Trilayered biomimetic hydrogel scaffolds with dual-differential microenvironment for articular osteochondral defect repair.

Commonly, articular osteochondral tissue exists significant differences in physiological architecture, mechanical function, and biological microenvironment. However, the development of biomimetic scaffolds incorporating upper cartilage, middle tidemark-like, and lower subchondral bone layers for precise articular osteochondral repair remains elusive. This study proposed here a novel strategy to construct the trilayered biomimetic hydrogel scaffolds with dual-differential microenvironment of both mechanical and biological factors. The cartilage-specific microenvironment was achieved through the grafting of kartogenin (KGN) into gelatin via p-hydroxyphenylpropionic acid (HPA)-based enzyme crosslinking reaction as the upper cartilage layer. The bone-specific microenvironment was achieved through the grafting of atorvastatin (AT) into gelatin via dual-crosslinked network of both HP-based enzyme crosslinking and glycidyl methacrylate (GMA)-based photo-crosslinking reactions as the lower subchondral bone layer. The introduction of tidemark-like middle layer is conducive to the formation of well-defined cartilage-bone integrated architecture. The in vitro experiments demonstrated the significant mechanical difference of three layers, successful grafting of drugs, good cytocompatibility and tissue-specific induced function. The results of in vivo experiments also confirmed the mechanical difference of the trilayered bionic scaffold and the ability of inducing osteogenesis and chondrogenesis. Furthermore, the articular osteochondral defects were successfully repaired using the trilayered biomimetic hydrogel scaffolds by the activation of endogenous recovery, which offers a promising alternative for future clinical treatment.

Deciphering feedback regulation of prostaglandin F2α in blood stasis syndrome using nitrogen-doped porous transition metal carbides.

Blood stasis syndrome (BSS) has persistent health risks; however, its pathogenesis remains elusive. This obscurity may result in missed opportunities for early intervention, increased susceptibility to chronic diseases, and reduced accuracy and efficacy of treatments. Metabolomics, employing the matrix-assisted laser desorption/ionization (MALDI) strategy, presents distinct advantages in biomarker discovery and unraveling molecular mechanisms. Nonetheless, the challenge is to develop efficient matrices for high-sensitivity and high-throughput analysis of diverse potential biomarkers in complex biosamples. This work utilized nitrogen-doped porous transition metal carbides and nitrides (NP-MXene) as a MALDI matrix to delve into the molecular mechanisms underlying BSS pathogenesis. Structural optimization yielded heightened peak sensitivity (by 1.49-fold) and increased peak numbers (by 1.16-fold) in clinical biosamples. Validation with animal models and clinical serum biosamples revealed significant differences in metabolic fingerprints between BSS and control groups, achieving an overall diagnostic efficacy of 0.905 (95% CI, 0.76-0.979). Prostaglandin F2α was identified as a potential biomarker (diagnostics efficiency of 0.711, specificity = 0.7, sensitivity = 0.6), and pathway enrichment analysis disclosed disruptions in arachidonic acid metabolism in BSS. This innovative approach not only advances comprehension of BSS pathogenesis, but also provides valuable insights for personalized treatment and diagnostic precision.

First-line treatment with sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists in type 2 diabetic population at low risk of cardiovascular disease: a meta-analysis.

