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Simple Summary: Integrin α6β4 makes triple-negative breast cancer (TNBC) more aggressive by controlling genes that drive tumor invasion and metastasis. PTPRZ1 is linked to cancer relapse, but its role in TNBC is not well understood. We discovered that PTPRZ1 expression is significantly increased by integrin α6β4 in TNBC. We also found that integrin β4 gene expression correlates with PTPRZ1 in breast cancer patient samples. Importantly, we found that integrin α6β4 controls PTPRZ1 through UCHL1, which in turn stabilized Hif-1α. When UCHL1 or PTPRZ1 are blocked, the aggressiveness driven by integrin β4 signaling decreased substantially. Data analysis showed that high levels of these genes (ITGB4, UCHL1, Hif1α, PTPRZ1) are linked to worse survival rates, especially in patients who received chemotherapy treatment. Our findings suggest that integrin α6β4 helps TNBC become invasive through UCHL1-Hif-1α regulation of PTPRZ1, pointing to a new approach to targeting integrin α6β4 signaling using PTPRZ1 and UCHL1 inhibitors. Integrin α6β4 drives triple-negative breast cancer (TNBC) aggressiveness through the transcriptional regulation of key genes. Here, we investigated how integrin α6β4 regulates protein tyrosine phosphatase receptor type Z1 (PTPRZ1). Using stable re-expression of integrin β4 (ITGB4) in cells naturally devoid of integrin α6β4 or knockdown or knockout (KO) of ITGB4, we found that integrin α6β4 regulates PTPRZ1 expression. To gain mechanistic insight, we focused on Hif-1α due to the impact of integrin α6β4 on a hypoxia-associated signature. We found that nuclear localization of Hif-1α, but not Hif-2α, was substantially enhanced with integrin α6β4 signaling. Hif-1α knockdown by shRNA or chemical inhibition decreased PTPRZ1 expression, while chemical activation of Hif-1α increased it. Upstream of Hif-1α, integrin α6β4 upregulates UCHL1 to stabilize Hif-1α and ultimately regulate PTPRZ1. Inhibition of UCHL1 and PTPRZ1 dramatically decreases integrin α6β4-mediated cell migration and three-dimensional invasive growth. Finally, public breast cancer database analyses demonstrated that ITGB4 correlates with PTPRZ1 and that high expression of ITGB4, UCHL1, HIF1A, and PTPRZ1 associated with decreased overall survival, distant metastasis free survival, post progression survival, and relapse-free survival. In summary, these findings provide a novel function of integrin α6β4 in promoting tumor invasive phenotypes through UCHL1-Hif-1α-mediated regulation of PTPRZ1. [ABSTRACT FROM AUTHOR]

The response of Hypoxia Inducible Gene Domain (HIGD) proteins to hypoxia plays a crucial role in plant development. However, the research on this gene family in soybean has been lacking. In this study, we aimed to identify and comprehensively analyze soybean HIGD genes using the Glycine max genome database. As a result, six GmHIGD genes were successfully identified, and their phylogeny, gene structures, and putative conserved motifs were analyzed in comparison to Arabidopsis and rice. Collinearity analysis indicated that the HIGD gene family in soybean has expanded to some extent when compared to Arabidopsis. Additionally, the cis-elements in the promoter regions of GmHIGD and the transcription factors potentially binding to these regions were identified. All GmHIGD genes showed specific responsiveness to submergence and hypoxic stresses. Expression profiling through quantitative real-time PCR revealed that these genes were significantly induced by PEG treatment in root tissue. Coexpressed genes of GmHIGD were primarily associated with oxidoreductase and dioxygenase activities, as well as peroxisome function. Notably, one of GmHIGD genes, GmHIGD3 was found to be predominantly localized in mitochondria, and its overexpression in Arabidopsis led to a significantly reduction in catalase activity compared to wild-type plants. These results bring new insights into the functional role of GmHIGD in terms of subcellular localization and the regulation of oxidoreductase activity. [ABSTRACT FROM AUTHOR]

