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Mouse xenograft models play a vital role in tumor studies for research as well as for screening of drugs for the pharmaceutical industry. In particular, models with compromised immunity are favorable to increase the success of transplantation, such as, e.g. NOD/SCID and BALB/c Nude strains. The genomic sequence and alterations of many of these models still remain elusive and might hamper a model's further optimization or proper adapted usage. This can be in respect to treatments (e.g. NOD/SCID sensitivity to radiation), experiments or analysis of derived sequencing data of such models. Here we present the genome assemblies for the NOD/SCID and BALB/c Nude strains to overcome this short-coming for the future and improve our understanding of these models in the process. We highlight as well first insights into observed genomic differences for these models compared to the C57BL/6 reference genome. Genome assemblies for both are close to full-chromosome representations and provided with liftover annotations from the GRCm39 reference genome. [ABSTRACT FROM AUTHOR]

Set operation is the essential operation of mathematical morphology, but it is difficult to complete the set operation quickly on the electronic computer. Therefore, the efficiency of traditional morphology processing is very low. In this paper, by adopting the method of the combination of quantum computation and image processing, though multiple quantum logical gates and combining the quantum image storage, quantum loading scheme and Boyer search algorithm, a novel quantum image processing method is proposed, which is the morphological image processing based on quantum set operation. The basic operations, such as erosion and dilation, are carried out for the images by using the quantum erosion algorithm and quantum dilation algorithm. Because the parallel capability of quantum computation can improve the speed of the set operation greatly, the image processing gets higher efficiency. The runtime of our quantum algorithm is $\mathrm {O}({\sqrt M N})$. As a result, this method can produce better results. [ABSTRACT FROM AUTHOR]

In 2012, Luo et al. proposed a new quantum public-key cryptosystems, which can encrypt both the classical and quantum information. (Luo et al. Int. J. Theor. Phys. 51(3), 912-924, 2012). However, it cannot be realized because there are some mistakes in the calculation and design process. This paper points out these failures and proposes an improvement to avoid the loophole. [ABSTRACT FROM AUTHOR]

The dispersibility of vermiculite is the key factor that affects the application of vermiculite. In this paper, the milled natural vermiculite was pillared by organic quaternary ammonium salts. Then the pillared vermiculite was ground and homogenized under the existence of dispersive agent to form a stable vermiculite hydrosol system. Small angle X-ray diffraction (SA-XRD), fourier transform infrared spectroscopy (FTIR), and thermogravimetric analyses (TGA) were used to characterize the structure and thermal property of the vermiculite. The results indicate that the exfoliated vermiculite is successfully obtained. The analyses of laser particle size analyzer, transmission electron microscope (TEM), and Tyndall phenomenon analyzer demonstrate that the vermiculite hydrosol prepared is a stable hydrosol system. [ABSTRACT FROM AUTHOR]

The article presents a study which describes the OstrinlysC, a c-type lysozomes from the Asian corn borer, and demonstrates its activity against Gram-positive and Gram-negative bacteria. It states that the OstrinlysC gene profile was studied by quantitative real-time polymerase chain reaction (PCR). It says that OstrinlysC gene was up-regulated in immune tissues after injection of the larvae with bacteria. It suggests that OstrinlysC gene plays a role in immune responses.

Soft hydrogels are excellent candidate materials for repairing various tissue defects, yet the mechanical strength, anti-swelling properties, and biocompatibility of many soft hydrogels need to be improved. Herein, inspired by the nanostructure of collagen fibrils, we developed a strategy toward achieving a soft but tough, anti-swelling nanofibrillar hydrogel by combining the self-assembly and chemical crosslinking of nanoparticles. Specifically, the collagen fibril-like injectable hydrogel was subtly designed and fabricated by self-assembling methylacrylyl hydroxypropyl chitosan (HM) with laponite (LAP) to form nanoparticles, followed by the inter-nanoparticle bonding through photo-crosslinking. The assembly mechanism of nanoparticles was elucidated by both experimental and simulation techniques. Due to the unique structure of the crosslinked nanoparticles, the nanocomposite hydrogels exhibited low stiffness (G’< 2 kPa), high compressive strength (709 kPa), and anti-swelling (swelling ratio of 1.07 in PBS) properties. Additionally, by harnessing the photo-crosslinking ability of the nanoparticles, the nanocomposite hydrogels were processed as microgels, which can be three-dimensionally (3D) printed into complex shapes. Furthermore, we demonstrated that these nanocomposite hydrogels are highly biocompatible, biodegradability, and can effectively promote fibroblast migration and accelerate blood vessel formation during wound healing. This work presents a promising approach to develop biomimetic, nanofibrillar soft hydrogels for regenerative medicine applications.

Diabetic kidney disease (DKD) is a clinical syndrome that is one of the major causes of end-stage renal disease (ESRD). The pathogenesis of DKD is complex and multifaceted, with most studies indicating its association with genetics, advanced glycosylation end-product deposition, polyol pathway and protein C activation, lipid metabolism abnormalities, microcirculatory dysfunction, oxidative stress, inflammatory factors, and the kallikrein-kinin system. Epigenetics is the science studying gene expression regulation without changes in the DNA sequence. In recent years, increasing evidence has shown that epigenetic mechanisms play a crucial role in the initiation and progression of DKD. For instance, epigenetic modifications such as DNA methylation, histone modifications, and non-coding RNAs can influence the expression of DKD-related genes, thereby regulating the development and progression of DKD. On the other hand, metabolic memory is an important concept in DKD research. Metabolic memory refers to the phenomenon where cells maintain a certain metabolic state even after the disappearance of metabolic stress factors. This state can influence cell function and fate. In DKD, metabolic stress factors such as hyperglycemia can lead to metabolic memory in renal cells, affecting their function and fate, ultimately leading to the development and progression of DKD. Therefore, to further explore the pathogenesis of DKD, research on epigenetics should be strengthened, aiming to provide new ideas and methods for the prevention and treatment of DKD. [ABSTRACT FROM AUTHOR]

