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PubMed2026

Impact of NR4A3 on wound healing in chronic venous ulcers and its association with the PI3K/Akt signaling pathway.

BACKGROUND: To investigate the role of NR4A3 in chronic venous ulcer (VU) wound healing and to explore its potential regulatory mechanism involving the PI3K/Akt pathway. METHODS: Differential expression and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the GSE174661 dataset. DEGs were filtered by |log2FC| > 1 and adjusted P < 0.05, with KEGG significance set at P < 0.05. NR4A3 was identified as the core gene. NR4A3 knockdown and overexpression were established in HaCaT cells to evaluate proliferation, migration, and inflammatory cytokines. TNF-α was used to mimic the inflammatory microenvironment. Western blotting assessed phosphorylation of GSK3β, mTOR, PI3K, and Akt. PI3K/Akt agonist 740Y-P and inhibitor LY294002 were used in rescue experiments. RESULTS: Bioinformatic analysis revealed that NR4A3 expression was markedly downregulated in chronic venous ulcer (VU) tissues relative to normal skin and ordinary acute wound tissues. Differentially expressed genes were significantly enriched in the PI3K/Akt signaling pathway. TNF-α stimulation significantly upregulated NR4A3 expression and increased phosphorylation of GSK3β and mTOR in HaCaT cells. In cultured HaCaT keratinocytes, NR4A3 knockdown suppressed cell proliferation and invasion, enhanced cell migration, and elevated the expression and secretion of pro-inflammatory cytokines (IL-6, IL-8, CXCL5), accompanied by reduced phosphorylation of PI3K and Akt. Conversely, NR4A3 overexpression promoted cell proliferation and invasion, restrained migration, and dampened inflammatory responses, while increasing PI3K/Akt phosphorylation. Treatment with the PI3K/Akt agonist 740Y-P partially rescued the impaired proliferation, aberrant migration, and excessive inflammation caused by NR4A3 silencing, whereas PI3K/Akt inhibitor LY294002 aggravated pathway suppression. These findings suggest that NR4A3-associated changes in keratinocyte functions and inflammatory reactions are functionally linked to PI3K/Akt pathway activity, and inflammatory stimulation activates GSK3β/mTOR signaling accompanied by compensatory NR4A3 upregulation. CONCLUSION: These findings suggest that NR4A3 is associated with keratinocyte behavior and inflammatory responses via the PI3K/Akt pathway, potentially affecting chronic VU progression and healing. Reduced NR4A3 may impair wound repair through inflammation and abnormal cell migration, while TNF-α induces compensatory NR4A3 elevation.

NR4A3↗

PubMed1979

Microenvironmental influences on the in vivo behavior of neoplastic lymphocytes.

A transplantable hamster lymphocytic neoplasma of probable monoclonal derivation, induced by the oncogenic DNA simian virus 40, has been adapted to grow in the allogeneic host either as leukemia (characterized by dissemination and poor prognosis) or as lymphoma (characterized by localization and favorable prognosis) [Diamandopoulos, G. Th. (1978) Proc. Natl. Acad. Sci. USA 75, 2011-2015]. In the present experiments the circumstances under which neoplastic lymphocytes that are transplanted in allogeneic animals retain, lose, or regain the capacity for dissemination or localization are assessed. Results indicate that the in vivo behavior of neoplastic lymphocytes is not a stable, irreversible characteristic that is transmitted to the cell progeny. On the contrary, it can be altered by the origin/tissue microenvironment in which the cells proliferate. It is suggested that, whereas neoplastic cell mutation followed by host selection could be responsible for changes in cell behavior, a more likely explanation is that the proliferating neoplastic lymphocytes acquire reversible nonmutational phenotypic characteristics during their interaction with the host microenvironment, which modify their behavior and, as a result, the prognosis of the neoplastic process.

Animals↗

PubMed2026

Myeloid-Mediated Immunoregulation and Resistance to Immune Checkpoint Inhibitor Therapy Across Squamous Cell Carcinomas: Mechanisms and Reprogramming Strategies.

Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have improved outcomes across squamous cell carcinomas (SCCs) of the head and neck, lung, esophagus, and skin, yet durable responses remain confined to a subset of patients in every subtype. Objective response rates vary substantially across SCCs despite overlapping genomic alterations, comparable tumor mutational burden, and high PD-L1 expression, indicating that tumor-intrinsic biomarkers alone do not explain this variability. Growing evidence points to the tumor immune microenvironment, and in particular the myeloid compartment, as a critical determinant of immunotherapy responsiveness. In this review, we synthesize current evidence on myeloid-mediated immune regulation across SCC subtypes, focusing on tumor-associated macrophages, myeloid-derived suppressor cells/tumor-associated neutrophils, and dendritic cells, and the mechanisms by which these populations impair antigen presentation, restrict T cell infiltration, and sustain immunologically "cold" tumor states. We further examine therapeutic strategies aimed at reprogramming rather than simply depleting suppressive myeloid populations, including radiation therapy, STING agonism, and myeloid-targeted agents (CSF1R, PI3Kγ, and CXCR2 inhibition), each of which has shown encouraging preclinical and early clinical activity in combination with ICI. Collectively, this evidence supports a model in which the myeloid compartment functions as an actionable, convergent determinant of ICI resistance across SCC subtypes, rather than merely a passive biomarker. We propose that through the integration of spatial and single-cell profiling of myeloid states with clinical history it will be possible to predict response to immune checkpoint therapy and personalize myeloid-directed combination strategies, though the specific biomarkers needed to match individual patients to a given myeloid-targeted approach remain to be defined. We further discuss the toxicity considerations associated with both immune checkpoint blockade and radiation-based combination approaches, the early-phase status of most myeloid-targeted agents currently in clinical development, and the extent to which mechanistic insight, derived predominantly from HNSCC, generalizes to squamous cell carcinomas arising at other anatomic sites.

dendritic cells↗

PubMed1975

Effect of antithymocyte globulin pretreatment on immunological reconstitution of lethally irradiated animals.

Clinical and experimental studies have shown that antithymocyte globulin pretreatment will reduce the severity of the graft-versus-host reaction after allogeneic bone marrow transplantation. To determine whether this was attributable to a persisting cytotoxic factor in the recipients' sera or a result of the "masking" of foreign antigens by the antihymocyte globulin, an experimental schema utilizing a syngeneic transfer of immunocompetent cells was devised. Lethally irradiated mice that had been pretreated with rabbit antimouse thymocyte globulin (RAMTG) were injected with syngeneic spleen or bone marrow cells and their immunological competence was measured by the response to a test antigen, sheep red blood cells. It was found that such pretreatment had an adverse effect on the immunological potential of the infused cells. Thus, the plaque-forming cell response to sheep red blood cell antigen in RAMTG-pretreated recipients injected with spleen cells was reduced when compared to the saline or normal rabbit globulin-treated controls. The immunological recovery of lethally irradiated animals protected with syngeneic bone marrow was also delayed, but not permanently impaired, when the recipients had been pretreated with RAMTG. These effects were evident although the spleen or bone marrow cells had been injected into the RAMTG-pretreated recipients at a time when their sera were devoid of any cytotoxic antibodies. It is speculated that two mechanisms may contribute to this alteration in immune function of the infused cells: (1) that RAMTG exists in the serum in amounts sufficient to attach to receptor sites on lymphocytes or their precursors but insufficient to kill the cells, interfering with the antigen recognition mechanism or migration and homing patterns, or (2) that the RAMTG treatment creates a temporary defect in the microenvironment of the spleen and other hemopoietic tissues, thereby affecting the transplantation and proliferation kinetics of the infused cells.

Animals↗

PubMed1979

Allogeneic marrow transplantation after total lymphoid irradiation (TLI): effect of dose/fraction, thymic irradiation, delayed marrow infusion, and presensitization.

BALB/c mice infused with 30 x 10(6) C57BL/Ka bone marrow (BM) cells 1 day after treatment with fractionated total lymphoid irradiation (TLI) (17 fractions of 200 rads each) became stable mixed chimeras without clinical graft-vs-host disease (GVHD). Mice given 18 fractions of 100, 50, or 25 rads each followed 1 day later by C57BL/Ka BM did not become chimeric, indicating that a critical cumulative radiation dose is required for this effect. Animals given TLI with lead shielding placed over the thymus also developed stable chimerism without GVHD. Thus susceptibility to tolerance induction and protection from GVHD after TLI and allogeneic BM transplantation is not due to alteration of the thymic microenvironment by fractionated irradiation. A delay of 7 or 21 days between completion of TLI and BM administration resulted in a high incidence of graft rejection. Sensitization to minor histocompatibility antigens of the BM donor strain by blood transfusion either before or during TLI resulted in marrow graft rejection in a high percentage of animals.

