Gold(I) N-heterocyclic carbene complexes show strong proapoptotic, antioxidant and anti-inflammatory effects in A2780 and endothelial cells.

A series of eight gold(I) N-heterocyclic carbene (NHC) complexes [Au(IMes)(HLn)] based on 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes) and 7-azaindole derivatives (HLn), where n = 1-8 for HL1 = 5-flouro-7-azaindole, HL2 = 5-bromo-7-azaindole, HL3 = 3-chloro-7-azaindole, HL4 = 3-iodo-7-azaindole, HL5 = 5-bromo-3-chloro-7-azaindole, HL6 = 5-bromo-3-iodo-7-azaindole, HL7 = 4-chloro-2-methyl-7-azaindole and HL8 = 7-azaindole, was prepared, characterised and studied for their in vitro anti-cancer and anti-inflammatory effects. The complexes showed significant cytotoxicity on human ovarian cancer cell lines (A2780, IC ≈ 8-19 μM and A2780R, IC ≈ 8-19 μM) and lowered toxicity in normal HaCat and MRC-5 cells. Cellular effects of the selected complexes 1 and 7 were evaluated in A2780 cells using flow cytometry.

Transport and inhibition of the sphingosine-1-phosphate exporter SPNS2.

Sphingosine-1-phosphate (S1P) is a signaling lysolipid critical to heart development, immunity, and hearing. Accordingly, mutations in the S1P transporter SPNS2 are associated with reduced white cell count and hearing defects. SPNS2 also exports the S1P-mimicking FTY720-P (Fingolimod) and thereby is central to the pharmacokinetics of this drug when treating multiple sclerosis.

BETA CELL DYSFUNCTION OCCURS INDEPENDENTLY OF INSULITIS IN TYPE 1 DIABETES PATHOGENESIS.

During type 1 diabetes (T1D) progression, beta cells become dysfunctional and exhibit reduced first-phase insulin release. While this period of beta cell dysfunction is well established, its cause and underlying mechanism remain unknown. To address this knowledge gap, live human pancreas tissue slices were prepared from autoantibody-negative organ donors without diabetes (ND), donors positive for one or more islet autoantibodies (AAb+), and donors with T1D within 0-4 years of diagnosis (T1D+).

The efflux pump ABCC1/MRP1 constitutively restricts PROTAC sensitivity in cancer cells.

Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that induce selective protein degradation by linking an E3 ubiquitin ligase enzyme to a target protein. This approach allows scope for targeting "undruggable" proteins, and several PROTACs have reached the stage of clinical candidates. However, the roles of cellular transmembrane transporters in PROTAC uptake and efflux remain underexplored.

Cytosolic S100A8/A9 promotes Ca supply at LFA-1 adhesion clusters during neutrophil recruitment.

S100A8/A9 is an endogenous alarmin secreted by myeloid cells during many acute and chronic inflammatory disorders. Despite increasing evidence of the proinflammatory effects of extracellular S100A8/A9, little is known about its intracellular function. Here, we show that cytosolic S100A8/A9 is indispensable for neutrophil post-arrest modifications during outside-in signaling under flow conditions in vitro and neutrophil recruitment in vivo, independent of its extracellular functions.

Human cold pain: a randomized crossover trial.

The mechanism causing cold pain in humans is unresolved. Animal data suggest a nonredundant contribution to cold pain for transient receptor potential channels TRPM8 and TRPA1 for detection and voltage-gated sodium channels NaV1.7 and NaV1.

Unveiling the insecticidal efficiency of against and : From chemical composition to cytotoxicity analysis.

Currently, there is a growing preference for eco-friendly bioinsecticides over chemical insecticides due to their safety. Plant extracts have emerged as a promising solution for this purpose. Therefore, this study aimed to evaluate the insecticidal effectiveness of extract against two key pests of rose aphid () and pistachio psylla ().

The paracetamol metabolite N-acetyl-4-benzoquinoneimine (NAPQI) prevents modulation of K7 channels via G-protein coupled receptors by interference with PIP and Ca sensitivity.

Background And Purpose: Paracetamol has been found to alleviate inflammatory pain by modulating K7 channels. Its metabolite N-acetyl-4-benzoquinoneimine (NAPQI) increases currents through these channels via a stretch of three cysteine residues in the channel S2-S3 linker. Through this effect, the excitability of neurons in the pain pathway is dampened.

Breast Implant-Associated Anaplastic Large Cell Lymphoma: A Case Report About a Patient with Cytology Negative for Malignancy.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare lymphoma primarily linked to textured breast implants. Symptoms are often non-specific (e.g.

Membrane transporters modulating the toxicity of arsenic, cadmium, and mercury in human cells.

