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Mechanisms of mitogenic and anti-apoptotic signaling by glucose-dependent insulinotropic polypeptide in beta(INS-1)-cells.

Glucose-dependent insulinotropic polypeptide (GIP) acts as a glucose-dependent growth factor for beta-cells. Here we show that GIP and glucose also act synergistically as anti-apoptotic factors for beta-cells, using the well-differentiated beta-cell line, INS-1. Mitogenic and anti-apoptotic signaling of GIP were dependent upon pleiotropic activation of protein kinase A (PKA)/cAMP regulatory element binder (CREB), mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-kinase)/PKB signaling modules. The signaling modules activated by GIP were dependent on glucose metaboli

Coordinated signaling through both G12/13 and G(i) pathways is sufficient to activate GPIIb/IIIa in human platelets.

Activation of GPIIb/IIIa is known to require agonist-induced inside-out signaling through G(q), G(i), and G(z). Although activated by several platelet agonists, including thrombin and thromboxane A(2), the contribution of the G(12/13) signaling pathway to GPIIb/IIIa activation has not been investigated. In this study, we used selective stimulation of G protein pathways to investigate the contribution of G(12/13) activation to platelet fibrinogen receptor activation. YFLLRNP is a PAR-1-specific partial agonist that, at low concentrations (60 microm), selectively activates the G(12/13) signaling

Cost analysis of iron-related complications in a single institute.

Background/aimsThe financial burden of caring for iron-related complications (IRCs) is an emerging medical problem in Korea, as in Western countries. We produced a preliminary estimate of the costs of treating patients for IRCs.MethodsThe medical records of patients who had received multiple transfusions were reviewed. Newly developed cardiomyopathy, heart failure, diabetes mellitus, liver cirrhosis, and liver cancer were defined as IRCs. The costs of laboratory studies, medication, oxygenation, intervention, and education were calculated using working criteria we defined. Costs that had a def

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… In Western countries, cost analyses of IRCs and iron-chelating agents are actively being conducted. In one analysis involving 31 thalassemia patients in America, IRCs were a major cost determinant and medical expenses increased sharply with the number of complications [ 3 ]. … The oral chelating agent deferasirox resulted in a gain of 4.5 QALY per patient at an additional expected lifetime cost of 126,018 USD per patient [ 8 ]. Our study revealed the considerable costs for IRCs in patients with hematologic diseases. …

Эпинефрин как терапевтический агент по гиперферритинемии в диабете и гипертенции.

ПЕРВЫЙ РАЗДЕЛ НЕИЗБИРАТЕЛЬНОГО БЕДСТВИЯ, ИСПОЛЬЗУЕМОГО 21st Пандемия века. Тип 2 диабет (T2DM) является результатом повышенного сопротивления инсулину (IR) или относительного дефицита инсулина. IR препятствует удалению глюкозы, что приводит к компенсационному гиперинсулимическому состоянию. Увеличение запасов железа, нашедшее отражение в высокой сыворотке феррита (SF), было связано с разработкой T2DM и оказывает воздействие на глюкозу гомеостаз, ослабляя реакцию тканей на инсулин. Железная перегрузка (IO) широко распространена в основной гипертонии (HTN). Первый клинический эффект эпинефрина н

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… Discussion This is the first clinical use of epinephrine as an iron chelating agent in a patient with T2DM and HTN. It resulted in normalization of elevated SF, hyperglycemia, and HTN. … Currently, IO is treated by phlebotomy, but this had known limitations and adverse effects [ 72 ], or by iron chelating agents, which has neurotoxic, hepatic, and renal adverse effects [ 73 ], and are more expensive than epinephrine. …

Functional selectivity of G protein signaling by agonist peptides and thrombin for the protease-activated receptor-1.

Thrombin activates protease-activated receptor-1 (PAR-1) by cleavage of the amino terminus to unmask a tethered ligand. Although peptide analogs can activate PAR-1, we show that the functional responses mediated via PAR-1 differ between the agonists. Thrombin caused endothelial monolayer permeability and mobilized intracellular calcium with EC(50) values of 0.1 and 1.7 nm, respectively. The opposite order of activation was observed for agonist peptide (SFLLRN-CONH(2) or TFLLRNKPDK) activation. The addition of inactivated thrombin did not affect agonist peptide signaling, suggesting that the di

Nuclear factor-kappaB activation by reactive oxygen species mediates voltage-gated K+ current enhancement by neurotoxic beta-amyloid peptides in nerve growth factor-differentiated PC-12 cells and hippocampal neurones.

Increased activity of plasma membrane K+ channels, leading to decreased cytoplasmic K+ concentrations, occurs during neuronal cell death. In the present study, we showed that the neurotoxic beta-amyloid peptide Abeta(25-35) caused a dose-dependent (0.1-10 microm) and time-dependent (> 12 h) enhancement of both inactivating and non-inactivating components of voltage-dependent K+ (VGK) currents in nerve growth factor-differentiated rat phaeochromocytoma (PC-12) cells and primary rat hippocampal neurones. Similar effects were exerted by Abeta(1-42), but not by the non-neurotoxic Abeta(35-25) pept

Antiapoptotic activity of Akt is down-regulated by Ca2+ in myocardiac H9c2 cells. Evidence of Ca(2+)-dependent regulation of protein phosphatase 2Ac.

