Neuroimmune interactions in the development and chronification of migraine headache.

Migraine is highly prevalent and debilitating. The persistent headaches in this condition are thought to arise from the activation and sensitization of the trigeminovascular pathway. Both clinical and animal model studies have suggested that neuroimmune interactions contribute to the pathophysiology of migraine headache.

Low-Dose Interleukin-2 Reverses Traumatic Brain Injury-Induced Cognitive Deficit and Pain in a Murine Model.

Objective: Despite the high prevalence, mild traumatic brain injury (mTBI)-induced chronic headache and cognitive deficits are poorly understood and lack effective treatments. Low-dose interleukin-2 (LD-IL-2) treatment soon after mTBI or overexpressing IL-2 in brain astrocytes prior to injury protects mice from developing post-traumatic headache (PTH)-related behaviors and cognitive decline. The present study addresses a clinically relevant knowledge gap: whether LD-IL-2 treatment long after the initial injury is still effective for chronic PTH and cognitive deficits.

Nanoparticle Polymeric Micellar Paclitaxel Versus Paclitaxel for Patients with Advanced Gastric Cancer.

Background: Nanoparticle polymeric micellar paclitaxel (NPMP) is a novel Cremophor EL (CrEL)-free nanoparticle micellar formulation of paclitaxel. This study evaluated the efficacy and toxicity of NPMP in the treatment of patients with advanced gastric cancer (AGC).

Methods: Patients with histologically confirmed AGC in Jiangsu Cancer Hospital were retrospectively collected and divided into two groups.

A Cataract-Causing Mutation in the TRPM3 Cation Channel Disrupts Calcium Dynamics in the Lens.

TRPM3 belongs to the melastatin sub-family of transient receptor potential (TRPM) cation channels and has been shown to function as a steroid-activated, heat-sensitive calcium ion (Ca) channel. A missense substitution (p.I65M) in the TRPM3 gene of humans () and mice () has been shown to underlie an inherited form of early-onset, progressive cataract.

Optimization of green deep eutectic solvent (DES) extraction of Willd. husks saponins by response surface methodology and their antioxidant activities.

Quinoa saponins have outstanding activity, and there are an increasing number of extraction methods, but there are few research programs on green preparation technology. The extraction conditions of quinoa saponins with deep eutectic solvents (DESs) were optimized by single-factor experiments combined with response surface methodology. The antioxidant capacity of saponins extracted by DESs and traditional methods was evaluated by the DPPH clearance rate, iron ion chelation rate and potassium ferricyanide reducing power.

Peripheral CCL2-CCR2 signalling contributes to chronic headache-related sensitization.

Migraine, especially chronic migraine, is highly debilitating and still lacks effective treatment. The persistent headache arises from activation and sensitization of primary afferent neurons in the trigeminovascular pathway, but the underlying mechanisms remain incompletely understood. Animal studies indicate that signalling through chemokine C-C motif ligand 2 (CCL2) and C-C motif chemokine receptor 2 (CCR2) mediates the development of chronic pain after tissue or nerve injury.

Transfer of the gene results in changes in egg adhesiveness and buoyancy in transgenic zebrafish.

Reproductive strategies and spawning habits play key roles in the evolution of endemic East Asian cyprinids. However, the molecular mechanisms underlying the regulation of spawning habits are not well understood. We recently identified zona pellucida (Zp) as the top differentially expressed protein between East Asian cyprinids that produce adhesive and semi-buoyant eggs, suggesting that Zp protein may play important roles in the regulation of egg type.

Low-dose interleukin-2 reverses chronic migraine-related sensitizations through peripheral interleukin-10 and transforming growth factor beta-1 signaling.

Low-dose interleukin-2 (LD-IL-2) treatment has been shown to effectively reverse chronic migraine-related behaviors and the sensitization of trigeminal ganglion (TG) neurons through expansion and activation of peripheral regulatory T cells (Tregs) in mice. In this study, we investigated the molecular mechanisms underlying the effects of LD-IL-2 and Treg cells. LD-IL-2 treatment increases the production of cytokines interleukin-10 (IL-10) and transforming growth factor beta-1 (TGFβ1) in T cells, especially Treg cells, suggesting that they may mediate the therapeutic effect of LD-IL-2.