The interplay between immune cells/macrophages and fibroblast‐like synoviocytes (FLSs) plays a pivotal role in initiating synovitis; however, their involvement in metabolic disorders, including diabetic osteoarthritis (DOA), is largely unknown. In this study, single‐cell RNA sequencing (scRNA‐seq) is employed to investigate the synovial cell composition of DOA. A significant enrichment of activated macrophages within eight distinct synovial cell clusters is found in DOA synovium. Moreover, it is demonstrated that increased glycolysis in FLSs is a key driver for DOA patients' synovial macrophage infiltration and polarization. In addition, the yes‐associated protein 1 (YAP1)/thioredoxin‐interacting protein (TXNIP) signaling axis is demonstrated to play a crucial role in regulating glucose transporter 1 (GLUT1)‐dependent glycolysis in FLSs, thereby controlling the expression of a series of adhesion molecules such as intercellular adhesion molecule‐1 (ICAM‐1) which may subsequently fine‐tune the infiltration of M1‐polarized synovial macrophages in DOA patients and db/db diabetic OA mice. For treatment, M1 macrophage membrane‐camouflaged Verteporfin (Vt)‐loaded PLGA nanoparticles (MVPs) are developed to ameliorate DOA progression by regulating the YAP1/TXNIP signaling axis, thus suppressing the synovial glycolysis and the infiltration of M1‐polarized macrophages. The results provide several novel insights into the pathogenesis of DOA and offer a promising treatment approach for DOA. [ABSTRACT FROM AUTHOR]

Abstract Background Human protein-protein interaction (PPIs) data are the foundation for understanding molecular signalling networks and the functional roles of biomolecules. Several human PPI databases have become available; however, comparisons of these datasets have suggested limited data coverage and poor data quality. Ongoing collection and integration of human PPIs from different sources, both experimentally and computationally, can enable disease-specific network biology modelling in translational bioinformatics studies. Results We developed a new web-based resource, the Human Annotated and Predicted Protein Interaction (HAPPI) database, located at http://bio.informatics.iupui.edu/HAPPI/. The HAPPI database was created by extracting and integrating publicly available protein interaction databases, including HPRD, BIND, MINT, STRING, and OPHID, using database integration techniques. We designed a unified entity-relationship data model to resolve semantic level differences of diverse concepts involved in PPI data integration. We applied a unified scoring model to give each PPI a measure of its reliability that can place each PPI at one of the five star rank levels from 1 to 5. We assessed the quality of PPIs contained in the new HAPPI database, using evolutionary conserved co-expression pairs called "MetaGene" pairs to measure the extent of MetaGene pair and PPI pair overlaps. While the overall quality of the HAPPI database across all star ranks is comparable to the overall qualities of HPRD or IntNetDB, the subset of the HAPPI database with star ranks between 3 and 5 has a much higher average quality than all other human PPI databases. As of summer 2008, the database contains 142,956 non-redundant, medium to high-confidence level human protein interaction pairs among 10,592 human proteins. The HAPPI database web application also provides …” should be “The HAPPI database web application also provides hyperlinked information of genes, pathways, protein domains, protein structure displays, and sequence feature maps for interactive exploration of PPI data in the database. Conclusion HAPPI is by far the most comprehensive public compilation of human protein interaction information. It enables its users to fully explore PPI data with quality measures and annotated information necessary for emerging network biology studies.

Abstract Background New systems biology studies require researchers to understand how interplay among myriads of biomolecular entities is orchestrated in order to achieve high-level cellular and physiological functions. Many software tools have been developed in the past decade to help researchers visually navigate large networks of biomolecular interactions with built-in template-based query capabilities. To further advance researchers' ability to interrogate global physiological states of cells through multi-scale visual network explorations, new visualization software tools still need to be developed to empower the analysis. A robust visual data analysis platform driven by database management systems to perform bi-directional data processing-to-visualizations with declarative querying capabilities is needed. Results We developed ProteoLens as a JAVA-based visual analytic software tool for creating, annotating and exploring multi-scale biological networks. It supports direct database connectivity to either Oracle or PostgreSQL database tables/views, on which SQL statements using both Data Definition Languages (DDL) and Data Manipulation languages (DML) may be specified. The robust query languages embedded directly within the visualization software help users to bring their network data into a visualization context for annotation and exploration. ProteoLens supports graph/network represented data in standard Graph Modeling Language (GML) formats, and this enables interoperation with a wide range of other visual layout tools. The architectural design of ProteoLens enables the de-coupling of complex network data visualization tasks into two distinct phases: 1) creating network data association rules, which are mapping rules between network node IDs or edge IDs and data attributes such as functional annotations, expression levels, scores, synonyms, descriptions etc; 2) applying network data association rules to build the network and perform the visual annotation of graph nodes and edges according to associated data values. We demonstrated the advantages of these new capabilities through three biological network visualization case studies: human disease association network, drug-target interaction network and protein-peptide mapping network. Conclusion The architectural design of ProteoLens makes it suitable for bioinformatics expert data analysts who are experienced with relational database management to perform large-scale integrated network visual explorations. ProteoLens is a promising visual analytic platform that will facilitate knowledge discoveries in future network and systems biology studies.

