Prostate cancer can be controlled by androgen‐hormone treatment until the cancer becomes refractory. It is believed that hormone sensitivity is largely dependent on androgen receptor (AR) activity. ...Here, we found the histone demethylase KDM7A which demethylates histone H3K27 to be overexpressed in enzalutamide resistant castration‐resistant prostate cancer cell line C4‐2b, and investigated the molecular mechanism whereby androgen receptor activity is regulated by KDM7A. We engineered AR‐positive LNCaP cells to stably express a short‐hairpin RNA against KDM7A mRNA from a lentiviral vector. By measuring AR downstream gene expression after androgen stimulation, we found that a KDM7A‐deficient cell line showed lower AR downstream gene expression compared to a control cell. KDM7A knock‐down in LNCaP cell line caused decreased cell proliferation. Western blot analysis with modified‐histone antibody revealed that the KDM7A‐knock‐down LNCaP cell line had increased H3K27 di‐methylation. We confirmed KDM7A binding on AR target‐gene promoters after hormone stimulation in chromatin‐immunoprecipitation experiments. And increased H3K27 di‐methylation was observed in KDM7A knock‐down LNCaP stable cell. Treatment with KDM7A inhibitor, TC‐E 5002, reduced proliferation and induced apoptosis of prostate cancer cells. Finally, we observed that the KDM7A protein was significantly upregulated in prostate cancer tissue, and that this difference correlated with the Gleason score. These data suggested that KDM7A is potentially a good therapeutic target for prostate cancer drugs and can be used as potentially a good prognostic indicator for prostate cancer and related treatment strategies.
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In castration‐resistant prostate cancers androgen receptor activity is often upregulated, but effectively targeting this enhanced activity remains challenging. Here the authors identified histone demethylase KDM7A as a new regulator of androgen receptor‐dependent gene expression. KDM7A protein was found upregulated in prostate cancer tissue, and chemical inhibition of KDM7A slowed prostate cancer cell growth. This suggests that KDM7A is potentially a new drug target for castration‐resistant prostate cancer.
Periodontal disease is a major public health issue, and various periodontal therapies have been performed to regenerate periodontal tissues. The periodontium is a complex structure composed of ...specialized tissues that support the teeth, and most periodontal surgeries are invasive procedures, including a resection of the gingiva or the alveolar bone. The periodontal wound healing process is slightly different from cutaneous wound healing and is similar to fetal healing, being almost scar-free. The aim of this review article is to provide an overview of periodontal wound healing and discuss various surgical and pharmaceutical approaches to achieve stable wound healing and improve the treatment outcomes. In addition, detrimental and limiting factors that induce a compromised prognosis are discussed, along with the perspective and future direction for successful periodontal tissue regeneration.
Kidney cancer is one of the most difficult cancers to treat by targeted and radiation therapy. Therefore, identifying key regulators in this cancer is especially important for finding new drugs. We ...focused on androgen receptor (AR) regulation by its epigenetic co-regulator lysine-specific histone demethylase 1 (LSD1) in kidney cancer development. LSD1 knock-down in kidney cancer cells decreased expression of AR target genes. Moreover, the binding of AR to target gene promoters was reduced and histone methylation status was changed in LSD1 knock-down kidney cancer cells. LSD1 knock-down also slowed growth and decreased the migration ability of kidney cancer cells. We found that pargyline, known as a LSD1 inhibitor, can reduce AR activity in kidney cancer cells. The treatment of kidney cancer cells with pargyline delayed growth and repressed epithelial-mesenchymal transition (EMT) markers. These effects were additively enhanced by co-treatment with the AR inhibitor enzalutamide. Down-regulation of LSD1 in renal cancer cells (RCC) attenuated in vivo tumor growth in a xenograft mouse model. These results provide evidence that LSD1 can regulate kidney cancer cell growth
epigenetic control of AR transcription factors and that LSD1 inhibitors may be good candidate drugs for treating kidney cancer.
Bone morphogenetic protein-2 (BMP-2) is a potent growth factor affecting bone formation. While recombinant human BMP-2 (rhBMP-2) has been commercially available in cases of non-union fracture and ...spinal fusion in orthopaedics, it has also been applied to improve bone regeneration in challenging cases requiring dental implant treatment. However, complications related to an initially high dosage for maintaining an effective physiological concentration at the defect site have been reported, although an effective and safe rhBMP-2 dosage for bone regeneration has not yet been determined. In contrast to protein delivery, BMP-2 gene transfer into the defect site induces BMP-2 synthesis in vivo and leads to secretion for weeks to months, depending on the vector, at a concentration of nanograms per milliliter. BMP-2 gene delivery is advantageous for bone wound healing process in terms of dosage and duration. However, safety concerns related to viral vectors are one of the hurdles that need to be overcome for gene delivery to be used in clinical practice. Recently, commercially available gene therapy has been introduced in orthopedics, and clinical trials in dentistry have been ongoing. This review examines the application of BMP-2 gene therapy for bone regeneration in the oral and maxillofacial regions and discusses future perspectives of BMP-2 gene therapy in dentistry.