Host-guest drug delivery systems (HGDDSs) provided a facile method for incorporating biomedical functions, including efficient drug-loading, passive targeting, and controlled drug release. However, developing HGDDSs with active targeting is hindered by the difficult functionalization of popular macrocycles. Herein, we report an active targeting HGDDS based on biotin-modified sulfonated azocalix[4]arene (Biotin-SAC4A) to efficiently deliver drug into cancer cells for improving anti-tumor effect. Biotin-SAC4A was synthesized by amide condensation and azo coupling. Biotin-SAC4A demonstrated hypoxia responsive targeting and active targeting through azo and biotin groups, respectively. DOX@Biotin-SAC4A, which was prepared by loading doxorubicin (DOX) in Biotin-SAC4A, was evaluated for tumor targeting and therapy in vitro and in vivo. DOX@Biotin-SAC4A formulation effectively killed cancer cells in vitro and more efficiently delivered DOX to the lesion than the similar formulation without active targeting. Therefore, DOX@Biotin-SAC4A significantly improved the in vivo anti-tumor effect of free DOX. The facilely prepared Biotin-SAC4A offers strong DOX complexation, active targeting, and hypoxia-triggered release, providing a favorable host for effective breast cancer chemotherapy in HGDDSs. Moreover, Biotin-SAC4A also has potential to deliver agents for other therapeutic modalities and diseases. [Display omitted] • Host-guest drug delivery systems (HGDDSs) offer efficient drug-loading, passive targeting, and controlled drug release • Active targeting in HGDDSs is challenging due to difficulties in functionalizing popular macrocycles • Biotin-SAC4A, a biotin-modified sulfonated azocalix[4]arene, enables hypoxia-responsive and active targeting in HGDDSs • DOX@Biotin-SAC4A shows improved tumor targeting and anti-tumor effect in vivo compared to free DOX [ABSTRACT FROM AUTHOR]

The reduced oxygen concentration is a distinctive feature of osteoarthritic (OA) cartilage, whereas the mechanical friction also contributes to the inflammatory hypoxia microenvironment of OA. Herein, novel hypoxia-responsive methylprednisolone (MP) delivery microgels combining the capability of reactive oxygen species (ROS)-depletion and lubrication were constructed for regulating the microenvironment of OA. Methacrylate-modified sulfonated azocalix[4] arene (MACA) loaded with MP, the copolymers consisting of bioinspired lubricant 2-methacryloxyethyl phosphorylcholine (MPC), and polyethylene glycol-modified ROS-responsive poly(thioketal) (PEG-4PTK) were crosslinked together to construct the microgels. The zwitterionic MPC offered a lubrication effect, while the ROS-elimination was contributed by the PTK segments and the phenol groups in MACA. The microgels responsively released cargos in inflammatory environment and decreased inflammation by inhibiting the production of ROS and regulating the expression of inflammatory cytokines, and showed the lowest hypoxia-inducible factor-1α (HIF-1α) positive area and presented more deposition of glycosaminoglycans and collagen II with a smoother and integrated cartilage structure in therapy of OA in rats in vivo. [Display omitted] ● Stimuli-responsive microgels deliver anti-inflammatory and immunomodulator in response to hypoxia. ● The microgels have very low viscosity and can be precisely delivered with the clinical convenience. ● The microgels dissipate stress, and sensitively respond to the physiological stimuli of inflammatory factors, ROS and hypoxia. ● The microgels improve intra-articular lubrication and ROS-elimination to adaptively regulate the inflammation of OA. [ABSTRACT FROM AUTHOR]

The response of Hypoxia Inducible Gene Domain (HIGD) proteins to hypoxia plays a crucial role in plant development. However, the research on this gene family in soybean has been lacking. In this study, we aimed to identify and comprehensively analyze soybean HIGD genes using the Glycine max genome database. As a result, six GmHIGD genes were successfully identified, and their phylogeny, gene structures, and putative conserved motifs were analyzed in comparison to Arabidopsis and rice. Collinearity analysis indicated that the HIGD gene family in soybean has expanded to some extent when compared to Arabidopsis . Additionally, the cis-elements in the promoter regions of GmHIGD and the transcription factors potentially binding to these regions were identified. All GmHIGD genes showed specific responsiveness to submergence and hypoxic stresses. Expression profiling through quantitative real-time PCR revealed that these genes were significantly induced by PEG treatment in root tissue. Co-expressed genes of GmHIGD were primarily associated with oxidoreductase and dioxygenase activities, as well as peroxisome function. Notably, one of GmHIGD genes, GmHIGD3 was found to be predominantly localized in mitochondria, and its overexpression in Arabidopsis led to a significantly reduction in catalase activity compared to wild-type plants. These results bring new insights into the functional role of GmHIGD in terms of subcellular localization and the regulation of oxidoreductase activity., 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 © 2024 Geng, Dong, Zhu, Yang, Zhang, Guo, Chen, Zhang and Song.)

