The impact of bone marrow stimulation on arthroscopic rotator cuff repair for small to large rotator cuff tears: a randomized controlled trial.

BACKGROUND: Bone marrow stimulation (BMS), a procedure involving the creation of multiple channels in the greater tuberosity, is often performed alongside arthroscopic rotator cuff repair (ARCR). This study evaluated the effect of BMS on clinical and structural outcomes following ARCR. METHOD: This study involved 204 patients with small, medium, and large full-thickness rotator cuff tears. In all, 103 patients who underwent BMS and ARCR made up the BMS group, while the 101 patients who only had ARCR made up the control group with randomization. Clinical and functional outcomes were assessed before and at 3 months, 6 months, 1 year, and 2 years after surgery, using parameters such as range of motion, functional scores (American Shoulder and Elbow Surgeons and Constant score), and clinical scores (Visual Analogue Scale). Tendon integrity was also examined postoperatively via ultrasound at 6 months and 2 years. RESULTS: There were no significant differences between the two groups concerning range of motion, functional scores (American Shoulder and Elbow Surgeons score and Constant score), and clinical score (Visual Analogue Scale) during the 2-year postsurgery period (all P > .05). Similarly, the rotator cuff retear rate, as assessed using ultrasonographic tendon integrity checks over 2 years postsurgery, did not significantly vary between the groups (all P > .05). CONCLUSION: There were no significant disparities in functional scores and clinical outcomes between the BMS and control groups. Further, no significant differences were observed in tendon integrity postsurgery. Therefore, the inclusion or exclusion of BMS is not anticipated to influence the postoperative outcome in ARCR for patients with small, medium, or large rotator cuff tears.

Optimization of Aging Temperature and Heat-Treatment Pathways in Additively Manufactured 17-4PH Stainless Steel.

This study investigates the tensile behaviors of additively manufactured (AM) 17-4PH stainless steels heat-treated within various temperature ranges from 400 °C to 700 °C in order to identify the effective aging temperature. Despite an aging treatment of 400-460 °C increasing the retained austenite content, an enhancement of the tensile properties was achieved without a strength-ductility trade-off owing to precipitation hardening by the Cu particles. Due to the intricate evolution of the microstructure, aging treatments above 490 °C led to a loss in yield strength and ductility. A considerable rise in strength and a decrease in ductility were brought about by the increase in the fraction of precipitation-hardened martensitic matrix in aging treatments over 640 °C. The impact of heat-treatment pathways on aging effectiveness and tensile anisotropy was then examined. Direct aging at 482 °C for an hour had hardly any effect on wrought 17-4PH, but it increased the yield strength of AM counterparts from 436-457 to 588-604 MPa. A solid-solution treatment at 1038 °C for one hour resulted in a significant drop in the austenite fraction, which led to an increase in the yield (from 436-457 to 841-919 MPa) and tensile strengths (from 1106-1127 to 1254-1256 MPa) with a sacrifice in ductility. Improved strength and ductility were realized by a solid-solution followed by an aging treatment, achieving 1371-1399 MPa. The tensile behaviors of AM 17-4PH were isotropic both parallel and perpendicular to the building direction.

Determining the Anticancer Activity of Sphingosine Kinase Inhibitors Containing Heteroatoms in Their Tail Structure.

