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PubMed2025

Genetic Downregulation of Interleukin-6 Signaling, Coagulation Function, and Risk of Thromboembolic Disease.

BACKGROUND: Although genetic evidence supports IL-6 (interleukin-6) signaling inhibition as protective against atherosclerotic disease, its potential effects on thromboembolic outcomes are not well established. We conducted a Mendelian randomization analysis to investigate the association of genetically proxied IL-6 signaling inhibition with venous thromboembolism, cardioembolic stroke, and coagulation cascade protein levels. METHODS: IL-6 signaling inhibition was proxied using the rs2228145 IL6R missense variant, which impairs classical IL-6 signaling and lowers CRP (C-reactive protein) levels. Genetic associations with thromboembolic disease outcomes were obtained from genome-wide association studies of venous thromboembolism (81 190 cases) and cardioembolic stroke (10 804 cases). As atherosclerotic comparator traits, we included coronary artery disease (181 522 cases) and large-artery atherosclerotic stroke (6399 cases). Genetic associations with 35 coagulation cascade protein levels were obtained from the UK Biobank (n=6218) and deCODE cohorts (n=35 559). Mendelian randomization estimates were derived using the Wald ratio method, scaled per 1-unit decrease in natural log-transformed CRP levels. RESULTS: Genetically proxied IL-6 signaling inhibition was associated with increased risk of venous thromboembolism (odds ratio [OR], 1.31 [95% CI, 1.16-1.47], P=6.5×10-6) but not with cardioembolic stroke (OR, 1.25 [95% CI, 0.73-2.14], P=0.42). Conversely, protective associations were observed for both coronary artery disease and large-artery atherosclerotic stroke. Proteomic analyses demonstrated significant reductions in levels of 5 procoagulant and 7 anticoagulant or antifibrinolytic proteins. CONCLUSIONS: These findings suggest that IL-6 signaling inhibition dysregulates coagulation homeostasis and increases venous thromboembolism risk. Further experimental, translational, and epidemiologic studies are warranted to delineate underlying mechanisms and to evaluate thromboembolic safety in pharmacologic IL-6 signaling inhibition.

Humans↗
PubMed2026

Downregulated lysyl oxidase in plasma extracellular vesicles: a biomarker linked to brain metastasis risk in lung adenocarcinoma.

BACKGROUND: Brain metastasis (BrM) is a leading cause of mortality in patients with lung adenocarcinoma (LUAD). Extracellular vesicles (EVs), which carry bioactive molecules, play a critical role in tumor microenvironment remodeling and exhibit metastatic organotropism, holding promise as liquid biopsy biomarkers. This study aims to identify plasma EV-derived proteins associated with LUAD-BrM. METHODS: A multi-omics framework was applied. Plasma EVs from 59 stage IV LUAD patients (30 BrM vs 29 non-BrM) were profiled using data-independent acquisition mass spectrometry proteomics. Candidate proteins were screened via bioinformatics and machine learning (LASSO/RF/SVM). Initial validation included tissue proteomics (n = 13), single-cell transcriptomics (TISCH2), and Western blot analysis of a subset of the discovery samples. Functional experiments were conducted in vitro. The lead candidate was ultimately validated in an independent plasma cohort (n = 158) through ELISA. RESULTS: Proteomic analysis implicated collagen-containing extracellular matrix (ECM) pathways. Lysyl oxidase (LOX), a key ECM cross-linking enzyme, was identified as a lead candidate. LOX and its family member LOXL1 were consistently downregulated in BrM tissues and plasma EVs. Single-cell analysis revealed decreased LOX expression specifically in BrM-associated fibroblasts, which showed suppressed ECM-related pathways. In vitro experiments supported a PI3K/AKT-LOX-ECM regulatory axis. Plasma EV-derived LOX demonstrated strong diagnostic performance in the independent cohort, with an AUC of 0.786 (95% CI 0.713iated fi. CONCLUSIONS: Our study establishes plasma EV-derived LOX as a promising non-invasive biomarker for LUAD-BrM through a comprehensive multi-omics validation strategy. We propose a model wherein downregulation of LOX, potentially driven by PI3K/AKT signaling in tumor-associated fibroblasts, contributes to ECM degradation and may promote brain-tropic metastasis. This finding offers new insights for risk stratification and timely intervention in LUAD patients.

Humans↗
PubMed2025

CCDC137 knockdown suppresses bladder cancer progression by downregulating SCD.

