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At least 217 records · Page 12Linked to original sources
PubMed1992

Mobilization of an intracellular glycoprotein (Mac-1) on monocytes and granulocytes during hemodialysis.

We studied the upregulation of the intracellular glycoprotein Mac-1 (CD11b/CD18, CR3) on monocytes and granulocytes during 36 bicarbonate hemodialyses in 12 patients who were randomly treated with Cuprophan (Cu), Hemophan (He) or Polysulfone (PS; low-flux) membranes. The degree of mobilization of this adhesion protein was related to changes in granulocyte and monocyte count, generation of C3a and production of interleukin-1 beta in plasma. Mac-1 expression on granulocytes was significantly higher after 5 and 15 min of Cu hemodialysis as compared to He or PS dialyses (p < 0.001) and correlated to changes in granulocyte count at 15 min (r = 0.62 and r = 0.76, p < 0.001). No differences in early Mac-1 mobilization on circulating monocytes was observed despite a decrease in cell count. Mac-1 expression on monocytes and granulocytes in the venous blood line at 180 min of treatment was significantly higher during Cu dialysis as compared to He and PS dialyses (p < 0.02 and p < 0.001, respectively). Early generation of C3a was higher in patients on Cu dialysis than in He or PS dialysis (p < 0.001) and correlated both to granulocytopenia (r = 0.45, p < 0.01) and to the subsequent increase in Mac-1 expression on granulocytes (r = 0.63, p < 0.001). An early increase in Mac-1 expression on monocytes was accompanied by an increase in plasma interleukin-1 beta later during dialysis (p < 0.05). Studies of Mac-1 expression during hemodialysis increased the sensitivity of biocompatibility measurements and correlated better than complement generation to changes in granulocyte count as it mediates adhesion to endothelial cells.

Adult↗
PubMed1992

A low-sodium diet corrects the defect in beta-adrenergic response in older subjects.

BACKGROUND: One of the prominent cardiovascular abnormalities in the elderly is reduced beta-adrenoceptor responsiveness. Because dietary sodium restriction corrects the defect in vascular and lymphocyte beta-adrenoceptor responsiveness in hypertensive subjects, we postulated an analogous effect in the elderly. Thus, vascular and lymphocyte beta-adrenergic responsiveness were studied in 10 older normotensive subjects (age, 56 +/- 2 years) on either a 400- or 10-meq/day sodium diet. METHODS AND RESULTS: In older subjects fed a high-sodium diet, maximal isoproterenol-mediated vasodilation was depressed compared with a group of normotensive younger subjects studied previously. When they were fed a low-sodium diet, however, maximal isoproterenol-mediated vasodilation in the elderly was increased significantly. Lymphocyte adenylyl cyclase sensitivity to isoproterenol was comparably increased. Blood pressure was significantly reduced on a low-sodium diet, and mean arterial pressure was significantly inversely correlated with the extent of isoproterenol-mediated vasodilation. CONCLUSIONS: These studies indicate that a low-sodium diet corrects the defect in both vascular and lymphocyte beta-adrenergic responsiveness with aging. This suggests an important role for dietary modification in the adrenergic regulation of vascular tone in the elderly.

Adenylyl Cyclases↗
PubMed1992

Isolated presynaptic inotropic beta-adrenergic supersensitivity of the transplanted denervated human heart in vivo.

