Sodium alginate coating simultaneously increases the biosafety and immunotherapeutic activity of the cationic mRNA nanovaccine

The extraordinary advantages associated with mRNA vaccines, including their high efficiency, relatively low severity of side effects, and ease of manufacture, have enabled them to be a promising immunotherapy approach against various infectious diseases and cancers. Nevertheless, most mRNA delivery carriers have many disadvantages, such as high toxicity, poor biocompatibility, and low efficiency in vivo, which have hindered the widespread use of mRNA vaccines. To further characterize and solve these problems and develop a new type of safe and efficient mRNA delivery carrier, a negatively charged SA@DOTAP-mRNA nanovaccine was prepared in this study by coating DOTAP-mRNA with the natural anionic polymer sodium alginate (SA). Intriguingly, the transfection efficiency of SA@DOTAP-mRNA was significantly higher than that of DOTAP-mRNA, which was not due to the increase in cellular uptake but was associated with changes in the endocytosis pathway and the strong lysosome escape ability of SA@DOTAP-mRNA. In addition, we found that SA significantly increased the expression of LUC-mRNA in mice and achieved certain spleen targeting. Finally, we confirmed that SA@DOTAP-mRNA had a stronger antigen-presenting ability in E. G7-OVA tumor-bearing mice, dramatically inducing the proliferation of OVA-specific CLTs and ameliorating the antitumor effect. Therefore, we firmly believe that the coating strategy applied to cationic liposome/mRNA complexes is of potential research value in the field of mRNA delivery and has promising clinical application prospects.

A small-molecule pan-HER inhibitor alone or in combination with cisplatin exerts efficacy against nasopharyngeal carcinoma / 医学前沿

The abnormal activation of HER family kinase activity is closely related to the development of human malignancies. In this study, we used HER kinases as targets for the treatment of nasopharyngeal carcinoma (NPC) and explored the anti-tumor effects of the novel pan-HER inhibitor HM781-36B, alone or in combination with cisplatin. We found that HER family proteins were positively expressed in tumor tissues of some NPC patients, and the high levels of those proteins were significantly related to poor prognosis. HM781-36B inhibited NPC in vitro and in vivo. HM781-36B exerted synergistic effects with cisplatin on inhibiting proliferation and promoting apoptosis of NPC cells. In NPC xenograft models in nude mice, HM781-36B and cisplatin synergistically inhibited tumor growth. Downregulating the activity of HER family proteins and their downstream signaling pathways and regulating tumor microenvironment may explain the synergistic anti-tumor effects of HM781-36B and cisplatin. In conclusion, our study provides evidence for HER family proteins as prognostic biomarkers and potential therapeutic targets for NPC. The pan-HER inhibitor HM781-36B alone or in combination with cisplatin represents promising therapeutic effects for the treatment of NPC patients, which provides a new idea for the comprehensive treatment of NPC.

Molecular mechanism of Chuanxiong Rhizoma in treating coronary artery diseases / 中草药·英文版

Objective: Most of the studies on the herb Chuanxiong Rhizoma (CR) have focused on the L-arginine-nitric oxide (NO) pathway, but the nitrate-nitrite-NO (NO

DNA-PK inhibition by M3814 enhances chemosensitivity in non-small cell lung cancer

A significant proportion of non-small cell lung cancer (NSCLC) patients experience accumulating chemotherapy-related adverse events, motivating the design of chemosensitizating strategies. The main cytotoxic damage induced by chemotherapeutic agents is DNA double-strand breaks (DSB). It is thus conceivable that DNA-dependent protein kinase (DNA-PK) inhibitors which attenuate DNA repair would enhance the anti-tumor effect of chemotherapy. The present study aims to systematically evaluate the efficacy and safety of a novel DNA-PK inhibitor M3814 in synergy with chemotherapies on NSCLC. We identified increased expression of DNA-PK in human NSCLC tissues which was associated with poor prognosis. M3814 potentiated the anti-tumor effect of paclitaxel and etoposide in A549, H460 and H1703 NSCLC cell lines. In the four combinations based on two NSCLC xenograft models and two chemotherapy, we also observed tumor regression at tolerated doses

Preliminary Study of Chidamide Combined with Hematopoietic Stem Cell Transplantation in the Treatment of Childhood Acute T-Lymphoblastic Leukemia / 中国实验血液学杂志

