D-mannose alleviates intervertebral disc degeneration through glutamine metabolism.

BACKGROUND: Intervertebral disc degeneration (IVDD) is a multifaceted condition characterized by heterogeneity, wherein the balance between catabolism and anabolism in the extracellular matrix of nucleus pulposus (NP) cells plays a central role. Presently, the available treatments primarily focus on relieving symptoms associated with IVDD without offering an effective cure targeting its underlying pathophysiological processes. D-mannose (referred to as mannose) has demonstrated anti-catabolic properties in various diseases. Nevertheless, its therapeutic potential in IVDD has yet to be explored. METHODS: The study began with optimizing the mannose concentration for restoring NP cells. Transcriptomic analyses were employed to identify the mediators influenced by mannose, with the thioredoxin-interacting protein (Txnip) gene showing the most significant differences. Subsequently, small interfering RNA (siRNA) technology was used to demonstrate that Txnip is the key gene through which mannose exerts its effects. Techniques such as colocalization analysis, molecular docking, and overexpression assays further confirmed the direct regulatory relationship between mannose and TXNIP. To elucidate the mechanism of action of mannose, metabolomics techniques were employed to pinpoint glutamine as a core metabolite affected by mannose. Next, various methods, including integrated omics data and the Gene Expression Omnibus (GEO) database, were used to validate the one-way pathway through which TXNIP regulates glutamine. Finally, the therapeutic effect of mannose on IVDD was validated, elucidating the mechanistic role of TXNIP in glutamine metabolism in both intradiscal and orally treated rats. RESULTS: In both in vivo and in vitro experiments, it was discovered that mannose has potent efficacy in alleviating IVDD by inhibiting catabolism. From a mechanistic standpoint, it was shown that mannose exerts its anti-catabolic effects by directly targeting the transcription factor max-like protein X-interacting protein (MondoA), resulting in the upregulation of TXNIP. This upregulation, in turn, inhibits glutamine metabolism, ultimately accomplishing its anti-catabolic effects by suppressing the mitogen-activated protein kinase (MAPK) pathway. More importantly, in vivo experiments have further demonstrated that compared with intradiscal injections, oral administration of mannose at safe concentrations can achieve effective therapeutic outcomes. CONCLUSIONS: In summary, through integrated multiomics analysis, including both in vivo and in vitro experiments, this study demonstrated that mannose primarily exerts its anti-catabolic effects on IVDD through the TXNIP-glutamine axis. These findings provide strong evidence supporting the potential of the use of mannose in clinical applications for alleviating IVDD. Compared to existing clinically invasive or pain-relieving therapies for IVDD, the oral administration of mannose has characteristics that are more advantageous for clinical IVDD treatment.

Trefoil factor 3 can stimulate Th17 cell response in the development of type 2 diabetes mellitus.

This study aims to evaluate the role of trefoil factor 3 (TFF3) peptides in type 2 diabetes mellitus (T2DM) from an inflammatory perspective. The focus was on exploring how TFF3 affects the function of T cells. TFF3 overexpression model was constructed using lentivirus in Jurkat cell lines. We evaluated the impact of TFF3 on the proliferation, apoptosis, and IL-17A levels of Jurkat cells cultured in high glucose. The T2DM model was induced in TFF3 knockout (KO) mice through streptozotocin combined with high-fat diet. The measurements included glucose tolerance, insulin tolerance, inflammation markers, Th17 cell proportion, and pancreatic pathological changes. The T2DM modeling led to splenomegaly in mice, and increased expression of TFF3 in their spleens. Overexpression of TFF3 increased the proportion of IL-17+ T cells and the levels of Th17-related cytokines in Jurkat cells. There was no difference in body weight and blood glucose levels between wild-type and TFF3 KO mice. However, T2DM mice lacking the TFF3 gene showed improved glucose utilization, ameliorated pancreatic pathology, decreased inflammation levels, and reduced Th17 cell ratio. TFF3 may be involved in the chronic inflammatory immune response in T2DM. Its mechanism may be related to the regulation of the RORγt/IL-17 signaling pathway and its impact on T cell proliferation and apoptosis.

