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The establishment of an osseointegration is crucial for the long-term stability and functionality of implant materials, and early angiogenesis is the key to successful osseointegration. However, the bioinertness of titanium implants affects osseointegration, limiting their clinical application. In this study, inspired by the rapid polarization of macrophages following the phagocytosis of bacteria, we developed bacteroid cerium oxide particles; these particles were composed of CeO 2 and had a size similar to that of Bacillus (0.5 μ m). These particles were constructed on the implant surfaces using a hydrothermal method. In vitro experiments demonstrated that the particles effectively decreased the reactive oxygen species (ROS) levels in macrophages (RAW264.7). Furthermore, these particles exerted effects on M1 macrophage polarization, enhanced nitric oxide (NO) secretion to promote vascular regeneration, and facilitated rapid macrophage transition to the M2 phenotype. Subsequently, the particles facilitated human umbilical vein endothelial cell (HUVEC) migration. In vivo studies showed that these particles rapidly stimulated innate immune responses in animal models, leading to enhanced angiogenesis around the implant and improved osseointegration. In summary, the presence of bacteroid cerium oxide particles on the implant surface regulated and accelerated macrophage polarization, thereby enhancing angiogenesis during the immune response and improving peri-implant osseointegration., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

RNA interference (RNAi)-based gene therapy that promotes anabolic bone formation is an effective approach for addressing osteoporosis. However, the selection of target gene and tissue-specific delivery systems has hindered the progression of this strategy. In this study, we identified casein kinase-2 interacting protein-1 encoding gene (Ckip-1), a negative regulator of bone formation, as an effective target of small interfering RNAs (siRNAs) for improving bone mass. Moreover, an impressive (DSS) 6 -Liposome (Lipos) nanoparticle system that could target the bone formation surface was synthesized to enhance the delivery of Ckip-1 siRNA to osteogenic lineage cells. The in vitro results confirmed that the (DSS) 6 -Lipos system could efficaciously improve the intracellular delivery of Ckip-1 siRNA without obvious cell toxicity. The in vivo application of the delivery system showed specific accumulation of siRNA in osteogenic cells located around the bone formation surface. Bone-related analysis indicated increased bone mass and improved bone microarchitecture in mice with ovariectomy-induced osteoporosis. Moreover, the biomechanical characteristics of the tibia were enhanced significantly, indicating increased resistance to fragile fracture induced by osteoporosis. Thus, (DSS) 6 -Lipos-Ckip-1 siRNA-based osteoanabolic therapy may be a promising option for the treatment of osteoporosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Based on the action of small molecule compounds, the efficiency of differentiation of mouse primary hepatocytes into insulin-producing cells (IPCs) was improved by changing the expression of miR-124-2p. Hepatocytes were transfected with microRNA-124-3p (miR-124-3p) mimic or inhibitor, followed by a chemical-defined culture system for maturation of IPCs. Then, detect the expression of insulin-related genes and protein and insulin secretion of each stage during differentiation. The expression of Foxa2, PDX1, NeuroD, insulin1, and insulin2 in IPCs in the miR-124-3p inhibition expression group was significantly upregulated, while the results were opposite in the miR-124-3p overexpression group. The results of cell immunofluorescence and glucose stimulation in vitro of the miR-124-3p inhibition expression group showed that the expression of insulin, PDX1, and C-peptide was increased, and the differentiation efficiency was higher than those of the control group and overexpression group. The primary mouse hepatocytes were successfully reprogrammed into IPCs by small-molecule compounds. We found that miR-124-3p plays a negative regulatory role in the differentiation of hepatocytes into IPCs in vitro. Inhibition of miR-124-3p expression significantly increased the expression of FOXA2 and PDX1, promoted the differentiation of hepatocytes into IPCs, and increased the induction efficiency., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Gastric cancer is one of the most fatal cancers worldwide. The incidence and death rates are still increasing for gastric cancer. Increasing studies have shown that proviral insertion in murine lymphomas 2 (PIM2) functions as critical regulator of multiple cancers. However, it remains unknown whether and how PIM2 regulates gastric cancer progression. In this study, PIM2 was increased in the gastric cancer tissues of patients. Patients with high PIM2 expression levels had significantly shorter survival than those with low PIM2 expression. PIM2 knockdown reduced proliferation, migration and invasion in vitro by up-regulating E-cadherin, and down-regulating N-cadherin and Vimentin. Knockdown of PIM2 induced apoptosis in gastric cancer cells, which was regulated by endoplasmic reticulum (ER) stress, as evidenced by the increased expression levels of Activating transcription factor (ATF) 6, ATF4, X-box- binding protein-1 (XBP-1) and C/EBP homologous protein (CHOP). In addition, our data showed that PIM2 silence induced reactive oxygen species (ROS) production, leading to the activation of c-Jun N-terminal kinase (JNK). Importantly, we found that PIM2 knockdown-induced apoptosis and ER stress could be abolished by reducing reactive oxygen species (ROS) generation. In vivo, PIM2 knockdown showed a significant reduction in SGC-7901 xenograft tumor size. In summary, our findings provided experimental evidence that PIM2 might function as an important oncogene in gastric cancer, which supplied promising target for developing new therapeutic strategy in gastric cancer., (Copyright © 2018. Published by Elsevier Inc.)