Sphingosine kinase (SK) enzyme, a central player of sphingolipid rheostat, catalyzes the phosphorylation of sphingosine to the bioactive lipid mediator sphingosine 1 phosphate (S1P), which regulates cancer cell proliferation, migration, differentiation, and angiogenesis through its extracellular five G protein-coupled S1P receptors (S1PR1-5). Recently, several research studies on SK inhibitors have taken place in order use them for the development of novel anticancer-targeted therapy. In this study, we designed and synthesized analog derivatives of known SK1 inhibitors, namely RB005 and PF-543, by introducing heteroatoms at their tail structure, as well as investigated their anticancer activities and pharmacokinetic parameters in vitro. Compounds 1-20 of RB005 and PF-543 derivatives containing an aliphatic chain or a tail structure of benzenesulfonyl were synthesized. All compounds of set 1 (1-10) effectively reduced cell viability in both HT29 and HCT116 cells, whereas set 2 derivatives (11-20) showed poor anticancer effect. Compound 10, having the highest cytotoxic effect (48 h, HT29 IC50 = 6.223 µM, HCT116 IC50 = 8.694 µM), induced HT29 and HCT116 cell death in a concentration-dependent manner through the mitochondrial apoptotic pathway, which was demonstrated by increased annexin V-FITC level, and increased apoptotic marker cleaved caspase-3 and cleaved PARP. Compound 10 inhibited SK1 by 20%, and, thus, the S1P level decreased by 42%. Unlike the apoptosis efficacy, the SK1 inhibitory effect and selectivity of the PF-543 derivative were superior to that of the RB005 analog. As a result, compounds with an aliphatic chain tail exhibited stronger apoptotic effects. However, this ability was not proportional to the degree of SK inhibition. Compound 10 increased the protein phosphatase 2A (PP2A) activity (1.73 fold) similar to FTY720 (1.65 fold) and RB005 (1.59 fold), whereas compounds 11 and 13 had no effect on PP2A activation. Since the PP2A activity increased in compounds with an aliphatic chain tail, it can be suggested that PP2A activation has an important effect on anticancer and SK inhibitory activities.

Graft isometry during anatomical ACL reconstruction has little effect on surgical outcomes.

PURPOSE: To investigate the surgical outcomes of anatomical anterior cruciate ligament (ACL) reconstruction according to the graft isometry measured during surgery. METHODS: Electrical medical records of patients who underwent an arthroscopic ACL reconstruction through the transportal technique using hamstring tendon autograft between 2012 and 2016 were retrospectively reviewed. The patients were classified into two groups based on the graft length change throughout the knee range of motion measured just before graft fixation (Group 1, graft length change ≤ 2 mm; Group 2, graft length change > 2 mm). Comparative analyses, including a non-inferiority trial, were performed regarding the clinical scores, knee laxity, and radiographic parameters between the groups. RESULTS: A total of 67 patients were included in the study. The total change in the length of ACL graft throughout the knee range of motion was 1.4 ± 0.4 mm in Group 1 (range, 0.2-2.0 mm), and 3.0 ± 0.7 mm in Group 2 (range, 2.2-5.0 mm). Group 1 showed a relatively high (proximal) femoral tunnel and shallow (anterior) tibial tunnel compared to Group 2 (P < 0.001 and P = 0.028, respectively), but there were no apparent differences in the macroscopic view. There were no statistically significant differences in the clinical outcomes between groups at 2 years after surgery, which satisfied the non-inferiority criterion of Group 1 in terms of clinical scores and knee laxity compared to Group 2. CONCLUSION: The surgical outcomes of anatomical ACL reconstruction in patients with non-isometric ACL graft were not inferior in terms of clinical scores and knee laxity, compared to those with nearly-isometric ACL graft. The graft tunnel placement in the isometric position during anatomical ACL reconstruction, which is technically challenging in the clinical setting, is not a crucial factor in terms of clinical outcomes. LEVEL OF EVIDENCE: Level IV.

The Quantitative Trait Loci Mapping of Rice Plant and the Components of Its Extract Confirmed the Anti-Inflammatory and Platelet Aggregation Effects In Vitro and In Vivo.

