Sulfur-Vacancy-Engineered Two-Dimensional Cu@SnS2-x Nanosheets Constructed via Heterovalent Substitution for High-Efficiency Piezocatalytic Tumor Therapy.

Ultrasound (US)-mediated piezocatalytic tumor therapy has attracted much attention due to its notable tissue-penetration capabilities, noninvasiveness, and low oxygen dependency. Nevertheless, the efficiency of piezocatalytic therapy is limited due to an inadequate piezoelectric response, low separation of electron-hole (e--h+) pairs, and complex tumor microenvironment (TME). Herein, an ultrathin two-dimensional (2D) sulfur-vacancy-engineered (Sv-engineered) Cu@SnS2-x nanosheet (NS) with an enhanced piezoelectric effect was constructed via the heterovalent substitution strategy of Sn4+ by Cu2+. The introduction of Cu2+ ion not only causes changes in the crystal structure to increase polarization but also generates rich Sv to decrease band gap from 2.16 to 1.62 eV and inhibit e--h+ pairs recombination, collectively leading to the highly efficient generation of reactive oxygen species under US irradiation. Moreover, Cu@SnS2-x shows US-enhanced TME-responsive Fenton-like catalytic activity and glutathione depletion ability, further aggravating the oxidative stress. Both in vitro and in vivo results prove that the Sv-engineered Cu@SnS2-x NSs can significantly kill tumor cells and achieve high-efficiency piezocatalytic tumor therapy in a biocompatible manner. Overall, this study provides a new avenue for sonocatalytic therapy and broadens the application of 2D piezoelectric materials.

Application of TCM Rehabilitation in Joint Function Recovery After Treatment of Distal Radius Fractures: A Meta-Analysis.

Objective: To evaluate the effect of traditional Chinese medicine (TCM) rehabilitation on the postoperative function of patients with distal radius fractures by Meta-analysis. Methods: PubMed, Embase, CNKI, Wanfang, and other databases were searched for retrospective controlled trials and prospective randomized controlled trials on the effect of traditional Chinese medicine rehabilitation on the function of patients with distal radius fractures after surgery from the establishment of the database to May 2023. Revman version 5.3 software was used to analyze the extracted and screened index data. Results: Eight studies involving 455 patients were included. Meta-analysis results showed Overall analysis showed that there was a significant difference in wrist function between the TCM rehabilitation group and the control group (MD = -12.16, 95%CI:-17.21 to -7.11, P < .00001), low heterogeneity (I2=40%, P = .17), the difference in dorsiflexion function between the TCM rehabilitation group and the control group was statistically significant (MD = -1.16, 95%CI:-2.24 to -0.08, P = .04), with high heterogeneity (I2=79%, P = .003), that there was a significant difference in grip strength between the TCM rehabilitation group and the control group at 6 weeks (MD= 0.48, 95%CI: 0.24 to 0.71, P < .0001) with low heterogeneity (I2=45%, P = .12), there was no significant difference between the TCM rehabilitation group and the control group (OR= -0.00, 95%CI: -0.08 to 0.08, P = .99), and there was no heterogeneity (I2=0%, P = .66). Conclusion: Traditional Chinese medicine rehabilitation treatment of distal radius fractures can increase the range of motion of wrist joints, reduce pain, shorten the rehabilitation time of patients, improve the quality of life, and is conducive to the standardized treatment of patients.

MCM2 is involved in subtyping and tamoxifen resistance of ERα-positive breast cancer by acting as the downstream factor of ERα.

Tamoxifen (TAM) resistance is finally developed in over 40% of patients with estrogen receptor α-positive breast cancer (ERα+ -BC), documenting that discovering new molecular subtype is needed to confer perception to the heterogeneity of ERα+ -BC. We obtained representative gene sets subtyping ERα+ -BC using gene set variation analysis (GSVA), non-negative matrix factorization (NMF), and COX regression methods on the basis of METABRIC, TCGA, and GEO databases. Furthermore, the risk score of ERα+ -BC subtyping was established using least absolute shrinkage and selection operator (LASSO) regression on the basis of genes in the representative gene sets, thereby generating the two subtypes of ERα+ -BC. We further found that minichromosome maintenance complex component 2 (MCM2) functioned as the hub gene subtyping ERα+ -BC using GO, KEGG, and MCODE. MCM2 expression was capable for specifically predicting 1-year overall survival (OS) of ERα+ -BC and correlated with T stage, AJCC stage, and tamoxifen (TAM) sensitivity of ERα+ -BC. The downregulation of MCM2 expression inhibited proliferation, migration, and invasion of TAM-resistant cells and promoted G0/G1 arrest. Altogether, tamoxifen resistance entails that MCM2 is a hub gene subtyping ERα+ -BC, providing a novel dimension for discovering a potential target of TAM-resistant BC.

