Peri-implant infections have been reported as one of the major complications that lead to the failure of orthopedic implants. An ideal solution to the peri-implant infection is to locally deliver antimicrobial agents through the implant surface. The rising problem of infections caused by multiple antibiotic-resistant bacteria makes traditional antibiotics less desirable for the prevention of peri-implant infections. One of the promising alternatives is the family of antimicrobial peptides (AMPs). In this study, we report the local delivery of AMPs through the nanotubular structure processed on titanium surface. Self-organized and vertically oriented TiO2 nanotubes, about 80 nm in diameter and 7 μm thick, were prepared by the anodization technique. HHC-36 (KRWWKWWRR), one of the most potent broad-spectrum AMPs, was loaded onto the TiO2 nanotubes via a simple vacuum-assisted physical adsorption method. Antimicrobial activity testing against Gram-positive bacterium, Staphylococcus aureus, demonstrated that this AMP-loaded nanotubular surface could effectively kill the bacteria (≈ 99.9% killing) and reduce the total bacterial number adhered to the surface after 4 h of culture. In vitro AMP elution from the nanotubes was investigated using liquid chromatography-mass spectrometry (LC-MS). The release profiles strongly depended on the crystallinity of the TiO2 nanotubes. Anatase TiO2 nanotubes released significantly higher amounts of AMP than amorphous nanotubes during the initial burst release stage. Both followed almost the same slow release profile from 4 h up to 7 days. Despite the differences in release kinetics, no significant difference was observed between these two groups in bactericidal efficiency.

Cancer cachexia is a kind of whole-body metabolic disorder syndrome accompanied by severe wasting of muscle tissue in which cancer exosomes may be involved. Analysis of clinical samples showed that the serum exosome concentrations were correlated with the development of cancer cachexia. Exosomes secreted by C26 cells could decrease the diameter of C2C12 myotubes in vitro and decrease mouse muscle strength and tibialis anterior (TA) muscle weight in vivo . GW4869, an inhibitor of exosome excretion, ameliorated muscle wasting in C26 tumor-bearing mice. MicroRNA (miRNA) sequencing (miRNA-seq) analysis suggested that miR-195a-5p and miR-125b-1-3p were richer in C26 exosomes than in exosomes secreted from MC38 cells (non-cachexic). Both miR-195a-5p and miR-125b-1-3p mimics could induce atrophy of C2C12 myoblasts. Downregulation of Bcl-2 and activation of the apoptotic signaling pathway were observed in C2C12 myoblasts transfected with miR-195a-5p and miR-125b-1-3p mimics, in the gastrocnemius muscle of C26 tumor-bearing mice and in the TA muscle injected with C26 exosomes. Results of dual-luciferase assay confirmed the targeting of miR-195a-5p/miR-125b-1-3p to Bcl-2. Overexpression of Bcl-2 successfully reversed atrophy of C2C12 myoblasts induced by the two miRNA mimics. These results suggested that cancer exosome enriched miRNAs might induce muscle atrophy by targeting Bcl-2-mediated apoptosis.

Background Cancer cachexia is a multifactorial debilitating syndrome that directly accounts for more than 20% of cancer deaths while there is no effective therapeutic approach for treatment of cancer cachexia. Carnosol (CS) is a bioactive diterpene compound present in Lamiaceae spp., which has been demonstrated to have antioxidant, anti‐inflammatory, and anticancer properties. But its effects on cancer cachexia and the possible mechanism remain a mystery. Methods The in vitro cell models of C2C12 myotube atrophy and 3T3‐L1 mature adipocyte lipolysis were used to check the activities of CS and its synthesized analogues. C26 tumour‐bearing BALB/c mice were applied as the animal model to examine their therapeutic effects on cancer cachexia in vivo. Levels of related signal proteins in both in vitro and in vivo experiments were examined using western blotting to study the possible mechanisms. Results Carnosol and its analogues [dimethyl‐carnosol (DCS) and dimethyl‐carnosol‐D6 (DCSD)] alleviated myotube atrophy of C2C12 myotubes and lipolysis of 3T3‐L1 adipocytes in vitro. Interestingly, CS and its analogues exhibited stronger inhibitive effects on muscle atrophy induced by tumour necrosis factor‐α (TNF‐α) (CS, P < 0.001; DCS, P < 0.001; DCSD, P < 0.001) in C2C12 myoblasts than on muscle atrophy induced by IL‐6 (CS, P < 0.05; DCS, P = 0.08; DCSD, P < 0.05). In a C26 tumour‐bearing mice model, administration of CS or its analogue DCSD significantly prevented body weight loss without affecting tumour size. At the end of the experiment, the body weight of mice treated with CS and DCSD was significantly increased by 11.09% (P < 0.01) and 11.38% (P < 0.01) compared with that of the C26 model group. CS and DCSD also improved the weight loss of epididymal adipose tissue in C26 model mice by 176.6% (P < 0.01) and 48.2% (P < 0.05) increase, respectively. CS and DCSD treatment partly preserved gastrocnemius myofibres cross‐sectional area. CS treatment decreased the serum level of TNF‐α (−95.02%, P < 0.01) but not IL‐6 in C26 tumour‐bearing mice. Inhibition on NF‐κB and activation of Akt signalling pathway were involved in the ameliorating effects of CS and its analogues on muscle wasting both in vitro and in vivo. CS and its analogues also alleviated adipose tissue loss by inhibiting NF‐κB and AMPK signalling pathways both in vitro and in vivo. Conclusions CS and its analogues exhibited anticachexia effects mainly by inhibiting TNF‐α/NF‐κB pathway and decreasing muscle and adipose tissue loss. CS and its analogues might be promising drug candidates for the treatment of cancer cachexia.

