Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human T-cell lymphotropic virus type I (HTLV-I) is capable of inducing a variety of host cellular genes including many of the cytokines responsible for immune regulation and osteoclast activation. This derangement in cytokine expression may contribute to the panoply of disease states associated with HTLV-I infection such as the adult T-cell leukemia (ATL) and HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). We wished to determine if there was a correlation between the expression of an array of cytokines and the diverse clinical manifestations of ATL and HAM/TSP. Utilizing the techniques of specific mRNA amplification by the polymerase chain reaction (PCR) as well as Northern blotting, we analyzed the ex vivo mRNA expression of gamma-interferon (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and transforming growth factor-beta 1 (TGF-beta 1) in the peripheral blood of HAM/TSP and ATL patients as well as asymptomatic seropositive carriers. IFN-gamma, TNF-alpha, and IL-1 beta transcripts were up-regulated in patients with HAM/TSP and seropositive carriers when compared to their levels in ATL and normal controls. In contrast, the ATL patients constitutively expressed higher levels of TGF-beta 1 mRNA than HAM/TSP and seropositive carriers. In addition, TNF-alpha and IL-1 beta serum levels were elevated in HAM/TSP, but not in ATL patients nor seropositive carriers. However, the circulating leukemic cells from ATL patients secreted increased levels of TGF-beta 1 protein into the culture medium than T-cells derived from HAM/TSP patients. Collectively these results suggest that induction of IFN-gamma, TNF-alpha, and IL-1 beta in HAM/TSP may initiate an inflammatory cascade with subsequent events leading to immune mediated destruction of the central nervous system in these patients. Expression of osteoclast activators such as TNF-alpha and IL-1 beta is not associated with hypercalcemia in ATL. Finally, impaired cellular and humoral immune responses present in ATL, but not in HAM/TSP, may be related to elevated levels of TGF-beta 1 produced by the leukemic cells. These differences in retroviral-induced host cytokine expression in ATL and HAM/TSP suggest alternate roles in disease pathogenesis.
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PMID:Cytokine induction in HTLV-I associated myelopathy and adult T-cell leukemia: alternate molecular mechanisms underlying retroviral pathogenesis. 175 74

Carbetimer is a new antineoplastic agent whose main side effects consist of neurotoxicity and long-term dose-dependent hypercalcemia. We previously showed that Carbetimer is a potent calcium chelator responsible for an acute decrease in ionized Ca levels observed in vivo. However, the mechanism of the progressive increase in serum Ca remains unknown. We have evaluated the bone-resorbing effects of Carbetimer on 45Ca-prelabelled neonatal mouse calvariae. Carbetimer induced a dose-dependent increase in 45Ca release which started at a concentration of 1 mg/ml and reached a mean of 3.3 times the control values at 10 mg/ml. This marked increase in 45Ca release was similar on previously killed bones and could not be inhibited by calcitonin. Such concentrations are probably therapeutically relevant given the known affinity of Carbetimer for bone and the large daily doses administered to cancer patients (10-15 g). Since Carbetimer could exert its antineoplastic action through immunomodulation, we also studied its effects on the production of TNF-alpha and IFN-gamma which are also known to affect bone metabolism. Carbetimer did not stimulate TNF-alpha release from isolated normal human monocytes or lymphocytes, but it markedly inhibited T-lymphocyte production of IFN-gamma, which became undetectable at a concentration of 1 mg of Carbetimer/ml. In summary, Carbetimer-induced hypercalcemia appears to be due to a direct stimulation of osteolysis, but possibly also to an inhibition of IFN-gamma production.
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PMID:Effects of Carbetimer, a new antineoplastic drug, on bone metabolism. 191 Sep 54

Tissue macrophages from patients with granuloma-forming disease, most notably sarcoidosis, express a 25-hydroxyvitamin D-1-hydroxylase which can produce in vivo sufficient quantities of the active vitamin D metabolite 1,25-dihydroxyvitamin D to cause hypercalcemia. In contrast to the NADPH-dependent cytochrome P450-linked mixed function oxidase which is normally only expressed in significant quantity in proximal renal tubular cells and regulated in an endocrine fashion, the mitochondrial-based 1-hydroxylase in the macrophage [1] is stimulated in a paracrine mode by cytokines (i.e., IFN-gamma) and lipopolysaccharide (LPS) [2] requires an extracellular source of L-arginine for full basal expression and [3] can be regulated in an intracrine fashion by nitric oxide (NO). In these experiments we employed inducible nitric oxide synthase (iNOS)-free, intact mitochondria preparations from the avain macrophage-like cell line HD-11, which constitutively express the 1-hydroxylase, and nonenzymatically-generated NO to investigate NO-mediated autoregulation of the macrophage 1-hydroxylase. Sodium nitroprusside (SNP)- or S-nitroso-N-acetyl-penicillamine (SNAP)-induced up-regulation of the 1-hydroxylase required the presence of either NADPH or NADP in the reaction mixture, while NO-induced inhibition of mitochondrial 1,25-(OH)2D3 synthesis was NO-dependent and NADP/NADPH-independent. These data suggest NO has bifunctional effects on the macrophage 1-hydroxylase. At relatively high concentrations NO competes with O2 for enzyme binding, inhibiting hormone synthesis. At lower production levels, NO serves as a source of reducing equivalents for the enzyme by providing for the reduction of NADP to NADPH.
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PMID:Autoregulation of 1,25-dihydroxyvitamin D synthesis in macrophage mitochondria by nitric oxide. 882 16

