Decellularized Tumor Tissues Integrated with Polydopamine for Wound Healing.

Natural biomaterials have been showing extensive potential in wound healing; attempts therefore focus on productions achieving both antimicrobial and tissue regenerative abilities. Here, we construct a decellularized human colon tumor (DHCT)-derived scaffold for wound remolding via microfluidic bioprinting. The DHCT retains a series of growth factors, fibrin, and the collagen configuration, that favor tissue repair and reconstruction. Specifically, the scaffold shows superior abilities in cell migration and angiogenesis. The biocompatible scaffold is also imparted with tissue adhesion ability and photothermal effect due to the coating of biologically derived polydopamine on the surface. The strong photothermal effect under near-infrared irradiation also present the scaffold with an antibacterial rate exceeding 90%. Furthermore, in vivo experiments convinced that the polydopamine-integrated DHCT scaffold can markedly expedite the healing process of acute extensive wounds. These findings indicate that composite materials derived from natural tumors have substantial potential in pertinent clinical applications.

Emerging mRNA Technology for Liver Disease Therapy.

Liver diseases have consistently posed substantial challenges to global health. It is crucial to find innovative methods to effectively prevent and treat these diseases. In recent times, there has been an increasing interest in the use of mRNA formulations that accumulate in liver tissue for the treatment of hepatic diseases. In this review, we start by providing a detailed introduction to the mRNA technology. Afterward, we highlight types of liver diseases, discussing their causes, risks, and common therapeutic strategies. Additionally, we summarize the latest advancements in mRNA technology for the treatment of liver diseases. This includes systems based on hepatocyte growth factor, hepatitis B virus antibody, left-right determination factor 1, human hepatocyte nuclear factor α, interleukin-12, methylmalonyl-coenzyme A mutase, etc. Lastly, we provide an outlook on the potential of mRNA technology for the treatment of liver diseases, while also highlighting the various technical challenges that need to be addressed. Despite these difficulties, mRNA-based therapeutic strategies may change traditional treatment methods, bringing hope to patients with liver diseases.

Viral Mimicking Polyplexes as Hierarchical Unpacking Vectors for Rheumatoid Arthritis Treatment.

Nano-delivery systems hold great promise for the treatment of rheumatoid arthritis (RA). Current research efforts are primarily focused on enhancing their targeting capabilities and efficacy. Here, this study proposes a novel viral-mimicking ternary polyplexes system for the controlled delivery of the anti-inflammatory drug Cyclosporin A (CsA) to effectively treat RA. The ternary polyplexes consist of a nanogel core loaded with CsA and a hyaluronic acid shell, which facilitates CD44-mediated targeting. By mimicking the Trojan Horse strategy employed by viruses, these polyplexes undergo a stepwise process of deshielding and disintegration within the inflamed joints. This process leads to the release of CsA within the cells and the scavenging of pathogenic factors. This study demonstrates that these viral-mimicking ternary polyplexes exhibit rapid targeting, high accumulation, and prolonged persistence in the joints of RA mice. As a result, they effectively reduce inflammation and alleviate symptoms. These results highlight the potential of viral-mimicking ternary polyplexes as a promising therapeutic approach for the targeted and programmed delivery of drugs to treat not only RA but also other autoimmune diseases.

Intestinal lymphatic transport of Smilax china L. pectic polysaccharide via Peyer's patches and its uptake and transport mechanisms in mononuclear phagocytes.

Recently, the intestinal lymphatic transport based on Peyer's patches (PPs) is emerging as a promising absorption pathway for natural polysaccharides. Herein, the aim of this study is to investigate the PP-based oral absorption of a pectic polysaccharide from Smilax china L. (SCLP), as well as its uptake and transport mechanisms in related immune cells. Taking advantages of the traceability of fluorescently labeled SCLP, we confirmed that SCLP could be absorbed into PPs and captured by their mononuclear phagocytes (dendritic cells and macrophages) following oral administration. Subsequently, the systematic in vitro study suggested that the endocytic mechanisms of SCLP by model mononuclear phagocytes (BMDCs and RAW264.7 cells) mainly involved caveolae-mediated endocytosis, macropinocytosis and phagocytosis. More importantly, SCLP directly binds and interacts with toll-like receptor 2 (TLR2) and galectin 3 (Gal-3) receptor, and was taken up by mononuclear phagocytes in receptor-mediated manner. After internalization, SCLP was intracellularly transported primarily through endolysosomal pathway and ultimately localized in lysosomes. In summary, this work reveals novel information and perspectives about the in vivo fate of SCLP, which will contribute to further research and utilization of SCLP and other pectic polysaccharides.

