Discovery of Potent Orally Bioavailable WD Repeat Domain 5 (WDR5) Inhibitors Using a Pharmacophore-Based Optimization.

WD repeat domain 5 (WDR5) is a nuclear scaffolding protein that forms many biologically important multiprotein complexes. The WIN site of WDR5 represents a promising pharmacological target in a variety of human cancers. Here, we describe the optimization of our initial WDR5 WIN-site inhibitor using a structure-guided pharmacophore-based convergent strategy to improve its druglike properties and pharmacokinetic profile. The core of the previous lead remained constant while a focused SAR effort on the three pharmacophore units was combined to generate a new in vivo lead series. Importantly, this new series of compounds has picomolar binding affinity, improved cellular antiproliferative activity and selectivity, and increased kinetic aqueous solubility. They also exhibit a desirable oral pharmacokinetic profile with manageable intravenous clearance and high oral bioavailability. Thus, these new leads are useful probes toward studying the effects of WDR5 inhibition.

Bone marrow mesenchymal stem cell-derived exosomes inhibit chondrocyte apoptosis and the expression of MMPs by regulating Drp1-mediated mitophagy.

Osteoarthritis (OA) is a joint degenerative disease commonly seen in the elderly. Bone marrow mesenchymal stem cell-exosomes (BMSC-exosomes) are closely associated with the progression of OA. Here, we investigated whether BMSC-exosomes can affect OA development by regulating mitophagy. Primary rat chondrocytes were treated with advanced glycation end products (AGEs) to induce cell damage. The results of flow cytometry showed that AGEs treatment significantly promoted apoptosis of chondrocytes. AGEs treatment also enhanced the expression of matrix metalloproteinases (MMPs), MMP-3 and MMP-13, and dynamin-related protein 1 (Drp1) in chondrocytes. To investigate the impact of BMSC-exosomes on chondrocytes, chondrocytes were treated with BMSC-exosomes. AGEs-mediated increase of apoptosis and up-regulation of MMP-3, MMP-13, and Drp1 in chondrocytes were abrogated by BMSC-exosomes. Western blot analysis of autophagy-related proteins and Mito-Keima assay revealed that BMSC-exosome treatment elevated the expression of autophagy-related proteins, LC3-II/LC3-I and Beclin-1, and promoted mitophagy in the AGEs-treated chondrocytes. Moreover, Drp1 overexpression repressed the expression of LC3-II/LC3-I and Beclin-1, and enhanced apoptosis and the expression of MMP-3 and MMP-13 in AGEs-treated chondrocytes. BMSC-exosomes reversed the impact of Drp1 overexpression on AGEs-treated chondrocytes. In conclusion, this work demonstrates that BMSC-exosomes inhibit chondrocyte apoptosis and the expression of MMPs, which attributes to regulate Drp1-mediated mitophagy. Thus, BMSC-exosomes may be a potential treatment for OA.

Suture repair of patellar inferior pole fracture: Transosseous tunnel suture compared with anchor suture.

Patellar inferior pole fracture is difficult to treat due to the inherent weakness of small comminuted distal fragments. However, suture fixation was recently introduced and reported. The aim of the present study was to evaluate and compare the clinical outcomes of two suture techniques, transosseous tunnel suture (TTS) and anchor suture (AS), for the fixation of patellar inferior pole fracture. A total of 35 patients with patellar inferior pole fracture treated at the Second Affiliated Hospital of Nanchang University (Nanchang, China) between June 2014 and April 2018 were retrospectively reviewed. Of these, 14 were treated with the TTS technique and 21 using AS fixation. The operation time, incision length and total cost were determined and compared. Functional outcomes were analyzed with the visual analog scale (VAS), Bostman and Lysholm scores and knee joint ranges of motion (ROMs). Postoperative complications were also observed and recorded. The mean follow-up was 22.6±9.7 and 18.7±5.9 months for TTS and AS, respectively. The groups were similar regarding age, sex, operative side and time to surgery. A smaller incision length and shorter operation time but higher hospital costs were observed in the AS group (P<0.01). For functional evaluation, there was no significant difference in VAS, Bostman and Lysholm scores or ROM between the 2 groups (P>0.05). No postoperative complications were observed in the TTS group. Only one patient in the AS group experienced a superficial minor wound infection. The TTS and AS techniques provided similarly satisfactory clinical outcomes for treating patellar inferior pole fracture. TTS had the advantage of cost-effectiveness due to saving anchors, while AS had a shorter operation time and a smaller incision length.

