Inhibition of SK Channels in VTA Affects Dopaminergic Neurons to Improve the Depression-Like Behaviors of Post-Stroke Depression Rats.

Purpose: This study aimed to investigate the effect of small-conductance calcium-activated potassium channels (SK channels) on the dopaminergic (DA) neuron pathways in the ventral tegmental area (VTA) during the pathogenesis of post-stroke depression (PSD) and explore the improvement of PSD by inhibiting the SK channels. Patients and Methods: Four groups of Sprague-Dawley rats were randomly divided: Control, PSD, SK channel inhibitor (apamin) and SK channel activator (CyPPA) groups. In both control and CyPPA groups, sham surgery was performed. In the other two groups, middle cerebral arteries were occluded. The behavioral indicators related to depression in different groups were compared. Immunofluorescence was used to measure the activity of DA neurons in the VTA, while qRT-PCR was used to assess the expression of SK channel genes. Results: The results showed that apamin treatment improved behavioral indicators related to depression compared to the PSD group. Furthermore, the qRT-PCR analysis revealed differential expression of the KCNN1 and KCNN3 subgenes of the SK channels in each group. Immunofluorescence analysis revealed an increase in the expression of DA neurons in the VTA of the PSD group, which was subsequently reduced upon apamin intervention. Conclusion: This study suggests that SK channel activation following stroke contributes to depression-related behaviors in PSD rats through increased expression of DA neurons in the VTA. And depression-related behavior is improved in PSD rats by inhibiting the SK channels. The results of this study provide a new understanding of PSD pathogenesis and the possibility of developing new strategies to prevent PSD by targeting SK channels.

Fine-Tuned Polymer Nanoassembly for Codelivery of Chemotherapeutic Drug and siRNA.

Successful clinical application of siRNA to liver-associated diseases reinvigorates the RNAi therapeutics and delivery vectors, especially for anticancer combination therapy. Fine tuning of copolymer-based assembly configuration is highly important for a desirable synergistic cancer cell-killing effect via the codelivery of chemotherapeutic drug and siRNA. Herein, an amphiphilic triblock copolymer methoxyl poly(ethylene glycol)-block-poly(L-lysine)-block-poly(2-(diisopropyl amino)ethyl methacrylate) (abbreviated as mPEG-PLys-PDPA or PLD) consisting of a hydrophilic diblock mPEG-PLys and a hydrophobic block PDPA is synthesized. Three distinct assemblies (i.e., nanosized micelle, nanosized polymersome, and microparticle) are acquired, along with the increase in PDPA block length. Furthermore, the as-obtained polymersome can efficiently codeliver doxorubicin hydrochloride (DOX) as a hydrophilic chemotherapeutic model and siRNA against ADP-ribosylation factor 6 (siArf6) as an siRNA model into cancer cell via lysosomal pH-triggered payload release. PC-3 prostate cell is synergistically killed by the DOX- and siArf6-coloading polymersome (namely PLD@DOX/siArf6). PLD@DOX/siArf6 may serve as a robust nanomedicine for anticancer therapy.

Prognostication of Pancreatic Cancer Using The Cancer Genome Atlas Based Ferroptosis-Related Long Non-Coding RNAs.