Abstract The interplay between immune cells/macrophages and fibroblast‐like synoviocytes (FLSs) plays a pivotal role in initiating synovitis; however, their involvement in metabolic disorders, including diabetic osteoarthritis (DOA), is largely unknown. In this study, single‐cell RNA sequencing (scRNA‐seq) is employed to investigate the synovial cell composition of DOA. A significant enrichment of activated macrophages within eight distinct synovial cell clusters is found in DOA synovium. Moreover, it is demonstrated that increased glycolysis in FLSs is a key driver for DOA patients’ synovial macrophage infiltration and polarization. In addition, the yes‐associated protein 1 (YAP1)/thioredoxin‐interacting protein (TXNIP) signaling axis is demonstrated to play a crucial role in regulating glucose transporter 1 (GLUT1)‐dependent glycolysis in FLSs, thereby controlling the expression of a series of adhesion molecules such as intercellular adhesion molecule‐1 (ICAM‐1) which may subsequently fine‐tune the infiltration of M1‐polarized synovial macrophages in DOA patients and db/db diabetic OA mice. For treatment, M1 macrophage membrane‐camouflaged Verteporfin (Vt)‐loaded PLGA nanoparticles (MVPs) are developed to ameliorate DOA progression by regulating the YAP1/TXNIP signaling axis, thus suppressing the synovial glycolysis and the infiltration of M1‐polarized macrophages. The results provide several novel insights into the pathogenesis of DOA and offer a promising treatment approach for DOA.

Abstract Despite the diverse roles of tripartite motif (Trim)-containing proteins in the regulation of autophagy, the innate immune response, and cell differentiation, their roles in skeletal diseases are largely unknown. We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast (OB) differentiation in osteosarcoma. However, how Trim21 contributes to skeletal degenerative disorders, including osteoporosis, remains unknown. First, human and mouse bone specimens were evaluated, and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients. Next, we found that global knockout of the Trim21 gene (KO, Trim21 −/−) resulted in higher bone mass compared to that of the control littermates. We further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and elevating the activity of OBs; moreover, Trim21 depletion suppressed osteoclast (OC) formation of RAW264.7 cells. In addition, the differentiation of OCs from bone marrow-derived macrophages (BMMs) isolated from Trim21 −/− and Ctsk-cre; Trim21 f/f mice was largely compromised compared to that of the littermate control mice. Mechanistically, YAP1/β-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs. More importantly, the loss of Trim21 prevented ovariectomy (OVX)- and lipopolysaccharide (LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 signaling. Our current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption, thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.

Abstract Osteoarthritis (OA) has been recognized as an age-related degenerative disease commonly seen in the elderly that affects the whole “organ” including cartilage, subchondral bone, synovium, and muscles. An increasing number of studies have suggested that the accumulation of senescent cells triggering by various stresses in the local joint contributes to the pathogenesis of age-related diseases including OA. In this review, we mainly focus on the role of the senescent skeletal cells (chondrocytes, osteoblasts, osteoclasts, osteocyte, and muscle cells) in initiating the development and progression of OA alone or through cross-talk with the macrophages/synovial cells. Accordingly, we summarize the current OA-targeted therapies based on the abovementioned theory, e.g., by eliminating senescent skeletal cells and/or inhibiting the senescence-associated secretory phenotype (SASP) that drives senescence. Furthermore, the existing animal models for the study of OA from the perspective of senescence are highlighted to fill the gap between basic research and clinical applications. Overall, in this review, we systematically assess the current understanding of cellular senescence in OA, which in turn might shed light on the stratified OA treatments.

Abstract Recent evidence has indicated that overexpression of the epigenetic reader bromodomain‐containing protein 4 (BRD4) contributes to a poor prognosis of lung cancers, and the suppression of its expression promotes cell apoptosis and leads to tumor shrinkage. Proteolysis targeting chimera (PROTAC) has recently emerged as a promising therapeutic strategy with the capability to precisely degrade targeted proteins. Herein, a novel style of versatile nano‐PROTAC (CREATE (CRV‐LLC membrane/DS‐PLGA/dBET6)) is developed, which is constructed by using a pH/GSH (glutathione)‐responsive polymer (disulfide bond‐linked poly(lactic‐co‐glycolic acid), DS‐PLGA) to load BRD4‐targeted PROTAC (dBET6), followed by the camouflage with engineered lung cancer cell membranes with dual targeting capability. Notably, CREATE remarkably confers simultaneous targeting ability to lung cancer cells and tumor‐associated macrophages (TAMs). The pH/GSH‐responsive design improves the release of dBET6 payload from nanoparticles to induce pronounced apoptosis of both cells, which synergistically inhibits tumor growth in both subcutaneous and orthotopic tumor‐bearing mouse model. Furthermore, the efficient tumor inhibition is due to the direct elimination of lung cancer cells and TAMs, which remodels the tumor microenvironment. Taken together, the results elucidate the construction of a versatile nano‐PROTAC enables to eliminate both lung cancer cells and TAMs, which opens a new avenue for efficient lung cancer therapy via PROTAC.

Abstract Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents, which is characterized by dysfunctional autophagy and poor differentiation. Our recent studies have suggested that the tripartite motif containing-21 (TRIM21) plays a crucial role in regulating OS cell senescence and proliferation via interactions with several proteins. Yet, its implication in autophagy and differentiation in OS is largely unknown. In the present study, we first showed that TRIM21 could promote OS cell autophagy, as determined by the accumulation of LC3-II, and the degradation of cargo receptor p62. Further, we were able to identify that Annexin A2 (ANXA2), as a novel interacting partner of TRIM21, was critical for TIRM21-induced OS cell autophagy. Although TRIM21 had a negligible effect on the mRNA and protein expressions of ANXA2, we did find that TRIM21 facilitated the translocation of ANXA2 toward plasma membrane (PM) in OS cells through a manner relying on TRIM21-mediated cell autophagy. This functional link has been confirmed by observing a nice co-expression of TRIM21 and ANXA2 (at the PM) in the OS tissues. Mechanistically, we demonstrated that TRIM21, via facilitating the ANXA2 trafficking at the PM, enabled to release the transcription factor EB (TFEB, a master regulator of autophagy) from the ANXA2-TFEB complex, which in turn entered into the nucleus for the regulation of OS cell autophagy. In accord with previous findings that autophagy plays a critical role in the control of differentiation, we also demonstrated that autophagy inhibited OS cell differentiation, and that the TRIM21/ANXA2/TFEB axis is implicated in OS cell differentiation through the coordination with autophagy. Taken together, our results suggest that the TRIM21/ANXA2/TFEB axis is involved in OS cell autophagy and subsequent differentiation, indicating that targeting this signaling axis might lead to a new clue for OS treatment.