[Cell membrane-coated nanoparticles in disease therapy].

Nanotechnology has attracted increasing attention in the field of medical applications due to its significant potential for development. However, one major challenge that has emerged with nanoparticles is their tendency to activate the host immune clearance system, which hampers the achievement of desired therapeutic outcomes and may lead to harmful side effects. In recent years, membrane-coated nanoparticles have emerged as a promising solution, demonstrating their effectiveness in evading immune system clearance. These innovative nanoparticles inherit essential biological attributes from natural cell membranes, such as anchoring proteins and antigens. Consequently, membrane-coated nanoparticles exhibit unique capabilities such as immune evasion, prolonged circulation, targeted drug release, and immune modulation, substantially enhancing their versatility and prospects within the realm of biomedical applications. This review provides a comprehensive overview of the current applications of cell membrane-coated nanoparticles in disease therapy, highlighting their immense potential in this rapidly evolving platform. Additionally, the review outlines the promising prospects of this technology in disease therapy.

HSD17B13 liquid-liquid phase separation promotes leukocyte adhesion in chronic liver inflammation.

The rs72613567:TA polymorphism in 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) has been found to reduce the progression from steatosis to nonalcoholic steatohepatitis. In this study, we sought to define the pathogenic role of HSD17B13 in triggering liver inflammation. Here we find that HSD17B13 forms liquid-liquid phase separation (LLPS) around lipid droplets in the livers of nonalcoholic steatohepatitis patients. The dimerization of HSD17B13 supports the LLPS formation and promotes its enzymatic function. HSD17B13 LLPS increases the biosynthesis of platelet activating factor (PAF), which in turn promotes fibrinogen synthesis and leukocyte adhesion. Blockade of PAFR or STAT3 pathway inhibited the fibrinogen synthesis and leukocyte adhesion. Importantly, adeno-associated viral-mediated xeno-expression of human HSD17B13 exacerbated western diet/carbon tetrachloride-induced liver inflammation in Hsd17b13-/- mice. In conclusion, our results suggest that HSD17B13 LLPS triggers liver inflammation by promoting PAF-mediated leukocyte adhesion, and targeting HSD17B13 phase transition could be a promising therapeutic approach for treating hepatic inflammation in chronic liver disease.

A naturally isolated symbiotic bacterium suppresses flavivirus transmission by Aedes mosquitoes.

The commensal microbiota of the mosquito gut plays a complex role in determining the vector competence for arboviruses. In this study, we identified a bacterium from the gut of field Aedes albopictus mosquitoes named Rosenbergiella sp. YN46 (Rosenbergiella_YN46) that rendered mosquitoes refractory to infection with dengue and Zika viruses. Inoculation of 1.6 × 103 colony forming units (CFUs) of Rosenbergiella_YN46 into A. albopictus mosquitoes effectively prevents viral infection. Mechanistically, this bacterium secretes glucose dehydrogenase (RyGDH), which acidifies the gut lumen of fed mosquitoes, causing irreversible conformational changes in the flavivirus envelope protein that prevent viral entry into cells. In semifield conditions, Rosenbergiella_YN46 exhibits effective transstadial transmission in field mosquitoes, which blocks transmission of dengue virus by newly emerged adult mosquitoes. The prevalence of Rosenbergiella_YN46 is greater in mosquitoes from low-dengue areas (52.9 to ~91.7%) than in those from dengue-endemic regions (0 to ~6.7%). Rosenbergiella_YN46 may offer an effective and safe lead for flavivirus biocontrol.

Composite Microparticles from Microfluidics for Chemo-/Photothermal Therapy of Hepatocellular Carcinoma.

