-
Cancer Cell Nov 2023Neoadjuvant immune checkpoint blockade (ICB) demonstrates promise in operable esophageal squamous cell carcinoma (ESCC), but lacks available efficacy biomarkers. Here,...
Neoadjuvant immune checkpoint blockade (ICB) demonstrates promise in operable esophageal squamous cell carcinoma (ESCC), but lacks available efficacy biomarkers. Here, we perform single-cell RNA-sequencing of tumors from patients with ESCC undergoing neoadjuvant ICB, revealing a subset of exhausted CD8 T cells expressing SPRY1 (CD8 Tex-SPRY1) that displays a progenitor exhausted T cell (Tpex) phenotype and correlates with complete response to ICB. We validate CD8 Tex-SPRY1 cells as an ICB-specific predictor of improved response and survival using independent ICB-/non-ICB cohorts and demonstrate that expression of SPRY1 in CD8 T cells enforces Tpex phenotype and enhances ICB efficacy. Additionally, CD8 Tex-SPRY1 cells contribute to proinflammatory phenotype of macrophages and functional state of B cells, which thereby promotes antitumor immunity by enhancing CD8 T cell effector functions. Overall, our findings unravel progenitor-like CD8 Tex-SPRY1 cells' role in effective responses to ICB for ESCC and inform mechanistic biomarkers for future individualized immunotherapy.
Topics: Humans; Esophageal Squamous Cell Carcinoma; CD8-Positive T-Lymphocytes; Programmed Cell Death 1 Receptor; Esophageal Neoplasms; Neoadjuvant Therapy; Biomarkers; Tumor Microenvironment; Membrane Proteins; Phosphoproteins
PubMed: 37832554
DOI: 10.1016/j.ccell.2023.09.011 -
Military Medical Research Aug 2023The treatment of chronic and non-healing wounds in diabetic patients remains a major medical problem. Recent reports have shown that hydrogel wound dressings might be an... (Review)
Review
The treatment of chronic and non-healing wounds in diabetic patients remains a major medical problem. Recent reports have shown that hydrogel wound dressings might be an effective strategy for treating diabetic wounds due to their excellent hydrophilicity, good drug-loading ability and sustained drug release properties. As a typical example, hyaluronic acid dressing (Healoderm) has been demonstrated in clinical trials to improve wound-healing efficiency and healing rates for diabetic foot ulcers. However, the drug release and degradation behavior of clinically-used hydrogel wound dressings cannot be adjusted according to the wound microenvironment. Due to the intricacy of diabetic wounds, antibiotics and other medications are frequently combined with hydrogel dressings in clinical practice, although these medications are easily hindered by the hostile environment. In this case, scientists have created responsive-hydrogel dressings based on the microenvironment features of diabetic wounds (such as high glucose and low pH) or combined with external stimuli (such as light or magnetic field) to achieve controllable drug release, gel degradation, and microenvironment improvements in order to overcome these clinical issues. These responsive-hydrogel dressings are anticipated to play a significant role in diabetic therapeutic wound dressings. Here, we review recent advances on responsive-hydrogel dressings towards diabetic wound healing, with focus on hydrogel structure design, the principle of responsiveness, and the behavior of degradation. Last but not least, the advantages and limitations of these responsive-hydrogels in clinical applications will also be discussed. We hope that this review will contribute to furthering progress on hydrogels as an improved dressing for diabetic wound healing and practical clinical application.
Topics: Humans; Hydrogels; Anti-Bacterial Agents; Bandages; Physicians; Diabetes Mellitus
PubMed: 37608335
DOI: 10.1186/s40779-023-00473-9 -
Molecular Plant Nov 2023Phosphorus is an essential macronutrient for plant development and metabolism, and plants have evolved ingenious mechanisms to overcome phosphate (Pi) starvation....
Phosphorus is an essential macronutrient for plant development and metabolism, and plants have evolved ingenious mechanisms to overcome phosphate (Pi) starvation. However, the molecular mechanisms underlying the regulation of shoot and root architecture by low phosphorus conditions and the coordinated utilization of Pi and nitrogen remain largely unclear. Here, we show that Nodulation Signaling Pathway 1 (NSP1) and NSP2 regulate rice tiller number by promoting the biosynthesis of strigolactones (SLs), a class of phytohormones with fundamental effects on plant architecture and environmental responses. We found that NSP1 and NSP2 are induced by Oryza sativa PHOSPHATE STARVATION RESPONSE2 (OsPHR2) in response to low-Pi stress and form a complex to directly bind the promoters of SL biosynthesis genes, thus markedly increasing SL biosynthesis in rice. Interestingly, the NSP1/2-SL signaling module represses the expression of CROWN ROOTLESS 1 (CRL1), a newly identified early SL-responsive gene in roots, to restrain lateral root density under Pi deficiency. We also demonstrated that GR24 treatment under normal conditions inhibits the expression of OsNRTs and OsAMTs to suppress nitrogen absorption but enhances the expression of OsPTs to promote Pi absorption, thus facilitating the balance between nitrogen and phosphorus uptake in rice. Importantly, we found that NSP1p:NSP1 and NSP2p:NSP2 transgenic plants show improved agronomic traits and grain yield under low- and medium-phosphorus conditions. Taken together, these results revealed a novel regulatory mechanism of SL biosynthesis and signaling in response to Pi starvation, providing genetic resources for improving plant architecture and nutrient-use efficiency in low-Pi environments.
