Automatically optimized radiomics modeling system for small gastric submucosal tumor (<2 cm) discrimination based on EUS images.

BACKGROUND AND AIMS: The clinical management of small gastric submucosal tumors (SMTs) (<2 cm) faces a non-negligible challenge because of the lack of guideline consensus and effective diagnostic tools. This article develops an automatically optimized radiomics modeling system (AORMS) based on EUS images to diagnose and evaluate SMTs. METHODS: A total of 205 patients with EUS images of small gastric SMTs (<2 cm) were retrospectively enrolled in the development phase of AORMS for the diagnosis and the risk stratification of GI stromal tumor (GIST). A total of 178 patients with images from different centers were prospectively enrolled in the independent testing phase. The performance of AORMS was compared to that of endoscopists in the development set and evaluated in the independent testing set. RESULTS: AORMS demonstrated an area under the curve (AUC) of 0.762 for the diagnosis of GIST and 0.734 for the risk stratification of GIST, respectively. In the independent testing set, AORMS achieved an AUC of 0.770 and 0.750 for the diagnosis and risk stratification of small GISTs, respectively. In comparison, the AUCs of 5 experienced endoscopists ranged from 0.501 to 0.608 for diagnosing GIST and from 0.562 to 0.748 for risk stratification. AORMS outperformed experienced endoscopists by more than 20% in diagnosing GIST. CONCLUSIONS: AORMS implements automatic parameter selection, which enhances its robustness and clinical applicability. It has demonstrated good performance in the diagnosis and risk stratification of GISTs, which could aid endoscopists in the diagnosis of small gastric SMTs (<2 cm).

Discovery and preclinical evaluations of TQB3616, a novel CDK4-biased inhibitor.

Among small-molecule CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) approved for metastatic breast cancers, abemaciclib has a more tolerable adverse effects in clinic. This is attributable to preferential inhibition of CDK4 over CDK6. In our search for a biased CDK4 inhibitor, we discovered a series of pyrimidine-indazole inhibitors. SAR studies led us to TQB3616 as a preferential CDK4 inhibitor. TQB3616 exhibited improvements in both enzymatic and cellular proliferation inhibitory potency when tested side-by-side with the FDA approved palbociclib and abemaciclib. TQB3616 also possessed favorable PK profile in multiple species. These differentiated properties, together with excellent GLP safety profile warranted TQB3616 moving to clinic. TQB3616 entered into clinical development in 2019 and currently in phase III clinical trials (NCT05375461, NCT05365178).

Endoscopic full-thickness resection, indication, methods and perspectives.

Minimally invasive surgery has emerged as the dominant theme of modern surgery, in which endoscopic surgery plays a key role. The technique of endoscopic surgery has evolved continuously with extensive research, improving the treatment modalities as well as expanding the indications for its use. As an active perforation endoscopic technique, endoscopic full-thickness resection (EFTR) is mainly used in the treatment of submucosal tumors (SMTs) of the gastrointestinal tract. With decades of evolution, EFTR has gradually developed into a mature endoscopic operation. Based on clinical experience and current research, indications, techniques, clinical outcomes and future perspectives for EFTR are discussed in this paper. We performed a bibliometric study on EFTR literature and showed robust data through a brief meta-analysis on the topic.

Puerarin Ameliorates 5-Fluorouracil-Induced Intestinal Mucositis in Mice by Inhibiting JAKs.

