Functional examination of novel kisspeptin phosphinic peptides

Kisspeptins acting on their cognate G protein-coupled receptor, kisspeptin receptor, play important roles in the suppression of cancer cell metastasis and regulation of the reproductive system, and therefore are important for therapeutic intervention. All native functional human kisspeptins (kisspeptin-54, kisspsptin-14 and kisspeptin-13) share the 10 amino acids of kisspeptin-10 at their C-terminus (45–54). However, they are inactivated rapidly by matrix metalloproteinases (MMPs) through the cleavage of the peptide bond between glycine51 and leucine52, which limits their clinical applications. Development of MMP-resistant analogues of kisspeptins may provide better therapeutic outputs. In the present study, two kisspeptin phosphinic peptides were designed and synthesized, and their ability to induce phosphorylation of ERK1/2 through kisspeptin receptor and their inhibition on MMP-2 and MMP-9 whose activity correlates with cancer metastasis were assessed. The results showed that one analogue, phosphinic kisspeptin R isomer (PKPR), exhibited kisspeptin receptor-agonistic activity and also inhibitory activity on MMP-2, indicating that PKPR may serve as a lead for the further development of kisspeptin analogues for therapeutic purpose

Superradiant anomaly magnification in evolution of vector bosonic condensates bounded by a Kerr black hole with near-horizon reflection

Ultralight vector particles can form evolving condensates around a Kerr black hole (BH) due to superradiant instability. We study the effect of near-horizon reflection on the evolution of this system; by matching three pieces of asymptotic expansions of the Proca equation in Kerr metric and considering the leading order in the electric mode, we present explicit analytical expressions for the corrected energy level shifts and the superradiant instability rates. Particularly, in high-spin BH cases, we identify an anomalous situation where the superadiance rate is temporarily increased by the reflection parameter $\mathcal{R}$, which also occurs in the scalar scenario, but is largely magnified in vector condensates due to a faster growth rate in dominant mode; we constructed several featured quantities to illustrate this anomaly, and formalized the magnification with relevant correction factors, which may be of significance in future studies of gravitational waveforms of this monochromatic type. In addition, the duration of superradiance for the whole evolution is prolonged with a delay factor, which is calculated to be $(1+\mathcal{R})/({1-\mathcal{R}})$ approximately

The Cortical and Striatal Gene Expression Profile of 100 Hz Electroacupuncture Treatment in 6-Hydroxydopamine-Induced Parkinson's Disease Model

Electroacupuncture (EA), especially high-frequency EA, has frequently been used as an alternative therapy for Parkinson disease (PD) and is reportedly effective for alleviating motor symptoms in patients and PD models. However, the molecular mechanism underlying its effectiveness is not completely understood. To implement a full-scale search for the targets of 100 Hz EA, we selected rat models treated with 6-hydroxydopamine into the unilateral MFB, which mimic end-stage PD. High-throughput microarray analysis was then used to uncover the regulated targets in the cortex and striatum after 4-week EA treatment. In the differentially regulated transcripts, the proportion of recovered expression profiles in the genes, the functional categories of targets in different profiles, and the affected pathways were analyzed. Our results suggested that the recovery of homeostasis in the transcript network and many regulated functional clusters in the cortex and striatum after EA treatment may contribute to the behavioral improvement of PD rats

Enzymatic post-crosslinking of printed hydrogels of methacrylated gelatin and tyramine-conjugated 8-arm poly(ethylene glycol) to prepare interpenetrating 3D network structures

Methacrylated gelatin (GelMA) has been intensively studied as a 3D printable scaffold material in tissue regeneration fields, which can be attributed to its well-known biological functions. However, the long-term stability of photo-crosslinked GelMA scaffolds is hampered by a combination of its fast degradation in the presence of collagenase and the loss of physical crosslinks at higher temperatures. To increase the longer-term shape stability of printed scaffolds, a mixture of GelMA and tyramine-conjugated 8-arm PEG (8PEGTA) was used to create filaments composed of an interpenetrating network (IPN). Photo-crosslinking during filament deposition of the GelMA and subsequent enzymatic crosslinking of the 8PEGTA were applied to the printed 3D scaffolds. Although both crosslinking mechanisms are radical based, they operate without interference of each other. Rheological data of bulk hydrogels showed that the IPN was an elastic hydrogel, having a storage modulus of 6 kPa, independent of temperature in the range of 10 – 40°C. Tensile and compression moduli were 110 kPa and 80 kPa, respectively. On enzymatic degradation in the presence of collagenase, the gelatin content of the IPN fully degraded in 7 days, leaving a stable secondary crosslinked 8PEGTA network. Using a BioMaker bioprinter, hydrogels without and with human osteosarcoma cells (hMG-63) were printed. On culturing for 21 days, hMG-63 in the GelMA/8PEGTA IPN showed a high cell viability (&gt;90%). Thus, the presence of the photoinitiator, incubation with H2O2, and mechanical forces during printing did not hamper cell viability. This study shows that the GelMA/8PEGTA ink is a good candidate to generate cell-laden bioinks for extrusion-based printing of constructs for tissue engineering applications.</p

