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At least 1,063 records · Page 59Linked to original sources
PubMed1997

Macrophage colony-stimulating factor gene transduction into human lung cancer cells differentially regulates metastasis formations in various organ microenvironments of natural killer cell-depleted SCID mice.

We investigated whether local production of macrophage colony-stimulating factor (M-CSF), responsible for migration and activation of monocytes/macrophages at a tumor growth site, affected the metastatic pattern of lung cancer. For this, highly metastatic human squamous (RERF-LC-AI) or small (H69/VP) cell lung carcinoma cells were transduced with the human M-CSF gene inserted into pRc/CMV-MCSF to establish M-CSF-producing clones (MCSF-AI-9-18, MCSF-AI-9-24, and MCSF-VP-5). M-CSF gene transduction had no effect on the expression of surface antigen or on in vitro proliferation. After s.c. injection into SCID mice, the growth rates of M-CSF-producing cells were slower than those of parent or mock-transduced cells. In the metastatic model in SCID mice depleted of natural killer cells, RERF-LC-AI cells formed metastases mainly in the liver and kidneys, whereas H69/VP cells metastasized mainly to the liver and systemic lymph nodes. The numbers of metastatic colonies of MCSF-AI-9-18 and MCSF-AI-9-24 cells in the liver but not the kidneys were significantly reduced. The development of lymph node metastases of MCSF-VP-5 cells was also less than that of parent or mock-transduced cells. Treatment of SCID mice with anti-human M-CSF antibody resulted in a significant increase in liver metastases of their M-CSF gene transfectants. No significant differences were observed in the distributions in mice or in the in vitro invasive potentials of MCSF-AI-9-18 cells and Neo-AI-3 cells. These findings indicate that the antimetastatic effect of M-CSF may be specific to particular organs, suggesting the influence of heterogeneity of organ microenvironments on the metastasis of lung cancer.

Animals↗
PubMedDate not supplied

Dendritic type, accessory cells within the mammalian thymic microenvironment. Antigen presentation in the dendritic neuro-endocrine-immune cellular network.

During mammalian ontogenesis, the thymic "pure" endodermal epithelial anlage develops and differentiates into a complex cellular microenvironment. Beginning the 7-8th week of intrauterine development, thymic epithelial cells chemotactically regulate (induce) numerous waves of migration of stem cells into the thymus, including the CD34+, yolk sac-derived, committed hematopoietic stem cells. In vitro experiments have established that CD34+ CD38dim human thymocytes differentiate into T lymphocytes when co-cultured with mouse fetal thymic organs. Hematopoietic stem cells for myeloid and thymic stromal dendritic cells (DCs) are present within the minute population of CD34+ progenitors within the mammalian thymus. The common myeloid, DC, natural killer (NK) and T lymphocyte progenitors have also been identified within the CD34+ stem cell population in the human thymus. Interactions between the endocrine and immune systems have been reported in various regions of the mammalian body including the anterior pituitary (AP), the skin, and the central (thymus) and peripheral lymphatic system. The network of bone marrow derived DCs is a part of the reticuloendothelial system (RES) and DCs represent the cellular mediators of these regulatory endocrine-immune interactions. Folliculo-stellate cells (FSC) in the AP, Langerhans cells (LCs) in the skin and lymphatic system, "veiled" cells, lympho-dendritic and interdigitating cells (IDCs) in a number of tissues comprising the lymphatic system are the cell types of the DC meshwork of "professional" antigen presenting cells (APCs). Most of these cells express the immunocytochemical markers S-100, CD1. CD45, CD54, F418, MHC class I and II antigens, Fc and complement receptors. FSCs are non-hormone secreting cells which communicate directly with hormone producing cells, a form of neuro-endocrine-immune regulation. As a result, an attenuation of secretory responses follows stimulation of these cells. FSCs are also the cells in the AP producing interleukin-6 (IL-6), and they have also been identified as the interferon-gamma responsive elements. FSCs also express lymphatic DC markers, such as DC specific aminopeptidase, leucyl-beta-naphthylaminidase, non-specific esterase, MHC class I and II molecules and various other lymphatic immunological determinants [platelet derived growth factor-alpha chain (PDGF-alpha chain), CD13, CD14 and L25 antigen]. There is strong evidence that such DCs in the AP, and similar ones in the developing thymus and peripheral lymphatic tissue are the components of a powerful "professional" antigen presenting DC network. These APCs contain a specialized late endocytic compartment, MIIC (MHC class II-enriched compartment), that harbors newly synthesized MHC class II antigens en route to the cell membrane. The limiting membrane of MIIC can fuse directly with the cell membrane, resulting in release of newly secreted intracellular MHC class II antigen containing vesicles (exosomes). DCs possess the ability to present foreign peptides complexed with the MHC molecules expressed on their surfaces to naive and resting T cells. There are a number of "molecular couples" that influence DC and T lymphocyte interaction during antigen presentation: CD/1/CD18 integrins, intercellular adhesion molecules (ICAMs), lymphocyte function associated antigen 3 (LFA-3). CD40, CD80/B7-1, CD86/B7-2, and heat-stable antigen. The "molecular couples" are involved in adhesive or co-stimulatory regulations, mediating an effective binding of DCs to T lymphocytes and the stimulation of specific intercellular communications. DCs also provide all of the known co-stimulatory signals required for activation of unprimed T lymphocytes. It has been shown that DCs initiate several immune responses, such as the sensitization of MHC-restricted T lymphocytes, resistance to infections and neoplasms, rejection of organ transplants, and the formation of T-dependent antibodies. (ABSTRACT TRUNCATED)

