Parkinson's disease (PD) is a common neurodegenerative disease that lacks therapies to prevent progressive neurodegeneration. Impaired energy metabolism and reduced ATP levels are common features of PD. Previous studies revealed that terazosin (TZ) enhances the activity of phosphoglycerate kinase 1 (PGK1), thereby stimulating glycolysis and increasing cellular ATP levels. Therefore, we asked whether enhancement of PGK1 activity would change the course of PD. In toxin-induced and genetic PD models in mice, rats, flies, and induced pluripotent stem cells, TZ increased brain ATP levels and slowed or prevented neuron loss. The drug increased dopamine levels and partially restored motor function. Because TZ is prescribed clinically, we also interrogated 2 distinct human databases. We found slower disease progression, decreased PD-related complications, and a reduced frequency of PD diagnoses in individuals taking TZ and related drugs. These findings suggest that enhancing PGK1 activity and increasing glycolysis may slow neurodegeneration in PD.
Background
Metalloproteinase-9 (MMP-9) is a type IV Collagenase found at elevated levels in chronic wounds. As wounds heal, MMP-9 diminishes. In this study, we investigated whether MMP-9 directly contributes to chronic wound pathogenesis.
Methods
Recombinant proMMP-9 was prepared using immortalized keratinocytes transduced by a lentivirus. ProMMP-9 was purified from cell culture media and activated using 4-aminophenylmercuric acetate. Active MMP-9 was then suspended in Xanthan Gum to a concentration paralleling that found in human chronic wounds. Two parallel 6mm punch biopsies were made on the backs of C57BL mice. Wounds were treated daily with MMP-9 or vehicle. Wound areas were measured and tissues examined by densitometry, real-time RT-PCR, histology, and immunohistochemistry at days 7, 10 and 12.
Results
Exogenous MMP-9, at the level found within chronic wounds, delayed wound healing in this animal model. By 7 days, wounds in the MMP-9-injected group were 12% larger than control wounds (p=0.008). By day 12, wounds in the MMP-9-injected group were 25% larger than those of the control group (p=0.03). Histologic examination shows that high levels of active MMP-9 impaired epithelial migrating tongues (p=0.0008). Moreover, consistent with elevated MMP-9, the collagen IV in the leading edge of the epithelial tongue was diminished.
Conclusion
MMP-9 appears to directly delay wound healing. Our data suggests that this may occur through interference with re-epithelialization. We propose that MMP-9 interferes with the basement membrane protein structure, which in turn impedes keratinocyte migration, attachment, and the reestablishment of the epidermis.
Long intergenic non-coding RNA Linc00472 has been considered as a tumor suppressor in some cancers. However, the function and mechanism of Linc00472 in colorectal cancer has not been well elucidated. In this study, we found that Linc00472 was down-regulated in colorectal cancer tissues and cells. Elevated Linc00472 expression suppressed proliferation and induced apoptosis in colorectal cancer cells. Moreover, Linc00472 acted as a competing endogenous RNA (ceRNA) of miR-196a to release programmed cell death 4 (PDCD4). Furthermore, miR-196a overexpression or PDCD4 knockdown reversed Linc00472-mediated proliferation inhibition and apoptosis induction in colorectal cancer cells. Ectopic Linc00472 expression hindered tumor growth in vivo. Our study demonstrated that Linc00472 suppressed proliferation and induced apoptosis through up-regulating PDCD4 by decoying miR-196a, which may be an effective therapeutic target for colorectal cancer.
Increasing evidence suggests that dysregulation of long non-coding RNAs (lncRNAs) is implicated in chemoresistance in cancers. However, the function and molecular mechanisms of lncRNAs in gastric cancer chemoresistance are still not well understood. In this study, we aimed to investigate the functional role and the underlying molecular mechanisms of lncRNA HOXD cluster antisense RNA 1 (HOXD-AS1) in cisplatin (DDP) resistance in gastric cancer. Our results revealed that HOXD-AS1 was upregulated in DDP-resistant gastric cancer tissues and cells. Patients with gastric cancer with high HOXD-AS1 expression levels had a poor prognosis. Knockdown of HOXD-AS1 facilitated the sensitivity of DDP-resistant gastric cancer cells to DDP. Additionally, HOXD-AS1 epigenetically silenced PDCD4 through binding to the histone methyltransferase enhancer of zeste homologue 2 (EZH2) on the promoter of PDCD4, thus increasing H3K27me3. More importantly, PDCD4 silencing counteracted HOXD-AS1 knockdown-mediated enhancement of DDP sensitivity in DDP-resistant gastric cancer cells. In summary, HOXD-AS1 led to DDP resistance in gastric cancer by epigenetically suppressing PDCD4 expression, providing a novel therapeutic strategy for patients with gastric cancer with chemoresistance.
To evaluate the diagnostic accuracy of combined computed tomography colonography (CTC) and dual-energy iodine map imaging for detecting colorectal masses using high-pitch dual-source CT, compared with optical colonography (OC) and histopathologic findings. Twenty-eight consecutive patients were prospectively enrolled in this study. All patients were underwent contrast-enhanced CTC acquisition using dual-energy mode and OC and pathologic examination. The size of the space-occupied mass, the CT value after contrast enhancement, and the iodine value were measured and statistically compared. The sensitivity, specificity, accuracy rate, and positive predictive and negative predictive values of dual-energy contrast-enhanced CTC were calculated and compared between conventional CTC and dual-energy iodine images. The iodine value of stool was significantly lower than the colonic neoplasia (P < 0.01). The sensitivity of conventional CTC was 95.6% (95% CI = 77.9%–99.2%), combined CTC and dual-energy iodine maps imaging was 95.6% (95% CI = 77.9%–99.2%). The specificity of the two methods was 42.8% (95% CI = 15.4%–93.5%) and 100% (95% CI = 47.9%–100%; P = 0.02), respectively. Compared with optical colonography and histopathology, combined CTC and dual-energy iodine maps imaging can distinguish stool and colonic neoplasia, distinguish between benign and malignant tumors initially and improve the diagnostic accuracy of CTC for colorectal cancer screening.
Expression of p130cas, E-cadherin andAbstract: p130cas (p130 Crk-associated substrate) is a scaffolding protein and plays an important role in regulating focal adhesion and driving cell migration. Also, the destruction of the E-cadherin/b-catenin adhesive complex is one of the changes that characterizes the invasive phenotype of tumors. The aim of this study is to evaluate the role of p130cas, E-cadherin, and b-catenin expression in patients with non-small cell lung cancer (NSCLC). We examined the expression of p130cas, E-cadherin, and b-catenin in 105 lung cancer tissues and paired adjacent normal lung tissues using immunohistochemistry. The overexpression of p130cas was observed in 61.9% (65/105) of lung cancer samples. The overexpression of p130cas was correlated with abnormal expression of E-cadherin and b-catenin (p = 0.002 and p = 0.006, respectively). Chi-square test showed that the overexpression of p130cas correlated positively with lymph node metastasis and high TNM stage. The LogRank test revealed that the mean survival time of patients with p130cas overexpression (36.31 ± 5.66 months) was markedly shorter than that of those with p130cas normal expression (60.57 ± 6.95 months). Multivariable analysis indicated p130cas overexpression (p < 0.001) to be an independent significant prognostic factor for NSCLC patients' survival. These results indicate that p130cas may impact a variety of clinicopathological features of NSCLC and may influence the prognosis of lung cancer patients.
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