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The process of generating type I/II collagen scaffolds is fraught with bubble formation, which can interfere with the three-dimensional structure of the scaffold. Herein, we applied low-temperature vacuum freeze-drying to remove mixed air bubbles under negative pressure. Type I and II rubber sponges were acid-solubilized via acid lysis and enzymolysis. Thereafter, vacuum negative pressure was applied to remove bubbles, and the cover glass press method was applied to shape the type I/II original scaffold. Vacuum negative pressure was applied for a second time to remove any residual bubbles. Subsequent application of carbamide/N-hydroxysuccinimide cross-linked the scaffold. The traditional method was used as the control group. The structure and number of residual bubbles and pore sizes of the two scaffolds were compared. Based on the relationship between the pressure and the number of residual bubbles, a curve was created, and the time of ice formation was calculated. The bubble content of the experimental group was significantly lower than that of the control group (P 0.05). The pore diameter of the type I/II collagen scaffold was higher in the experimental group than in the control group. The time of icing effect of type I and II collagen solution was 136.54 ± 5.26 and 144.40 ± 6.45 s, respectively. The experimental scaffold had a more regular structure with actively proliferating chondrocytes that possessed adherent pseudopodia. The findings indicated that the vacuum negative pressure method did not affect the physical or chemical properties of collagen, and these scaffolds exhibited good biocompatibility with chondrocytes.

Background and ObjectivesWhether acupuncture is effective for chronic tension-type headache (CTTH) is inconclusive. We aimed to examine the effectiveness of acupuncture with a follow-up period of 32 weeks.MethodsWe conducted a randomized controlled trial, and 218 participants who were diagnosed with CTTH were recruited from June 2017 to September 2020. The participants in the intervention group received 20 sessions of true acupuncture (TA) over 8 weeks. The acupuncture treatments were standardized across participants, and each acupuncture site was needled to achieve deqi sensation. Each treatment session lasted 30 minutes. The participants in the control group received the same sessions and treatment frequency as those in the superficial acupuncture (SA) group—defined as a type of sham control by avoiding deqi sensation at each acupuncture site. The main outcome was the responder rate at 16 weeks after randomization (week 16) and was followed up at week 32. A responder was defined as a participant who reported at least a 50% reduction in the monthly number of headache days (MHDs).ResultsOur study included 218 participants (mean age: 43.1 years, mean disease duration: 130 months, MHDs: 21.5 days). The responder rate was 68.2% in the TA group (n = 110) vs 48.1% in the SA group (n = 108) at week 16 (OR, 2.65; 95% CI, 1.5 to 4.77; p < 0.001); and it was 68.2% in the TA group vs 50% in the SA group at week 32 (OR, 2.4; 95%CI, 1.36 to 4.3; p < 0.001). The reduction in MHDs was 13.1 ± 9.8 days in the TA group vs 8.8 ± 9.6 days in the SA group at week 16 (mean difference, 4.3 days; 95%CI, 2.0 to 6.5; p < 0.001), and the reduction was 14 ± 10.5 days in the TA group vs 9.5 ± 9.3 days in the SA group at week 32 (mean difference, 4.5 days; 95%CI, 2.1 to 6.8; p < 0.001). Four mild adverse events were reported; 3 in the TA group vs 1in the SA group.DiscussionThe 8-week TA treatment was effective for the prophylaxis of CTTH. Further studies might focus on the cost-effectiveness of the treatment.Trial Registration InformationClinicalTrials.gov: NCT03133884 (clinicaltrials.gov/ct2/show/NCT03133884).Classification of EvidenceThis study provides Class I evidence that acupuncture (achieving deqi sensation) reduces the mean headache days (per month) in patients with CTTH.

Acute lung injury (ALI) can be induced by various injury factors, which is closely related to the inflammatory reaction and cellular ferroptosis reported recently. Glutathione peroxidase (GPX4) palys an important role in the inflammatory reaction, which also is the core regulatory protein of ferroptosis. Up-regulation of GPX4 can be helpful to inhibit the cellular ferroptosis and inflammatory reaction to treat ALI. mPEI/pGPX4 gene therapeutic system based on mannitol-modified polyethyleneimine (mPEI) was constructed. Compared with PEI/pGPX4 nanoparticles using commoditized gene vector PEI 25k, mPEI/pGPX4 nanoparticles achieved caveolae-mediated endocytosis and improved the gene therapeutic effect. mPEI/pGPX4 nanoparticles could up-regulate the gene expression of GPX4, inhibit inflammatory reaction and the cellular ferroptosis, thereby alleviating the acute lung injury in vitro and in vivo. The finding indicated that gene therapy with pGPX4 is a potential therapeutic system for the effective treatment of acute lung injury.