Animals↗
PubMed1997

Destruction of hematopoietic microenvironment by cytotoxic T cells.

Coculture of cytotoxic T cells (STIL-3 C5) derived from L8313 leukemic mice with hematopoietic supportive stromal cells (MS-5) resulted in the detachment of MS-5 cells from the culture dish, whereas helper T cells (STIL-3 DF) did not induce this detachment. The response of bone marrow (BM) adherent cells to the same treatment was similar to that of MS-5 cells. The detached cells were unable to proliferate further, and genomic DNA of these cells showed fragmentation, suggesting that hematopoietic stromal cells died of apoptosis. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that STIL-3 C5 cells, but not STIL-3 DF cells expressed perforin, granzyme A & B, and Fas ligand. Fas was expressed in MS-5, BM adherent cells, MS-K and NIH/3T3 cells, which do not support hematopoiesis. These data suggest that the aforementioned factors mediate induction of apoptosis in MS-5 cells induced by direct cell-to-cell interaction with STIL-3 C5. This may explain the mechanism responsible for the destruction of the hematopoietic microenvironment by cytotoxic T cells in L8313 leukemia, from which STIL-3 cells are derived; it also suggests that destruction of hematopoietic tissue may be caused by leukemic cytotoxic T cells in some cases of leukemia.

Animals↗
PubMed1997

Tuberculosis generates a microenvironment enhancing the productive infection of local lymphocytes by HIV.

Tuberculosis (TB) contributes to the progression of HIV disease but, so far, the mechanism involved is not clear. Several cytokines accumulating in vivo at the site of mycobacterial infection up-regulate HIV expression in vitro. In this study, we assessed the role of pleural fluids recovered from seronegative patients with TB on HIV replication in acutely infected blast cells. Pleural fluids from subjects with congestive heart failure served as controls. In all cases, TB pleural fluids stimulated HIV replication in vitro. TNF-alpha, IL-6, IFN-gamma, and granulocyte/macrophage (GM)-CSF, as well as very low levels of IL-2, were detected in TB pleural fluids. An anti-IL-2 Ab preincubated with TB pleural fluids exhibited no blocking effect on HIV replication similarly to anti-IFN-gamma and anti-GM-CSF Abs. In contrast, anti-TNF-alpha and anti-IL-6 Abs decreased HIV replication by 60 and 90%, respectively. Recombinant TNF-alpha and IL-6 stimulated HIV replication, while IFN-gamma and GM-CSF had a more ambiguous role. The capacity of pleural fluids to stimulate HIV replication was specific for TB, since the capacity of control fluids was significantly lower. Finally, in contrast to PBL, which require in vitro activation for their productive infection by HIV, unstimulated tuberculous pleural lymphocytes were productively infectable by HIV. Taken together, our data suggest that the microenvironment generated by TB might increase the HIV burden in infected subjects, partly through cytokines other than IL-2, namely TNF-alpha and IL-6.

