Biointerface-Engineered Hybrid Nanovesicles for Targeted Reprogramming of Tumor Microenvironment.

The tumor microenvironment (TME) of typical tumor types such as triple-negative breast cancer is featured by hypoxia and immunosuppression with abundant tumor-associated macrophages (TAMs), which also emerge as potential therapeutic targets for antitumor therapy. M1-like macrophage-derived exosomes (M1-Exos) have emerged as a promising tumor therapeutic candidate for their tumor-targeting and macrophage-polarization capabilities. However, the limited drug-loading efficiency and stability of M1-Exos have hindered their effectiveness in antitumor applications. Here, a hybrid nanovesicle is developed by integrating M1-Exos with AS1411 aptamer-conjugated liposomes (AApt-Lips), termed M1E/AALs. The obtained M1E/AALs are loaded with perfluorotributylamine (PFTBA) and IR780, as P-I, to construct P-I@M1E/AALs for reprogramming TME by alleviating tumor hypoxia and engineering TAMs. P-I@M1E/AAL-mediated tumor therapy enhances the in situ generation of reactive oxygen species, repolarizes TAMs toward an antitumor phenotype, and promotes the infiltration of T lymphocytes. The synergistic antitumor therapy based on P-I@M1E/AALs significantly suppresses tumor growth and prolongs the survival of 4T1-tumor-bearing mice. By integrating multiple treatment modalities, P-I@M1E/AAL nanoplatform demonstrates a promising therapeutic approach for overcoming hypoxic and immunosuppressive TME by targeted TAM reprogramming and enhanced tumor photodynamic immunotherapy. This study highlights an innovative TAM-engineering hybrid nanovesicle platform for the treatment of tumors characterized by hypoxic and immunosuppressive TME.

Identification of carbohydrate in Polygonatum kingianum Coll. et Hemsl and inhibiting oxidative stress.

The specific structure of Polygonatum kingianum Coll. et Hemsl polysaccharide (PKP) has been rarely reported. In this study, an inulin-type fructan PKP-1, was extracted and purified from Polygonatum kingianum Coll. et Hemsl, and its structural characteristics and antioxidants activity were evaluated. The molecular weights of PKP-1 was determined to be 4.802 kDa. Monosaccharide composition analysis evidenced that PKP-1 was composed of galactose, glucose and fructose in a molar ratio of 0.8 %:7.2 %:92.0 %. Glycosidic linkage and Nuclear Magnetic Resonance (NMR) analysis revealed that PKP-1 exhibited a primary sugar residue linkage of →1-ß-d-Fruf-2→2,6-ß-d-Fruf-1→, where ß-d-Fruf-2→ acts as the side chain and links to the C-6 position of →2,6-ß-d-Fruf-1→. In vitro antioxidant activity assays demonstrated that PKP-1 enhanced the mitigation of hepatic oxidative stress in HepG2 cells induced by free fatty acids. This effect was marked by increased enzymatic activities of superoxidase dismutase (SOD) and catalase (CAT), along with elevated glutathione (GSH) levels. These findings indicate that PKP-1 could be used as a potential natural antioxidant.

Mobility, binding behavior and potential risks of trace metals in the sediments of the fifth largest freshwater lake, China.

The trace metal pollution of sediments in Chaohu Lake, one of the most highly eutrophic lakes in East China, was investigated. Surface sediment (0-5 cm) samples were collected from 35 different positions and analyzed by inductively coupled plasma optical emission spectrometry to determine trace metal contents. Results showed that the mean content of trace metals was as follows: Cr, 85.09 mg kg(-1); Cu, 34.49 mg kg(-1); Ni, 26.46 mg kg(-1); Pb, 34.17 mg kg(-1) and Zn, 107.46 mg kg(-1). The trace metal concentrations from different sampling sites displayed spatial diversity; the heavily polluted sampling sites were close to where estuaries flow in to the lake. A four-step sequential extraction was used to examine the partitioning of the trace metals. Results demonstrated that the percentage of the species bound to the oxidizable phase for all trace metals ranged from 15.6 to 37.7%, while for Cu, Cr and Ni, the main forms were residual (41.3, 62.3 and 69.8%, respectively). Trace metals in the oxidizable fraction may mainly exist in the form of sulfides. The ecological potential risks of trace metals decreased as follows: Pb > Zn > Cu > Cr > Ni.

