Discovery of a novel homocysteine thiolactone hydrolase and the catalytic activity of its natural variants.

Homocysteine thiolactone (HTL), a toxic metabolite of homocysteine (Hcy) in hyperhomocysteinemia (HHcy), is known to modify protein structure and function, leading to protein damage through formation of N-Hcy-protein. HTL has been highly linked to HHcy-associated cardiovascular and neurodegenerative diseases. The protective role of HTL hydrolases against HTL-associated vascular toxicity and neurotoxicity have been reported. Although several endogeneous enzymes capable of hydrolyzing HTL have been identified, the primary enzyme responsible for its metabolism remains unclear. In this study, three human carboxylesterases were screened to explore new HTL hydrolase and human carboxylesterase 1 (hCES1) demonstrates the highest catalytic activity against HTL. Given the abundance of hCES1 in the liver and the clinical significance of its single-nucleotide polymorphisms (SNPs), six common hCES1 nonsynonymous coding SNP (nsSNPs) variants were examined and characterized for their kinetic parameters. Variants E220G and G143E displayed 7.3-fold and 13.2-fold lower catalytic activities than its wild-type counterpart. In addition, the detailed catalytic mechanism of hCES1 for HTL hydrolysis was computational investigated and elucidated by Quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) method. The function of residues E220 and G143 in sustaining its hydrolytic activity of hCES1 was analyzed, and the calculated energy difference aligns well with experimental-derived results, supporting the validity of our computational insights. These findings provide insights into the potential protective role of hCES1 against HTL-associated toxicity, and warrant future studies on the possible association between specific genetic variants of hCES1 with impaired catalytic function and clinical susceptibility of HTL-associated cardiovascular and neurodegenerative diseases.

Tailor-Made Heterocharged Covalent Organic Framework Membrane for Efficient Ion Separation.

Pore size sieving, Donnan exclusion, and their combined effects seriously affect ion separation of membrane processes. However, traditional polymer-based membranes face some challenges in precisely controlling both charge distribution and pore size on the membrane surface, which hinders the ion separation performance, such as heavy metal ion removal. Herein, the heterocharged covalent organic framework (COF) membrane is reported by assembling two kinds of ionic COF nanosheets with opposite charges and different pore sizes. By manipulating the stacking quantity and sequence of two kinds of nanosheets, the impact of membrane surface charge and pore size on the separation performance of monovalent and multivalent ions is investigated. For the separation of anions, the effect of pore size sieving is dominant, while for the separation of cations, the effect of Donnan exclusion is dominant. The heterocharged TpEBr/TpPa-SO3H membrane with a positively charged upper layer and a negatively charged bottom layer exhibits excellent rejection of multivalent anions and cations (Ni2+, Cd2+, Cr2+, CrO4 2-, SeO3 2-, etc). The strategy provides not only high-performance COF membranes for ion separation but also an inspiration for the engineering of heterocharged membranes.

Performance and mechanistic studies of rapid atenolol degradation through peroxymonosulfate activation by V, Co, and bamboo carbon catalyst.

Developing the Co-based catalysts with high reactivity for the sulfate radical (SO4-·)-based advanced oxidation processes (SR-AOPs) has been attracting numerous attentions. To improve the peroxymonosulfate (PMS) activation process, a novel Co-based catalyst simultaneously modified by bamboo carbon (BC) and vanadium (V@CoO-BC) was fabricated through a simple solvothermal method. The atenolol (ATL) degradation experiments in V@CoO-BC/PMS system showed that the obtained V@CoO-BC exhibited much higher performance on PMS activation than pure CoO, and the V@CoO-BC/PMS system could fully degrade ATL within 5 min via the destruction of both radicals (SO4-· and O2-··) and non-radicals (1O2). The quenching experiments and electrochemical tests revealed that the enhancing mechanism of bamboo carbon and V modification involved four aspects: (i) promoting the PMS and Co ion adsorption on the surface of V@CoO-BC; (ii) enhancing the electron transfer efficiency between V@CoO-BC and PMS; (iii) activating PMS with V3+ species; (iv) accelerating the circulation of Co2+ and Co3+, leading to the enhanced yield of reactive oxygen species (ROS). Furthermore, the V@CoO-BC/PMS system also exhibited satisfactory stability under broad pH (3-9) and good efficiency in the presence of co-existing components (HCO3-, NO3-, Cl-, and HA) in water. This study provides new insights to designing high-performance, environment-friendly bimetal catalysts and some basis for the remediation of antibiotic contaminants with SR-AOPs.

