A pathological feature in atherosclerosis is the dysfunction and death of vascular endothelial cells (EC). Oxidized low‐density lipoprotein (LDL), known to accumulate in the atherosclerotic arterial walls, impairs endothelium‐dependent relaxation and causes EC apoptosis. A major bioactive ingredient of the oxidized LDL is lysophosphatidylcholine (LPC), which at higher concentrations causes apoptosis and necrosis in various EC. There is hitherto no report on LPC‐induced cytotoxicity in brain EC. In this work, we found that LPC caused cytosolic Ca2+ overload, mitochondrial membrane potential decrease, p38 activation, caspase 3 activation and eventually apoptotic death in mouse cerebral bEND.3 EC. In contrast to reported reactive oxygen species (ROS) generation by LPC in other EC, LPC did not trigger ROS formation in bEND.3 cells. Pharmacological inhibition of p38 alleviated LPC‐inflicted cell death. We examined whether heparin could be cytoprotective: although it could not suppress LPC‐triggered Ca2+ signal, p38 activation and mitochondrial membrane potential drop, it did suppress LPC‐induced caspase 3 activation and alleviate LPC‐inflicted cytotoxicity. Our data suggest LPC apoptotic death mechanisms in bEND.3 might involve mitochondrial membrane potential decrease and p38 activation. Heparin is protective against LPC cytotoxicity and might intervene steps between mitochondrial membrane potential drop/p38 activation and caspase 3 activation. 相似文献
Introduction: It is now clear that circulating cell-free ribonucleic acids (ccfRNAs), including messenger RNA (mRNA) and miRNA, are potential cancer biomarkers. As ccfmiRNA is relatively more stable than ccfmRNA, research should concentrate on developing novel methods to preserve the stability of ccfmRNA and standardization of the protocol which includes extraction, detection, and multicenter validation.
Areas covered: This literature review concentrates on the potential of ccfRNA being used as a biomarker in cancer, with special focus on mRNAs and microRNAs (miRNAs).
Expert opinion: With the advancement of high-throughput technologies such as RNA sequencing, a panel of biomarkers will be used for the diagnosis, prognosis and therapeutic monitoring of cancer patients. In order to achieve this important target, bioinformatics education to pathologists, scientists, and technologists in molecular diagnostic laboratories is essential. Moreover, the panel of these new ccfRNAs biomarkers has to obtain approval or clearance from an authority such as the US Food and Drug Administration (FDA), and the standard of utilizing these new protocols has to be recognized via accreditation exercise. Therefore, there is still a long way to go before an extensively use of ccfRNA biomarkers in cancer patients can be realized. 相似文献
Upon infection or brain damage, microglia are activated to play roles in immune responses, including phagocytosis and soluble factor release. However, little is known whether the event of phagocytosis could be a trigger for releasing soluble factors from microglia. In this study, we tested if microglia secrete a neurovascular mediator matrix metalloproteinase-9 (MMP-9) after phagocytosis in vitro. Primary microglial cultures were prepared from neonatal rat brains. Cultured microglia phagocytosed Escherichia coli bioparticles within 2 hr after incubation and started to secrete MMP-9 at around 12 hr after the phagocytosis. A TLR4 inhibitor TAK242 suppressed the E. coli-bioparticle-induced MMP-9 secretion. However, TAK242 did not change the engulfment of E. coli bioparticles in microglial cultures. Because lipopolysaccharides (LPS), the major component of the outer membrane of E. coli, also induced MMP-9 secretion in a dose–response manner and because the response was inhibited by TAK242 treatment, we assumed that the LPS-TLR4 pathway, which was activated by adhering to the substance, but not through the engulfing process of phagocytosis, would play a role in releasing MMP-9 from microglia after E. coli bioparticle treatment. To support the finding that the engulfing step would not be a critical trigger for MMP-9 secretion after the event of phagocytosis in microglia, we confirmed that cell debris and amyloid beta were both captured into microglia via phagocytosis, but neither of them induced MMP-9 secretion from microglia. Taken together, these data demonstrate that microglial response in MMP-9 secretion after phagocytosis differs depending on the types of particles/substances that microglia encountered. 相似文献
Advanced low-grade ovarian carcinoma (LGOC) is difficult to treat. In several studies, high estrogen receptor (ER) protein expression was observed in patients with LGOC, which suggests that antihormonal therapy (AHT) is a treatment option. However, only a subgroup of patients respond to AHT, and this response cannot be adequately predicted by currently used immunohistochemistry (IHC). A possible explanation is that IHC only takes the ligand, but not the activity, of the whole signal transduction pathway (STP) into account. Therefore, in this study, the authors assessed whether functional STP activity can be an alternative tool to predict response to AHT in LGOC.
Methods
Tumor tissue samples were obtained from patients with primary or recurrent LGOC who subsequently received AHT. Histoscores of ER and progesterone receptor (PR) were determined. In addition, STP activity of the ER STP and of six other STPs known to play a role in ovarian cancer was assessed and compared with the STP activity of healthy postmenopausal fallopian tube epithelium.
Results
Patients who had normal ER STP activity had a progression-free survival (PFS) of 16.1 months. This was significantly shorter in patients who had low and very high ER STP activity, with a median PFS of 6.0 and 2.1 months, respectively (p < .001). Unlike ER histoscores, PR histoscores were strongly correlated to the ER STP activity and thus to PFS.
Conclusions
Aberrant low and very high functional ER STP activity and low PR histoscores in patients with LGOC indicate decreased response to AHT. ER IHC is not representative of functional ER STP activity and is not related to PFS. 相似文献
The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial was designed to determine whether maintenance interferon therapy could slow disease progression in patients who had failed to eradicate hepatitis C virus (HCV) during prior interferon treatment (nonresponders). Ten clinical sites, a virological testing center, and a data coordinating center (DCC) were selected to collaborate in the design and implementation of the final protocol. Eligible patients had been treated previously with interferon for at least 12 weeks, with or without another antiviral, ribavirin, but still had persistent viremia. Because patients had received a variety of prior treatments, and as a perceived benefit of enrollment, we incorporated a Lead-in period of treatment with long-acting pegylated interferon alfa-2a plus ribavirin into the study design, a combination believed to be more effective but not approved by the Food and Drug Administration at the Trial's inception. If patients failed to achieve clearance of virus from the blood after 20 weeks of this Lead-in therapy, they were entered into the main trial at week 24 and randomized to receive either a lower dose of pegylated interferon weekly alone or no further therapy for an additional 3 1/2 years. The original protocol was amended later in three respects to improve enrollment and to adapt to Food and Drug Administration approval of the Lead-in therapy, including allowing patients to proceed directly to the randomized part of the study if treatment resembling the Lead-in had been completed. The protocol changes enhanced enrollment while upholding the original goals of the study and its integrity. 相似文献