Topics: Oryza; Lactones; Phosphorus; Phosphates; Signal Transduction; Nitrogen; Plant Roots; Gene Expression Regulation, Plant; Plant Proteins
PubMed: 37794682
DOI: 10.1016/j.molp.2023.09.022 -
Science Advances Sep 2023Pattern recognition receptor-mediated innate immunity is critical for host defense against viruses. A growing number of coding and noncoding genes are found to encode...
Pattern recognition receptor-mediated innate immunity is critical for host defense against viruses. A growing number of coding and noncoding genes are found to encode microproteins. However, the landscape and functions of microproteins in responsive to virus infection remain uncharacterized. Here, we systematically identified microproteins that are responsive to vesicular stomatitis virus infection. A conserved and endoplasmic reticulum-localized membrane microprotein, MAVI1 (microprotein in antiviral immunity 1), was found to interact with mitochondrion-localized MAVS protein and inhibit MAVS aggregation and type I interferon signaling activation. The importance of MAVI1 was highlighted that viral infection was attenuated and survival rate was increased in knockout mice. A peptide inhibitor targeting the interaction between MAVI1 and MAVS activated the type I interferon signaling to defend viral infection. Our findings uncovered that microproteins play critical roles in regulating antiviral innate immune responses, and targeting microproteins might represent a therapeutic avenue for treating viral infection.
Topics: Animals; Mice; Immunity, Innate; Antiviral Agents; Endoplasmic Reticulum; Mice, Knockout; Mitochondria; Interferon Type I; Micropeptides
PubMed: 37656786
DOI: 10.1126/sciadv.adg7053 -
Biomolecules Jul 2023Aging attenuates the overall responsiveness of the immune system to eradicate pathogens. The increased production of pro-inflammatory cytokines by innate immune cells... (Review)
Review
Aging attenuates the overall responsiveness of the immune system to eradicate pathogens. The increased production of pro-inflammatory cytokines by innate immune cells under basal conditions, termed inflammaging, contributes to impaired innate immune responsiveness towards pathogen-mediated stimulation and limits antigen-presenting activity. Adaptive immune responses are attenuated as well due to lowered numbers of naïve lymphocytes and their impaired responsiveness towards antigen-specific stimulation. Additionally, the numbers of immunoregulatory cell types, comprising regulatory T cells and myeloid-derived suppressor cells, that inhibit the activity of innate and adaptive immune cells are elevated. This review aims to summarize our knowledge on the cellular and molecular causes of immunosenescence while also taking into account senescence effects that constitute immune evasion mechanisms in the case of chronic viral infections and cancer. For tumor therapy numerous nanoformulated drugs have been developed to overcome poor solubility of compounds and to enable cell-directed delivery in order to restore immune functions, e.g., by addressing dysregulated signaling pathways. Further, nanovaccines which efficiently address antigen-presenting cells to mount sustained anti-tumor immune responses have been clinically evaluated. Further, senolytics that selectively deplete senescent cells are being tested in a number of clinical trials. Here we discuss the potential use of such drugs to improve anti-aging therapy.
Topics: Humans; Immunosenescence; Inflammation; Aging; Cytokines; Immune System
PubMed: 37509121
DOI: 10.3390/biom13071085 -
Nature May 2024Cancer-specific TCF1 stem-like CD8 T cells can drive protective anticancer immunity through expansion and effector cell differentiation; however, this response is...
Cancer-specific TCF1 stem-like CD8 T cells can drive protective anticancer immunity through expansion and effector cell differentiation; however, this response is dysfunctional in tumours. Current cancer immunotherapies can promote anticancer responses through TCF1 stem-like CD8 T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1CD8 T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE) restricts the proliferative expansion and effector differentiation of TCF1CD8 T cells within tumours, which promotes cancer immune escape. PGE does not affect the priming of TCF1CD8 T cells in draining lymph nodes. PGE acts through EP and EP (EP/EP) receptor signalling in CD8 T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1 tumour-infiltrating CD8 T lymphocytes (TILs). Ablation of EP/EP signalling in cancer-specific CD8 T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE-mediated inhibition of TCF1 TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1 TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE-EP/EP axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.
Topics: Animals; Female; Humans; Male; Mice; CD8-Positive T-Lymphocytes; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Dinoprostone; Disease Models, Animal; Hepatocyte Nuclear Factor 1-alpha; Interleukin-2; Lymph Nodes; Lymphocytes, Tumor-Infiltrating; Mice, Inbred C57BL; Neoplasms; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Signal Transduction; Stem Cells; Tumor Escape
PubMed: 38658748
DOI: 10.1038/s41586-024-07254-x -
The Journal of Clinical Investigation Dec 2023Itaconate has emerged as a critical immunoregulatory metabolite. Here, we examined the therapeutic potential of itaconate in atherosclerosis. We found that both...