Bronchoalveolar Lavage Fluid↗
PubMed1998

[Colonic microenvironment in familial helicobacter infection].

To elucidate the significance of the familial microenvironment in the genesis of Helicobacter infection, a clinical and instrumental investigation was made of 13 families selected by the probands who had digestive diseases associated with H. pylori: gastroduodenitis and duodenal ulcer disease. The occurrence of Helicobacter infection and gastritis in the family members was ascertained to be largely determined by their concurrent residence in the limited area, i.e. by the way of life. The contribution of the "family" factor in antral gastritis, fundal gastritis, and H. pylori infection was 60.0, 40.0, and about 90.0%, respectively. The patients with gastroenterological abnormalities associated with H. pylori were found to show changes in the species-specific and quantitative composition of the colonic microbiocenosis, which were symptomatic and revealed by bacteriological studies in 47.5% of cases and severe in 32.5%. When antihelicobacter therapy is planned, a through treatment of all family members and, if possible, pets should be made. Colonic microbiocenosis should be monitored while treating Helicobacter infection.

Adolescent↗
PubMed1998

Mouse spermatozoa modify their motility parameters and chemotactic response to factors from the oocyte microenvironment.

The aim of this work was to evaluate the period of time required for the induction of changes in motility of mouse spermatozoa in response to factors from the microenvironment of oocytes. To determine the effects of the latency time, the period of preincubation before contact with the oocyte product(s), sperm samples were incubated for 15 or 90 min and then exposed to either Dulbecco's Modified Eagle's Medium (DMEM) or to a crude extract of superovulated oocytes (CE). The assays were performed in a Zigmond chamber by filling one compartment with either DMEM or CE, and the other compartment with the sperm suspension. A videomicroscopy system was used for tracking the spermatozoa. Sperm motility analysis was assessed using a semiautomatic objective method, and the following parameters were determined; (1) dynamic parameters: curvilinear velocity, linear velocity and linearity; (2) progressive motility: percentage of spermatozoa showing either circular or linear patterns of movement; and (3) directional motility: percentage of spermatozoa that moved towards either the DMEM or the CE. The results of this work showed that when the spermatozoa contacted soluble factors in CE after only 15 min of previous incubation, there was a significant increase in their dynamic parameters, change in their progressive motility, and induction of directional movement of the spermatozoa towards the CE components, while a longer period of preincubation did not significantly modify these effects. On the other hand, in the presence of culture medium (with or without addition of bovine serum albumin), the spermatozoa needed a more extended period of incubation to significantly increase their dynamic parameters and to modify their progressive motility, while maintaining a random direction of movement.

Animals↗
PubMed1998

Tumor microenvironment can restrict the effectiveness of activated antitumor lymphocytes.

Transgenic mice expressing the oncogene SV40 T antigen (Tag) in the insulin-producing beta cells of the pancreas develop islet cell carcinomas. Expression of the oncogene beginning in adult life leads to autoimmunity and lymphocytic infiltration of premalignant lesions. Nevertheless, Tag-expressing solid tumors escape the immune surveillance and are devoid of infiltrating lymphocytes. Attempting to elicit a tumor inflammatory response, we have both expressed a potent costimulator in oncogene-expressing beta cells and increased the abundance of reactive T cells. Coexpression of the costimulator B7.1 and the Tag oncoprotein leads to destruction of normal and premalignant islets and severe diabetes. Nevertheless, Tag+ tumors eventually develop, evidencing significantly reduced B7.1 expression and no infiltration. Another approach, whereby the abundance of reactive T cells was increased in double transgenic mice expressing Tag and a Tag-specific, CD4+-restricted T-cell receptor, was similarly unable to elicit tumor infiltration and destruction. Thus, neither costimulatory tumor cells nor hyperactivated antitumor lymphocytes were sufficient to produce an effective tumor immune response. In contrast, adoptive transfer of lymphocytes activated ex vivo did result in modest tumor infiltration with a limited induction of high endothelial venules on tumor vasculature, provided that T cells were transferred into irradiated recipients. However, adoptive transfer of ex vivo activated lymphocytes did not produce the dramatic inflammation seen in premalignant lesions. Thus, in addition to the parameters of activation and abundance of antitumor lymphocytes, the tumor microenvironment is evidently a critical parameter that can suppress lymphocyte extravasation and/or function inside tumors, likely in part via distinctive properties of the tumor vasculature.

