Upregulated hepatokine fetuin B aggravates myocardial ischemia/reperfusion injury through inhibiting insulin signaling in diabetic mice.

Patients with type 2 diabetes mellitus (T2DM) are more susceptible to acute myocardial ischemia/reperfusion (MI/R) injury. However, the mechanism remains largely elusive. Clinical observation showed that high levels of hepatokine fetuin-B (FetB) in plasma are significantly associated with both diabetes and coronary artery diseases. This study was aimed to determine whether FetB mostly derived from liver exacerbates MI/R-induced injury and the underlying mechanisms in T2DM. Mice were given high-fat diet and streptozotocin to induce T2DM model and subjected to 30 min MI followed by reperfusion. Diabetes caused increased hepatic FetB expression and greater myocardial injury as evidenced by increased apoptosis and myocardial enzymes release following MI/R. In T2DM hearts, insulin-induced phosphorylations of insulin receptor substrate 1 at Tyr608 site and Akt at Ser473 site and glucose transporter 4 membrane translocation were markedly reduced. Interaction between FetB and insulin receptor-ß subunit (IRß) was enhanced assessed by immunoprecipitation analysis. More importantly, FetB knockdown via AAV9 alleviated MI/R injury and improved cardiac insulin-induced signaling in T2DM mice. Conversely, upregulation of FetB in normal mice caused exacerbated MI/R injury and impairment of insulin-mediated signaling. In cultured neonatal mouse cardiomyocytes, incubation of FetB significantly reduced tyrosine kinase activity of IR and insulin-induced glucose uptake, and increased hypoxia/reoxygenation-induced apoptosis. Furthermore, FoxO1 knockdown by siRNA suppressed FetB expressions in hepatocytes treated with palmitic acid. In conclusion, upregulated FetB in diabetic liver contributes to increased MI/R injury and cardiac dysfunction via directly interacting with IRß and consequently impairing cardiac insulin signaling.

Distributed gas sensing with optical fibre photothermal interferometry.

We report the first distributed optical fibre trace-gas detection system based on photothermal interferometry (PTI) in a hollow-core photonic bandgap fibre (HC-PBF). Absorption of a modulated pump propagating in the gas-filled HC-PBF generates distributed phase modulation along the fibre, which is detected by a dual-pulse heterodyne phase-sensitive optical time-domain reflectometry (OTDR) system. Quasi-distributed sensing experiment with two 28-meter-long HC-PBF sensing sections connected by single-mode transmission fibres demonstrated a limit of detection (LOD) of ∼10 ppb acetylene with a pump power level of 55 mW and an effective noise bandwidth (ENBW) of 0.01 Hz, corresponding to a normalized detection limit of 5.5ppb⋅W/Hz. Distributed sensing experiment over a 200-meter-long sensing cable made of serially connected HC-PBFs demonstrated a LOD of ∼ 5 ppm with 62.5 mW peak pump power and 11.8 Hz ENBW, or a normalized detection limit of 312ppb⋅W/Hz. The spatial resolution of the current distributed detection system is limited to ∼ 30 m, but it is possible to reduce down to 1 meter or smaller by optimizing the phase detection system.

Performance optimization of hollow-core fiber photothermal gas sensors.

We report performance optimization of hollow-core photonic bandgap fiber (HC-PBF) photothermal (PT) gas sensors. The PT phase modulation efficiency of a C2H2 filled HC-PBF (HC-1550-02) is found independent of the pump modulation frequency for up to ∼330 kHz, but starts to drop quickly to 10% of the maximum value at a couple of megahertz. With a 1.1 m long HC-PBF gas cell with angle-cleaved single-mode fiber/HC-PBF joints to reduce reflection and a modified 3×3 Sagnac interferometer with balanced detection for phase demodulation, a noise equivalent concentration of ∼67 ppbC2H2 is achieved with a 1 s time constant, and it goes down to ∼18 ppb with 145 s integration time. The system has good long-term stability and exhibits signal fluctuations of <1% over a ∼5 h period.

Hollow-core fiber Fabry-Perot photothermal gas sensor.