Unpredictable climate change might cause serious lack of food in the world. Therefore, in the present world, it is urgent to prepare countermeasures to solve problems in terms of human survival. In this research, quantitative trait loci (QTLs) were analyzed when rice attacked by white backed planthopper (WBPH) were analyzed using 120 Cheongcheong/Nagdong double haploid lines. Moreover, from the detected QTLs, WBPH resistance-related genes were screened in large candidate genes. Among them, OsCM, a major gene in the synthesis of Cochlioquinone-9 (cq-9), was screened. OsCM has high homology with the sequence of chorismate mutase, and exists in various functional and structural forms in plants that produce aromatic amino acids. It also induces resistance to biotic stress through the synthesis of secondary metabolites in plants. The WBPH resistance was improved in rice overexpressed through map-based cloning of the WBPH resistance-related gene OsCM, which was finally detected by QTL mapping. In addition, cq-9 increased the survival rate of caecal ligation puncture (CLP)-surgery mice by 60%. Moreover, the aorta of rat treated with cq-9 was effective in vasodilation response and significantly reduced the aggregation of rat platelets induced by collagen treatment. A cq-9, which is strongly associated with resistance to WBPH in rice, is also associated with positive effect of CLP surgery mice survival rate, vasodilation, and significantly reduced rat platelet aggregation induced by collagen treatment. Therefore, cq-9 presents research possibilities as a substance in a new paradigm that can act on both Plant-Insect in response to the present unpredictable future.

Nano zero-valent iron improves anammox activity by promoting the activity of quorum sensing system.

The addition of nano zero-valent iron (nZVI) has been proven to improve the efficiency of the anammox process, however, the mechnism is not clear. Here, the effect of nZVI on anammox microbial community was studied by metagenomic sequencing methods. It was found that 50 mg/L nZVI indeed promoted the removal of NH4+ and NO2- of the anammox reactor and significantly improved the relative abundance of AnAOB (Ca. Brocadia) from 42.1% to 52.5%. What's more, 50 mg/L nZVI increased the abundance of c-di-GMP synthesized protein from 148 rpmr to 252 rpmr in the microbial community and decreased the abundance of c-di-GMP degradation protein from 238 rpmr to 204 rpmr, which indirectly led to the enrichment of c-di-GMP in the microbial community. The enrichment of c-di-GMP reduced the motility of microorganisms in the reactor and promoted the secretion of extracellular polymers by bacteria, which is beneficial to the formation of sludge particles in the anammox reactor. In conclusion, this research clarified the mechanism of nZVI promoting the anammox process and provided theoretical guidance for the engineering application of anammox.

Strain hardening recovery mediated by coherent precipitates in lightweight steel.

We investigated the effect of κ-carbide precipitates on the strain hardening behavior of aged Fe-Mn-Al-C alloys by microstructure analysis. The κ-carbides-strengthened Fe-Mn-Al-C alloys exhibited a superior strength-ductility balance enabled by the recovery of the strain hardening rate. To understand the relation between the κ-carbides and strain hardening recovery, dislocation gliding in the aged alloys during plastic deformation was analyzed through in situ tensile transmission electron microscopy (TEM). The in situ TEM results confirmed the particle shearing mechanism leads to planar dislocation gliding. During deformation of the 100 h-aged alloy, some gliding dislocations were strongly pinned by the large κ-carbide blocks and were prone to cross-slip, leading to the activation of multiple slip systems. The abrupt decline in the dislocation mean free path was attributed to the activation of multiple slip systems, resulting in the rapid saturation of the strain hardening recovery. It is concluded that the planar dislocation glide and sequential activation of slip systems are key to induce strain hardening recovery in polycrystalline metals. Thus, if a microstructure is designed such that dislocations glide in a planar manner, the strain hardening recovery could be utilized to obtain enhanced mechanical properties of the material.

Nontargeted Metabolomics by High-Resolution Mass Spectrometry to Study the In Vitro Metabolism of a Dual Inverse Agonist of Estrogen-Related Receptors ß and γ, DN203368.