The cytokine gamma interferon (IFN-gamma) and the calcitropic steroid hormone 1,25-dihydroxyvitamin D (1,25D) are activators of macrophage immune function. In sarcoidosis, tuberculosis, and several granulomatoses, IFN-gamma induces 1,25D synthesis by macrophages and inhibits 1,25D induction of 24-hydroxylase, a key enzyme in 1,25D inactivation, causing high levels of 1,25D in serum and hypercalcemia. This study delineates IFN-gamma-1,25D cross talk in human monocytes-macrophages. Nuclear accumulation of Stat1 and vitamin D receptor (VDR) by IFN-gamma and 1,25D promotes protein-protein interactions between Stat1 and the DNA binding domain of the VDR. This prevents VDR-retinoid X receptor (RXR) binding to the vitamin D-responsive element, thus diverting the VDR from its normal genomic target on the 24-hydroxylase promoter and antagonizing 1,25D-VDR transactivation of this gene. In contrast, 1,25D enhances IFN-gamma action. Stat1-VDR interactions, by preventing Stat1 deactivation by tyrosine dephosphorylation, cooperate with IFN-gamma/Stat1-induced transcription. This novel 1,25D-IFN-gamma cross talk explains the pathogenesis of abnormal 1,25D homeostasis in granulomatous processes and provides new insights into 1,25D immunomodulatory properties.
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PMID:Stat1-vitamin D receptor interactions antagonize 1,25-dihydroxyvitamin D transcriptional activity and enhance stat1-mediated transcription. 1190 70

Aminobisphosphonates are drugs used in the treatment of hypercalcemia, Paget's disease, osteoporosis, and malignancy. Some patients treated with aminobisphosphonates have a transient febrile reaction that may be caused by an increased serum concentration of proinflammatory cytokines. Aminobisphosphonates induce the production of certain proinflammatory cytokines in vitro, especially in cells of monocytic lineage. A unique feature of aminobisphosphonates is that they bind the Vgamma2Vdelta2 class of T cells, which are found only in primates, and stimulate cytokine production. The effects of aminobisphosphonates on other cells, including macrophages, are incompletely understood. We show in this study that treatment of murine macrophages with pamidronate, a second generation aminobisphosphonate, induces TNF-alpha production. Furthermore, pretreatment of murine macrophages with pamidronate before stimulation with IFN-gamma significantly augments IFN-gamma-dependent production of TNF-alpha. This pamidronate-mediated augmentation of TNF-alpha production results in sustained phosphorylation of the tyrosine residue at position 701 of STAT1 after IFN-gamma treatment. Our data suggest that this sustained phosphorylation results from inhibition of protein tyrosine phosphatase activity. We also show that pamidronate treatment increases TNF-alpha production in vivo in mice. Pamidronate-augmented TNF-alpha production by macrophages might be a useful strategy for cytokine-based anticancer therapy.
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PMID:Modulation of TNF-alpha gene expression by IFN-gamma and pamidronate in murine macrophages: regulation by STAT1-dependent pathways. 1569 6

A 75-year-old woman was admitted with fever of unknown origin and liver damage, and treated with prednisolone. Hypercalcemia appeared when of the dose of prednisolone was reduced, and human T-cell lymphotropic virus type-I (HTLV-I) proviral DNA was detected in the leukemic cells by Southern blot analysis, and a diagnosis of acute adult T-cell lymphoma (ATL) was made. After chemotherapy with sobuzoxane was started, she went into septic shock caused by multiple resistant Serratia marcesense, and was treated with PMX-DHP and antibiotics. Although ner general condition and her serum cytokine leyels improved, the septic shock became more severe, and the patient died. Serratia marcesense expreses lipopolysaccharide (LPS), a biologically active substance that is present in gram-negative bacteria. Exposure to LPS leads to activation of cytokines, including TNF-alpha, IL-1beta, IL-6, and IFN-gamma. After treatment with PMX-DHP, the patient's general condition improved, but she died of septic shock. Bacterial infection may be a life-threatening complication in the immunocompromised hosts and elderly patients, particularly when granulocytopenia has been induced by chemotherapy, and thus such these patients require careful management.
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PMID:[Septic shock induced by Serratia marcescens complicating adult T-cell leukemia (ATL)]. 1678 Jan 33

