Cyclo His-Pro Attenuates Muscle Degeneration in Murine Myopathy Models.

Among the inherited myopathies, a group of muscular disorders characterized by structural and metabolic impairments in skeletal muscle, Duchenne muscular dystrophy (DMD) stands out for its devastating progression. DMD pathogenesis is driven by the progressive degeneration of muscle fibers, resulting in inflammation and fibrosis that ultimately affect the overall muscle biomechanics. At the opposite end of the spectrum of muscle diseases, age-related sarcopenia is a common condition that affects an increasing proportion of the elderly. Although characterized by different pathological mechanisms, DMD and sarcopenia share the development of progressive muscle weakness and tissue inflammation. Here, the therapeutic effects of Cyclo Histidine-Proline (CHP) against DMD and sarcopenia are evaluated. In the mdx mouse model of DMD, it is shown that CHP restored muscle contractility and force production, accompanied by the reduction of fibrosis and inflammation in skeletal muscle. CHP furthermore prevented the development of cardiomyopathy and fibrosis in the diaphragm, the two leading causes of death for DMD patients. CHP also attenuated muscle atrophy and functional deterioration in a mouse model of age-related sarcopenia. These findings from two different models of muscle dysfunction hence warrant further investigation into the effects of CHP on muscle pathologies in animal models and eventually in patients.

Inhibition of chloride intracellular channel protein 1 (CLIC1) ameliorates liver fibrosis phenotype by activating the Ca2+-dependent Nrf2 pathway.

Persistent damage to liver cells leads to liver fibrosis, which is characterized by the accumulation of scar tissue in the liver, ultimately leading to cirrhosis and serious complications. Because it is difficult to reverse cirrhosis once it has progressed, the primary focus has been on preventing the progression of liver fibrosis. However, studies on therapeutic agents for liver fibrosis are still lacking. Here, we investigated that the natural dipeptide cyclic histidine-proline (CHP, also known as diketopiperazine) shows promising potential as a therapeutic agent in models of liver injury by inhibiting the progression of fibrosis through activation of the Nrf2 pathway. To elucidate the underlying biological mechanism of CHP, we used the Cellular Thermal Shift Assay (CETSA)-LC-MS/MS, a label-free compound-based target identification platform. Chloride intracellular channel protein 1 (CLIC1) was identified as a target whose thermal stability is increased by CHP treatment. We analyzed the direct interaction of CHP with CLIC1 which revealed a potential interaction between CHP and the E228 residue of CLIC1. Biological validation experiments showed that knockdown of CLIC1 mimicked the antioxidant effect of CHP. Further investigation using a mouse model of CCl4-induced liver fibrosis in wild-type and CLIC1 KO mice revealed the critical involvement of CLIC1 in mediating the effects of CHP. Taken together, our results provide evidence that CHP exerts its anti-fibrotic effects through specific binding to CLIC1. These insights into the mechanism of action of CHP may pave the way for the development of novel therapeutic strategies for fibrosis-related diseases.

Cyclo(His-Pro): A further step in the management of steatohepatitis.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) have become the world's most common liver diseases, placing a growing strain on healthcare systems worldwide. Nonetheless, no effective pharmacological treatment has been approved. The naturally occurring compound cyclo histidine-proline (His-Pro) (CHP) is an interesting candidate for NAFLD management, given its safety profile and anti-inflammatory effects. Methods: Two different mouse models of liver disease were used to evaluate protective effects of CHP on disease progression towards fibrosis: a model of dietary NAFLD/NASH, achieved by thermoneutral housing (TN) in combination with feeding a western diet (WD), and liver fibrosis caused by repeated injections with carbon tetrachloride (CCl4). Results: Treatment with CHP limited overall lipid accumulation, lowered systemic inflammation, and prevented hyperglycaemia. Histopathology and liver transcriptomics highlighted reduced steatosis and demonstrated remarkable protection from the development of inflammation and fibrosis, features which herald the progression of NAFLD. We identified the extracellular signal-regulated kinase (ERK) pathway as an early mediator of the cellular response to CHP. Conclusions: CHP was active in both the preventive and therapeutic setting, reducing liver steatosis, fibrosis, and inflammation and improving several markers of liver disease. Impact and implications: Considering the incidence and the lack of approved treatments, it is urgent to identify new strategies that prevent and manage NAFLD. CHP was effective in attenuating NAFLD progression in two animal models of the disease. Overall, our work points to CHP as a novel and effective strategy for the management of NAFLD, fuelling optimism for potential clinical studies.