Expression of HLA-DR and KLRG1 enhances the cytotoxic potential and cytokine secretion capacity of CD3+ T cells in tuberculosis patients.

BACKGROUND: Human T cells play an important role in immunity against tuberculosis (TB) infection. Activating receptor HLA-DR and inhibitory receptor KLRG1 are critical regulators of T cell function during viral infection and tumorigenesis, but they have been less studied in TB infection. METHODS: In this study, we explored the relationship between CD3+ T cell expression of HLA-DR and KLRG1 receptors and function against TB infection. Flow cytometry was conducted to assess the immunomodulatory effects of HLA-DR and KLRG1 receptors on CD3+ T cells in patients with different TB infection status. RESULTS: We found activating receptors HLA-DR, NKG2C, CD57 and NKP46, and inhibitory receptors KLRG1 and KIR on CD3+ T cells in different TB infection status showed different distribution patterns; the cytotoxic potential and cytokine secretion capacity of CD3+ T cells after Mtb-specific antigen stimulation were significantly enhanced in TB infection groups. Further studies revealed HLA-DR+ T and KLRG1+ T cells expressed higher activating and inhibitory receptors than the negative population. In addition, the expression of cytotoxic potential and cytokine secretion capacity of HLA-DR+ T and KLRG1+ T cells was significantly higher than that of HLA-DR- T and KLRG1- T cells. CONCLUSIONS: Expression of HLA-DR and KLRG1 enhances the cytotoxic potential and cytokine secretion capacity of CD3+ T cells in TB patients, suggesting CD3+ T cells expressing HLA-DR and KLRG1 are important effector cell phenotypes involved in the host anti-TB infection. HLA-DR and KLRG1 expressed by CD3+ T cells may be potential predictive markers of TB disease progression and clinical immune assessment.

High-quality acrylic fibers from waste textiles.

The objective of this work is to develop a closed-loop recycling method specifically tailored for acrylic fibers. Recycling waste acrylic is essential, given the vast volumes of acrylic-containing textiles produced yearly and the strong capability of acrylics to generate toxic microplastics. However, none of the available closed-loop recycling, mechanical recycling, chemical recycling, and direct extrusion technologies work for acrylics. Acrylic fibers are always blended with other textile fibers, making fiber separation via mechanical recycling almost impossible. Polyacrylonitrile, an addition-polymerized thermoplastic material, cannot be depolymerized into its original monomer. Direct extrusion of waste acrylics faces issues of uncontrollable colors on fibers and pollution of spinning lines due to the influence of existing colorants. In our method, acrylic fibers were extracted from waste textiles using a novel approach involving maximized acrylic swelling and dissolution with dimethyl sulfoxide and butanediol. Cationic dyes were effectively removed through cost-effective recycling technology. This work demonstrates that cationic dyes seriously affect the acrylic dissolution, color consistency, and dyeability of regenerated fibers via direct wet extrusion. Such negative impacts of dyes have been eliminated by our cost-effective and closed-loop acrylic recycling technology, which enables the efficient separation of non-acrylic fibers and dyes from acrylic fibers. Our recycling system achieved zero discharges through recycling solvents, dyes, and acrylics. The regenerated acrylic fibers exhibited mechanical properties and dyeability comparable to virgin acrylic fibers. The material and energy costs to produce pure acrylic from waste textiles were only 40 % of those from fossils. This study successfully introduces a closed-loop recycling method for acrylic fibers from waste textiles, addressing key challenges in acrylic fiber recycling. Further research and implementation of this technology are recommended to advance its commercial viability and widespread adoption.

Press Needle: A Traditional Chinese Medicine Therapy for Myopia Patients with Dry Eye.

Most patients with myopia have dry eye, which has been shown to adversely affect ocular symptoms, myopia progression, and quality of life in patients with myopia. Needle prickling has been shown to be effective in providing symptom relief in patients with myopia and dry eye. Press needle is a long-lasting, easy-to-operate, and inexpensive traditional Chinese medicine treatment. The standard practice of needle insertion is very important for the treatment of myopia and dry eye. The specific steps include selecting the appropriate acupoints, piercing them with appropriate needles, and fixing them in the skin or subcutaneously at the acupoints, burying them for 2 days, resting for 1 day; the course of treatment lasts for 2 weeks. Specifically, the following indicators were assessed: uncorrected visual acuity and the ocular surface disease index. This article will explain how to standardize the operation of a press needle in the treatment of myopia and dry eye.