Precise assembly of inside-out cell membrane camouflaged nanoparticles via bioorthogonal reactions for improving drug leads capturing.

Cell membrane camouflaged nanoparticles have been widely used in the field of drug leads discovery attribute to their unique biointerface targeting function. However, random orientation of cell membrane coating does not guarantee effective and appropriate binding of drugs to specific sites, especially when applied to intracellular regions of transmembrane proteins. Bioorthogonal reactions have been rapidly developed as a specific and reliable method for cell membrane functionalization without disturbing living biosystem. Herein, inside-out cell membrane camouflaged magnetic nanoparticles (IOCMMNPs) were accurately constructed via bioorthogonal reactions to screen small molecule inhibitors targeting intracellular tyrosine kinase domain of vascular endothelial growth factor recptor-2. Azide functionalized cell membrane acted as a platform for specific covalently coupling with alkynyl functionalized magnetic Fe3O4 nanoparticles to prepare IOCMMNPs. The inside-out orientation of cell membrane was successfully verified by immunogold staining and sialic acid quantification assay. Ultimately, two compounds, senkyunolide A and ligustilidel, were successfully captured, and their potential antiproliferative activities were further testified by pharmacological experiments. It is anticipated that the proposed inside-out cell membrane coating strategy endows tremendous versatility for engineering cell membrane camouflaged nanoparticles and promotes the development of drug leads discovery platforms.

Bioinspired nano-plate-coral platform enabled efficient detection of circulating tumor cells via the synergistic capture of multivalent aptamer and tumor cell membrane.

Circulating tumor cells (CTCs) offer rich information for early disease diagnosis and therapy evaluation. However, the limited sensitivity, binding affinity, and stability of current monovalent recognition-based CTCs detection techniques remain a challenge for extending their applications. Inspired by the highly efficient predation manner of plate corals, we firstly introduce an efficient and sensitive biomimetic CTCs recognition platform based on the conjugation of multivalent aptamer onto tumor cell membrane-coated magnetic graphene oxide to form a plate coral-like CTCs capture nanoprobe (MNPA-TCMMGO). In this method, the tumor cell membrane was employed to provide a biomimetic homologous fluidic interface for targeting homologous tumor cells. At the same time, multivalent aptamers were used as capture probes, which greatly enhanced the binding affinity and association probability between aptamer and target cells via cooperative multivalent effect. The unique features (robustness, high binding affinity and specificity, and biocompatibility) of MNPA-TCMMGO allow efficient, sensitive, and specific capture of rare tumor cells from biological samples. More importantly, the captured cells could maintain good viability, which is crucial for downstream analysis. Therefore, our developed biomimetic approach offers a new way to address the limitations of current CTCs detection methods and presents considerable potential for clinical cancer diagnostics.

Rational construction of fluorescent molecular imprinted polymers for highly efficient glycoprotein detection.

The enrichment of glycoproteins by fluorescence molecular imprinting has shown an attractive application prospect, however, its specificity and sensitivity in actual sample analysis remain a significant challenge. In this work, a novel fluorescent molecular imprinted nanoplatform (MMIPs@QDs) was constructed for the efficient recognition and determination of glycoproteins by combining the glycopeptide template and the post-imprinting modification of nitrogen-doped graphene quantum dots. The synthetic MMIPs@QDs exhibited high adsorption capacity and rapid binding kinetics. Satisfying selectivity and sensitivity were obtained using MMIPs@QDs, with an imprinting factor of 7.71 and a limit of detection of 0.20 µg mL-1, respectively. The efficiency and applicability of this proposed method were validated by the detection of ovalbumin in egg white samples, showed high recoveries (94.3%-100.2%) and acceptable relative standard deviation (1.79%-7.36%). This fluorescent molecular imprinted nanoplatform provides a new approach to address the limitations of existing protein detection techniques.