A new paraherquamide named aculeaquamide A (1) was isolated from an EtOAc extract of Aspergillus aculeatinus WHF0198 culture media together with five known compounds. The structures of the isolated compounds were elucidated by analysis of NMR and MS data, and the absolute configurations of compound 1 was confirmed by CD spectroscopic methods. All isolated compounds were evaluated for their cytotoxicity against three human cancer cell lines, Bel-7402, A549, and HCT-116. Compounds 1 and 2 showed cytotoxicity against Bel-7402 with IC50 values of 3.3 and 1.9 μM, respectively.

Currently, clinical treatment for temozolomide (TMZ)-resistant glioblastoma multiforme (GBM) is still a difficult problem. The aim of this paper is to set up a new GBM-targeted drug delivery system to treat TMZ-resistant GBM. Zoledronate (ZOL) not only induces apoptosis of TMZ-resistant GBM cells by down-regulation of farnesyl pyrophosphate synthetase (FPPS) but also increases the proportion of M1-type GBM associated macrophages (GAM). Based on chemoattractants secreted by GBM cells, a ZOL loaded nanoparticle coated with microglia cell membrane (ZOL@CNPs) was prepared to deliver ZOL to central nervous system to treat TMZ-resistant GBM. ZOL@CNPs was actively recruited to TMZ-resistant GBM region by CX3CL1/CX3CR1 and CSF-1/CSF-1R signal axis, and the release of ZOL from ZOL@CNPs was triggered by glutathione in GBM cells. ZOL@CNPs inhibited the growth of TMZ-resistant GBM through inducing apoptosis and inhibiting the migration and invasion of TMZ-resistant GBM cells. Besides, the immunosuppressive and hypoxic microenvironment, playing an important role in the growth of TMZ-resistant GBM, was significantly improved by ZOL@CNPs through increasing the proportion of M1-type GAM and blocking the expression of HIF-1α. ZOL@CNPs has a great potential application in the treatment for TMZ-resistant GBM.

The serious side effects of cisplatin hindered its clinical application and the nanotechnology might be the potential strategy to address the limitation. However, rapid clearance in the blood circulation and ineffective controlled drug release from nanocarriers hamper the therapeutic efficacy of the nano-delivery system. We constructed a tumor microenvironment and redox dual stimuli-responsive nano-delivery system PEG-c-(BPEI-SS-Pt) by cross-linking the disulfide-containing polymeric conjugate BPEI-SS-Pt with the dialdehyde group-modified PEG2000 via Schiff base. After optimized the cross-linking time, 72 h was selected to get the nano-delivery system. 1H NMR and drug release assays showed that under the acidic tumor microenvironment (pH 6.5–6.8), the Schiff base can be broken and detached the PEG cross-linked outer shells, displaying the capability to release the drugs with a sequential pH- and redox-responsive manner. Moreover, PEG-c-(BPEI-SS-Pt) showed more effective anti-tumor therapeutic efficacy in vivo with no significant side effects when compared with the drug of cisplatin used in the clinic. This strategy highlights a promising platform with the dual stimuli-responsive profile to achieve better therapeutic efficacy and minor side effects for platinum-based chemotherapy.

Background Gene therapy remains a significant challenge due to lots of barriers limiting the genetic manipulation technologies. As for non-viral delivery vectors, they often suffer insufficient performance due to inadequate cellular uptake and gene degradation in endosome or lysosome. The importance of overcoming these conserved intracellular barriers is increasing as the delivery of genetic cargo. Results A surface-functionalized non-viral vector involving the biomimetic mannitol moiety is initiated, which can control the cellular uptake and promote the caveolae-mediated pathway and intracellular trafficking, thus avoiding acidic and enzymatic lysosomal degradation of loaded gene internalized by clathrin-mediated pathway. Different degrees of mannitol moiety are anchored onto the surface of the nanoparticles to form bio-inspired non-viral vectors and CaP-MA-40 exhibits remarkably high stability, negligible toxicity, and significantly enhanced transgene expression both in vitro and in vivo. Conclusions This strategy highlights a paradigmatic approach to construct vectors that need precise intracellular delivery for innovative applications.