OBJECTIVE@#To investigate the efficacy and safety of combination chidamide and hematopoietic stem cell transplantation (HSCT) in the treatment of childhood acute T lymphoblastic leukemia (T-ALL).@*METHODS@#Seven children with acute T lymphoblastic leukemia received hematopoietic stem cell transplantation in SUN Yat-Sen Memorial Hospital of SUN Yat-Sen University were selected. 7 cases of T-ALL were divided into 2 groups: HSCT plus chidamide-treated group (4 cases) and traditional HSCT-treated group (3 cases) as control. The incidence of GVHD and other related complications, as well as implantation, recurrence and survival were compared between the two groups, and the side effects of chidamide were observed. All the patients were follow-up until January 2019.@*RESULTS@#All the 7 patients were alive and, there was no difference in the incidence of acute GVHD between the HSCT plus chidamides treated group and the traditional HSCT-treated group. The implantation rate of HSCT was 100%, and there were no recurrence occurred. During the application of chidamide, 3 cases showed adverse reactions, of which 2 cases had adverse reactions of grade 3 or higher, and 2 cases were hematological adverse reactions (neutropenia, thrombocytopenia), other adverse reactions were non-hematologic adverse reactions (transaminase elevation, fatigue, nausea, vomiting), there were no serious adverse reactions occurred. In the HSCT plus chidamide-treated group, 2 cases were found that mature lymphocytes were not expressed by tumors, during examing for minimal redidaul disease (MRD). Compared with the immunophenotype and TCR rearrangement at first diagnosis, the results did not support the source of residual T-ALL tumor cells. During the review of MRD, it was found that the abnormal T cells showed an increasing trend, indicating that chidamide might induce leukemia cell differentiation through some pathways.@*CONCLUSION@#Hematopoietic stem cell transplantation is still an effective method to cure children's T-ALL. In some cases, abnormal T-cell nonclonal amplification occurs during the application of chidamide, and the children with T-ALL can tolerable adverse reactions of chidamide.

Efficacy and Safety of Kuanxiong Aerosol in the Treatment of Coronary Heart Disease Angina ：A Meta-analysis / 中国药房

OBJECTIVE：To systematically evaluate the efficacy and safety of Kuanxiong aerosol in the treatment of coronary heart disease angina ，and to provide evidence-based reference for climical drug use . METHODS ：Retrieved from Cochrane Library，PubMed，Embase，CKNI，Wanfang data ，VIP，and CBM ，randomized controlled trials （RCTs）about Kuanxiong aerosol （trial group ）versus nitroglycerin （control group ）in the treatment of coronary heart disease angina were collected during the inception to Mar. 20th，2020. After literature screening and data extraction ，quality assessment was performed using the bias risk assessment tool recommended by the Cochrane System Evaluator Manual 5.1.0. Meta-analysis was performed by using Rev Man 5.3 statistical software. Sensitivity analysis was conducted for the stability of the result ，and trial sequential analysis （TSA）was performed by using TSA 0.9 software. RESULTS ：A total of 11 RCTs were included ，with a total of 1 847 cases. Meta-analysis showed that improvement rate of angina pectoris （within 3 min）[RR＝1.11，95％CI（1.02，1.22），P＝0.02] and total response rate of angina pectoris （within 5 min）[RR＝1.04，95％ CI（1.01，1.07），P＝0.01] in trial group were significantly higher than control group；the incidence of ADR [RR＝0.44，95％CI（0.35，0.57），P＜0.000 01] in trial group was significantly lower than control group. There was no statistical significance in total response rate of ECG [RR＝1.02，95％CI（0.97，1.09），P＝0.42] or the level of NO after treatment [SMD ＝－0.08，95％CI（－0.61，0.45），P＝0.76] between 2 groups. The results of sensitiv ity analysis and TSA showed that the efficacy evidence of Kuanxiong aerosol in the treatment of coronary heart disease pectoris was not accurate ，but the evidence of safety was accurate. CONCLUSIONS ：Kuanxiong aerosol can improve the efficacy in patients with coronary heart disease angina ，and the safety is better ，but the conclusions of efficacy needs to be further confirmed by enlarging sample size.

Balancing Effect of Biejiajian Oral Liquid () on ACE-Ang II-AT1R Axis and ACE2-Ang-(1-7)-Mas Axis in Rats with CCl-Induced Hepatic Fibrosis / 中国结合医学杂志