Background: The benefit of first-line use of sodium-dependent glucose transport 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) in type 2 diabetes mellitus (T2DM) with low risk of cardiovascular diseases are not clear. Methods: PubMed, EMBASE and Cochrane Library databases were searched to identify eligible randomized controlled trials. We used the odds ratio (OR) and mean difference (MD) and the corresponding 95% confidence interval (CI) to assess the dichotomous and continuous variable, respectively. Results: Thirteen studies involving 2,885 T2DM at low risk of cardiovascular diseases were included. Compared to placebo, first line use of SGLT2i significantly reduced glycosylated hemoglobin type A1C (HbA1c) (MD: -0.72), weight (MD: -1.32) and fasting plasma glucose (FPG) (MD: -27.05) levels. Compared with metformin, SGLT2i reduced body weight (MD: -1.50) and FPG (MD: -10.13) more effectively, with similar reduction for HbA1c (MD: -0.05). No significant increased safety adverse was found for SGLT2i, including nasopharyngitis (OR: 1.07), urinary tract infection (OR: 2.31), diarrhea (OR: 1.18) and hypoglycemia (OR: 1.06). GLP-1RAs significantly reduced HbA1c (MD: -1.13), weight (MD: -2.12) and FPG (MD: -31.44) levels as first-line therapy compared to placebo. GLP-1RAs significantly increased occurrence of diarrhea (OR: 2.18), hypoglycemia (OR: 3.10), vomiting (OR: 8.22), and nausea (OR: 4.41). Conclusion: First line use of SGLT2i and GLP-1RAs is effective in reducing HbA1c, weight, and FPG levels in T2DM patients at low risk for cardiovascular disease. SGLT2i may be superior to metformin in controlling body weight and FPG. GLP-1RAs may increase the occurrence of diarrhea, hypoglycemia, vomiting, and nausea. Systematic review registration: PROSPERO (International Prospective Register of Systematic Reviews. https://www.york.ac.uk/inst/crd, CRD42022347233).

Differential influences of forest floor-pyrolyzed biochar-derived and leached dissolved organic matter interaction with natural iron-bearing minerals in forest subsoil on the formation of mineral-associated soil organic matter.

The vertical sequestration of dissolved organic matter (DOM) by iron minerals along the soil profile is assumed to be central to the long-term storage of the soil organic matter (SOM) pool. However, there is limited information available about how the interaction between DOM and natural iron-bearing minerals shape mineral SOM associations quantitatively and qualitatively in forest subsoils. Here, we systematically investigated the influences of forest organic layer-pyrolyzed biochar-derived DOM (BDOM) and leached DOM (LDOM) on quantity, molecular composition, and diversity of deposition layer-derived iron minerals-associated OM by using Fourier transform ion cyclotron resonance mass spectrometry and other complementary spectroscopy. Results indicated natural iron minerals (FeOx1 and FeOx2) had a greater capacity for sorbing LDOM with higher aromaticity and molecular weight than those of BDOM, and the higher proportion of goethite and short-order-range phase in natural iron minerals was closely related to the increased OM adsorption capacity. We also observed the preferential sorption of oxygen/nitrogen-rich polycyclic aromatic compounds and carboxylic-containing compounds in LDOM and concurrent the potential release of lignin-like/aromatics compounds and carboxyl/nitrogen-less aliphatic compounds from native OM coprecipitates into the solution. However, unsaturated and oxidized phenolic compounds in BDOM had a stronger affinity for FeOx through hydrophobic partitioning and specific polar interactions, and concomitantly the partial release of nitrogen-free aliphatic and other carboxyl-rich compounds. More nitrogen structures in aromatic-containing compounds can improve the saturation level and polarity of BDOM. Compared with BDOM, LDOM exerted a stronger control over the exchange of native OM from subsoil natural iron-bearing minerals and substantially enhanced the molecular diversity of the reconstituted mineral-associated OM during the adsorptive fractionation. Overall, these findings suggest the compositional evolution of DOM profoundly shapes SOM formation and persistence in forest subsoils, which is the key to understanding DOM cycling and contaminant fate during its passage through the soil.

A tissue-adhesive F127 hydrogel delivers antioxidative copper-selenide nanoparticles for the treatment of dry eye disease.