BACKGROUND: The regulation of contractility of the transplanted heart depends on circulating catecholamines resulting from cardiac denervation. Supersensitivity to circulating catecholamines may result from loss of presynaptic neuronal uptake or upregulation of postsynaptic beta-adrenergic receptors. METHODS AND RESULTS: Dose-response curves using the beta-adrenergic receptor agonists isoprenaline (no neuronal uptake) and epinephrine (neuronal uptake) were performed in vivo. The inotropic response was measured echocardiographically as the increase of fractional shortening (delta FS) and the increase of the systolic pressure/dimension ratio (delta P/D). The inotropic response to increasing doses of isoprenaline (5-20 ng/kg.min) was identical in 36 heart transplant recipients compared with 13 control subjects: delta FS during 20 ng/kg.min isoprenaline amounted to 18.2 +/- 6.2% versus 17.4 +/- 4.0% (NS) and delta P/D to 2.3 +/- 1.2 mm Hg/mm versus 2.2 +/- 0.5 mm Hg/mm (NS), respectively. A vagally mediated indirect negative inotropic effect in the innervated hearts was excluded by identical inotropic responses to isoprenaline in control subjects without and after atropine pretreatment. The inotropic response to increasing doses of epinephrine (10-40 ng/kg.min) was significantly augmented in 13 heart transplant recipients compared with 11 control subjects: delta FS during 40 ng/kg.min epinephrine amounted to 19.9 +/- 2.6% versus 8.6 +/- 2.0% (p less than 0.001) and delta P/D to 2.3 +/- 0.9 mm Hg/mm versus 0.6 +/- 0.3 mm Hg/mm (p less than 0.001), respectively. Pretreatment with desipramine (blockade of neuronal uptake) in control subjects resulted in a significantly increased inotropic response: delta FS during 40 ng/kg.min epinephrine amounted to 17.6 +/- 3.6% (p less than 0.001 versus untreated controls, NS versus heart transplant recipients) and delta P/D to 1.7 +/- 0.8 mm Hg/mm (p less than 0.001 versus untreated controls, NS versus heart transplant recipients). CONCLUSIONS: These findings provide evidence against a postsynaptic inotropic supersensitivity or subsensitivity of the beta-adrenergic receptor-effector system of the transplanted denervated human heart in vivo. However, a marked presynaptic inotropic supersensitivity is present because of denervation-associated loss of neuronal catecholamine uptake.

Adult↗
PubMed1992

The immediate early genes of human cytomegalovirus require only proximal promoter elements to upregulate expression of interleukin-1 beta.

Human cytomegalovirus (HCMV) can infect monocytes and macrophages. The immediate early one (IE1) gene product of HCMV positively regulates its own expression, as well as the expression of the interleukin-1 beta (IL-1) gene. This study describes the IL-1 promoter proximal region required for upregulation of IL-1 gene expression by the HCMV IE1 or IE1 plus IE2 gene products. An IL-1 chloramphenicol acetyltransferase (CAT) construct containing the IL-1 genomic upstream sequence from position -1097 to +14 and four additional IL-1CAT plasmids containing progressive deletions of the -1097 to -131 sequence were used to evaluate the effect of the HCMV IE gene products on IL-1 gene expression. IL-1CAT plasmids were transfected into a monocytic cell line, THP-1, with plasmids containing either the IE promoter-regulatory region upstream of the bona fide IE1 (pIE1), IE2 (pIE2), or IE1+2 genes (pIE1+2) or a control plasmid containing the IE promoter-regulatory region alone (pLink760). In the presence of pIE1+2, there was an approximate 15-fold increase in CAT activity compared with the control, pLink760, in cells with CAT plasmids containing the -1097 to +14 IL-1 sequence. Plasmids with progressive deletions of this sequence, including the plasmid containing the shortest upstream segment (-131 to +14) also had an approximate 15-fold increase in CAT activity. The upregulation of IL-1 expression was mediated, primarily, by IE1 and not by IE2. This effect was promoter specific because an IL-1CAT plasmid with a complete deletion of the proximal promoter elements (-234 to +146) did not respond to the HCMV IE gene products.(ABSTRACT TRUNCATED AT 250 WORDS)

Chloramphenicol O-Acetyltransferase↗
PubMed1992

Beta-adrenergic upregulation of the Na(+)-K(+)-2Cl- cotransporter in rat parotid acinar cells.