A highly sensitive, compact, and low-cost trace gas sensor based on photothermal effect in a hollow-core fiber Fabry-Perot interferometer (FPI) is described. The Fabry-Perot sensor is fabricated by splicing a piece of hollow-core photonic bandgap fiber (HC-PBF) to single-mode fiber pigtails at both ends. The absorption of a pump beam in the hollow core results in phase modulation of probe beam, which is detected by the FPI. Experiments with a 2 cm long HC-PBF with femtosecond laser drilled side-holes demonstrated a response time of less than 19 s and noise equivalent concentration (NEC) of 440 parts-per-billion (ppb) using a 1 s lock-in time constant, and the NEC goes down to 117 ppb (2.7×10-7 in absorbance) by using 77 s averaging time.

Near orthogonal launch of SPR modes in Au films.

We report the excitation of a surface plasmon resonance (SPR) close to the orthogonal axis of a gold (Au) film on borosilicate glass. Direct spectroscopic measurement of SPR shifts using different liquids are made at ∼5° incidence within a reflection spectrophotometer. The proposed mechanism to establish coupling and plasmon localization is the scattering of light able to penetrate across the film at the interfaces.

Construction of a novel expression system for use in Corynebacterium glutamicum.

Corynebacterium glutamicum is an important microorganism for production of amino acids in industrial fermentation. Suitable vectors are needed for metabolic engineering in C. glutamicum. Most available vectors used in C. glutamicum carry antibiotic resistant genes as a genetic labeling for rapid identification of recombinant strains, and antibiotics have to be added to maintain the vector when growing the cells. These vectors, though excellent for laboratory use, are not preferable choices for industry-scale fermentation. In this work, we developed a novel expression system for use in C. glutamicum, which do not require antibiotics when used for industrial fermentation. This system includes two vectors: the shuttle vector pJYW-4 for expression of genes and the vector pJYW-6 for deletion of the essential gene alr in C. glutamicum. The vector pJYW-4 contains a large multiple cloning site for cloning multiple genes and two selective markers: one is the kanamycin-resistant gene kan and the other is an essential gene alr. The selective marker kan facilitates molecular manipulation or fermentations in the laboratory, and the selection marker alr is good for use in industry-scale fermentation, allowing in vivo maintenance of the expression vector through auxotrophic complementation; therefore, the two selection markers in pJYW-4 make it useful for both laboratory research and industrial fermentation, and convenient to transfer valuable laboratory-developed strains into industrial production. This newly-constructed expression system was successfully used to increase L-valine production in C. glutamicum ATCC 14067, indicating its potential on developing amino acid-producing C. glutamicum strains.

CTRP3 alleviates mitochondrial dysfunction and oxidative stress injury in pathological cardiac hypertrophy by activating UPRmt via the SIRT1/ATF5 axis.

Pathological cardiac hypertrophy is an independent risk factor for heart failure. Disruption of mitochondrial protein homeostasis plays a key role in pathological cardiac hypertrophy; however, the mechanism of maintaining mitochondrial homeostasis in pathological cardiac hypertrophy remains unclear. In this study, we investigated the regulatory mechanisms of mitochondrial protein homeostasis in pathological cardiac hypertrophy. Wildtype (WT) mice, knockout mice, and mice transfected with lentivirus overexpressing mouse C1q-tumor necrosis factor-related protein-3 (CTRP3) underwent transverse aortic constriction or sham surgery. After 4 weeks, cardiac function, mitochondrial function, and oxidative stress injury were examined. For mechanistic studies, neonatal rat cardiomyocytes were treated with small interfering RNA or overexpression plasmids for the relevant genes. CTRP3 overexpression attenuated transverse aortic constriction (TAC) induced pathological cardiac hypertrophy, mitochondrial dysfunction, and oxidative stress injury compared to that in WT mice. TAC or Ang II resulted in compensatory activation of UPRmt, but this was not sufficient to counteract pathologic cardiac hypertrophy. CTRP3 overexpression further induced activation of UPRmt during pathologic cardiac hypertrophy and thereby alleviated pathologic cardiac hypertrophy, whereas CTRP3 knockout or knockdown inhibited UPRmt. ATF5 was a key regulatory molecule of UPRmt, as ATF5 knockout prevented the cardioprotective effect of CTRP3 in TAC mice. In vitro, SIRT1 was identified as a possible downstream CTRP3 effector molecule, and SIRT1 knockout blocked the cardioprotective effects of CTRP3. Our results also suggest that ATF5 may be regulated by SIRT1. Our study demonstrates that CTRP3 activates UPRmt via the SIRT1/ATF5 axis under pathological myocardial hypertrophy, thus attenuating mitochondrial dysfunction and oxidative stress injury.