Design, synthesis and biological evaluation of novel chroman derivatives as non-selective acetyl-CoA carboxylase inhibitors.

Acetyl-CoA carboxylases (ACCs) are the rate-limiting enzymes in the de no lipogenesis, which play an important role in the synthesis and oxidation of fatty acid. Recent research reveals that ACCs are tightly relevant to many kinds of metabolic diseases and cancers. In this study, we synthesized a series of chroman derivatives and evaluated their ACCs inhibitory activities, obtaining compound 4s with IC50 value of 98.06 nM and 29.43 nM of binding activities in ACC1 and ACC2, respectively. Compound 4s exhibited the most potent anti-proliferation activity against A549, H1975, HCT116 and H7901 cell lines (values of IC50: 0.578 µΜ, 1.005 µΜ, 0.680 µΜ and 1.406 µΜ, respectively). Docking studies were performed to explain the structure-activity relationships. These results indicate that compound 4s is a promising ACC1/2 inhibitor for the potent treatment of cancer.

Design, synthesis and biological evaluation of novel spiro-pentacylamides as acetyl-CoA carboxylase inhibitors.

Acetyl-CoA carboxylase (ACC) catalyzes the rate-determining step in de novo lipogenesis and plays an important role in the regulation of fatty acid oxidation. Therefore, ACC inhibition offers a promising option for intervention in nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2DM) and cancer. In this paper, a series of spiropentacylamide derivatives were synthesized and evaluated for their ACC1/2 inhibitory activities and anti-proliferation effects on A549, H1975, HCT116, SW620 and Caco-2 cell lines in vitro. Compound 6o displayed potent ACC1/2 inhibitory activity (ACC1 IC50 = 0.527 µM, ACC2 IC50 = 0.397 µM) and the most potent anti-proliferation activities against A549, H1975, HCT116, SW620 and Caco-2 cell lines, with IC50 values of 1.92 µM, 0.38 µM, 1.22 µM, 2.05 µM and 5.42 µM respectively. Further molecular docking studies revealed that compound 6o maintained hydrogen bonds between the two carbonyls and protein backbone NHs (Glu-B2026 and Gly-B1958). These results indicate that compound 6o is a promising ACC1/2 inhibitor for the potent treatment of cancer.

Two cases in which 3D MRI was used to differentiate between a disc mass that mimics a tumor and neurinoma.

BACKGROUND: Since disc sequestration that mimics a tumor is rare and sometimes presents with an atypical appearance upon magnetic resonance imaging (MRI), it is often confused with other more common epidural and intradural neoplasms, particularly neurinoma. Open surgery is necessary due to the difficult of achieving a definitive diagnosis using computed tomography, MRI, and gadolinium- enhanced MRI prior to operation. Herein, we describe the use of coronal MR images of 3D fast-field echo with water selective excitation in the diagnosis of disc sequestration mimicking a tumor. CASE PRESENTATION: Two patients were admitted to our hospital with back pain, radiating pain, and hypoesthesia in the right lower limb. MRI revealed tumor-like masses in the lateral recess of L3 and posterior to the body of L4. The initial diagnosis indicated disc sequestration mimicking a tumor and neurinoma. The coronal MR images of 3D fast-field echo with water selective excitation showed a clear boundary between the tumor-like mass and the nerve root. Moreover, the mass was also completely separated from the dura. Therefore, neurinoma was excluded as a possible diagnosis prior to operation. Surgical excision to perform removal of the gross mass was performed in one patient. The histopathological diagnosis was consistent with the 3D fast-field echo with water-selective excitation MRI. Another patient was successfully treated by minimally invasive endoscopic surgery. CONCLUSIONS: Disc sequestration that mimics a tumor is difficult to diagnose preoperatively. As a non-invasive strategy, coronal MR images of 3D fast-field echo with water selective excitation is a helpful imaging tool for differentiating between diagnosis of disc sequestration that mimics a tumor and neurinoma prior to operation. If the disc fragment of mimicking tumor can be identified prior to operation, open surgery may not be necessary for all patients. Minimally invasive endoscopic surgery also is an alternative strategy.