Adenoma, Islet Cell↗
PubMed1998

Development of a model for evaluating the interaction between human pre-B acute lymphoblastic leukemic cells and the bone marrow stromal cell microenvironment.

Clonal expansion of B-cell precursor acute lymphoblastic leukemia (ALL) is potentially regulated by survival, growth, and death signals transduced by the bone marrow (BM) microenvironment. Using a human BM stromal cell culture that supports the growth of normal human B-cell precursors, we established a pre-B ALL cell line designated BLIN-2. BLIN-2 has a clonal rearrangement of the Ig heavy chain locus, a dic(9;20) chromosomal abnormality, and a bi-allelic deletion of the p16(INK4a) and p19(ARF) genes. The most interesting feature of BLIN-2 is an absolute dependence on adherent human BM stromal cells for sustained survival and growth. BLIN-2 cultured in the absence of BM stromal cells undergo apoptosis, and direct contact with viable BM stromal cells is essential for optimal growth. BLIN-2 cells also grow on vascular cell adhesion molecule-1 (VCAM-1)-negative human skin fibroblasts, making it unlikely that a very late antigen-4 (VLA-4)/VCAM-1 interaction is required for BLIN-2 growth. Western blot analysis of BLIN-2 cells cultured in the presence or absence of BM stromal cells demonstrates that contact of BLIN-2 with BM stromal cells induces hyperphosphorylation of Rb. In contrast, the pre-B ALL cell line BLIN-1, which has a bi-allelic deletion of p16(INK4a) p19(ARF) but does not require BM stromal cells for growth, does not undergo Rb phosphorylation after BM stromal cell contact. The BLIN-2 cell line will facilitate identification of ligand/receptor interactions at the B-cell precursor/BM stromal cell interface and may provide new insight into microenvironmental regulation of leukemic cell survival and growth.

Apoptosis↗
PubMed1998

[What determines the characteristics of the intrinsic UV-fluorescence of proteins? Analysis of the properties of the microenvironment and features of the localization of their tryptophan residues].

To elucidate the dependence of protein intrinsic fluorescence characteristics on the microenvironment of their tryptophan residue localization, more than a hundred tryptophan residues of a number of proteins were analysed and compared with experimental data on their intrinsic fluorescence. Some factors were revealed, which determine the fluorescence spectrum position of certain tryptophan residues and their contribution to the total protein fluorescence. Specifically, the role of aromatic residues and proline, as well as of tryptophan residue side chain conformation, in the formation of the unique blue fluorescence spectrum of a number of proteins was demonstrated. It was shown that the quenching effect of sulphur atoms of cysteine and methionine, imidazole rings of histidine, guanyl groups of arginine, etc. depends not only on their distance from the indole ring of the tryptophan residue but, to a great extent, on their orientation to indole ring.

Fluorescence Polarization↗
PubMed1999

Maturation of CD4+ lymphocytes in the aged microenvironment results in a memory-enriched population.

With advancing age the CD4+ T lymphocyte compartment becomes enriched for memory cells in both humans and experimental animals. Although it has been assumed that the shift from a naive to a memory-dominant population is due to a lifetime of antigenic exposure and selection as well as a loss of naive cell input due to reduced thymopoiesis, the present data suggest that the aged microenvironment influences the maturation of newly produced CD4+ T cells. In two models, aged and young mice were compared for the ability to reconstitute their peripheral CD4+ T cell pools following depletion, and both age groups were found to be competent to renew this population. However, the phenotype and lymphokine profile of populations arising in aged animals were distinctly different from those in the young mice. In contrast to the expectation that depletion and reconstitution might give rise to a naive-dominant T cell pool, aged mice reconstituted a population nearly indistinguishable from that found in control age-matched individuals. The majority of the CD4+ pool were CD44(high) CD45RB(low) Mel-14(low) and upon activation with anti-CD3 these CD4+ T cells produced mRNA for IL-2, IL-4, IL-5, and IFN-gamma. In aged bone marrow-transplanted mice, the same phenotypic profile and cytokine mRNA pattern were found in CD4+ T cells of host and donor origin. In contrast, the majority of CD4+ T cells in young reconstituted mice were CD44(low) CD45RB(high) Mel-14(high). These lymphocytes, when activated, produced high levels of mRNA for IL-2, with little or no IL-4, IL-5, or IFN-gamma mRNA.