Hydrogel microcarrier-based drug delivery systems are of great value in the combination therapy of tumors. Current research directions concentrate on the development of more economic, convenient, and effective combined therapeutic platforms. Herein, we developed novel adhesive composite microparticles (MPPMD) with combined chemo- and photothermal therapy ability via microfluidic electrospray technology for local hepatocellular carcinoma treatment. These composite microparticles consisted of doxorubicin (DOX)-loaded and polydopamine-wrapped mesoporous silicon and alginate. Benefiting from such a strategy of hierarchical structure drug loading, DOX could be gradually released from the system, effectively avoiding the direct toxicity of chemotherapeutics to the body. Additionally, the designed microparticles could not only effectively treat tumors by releasing the chemotherapy drug DOX but also show excellent photothermal properties under the irradiation of near-infrared light, achieving combined chemo- and photothermal treatment effects. Based on these advantages, the MPPMD could remarkably eliminate tumor cells in vitro and enormously restrict tumor development in vivo. These results illustrate that such composite microparticles are ideal combination treatment platforms, possessing promising expectations for cancer therapy.

Biopolymer-Assembled Porous Hydrogel Microfibers from Microfluidic Spinning for Wound Healing.

Hydrogels are considered as a promising medical patch for wound healing. Researches in this aspect are focused on improving their compositions and permeability to enhance the effectiveness of wound healing. Here, novel prolamins-assembled porous hydrogel microfibers with the desired merits for treating diabetes wounds are presented. Such microfibers are continuously generated by one-step microfluidic spinning technology with acetic acid solution of prolamins as the continuous phase and deionized water as the dispersed phase. By adjusting the prolamin concentration and flow rates of microfluidics, the porous structure and morphology as well as diameters of microfibers can be well tailored. Owing to their porosity, the resultant microfibers can be employed as flexible delivery systems for wound healing actives, such as bacitracin and vascular endothelial growth factor (VEGF). It is demonstrated that the resultant hydrogel microfibers are with good cell-affinity and effective drug release efficiency, and their woven patches display superior in vivo capability in treating diabetes wounds. Thus, it is believed that the proposed prolamins-assembled porous hydrogel microfibers will show important values in clinic wound treatments.

Engineering Heterogeneous Tumor Models for Biomedical Applications.

Tumor tissue engineering holds great promise for replicating the physiological and behavioral characteristics of tumors in vitro. Advances in this field have led to new opportunities for studying the tumor microenvironment and exploring potential anti-cancer therapeutics. However, the main obstacle to the widespread adoption of tumor models is the poor understanding and insufficient reconstruction of tumor heterogeneity. In this review, the current progress of engineering heterogeneous tumor models is discussed. First, the major components of tumor heterogeneity are summarized, which encompasses various signaling pathways, cell proliferations, and spatial configurations. Then, contemporary approaches are elucidated in tumor engineering that are guided by fundamental principles of tumor biology, and the potential of a bottom-up approach in tumor engineering is highlighted. Additionally, the characterization approaches and biomedical applications of tumor models are discussed, emphasizing the significant role of engineered tumor models in scientific research and clinical trials. Lastly, the challenges of heterogeneous tumor models in promoting oncology research and tumor therapy are described and key directions for future research are provided.

Sprayable Multifunctional Black Phosphorus Hydrogel with On-Demand Removability for Joint Skin Wound Healing.

Wound healing remains a critical challenge in regenerative engineering. Great efforts are devoted to develop functional patches for wound healing. Herein, a novel sprayable black phosphorus (BP)-based multifunctional hydrogel with on-demand removability is presented as a joints' skin wound dressing. The hydrogel is facilely prepared by mixing dopamine-modified oxidized hyaluronic acid, cyanoacetategroup-functionalized dextran containing black phosphorus, and the catalyst histidine. The catechol-containing dopamine can not only enhance tissue adhesiveness, but also endow the hydrogel with antioxidant capacity. In addition, benefiting from the photothermal conversion ability of the BP and thermally reversible performance of the formed C═C double bonds between aldehyde groups and cyanoacetate groups, the resulting hydrogel displays excellent antibacterial performance and on-demand dissolving ability under NIR irradiation. Moreover, by loading vascular endothelial growth factor into the hydrogel, the promoted migration and angiogenesis effects of endothelial cells can also be achieved. Based on these features, it is demonstrated that such sprayable BP hydrogels can effectively facilitate joint wounds healing by accelerating angiogenesis, alleviating inflammation, and improving wound microenvironment. Thus, it is believed that this NIR-responsive removable BP hydrogel dressing will put forward an innovative concept in designing wound dressings.