Angiotensin II inhibits osteogenic differentiation of isolated synoviocytes by increasing DKK-1 expression.

The renin-angiotensin system contributes to the pathogenesis of rheumatoid arthritis, but that the mechanism is unclear. This study aims to investigate the effect of angiotensin II (Ang II) on osteogenic differentiation of synoviocytes and the underlying mechanism. Ang II was showed to inhibite osteogenic differentiation of synoviocytes, which was mitigated by a Dickkopf-1 (DKK-1) inhibitor. DKK-1 was upregulated by Ang II, which was weakened by the Ang II type 1 receptor (AT1R) blocker, reactive oxygen species (ROS) scavenger, and p38 inhibitor. Ang II increased the levels of AT1R, ROS, and NADPH oxidase (NOX), and the upregulations were mitigated by the AT1R blocker or NOX inhibitor. Furthermore, Ang II activated the p38 pathway, which was blocked by the AT1R blocker, ROS scavenger, or siRNA-MKK3. In brief, these results indicate that Ang II upregulates NOX expression and ROS production via AT1R, activates the MKK3/p38 signaling, and in turn upregulates DKK-1 expression, participating in the inhibition of osteogenic differentiation of synoviocytes.

Minimally invasive unicompartmental knee replacement: Midterm clinical outcome.

OBJECTIVE: The purpose of this study was to explore the midterm clinical outcomes of unicompartmental knee replacement (UKR) for medial knee arthropathy through a minimally invasive approach (MIA). METHODS: From January 2006 to June 2010, 442 consecutive patients (485 knees) were included in the study. All patients underwent MIA-UKR with the mobile bearing Oxford phrase III prosthesis. The incision was made starting 1 cm medial to the medial pole of the patella and extending distally to the tibial tubercle. Radiographic evaluations include femorotibial angle (FTA) from coronal x-rays and rectified varus deformity angle, while clinical evaluations included Knee Society Score (KSS, clinical score and function score), the Western Ontario and McMaster Universities Arthritis Index (WOMAC) osteoarthritis index and visual analog scale (VAS) for pain. Patients followed-up at 1, 3, 6, 12 months after surgery and each year thereafter. RESULTS: Four hundreds and two patients completed the entire follow-up, 40 patients (45 knees) were lost to follow-up. The average follow-up time was 73.0 ± 1.9 months. The mean length of the incisions was 5.0 ± 0.2 cm. The average FTA decreased from 183.6° ± 5.1° preoperatively to 174.3° ± 4.2° postoperatively, and the mean rectified varus deformity angle was 9.3° ± 1.2°. The KSS clinical score improved from 42.4 ± 2.9 to 92.9 ± 3.8, and the function score improved from 53.5 ± 3.8 to 93.5 ± 4.0. The WOMAC score improved from 47.5 ± 3.1 preoperatively to 12.3 ± 1.5 at the last evaluation. The VAS dropped from 7.8 ± 1.9 preoperatively to 1.6 ± 0.2 postoperatively. All clinical evaluations (KSS, WOMAC, VAS) were significantly different (p < 0.05) from pre and post-operative evaluations. The survival rate was 99.1% at 73 months, and the revision rate was 0.9%. CONCLUSION: The midterm clinical outcomes of MIA-UKR are satisfactory in a Chinese patient population, which is a good surgical option for patients with medial arthropathy of the knee. However, longer-term follow-up studies should be performed in these patients.

PAI-1 4G/5G polymorphism contributes to cancer susceptibility: evidence from meta-analysis.