Dry eye disease (DED) is currently the most prevalent condition seen in ophthalmology outpatient clinics, representing a significant public health issue. The onset and progression of DED are closely associated with oxidative stress-induced inflammation and damage. To address this, an aldehyde-functionalized F127 (AF127) hydrogel eye drop delivering multifunctional antioxidant Cu2-xSe nanoparticles (Cu2-xSe NPs) was designed. The research findings revealed that the Cu2-xSe nanoparticles exhibit unexpected capabilities in acting as superoxide dismutase and glutathione peroxidase. Additionally, Cu2-xSe NPs possess remarkable efficacy in scavenging reactive oxygen species (ROS) and mitigating oxidative damage. Cu2-xSe NPs displayed promising therapeutic effects in a mouse model of dry eye. Detailed investigation revealed that the nanoparticles exert antioxidant, anti-apoptotic, and inflammation-mitigating effects by modulating the NRF2 and p38 MAPK signalling pathways. The AF127 hydrogel eye drops exhibit good adherence to the ocular surface through the formation of Schiff-base bonds. These findings suggest that incorporating antioxidant Cu2-xSe nanoparticles into a tissue-adhesive hydrogel could present a highly effective therapeutic strategy for treating dry eye disease and other disorders associated with reactive oxygen species. STATEMENT OF SIGNIFICANCE: A new formulation for therapeutic eye drops to be used in the treatment of dry eye disease (DED) was developed. The formulation combines copper-selenium nanoparticles (Cu2-xSe NPs) with aldehyde-functionalized Pluronic F127 (AF127). This is the first study to directly examine the effects of Cu2-xSe NPs in ophthalmology. The NPs exhibited antioxidant capabilities and enzyme-like properties. They effectively eliminated reactive oxygen species (ROS) and inhibited apoptosis through the NRF2 and p38 MAPK signalling pathways. Additionally, the AF127 hydrogel enhanced tissue adhesion by forming Schiff-base links. In mouse model of DED, the Cu2-xSe NPs@AF127 eye drops demonstrated remarkable efficacy in alleviating symptoms of DED. These findings indicate the potential of Cu2-xSe NPs as a readily available and user-friendly medication for the management of DED.

Tolerant and Rapid Endochondral Bone Regeneration Using Framework-Enhanced 3D Biomineralized Matrix Hydrogels.

Tissue-engineered bone has emerged as a promising alternative for bone defect repair due to the advantages of regenerative bone healing and physiological functional reconstruction. However, there is very limited breakthrough in achieving favorable bone regeneration due to the harsh osteogenic microenvironment after bone injury, especially the avascular and hypoxic conditions. Inspired by the bone developmental mode of endochondral ossification, a novel strategy is proposed for tolerant and rapid endochondral bone regeneration using framework-enhanced 3D biomineralized matrix hydrogels. First, it is meticulously designed 3D biomimetic hydrogels with both hypoxic and osteoinductive microenvironment, and then integrated 3D-printed polycaprolactone framework to improve their mechanical strength and structural fidelity. The inherent hypoxic 3D matrix microenvironment effectively activates bone marrow mesenchymal stem cells self-regulation for early-stage chondrogenesis via TGFß/Smad signaling pathway due to the obstacle of aerobic respiration. Meanwhile, the strong biomineralized microenvironment, created by a hybrid formulation of native-constitute osteogenic inorganic salts, can synergistically regulate both bone mineralization and osteoclastic differentiation, and thus accelerate the late-stage bone maturation. Furthermore, both in vivo ectopic osteogenesis and in situ skull defect repair successfully verified the high efficiency and mechanical maintenance of endochondral bone regeneration mode, which offers a promising treatment for craniofacial bone defect repair.

Gelatin-modified 3D printed PGS elastic hierarchical porous scaffold for cartilage regeneration.

Regenerative cartilage replacements are increasingly required in clinical settings for various defect repairs, including bronchial cartilage deficiency, articular cartilage injury, and microtia reconstruction. Poly (glycerol sebacate) (PGS) is a widely used bioelastomer that has been developed for various regenerative medicine applications because of its excellent elasticity, biodegradability, and biocompatibility. However, because of inadequate active groups, strong hydrophobicity, and limited ink extrusion accuracy, 3D printed PGS scaffolds may cause insufficient bioactivity, inefficient cell inoculation, and inconsistent cellular composition, which seriously hinders its further cartilage regenerative application. Here, we combined 3D printed PGS frameworks with an encapsulated gelatin hydrogel to fabricate a PGS@Gel composite scaffold. PGS@Gel scaffolds have a controllable porous microstructure, with suitable pore sizes and enhanced hydrophilia, which could significantly promote the cells' penetration and adhesion for efficient chondrocyte inoculation. Furthermore, the outstanding elasticity and fatigue durability of the PGS framework enabled the regenerated cartilage built by the PGS@Gel scaffolds to resist the dynamic in vivo environment and maintain its original morphology. Importantly, PGS@Gel scaffolds increased the rate of cartilage regeneration concurrent with scaffold degradation. The scaffold was gradually degraded and integrated to form uniform, dense, and mature regenerated cartilage tissue with little scaffold residue.