Th17 cells: A new target in kidney disease research.

Type 17 T helper (Th17) cells, which are a subtype of CD4+ T helper cells, secrete pro-inflammatory cytokines such as IL-17A, IL-17F, IL-21, IL-22, and GM-CSF, which play crucial roles in immune defence and protection against fungal and extracellular pathogen invasion. However, dysfunction of Th17 cell immunity mediates inflammatory responses and exacerbates tissue damage. This pathological process initiated by Th17 cells is common in kidney diseases associated with renal injury, such as glomerulonephritis, lupus nephritis, IgA nephropathy, hypertensive nephropathy, diabetic kidney disease and acute kidney injury. Therefore, targeting Th17 cells to treat kidney diseases has been a hot topic in recent years. This article reviews the mechanisms of Th17 cell-mediated inflammation and autoimmune responses in kidney diseases and discusses the related clinical drugs that modulate Th17 cell fate in kidney disease treatment.

IL-17 and IL-17-producing cells (mainly Th17 cells) are crucial for kidney diseases. Multiple factors and mechanisms are involved in Th17 cell polarization, including oxidative stress, abnormal glucolipid metabolism, miRNA dysfunction, and microbial metabolism. This pathological process initiated by Th17 cells is common in kidney diseases associated with renal injury, such as glomerulonephritis, lupus nephritis, IgA nephropathy, hypertensive nephropathy, diabetic kidney disease and acute kidney injury. Modulating the direction of Th17 cell differentiation is a highly attractive therapeutic approach. This article reviews the mechanisms of Th17 cell-mediated inflammation and autoimmune responses in kidney diseases and discusses the related clinical drugs that modulate Th17 cell fate in kidney disease treatment.

Long Non-Coding RNAs as Regulators for Targeting Breast Cancer Stem Cells and Tumor Immune Microenvironment: Biological Properties and Therapeutic Potential.

Breast cancer stem cells (BCSCs) is a subpopulation of cancer cells with self-renewal and differentiation capacity, have been suggested to give rise to tumor heterogeneity and biologically aggressive behavior. Accumulating evidence has shown that BCSCs play a fundamental role in tumorigenesis, progression, and recurrence. The development of immunotherapy, primarily represented by programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors, has greatly changed the treatment landscape of multiple malignancies. Recent studies have identified pervasive negative associations between cancer stemness and anticancer immunity. Stemness seems to play a causative role in the formation of cold tumor immune microenvironment (TIME). The multiple functions of long non-coding RNAs (lncRNAs) in regulating stemness and immune responses has been recently highlighted in breast cancer. The review focus on lncRNAs and keys pathways involved in the regulation of BCSCs and TIME. Potential clinical applications using lncRNAs as biomarkers or therapies will be discussed.

Natural polysaccharides and proteins-based films for potential food packaging and mulch applications: A review.

Conventional nondegradable packaging and mulch films, after reaching the end of their use, become a major source of waste and are primarily disposed of in landfills. Accumulation of non-degradable film residues in the soil leads to diminished soil fertility, reduced crop yield, and can potentially affect humans. Application of degradable films is still limited due to the high cost, poor mechanical, and gas barrier properties of current biobased synthetic polymers. In this respect, natural polysaccharides and proteins can offer potential solutions. Having versatile functional groups, three-dimensional network structures, biodegradability, ease of processing, and the potential for surface modifications make polysaccharides and proteins excellent candidates for quality films. Besides, their low-cost availability as industrial waste/byproducts makes them cost-effective alternatives. This review paper covers the performance properties, cost assessment, and in-depth analysis of macromolecular structures of some natural polysaccharides and proteins-based films that have great potential for packaging and mulch applications. Proper dissolution of biopolymers to improve molecular interactions and entanglement, and establishment of crosslinkages to form an ordered and cohesive polymeric structure can help to obtain films with good properties. Simple aqueous-based film formulation techniques and utilization of waste/byproducts can stimulate the adoption of affordable biobased films on a large-scale.

