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At least 19 recordsLinked to original sources
PubMed1992

Multiple cholinergic differentiation factors are present in footpad extracts: comparison with known cholinergic factors.

Sweat glands in rat footpads contain a neuronal differentiation activity that switches the phenotype of sympathetic neurons from noradrenergic to cholinergic during normal development in vivo. Extracts of developing and adult sweat glands induce changes in neurotransmitter properties in cultured sympathetic neurons that mimic those observed in vivo. We have characterized further the factors present in the extract and compared their properties to those of known cholinergic factors. When assayed on cultured rat sympathetic neurons, the major activities in footpad extracts from postnatal day 21 rat pups that induce choline acetyltransferase (ChAT) and vasoactive intestinal peptide (VIP) and reduce catecholamines and neuropeptide Y (NPY) are associated with a soluble protein of 22-26 x 10(3) M(r) and a pI of 5.0. These properties are similar to those of ciliary neurotrophic factor (CNTF). Moreover, the purified fraction from footpads has ciliary neurotrophic activity. Antibodies to CNTF that immunoprecipitate all differentiation activity from sciatic nerve extracts, a rich source of CNTF, immunoprecipitate 80% of the cholinergic activity in the footpad extracts, 50% of the VIP and 20% of the NPY activities. Neither CNTF protein nor CNTF mRNA, however, can be detected in immunoblot and northern analysis of footpads even though both CNTF protein and mRNA are evident in sciatic nerve. CNTF-immunoreactivity is associated with a sparse plexus of sensory fibers in the footpad but not with sweat glands or the Schwann cells associated with them. In addition, in situ hybridization studies with oligonucleotide probes failed to reveal CNTF mRNA in sweat glands. Comparison of the sweat gland differentiation activity with the cholinergic differentiation factor from heart cells (CDF; also known as leukemia inhibitory factor or LIF) suggests that most of the cholinergic activity in foot pads is biochemically distinct from CDF/LIF. Further, antibodies that block the activity of CDF/LIF purified from heart-cell-conditioned medium do not block the ChAT-inducing activity present in footpad extracts of postnatal day 8 animals. A differentiation factor isolated from skeletal muscle did not induce cholinergic properties in sympathetic neuron cultures and therefore is unlikely to be the cholinergic differentiation factor produced by sweat glands. Taken together, our data suggest that there are at least two differentiation molecules present in the extracts and that the major cholinergic activity obtained from footpads is related to, but distinct from, CNTF. The second factor remains to be characterized. In addition, CNTF associated with sensory fibers may make a minor contribution to the cholinergic inducing activity present in the extract.

Animals↗
PubMed2025

Blockade of interleukin-6 (IL-6) signaling in dedifferentiated liposarcoma (DDLPS) decreases mouse double minute 2 (MDM2) oncogenicity via alternative splicing.

Effective therapies for retroperitoneal (RP) dedifferentiated liposarcoma (DDLPS) remain unavailable. Loco-regional recurrence occurs in >80% of cases; 5-year disease-specific survival is only 20%. DDLPS is especially prevalent in the retroperitoneum and abdomen; evaluation of the DDLPS microenvironment in these high-fat compartments appears pertinent. Adipose is a main supplier of interleukin-6 (IL6); excessive activation of IL6 signal transducer glycoprotein 130 (GP130) underlies the development of some diseases. The role of GP130 pathway activation remains unstudied in DDLPS, so we examined the role of microenvironment fat cell activation of the IL6/GP130 signaling cascade in DDLPS. All DDLPS tumors and cell lines studied expressed elevated levels of the GP130-encoding gene IL6ST and GP130 protein compared to normal tissue and cell line controls. IL6 increased DDLPS cell growth and migration, possibly through increased signal transducer and activator of transcription 1 (STAT1) and 3 (STAT3) activation, and upregulated mouse double minute 2 (MDM2). GP130 loss conveyed opposite effects; pharmacological blockade of GP130 by SC144 produced the MDM2 splice variant MDM2-ALT1, known to inhibit full length MDM2 (MDM2-FL). Although genomic MDM2 amplification is pathognomonic for DDLPS, mechanisms driving MDM2 expression, regulation, and function beyond the MDM2:p53 negative feedback loop are poorly understood. Our findings suggest a novel preadipocyte DDLPS-promoting role due to IL6 release, via upregulation of DDLPS MDM2 expression. Pharmacological GP130 blockade reduced the IL6-induced increase in DDLPS MDM2 mRNA and protein levels, possibly through enhanced expression of MDM2-ALT1, a possibly targetable pathway with potential as future DDLPS patient therapy.

