Intraperitoneal injection of the SIRT1 activator SRT1720 attenuates the progression of experimental osteoarthritis in mice.

OBJECTIVES: This study aimed to examine the effects of SRT1720, a potent SIRT1 activator, on osteoarthritis (OA) progression using an experimental OA model. METHODS: Osteoarthritis was surgically induced by destabilization of the medial meniscus in eight-week-old C57BL/6 male mice. SRT1720 was administered intraperitoneally twice a week after surgery. Osteoarthritis progression was evaluated histologically using the Osteoarthritis Research Society International (OARSI) score at four, eight, 12 and 16 weeks. The expression of SIRT1, matrix metalloproteinase 13 (MMP-13), a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), cleaved caspase-3, PARP p85, and acetylated nuclear factor (NF)-κB p65 in cartilage was examined by immunohistochemistry. Synovitis was also evaluated histologically. Primary mouse epiphyseal chondrocytes were treated with SRT1720 in the presence or absence of interleukin 1 beta (IL-1ß), and gene expression changes were examined by real-time polymerase chain reaction (PCR). RESULTS: The OARSI score was significantly lower in mice treated with SRT1720 than in control mice at eight and 12 weeks associated with the decreased size of osteophytes at four and eight weeks. The delayed OA progression in the mice treated with SRT1720 was also associated with increased SIRT1-positive chondrocytes and decreased MMP-13-, ADAMTS-5-, cleaved caspase-3-, PARP p85-, and acetylated NF-κB p65-positive chondrocytes and decreased synovitis at four and eight weeks. SRT1720 treatment partially rescued the decreases in collagen type II alpha 1 (COL2A1) and aggrecan caused by IL-1ß, while also reducing the induction of MMP-13 by IL-1ß in vitro. CONCLUSION: The intraperitoneal injection of SRT1720 attenuated experimental OA progression in mice, indicating that SRT1720 could be a new therapeutic approach for OA.Cite this article: K. Nishida, T. Matsushita, K. Takayama, T. Tanaka, N. Miyaji, K. Ibaraki, D. Araki, N. Kanzaki, T. Matsumoto, R. Kuroda. Intraperitoneal injection of the SIRT1 activator SRT1720 attenuates the progression of experimental osteoarthritis in mice. Bone Joint Res 2018;7:252-262. DOI: 10.1302/2046-3758.73.BJR-2017-0227.R1.

Internalization of a novel, huge lectin from Ibacus novemdentatus (slipper lobster) induces apoptosis of mammalian cancer cells.

An N-acetyl sugar-binding lectin (termed iNoL) displaying cytotoxic activity against human cancer cells was isolated from the slipper lobster Ibacus novemdentatus (family Scyllaridae). iNoL recognized monosaccharides containing N-acetyl group, and glycoproteins (e.g., BSM) containing oligosaccharides with N-acetyl sugar. iNoL was composed of five subunits (330, 260, 200, 140, and 30 kDa), which in turn consisted of 70-, 40-, and 30-kDa polypeptides held together by disulfide bonds. Electron microscopic observations and gel permeation chromatography indicated that iNoL was a huge (500-kDa) molecule and had a polygonal structure under physiological conditions. iNoL displayed cytotoxic (apoptotic) effects against human cancer cell lines MCF7 and T47D (breast), HeLa (ovarian), and Caco2 (colonic), through incorporation (internalization) into cells. The lectin was transported into lysosomes via endosomes. Its cytotoxic effect and incorporation into cells were inhibited by the co-presence of N-acetyl-D-mannosamine (ManNAc). Treatment of HeLa cells with iNoL resulted in DNA fragmentation and chromatin condensation, through activation of caspase-9 and -3. In summary, the novel crustacean lectin iNoL is incorporated into mammalian cancer cells through glycoconjugate interaction, and has cytotoxic (apoptotic) effects.

Pre- and post-transplant quantification of measurable ('minimal') residual disease via multiparameter flow cytometry in adult acute myeloid leukemia.

Measurable ('minimal') residual disease (MRD) before or after hematopoietic cell transplantation (HCT) identifies adults with AML at risk of poor outcomes. Here, we studied whether peri-transplant MRD dynamics can refine risk assessment. We analyzed 279 adults receiving myeloablative allogeneic HCT in first or second remission who survived at least 35 days and underwent 10-color multiparametric flow cytometry (MFC) analyses of marrow aspirates before and 28±7 days after transplantation. MFC-detectable MRD before (n=63) or after (n=16) transplantation identified patients with high relapse risk and poor survival. Forty-nine patients cleared MRD with HCT conditioning, whereas two patients developed new evidence of disease. The 214 MRD(neg)/MRD(neg) patients had excellent outcomes, whereas both MRD(neg)/MRD(pos) patients died within 100 days following transplantation. For patients with pre-HCT MRD, outcomes were poor regardless of post-HCT MRD status, although survival beyond 3 years was only observed among the 58 patients with decreasing but not the seven patients with increasing peri-HCT MRD levels. In multivariable models, pre-HCT but not post-HCT MRD was independently associated with overall survival and risk of relapse. These data indicate that MRD(pos) patients before transplantation have a high relapse risk regardless of whether or not they clear MFC-detectable disease with conditioning and should be considered for pre-emptive therapeutic strategies.