Zr- and Ti-based metal-organic frameworks: synthesis, structures and catalytic applications.

Recently, Zr- and Ti-based metal-organic frameworks (MOFs) have gathered increasing interest in the field of chemistry and materials science, not only for their ordered porous structure, large surface area, and high thermal and chemical stability, but also for their various potential applications. Particularly, the unique features of Zr- and Ti-based MOFs enable them to be a highly versatile platform for catalysis. Although much effort has been devoted to developing Zr- and Ti-based MOF materials, they still suffer from difficulties in targeted synthesis, especially for Ti-based MOFs. In this Feature Article, we discuss the evolution of Zr- and Ti-based MOFs, giving a brief overview of their synthesis and structures. Furthermore, the catalytic uses of Zr- and Ti-based MOF materials in the previous 3-5 years have been highlighted. Finally, perspectives on the Zr- and Ti-based MOF materials are also proposed. This work provides in-depth insight into the advances in Zr- and Ti-based MOFs and boosts their catalytic applications.

Inhibition of MYC suppresses programmed cell death ligand-1 expression and enhances immunotherapy in triple-negative breast cancer.

BACKGROUND: Cancer immunotherapy has emerged as a promising strategy against triple-negative breast cancer (TNBC). One of the immunosuppressive pathways involves programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), but many patients derived little benefit from PD-1/PD-L1 checkpoint blockades treatment. Prior research has shown that MYC, a master transcription amplifier highly expressed in TNBC cells, can regulate the tumor immune microenvironment and constrain the efficacy of immunotherapy. This study aims to investigate the regulatory relationship between MYC and PD-L1, and whether a cyclin-dependent kinase (CDK) inhibitor that inhibits MYC expression in combination with anti-PD-L1 antibodies can enhance the response to immunotherapy. METHODS: Public databases and TNBC tissue microarrays were used to study the correlation between MYC and PD-L1. The expression of MYC and PD-L1 in TNBCs was examined by quantitative real-time polymerase chain reaction and Western blotting. A patient-derived tumor xenograft (PDTX) model was used to evaluate the influence of a CDK7 inhibitor THZ1 on PD-L1 expression. Cell proliferation and migration were detected by 5-ethynyl-2'-deoxyuridine (EdU) cell proliferation and cell migration assays. Tumor xenograft models were established for in vivo verification. RESULTS: A high MYC expression level was associated with a poor prognosis and could alter the proportion of tumor-infiltrating immune cells (TIICs). The positive correlation between MYC and PD-L1 was confirmed by immunostaining samples from 165 TNBC patients. Suppression of MYC in TNBC caused a reduction in the levels of both PD-L1 messenger RNA and protein. In addition, antitumor immune response was enhanced in the TNBC cancer xenograft mouse model with suppression of MYC by CDK7 inhibitor THZ1. CONCLUSIONS: The combined therapy of CDK7 inhibitor THZ1 and anti-PD-L1 antibody appeared to have a synergistic effect, which might offer new insight for enhancing immunotherapy in TNBC.

Effects of the Yaw Angle on Air Drag Reduction for Various Riblet Surfaces.

Biomimetic riblet surfaces, such as blade, wavy, sinusoidal, and herringbone riblet surfaces, have widespread applications for drag reduction in the energy, transportation, and biomedicine industries. The drag reduction ability of a blade riblet surface is sensitive to the yaw angle, which is the angle between the design direction of the riblet surface and the average flow direction. In practical applications, the average flow direction is often misaligned with the design direction of riblet surfaces with different morphologies and arrangements. However, previous studies have not reported on the drag reduction characteristics and regularities related to the yaw angle for surfaces with complex riblet microstructures. For the first time, we systematically investigated the aerodynamic drag reduction characteristics of blade, wavy, sinusoidal, and herringbone riblet surfaces affected by different yaw angles. A precisely adjustable yaw angle measurement method was proposed based on a closed air channel. Our results revealed the aerodynamic behavior regularities of various riblet surfaces as affected by yaw angles and Reynolds numbers. Riblet surfaces with optimal air drag reduction were obtained in yaw angles ranging from 0 to 60° and Reynolds numbers ranging from 4000 to 7000. To evaluate the effects of the yaw angle, we proposed a criterion based on the actual spanwise spacing (d+) of microstructure surfaces with the same phase in a near-wall airflow field. Finally, we established conceptual models of aerodynamic behaviors for different riblet surfaces in response to changes in the airflow direction. Our research lays a foundation for practical various riblet surface applications influenced by yaw angles to reduce air drag.