Abstract Chondrosarcoma (CHS) is the second most common bone malignancy with limited therapeutic approaches. Our previous study has found that Yes associated protein 1 (YAP1) is downregulated in CHS cells treated with bromodomain and extraterminal domain (BET) inhibitor JQ1. However, the precise role of YAP1 in CHS is largely unknown. Herein, we found that YAP1 expression was upregulated in CHS tissues, and positively correlated with its grading score. Loss of YAP1 inhibited CHS proliferation and induced cellular senescence, while expression of YAP1 mutants revealed YAP1/TEA domain family member (TEAD)-dependent negative regulation of p21 and subsequent cellular senescence. These results were validated by in vivo experiments using stable shYAP1 cell lines. Mechanistically, negative regulation of p21 by YAP1 occurred post-transcriptionally via Dicer-regulated miRNA networks, specifically, the miR-17 family. Furthermore, we demonstrated that sequential targeting of YAP1 and p21 enhanced the elimination of JQ1-induced senescent cells in a Bcl-2-like 1 (Bcl-XL)/Caspase-3 dependent manner. Altogether, we unveil a novel role of YAP1 signaling in mediating CHS cell senescence and propose a one-two punch approach that sequentially targets the YAP1/p21 axis to eliminate senescent cells.

Chondrosarcoma (CHS) is the second most common bone malignant tumor and currently has limited treatment options. We have recently demonstrated that thioredoxin interacting protein (TXNIP) plays a crucial role in the oncogenesis of bone sarcoma, yet its implication in CHS is underdetermined. In the present study, we first found that knockdown of TXNIP promotes the proliferation of CHS cell largely through increasing their glycolytic metabolism, which is well-known as Warburg effect for providing energy. Consistent with our previous report that YAP is fundamental for CHS cell growth, herein we revealed that YAP functioned as an upstream molecule of TXNIP, and that YAP negatively regulated TXNIP mRNA and protein expression both in vitro and in vivo. Mechanistically, although knockdown of YAP upregulated both the nuclear and cytoplasmic TXNIP expression, we did not observe any obvious interaction between YAP and TXNIP; instead, miRNA-524-5p was demonstrated to be required for YAP-regulated TXNIP expression and thus controlling CHS cell growth. Together, our study reveals that TXNIP is a tumor suppressor in terms of CHS, and that the YAP/miRNA-524-5p/TXNIP signaling axis may provide a novel clue for CHS targeted therapy. [Display omitted] • TXNIP inhibits tumor growth in chondrosarcoma. • YAP negatively regulates TXNIP in vitro and in vivo. • YAP negatively regulates TXNIP expression by accumulating the miR-524-5p. • TXNIP is detected as a direct target gene of miR-524-5p in chondrosarcoma. [ABSTRACT FROM AUTHOR]

Bromodomain-containing protein 4 (BRD4) is the most well-studied BET protein that is important for the innate immune response. We recently revealed that targeting BRD4 triggers apoptosis in tumor-associated macrophages, but its role in synovial macrophages and joint inflammation is largely unknown. Herein, we demonstrated that BRD4 was highly expressed in the iNOS-positive M1 macrophages in the human and mouse osteoarthritis (OA) synovium, and conditional knockout of BRD4 in the myeloid lineage using Lyz2-cre; BRD4 flox/flox mice significantly abolished anterior cruciate ligament transection (ACLT)-induced M1 macrophage accumulation and synovial inflammation. Accordingly, we successfully constructed apoptotic body-inspired p ho s phatidylserine-containing nano l iposome s (PSLs) loaded with the BRD4 inhibitor JQ1 to regulate inflammatory macrophages. JQ1-loaded PSLs (JQ1@PSLs) exhibited a higher cellular uptake by macrophages than fibroblast-like synoviocytes (FLSs) in vitro and in vivo , as well as the reduction in proinflammatory M1 macrophage polarization. Intra-articular injections of JQ1@PSLs showed prolonged retention within the joint, and remarkably reduced synovial inflammation and joint pain via suppressing M1 polarization accompanied by reduced TRPA1 expression by targeted inhibition of BRD4 in the macrophages, thus attenuating cartilage degradation during OA development. The results show that BRD4-inhibiting JQ1@PSLs can targeted-modulate macrophage polarization, which opens a new avenue for efficient OA therapy via a "Trojan horse". [ABSTRACT FROM AUTHOR]

[Display omitted] • Joint fluid was analyzed by aquaphotomics and near infrared spectroscopy. • Focusing the analysis on water avoids the need for tedious component analysis. • The number of hydrogen bonds of different water species was found to be strongly correlated with the occurrence and development of OA. Osteoarthritis (OA) is the most common joint disease and the leading cause of disability in elderly individuals. Despite rapid advances in imaging techniques, early OA diagnosis remains a clinical challenge. In the present study, the feasibility of early OA diagnosis was explored via near-infrared spectroscopy (NIRS) combined with aquaphotomics. Synovial fluid samples from 65 cases of OA categorized as mild, moderate, and severe according to the Kellgren and Lawrence classification criteria were analyzed via NIRS. The 1st overtone of water (1300–1600 nm) was considered as the research object for an aquaphotomics model, and aquagrams of the mild, moderate, and severe OA cases were generated using 12 water absorption patterns for early OA diagnosis.The aquaphotomics results exhibited clear differences in the region of 1300–1500 nm, and the number of hydrogen bonds of different water species (1412,1424, 1482, and 1496 nm) evidently correlated with OA occurrence and development. With OA progression, the absorption intensity of water molecules without hydrogen bonds (1412 nm/1424 nm) became stronger, while the absorption intensity of water molecules with four hydrogen bonds (1482 nm/1496 nm) decreased.These results together reveal that the established accurate and rapid early OA diagnosis model based on NIRS combined with aquaphotomics is effective and feasible, and that the number of hydrogen bonds can be used as a biomarker for early OA diagnosis. [ABSTRACT FROM AUTHOR]