Aging↗
PubMed2026

Identification of molecular subtypes in clear cell renal cell carcinoma based on chromatin regulators and tumor immune microenvironment profiling.

In the histological classification of renal cell carcinoma, clear cell renal cell carcinoma (ccRCC) accounts for the highest proportion and is the most common subtype. Despite advances in management, it continues to be associated with considerable incidence and mortality. Although surgery and systemic therapies are available, their efficacy is constrained by pronounced intratumoral heterogeneity and treatment resistance. Identifying robust biomarkers and clarifying the underlying biological mechanisms are therefore essential to improving diagnosis, risk stratification and therapeutic decision-making. In this work, we identified two ccRCC molecular subtypes displaying divergent chromatin regulator (CR) profiles and different clinical prognoses. Using the genes differentially expressed between these subgroups, we constructed a CR-related score (CRS) that effectively stratified patients according to survival. More analysis concluded that the low expression of CR was more linked with the immune-activated tumors, which encompassed the immune pathway enrichment, as well as the elevation of numerous immune cell subtypes. Moreover, elevated CRS was associated with improved immunotherapy responsiveness. Drug-sensitivity analyses nominated several candidate agents, and SMARCD3 knockdown in 786-O cells inhibited proliferation and migration and reduced sensitivity to masitinib. Collectively, these findings support the prognostic and therapeutic relevance of CR-related states in ccRCC and provide a framework for future experimental validation of chromatin-regulated tumor-immune interactions.

Humans↗
PubMed2026

Mapping subcellular microenvironments using oligonucleotide-directed proximity labeling.

Understanding how cells compartmentalize their biomolecules into discrete structures remains one of the fundamental goals of cell biology. The proliferation of proximity labeling (PL) technologies has been invaluable toward this goal, enabling biochemical "dissection" of compartments that would be intractable to classical biochemical methods. While robust PL approaches have long been established for targeting proteins of interest, targeting nucleic acids-RNAs and genomic loci-has remained significantly more challenging. Here, we review recent advancements in the field that overcome this longstanding roadblock by using programmable DNA oligonucleotides to direct PL enzyme localization. These tools are already revealing new insights into the molecular architecture of cellular compartments that lie at the heart of gene expression. They also provide a foundation for developing a new generation of PL tools that exploit the modularity and programmability of oligonucleotide-based devices to enable precise spatiotemporal control at previously inaccessible targets and in challenging specimen types.

Oligonucleotides↗
PubMed2026

Spatial Proteomics of the Human Atherosclerotic Microenvironment Reveals Heterogeneity in Intraplaque Proteomes and Extracellular Matrix Remodeling.

Plaque heterogeneity underlies the propensity of atherosclerotic lesions to rupture and trigger cardiovascular events. Most proteomic studies examine bulk changes, obscuring key spatial differences in protein abundance. We report a high-resolution spatial proteomics workflow exploring the molecular landscape of human plaques and a murine myocardium. By combining laser capture microdissection with high-sensitivity ion-mobility mass spectrometry, spatial profiling of cellular and extracellular matrix (ECM) proteomes was achieved. Over 2700 proteins were detected from 50,000 μm2 areas, revealing substantial intraplaque heterogeneity across distinct regions (lipid-rich, media, shoulder, necrotic core, intima) and distance from the artery lumen. Inverse correlations between proteases (cathepsin B) and core structural ECM proteins (perlecan, HSPG2) indicated active ECM remodeling. Analysis of media layers indicated distinct protein signatures associated with smooth muscle contraction and cell-cell communication. Blood coagulation signatures, including platelet degranulation and fibrin formation, were enriched at the intima. Inflammatory (clusters of differentiation 4/68, CD4/CD68; vascular cell adhesion molecule 1, VCAM1) and vascular damage markers (tenascin-C, TNC) were enriched in shoulder regions. The necrotic core was dominated by blood proteins, consistent with intraplaque hemorrhage. This workflow resolves proteomic changes over ∼200 μm distances, providing unprecedented insights into plaque morphology and offers a powerful tool for elucidating plaque biology.

