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CX3CL1 and its unique receptor, CX3CR1, are leukocyte migration factors and are involved in the pathogenesis and progression of many inflammatory diseases and malignancies. The CX3CL1-CX3CR1 axis induces a variety of responses, including cell proliferation, migration, invasion, and apoptosis resistance. CX3CL1 is a transmembrane protein, and proteolysis generates a soluble form. The membrane and soluble forms of CX3CL1 exhibit different functions, but both bind to the chemokine receptor CX3CR1. The CX3CL1-CX3CR1 axis is a chemokine system that has attracted attention not only as a therapeutic target but also as a potentially useful diagnostic and prognostic marker for disease. Many studies have reported that the CX3CL1-CX3CR1 axis is involved in disease progression, but more recently there are scattered reports suggesting that it is involved in disease suppression. In this article, we summarize the latest findings on the pathophysiological role of the CX3CL1-CX3CR1 axis, with a particular focus on renal disease, cardiovascular disease, and cancer.

Skin-wound healing is an orchestrated biological phenomena consisting of three sequential phases, inflammation, proliferation, and maturation. Many biological substances are involved in the process of wound repair, and this short and simplified overview of wound healing can be adopted to determine wound vitality or wound age in forensic medicine. With the development of genetically engineered animals, essential molecules for skin-wound healing have been identified. Especially, cytokines, and growth factors are useful candidates and markers for the determination of wound vitality or age. Moreover, bone marrow-derived progenitor cells would give significant information to wound age determination. In this review article, some interesting observations are presented, possibly contributing to the future practice of forensic pathologists.

Inflammatory mediators such as cytokines and chemokines are crucially involved in the development of abdominal aortic aneurysm (AAA). Here we report that CaCl 2 application into abdominal aorta induces AAA with intra-aortic infiltration of macrophages as well as enhanced expression of chemokine (C-C motif) ligand 3 (CCL3) and MMP-9. Moreover, infiltrating macrophages express C-C chemokine receptor 5 (CCR5, a specific receptor for CCL3) and MMP-9. Both Ccl3 −/− mice and Ccr5 −/− but not Ccr1 −/− mice exhibit exaggerated CaCl 2 -inducced AAA with augmented macrophage infiltration and MMP-9 expression. Similar observations are also obtained on an angiotensin II-induced AAA model. Immunoneutralization of CCL3 mimics the phenotypes observed in CaCl 2 -treated Ccl3 −/− mice. On the contrary, CCL3 treatment attenuates CaCl 2 -induced AAA in both wild-type and Ccl3 −/− mice. Consistently, we find that the CCL3–CCR5 axis suppresses PMA-induced enhancement of MMP-9 expression in macrophages. Thus, CCL3 can be effective to prevent the development of CaCl 2 -induced AAA by suppressing MMP-9 expression. Inflammatory cytokines and chemokines are involved in the development of abdominal aortic aneurysm (AAA). Here the authors show that CCL3 prevents the development of CaCl 2 -induced AAA by suppressing MMP-9 expression.

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We investigated the dynamics of the gene expression of M1 and M2 macrophage markers during skin wound healing in mice. Expression of M1-macrophage markers, such as Il12a, Tnf, Il6, Il1b, and Nos2 was upregulated after wounding and peaked at 1 or 3 days after injury, and that of M2-macrophage markers such as Mrc1, Cd163, Ccl17, Arg, and Tgfb1, peaked at 6 days after injury. Consistent with these findings, using triple-color immunofluorescence analysis revealed that F4/80 + CD80 + M1 macrophages were more abundant than F4/80 + CD206 + M2 macrophages on day 3 in mouse wound specimens, and that M2 macrophages were prominently detected in day 6 wounds. For application in forensic practice, we examined macrophage polarization using human wound specimens. The average ratios of CD68 + iNOS + M1 macrophages to CD68 + CD163 + M2 macrophages (M1/M2 ratios) were greater than 2.5 for the wounds aged 2–5 days. Out of 11 wounds aged 1–5 days, five samples had the M1/M2 ratios of > 3.0. These observations propose that the M1/M2 ratios of 3.0 would indicate a wound age of 1–5 days as the forensic opinion. This study showed that M1 and M2 macrophages in human skin wound might be a promising marker for wound age determination.

Over-expression of transmembrane serine protease 4 (TMPRSS4), which promotes epithelial-to-mesenchymal transition and cancer cell invasion, is associated with poor prognosis in patients with gastric cancer. This study aimed to develop a new anti-TMPRSS4 small interfering RNA (siRNA) therapeutic strategy by engineering lipid nanoparticles (LNPs). The biodistribution and anti-tumor effect of anti-TMPRSS4-siRNA loaded LNPs were evaluated in vitro and in vivo in mice with gastric cancer tumors (subcutaneous xenograft NUGC-3 cell tumors). LNPs demonstrated enhanced accumulation in the tumor compared with naked siRNA. A significant reduction in gastric cancer tumor growth was observed in mice undergoing combination therapy with LNPs and fluorouracil (5-FU) compared to mice receiving 5-FU alone. Anti-TMPRSS4-siRNA loaded LNPs may be considered a promising therapeutic modality for gastric cancer.