Effect of occlusal rehabilitation on spatial memory and hippocampal neurons after long-term loss of molars in rats.

Experimental loss of occlusal support caused by the extraction or grinding of molar teeth has been reported to foment the impairment of learning and memory in laboratory animals. The purpose of this study was to examine the effect of occlusal reconstruction after long-term loss of molars on spatial memory by using 8-arm radial maze and by assessing histopathological changes of neuron density in the hippocampus. Experimental dentures were inserted into the oral cavities of molarless rats to recover the occlusal support. Age-matched groups of control, molarless and denture-wearing rats were trained to perform the maze tasks. The difference of the error incidence in the maze task was evaluated between three groups. The difference of neuron density between three groups was also evaluated at the end of the maze task. Serum corticosterone levels were also measured to estimate the chronic stress, which could be caused by extraction, insertion of the experimental denture or any experimental procedure. The error incidence in the denture-wearing group was significantly higher than that of the control group, but significantly lower than that of the molarless group. Significant differences of neuron density were observed between three groups in each of the hippocampal CA1, CA3 and DG subfields. No significant difference of the serum corticosterone levels between three groups could be observed. From the results of this study, it was suggested that the recovery of occlusal support would bring amelioration of cognitive impairment concomitant with long period loss of molars in rats.

Inference of S-system models of genetic networks by solving one-dimensional function optimization problems.

Voit and Almeida have proposed the decoupling approach as a method for inferring the S-system models of genetic networks. The decoupling approach defines the inference of a genetic network as a problem requiring the solutions of sets of algebraic equations. The computation can be accomplished in a very short time, as the approach estimates S-system parameters without solving any of the differential equations. Yet the defined algebraic equations are non-linear, which sometimes prevents us from finding reasonable S-system parameters. In this study, we propose a new technique to overcome this drawback of the decoupling approach. This technique transforms the problem of solving each set of algebraic equations into a one-dimensional function optimization problem. The computation can still be accomplished in a relatively short time, as the problem is transformed by solving a linear programming problem. We confirm the effectiveness of the proposed approach through numerical experiments.

Dose-dependent effects of mandibular advancement on pharyngeal mechanics and nocturnal oxygenation in patients with sleep-disordered breathing.

STUDY OBJECTIVES: To examine dose-dependent effects of mandibular advancement on collapsibility of the passive pharynx and sleep-disordered breathing (SDB). DESIGN: Prospective, randomized study. SETTING: University hospital. PATIENTS: Thirty-seven adult patients with SDB. INTERVENTIONS: Oral appliances with 2-, 4-, and 6-mm advancement of the mandible. MEASUREMENTS AND RESULTS: Overnight oximetry was performed with and without oral appliances. Each 2-mm mandibular advancement coincided with approximately 20% improvement in number and severity of nocturnal desaturations. Percentages of patients producing a > 50% improvement rate of the number of desaturations were 25%, 48%, and 65% with use of oral appliances with 2-, 4-, and 6-mm mandibular advancement, respectively. Static pharyngeal mechanics were evaluated in six completely paralyzed patients with SDB under general anesthesia with and without the oral appliances. Advancement of mandibular position was found to produce dose-dependent closing pressure reduction of all pharyngeal segments. Normalization of nocturnal oxygenation was associated with negative closing pressure, especially at the velopharynx. CONCLUSIONS: We conclude that improvement of both nocturnal oxygenation and pharyngeal collapsibility significantly depends on the mandibular position.

Total occlusion of the common carotid artery with patent internal carotid artery. Identification with color flow Doppler imaging.

With common carotid artery occlusion there is usually no flow in the distal vessels. However, flow to the ipsilateral internal common carotid artery may be maintained by collateral vessels. Nine of 1100 patients referred for carotid duplex sonography were found to have occluded common carotid arteries. Five of these patients had collateral circulation with reconstitution of flow via the external carotid artery. The color Doppler sonograms of three representative patients are presented. There was antegrade flow in the internal carotid artery with retrograde flow in the external carotid artery.

Differentiation of detached retina and vitreous membrane with color flow Doppler.

The sonographic criteria for diagnosis of retinal detachment and vitreous membranes are well established, and in most cases a diagnosis can be made. However, in difficult cases, differentiation between the two may be difficult. In this study the use of high-resolution color flow Doppler was evaluated for differentiating between retinal detachments and vitreous membranes. Sonographic evaluation, including color flow Doppler, was performed in 25 symptomatic eyes. Seven eyes had areas of retinal detachment, all of which had detectable blood flow within at least a portion of the detached retina. Fifteen eyes had vitreous hemorrhages or membranes in which no flow was detected. Two diabetic patients with vitreous membranes and no retinal detachment did have flow detectable within the neovascular membranes. Another patient, who had a complete choroid detachment after surgery, demonstrated good flow within the area of detachment. It is concluded that in difficult cases high-resolution color flow Doppler can enable differentiation of an area of retinal detachment from a vitreous membrane in a patient without diabetes.