Humans↗
PubMed2026

Radiogenomics predicts immune microenvironment heterogeneity and response to combination immunotherapy in hepatocellular carcinoma.

BACKGROUND: The combination of immune checkpoint inhibitors (ICIs) with anti-angiogenic agents is the preferred first-line therapy option for patients with advanced hepatocellular carcinoma (HCC), yet only a subset of patients responds, urging the quest for prediction biomarkers. We aimed to integrate genomics with radiology to propose an immune-derived radiogenomics biomarker of response to such combination immunotherapy and evaluate its added value in clinical context. METHODS: We integrated bulk RNA sequencing (RNA-seq) and proteomics data of 994 HCC patients with single-cell RNA-seq data of 11 samples across multiple datasets to identify an immune-related signature (IRS) that may influence sensitivity or resistance to such combined immunotherapy strategy, followed by verification of selected marker genes using immunohistochemistry and cytological experiments. We then trained/validated a cross-modality radiogenomics biomarker using machine learning based on TCIA database that was further tested in multi-scale independent cohorts covering 754 HCC patients. RESULTS: Integrative multi-omics analysis identifed a parsimonious 2-gene prognostic signature including KPNA2 and SMG5 that was significantly associated with immune heterogeneity and response to combination immunotherapy. Machine-learning pipeline exported the optimal 4-feature radiogenomics biomarker using support vector machine that significantly discriminated prognosis (hazard ratio 1.415&#x2013;1.890; p&#x2009;<&#x2009;0.05 for all) and modestly predicted response to ICI plus anti-angiogenic therapy (area under the curve 0.720&#x2013;0.829) in independent retrospective series across major imaging modalities (computed tomography/magnetic resonance imaging). In a prospective neoadjuvant cohort, this biomarker also showed favorable performance for predicting pathological response and tumor recurrence, accompanied by biological validation through single-cell RNA-seq analysis of pre-treatment biopsies. CONCLUSIONS: Our study provides a cross-device-cross-modal radiogenomics biomarker that can improve patient selection for emerging ICI plus anti-angiogenic therapy with novel potential therapeutic targets in HCC.

Humans↗
PubMed2026

Increased IL4I1 expression predicts poor survival and modulates the immune microenvironment in acute myeloid leukemia.

BACKGROUND: The immunometabolic enzyme Interleukin-4-induced-1 (IL4I1) is implicated in cancer pathogenesis, yet its specific function and clinical relevance in acute myeloid leukemia (AML) remain unclear. METHODS: Comparative analysis of IL4I1 mRNA levels between AML patients and normal controls was performed using the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. The Kaplan&#x2013;Meier survival analysis was conducted to evaluate the prognostic value of IL4I1. Functional insights were derived from analyses of differentially expressed genes (DEGs), Gene Set Enrichment Analysis (GSEA), and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Immune infiltration was evaluated using the ssGSEA, ESTIMATE, quanTIseq and single-cell RNA sequencing (scRNA-seq) analysis. Finally, in vitro and in vivo functional experiments were perfromed to explore the impact of IL4I1 on AML progression and immunoregulation. RESULTS: IL4I1 expression was significantly elevated in AML compared to normal controls (p&#x2009;=&#x2009;0.0004) and associated with poorer overall survival (p&#x2009;=&#x2009;0.003). Bioinformatic analysis revealed that IL4I1 was linked to immune-related pathways&#x2014;including humoral immune response, leukocyte interactions, and chemokine signaling&#x2014;and to cellular amino acid metabolism. Its expression correlated with immune cell infiltration and checkpoint molecule expression. Experimentally, IL4I1 promoted leukemia cell proliferation in vitro and in vivo (p&#x2009;<&#x2009;0.05). Furthermore, silencing IL4I1 suppressed M2 macrophage polarization and reduced secretion of inflammatory factors (p&#x2009;<&#x2009;0.05). CONCLUSIONS: IL4I1 may serve as a potential biomarker for poor prognosis and an attractive target for immune-based therapeutic interventions in AML.

