Discovery of Novel Insulin Sensitizers: Promising Approaches and Targets

Insulin resistance is the undisputed root cause of type 2 diabetes mellitus (T2DM). There is currently an unmet demand for safe and effective insulin sensitizers, owing to the restricted prescription or removal from market of certain approved insulin sensitizers, such as thiazolidinediones (TZDs), because of safety concerns. Effective insulin sensitizers without TZD-like side effects will therefore be invaluable to diabetic patients. The specific focus on peroxisome proliferator-activated receptor γ- (PPARγ-) based agents in the past decades may have impeded the search for novel and safer insulin sensitizers. This review discusses possible directions and promising strategies for future research and development of novel insulin sensitizers and describes the potential targets of these agents. Direct PPARγ agonists, selective PPARγ modulators (sPPARγMs), PPARγ-sparing compounds (including ligands of the mitochondrial target of TZDs), agents that target the downstream effectors of PPARγ, along with agents, such as heat shock protein (HSP) inducers, 5′-adenosine monophosphate-activated protein kinase (AMPK) activators, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) selective inhibitors, biguanides, and chloroquines, which may be safer than traditional TZDs, have been described. This minireview thus aims to provide fresh perspectives for the development of a new generation of safe insulin sensitizers

Clinical effects of unilateral biportal endoscopic decompression for lumbar posterior apophyseal ring separation

ObjectiveThe purpose of the study was to investigate the feasibility and effects of unilateral biportal endoscopic decompression for lumbar posterior apophyseal ring separation (PARS).MethodsPatients with lumbar PARS who received unilateral biportal endoscopic decompression from June 2020 to September 2021 were analyzed, including 11 females and 15 males. The clinical symptoms were consistent with the imaging findings. Operation time, length of postoperative hospital stay and complications were recorded, and the clinical efficacy was evaluated by Visual Analogue Scale (VAS), Oswestry Disability Index (ODI) and modified Macnab scale at preoperative, postoperative 1, 3, 6 months and the last follow-up.ResultsPreoperative VAS scores of low back pain were (5.04 ± 1.37) and respectively decreased to (2.81 ± 0.75), (2.35 ± 0.98), (1.65 ± 0.69) and (1.15 ± 0.68) at postoperative 1, 3, 6 months and at the last follow-up, and the difference was statistically significant (F = 127.317, P = 0.000). Preoperative VAS scores of lower limb pain were (6.92 ± 1.38) and respectively decreased to (2.88 ± 1.07), (2.54 ± 1.03), (1.81 ± 0.80) and (1.00 ± 0.69) at postoperative 1, 3, 6 months and at the last follow-up, and the difference was statistically significant (F = 285.289, P = 0.000). Preoperative ODI scores were (60.47 ± 8.89) and respectively decreased to (34.72 ± 4.13), (25.80 ± 3.65), (17.71 ± 3.41) and (5.65 ± 2.22) at postoperative 1, 3, 6 months and at the last follow-up, and the difference was statistically significant (F = 725.255, P = 0.000). According to the modified Macnab criteria, the final outcome was excellent in 22 cases, good in 3 cases, fair in 1 cases. 26 patients could return to work or normal activities within 3 weeks.ConclusionsUnilateral biportal endoscopic decompression has the advantages of clear and wide field of vision, large operating space, relatively simple need of surgical instrument and convenient and flexible operation procedure. It can achieve excellent clinical results with favorable efficacy and safety and may become a new minimally invasive endoscopic treatment for lumbar PARS

Stock Market Simulation

Simulation tools and information available on the internet were used to conduct a 5-week stock market simulation with four different trading strategies: swing, technical, position and day trading. Trading results were analyzed and compared to find out the differences of the trading methods and determine the most profitable one. This project was helpful for the team members to have a better knowledge of the stock market and gain valuable trading experiences to become more competent and more confident investors in the future

Effects of U-shaped two-step throttling groove parameters on cavitation erosion characteristics

Throttling usually occurs when a fluid passes through an orifice, sometimes even severe cav- itation erosion may occur. In this study, the equation for the cavitation index of a throttling valve was proposed and the cavitation erosion area in the throttle valve was found to change its position with the orifice opening (X). Cavitation features of singular and two-port se- ries throttling grooves were characterized by defining cavitation indexes σ1and σ2, because the cavitation index-σ can determine the occurrence and intensity of cavitation. Then the indexes σ1 and σ2 included internal geometric parameters and external pressure boundaries were obtained, and cavitation indexes curves σ1-X and σ2-X were also plotted. From the curves of the cavitation index, it was observed that cavitation concentration section also would transfer with opening X changes in the U-shaped groove. The depth of the U-shaped groove had a more evident impact on cavitation, whereas the effect of width on cavitation erosion was not so obvious. The intensity of cavitation erosion when the fluid flowed into the orifice section of the U-shaped groove was always larger than that when the fluid flowed away

Molecular dynamics study on the mechanical properties of nanocrystalline Ni-W alloys with bimodal structure

In order to study the effects of coarse grain size and Ni content on the mechanical properties, the molecular dynamics (MD) simulation of nanocrystalline (NC) Ni-W alloys with bimodal structure is carried out. The bimodal NC Ni-W alloys samples are established by embedding coarse grain into the fine grain matrix. The solute Ni atoms in the alloys are segregated in the grain boundary affected zone (GBAZ) through severe plastic deformation (SPD). The uniaxial tensile simulation of the samples shows that the coarse grain size and Ni content have obvious effects on the mechanical properties of bimodal NC Ni-W alloys. The dislocation activities and deformation mechanism of the NC Ni-W alloys are discussed in detail by observing the atomic configurations and strain evolutions diagrams obtained by MD simulation. At the same time, the phenomenon of Hall-Petch relationship and inverse Hall-Petch relationship is also observed in the research process

Iron regulates chondrocyte phenotype in haemophilic cartilage through the PTEN/PI3 K/AKT/FOXO1 pathway

ABSTRACTObjective Our previous study demonstrated that iron overload could lead to haemophilic cartilage destruction by changing chondrocyte phenotype. This change was caused by iron’s effect on chondrocyte expression of FGF23 and SOX9, in addition to iron-induced chondrocyte apoptosis and cartilage extracellular matrix degradation. However, the underlying mechanisms remain unclear. This study aimed to determine the mechanism by which iron influences chondrocyte phenotype in the pathogenesis of haemophilic cartilage destruction.Methods The expression of the PTEN/PI3K/AKT/FOXO1 signal pathway in the articular cartilage of patients with haemophilic arthritis (HA) or osteoarthritis (OA) was determined using western blot (WB). Additionally, we quantified the expression of iron-induced PTEN, PI3K, p-PI3K, AKT, p-AKT, FOXO1, and p-FOXO1 in primary human normal chondrocyte cells (HUM-iCell-s018) using WB.Results We found that compared to that in patients with OA, the expression of PTEN, PI3K, AKT, and FOXO1 in the articular cartilage of patients with HA was up-regulated, while the expression of p-PI3K, p-AKT, and p-FOXO1 was down-regulated. Additionally, iron increased the expression of PTEN, PI3K, AKT, and FOXO1 and suppressed that of p-PI3K, p-AKT, and p-FOXO1 in chondrocytes in a dose-dependent manner.Conclusions Our findings demonstrated that iron was involved in the pathogenesis of haemophilic cartilage destruction by affecting chondrocyte phenotype through the inhibition of the PTEN/PI3K/AKT/FOXO1 pathway