Hydroxynitrile lyase (HNL) catalyzes the degradation of cyanohydrins and causes the release of hydrogen cyanide (cyanogenesis). HNL can enantioselectively produce cyanohydrins, which are valuable building blocks for the synthesis of fine chemicals and pharmaceuticals, and is used as an important biocatalyst in industrial biotechnology. Currently, HNLs are isolated from plants and bacteria. Because industrial biotechnology requires more efficient and stable enzymes for sustainable development, we must continuously explore other potential enzyme sources for the desired HNLs. Despite the abundance of cyanogenic millipedes in the world, there has been no precise study of the HNLs from these arthropods. Here we report the isolation of HNL from the cyanide-emitting invasive millipedeChamberlinius hualienensis, along with its molecular properties and application in biocatalysis. The purified enzyme displays a very high specific activity in the synthesis of mandelonitrile. It is a glycosylated homodimer protein and shows no apparent sequence identity or homology with proteins in the known databases. It shows biocatalytic activity for the condensation of various aromatic aldehydes with potassium cyanide to produce cyanohydrins and has high stability over a wide range of temperatures and pH values. It catalyzes the synthesis of (R)-mandelonitrile from benzaldehyde with a 99% enantiomeric excess, without using any organic solvents. Arthropod fauna comprise 80% of terrestrial animals. We propose that these animals can be valuable resources for exploring not only HNLs but also diverse, efficient, and stable biocatalysts in industrial biotechnology.

Matrix metalloproteinase-9 (MMP-9) is involved in tissue remodeling and in skin wound healing. The present study focuses on the MMP-9 expression in epidermal wound healing within 1 h after injury, to test whether MMP-9 can be used to estimate the time of injury in forensic practice. A sample consisting of 5 individuals undergoing surgery was analyzed. With the consent of the patients, sections of skin were removed from the surgical wound at predefined time intervals. For each subject, 8 sections were taken, one for each time interval defined at 0 ‘- 1’ − 3 ‘- 5’ − 10 ‘- 15’ − 30 ‘- 60’ minutes. The specimens were immunostained with MMP-9, and the number of positively stained cells was examined. The number of positively stained cells showed an increasing trend as a function of time. Less than 30 positively stained cells were found in all cases within 3 min. At the post-infliction time of 5 min, the number of positively stained cells exceeded 30 in 3 out of 5 cases. The number of MMP-positive cells exceeded 40 in all cases in over 10 min. In the light of these results, the count of MMP-9 positive cells might be a useful marker in the wound-age estimation within 1 h in forensic setting. More research is required to collect more samples and to compare samples from the hyperacute phase with those from several days after injury.

We report the synthesis, phase-transition behavior, and mesophase structures of the first homologous series of thioether-linked liquid crystal (LC) trimers, 4,4′-bis[ω-(4-cyanobiphenyl-4′-ylthio)alkoxy]biphenyls (CBSnOBOnSCB with a wide range of spacer carbon numbers, n = 3–11). All CBSnOBOnSCB homologs exhibited LC phases. Interestingly, even-n and odd-n homologs showed monotropic layered smectic A (SmA) and pseudo-layered twist-bend nematic (NTB) phases, respectively, below a nematic (N) phase. This alternate formation, which depends on spacer chain parity, is attributed to different average molecular shapes, which are associated with the relative orientations of the biphenyl moieties: linear and bent shapes for even-n and odd-n homologs, respectively. In addition, X-ray diffraction analysis indicated a strong cybotactic N phase tendency, with a triply intercalated structure. The phase-transition behavior and LC phase structures of thioether-linked CBSnOBOnSCB were compared with those of the all-ether-linked classic LC trimers CBOnOBOnOCB. Overall, thioether linkages endowed CBSnOBOnSCB with a monotropic LC tendency and lowered phase-transition temperatures, compared to those of CBOnOBOnOCB, for the same n. This is attributed to enhanced flexibility and bending (less molecular anisotropy) of the molecules, caused by the greater bond flexibility and smaller inner bond angles of the C–S–C bonds, compared to those of the C–O–C bonds.

The potential role of macrophages in pulmonary fibrosis (PF) prompted us to evaluate the roles of CX3CR1, a chemokine receptor abundantly expressed in macrophages during bleomycin (BLM)-induced PF. Intratracheal BLM injection induced infiltration of leukocytes such as macrophages into the lungs, which eventually resulted in fibrosis. CX3CR1 expression was mainly detected in the majority of macrophages and in a small portion of α-smooth muscle actin-positive cells in the lungs, while CX3CL1 was expressed in macrophages. BLM-induced fibrotic changes in the lungs were reduced without any changes in the number of leukocytes in Cx3cr1 −/− mice, as compared with those in the wild-type (WT) mice. However, intrapulmonary CX3CR1 + macrophages displayed pro-fibrotic M2 phenotypes; lack of CX3CR1 skewed their phenotypes toward M1 in BLM-challenged lungs. Moreover, fibrocytes expressed CX3CR1, and were increased in BLM-challenged WT lungs. The number of intrapulmonary fibrocytes was decreased in Cx3cr1 −/− mice. Thus, locally-produced CX3CL1 can promote PF development primarily by attracting CX3CR1-expressing M2 macrophages and fibrocytes into the lungs.