BACKGROUND: The Coiled-coil domain-containing (CCDC) family, due to its unique protein structural domain and broad involvement in diverse biological processes, has emerged as a focus in oncology research. Nevertheless, its clinical significance and function in bladder cancer (BLCA) remain poorly defined. METHODS: Machine learning algorithms were employed to identify pivotal CCDC genes in the cancer genome atlas (TCGA), and a prognostic model was subsequently constructed. Multi-omics data encompassing pan-cancer cohorts, single-cell sequencing, and spatial transcriptomics were integrated to characterize the expression patterns and prognostic significance of Coiled-coil domain-containing 137 (CCDC137), a previously uncharacterized CCDC family member in BLCA. Tissue microarray confirmed CCDC137 abnormal expression in bladder carcinoma specimens. The effect of CCDC137 knockdown on BLCA progression was evaluated through CCK8 assay, clonogenic formation, wound healing, Transwell, and subcutaneous xenograft models. RNA sequencing, quantitative RT-PCR, and western blot were utilized to delineate its regulatory network. RESULTS: A prognostic model incorporating 10 CCDC genes was successfully established in the TCGA-BLCA cohort. Then, we found that CCDC137 exhibited pan-cancer overexpression and usually correlation with poor clinical outcomes. Immunohistochemistry further substantiated its dysregulation in bladder carcinoma. Integrated multi-omics analyses suggested associations between CCDC137 expression and a tumor immunosuppressive microenvironment. CCDC137 knockdown significantly suppressed bladder cancer cell proliferation and migratory capacity in vitro. Correspondingly, subcutaneous xenograft tumor growth was inhibited in vivo. Moreover, decreased expression of stearoyl-CoA desaturase (SCD), a key lipid metabolic enzyme, accompanied CCDC137 depletion. These findings collectively suggest a cancer-promoting role for CCDC137 in bladder carcinoma. CONCLUSIONS: This systematic investigation combining multi-omics bioinformatics analyses and experimental validation demonstrates the role of CCDC137 in bladder carcinoma progression, providing novel mechanistic insights into the pathogenesis of BLCA and offering a theoretical foundation for therapeutic targeting of CCDC137 in urothelial malignancies.

Urinary Bladder Neoplasms↗
PubMed2026

miR-2116-5p functions as a tumor suppressor in lung adenocarcinoma by targeting ADAM12 and serves as a prognostic biomarker.

BACKGROUND: MicroRNAs play key roles in tumor progression. miR-2116-5p is downregulated in lung adenocarcinoma (LUAD), and this study investigated its prognostic value and functional role in the disease. MATERIALS AND METHODS: A total of 125 LUAD patients contributed tissue samples. miR-2116-5p and ADAM12 expression in tissues and cell lines were detected by RT&#x2011;qPCR. Clinicopathological correlations of miR-2116-5p were analyzed using the chi-square test. Kaplan&#x2011;Meier and Cox regression were employed to assess prognostic significance. CCK&#x2011;8, Transwell, and dual&#x2011;luciferase reporter assays were performed to investigate miR&#x2011;2116-5p function and its targeting of ADAM12. Rescue experiments validated the functional involvement of ADAM12. RESULTS: Significant downregulation of miR-2116-5p was observed in LUAD tissues and cell lines. Low expression was markedly linked to lymph node metastasis (P&#x2009;=&#x2009;0.013) and advanced TNM stage (P&#x2009;=&#x2009;0.002). Patients exhibiting reduced miR-2116-5p levels showed worse overall survival, and it was identified as an independent prognostic factor (HR&#x2009;=&#x2009;2.521, 95% CI: 1.129-5.628, P&#x2009;=&#x2009;0.020). Functional experiments showed that increasing miR-2116-5p expression suppressed LUAD cell proliferation, migration, and invasion, whereas its knockdown promoted these processes. ADAM12 was confirmed as a direct target, with expression inversely correlated in LUAD tissues (r = -0.749, P&#x2009;<&#x2009;0.001). ADAM12 overexpression effectively counteracted the ability of miR-2116-5p to suppress proliferation, migration, and invasion. CONCLUSION: miR&#x2011;2116-5p suppresses LUAD progression by targeting ADAM12, suggesting it may serve as a prognostic biomarker and therapeutic target.

Humans↗
PubMed1992

Expression and regulation of L-selectin on eosinophils from human adults and neonates.