Intestinal mucositis resulting from 5-fluorouracil (5-FU)-based chemotherapy subjects patients to great pain and hampers cancer treatment progress. Puerarin, the major active ingredient in Pueraria lobata, exerts anti-inflammatory and antioxidative effects. However, whether puerarin has an effect on 5-FU-induced intestinal mucositis remains unknown. We established a mice model of intestinal mucositis through the intraperitoneal injection of 5-FU and then injected puerarin (50 and 100 mg/kg) intraperitoneally for 7 consecutive days. Routine parameters, such as body weight, food intake, and diarrheal incidence, were examined to evaluate the effects of puerarin on intestinal mucositis in mice. The intestinal barrier's functions were also evaluated by measuring the serum recovery of fluorescein isothiocyanate-4kD dextran in this study. The expression levels of inflammatory cytokines, inflammatory mediators, oxidative reactions, as well as apoptotic marker proteins were determined to elucidate the underlying mechanisms of puerarin on intestinal mucositis. The model mice presented symptoms and histopathological changes typical of 5-FU-induced intestinal mucositis. In addition to vigorous inflammatory reactions, oxidative reactions, and cell apoptosis, Janus kinase (JAK) was markedly activated. Puerarin decreased the expression levels of those of inflammatory mediators, oxidative reactions, and apoptosis-related proteins in 5-FU-induced mucositis by blocking the activation of JAK. Puerarin decreased inflammation, oxidative reactions, and apoptosis and protected intestinal barrier functions to ameliorate 5-FU-induced intestinal mucositis by inhibiting the activation of JAK. This study provides novel insights into the pathologic mechanisms of (and treatment alternatives for) 5-FU-induced intestinal mucositis. SIGNIFICANCE STATEMENT: This study reveals the mechanism responsible for the protective effects of puerarin in 5-fluorouracil-induced intestinal mucositis. Puerarin inhibits the activation of JAK, thereby suppressing inflammation, oxidative reactions, cell apoptosis, and protected intestinal barrier functions to ameliorate 5-FU-induced intestinal mucositis. Overall, our results suggest that puerarin can serve as a potential natural JAK inhibitor in the treatment of 5-FU-induced intestinal mucositis.

Targeting JAK/STAT signaling pathways in treatment of inflammatory bowel disease.

Janus kinase/signal transduction and transcriptional activator (JAK/STAT) signaling pathway is a transport hub for cytokine secretion and exerts its effects. The activation of JAK/STAT signaling pathway is essential for the regulation of inflammatory responses. Inappropriate activation or deletion of JAK/STAT signaling pathway is the initiator of the inflammatory response. JAK/STAT signaling pathway has been demonstrated to be involved in the process of innate and adaptive immune response to inflammatory bowel disease (IBD). In this review, we discuss the role of the JAK/STAT signaling pathway in the regulation of different cells in IBD, as well as new findings on the involvement of the JAK/STAT signaling pathway in the regulation of the intestinal immune response. The current status of JAK inhibitors in the treatment of IBD is summarized as well. This review highlights natural remedies that can serve as potential JAK inhibitors. These phytochemicals may be useful in the identification of precursor compounds in the process of designing and developing novel JAK inhibitors.

Tumor Microenvironment Stimuli-Responsive Nanoparticles for Programmed Anticancer Drug Delivery.

It is well-known that large size nanoparticles stay for a long time in the circulation system, but show poor tissue penetration and low cellular uptake. In order to reconcile the conflicting needs for extended circulation time, extensive tumor tissue penetration, and enhanced cellular uptake for nanodrug delivery systems, we designed DOX-containing hypersensitive nanoparticles that responded to the tumor microenvironment for programmed DOX delivery. A supersensitive polymer material, poly(2-ethyl-2-oxazoline)-poly(methacryloyl sulfadimethoxine), was synthesized (PEOz-b-PSD, pKa = 6.96). At the physiological environment, PEOz-b-PSD and polyamidoamine/DOX (PAMAM/DOX) can form nanoparticles, PEOz-b-PSD/PAMAM/DOX (PEPSD/PAM/DOX), via electrostatic adsorption. The PEPSD/PAM/DOX has an intact structure, which can prolong circulation time. While in the tumor environment, the PEOz-b-PSD was rapidly protonated and showed charge reversal, leading the detachment of PEOz-b-PSD from the nanoparticles; then the large size nanoparticles with a negative charge (PEPSD/PAM/DOX) instantaneously turn into positively charged ultrafine nanoparticles. The sudden inversion of size and charge can effectively improve tumor accumulation and internal penetration. After entering tumor cells, nanoparticles can release drugs quickly through the action of a PAMAM proton sponge, resulting in enhanced tumor inhibition. Our results proved that the programmed nanoparticles could remarkably enhance the in vivo antitumor efficacy and reduce cardiotoxicity of DOX. This study designed ultrasensitive nanoparticles in the tumor microenvironment, which appear to be beneficial for enhancing the treatment efficacy of DOX in solid tumors.