3D Printed Conductive Hydrogel Patch Incorporated with MSC@GO for Efficient Myocardial Infarction Repair.

Myocardial infarction (MI) results in an impaired heart function. Conductive hydrogel patch-based therapy has been considered as a promising strategy for cardiac repair after MI. In our study, we fabricated a three-dimensional (3D) printed conductive hydrogel patch made of fibrinogen scaffolds and mesenchymal stem cells (MSCs) combined with graphene oxide (GO) flakes (MSC@GO), capitalizing on GO's excellent mechanical property and electrical conductivity. The MSC@GO hydrogel patch can be attached to the epicardium via adhesion to provide strong electrical integration with infarcted hearts, as well as mechanical and regeneration support for the infarcted area, thereby up-regulating the expression of connexin 43 (Cx43) and resulting in effective MI repair in vivo. In addition, MI also triggers apoptosis and damage of cardiomyocytes (CMs), hindering the normal repair of the infarcted heart. GO flakes exhibit a protective effect against the apoptosis of implanted MSCs. In the mouse model of MI, MSC@GO hydrogel patch implantation supported cardiac repair by reducing cell apoptosis, promoting gap connexin protein Cx43 expression, and then boosting cardiac function. Together, this study demonstrated that the conductive hydrogel patch has versatile conductivity and mechanical support function and could therefore be a promising candidate for heart repair.

A randomized, controlled single, and multiple ascending dose trial of the safety, pharmacokinetics and pharmacodynamics of SN1011 in healthy subjects.

The purpose of this study was to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of SN1011, a novel Bruton tyrosine kinase (BTK) inhibitor, and food effects in healthy subjects. In this phase I trial, subjects received single ascending doses (SADs) of SN1011 (100 to 800 mg), multiple ascending doses (MADs) of SN1011 (200 to 600 mg), or placebo q.d. Additionally, 12 subjects randomly received a single dose of SN1011 600 mg under fasting states and then fed states, vice versa. Safety was assessed per Common Terminology Criteria for Adverse Events version 5.0. Pharmacokinetic parameters were calculated by noncompartmental analysis and BTK receptor occupancy in peripheral blood monocytes was determined. Seventy-one healthy subjects were dosed in five SAD cohorts, three MAD cohorts, and one food effect cohort, with 57 receiving SN1011 and 14 receiving placebo. No serious adverse events (AEs) were reported. There was no correlation between AE occurrences and SN1011 exposure. The three most frequent AEs with SN1011 were increased blood triglycerides, decreased neutrophil count, and decreased leucocyte count. SN1011 exhibited a dose-proportional increase in maximum plasma concentration and area under the time concentration curve following single and multiple dose administrations, with an accumulation ratio of 1.5 to 2.2 after multiple dose administrations. No difference in SN1011 exposure was observed between fed states. BTK receptor occupancy remained above 83% over 24 h after single administration and remained above 80% for the MAD groups for 10 days of continuous q.d. administration. SN1011 was well-tolerated and safe after single or multiple exposures to healthy subjects, supporting further clinical development of SN1011 for treatment of autoimmune diseases.

Rapid PFOS mineralization with peroxydisulfate activation process mediated by N modified Fe-based catalyst.

