The mRNA expression of caspase-9 can be used as an independent prognostic factor for patients with stage II colorectal cancer.
Dopamine transporter (DAT) internalization is a mechanism underlying the decreased dopamine reuptake caused by addictive drugs like methamphetamine (METH). We found that Piccolo, a presynaptic scaffolding protein, was overexpressed in the nucleus accumbens (NAc) of the mice repeatedly administrated with METH. Piccolo downexpression by antisense technique augmented METH-induced behavioral sensitization, conditioned reward and synaptic dopamine accumulation in NAc. Expression of Piccolo C 2 A domain attenuated METH-induced inhibition of dopamine uptake in PC12 cells expressing human DAT. Consistent with this, it slowed down the accelerated DAT internalization induced by METH, thus maintaining the presentation of plasmalemmal DAT. In immunostaining and structural modeling Piccolo C 2 A domain displays an unusual feature of sequestering membrane phosphatidylinositol 4,5-bisphosphate, which may underlie its role in modulating DAT internalization. Together, our results indicate that Piccolo upregulation induced by METH represents a homeostatic response in the NAc to excessive dopaminergic transmission. Piccolo C 2 A domain may act as a cytoskeletal regulator for plasmalemmal DAT internalization, which may underlie its contributions in behavioral plasticity.
Amelanotic malignant melanoma in the oral region is extremely rare and has not previously been reported in the parotid gland. This present case report describes an amelanotic malignant melanoma in the parotid gland, with no other primary lesion detectable. The medical history, pathology and immunohistochemical analysis of the case are described and the relevant literature is reviewed in order to help in the recognition of this uncommon tumour. Amelanotic malignant melanoma is a melanoma subtype with little or no pigmentation and, because of this lack of pigmentation and its wide-ranging clinical appearance, it often defies clinical diagnosis. A high level of vigilance is, therefore, necessary in diagnosing such a tumour in the parotid gland. Where it is suspected, positive expression of S-100 protein and human melanoma black 45 (HMB45) using immunohistochemical analysis can be considered reliable methods of confirming diagnosis.
To study the tumor specificity and antitumor activity of the replication-competent oncolytic adenovirus TOA02, which is controlled by a modified human telomerase reverse transcriptase (hTERT) promoter and expresses granulocyte macrophage colony-stimulating factor (GM-CSF). The wild-type hTERT promoter was modified, by inserting two E2F-binding sites. The effect of the modified hTERT on the viral yield and cytotoxicity of TOA02 were determined in vitro with a panel of tumor cells and normal cells, to evaluate tumor specificity; the effect on the antitumor efficacy and toxicity of TOA02 were determined in vivo, to evaluate the therapeutic potential of the adenovirus. The TOA02 adenovirus, which contained the modified hTERT promoter, produced a higher yield of virus in telomerase-positive and retinoblastoma-defective human cells, and a lower yield of virus in normal human cells than the wild-type adenovirus. A single injection of TOA02 showed strong antitumor efficacy in nude mice with human head/neck and hepatocellular carcinoma xenografts, and the efficacy further improved when used in combination with chemotherapy and with different routes of administration and regimens. In immunocompetent mice, the addition of GM-CSF produced a stronger antitumor activity and induced more mature dendritic cells and macrophages. The TOA02 adenovirus showed strong tumor-cell selectivity in vitro and antitumor efficacy in mouse models of human head/neck and hepatocellular cancer, suggesting that TOA02 has potential clinical applications for the treatment of solid tumors.
Background & AimsRifampicin (RFP)‐induced cholestatic liver injury is characterized by impaired hepatic bile acid (BA) transport. Bile salt efflux pump (BSEP) and Na+/taurocholate cotransporter (NTCP) are the major BA transporters. However, little is known about the mechanisms underlying these transporters.MethodsThe role of tanshinone IIA (TAN IIA) in preventing RFP‐induced liver injury was evaluated in vitro and in vivo, based on the regulatory mechanism of nuclear factor erythroid 2‐related factor 2 (NRF2)‐BSEP/NTCP signalling. The epigenetic induction of NRF2 by TAN IIA was investigated as well as the influence on BSEP and NTCP transcriptional activation and NRF2 DNA‐binding ability.ResultsTAN IIA strongly induced BSEP and NTCP expression in hepatocytes. NRF2 knockdown abrogated the induction. We found two NRF2 binding sites on the human BSEP promoter, called musculoaponeurotic fibrosarcoma recognition elements (MAREs), and one MARE on the NTCP promoter. Human BSEP and NTCP promoter luciferase reporter gene plasmids were stimulated by NRF2. Mutations of the predicted MAREs abolished NRF2 transcriptional activation. TAN IIA induced the expression of ten‐eleven translocation 2 (TET2) to mediate the demethylation of NRF2, which promoted NRF2 DNA‐binding on the BSEP and NTCP promoters and their transcriptional activation. Finally, in vivo, Nrf2 played an important role in RFP‐induced liver injury (more serious liver injury in Nrf2‐/‐ mice), and TAN IIA prevented it.ConclusionsThese results indicate that NRF2 regulates the target transporters BSEP and NTCP, depending on the DNA demethylation by TET2. Pharmacological activation of NRF2 by TAN IIA may be beneficial for RFP‐induced liver injury.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.