L-Selectin, previously known as LEC.CAM-1, LECAM-1, LAM1, and as the MEL-14, Leu-8, TQ1, and DREG-56 antigens, is a leukocyte membrane protein that participates in adhesion to endothelium. We studied its expression on eosinophils using flow cytometry and the MAb Dreg-56 and Leu-8. Unstimulated peripheral blood eosinophils from healthy adults expressed about one third the level of L-selectin as neutrophils (mean +/- SD specific fluorescence: 20.9 +/- 3.2 versus 54.5 +/- 8.4, p = 0.0001, n = 18). After stimulation with A23187, L-selectin expression on eosinophils was rapidly lost. This was temporally correlated with increased expression of Mac-1 (CD11b/CD18); the kinetics on eosinophils and neutrophils were similar. Eosinophil expression of L-selectin decreased modestly after stimulation with platelet activating factor, but was minimally affected by N-formyl-methionyl-leucyl-phenylalanine, leukotriene B4, or C5a compared with their effects on neutrophils. Eosinophils from cord blood of healthy neonates born at term expressed less L-selectin than adult eosinophils (10.4 +/- 3.8 versus 19.4 +/- 2.7, p = 0.0001, n = 9); the relative reduction was the same as on cord blood neutrophils (36.4 +/- 8.2 versus 55.5 +/- 4.8, p = 0.0001, n = 9). Relative to baseline expression, the responses of neonatal and adult cells to stimulation did not differ. We conclude that neonatal eosinophils have abnormalities in L-selectin expression similar to neonatal neutrophils and suggest that decreased expression of L-selectin and a diminished responsiveness to direct stimulation with chemotactic factors are possible mechanisms that may limit the exudation of eosinophils.

Adult↗
PubMed2004

Genetic analysis of pathways regulated by the von Hippel-Lindau tumor suppressor in Caenorhabditis elegans.

The von Hippel-Lindau (VHL) tumor suppressor functions as a ubiquitin ligase that mediates proteolytic inactivation of hydroxylated alpha subunits of hypoxia-inducible factor (HIF). Although studies of VHL-defective renal carcinoma cells suggest the existence of other VHL tumor suppressor pathways, dysregulation of the HIF transcriptional cascade has extensive effects that make it difficult to distinguish whether, and to what extent, observed abnormalities in these cells represent effects on pathways that are distinct from HIF. Here, we report on a genetic analysis of HIF-dependent and -independent effects of VHL inactivation by studying gene expression patterns in Caenorhabditis elegans. We show tight conservation of the HIF-1/VHL-1/EGL-9 hydroxylase pathway. However, persisting differential gene expression in hif-1 versus hif-1; vhl-1 double mutant worms clearly distinguished HIF-1-independent effects of VHL-1 inactivation. Genomic clustering, predicted functional similarities, and a common pattern of dysregulation in both vhl-1 worms and a set of mutants (dpy-18, let-268, gon-1, mig-17, and unc-6), with different defects in extracellular matrix formation, suggest that dysregulation of these genes reflects a discrete HIF-1-independent function of VHL-1 that is connected with extracellular matrix function.

Animals↗
PubMed2023

Dominant negative variants in KIF5B cause osteogenesis imperfecta via down regulation of mTOR signaling.

BACKGROUND: Kinesin motor proteins transport intracellular cargo, including mRNA, proteins, and organelles. Pathogenic variants in kinesin-related genes have been implicated in neurodevelopmental disorders and skeletal dysplasias. We identified de novo, heterozygous variants in KIF5B, encoding a kinesin-1 subunit, in four individuals with osteogenesis imperfecta. The variants cluster within the highly conserved kinesin motor domain and are predicted to interfere with nucleotide binding, although the mechanistic consequences on cell signaling and function are unknown. METHODS: To understand the in vivo genetic mechanism of KIF5B variants, we modeled the p.Thr87Ile variant that was found in two patients in the C. elegans ortholog, unc-116, at the corresponding position (Thr90Ile) by CRISPR/Cas9 editing and performed functional analysis. Next, we studied the cellular and molecular consequences of the recurrent p.Thr87Ile variant by microscopy, RNA and protein analysis in NIH3T3 cells, primary human fibroblasts and bone biopsy. RESULTS: C. elegans heterozygous for the unc-116 Thr90Ile variant displayed abnormal body length and motility phenotypes that were suppressed by additional copies of the wild type allele, consistent with a dominant negative mechanism. Time-lapse imaging of GFP-tagged mitochondria showed defective mitochondria transport in unc-116 Thr90Ile neurons providing strong evidence for disrupted kinesin motor function. Microscopy studies in human cells showed dilated endoplasmic reticulum, multiple intracellular vacuoles, and abnormal distribution of the Golgi complex, supporting an intracellular trafficking defect. RNA sequencing, proteomic analysis, and bone immunohistochemistry demonstrated down regulation of the mTOR signaling pathway that was partially rescued with leucine supplementation in patient cells. CONCLUSION: We report dominant negative variants in the KIF5B kinesin motor domain in individuals with osteogenesis imperfecta. This study expands the spectrum of kinesin-related disorders and identifies dysregulated signaling targets for KIF5B in skeletal development.