<p><b>OBJECTIVE</b>To explore the effect of Biejiajian Oral Liquid (, BOL) on CCl-induced hepatic fibrosis in rats by detecting the changes in the levels of angiotensin II (Ang II), angiotensin-(1-7) [Ang-(1-7)], angiotensin-converting enzyme (ACE), ACE2, angiotensin II type 1 receptor (AT1R), Mas, etc. METHODS: A total of 180 Wistar rats were randomly divided into two groups by random digital table method: prevention experiment and treatment experiment. Each group was further subdivided into the following 6 subgroups: normal control group, model group, vitamin E [100 mg/(kg·d), VE] group, enalapril [10 mg/(kg·g), Ena] group, high-dosage [20 g/(kg·d)] BOL group, and low-dosage [10 g/(kg·d)] BOL group. The hepatic fibrosis rat model was established by subcutaneous injection of CCl for 6 weeks. Prevention experiment and treatment experiment were administered with specific drugs at different times. At the end of treatment experiment, the pathological changes of liver were observed after hematoxylin-eosin staining. The expressions of ingredients in renin-angiotensin-aldosterone system (RAAS) such as AngII, Ang-(1-7), ACE, ACE2, AT1R, Mas, renin, CYP11B2 and angen in liver were detected by enzyme linked immunosorbent assay, immunohistochemistry method or reverse transcription-polymerase chain reaction, respectively.</p><p><b>RESULTS</b>The levels of AngII and Ang-(1-7) at the 6th week increased by 496.10% and 73.64%, respectively, compared with those at the 2nd week in the model group (P<0.01). With prevention or treatment with high-dosage BOL, there was an evident reduction of AngII level but an improvement of Ang-(1-7) level. Specifically, AngII level of high-dosage group decreased by 77.50% in prevention experiment (P=0.000) and by 76.93% in treatment experiment (P=0.002) compared with that in the model group. Ang-(1-7) level increased by 91.69% in prevention experiment (P=0.006) and by 70.77% in the treatment experiment (P=0.010) compared with that in the model group. The expression levels of mRNA of renin, ACE, CYP11B2, angen and AT1R decreased by 58.15%, 99.90%, 99.84%, 99.99% and 99.99% (all P<0.01), respectively.</p><p><b>CONCLUSIONS</b>BOL could help resist liver fibrosis in rats by enhancing the level of each ingredient in ACE2-Ang-(1-7)-Mas axis, while decreasing the level of each ingredient in ACE-AngII-AT1R axis. To some extent, BOL could enhance the regulation of RAAS in rats with CCl-induced hepatic fibrosis.</p>

Mitochondrial DNA in the regulation of innate immune responses

Mitochondrion is known as the energy factory of the cell, which is also a unique mammalian organelle and considered to be evolved from aerobic prokaryotes more than a billion years ago. Mitochondrial DNA, similar to that of its bacterial ancestor’s, consists of a circular loop and contains significant number of unmethylated DNA as CpG islands. The innate immune system plays an important role in the mammalian immune response. Recent research has demonstrated that mitochondrial DNA (mtDNA) activates several innate immune pathways involving TLR9, NLRP3 and STING signaling, which contributes to the signaling platforms and results in effector responses. In addition to facilitating antibacterial immunity and regulating antiviral signaling, mounting evidence suggests that mtDNA contributes to inflammatory diseases following cellular damage and stress. Therefore, in addition to its well-appreciated roles in cellular metabolism and energy production,mtDNA appears to function as a key member in the innate immune system. Here, we highlight the emerging roles of mtDNA in innate immunity.

Clinical significance of mast cells and IL-9 in B-NHL / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the role of mast cells and interleukin-9 (IL-9) in B-cell non-Hodgkin lymphoma (B-NHL) development and its clinical significance.</p><p><b>METHODS</b>The expression level of CD117 in tumor tissues of 32 B-NHL patients was determined by Western blot. The infiltration of CD117⁺ mast cells (MCs) in human B-NHL tumor tissues was observed by immunohistochemistry staining. To evaluate the correlations between the data from CD117⁺ MCs and biological markers of human B-NHL, a Spearman correlation coefficient (rs) was calculated. IL-9 levels in sera of B-NHL patients were measured by ELISA. Effects of IL-9 on expressions of functional genes of mouse bone marrow-derived mast cells (BMMCs) were detected by real-time quantitative RT-PCR.</p><p><b>RESULTS</b>The expression of CD117 was upregulated significantly in human B-cell NHL involved tissues when compared with that of controls (0.0551±0.0064 vs 0.0192±0.0072, P<0.01). Infiltration of more CD117⁺ MCs was found in tissues from B-cell NHL subjects compared with that of controls. IL-9 level in serum samples from patients with B-cell NHL was higher than that from healthy controls. Addition of rIL-9 to the culture gave rise to increase in the purity of mouse BMMCs in the first three weeks. In vitro culture experiments showed that the addition of IL-9 could induce the differentiation of mouse BMMC and the expressions of MC-related genes, including CD117, Fcer1α, Mcpt1 and Mcpt5.</p><p><b>CONCLUSION</b>Our study showed that IL-9 promoted immune response mediated by MCs, and probably played important roles in B-NHL growth. Pharmacological or targeted inhibition of mast cells or IL-9 activity may provide new strategy for B-cell NHL therapy.</p>

An assessment of the RIFLE criteria for acute kidney injury in patients requiring renal replacement therapy after surgical operation / 中华急诊医学杂志

1 ml/kg)and the ICU stay.Results The hospital mortality of AKI phaseⅢwas significantly higher than that of AKI phaseⅠorⅡ(P