[Early diagnosis and treatment for trauma around the knee with popliteal vascular injury].

OBJECTIVE: To investigate the early diagnosis and treatment for trauma around the knee with popliteal vascular injury. METHODS: A retrospective analysis was employed to analyze the clinical data from 15 patients (9 males and 6 females were with a mean age of 39.2 years old,ranging from 26 to 62 years old) with fracture or dislocation around the knee with popliteal vascular injury from January 2007 to January 2013. Combined with clinical symptoms and signs, oxygen saturation monitors, color ultrasound, DSA angiography and interventional surgery were used to determine the vascular injury. The knee fracture and dislocation were fixed with hybrid external fixation and plate-screw fixation, respectively. Then, the blood circulation was reconstructed by thrombectomy, repair and autologous vein graft for individual injured vascular. The average total operation time, average hospitalization days, predictive salvage index (PSI), average blood transfusion amount, average medical expenses and infection cases were recorded to determine the effect of early diagnosis and treatment. RESULTS: There was one patient with death, 8 patients with amputation, and 6 patients with successful repair surgery for popliteal artery, anterior tibial and posterior tibial arteries. These six patients with surviving limbs were followed up for an average of 28.3 months (ranged, 12 to 60 months). Among the 6 successful patients, the joint function of 4 patients was good and excellent. CONCLUSION: The trauma around the knee with popliteal vascular injury is characterized by complex and serious injury, easy misdiagnosis and loss diagnosis, poor prognosis and high risk of amputation. The early diagnosis of trauma around the knee with popliteal vascular injury should depend on the mechanism of trauma, local anatomical characteristics of injury site, clinical presentations and appropriate auxiliary examinations. The appropriate indications for limb salvage and amputation should be used to achieve more effective clinical results.

[Effects of total flavones of Chrysanthemum indicum on proliferation and apoptosis of human osteosarcoma Saos-2 cells].

OBJECTIVE: To study the effects of total flavones of Chrysanthemum indicum on proliferation and apoptosis of human osteosarcoma Saos-2 cells and its mechanism. METHODS: The effect of the total flavones of Chrysanthemum indicum on the proliferation of human osteosarcoma Saos-2 cells was detected by CCK assay, and the morphological changes of cells treated with total flavones of Chrysanthemum indicum were observed using contrast microscope. Flow cytomerty was performed to analyze the apoptotic rate of the cells, and the gene expression levels of Caspase-3, BCL-2, BAX were detected by RT-PCR. RESULTS: The total flavones of Chrysanthemum indicum suppressed the proliferation of osteosarcoma cells in a dose-and time-dependent manner. Under a microscope observation of cell morphology, the volume became smaller ,the number of internal particles was increased. Cell apoptosis rate was positively related to the drug concentration. After treated for 48 hours, Caspase-3 and BAX expression were up-regulated, BCL-2 and BCL-2/BAX were decreased. CONCLUSION: The total flavones of Chrysanthemum indicum can inhibit the proliferation of osteosarcoma cell line Saos-2 by inducing cell apoptosis,the mechanism of which might be related with reducing BCL-2/BAX and activating Caspase-3.

[Research progress of protective effects of alendronate on articular cartilage in osteoarthritis].

OBJECTIVE: To summarize the recent development on chondroprotective effect of alendronate (ALN) on articular cartilage in osteoarthritis (OA). METHODS: The related literature was reviewed and the main achievements in vitro/vivo studies in the fields were summarized. RESULTS: ALN can improve the metabolic microenvironment of the articular cartilage in OA, inhibit subchondral bone remodeling, so it has potential protective effect on articular cartilage. CONCLUSION: ALN is expected to become a disease-modifying OA drug in future, but OA treatment still lack a uniform basic and clinical evaluation criteria, so it has guiding significance in development and application of ALN to develope a uniform standard and obtain the clinical data.