Ternary supramolecular nanocomplexes for superior anticancer efficacy of natural medicines.

The discovery of effective anticancer drug delivery systems and elucidation of the mechanism are enormous challenges. Using two drug administration-approved biomaterials, we constructed a natural medicine (NM)-loaded ternary supramolecular nanocomplex (TSN) suitable for large-scale production. The TSN has a better effect against cancer cells/stem cells than NM with differentially upregulated (27 versus 59) and downregulated (165 versus 66) proteins, respectively. Treatment with the TSN induced apoptosis and G2/M arrest, inhibited cell proliferation, metastasis and invasion, reduced colony/sphere formation, and decreased the frequency of side population cells and CD133+CD44+ABCG2+ cells. These results were revealed by multiple analyses (proteomic analysis, transwell migration and colony/sphere formation assays, biomarker profiling, etc.). We first reported the proteomic analysis of small lung cancer cells responding to a drug or its nanovesicles. We first conducted a proteomic evaluation of tumor cells responding to a drug supramolecular nanosystem. The supramolecular conformation of the TSN and the interactions of the TSN with albumin were verified by molecular docking experiments. The dominant binding forces in the TSN complexation process were electrostatic interactions, van der Waalsinteractions and bond stretching. The TSN binds to albumin more readily than NM does. The TSN has good in situ absorptive and in vitro/vivo kinetic properties. The relative bioavailability of the TSN to EA was 458.39%. The NM-loaded TSN is a supramolecular vesicle that can be produced at an industrial scale for efficient cancer therapy.

Oral administration of natural polyphenol-loaded natural polysaccharide-cloaked lipidic nanocarriers to improve efficacy against small-cell lung cancer.

Oral administration shows good tolerance in patients. Botanic anticancer drugs without serious side effects have attracted increased attention worldwide. However, oral delivery of natural anticancer drugs faces great challenges due to low solubility, gastrointestinal side effects, first-pass effects, and P-glycoprotein efflux. Here, we loaded the natural polyphenol curcumin (Cc) into natural polysaccharide-cloaked lipidic nanocarriers (Cc@CLNs) to improve the efficacy in small-cell lung cancer (SCLC) associated with oral administration. Compared to other nanoformulations, Cc@CLNs have advantages of simple operation, easy scale-up, low cost, and high safety. Cc@CLNs improve bioavailability by inducing synergistic effects (efficient cell membrane penetration, inherent muco-adhesiveness, resistance to pepsin and trypsin degradation, promoted dissolution, enhanced epithelia/M cellular uptake and inhibition of efflux transporters) and countering the tendency of nanocarriers to aggregate and fuse, which limit lipid-based nanosystems. In this study, we first evaluated the oral bioavailability of Cc@CLNs in rats and their efficacy in H446 tumor-bearing mice. The oral bioavailability increased by 8.94-fold, and the tumor growth inhibition rate doubled compared to that achieved with free Cc. We investigated the action of Cc against SCLC stem cells, and Cc@CLNs greatly enhanced this action. The expression of CD133 and ABCG2 in the Cc@CLNs group decreased by 38.05% and 32.57%, respectively, compared to the respective expression levels in the control.

Natural Oral Anticancer Medication in Small Ethanol Nanosomes Coated with a Natural Alkaline Polysaccharide.

Oral medication is the most acceptable therapy to treat chronic diseases. Natural drugs and excipients have unique advantages, such as low cost and high safety. We first investigated modified ethanol nanosomes for tumor treatment via oral administration. We loaded curcumin (CM) into small ethanol nanosomes coated with the natural alkaline polysaccharide chitosan (CCSET) for increased absorption and bioavailability and enhanced efficacy against small cell lung cancer (SCLC). Compared to CM and noncoated ethanol nanosomes, CCSETs exhibited superior physicochemical, in vitro-in vivo kinetic, and absorptive properties and treatment efficacy at the cellular and animal levels. The interaction of CM and serum albumin (the quantitative binding force) was analyzed. The bioavailability of CCSET increased by 11.84-fold and the tumor growth inhibition rate increased markedly compared to CM. We first confirmed the effect of CM on SCLC stem cells, and CCSET greatly enhanced this action. We first reported that CM had an antitumor effect on SCLC at the animal level and that CCSET enhanced this effect. Natural alkaline polysaccharide-coated small ethanol nanosomes delivering natural medicine may be a potential oral anticancer strategy.