Folate Modified Long Circulating Nano-Emulsion as a Promising Approach for Improving the Efficiency of Chemotherapy Drugs in Cancer Treatment.

PURPOSE: In order to improve the therapeutic efficiency of the chemotherapeutic drug paclitaxel in tumors, a folate-based Paclitaxel nanoemulsion (FNEs) was developed for tumor targeted treatment. METHODS: In this study, we designed a folate-targeted nanoemulsion (folate/PEG-DSPE/nanoemulsion, FNEs) based on the traditional nanoemulsion using the principle of long-circulation targeting receptor mediated. The nanoemulsion (folate/PEG-DSPE/nanoemulsion, FNEs) was fabricated using high-pressure homogenization with a microfluidizer. RESULTS: The nanoemulsion (folate/PEG-DSPE/nanoemulsion, FNEs) can improve the delivery efficiency of nanocarriers at the tumor site by virtue of the high expression of folate receptors on the tumor surface. Malvern Nanoseries device and transmission electron microscopy (TEM) analyses showed that the nanoemulsions were spherical with an average diameter of 140 nm. The nanoemulsions can effectively carry paclitaxel (PTX) with an encapsulation rate of about 95%. And in vitro experiments have shown that it can efficiently increase the uptake of PTX in 4 T1 breast cancer cells and FNEs had a targeting capability hundredfold higher than that of PTX-loaded nanoemulsions (PTX-NEs) without folate. In vivo experiments have shown that the pharmacokinetic parameters of FNEs were better than those of other PTX groups and FNEs can significantly enhance circulation time in the body of the subcutaneously implanted 4 T1 breast cancer in mice, increase the accumulation of chemotherapy drugs at tumor sites and effectively inhibit tumor growth with lower system toxicity. CONCLUSIONS: This study can effectively improve the therapeutic efficiency of chemotherapy drugs for tumors, and provide an useful reference for solving the problem of low efficacy of chemotherapy drugs in clinical treatment of tumors. Graphical Abstract Schematic representation of Folic acid/PEG-DSPE/nano-emulsion (FNEs) specifically target tumor cells and enhanced anti-tumor effects.

Evaluation of skin-on goat meat processing on processing efficiency, carcass yield, meat quality, and sensory attributes.

The objective of this study was to evaluate the properties of skin-on and skin-off goat processing and carcasses for processing efficiency, fabrication time, biochemical factors, and sensory attributes for stewed goat meat. Thirty-one goats were harvested in 2 separate experiments, either skin-on (n = 16) or off (n = 15). The carcasses were fabricated into four primals and each primal was cut into cubes. Processing efficiency, carcasses yield, collagen content, moisture, lipid, ultimate pH, and sensory attributes were measured, and multivariate regression analysis were conducted. The skin-on group had greater overall yield compared to the skin-off group (P < 0.01). Consumers rated goat shoulder meat with the highest overall liking compared to the other primals (P < 0.01), regardless of skin present (P > 0.10). Finally, lipid % was found to be the most essential palatability trait to American Asian consumers.

Enhancing TNBC Chemo-immunotherapy via combination reprogramming tumor immune microenvironment with Immunogenic Cell Death.