Multifunctional nanocoatings with synergistic controlled release of zinc ions and cytokines for precise modulation of vascular intimal reconstruction.

Vascular stent implantation remains the major therapeutic method for cardiovascular diseases currently. We here introduced crucial biological functional biological function factors (SDF-1α, VEGF) and vital metal ions (Zn2+) into the stent surface to explore their synergistic effect in the microenvironment. The combination of the different factors is known to effectively regulate cellular inflammatory response and selectively regulate cell biological behavior. Meanwhile, in the implemented method, VEGF and Zn2+ were loaded into heparin and poly-l-lysine (Hep-PLL) nanoparticles, ensuring a controlled release of functional molecules with a multi-factor synergistic effect and excellent biological functions in vitro and in vivo. Notably, after 150 days of implantation of the modified stent in rabbits, a thin and smooth new intima was obtained. This study offers a new idea for constructing a modified surface microenvironment and promoting tissue repair.

MiR-204-5p-targeted AP1S2 is necessary for papillary thyroid carcinoma.

MiR-204-5p, as a tumour suppressor, has been found in several cancers. However, whether miR-204-5p is involved in papillary thyroid carcinoma (PTC) has not yet been investigated. In this study, we identified miR-204-5p as a down-regulated miRNA in PTC tissues, unveiling that the levels of miR-204-5p in serum of patients with PTC were linked to PTC risk, and that the expression in patients concomitant with both PTC and benign lesions was much lower than that in patients only with PTC. Furthermore, we documented that miR-204-5p inhibited proliferation, migration, invasion, and cell cycle progression and triggered apoptosis of PTC cells via cell biology experiments. Finally, we identified that AP1S2 was a target of miR-204-5p using RNA-seq, iTRAQ, and bioinformatics prediction. Overall, miR-204-5p functions as a suppressor for PTC pathogenesis via the miR-204-5p/AP1S2 axis.

Iron oxide-EDTA nanoparticles for chelation-enhanced chemodynamic therapy and ion interference therapy.

As an emerging anti-tumor strategy, chemodynamic therapy (CDT) utilizes a Fenton/Fenton-like reaction to generate highly toxic hydroxyl radicals to kill tumor cells. However, the efficiency of CDT is still hindered by the low Fenton/Fenton-like reaction rate. Herein, we report the combination of ion interference therapy (IIT) and chemodynamic therapy (CDT) via an amorphous iron oxide (AIO) nanomedicine with encapsulated EDTA-2Na (EDTA). Iron ions and EDTA are released from the nanomedicine in acidic tumors and chelate to form iron ion-EDTA, which improves the efficiency of CDT and promotes the generation of reactive oxygen species (ROS). In addition, EDTA can disrupt the homeostasis of Ca2+ in tumor cells by chelating with Ca2+ ions, which induces the separation of tumor cells and affects normal physiological activities. Both in vitro and in vivo experiments show that the nano chelating drugs exhibit significant improvement in Fenton reaction performance and excellent anti-tumor activity. This study based on chelation provides a new idea for designing efficient catalysts to enhance the Fenton reaction and provides more revelations on future research on CDT.

Construction of Multiform Hollow-Structured Covalent Organic Frameworks via a Facile and Universal Strategy for Enhanced Sonodynamic Cancer Therapy.

The special structural morphology of hollow covalent organic frameworks (HCOFs) has an important influence on their applications. However, the rapid and precise control of morphology for HCOFs still remains largely challenging. Herein, we present a facile and universal two-step strategy based on solvent evaporation and oxidation of imine bond for the controllable synthesis of HCOFs. The strategy enables to prepare HCOFs in a greatly shortened reaction time and seven kinds of HCOFs are fabricated by the oxidation of imine bond via hydroxyl radicals (⋅OH) generated from Fenton reaction. Importantly, a fascinating library of HCOFs with diverse nanostructures, including bowl-like, yolk-shell, capsule-like and flower-like morphologies, has been ingeniously constructed. Owing to the large cavities, the obtained HCOFs are ideal candidates for drug delivery, which are employed to load five small molecule drugs, achieving the enhanced sonodynamic cancer therapy in vivo.