We used the pH-sensitive fluorescent dye 2',7'-bis(2-carboxyethyl)-5(6')-carboxyfluorescein to monitor the recovery of the intracellular pH (pHi) of rat parotid acini from an NH4(+)-induced alkaline load. This recovery was markedly inhibited by the loop diuretic bumetanide and by Cl- removal, indicating that it is largely due to NH4+ entry via the basolateral Na(+)-K(+)-2Cl- cotransporter. The rate of recovery of pHi was enhanced threefold by pretreatment (37.5 s) with isoproterenol (K1/2 = 21.5 nM) or norepinephrine (in the presence of phentolamine), and blocked by the beta 1-specific antagonist atenolol, indicating an upregulation of cotransport activity by beta 1-adrenergic stimulation. The effect of isoproterenol was prevented by protein kinase inhibitors and mimicked by cAMP analogues, and by maneuvers known to increase cytosolic cAMP levels in these cells, consistent with the involvement of protein kinase A. Physiologically, such an upregulation of the acinar Na(+)-K(+)-2Cl- cotransporter would lead to an increase in acinar chloride uptake across the basolateral membrane, and consequently, an increase in overall chloride and fluid secretion. Prevention of this upregulation by beta-blockers and possibly by other commonly used clinical agents may account for the dry mouth and dry eyes experienced by some patients taking these medications.

Animals↗
PubMed2025

MEIS1 knockdown upregulates WNT signaling pathway genes in esophageal squamous cell carcinoma.

BACKGROUND: The transcription factor MEIS1 belongs to the 3-amino acid loop extension (TALE) family of homeodomain proteins which plays various functions in normal and tumor cell progression. The canonical WNT/&#x3b2;-catenin pathway governs a plethora of biological processes including cell proliferation, differentiation, and tumor development. In the present study, the effect of MEIS1 gene silencing was assessed on WNT pathway genes in esophageal squamous cell carcinoma (ESCC) cells. MATERIALS AND METHODS: Along with the packaging plasmids, the pLKO.1-MEIS1 plasmid was cotransfected into HEK293T to generate lentiviral particles, followed by transduction of a semi-confluent KYSE-30 cell culture. After total RNA extraction and cDNA synthesis, comparative real-time PCR was applied to assess the efficiency of MEIS1 knockdown and the expression of genes related to the WNT signaling pathway. RESULTS: The results revealed effective downregulation of MEIS1 in KYSE-30 cells. Interestingly, MEIS1 silencing led to a substantial overexpression of WNT pathway key components while the expression of negative regulators of this pathway was substantially decreased. CONCLUSIONS: Our data suggest that MEIS1 gene probably induces WNT/&#x3b2;-catenin pathway deactivation in ESCC cells. Consequently, the inverse correlation of MEIS1 expression and WNT signaling pathway activation may introduce a new molecular linkage through ESCC progression and aggressiveness.

Humans↗
PubMed2025

Elevated triglyceride-glucose index and risk of thymoma-associated myasthenia gravis: a prospective analysis from the UK Biobank.