Cell survival signaling of the Akt/protein kinase B pathway was influenced by a change in the cytoplasmic free calcium concentration ([Ca2+]i) for over 2 h via the regulation of a Ser/Thr phosphatase, protein phosphatase 2Ac (PP2Ac), in rat myocardiac H9c2 cells. Akt was down-regulated when [Ca2+]i was elevated by thapsigargin, an inhibitor of the endoplasmic reticulum Ca(2+)-ATPase, but was up-regulated when it was suppressed by 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl)ester (BAPTA-AM), a cell permeable Ca2+ chelator. The inactivation of Akt was well correl

Differential activation of MAP kinase family members triggered by CD99 engagement.

The molecular basis for the modulatory properties of CD99 is not well understood. Treatment of human Jurkat T lymphocytes with anti-CD99 antibody led to activation of three mitogen-activated protein kinase (MAPK) members, ERK, JNK, and p38 MAPK, along with homotypic aggregation. While phosphorylation of ERK and JNK was inhibited by the pretreatment of a PKC inhibitor, bisindolylmaleimide I, activation of p38 MAPK was upregulated by the same pretreatment. The signaling pathways to MAPKs by CD99 engagement were independent of PI-3 kinase, distinguishing from those by CD3 engagement. Among MAPKs,

Targeted Alpha Therapy: Progress in Radionuclide Production, Radiochemistry, and Applications.

This review outlines the accomplishments and potential developments of targeted alpha (α) particle therapy (TAT). It discusses the therapeutic advantages of the short and highly ionizing path of α-particle emissions; the ability of TAT to complement and provide superior efficacy over existing forms of radiotherapy; the physical decay properties and radiochemistry of common α-emitters, including 225Ac, 213Bi, 224Ra, 212Pb, 227Th, 223Ra, 211At, and 149Tb; the production techniques and proper handling of α-emitters in a radiopharmacy; recent preclinical developments; ongoing and completed clinica

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… agents. … It has also been suggested that acyclic chelating agents such as linear polyaminocarboxylates are not good ligands for 225 Ac due to high liver uptake and poor whole body clearance resulting from the loss of 225 Ac from these chelating agents [ 52 ]. …

Radionuclide-labelled nanoparticles for cancer combination therapy: a review.

Radionuclide therapy (RT) is widely used to advanced local cancers. However, its therapeutic efficacy is limited to the radiation resistance of cancer cells. Combination therapy aims to circumvent tumor resistance, and the combination of RT with photothermal therapy (PTT), photodynamic therapy (PDT), chemotherapy (CMT), and immunotherapy has shown promising treatment outcomes. Nanotechnology holds promise in advancing combination therapy by integrating multiple therapies on a nanostructure platform. This is due to the increased surface area, passive/active targeting capabilities, high payload

Iron Overload and Platelet Function Defects: Possible Correlation.

Acquired platelet function defect might be a consequence of iron overload. Even though there are various complications of iron overload, only few reports have indicated some correlations with platelets dysfunction. We report a child with Diamond-Blackfan anemia who has significant complications from iron overload due to chronic blood transfusion, and one of these complications is acquired platelet function defect that manifests with frequent episodes of epistaxis. Therefore, we emphasize the necessity for further studies to confirm direct correlation between iron overload as a causative agent

Next-Generation HDAC Inhibitors: Advancing Zinc-Binding Group Design for Enhanced Cancer Therapy.

Histone deacetylases (HDACs) are pivotal epigenetic regulators that control gene expression, cell proliferation, and differentiation, and their dysregulation is closely associated with the onset and progression of multiple cancers. The therapeutic importance of these enzymes is reflected by FDA approval of HDAC inhibitors for oncology indications. Despite this clinical success, most FDA-approved agents employ conventional zinc-binding groups (ZBGs) such as hydroxamic acid and 2-aminoanilide, which are frequently linked to metabolic instability, genotoxicity, and poor pharmacokinetic behavior.

Meeting abstracts from the 21st European Symposium on Radiopharmacy and Radiopharmaceuticals

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… However, the clinical utilization of 197m/g Hg as a theranostic agent is hindered by the lack of chelating agents capable of securely binding them to tumor-seeking vectors. … Conclusion: Through the identification of viable chelators and the elucidation of the impact of specific structural modifications, our research significantly contributes to addressing the scarcity of suitable chelating agents for 197m/g Hg. …

Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach.

