Ginsenoside Rg1 ameliorates hypoxia-induced pulmonary arterial hypertension by inhibiting endothelial-to-mesenchymal transition and inflammation by regulating CCN1.

Pulmonary arterial hypertension (PAH) is a chronic obstructive disease characterized by vascular remodeling. Studies have confirmed that ginsenoside Rg1 can improve pulmonary hypertension to a certain extent, but the potential mechanism by which it improves hypoxia-induced PAH remains unclear. The aim of this study was to investigate the therapeutic effect of ginsenoside Rg1 on hypoxia-induced PAH. The results showed that hypoxia promoted inflammation, EndMT, and vascular remodeling, which were accompanied by decreased CCN1 levels and increased p-NFκB p65, TGF-ß1, and p-Smad 2/3 levels. Treatment with ginsenoside Rg1, recombinant CCN1, BAY-11-7082, and SB-431542 could prevent hypoxia-induced vascular remodeling, reduce the expression of the hypoxia-induced inflammatory cytokines TNF-α and IL-1ß, inhibit the expression of the mesenchymal markers α-SMA and Vimentin and restore the expression of the endothelial markers CD31 and VE-cadherin to improve hypoxia-induced EndMT, which may be associated with the upregulation of CCN1 protein expression and downregulation of p-NFκB p65, TGF-ß1, and p-Smad 2/3 in rats and cells. siRNA CCN1 transfection increased the expression of p-NFκB p65, TGF-ß1, and p-Smad 2/3 and accelerated the occurrence and development of inflammation and EndMT after hypoxia. In summary, our study indicated that hypoxia-induced EndMT and inflammation play a role in hypoxic pulmonary hypertension (HPH). Ginsenoside Rg1 treatment could reverse hypoxia-induced EndMT and inflammation by regulating CCN1 and has potential value in the prevention and treatment of HPH.

VIM­AS1 promotes proliferation and drives enzalutamide resistance in prostate cancer via IGF2BP2­mediated HMGCS1 mRNA stabilization.

VIM­AS1, a cancer­specific long non­coding RNA, has been recognized as a pivotal regulator in multiple types of cancer. However, the role of VIM­AS1 in the proliferation and resistance to anti­androgen therapy of LNCaP and C4­2 prostate cancer cells remains to be determined. In the current study, gain­and­loss experiments were used to investigate the effects of VIM­AS on the proliferation and anti­androgen therapy of LNCaP and C4­2 cells. RNA sequencing, RNA pulldown and RNA immunoprecipitation were used to elucidate the underlying mechanism of VIM­AS1 driving prostate progression. It was demonstrated that VIM­AS1 was upregulated in C4­2 cells, an established castration­resistant prostate cancer (CRPC) cell line, compared with in LNCaP cells, an established hormone­sensitive prostate cancer cell line. The present study further demonstrated that VIM­AS1 was positively associated with the clinical stage of prostate cancer. Functionally, overexpression of VIM­AS1 decreased the sensitivity to enzalutamide treatment and enhanced the proliferation of LNCaP cells in vitro, whereas knockdown of VIM­AS1 increased the sensitivity to enzalutamide treatment and reduced the proliferation of C4­2 cells in vitro and in vivo. Mechanistically, 3­hydroxy­3­methylglutaryl­CoA synthase 1 (HMGCS1) was identified as one of the direct downstream targets of VIM­AS1, and VIM­AS1 promoted HMGCS1 expression by enhancing HMGCS1 mRNA stability through a VIM­AS1/insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2)/HMGCS1 RNA­protein complex. Rescue assays indicated that knockdown of HMGCS1 expression ameliorated the increase in proliferation and enzalutamide resistance of prostate cancer cells induced by VIM­AS1 overexpression. Overall, the present study determined the roles and mechanism of the VIM­AS1/IGF2BP2/HMGCS1 axis in regulating proliferation and enzalutamide sensitivity of prostate cancer cells and suggested that VIM­AS1 may serve as a novel therapeutic target for the treatment of patients with CRPC.

Traumatic Stress Produces Delayed Alterations of Synaptic Plasticity in Basolateral Amygdala.