BACKGROUND: The plasminogen activator inhibitor-1 (PAI-1) is expressed in many cancer cell types and allows the modulation of cancer growth, invasion and angiogenesis. To date, studies investigated the association between a functional polymorphism in PAI-1 (4G/5G) and risk of cancer have shown inclusive results. METHODS: A meta-analysis based on 25 case-control studies was performed to address this issue. Odds ratios (OR) with corresponding 95% confidence intervals (CIs) were used to assess the association. The statistical heterogeneity across studies was examined with I(2) test. RESULTS: Overall, a significant increased risk of cancer was associated with the PAI-1 4G/4G polymorphism for the allele contrast (4G vs. 5G: OR = 1.10, CI = 1.03-1.18, I(2) = 49.5%), the additive genetic model (4G/4G vs. 5G/5G: OR = 1.21, CI = 1.06-1.39, I(2) = 51.9%), the recessive genetic model (4G/4G vs. 4G/5G+5G/5G: OR = 1.11, CI = 1.04-1.18, I(2) = 20.8%). In the subgroup analysis by ethnicity, the results indicated that individuals with 4G/4G genotype had a significantly higher cancer risk among Caucasians (4G/4G vs. 5G/5G: OR = 1.31, 95%CI = 1.09-1.59, I(2) = 59.6%; 4G/4G vs. 4G/5G: OR = 1.12, 95%CI = 1.04-1.21, I(2) = 3.6%; recessive model: OR = 1.12, 95%CI = 1.05-1.21, I(2) = 25.3%). CONCLUSIONS: The results of the present meta-analysis support an association between the PAI-1 4G/5G polymorphism and increasing cancer risk, especially among Caucasians, and those with 4G allele have a high risk to develop colorectal cancer and endometrial cancer.

MspI and Ile462Val polymorphisms in CYP1A1 and overall cancer risk: a meta-analysis.

BACKGROUND: Cytochrome P450 1A1 (CYP1A1) is a member of the CYP1 family, which is a key enzyme in the metabolism of many endogenous substrates and exogenous carcinogens. To date, many studies have examined the association between CYP1A1 MspI and Ile462Val polymorphisms and cancer risk in various populations, but their results have been conflicting rather than consistent. METHODS: To assess this relationship more precisely, a meta-analysis based on 198 publications was performed. Odds ratios (OR) and corresponding 95% confidence intervals (CIs) were used to assess the association. The statistical heterogeneity across studies was examined with a chi-square-based Q-test. RESULTS: Overall, a significant elevated risk of cancer was associated with CYP1A1 MspI and Ile462Val polymorphisms for all genetic models studied. Further stratified analysis by cancer types revealed that the MspI polymorphism may increase the risk of lung cancer and cervical cancer whereas the Ile462Val polymorphism may contribute to a higher risk of lung cancer, leukemia, esophageal carcinoma, and prostate cancer. In the subgroup analysis by ethnicity, obvious associations were found in the Asian population for the MspI polymorphism while an increased risk of cancer was observed in Asians and Caucasians for the Ile462Val polymorphism. CONCLUSIONS: The results of this meta-analysis suggest that CYP1A1 MspI and Ile462Val polymorphisms contribute to increased cancer susceptibility among Asians. Additional comprehensive system analyses are required to validate this association and other related polymorphisms.

[A prospective randomized trial of poly-DL-lactic acid absorbable and metallic screws for treatment of syndesmotic disruptions].

OBJECTIVE: To compare the clinical effect of poly-DL-lactic acid (PDLLA) absorbable screws and titanium metallic screws in the treatment of syndesmotic disruptions in ankle fractures. METHODS: In this prospective, randomized clinical trial, 58 patients with or suspected of syndesmotic disruption associated with ankle fractures were randomly allocated to receive either bioabsorbable PDLLA or metallic titanium screwing fixation. Using preoperative radiography and intraoperative hook test, syndesmotic disruption was confirmed in 47 cases (25 with metallic screwing and 22 with PLLA screwing). Statistical analyses were performed at 6 months postoperatively to compare the AOFAS score, range of motion of the joint, TFCS width and TFO width on anteroposterior view radiographs, and inflammatory reactions between the two groups. RESULTS: The PDLLA screws showed good therapeutic effect similar to that of titanium metallic screws in syndesmosis fixation in these patients. No significant differences were found in the AOFAS score, range of motion of the joint, or TFCS width or TFO width between two groups (P>0.05). One patient in PDLLA screw group showed inflammatory reactions to the implants. CONCLUSION: PDLLA screws allow effective and reliable stabilization of syndesmotic disruptions without a second operation for screw removal.