Experience of robot-assisted lung segmentectomy through anterior approach / 中国胸心血管外科临床杂志

@#Objective    To evaluate the feasibility and clinical value of robot-assisted lung segmentectomy through anterior approach. Methods    We retrospectively analyzed the clinical data of 77 patients who underwent robotic lung segmentectomy through anterior approach in our hospital between June 2018 to October 2019. There were 22 males and 55 females, aged 53 (30-71) years. Patients' symptoms, general conditions, preoperative imaging data, distribution of resected lung segments, operation time, bleeding volume, number of lymph node dissected, postoperative duration of chest tube insertion, drainage volume, postoperative hospital stay, postoperative complications, perioperative death and other indicators were analyzed. Results    All operations were successfully completed. There was no conversion to thoracotomy, serious complications or perioperative death. The postoperative pathology revealed early lung cancer in 48 patients, and benign tumors in 29 patients. The mean clinical parameters were following: the robot Docking time 1-30 (M=4) min, the operation time 30-170 (M=76) min, the blood loss 20-400 (M=30) mL, the drainage tube time 2-15 (M=4) days, the drainage fluid volume 200-3 980 (M=780) mL and the postoperative hospital time 3-19 (M=7) days. Conclusion    Robotic lung segmentectomy through anterior approach is a safe and convenient operation method for pulmonary nodules.

Short-term effects of Da Vinci robot Nissen fundoplication in the treatment of refractory gastroesophageal reflux disease / 中国胸心血管外科临床杂志

@#Objective    To investigate the short-term effects of Da Vinci robot-assisted Nissen fundoplication in the treatment of refractory gastroesophageal reflux disease (rGERD), and to evaluate the safety and efficacy of its surgical treatment. Methods    A total of 40 patients with rGERD treated by Da Vinci robot-assisted surgery from October 2016 to November 2019 in our hospital were collected. There were 23 males and 17 females at age of 34-76 (61±23) years. The related clinical data were retrospectively analyzed, and the operation skills of Da Vinci robot-assisted Nissen fundoplication with rGERD were summarized. Results    There was no perioperative death or serious complication such as esophagogastric fistula. Postoperative reflux symptoms were significantly improved. DeMeester scores after surgery (39.79±35.01 points vs. 2.61±2.40 points, P=0.029), lower esophageal sphincter pressure (8.74±7.21 mm Hg vs. 24.56±8.76 mm Hg, P=0.020), integrated relaxation pressure (7.29±7.21 mm Hg vs. 16.49±9.99 mm Hg, P=0.023), distal contractile integral (600.49 ± 665.30 mm Hg·s·m vs. 510.99 ± 580.60 mm Hg·s·m, P=0.042), GERD-Q scale score (12.98±2.39 points vs. 7.59±1.11 points, P=0.033) were significantly improved compared with those before surgery. Postoperative dysphagia was found in 2 patients. And dysphagia was alleviated after diet adjustment and other treatments. Conclusion    Da Vinci robot-assisted Nissen fundoplication is a safe and effective treatment for rGERD.

Stereochemical considerations in pharmacokinetic processes of representative antineoplastic agents.

The vast majority of chemical drugs or drug candidates contain stereocenter(s) in their molecular structures. In these molecules, stereochemical properties are vital properties that influence or even determine their drug actions. Therefore, studying the stereochemical issues of drugs (or drug candidates) is necessary for rational drug use. These stereochemical issues are usually involved with the stereoselectivity in pharmacokinetic processes, especially in the metabolism process. Thus, the investigation of the stereochemical issues in drug metabolism process deserves great attention, especially in those chiral/prochiral antineoplastic agents exhibiting pharmacodynamics and toxicologic differences between stereoisomers. Published reviews concerning this certain issue are inspiring, however they were covering all drug types and only limited antineoplastic drugs were discussed. Here in this review, the research on stereochemical issues in pharmacokinetic processes of some representative antineoplastic agents were described, especially focusing on some newly developed compounds. We highlight the chemical transformations in pharmacokinetic processes of these chiral/prochiral compounds and discuss their different behaviors with metabolic enzymes or transporter proteins, to explicate the observed stereoselectivity intrinsically.

CCR7 promote lymph node metastasis via regulating VEGF-C/D-R3 pathway in lung adenocarcinoma.

