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Titanium (Ti) alloys can be applied for biomaterials of artificial bone and bone repair. However, Ti alloys are bioinert materials, i.e., they have low bone formation ability. The heat treatments of Ti alloys promote bone formation ability, but the mechanism for the promotion has not been well understood. The effects of heat treatment of titanium, zirconium, niobium, and tantalum metals on the behavior of MC3T3-E1 osteoblast-like cells during culturing in vitro were examined. The specimens were heated at temperatures from 400 to 800 °C in the air for oxidation. The oxidation of the metal surface by the heat treatment changed its surface to hydrophilic and increased the surface roughness. Cell extension and proliferation were influenced not by metal species and their oxides but by surface roughness and wettability. The hydrophilicity and smooth surface improved cell extension and cell proliferation. Graphical abstract

The effective use of oxygen as an alloying element in Ti alloys is attractive due to the reduction of production cost and the increase in strength and hardness of the alloy. Although the oxygen addition in a Ti alloy increases strength and hardness, it may induce brittleness. An appropriate combination of alloying elements and thermomechanical treatment must be clarified for the use of oxygen as an alloying element. Ti-(0, 1.0, 2.0, 3.0)Mo-(0, 1.5, 3.0)O alloys were developed, and their microstructure and mechanical properties were examined. Ti-1Mo-3O alloy exhibited fine grains of α+β two phases having the tensile strength of 1,297 MPa with 15.5% for total strain at fracture. The Ti-1Mo-3O alloy has 1.5 times the tensile strength and the same total strain as the Ti-6Al-4V ELI alloy. Ti-(1.0, 2.0, 3.0)Mo-1.5O alloys also have excellent mechanical properties, with tensile strength of about 1,050–1,150 MPa and a total strain of about 20%–25%. In order to develop a high strength and moderate ductility Ti-Mo alloy using oxygen as an alloying element, the microstructure should have fine grains of α+β two phases with proper volume fraction of α and β phases and specific molybdenum concentration in β phase.

Cryptochrome proteins (CRYs), which can bind noncovalently to cofactor (chromophore) flavin adenine dinucleotide (FAD), occur widely among organisms. CRYs play indispensable roles in the generation of circadian rhythm in mammals. Transgenic mice (Tg mice), ubiquitously expressing mouse CRY1 having a mutation in which cysteine414 (the zinc-binding site of CRY1) being replaced with alanine, display unique phenotypes in their circadian rhythms. Moreover, male Tg mice exhibit symptoms of diabetes characterized by beta-cell dysfunction, resembling human maturity onset diabetes of the young (MODY). The lowered proliferation of β-cells is a primary cause of age-dependent β-cell loss. Furthermore, unusually enlarged duct-like structures developed prominently in the Tg mice pancreases. The duct-like structures contained insulin-positive cells, suggesting neogenesis of β-cells in the Tg mice. This review, based mainly on the author’s investigation of the unique features of Tg mice, presents reported results and recent findings related to molecular processes associated with mammalian cryptochromes, especially their involvement in the regulation of metabolism. New information is described with emphasis on the aspects of islet architecture, pancreatic β-cell dysfunction, and regeneration.

Heme serves as a prosthetic group in hemoproteins, including subunits of the mammalian mitochondrial electron transfer chain. The first enzyme in vertebrate heme biosynthesis, 5-aminolevulinic acid synthase 1 (ALAS1), is ubiquitously expressed and essential for producing 5-aminolevulinic acid (ALA). We previously showed that Alas1 heterozygous mice at 20–35 weeks (aged- A1 +/− s) manifested impaired glucose metabolism, mitochondrial malformation in skeletal muscle, and reduced exercise tolerance, potentially linked to autophagy dysfunction. In this study, we investigated autophagy in A1 +/− s and a sarcopenic phenotype in A1 +/− s at 75–95 weeks (senile- A1 +/− s). Senile- A1 +/− s exhibited significantly reduced body and gastrocnemius muscle weight, and muscle strength, indicating an accelerated sarcopenic phenotype. Decreases in total LC3 and LC3-II protein and Map1lc3a mRNA levels were observed in aged- A1 +/− s under fasting conditions and in Alas1 knockdown myocyte-differentiated C2C12 cells ( A1 KD-C2C12s) cultured in high- or low-glucose medium. ALA treatment largely reversed these declines. Reduced AMP-activated protein kinase (AMPK) signaling was associated with decreased autophagy in aged- A1 +/− s and A1 KD-C2C12s. AMPK modulation using AICAR (activator) and dorsomorphin (inhibitor) affected LC3 protein levels in an AMPK-dependent manner. Our findings suggest that heme deficiency contributes to accelerated sarcopenia-like defects and reduced autophagy in skeletal muscle, primarily due to decreased AMPK signaling.

Surface wettability is thought to influence the osteoconductivity of bone-substituting materials; however, the effects of surface wettability on osteoblast behavior are not well understood. In this study, we prepared both an as-polished pure titanium with a water contact angle (WCA) of 57° and heat-treated pure titanium with more hydrophobic surface and WCAs of 68°-98°. The effects of the surface wettability of pure titanium on osteoblast behaviors were evaluated by in vitro assays. Compared with the as-polished titanium, the proliferation rate of osteoblast increased on heat-treated titanium. This suggested that surface wettability affects osteoblast behaviors, meaning osteoconductivity is influenced by surface wettability.

