Enhancing Osteogenic Potential: Controlled Release of Dopamine D1 Receptor Agonist SKF38393 Compared to Free Administration.

Osteoporosis is the most common metabolic bone disorder and is characterized by decreased bone density, which has a relationship with the quality of life among the aging population. Previous research has found that activation of the dopamine D1 receptor can improve bone mass formation. SKF38393 is an agonist of dopamine D1 receptors. However, as a small-molecule drug, SKF38393 is unstable and releases quickly. The aim of this study was to prototype polylactic-co-glycolic acid (PLGA)/SKF38393 microspheres and assess their potential osteogenic effects compared to those under the free administration of SKF38393. The cytocompatibility of PLGA/SKF38393 was determined via CCK-8 and live/dead cell staining; the osteogenic effects in vitro were determined with ALP and alizarin red staining, qRT-PCR, and Western blotting; and the in vivo effects were assessed using 25 Balb/c mice. We also used a PCR array to explore the possible signaling pathway changes after employing PLGA/SKF38393. Our experiments demonstrated that the osteogenic effect of D1Rs activated by the PLGA/SKF38393 microsphere was better than that under free administration, both in vitro and in vivo. According to the PCR array, this result might be associated with six signaling pathways (graphical abstract). Ultimately, in this study, we prototyped PLGA/SKF38393, demonstrated its effectiveness, and preliminarily analyzed its mechanism of action.

[Retracted] NCTD elicits proapoptotic and antiglycolytic effects on colorectal cancer cells via modulation of Fam46c expression and inhibition of ERK1/2 signaling.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the GAPDH control western blotting data shown in Fig. 2C were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes. Moreover, certain of the western blotting data shown internally within Fig. 4E and F appeared to be strikingly similar, even though the experiments portrayed in these Figure parts were intended to show the results obtained from different cell lines. Owing to the fact that the contentious data in the above article were already under consideration for publication, or had already been published, prior to its submission to Molecular Medicine Reports, and based on an overall lack in the confidence in the data, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 22: 774­782, 2020; DOI: 10.3892/mmr.2020.11151].

Sema3A accelerates bone formation during distraction osteogenesis in mice.

Distraction osteogenesis (DO) is a bone regeneration technique used to treat maxillofacial disorders, fracture nonunion, and large bone defects. It is well known for its amazing regenerative potential, but an extended consolidation period limits its clinical use. The interaction between the nervous system and bone regeneration has attracted great attention in recent years. Sema3A is a key axonal chemorepellent which has been proved to have bone-protective effects. In this article, we try to improve DO by local administration of Sema3A and explore the possible mechanisms. Forty wildtype, male, adult mice were divided into two groups after tibia osteotomy surgery. Sema3A or Saline was daily injected transcutaneous into the center of the distraction zone during the consolidation period. Micro-CT images were taken at 4, 6,8 and 10 weeks post-surgery; vascular density and biomechanical testing were performed at 10 weeks post-surgery. We also set up in vitro vessel growth assay to evaluate the effect of Sema3A on angiogenesis. Compared with the Saline group, Sema3A treatment significantly accelerated bone regeneration, improved angiogenesis and callus' biomechanical strength. At 10 weeks post-surgery, compared with the Saline group, the BV/TV, BMD, TMD increased by about 23%, 22%, 18% respectively, vascular density increased by about 49% in the Sema3A group. Histological images and western-blot showed decreased expression of VEGF-A and increased expression of Ang-1 at 4 weeks post-surgery in the Sema3A group. In vitro, Sema3A suppressed VEGF-induced angiogenesis but had little effect on Ang-induced angiogenesis. Conclusion: Sema3A could accelerate bone regeneration and improve angiogenesis during DO.

NCTD elicits proapoptotic and antiglycolytic effects on colorectal cancer cells via modulation of Fam46c expression and inhibition of ERK1/2 signaling.

Colorectal cancer is a digestive tract malignancy and the third leading cause of cancer­related mortality worldwide. Norcantharidin (NCTD), the demethylated form of cantharidin, has been reported to possess anticancer properties. Family­with­sequence­similarity­46c (Fam46c), a non­canonical poly(A) polymerase, has been reported to be critical in NCTD­mediated effects in numerous types of cancer, including hepatoma. In the current study, it was found that Fam46c expression was reduced in colorectal cancer tissues and cells. Treatment with NCTD was observed to significantly enhance apoptosis and inhibit glycolysis in colorectal cancer cells. In addition, Fam46c and cleaved caspase 3 expression levels were found to be increased in response to NCTD treatment, in contrast to tumor­specific pyruvate kinase M2 and phosphorylated ERK expression, which was reduced. Importantly, overexpression of Fam46c exerted similar effects as NCTD treatment on the apoptosis and glycolysis of colorectal cancer cells, whereas Fam46c knockdown strongly attenuated the effect of NCTD. Moreover, epidermal growth factor, which acts as an agonist of ERK1/2 signaling, weakened the effects of NCTD on colorectal cancer cells. Taken together, the results indicated that NCTD promotes apoptosis and suppresses glycolysis in colorectal cancer cells by possibly targeting Fam46c and inhibiting ERK1/2 signaling, hence suggesting that Fam46c may act as a tumor suppressor in colorectal cancer. Thus, the present study identified a novel therapeutic target of NCTD in the clinical treatment of colorectal cancer.