Protective effect of Angelica sinensis polysaccharide on pregnant rats suffering from iron deficiency anemia via regulation of the hepcidin-FPN1 axis.

Iron deficiency anemia (IDA) is a common micronutrient deficiency among pregnant women with deleterious maternal and fetal outcomes. Angelica sinensis polysaccharide (ASP) has been shown to reduce hepcidin expression in IDA rats. However, the role of ASP in the treatment of IDA during pregnancy and its potential mechanisms have not been investigated. Moreover, the effect of ASP on duodenal iron absorption is not clear. The aim of this study was to investigate the preventive efficacy of ASP against IDA during pregnancy and clarify the underlying mechanisms. Our results showed that ASP improved maternal hematological parameters, increased serum iron, maternal tissue iron, and fetal liver iron content, and improved pregnancy outcomes. Additionally, ASP combated oxidative stress caused by iron deficiency by improving the body's antioxidant capacity. Western blot results demonstrated that ASP downregulated hepcidin expression by blocking the BMP6/SMAD4, JAK2/STAT3 and TfR2/HFE signaling pathways, which in turn increased the expression of FPN1 in the liver, spleen, and duodenum and promoted iron cycling in the body. Furthermore, ASP increased the expression of DMT1 and Dcytb in the duodenum, thereby facilitating duodenal iron uptake. Our results suggest that ASP is a potential agent for the prevention and treatment of IDA during pregnancy.

Engineered stem cells by emerging biomedical stratagems.

Stem cell therapy holds immense potential as a viable treatment for a widespread range of intractable disorders. As the safety of stem cell transplantation having been demonstrated in numerous clinical trials, various kinds of stem cells are currently utilized in medical applications. Despite the achievements, the therapeutic benefits of stem cells for diseases are limited, and the data of clinical researches are unstable. To optimize tthe effectiveness of stem cells, engineering approaches have been developed to enhance their inherent abilities and impart them with new functionalities, paving the way for the next generation of stem cell therapies. This review offers a detailed analysis of engineered stem cells, including their clinical applications and potential for future development. We begin by briefly introducing the recent advances in the production of stem cells (induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs)). Furthermore, we present the latest developments of engineered strategies in stem cells, including engineered methods in molecular biology and biomaterial fields, and their application in biomedical research. Finally, we summarize the current obstacles and suggest future prospects for engineered stem cells in clinical translations and biomedical applications.

Toxicity Spectrum of Anti-GD2 Immunotherapy: A Real-World Study Leveraging the US Food and Drug Administration Adverse Event Reporting System.

BACKGROUND: Anti-disialoganglioside (anti-GD2) monoclonal antibodies are effective immunotherapeutic drugs for treating neuroblastoma, yet their toxicity spectrum is unclear. OBJECTIVE: This study aimed to assess the toxicity profiles of three anti-GD2 monoclonal antibodies (dinutuximab, dinutuximab ß, and naxitamab) in clinical applications by mining and evaluating the adverse drug reaction (ADR) signals from the US Food and Drug Administration Adverse Event Reporting System. METHODS: Data in the US Food and Drug Administration Adverse Event Reporting System from the time anti-GD2 monoclonal antibodies became available in the market to the first quarter of 2023 were searched. The signals of anti-GD2 monoclonal antibody-associated ADRs were quantified using four types of algorithms, including the reporting odds ratio, the proportional reporting ratio, the combination of the proportional reporting ratio and χ2 statistic method used by the UK Medicines and Healthcare Products Regulatory Agency, and the Bayesian confidence propagation neural network. The ADRs were categorized by System Organ Class based on the Medical Dictionary for Regulatory Activities, and were sorted according to the frequency and signal strength of ADRs. RESULTS: A total of 370 adverse drug event reports with anti-GD2 monoclonal antibodies listed as the 'primary suspected drugs' were identified, with 116 ADR signals detected, of which 22 were not in the drug labels. Among the adverse drug event reports, 276 reports concerned dinutuximab/dinutuximab ß as primary suspected drugs with 90 ADR signals, involving 19 System Organ Classes, of which 21 signals were not in the label; 94 adverse drug event reports concerned naxitamab as the primary suspected drug with 26 ADR signals, involving 11 System Organ Classes, of which one was not in the label. For dinutuximab/dinutuximab ß-related ADRs, the top five most frequent were "fever", "abdominal pain", "elevated aspartate aminotransferase (AST)", "elevated alanine aminotransferase (ALT)" and "hypotension"; the top five most intensive signals were "hypoalbuminemia", "elevated AST", "capillary leakage syndrome", "hypoxia" and "elevated ALT". For naxitamab-related ADRs, the top five most frequent were "hypotension", "pain", "urticarial", "hypertension" and "rash"; the top five most intensive signals were "hypotension", "urticaria", "hypoxemia", "bronchospasm" and "hypertension". Involved System Organ Classes included "investigations" and "respiratory, thoracic and mediastinal disorders" containing the most types of ADR signals in dinutuximab/dintuximab ß-related ADRs and naxitamab-related ADRs, respectively. CONCLUSIONS: Our study comprehensively analyzed the toxicity profiles of anti-GD2 monoclonal antibodies and provides an important reference for clinical monitoring and ADR identification of these drugs.