Lymph node metastasis is still an important issue in metastatic process of lung adenocarcinoma. C-C chemokine receptor 7 (CCR7) has been proved to be closely associated with the metastasis of lung adenocarcinoma, and the mechanism is poorly understood. In order to investigate the relationship between CCR7 and lymph node metastasis in lung adenocarcinoma, and to explore the role of CCR7 in treating lung adenocarcinoma, 40 clinical specimens were collected to define the relationship between CCR7 and lymph node metastasis in lung adenocarcinoma by immunohistochemistry. The siRNA was used to suppress CCR7 expression in A549 cells. The scratch test, transwell test, qRT-PCR, western blot, flow cytometry and immunofluorescence were used to investigate the lymph node metastasis-related function of CCR7 in vitro. The athymic mice subcutaneous injection was used to research lung adenocarcinoma formation in vivo. Clinical case studies show that higher expression of CCR7 in lung adenocarcinoma tissues was associated with a higher lymph node metastasis. Inhibition of expression of CCR7 can reduce the migration and invasion and suppress the expression of VEGF-C, VEGF-D and VEGF-R3 in vitro and in vivo. Moreover, CCR7 silence also suppressed WNT and p-ERK pathways in vitro. All the results indicate that CCR7 can promote lymph node metastasis in lung adenocarcinoma by regulating VEGF-C/D-R3 pathway. Thus CCR7 is proposed to be a potential prediction for poor prognosis of lung adenocarcinoma, and a therapeutic target for lymph node metastasis.

Catanionic lipid nanosystems improve pharmacokinetics and anti-lung cancer activity of curcumin.

Novel catanionic lipid nanosystems (CLNs) incorporating curcumin (CCM) were developed, and improvements in pharmacokinetics and enhanced anti-lung cancer activity were observed. CCM was present in a lipid matrix surrounded by cationic, anionic and zwitterionic surfactants, forming the core-shell nanosystems. Compared with free CCM, the CCM-CLNs had much higher oral and intravenous bioavailabilities due to enhanced absorption and reduced clearance. The CCM-CLNs exhibited greater cytotoxicity in Lewis lung cancer (LLC) cells, which might have been due to increased antiproliferative, proapoptotic and anti-invasive activities and induction of cell cycle arrest. The CCM-CLNs increased the antitumor efficacy of CCM and decreased the tumor growth rate in tumor-bearing mice. This is the first report of induction of apoptosis in LLC cells by CCM through the PI3K/Akt/FoxO1/Bim signaling pathway. Catanionic lipid nanocarriers show promise for the therapeutic delivery of insoluble anti-tumor drugs.

The microRNA-520a-3p inhibits proliferation, apoptosis and metastasis by targeting MAP3K2 in non-small cell lung cancer.

Growing evidence indicates that miR-520a was involved in the complement attack and migration of tumor cells, but nonetheless, the role of miR-520a-3p in non-small cell lung cancer (NSCLC) is not clear. Mitogen-activated protein kinase kinase kinase 2 (MAP3K2) is a kinase belonging to the serine/threonine protein kinase family. To develop potential therapy targeting MAP3K2, we studied the roles of miR-520a-3p in the proliferation, apoptosis and metastasis of NSCLC. The expression levels of miR-520a-3p were quantified in tumor tissues of NSCLC by qRT-PCR, and the mimics and inhibitors were used to verify the function of miR-520a-3p. The cell proliferation was evaluated by MTT assay, and the migration and invasion was evaluated by transwell assay. The athymic mice subcutaneous injection was used to research NSCLC cell tumor formation. The bioinformatics tools and luciferase assay was applied to detect the relationship between miR-520a-3p and its target. Protein levels of miR-520a-3p target was determined by western blot analysis. MiR-520a-3p expression was decreased in the NSCLC tissues compared with their normal counterparts and lower expression of miR-520a-3p in NSCLC tissues was associated with a higher clinical stage, NSCLC metastasis and poor prognosis. Inhibition of expression of miR-520a-3p can reduce in vitro NSCLC cell migration and invasion as well as in vivo metastasis. MAP3K2 mRNA contains a binding site for miR-520a-3p in the 3'UTR. MAP3K2 is one of target of miR-520a-3p. Together, our data demonstrated that miR-520a-3p inhibits proliferation, apoptosis and metastasis in NSCLC by targeting MAP3K2, and miR-520a-3p may be used as a prognosis marker for NSCLC in clinical research.

Evodiamine induces G2/M arrest and apoptosis via mitochondrial and endoplasmic reticulum pathways in H446 and H1688 human small-cell lung cancer cells.

