Non-Steady State NMR Effect and Application on Time-Varying Magnetic Field Measurement.

The measurement of a time-varying magnetic field is different from a constant magnetic field, due to its field intensity variation with time. Usually, the time-varying magnetic field measurement converts the solution of the magnetic induction intensity into the calculation of the induced electromotive force (EMF); then, the magnetic induction intensity is obtained by the time integration of the EMF, but the process is vulnerable to external interference. In this paper, a non-steady state nuclear magnetic resonance (NSS-NMR) scheme for the measurement of a time-varying magnetic field is proposed. In a time-varying magnetic field environment, an RF excitation signal with a certain frequency bandwidth is applied to excite the nuclear spin system. The NSS-NMR signal, which varies with time in the frequency range corresponding to the frequency bandwidth of the RF excitation, could finally be obtained after a series of processing of the probe output signal. During the NSS-NMR experiment, an orthogonal dual-coil probe is adopted to synchronously generate the RF excitation and induce the probe output signal. Moreover, a directional coupler that utilized in the experiment outputs a reference signal from the coupling port for the subsequent signal processing. The experimental results show that the weak NSS-NMR signal is indeed observed. The longitudinal time-varying magnetic field ranges from 0.576 T to 0.582 T, which is inverted by the Larmor precession relationship, have been successfully detected based on the so-called NSS-NMR effect.

Blocking MG53S255 Phosphorylation Protects Diabetic Heart From Ischemic Injury.

BACKGROUND: As an integral component of cell membrane repair machinery, MG53 (mitsugumin 53) is important for cardioprotection induced by ischemia preconditioning and postconditioning. However, it also impairs insulin signaling via its E3 ligase activity-mediated ubiquitination-dependent degradation of IR (insulin receptor) and IRS1 (insulin receptor substrate 1) and its myokine function-induced allosteric blockage of IR. Here, we sought to develop MG53 into a cardioprotection therapy by separating its detrimental metabolic effects from beneficial actions. METHODS: Using immunoprecipitation-mass spectrometry, site-specific mutation, in vitro kinase assay, and in vivo animal studies, we investigated the role of MG53 phosphorylation at serine 255 (S255). In particular, utilizing recombinant proteins and gene knock-in approaches, we evaluated the potential therapeutic effect of MG53-S255A mutant in treating cardiac ischemia/reperfusion injury in diabetic mice. RESULTS: We identified S255 phosphorylation as a prerequisite for MG53 E3 ligase activity. Furthermore, MG53S255 phosphorylation was mediated by GSK3ß (glycogen synthase kinase 3 beta) and markedly elevated in the animal models with metabolic disorders. Thus, IR-IRS1-GSK3ß-MG53 formed a vicious cycle in the pathogenesis of metabolic disorders where aberrant insulin signaling led to hyper-activation of GSK3ß, which in turn, phosphorylated MG53 and enhanced its E3 ligase activity, and further impaired insulin sensitivity. Importantly, S255A mutant eliminated the E3 ligase activity while retained cell protective function of MG53. Consequently, the S255A mutant, but not the wild type MG53, protected the heart against ischemia/reperfusion injury in db/db mice with advanced diabetes, although both elicited cardioprotection in normal mice. Moreover, in S255A knock-in mice, S255A mutant also mitigated ischemia/reperfusion-induced myocardial damage in the diabetic setting. CONCLUSIONS: S255 phosphorylation is a biased regulation of MG53 E3 ligase activity. The MG53-S255A mutant provides a promising approach for the treatment of acute myocardial injury, especially in patients with metabolic disorders.

Celastrol-conjugated chitosan oligosaccharide for the treatment of pancreatic cancer.

Celastrol is a promising antitumor drug candidate, but the poor water solubility and cytotoxicity limit its clinical application. Herein, we synthesized a Celastrol (Cel)-chitosan oligosaccharide (CSO) conjugate (Cel-CSO) for drug delivery. Celastrol was conjugated to a CSO backbone via amide bond formation, which was verified by infrared spectrum (IR) analyses. The Cel-CSO contained ∼10 wt% of Celastrol showed excellent aqueous solubility (18.6 mg/mL) in comparation with the parent Celastrol. Cel-CSO significantly inhibited tumor growth, induced apoptosis, and effectively suppressed tumor metastasis in human pancreatic cancer cells (BxPC-3). While the cytotoxicity of Cel-CSO in hepatic cells (HL7702) was lower than that of the free Celastrol. Cel-CSO enhanced the anticancer efficacy, promoted the circulation time of Celastrol, and reduced the subacute toxicity, which indicated that CSO can be a promising Celastrol delivery system for pancreatic cancer therapy.