Discovery of novel itaconimide-based derivatives as potent HDAC inhibitors for the efficient treatment of prostate cancer.

Histone deacetylases (HDACs) are a family of enzymes that play important roles in the development and progression of cancers. Inhibition of HDACs has been widely studied as a therapeutic strategy in the development of anticancer drugs. However, developing HDAC inhibitors that are effective for solid tumors remains a great challenge. In this work, we designed and synthesized a series of itaconimide-based derivatives as potent HDAC inhibitors. Among them, compound 17q exhibited potent inhibition of HDAC1/2/3/6, with good antiproliferative activity in vitro and an excellent pharmacokinetic profile. Compound 17q significantly inhibited tumor growth in a DU145 xenograft tumor model and showed no obvious toxicity. Moreover, when 17q was combined with other prostate cancer therapeutics, outstanding synergistic effects were observed and the toxic side effects of DTX were reduced. Overall, based on the data, these inhibitors may offer promising new targeted therapies for prostate cancer.

Quantitative OCT angiography of the retinal microvasculature and choriocapillaris in highly myopic eyes with myopic macular degeneration.

PURPOSE: To quantify retinal and choriocapillaris (CC) microvasculature in highly myopic (HM) eyes with myopic macular degeneration (MMD) using swept-source optical coherence tomography angiography (SS-OCTA). METHODS: 162 HM eyes (spherical equivalent ≤ -6.0 dioptres or axial length (AL) ≥26.5 mm) from 98 participants were enrolled, including 60 eyes (37.0%) with tessellated fundus, 54 eyes (33.3%) with peripapillary diffuse chorioretinal atrophy (PDCA), 27 eyes (16.7%) with macular diffuse chorioretinal atrophy (MDCA) and 21 eyes (13.0%) with patchy or macular atrophy. PLEX Elite 9000 SS-OCTA was performed to obtain perfusion densities (PD) of the superficial and deep retinal capillary plexus, and CC signal voids (number, area and density). RESULTS: Retinal PD decreased with increasing severity of MMD. Multivariable analysis showed that after adjustment of age and other factors, retinal PD decreased significantly in eyes with longer AL (ß≤-0.51, p<0.001) and with an MMD severity of MDCA or worse (ß≤-1.63, p<0.001). Reduced retinal PD were significantly associated with worse vision (ß≤-0.01, p≤0.04). In terms of CC signal voids, multivariable analysis showed that longer AL (p<0.001), but not MMD severity (p≥0.12) was significantly associated with CC signal void changes in the earliest stage of MMD. CONCLUSION: We demonstrate significant OCTA alterations in the retina and CC in HM eyes with varying severities of MMD. In eyes with early-stage PDCA, lower retinal PD and more extensive CC signal voids are predominantly associated with increasing AL. In contrast, in eyes with MDCA or worse, MMD itself was associated with sparser retinal and CC circulation.

Retinal microvasculature dysfunction is associated with Alzheimer's disease and mild cognitive impairment.

BACKGROUND: The retina and brain share many neuronal and vasculature characteristics. We investigated the retinal microvasculature in Alzheimer's disease (AD) and mild cognitive impairment (MCI) using optical coherence tomography angiography (OCTA). METHODS: In this cross-sectional study, 24 AD participants, 37 MCI participants, and 29 controls were diagnosed according to internationally accepted criteria. OCTA images of the superficial and deep capillary plexus (SCP, DCP) of the retinal microvasculature were obtained using a commercial OCTA system (Zeiss Cirrus HD-5000 with AngioPlex, Carl Zeiss Meditec, Dublin, CA). The main outcome measures were vessel density (VD) and fractal dimension (FD) in the SCP and DCP within a 2.5-mm ring around the fovea which were compared between groups. Perfusion density of large vessels and foveal avascular zone (FAZ) area were additional outcome parameters. RESULTS: Age, gender, and race did not differ among groups. However, there was a significant difference in diabetes status (P = 0.039) and systolic blood pressure (P = 0.008) among the groups. After adjusting for confounders, AD participants showed significantly decreased VD in SCP and DCP (P = 0.006 and P = 0.015, respectively) and decreased FD in SCP (P = 0.006), compared to controls. MCI participants showed significantly decreased VD and FD only in SCP (P = 0.006 and P < 0.001, respectively) and not the DCP (P > 0.05) compared with controls. There was no difference in the OCTA variables between AD and MCI (P > 0.05). Perfusion density of large vessels and FAZ area did not differ significantly between groups (P > 0.05). CONCLUSIONS AND RELEVANCE: Eyes of patients with AD have significantly reduced macular VD in both plexuses whereas MCI participants only showed reduction in the superficial plexus. Changes in the retinal microvasculature and capillary network may offer a valuable insight on the brain in AD.

miR-636 represses cell survival by targeting CDK6/Bcl-2 in cervical cancer.