Background At present, patients with myocardial infarction remain an increased risk for myocardial ischemia/reperfusion injury (MI/RI), which currently lacks an effective therapeutic method. It is still a bottleneck that effectively deliver drug to ischemic myocardium to treat MI/RI. Inspired by the protective effect of regulatory T cells (Tregs) on MI/RI and natural role of platelets in adhesion with damaged blood vessel in heart during myocardial infarct, a Tregs biomimetic nanoparticle (CsA@PPTK) was prepared by camouflaging a cyclosporin A (CsA)-loaded and reactive oxygen species (ROS)-sensitive nanoparticle with platelet membrane. Results In MI/RI mice, CsA@PPTK could be preferentially delivered to ischemic myocardium. CsA@PPTK significantly scavenged ROS in ischemic myocardium, while it also markedly increased the generation of Tregs and the ratio of M2 type macrophage to M1 type macrophage in ischemic myocardium. Furthermore, CsA@PPTK significantly attenuated apoptosis of cardiomyocytes in ischemic myocardium. At the same time, CsA@PPTK obviously reduced the infarct size, fibrosis area and the protein expression of MMP-9, while increased the protein expression of CX43. Subsequently, the remodeling of the left ventricle was significant alleviated. Finally, heart function of MI/RI mice was markedly improved. Conclusion CsA@PPTK has great potential in the treatment of MI/RI. This study provides a novel class of heart protective biomimetic platform that is beneficial for treatment of MI/RI.

A new paraherquamide named aculeaquamide A (

In blood vessels, endothelial cells (ECs) grow along the direction of blood flow, while smooth muscle cells (SMCs) grow circumferentially along the vessel wall. To mimic this structure, a polycaprolactone (PCL) tubular scaffold with orthogonally oriented bilayer nanofibers was prepared via electrospinning and winding. ECs were cultured on the inner layer of the scaffold with axial nanofibers and SMCs were cultured on the outer layer of the scaffold with circumferential nanofibers. Fluorescence images of the F-actin distribution of ECs and SMCs indicated that cells adhered, stretched, and proliferated in an oriented manner on the scaffold. Moreover, layers of ECs and SMCs formed on the scaffold after one month of incubation. The expression levels of platelet-endothelial cell adhesion molecule 1 (PECAM-1) and a contractile SMC phenotype marker in the EC/SMC co-culture system were much higher than those in individual culture systems, thus demonstrating that the proposed biomimetic scaffold promoted the intercellular junction of ECs and preserved the contractile phenotype of SMCs.

Two octahydro-protoberberine alkaloids, alangiifoliumines A (1) and B (2), and two new protoemetine derivatives, alangiifoliumines C (3) and D (4), together with 11 known compounds, have been isolated from the stems of Alangium salviifolium. While the structures of these compounds were elucidated by spectroscopic methods, the absolute configurations of the new alkaloids were determined by conformational analysis and time-dependent density functional theory-electronic circular dichroism spectra calculations on selected stereoisomers. Compounds 1 and 2 represent the first 5,8,8a,9,12,12a,13,13a-octahydro-protoberberine derivatives, in which the aromatic ring D was reduced to cyclohexene. All the compounds isolated were evaluated for their cytotoxic activity against three human cancer cell lines: A-549, HeLa, and SKOV-3. Alkaloids 1, 3, and 6-14 exhibited inhibitory effects against all three human cancer cell lines, with half-maximal inhibitory concentration (IC50) values in the range of 3 nM to 9.4 μM.

Aim: The objective of this study was to deliver a ring-closed form of 10-hydroxycamptothecin (HCPT) to the mitochondria and nucleus to treat colorectal cancer. Materials & methods: HCPT-loaded nanoparticle HCPT@PLGA-PEG2k-triphenylphosphonium/PLGA-hyd-PEG4k-folic acid (PT/PHF) and HCPT@PT/PLGA-SS-PEG4k-folic acid (PSF) were prepared by using emulsion-solvent evaporation method. Results: In vitro experimental results indicated HCPT@PT/PHF and HCPT@PT/PSF maintained a large amount of HCPT in active form, and delivered more HCPT to the nucleus and mitochondria of the tumor cell, which resulted in the enhancement of cytotoxicity of HCPT. In vivo experimental results indicated that HCPT@PT/PHF and HCPT@PT/PSF delivered more ring-closed form of HCPT to tumor tissue, which led to strong antitumor activity. Conclusion: HCPT@PT/PHF and HCPT@PT/PSF could enhance therapeutic efficacy of HCPT to colorectal cancer.

Efficient delivery of antioxidant drugs into mitochondria of ischemic cardiomyocytes where reactive oxygen species largely induced is a major challenge for precise treatment of myocardial ischemia-reperfusion injury. Herein, we report a smart dual-shell polymeric nanoparticle, MCTD-NPs, which utilizes multistage continuous targeted strategy to deliver reactive oxygen species scavenger specifically to mitochondria of ischemic cardiomyocytes upon systemic administration. In vitro experiments indicated that the intracellular uptake of MCTD-NPs was specifically enhanced in hypoxia reoxygenation injured H9c2 cells. MCTD-NPs selectively delivered resveratrol to mitochondria of hypoxia reoxygenation injured H9c2 cells. In addition, MCTD-NPs increased the viability of H/R injured H9c2 cell through eliminating mitochondrial ROS, decreasing mPTP opening and blocking mitochondria-dependent apoptotic pathway. In vivo experiments revealed that MCTD-NPs increased the distribution of resveratrol in the ischemic myocardium and subsequently reduced infarct size in MI/RI rats. These results demonstrated a novel platform for specific delivery of antioxidant to mitochondria to treat MI/RI.