Microstructure and Properties of Nickel-Based Gradient Coatings Prepared Using Cold Spraying Combined with Laser Cladding Methods.

A cold spray-laser cladding composite gradient coating (CLGC) was successfully formed on a Cu substrate. In comparison with traditional laser cladding gradient coatings (LGC), cold spraying the pre-set Ni-Cu alloy's intermediate transition layer not only mitigates the negative impacts due to the high reflectivity of the copper substrate but also helps to minimize the difference in the coefficients of thermal expansion (CTE) between the substrate and coating. This reduces the overall crack sensitivity and improves the cladding quality of the coating. Besides this, the uniform distribution of hard phases in CLGC, such as Ni11Si12 and Mo5Si3, greatly increases its microhardness compared to the Cu substrate, thus resulting in the value of 478.8 HV0.5 being approximately 8 times that of the Cu substrate. The friction coefficient of CLGC is lowered compared to both the Cu substrate and LGC with respective values of 0.28, 0.54, and 0.43, and its wear rate is only one-third of the Cu substrate's. These results suggest CLGC has excellent anti-wear properties. In addition, the wear mechanism was determined from the microscopic morphology and element distribution and was found to be oxidative and abrasive. This approach combines cold spraying and laser cladding to form a nickel-based gradient coating on a Cu substrate without cracks, holes, or other faults, thus improving the wear resistance of the Cu substrate and improving its usability.

Fe(III)-Naphthazarin Metal-Phenolic Networks for Glutathione-Depleting Enhanced Ferroptosis-Apoptosis Combined Cancer Therapy.

Nowadays, Fenton chemistry-based chemodynamic therapy (CDT) is an emerging approach to killing tumor cells by converting endogenous H2 O2 into cytotoxic hydroxyl radicals (·OH). However, the elimination of ·OH by intracellular overexpressed glutathione (GSH) results in unsatisfactory antitumor efficiency. In addition, the single mode of consuming GSH and undesirable drug loading efficiency cannot guarantee the efficient cancer cells killing effect. Herein, a simple one-step strategy for the construction of Fe3+ -naphthazarin metal-phenolic networks (FNP MPNs) with ultrahigh loading capacity, followed by the modification of NH2 -PEG-NH2 , is developed. The carrier-free FNP MPNs can be triggered by acid and GSH, and rapidly release naphthazarin and Fe3+ , which is further reduced to Fe2+ that exerts Fenton catalytic activity to produce abundant ·OH. Meanwhile, the Michael addition between naphthazarin and GSH can lead to GSH depletion and thus achieve tumor microenvironment (TME)-triggered enhanced CDT, followed by activating ferroptosis and apoptosis. In addition, the reduced Fe2+ as a T1 -weighted contrast agent endows the FNP MPNs with magnetic resonance imaging (MRI) functionality. Overall, this work is the debut of naphthazarin as ligands to fabricate functional MPNs for effectively depleting GSH, disrupting intracellular redox homeostasis, and enhancing CDT effects, which opens new perspectives on multifunctional MPNs for tumor synergistic therapy.

Double-activation of mitochondrial permeability transition pore opening via calcium overload and reactive oxygen species for cancer therapy.