Low-Dose Interleukin-2 and Regulatory T Cell Treatments Attenuate Punctate and Dynamic Mechanical Allodynia in a Mouse Model of Sciatic Nerve Injury.

Purpose: Nerve injury-induced mechanical hyper-sensitivity, in particular stroking-induced dynamic allodynia, is highly debilitating and difficult to treat. Previous studies indicate that the immunosuppressive regulatory T (Treg) cells modulate the magnitude of punctate mechanical allodynia resulting from sciatic nerve injury. However, whether enhancing Treg-mediated suppression attenuates dynamic allodynia is not known.

Electric Field Stimulation for the Functional Assessment of Isolated Dorsal Root Ganglion Neuron Excitability.

Genetically encoded calcium indicators have proven useful for characterizing dorsal root ganglion neuron excitability in vivo. Challenges persist in achieving high spatial-temporal resolutions in vivo, however, due to deep tissue imaging and motion artifacts that may be limiting technical factors in obtaining measurements. Here we report an ex vivo imaging method, using a peripheral neuron-specific Advillin-GCaMP mouse line and electric field stimulation of dorsal root ganglion tissues, to assess the sensitivity of neurons en bloc.

Increase in trigeminal ganglion neurons that respond to both calcitonin gene-related peptide and pituitary adenylate cyclase-activating polypeptide in mouse models of chronic migraine and posttraumatic headache.

A large body of animal and human studies indicates that blocking peripheral calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) signaling pathways may prevent migraine episodes and reduce headache frequency. To investigate whether recurring migraine episodes alter the strength of CGRP and PACAP signaling in trigeminal ganglion (TG) neurons, we compared the number of TG neurons that respond to CGRP and to PACAP (CGRP-R and PACAP-R, respectively) under normal and chronic migraine-like conditions. In a mouse model of chronic migraine, repeated nitroglycerin (NTG) administration significantly increased the number of CGRP-R and PACAP-R neurons in TG but not dorsal root ganglia.

Low-dose interleukin-2 reverses behavioral sensitization in multiple mouse models of headache disorders.

Headache disorders are highly prevalent and debilitating, with limited treatment options. Previous studies indicate that many proinflammatory immune cells contribute to headache pathophysiology. Given the well-recognized role of regulatory T (Treg) cells in maintaining immune homeostasis, we hypothesized that enhancing Treg function may be effective to treat multiple headache disorders.

MicroRNA-498 promotes proliferation, migration, and invasion of prostate cancer cells and decreases radiation sensitivity by targeting PTEN.

Prostate cancer (PCa) remains the secondary highest cause of cancer-related death in the United States in men. It has been reported that microRNAs can serve as key regulators in tumor development and progression in various cancers including PCa. In this study, we examined the effect of miR-498 on proliferation, radiosensitivity, invasion, and migration of PCa cells.

TRESK K Channel Activity Regulates Trigeminal Nociception and Headache.

Although TWIK-related spinal cord K (TRESK) channel is expressed in all primary afferent neurons in trigeminal ganglia (TG) and dorsal root ganglia (DRG), whether TRESK activity regulates trigeminal pain processing is still not established. Dominant-negative TRESK mutations are associated with migraine but not with other types of pain in humans, suggesting that genetic TRESK dysfunction preferentially affects the generation of trigeminal pain, especially headache. Using TRESK global knock-out mice as a model system, we found that loss of TRESK in all TG neurons selectively increased the intrinsic excitability of small-diameter nociceptors, especially those that do not bind to isolectin B4 (IB4).

Deficits in Burrowing Behaviors Are Associated With Mouse Models of Neuropathic but Not Inflammatory Pain or Migraine.

Burrowing, or the removal of material from an enclosed tube, is emerging as a prominent means of testing changes in a voluntary behavior in rodent models of various pain states. Here, we report no significant differences between male and female mice in terms of burrowing performance, in a substantially shorter time frame than previous reports. We found that the color of the burrow tube affects the variability of burrowing performance when tested in a lit room, suggesting that light aversion is at least a partial driver of this behavior.

Quantitative Analysis of Mouse Dural Afferent Neurons Expressing TRPM8, VGLUT3, and NF200.

Objective: To quantify the abundance of dural afferent neurons expressing transient receptor potential channel melastatin 8 (TRPM8), vesicular glutamate transporter 3 (VGLUT3), and neurofilament 200 (NF200) in adult mice.