In leading the high-quality development of Chinese medicine preparations, it is an important link to formulate the scientific, reasonable, and feasible guidelines for the change of Chinese medicines in accordance with the change characteristics and principles of the Chinese medicines is an important work to promote the Technical guidelines for the study of pharmaceutical changes in traditional Chinese medicines was formed by a broad consensus based on the characteristics and research results of the pharmaceutical changes in Traditional Chinese Medicines(TCM)with the principles of science and risk management. This guideline has clarified the basic principles and requirements for the evaluation of changes in TCM, specified the research and verification work of common change scenarios, defined the boundaries of changes in TCM, and proposed to encourage the use of new technologies, new methods, and new excipients that meet product characteristics. It will definitely promote the quality improvement and the secondary development of TCM. In this article, the revision background and main content of the guideline were introduced, and the main features of the Guideline were analyzed, in order to provide references for the industry.

To observe the effect of electroacupuncture (EA) on the expression of Pirt (a regulator of TRPV1) in the dorsal root ganglia (DRG) and transient receptor potential vanilloid 1 (TRPV1, a molecular sensor of noxious heat and capsaicin) in the colonic mucosa in rats suffering from diarrhea-predominant irritable bowel syndrome (IBS-D), so as to explore its mechanisms underlying alleviation of visceral hypersensitivity of IBS-D.Forty SD rats (half male and half female) were randomly assigned to control, model, EA, and medication groups by lottery, with 10 rats in each group. The IBS-D model was established by chronic unpredictable mild stress (CUMS) and gavage of senna soaking fluid. Rats in the EA group received EA (2 Hz/15 Hz,0.1-1 mA) stimulation of unilateral "Tianshu"(ST25), "Zusanli" (ST36), "Sanyinjiao"(SP6) and "Taichong"(LR3) for 15 min once a day for 14 days, and rats of the medication group received intragastric administration of pinave-rium bromide (10 mL/kg, 2.7 mg/mL) once daily for 14 days. The visceral pain threshold (VPT) was measured by using abdominal wall withdrawal reflex (AWR) test. The diarrhea index （loose stool rate ［total number of loose stool/total number of defecation］ X mean loose degree ［0-4 grades according to the filter paper stain diameter］ in 6 h/d） was used to assess the severity of diarrhea. The expression of Pirt in the DRG and TRPV1 in the colonic mucosa tissue was detected using immunohistochemistry.After modeling, the VPT was obviously reduced (EA can effectively alleviate visceral hypersensitivity in IBS-D rats, which may be related to its effect in down-regulating the expression level of DRG Pirt and colonic TRPV1.

Hepatic fibrosis is a key pathological process of chronic liver diseases, caused by alcohol, toxic and aberrant energy metabolism. It progresses to cirrhosis or even hepatic carcinoma without effective treatment. Studies have shown that autophagy has important regulatory effects on hepatic stellate cells (HSCs) energy metabolism, and then affect the activation state of HSCs. Autophagy maintains hepatic energy homeostasis, and the dysregulation of autophagy can lead to the activation of HSCs and the occurrence and development of hepatic fibrosis. It is necessary to explore the mechanism of autophagy in energy metabolism-related hepatic fibrosis. Herein, the current study summarizes the regulating mechanisms of autophagy through different targets and signal pathways in energy metabolism-related hepatic fibrosis, and discusses the regulatory effect of autophagy by natural plant-derived, endogenous and synthetic compounds for the treatment of hepatic fibrosis. A better comprehension of autophagy in hepatic stellate cells energy metabolism-related hepatic fibrosis may provide effective intervention of hepatic fibrosis, explore the potential clinical strategies and promote the drug treatment of hepatic fibrosis.