Itaconate has emerged as a critical immunoregulatory metabolite. Here, we examined the therapeutic potential of itaconate in atherosclerosis. We found that both itaconate and the enzyme that synthesizes it, aconitate decarboxylase 1 (Acod1, also known as immune-responsive gene 1 [IRG1]), are upregulated during atherogenesis in mice. Deletion of Acod1 in myeloid cells exacerbated inflammation and atherosclerosis in vivo and resulted in an elevated frequency of a specific subset of M1-polarized proinflammatory macrophages in the atherosclerotic aorta. Importantly, Acod1 levels were inversely correlated with clinical occlusion in atherosclerotic human aorta specimens. Treating mice with the itaconate derivative 4-octyl itaconate attenuated inflammation and atherosclerosis induced by high cholesterol. Mechanistically, we found that the antioxidant transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), was required for itaconate to suppress macrophage activation induced by oxidized lipids in vitro and to decrease atherosclerotic lesion areas in vivo. Overall, our work shows that itaconate suppresses atherogenesis by inducing Nrf2-dependent inhibition of proinflammatory responses in macrophages. Activation of the itaconate pathway may represent an important approach to treat atherosclerosis.
Topics: Mice; Humans; Animals; NF-E2-Related Factor 2; Macrophages; Atherosclerosis; Inflammation; Aortic Diseases; Succinates
PubMed: 38085578
DOI: 10.1172/JCI173034 -
World Journal of Cardiology Apr 2024Hypoxia-inducible factor 1 (HIF1) has a crucial function in the regulation of oxygen levels in mammalian cells, especially under hypoxic conditions. Its importance in...
Hypoxia-inducible factor 1 (HIF1) has a crucial function in the regulation of oxygen levels in mammalian cells, especially under hypoxic conditions. Its importance in cardiovascular diseases, particularly in cardiac ischemia, is because of its ability to alleviate cardiac dysfunction. The oxygen-responsive subunit, HIF1α, plays a crucial role in this process, as it has been shown to have cardioprotective effects in myocardial infarction through regulating the expression of genes affecting cellular survival, angiogenesis, and metabolism. Furthermore, expression induced reperfusion in the ischemic skeletal muscle, and hypoxic skin wounds in diabetic animal models showed reduced expression. Increased expression of has been shown to reduce apoptosis and oxidative stress in cardiomyocytes during acute myocardial infarction. Genetic variations in have also been found to correlate with altered responses to ischemic cardiovascular disease. In addition, a link has been established between the circadian rhythm and hypoxic molecular signaling pathways, with HIF1α functioning as an oxygen sensor and circadian genes such as period circadian regulator 2 responding to changes in light. This editorial analyzes the relationship between HIF1α and the circadian rhythm and highlights its significance in myocardial adaptation to hypoxia. Understanding the changes in molecular signaling pathways associated with diseases, specifically cardiovascular diseases, provides the opportunity for innovative therapeutic interventions, especially in low-oxygen environments such as myocardial infarction.
PubMed: 38690212
DOI: 10.4330/wjc.v16.i4.181 -
Gels (Basel, Switzerland) Oct 2023Proteins and peptides are potential therapeutic agents, but their physiochemical properties make their use as drug substances challenging. Hydrogels are hydrophilic... (Review)
Review
Proteins and peptides are potential therapeutic agents, but their physiochemical properties make their use as drug substances challenging. Hydrogels are hydrophilic polymeric networks that can swell and retain high amounts of water or biological fluids without being dissolved. Due to their biocompatibility, their porous structure, which enables the transport of various peptides and proteins, and their protective effect against degradation, hydrogels have gained prominence as ideal carriers for these molecules' delivery. Particularly, stimuli-responsive hydrogels exhibit physicochemical transitions in response to subtle modifications in the surrounding environment, leading to the controlled release of entrapped proteins or peptides. This review is focused on the application of these hydrogels in protein and peptide delivery, including a brief overview of therapeutic proteins and types of stimuli-responsive polymers.
PubMed: 37888375
DOI: 10.3390/gels9100802 -
Beilstein Journal of Organic Chemistry 2024Switchable molecular tweezers are a unique class of molecular switches that, like their macroscopic analogs, exhibit mechanical motion between an open and closed... (Review)
Review
Switchable molecular tweezers are a unique class of molecular switches that, like their macroscopic analogs, exhibit mechanical motion between an open and closed conformation in response to stimuli. Such systems constitute an essential component of artificial molecular machines. This review will present selected examples of switchable molecular tweezers and their potential applications. The first part will be devoted to chemically responsive tweezers, including stimuli such as pH, metal coordination, and anion binding. Then, redox-active and photochemical tweezers will be presented.
PubMed: 38440175
DOI: 10.3762/bjoc.20.45