Cell-cell contacts prevent t-BuOOH-triggered ferroptosis and cellular damage in vitro by regulation of intracellular calcium.

Tert-butyl hydroperoxide (t-BuOOH) is an organic hydroperoxide widely used as a model compound to induce oxidative stress. It leads to a plethora of cellular damage, including lipid peroxidation, DNA double-strand breaks (DNA DSBs), and breakdown of the mitochondrial membrane potential (MMP). We could show in several cell lines that t-BuOOH induces ferroptosis, triggered by iron-dependent lipid peroxidation.

Impact of cryopreservation on viability, gene expression and function of enteric nervous system derived neurospheres.

Impairment of both the central and peripheral nervous system is a major cause of mortality and disability. It varies from an affection of the brain to various types of enteric dysganglionosis. Congenital enteric dysganglionosis is characterized by the local absence of intrinsic innervation due to deficits in either migration, proliferation or differentiation of neural stem cells.

Temporal and spatial summation of laser heat stimuli in cultured nociceptive neurons of the rat.

We studied the efficacy of a near-infrared laser (1475 nm) to activate rat dorsal root ganglion (DRG) neurons with short punctate radiant heat pulses (55 µm diameter) and investigated temporal and spatial summation properties for the transduction process for noxious heat at a subcellular level. Strength-duration curves (10-80 ms range) indicated a minimum power of 30.2mW for the induction of laser-induced calcium transients and a chronaxia of 13.

Evidence for Recombinant GRP78, CALR, PDIA3 and GPI as Mediators of Genetic Instability in Human CD34+ Cells.

Soluble factors released from irradiated human mesenchymal stromal cells (MSC) may induce genetic instability in human CD34+ cells, potentially mediating hematologic disorders. Recently, we identified four key proteins in the secretome of X-ray-irradiated MSC, among them three endoplasmic reticulum proteins, the 78 kDa glucose-related protein (GRP78), calreticulin (CALR), and protein disulfide-isomerase A3 (PDIA3), as well as the glycolytic enzyme glucose-6-phosphate isomerase (GPI). Here, we demonstrate that exposition of CD34+ cells to recombinant GRP78, CALR, PDIA3 and GPI induces substantial genetic instability.

TRPM3-mediated dynamic mitochondrial activity in nerve growth factor-induced latent sensitization of chronic low back pain.

The transient receptor potential ion channel TRPM3 is highly prevalent on nociceptive dorsal root ganglion (DRG) neurons, but its functions in neuronal plasticity of chronic pain remain obscure. In an animal model of nonspecific low back pain (LBP), latent spinal sensitization known as nociceptive priming is induced by nerve growth factor (NGF) injection. Here, we address the TRPM3-associated molecular basis of NGF-induced latent spinal sensitization at presynaptic level by studying TRPM3-mediated calcium transients in DRG neurons.

Contribution of the P2X4 Receptor in Rat Hippocampus to the Comorbidity of Chronic Pain and Depression.

The hippocampus is an important region for the interaction between depression and pain. Studies show that the P2X4 receptor plays key role in neuropathic pain. This work investigated the potential implication of the P2X4 receptor in the hippocampus in comorbidity of chronic pain and depression.

Modality-specific facilitation of noninjurious sharp mechanical pain by topical capsaicin.

We had previously shown that a "blunt blade" stimulator can mimic the noninjurious strain phase of incisional pain, but not its sustained duration. Here, we tested whether acute sensitization of the skin with topical capsaicin can add the sustained phase to this noninvasive surrogate model of intraoperative pain. Altogether, 110 healthy volunteers (55 male and 55 female; 26 ± 5 years) participated in several experiments using the "blunt blade" (0.

The capsaicin receptor TRPV1 is the first line defense protecting from acute non damaging heat: a translational approach.

Background: Pain is the vital sense preventing tissue damage by harmful noxious stimuli. The capsaicin receptor TRPV1 is activated by noxious temperatures, however, acute heat pain is only marginally affected in mice after TRPV1 knockout but completely eliminated in mice lacking TRPV1 positive fibers. Exploring contribution of candidate signal transduction mechanisms to heat pain in humans needs translational models.

