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Cell Reports. Medicine Jun 2023Single-cell transcriptomics can provide quantitative molecular signatures for large, unbiased samples of the diverse cell types in the brain. With the advances of...
Single-cell transcriptomics can provide quantitative molecular signatures for large, unbiased samples of the diverse cell types in the brain. With the advances of multi-omics datasets, a major challenge is to validate and integrate results into a biological understanding of spatial organization and functional orientation. Here, we generate spatial transcriptomes and metabolites from six patients with brain trauma with surgical samples. The resulting spatial marker gene, which is highly replicable across analysis methods, sequencing technologies, and modalities, is a comprehensive molecular marker of the diverse metabolic changes in human injured brains. The atlas includes an area of lipid peroxidation that resembles injured neurons in the brain. We further discover imbalanced myo-inositol and myo-inositol phosphate and related spatial markers. Our results highlight the complex transcriptomic regulation and metabolic alterations in the injured brain and will directly enable the design of reagents to target specific genes in the human brain for functional analysis.
Topics: Humans; Transcriptome; Gene Expression Profiling; Brain
PubMed: 37263268
DOI: 10.1016/j.xcrm.2023.101057 -
International Journal of Biological... 2023Cancer is a multi-step disease caused by the accumulation of genetic mutations and/or epigenetic changes, and is the biggest challenge around the world. Cytokines,... (Review)
Review
Cancer is a multi-step disease caused by the accumulation of genetic mutations and/or epigenetic changes, and is the biggest challenge around the world. Cytokines, including chemokines, exhibit expression changes and disorders in all human cancers. These cytokine abnormalities can disrupt homeostasis and immune function, and make outstanding contributions to various stages of cancer development such as invasion, metastasis, and angiogenesis. Chemokines are a superfamily of small molecule chemoattractive cytokines that mediate a variety of cellular functions. Importantly, the interactions of chemokine members CXCL12 and its receptors CXCR4 and CXCR7 have a broad impact on tumor cell proliferation, survival, angiogenesis, metastasis, and tumor microenvironment, and thus participate in the onset and development of many cancers including leukemia, breast cancer, lung cancer, prostate cancer and multiple myeloma. Therefore, this review aims to summarize the latest research progress and future challenges regarding the role of CXCL12-CXCR4/CXCR7 signaling axis in cancer, and highlights the potential of CXCL12-CXCR4/CXCR7 as a biomarker or therapeutic target for cancer, providing essential strategies for the development of novel targeted cancer therapies.
Topics: Humans; Breast Neoplasms; Chemokine CXCL12; Chemotaxis; Lung Neoplasms; Prostatic Neoplasms; Receptors, CXCR4; Signal Transduction; Tumor Microenvironment
PubMed: 37497001
DOI: 10.7150/ijbs.82317 -
Nature Nov 2023Inflammation is a hallmark of cancer. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with...
Inflammation is a hallmark of cancer. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with shorter survival and treatment resistance across malignancies and therapeutic modalities. Whether myeloid inflammation drives progression of prostate cancer in humans remain unclear. Here we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of patients with metastatic castration-resistant prostate cancer (CRPC). We show that a higher blood neutrophil-to-lymphocyte ratio reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species, including those that encode myeloid-chemoattracting CXCR2 ligands. To determine whether myeloid cells fuel resistance to androgen receptor signalling inhibitors, and whether inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with metastatic CRPC that is resistant to androgen receptor signalling inhibitors. This combination was well tolerated without dose-limiting toxicity and it decreased circulating neutrophil levels, reduced intratumour CD11bHLA-DRCD15CD14 myeloid cell infiltration and imparted durable clinical benefit with biochemical and radiological responses in a subset of patients with metastatic CRPC. This study provides clinical evidence that senescence-associated myeloid inflammation can fuel metastatic CRPC progression and resistance to androgen receptor blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.
Topics: Humans; Male; Chemotaxis; Disease Progression; Drug Resistance, Neoplasm; Inflammation; Lewis X Antigen; Myeloid Cells; Neoplasm Metastasis; Prostate; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Androgen Receptor Antagonists; Antineoplastic Agents
PubMed: 37844613
DOI: 10.1038/s41586-023-06696-z -
Theranostics 2023Liver ischemia-reperfusion (LI/R) injury is characterized by two interconnected phases: local ischemia that causes hepatic cell damage to release damage-associated...
Hepatocyte HSPA12A inhibits macrophage chemotaxis and activation to attenuate liver ischemia/reperfusion injury via suppressing glycolysis-mediated HMGB1 lactylation and secretion of hepatocytes.