Acute traumatic event exposure is a direct cause of post-traumatic stress disorder (PTSD). Amygdala is suggested to be associated with the development of PTSD. In our previous findings, different activation patterns of GABAergic neurons and glutamatergic neurons in early or late stages after stress were found. However, the neural plastic mechanism underlying the role of basolateral amygdala (BLA) in post-traumatic stress disorder remains unclear. Therefore, this study mainly aimed at investigating time-dependent morphologic and electrophysiological changes in BLA during the development of PTSD. We used single prolonged stress (SPS) procedure to establish PTSD model of rats. The rats showed no alterations in anxiety behavior as well as in dendritic spine density or synaptic transmission in BLA 1 day after SPS. However, 10 days after SPS, rats showed enhancement of anxiety behavior, and spine density and frequency of miniature excitatory and inhibitory postsynaptic currents in BLA. Our results suggested that after traumatic stress, BLA displayed delayed increase in both spinogenesis and synaptic transmission, which seemed to facilitate the development of PTSD.

Therapeutic effects of human monoclonal PSMA antibody-mediated TRIM24 siRNA delivery in PSMA-positive castration-resistant prostate cancer.

Background and Aims: Prostate specific membrane antigen (PSMA) is specifically expressed on prostate epithelial cells and markedly overexpressed in almost all prostate cancers. TRIM24 is also up-regulated from localized prostate cancer to metastatic castration-resistant prostate cancer (CRPC). Because of the high relevance of TRIM24 for cancer development and the universal expression of PSMA in CPRC, we investigated the efficacy of human monoclonal PSMA antibody (PSMAb)-based platform for the targeted TRIM24 siRNA delivery and its therapeutic efficacy in CRPC in vivo and in vitro. Methods: The therapeutic complexes were constructed by conjugating PSMAb and sulfo-SMCC-protamine, and encapsulating TRIM24 siRNA. Flow cytometry, immunofluorescence, and fluorescence imaging were performed to detect the receptor-binding, internalization, and targeted delivery of PSMAb-sulfo-SMCC-protamine (PSP)-FAM-siRNA complex (PSPS) in vitro and in vivo. CCK-8, plate-colony formation, apoptosis, cell cycle, and Transwell assays were performed to evaluate the therapeutic potential of the PSP-TRIM24 siRNA complex in vitro, whereas the in vivo therapeutic efficacy was monitored by small animal imaging, radiography, and micro CT. Results: We confirmed that PSP could efficiently protect siRNA from enzymatic digestion, enable targeted delivery of siRNA, and internalize and release siRNA into PSMA-positive (PSMA+) prostate cancer cells in vitro and in vivo. Silencing TRIM24 expression by the PSP-TRIM24 siRNA complex could dramatically suppress proliferation, colony-formation, and invasion of PSMA+ CRPC cells in vitro, and inhibit tumor growth of PSMA+ CRPC xenografts and bone loss in PSMA+ CRPC bone metastasis model without obvious toxicity at therapeutic doses in vivo. Conclusion: PSMAb mediated TRIM24 siRNA delivery platform could significantly inhibit cell proliferation, colony-formation, and invasion in PSMA+ CRPC in vitro and suppressed tumor growth and bone loss in PSMA+ CRPC xenograft and bone metastasis model.

Propofol Inhibits Proliferation, Migration, Invasion and Promotes Apoptosis Through Down-Regulating miR-374a in Hepatocarcinoma Cell Lines.

BACKGROUND: Propofol is a commonly used anaesthetic with controversial effects on cancer cells. We aimed to explore the functional roles of propofol in hepatocellular carcinoma (HCC) cells as well as the underlying mechanisms. METHODS: HepG2 and SMMC-7721 cells were used in this study. Firstly, the effects of propofol on cell viability, migration, invasion, apoptosis, and involved proteins were assessed by Cell Counting Kit-8 assay, Transwell assay, flow cytometry assay and Western blot analysis, respectively. Subsequently, alteration of miR-374a after stimulation of propofol was analyzed by qRT-PCR. miR-374a was overexpressed and the alteration of proteins in the Wnt/ß-catenin and PI3K/AKT pathways was detected by Western blot analysis. The downstream factor of miR-374a was finally studied. RESULTS: Propofol inhibited cell viability, migration and invasion but promoted apoptosis of HepG2 and SMMC-7721 cells. Meanwhile, cyclinD1, matrix metalloproteinase (MMP)-2 and MMP-9 were down-regulated while Bax/Bcl-2, cleaved caspase-3 and cleaved caspase-9 were up-regulated by propofol. Then, miR-374a level was reduced by propofol. Expression of Wnt3a, ß-catenin, p-PI3K and p-AKT was decreased by propofol, whereas these decreases were reversed by miR-374a overexpression. Finally, TP53 was proven to be target of miR-374a in HepG2 cells. CONCLUSION: Propofol inhibited cell proliferation, migration and invasion while promoted cell apoptosis of HepG2 and SMMC-7721 cells through inhibiting the Wnt/ß-catenin and PI3K/ AKT pathways via down-regulation of miR-374a. Besides, miR-374a affected propofol-treated HepG2 cells by targeting TP53.