In vertebrates, the initial step in heme biosynthesis is the production of 5-aminolevulinic acid (ALA) by ALA synthase (ALAS). ALA formation is believed to be the rate-limiting step for cellular heme production. Recently, several cohort studies have demonstrated the potential of ALA as a treatment for individuals with prediabetes and type-2 diabetes mellitus. These studies imply that a mechanism exists by which ALA or heme can control glucose metabolism. The ALAS1 gene encodes a ubiquitously expressed isozyme. Mice heterozygous null for ALAS1 (A1+/-s) experience impaired glucose tolerance (IGT) and insulin resistance (IR) beyond 20-weeks of age (aged A1+/-s). IGT and IR were remedied in aged A1+/-s by the oral administration of ALA for 1 week. However, the positive effect of ALA proved to be reversible and was lost upon termination of ALA administration. In the skeletal muscle of aged A1+/-s an attenuation of mitochondrial function is observed, coinciding with IGT and IR. Oral administration of ALA for 1-week brought about only a partial improvement in mitochondrial activity however, a 6-week period of ALA treatment was sufficient to remedy mitochondrial function. Studies on differentiated C2C12 myocytes indicate that the impairment of glucose metabolism is a cell autonomous effect and that ALA deficiency ultimately leads to heme depletion. This sequela is evidenced by a reduction of glucose uptake in C2C12 cells following the knockdown of ALAS1 or the inhibition of heme biosynthesis by succinylacetone. Our data provide in vivo proof that ALA deficiency attenuates mitochondrial function, and causes IGT and IR in an age-dependent manner. The data reveals an unexpected metabolic link between heme and glucose that is relevant to the pathogenesis of IGT/IR.

Surface morphology and composition of anodized Ti-15Zr-4Nb-4Ta alloys with nanotube were examined by using X-ray diffractometry and analytical scanning electron microscopy. The Ti alloy consisted of α and β phases. Anodizing to form nanotube on the Ti alloy was carried out using electrolyte of 0.2 wt.% NH4F and 2 Vol.% H2O in ethylene glycol under different potential at from 30 to 60V. SEM observation showed that nanotubes were vertically aligned on surface of the Ti alloy. Inner diameter of these nanotubes varied from 45 to 127 nm with increasing applied potential to the specimen from 30 to 60 V. Surface of the Ti alloy with nanotube was ragged due to the difference in dissolution rate of the internal structure of α and β phases.

The addition of oxygen or nitrogen in titanium alloys increases the hardness by the solid solution strengthening. Spinodal decomposition in titanium alloys is also the way to increase the hardness. This study aimed to reveal the effect of oxygen or nitrogen addition on spinodal decomposition in Ti-10at%V. Ti-10at%V-(0, 1, 3)at%O or N alloys were prepared by arc-melting. They were solution-treated at 1200 or 1300 °C for 0.6 ks and then quenched in iced brine. The solution treated specimens were aged at 375 °C. The increase of hardness was decreased by the oxygen or nitrogen addition in the alloys. The addition of nitrogen more suppressed the age-hardening than the case of oxygen addition. The modulated structure caused by spinodal decomposition in the laths was observed in all the aged specimens. The wavelength of spinodal decomposition of the aged specimens increased with the addition of oxygen or nitrogen, leading to a decrease in age-hardening by spinodal decomposition.

The surface wettability of biomaterials influences on osteoblast behavior and bone formation. In this research, the variation of wettability of nacre by heat treatments was examined. Plates of the nacre were fabricated from shells of the Akoya pearl oyster. The specimens were heated at 100, 200, 300, 400, 500, and 600 °C. Characterizations of the specimens during and after heat treatments were carried out using scanning electron microscopy, X-ray diffractometry, and thermogravimetry-differential thermal analysis. The water contact angle (WCA) of the specimen was measured to evaluate wettability. The color of nacre changed from iridescent color to brownish weak-iridescence by the heating at and over 300 °C. The nacre heated at and over 300 °C became brittle because organic substances in nacre, which acts as the glue between the aragonite platelets were evaporated by the heating. The WCA of the specimen was decreased with increasing heating temperature, which should be related to the decrease in the number of organic substances in nacre by the heating.

Oxidative DNA damage causes blocks and errors in transcription and replication, leading to cell death and genomic instability. Although repair mechanisms of the damage have been extensively analyzed in vitro, the actual in vivo repair processes remain largely unknown. Here, by irradiation with an UVA laser through a microscope lens, we have conditionally produced single-strand breaks and oxidative base damage at restricted nuclear regions of mammalian cells. We showed, in real time after irradiation by using antibodies and GFP-tagged proteins, rapid and ordered DNA repair processes of oxidative DNA damage in human cells. Furthermore, we characterized repair pathways by using repair-defective mammalian cells and found that DNA polymerase β accumulated at single-strand breaks and oxidative base damage by means of its 31-and 8-kDa domains, respectively, and that XRCC1 is essential for both polymerase β-dependent and proliferating cell nuclear antigen-dependent repair pathways of single-strand breaks. Thus, the repair of oxidative DNA damage is based on temporal and functional interactions among various proteins operating at the site of DNA damage in living cells.