CycloZ Improves Hyperglycemia and Lipid Metabolism by Modulating Lysine Acetylation in KK-Ay Mice.

BACKGRUOUND: CycloZ, a combination of cyclo-His-Pro and zinc, has anti-diabetic activity. However, its exact mode of action remains to be elucidated. METHODS: KK-Ay mice, a type 2 diabetes mellitus (T2DM) model, were administered CycloZ either as a preventive intervention, or as a therapy. Glycemic control was evaluated using the oral glucose tolerance test (OGTT), and glycosylated hemoglobin (HbA1c) levels. Liver and visceral adipose tissues (VATs) were used for histological evaluation, gene expression analysis, and protein expression analysis. RESULTS: CycloZ administration improved glycemic control in KK-Ay mice in both prophylactic and therapeutic studies. Lysine acetylation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, liver kinase B1, and nuclear factor-κB p65 was decreased in the liver and VATs in CycloZ-treated mice. In addition, CycloZ treatment improved mitochondrial function, lipid oxidation, and inflammation in the liver and VATs of mice. CycloZ treatment also increased the level of ß-nicotinamide adenine dinucleotide (NAD+), which affected the activity of deacetylases, such as sirtuin 1 (Sirt1). CONCLUSION: Our findings suggest that the beneficial effects of CycloZ on diabetes and obesity occur through increased NAD+ synthesis, which modulates Sirt1 deacetylase activity in the liver and VATs. Given that the mode of action of an NAD+ booster or Sirt1 deacetylase activator is different from that of traditional T2DM drugs, CycloZ would be considered a novel therapeutic option for the treatment of T2DM.

Active Reinforcing Fiber of Cementitious Materials Using Crimped NiTi SMA Fiber for Crack-Bridging and Pullout Resistance.

This study investigated the recovery stress and bond resistance of cold drawn crimped SMA fiber using two different initial diameters of 1.0 and 0.7 mm. These characteristics are important to the active prestressing effect and crack-closing of the fiber. NiTi SMA fiber was used for the cold drawing, and then crimped shapes were manufactured with various wave heights. After that, tensile, recovery, and pullout tests were conducted. The cold drawn crimped fiber showed softening tensile behavior more clearly than the cold drawn straight fiber when not subjected to heating, whereas they had the same tensile behavior under heating. The recovery stress and the residual stress of the crimped fibers were less than those of the straight fiber with the same diameter. Moreover, crimped fibers with a large diameter and higher wave height would induce more recovery stress and residual stress. The maximum pullout resistance of the crimped fiber was a function of the wave depth, embedded length, yield strength, and flexural rigidity of the fiber.

Myricetin improves endurance capacity and mitochondrial density by activating SIRT1 and PGC-1α.

Robust mitochondrial respiration provides energy to support physical performance and physiological well-being, whereas mitochondrial malfunction is associated with various pathologies and reduced longevity. In the current study, we tested whether myricetin, a natural flavonol with diverse biological activities, may impact mitochondrial function and longevity. The mice were orally administered myricetin (50 mg/kg/day) for 3 weeks. Myricetin significantly potentiated aerobic capacity in mice, as evidenced by their increased running time and distance. The elevated mitochondrial function was associated with induction of genes for oxidative phosphorylation and mitochondrial biogenesis in metabolically active tissues. Importantly, myricetin treatment led to decreased PGC-1α acetylation through SIRT1 activation. Furthermore, myricetin significantly improved the healthspan and lifespan of wild-type, but not Sir-2.1-deficient, C. elegans. These results demonstrate that myricetin enhances mitochondrial activity, possibly by activating PGC-1α and SIRT1, to improve physical endurance, strongly suggesting myricetin as a mitochondria-activating agent.

Pellet feed adsorbed with the recombinant Lactococcus lactis BFE920 expressing SiMA antigen induced strong recall vaccine effects against Streptococcus iniae infection in olive flounder (Paralichthys olivaceus).