DN203368 ((E)-3-[1-(4-[4-isopropylpiperazine-1-yl]phenyl) 3-methyl-2-phenylbut-1-en-1-yl] phenol) is a 4-hydroxy tamoxifen analog that is a dual inverse agonist of estrogen-related receptor ß/γ (ERRß/γ). ERRγ is an orphan nuclear receptor that plays an important role in development and homeostasis and holds potential as a novel therapeutic target in metabolic diseases such as diabetes mellitus, obesity, and cancer. ERRß is also one of the orphan nuclear receptors critical for many biological processes, such as development. We investigated the in vitro metabolism of DN203368 by conventional and metabolomic approaches using high-resolution mass spectrometry. The compound (100 µM) was incubated with rat and human liver microsomes in the presence of NADPH. In the metabolomic approach, the m/z value and retention time information obtained from the sample and heat-inactivated control group were statistically evaluated using principal component analysis and orthogonal partial least-squares discriminant analysis. Significant features responsible for group separation were then identified using tandem mass spectra. Seven metabolites of DN203368 were identified in rat liver microsomes and the metabolic pathways include hydroxylation (M1-3), N-oxidation (M4), N-deisopropylation (M5), N,N-dealkylation (M6), and oxidation and dehydrogenation (M7). Only five metabolites (M2, M3, and M5-M7) were detected in human liver microsomes. In the conventional approach using extracted ion monitoring for values of mass increase or decrease by known metabolic reactions, only five metabolites (M1-M5) were found in rat liver microsomes, whereas three metabolites (M2, M3, and M5) were found in human liver microsomes. This study revealed that nontargeted metabolomics combined with high-resolution mass spectrometry and multivariate analysis could be a more efficient tool for drug metabolite identification than the conventional approach. These results might also be useful for understanding the pharmacokinetics and metabolism of DN203368 in animals and humans.

The Graft Insertion Length in the Femoral Tunnel During Anterior Cruciate Ligament Reconstruction With Suspensory Fixation and Tibialis Anterior Allograft Does Not Affect Surgical Outcomes but Is Negatively Correlated With Tunnel Widening.

PURPOSE: To investigate the surgical outcomes of anterior cruciate ligament (ACL) reconstruction using a low-dose irradiated tibialis anterior allograft with a fixed-loop cortical suspension device for the femur based on the graft insertion length (GIL) in the femoral tunnel. METHODS: Between January 2010 and January 2018, the medical records of consecutive patients who underwent arthroscopic ACL reconstruction with a tibialis anterior allograft fixed with the EndoButton CL for the femur and who had at least 2 years of follow-up were retrospectively evaluated. Patients were classified into 3 groups based on the GIL in the femoral tunnel (group 1, GIL < 15 mm; group 2, GIL of 15-20 mm; and group 3, GIL > 20 mm), and their functional scores, knee laxity, and radiographic parameters were evaluated. RESULTS: A total of 91 patients were analyzed. There were no statistically significant differences in the functional scores and knee laxity between the 3 groups at 2 years postoperatively. However, significant differences were observed in tunnel widening at 1 year postoperatively in the femur (P = .045 for absolute value and P = .004 for relative value) and the tibia (P = .014 for absolute value and P = .012 for relative value), revealing that both the femoral and tibial tunnels widened as the GIL decreased. Additional linear regression analyses were performed to identify whether the GIL independently affects tunnel widening. Consequently, the femoral tunnel depth, tunnel diameter, and GIL were found to independently influence femoral tunnel widening (P = .008, P = .019, and P < .001, respectively), whereas the tunnel diameter and GIL affected tibial tunnel widening (P < .001 and P = .004, respectively). CONCLUSIONS: The GIL in the femoral tunnel during ACL reconstruction using a tibialis anterior allograft with a fixed-loop cortical suspension device for the femur has no significant association with the postoperative functional outcomes and knee laxity, but it has a negative correlation with tunnel widening in the femur and the tibia. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Mild to Moderate Varus Alignment in Relation to Surgical Repair of a Medial Meniscus Root Tear: A Matched-Cohort Controlled Study With 2 Years of Follow-up.