Cervical cancer is widely known as one of the most common types of cancer diagnosed in women, and microRNAs (miRNAs) has been characterized as an important regulator in tumor progression, such as cervical cancer. MiR-636 was found to play a tumor suppressor role in hepatocellular carcinoma tumorigenesis. However, the tumorigenic mechanism of miR-636 on cervical cancer has not yet been found. In the present study, we first found that miR-636 was significantly downregulated in cervical cancer tissues and cell lines. in vitro gain- and loss-of-function assays revealed that overexpression of miR-636 inhibited cell proliferation and induced cell apoptosis, while knockdown of miR-636 reversed the effect on cervical tumorigenesis. Furthermore, cyclin-dependent kinase 6 (CDK6) and B-cell lymphoma 2 (Bcl-2) were characterized as targets of miR-636. Notably, overexpression of CDK6 or Bcl-2 could reverse the inhibitory effect of miR-636 on cervical cancer progression. Mechanistically, miR-636 repressed cell survival by targeting CDK6/Bcl-2 in cervical cancer, which may be the underlying mechanism of miR-636-inhibited cervical progression. In conclusion, our findings clarified the biologic significance of miR-636/CDK6/Bcl-2 axis in cervical cancer progression and suggested the potential therapeutic target ability of miR-636 in treatment of cervical cancer.

Serum alkaline phosphatase levels correlate with long-term mortality solely in peritoneal dialysis patients with residual renal function.

Introduction: Increased serum alkaline phosphatase (ALP) is predictive of a higher mortality in patients with end-stage renal disease. However, it remains unknown whether residual renal function (RRF) influences the outcome-association of serum ALP among peritoneal dialysis (PD) patients. Methods: A total of 650 incident PD patients receiving PD catheter implantation in an institute between 1 November 2005 and 28 February 2017 were retrospectively enrolled. These patients were divided into groups with and without RRF (RRF and non-RRF groups) and those with serum ALP levels in tertiles. The Kaplan-Meier method and multivariate Cox proportional hazard models were used to analyze their outcomes based on RRF and serum ALP levels. Results: These 650 patients had a mean age of 49.4 ± 14.0 years old, their median ALP level was 74 U/L (interquartile range (IQR): 59-98). After 28-month (IQR: 14-41) follow-up, 80 patients in RRF group and 40 patients in non-RRF group died. PD patients with the highest serum ALP tertile had significant lower survival (p = .014), when compared to other patients in the RRF group. However, this relationship was not observed in patients in the non-RRF group. After multivariate adjustment, in the RRF group, patients with the highest ALP tertile had a significantly higher risk of mortality (hazard ratio (HR): 2.26, 95% confidence interval (CI): 1.06-4.82, p = .034). Each 10-U/L increase in ALP level was associated with a 4% (HR: 1.04, 95% CI: 1.00-1.08, p = .045) higher mortality risk. Conclusions: Higher serum ALP level is associated with increased mortality solely in PD patients with RRF.

Application of biopolymers for improving the glass transition temperature of hairtail fish meat.

BACKGROUND: Glass transition temperature (Tg ) and food moisture content are closely related, especially in foods with a high moisture content, such as surimi products. In order to improve storage condition and maintain food quality, the influence of six biopolymers on the Tg of hairtail fish meat paste was investigated by differential scanning colorimetry. RESULTS: Samples were stored at -8 °C (>Tg ), -14 °C (Tg ) and -18 °C (

Loureirin B, an essential component of Sanguis Draxonis, inhibits Kv1.3 channel and suppresses cytokine release from Jurkat T cells.

Sanguis draxonis (SD), also known as "Dragon's Blood", is a traditional herb medicine that has been used to treat a variety of complications with unknown mechanisms. Recent studies show that SD displays immunosuppressive activities and improves symptoms of type I diabetes in animal models. However, the mechanisms underlying SD's immunosuppressive actions are not completely understood. The voltage-gated Kv1.3 channel plays a critical role in the pathogenesis of autoimmune diseases by regulating the functions of both T cells and B cells. Here we investigated the effect of SD and one of its active components loureirin B (LrB) on Kv1.3. Both SD and LrB inhibited Kv1.3-mediated currents, produced a membrane depolarization, and reduced Ca(2+) influx in Jurkat T cells. In addition, application of LrB inhibited phytohemagglutinin (PHA)-induced IL-2 release from activated Jurkat T cells. Furthermore, point mutations in the selective filter region significantly reduced the inhibitory effect of LrB on Kv1.3. The results of these experiments provide evidence that LrB is a channel blocker of Kv1.3 by interacting with amino acid residues in its selective filter region. Direct inhibition of Kv1.3 in T cells by SD and LrB might be the cellular and molecular basis of SD-mediated immunosuppression.

[Analysis of human papilloma virus infection of women in early pregnancy and postpartum].

OBJECTIVE: To explore the clinical value of examination of cervical HPV infection in women in early pregnancy and postpartum. METHODS: Using flow-through hybridization and gene chip techniques, we examined 3 806 cervical specimens of pregnant and postpartum women of different ages with different cervical diseases. The women were grouped into different age groups by every 5 years for HPV DNA genotyping of the specimens, with another 4080 women without pregnancy serving as the control. RESULTS: Of the total of 7886 specimens, high-risk HPV infection was detected a the rate of 12.5%. In pregnancy, postpartum and nonpregnancy, the infection rate was 14.3%,, 10.5%, and 11.7%, respectively. In the 4 age groups, the infection rate was 16.9%, 12.1%, 13.8%, and 22.1%, respectively. CONCLUSION: The high-risk HPV infection rate in pregnancy differs significantly from that in nonpregnancy and postpartum. The infection rate also differs with age during pregnancy and postpartum. Examination of HPV infection during pregnancy is safe and feasible.