microm slices, which were stained with hematoxylin-eosin (HE) and Masson for morphological analysis; Western-blot analysis was performed to investigate the effects of Cornus officinalis fruit core extract on the expression of P47phox, Nox4 in myocardium.Compared with sham-operated group, the blood pressure and LVM/BM ratios were markedly elevated in model groups. Meanwhile cardiomyocyte cross sectional areas was markedly increased and myocardial fibers showed disordered arrangement while these parameters were markedly reversed after treatment with Cornus officinalis fruit core extract for 4 weeks. At 8th weeks after operation, model rats developed obvious LV hypertrophy. Cornus officinalis fruit core extract, more significant in high dose, decreased the blood pressure and LVM/BM ratios and reversed the cardiomyocyte hypertrophy and myocardial fibrosis. Moreover, Cornus officinalis fruit core extract decreased the expression of P47phox and Nox4 which elevated in LV in model rats.Cornus officinalis fruit core extract could significantly decrease the blood pressure, reverse cardiac hypertrophy and improve the function of heart which is possibly associated with the down-regulation of P47phox and Nox4.

We propose a duplex multiple-user radio over fiber-passive optical network (ROF-PON) system based on multitone generation and sextupling technique. A dual-drive Mach-Zehnder modulator (DD-MZM) is used to realize the multitone generation. By controlling the modulation voltage of the DD-MZM, the odd carriers can be suppressed which makes the adjacent frequency gap twice the frequency of the local oscillator fre- quency. Due to the multitone generation and pure carrier reuse technique, the base stations (BSs) are also source-free. The system can support more than one BS simultaneously for a transmission length more than 50 km. The proposed multiuser ROF-PON is scalable and cost-effective, and its feasibility is successfully verified by simulation. © 2013 Society of Photo

We propose and demonstrate a full-duplex dense wavelength division multiplexing (DWDM) radio over fiber (ROF) system transmitting multibands wired and wireless orthogonal frequency division multiplexing (OFDM) signals. In a central station, an optical signal noise ratio (OSNR)-boosted multicarriers generator based on recirculation frequency shifter (RFS) is used to generate multicarriers. Sixty-six frequency-lock and coherent, 25 GHz frequency-spacing subcarriers with OSNR larger than 26 dB with an amplitude difference of 5 dB are generated and used to transmit downstream data. Since these subcarriers are coherent with each other, n-fold frequency optical millimeter-wave signals can be generated. Without using costly W-band components, a 20 Gbps downstream transmission operation at 75 GHz is experimentally validated. The power penalty of less than 3 dB was observed after a 50-km single mode fiber (SMF) and 4-m wireless transmission. In order to realize the full duplex system, a 1.2 GHz bandwidth reflective semiconductor optical amplifier (RSOA) is used to achieve 5 Gbps upstream traffic for 16QAM-OFDM signals. The measured power penalty of 3 dB is observed after a 50-km SMF transmission at the bit error rate of 3.8×10 −3 .

We propose and demonstrate a full duplex dense-wavelength-division-multiplexing radio-over-fiber (DWDM-ROF) system for transmitting 75-GHz W-band frequency multiple-input multiple-output orthogonal-frequency-division-multiplexing (MIMO-OFDM) signals with 12 Gbps downstream and 6 Gbps upstream. The downstream transmitting terminal is based on a three-channels sextupling-frequency scheme using an external modulation of a distributed feedback laser diode (DFB-LD) and dual drive Mach-Zehnder modulator (DD-MZM) for carrying downstream signals. MIMO-OFDM algorithms effectively compensate for impairments in the wireless link. Without using costly W-band components in the transmitter, a 12 Gbps downstream transmission system operation at 75 GHz is experimentally validated. For the downstream transmission, a power penalty of less than 3 dB was observed after a 50 km single mode fiber (SMF) and 4 m wireless transmission at a bit error rate (BER) of 3.8×10−3. For the upstream transmission, we use a commercially available 1.5 GHz bandwidth reflective semiconductor optical amplifier (RSOA) to achieve 6 Gbps upstream traffic for 16 QAM-OFDM signals. A power penalty of 3 dB was observed after a 50 km SMF transmission at a BER of 3.8×10−3. The frequency of the local oscillator is reduced due to the frequency sextupling scheme. The cost of the proposed system is largely reduced.