Humans↗
PubMed2025

Effect of acupuncture on brain microenvironment in rats with post-stroke limb spasticity based on single-cell transcriptome sequencing technology.

OBJECTIVE: To investigate the possible mechanisms by which acupuncture improves post-stroke limb spasticity using single-cell sequencing technology. METHODS: Thirty-two rats were randomly assigned to four groups: Control, Sham, Model, and Acupuncture. The middle cerebral artery occlusion (MCAO) model was established, and the acupuncture groups received acupuncture treatment. After treatment, brain morphological changes and the degree of neurological impairment were assessed. The effect of acupuncture on the proportion of brain cell types in the ischemic penumbra of MCAO rats was analyzed using single-cell transcriptomics, and the expression and enrichment of differentially expressed genes were examined. Finally, selected differential genes were validated by Western blot and quantitative real-time polymerase chain reaction. RESULTS: Triphenyltetrazolium chloride staining showed that the infarct area in MCAO rats was significantly reduced after acupuncture. Garcia scoring, hematoxylin-eosin staining, Nissl staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling demonstrated that acupuncture reduced brain damage. Enzyme-linked immunosorbent assay results showed that acupuncture significantly decreased serum inflammatory factors, including interleukin-1 beta (IL-1&#x3b2;), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-&#x3b1;). Single-cell transcriptome analysis revealed marked changes in cell type proportions between the Acupuncture and Model groups. A total of 207 differential genes were identified, including 157 upregulated and 50 downregulated genes. Analysis of macrophage-specific differential genes in the ischemic penumbra showed enrichment in Gene Ontology terms such as Ras protein signal transduction and regulation of GTPase activity, and Kyoto Encyclopedia of Genes and Genomes pathways including lysosome, axon guidance, and mitogen-activated protein kinase signaling. S100a8 and leukocyte specific transcript 1 (LST1) were identified as key differential genes. CONCLUSION: These findings suggest that the key differential genes S100a8 and LST1 may alleviate post-stroke limb spasticity by regulating the inflammatory response in the ischemic penumbra.

Animals↗
PubMed2026

Single-section multiplex spatial proteomics of immune microenvironments in kidney transplantation.

Characterizing kidney disease is challenged by marked cellular heterogeneity and limited tissue availability from renal biopsies. Conventional diagnostic workflows rely on multiple serial sections for parallel staining, increasing tissue consumption, sampling bias, and loss of spatial information, thereby constraining molecular characterization within intact tissue architecture. High-plex spatial proteomics may overcome these limitations by enabling comprehensive molecular profiling on a single section. Here, we present and evaluate a high-plex cyclic immunofluorescence imaging workflow (MACSima&#x2122;, Miltenyi Biotec) applied to kidney transplant biopsies, including BK virus nephropathy (BKVN) and focal segmental glomerulosclerosis (FSGS), to characterize spatial immune organization with a focus on complement system components. Feasibility and subcellular resolution were first assessed in a lupus nephritis section, demonstrating compatibility with diagnostic immune panels and preservation of tissue morphology. A 48-marker multiplex panel interrogating immunity, oxidative stress, senescence, and fibrosis was then applied to BKVN samples, including paired pre- and post-treatment biopsies, revealing distinct proteomic patterns and dynamic changes following therapy. In FSGS, a glomerulus-focused panel identified spatially resolved innate and adaptive immune signatures, including complement-related patterns supporting exploratory analysis of glomerular immune architecture. Structural, nuclear, membrane, and phosphorylated signaling markers enabled precise delineation of renal compartments and assessment of cellular states such as proliferation, DNA damage, and pathway activation. The workflow also supported detection of extracellular vesicles in cultured renal cells, highlighting its versatility. Overall, this approach provides a robust, tissue-sparing platform for integrated spatial and molecular profiling of renal biopsies, reducing sampling bias while enabling discovery-level phenotyping from a single section. This unified strategy is particularly suited to kidney transplantation, where diagnosis, therapeutic decision-making, and longitudinal monitoring are closely interconnected.

Kidney Transplantation↗