BACKGROUND: Calcium ions (Ca2+) participates in various intracellular signal cascades and especially plays a key role in pathways relevant to cancer cells. Mitochondrial metabolism stimulated by calcium overload can trigger the opening of the mitochondrial permeability transition pore (MPTP), which leads to cancer cell death. METHODS: Herein, a mitochondrial pathway for tumour growth inhibition was built via the double-activation of MPTP channel. Fe2+ doped covalent organic frameworks (COF) was synthesised and applied as template to grow CaCO3 shell. Then O2 was storaged into Fe2+ doped COF, forming O2-FeCOF@CaCO3 nanocomposite. After modification with folic acid (FA), O2-FeCOF@CaCO3@FA (OFCCF) can target breast cancer cells and realize PDT/Ca2+ overload synergistic treatment. RESULTS: COF can induce the production of 1O2 under 650 nm irradiation for photodynamic therapy (PDT). Low pH and hypoxia in tumour microenvironment (TME) can activate the nanocomposite to release oxygen and Ca2+. The released O2 can alleviate hypoxia in TME, thus enhancing the efficiency of COF-mediated PDT. Abundant Ca2+ were released and accumulated in cancer cells, resulting in Ca2+ overload. Notably, the reactive oxygen species (ROS) and Ca2+ overload ensure the sustained opening of MPTP, which leads to the change of mitochondria transmembrane potential, the release of cytochrome c (Cyt c) and the activation of caspases 3 for cancer cell apoptosis. CONCLUSION: This multifunctional nanosystem with TME responded abilities provided a novel strategy for innovative clinical cancer therapy.

Circulating miR-3656 induces human umbilical vein endothelial cell injury by targeting eNOS and ADAMTS13: a novel biomarker for hypertension.

BACKGROUND: Hypertension, as one of the most common chronic diseases, is a major public health issue. Previous studies have shown that there are miRNAs differentially expressed in hypertensive patients. In addition, hypertension is closely related to endothelial dysfunction, and miRNAs have been identified as important molecular mediators for endothelial function. Therefore, it is necessary to identify specific miRNAs related to hypertension and explore their molecular mechanism in the progression of hypertension. METHODS: We investigated the association of circulating levels of miR-3656 with hypertension. Furthermore, in-vitro studies were performed to investigate its possible mechanisms for hypertension in that the direct target genes of miR-3656 were confirmed using dual-luciferase reporter assay; moreover, the effects of miR-3656 on proliferation, migration, apoptosis, and microvascular rarefaction of HUVECs were investigated using MTS kit, wound-healing assay, FITC Annexin V apoptosis detection kit, and tube formation assay, correspondingly. RESULTS: Circulating miR-3656 was upregulated in patients with hypertension. MiR-3656 suppressed the proliferation, migration, and angiogenesis of HUVECs, but promoted the apoptosis of HUVECs. In addition, eNOS and ADAMTS13 were direct target genes of miR-3656, and overexpression of eNOS and ADAMTS13 abolished the effect of miR-3656 on HUVECs. CONCLUSION: MiR-3656 is a potential biomarker for hypertension. MiR-3656 is involved in endothelial cellular injury implicated in hypertension by targeting eNOS and ADAMTS13.

Facile Synthesis of a Cubic Porphyrin-Based Covalent Organic Framework for Combined Breast Cancer Therapy.

A cubic porphyrin-based covalent organic framework (COF) named CTP with excellent hydrophilicity was prepared with a facile method for the first time. Different from the conventional methods for the synthesis of porphyrin-based COFs, this facile strategy has greatly shortened the reaction time under mild conditions. Linking the porphyrin monomer into the COF overcame its poor solubility and biocompatibility and also narrowed the band gap owing to the formation of the π-conjugation structure. The improved biocompatibility and narrowed band gap enabled CTP to be an excellent sonosensitizer with an enhanced sonodynamic effect. Moreover, CTP could also effectively realize photothermal conversion under external irradiation due to the extended conjugated structure. This work developed a novel synthesis method for COFs and employed a COF as a sonosensitizer for the first time, which not only provided a new strategy to improve the efficiency of organic sonosensitizers but also inspired us to design more functional COFs for versatile applications.

Synthesis of porphyrin-incorporating covalent organic frameworks for sonodynamic therapy.

Porphyrin-incorporating covalent organic frameworks were synthesized at room temperature. The resulting products with uniform morphology and excellent crystallinity exhibited good singlet oxygen generation ability. Both in vitro and in vivo experiments demonstrated the significant antitumor efficiency via sonodynamic therapy.