Proto-Oncogene Proteins c-mdm2↗
PubMed1992

Anti-diabetogenic effect of fusidic acid in diabetes prone BB rats.

Fusidic acid and its sodium salt (fusidin) are anti-staphylococcal drugs. In vitro studies have shown that they prevent the lymphocyte co-stimulatory activities of the cytokines IL-1 and IL-6 in a manner similar to that of cyclosporin A, and prevent the inhibitory effect of IL-1 on glucose-induced insulin production. As IL-1 and IL-6 are thought to play a role in the pathogenesis of Type 1 diabetes, the aim of this study was to investigate whether fusidin could influence the disease incidence of the spontaneously diabetic BB rat model. Accordingly, a group of 50 BB rats receiving fusidin dissolved in their drinking water were compared to a control group of 55 rats over a period of 200 days. The incidence of diabetes was found to be 52% in the experimental group and 71% in the control group (P < 0.05). The degree of insulitis and the number of islets at histological examination were similar among the non-diabetic animals whereas the diabetic fusidin-treated animals showed a higher degree of islet preservation than the diabetic control rats. The results are highly indicative of an anti-diabetogenic effect of fusidin.

Administration, Oral↗
PubMed1992

Interleukin-6 does not regulate interstitial collagenase, stromelysin and tissue inhibitor of metalloproteinases synthesis by cultured human fibroblasts.

We have examined the effect of interleukin-6 (IL-6) on the synthesis of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMP) by human skin fibroblasts, both at protein and messenger RNA levels. IL-6 did not modulate the production of MMPs and TIMP. Furthermore IL-6 did not modify the stimulatory effect exerted by interleukin-1 (IL-1) on the expression of MMPs and TIMP. These results strongly suggest that IL-6 is not involved in the extracellular matrix breakdown, either directly by acting on cell production of MMPs or TIMP, or indirectly by modulating the effect of IL-1 on the synthesis of MMPs and TIMP.

Cells, Cultured↗
PubMed1992

Effect of recombinant human D-factor on the growth of leukemic blast progenitors from acute myeloblastic leukemia patients.

We studied the effects of D-factor on the growth of leukemic blast progenitors from 15 patients with acute myeloblastic leukemia and two leukemia cell lines in methylcellulose and suspension cultures. When stimulated by granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor or interleukin-3, leukemic blast progenitors undergo terminal division with limited differentiation in methylcellulose culture, forming blast colonies. Leukemic blast progenitors can renew themselves. The self-renewal can be detected as secondary colony formation after replating primary blast colonies in fresh methylcellulose media and by the growth of clonogenic cells in suspension culture. D-Factor suppressed primary and secondary colony formation in methylcellulose culture. Furthermore, D-factor suppressed clonogenic cell recovery in suspension culture. The suppression by D-factor of the growth of leukemic blast progenitors was not significantly dependent upon the colony-stimulating factors used as growth-stimulating factors. High concentration of G-CSF did not overcome the suppressive effect of D-factor. The results indicate that D-factor is effective in suppressing not only terminal division but also self-renewal of leukemic blast progenitors.

Adult↗
PubMed1992

Effect of metals on interleukin-6 (IL-6) mitogenic stimulation of murine hybridoma cells.

The effect of several divalent metal cations (Co, Cu, Zn, Hg and Pb) on the proliferative response of B9 hybridoma cells to IL-6 has been investigated. At concentrations which are not cytotoxic all the metals inhibited proliferation. The inhibition by Cd and Pb was dependent on both time of addition of the metal and IL-6 concentration. Cd (10 microM) and Pb (50 microM) added at the same time as IL-6 were inhibitory but added 24h later had no effect. Increasing the concentration of IL-6 overcame the inhibitory effect of Cd (10 microM) and Pb (50 microM). Inhibition caused by the other metals was independent of either time of addition or IL-6 concentration. IL-6 did not stimulate an increased intracellular concentration of metallothionein suggesting that the protective effect of IL-6 is not mediated via induction of metallothionein. The results suggest that there are at least two distinct metal sensitive events in B9 proliferation, i) IL-6 reversible inhibition by Cd and Pb ii) IL-6 independent inhibition by Co, Cu and Hg.