As the cheap and efficient catalysts, the iron-based catalysts have been considered as one of the most promising catalysts for peroxydisulfate (PDS) activation and the development of high-performance iron-based catalysts are attracting growing attentions. In this work, a magnetic Fe-based catalysts (Fe/NC-1000) was obtained by using Fe modified ZIF-8 as the precursor and used to activate the PDS for the degradation of perfluorooctane sulphonate (PFOS). Morphology and structure analysis showed that the resulted Fe/NC-1000 catalyst was displayed porous spheres (40-60 nm) and mainly composed of Fe0, FeNx and carbon. When Fe/NC-1000 was employed to activate the PDS (0.1 g/L of catalyst dosage, 0.5 g/L of PDS dosage and at initial pH of 4.6), the Fe/NC-1000/PDS system exhibited excellent efficiency (97.9 ± 0.1) % for PFOS (10 mg/L) degradation within 30 min. The quenching tests and EPR results revealed that the Fe/NC-1000/PDS system degraded PFOS primarily through singlet oxygen (1O2) evolution and electron-transfer process. Besides, based on the degradation byproducts determined by LC-MS-MS, the PFOS first occurred de-sulfonation to form PFOA, and then the resulted PFOA underwent stepwise defluorination in the Fe/NC-1000/PDS system. Density Functional Theory (DFT) calculations and electrochemistry tests strongly confirmed that Fe/NC-1000 exhibited high electron transfer efficiency, resulting in promoted performance on activating PDS. Importantly, the results of Ecological Structure-Activity Relationship (ECOSAR) analysis showed that the intermediates were lowly toxic during the PFOS degradation, manifesting a green process for PFOS removal. This study would provide more understandings for the persulfate activation process mediated by Fe-based catalysts for Perfluorinated alkyl substances (PFAS) elimination.

Liquid nitrogen frozen cells for chemotherapy drug delivery and vaccination of melanoma.

PURPOSE: Cancer vaccine (CV) has thrived as a promising tool for cancer prevention and treatment. However, how to maintain the integrity and diversity of individualized vaccine antigens and activate the adaptive immune system is still challenging. METHODS: Herein, a preventive and therapeutic vaccine platform for in situ effective multi-model synergistic therapy is developed. In our study, we process B16F10 cells by liquid nitrogen frozen (LNF) to obtain LNF cells, the characterization of LNF cells were conducted. Moreover,  the anti-tumor effect and immune activation ability were studied, and the role as a CV were investigated. RESULTS: The LNF cells preserve intact cellular structure and tumor-associated self-antigen gp100. Moreover, LNF cells have the ability of loading and releasing doxorubicin (DOX). Except for the anti-tumor effect of chemotherapy brought by DOX, the LNF cells can promote the maturation of dendritic cells (DCs) and induce immune response by activating CD4+ and CD8+ T cells, particularly with the existence of adjuvant, R848. Specifically, the CD8+ T cells of mice in LNF-DOX/R848 group are 6 times of that in PBS group in tumor microenvironment, and twice in spleen. Therefore, LNF cells can also be utilized as a CV. Vaccination with LNF/R848 cells effectively suppress the tumor growth in mice by fivefold as compared to the control group. CONCLUSION: In this work, we obtain the LNF cells with a simple procedure. The LNF cells not only provides a tumor cells-based multi-modal system for cancer therapy but inspires new insights into future development of individualized CVs strategies. This study processes live B16F10 cells by liquid nitrogen frozen to obtain LNF cells, which preserve cell integrity and homologous targeting ability. The LNF cells can load and deliver drug and can serve as tumor vaccine. Results demonstrated the LNF cells have effective prophylactic ability, and ideal anti-tumor ability with the loaded drug and adjuvant.

Nanoscale MOFs in nanomedicine applications: from drug delivery to therapeutic agents.

Metal-organic frameworks (MOFs) hold great promise for widespread applications in biomedicine and nanomedicine. MOFs are one of the most fascinating nanocarriers for drug delivery, benefiting from their high porosity and facile modification. Furthermore, the tailored components of MOFs can be therapeutic agents for various treatments, including drugs as organic ligands of MOFs, active metal as central metal ions of MOFs, and their combinations as carrier-free MOF-based nanodrug. In this review, the advances in delivery systems and applications as therapeutic agents for nanoscale MOF-based materials are summarized. The challenges of MOFs in clinical translation and the future directions in the field of MOFs therapy are also discussed. We hope that more researchers will focus their attention on advancing and translating MOF-based nanodrugs into pre-clinical and clinical applications.

A real-time rural domestic garbage detection algorithm with an improved YOLOv5s network model.