Liver ischemia-reperfusion (LI/R) injury is characterized by two interconnected phases: local ischemia that causes hepatic cell damage to release damage-associated molecular pattern (DAMPs), and DAMPs that recruit immune cells to elicit inflammatory cascade for further injury of hepatocytes. High-mobility group box 1 (HMGB1) is a representative DAMP. Studies in macrophages demonstrated that HMGB1 is secreted after lactylation during sepsis. However, whether lactylation mediates HMGB1 secretion from hepatocytes after LI/R is known. Heat shock protein A12A (HSPA12A) is an atypical member of HSP70 family. Gene expression was examined by microarray analysis and immunoblotting. The hepatic injury was analyzed using released ALT and AST activities assays. Hepatic macrophage chemotaxis was evaluated by Transwell chemotaxis assays. Inflammatory mediators were evaluated by immunoblotting. HMGB1 secretion was examined in exosomes or serum. HMGB1 lactylation was determined using immunoprecipitation and immunoblotting. Here, we report that LI/R decreased HSPA12A expression in hepatocytes, while hepatocyte-specific HSPA12A overexpression attenuated LI/R-induced hepatic dysfunction and mortality of mice. We also noticed that hepatocyte HSPA12A overexpression suppressed macrophage chemotaxis to LI/R-exposed livers and to hypoxia/reoxygenation (H/R)-exposed hepatocytes . The LI/R-increased serum HMGB1 levels of mice and the H/R-increased HMGB1 lactylation and secretion levels of hepatocytes were also inhibited by hepatocyte HSPA12A overexpression. By contrast, HSPA12A knockout in hepatocytes promoted not only H/R-induced HMGB1 lactylation and secretion of hepatocytes but also the effects of H/R-hepatocytes on macrophage chemotaxis and inflammatory activation, while all these deleterious effects of HSPA12A knockout were reversed following hepatocyte HMGB1 knockdown. Further molecular analyses showed that HSPA12A overexpression reduced glycolysis-generated lactate, thus decreasing HMGB1 lactylation and secretion from hepatocytes, thereby inhibiting not only macrophage chemotaxis but also the subsequent inflammatory cascade, which ultimately protecting against LI/R injury. Taken together, these findings suggest that hepatocyte HSPA12A is a novel regulator that protects livers from LI/R injury by suppressing glycolysis-mediated HMGB1 lactylation and secretion from hepatocytes to inhibit macrophage chemotaxis and inflammatory activation. Therefore, targeting hepatocyte HSPA12A may have therapeutic potential in the management of LI/R injury in patients.
Topics: Animals; Mice; Heat-Shock Proteins; HMGB1 Protein; Chemotaxis; Liver; Hepatocytes; Liver Diseases; Macrophages; Glycolysis; Reperfusion Injury; Mice, Inbred C57BL
PubMed: 37441587
DOI: 10.7150/thno.82607 -
Nature Aging Oct 2023In Alzheimer's disease (AD), sensome receptor dysfunction impairs microglial danger-associated molecular pattern (DAMP) clearance and exacerbates disease pathology....
In Alzheimer's disease (AD), sensome receptor dysfunction impairs microglial danger-associated molecular pattern (DAMP) clearance and exacerbates disease pathology. Although extrinsic signals, including interleukin-33 (IL-33), can restore microglial DAMP clearance, it remains largely unclear how the sensome receptor is regulated and interacts with DAMP during phagocytic clearance. Here, we show that IL-33 induces VCAM1 in microglia, which promotes microglial chemotaxis toward amyloid-beta (Aβ) plaque-associated ApoE, and leads to Aβ clearance. We show that IL-33 stimulates a chemotactic state in microglia, characterized by Aβ-directed migration. Functional screening identified that VCAM1 directs microglial Aβ chemotaxis by sensing Aβ plaque-associated ApoE. Moreover, we found that disrupting VCAM1-ApoE interaction abolishes microglial Aβ chemotaxis, resulting in decreased microglial clearance of Aβ. In patients with AD, higher cerebrospinal fluid levels of soluble VCAM1 were correlated with impaired microglial Aβ chemotaxis. Together, our findings demonstrate that promoting VCAM1-ApoE-dependent microglial functions ameliorates AD pathology.
Topics: Humans; Alzheimer Disease; Microglia; Interleukin-33; Chemotaxis; Amyloid beta-Peptides; Apolipoproteins E
PubMed: 37735240
DOI: 10.1038/s43587-023-00491-1 -
Journal of Vision Jul 2023To investigate the mechanisms underlying elongated spatial summation with a pattern-masking paradigm, we measured the contrast detection thresholds for elongated Gabor...
To investigate the mechanisms underlying elongated spatial summation with a pattern-masking paradigm, we measured the contrast detection thresholds for elongated Gabor targets situated at 3° eccentricity to either the left or right of the fixation and elongated along an arc of the same radius to access homogeneous retinal sensitivity. The mask was a ring with a Gabor envelope of the same 3° center radius containing either a concentric (iso-orientation mask) or a radial (orthogonal mask) modulation. The task of the observer was to indicate whether the target in each trial was on the left or the right of the fixation. With orthogonal or low contrast iso-orientation masks, target thresholds first decreased with size with slope -1 on log-log coordinates until the target length reached 45' (specified as the half-height full-width of the Gabor envelope) and then further decreased according to a slope of -1/2, the latter being the signature of an ideal summation process. When the contrast of the iso-orientation mask was sufficiently high, however, the target thresholds, while still showing a -1 slope up to ∼10', asymptoted up to about 50' length, suggesting that the presence of the mask eliminated the ideal summation regime. Beyond about 50', the data approximated another -1 slope decrease in threshold, suggesting the existence of an extra-long channel that is not revealed by the conventional spatial summation paradigm. The full results could be explained by a divisive inhibition model, in which second-order filters sum responses across local oriented channels, combined with a single extra-long filter at least 300' in extent. In this model, the local filter response is given by the linear excitation of the local channels raised to a power, and scaled by divisive inhibition from all channels in the neighborhood. With the high-contrast iso-orientation masks, such divisive inhibition swamps the response to eliminate the ideal summation regime until the stimulus is long enough to activate the extra-long filter.
Topics: Humans; Contrast Sensitivity; Sensory Thresholds; Perceptual Masking; Inhibition, Psychological
PubMed: 37505916
DOI: 10.1167/jov.23.7.17