Advanced biology最新文献

Each year, ≈1.6 million women are diagnosed with breast cancer worldwide. Of these cases, 0.5 million result in death, with over 90% of these deaths resulting from metastasis. Since it is one of the top 5 cancers with the highest mortality rates, the development of breast cancer models that are physiologically relevant to the human body is severely needed. This includes models of the breast tissue microenvironment, the microenvironment of metastatic sites (e.g., brain, lungs, bone, liver), and models specifically mimicking each individual step of the cancer metastatic cascade. This review focuses on models of the primary tumor environment for studying cell invasion and spread within the mammary tissue, prior to metastatic outgrowth. Using a combination of methods such as tumor spheroids, 3D printed biomaterials, and microfluidic designs, a variety of 3D in vitro modeling methods exist to recapitulate specific aspects of the tumor microenvironment and understand sources of tumor heterogeneity. An effective model can be specified for each patient, eliminating the need for human trials. Subsequently, as the mechanisms involved in breast cancer metastasis are studied utilizing more effective in vitro models, targeted therapeutics can be discovered, thus advancing clinical treatment strategies.

Solasonine, extracted from Solanum nigrum, has been proven to exert anti-tumor effects in various tumors. However, the role of solasonine in gastric cancer remains unclear. This study aims to elucidate the therapeutic effects of solasonine in suppressing gastric cancer progression. This study explores the regulatory mechanism of solasonine in vitro cells and xenograft tumor mouse models. Methylation-specific PCR (MSP) is used for DNA methylation analysis; immunohistochemical and flow cytometry are performed for MHC class I polypeptide-related sequence A (MICA) expression profiling. Solasonine inhibits the proliferation and migration of gastric cancer cells. MICA is identified as a regulatory target for solasonine in gastric cancer cells. Mechanistically, DNA methylation of MICA is suppressed by solasonine. DNA methyltransferases (DNMT) family members, DNMT1, DNMT3A, and DNMT3B, are downregulated in solasonine-treated tumor tissues. Importantly, solasonine restores the sensitivity of HGC-27 cells to natural killer (NK) cells through upregulating MICA, suggesting the potential value of solasonine as an immunotherapy drug in gastric cancer. Solasonine inhibits gastric cancer progression and restores sensitivity of gastric cancer to NK cells through inducing DNA demethylation of the MICA promoter in vitro and in vivo. This study provides application prospects for solasonine anti-tumor therapy.

Adipose mesenchymal stem cell-derived exosomes and the PDE4 inhibitor roflumilast (ROF) are investigated as potential treatments for chronic kidney disease (CKD). The exosomes are extracted and analyzed using electron microscopy and flow cytometry, then employed with ROF for in vivo implantation in a CKD animal model. Animals aredivided into seven groups. Group (I) Control; (II) exosomes; (III) ROF; (IV) Adriamycin (ADR); (V) ADR + exosomes, (VI) ADR + ROF, and (VII) ADR + Exosomes+ ROF. Biochemical serum indicators (creatinine, BUN), antioxidant status (GSH, MDA), and the mRNA expressions of TGF-β1, Smad3, IL-6, BAX, Wnt-7, FN, and miRNA145-5p are determined using qRT-PCR. Histology assessment using H&E staining, ultrastructural observation using TEM, and protein expression in kidney tissue (FN1 and BAX) are assessed. The isolated exosomes showed cup-shaped morphologyand expressed CD81, CD9, and CD63. Exosomes and ROF increased glutathione (GSH) levels while decreasing malondialdehyde (MDA) levels. Further, ROF and exosomes treatment lowered the expression of the apoptotic indicators BAX, the fibrotic markers TGFβ1, Smad3, Wnt7a, and FN1, and the inflammatory marker IL6, and increased the expression of miRNA-145. Moreover, ROF and exosomes improved histological and ultrastructural examination. In conclusion, exosomes and ROF can protect against CKD by reducing apoptosis and fibrosis.

Local anesthetics (LAs), commonly used for regional and general anesthesia, have gained attention in recent years for their potential role during cancer curative surgery, as they may reduce cancer recurrence and progression. Studies in both laboratory and animal models have shown that LAs can inhibit tumor growth and cell proliferation, trigger apoptosis, and reduce metastasis by limiting cancer cell invasion and migration. In addition, LAs impact the tumor microenvironment by modulating inflammation, enhancing the immune response, blocking angiogenesis, and interfering with tumor innervation. The mechanisms behind these effects involve both voltage-gated sodium channel-dependent and independent pathways, such as AKT/mTOR, RAS/ERK, and SRC/STAT3, as well as regulating microRNAs, circular RNAs, and apoptosis-related proteins, among others. Furthermore, LAs may enhance the efficacy of chemotherapy and counteract chemoresistance. The aim of this review is to provide a comprehensive summary of the current literature on the various mechanisms through which LAs influence tumorigenesis, alter metastasis processes, modulate immune responses, and affect angiogenesis within the tumor microenvironment.

Spheroids are being widely studied as potential building blocks for complex organ engineering, tools for drug screening and cancer study. However, formation time has become the bottleneck of applications due to the need for large-scale high-quality spheroids production. Formation time is often dominated by ECM construction and not cell aggregation. Therefore, this study focuses on the influence of ultrasound detachment replacing conventional enzyme detachment on spheroid formation processes. Thanks to cell surface protein preservation in ultrasound detachment, cell aggregation time is reduced while decreasing the formation variabilities. Moreover, it is confirmed that cells are intrinsically more capable of aggregating through enzyme-free detachment. On top of that, transplantations into rats showed equally successful engraftment properties for enzyme-free detached cells. Finally, the impact on the real co-cultured spheroid application was shown to be beneficial through more localized cell groups inside of the spheroids, possibly improving therapeutic effects and vascularization. Through this study, it is proved that ultrasound detachment can replace enzyme detachment without degrading the final spheroid properties but reducing the formation time, and variability and improving robustness and cell distribution. This opens up a new range of applications for better and faster spheroid formation in numerous bioengineering applications.