Background: Long non-coding RNAs (lncRNAs) are key regulators of pancreatic cancer development and are involved in ferroptosis regulation. LncRNA transcript levels serve as a prognostic factor for pancreatic cancer. Therefore, identifying ferroptosis-related lncRNAs (FRLs) with prognostic value in pancreatic cancer is critical. Methods: In this study, FRLs were identified by combining The Cancer Genome Atlas (TCGA) and FerrDb databases. For training cohort, univariate Cox, Lasso, and multivariate Cox regression analyses were applied to identify prognosis FRLs and then construct a prognostic FRLs signature. Testing cohort and entire cohort were applied to validate the prognostic signature. Moreover, the nomogram was performed to predict prognosis at different clinicopathological stages and risk scores. A co-expression network with 76 lncRNA-mRNA targets was constructed. Results: Univariate Cox analysis was performed to analyze the prognostic value of 193 lncRNAs. Furthermore, the least absolute shrinkage and selection operator and the multivariate Cox analysis were used to assess the prognostic value of these ferroptosis-related lncRNAs. A prognostic risk model, of six lncRNAs, including LINC01705, AC068620.2, TRAF3IP2-AS1, AC092171.2, AC099850.3, and MIR193BHG was constructed. The Kaplan Meier (KM) and time-related receiver operating characteristic (ROC) curve analysis were performed to calculate overall survival and compare high- and low-risk groups. There was also a significant difference in survival time between the high-risk and low-risk groups for the testing cohort and the entire cohort, with AUCs of .723, .753, respectively. Combined with clinicopathological characteristics, the risk model was validated as a new independent prognostic factor for pancreatic adenocarcinoma through univariate and multivariate Cox regression. Moreover, a nomogram showed good prediction. Conclusion: The signature of six FRLs had significant prognostic value for pancreatic adenocarcinoma. They may be a promising therapeutic target in clinical practice.

The role of vascular endothelial growth factor in ischemic stroke.

Ischemic stroke is an injury caused by temporary or permanent cerebral vascular occlusion. It has a high incidence, mortality, and disability rate in clinical practice, and thus poses a considerable threat to public health as one of the top three major conditions endangering human health. Vascular endothelial growth factor is a specific mitogen of endothelial cells and a protein factor that is closely related to ischemic stroke. Vascular endothelial growth factor plays an important role in a multitude of physiological and pathological conditions. As a potential angiogenic protein for the treatment of ischemic stroke, vascular endothelial growth factor plays a role in promoting angiogenesis and neuroprotection and regeneration. At the same time, it plays a role in brain edema, collateral artery formation, and atherosclerosis. An increase in vascular endothelial growth factor levels contributes to the early pathological changes in patients with stroke and is closely related to the formation of cerebral edema in ischemic stroke complications. In theory, the neuroprotective and angiogenic effects of vascular endothelial growth factor make it an ideal candidate for the treatment of stroke. Here, we review the mechanism by which vascular endothelial growth factor participates in various stages of ischemic stroke and its prospects for use in the treatment of ischemic stroke.

Expression and role of CaMKII and Cx43 in a rat model of post-stroke depression.

Expression of Ca2+/CaM-dependent protein kinase II (CaMKII) and connexin 43 (Cx43) in a rat model of post-stroke depression (PSD) was investigated. Rats were separated into control group (10 rats underwent a sham operation and were not ligated after incision), PSD group (13 PSD rats) and KN93 group (12 rats were treated with KN93, an inhibitor of CaMKII, on the basis of the PSD group). After PSD modeling, Longa scoring was performed, and an open field test as well as a step-through test were carried out to observe rat behavior. RT-qPCR and western blot analysis were used to detect the expression of CaMKII and CX43 in the hippocampus tissue. On the 14th day, the Longa scores in the PSD and KN93 groups were higher than that in the control group (P<0.05), while on the 18th day, Longa score was higher in the PSD group than that in the control and KN93 groups, and higher in the KN93 group than that in the control group (both P<0.05). In the PSD group, the Longa score on the 18th day was significantly higher than that on the 14th day, whereas in the KN93 group, the Longa score on the 18th day was significantly lower than that on the 14th day (both P<0.05). Compared with the PSD group on the 18th day, the passive avoidance defects in the KN93 group were improved, and the frequency of activity in the open field test was significantly increased. On the 18th day, the expression levels of the mRNA and protein of CaMKII were higher in the PSD group than in the control group, whereas those of Cx43 were lower in the PSD group than those in the control group (P<0.05). The mRNA and protein expression levels of CaMKII in the KN93 group were lower than those in the PSD group, but higher than those in the control group. In PSD rats, CaMKII expression is upregulated, but Cx43 expression is downregulated, and both CaMKII and Cx43 may participate in PSD. The inhibitor of CaMKII, KN93, can improve the depression in PSD rats.