Advancements in the pathogenesis of hepatic osteodystrophy and the potential therapeutic of mesenchymal stromal cells.

Hepatic osteodystrophy (HOD) is a metabolically associated bone disease mainly manifested as osteoporosis with the characteristic of bone loss induced by chronic liver disease (CLD). Due to its high incidence in CLD patients and increased risk of fracture, the research on HOD has received considerable interest. The specific pathogenesis of HOD has not been fully revealed. While it is widely believed that disturbance of hormone level, abnormal secretion of cytokines and damage of intestinal barrier caused by CLD might jointly affect the bone metabolic balance of bone formation and bone absorption. At present, the treatment of HOD is mainly to alleviate the bone loss by drug treatment, but the efficacy and safety are not satisfactory. Mesenchymal stromal cells (MSCs) are cells with multidirectional differentiation potential, cell transplantation therapy based on MSCs is an emerging therapeutic approach. This review mainly summarized the pathogenesis and treatment of HOD, reviewed the research progress of MSCs therapy and the combination of MSCs and scaffolds in the application of osteoporotic bone defects, and discussed the potential and limitations of MSCs therapy, providing theoretical basis for subsequent studies.

Temporal and structural patterns of hepatitis B virus integrations in hepatocellular carcinoma.

Chronic infection of hepatitis B virus (HBV) is the major cause of hepatocellular carcinoma (HCC). Notably, 90% of HBV-positive HCC cases exhibit detectable HBV integrations, hinting at the potential early entanglement of these viral integrations in tumorigenesis and their subsequent oncogenic implications. Nevertheless, the precise chronology of integration events during HCC tumorigenesis, alongside their sequential structural patterns, has remained elusive thus far. In this study, we applied whole-genome sequencing to multiple biopsies extracted from six HBV-positive HCC cases. Through this approach, we identified point mutations and viral integrations, offering a blueprint for the intricate tumor phylogeny of these samples. The emergent narrative paints a rich tapestry of diverse evolutionary trajectories characterizing the analyzed tumors. We uncovered oncogenic integration events in some samples that appear to happen before and during the initiation stage of tumor development based on their locations in reconstituted trajectories. Furthermore, we conducted additional long-read sequencing of selected samples and unveiled integration-bridged chromosome rearrangements and tandem repeats of the HBV sequence within integrations. In summary, this study revealed premalignant oncogenic and sequential complex integrations and highlighted the contributions of HBV integrations to HCC development and genome instability.

Premature aging and reduced cancer incidence associated with near-complete body-wide Myc inactivation.

MYC proto-oncogene dysregulation alters metabolism, translation, and other functions in ways that support tumor induction and maintenance. Although Myc+/- mice are healthier and longer-lived than control mice, the long-term ramifications of more complete Myc loss remain unknown. We now describe the chronic consequences of body-wide Myc inactivation initiated postnatally. "MycKO" mice acquire numerous features of premature aging, including altered body composition and habitus, metabolic dysfunction, hepatic steatosis, and dysregulation of gene sets involved in functions that normally deteriorate with aging. Yet, MycKO mice have extended lifespans that correlate with a 3- to 4-fold lower lifetime cancer incidence. Aging tissues from normal mice and humans also downregulate Myc and gradually alter many of the same Myc target gene sets seen in MycKO mice. Normal aging and its associated cancer predisposition are thus highly linked via Myc.