An increasing number of researchers are using deep learning technology to classify and process garbage in rural areas, and have achieved certain results. However, the existing garbage detection models still have problems such as high complexity, missed detection of small targets, low detection accuracy and poor real-time performance. To address these issues, we train a model and apply it to garbage classification and detection in rural areas. In general, we propose an attention combination mechanism based on the YOLOv5 algorithm to build a better backbone network structure, add a new small object detection layer in the head network to enhance the model's ability to detect small objects, adopt the CIoU loss function to optimize the output prediction bounding box, and choose the Adam optimization algorithm to train the model. Our proposed YOLOv5s-CSS model detects a single garbage image in 0.021 s with a detection accuracy of 96.4%. Compared with the YOLOv5 algorithm and the classic detection algorithm, the improved algorithm has better detection speed and detection accuracy. At the same time, the complexity of the network model is reduced to a certain extent, which can meet the requirements of real-time detection of rural domestic garbage.

One Stone Two Birds: Redox-Sensitive Colocalized Delivery of Cisplatin and Nitric Oxide through Cascade Reactions.

Bio-orthogonal bond-cleavage reactions have been used in cancer therapy for improving the biological specificity of prodrug activation, but the spatiotemporal consistency of reactants is still a huge challenge. Although, in most cases, the cleavage catalysts and caged prodrugs are administrated separately, it is difficult to avoid the reactions in advance before they meet at the tumor site. Herein, we design and construct novel coordinative nanoparticles, integrating two prodrugs A and B as ligands and ferric ions as coordinative centers. After nanoparticles accumulated in tumor through passive targeting, inert Pt(IV) prodrug A is specifically and spontaneously reduced into active Pt(II) cisplatin, which acts as the cleavage catalyst to subsequently initiate the in situ bio-orthogonal depropargylation of B, that is, O 2-propargyl nitric oxide (NO) donor. The unique structure of coordinative nanoparticles ensures the spatiotemporal consistency of reactants (prodrugs A and B) and products (cytotoxic cisplatin and tumoricidal NO) for the bio-orthogonal bond-cleavage reaction, which leads to an improved synergistic therapeutic activity for triple-negative breast cancer (TNBC). This new concept of bio-orthogonal dual-prodrug coordinative nanoparticles may inspire further applications in bio-orthogonal chemistry and drug delivery for combination chemotherapy.

Silk Fibroin-Induced Gadolinium-Functionalized Gold Nanoparticles for MR/CT Dual-Modal Imaging-Guided Photothermal Therapy.

The development of multifunction nanoplatforms integrating accurate diagnosis and efficient therapy is of great significance for the precise treatment of tumors. Gold nanoparticles (AuNPs) possessing hallmark features of computed tomography (CT) imaging and photothermal conversion capability hold great potential in tumor theranostics. In this study, taking the advantages of outstanding biocompatibility, interesting anti-inflammatory and immunomodulatory properties, and abundant amino acid residues of silk fibroin (SF), a multifunctional Gd-hybridized AuNP nanoplatform was constructed using SF as a stabilizer and reductant via a facile one-pot biomimetic method, denoted as Gd:AuNPs@SF. The obtained Gd:AuNPs@SF possessed fascinating biocompatibility and excellent photothermal conversion efficiency. Functionalized with Gd, Gd:AuNPs@SF exhibited super tumor-contrasted imaging performance in magnetic resonance (MR) and CT imaging modalities. Moreover, Gd:AuNPs@SF, with strong NIR absorbance, demonstrated that it could effectively kill tumor cells in vitro, and was also proved to successfully ablate tumor tissues through MR/CT imaging-guided photothermal therapy (PTT) without systemic toxicity in Pan02 xenograft C57BL/6 mouse models. We successfully synthesized Gd:AuNPs@SF for MR/CT dual-mode imaging-guided PTT via a facile one-pot biomimetic method, and this biomimetic strategy can also be used for the construction of other multifunction nanoplatforms, which is promising for precise tumor theranostics.

A novel salt-tolerant strain Trichoderma atroviride HN082102.1 isolated from marine habitat alleviates salt stress and diminishes cucumber root rot caused by Fusarium oxysporum.