Single-cell RNA sequencing reveals cell heterogeneity and transcriptome profile of breast cancer lymph node metastasis.

Molecular mechanisms underlying breast cancer lymph node metastasis remain unclear. Using single-cell sequencing, we investigated the transcriptome profile of 96,796 single cells from 15 paired samples of primary tumors and axillary lymph nodes. We identified nine cancer cell subclusters including CD44 + / ALDH2 + /ALDH6A1 + breast cancer stem cells (BCSCs), which had a copy-number variants profile similar to that of normal breast tissue. Importantly, BCSCs existed only in primary tumors and evolved into metastatic clusters infiltrating into lymph nodes. Furthermore, transcriptome data suggested that NECTIN2-TIGIT-mediated interactions between metastatic breast cancer cells and tumor microenvironment (TME) cells, which promoted immune escape and lymph node metastasis. This study is the first to delineate the transcriptome profile of breast cancer lymph node metastasis using single-cell RNA sequencing. Our findings offer novel insights into the mechanisms underlying breast cancer metastasis and have implications in developing novel therapies to inhibit the initiation of breast cancer metastasis.

Clinical considerations of CDK4/6 inhibitors in triple-negative breast cancer.

The formation of cyclinD-CDK4/6 complex plays vital roles in the cell cycle transition from G1 phase to S phase which is characterized by vigorous transcription and synthesis. Through cyclinD-CDK4/6-Rb axis, CDK4/6 inhibitors arrest the cell cycle in the G1 phase and block the proliferation of aggressive cells, exhibiting promising effects in containing the aggressiveness of breast cancers. To date, there are three CDK4/6 inhibitors approved by the U.S. Food and Drug Administration in treating advanced hormone receptor-positive breast cancer, including palbociclib, abemaciclib, and ribociclib. In fact, several preclinical experiments and clinical trials presented therapeutic effects of CDK4/6 inhibitor-based treatment in triple-negative breast cancer.

A six-gene signature related with tumor mutation burden for predicting lymph node metastasis in breast cancer.

BACKGROUND: Breast cancer (BC) is one of the most common cancers worldwide and patients with lymph node metastasis always suffer from a worse prognosis. Tumor mutation burden (TMB) has been reported as a potential predictor for tumor behaviors. However, the correlation between TMB and lymph node metastasis of BC remains unclear. This study aimed to explore TMB-related biomarkers to predict the lymph node metastasis in BC patients. METHODS: A total of 949 BC patients with RNA-seq data, mutation data and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. We visualized mutation data by "maftools" package. We calculated TMB of each patient and investigated its association with lymph node metastasis. BC patients were divided into lymph node positive and negative groups and we respectively identified TMB-related and lymph node-related differentially expressed genes (DEGs) to figure out intersected genes. Functional enrichment analysis and protein-protein interaction (PPI) network were performed to observe relevant biological functions. We constructed a TMB-related signature for predicting lymph node metastasis through Logistic regression analysis. A validation database (GSE102484) from the Gene Expression Omnibus (GEO) database was downloaded to verify the accuracy. RESULTS: Single nucleotide polymorphism (SNP) occupied the highest proportion in variant types while C>T appeared most frequently in single nucleotide variant (SNV). TMB was regarded as negatively correlated with lymph node metastasis in BC (P=0.003). We identified 125 common DEGs through venn diagram, which were enriched in vesicle localization, calcium signaling pathway and salmonella infection. A TMB-related signature based on six genes (BAHD1, PPM1A, PQLC3, SMPD3, EEF1A1 and S100B) had reliable efficacy for predicting lymph node metastasis in BC and was proven as an independent predictive factor. The accuracy of this signature was further validated by GSE102484 database. CONCLUSIONS: Our results indicated that TMB was associated with lymph node metastasis of BC. We built a TMB-related signature consisting of six genes which might function as a novel biomarker for predicting lymph node metastasis in BC.