Pancreatic cancer is a malignant tumor with a high mortality rate. The rich stroma in tumor tissue is a major barrier to drug penetration and tumor killing. Cisplatin and cisplatin-based nano-delivery systems are widely used as chemotherapeutic agents. However, the side effects and the inability of permeating tumor tissue in depth have limited their application in the clinic. Hyaluronan is an important component of the extracellular matrix in the tumor tissue and has the potential to be targeted for tumor stroma degradation. Therefore, a nanocarrier-mediated cisplatin co-delivery system BPEI-SS-Pt/HAase@CaP consisting of hyaluronidase (HAase) and polymer-cisplatin conjugate BPEI-SS-Pt through disulfide bonding to branched polyethyleneimine (BPEI) was constructed. In the construction of the co-delivery system of BPEI-SS-Pt and HAase, amorphous calcium phosphate is introduced to obtain the tumor microenvironment responsive release of HAase. The particle size of optimized BPEI-SS-Pt/HAase@CaP nano-complexes is 143 ± 14 nm. In the tumor microenvironment, BPEI-SS-Pt/HAase@CaP nano-complexes were able to release HAase to degrade the hyaluronan in the tumor stroma. The results of histochemical and fluorescent labeling showed that hyaluronan was degraded in vivo by BPEI-SS-Pt/HAase@CaP and the nanocarrier-mediated BPEI-SS-Pt can be easily across the loosened stroma and penetrated the tumor tissue more deeply compared with BPEI-SS-Pt without loading HAase. When they were uptaken into tumor cells and responded to high glutathione in the intracellular environment to release cisplatin, more effective chemotherapy to pancreatic cancer was obtained. Compared with the free cisplatin or BPEI-SS-Pt group, BPEI-SS-Pt/HAase@CaP nano-complexes achieved the best antitumor effect in vivo, promising the future clinic use of cisplatin for effective chemotherapy to pancreatic cancer.

Prostate cancer is the most common malignant tumor with bone metastasis, and there is still no ideal treatment for bone metastasis of prostate cancer. In this study, a pH and GSH dual sensitive calcium phosphate-polymer hybrid nanoparticle (DTX@Cap/HP) was prepared to co-deliver zoledronate (ZOL) and docetaxel (DTX) to treat bone metastasis of prostate cancer. DTX@Cap/HP exhibited high bone binding affinity and released more DTX and ZOL in acidic and high GSH concentration environment. A large amount of DTX@Cap/HP was uptaken by PC-3 cell in acidic medium than that in neutral medium. DTX@Cap/HP obviously reduced PC-3 cell proliferation and bone lesion in in-vitro 3D model of bone metastases of prostate cancer. Besides, DTX@Cap/HP also exhibited stronger anti bone metastases of prostate cancer activity in vivo as compared with the same dose of DTX + ZOL, which resulted from the co-delivery of DTX and ZOL to bone metastases of prostate cancer by DTX@Cap/HP and the synergistic effects of DTX and ZOL. DTX@Cap/HP has great potential in the treatment of bone metastases of prostate cancer.

To observe the effect of electroacupuncture (EA) on intestinal epithelial mucosal barrier function in diarrhea-predominant irritable bowel syndrome(IBS-D) rats, so as to explore its mechanisms underlying improvement of IBS-D.Forty SD rats (half male and half female) were randomly divided into control, model, EA and medication (Pinaverium Bromide, PB) groups, with 10 rats in each group. The IBS-D model was established by chronic unpredictable mild stress combined with gavage of Senna-leaf solution. EA (2 Hz/15 Hz，0.1-1 mA) was applied to unilateral "Zusanli"(ST36),"Tianshu" (ST25), "Sanyinjiao"(SP6) and "Taichong"(LR3) alternatively for 15 min, once daily for 14 days. Rats of the medication group was treated by gavage of PB (10 mL·kgCompared with the control group, the diarrhea index and plasma DAO activity in the model group were significantly increased (Electroacupuncture can significantly improve abdominal pain and diarrhea in IBS-D model rats, which may be closely associated with its effects in up-regulating the expression of intestinal epithelial tight junction proteins Claudin-1 and Occludin to restore the function of intestinal epithelial mucosal barrier.

Polyethylenimine (PEI), a kind of cationic non-viral gene delivery vector, is capable of stable and efficient transgene expression for gene delivery. However, low transfection efficiency in vivo along with high toxicity limited the further application of gene therapy in the clinic. To enhance gene transfection performance and reduce cytotoxicity of polyethylenimine, branched polyethylenimine-derived cationic polymers BPEI25 k-man-S/L/M/H with different grafting degree with mannitol moieties were prepared and the transfection efficiency was evaluated. Among them, BPEI25 k-man-L showed the best transfection efficiency, lower toxicity, and significantly enhanced long-term systemic transgene expression for 96 h in vivo even at a single-dose administration. The results of cellular uptake mechanism and western-blot experiments revealed that the mannitol modification of BPEI25 k induced and up-regulated the phosphorylation of caveolin-1 and thus enhanced the caveolae-mediated cellular uptake. This class of gene delivery system highlights a paradigmatic approach for the development of novel and safe non-viral vectors for gene therapy.