Non-essential metals are extremely toxic to living organisms, posing significant health risks, particularly in developing nations where they are a major contributor to illness and death. Although their toxicity is widely acknowledged, the mechanisms by which they are regulated within human cells remain incompletely understood. Specifically, the role of membrane transporters in mediating heavy metal toxicity is not well comprehended.

Critical transitions in pancreatic islets.

Calcium signals in pancreatic cells collectives show a sharp transition from uncorrelated to correlated state resembling a phase transition as the slowly increasing glucose concentration crosses the tipping point. However, the exact nature or the order of this phase transition is not well understood. Using confocal microscopy to record the collective calcium activation of cells in an intact islet under changing glucose concentration in increasing and then decreasing way, we first show that in addition to the sharp transition, the coordinated calcium response exhibits a hysteresis indicating a critical, first order transition.

Short-term cognitive learning outcomes in team-based learning: is the permanent team important?

Assigning students to work in permanent teams is a design principle in Team-based learning (TBL). It has been assumed that a stable team composition supports the emergence of collaborative problem-solving and learning: when students became more familiar with each other, they shared more information and resolved discrepancies together, which in turn stimulated knowledge acquisition and comprehension. However, this assumption had not been probed by a randomized controlled trial with performance assessment as an outcome.

Candidate Signature miRNAs from Secreted miRNAome of Human Lung Microvascular Endothelial Cells in Response to Different Oxygen Conditions: A Pilot Study.

Oxygen conditions in the lung determine downstream organ functionality by setting the partial pressure of oxygen, regulating the redox homeostasis and by activating mediators in the lung that can be propagated in the blood stream. Examples for such mediators are secreted soluble or vesicle-bound molecules (proteins and nucleic acids) that can be taken up by remote target cells impacting their metabolism and signaling pathways. MicroRNAs (miRNAs) have gained significant interest as intercellular communicators, biomarkers and therapeutic targets in this context.

Sensory Neurons Release Cardioprotective Factors in an In Vitro Ischemia Model.

Sensory neurons densely innervate the myocardium. The role of their sensing and response to acute and prolonged ischemia is largely unclear. In a cellular model of ischemia-reperfusion injury, the presence of sensory neurons increases cardiomyocyte survival.

Identification and Characterization of Novel Small-Molecule Enhancers of the CUL3 E3 Ligase KRAS Complex.

The RAS family of GTPases is among the most frequently mutated proteins in human cancer, creating a high clinical demand for therapies that counteract their signaling activity. An important layer of regulation that could be therapeutically exploited is the proteostatic regulation of the main RAS GTPases KRAS, NRAS, and HRAS, as well as the closely related members, MRAS and RIT1, by the leucine zipper-like transcriptional regulator 1 cullin 3 RING E3 ubiquitin ligase complex (CUL3). Genetic inactivation of , as observed in different cancer entities and Noonan syndrome leads to enhanced RAS GTPase abundance and altered MAPK pathway activation state.

Sodium butyrate prevents cytokine-induced β-cell dysfunction through restoration of stromal interaction molecule 1 expression and activation of store-operated calcium entry.

Sodium butyrate (NaB) improves β-cell function in preclinical models of diabetes; however, the mechanisms underlying these beneficial effects have not been fully elucidated. In this study, we investigated the impact of NaB on β-cell function and calcium (Ca) signaling using ex vivo and in vitro models of diabetes. Our results show that NaB significantly improved glucose-stimulated insulin secretion in islets from human organ donors with type 2 diabetes and in cytokine-treated INS-1 β cells.

Diet enriched with high-phenolic cocoa potentiates hippocampal brain-derived neurotrophic factor expression and neurogenesis in healthy adult micewith subtle effects on memory.

Cocoa is widely known for its health benefits, but its neurocognitive impact remains underexplored. This preclinical study aimed to investigate the effects of cocoa and cocoa polyphenols on hippocampal neuroplasticity, cognitive function and emotional behavior. Seventy young-adult C57BL/6JRj male and female mice were fed either a standard diet (CTR) or a diet enriched with 10% high-phenolic content cocoa (HPC) or low-phenolic content cocoa (LPC) for at least four weeks.

Cleavage site-directed antibodies reveal the prion protein in humans is shed by ADAM10 at Y226 and associates with misfolded protein deposits in neurodegenerative diseases.

Proteolytic cell surface release ('shedding') of the prion protein (PrP), a broadly expressed GPI-anchored glycoprotein, by the metalloprotease ADAM10 impacts on neurodegenerative and other diseases in animal and in vitro models. Recent studies employing the latter also suggest shed PrP (sPrP) to be a ligand in intercellular communication and critically involved in PrP-associated physiological tasks. Although expectedly an evolutionary conserved event, and while soluble forms of PrP are present in human tissues and body fluids, for the human body neither proteolytic PrP shedding and its cleavage site nor involvement of ADAM10 or the biological relevance of this process have been demonstrated thus far.