Background:. Sevoflurane preconditioning (SP) has been shown to invoke potent myocardial protection in animal studies and clinical trials. However, the mechanisms underlying SP are complex and not yet well understood. We investigated the hypothesis that the cardioprotection afforded by SP is mediated via the Wnt/glycogen synthase kinase 3β (GSK3β)/β-catenin signaling pathway. Methods:. Two models were established: A Langendorff perfused rat heart model and the H9C2 cell hypoxia/reoxygenation model. Both rats and H9C2 cells were randomly divided into 6 groups as follows: S group, ischemia-reperfusion (I/R) group, DMSO group, IWP group, SP group, and SP + IWP group. Hemodynamic parameters, lactate dehydrogenase (LDH) activity in coronary effluent and cell culture supernatant, and the infarct size were measured to evaluate myocardial ischemia-reperfusion injuries. To determine the activity of Wnt/GSK3β/β-catenin signaling pathway, the expressions of Wnt3a, phospho-GSK3β, and β-catenin were measured by Western blotting. Results:. SP improved cardiac function recovery, reduced infarct size (18 ± 2% in the SP group compared with 35 ± 4% in the I/R group; P < 0.05), decreased LDH activity in coronary effluent, and culture supernatant. IWP-2, an inhibitor of Wnt, abolished the cardioprotection by SP. In addition, Western blotting analysis demonstrated that the expressions of Wnt3a, phospho-GSK3β, and β-catenin significantly (P < 0.05) increased in the I/R group, compared with the S group; and compared to I/R group, SP significantly (P < 0.05) increased Wnt3a, phospho-GSK3β, and β-catenin expressions. Pretreatment with IWP-2 significantly (P < 0.05) abolished SP-induced Wnt/GSK3β/β-catenin signaling activation. Conclusions:. The results showed for the first time that cardioprotection afforded by SP may be mediated partly via the Wnt/GSK3β/β-catenin signaling pathway.

The development of shape-memory sponge dressings with functions, such as hemostasis, antibacterial activity, and wound healing, is of great significance in clinical applications. Herein, a novel AuNPs@corn stalk/chitin composite sponge (CCAu) was fabricated by crosslinking the chitin matrix with corn stalk-embedded gold nanoparticles (AuNPs). The addition of AuNPs@corn stalk gave the porous chitin sponge shape-recovery ability with improved softness, porosity, and water absorption. Correspondingly, the composite sponge showed better hemostatic effects than commercial PVF sponges. The photothermal effect of AuNPs endowed the composite sponge with excellent antibacterial activity. In addition, the wound treated with composite sponge containing antioxidant AuNPs exhibited a significantly faster wound healing rate (reaching 41.6 % on day 3) than the CH (33.2 %) and control (12.6 %) group through promoting cell migration, angiogenesis and collagen deposition. Therefore, the multifunctional composite sponge with great biocompatibility in this work provides a potential strategy for wound healing. [ABSTRACT FROM AUTHOR]

Engineered T cells expressing chimeric antigen receptors (CARs) have shown remarkable therapeutic effects on haematological malignancies. However, CART cells are less effective on solid tumours mainly due to their weak persistence, which might be caused by activation-induced cell death (AICD). To overcome this limitation, CART cell with the antigen, Epidermal growth factor receptor variant III (EGFRvIII), targeting was modified to carry the anti-apoptotic molecule B cell lymphoma 2 (Bcl-2), and the final construct was named as EGFRvIII·CART-Bcl2 cells. Compared with the EGFRvIII·CART cells, EGFRvIII·CART-Bcl2 cells revealed higher capacities of proliferation, anti-apoptosis and tumour cell killing in vitro. Moreover, EGFRvIII·CART-Bcl2 cells had a longer persistence rate and exerted better anti-tumour effects than EGFRvIII·CART cells in cervical carcinoma xenograft model. Taken together, our findings suggest that incorporating anti-apoptotic molecules into CART cells may enhance its therapeutic effects against solid tumours., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)

Background: Jianpi Gushen Huayu Decoction (JPGS) has been used to clinically treat diabetic nephropathy (DN) for many years. However, the protective mechanism of JPGS in treating DN remains unclear., Aim: To evaluate the therapeutic effects and the possible mechanism of JPGS on DN., Methods: We first evaluated the therapeutic potential of JPGS on a DN mouse model. We then investigated the effect of JPGS on the renal metabolite levels of DN mice using non-targeted metabolomics. Furthermore, we examined the effects of JPGS on c-Jun N-terminal kinase (JNK)/P38-mediated apoptosis and the inflammatory responses mediated by toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB)/NOD-like receptor family pyrin domain containing 3 (NLRP3)., Results: The ameliorative effects of JPGS on DN mice included the alleviation of renal injury and the control of inflammation and oxidative stress. Untargeted metabolomic analysis revealed that JPGS altered the metabolites of the kidneys in DN mice. A total of 51 differential metabolites were screened. Pathway analysis results indicated that nine pathways significantly changed between the control and model groups, while six pathways significantly altered between the model and JPGS groups. Pathways related to cysteine and methionine metabolism; alanine, tryptophan metabolism; aspartate and glutamate metabolism; and riboflavin metabolism were identified as the key pathways through which JPGS affects DN. Further experimental validation showed that JPGS treatment reduced the expression of TLR4/NF-κB/NLRP3 pathways and JNK/P38 pathway-mediated apoptosis related factors., Conclusion: JPGS could markedly treat mice with streptozotocin (STZ)-induced DN, which is possibly related to the regulation of several metabolic pathways found in kidneys. Furthermore, JPGS could improve kidney inflammatory responses and ameliorate kidney injuries in DN mice via the TLR4/NF-κB/NLRP3 pathway and inhibit JNK/P38 pathway-mediated apoptosis in DN mice., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Brown adipose tissue undergoes rapid postnatal development to mature and plays a crucial role in thermoregulation and energy expenditure, which protects against cold and obesity. Herein, it is shown that the expression of Trim21 mRNA level of interscapular brown adipose tissue elevates after birth, and peaks at P14 (postnatal day 14). Trim21 depletion severely impairs the maturation of interscapular brown adipose tissue, decreases the expression of a series of thermogenic genes, and reduces energy expenditure. Consistently, the loss of Trim21 also leads to a suppression of white adipose tissue "browning", in response to cold exposure and a β-adrenergic agonist, CL316,243. In addition, Trim21 -/- mice are more prone to high-fat diet-induced obesity compared with the control littermates. Taken together, the study for the first time reveals a critical role of Trim21 in regulating iBAT postnatal development and thermogenesis., (© 2023 Wiley-VCH GmbH.)