BACKGROUND: Salt stress threaten the growth of plants, and even aggravate plant disease. In this article, salt-tolerant Trichoderma strain was isolated, and its potential to alleviate salt stress and diminish cucumber root rot caused by Fusarium oxysporum was evaluated. RESULTS: Twenty-seven Trichoderma isolates were isolated from samples of sea muds and algae collected from the South Sea of China. Among these, the isolate HN082102.1 showed the most excellent salt tolerance and antagonistic activity against F. oxysporum causing root rot in cucumber and was identified as T. atroviride. Its antagonism ability may be due to mycoparasitism and inhibition effect of volatile substances. The application of Trichoderma mitigated the adverse effects of salt stress and promoted the growth of cucumber under 100 mM and 200 mM NaCl, especially for the root. When T. atroviride HN082102.1 was applied, root fresh weights increased by 92.55 and 84.86%, respectively, and root dry weights increased by 75.71 and 53.31%, respectively. Meanwhile, the application of HN082102.1 reduced the disease index of cucumber root rot by 63.64 and 71.01% under 100- and 0-mM saline conditions, respectively, indicating that this isolate could inhibit cucumber root rot under salt stress. CONCLUSIONS: This is the first report of salt-tolerant T. atroviride isolated from marine habitat showing antagonistic activity to F. oxysporum, and the results provide evidence for the novel strain T. atroviride HN082102.1 in alleviating salt stress and diminishing cucumber root rot, indicating that T. atroviride strain HN082102.1 can be used as biological control agent in saline alkali land.

hESCs-Derived Early Vascular Cell Spheroids for Cardiac Tissue Vascular Engineering and Myocardial Infarction Treatment.

Transplanting functional cells to treat myocardial infarction (MI), a major disease threatening human health, has become the focus of global therapy. However, the efficacy has not been well anticipated, partly due to the lack of microvascular system that supplies nutrients and oxygen. Here, spheroids of early vascular cells (EVCs) derived from human embryonic stem cells (hESCs), rather than single-cell forms, as transplant "seeds" for reconstructing microvascular networks, are proposed. Firstly, EVCs containing CD34+ vascular progenitor cells are identified, which effectively differentiate into endothelial cells in situ and form vascular networks in extracellular matrix (ECM) hydrogel. Secondly, cardiac microtissues and cardiac patches with well-organized microvasculature are fabricated by three-dimensional (3D) co-culture or bioprinting with EVCs and cardiomyocytes in hydrogel. Notably, in 3D-bioprinted myocardial models, self-assembly vascularization of EVC spheroids is found to be significantly superior to EVC single cells. EVC spheroids are also injected into ischemic region of MI mouse models to explore its therapeutic potential. These findings uncover hESCs-derived EVC spheroids rather than single cells are more accessible for complex vasculature engineering, which is of great potential for cardiac tissue vascular engineering and MI treatment by cell therapy.

Medical Image Classification Based on Information Interaction Perception Mechanism.

Colorectal cancer originates from adenomatous polyps. Adenomatous polyps start out as benign, but over time they can become malignant and even lead to complications and death which will spread to adherent and surrounding organs over time, such as lymph nodes, liver, or lungs, eventually leading to complications and death. Factors such as operator's experience shortage and visual fatigue will directly affect the diagnostic accuracy of colonoscopy. To relieve the pressure on medical imaging personnel, this paper proposed a network model for colonic polyp detection using colonoscopy images. Considering the unnoticeable surface texture of colonic polyps, this paper designed a channel information interaction perception (CIIP) module. Based on this module, an information interaction perception network (IIP-Net) is proposed. In order to improve the accuracy of classification and reduce the cost of calculation, the network used three classifiers for classification: fully connected (FC) structure, global average pooling fully connected (GAP-FC) structure, and convolution global average pooling (C-GAP) structure. We evaluated the performance of IIP-Net by randomly selecting colonoscopy images from a gastroscopy database. The experimental results showed that the overall accuracy of IIP-NET54-GAP-FC module is 99.59%, and the accuracy of colonic polyp is 99.40%. By contrast, our IIP-NET54-GAP-FC performed extremely well.

One-Pot Preparation of Peptide-Doped Metal-Amino Acid Framework for General Encapsulation and Targeted Delivery.