Plant derived compounds, as potentially safe and effective skin lightening agents (SLAs), have attracted great attention from many researchers. Curcumin is a plant-derived polyphenol, which has been reported to suppress melanogenesis in B16 melanoma cells. However, little is known about whether curcumin affects melanogenesis in cultured human melanocytes. In addition, the molecular mechanism for the antimelanogenic effects of curcumin remains largely unknown. The present study assessed the effects of curcumin on melanin synthesis, cellular tyrosinase activity, the expression of melanogenesis-related proteins (microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein 1 and 2 (TRP-1, TRP-2)), and activation of melanogenesis-regulating signals including phosphatidylinositol 3-kinase (PI3K)/Akt/ glycogen synthase kinase 3 (GSK 3β), extracellular signal-regulated kinase (ERK) and p38 MAPK in human melanocytes. The results showed that the melanin content and tyrosinase activity, as well as the expression of melanogenesis-related proteins in human melanocytes, were significantly inhibited by curcumin in a dose dependent manner. In addition, PI3K/Akt/ GSK 3β, ERK and p38 MAPK were activated by curcumin, while inhibitors of these signals attenuated the inhibitory effects of curcumin on melanogenesis. These results suggest that curcumin inhibits melanogenesis in human melanocytes through activation of Akt/GSK 3β, ERK or p38 MAPK signaling pathways.

The ontogeny of macrophages in most organ/tissues in human body has been proven. Due to the limited number and inaccessibility of synovial macrophages (SM), the origin of SM has not been fully illuminated. The objective of this study was designed to investigate the ontogeny of SM and to evaluate the role of SM from different origins in arthritis. Two origins of SM, embryonic SM (ESM) and bone marrow SM (BMSM) were identified in Cx3cr1-EGFP mice, CCR2 −/− mice and bone marrow (BM) chimera model by using a stringent sorting strategy. The cellular features, including dynamic total cell number, in situ proliferation, phagocytosis and expressions of pro-inflammatory and anti-inflammatory genes, of ESM and BMSM were compared. In addition, ESM and BMSM showed different expression patterns in Rheumatoid Arthritis (RA) patients' synovium and during the developmental process of collagen-induced arthritis (CIA) mice. Taken together, these results demonstrated that the SM at least has two origins, ESM and BMSM. The different cellular property and dynamic expression patterns in RA patients/CIA mice highlight the notion that ESM and BMSM might play different role in arthritis.

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Recent studies suggest that Src family kinase (SFK) plays important roles in systemic sclerosis and pulmonary fibrosis. However, how SFKs contributed to the pathogenesis of liver fibrosis remains largely unknown. Here, we investigated the role of Fyn, a member of SFK, in hepatic stellate cell (HSC) activation and liver fibrosis, and evaluated the anti-fibrotic effects of Saracatinib, a clinically proven safe Fyn inhibitor. Fyn activation was examined in human normal and fibrotic liver tissues. The roles of Fyn in HSC activation and liver fibrosis were evaluated in HSC cell lines by using Fyn siRNA and in Fyn knockout mice. The effects of Saracatinib on HSC activation and liver fibrosis were determined in primary HSCs and CCl 4 induced liver fibrosis model. We showed that the Fyn was activated in the liver of human fibrosis patients. TGF-β induced the activation of Fyn in HSC cell lines. Knockdown of Fyn significantly blocked HSC activation, proliferation, and migration. Fyn deficient mice were resistant to CCl 4 induced liver fibrosis. Saracatinib treatment abolished the activation of Fyn, downregulated the Fyn/FAK/N-WASP signaling in HSCs, and subsequently prevented the activation of HSCs. Saracatinib treatment significantly reduced the severity liver fibrosis induced by CCl 4 in mice. In conclusions, our findings supported the critical role of Fyn in HSC activation and development of liver fibrosis. Fyn could serve as a promising drug target for liver fibrosis treatment. Fyn inhibitor Saracatinib significantly inhibited HSC activation and attenuated liver fibrosis in mouse model.

Objective. As a first-line treatment for non-small cell lung cancer (NSCLC), the efficacy of chemotherapy is still unsatisfactory. Moxibustion has been shown to improve the side effects of radiotherapy and chemotherapy and regulate immune function. This study aimed to explore the antitumor effects and potential mechanisms of combinatorial cisplatin and moxibustion treatment for NSCLC by targeting the tumor microenvironment. Methods. Lewis lung cancer (LLC)-bearing mice were induced and treated with cisplatin or/and moxibustion at ST36 (Zusanli), and the growth, weight, and area of the tumor were evaluated. The numbers of various T cell subsets and myeloid cells in the tumor were assessed by flow cytometry, and the gene expression of related markers and cytokines was detected with real-time quantitative polymerase chain reaction (RT-qPCR). In addition, the tumor vascular structure was investigated using CD31 and α-smooth muscle actin (α-SMA) immunofluorescence staining. The expression of the vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) was detected by immunohistochemical staining. Results. Both cisplatin and moxibustion inhibited LLC tumor growth and reduced both the tumor area and weight, with the combinatorial therapy showing superior outcomes. Moxibustion upregulated the infiltration of CD4+ T cells and Th1 cells in the tumor, and the combinatorial therapy increased the proportion of CD8+ cytotoxic T cells (CTLs), CD4+T cells, Th1, Th9 cells, and M1 macrophages, as well as the expression of Cd69, Ifng, and Cd86 mRNA. The combinatorial therapy improved vascular normalization by increasing both the microvessel density (MVD) and pericyte coverage (α-SMA area density) and inhibiting the expression of the VEGF. Conclusions. Combinatorial cisplatin and moxibustion treatment inhibited the LLC tumor growth by mechanisms related to the improvement of the tumor immune microenvironment and vascular normalization, providing an effective combinatorial therapy beneficial for patients with NSCLC.