BACKGROUND: Thymoma-associated myasthenia gravis (MG) is a clinically significant but uncommon condition, affecting up to half of thymoma patients and associated with worse outcomes than either disease alone. Reliable biomarkers for early risk stratification remain scarce. The triglyceride-glucose (TyG) index and triglyceride-to-high-density lipoprotein cholesterol (TG/HDL-C) ratio are established biomarkers reflecting insulin resistance and dyslipidemia. However, their clinical associations with thymoma-associated MG remain incompletely characterized. METHODS: A total of 501,954 UK Biobank participants were included. After exclusions, 422,397 (313 cases) were analyzed for TyG index and 422,691 (314 cases) for TG/HDL-C ratio. Exposures were stratified into quartiles, and assessed continuously per unit increase. Cox proportional hazards models estimated hazard ratios (HRs), restricted cubic splines (RCS) assessed non-linear associations, and subgroup analyses were stratified by body mass index (BMI). Sensitivity analyses examined TyG index and MG alone. RESULTS: An elevated TyG index was associated with increased risk of thymoma-associated MG. Compared to Q1, Q4 had higher risk (HR&#x2009;=&#x2009;1.66, 95% CI: 1.20-2.31, P&#x2009;=&#x2009;0.003); the overall HR per unit increase was 1.42 (95% CI: 1.17-1.73, P&#x2009;=&#x2009;0.0005). TG/HDL-C ratio showed similar patterns: Q4 vs Q1 HR&#x2009;=&#x2009;1.54 (95% CI: 1.11-2.15, P&#x2009;=&#x2009;0.01); overall HR per unit increase was 1.06 (95% CI: 1.02-1.10, P&#x2009;=&#x2009;0.002). Non-linear relationships were observed, with suggested inflection points at TyG index 8.7 and TG/HDL-C ratio 2.8, rather than strict thresholds. Subgroup analyses revealed stronger associations in normal-weight and obese participants, although tests for interaction were not statistically significant. Sensitivity analyses confirmed consistent associations between TyG index and MG risk, including for isolated MG. CONCLUSION: Elevated TyG index and TG/HDL-C ratio were independently associated with higher thymoma-associated MG risk in this large prospective cohort, with evidence of non-linear relationships and BMI-related heterogeneity. These findings provide novel epidemiologic evidence linking metabolic markers of insulin resistance with thymoma-associated MG, but clinical translation requires further validation.

Humans↗
PubMed2025

TNF-&#x3b1;/NF-&#x3ba;B mediated upregulation of Dectin-1 in hyperglycemic obesity: implications for metabolic inflammation and diabetes.

BACKGROUND: Dectin-1, a key innate immune receptor, plays a critical role in cellular responses and is implicated in chronic inflammation and metabolic syndromes. This study addresses a pivotal gap in elucidating the regulatory mechanism governing Dectin-1 expressionin obesity and diabetes, hypothesizing that hyperglycemia and TNF-&#x3b1; synergistically upregulate Dectin-1 in adipose tissue (AT), thereby exacerbating inflammatory responses and contributing to metabolic dysfunction. METHODS: The study included 95 overweight and obese Kuwaiti individuals, categorized into prediabetic (HbA1c&#x2009;<&#x2009;6.5%) and diabetic (HbA1c&#x2009;&#x2265;&#x2009;6.5%) groups. Anthropometric and clinical measurements were recorded. AT biopsies were obtained for RNA extraction and immunohistochemistry. Pre-adipocytes from lean and obese individuals were cultured, differentiated into adipocytes, and treated with TNF-&#x3b1; under normal or high-glucose conditions to assess Dectin-1 expression. Chromatin immunoprecipitation (ChIP) assays analyzed NF-&#x3ba;B binding to the Dectin-1 promoter. Wildtype and TNF-&#x3b1;-/- mice were used to evaluate TNF-&#x3b1;'s effect on Dectin-1 expression in AT. RESULTS: Our data demonstrate that hyperglycemic obesity significantly induces Dectin-1 expression in AT through the TNF-&#x3b1;/NF-&#x3ba;B signaling pathway. In a cohort of 95 obese individuals, subdivided into prediabetics (HbA1c&#x2009;<&#x2009;6.5%, n&#x2009;=&#x2009;49) and diabetics (HbA1c&#x2009;&#x2265;&#x2009;6.5%, n&#x2009;=&#x2009;46), a strong positive correlation was observed between AT Dectin-1 transcripts and plasma HbA1c levels exclusively in diabetic participants, underscoring the specificity of Dectin-1 upregulation in hyperglycemic conditions. Elevated Dectin-1 expression was consistently associated to increased inflammation markers. Immunohistochemical analysis revealed co-localization and concurrent upregulation of Dectin-1 and TNF-&#x3b1; proteins in hyperglycemic AT. Functional assays in TNF-&#x3b1; deficient mice and human adipocytes further validated that TNF-&#x3b1; and hyperglycemia act cooperatively to regulate Dectin-1 expression. Mechanistically, we demonstrated that NF-&#x3ba;B directly binds to the Dectin-1 promoter, mediating its transcriptional activation in response to glucose and TNF-&#x3b1;. CONCLUSION: This study significantly advances the understanding of upregulation Dectin-1 in metabolic inflammation, filling a crucial niche in diabetes research and suggesting new therapeutic targets for obesity-related metabolic disorders.