Aim: To prepare pH-sensitive nanoparticle composed of alendronate (ALN) and poly(amidoamine) (PAMAM) to treat bone metastases of lung cancer. Methods: The solvent evaporation method was used to prepare docetaxel (DTX)-loaded ALN-PAMAM nanoparticles (DTX@ALN-PAMAM). Results: The in vitro results showed DTX@ALN-PAMAM significantly enhanced the anticancer activity of DTX and inhibited the formation of osteoclasts. DTX@ALN-PAMAM concentrated at bone metastasis site in mice, which resulted in the suppression of bone resorption, pain response and growth of bone metastases. Eventually, the therapeutic effect of DTX on bone metastases of lung cancer was obviously improved. Conclusion: ALN modified PAMAM nanoparticle could be an effective platform for the treatment of bone metastases of lung cancer.

To study the biopharmaceutics characteristics of paris saponin VII (PSVII). The solubility of PSVII was evaluated by measurement of the equilibrium solubility in different solvents and media. The permeability of PSVII was evaluated by measuring the oil/water partition coefficient (lgPapp) and determining the apparent permeability coefficient (PCapp) on a mono-layer Caco-2 cell model. The effects of p-glycoprotein and multidrug resistance related protein 2 on PSVII transport in mono-layer Caco-2 cell model were further investigated. Finally, the small intestinal absorption of PSVII was investigated in rat. In solvents of different pH, the equilibrium solubility of PSVII was quite low, and the dose number of PSVII was larger than 1. The lgPapp of PSVII was less than 0. The apparent permeability coefficient [PCapp(AP-BL)] of PSVII in mono-layer Caco-2 cell model was less than 14.96 × 10-6 cm·s-1, and the efflux ratio of PSVII in mono-layer Caco-2 cell model was less than 1. The transport rate of PSVII in mono-layer Caco-2 cell model was not affected by the inhibitors of p-glycoprotein and multidrug resistance related protein 2. After oral administration, PSVII could be detected in rat intestinal contents, but could not be detected in the small intestinal mucosa. PSVII showed low solubility and permeability, which would result in low oral bioavailability in clinic. PSVII belonged to Class IV compound in biopharmaceutics classification system.

Background: Bone is a frequent site of metastasis in lung cancer patients. So far, the treatment in bone metastasis of lung cancer still has not achieved any satisfactory effects in clinic. In this paper, alendronate (ALN) was selected to be connected with PAMAM via pH sensitive cis-aconitine anhydride (CA) to prepare bone-targeted micelle (DTX@ALN-PAMAM) to treat bone metastasis of lung cancer. Results: It was discovered that DTX@ALN-PAMAM released docetaxel (DTX) and ALN in pH-dependent manner. Besides, DTX@ALN-PAMAM showed high bind affinity with bone matrix, and quickly desorbed from bone matrix in weak acidic medium due to the rupture of cis-aconitamide bond between ALN and PAMAM. The in vitro results showed that DTX@ALN-PAMAM significantly enhanced the antitumor activity of DTX and decreased bone resorption through inhibiting the formation of osteoclasts in in-vitro 3D bone metastases model of lung cancer. In addition, DTX@ALN-PAMAM accumulated at bone metastases tissues for a relatively long time in tumor-bearing nude mice, which significantly reduced the bone resorption, relieved the pain response of tumor-bearing nude mice, and delayed the growth of bone metastases. Eventually, the therapeutic effect of DTX was improved on bone metastases of lung cancer. Conclusion: ALN modified PAMAM is a new and an effective platform for the treatment of bone metastasis of lung cancer.

The amoxicillin-UCCs-2/TPP nanoparticles constructed with ureido-modified chitosan derivative UCCs-2 and sodium tripolyphosphate (TPP) played an important role to deliver drug to achieve more efficacious and specific eradication of Helicobacterpylori (H. pylori) in vitro. In this study, the anti-H. pylori effectiveness in vivo and uptake mechanism was investigated in details, including the effect of temperature, pH values and the addition of competitive substrate urea on uptake. Compared with unmodified nanoparticles, a more efficacious and specific anti-H. pylori activities were obtained in vivo by using this biological chitosan derivative UCCs-2. Histological staining and immunological analysis verified that the amoxicillin-UCCs-2/TPP nanoparticles could diminish the proinflammatory cytokines levels and alleviate the inflammatory damages caused by H. pylori infection. The uredio-modified nanoparticles also have favorable gastric retention property, which is beneficial for the oral drug delivery to targeted eradicate H. pylori infection in stomach. These findings suggest that this targeted drug delivery system may serve for specific treatment of H. pylori infection both in vitro and in vivo, which can also be used as promising nanocarriers for other therapeutic reagents to target H. pylori.