Tumor-associated fibroblasts (TAFs) play an important role in tumor progression and therapeutic response, especially in the immunosuppressive tumor microenvironment (TME). To remodel immunosuppressive TME of 4T1 tumor, we developed a nano liposome to deliver silybin (SLN, an anti-liver fibrosis Chinese Traditional Medicine). Liposomal silybin (SLN/LIP) possessed a spherical shape with particle sizes of 75.2 nm, high stability, and good accumulation in the tumor site. After treated with SLN/LIP, α-SMA positive TAFs and the deposition of stroma were decreased significantly. SLN/LIP also changed the tumor immune microenvironment through the increase of IFN-γ and IL-12, as well as reduced of TGF-ß, SDF-1, IL6 and TNF-α. Importantly, SLN/LIP enhanced the infiltration of cytotoxic T cells (CTLs) and transformed a "cold" tumor into a "hot" tumor. To achieve the higher antitumor efficacy, an immunogenic cell death (ICD) inducer, liposomal doxorubicin (DOX/LIP) was combined with SLN/LIP. The combination treatment led to trigger immunogenic tumor apoptosis, and enhance antitumor immunity, therefore, improved anti-tumor efficiency, and further prolonged survival duration. The combination of liposomal silybin and liposomal doxorubicin might be a new chemo-immunotherapy approach for triple negative breast cancer (TNBC) tumor treatment.

Heat Shock Protein Beta 1 is a Prognostic Biomarker and Correlated with Immune Infiltrates in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most serious malignancies. The main features of HCC are vascular invasion and drug resistance. Ferroptosis is a novel cell program that is involved in several diseases, such as cancer. Heat shock protein beta 1 (HSPB1) is a major component of heat shock proteins. A recent study showed that HSPB1 could be a new therapeutic target for colorectal cancer with 5-fluorouracil-acquired resistance. However, the functional role of HSPB1 in HCC remains unclear. AIM: The aim of this study is to clarify HSPB1 expression in HCC and its potential therapeutic and prognostic value. METHODS: We collected data on HSPB1 expression levels in HCC and normal liver tissues from The Cancer Genome Atlas and Gene Expression Omnibus databases. We then validated it using immunohistochemistry (IHC). Receiver operating characteristic and Kaplan-Meier survival curves were used to investigate the role of HSPB1 in the prognosis analysis of HCC. Further, we used the online Search Tool for the Retrieval of Interacting Genes/Proteins website, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes to conduct enrichment analysis and identify the predictive signaling pathways. Meanwhile, we used the TIMER and GSVA package of R (v3.6.3) to analyze the association between HSPB1 and immunocyte infiltration. RESULTS: Compared to normal tissues, there was differential expression of HSPB1 in pan-cancers. HSPB1 expression was higher in HCC tissues than in normal tissues (p<0.05). There was an evident significant difference between HSPB1 mRNA levels and histologic grade, vascular invasion, and alpha-fetoprotein level (all p values<0.05). Univariate analysis indicated that HCC patients with high HSPB1 levels had shorter overall survival rates than those with low HSPB1 levels (p<0.05). MAPK14, HSPA8, MAPKAPK3, MAPKAPK5, and MAPKAPK2 are essential proteins that interact with HSPB1. There was a significant correlation between HSPB1 expression levels and immune cell infiltration, including CD4+ T cells (r=0.203, p<0.05). CONCLUSION: High HSPB1 expression is closely associated with a worse prognosis in HCC patients, and HSPB1 may be a target of immunotherapy in HCC.

[Effects of the construction of fertile and cultivated upland soil layer on soil fertility and maize yield in black soil region in Northeast China.] / 肥沃耕层构建对东北黑土区旱地土壤肥力和玉米产量的影响.