Microfiber Mach-Zehnder interferometer based on long period grating for sensing applications.

A Mach-Zehnder interferometer (MZI) composed by a pair of long period gratings (LPGs) fabricated in silica microfiber for sensing applications is demonstrated. Each LPG is fabricated with a pulsed CO2 laser by creating six periodical deformations along fiber length with only one scanning cycle. The length of the MZI can reach as short as 8.84 mm when the diameter of the microfiber is 9.5 µm. Compared with the ones fabricated in single-mode fibers, the present MZI is much shorter owing to the large effective-index difference between the fundamental and higher order modes. The microfiber MZI exhibits a sensitivity to surrounding refractive index (RI) of 2225 nm per refractive index unit and the temperature sensitivity of only 11.7 pm/°C. Theoretical analysis suggests that the performances of the MZI sensor can be improved by using thinner microfibers with a diameter down to 3.5 µm: The sensitivity can be greatly enhanced due to the stronger evanescent-field interaction and reduced dispersion factor; the transmission dips become narrower which benefits high-resolution measurement; the thinner fiber also allows further reduction in device length. The present device has great potential in biochemical and medical sensing due to the advantages including easy fabrication, excellent compactness and high sensitivity.

Bending effect on modal interference in a fiber taper and sensitivity enhancement for refractive index measurement.

We demonstrate the bending effect of microfiber on interference fringes in a compact taper-based modal interferometer and sensitivity for refractive index (RI) measurement. For the bend curvature ranging from 0 to 0.283 mm(-1), the measured RI sensitivity distinctively increases from 342.5 nm/RIU (refractive-index unit) to 1192.7 nm/RIU around RI = 1.333 and from 3847.1 nm/RIU to 11006.0 nm/RIU around RI = 1.430, respectively. Theoretical analysis reveals that such enhancement is determined by the dispersion property of the intermodal index rather than other parameters, such as the variation of the straightforward evanescent field. The magnitude of sensitivity varies as a function of the microfiber bend curvature. Approaching a critical curvature (the intermodal-index dispersion factor approaches zero), the sensitivity is significantly enhanced, exhibiting great potential in RI sensing areas.

Construction and application of an efficient multiple-gene-deletion system in Corynebacterium glutamicum.

Gene deletion techniques are important for modifying Corynebacterium glutamicum, the bacterium for industrial production of amino acids. In this study, a novel multiple-gene-deletion system for C. glutamicum was developed. The system is composed of three plasmids pDTW109, pDTW201 and pDTW202. pDTW109 is a temperature-sensitive vector which harbors a cat gene under the tacM promoter, a cre gene under the tac promoter, an origin oriE for replicating in Escherichia coli, and another origin rep(TS) for replicating in C. glutamicum only at low temperatures; it has high transformation efficiency in C. glutamicum and can be easily eliminated by growing at 37°C. pDTW201 and pDTW202 carry loxp-flanked or mutant lox-flanked kan, respectively. This deletion system combines homologous recombination and Cre/lox site-specific recombination, could efficiently delete the aceE gene from the chromosome of C. glutamicum ATCC13032, ATCC13869 or ATCC14067, respectively, and could also delete both genes of aceE and ilvA from the chromosome of C. glutamicum ATCC14067. The system is simple and efficient, and can be easily implemented for multiple-gene-deletion in C. glutamicum.

Construction of monophosphoryl lipid A producing Escherichia coli mutants and comparison of immuno-stimulatory activities of their lipopolysaccharides.