The goal of this study was to evaluate the ability of EVO to decrease cell viability and promote cell cycle arrest and apoptosis in small cell lung cancer (SCLC) cells. Lung cancer has the highest incidence and mortality rates among all cancers. Chemotherapy is the primary treatment for SCLC; however, the drugs that are currently used for SCLC are less effective than those used for non-small cell lung cancer (NSCLC). Therefore, it is necessary to develop new drugs to treat SCLC. In this study, the effects of evodiamine (EVO) on cell growth, cell cycle arrest and apoptosis were investigated in the human SCLC cell lines NCI-H446 and NCI-H1688. The results represent the first report that EVO can significantly inhibit the viability of both H446 and H1688 cells in dose- and time-dependent manners. EVO induced cell cycle arrest at G2/M phase, induced apoptosis by up-regulating the expression of caspase-12 and cytochrome C protein, and induced the expression of Bax mRNA and by down-regulating of the expression of Bcl-2 mRNA in both H446 and H1688 cells. However, there was no effect on the protein expression of caspase-8. Taken together, the inhibitory effects of EVO on the growth of H446 and H1688 cells might be attributable to G2/M arrest and subsequent apoptosis, through mitochondria-dependent and endoplasmic reticulum stress-induced pathways (intrinsic caspase-dependent pathways) but not through the death receptor-induced pathway (extrinsic caspase-dependent pathway). Our findings suggest that EVO is a promising novel and potent antitumor drug candidate for SCLC. Furthermore, the cell cycle, the mitochondria and the ER stress pathways are rational targets for the future development of an EVO delivery system to treat SCLC.

Supermolecular evodiamine loaded water-in-oil nanoemulsions: enhanced physicochemical and biological characteristics.

The purpose of this study was to develop and evaluate the supermolecular evodiamine (EVO) loaded water-in-oil nanoemulsions containing brucea javanica oil (NESEB) with enhanced physicochemical and biological characteristics. NESEB was fabricated by applying supermolecular phytosome nanotechnology and nanoemulsification technology together, in addition to using synergistic plant essential oil as a basic composition. Preferred physicochemical and biological characteristics of NESEB were investigated and compared with free EVO and other nanoemulsive EVO carriers. The possible explanations for improved absorption and bioavailability were put forward here. NESEB had high absorption and bioavailability, for example: the absorption rate constants and permeabilities of NESEB in different intestinal segments were 3.65-6.76 times that of free EVO; the relative bioavailability of NESEB to free EVO was 846.97%. NESEB markedly improved the oral bioavailability of EVO, which was most likely due to the increased gastrointestinal absorption. The development of nanoemulsion-based supermolecular EVO nanocarriers provides valuable tactics in insoluble natural antitumor drug delivering.

Experimental study on an airway prosthesis made of a new metastable ß-type titanium alloy.

OBJECTIVE: Surgical treatment of a subglottic stenosis can lead to a cricoid cartilage resection, cervical trachea resection, or both that has to be reconstructed with an artificial prosthesis. However, there is at present no standard treatment in the numerous reconstruction procedures, and many prostheses encounter inflammatory rejection and mechanical constraint problems. A porous, metastable ß-type titanium alloy prosthesis was developed to improve subglottic rehabilitation. METHODS: We have designed a porous type of airway prosthesis made of porous metastable ß-type titanium alloy. We used this prosthesis (20 mm in length) to reconstruct the cricoid cartilage and the first tracheal ring in 10 mongrel dogs and evaluated its efficacy. RESULTS: One dog died of an accident with anesthesia at 1 week, 1 dog died of pneumonia about 1 month after the operation, and 6 dogs were killed between the third and eighth months after the operation. At death, all the prostheses had become completely incorporated into the host tissue. Endoscopic examination showed no airway obstruction for a postoperative period of 3 to 8 months in 8 dogs. Granulation was observed in 4 cases, and the porous, metastable ß-type titanium alloy plate was exposed in 1 case, but these dogs were asymptomatic. Light microscopic and electron microscopic analysis showed a normal mucous membrane growth on the surface of the prosthesis and no visible granulation tissue in the reconstructed cricoid and tracheal cavity. CONCLUSIONS: This airway prosthesis provided good results in canine cricotracheal reconstruction, and this study presents the possibility of successful reconstruction of the cricoid and trachea with epithelial regeneration.