Molecular optogenetics allows the control of molecular signaling pathways in response to light. This enables the analysis of the kinetics of signal activation and propagation in a spatially and temporally resolved manner. A key strategy for such control is the light-inducible clustering of signaling molecules, which leads to their activation and subsequent downstream signaling. In this work, an optogenetic approach is developed for inducing graded clustering of different proteins that are fused to eGFP, a widely used protein tag. To this aim, an eGFP-specific nanobody is fused to Cryptochrome 2 variants engineered for different orders of cluster formation. This is exemplified by clustering eGFP-IKKα and eGFP-IKKβ, thereby achieving potent and reversible activation of NF-κB signaling. It is demonstrated that this approach can activate downstream signaling via the endogenous NF-κB pathway and is thereby capable of activating both an NF-κB-responsive reporter construct as well as endogenous NF-κB-responsive target genes as analyzed by RNA sequencing. The generic design of this system is likely transferable to other signaling pathways to analyze the kinetics of signal activation and propagation.

Degenerative disc disease is strongly associated with low back pain, making it a leading cause of disability. With injury and age, cellular remodeling of the disc tissue leads to compositional changes, stiffening, and loss of stress relaxation, particularly in the central gelatinous nucleus pulposus (NP) region of the disc. As part of this extracellular matrix (ECM) remodeling, there is an increase in the deposition of fibronectin, a strongly adhesive integrin ligand that is known to regulate inflammatory signaling. However, it is unclear how these pathological changes in cellular adhesion regulate cell phenotype, and which domains of fibronectin are specifically involved. Here, a dextran vinyl sulfone (DexVS) hydrogel system is employed for presentation of specific fibronectin domains. Fibronectin peptides are found to enhance YAP signaling, inflammatory NF-κB signaling, cellular adhesion, and cellular contractility in NP cells, which leads to a decrease in aggrecan gene expression. Covalent modification of these DexVS hydrogels with bioactive peptides allows for targeted interactions with specific integrin receptors that are involved in healthy or degenerative signaling. In doing so, the integrin binding peptides from fibronectin are identified to activate a contractile phenotype in NP cells.

Interaction between a growing tumor and the host immune system has various facets, which eventually influence the fate of both the tumor and the host. In the last decade, multiple efforts have been undertaken to mimic the heterogeneous consortium of tumors to comprehend tumor biology. Understanding the tumor-stromal or tumor-immune crosstalk is also crucial for screening and pre-clinical evaluation of therapeutic candidates. The development of human-relevant and physiologically similar models is the need of the hour to bridge the gap. Existing models relevant to tissue engineering, including porous scaffolds, hydrogel, and fibrous mats, are widely utilized to recapitulate the tumor microenvironment. In spite of their inherent limitations, they are employed to study tumor-immune interactions in the past. In the recent decade, emerging techniques such as Microfluidics, organ on a chip, and 3D Bioprinting have been used prevalently to mimic the heterogeneous landscape of tumors. This review is intended to discuss the current developments in the field of in vitro 3D tumor models while focusing on the tumor-immune crosstalk. Furthermore, the theoretical and practical limitations of the conventional model mimicking the tumorimmune crosstalk and the need for ‘out of the box’ ideas by converging the existing models are highlighted.

Cancer is one of the most pervasive and severe global diseases that cause millions of death annually. Numerous bacterial strains are found to play fundamental roles in tumor formation, growth, and metastasis. On the other hand, specific bacterial strains are discovered to induce beneficial changes to restrict tumoral growth and progression or alter the tumor microenvironment. Studies have also suggested bacteria are potential microorganisms that transfer synthetic genes or anti-tumor drugs. A particularly interesting area of study is bacterial communication, known as quorum sensing (QS), in which signal peptides adjust bacterial pathogenic traits such as virulence factor, drug resistance, and biofilm after a threshold volume of signals is reached. QS signals raised a propitious future perspective against diseases and cancer. Future comprehension of the QS system can lead to novel bacterial-based therapeutic procedures with the minimum healthy cell toxicity and higher target specificity rather than long-established methods. This review aims to highlight significant research and advancements in the field of QS to combat cancer and find more non-toxic and less-invasive treatments.

Neuroblastoma represents a major challenge in pediatric oncology with over 50% of cases involving metastasis. High-risk patients face an unfavorable prognosis, with survival rates below 40%. LIN28B plays a pivotal role in neuroblastoma development, being overexpressed in a subset of high-risk patients with widespread metastases. Here, the effect of induced LIN28B (iLIN28B) expression on neuroblastoma cells is investigated with a focus on key aspects of the metastatic cascade including anchorage, migration, invasion, and angiogenesis. iLIN28B cells show substrate-selective adherence, coating-dependent migration, and the context-guided ability to degrade the extracellular matrix. In response to tumor cell-derived IGF2, endothelial cells show enhanced motility and proliferation, while inhibition of IGF2 activity impairs LIN28B-induced angiogenesis in vitro and in vivo. These findings underscore the hub role of LIN28B in favoring pre-metastatic processes in neuroblastoma. The intricate interplay between LIN28B, endothelial cells, and the extracellular matrix contributes to the development of the aggressive neuroblastoma phenotypes.