Animals↗
PubMed2025

Proteomic Profiling of the Large-Vessel Vasculitis Spectrum Identifying Shared Signatures of Innate Immune Activation and Stromal Remodeling.

OBJECTIVE: Takayasu arteritis (TAK) and giant cell arteritis (GCA), the most common forms of large-vessel vasculitis (LVV), can result in serious morbidity. Understanding the molecular basis of LVV should aid in developing better biomarkers and treatments. METHODS: Plasma proteomic profiling of 184 proteins was performed in two cohorts. Cohort 1 included patients with established TAK (n = 96) and large-vessel GCA (LV-GCA) (n = 35) in addition to healthy control participants (HCs) (n = 35). Cohort 2 comprised patients presenting acutely with possible cranial GCA (C-GCA) in whom the diagnosis was subsequently confirmed (C-GCA, n = 150) or excluded (Not C-GCA, n = 89). Proteomic findings were compared to published transcriptomic data from LVV-affected arteries. RESULTS: In cohort 1, comparison to HCs revealed 52 differentially abundant proteins (DAPs) in TAK and 72 DAPs in LV-GCA. Within-case analyses identified 16 and 18 disease activity-associated proteins in TAK and LV-GCA, respectively. In cohort 2, comparing C-GCA versus not C-GCA revealed 31 DAPs. Analysis within C-GCA cases suggested the presence of distinct endotypes, with more pronounced proteomic changes in the biopsy-proven subgroup. Cross-comparison of TAK, LV-GCA, and biopsy-proven C-GCA revealed highly similar plasma proteomic profiles, with 26 shared DAPs including interleukin 6 (IL-6), monocyte/macrophage-related proteins (CCL7, CSF1), tissue remodeling proteins (TIMP1, TNC), and novel associations (TNFSF14, IL-7R). Plasma proteomic findings reflected LVV arterial phenotype; for 42% of DAPs, the corresponding gene was differentially expressed in tissue. CONCLUSION: These findings suggest shared pathobiology across the LVV spectrum involving innate immunity, lymphocyte homeostasis, and tissue remodeling. Network-based analyses highlighted immune-stromal cross-talk and identified novel therapeutic targets (eg, TNFSF14).

Humans↗
PubMed1992

A simple, quantitative method for assessing angiogenesis and antiangiogenic agents using reconstituted basement membrane, heparin, and fibroblast growth factor.

BACKGROUND: Blood vessel growth is necessary for normal tissue homeostatis and contributes to solid tumor growth. Methods to quantitate neovascularization should be useful in testing biological factors and drugs that regulate angiogenesis or to induce a vascular supply to promote wound healing. EXPERIMENTAL DESIGN: An extract of basement membrane proteins (Matrigel) was found to reconstitute into a gel when injected subcutaneously into C57/BL mice and to support an intense vascular response when supplemented with angiogenic factors. RESULTS: New vessels and von Willebrand factor antigen staining were apparent in the gel 2-3 days after injection, reaching a maximum after 3-5 days. Hemoglobin content of the gels was found to parallel the increase in vessels in the gel allowing ready quantitation. Angiogenesis was obtained with both acidic and basic fibroblast growth factors and was enhanced by heparin. Several substances were tested for angiostatic activity in this assay by coinjection in Matrigel with fibroblast growth factor and heparin. Platelet-derived growth factor BB, interleukin 1-beta, interleukin-6, and transforming growth factor-beta were potent inhibitors of neovascularization induced by fibroblast growth factor. Tumor necrosis factor-alpha did not alter the response but was alone a potent inducer of neovascularization when coinjected with Matrigel and heparin. Consistent with the previously demonstrated importance of collagenase in mediating endothelial cell invasion, a tissue inhibitor of metalloproteinases that also inhibits collagenases was found to be a potent inhibitor of fibroblast growth factor-induced angiogenesis. CONCLUSIONS: Our assay allows the ready quantitative assessment of angiogenic and anti-angiogenic factors and should be useful in the isolation of endothelial cells from the capillaries that penetrate into the gel.