Animals↗
PubMedDate not supplied

Pardaxin-stimulated calcium uptake in PC12 cells is blocked by cadmium and is not mediated by L-type calcium channels.

Pardaxin is an excitatory neurotoxin which triggers neurotransmitter release as a result of voltage-dependent pore formation within the neuronal membrane. We have used several pharmacological manipulations of calcium influx to characterize pardaxin pore activity in PC12 cells in culture. Pardaxin stimulates the uptake of radioactive calcium into PC12 cells in a dose dependent fashion (ED50 of 0.4 microM). This stimulation is partially inhibited by nifedipine, a blocker of L-type calcium channels. Effective blockade of pardaxin stimulation was produced by the inorganic calcium channel blockers cadmium (IC50 of 10 microM) and nickel (2 mM). Homologous down regulation of L-calcium channels by the agonist Bay K-8644, inhibited the subsequent stimulation of calcium uptake by this drug, but not by pardaxin. A fluorometric analysis of pardaxin pore formation in unilamellar large liposomes indicates pardaxin pores are blocked by cadmium (10-200 microM). These data distinguish between pardaxin pores and L-type calcium channels in PC12 cells. We suggest pardaxin as a pharmacological ionophore tool to modulate neuronal calcium homeostasis and neurotransmitter release.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2026

The Anti-Osteoporosis Effects of Panax japonicus via Downregulation of Inflammatory Factors: A Network Pharmacology and Ovariectomized Rat Model Study.

OBJECTIVE: Osteoporosis is a major and growing public health problem characterized by decreased bone mineral density and destroyed bone microarchitecture. Panax japonicus has been clinically used in the treatment of bone diseases, especially osteoporosis. However, there is a lack of study on the mechanism of osteoporosis treatment with Panax japonicus. MATERIALS AND METHODS: A network pharmacology approach was employed to identify the targets of osteoporosis and Panax japonicus. Cytoscape 3.7.2 and DAVID were used to visualize the pharmacological mechanism of Panax japonicus in treating osteoporosis by building up compound-target and protein-protein interaction (PPI) networks and conducting Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. An ovariectomized SD rat osteoporosis model was used to assess the potential therapeutic effect of Panax japonicus in vivo. The biomechanical properties, pathological changes, inflammatory cytokines, bone density, and bone microstructural parameters in rat bone tissue were carefully measured. The biochemical markers of bone metabolism in serum were detected by Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS AND DISCUSSION: Fifty-two active components and sixty-five target genes of Panax japonicus involved in the treatment of osteoporosis were identified. The PPI network revealed IL-6, TNF, NR3C1, IL-1&#x3b2;, CASP3, ESR1, PGR, and AR to be involved in the treatment of osteoporosis with Panax japonicus. Chikusetsusaponin IVa and Radix ginsenoside-Ro were the main saponins found in Panax japonicus. Panax japonicus was found to exert potent preventive effects on osteoporosis by maintaining biomechanical properties, increasing bone mineral density, and protecting the trabecular microstructure in an ovariectomized rat osteoporosis model. Panax japonicus hindered the initiation of osteoporosis induced by ovariectomy by regulating bone metabolism and downregulating the expression of IL-6 and TNF-&#x3b1;. CONCLUSION: Panax japonicus was found to contain 52 compounds and 65 targets in the treatment of osteoporosis. The administration of Panax japonicus could mitigate osteoporosis in rats induced by ovariectomy, and one of the mechanisms was associated with downregulating the expression of inflammatory factors.

Animals↗
PubMed1992

Down regulation of stem cell colony formation by purified CD8 lymphocytes and CD8 conditioned medium: potential importance for bone marrow transplantation in leukemia.