BACKGROUND: Increased varus alignment of the lower extremity is known to be a poor prognostic factor for the surgical repair for a medial meniscus root tear (MMRT). However, given the concept of constitutional varus, which is present in a substantial portion of the normal population, the generally accepted surgical indication for MMRT concerning a varus alignment of 5° may be unnecessarily narrow. PURPOSE: To compare the surgical outcomes of arthroscopic transtibial pullout repair of MMRT according to the degree of varus alignment of the lower extremity. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Patients who underwent isolated arthroscopic transtibial pullout repair of MMRT between January 2010 and July 2017 at one institution and had a minimum follow-up of 2 years were included in this study. Patients were classified into 1 of 2 groups: the experimental group (n = 22) included patients with a preoperative hip-knee-ankle angle between 5° and 10° varus (mild to moderate varus alignment) and the control group (n = 51) included those with a preoperative hip-knee-ankle angle <5° varus (neutral alignment). Clinical scores and radiographic parameters were compared between the groups to assess surgical outcomes, which were statistically matched for potential confounders (age, body mass index, the severity of cartilage lesion) by use of the inverse probability of treatment weighting. A noninferiority trial was performed comparing the experimental and control groups in terms of subjective outcomes (International Knee Documentation Committee subjective and Lysholm scores) and objective outcomes (postoperative medial meniscal extrusion and the rate of osteoarthritis progression). RESULTS: There were no statistically significant differences in surgical outcomes between the groups in subjective and objective aspects, which were consistent before and after inverse probability of treatment weighting. Apart from the clinical improvement observed in both groups, overall degenerative changes in the knee were found, although progression rates did not differ between the groups. In terms of the noninferiority trial, the overall surgical outcomes in the experimental group were not inferior to those in the control group. CONCLUSION: The short-term surgical outcomes of arthroscopic transtibial pullout repair for MMRT of patients with mild to moderate varus alignment were not inferior to but rather comparable with those with neutral alignment in terms of subjective and objective aspects. Therefore, it would be inappropriate to exclude patients with a diagnosis of MMRT from being indicated for the surgery simply because of mild to moderate varus alignment.

Selective inhibitory effects of HYIpro-3-1 on CYP1A2 in human liver microsomes.

CYP1A2 is one of the main Cytochrome P450 enzymes in the human liver associated with the metabolism of several xenobiotics. CYP1A2 is especially involved in the metabolic activation of different procarcinogens. Therefore, the development of cancer may be inhibited by inhibiting CYP1A2 activity. Here, the inhibitory effect of HYIpro-3-1 and its derivatives on CYP1A2 activity in human liver microsomes (HLM) was studied through LC-MS/MS using a cocktail assay. Among the four compounds, HYIpro-3-1 showed the most selective and strongest inhibitory effect on CYP1A2 at IC50 values of 0.1 µM in HLMs and inhibition was confirmed using purified human CYP1A2. It was determined that inhibition is reversible because the inhibitory effect of HYIpro-3-1 is not dependent on preincubation time. HYIpro-3-1 showed a typical pattern of competitive inhibition for CYP1A2-catalyzed phenacetin O-deethylation, based on the Lineweaver-Burk plot, with a Ki value of 0.05 µM in HLMs; the secondary plot also showed a linear pattern. In our study, HYIpro-3-1 was proposed as a novel inhibitor with the capacity to selectively inhibit CYP1A activity in HLMs.

An Increase in Medial Joint Space Width After Medial Open-Wedge High Tibial Osteotomy Is Associated With an Increase in the Postoperative Weight-Bearing Line Ratio Rather Than With Cartilage Regeneration: Comparative Analysis of Patients Who Underwent Second-Look Arthroscopic Assessment.