Runx1 is a key factor in the generation and maintenance of hematopoietic stem cells. Improper expression and mutations in Runx1 are frequently implicated in human leukemia. Here, we report that CHIP, the carboxyl terminus of Hsc70-interacting protein, also named Stub1, physically interacts with Runx1 through the TPR and Charged domains in the nucleus. Over-expression of CHIP directly induced Runx1 ubiquitination and degradation through the ubiquitin-proteasome pathway. Interestingly, we found that CHIP-mediated degradation of Runx1 is independent of the molecular chaperone Hsp70/90. Taken together, we propose that CHIP serves as an E3 ubiquitin ligase that regulates Runx1 protein stability via an ubiquitination and degradation mechanism that is independent of Hsp70/90.

Vanilloid receptor subtype 1 (VR1) was cloned as a capsaicin receptor from neuronal cells of dorsal root ganglia. VR1 was subsequently found in a few non-neuronal tissues, including skeletal muscle [Onozawa et al., Tissue distribution of capsaicin receptor in the various organs of rats, Proc. Jpn. Acad. Ser. B 76 (2000) 68-72]. We confirmed the expression of VR1 in muscle cells using the RT-PCR method and Western blot analysis. Immunostaining studies with a confocal microscope and an electron microscope indicated that VR1 was present in the sarcoplasmic reticulum (SR), a store of Ca2+. The SR releases Ca2+ to cause a contraction when a muscle is excited. However, SR still releases a small amount of Ca2+ under relaxed conditions. We found that this leakage was enhanced by capsaicin and was antagonized by capsazepine, a capsaicin blocker, indicating that leakage of Ca2+ occurs through a channel composed of VR1.

FK506 binding protein (FKBP) is a cytosolic receptor for the immunosuppressive drug FK-506. The common isoform, FKBP12, was found to be associated with the calcium release channel (ryanodine receptor 1) of different species of vertebrate skeletal muscle, whereas 12.6, a novel FKBP isoform was found to be associated with canine cardiac ryanodine receptor (ryanodine receptor 2). Until recently, canine cardiac sarcoplasmic reticulum was considered to be the prototype for studying heart RyR2 and its interactions with FKBP. In this study, cardiac microsomes were isolated from diverse vertebrates: human, rabbit, rat, mice, dog, chicken, frog, and fish and were analyzed for their ability to bind or exchange with FKBP isoforms 12 and 12.6. Our studies indicate that RyR2 from seven out of the eight animals contain both FKBP12 and 12.6. Dog is the exception. It can now be concluded that the association of FKBP isoforms with RyR2 is widely conserved in the hearts of different species of vertebrates., (Copyright 2001 Academic Press.)

The ryanodine receptor (RyR)/calcium release channel isolated from skeletal muscle terminal cisternae (TC) of sarcoplasmic reticulum (SR) is tightly associated with FK506 binding protein of 12.0 kDa (FKBP12) (Jayaraman et al., (1992) J.Biol.Chem. 267, 9474-9477). In this study, we describe a new method of affinity chromatography for purifying the RyR from skeletal muscle SR based on: 1) its tight association with FKBP12; and 2) the finding that bound FKBP on the RyR can be exchanged with soluble FKBP12 (Timerman et al., (1995) J.Biol.Chem. 270, 2451-2459). Soluble glutathione S-transferase/FKBP12 (GST/FKBP12) fusion protein was first exchanged with bound FKBP12 on the RyR of TC. The TC were then solubilized with CHAPS and the complex of RyR.GST/FKBP12 was specifically adsorbed by glutathione Sepharose 4B and then eluted with glutathione. The RyR, purified by this method, has similar characteristics by SDS-PAGE, radioligand binding and immuno-reactivity as the RyR purified by multiple sequential column chromatography.