Technical and clinical performance of the thermo-test device "Q-Sense" to assess small fibre function: A head-to-head comparison with the "Thermal Sensory Analyzer" TSA in diabetic patients and healthy volunteers.

Background: Thermo-test devices are rarely used outside specialized pain centres because of high acquisition costs. Recently, a new, portable device ("Q-Sense") was introduced, which is less expensive but has reduced cooling capacity (20°C). We assessed the reliability/validity of the "Q-Sense" by comparing it with the Thermal Sensory Analyzer (TSA).

The Inhibition by Guanfu Base A of Neuropathic Pain Mediated by P2Y Receptor in Dorsal Root Ganglia.

Activation of satellite glial cells (SGCs) in the dorsal root ganglia (DRG) is involved in mechanical and thermal hyperalgesia. The upregulated P2Y receptor expressed in SGCs of the DRG participates in the nociceptive transmission of neuropathic pain. Guanfu base A (GFA) has been reported to exhibit antiarrhythmic and anti-inflammatory effects.

Hypertriglyceridaemia and the risk of pancreatitis six months post lopinavir/ritonavir initiation.

Background: Hypertriglyceridaemia (HTG) is an important risk factor for pancreatitis and cardiovascular disease (CVD), depending on severity. Hypertriglyceridaemia is common in human immunodeficiency virus (HIV) infection and is also a common complication of lopinavir/ritonavir (LPV/r).

Objectives: To evaluate the risk of pancreatitis associated with HTG in patients six months post initiation of LPV/r-based therapy in a regional public hospital.

Analyses of Synthetic N-Acyl Dopamine Derivatives Revealing Different Structural Requirements for Their Anti-inflammatory and Transient-Receptor-Potential-Channel-of-the-Vanilloid-Receptor-Subfamily-Subtype-1 (TRPV1)-Activating Properties.

We studied the chemical entities within N-octanoyl dopamine (NOD) responsible for the activation of transient-receptor-potential channels of the vanilloid-receptor subtype 1 (TRPV1) and inhibition of inflammation. The potency of NOD in activating TRPV1 was significantly higher compared with those of variants in which the ortho-dihydroxy groups were acetylated, one of the hydroxy groups was omitted ( N-octanoyl tyramine), or the ester functionality consisted of a bulky fatty acid ( N-pivaloyl dopamine). Shortening of the amide linker (ΔNOD) slightly increased its potency, which was further increased when the carbonyl and amide groups (ΔNODR) were interchanged.

Variable transcriptional responsiveness of the P2X3 receptor gene during CFA-induced inflammatory hyperalgesia.

The purinergic receptor P2X3 (P2X3-R) plays important roles in molecular pathways of pain, and reduction of its activity or expression effectively reduces chronic inflammatory and neuropathic pain sensation. Inflammation, nerve injury, and cancer-induced pain can increase P2X3-R mRNA and/or protein levels in dorsal root ganglia (DRG). However, P2X3-R expression is unaltered or even reduced in other pain studies.

Anti-nociceptive action of peripheral mu-opioid receptors by G-beta-gamma protein-mediated inhibition of TRPM3 channels.

Opioids, agonists of µ-opioid receptors (µORs), are the strongest pain killers clinically available. Their action includes a strong central component, which also causes important adverse effects. However, µORs are also found on the peripheral endings of nociceptors and their activation there produces meaningful analgesia.

Radiofluorinated N-Octanoyl Dopamine ([F]F-NOD) as a Tool To Study Tissue Distribution and Elimination of NOD in Vitro and in Vivo.

To mitigate pretransplantation injury in organs of potential donors, N-octanoyl dopamine (NOD) treatment might be considered as it does not affect hemodynamic parameters in braindead (BD) donors. To better assess optimal NOD concentrations for donor treatment, we report on the fast and facile radiofluorination of the NOD-derivative [F]F-NOD [F]5 for in vivo assessment of NOD's elimination kinetics by means of PET imaging. [F]5 was synthesized in reproducibly high radiochemical yields and purity (>98%) as well as high specific activities (>20 GBq/μmol).