PURPOSE: To investigate relevant factors influencing increases in medial joint space width (JSW) after medial open-wedge high tibial osteotomy (MOWHTO). METHODS: Between January 2010 and December 2018, the electronic medical records of consecutive patients who underwent MOWHTO and subsequent second-look arthroscopic assessment at least 12 months after MOWHTO were retrospectively evaluated. The patients were classified into 2 groups according to changes in the medial JSW of the knee at the time of the second-look operation compared with that at baseline before the initial surgical procedure. Various radiographic parameters, arthroscopic findings, and clinical scores were compared between the groups, and regression analysis was performed to identify factors related to increases in medial JSW. RESULTS: A total of 114 patients were analyzed. In a bivariate analysis, patients who experienced an increase in medial JSW showed a significantly higher postoperative weight-bearing line ratio (WBLR) (P = .008) and a greater proportion of severe preoperative cartilage lesions in the medial compartment of the knee compared with patients with a maintained or reduced medial JSW (P = .035). In terms of clinical scores, patients with an increased medial JSW showed relatively favorable clinical outcomes at the time of the second-look operation. Regression analysis indicated only postoperative WBLR as a relevant factor associated with an increase in medial JSW after MOWHTO (odds ratio, 1.057; P = .01). Additional analysis with patients reclassified according to the postoperative WBLR showed that as the postoperative WBLR increased, the medial JSW increased, without a significant change in the lateral JSW. CONCLUSIONS: An increase in the medial JSW of the knee joint after MOWHTO appears to be associated with an increase in the postoperative WBLR, not with cartilage regeneration. Obtaining adequate correction so that the postoperative WBLR is within 60% to 70% would be desirable in terms of postoperative changes in the medial JSW, as well as clinical outcomes. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Inhibitory functions of cardamonin against particulate matter-induced lung injury through TLR2,4-mTOR-autophagy pathways.

Particulate matter with an aerodynamic diameter equal to or less than 2.5 µm (PM2.5) is a form of air pollutant that causes significant lung damage when inhaled. Cardamonin, a flavone found in Alpinia katsumadai Heyata seeds, has been reported to have anti-inflammatory and anticoagulative activity. The aim of this study was to determine the protective effects of cardamonin on PM2.5-induced lung injury. Mice were treated with cardamonin via tail-vein injection 30 min after the intratracheal instillation of PM2.5. The results showed that cardamonin markedly reduced the pathological lung injury, lung wet/dry weight ratio, and hyperpermeability caused by PM2.5. Cardamonin also significantly inhibited PM2.5-induced myeloperoxidase (MPO) activity in lung tissue, decreased the levels of PM2.5-induced inflammatory cytokines and effectively attenuated PM2.5-induced increases in the number of lymphocytes in the bronchoalveolar lavage fluid (BALF). And, cardamonin increased the phosphorylation of mammalian target of rapamycin (mTOR) and dramatically suppressed the PM2.5-stimulated expression of toll-like receptor 2 and 4 (TLR 2,4), MyD88, and the autophagy-related proteins LC3 II and Beclin 1. In conclusion, these findings indicate that cardamonin has a critical anti-inflammatory effect due to its ability to regulate both the TLR2,4-MyD88 and mTOR-autophagy pathways and may thus be a potential therapeutic agent against PM2.5-induced lung injury.

The Evolution of an Invasive Plant, Sorghum halepense L. ('Johnsongrass').

From noble beginnings as a prospective forage, polyploid Sorghum halepense ('Johnsongrass') is both an invasive species and one of the world's worst agricultural weeds. Formed by S. bicolor x S. propinquum hybridization, we show S. halepense to have S. bicolor-enriched allele composition and striking mutations in 5,957 genes that differentiate it from representatives of its progenitor species and an outgroup. The spread of S. halepense may have been facilitated by introgression from closely-related cultivated sorghum near genetic loci affecting rhizome development, seed size, and levels of lutein, a photochemical protectant and abscisic acid precursor. Rhizomes, subterranean stems that store carbohydrates and spawn clonal propagules, have growth correlated with reproductive rather than other vegetative tissues, and increase survival of both temperate cold seasons and tropical dry seasons. Rhizomes of S. halepense are more extensive than those of its rhizomatous progenitor S. propinquum, with gene expression including many alleles from its non-rhizomatous S. bicolor progenitor. The first surviving polyploid in its lineage in ∼96 million years, its post-Columbian spread across six continents carried rich genetic diversity that in the United States has facilitated transition from agricultural to non-agricultural niches. Projected to spread another 200-600 km northward in the coming century, despite its drawbacks S. halepense may offer novel alleles and traits of value to improvement of sorghum.