Angiogenesis Inducing Agents↗
PubMed2025

Proteomic-based biomarker discovery reveals panels of diagnostic biomarkers for early identification of heart failure subtypes.

BACKGROUND: Limited access to echocardiography can delay the diagnosis of suspected heart failure (HF), which in turn postpones the initiation of optimal guideline-directed medical therapy. Although natriuretic peptides like B-type natriuretic peptide (BNP) are valuable biomarkers for diagnosing and managing HF, the utility of combining BNP with other blood-based biomarkers to predict subtypes of new-onset HF remains underexplored. OBJECTIVES: This study sought to investigate and evaluate the diagnostic significance of adding blood-based biomarkers to BNP for identifying heart failure with preserved ejection fraction (HFpEF) or reduced ejection fraction (HFrEF), with the goal of enhancing diagnostic assays beyond BNP measurements. METHODS: We identified candidate blood protein biomarkers using untargeted proteomics workflows from a cohort of individuals recruited to the STOP-HF trial who were at risk of HF and subsequently developed either HFpEF or HFrEF over time ("HF progressors"; n&#x2009;=&#x2009;40). Candidate biomarkers were verified in an independent cohort (n&#x2009;=&#x2009;52) from a community-based rapid access HF diagnostic clinic. The biological processes associated with these proteins were assessed, and the diagnostic values of biomarker panels were evaluated using a machine learning approach. RESULTS: Within HF progressors, we identified 3 proteins associated with HFpEF development: vascular cell adhesion protein 1 (VCAM1), insulin-like growth factor 2 (IGF2), and inter-alpha-trypsin inhibitor heavy chain 3 (ITIH3). Additionally, 4 proteins were linked to HFrEF development: C-reactive protein (CRP), interleukin-6 receptor subunit beta (IL6RB), phosphatidylinositol-glycan-specific phospholipase D (PHLD), and noelin (NOE1). These findings were verified in an independent cohort to distinguish HF subtypes from controls. Moreover, a random forest algorithm demonstrated that combining these candidate biomarkers with BNP measurement significantly improved the prediction of HF subtypes. CONCLUSIONS: We identified candidate proteins linked to HFpEF and HFrEF in a longitudinal HF progressor cohort and validated them in a community-based cohort. Adding these proteins to BNP led to a significant improvement in HF subtype prediction. Study results have clinical implications for blood-based screening of HF subtypes using panels of biomarkers, particularly in resource-limited settings.

Humans↗
PubMed2025

Cancer-induced nerve injury promotes resistance to anti-PD-1 therapy.

Perineural invasion (PNI) is a well-established factor of poor prognosis in multiple cancer types1, yet its mechanism remains unclear. Here we provide clinical and mechanistic insights into the role of PNI and cancer-induced nerve injury (CINI) in resistance to anti-PD-1 therapy. Our study demonstrates that PNI and CINI of tumour-associated nerves are associated with poor response to anti-PD-1 therapy among patients with cutaneous squamous cell carcinoma, melanoma and gastric cancer. Electron microscopy and electrical conduction analyses reveal that cancer cells degrade the nerve fibre myelin sheets. The injured neurons respond by autonomously initiating IL-6- and type I interferon-mediated&#xa0;inflammation to promote nerve healing and regeneration. As the tumour grows, the CINI burden increases, and&#xa0;its associated inflammation becomes chronic and skews the general immune tone within the tumour microenvironment into a suppressive and exhaustive state. The CINI-driven anti-PD-1 resistance can be reversed by targeting multiple steps in the CINI signalling process: denervating the tumour, conditional knockout of the transcription factor mediating the injury signal within neurons (Atf3), knockout of interferon-&#x3b1; receptor signalling (Ifnar1-/-) or by combining anti-PD-1 and anti-IL-6-receptor blockade. Our findings demonstrate the direct immunoregulatory roles of CINI and its therapeutic potential.