Organic amendment return could enhance soil fertility, improve soil structure, and increase crop yield. However, how construction of soil layers can affect soil fertility and crop yield are not fully understood. We examined the effects of constructions of fertile and cultivated soil layer on soil fertility and maize yield in the upland black soil region in Northeast China, to provide theoretical guidance in increasing soil fertility and sustainable development of agriculture. Based on the combination of field plot experiments and demonstration regions, nine study sites with different ecological characteristics were selected from Heilongjiang, Jilin and Liaoning provinces from northeast China, covering dark brown, black, meadow, chernozem, albic, brown and cinnamon soils. There were three treatments in each study site, including maize straw return within 0-35 cm soil layer (CFⅠ), the combination of maize straw and organic manure return within 0-35 cm soil layer (CFⅡ) and conventional agricultural practice without organic amendmentas control (CK). The rate of straw return in CFⅠ and CFⅡ treatments were 10000 kg·hm-2, and full straw for demonstration regions. The rate of organic manure in CFⅡ treatment was 30000 kg·hm-2. Considerable difference in soil fertility were recorded among the nine study sites with the trend of tillage layer > sub-tillage layer, especially for dark brown soil and albic soil. Soil fertility of tillage layer and sub-tillage layer was relatively low both for brown soil and cinnamon soil. The heavy clay and plow pan were pivotal limiting factors of soil fertility for the black soil and the meadow soil. Compared with CK, the concentrations of soil organic matter (SOM), available nitrogen (AN), available phosphorous (AP), and available potassium (AK) in tillage layers was increased on average by 1.85 g·kg-1, 20.16 mg·kg-1, 1.56 mg·kg-1 and 17.2 mg·kg-1 in the CFⅠ and CFⅡ treatments in five study sites with more than two years of treatments. The contents of SOM, AN, AP and AK in sub-tillage layer increased by 2.09 g·kg-1, 12.06 mg·kg-1, 2.18 mg·kg-1 and 3.84 mg·kg-1, compared with tillage layer. CFⅠ treatment significantly enhanced the contents of SOM and AP in both tested soil layers, while CFⅡ treatment significantly enhanced all fertility indices in both tested soil layers. This indicated that the increase of organic amendment return is an effective way to improve soil fertility. Maize yield fluctuated under the combined effect of climatic conditions and soil types. The significant differences in maize yield under CK, CFⅠ and CFⅡ treatments were observed with a trend of CFⅡ > CFⅠ > CK. This result indicated that the construction of fertile and cultivated soil layer could significantly increase maize yield independent of soil types. The construction of fertile and cultivated soil layer based on maize straw return or maize straw and organic manure combined return within 0-35 cm soil layer, could simultaneously increase soil fertility in both tillage and sub-tillage layer, as well as maize yield. We suggested that the selection of approaches of the constructions of fertile and cultivated soil layer should consider soil types and the sources of organic amendments. It should also give priority to soil layers rich in organic manure source to construct fertile and cultivated soil layers.

Chemically modified heparin inhibits in vitro L-selectin-mediated human ovarian carcinoma cell adhesion.

Accumulating evidence indicates that hematogenous metastasis is facilitated by tumor cell-leukocyte emboli formation, and L-selectin plays a major role in the process. Several independent studies have indicated that tumor metastasis can be inhibited by chemically modified heparin with low anticoagulant activity in the different tumor models. In the present study, we demonstrated that chemically modified nonanticoagulation heparin derivate (periodate-oxidized, borohydride-reduced heparin [RO-heparin]) can inhibit the binding of L-selectin to HO-8910 cells, block the adhering of HO-8910 to Chinese hamster ovary cells expressing a transfected human L-selectin complementary DNA, and affect the interactions of neutrophils with HO-8910 cells. Flow cytometric analysis with the heparan sulfate-specific monoclonal antibody revealed that HO-8910 cells express heparan sulfate-like proteoglycans. Furthermore, heparinase treatment impaired L-selectin binding, indicating that heparan sulfate-like proteoglycans on the tumor cell surface are implicated in the binding of L-selectin to HO-8910 cells. These findings suggest that RO-heparin with low anticoagulant activities may have potential value as therapeutic agents that block L-selectin-mediated cell adhesion and prevent tumor metastasis.

An Effective Cationic Human Serum Albumin-Based Gene-Delivery Carrier Containing the Nuclear Localization Signal.