Verification of the Necessity of the Tolyl Group of PF-543 for Sphingosine Kinase 1 Inhibitory Activity.

PF-543, the most potent sphingosine kinase (SK) inhibitor, does not demonstrate effective anticancer activity in some cancer cells, unlike other known SK1 inhibitors. PF-543 has a non-lipid structure with a unique toluene backbone; however, the importance of this structure remains unclear. Therefore, the purpose of this study was to investigate changes in SK inhibitory and anticancer activities and to explore the role of the tolyl group structure of PF-543 through various modifications. We transformed the methyl group of PF-543 into hydrogen, fluorine, and hydroxy. PF-543 derivatives in which the methyl group was substituted by hydrogen and fluorine (compound 5) demonstrated SK1 inhibitory and anticancer activities similar to PF-543. Moreover, we performed molecular modeling studies of PF-543 and compound 5. To assess the metabolic stability of PF-543 and compound 5, we determined their degree of degradation using the liver microsomes of four different animal species (human, dog, rat, and mouse). However, both PF-543 and compound 5 showed poor microsomal stability. Therefore, for the medical applications of PF-543, the structural modifications of its other parts may be necessary. Our results provide important information for the design of additional PF-543 analogs.

Synthesis and Biological Evaluation of BODIPY-PF-543.

Sphingosine-1-phosphate (S1P) regulates the proliferation of various cells and promotes the growth of cancer cells. Sphingosine kinase (SK), which transforms sphingosine into S1P, has two isotypes: SK1 and SK2. To date, both isotypes are known to be involved in the proliferation of cancer cells. PF-543, an SK1 inhibitor developed by Pfizer, strongly inhibits SK1. However, despite its strong SK1 inhibitory effect, PF-543 shows low anticancer activity in vitro. Therefore, additional biological evidence on the anticancer activity of SK1 inhibitor is required. The present study aimed to investigate the intracellular localization of PF-543 and identify its association with anticancer activity by introducing a fluoroprobe into PF-543. Boron-dipyrromethene (BODIPY)-introduced PF-543 has a similar SK1 inhibitory effect as PF-543. These results indicate that the introduction of BODIPY does not significantly affect the inhibitory effect of SK1. In confocal microscopy after BODIPY-PF-543 treatment, the compound was mainly located in the cytosol of the cells. This study demonstrated the possibility of introducing fluorescent material into an SK inhibitor and designing a synthesized compound that is permeable to cells while maintaining the SK inhibitory effect.

Direct observation of dislocation plasticity in high-Mn lightweight steel by in-situ TEM.

To gain the fundamental understanding of deformation mechanisms in an aluminum-containing austenitic high-Mn steel (Fe-32Mn-8.9Al-0.78 C (wt.%)), in-situ straining transmission electron microscopy (TEM) analysis is conducted. The in-situ observation during the deformation demonstrates that the plastic deformation is accommodated by the pronounced planar dislocation gliding followed by the formation of slip bands (SBs) and highly dense dislocation walls (HDDWs). Experimental evidences of the glide plane softening can be obtained from the interaction between the gliding perfect dislocations and the L'12 ordered precipitates in the austenite matrix. Furthermore, the observation of the localized cross-slip of dislocations at the slip band intersections enables to understand why slip bands are extensively developed without mutual obstructions between the slip bands. The enhanced strain hardening rate of the aluminum-containing austenitic high-Mn steels can be attributed to the pronounced planar dislocation glides followed by formation of extensive slip band which prevent premature failure by suppressing strain localization.