Alisol B 23-acetate (AB23A) has been demonstrated to have beneficial effects on nonalcoholic steatohepatitis (NASH). However, the mechanisms of AB23A on NASH remain unclear. This study aimed to investigate the mechanisms underlying the metabolic regulatory effects of AB23A on NASH. We used AB23A to treat mice with NASH, which was induced by a methionine and choline deficient (MCD) diet. We initially investigated therapeutic effect and resistance to oxidation and inflammation of AB23A on NASH. Subsequently, we performed untargeted metabolomic analyses and relative validation assessments to evaluate the metabolic regulatory effects of AB23A. AB23A reduced lipid accumulation, ameliorated oxidative stress and decreased pro-inflammatory cytokines in the liver. Untargeted metabolomic analysis found that AB23A altered the metabolites of liver. A total of 55 differential metabolites and three common changed pathways were screened among the control, model and AB23A treatment groups. Further tests validated the effects of AB23A on modulating common changed pathway-involved factors. AB23A treatment can ameliorate NASH by inhibiting oxidative stress and inflammation. The mechanism of AB23A on NASH may be related to the regulation of alanine, aspartate and glutamate metabolism, d-glutamine and d-glutamate metabolism, and arginine biosynthesis pathways., (© 2023 John Wiley & Sons Ltd.)

Soft hydrogels are excellent candidate materials for repairing various tissue defects, yet the mechanical strength, anti-swelling properties, and biocompatibility of many soft hydrogels need to be improved. Herein, inspired by the nanostructure of collagen fibrils, we developed a strategy toward achieving a soft but tough, anti-swelling nanofibrillar hydrogel by combining the self-assembly and chemical crosslinking of nanoparticles. Specifically, the collagen fibril-like injectable hydrogel was subtly designed and fabricated by self-assembling methylacrylyl hydroxypropyl chitosan (HM) with laponite (LAP) to form nanoparticles, followed by the inter-nanoparticle bonding through photo-crosslinking. The assembly mechanism of nanoparticles was elucidated by both experimental and simulation techniques. Due to the unique structure of the crosslinked nanoparticles, the nanocomposite hydrogels exhibited low stiffness (G'< 2 kPa), high compressive strength (709 kPa), and anti-swelling (swelling ratio of 1.07 in PBS) properties. Additionally, by harnessing the photo-crosslinking ability of the nanoparticles, the nanocomposite hydrogels were processed as microgels, which can be three-dimensionally (3D) printed into complex shapes. Furthermore, we demonstrated that these nanocomposite hydrogels are highly biocompatible, biodegradability, and can effectively promote fibroblast migration and accelerate blood vessel formation during wound healing. This work presents a promising approach to develop biomimetic, nanofibrillar soft hydrogels for regenerative medicine applications., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Osteophyte is an outgrowth of cartilage formed at the margins of the affected joint through endochondral ossification-like processes, and is one of the most common radiographic features of osteoarthritis (OA) that has been used to define the stage of disease. Osteophyte has been regarded to adapt the joint to the altered biomechanics of OA patients, limits joint movement and represent a source of joint pain, however, the mechanism of osteophyte formation, the morphology characteristics and biomechanical properties of osteophyte cells are remained unclear. In the present study, we isolated osteophyte cells and chondrocytes from late-stage OA patients who underwent total knee replacement surgeries, by applying Atomic Force Microscopy (AFM), we identified osteophyte cells were in irregular shape with dendrites, shrunk cell body, smooth surface and high elastic modulus (23.3 ± 5.4 kPa) when compared with chondrocytes (6.5 ± 1.8 kPa). In addition, osteophyte cells showed higher proliferation ability and colony formation capacity than chondrocytes. Mechanistically, we identified YAP1, the core transcriptional factor of Hippo signaling pathway, was highly expressed in osteophyte cell both at protein and RNA levels. Inactivation of Hippo/YAP1 signaling pathway by Verteporfin is sufficient to inhibit osteophyte cell proliferation in vitro and attenuate osteophyte formation in vivo. In conclusion, the morphology characteristic and biomechanical property of osteophyte cells at single cell level are quite different from chondrocytes, although we could not exclude other regulatory mechanisms, our findings suggested that Hippo/YAP1 is of great importance for osteophyte formation., Competing Interests: Declaration of competing interest The authors have declared that no competing interests exist., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Radiotherapy (RT) is a traditional therapeutic regime that focuses on ionizing radiation, however, RT maintains largely palliative due to radioresistance. Factors such as hypoxia, the radiosensitivity of immune cells, and cancer stem cells (CSCs) all come into play in influencing the significant impact of radioresistance in the irradiated tumor microenvironment (TME). Due to the substantial advances in the treatment of malignant tumors, a promising approach is the genetically modified T cells with chimeric antigen receptors (CARs) to eliminate solid tumors. Moreover, CAR-T cells targeting CSC-related markers would eliminate radioresistant solid tumors. But solid tumors that support an immune deserted TME, are described as immunosuppressive and typically fail to respond to CAR-T cell therapy. And RT could overcome these immunosuppressive features; thus, growing evidence supports the combination of RT with CAR-T cell therapy. In this review, we provide a deep insight into the radioresistance mechanisms, advances, and barriers of CAR-T cells in response to solid tumors within TME. Therefore, we focus on how the combination strategy can be used to eliminate these barriers. Finally, we show the challenges of this therapeutic partnership., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huan, Li and Tang.)