Humans↗
PubMed2025

CAFs activated by YAP1 upregulate cancer matrix stiffness to mediate hepatocellular carcinoma progression.

BACKGROUND: The stiffness of the matrix is closely related to the progression of hepatocellular carcinoma (HCC). Although direct targeting of stromal rigidity in HCC remains a clinical challenge, cancer-associated fibroblasts (CAFs) are considered key contributors to this process. Given the heterogeneity of CAFs, this study explored the relationship between specific CAF subsets and liver cancer matrix stiffness, aiming to identify novel therapeutic targets for HCC patients. METHODS: Single-cell sequencing datasets were leveraged to identify cell types within liver cancer and characterize the transcriptomic profiles of CAFs. Prognostic analysis, utilizing the Gene Expression Profiling Interactive Analysis (GEPIA) and The Cancer Genome Atlas (TCGA) liver cancer datasets, assessed the correlation between matrix stiffness-related genes and HCC patient outcomes. Pseudo-time analysis was applied to trace the developmental trajectories of CAFs. By calculating intercellular communication probabilities and analyzing transcription factor activity, the functions and interactions of different CAF subsets were elucidated. Gene Ontology (GO) analysis was used to explore the functional roles of CAFs in distinct Yes-associated protein 1 (YAP1) groups. Finally, cellular experiments and animal experiments were further conducted to validate the hypotheses of this study. RESULTS: This study identified CAF subpopulations based on single-cell sequencing data and analyzed transcriptional changes within these subpopulations. Key findings include the identification of collagen type I alpha 1 (COL1A1), collagen type III alpha 1 (COL3A1), and lysyloxidase (LOX) as pivotal node genes during CAF development. Moreover, the expression of matrix stiffness-related genes was inversely correlated with the prognosis of HCC patients. Notably, the YAP1-positive CAF subpopulation emerged as the primary contributor to matrix stiffness in liver cancer. This subpopulation upregulates the expression of matrix stiffness-related genes and promotes tumor progression by activating signaling pathways such as autophagy and GTPase activity regulation. Cellular experiments and animal studies further validated this conclusion. CONCLUSION: This single-cell analysis uncovered the functional roles of CAFs in liver cancer. The YAP1-positive CAF subpopulation, in particular, was shown to contribute to matrix stiffness by upregulating the expression of relevant genes and promoting tumor progression through the activation of specific signaling pathways.

Carcinoma, Hepatocellular↗
PubMed2026

FMRP promotes gastric cancer progression via m6A-dependent stabilization of DVL2 and activation of the Wnt/PCP-JNK pathway.

BACKGROUND: N6-methyladenosine (m6A) modification has emerged as a critical regulator in gastric cancer progression. Fragile X messenger ribonucleoprotein 1 (FMRP), an RNA-binding protein with tumorigenic potential, remains poorly characterized in gastric cancer. METHODS: FMRP expression in gastric cancer was assessed through bioinformatic analyses and tissue microarray-based immunohistochemistry. Its biological functions were examined through loss-of-function experiments in vitro and in vivo. Mechanistic investigations, including RNA interaction, m6A site mutation, and RNA stability analyses, were performed to identify downstream targets and pathways regulated by FMRP. RESULTS: Bioinformatic analyses and tissue microarray-based immunohistochemistry showed that FMRP was significantly upregulated in gastric cancer tissues. FMRP depletion suppressed tumor growth and metastasis. Subsequently, Dishevelled segment polarity protein 2 (DVL2) was identified as a candidate downstream target of FMRP. DVL2 was also significantly upregulated in gastric cancer tissues, and its expression positively correlated with FMRP expression. Mechanistically, FMRP bound to DVL2 mRNA and enhanced its stability in an m6A-dependent manner. Among the candidate sites tested, mutation of 1271A attenuated FMRP-mediated regulation of DVL2 reporter activity, supporting the involvement of this site. Functionally, FMRP promoted activation of the noncanonical Wnt/planar cell polarity (PCP) signaling pathway and enhanced the proliferative, migratory, and invasive capacities of gastric cancer cells via DVL2. CONCLUSIONS: These results define FMRP as an oncogenic driver in gastric cancer that operates via the DVL2/Wnt/PCP axis. Targeting this pathway may provide a potential therapeutic strategy for gastric cancer.