Histone demethylase KDM7A regulates many biological processes, including differentiation, development, and the growth of several cancer cells. Here, we have focused on the role of KDM7A in bladder ...cancer cells, especially under drug-resistant conditions. When the
gene was knocked down, bladder cancer cell lines showed impaired cell growth, increased cell death, and reduced rates of cell migration. Biochemical studies revealed that KDM7A knockdown in the bladder cancer cells repressed the activity of androgen receptor (AR) through epigenetic regulation. When we developed a cisplatin-resistant bladder cancer cell line, we found that AR expression was highly elevated. Upon treatment with TC-E 5002, a chemical inhibitor of KDM7A, the cisplatin-resistant bladder cancer cells, showed decreased cell proliferation. In the mouse xenograft model, KDM7A knockdown or treatment with its inhibitor reduced the growth of the bladder tumor. We also observed the upregulation of KDM7A expression in patients with bladder cancer. The findings suggest that histone demethylase KDM7A mediates the growth of bladder cancer. Moreover, our findings highlight the therapeutic potential of the KMD7A inhibitor, TC-E 5002, in patients with cisplatin-resistant bladder cancer.
Specific orientations of regenerated ligaments are crucially required for mechanoresponsive properties and various biomechanical adaptations, which are the key interplay to support mineralized ...tissues. Although various 2D platforms or 3D printing systems can guide cellular activities or aligned organizations, it remains a challenge to develop ligament-guided, 3D architectures with the angular controllability for parallel, oblique or perpendicular orientations of cells required for biomechanical support of organs. Here, we show the use of scaffold design by additive manufacturing for specific topographies or angulated microgroove patterns to control cell orientations such as parallel (0°), oblique (45°) and perpendicular (90°) angulations. These results demonstrate that ligament cells displayed highly predictable and controllable orientations along microgroove patterns on 3D biopolymeric scaffolds. Our findings demonstrate that 3D printed topographical approaches can regulate spatiotemporal cell organizations that offer strong potential for adaptation to complex tissue defects to regenerate ligament-bone complexes.
Atrial fibrillation (AF) is a common cardiac arrhythmia associated with poor health-related quality of life (HRQoL). However, the factors influencing HRQoL in patients with AF are not well ...understood. The purpose of integrative review was to investigate the factors affecting HRQoL in patients with AF based on the six domains of Ferrans and colleagues' HRQoL model. A total of 23 relevant articles published between January 2000 and March 2018 were identified using four databases and analyzed in this study. Our review showed that the HRQoL in patients with AF was consistently lower than both healthy individuals and patients with other cardiovascular diseases. The most common factor associated with HRQoL in patients with AF was anxiety-specific to AF in the symptoms domain, followed by frequency and severity of symptoms and the New York Heart Association functional class. This study highlights that monitoring and assessing patients' symptoms is vital for improving HRQoL in patients with AF. Disease-specific and cross-culturally validated tools can allow healthcare professionals to provide tailored interventions for patients with AF.
•Ischemic brain injury impaired cognitive function at 28 days post-stroke in mice.•Ischemic brain injury triggered AIM2 inflammasome-mediated inflammation within 7 days post-stroke.•Microglia- or ...endothelial cell-induced AIM2 production mediated PSCI pathogenesis.•AIM2 inflammasome-induced pyroptosis may contribute to acute and chronic neuronal death after stroke.•AIM2 KO and administration of the caspase-1 inhibitor, Ac-YVAD-CMK, attenuated long-term cognitive deficits.