Modified Glucose-Insulin-Potassium Regimen Provides Cardioprotection With Improved Tissue Perfusion in Patients Undergoing Cardiopulmonary Bypass Surgery

Background Laboratory studies demonstrate glucose-insulin-potassium (GIK) as a potent cardioprotective intervention, but clinical trials have yielded mixed results, likely because of varying formulas and timing of GIK treatment and different clinical settings. This study sought to evaluate the effects of modified GIK regimen given perioperatively with an insulin-glucose ratio of 1:3 in patients undergoing cardiopulmonary bypass surgery. Methods and Results In this prospective, randomized, double-blinded trial with 930 patients referred for cardiac surgery with cardiopulmonary bypass, GIK (200 g/L glucose, 66.7 U/L insulin, and 80 mmol/L KCl) or placebo treatment was administered intravenously at 1 mL/kg per hour 10 minutes before anesthesia and continuously for 12.5 hours. The primary outcome was the incidence of in-hospital major adverse cardiac events including all-cause death, low cardiac output syndrome, acute myocardial infarction, cardiac arrest with successful resuscitation, congestive heart failure, and arrhythmia. GIK therapy reduced the incidence of major adverse cardiac events and enhanced cardiac function recovery without increasing perioperative blood glucose compared with the control group. Mechanistically, this treatment resulted in increased glucose uptake and less lactate excretion calculated by the differences between arterial and coronary sinus, and increased phosphorylation of insulin receptor substrate-1 and protein kinase B in the hearts of GIK-treated patients. Systemic blood lactate was also reduced in GIK-treated patients during cardiopulmonary bypass surgery. Conclusions A modified GIK regimen administered perioperatively reduces the incidence of in-hospital major adverse cardiac events in patients undergoing cardiopulmonary bypass surgery. These benefits are likely a result of enhanced systemic tissue perfusion and improved myocardial metabolism via activation of insulin signaling by GIK. Clinical Trial Registration URL: clinicaltrials.gov. Identifier: NCT01516138

Nitrooleic Acid Attenuates Lipid Metabolic Disorders and Liver Steatosis in DOCA-Salt Hypertensive Mice

Nitrooleic acid (OA-NO2) is endogenous ligands for peroxisome proliferator-activated receptors. The present study was aimed at investigating the beneficial effects of OA-NO2 on the lipid metabolism and liver steatosis in deoxycorticosterone acetate- (DOCA-) salt induced hypertensive mice model. Male C57BL/6 mice were divided to receive DOCA-salt plus OA-NO2 or DOCA-salt plus vehicle and another group received neither DOCA-salt nor OA-NO2 (control group). After 3-week treatment with DOCA-salt plus 1% sodium chloride in drinking fluid, the hypertension was noted; however, OA-NO2 had no effect on the hypertension. In DOCA-salt treated mice, the plasma triglyceride and total cholesterol levels were significantly increased compared to control mice, and pretreatment with OA-NO2 significantly reduced these parameters. Further, the histopathology of liver exhibited more lipid distribution together with more serious micro- and macrovesicular steatosis after DOCA-salt treatment and that was consistent with liver tissue triglyceride and nonesterified fatty acids (NEFA) content. The mice pretreated with OA-NO2 showed reduced liver damage accompanied with low liver lipid content. Moreover, the liver TBARS, together with the expressions of gp91phox and p47phox, were parallelly decreased. These findings indicated that OA-NO2 had the protective effect on liver injury against DOCA-salt administration and the beneficial effect could be attributed to its antihyperlipidemic activities

Flavonoids from Saussurea stella Maxim as superoxide scavengers and antioxidants

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