A comprehensive LC-MS/MS method for simultaneous analysis of 65 synthetic cannabinoids in human hair samples and application to forensic investigations.

Synthetic cannabinoids (SCs) represent a diverse class of new psychoactive substances characterized by extensive substance variety and severe abuse implications. The current situation of synthetic cannabinoid abuse in China is getting worse, with an increasing number of SC variants emerging. Therefore, it is imperative to improve synthetic cannabinoid detecting methods to align with the prevalent abuse situation in the region. In this study, a reliable and validated liquid chromatography-tandem mass spectrometry method was developed for the qualitative and quantitative analysis of 65 SC analogues in human hair samples. The validation results demonstrated satisfactory linearity (r ≥ 0.99) within the range of 25-2500 pg/mg for each SC analogue. The method exhibited limits of detection ranging from 10 to 15 pg/mg and limits of quantification ranging from 25 to 40 pg/mg. The relative standard deviations of intra-day precision and inter-day precision were below 15 %. Furthermore, negligible matrix effects were observed, with recovery rates ranging from 85.70 % to 119.43 %. Analysis of abuser demographics revealed that the primary group engaged in SC analogue abuse consisted of adolescents, predominantly males, accounting for 79.5 % of cases. Among the suspected individuals, ADB-BUTINACA and MDMB-4en-PINACA were the most frequently detected substances. The present study develops a highly sensitive analytical method and provides a comprehensive overview of the prevalence of SC abuse in the eastern region of China.

Intestinal Trefoil Factor 3: a new biological factor mediating gut-kidney crosstalk in diabetic kidney disease.

PURPOSE: To investigate the effect of TFF3 in the pathogenesis of Diabetic Kidney Disease (DKD), and explore the dynamic changes of TFF3 expression pattern in renal injury process. METHODS: DKD animal model was established by streptozotocin (STZ) (40 mg/kg/d, ip, for 5 days, consecutively) combined with the high fat diet (HFD) for 12 weeks. While animals were sacrificed at different time stages in DKD process (4 weeks, 8 weeks and 12 weeks, respectively). RESULTS: STZ combined with high-fat diet induced weight gain, increased blood glucose and decreased glucose tolerance in DKD mice. Compared to the control group, the DKD group exhibits extracellular matrix (ECM) accumulation and the renal injury was aggravated in a time-dependent manner. The TFF3 expression level was decreased in kidney, and increased in colon tissue. CONCLUSION: TFF3 is not only expressed in colon, but also expressed in renal medulla and cortex. TFF3 might be play a pivotal role in renal mucosal repair by gut-kidney crosstalk, and protect renal from high glucose microenvironment damage.

A multifunctional optoelectronic device based on 2D material with wide bandgap.

Low-dimensional materials exhibit unique quantum confinement effects and morphologies as a result of their nanoscale size in one or more dimensions, making them exhibit distinctive physical properties compared to bulk counterparts. Among all low-dimensional materials, due to their atomic level thickness, two-dimensional materials possess extremely large shape anisotropy and consequently are speculated to have large optically anisotropic absorption. In this work, we demonstrate an optoelectronic device based on the combination of two-dimensional material and carbon dot with wide bandgap. High-efficient luminescence of carbon dot and extremely large shape anisotropy (>1500) of two-dimensional material with the wide bandgap of >4 eV cooperatively endow the optoelectronic device with multi-functions of optically anisotropic blue-light emission, visible light modulation, wavelength-dependent ultraviolet-light detection as well as blue fluorescent film assemble. This research opens new avenues for constructing multi-function-integrated optoelectronic devices via the combination of nanomaterials with different dimensions.

Cell-free fat extract-loaded microneedles attenuate inflammation-induced apoptosis and mitochondrial damage in tendinopathy.