Metal-organic frameworks (MOFs), especially those made by biological molecules (bio-MOFs), have been proved to be prospective candidates for biomedical applications. However, a simple and universal bio-MOF to load different substances for precise targeting is still lacking. In this work, we propose a facile one-pot method to prepare a peptide-doped bio-MOF for general encapsulation and targeted delivery. This bio-MOF is constructed by 9-fluorenylmethyloxycarbonyl-modified histidine (Fmoc-His) as a bridging linker that coordinates with Zn2+ ions, denoted as ZFH. The Fmoc-His-Asp-Gly-Arg peptide (Fmoc-HDGR) can be easily doped into the ZFH structure with different ratios to modulate the targeting ability of ZFH-DGR. Containing both hydrophobic Fmoc and hydrophilic His moieties, this framework is compatible with encapsulating various types of payloads, including hydrophobic chemotherapeutic, hydrophilic protein, and positively/negatively charged inorganic nanoparticles. It has also been proved to be highly biocompatible and stable in circulation, exhibit the capabilities to target ανß3 integrin overexpressed on tumor cells, and trigger drug release in a low pH microenvironment at the tumor site. As a proof of concept, Doxorubicin (Dox)-loaded ZFH-DGR (ZFH-DGR/Dox) demonstrated high cell selectivity between liver hepatocellular carcinoma (HepG2) cells and normal liver (L02) cells, which express high and low ανß3 integrin, respectively. This selectivity endows ZFH-DGR/Dox precise treatment and low toxicity in Heps-bearing liver cancer mice. This work develops a de novo approach to construct a peptide-doped bio-MOF system for universal load, precise delivery, and peptide drug combination therapy in the future.

Dual-targeted and MRI-guided photothermal therapy via iron-based nanoparticles-incorporated neutrophils.

Nanoparticle-mediated photothermal therapy (PTT) has shown promising capability for tumor therapy through the high local temperature at the tumor site generated by a photothermal agent (PTA) under visible or near-infrared (NIR) irradiation. Improving the accumulation of PTA at the tumor site is crucial to achieving effective photothermal treatment. Here, we developed temperature-activatable engineered neutrophils (Ne) by combining indocyanine green (ICG)-loaded magnetic silica NIR-sensitive nanoparticles (NSNP), which provide the potential for dual-targeted photothermal therapy. The combined effect of neutrophil targeting and magnetic targeting increased the accumulation of PTA at the tumor site. According to magnetic resonance imaging (MRI), the retention of intravenous injected NSNP-incorporated neutrophils within the tumor site was markedly augmented as compared to free NSNP. Furthermore, when irradiated by NIR, NSNP could cause a high local temperature at the tumor site and the thermal stimulation of neutrophils. The heat can kill tumor cells directly, and also lead to the death of neutrophils, upon which active substances with tumor-killing efficacy will be released to kill residual tumor cells and thus reduce tumor recurrence. Thereby, our therapy achieved the elimination of malignancy in the mouse model of the pancreatic tumor without recurrence. Given that all materials used in this system have been approved for use in humans, the transition of this treatment method to clinical application is plausible.

2D CoOOH nanosheets as oxidase mimic for the colorimetric assay of sulfite in food.

Here, we report a rapid, sensitive and selective colorimetric assay for sulfite (SO32-) based on the intrinsic oxidase-like activity of 2D cobalt oxyhydroxide nanosheets (CoOOH NSs). The 2D CoOOH nanozyme could directly oxidize 3,3',5,5'-tetramethylbenzidine (TMB) into blue products (TMBox) in an aerobic solution without H2O2. Interestingly, the presence of SO32- could effectively inhibit the CoOOH NS-O2-TMB reaction system and thus caused changes in color and absorbance, which facilitated a colorimetric sensor for sulfite. After optimizing detection conditions, a facile and robust approach was developed for SO32- detection in food.

A bilayered scaffold with segregated hydrophilicity-hydrophobicity enables reconstruction of goat hierarchical temporomandibular joint condyle cartilage.

Temporomandibular joint (TMJ) supports chewing, talking or other daily oral activities. So far, it still remains a great challenge to treat the defected TMJ condyle cartilage through tissue engineering technology. Herein, a bilayered scaffold is designed to fully reconstruct the different cartilage matrices of TMJ condyle under same induction condition. The bilayered scaffold with segregated hydrophobicity-hydrophilicity in top and bottom layer is prepared from a low and high content of polyethylene glycol (PEG) crosslinked poly (L-glutamic acid)-g-polycaprolactone (PLGA-g-PCL). The hydrophobic aggregates in top layer support the adhesion and spread of bone mesenchymal stem cells (BMSCs), thus inducing the differentation towards fibrocartilage; while aggregates (spheroids) are formed on the hydrophlic bottom layer, showing a preferable hyaline differentiation pathway under same chondrogenic induction in vitro. After 14 d in vitro induction, the scaffold/BMSCs construct is implanted in goat TMJ condyle defects. The post-operative outcome after 2 months demonstrates that the defects are fully covered by neo-cartilage. And the regenerated hierarchical TMJ condyle cartilage perfectly consist of ordered fibrocartilage and hyaline cartilage, which is same as natural condyle cartilage. These results corroborate that this bilayered scaffold with segregated hydrophilicity-hydrophobicity carrying induced BMSCs is a promising for treatment of TMJ condyle cartilage defects.