Metastases are the primary cause of death among cancer patients and efficacious new treatments are sorely needed. Targeted alpha-emitting radiopharmaceuticals that are highly cytotoxic may fulfill this critical need. The focus of this paper is to describe and explore a novel technology that may improve the therapeutic effect of targeted alpha therapy by combining two radionuclides from the same decay chain in the same solution. We hypothesize that the dual targeting solution containing bone-seeking 224Ra and cell-directed complexes of progeny 212Pb is a promising approach to treat metastatic c

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… Evaluation of potential chelating agents for radium. Appl Radiat Isot. ( 2002 ) 56 : 667 – 71 . 10.1016/s0969-804300282-2 11993940 33. Abou D Thiele N Gutsche N Villmer A Zhang H Woods J Towards the stable chelation of radium for biomedical applications with an 18-membered macrocyclic ligand. …

The Role of Real-World Evidence in UK Reimbursement: Case Study of Lenalidomide in Myelodysplastic Syndrome Deletion 5q.

BackgroundUncertainty within cost-effectiveness analysis, often driven by lack of mature data from large clinical trials, plays a key role in decisions made by the National Institute for Health and Care Excellence (NICE), particularly for early access medicines and orphan drugs.ObjectivesIn this case study, we used real-world evidence to address the uncertainty in the cost-effectiveness case for lenalidomide in transfusion-dependent low- and intermediate-1-risk myelodysplastic syndrome (MDS) deletion 5q [del(5q)], affecting a small but unique subpopulation with an orphan disease.MethodsAs part

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… However, the clinical and economic burden of MDS increases quickly due to the cost of frequent transfusions and the administration of chelating agents (in centres where this is available) to remove iron accumulation as a consequence of transfusions [ 7 – 10 ]. …

Iron protects childhood acute lymphoblastic leukemia cells from methotrexate cytotoxicity.

Drug resistance is a fundamental clinical concern in pediatric acute lymphoblastic leukemia (pALL), and methotrexate (MTX) is an essential chemotherapy drug administered for the treatment. In the current study, the effect of iron in response to methotrexate and its underlying mechanisms were investigated in pALL cells. CCRF-CEM and Nalm6 cell lines were selected as T and B-ALL subtypes. Cells were pretreated with ferric ammonium citrate, exposed to the IC50 concentration of MTX and cell viability was assessed using MTT, colony formation, and flow cytometry assays. Iron-loaded cells were strong

Glutamate stimulates oligodendrocyte progenitor migration mediated via an alphav integrin/myelin proteolipid protein complex.

In the mammalian CNS, oligodendrocyte precursor cells (OPCs) express most neurotransmitter receptors, but their function remains unclear. The current studies suggest a physiological role for glutamate (AMPA and/or kainate) receptors in OPC migration. AMPA stimulated alphav integrin-mediated OPC migration by increasing both the rate of cell movement and the frequency of Ca2+ transients. A protein complex containing the myelin proteolipid protein (PLP) and alphav integrin modulated the AMPA-stimulated migration, and stimulation of OPC AMPA receptors resulted in increased association of the AMPA

[Role of Nrf2/GPX4 mediated ferroptosis in intestinal injury in sepsis].

OBJECTIVE: To investigate whether ferroptosis exists in sepsis induced intestinal injury, and to verify the association between ferroptosis in sepsis induced intestinal injury and intestinal inflammation and barrier function by stimulating and inhibiting the nuclear factor E2-related factor 2/glutathione peroxidase 4 (Nrf2/GPX4) pathway. METHODS: Forty-eight SPF grade male Sprague-Darvley (SD) rats with a body weight of 220-250 g were divided into sham operation group (Sham group), sepsis group (CLP group), sepsis+iron chelating agent deferoxamine (DFO) group (CLP+DFO group) and sepsis+ferrop

Natural extract-derived compounds for the treatment of hematological diseases through modulation of the bone marrow microenvironment.

The bone marrow microenvironment comprises a complex network of hematopoietic stem cells, immune cells, stromal cells, and non-cellular components such as the extracellular matrix and soluble factors, collectively maintaining the homeostasis of hematopoietic stem and progenitor cells. It is highly vulnerable to pathological perturbations induced by hematologic malignancies, solid tumors, inflammatory stress, and therapeutic exposure, which collectively destabilize microenvironmental homeostasis and promote hematopoietic failure, malignant progression, and immune dysregulation. Natural products

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… Novel insights into ethanol-soluble oyster Peptide–zinc-chelating agents: structural characterization, chelation mechanism, and potential protection on MEHP-induced leydig cells . Mar. Drugs 22 ( 10 ), 465 . 10.3390/md22100465 39452873 PMC11509544 Lu Y. T. Chen T. Y. Lin H. H. Chen Y. W. Lin Y. X. …

Arf6-GEF BRAG1 regulates JNK-mediated synaptic removal of GluA1-containing AMPA receptors: a new mechanism for nonsyndromic X-linked mental disorder.

Activity-dependent modifications of excitatory synapses contribute to synaptic maturation and plasticity, and are critical for learning and memory. Consequently, impairments in synapse formation or synaptic transmission are thought to be responsible for several types of mental disabilities. BRAG1 is a guanine nucleotide exchange factor for the small GTP-binding protein Arf6 that localizes to the postsynaptic density of excitatory synapses. Mutations in BRAG1 have been identified in families with X-linked intellectual disability (XLID). These mutations mapped to either the catalytic domain or a