One new cepheline-type alkaloid 8-hydroxyl-cepheline (1) and one new natural product Δ1′,2′-deoxytubulosine (2), together with 9 known alkaloids have been isolated from the fruits and seeds of Alangium salviifolium (L.f.) Wangerin. The structures of the new alkaloids were elucidated by means of extensive spectroscopic analysis (2D NMR, HRESIMS). All alkaloids were evaluated for their cytotoxic activity against three human cancer cell lines, A-549, Hela and SKOV-3. Compounds 1-4, 6, 8 and 9 exhibited significant inhibitory effects against three human cancer cells with IC50 values (0.1–14 μM) comparable to those of cisplatin.

The acidic environment of the stomach is a threat to the curative effect of antimicrobial drugs for the eradication of Helicobacter pylori (H. pylori) in the infected area. The conventional clinical formulations of antibiotics have low specificity to H. pylori, which disrupts the normal balance of intestinal microbiomes. Therefore, oral drug delivery system with better stability at low pH as well as higher specificity to target H. pylori would provide more effective strategy to eradicate H. pylori and reduce the side effect of antibiotics. Based on the construction of UreI-mediated targeted drug delivery system developed by our group, in this work, using urea-modified UCCs-2 as targeting moiety to the UreI channel protein which is specifically expressed on H. pylori, pH-sensitive amoxicillin-loaded AMX-PLGA/UCCs-2 nanoparticles produced by UCCs-2 and PLGA for targeted treatment of H. pylori infection were established. The nanoparticles were prepared by double emulsion-solvent evaporation method. To achieve a promising drug delivery system with favorable pH-sensitive properties, we adopted an orthogonal design to obtain the optimal formulation. The results showed that the optimized AMX-PLGA/UCCs-2 nanoparticles were in a favorable pH sensitive manner and exhibited low cytotoxicity, higher specificity and better anti-H. pylori efficiency than amoxicillin and non-targeting AMX-PLGA/Cs nanoparticle both in vitro and in vivo, which can protect the antimicrobial drugs against acidic environment and deliver them to targeted eradicate H. pylori in the infected location. The cellular uptake mechanism showed that AMX-PLGA/UCCs-2 nanoparticles are an effective UreI-mediated targeted drug delivery system for anti-H. pylori treatment, which can also be used as promising nanocarriers for oral delivery of other therapeutic drugs to targeted treat H. pylori.

In order to enhance the penetration of small interference RNA against the polo-like kinase I (siPLK1) across BBB to treat glioblastoma (GBM), transferrin (Tf) modified magnetic nanoparticle (Tf-PEG-PLL/MNP@siPLK1) was prepared. The in vitro experiments indicated that Tf-PEG-PLL/MNP@siPLK1 enhanced the cellular uptake of siPLK1, which resulted in an increase of gene silencing effect and cytotoxicity of Tf-PEG-PLL/MNP@siPLK1 on U87 cells. Besides, Tf-PEG-PLL/MNP@siPLK1 significantly inhibited the growth of U87 glioblastoma spheroids and markedly increased the BBB penetration efficiency of siPLK1 with the application of external magnetic field in in-vitro BBB model. The in vivo experiments indicated that siPLK1 selectively accumulated in the brain tissue, and markedly reduced tumor volume and prolonged the survival time of GBM-bearing mice after Tf-PEG-PLL/MNP@siPLK1 was injected to GBM-bearing mice via tail vein. The above data indicated that magnet and transferrin co-modified nanoparticle enhanced siPLK1 penetration across BBB and increased its anti GBM activity in vivo.

The experiment aims to increase antitumor activity while decreasing the systemic toxicity of doxorubicin (DOX). Charge reversible and mitochondria/nucleus dual target lipid hybrid nanoparticles (LNPs) was prepared. The in vitro experimental results indicated that LNPs released more amount of DOX in acidic environment and delivered more amount of DOX to the mitochondria and nucleus of tumor cells than did free DOX, which resulted in the reduction of mitochondrial membrane potential and the enhancement of cytotoxicity of LNPs on tumor cells. Furthermore, the in vivo experimental results indicated that LNPs delivered more DOX to tumor tissue and significantly prolonged the retention time of DOX in tumor tissue as compared with free DOX, which consequently resulted in the high antitumor activity and low systemic toxicity of LNPs on tumor-bearing nude mice. The above results indicated that charge reversible mitochondria/nucleus dual targeted lipid hybrid nanoparticles greatly enhanced therapeutic efficacy of DOX for treating lung cancer.