Background: With the increasing use of mice as a model system to study headache mechanisms, it is important to understand the composition of dural afferent neurons in mice. In a previous study, we have measured the abundance of mouse dural afferent neurons that express neuropeptide calcitonin gene-related peptide as well as two TRP channels TRPV1 and TRPA1, respectively.

TRPM8 and Migraine.

Migraine is among the most common diseases on earth and one of the most disabling, the latter due in large part to poor treatment efficacy. Development of new therapeutics is dependent on the identification of mechanisms contributing to migraine and discovery of targets for new drugs. Numerous genome-wide association studies (GWAS) have implicated the transient receptor-potential M8 (TRPM8) channel in migraine.

Characterization of a mouse model of headache.

Migraine and other primary headache disorders affect a large population and cause debilitating pain. Establishing animal models that display behavioral correlates of long-lasting and ongoing headache, the most common and disabling symptom of migraine, is vital for the elucidation of disease mechanisms and identification of drug targets. We have developed a mouse model of headache, using dural application of capsaicin along with a mixture of inflammatory mediators (IScap) to simulate the induction of a headache episode.

Function and postnatal changes of dural afferent fibers expressing TRPM8 channels.

Background: Genome-wide association studies have identified TRPM8 (transient receptor potential melastatin 8) as one of the susceptibility genes for common migraine. Here, we investigated the postnatal changes of TRPM8-expressing dural afferent fibers as well as the function of dural TRPM8 channels in mice.

Results: First, we quantified the density and the number of axonal branches of TRPM8-expressing fibers in the dura of mice expressing farnesylated enhanced green fluorescent protein (EGFPf) from one TRPM8 allele between postnatal day 2 (P2) to adulthood.

[Design, synthesis and evaluation of 5-aminobenzimidazolone derivatives as acetylcholinesterase inhibitors].

The target compounds were prepared from 5-aminobenzimidazolone by two steps reaction, and their AChE inhibitory activities were measured by Ellman method in vitro. The AChE inhibitory activity of compound 4d is the best of them, and its IC50 value is equal to 7.2 μmol·L(-1), which is better than that of rivastigmine; moreover the 4d had no inhibitory activities to BuChE.

Nonmigraine-associated TRESK K+ channel variant C110R does not increase the excitability of trigeminal ganglion neurons.

Recent genetic studies suggest that dysfunction of ion channels and transporters may contribute to migraine pathophysiology. A migraine-associated frameshift mutation in the TWIK-related spinal cord K+ (TRESK) channel results in nonfunctional channels. Moreover, mutant TRESK subunits exert a dominant-negative effect on whole cell TRESK currents and result in hyperexcitability of small-diameter trigeminal ganglion (TG) neurons, suggesting that mutant TRESK may increase the gain of the neuronal circuit underlying migraine headache.

Over-expression of TRESK K(+) channels reduces the excitability of trigeminal ganglion nociceptors.

TWIK-related spinal cord K(+) (TRESK) channel is abundantly expressed in trigeminal ganglion (TG) and dorsal root ganglion neurons and is one of the major background K(+) channels in primary afferent neurons. Mutations in TRESK channels are associated with familial and sporadic migraine. In rats, both chronic nerve injury and inflammation alter the expression level of TRESK mRNA.

Functional analysis of a migraine-associated TRESK K+ channel mutation.

Recent genetic and functional studies suggest that migraine may result from abnormal activities of ion channels and transporters. A frameshift mutation in the human TWIK-related spinal cord K(+) (TRESK) channel has been identified in migraine with aura patients in a large pedigree. In Xenopus oocytes, mutant TRESK subunits exert a dominant-negative effect on whole-cell TRESK currents.

Serine 363 is required for nociceptin/orphanin FQ opioid receptor (NOPR) desensitization, internalization, and arrestin signaling.

We determined the role of carboxyl-terminal regulation of NOPR (nociceptin, orphanin FQ receptor) signaling and function. We mutated C-terminal serine and threonine residues and examined their role in NOPR trafficking, homologous desensitization, and arrestin-dependent MAPK signaling. The NOPR agonist, nociceptin, caused robust NOPR-YFP receptor internalization, peaking at 30 min.