Existing clinical treatments for tendinopathy mainly focus on reducing pain, whereas inhibiting or reversing disease progression remains challenging. Local therapeutic drugs, such as glucocorticoids, cause adverse effects on the metabolism of tendon tissues and injection-related complications. Therefore, new administration modalities for tendinopathy need to be developed. In this study, we designed a hydrogel-based microneedle (MN) system for the long-term transdermal delivery of our novel biological cell-free fat extract (CEFFE) to treat tendinopathies. We found that CEFFE-loaded MNs (CEFFE-MNs) had good biosafety and inhibited lipopolysaccharide (LPS)-induced apoptosis and matrix degradation in Achilles tendon cells of rats. The Achilles tendons of rats returned to their maximum mechanical strength after applying CEFFE-MNs. The administration of CEFFE-MNs had better anti-apoptosis and tendon repair-promoting effects than CEFEF injections in vivo. Transcriptome sequencing indicated that the anti-apoptosis effect of CEFFE-MNs was highly related to tumor necrosis factor (TNF) signaling. CEFFE-MNs inhibited the expression of TNF, TNF receptor 1, and downstream nuclear factor-kappa B signaling. Additionally, CEFFE-MNs rescued LPS-induced mitochondrial dynamics in tendon cells via the TNF-Drp1 axis. Our study reports a novel CEFFE-MN system that exhibits long-term anti-inflammatory and anti-apoptotic effects, suggesting it as a new treatment route for tendinopathy with broad clinical translation prospects.

Osteosarocma progression in biomimetic matrix with different stiffness: Insights from a three-dimensional printed gelatin methacrylamide hydrogel.

Recent studies on osteosarcoma and matrix stiffness are still mostly performed in a 2D setting, which is distinct from in vivo conditions. Therefore, the results from the 2D models may not reflect the real effect of matrix stiffness on cell phenotype. Here, we employed a 3D bioprinted osteosarcoma model, to study the effect of matrix stiffness on osteosarcoma cells. Through density adjustment of GelMA, we constructed three osteosarcoma models with distinct matrix stiffnesses of 50, 80, and 130 kPa. In this study, we found that osteosarcoma cells proliferated faster, migrated more actively, had a more stretched morphology, and a lower drug sensitivity in a softer 3D matrix. When placed in a stiffer matrix, osteosarcoma cells secrete more MMP and VEGF, potentially to fight for survival and attract vascular invasion. Transcriptomic analysis showed that matrix stiffness could impact the signaling pathway of integrin α5-MAPK. The transplantation of 3D printed models in nude mice showed that cells encapsulated in the softer hydrogel were more likely to form subcutaneous tumors. These results suggest that matrix stiffness plays an important role in the development of osteosarcoma in a 3D environment and that inhibition of integrin α5 could block the signal transduction of matrix stiffness.

Metallacage-based enhanced PDT strategy for bacterial elimination via inhibiting endogenous NO production.

Antibiotics are among the most used weapons in fighting microbial infections and have greatly improved the quality of human life. However, bacteria can eventually evolve to exhibit antibiotic resistance to almost all prescribed antibiotic drugs. Photodynamic therapy (PDT) develops little antibiotic resistance and has become a promising strategy in fighting bacterial infection. To augment the killing effect of PDT, the conventional strategy is introducing excess ROS in various ways, such as applying high light doses, high photosensitizer concentrations, and exogenous oxygen. In this study, we report a metallacage-based PDT strategy that minimizes the use of ROS by jointly using gallium-metal organic framework rods to inhibit the production of bacterial endogenous NO, amplify ROS stress, and enhance the killing effect. The augmented bactericidal effect was demonstrated both in vitro and in vivo. This proposed enhanced PDT strategy will provide a new option for bacterial ablation.

A time-resolved fluorescence immunoassay for rapid and precise automatic quality control of human papillomavirus type 68 VLPs in human papillomavirus vaccine.