Considerable effort has been devoted to the development of gene carriers over the years. However, toxicity, immunogenicity, and low transfection efficiency are still major barriers. How to overcome these obstacles has become a burning question in gene delivery. In the present study, a simple cationic human serum albumin (CHSA)-based gene-delivery system containing nuclear localization signals (NLSs) was constructed to conquer the limitations. CHSA/NLS/plasmid DNA (pDNA) complexes were prepared and characterized by Hoechst 33258 intercalation, gel retardation assay, morphological analysis, circular dichroism (CD) spectroscopy, particle size, and zeta potential measurements. Results showed that CHSA/NLS/pDNA complexes were able to condense and protect pDNA with high encapsulation efficiency. The complexes displayed a nutritional effect on cells at a low concentration and there was no significant cytotoxicity or immunogenicity. In addition, CHSA/NLS/pDNA complexes exhibited excellent cellular uptake rates and the mechanism was mainly the clathrin or macropinocytosis-dependent endocytosis pathway. Furthermore, CHSA/NLS/pDNA significantly enhanced gene expression efficiency in vitro. More importantly, CHSA/NLS/pDNA complexes showed a desired antitumor effect in vivo, exhibiting the highest inhibition rate (57.3%) and significant upregulation in p53 protein. All these results confirm that CHSA/NLS/pDNA complexes have a bright future as a safe and effective delivery system for gene therapy.

[Prophylactic immunization of dangguibuxue decoction against Cryptosporidium infection in immune suppressed mice].

OBJECTIVE: To explore the prophylaxis of dangguibuxue decoction, a traditional Chinese medicine made from Angelica sinensis and Radix astragalus, on immunosuppressed mice infected by Cryptosporidium parvum. METHODS: 48 BALB/c mice were randomly divided into 4 groups: normal control (A), immunosuppressed control (B), high dose (C), and low dose (D). Mice in groups B, C and D were intragastrically administered with dexamethasone (DXM) for 8 days, and in the same time mice in groups C and D were given high dose (2 g/kg) and low dose (1 g/kg) dangguibuxue decoction respectively. On the ninth day all mice in groups B, C and D were orally inoculated by 1 x 10(6) oocysts of C. parvum. The amount of oocysts in feces was examined daily since being infected. 11 days after infection, the subset of T lymphocytes in peripheral blood was analyzed with flow cytometry, sIL-2R in serum and sIgA of intestinal fluid were detected by ELISA. Pathological change of duodenum and jejunum was observed microscopically. RESULTS: Compared with the immuno-suppressed control group, there were less oocysts in feces (35.0 +/- 4.21) (P < 0.01) and lighter injury in the intestinal mucosa in mice of the high dose dangguibuxue decoction group. Both the number of CD4+ T lymphocytes (47.483 +/- 4.082) and the ratio of CD4+/CD8+ (2.271 +/- 0.378) increased, sIgA [(320.19 +/- 1.94) ng/ml] in the intestinal fluid elevated and sIL-2R [(321.34 +/- 6.66) ng/ml] in peripheral blood decreased in the high dose group, with a significant difference in comparison to the immunosuppressed group (P < 0.01). All the above-mentioned indices in low dose dangguibuxue decoction group showed no significant difference with the immunosuppressed control group (P > 0.05). CONCLUSION: Administration of high dose dangguibuxue decoction plays a role of prophylaxis on the infection of C. parvum in immunosuppressed mice through improving the immune status.

Adenovirus­mediated knockdown of activin A receptor type 2A attenuates immune­induced hepatic fibrosis in mice and inhibits interleukin­17­induced activation of primary hepatic stellate cells.