The aim of this study was to develop a fish feed vaccine that provides effective disease prevention and convenient application. A lactic acid bacterium (LAB), Lactococcus lactis BFE920, was modified to express the SiMA antigen, a membrane protein of Streptococcus iniae. The antigen was engineered to be expressed under the nisin promoter, which is induced by nisin produced naturally by the host LAB. Various sizes (40 ± 3.5 g, 80 ± 2.1 g, and 221 ± 2.4 g) of olive flounder (Paralichthys olivaceus) were vaccinated by feeding the extruded pellet feed, onto which the SiMA-expressing L. lactis BFE920 (1.0 × 10(7) CFU/g) was adsorbed. Vaccine-treated feed was administered twice a day for 1 week, and priming and boosting were performed with a 1-week interval in between. The vaccinated fish had significantly elevated levels of antigen-specific serum antibodies and T cell marker mRNAs: CD4-1, CD4-2, and CD8a. In addition, the feed vaccine significantly induced T cell effector functions, such as the production of IFN-γ and activation of the transcription factor that induces its expression, T-bet. When the flounder were challenged by intraperitoneal infection and bath immersion with S. iniae, the vaccinated fish showed 84% and 82% relative percent survival (RPS), respectively. Furthermore, similar protective effects were confirmed even 3 months after vaccination in a field study (n = 4800), indicating that this feed vaccine elicited prolonged duration of immunopotency. In addition, the vaccinated flounder gained 21% more weight and required 16% less feed to gain a unit of body weight compared to the control group. The data clearly demonstrate that the L. lactis BFE920-SiMA feed vaccine has strong protective effects, induces prolonged vaccine efficacy, and has probiotic effects. In addition, this LAB-based fish feed vaccine can be easily used to target many different pathogens of diverse fish species.

The effects of combined dietary probiotics Lactococcus lactis BFE920 and Lactobacillus plantarum FGL0001 on innate immunity and disease resistance in olive flounder (Paralichthys olivaceus).

The effects of a dietary probiotic mixture containing Lactococcus (Lc.) lactis BFE920 isolated from bean sprout and autochthonous Lactobacillus (Lb.) plantarum FGL0001 originally isolated from the hindgut of olive flounder (Paralichthys olivaceus) were investigated for the purpose of improving the probiotic effects of Lc. lactis BFE920 on the olive flounder. The immunostimulatory, disease protective, and weight gain effects of Lc. lactis BFE920 were significantly improved when olive flounder (average weight 37.5±1.26 g) were fed the probiotic mixture (log10 7.0 CFU each/g feed pellet) for 30 days. Flounder fed the mixture showed improved skin mucus lysozyme activity and phagocytic activity of innate immune cells compared to flounder fed a single probiotic agent or a control diet. While the levels of neutrophil activity in flounder fed the single probiotic agent or the mixture were similar, they were significantly higher than levels in a control group. Additionally, probiotic-fed flounder showed significantly increased expressions of IL-6, IL-8, and TNF-α in the intestine compared to the control group. Following a 30-day period of being fed probiotics or a control diet, the olive flounder were challenged with an i.p. injection of Streptococcus iniae (log10 6.0 CFU/fish). The groups fed the mixed probiotics, Lc. lactis BFE920, Lb. plantarum FGL0001, and the control diet had survival rates of 55%, 45%, 35%, and 20%, respectively. Flounder fed the probiotic mixture gained 38.1±2.8% more body weight compared to flounder fed the control diet during the 30-day study period. These data strongly suggest that a mixture of Lc. lactis BFE920 and Lb. plantarum FGL0001 may serve as an immunostimulating feed additive useful for disease protection in the fish farming industry.

Conceptual design of new polychromator on Thomson scattering system to measure Zeff.

To measure the Z(eff) with electron temperature (T(e)) and electron density (n(e)) profiles at the same time and the same position in the KSTAR tokamak, we design a new polychromator for Thomson scattering system that has additional function. The additional function is measuring bremsstrahlung intensity to calculate Z(eff) independent of Thomson signals. For this new polychromator, we design and fabricate a collimation lens set, and interference filter that has center wavelength of 523 nm and 2 nm FWHM. Finally, we change the lenses, detector diodes, and add the bremsstrahlung filter on the KSTAR edge Thomson scattering polychromator. Then this new polychromator was tested by Tungsten light and monochromator.

Personalized medicine in breast cancer: a systematic review.

The recent advent of "-omics" technologies have heralded a new era of personalized medicine. Personalized medicine is referred to as the ability to segment heterogeneous subsets of patients whose response to a therapeutic intervention within each subset is homogeneous. This new paradigm in healthcare is beginning to affect both research and clinical practice. The key to success in personalized medicine is to uncover molecular biomarkers that drive individual variability in clinical outcomes or drug responses. In this review, we begin with an overview of personalized medicine in breast cancer and illustrate the most encountered statistical approaches in the recent literature tailored for uncovering gene signatures.