A 62-year-old man visited our hospital complaining of asymptomatic gross hematuria. Right radical Computed tomography (CT) demonstrated an 8 cm mass in the right kidney. nephrectomy was done in March 1995, and the pathological examination revealed renal cell carcinoma (RCC), clear cell type, G2>G1. Interferon (IFN)-alpha was administered for 10 months. About 3 years later, in March 1998, CT showed 1 cm mass in the left kidney. Left partial nephrectomy was done and the pathological finding was RCC, G1. IFN-alpha2b was administered for a year. About 2 years later, CT showed 2.7 cm mass in the left lung. Left upper lobectomy was performed in August 2000, and it was a metastasis of RCC, G2. IFN-alpha and IFN-gamma were administered. Nine months later, in June 2001, the recurrence of the left kidney and the left adrenal gland was found and partial nephrectomy and adrenalectomy was performed. Pathological finding was RCC, G3. IFN-alpha and tegafur-uracil (UFT) were administered. Only 3 months later, recurrence of the left kidney and the left adrenal gland and the lymph node of renal hilus was found. We gave up for surgical resection and chemotherapy of MVP (Methotrexate, Vinblastine, Pepleomycin) was performed. Despite the therapy, disease progressed. 10 months after the last recurrence, in July 2002, patient became disoriented and hypercalcemia and the MVP therapy was stopped. After that, medroxyprogesterone acetate (MPA) and UFT were administered; the patient lived 20 months with relatively good performance status and died in February 2004. MPA might be considered as a drug for advanced renal cell carcinoma.
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PMID:[A case of recurrent renal cell carcinoma which recurred after fourth surgical resection and survived for about 2 years by medroxyporgesterone acetate administration]. 1793 37

Patients with uterine leiomyosarcoma (LMS) typically present with vaginal bleeding, pain, and a pelvic mass. Typical presentations with hypercalcemia or eosinophilia have been reported. Radiographic evaluation with combined positron emission tomography/computed tomography may assist in the diagnosis and surveillance of women with uterine LMS. A recently developed risk-assessment index is highly predictive of disease-specific survival. Ovarian preservation does not appear to negatively impact outcome, and the addition of adjuvant therapy after surgical treatment does not seem to improve survival. It is noteworthy that LMP2-deficient mice exhibit spontaneous development of uterine LMS with a disease prevalence of approximately 37% by 12 months of age. The LMP2 gene is transcribed from a promoter containing an interferon (IFN)-gamma-response factor element; thus, the IFN-gamma-signal strongly induces LMP2 expression. Furthermore, a recent report demonstrated the loss of ability to induce LMP2 expression, which is an interferon (IFN)-gamma-inducible factor, in human uterine LMS tissues and cell lines. Analysis of human uterine LMS shows somatic mutations in the IFN gamma signalling pathway, thus the loss of LMP2 induction is attributable to a defect in the earliest steps of the IFN-gamma signalling pathway. The discovery of an impaired key cell-signalling pathway may provide new targets for diagnostic approaches and therapeutic intervention.
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PMID:Molecular mechanisms of uterine leiomyosarcomas: involvement of defect in LMP2 expression. 1978 91

Deficiency in 1alpha,25-dihydroxyvitamin D(3) (1,25D(3)) has been suggested as an important environmental factor for immuno-mediated disorders including inflammatory bowel diseases (IBD), comprising Crohn's disease and ulcerative colitis, both characterized by chronic intestinal inflammation. Administration of vitamin D receptor (VDR) agonists can ameliorate spontaneous and induced animal models of colitis, but hypercalcemia is a dose-limiting adverse event. Previous work in our laboratory has identified 1alpha,25(OH)(2)-16-ene-20-cyclopropyl-vitamin D(3) (BXL-62) as a potent anti-inflammatory VDR agonist with a low calcemic activity. In the present study, we confirm the marked anti-inflammatory properties of BXL-62 and show its capacity to induce VDR primary response genes, like CYP24A1 and CAMP, at lower concentrations than 1,25D(3), in PBMCs from IBD patients. Its higher anti-inflammatory potency compared to 1,25D(3) was demonstrated by the significantly more potent inhibition in PBMCs and in lymphocyte-enriched lamina propria mononuclear cells of the pro-inflammatory cytokines TNF-alpha, IL-12/23p40, IL-6 and IFN-gamma, both at mRNA and protein level. The therapeutic efficacy of intra-rectal administration of BXL-62 in experimental IBD is shown by its beneficial effects, significantly higher than 1,25D(3), to induce recovery of clinical symptoms of colitis at normocalcemic doses in mice undergoing dextran sodium sulfate-induced colitis. These results confirm the therapeutic efficacy of VDR agonists in experimental colitis, and suggest BXL-62 as a promising compound for IBD treatment.
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PMID:Efficacy of a potent and safe vitamin D receptor agonist for the treatment of inflammatory bowel disease. 2035 May 69