The lipid A moiety of Escherichia coli lipopolysaccharide is a hexaacylated disaccharide of glucosamine phosphorylated at the 1- and 4'-positions. It can be recognized by the TLR4/MD-2 complex of mammalian immune cells, leading to release of proinflammatory cytokines. The toxicity of lipid A depends on its structure. In this study, two E. coli mutants, HW001 and HW002, were constructed by deleting or integrating key genes related to lipid A biosynthesis in the chromosome of E. coli W3110. HW001 was constructed by deleting lacI and replacing lacZ with the Francisella novicida lpxE gene in the chromosome and only synthesizes monophosphoryl lipid A. HW002 was constructed by deleting lpxM in HW001 and synthesizes only the pentaacylated monophosphoryl lipid A. The structures of lipid A made in HW001 and HW002 were confirmed by thin layer chromatography and electrospray ionization mass spectrometry. HW001 and HW002 grew as well as the wild-type W3110. LPS purified from HW001 or HW002 was used to stimulate murine macrophage RAW264.7 cells, and less TNF-α were released. This study provides a feasible way to produce interesting lipid A species in E. coli.

Bergenin alleviates myocardial ischemia-reperfusion injury via SIRT1 signaling.

Myocardial ischemia-reperfusion (MI/R) is a major risk factor for cardiovascular disease. At present, reducing oxidative stress and apoptosis is a crucial therapeutic strategy for ameliorating MI/R injury. However, there is a lack of drugs targeting oxidative stress and apoptosis for the clinical therapy of MI/R. Bergenin is a reportedly effective agent with antioxidative and antiapoptotic activity against acute injury. Nevertheless, the roles and potential mechanisms of bergenin against MI/R injury remain unknown. Here, we hypothesized that bergenin attenuated MI/R-induced apoptosis and reactive oxygen species (ROS) production via SIRT1. Mice were subjected to MI/R and treated with bergenin, after which the cardiac function, cardiomyocyte apoptosis, LDH release, and MDA content were evaluated. In vitro, myocardial injury model of H9c2 cells was induced by simulated ischemia/reperfusion (SI/R), apoptosis and oxidative stress was decreased after treated with bergenin. Bergenin significantly reduced myocardial apoptosis and ROS generation in vitro and improved cardiac function in vivo. Intriguingly, bergenin remarkably decreased apoptosis in cardiac tissue accompanied by SIRT1 upregulation following MI/R injury. Further studies showed that inhibiting SIRT1 blocked bergenin's beneficial impact against apoptosis following SI/R injury through excessive oxidative stress and depression of the Bcl2 to Bax ratio. Collectively, these findings indicate that bergenin alleviates MI/R injury by ameliorating myocardial apoptosis and oxidative damage via the SIRT1 signaling pathway.

ZIF-90-Derived Porous ZnO Coated Optical Microfiber Interferometer Sensor for Enhanced Humidity Sensing and Breath Monitoring.

Humidity plays an important role in many fields, and the realization of high sensitivity and fast response simultaneously for humidity detection is a great challenge in practical application. In this work, we demonstrated a high-performance relative humidity (RH) sensor made by supporting zeolitic imidazolate framework-90 (ZIF-90)-derived porous zinc oxide (ZnO) onto an optical microfiber Sagnac interferometer (OMSI). The ZIF-90-modified OMSI (ZIF-90-OMSI) sensor was in situ heated at different temperatures to obtain porous ZnO, and their humidity-sensing properties were investigated ranging from 25 to 80% RH. The experimental results showed that the porous ZnO fiber sensor prepared at 500 °C (Z500-OMSI) exhibited best humidity-sensing performance with a high sensitivity of 96.2 pm/% RH (25-45% RH) and 521 pm/% RH (50-80% RH) and ultrafast response/recovery time (62.37/206.67 ms) at 22.3% RH. These performances were attributed to the complete transformation of ZIF-90 to ZnO at 500 °C. The obtained Z500 not only retained the high porosity and specific surface area of ZIF-90 but also exhibited the exceptional hydrophilicity of ZnO. In addition, the signals of the proposed Z500-OMSI sensor changed with different breathing patterns, indicating the possibility for human respiration monitoring. This work provided a reliable candidate for an effective RH monitoring system with potential application in medical diagnoses, industrial production, environmental detection, and human health monitoring.

GLUT4 mediates the protective function of gastrodin against pressure overload-induced cardiac hypertrophy.