Animals↗

PubMed1977

The influence of changes in the phospholipid pattern of intact fibroblasts on the activities of four membrane-bound enzymes.

Human skin fibroblasts, grown to confluency in the presence of 32P for random labelling of the phospholipids, showed upon 24 h incubation in the presence of either 8 mM L-serine or 4 mM ethanolamine an increased content of phosphatidylserine (150% of control cells) or phosphatidylethanolamine (116% of control cells), respectively. Concomitantly the phosphatidylcholine correspondingly decreased. Upon cell harvesting and gentle enzyme preparation the base-treated cells demonstrated a significantly higher unstimulated, fluoride- and thyrotropin-stimulated activity of adenylate cyclase. The activities of total ATPase, ouabain-sensitive ATPase, 5'-nucleotidase and gamma-glutamyltransferase remained unaltered. When subjecting enzyme preparations from fibroblasts to ultrasonication the activity of adenylate cyclase decreased progressively with energy applied, whereas the activities of the other enzymes were unaltered ((K+ + Na+)-ATPase, 5'-nucleotidase) or even increased (Mg2+-ATPase, gamma-glutamyltransferase). The results have a bearing upon the regulatory function of the phospholipid microenvironment of membrane-bound enzymes.

Adenosine Triphosphatases↗

PubMed2026

A conserved grain-associated immunosuppressive niche in Sudanese patients with mycetoma.

Mycetoma is a neglected tropical disease caused by various bacterial and fungal pathogens that has a significant health impact across a broad geographically defined "mycetoma belt" spanning South America, Africa and Asia. Histologically, mycetoma is characterised by invasive and destructive granuloma development in the skin, deep tissues and bone, leading to tissue destruction, deformities and high morbidity. The presence of macroscopic, highly compacted pathogen microcolonies, or "grains," is a key diagnostic feature, and the formation of grains supports pathogen persistence and disease chronicity. However, there is a paucity of information on immune responses in mycetoma patients and on the relative importance of phylogeny and/or grains in establishing the local immune landscape. Here, we used spatial proteomics to examine the distribution of 43 immune-related proteins in surgical biopsies from 11 patients with mycetoma of bacterial (actinomycetoma; Actinomadura pelletierii and Streptomyces somaliensis; n = 6) and fungal (eumycetoma; Madurella mycetomatis; n = 5) origin. Using mixed-effects modelling, an exploratory analysis across species and pathogen classes revealed few significant differences in immune marker expression. In contrast, and independently of pathogen class, the cellular infiltrate closest to grain boundaries had higher per-cell expression of CD66b+ neutrophils, ARG1, and VISTA. The preferential accumulation of CD66b+ARG1+VISTA+ cells at grain boundaries was confirmed by quantitative immunofluorescence analysis. Hence, the local tissue microenvironment surrounding the mycetoma grain represents a specialised immunosuppressive niche, with parallels to the tumour microenvironment. Trial Registration The study was prospectively registered on ClinicalTrials.gov NCT04401969.

Adult↗

PubMedDate not supplied

Clinical assessment of laboratory rodents on long term bioassay studies.

The disease status of laboratory rodents should be clinically assessed before the animals are placed on toxicological bioassay programs. This is especially important when the stress of dietary or parenteral intake of toxic substances may trigger the clinical onset of latent diseases in research animals. In clinical evaluation of rodents, the environmental influence on biochemical, physiological and behavioral status of the animals must be continually monitored. Temperature, humidity, ventilation, lighting, and the microenvironment of the cage will all influence, independently or in consort, the response of the animal to various microbial or chemical insults. Unwanted variables in the diet can also markedly after the biological response of the animal and thus alter interpretation of experimental data. Adequately trained personnel, both professional and technical, must be available to provide daily care, clinical observation, and necessary treatment if signs of illness are noted in the laboratory rodent or bioassay experimentation. Clinical signs associated with commonly encountered diseases in laboratory rodents are briefly described. Clinical surveillance and assessment of rodents in part consists of recognition of and detailed recording of clinical signs, coupled with proper diagnostic resources to substantiate clinical observations. It is possible, with proper diagnosis, to evaluate the overall effect of a particular disease on the animal's health, the likelihood that the disease is jeopardizing the health of the other animals on test, and the effect of the disorder on interpretation of experimental results.

Animal Husbandry↗