Stomach Neoplasms↗
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↗
PubMed2025

Expression of long noncoding RNAs in peripheral blood mononuclear cells of patients with type 1 diabetes mellitus: potential biomarkers for disease onset.

OBJECTIVE: Long non-coding RNAs (lncRNAs) do not encode proteins and are transcripts longer than 200 nucleotides. The precise involvement of lncRNAs in type 1 diabetes mellitus (T1DM) pathogenesis remains unclear. Therefore, this study aimed to analyze the expressions of five lncRNAs in peripheral blood mononuclear cells of individuals with T1DM and without DM. MATERIALS AND METHODS: This study comprised 27 patients with T1DM (cases) and 13 individuals without DM (controls). The case group was divided into two subgroups based on T1DM duration: < 5 years of diagnosis group and long-term diabetes group (&#x2265;5 years). LncRNA expression was evaluated by qPCR. RESULTS: MALAT1 and TUG1 were upregulated in patients within the first five years of diagnosis of T1DM compared to the other groups. MEG3 was upregulated in the case group of < 5 years of diagnosis compared to controls. TUG1 and MALAT1 levels were negatively correlated with the duration of T1DM, while TUG1 and MEG3 were positively correlated with glycated hemoglobin levels. Bioinformatics analysis revealed that MALAT1, MEG3, and TUG1 regulate and interact with protein-codifying genes and microRNAs involved in T1DM-related pathways. CONCLUSION: Our study revealed MALAT1, MEG3, and TUG1 upregulation in patients within the first five years of diagnosis of T1DM.

Humans↗
PubMed2026

Noise-Induced Hepatic Stress Is Associated with Transglutaminase Activation and TG7 Upregulation in Rats.

OBJECTIVE: Environmental noise is increasingly recognized as a systemic stressor capable of inducing oxidative and inflammatory responses beyond the auditory system. This study aimed to investigate the effects of chronic noise exposure on transglutaminase (TG) activation, particularly TG7, and its association with hepatic stress responses in rat liver tissue. METHODS: Thirty adult male Wistar albino rats were randomly assigned to control, short-term noise exposure (LT1), and long-term noise exposure (LT2) groups. Gene expression of TG isoforms (TG1, TG2, TG3, TG6, and TG7), inflammatory markers (IL6 and TNF-&#x3b1;), and apoptotic markers (CASP3 and P53) was evaluated using quantitative real-time PCR. Total TG enzymatic activity was assessed colorimetrically. TG7 protein expression and localization were examined by immunohistochemistry and immunofluorescence. DNA integrity was evaluated by agarose gel electrophoresis. Biochemical parameters, including serum malondialdehyde (MDA), interleukin-1 beta (IL1&#x3b2;), cortisone, aspartate aminotransferase, alanine aminotransferase, glucose, insulin, and total cholesterol, were also measured. RESULTS: Noise exposure induced selective upregulation of TG isoforms, with TG7 showing the highest increase (&#x223c;10-12-fold). Total transglutaminase enzymatic activity was significantly increased in both noise-exposed groups, with a higher increase in LT1 (*** P < 0.001) and a significant increase in LT2 (** P < 0.01) compared with control, while no significant difference was observed between LT1 and LT2. IL6 and TNF-&#x3b1; increased progressively, particularly in LT2, whereas CASP3 expression was elevated in LT1 but reduced in LT2. DNA analysis revealed mild alterations in genomic integrity without clear internucleosomal fragmentation. TG7 protein showed strong localization within hepatocyte cytoplasm and perisinusoidal regions. Biochemical analysis demonstrated significant increases in MDA (up to 61.28%), IL1&#x3b2;, cortisone, liver enzymes, glucose, insulin, and total cholesterol. CONCLUSION: Chronic noise exposure induces early TG activation, particularly TG7, accompanied by sustained oxidative stress and inflammatory responses in liver tissue. These findings identify TG7 as a potential stress-responsive mediator in noise-induced hepatic injury.