Gastrodia elata exhibits extensive pharmacological activity; its extract gastrodin (GAS) has been used clinically to treat cardiovascular diseases. In the present study, we examined the effect of GAS in a mice model of pathological cardiac hypertrophy, which was induced using transverse aortic constriction (TAC). Male C57BL/6 J mice underwent either TAC or sham surgery. GAS was administered post-surgically for 6 weeks and significantly improved the deterioration of cardiac contractile function caused by pressure overload, cardiac hypertrophy, and fibrosis in mice. Treatment with GAS for 6 weeks upregulated myosin heavy chain α and down-regulated myosin heavy chain ß and atrial natriuretic peptide, while insulin increased the effects of GAS against cardiac hypertrophy. In vitro studies showed that GAS could also protect phenylephrine-induced cardiomyocyte hypertrophy, and these effects were attenuated by BAY-876, and increased by insulin. Taken together, our results suggest that the anti-hypertrophic effect of gastrodin depends on its entry into cardiomyocytes through GLUT4.

Epicardial adipose tissue, metabolic disorders, and cardiovascular diseases: recent advances classified by research methodologies.

Epicardial adipose tissue (EAT) is located between the myocardium and visceral pericardium. The unique anatomy and physiology of the EAT determines its great potential in locally influencing adjacent tissues such as the myocardium and coronary arteries. Classified by research methodologies, this study reviews the latest research progress on the role of EAT in cardiovascular diseases (CVDs), particularly in patients with metabolic disorders. Studies based on imaging techniques demonstrated that increased EAT amount in patients with metabolic disorders is associated with higher risk of CVDs and increased mortality. Then, in-depth profiling studies indicate that remodeled EAT may serve as a local mediator of the deleterious effects of cardiometabolic conditions and plays a crucial role in CVDs. Further, in vitro coculture studies provided preliminary evidence that the paracrine effect of remodeled EAT on adjacent cardiomyocytes can promote the occurrence and progression of CVDs. Considering the important role of EAT in CVDs, targeting EAT might be a potential strategy to reduce cardiovascular risks. Several interventions have been proved effective in reducing EAT amount. Our review provides valuable insights of the relationship between EAT, metabolic disorders, and CVDs, as well as an overview of the methodological constructs of EAT-related studies.

Forkhead box O6 (FoxO6) promotes cardiac pathological remodeling and dysfunction by activating Kif15-TGF-ß1 under aggravated afterload.

Pathological cardiac hypertrophy exhibits complex and abnormal gene expression patterns and progresses to heart failure. Forkhead box protein O6 (FoxO6) is a key transcription factor involved in many biological processes. This study aimed to explore the role of FoxO6 in cardiac hypertrophy. Three groups of mice were established: wild-type, FoxO6 knockout, and FoxO6-overexpressing. The mice received daily administration of angiotensin-II (Ang-II) or saline for 4 weeks, after which they were examined for cardiac hypertrophy, fibrosis, and function. Elevated cardiac expression of FoxO6 was observed in Ang-II-treated mice. FoxO6 deficiency attenuated contractile dysfunction and cardiac remodeling, including cardiomyocyte hypertrophy and fibroblast proliferation and differentiation. Conversely, FoxO6 overexpression aggravated the cardiomyopathy and heart dysfunction. Further studies identified kinesin family member 15 (Kif15) as downstream molecule of FoxO6. Kif15 inhibition attenuated the aggravating effect of FoxO6 overexpression. In vitro, FoxO6 overexpression increased Kif15 expression in cardiomyocytes and elevated the concentration of transforming growth factor-ß1 (TGF-ß1) in the medium where fibroblasts were grown, exhibiting increased proliferation and differentiation, while FoxO6 knockdown attenuated this effect. Cardiac-derived FoxO6 promoted pathological cardiac remodeling induced by aggravated afterload largely by activating the Kif15/TGF-ß1 axis. This result further complements the mechanisms of communication among different cells in the heart, providing novel therapeutic targets for heart failure.

Low-dose exercise protects the heart against established myocardial infarction via IGF-1-upregulated CTRP9 in male mice.