Resveratrol treatment promotes titanium implant osseointegration in diabetes mellitus rats.

Type II diabetes mellitus (T2DM) is the most common metabolic disorder; it is characterized by hyperglycemia and causes implant failure by influencing implant osseointegration. Resveratrol promotes bone formation, but it is unclear if resveratrol improves implant osseointegration. Thirty 12-week-old Sprague-Dawley rats were divided into control (CTL), diabetes mellitus (DM), and resveratrol treatment (DM + Res) groups. In the DM and DM + Res groups (n = 10 each), T2DM was induced via streptozotocin injections; the remaining 10 rats were considered the CTL group. Eight weeks after the insertion of a rod-like Ti implant with a 12-mm length and 1-mm diameter in the left leg, the rats were euthanized. We analyzed implant osseointegration using microcomputed tomography (micro-CT), histological analyses, and biomechanical tests. The parameters showed that T2DM negatively influenced implant osseointegration in the tibia. Compared to that in the DM group, the bone loss of peri-implant bone mass in the DM + Res group was decreased significantly. However, resveratrol still did not induce the same level of implant osseointegration as that observed in the CTL group according to the histological and micro-CT analyses. These results indicated that resveratrol reduced the influence of DM in implant osseointegration, resulting in increased peri-implant bone density, improved trabecular architecture, and enhanced biomechanical fixation.

Different bone sites-specific response to diabetes rat models: Bone density, histology and microarchitecture.

BACKGROUND AND PURPOSE: Diabetes mellitus (DM) is the most common metabolic disorder that is characterized by hyperglycemia, it can be categorized by T1DM and T2DM. T1DM is also reported to cause bone loss. However, most reports regarding this aspect of T1DM have only investigated a single site; a comparison of bone loss from different areas of the body is still lacking. METHODS: Thirty-five 12-week-old Sprague Dawley® (SD) rats were separated to seven groups. Five rats were euthanized without any surgery at 0 weeks for histological examination and determination of baseline characteristics. In 15 of the rats, DM was induced via Streptozotocin (STZ)-injection, and they were separated to 3 groups (4 weeks, 8 weeks and 12 weeks after STZ-injection). The remaining 15 rats were used as the control group (4 weeks, 8 weeks and 12 weeks after saline-injection). We tested bone-mass loss at four skeletal sites, the tibia, the femur greater trochanter, the spine, and the mandibular bones using micro-computed tomography (CT) and histological tests. RESULTS: Tibia was influenced the most obvious(BV/TV decreased by 27.3%, 52.5%, and 81.2% at 4 weeks, 8 weeks, and 12 weeks, respectively. p<0.05). In contrast, the other three sites were influenced to a lesser extent and bone loss became prominent at a later time point according to the histological and micro-CT tests(Femur: BV/TV did not decrease significantly at the first month or second month. However, and decreased by 49.4% at the third month, P<0.05. Mandible: the BV/TV only decreased by 6.5% at 1 month after STZ-injection. There was still a significant difference between the second and third months. The BV/TV decreased by 47.0% and 68.1% at 2 months and 3 months, respectively, (p<0.05) Spine: the BV/TV only decreased by 6.7%. However, significant change was observed in the spine at the second month and third month after STZ injection. The BV/TV decreased by 45.4% and 64.3%, respectively, p<0.05). CONCLUSION: The results indicate that T1DM can severely influence the bone structure of the 4 skeletal sites. Further, areas with dense trabecular bones were influenced less and at a later time point in comparison to the tibial region. CLINICAL RELEVANCE: Our research can serve as a guide to help increase the success rate of implant treatment, and help decrease the fracture risk in different bone types with greater accuracy.

Effect of osteoporosis on fixation of osseointegrated implants in rats.

The effect of osteoporosis on implant osseointegration has been widely investigated, whereas osteoporosis may also newly occur in patient with previously osseointegrated implant. This study was designed to investigate the effect of osteoporosis on implant fixation in rats after successful osseointegration had been obtained. Seventy female Sprague-Dawley rats were included, and each animal received two titanium implants in the distal metaphysis of femur bilaterally. Eight weeks later, ten rats were sacrificed to confirm the establishment of implant osseointegration. All left rats were randomly subjected to bilateral ovariectomy (OVX) or sham operation. Three, six, and twelve weeks later, implant osseointegration, peri-implant bone tissue, and biomechanical properties of implant were analyzed. Right femurs with implants were used for micro-CT and histological analysis, and left femurs with implants were used for biomechanical test. Micro-CT, histology, and biomechanical test confirmed the destructive effect of OVX on previously osseointegrated implant in rats; when compared to sham-operated rats, peri-implant bone volume, trabecular architecture, bone-to-implant contact ratio, as well as biomechanical parameters decreased progressively within 12 weeks. Results also indicated that the effect of OVX on undisturbed bone (proximal tibiae) was much stronger than that on peri-implant bone. Osteoporosis produced a progressive negative effect on previously osseointegrated implant in distal femora of rats during 12 weeks. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2426-2432, 2017.