Endovascular treatment and morphology typing of chronic ostial occlusion of the subclavian artery.

Chronic obstructive lesions of the subclavian artery (SCA) often result in subclavian steal syndrome, which leads to arm claudication, transient cerebral ischemia, and other serious complications. The lesions are classified as stenosis and occlusion, according to the degree of obstruction. Unlike totally occlusive lesions, including ostial occlusions, stenotic lesions have an excellent technical success rate. In the present study, ostial occlusions were classified into 4 types according to their angiographic appearance. A total of 8 patients (6 male, 2 female) with SCA occlusions were treated with percutaneous transluminal angioplasty and stenting over a 4-year period. Mean patient age was 65.6 years (range, 60-72 years). In total, 9 self-expanding and 1 balloon-expandable stent were implanted at the ostia of the SCA in 7 of the patients. One female patient did not undergo stenting. Bleeding at the access site was noted in 2 patients and was controlled by gauze pressure. The patient that did not undergo stenting was lost to follow-up with symptoms of a transient ischemic attack at 3 months. The mean follow-up time for the remaining 7 patients was 15.7 months (range, 1-36 months). No ischemic symptoms, neointimal hyperplasia, or restenosis was observed in these patients. The transfemoral artery operation approach is preferred for rat-tail and peak type occlusions, whereas the dual approach involving both femoral and radial arteries is preferred for hilly and plain type occlusions. The angiographic morphology typing used in the present study may serve as a reference to decide upon the interventional operation strategy to be used for improving the technical success rate.

[Association between ESR1 gene polymorphisms and haplotypes with schizophrenia].

OBJECTIVE: To assess the association between single nucleotide polymorphisms (SNPs) and haplotypes of estrogen receptor 1 (ESR1) gene with schizophrenia. METHODS: Three SNPs (rs2234693, rs9340799 and rs3798759) were determined in 333 schizophrenic patients and 315 healthy subjects with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Allelic and genotypic frequencies and particular haplotypes were compared between the two groups using Chi-square test. RESULTS: The allelic and genotypic frequencies of rs2234693 and rs9340799 showed no significant difference between the two groups (P U+003E 0.05). However, a significant difference was detected in the frequencies of rs3798759 G allele and GG genotype between the two groups (P U+003C 0.01). Single factor analysis stratified by sex also found that frequencies of rs3798759 GG and TG genotypes and G allele were significantly higher in female schizophrenia patients compared with healthy females (P U+003C 0.05). Haplotypes C-A-G and C-G-G were more common in schizophrenia group (P U+003C 0.05). CONCLUSION: polymorphisms of rs3798759 may be a risk factor for female patients with schizophrenia, and haplotypes C-A-G and C-G-G may be risk factors for schizophrenia.

[Hemostatic aerosol for emergent management of artery rupture].

OBJECTIVE: To investigate the effect of the hemostatic aerosol (HA) for emergent management of artery rupture in pigs. METHODS: Thirty pigs were used to establish animal models of complete femoral artery rupture by cutting off the arteries. The pigs were divided equally into 3 groups according to the hemostatic measures taken before the application of HA, namely HA spray alone, temporary hemostasis by compressing the wound with fingers, or tourniquet in another group, before HA sprays. In the late groups the finger compression or tournigut was removed 10 min after HA spray. The main indexes including average arterial blood pressure (AABP), times of spray, hemostatic time, time for membrane formation and the thickness of the HA membrane shaped while spraying, and the success rates of each method, were assessed 12 h postoperatively. RESULTS: The rate of successful hemostasis achieved by tourniquet and HA spray was 90%, 30% by finger compression and HA spray, and only 10% by direct HA spray. CONCLUSIONS: For complete artery rupture, application of tourniquet for temporary hemostasis 10 min before HA spay can be the best choice for emergent management of artery rupture.

[Finger reconstruction with extended free second toe flap transfer].

OBJECTIVE: To investigate an ideal method for finger reconstruction with extended the second toe flap transfer. METHODS: The second toe free flap was created, combined with an pedicled skin flap from the fibular side of the great toe inlaid in the ventral side of the second toe, a double-wing flap and the distal part of the metatarsal bone. The composite free flap was transferred by vascular anastomosis for finger reconstruction. RESULTS: The reconstructed finger exhibited nice looking and better function. The procedure had little influence to the appearance and function of the donor foot. CONCLUSION: This method is effective in ameliorating the appearance and function of the reconstructed finger with the second toe transfer.