Animals↗
PubMed2026

Anti-inflammatory agents after hip and shoulder arthroplasty: A systematic review and meta-analysis.

BACKGROUND: Postoperative inflammation after arthroplasty contributes to pain, delayed mobilization and prolonged hospitalization. Recent randomized trials have evaluated pharmacological anti-inflammatory strategies within contemporary enhanced recovery pathways, but evidence after hip and shoulder arthroplasty remains scattered across different drug classes and perioperative regimens. OBJECTIVES: To synthesize recent randomized controlled trial (RCT) evidence on perioperative anti-inflammatory agents after hip and shoulder arthroplasty. METHODS: PubMed, Embase, Cochrane Library and Web of Science were searched for English-language RCTs published from January 2020 to March 2026. The 2020-2026 window was selected to update evidence generated under modern arthroplasty, anesthesia, multimodal analgesia and enhanced recovery after surgery (ERAS) pathways. Eligible trials included adults undergoing hip or shoulder arthroplasty and compared corticosteroids, cyclooxygenase-2 (COX-2) inhibitors, nonsteroidal anti-inflammatory drug (NSAID)-based/local anti-inflammatory regimens, or related anti-inflammatory interventions with placebo, saline, no treatment, or the same regimen without the target component. Weighted mean differences (WMDs) were pooled using random-effects models. RESULTS: Nine RCTs involving 800 patients were included. Anti-inflammatory interventions significantly reduced postoperative C-reactive protein (CRP) [WMD=-32.18, 95% confidence interval (CI) (-41.16, -23.21), P<0.001], interleukin-6 (IL-6) [WMD=-31.25, 95% CI (-41.79, -20.77), P<0.001], rest pain [WMD=-0.41, 95% CI (-0.58, -0.23), P<0.001], activity pain [WMD=-0.56, 95% CI (-0.83, -0.29), P<0.001] and hospital stay [WMD=-0.54, 95% CI (-0.92, -0.15), P=0.006]. CONCLUSION: Recent RCT evidence suggests that perioperative anti-inflammatory interventions can attenuate early inflammatory responses and improve short-term pain and recovery after hip and shoulder arthroplasty. Because data were limited and clinically heterogeneous, the findings should not be interpreted as evidence favoring a specific drug class, dose, route, or timing.

Humans↗
PubMed2026

CST2 promotes melanoma malignant phenotypes through the IL-6-STAT3-NF-&#x3ba;B signaling axis.

BACKGROUND: Melanoma is a highly aggressive malignancy with increasing incidence and mortality over recent decades. Cystatin SA (CST2) encodes a secreted cysteine protease inhibitor that is overexpressed in various cancers and promotes tumor progression; however, its role in melanoma remains unclear. This study aimed to investigate the expression and clinical significance of CST2 in melanoma as well as its biological functions and underlying molecular mechanisms in melanoma progression. METHODS: CST2 expression was analyzed in melanoma tissues using The Cancer Genome Atlas (TCGA) dataset. The prognostic value of CST2 was assessed using Kaplan-Meier analysis. In vitro gain- and loss-of-function experiments were performed to evaluate the effect of CST2 on melanoma cell proliferation, colony formation, and migration. Mechanistic studies included protein-protein docking and co-immunoprecipitation to detect the interaction between CST2 and interleukin-6 (IL-6). Western blotting was used to examine the activation status of IL-6 downstream signaling pathways. RESULTS: CST2 was significantly upregulated in melanoma tissues and was correlated with poor patient prognosis. Overexpression of CST2 promoted melanoma cell proliferation, clonogenicity, and migration, whereas CST2 knockdown suppressed these malignant behaviors. CST2 interacted with IL-6, and its knockdown reduced the expression of IL-6, phospho-STAT3, and phospho-NF-&#x3ba;B. These suppressive effects were reversed by IL-6 overexpression, indicating that CST2 exerted its oncogenic effects through the IL-6-STAT3-NF-&#x3ba;B axis. CONCLUSIONS: CST2 promotes melanoma progression by activating the IL-6-STAT3-NF-&#x3ba;B signaling pathway, and may serve as a potential prognostic biomarker and therapeutic target in melanoma.

CST2↗
PubMed1992

Modulation of GM-CSF receptor beta-subunit and interleukin-6 receptor mRNA expression in a human megakaryocytic leukemia cell line.