FOXO1 regulates Th17 cell-mediated hepatocellular carcinoma recurrence after hepatic ischemia-reperfusion injury.

BACKGROUND: Hepatic ischemia-reperfusion injury (IRI) is considered as an effecting factor for hepatocellular carcinoma (HCC) recurrence. Th17/Treg cells are a pair of essential components in adaptive immune response in liver IRI, and forkhead box O1 (FOXO1) has the properties of maintaining the function and phenotype of immune cells. Herein, we illuminated the correlation and function between Th17/Treg cell balance and FOXO1 in IRI-induced HCC recurrence. METHODS: RNA sequencing was performed on naive CD4+ T cells from normal and IRI model mice to identify relevant transcription factors. Western blotting, qRT-PCR, immunohistochemical staining, and flow cytometry were performed in IRI models to indicate the effect of FOXO1 on the polarization of Th17/Treg cells. Then, transwell assay of HCC cell migration and invasion, clone formation, wound healing assay, and Th17 cells adoptively transfer was utilized to assess the function of Th17 cells in IRI-induced HCC recurrence in vitro and in vivo. RESULTS: Owning to the application of RNA sequencing, FOXO1 was screened and assumed to perform a significant function in hepatic IRI. The IRI model demonstrated that up-regulation of FOXO1 alleviated IR stress by attenuating inflammatory stress, maintaining microenvironment homeostasis, and reducing the polarization of Th17 cells. Mechanistically, Th17 cells accelerated IRI-induced HCC recurrence by shaping the hepatic pre-metastasis microenvironment, activating the EMT program, promoting cancer stemness and angiogenesis, while the upregulation of FOXO1 can stabilize the liver microenvironment homeostasis and alleviate the negative effects of Th17 cells. Moreover, the adoptive transfer of Th17 cells in vivo revealed its inducing function in IRI-induced HCC recurrence. CONCLUSIONS: These results indicated that FOXO1-Th17/Treg axis exerts a crucial role in IRI-mediated immunologic derangement and HCC recurrence, which could be a promising target for reducing the HCC recurrence after hepatectomy. Liver IRI affects the balance of Th17/Treg cells by inhibiting the expression of FOXO1, and the increase of Th17 cells has the ability to induce HCC recurrence through EMT program, cancer stemness pathway, the formation of premetastatic microenvironment and angiogenesis.

Identification of microRNAs implicated in modulating resveratrol-induced apoptosis in porcine granulosa cells.

MicroRNAs (miRNAs) are small, noncoding RNAs that play a crucial role in the complex and dynamic network that regulates the apoptosis of porcine ovarian granulosa cells (POGCs). Resveratrol (RSV) is a nonflavonoid polyphenol compound that is involved in follicular development and ovulation. In previous study, we established a model of RSV treatment of POGCs, confirming the regulatory effect of RSV in POGCs. To investigate the miRNA-level effects of RSV on POGCs to reveal differentially expressed miRNAs, a control group (n = 3, 0 µM RSV group), a low RSV group (n = 3, 50 µM RSV group), and a high RSV group (n = 3, 100 µM RSV group) were created for small RNA-seq. In total, 113 differentially expressed miRNAs (DE-miRNAs) were identified, and a RT-qPCR analysis showed a correlation with the sequencing data. Functional annotation analysis revealed that DE-miRNAs in the LOW vs. CON group may be involved in cell development, proliferation, and apoptosis. In the HIGH vs. CON group, RSV functions were associated with metabolic processes and responses to stimuli, while the pathways were related to PI3K24, Akt, Wnt, and apoptosis. In addition, we constructed miRNA-mRNA networks related to Apoptosis and Metabolism. Then, ssc-miR-34a and ssc-miR-143-5p were selected as key miRNAs. In conclusion, this study provided an improved understanding of effects of RSV on POGCs apoptosis through the miRNA modulations. The results suggest that RSV may promote POGCs apoptosis by stimulating the miRNA expressions and provided a better understanding of the role of miRNAs combined with RSV in ovarian granulosa cell development in pigs.