Purpose: Subchondral insufficiency fracture of the knee (SIFK) is a common cause of knee joint pain that mainly afflicts the elderly. Until now, how a sudden insufficiency fracture of subchondral bone affects the transcriptomic profiles of cartilage in SIFK and OA patients are largely unknown., Methods: Single-cell RNA sequencing (scRNA-seq) was used to identify various cell subsets and evaluate transcriptomic differences in cartilage of SIFK and OA patients. In addition, the above findings were confirmed by histological evaluation and immunohistochemical (IHC) staining., Results: We found that the transcriptomic profiles of cartilage in the SIFK patient was completely different from those of normal and OA patients. Accordingly, several novel cell clusters with activation of hypoxia and endochondral ossification signaling were identified in the SIFK cartilage. Chondrocyte trajectories analysis and IHC staining revealed that transcription factors including TCF4 were found to be highly up-regulated during the occurrence of SIFK, which might drive the reactive formation of cartilage and fibrous tissue and the activation of endochondral ossification., Conclusion: This is the first report to elucidate the transcriptomic alterations and distinct cell type subpopulations in the cartilage of SIFK and OA by the use of scRNA-seq, which provides a new insight in the understanding of the initiation and progression of SIFK., Competing Interests: The authors have no relevant financial or non-financial interests to disclose in this work., (© 2022 Tang et al.)

Recent evidence has indicated that overexpression of the epigenetic reader bromodomain-containing protein 4 (BRD4) contributes to a poor prognosis of lung cancers, and the suppression of its expression promotes cell apoptosis and leads to tumor shrinkage. Proteolysis targeting chimera (PROTAC) has recently emerged as a promising therapeutic strategy with the capability to precisely degrade targeted proteins. Herein, a novel style of versatile nano-PROTAC (CREATE (CRV-LLC membrane/DS-PLGA/dBET6)) is developed, which is constructed by using a pH/GSH (glutathione)-responsive polymer (disulfide bond-linked poly(lactic-co-glycolic acid), DS-PLGA) to load BRD4-targeted PROTAC (dBET6), followed by the camouflage with engineered lung cancer cell membranes with dual targeting capability. Notably, CREATE remarkably confers simultaneous targeting ability to lung cancer cells and tumor-associated macrophages (TAMs). The pH/GSH-responsive design improves the release of dBET6 payload from nanoparticles to induce pronounced apoptosis of both cells, which synergistically inhibits tumor growth in both subcutaneous and orthotopic tumor-bearing mouse model. Furthermore, the efficient tumor inhibition is due to the direct elimination of lung cancer cells and TAMs, which remodels the tumor microenvironment. Taken together, the results elucidate the construction of a versatile nano-PROTAC enables to eliminate both lung cancer cells and TAMs, which opens a new avenue for efficient lung cancer therapy via PROTAC., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Engineered T cells expressing chimeric antigen receptors (CARs) with tumor specificity have shown remarkable therapeutic effects on hematologic malignancies. However, CAR-T cells are less effective on solid tumors mainly due to the weak persistence of CAR-T cells, which might be caused by T cell death. Significant activation-induced cell death (AICD) of CAR-T cells was triggered by repeated antigen stimulation. AICD of T cell is characterized by the upregulation of death receptors and low persistence of T cells. Understanding the mechanism of AICD is crucial to improve the anti-tumor effect of CAR-T cells against solid tumors. Many approaches have been applied in CAR-T cell modification to enhance their anti-apoptosis ability. In this review, we summarized the molecular mechanisms of AICD in CAR-T cells and the progresses of anti-AICD in CAR-T cells therapy., (© 2022. The Author(s) under exclusive licence to Japan Human Cell Society.)

Oncolytic therapy is a treatment method used to directly combat tumor cells by modifying the genes of naturally occurring low pathogenic viruses to form "rhizobia" virus. By taking the advantage of abnormal signal pathways in cancer cells, it selectively replicates in tumor cells leading to tumor cell lysis and death. At present, clinical studies widely employ biomolecular technology to transform oncolytic viruses to exert stronger oncolytic effects and reduce their adverse reactions. This review summarizes the current progresses and the molecular mechanism of oncolytic viruses towards tumor treatment and management., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Objective: The aim of this study is to discover the possible working mechanisms of Ardisiae Japonicae Herba (AJH) on hepatoma carcinoma (HCC)., Methods: In this study, ethanol extract of AJH was prepared and used to treat HCC cell in vitro . Furthermore, a genomic wide RNA sequencing (RNA-seq) was performed to screen deregulated genes in HCC cells after the treatment of AJH extract. The gene and protein expression related to lipid metabolism in HCC cells were also investigated to validate the results obtained from RNA-seq., Results: AJH extract could inhibit HCC cell proliferation in vitro . RNA-seq analysis has identified 1,601 differentially expressed genes (DEGs, fold change ≥ 2.0 or fold change ≤ 0.5, P  < 0.05) in HCC after AJH extract treatment, which included 225 up-regulated genes and 1,376 down-regulated genes. KEGG pathway analysis of DEGs demonstrated that lipid metabolism was a potential pathway related to AJH treatment. In agreement with the RNA-seq data, qPCR and Western-blot analysis indicated that expression of genes and proteins related to lipid metabolism (SREBP1, ACC, ACLY and FASN) were significantly down-regulated in AJH treatment group as compared with the control group. Furthermore, AJH extract could also decrease lipid contents and cellular free fatty acid levels in HCC cells., Conclusion: Ethanol extract of AJH could inhibit HCC cell proliferation in vitro , the possible mechanism may be related to the inhibition of lipid metabolism., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Tianjin Press of Chinese Herbal Medicines. Published by ELSEVIER B.V.)