The effectiveness and necessity of human papillomavirus (HPV) vaccination to prevent HPV infection and cervical cancer are increasingly recognized by people. The 15-valent HPV vaccine, which protects against almost high-risk types of HPV viruses identified by WHO, has attracted much attention. However, as the valence of vaccines increases, quality control in the HPV vaccine production process is facing more challenges. The precise quality control of the HPV type 68 virus-like particles (VLPs), one of the unique components of the 15-valent HPV vaccine that distinguishes it from existing vaccines, is the new requirement for vaccine manufacturers. Here we developed a novel time-resolved fluorescence immunoassay (TRFIA) for rapid and precise automatic quality control of HPV68 VLPs in HPV vaccine. Two murine monoclonal antibodies specifically targeting the HPV68 L1 protein were used to establish a classical sandwich assay. Except for pretreating the vaccine sample, the whole analysis process was performed by a fully automated machine, which saves detection time and gets rid of manual error. Multiple experiments established that the current novel TRFIA can efficiently and reliably analyses HPV68 VLPs. Present novel TRFIA has exhibited merits with speed, robustness, high sensitivity with a minimum detection value of 0.08 ng/mL, considerable accuracy, a wide detection range (up to 1000 ng/mL) and excellent specificity. It is also expected to provide a new detection method for quality control for each HPV type VLPs. To summarize, the novel TRFIA is of great interest for application in HPV vaccine quality control.

CH02 peptide promotes ex vivo expansion of umbilical cord blood-derived CD34 + hematopoietic stem/progenitor cells.

Umbilical cord blood (UCB) is an advantageous source for hematopoietic stem/progenitor cell (HSPC) transplantation, yet the current strategies for large-scale and cost-effective UCB-HSPC preparation are still unavailable. To overcome these obstacles, we systematically evaluate the feasibility of our newly identified CH02 peptide for ex vivo expansion of CD34 + UCB-HSPCs. We herein report that the CH02 peptide is specifically enriched in HSPC proliferation via activating the FLT3 signaling. Notably, the CH02-based cocktails are adequate for boosting 12-fold ex vivo expansion of UCB-HSPCs. Meanwhile, CH02-preconditioned UCB-HSPCs manifest preferable efficacy upon wound healing in diabetic mice via bidirectional orchestration of proinflammatory and anti-inflammatory factors. Together, our data indicate the advantages of the CH02-based strategy for ex vivo expansion of CD34 + UCB-HSPCs, which will provide new strategies for further development of large-scale HSPC preparation for clinical purposes.

A custom-made time-resolved fluoroimmunoassay for the quantitation of the host cell protein of Vero in rabies vaccine.

Host cell proteins (HCPs) are the process-specific and inevitable impurities during the manufacture via a host cell, which affect the safety or efficacy of the bio-product. However, the commercial HCP enzyme-linked immunosorbent assay (ELISA) kits may not apply to specific products such as rabies vaccine from Vero cells. More advanced and process-specific assay methods are needed in the quality control of rabies vaccine throughout the whole manufacturing process. Therefore, a novel time-resolved fluoroimmunoassay (TRFIA) for the detection of process-specific HCP of Vero cells in rabies vaccine was established in this study. Liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) was used during the preparation of HCP antigen. Based on a sandwich-type immunoassay format, analytes in samples were captured by one antibody coating in the wells and "sandwiched" by another antibody labeled with europium chelates. Due to the complex composition of HCP, both the capture and detected antibodies are polyclonal antibodies from the same anti-HCP antibodies pool. Multiple experiments have identified the optimal conditions to allow the valid and reliable detection of HCP in rabies vaccine. The TRFIA had a satisfactory limit of detection value (0.011 µg/ml) under optimal conditions, with the linear range from 0.0375 to 2.4 µg/ml of HCP. The coefficient variations (CVs) were all < 10%, and the recoveries were in the range of 97.00-102.42%. All the test results of Vero cell protein reference substance were included in the expected concentration, which demonstrated that the present method was available for the test of HCP in rabies vaccine. Based on these results, the novel TRFIA to detect HCP appears to be important for application in modern vaccine quality control during the whole manufacturing process.

Fine and high-performance protein fibers from meat goat hairs via manipulation of keratin alignment and crosslinkages.