Down-regulated FST expression is involved in the poor prognosis of triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is more commonly associated with young patients, featuring high histological grade, visceral metastasis, and distant recurrence. Follistatin (FST) is a secreted extracellular regulatory protein that antagonizes TGF-ß superfamily such as activin and TGF-ß related superfamily such as bone morphogenetic protein (BMP). The implication of FST in the proliferation, angiogenesis, and metastasis of solid tumors documents good or poor outcome of patients with BC. However, the role of FST in TNBC remains unclear. METHODS: Data of 935 patients with breast cancer (BC) were extracted from TCGA. Case-control study, Kaplan-Meier, uni-multivariate COX, and ROC curve were utilized to investigate the relationship between FST expression and the clinical characteristics and prognosis of BC. Functional studies were used to analyze the effect of FST expression on proliferation, apoptosis, migration, and invasion of TNBC cell lines. Bioinformatic methods such as volcanoplot, GO annd KEGG enrichment, and protein-protein interactions (PPI) analyses were conducted to further confirm the different roles of FST in the apoptotic pathways among mesenchymal and mesenchymal stem-like cells of TNBC. RESULTS: Data from TCGA showed that low FST expression correlated with poor prognosis (for univariate analysis, HR = 0.47, 95% CI: 0.27-0.82, p = 0.008; for multivariate analysis, HR = 0.40, 95% CI: 0.21-0.75, p = 0.004). Low FST expression provided high predicted value of poor prognosis in TNBC amongst BCs. FST knockdown promoted the proliferation, migration and invasion of BT549 and HS578T cell lines. FST inhibited the apoptosis of mesenchymal cells by targeting BMP7. CONCLUSIONS: Low FST expression is associated with poor prognosis of patients with TNBC. FST expressions exhibit the anisotropic roles of apoptosis between mesenchymal and mesenchymal stem-like cells but promote the proliferation, migration, invasion in both of two subtypes of TNBC in vitro. FST may be a subtype-heterogeneous biomarker for monitoring the progress of TNBC.

OLFML2A is necessary for anti-triple negative breast cancer effect of selective activator protein-1 inhibitor T-5224.

Previous studies have shown that expression of activator protein-1 (AP-1) family is significantly elevated in triple-negative breast cancer (TNBC), compared with that in other breast cancer subtypes. Here we investigated the anti-tumor effect and mechanism of T-5224, an inhibitor of c-Fos/AP-1, on TNBC. We identified that T-5224 inhibited the proliferation, migration, and invasion of TNBC cells and resulted in an increase in apoptosis. Furthermore, we found that OLFML2A is a key regulatory protein acting downstream of AP-1 and is involved in T-5224-targeted AP-1 action. Multiple clinical databases online have identified that high OLFML2A level is associated with poor prognosis in TNBC patients. In summary, our experimental and bioinformatic studies indicated that OLFML2A is necessary for AP-1-overexpressing TNBC. These findings demonstrate that AP-1-overexpressing TNBC dependent on OLFML2A, and targeting both AP-1 and OLFML2A through T-5224 may be a synergistic therapeutic strategy for this clinically challenging subset of breast cancer.

Facile synthesis of Fe-baicalein nanoparticles for photothermal/chemodynamic therapy with accelerated FeIII/FeII conversion.

Fe2+-baicalein-polyethylene glycol (Fe-BaP) nanoparticles were synthesized by a room temperature wet chemical method via coordination between Fe2+ and baicalein. Fe-BaP possessed high photothermal conversion efficiency (η = 45.6%) and excellent antitumor efficacy was achieved with the synergistic photothermal/chemodynamic tumor therapy.

Covalent Organic Framework-Titanium Oxide Nanocomposite for Enhanced Sonodynamic Therapy.

Sonodynamic therapy (SDT) has attracted wide attention for its high tissue-penetration depth capacity. However, developing new kinds of sonosensitizers that are capable of generating large amounts of reactive oxygen species (ROS) still remains a challenge. Herein, covalent organic framework-titanium oxide nanoparticles (COF-TiO2 NPs) were successfully synthesized by using COF as a template. Under ultrasound (US) irradiation, large quantities of ROS can be generated, and compared with pure TiO2 NPs, the SDT performance of COF-TiO2 nanoparticles was significantly improved due to the narrower band gap. Both in vitro and in vivo experiments demonstrated the great tumor inhibitory effect via COF-TiO2-mediated SDT. This work broadens the biomedical applications of COF-based composites.

Biofunctionalized fibrin gel co-embedded with BMSCs and VEGF for accelerating skin injury repair.