Animals↗
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

Regulation of formyl peptide receptor expression and its mRNA levels during differentiation of HL-60 cells.

When incubated with N6-2'-O-dibutyryladenosine 3',5'-cyclic monophosphate (dbcAMP), HL-60 cells expressed formyl peptide receptor (FPR) (as assessed by ligand binding) and FPR transcripts in a time- and concentration-dependent fashion. Experiments using dbcAMP analogs modified at either the C-6 or C-8 position indicated that the process was mediated by a protein kinase A type I, and protein kinase A type I activity was isolated from undifferentiated HL-60 cells by DEAE-Sephacel chromatography. Forskolin mimicked the effects of dbcAMP. Forskolin and dbcAMP-dependent expression of FPR and FPR transcript was inhibited by staurosporine. Retinoic acid (but not retinal or retinol) was capable of inhibiting dbcAMP-dependent expression of FPR mRNA half-life. Dexamethasone enhanced the effects of dbcAMP and blocked the inhibitory effect of retinoic acid on expression of FPR and FPR transcripts. Phorbol 12-myristate 13-acetate (PMA) alone (1.5-15 nM) failed to induce HL-60 to express FPR and FPR transcripts. Low concentrations (1.5 nM) of PMA enhanced the ability of dbcAMP to induce HL-60 cells to express FPR and FPR transcript, whereas high (15 nM) concentrations of PMA inhibited dbcAMP effects. These results indicate that expression of FPR and FPR transcripts by HL-60 cells can be up- and down-regulated by agents that induce HL-60 cells to differentiate and that a "cross-talk" effect exists between protein kinase A and protein kinase C that modulates FPR gene transcription (and receptor expression) by these cells.

Alkaloids↗
PubMed1992

Characterization of kinin receptors on human synovial cells and upregulation of receptor number by interleukin-1.

Bradykinin has been implicated in the pathogenesis of inflammatory arthritis by virtue of its potent proinflammatory properties. We have previously shown bradykinin to be a potent stimulus for the release of prostanoids from interleukin-1 (IL-1)-treated, but not untreated, human synovial cells. We hypothesize that one mechanism by which IL-1 induces responsiveness to bradykinin is by upregulation of number or affinity of kinin receptors on human synovial cells. We performed [3H]bradykinin binding studies in intact human synovial tissue and in cultured human synovial cells. Specific, saturable [3H]bradykinin binding sites in intact synovia were identified by autoradiographic localization and were present in much higher density in rheumatoid, than in osteoarthritis, synovia. In untreated human synovial cells in culture, a single (B2) class of kinin binding sites with a Kd of 2.3 nM and Bmax of 58 +/- 9 fmol/10(6) cells was demonstrated. In matched experiments, IL-1 treatment enhanced specific [3H]bradykinin binding 1.5- to 2.0-fold above that observed in untreated cells. This enhancement was attributable to an increase in Bmax (53 +/- 4 vs. 105 +/- 24 fmol/10(6) cells in untreated and IL-1-treated cells, respectively), rather than an alteration in Kd (1.7 and 1.4 nM, respectively). The potencies of a series of kinin analogs and antagonists and unrelated peptides in displacing [3H]bradykinin from IL-1-treated cells correlated well with their abilities to induce prostanoid release. These studies provide novel information regarding the nature of kinin receptors in intact human synovia and in cultured human synovial cells, their regulation by IL-1 and their role in IL-1-treated cells in kinin-mediated prostaglandin E2 production.

Autoradiography↗