We have converted waste coarse and short hairs of meat goats to high-value, fine, long, and elastic protein fibers via manipulation of keratin alignment and crosslinkages. The shortage of non-petroleum-based fibers has become one of the most prominent concerns. However, few technologies could convert such coarse hairs to fine and flexible fibers for textile uses due to limitations in extensions of fibers, less than 100% of their initial length, and poor flexibility retention of extended fibers, less than 20% of breaking elongation. Limited stretchability and flexibility retention of hair fibers mainly resulted from the difficulty in recovery of crosslinkages in stretched fibers. Here, we used a series of dithiols via multiple cycles of reduction, drawing, and oxidation to produce fine and flexible fibers from coarse and short wool for the first time. Dithiols with long backbones ensured sufficient crosslinkages in proteins after high ratios of drawings. Besides, long crosslinkages brought by dithiols secured sufficient movement between protein molecules and prevented of rupturing chains of protein molecules. As a result, short and coarse hairs of meat goats were turned into long and fine fibers, 350% of their original lengths and 54% of their original diameters, with excellent performance properties, with retentions of 170% of tenacity, and 50% of breaking elongation compared to original hairs. Also, a set of models developed to quantify the effects of extensions of fibers and structures of crosslinkers on the mechanical properties of fibers guides scientists and engineers on property improvement of materials via controlled crosslinkings.

Constitutively activated AMPKα1 protects against skeletal aging in mice by promoting bone-derived IGF-1 secretion.

Senile osteoporosis is characterized by age-related bone loss and bone microarchitecture deterioration. However, little is known to date about the mechanism that maintains bone homeostasis during aging. In this study, we identify adenosine monophosphate-activated protein kinase alpha 1 (AMPKα1) as a critical factor regulating the senescence and lineage commitment of mesenchymal stem cells (MSCs). A phospho-mutant mouse model shows that constitutive AMPKα1 activation prevents age-related bone loss and promoted MSC osteogenic commitment with increased bone-derived insulin-like growth factor 1 (IGF-1) secretion. Mechanistically, upregulation of IGF-1 signalling by AMPKα1 depends on cAMP-response element binding protein (CREB)-mediated transcriptional regulation. Furthermore, the essential role of the AMPKα1/IGF-1/CREB axis in promoting aged MSC osteogenic potential is confirmed using three-dimensional (3D) culture systems. Taken together, these results can provide mechanistic insight into the protective effect of AMPKα1 against skeletal aging by promoting bone-derived IGF-1 secretion.

FGFR4 and EZH2 inhibitors synergistically induce hepatocellular carcinoma apoptosis via repressing YAP signaling.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide, but current treatment options remain limited and cause serious life-threatening side effects. Aberrant FGFR4 signaling has been validated as an oncogenic driver of HCC, and EZH2, the catalytic subunit of the PRC2 complex, is a potential factor that contributes to acquired drug resistance in many tumors, including HCC. However, the functional relationship between these two carcinogenic factors, especially their significance for HCC treatment, remains unclear. In this study, we systematically evaluated the feasibility of a combination therapy targeting FGFR4 and EZH2 for HCC. METHODS: RNA sequencing data of patients with Liver hepatocellular carcinoma (LIHC) from The Cancer Genome Atlas (TCGA) were analyzed to determine FGFR4 and EZH2 expression and their interaction with prognosis. Moreover, the HCC cell lines, zebrafish/mouse HCC xenografts and zebrafish HCC primary tumors were treated with FGFR4 inhibitor (Roblitinib) and/or EZH2 inhibitor (CPI-169) and then subjected to cell proliferation, viability, apoptosis, and tumor growth analyses to evaluate the feasibility of combination therapy for HCC both in vitro and in vivo. Furthermore, RNA-Seq was performed in combination with ChIP-Seq data analysis to investigate the critical mechanism underlying the combination treatment with Roblitinib and CPI-169. RESULTS: EZH2 accumulated through the non-canonical NF-kB signaling in response to FGFR4 inhibitor treatment, and the elevated EZH2 levels led to the antagonism of HCC against Roblitinib (FGFR4 inhibitor). Notably, knockdown of EZH2 sensitized HCC cells to Roblitinib, while the combination treatment of Roblitinib and CPI-169 (EZH2 inhibitor) synergistically induced the HCC cell apoptosis in vitro and suppressed the zebrafish/mouse HCC xenografts and zebrafish HCC primary tumors development in vivo. Moreover, Roblitinib and CPI-169 synergistically inhibited HCC development via repressing YAP signaling. CONCLUSIONS: Collectively, our study highlighted the potential of the therapeutic combination of FGFR4 and EZH2 inhibitors, which would provide new references for the further development of clinical treatment strategies for HCC.