Synthesis and Biological Evaluation of PF-543 Derivative Containing Aliphatic Side Chain.

The PF-543 is known as a potent and selective inhibitor of sphingosine kinase (SK) 1 amongst all the SK inhibitors known to date. In a recently reported study by Pfizer on the synthesis of PF-543 derivatives and the SK inhibitory effects, the introduction of propyl moiety into sulfonyl group of PF-543 in the case of 26b revealed an excellent result of 1.7 nM of IC50 of SK1, suggesting the potential substitution of chain structure for benzenesulfonyl structure. In the present work, we aimed for identification of antitumor activity and inhibitory effects of PF-543 derivative containing aliphatic long chain (similar to known SK inhibitors) on SK1. The synthesized compound 2 exhibited an inhibitory effect on SK1 in a manner similar to that of PF-543; the PF-543 derivative manifested similar antitumor activity on HT29, HCT116 (colorectal cancer cell line), and AGS (gastric cancer cell line) cells. Also, from the docking study conducted with PF-543 and compound 2, it was apparent that the aliphatic chain in compound 2 could probably replace benzenesulfonyl structure of PF-543.

Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype.

Metabolic reprogramming during macrophage polarization supports the effector functions of these cells in health and disease. Here, we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the pyruvate dehydrogenase-mediated conversion of cytosolic pyruvate to mitochondrial acetyl-CoA, functions as a metabolic checkpoint in M1 macrophages. Polarization was not prevented by PDK2 or PDK4 deletion but was fully prevented by the combined deletion of PDK2 and PDK4; this lack of polarization was correlated with improved mitochondrial respiration and rewiring of metabolic breaks that are characterized by increased glycolytic intermediates and reduced metabolites in the TCA cycle. Genetic deletion or pharmacological inhibition of PDK2/4 prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus IFN-γ). Transplantation of PDK2/4-deficient bone marrow into irradiated wild-type mice to produce mice with PDK2/4-deficient myeloid cells prevented M1 polarization, reduced obesity-associated insulin resistance, and ameliorated adipose tissue inflammation. A novel, pharmacological PDK inhibitor, KPLH1130, improved high-fat diet-induced insulin resistance; this was correlated with a reduction in the levels of pro-inflammatory markers and improved mitochondrial function. These studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages, which could potentially be exploited as a novel therapeutic target for obesity-associated metabolic disorders and other inflammatory conditions.

Inhibitory Effect of KP-A038 on Osteoclastogenesis and Inflammatory Bone Loss Is Associated With Downregulation of Blimp1.

Excessive osteoclastic activity results in pathological bone resorptive diseases, such as osteoporosis, periodontitis, and rheumatoid arthritis. As imidazole-containing compounds possess extensive therapeutic potential for the management of diverse diseases, we synthesized a series of imidazole derivatives and investigated their effects on osteoclast differentiation and function. In the present study, we found that a novel imidazole derivative, KP-A038, suppressed receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis and bone-resorbing activity in vitro and attenuated lipopolysaccharide (LPS)-induced bone destruction in vivo. KP-A038 significantly inhibited the induction of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and the expression of its target genes, including tartrate-resistant acid phosphatase (Acp5), cathepsin K (Ctsk), dendritic cell-specific transmembrane protein (Dcstamp), and matrix metallopeptidase 9 (Mmp9). KP-A038 upregulated the expression of negative regulators of osteoclast differentiation, such as interferon regulatory factor-8 (Irf8) and B-cell lymphoma 6 (Bcl6). Consistently, KP-A038 downregulated the expression of B lymphocyte-induced maturation protein-1 (Blimp1 encoded by Prdm1), a repressor for Irf8 and Bcl6. Moreover, administration of KP-A038 reduced LPS-induced bone erosion by suppressing osteoclast formation in vivo. Thus, our findings suggest that KP-A038 may serve as an effective therapeutic agent for the treatment and/or prevention of bone loss in pathological bone diseases, including osteoporosis and periodontitis.