Although over one-third of stroke patients may develop post-stroke cognitive impairment (PSCI), the mechanisms underlying PSCI remain unclear. We explored here, the involvement of post-stroke inflammasomes in long-term PSCI development, using a 45 min-middle cerebral artery occlusion (MCAO)/reperfusion-induced PSCI model. Immunohistological assessment on day 1, 3, and 7 was followed by cognitive function test 28 days post-stroke. Evaluation of inflammasome sensor gene expression in aged mouse brains showed dominant expression of absent in melanoma 2 (Aim2) in 6-, 12-, and 18-month-old mouse brains. AIM2 mRNA and protein increased until 7 days post-stroke. PSCI decreased anxiety in elevated plus maze test and impaired spatial learning and memory functions in Morris water maze test 28 days post-stroke. AIM2 and other inflammasome subunit immunoreactivities, including those for caspase-1, interleukin (IL)-1β, and IL-18, were higher in the hippocampus and cortex of the PSCI than in those of the sham group 7 days post-stroke. AIM2 immunoreactivity of the PSCI group was primarily co-localized with Iba-1 (microglial marker) and CD31 (endothelial cell marker) immunoreactivities but not NeuN (neuronal marker) and GFAP (astrocyte marker) immunoreactivities, suggesting that microglia or endothelial cell-induced AIM2 production mediated PSCI pathogenesis. Additionally, inflammasome-induced pyroptosis might contribute to acute and chronic neuronal death after stroke. AIM2 knockout (KO) and Ac-YVAD-CMK-induced caspase-1 inhibition in mice significantly improved cognitive function and reversed brain volume in the hippocampus relative to those in stroke mice. Conclusively, AIM2 inflammasome-mediated inflammation and pyroptosis likely aggravated PSCI; therefore, targeting and controlling AIM2 inflammasome could potentially treat PSCI.
The sodium-glucose cotransporter-2 inhibitors (SGLT2is) reduce the incidence of macrovascular complications of diabetes, while their effect on diabetic retinopathy has not been clarified. We compared ...the effects of SGLT2is with those of dipeptidyl peptidase-4 inhibitors (DPP4is) on the risk of diabetic retinopathy and its progression in people with type 2 diabetes. We performed a retrospective cohort study among people with type 2 diabetes who started on a SGLT2i or DPP4i from 2014 to 2016 according to the Korean National Health Insurance Service database. Subjects initiated on a SGLT2i or DPP4i were matched on a 1:1 basis according to their propensity scores, and Cox proportional hazards regression models were used to calculate the hazard ratios for the risk of diabetic retinopathy and its progression. After propensity score-matching, 41,430 patients without a history of diabetic retinopathy were identified as new users of a SGLT2i (n = 20,175) or DPP4i (n = 20,175). The hazard ratio (95% CI) for diabetic retinopathy was 0.89 (0.83-0.97) for SGLT2i initiators compared with DPP4i initiators. In patients with a history of diabetic retinopathy (n = 4,663 pairs), there was no significant difference in diabetic retinopathy progression between SGLT2i initiators and DPP4i initiators (hazard ratio 0.94, 95% CI 0.78-1.13). This real-world cohort study showed that SGLT2is might be associated with lower risk of diabetic retinopathy compared with DPP4is. Randomized controlled trials are needed to investigate the long-term effect of SGLT2is in diabetic retinopathy in people with diabetes.
Despite the potential therapeutic efficacy of epithelial growth factor receptor (EGFR) inhibitors in the treatment of advanced stage bladder cancer, there currently is no clear evidence to support ...this hypothesis. In this study, we investigate whether the concurrent treatment of autophagy-blocking agents with EGFR inhibitors exerts synergistic anti-cancer effects in T24 and J82 human bladder cancer cells. Lapatinib and gefitinib were used as EGFR inhibitors, and bafilomycin A1 (BFA1), chloroquine (CQ) and 3-methyladenine (3-MA) were used as the pharmacologic inhibitors of autophagy activities. To assess the proliferative and self-renewal capabilities, the Cell Counting Kit-8 (CCK-8) assay and a clonogenic assay were performed, respectively. To examine apoptotic cell death, flow cytometry using annexin-V/propidium iodide (PI) was used. To measure the autophagy activities, the expression levels of LC3I and II was determined by Western blot analysis. To validate the synergistic effects of autophagy inhibition with EGFR inhibitors, we specifically blocked key autophagy regulatory gene ATG12 by transfection of small interference RNA and examined the phenotypic changes. Of note, lapatinib and gefitinib triggered autophagy activities in T24 and J82 human bladder cancer cells, as indicated by upregulation of LC3II. More importantly, inhibiting autophagy activities with pharmacologic inhibitors (BFA1, CQ or 3-MA) remarkably reduced the cell viabilities and clonal proliferation of T24 and J82 cells, compared to those treated with either of the agents alone. We also obtained similar results of the enhanced anti-cancer effects of EGFR inhibitors by suppressing the expression of ATG12. Notably, the apoptotic assay showed that synergistic anti-cancer effects were induced via the increase of apoptotic cell death. In summary, concomitant inhibition of autophagy activities potentiated the anti-cancer effects of EGFR inhibitors in human bladder cancer cells, indicating a novel therapeutic strategy to treat advanced bladder cancer.
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