A methodology for selection of the CD8 cell subset from the peripheral blood and bone marrow mononuclear cells was developed using anti-T8 (CD8) antibody and magnetic microspheres coated with anti-mouse IgG. Following optimization of antibody:cell binding ratio and microsphere:cell ratios, CD8(+)-cells in the peripheral blood and bone marrow were effectively removed, with an overall final recovery of 34.9% +/- 8.6%, and 56% +/- 8.5% respectively with complete recovery of stem cells and very little contamination with effector cells. CD8(+)-depleted cell preparations demonstrated a 3-4 fold increase in CFU-C and CFU-E colony formation over non-depleted preparations when stimulated with G-CSF, GM-CSF or IL-3 and erythropoietin. The largest increase in colony formation was evident when IL-3 was used to stimulate colony formation. Purified autologous CD8+ T-cells or culture supernatant from in vitro cultures of purified autologous CD8+ T-cells added back to CD8 depleted preparations, induced 20%-90% suppression of CFU-C and CFU-E colony formation in a dose dependent manner. Colony formation by CD34+ cells, purified by anti CD34 antibodies and magnetic microspheres, were also inhibited by either pure CD8(+)-cell populations or CD8-culture supernatant. Preliminary fractionation studies indicate that the inhibitory factor is a protein of > 50 kd. In contrast, when purified autologous CD4+ cells were added to purified CD34+ stem cells, an increase (< 50%) in colony formation was observed. These results, taken together, suggest that CD8+ T-cells are negative effectors of normal hematopoiesis whereas CD4+ T-cells function as positive effectors.

Animals↗
PubMed1992

Terbutaline-induced downregulation of beta 2-adrenoceptors without Gi-protein alterations in human lymphocytes.

Recent evidence suggests that agonist-induced desensitization of Gs protein-coupled beta-adrenoceptors is accompanied by sensitization of Gi protein-coupled receptors and/or an increase in Gi protein. To find out whether such "cross-regulation" between Gs protein- and Gi protein-coupled receptors can be also demonstrated in vivo in humans, we studied the effects of a 2 week treatment of eight male volunteers with the beta 2-adrenoceptor agonist terbutaline (3 x 5 mg/day) on beta 2-adrenoceptor density and Gi-protein content in lymphocytes and on alpha 2-adrenoceptor density (Gi-coupled receptors) in platelets. Terbutaline decreased the lymphocyte beta 2-adrenoceptor density by about 30%, but had no significant influence on lymphocyte Gi-protein levels (assessed by pertussis toxin-catalyzed [32P]ADP ribosylation) or on platelet alpha 2-adrenoceptor density. We conclude that circulating blood cells are not suitable to demonstrate in humans in vivo a "cross-regulation" between Gs- and Gi-coupled beta- and alpha-adrenoceptors.

Adult↗
PubMed1992

Lipoproteins, lipases, and the metabolic cardiovascular syndrome.

High levels of plasma triglycerides and very-low-density lipoproteins and low levels of high-density lipoproteins are consistently found in the metabolic cardiovascular syndrome. These changes are exaggerated postprandially. In the liver, synthesis and secretion of triglyceride-rich particles are increased. In addition, the removal capacity of plasma triglycerides is decreased, due to downregulation of lipoprotein lipase in skeletal muscles by hyperinsulinemia. Resistance to insulin-stimulated glucose uptake is believed to be the main pathogenetic factor. However, increased flux of free fatty acids from abdominally localized adipose tissue must also be considered when discussing pathogenesis. Treatment is primarily nonpharmacological, with diet and increased physical activity.

Blood Glucose↗
PubMedDate not supplied

Endotoxin tolerance: regulation of cytokine production and cellular changes in response to endotoxin application in cancer patients.