The covalently cross-linked chitosan-poly(ethylene glycol)1540 derivatives have been developed as a controlled release system with potential for the delivery of protein drug. The swelling characteristics of the hydrogels based on these derivatives as the function of different PEG content and the release profiles of a model protein (bovine serum albumin, BSA) from the hydrogels were evaluated in simulated gastric fluid with or without enzyme in order to simulate the gastrointestinal tract conditions. The derivatives cross-linked with difunctional PEG1540-dialdehyde via reductive amination can swell in alkaline pH and remain insoluble in acidic medium. The cumulative release amount of BSA was relatively low in the initial 2h and increased significantly at pH 7.4 with intestinal lysozyme for additional 12h. The results proved that the release-and-hold behavior of the cross-linked CS-PEG1540H-CS hydrogel provided a swell and intestinal enzyme controlled release carrier system, which is suitable for oral protein drug delivery.

Bone is an especially prone metastatic site for breast cancer, and to block the vicious cycle between bone resorption and tumor growth is an important strategy for the treatment of breast cancer bone metastasis. In this paper, pH- and redox-sensitive as well as breast cancer bone metastasis-targeting nanoparticles (DOX@ALN-(HA-PASP)CL) were prepared, and also their anti-tumor activity and anti-bone resorption effect were investigated in detail. The in vitro experimental results indicated that DOX released from DOX@ALN-(HA-PASP)CL exhibited a GSH-, DTT- and pH-dependent manner. Moreover, in an in vitro 3D breast cancer bone metastasis model, DOX@ALN-(HA-PASP)CL decreased bone resorption through inhibiting the proliferation of human breast cancer cells (MDA-MB-231 cells) and reducing the activity of osteoclasts. The in vivo experimental results indicated that a large amount of DOX was delivered to a breast cancer bone metastasis site after tumor-bearing mice were treated with DOX@ALN-(HA-PASP)CL; meanwhile, DOX@ALN-(HA-PASP)CL significantly decreased the tumor volume and bone resorption in tumor-bearing mice without causing obvious systemic toxicity. In conclusion, the in vitro and in vivo experimental results indicate that DOX@ALN-(HA-PASP)CL has great potential in the treatment of breast cancer bone metastasis.

This work focus on investigating the thermal fracture behavior of a sub-interface crack on the base of the former work[1], in which the bonded materials are assumed to have the same mechanical properties but dissimilar thermal parameters. However, the constituent materials of composites generally are different in both thermal and mechanical performance, the role of mechanical properties of the bonded materials play in the crack thermal fracture may not be simply ignored. Hence this work consider a more general case that the two bonded semi-infinite plates are of both thermally and mechanically difference, in one of which there exists a crack paralleling to the thermally imperfect bonding interface, a remote heat flux is applied. By using an integral transform/integral equation method, the influence of interfacial thermal resistance on the temperature difference along the crack line, the thermal stress intensity factors (TSIFs) and the crack opening/sliding displacements are researched. The results for steel/chrome bi-material combination show that the thermal fracture behavior of the sub-interface crack is significantly influenced by the interfacial thermal resistance and the crack-interface distance..

This paper aims at developing a simplified analytical model, as verified by the Hilbert-Riemann theoretical solution of interfacial cracks, to study the thermal stress distributions in solar cell laminated structures under thermal loadings. The interface thermal failure problem is analyzed in terms of the packaging materials and solar cell materials of simulated models, maximum interfacial normal stress, and stress critical point. It provides some guidance for the design and optimization of solar modules.

Two octahydro-protoberberine alkaloids, alangiifoliumines A (

Stimuli-responsive materials are promising paradigm applied to construct diagnostic and therapeutic intracellular controlled release vectors, while highlighting many challenges and opportunities. In this paper, six

The purpose of this paper is to analyze the properties of porcine cartilage type II collagen scaffolds crosslinked with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxy-succinamide (EDC/NHS) under different conditions. The porous EDC/NHS-crosslinked scaffolds were obtained through a two-step freeze-drying process. To determine the optimal crosslinking condition, we used different solvents and various crosslinking temperatures to prepare the scaffolds. Three crosslinking solutions were prepared with different solvents, photographs were taken with a flash in the darkroom, and light transmission was observed. Type II collagen was crosslinked on a horizontal shaker at a speed of 60 r/min according to the above grouping conditions, and then the structural change of the scaffold in each group was observed. To investigate the swelling ratio and the in vitro degradation of the collagen scaffold, tests were also carried out by immersion of the scaffolds in a PBS solution and digestion in type II collagenase, respectively. The influence of the scaffolds on the proliferation of chondrocytes was assessed by the methyl thiazolyl tetrazolium colorimetric assay. The morphology of the crosslinked scaffolds cocultured with chondrocytes was characterized by a scanning electron microscope. The results proved that 75% alcohol and a crosslinking temperature of 37 °C are recommended. Collagen fibrils are more densely packed after crosslinking with EDC/NHS and have a more uniform structure than that of noncrosslinked ones. The EDC-crosslinked scaffolds possessed excellent mechanical property and biocompatibility.