Rapid and effective repair of epithelial tissue is desirable for improving the success rate of operation and reducing postoperative complications. Hydrogel is a widely studied wound repair material, especially as a wound dressing for damaged epithelial tissue. Based on the catalytic effect of thrombin on fibrinogen, in this study, a three-dimensional fibrin gel which of adequate epithelial cell compatibility was constructed by using thrombin and fibrinogen under the cross-linking action of calcium ion. Immunofluorescence staining and hematoxylin-eosin (H&E) staining showed that bone marrow mesenchymal stem cell (BMSC) was embedded in fibrin gel. Furthermore, vascular endothelial growth factor (VEGF) was used to induce BMSC to differentiate into CD31+ and vWF+ endothelial cell (EC) in fibrin gel. The results showed that the fibrin gel surface may effectively promote the adhesion and proliferation of EC and smooth muscle cell (SMC). After 15 days of culture, it was found that the BMSC embedded in the hydrogel had differentiated into EC. The results of in vivo skin wound experiment in rats further proved that the fibrin gel containing BMSC could promote wound healing and repair, and showed the potential to promote neovascularization at the injured site. The construction method of hydrogel materials proposed in this study has potential application value in the field of regenerative medicine.

A Multifunctional Nanovaccine based on L-Arginine-Loaded Black Mesoporous Titania: Ultrasound-Triggered Synergistic Cancer Sonodynamic Therapy/Gas Therapy/Immunotherapy with Remarkably Enhanced Efficacy.

In order to achieve better antitumor therapeutic efficacy and inhibit tumor metastasis, a multifunctional nanovaccine based on L-arginine (LA)-loaded black mesoporous titania (BMT) is fabricated. In this system, LA is utilized as the exogenous NO supplementation for gas therapy, and BMT is served as acoustic sensitizer for sonodynamic therapy. The ultrasound (US) as the exogenous stimulus can simultaneously trigger BMT and LA to produce singlet oxygen (1 O2 ) and NO gas at tumor sites, respectively. Interestingly, 1 O2 from US-excited BMT can promote the oxidation of LA to produce more NO. The high concentration of 1 O2 and NO in cancer cell can cause intracellular strong oxidative stress level and DNA double-strand breaks to induce cancer cell apoptosis ultimately. The US-triggered BMT@LA "nanovaccine" combining with immune checkpoint inhibitor PD-L1 antibody (αPD-L1) can induce strong antitumor immune response thus effectively killing primary tumors and further inhibiting metastatic tumors. Hence, BMT@LA-based "nanovaccine" combining with αPD-L1 checkpoint blockade treatment can realize synergetic sonodynamic/gas/immunotherapy with enhanced antitumor therapeutic effects.

Urchin-Shaped Metal Organic/Hydrogen-Bonded Framework Nanocomposite as a Multifunctional Nanoreactor for Catalysis-Enhanced Synergetic Therapy.

Ultrasound (US)-induced sonodynamic therapy (SDT) is an efficient and precise method against tumor, and the integration of multiple cancer therapies has been proved as a promising strategy for better therapeutic effects. Herein, for the first time, a multifunctional nanoreactor has been fabricated by integrating Fe-MIL-88B-NH2, PFC-1, and glucose oxidase (GOx) to form urchin-like Fe-MIL-88B-NH2@PFC-1-GOx (MPG) nanoparticles as Fenton's reagent, a sonosensitizer, and a tumor microenvironment (TME) modulator. In detail, MPG can generate •OH for chemodynamic therapy (CDT) and deplete glutathione (GSH) to alleviate the antioxidant ability of cancer cells. Moreover, catalase (CAT)-like MPG can react with H2O2 to generate O2 for relieving hypoxia in TME, enhancing GOx-catalyzed glucose oxidation to produce H2O2 and gluconic acid. Then, the regenerated H2O2 can promote the Fenton reaction to achieve GOx catalysis-enhanced CDT. Owing to its large π-electron conjugated system, MPG also serves as an ideal sonosensitizer, realizing a burst generation of 1O2 under US irradiation for efficient SDT. Therefore, the tumor treatment will be notably enhanced by MPG-based synergetic CDT/SDT/starvation therapy via a series of cascade reactions. Overall, this work develops a versatile nanoreactor with improved tumor treatment effectiveness and broadens the application prospects of porous materials in the field of biomedical research.