CircGCN1L1 promotes synoviocyte proliferation and chondrocyte apoptosis by targeting miR-330-3p and TNF-α in TMJ osteoarthritis.

Altered expression of circular RNAs (circRNAs) has been identified in various human diseases. In this study, we investigated whether circRNAs function as competing endogenous RNAs to regulate the pathological process of temporomandibular joint osteoarthritis (TMJOA). High-throughput sequencing of mRNA (RNA seq) was performed to detect the expression of circRNAs in TMJOA and control synovial tissues isolated from humans. The differentially upregulated circGCN1L1 (hsa_circ_0000448) in synoviocyte was validated in vitro and in vivo. Here we demonstrate the interactions between circGCN1L1 and both miR-330-3p and tumor necrosis factor-α (TNF-α) through bioinformatics predictions, luciferase report assays, and fluorescence in situ hybridization. mRNA expression profiles of TNF-α-stimulated synoviocyte showed that circGCN1L1 and p65 expressions were upregulated by TNF-α. Moreover, miR-330-3p was negatively correlated with TNF-α secretion. Further, we found that miR-330-3p directly targeted TNF and restrained the production of matrix-degrading enzymes (MMP3, MMP13, and ADAMTS4). Mechanistic studies unveiled that circGCN1L1 in TMJOA synovial tissues and cells may be associated with condylar chondrocyte apoptosis and synoviocyte hyperplasia. Moreover, intra-articular injection of shcircGCN1L1 alleviated TMJOA progression in rat models. Altogether, we elucidated the important roles of a novel circRNA, namely, circGCN1L1, which induced inflammation in TMJ synoviocytes and decreased anabolism of the extracellular matrix (ECM) through miR-330-3p and TNF-α gene. This circRNA may represent a potentially effective therapeutic strategy against TMJOA progression at an early stage.

Vitamin E-based prodrug self-delivery for nanoformulated irinotecan with synergistic antitumor therapeutics.

Irinotecan (Ir) is a potent antitumor chemotherapeutics in clinic and used for the treatment of a various cancers, but the degree of its application is critically limited by toxic side-effects and marked heterogeneities. Nano-formulation of prodrugs, based on "all-in-one" carrier-free self-assemblies offers an effective approach to alter pharmacokinetics and safety profiles of cytotoxic agents. In this study, a novel vitamin E succinate-based formulation of Ir (VES-Ir) combined with nanoscaled characteristics and synergistic combination was constructed through esterification. The conjugation makes amphiphilic VES-Ir prodrug self-assemble into nanoparticles with a fine diameter (VES-Ir NPs, 75.4 nm) of spherical morphology. Furthermore, VES-Ir NPs with a 1:1 drug-to-drug ratio was demonstrated to possess respectable physiological stability within 72 h test, while can react to pH/esterase-sensitive drug release in lysosomes internalized into tumor cells, potentially highlighting their alleviating side effects. Compared with single and mixture drugs administration, the nanoformulated VES-Ir NPs codelivered both VES and Ir with different anticancer mechanisms to induce the highest suppress proliferation of MCF-7 (IC50 0.18 µM) and A549 (IC50 0.29 µM) cells in a synergistic way (CI < 1). More importantly, the formulating nanoparticulate Ir is to significantly enhance its bioavailability in vivo with long retention time in bloodstream and thereby, resulting the superior tumor inhibitory rate (TIR) of 85.2% versus controls. This simple nanoformulation of Ir drug deprived from VES conjugation, together with self-delivery and synergistic property, may provide an effective strategy for multiple chemotherapeutics delivery to treat cancers or other diseases.