Fibrosis induces a progressive loss of liver function, thus leading to organ failure. Activins are secreted proteins that belong to the transforming growth factor (TGF)­ß superfamily, which initiate signaling by binding to their two type II receptors: Activin A receptor type 2A (ACVR2A) and activin A receptor type 2B. Previous studies that have explored the mechanisms underlying immune­induced hepatic fibrosis have mainly focused on TGF­ß signaling, not activin signaling. To investigate the role of the activin pathway in this disease, adenovirus particles containing short hairpin (sh)RNA targeting ACVR2A mRNA (Ad­ACVR2A shRNA) were administered to mice, which were chronically treated with concanavalin A (Con A). The pathological changes in the liver were evaluated with hematoxylin/eosin staining, Masson trichrome staining and immunohistochemical assay. The results detected an increase in serum activin A and liver ACVR2A in Con A­treated animals. Conversely, liver function was partially restored and fibrotic injury was attenuated when activin signaling was blocked. In addition, the activation of hepatic stellate cells (HSCs) in response to Con A was suppressed by Ad­ACVR2A shRNA, as evidenced by decreased α­smooth muscle actin, and type I and IV collagen expression. Furthermore, primary mouse HSCs (mHSCs) were activated when exposed to interleukin (IL)­17A or IL­17F, which are two major cytokines produced by cluster of differentiation 4+ T helper 17 cells. The levels of activin A, type I and IV collagen were determined with ELISA kits and the expression of fibrotic molecules was determined with western blot analysis. Conversely, blocking activin/ACVR2A impaired the potency of HSCs to produce collagens in response to IL­17s. In addition, C terminus phosphorylation of Smad2 on Ser465 and Ser467, induced by either Con A in the liver or by IL­17s in mHSCs, was partly inhibited when activin A/ACVR2A signaling was suppressed. Collectively, the present study demonstrated an involvement of activated activin A/ACVR2A/Smad2 signaling in immune­induced hepatic fibrosis.

A novel disulfide bond-mediated cleavable RGD-modified PAMAM nanocomplex containing nuclear localization signal HMGB1 for enhancing gene transfection efficiency.

BACKGROUND: Polyamidoamine (PAMAM) dendrimers modified by polyethylene glycol (PEG) have frequently been investigated as a delivery carrier for gene therapy. However, modification of PAMAM with PEG using covalent linkage significantly reduces the cellular uptake rate and the transfection efficiency. How to conquer these barriers becomes a burning question in gene delivery. MATERIALS AND METHODS: The present study constructed an effective disulfide bond-mediated cleavable RGD modified gene delivery system to overcome the aforementioned limitations. The disulfide bond was introduced between PAMAM dendrimers and PEG chains to realize the cleavage of PEG from the carrier system, whereas the arginine-glycine-aspartate (RGD) peptide was expected to promote the cellular uptake rate. A high mobility group Box 1 (HMGB1) protein containing nuclear localization signal (NLS) was simultaneously introduced to further promote gene expression efficiency. A pDNA/HMGB1/PAMAM-SS-PEG-RGD (DHP) nanocomplex was prepared via electrostatic interaction and characterized. RESULTS: The results showed that DHP generated small particles and was able to condense and protect pDNA against degradation. In addition, the RGD peptide could significantly promote the cellular uptake of a nanocomplex. Intracellular trafficking and in vitro expression study indicated that the DHP nanocomplex escaped from lysosomes and the disulfide bonds between PAMAM and PEG cleaved due to the high concentration of GSH in the cytoplasm, pDNA consequently became exclusively located in the nucleus under the guidance of HMGB1, thereby promoting the red fluorescence protein (RFP) expression. Importantly, an in vivo antitumor activity study demonstrated that the DHP nanocomplex had higher antitumor activity than any other reference preparation. CONCLUSION: All these results confirm that DHP could be a new strategy for improving the transfection and expression efficiency in gene delivery.

[Effect of yupingfengsan on the growth of tumor and immunological function in tumor-bearing mice].

AIM: To explore the effect of yupingfengsan on the growth of tumor and immunological function in tumor-bearing mice. METHODS: The models of tumor-bearing mice were established by inoculating the healthy mice with S180 tumor carneus cells cultured in vitro. Then the ratio of tumor restriction was calculated. The phagocytosis activity of phagocytes, the level of NO secreted by phagocytes, the proliferating activity of T lymphocytes and the level of IL-2 were detected in the mice after being treated with yupingfengsan 12 days. RESULTS: yupingfengsan elevated the phagocytosis of phagocytes and the level of NO secreted by phagocytes. It promoted T lymphocytes to transform, and increased the level of IL-2 and the activity of NK cells. CONCLUSION: yupingfengsan can increase the immunological function of tumor-bearing mice and suppress the development of tumor in mice.