Cycloartanes from Oxyanthus pallidus and derivatives with analgesic activities.

Background: The leaves of Oxyanthus pallidus Hiern (Rubiaceae) are extensively used in the west region of Cameroon as analgesic. These leaves are rich in cycloartanes, a subclass of triterpenes known to possess analgesic and anti-inflammatory properties. The present study aimed at evaluating the analgesic properties of three cycloartanes isolated from Oxyanthus pallidus leaves as well as their aglycones and acetylated derivatives.

Gasotransmitters in Vascular Complications of Diabetes.

In the past decades three gaseous signaling molecules-so-called gasotransmitters-have been identified: nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S). These gasotransmitters are endogenously produced by different enzymes in various cell types and play an important role in physiology and disease. Despite their specific functions, all gasotransmitters share the capacity to reduce oxidative stress, induce angiogenesis, and promote vasorelaxation.

N-octanoyl dopamine treatment exerts renoprotective properties in acute kidney injury but not in renal allograft recipients.

Background: N-octanoyl dopamine (NOD) treatment improves renal function when applied to brain dead donors and in the setting of warm ischaemia-induced acute kidney injury (AKI). Because it also activates transient receptor potential vanilloid type 1 (TRPV1) channels, we first assessed if NOD conveys its renoprotective properties in warm ischaemia-induced AKI via TRPV1 and secondly, if renal transplant recipients also benefit from NOD treatment.

Methods: We induced warm renal ischaemia in Lewis, wild-type (WT) and TRPV1(-/-) Sprague-Dawley (sd) rats by clamping the left renal artery for 45 min.

Impact of preconditioning with retinoic acid during early development on morphological and functional characteristics of human induced pluripotent stem cell-derived neurons.

Human induced pluripotent stem cells (hiPSCs) are a suitable tool to study basic molecular and cellular mechanisms of neurodevelopment. The directed differentiation of hiPSCs via the generation of a self-renewable neuronal precursor cell line allows the standardization of defined differentiation protocols. Here, we have investigated whether preconditioning with retinoic acid during early neural induction impacts on morphological and functional characteristics of the neuronal culture after terminal differentiation.

Capsaicin-sensitive C- and A-fibre nociceptors control long-term potentiation-like pain amplification in humans.

Long-term potentiation in the spinal dorsal horn requires peptidergic C-fibre activation in animals. Perceptual correlates of long-term potentiation following high-frequency electrical stimulation in humans include increased sensitivity to electrical stimuli at the high frequency stimulation site (homotopic pain-long-term potentiation) and increased sensitivity to pinprick surrounding the high frequency stimulation site (heterotopic pain-long-term potentiation, equivalent to secondary hyperalgaesia). To characterize the peripheral fibre populations involved in induction of pain-long-term potentiation, we performed two selective nerve block experiments in 30 healthy male volunteers.

Acetylsalicylic acid enhances tachyphylaxis of repetitive capsaicin responses in TRPV1-GFP expressing HEK293 cells.

Since many years acetylsalicylic acid (ASA) is known for its antithrombotic, antiphlogistic and analgesic effects caused by irreversible acetylation of cyclooxygenase. ASA also inhibits capsaicin- and heat-induced responses in cultured dorsal root ganglia (DRG) neurons, suggesting TRPV1 (transient receptor potential channel of the vanilloid receptor family, subtype 1) to be an additional target of ASA. We now studied the effect of ASA on heterologously expressed rat TRPV1 using calcium microfluorimetry.

Contact heat and cold, mechanical, electrical and chemical stimuli to elicit small fiber-evoked potentials: merits and limitations for basic science and clinical use.

Laser-evoked potentials are the most extensively validated method to objectively assess nociceptive pathway function in humans. Here, we review merits and shortcomings of alternative techniques using different principles of stimulus generation to stimulate Aδ- or C-fibers. Fast ramp contact heat stimuli yield reproducible responses; however, stimulus location needs to be changed to reduce peripheral habituation, and the limited steepness of temperature ramps may result in response jitter and absence of averaged responses even in some healthy subjects.