The aim of this study was to elucidate the mechanism of nuciferine on alleviating obesity based on modulating gut microbiota, ameliorating chronic inflammation, and improving gut permeability. In this study, the obese model mice were induced by high-fat diet and then randomly divided into model group, and nuciferine group; some other mice of the same week age were fed with normal diet as normal group. In the modeling process, the mice were administered intragastrically(ig) for 12 weeks. In the course of both modeling and treatment, the body weight and food intake of mice in each group were measured weekly. After modeling and treatment, the Lee's index, weight percentage of inguinal subcutaneous fat, and the level of blood lipid in each group were measured. The pathological changes of adipocytes were observed by HE staining to evaluate the efficacy of nuciferine treatment in obese model mice. 16 S rRNA sequencing analysis was conducted to study the changes in diversity and abundance of gut microbiota after nuciferine treatment. Enzyme-linked immunosorbent assay(ELISA) and quantitative Real-time polymerase chain reaction(qPCR) were used to detect the levels of inflammatory factors interleukin-6(IL-6), interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α) and the expression of related genes in adipose tissue of mice in each group, so as to evaluate the effect of nuciferine on chronic inflammation of mice in obese model group. qPCR was used to detect the expression of occludin and tight junction protein 1(ZO-1)gene in colon tissure, so as to evaluate the effect of nuciferine on intestinal permeability of mice in obese group. Nuciferine decreased the body weight of obese mice, Lee's index, weight percentage of inguinal subcutaneous fat(P&lt;0.05), and reduced the volume of adipocytes, decreased the level of total cholesterol(TC), triglyceride(TG), and low density lipoprotein cholesterol(LDL-C)(P&lt;0.05) in serum, improved dysbacteriosis, increased the relative abundance of Alloprevotella, Turicibacter, and Lactobacillus, lowered the relative abundance of Helicobac-ter, decreased the expression of inflammatory cytokines IL-6, IL-1β, and TNF-α genes in adipose tissue(P&lt;0.01), decreased the levels of inflammatory cytokines IL-6, IL-1β, and TNF-α in serum(P&lt;0.05), and increased the expression of occludin and ZO-1 genes related to tight junction in colon tissue(P&lt;0.01). Nuciferine could treat obesity through modulating gut microbiota, decreasing gut permeability and ameliorating inflammation.

Chondrosarcoma (CHS) is the second most common bone malignancy with limited therapeutic approaches. Our previous study has found that Yes associated protein 1 (YAP1) is downregulated in CHS cells treated with bromodomain and extraterminal domain (BET) inhibitor JQ1. However, the precise role of YAP1 in CHS is largely unknown. Herein, we found that YAP1 expression was upregulated in CHS tissues, and positively correlated with its grading score. Loss of YAP1 inhibited CHS proliferation and induced cellular senescence, while expression of YAP1 mutants revealed YAP1/TEA domain family member (TEAD)-dependent negative regulation of p21 and subsequent cellular senescence. These results were validated by in vivo experiments using stable shYAP1 cell lines. Mechanistically, negative regulation of p21 by YAP1 occurred post-transcriptionally via Dicer-regulated miRNA networks, specifically, the miR-17 family. Furthermore, we demonstrated that sequential targeting of YAP1 and p21 enhanced the elimination of JQ1-induced senescent cells in a Bcl-2-like 1 (Bcl-XL)/Caspase-3 dependent manner. Altogether, we unveil a novel role of YAP1 signaling in mediating CHS cell senescence and propose a one-two punch approach that sequentially targets the YAP1/p21 axis to eliminate senescent cells.

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents, which is characterized by dysfunctional autophagy and poor differentiation. Our recent studies have suggested that the tripartite motif containing-21 (TRIM21) plays a crucial role in regulating OS cell senescence and proliferation via interactions with several proteins. Yet, its implication in autophagy and differentiation in OS is largely unknown. In the present study, we first showed that TRIM21 could promote OS cell autophagy, as determined by the accumulation of LC3-II, and the degradation of cargo receptor p62. Further, we were able to identify that Annexin A2 (ANXA2), as a novel interacting partner of TRIM21, was critical for TIRM21-induced OS cell autophagy. Although TRIM21 had a negligible effect on the mRNA and protein expressions of ANXA2, we did find that TRIM21 facilitated the translocation of ANXA2 toward plasma membrane (PM) in OS cells through a manner relying on TRIM21-mediated cell autophagy. This functional link has been confirmed by observing a nice co-expression of TRIM21 and ANXA2 (at the PM) in the OS tissues. Mechanistically, we demonstrated that TRIM21, via facilitating the ANXA2 trafficking at the PM, enabled to release the transcription factor EB (TFEB, a master regulator of autophagy) from the ANXA2-TFEB complex, which in turn entered into the nucleus for the regulation of OS cell autophagy. In accord with previous findings that autophagy plays a critical role in the control of differentiation, we also demonstrated that autophagy inhibited OS cell differentiation, and that the TRIM21/ANXA2/TFEB axis is implicated in OS cell differentiation through the coordination with autophagy. Taken together, our results suggest that the TRIM21/ANXA2/TFEB axis is involved in OS cell autophagy and subsequent differentiation, indicating that targeting this signaling axis might lead to a new clue for OS treatment.