The occurrence of osteoarthritis (OA) is highly associated with the inflammatory hypoxic microenvironment. Yet currently no attention has been paid to fabricating hypoxia-responsive platforms for OA treatment. Herein, an injectable hydrogel microsphere system (HAM-SA@HCQ) focusing on the hypoxic inflamed joint is prepared with methacrylate-modified sulfonated azocalix[4]arene (SAC4A-MA), methacrylated hyaluronic acid (HA-MA), and dithiol-terminated matrix metalloproteinase 13 (MMP-13) sensitive peptide via a microfluidic device and photo crosslinking technique, followed by encapsulation of the anti-inflammatory drug hydroxychloroquine (HCQ) through host-guest interaction. Owing to the hydrophobic deep cavity, phenolic units, and azo bonds of SAC4A-MA, the hydrogel microspheres show strong drug loading capacity, prominent reactive oxygen species (ROS) scavenging capability, and specific hypoxia-responsive drug release ability. In the OA tissue microenvironment, the hydrogel microspheres undergo degradation by excessive MMP-13 and release HCQ under the hypoxia condition, which synergizes with the ROS-scavenging calixarene to inhibit the inflammatory response of macrophages. After being injected into the OA-inflamed joint, the HAM-SA@HCQ can significantly attenuate the oxidative stress, downregulate the expression of hypoxia-induced factor-1α and inflammatory cytokines, and prevent the cartilage from being destroyed., (© 2023 Wiley‐VCH GmbH.)

Water-soluble inorganic ions (WSIIs, primarily NH 4 + , SO 4 2- , and NO 3 - ) are major components in ambient PM 2.5 , but their reproductive toxicity remains largely unknown. An animal study was conducted where parental mice were exposed to PM 2.5 WSIIs or clean air during preconception and the gestational period. After delivery, all maternal and offspring mice lived in a clean air environment. We assessed reproductive organs, gestation outcome, birth weight, and growth trajectory of the offspring mice. In parallel, we collected birth weight and placenta transcriptome data from 150 mother-infant pairs from the Rhode Island Child Health Study. We found that PM 2.5 WSIIs induced a broad range of adverse reproductive outcomes in mice. PM 2.5 NH 4 + , SO 4 2- , and NO 3 - exposure reduced ovary weight by 24.22% (p = 0.005), 14.45% (p = 0.048), and 16.64% (p = 0.022) relative to the clean air controls. PM 2.5 SO 4 exposure all led to lower birth than controls. In mice, 557 placenta genes were perturbed by exposure. Integrative analysis of mouse and human data suggested hypoxia response in placenta as an etiological mechanism underlying PM 2- exposure reduced the weight of testicle by 5.24% (p = 0.025); further, mice in the PM 2.5 SO 4 2- exposure group had 1.81 (p = 0.027) fewer offspring than the control group. PM 2.5 NH 4 + , SO 4 2- , and NO 3 - exposure all led to lower birth than controls. In mice, 557 placenta genes were perturbed by exposure. Integrative analysis of mouse and human data suggested hypoxia response in placenta as an etiological mechanism underlying PM 2.5 WSII exposure's reproductive toxicity.

Tissue transglutaminase (TG2) is a widely distributed multifunctional protein involved in a broad range of cellular and metabolic functions carried out in a variety of cellular compartments. In addition to transamidation, TG2 also functions as a Gα signaling protein, a protein disulfide isomerase (PDI), a protein kinase, and a scaffolding protein. In the nucleus, TG2 modifies histones and transcription factors. The PDI function catalyzes the trimerization and activation of heat shock factor-1 in the nucleus and regulates the oxidation state of several mitochondrial complexes. Cytosolic TG2 modifies proteins by the addition of serotonin or other primary amines and in this way affects cell signaling. Modification of protein-bound glutamines reduces ubiquitin-dependent proteasomal degradation. At the cell membrane, TG2 is associated with G protein-coupled receptors (GPCRs), where it functions in transmembrane signaling. TG2 is also found in the extracellular space, where it functions in protein cross-linking and extracellular matrix stabilization. Of particular importance in transglutaminase research are recent findings concerning the role of TG2 in gene expression, protein homeostasis, cell signaling, autoimmunity, inflammation, and hypoxia. Thus, TG2 performs a multitude of functions in multiple cellular compartments, making it one of the most versatile cellular proteins. Additional evidence links TG2 with multiple human diseases including preeclampsia, hypertension, cardiovascular disease, organ fibrosis, cancer, neurodegenerative diseases, and celiac disease. In conclusion, TG2 provides a multifunctional and multisite response to physiological stress.