Our present study was designed to clarify the mechanism by which the same megakaryocyte progenitor cells respond to various cytokines at different stages of megakaryocyte development. We examined the changes in mRNA expression of granulocyte macrophage colony-stimulating factor receptor beta-subunit (GM-CSFR beta-subunit), which was a common subunit of a high-affinity interleukin-3 receptor (IL-3R) and a high-affinity GM-CSFR, and interleukin-6 receptor (IL-6R) during megakaryocyte development in a human megakaryocytic leukemia cell line (CMK) which could proliferate and/or differentiate in the presence of 12-O-tetradecanoylphorbol 13-acetate (TPA), IL-3, GM-CSF, and IL-6. We found that GM-CSFR beta-subunit mRNA was expressed constitutively in CMK cells and was transiently down-regulated by TPA and IL-6, while the expression of IL-6R mRNA was increased by TPA in association with the differentiation of megakaryocytes. Furthermore, the TPA-induced down-regulation of GM-CSFR beta-subunit mRNA expression and its recovery were blocked by cycloheximide (CHX), a protein synthesis inhibitor, suggesting that these modulations required de novo protein synthesis. These findings imply that multi-lineage cytokines such as GM-CSF and IL-3 may contribute preferentially to the regulation of the earlier development of megakaryocyte progenitor cells with high densities of multi-lineage cytokine receptors, while IL-6 may be limited in its action to supporting the maturation of more differentiated megakaryocyte progenitor cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Differentiation↗
PubMed2026

Type I Interferon Signature is Associated With Lung Disease, Drug-Associated Immune Reactions, and Genetic Variation in Interferon-Linked Pathways in Still Disease.

OBJECTIVE: To evaluate the relationship across type I interferon (IFN-I)-stimulated gene (ISG) expression, Still disease, and the development of lung disease (LD) and drug-associated immune reactions (DAIR) to interleukin-1 (IL-1) and/or IL-6 inhibitors. METHODS: Whole blood ISG expression was quantified by NanoString array. ISG-28 scores were calculated in consecutive patients with Still or Still-like disease. Exome sequencing with family-based variant prioritization identified candidate genes harboring rare candidate causative variants. Lists of candidate genes were subjected to functional enrichment analysis. RESULTS: Among 57 patients (32 children, 25 adults), 16 had elevated ISG-28 scores. This group exhibited higher prevalence of LD (0.44 vs 0.1, P&#xa0;=&#xa0;0.007) and DAIR (0.63 vs 0.17, P&#xa0;=&#xa0;0.003) and lower IL-6 inhibitor use (0 vs 0.25, P&#xa0;=&#xa0;0.048) compared to others. No significant differences were found in the rates of macrophage activation syndrome, active disease, elevated IL-18, or current IL-1 inhibition. The combination of HLA-DRB1*15 with high ISG-28 scores is associated with LD and DAIR with high specificity, whereas absence of both biomarkers had high negative predictive value. Candidate genes from high ISG-28 individuals were enriched in IFN-related pathways, including autophagy, IFN-I production, toll-like receptor signaling, macrophage activation, cytoskeletal organization, and responses to stress. CONCLUSION: High IFN-I expression correlates with LD and DAIR in Still disease, linked to rare genetic variation in immune pathways. Combining high ISG-28 with HLA-DRB1*15 significantly improves post hoc stratification of patients for these complications. If prospectively validated, these findings may guide molecular risk assessment and targeted therapies, including IFN-I directed treatments in Still disease with IFN-I signature.

Humans↗
PubMed1992

T-kininogen, processing and functions.

Studies are presented which indicate that T-kininogen, the acute phase kininogen of the rat, could be a healing protein because of its properties as a cysteine protease inhibitor. Evidence is also presented that mRNA of T-kininogen synthesis may be a function of interleukin 6 production. A regulatory mechanism is postulated by which SH cofactors could determine if T-kinin is released or whether the T-kininogen molecule would remain intact. Evidence is also presented that T-kinin acts through kinin B2 receptors. No specific binding of bradykinin or T-kinin could be detected in rat heart preparations.

Acute-Phase Proteins↗