Endotoxin (lipopolysaccharide, LPS) has the property of inducing tolerance to its own biological effects. This phenomenon has been extensively studied in animal models but only few studies exist on the regulation in humans. Here we describe experiments designed to determine the cytokine regulation and cellular changes in humans during induction of LPS tolerance after repeated LPS injections. Intravenous administration of purified LPS Salmonella abortus equi to cancer patients induces high amounts of circulating tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-8 (IL-8), granulocyte colony-stimulating factor (G-CSF), and macrophage colony-stimulating factor (M-CSF). Repeated injections of LPS at daily intervals resulted in a marked downregulation of the cytokine response and in the case of TNF-alpha, IL-8, G-CSF, and M-CSF the cytokine response was reduced to baseline levels. In contrast, significant increases in serum IL-6 were detected up to day 5 of repeated LPS injections. Hematological changes included transient decreases in WBCs affecting granulocytes, monocytes, and lymphocytes, followed by a marked granulocytosis. The drop in WBCs remained unaltered throughout the 5 day course of repeated LPS injections whereas the granulocyte overshoot recovery diminished gradually. When PBMCs of the cancer patients were restimulated ex vivo a marked enhancement of the capacity to produce TNF-alpha, IL-113, and IL-6 occurred, which is in contrast to the decreasing TNF-alpha serum levels obtained in vivo. In parallel, a shift in monocyte subpopulations from CD14+/CD16- to CD14+/CD16+ cells was observed. The data provide evidence that different mechanisms are implicated in the cytokine downregulation following repeated LPS injections to cancer patients. Furthermore, PBMCs from LPS tolerant patients do not demonstrate a reduction in their capacity to produce cytokines.

Antigens, CD↗
PubMedDate not supplied

Biological roles of HIV Nef proteins. A minireview.

The nef gene, its protein products and diverse mechanisms by which HIV pathogenicity is nef-mediated in vivo and in vitro explain the huge amount of works on this topic. Until now the following functional roles have been assigned for nef: 1. downregulation of virus replication; 2. GTP binding and GTPase activities; 3. modulation of cytoplasmic signalling; and 4. cellular (CD4 and IL-2) gene regulation. Many reports which demonstrate the possible functions of nef in viral replication and in development of AIDS have been refuted by other scientists who failed to confirm some biological activities. Host immune response against nef proteins has been claimed as an early diagnosis marker or to be involved in disease progression. Also, nef proteins have been involved in blocking of HLA antigens, in superantigen production or in crossreactivity with some cellular antigens. The role of nef is a complex one, important in establishing and maintaining viral latency in vivo and regulating virus replication in vitro.

Down-Regulation↗
PubMed1992

Downregulation of saturated fatty acid and upregulation of unsaturated fatty acid by 13-cis-retinoic acid in human prostate cancer cells.

Retinoids play a major role in regulation of epithelial cell growth and cellular differentiation, but their mechanism(s) of action are still unclear. In the present study, we examined the effects of 13-cis-retinoic acid (13-cis-RA) on cytotoxicity, growth properties, morphology, neutral lipids, phospholipids and fatty acids in cultured human prostate cancer cell lines. The results of these experiments suggest that 13-cis-RA (10 microM) inhibits the DNA synthesis and nude mice tumorigenicity by 2- to 3-fold, compared to control. Electron microscopy revealed more differentiated phenotypes after 13-cis-RA treatment. There was a significant increase in phosphatidylcholine and decrease in sphingomyelin in 13-cis-RA treated cells compared to control. The saturated fatty acids significantly decreased whereas unsaturated fatty acids were increased after 13-cis-RA treatment in prostate cancer cells. This study demonstrates for the first time that retinoic acid mediated downregulation of saturated fatty acids and upregulation of unsaturated fatty acid in human prostate cancer cells.

Animals↗
PubMed1992

Tissue distribution of MHC class II--positive cells, their down-manipulation by monoclonal antibodies and potential role in organ allograft immunogenicity.

This review article presents current state of knowledge of tissue distribution of MHC class II antigens in rat kidney. Our attention focuses particularly on down manipulation of these antigens by monoclonal antibodies. The results of organ perfusion procedure on prolongation of graft survival and perspectives of further studies are also discussed.

Animals↗
PubMed1992

The role of Ca2+ in cadmium-induced renal tubular cell injury.

Changes in rat renal proximal tubule cell gene expression were studied in vitro using a cadmium metallothionein (CdMT) exposure model. Increased expression of MT together with alterations in the expression of several other stress protein products were demonstrated by 35S-two-dimensional gel electrophoresis. Stress proteins with estimated molecular masses of 32, 70 and 90 kDa were observed to be increased after 4 h of exposure. These changes preceded the onset of cell injury. Internal stores of Ca2+ were not found to be measurably altered, as measured by the changes in fluorescence of the dye FURA-2. These data suggest that the observed alterations in gene expression are directly mediated by Cd2+ and not secondary to increased availability of Ca2+ within the target cell population, perhaps mediated by the transacting factor which regulates MT synthesis. The calcuria resulting from in vivo exposure to Cd2+ in workers or CdMT exposure in animal models may be secondary to alterations in renal proximal tubule cell gene expression.

Animals↗