Regular exercise is recommended as an important component of therapy for cardiovascular diseases in clinical practice. However, there are still major challenges in prescribing an optimized exercise regimen to individual patients with established cardiac disease. Here, we tested the effects of different exercise doses on cardiac function in mice with established myocardial infarction (MI). Exercise was introduced to mice with MI after 4 weeks of surgery. Low-dose exercise (15 min/day for 8 weeks) improved mortality and cardiac function by increasing 44.39% of ejection fractions while inhibiting fibrosis by decreasing 37.74% of distant region. Unlike higher doses of exercise, low-dose exercise consecutively upregulated cardiac expression of C1q complement/tumor necrosis factor-associated protein 9 (CTRP9) during exercise (>1.5-fold). Cardiac-specific knockdown of CTRP9 abolished the protective effects of low-dose exercise against established MI, while cardiac-specific overexpression of CTRP9 protected the heart against established MI. Mechanistically, low-dose exercise upregulated the transcription factor nuclear receptor subfamily 2 group F member 2 by increasing circulating insulin-like growth factor 1 (IGF-1), therefore, upregulating cardiac CTRP9 expression. These results suggest that low-dose exercise protects the heart against established MI via IGF-1-upregulated CTRP9 and may contribute to the development of optimized exercise prescriptions for patients with MI.

Miniature highly-birefringent microfiber loop with extremely-high refractive index sensitivity.

A miniature polarimetric interferometer with the twist of a highly-birefringent microfiber is demonstrated. Good transmission spectral characteristics, which are co-governed by the birefringence and the twist degree of the microfiber, are investigated. The structure exhibits extremely-high sensitivity of around 24,373 nm per refractive-index unit and excellent temperature stability of better than 0.005 nm/°C. Featured with compactness, reconfigurability, stability, robustness, and compatibility with other fiberized components, our device has potential in tunable filtering, sensing, multi-wavelength lasing, and etc.

Construction of a novel sacB-based system for marker-free gene deletion in Corynebacterium glutamicum.

Bacillus subtilis sacB gene with its 463bp upstream region including its native promoter has been used for marker-free gene deletion in Corynebacterium glutamicum, but the role of this upstream region is not clear. In this study, it was demonstrated that the upstream region of sacB failed to efficiently promote its expression in C. glutamicum, and the native promoter of sacB is weak in C. glutamicum. The expression level of sacB under its native promoter in C. glutamicum is not high enough for cells to confer sucrose sensitivity. Therefore, a new promoter PlacM and a novel vector pDXW-3 were constructed. PlacM is 18 times stronger than the native promoter of sacB in C. glutamicum. The pDXW-3 contains B. subtilissacB with the PlacM fused at the 5'-end, a general Escherichia coli replicon oriE for easy cloning, a kanamycin resistance marker for selection, and a multiple unique restriction sites for XhoI, NotI, EagI, SalI, SacI, BamHI, and NheI, respectively. By using pDXW-3, the aceE gene in the chromosome of C. glutamicum was deleted. This sacB-based system should facilitate gene disruption and allelic exchange by homologous recombination in many bacteria.

Alternate-Day Ketogenic Diet Feeding Protects against Heart Failure through Preservation of Ketogenesis in the Liver.

As heart failure develops, the heart utilizes ketone bodies at increased rates, indicating an adaptive stress response. Thus, increasing ketone body availability exerts protective effects against heart failure. However, although it is the widely used approach for increasing ketone body availability, the ketogenic diet shows limited cardioprotective effects against heart failure. This study was aimed at examining the effects of the ketogenic diet on heart failure and the underlying mechanisms. Pressure overload-induced heart failure was established by transverse aortic constriction (TAC) in mice. Continuous ketogenic diet feeding for 8 weeks failed to protect the heart against heart failure. It showed no significant effects on cardiac systolic function and fibrosis but aggravated cardiac diastolic function in TAC mice. Specifically, it induced systemic lipid metabolic disorder and hepatic dysfunction in TAC mice. It decreased the content of 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL), a key enzyme in ketogenesis, and impaired the capacity of hepatic ketogenesis in TAC mice. It preserved the capacity of hepatic ketogenesis and exerted cardioprotective effects against heart failure, increasing cardiac function and decreasing cardiac fibrosis, in liver-specific HMGCL-overexpressed TAC mice. Importantly, we found that alternate-day ketogenic diet feeding did not impair the capacity of hepatic ketogenesis and exerted potent cardioprotective effects against heart failure. These results suggested that alternate-day but not continuous ketogenic diet protects against heart failure through preservation of ketogenesis in the liver.