Activation of voltage-gated KCNQ/Kv7 channels by anticonvulsant retigabine attenuates mechanical allodynia of inflammatory temporomandibular joint in rats

<p>Abstract</p> <p>Background</p> <p>Temporomandibular disorders (TMDs) are characterized by persistent orofacial pain and have diverse etiologic factors that are not well understood. It is thought that central sensitization leads to neuronal hyperexcitability and contributes to hyperalgesia and spontaneous pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently the first choice of drug to relieve TMD pain. NSAIDS were shown to exhibit anticonvulsant properties and suppress cortical neuron activities by enhancing neuronal voltage-gated potassium KCNQ/Kv7 channels (M-current), suggesting that specific activation of M-current might be beneficial for TMD pain.</p> <p>Results</p> <p>In this study, we selected a new anticonvulsant drug retigabine that specifically activates M-current, and investigated the effect of retigabine on inflammation of the temporomandibular joint (TMJ) induced by complete Freund's adjuvant (CFA) in rats. The results show that the head withdrawal threshold for escape from mechanical stimulation applied to facial skin over the TMJ in inflamed rats was significantly lower than that in control rats. Administration of centrally acting M-channel opener retigabine (2.5 and 7.5 mg/kg) can dose-dependently raise the head withdrawal threshold of mechanical allodynia, and this analgesic effect can be reversed by the specific KCNQ channel blocker XE991 (3 mg/kg). Food intake is known to be negatively associated with TMJ inflammation. Food intake was increased significantly by the administration of retigabine (2.5 and 7.5 mg/kg), and this effect was reversed by XE991 (3 mg/kg). Furthermore, intracerebralventricular injection of retigabine further confirmed the analgesic effect of central retigabine on inflammatory TMJ.</p> <p>Conclusions</p> <p>Our findings indicate that central sensitization is involved in inflammatory TMJ pain and pharmacological intervention for controlling central hyperexcitability by activation of neuronal KCNQ/M-channels may have therapeutic potential for TMDs.</p

Lyn mediates FIP1L1-PDGFRA signal pathway facilitating IL-5RA intracellular signal through FIP1L1-PDGFRA/JAK2/Lyn/Akt network complex in CEL

The Fip1-like1 (FIP1L1)–platelet-derived growth factor receptor alpha (PDGFRA) (F/P) oncogene can cause chronic eosinophilic leukemia (CEL), but requires IL-5 cytokine participation. In this study, we investigate the mechanism of F/P in collaboration with IL-5 in CEL. The results showed that Lyn, a key effector in the IL-5-motivated eosinophil production, is extensively activated in F/P-positive CEL cells. Lyn can associate and phosphorylate IL-5 receptor α (IL-5RA) in F/P-positive cells. Moreover, the activation of Lyn and IL-5R kinase were strengthened when the cells were stimulated by IL-5. Lyn inhibition in F/P-positive CEL cells attenuated cellular proliferation, induced apoptosis, and blocked cell migration and major basic protein (MBP) release. We identified the FIP1L1-PDGFRA/JAK2/Lyn/Akt complex in the F/P-expressing cells which can be disrupted by dual inhibition of JAK2 and Lyn, repressing cell proliferation in both EOL-1(F/P-positive human eosinophilic cell line) and imatinib-resistance (IR) cells. Altogether, our data demonstrate that Lyn is a vital downstream kinase activated by F/P converged with IL-5 signals in CEL cells. Lyn activate and expand IL-5RA intracellular signaling through FIP1L1-PDGFRA/JAK2/Lyn/Akt network complex, provoking eosinophils proliferation and exaggerated activation manifested as CEL

Shock therapy to treat the Novel Coronavirus Disease (COVID-19) by ddNTPs

The Novel Coronavirus (SARS-CoV-2) has caused a massive global outbreak, presenting a significant public health emergency and international concern. Thousands of critically ill patients are dying daily. To date, there are no clinically approved antiviral drug available to cure the Novel Coronavirus infections.&nbsp; I highly recommend the clinical trial of 2’,3’-dideoxyribonucleoside triphosphate (ddNTPs, except ddTTP) to be used for the Novel Coronavirus Disease (COVID-19) antiviral therapy.</p

Challenges of Animal Derived Food Safety and Counter-measures

The safety of animal derived food has been at the forefront of societal concerns in recent years. In this paper, we stress major animal derived food issues and challenges including microbial pathogens, food additives and chemical residues. In addition, the countermeasures to animal derived food issues including animal health and welfare, animal identification and traceability, antimicrobial interventions, new processes and technologies in the processing and preservation of animal derived food products, and Risk assessment are discussed

Dynamic response analysis of an onshore LNG-storage tank interaction system subject to impact or earthquake loads

Liquefied Natural Gas (LNG) has become an increasingly important element for energy supplies and LNG terminals are planned and built to enable the import and export of LNG from producers to consumers. There are concerns from the communities near LNG terminals about the safety and security of onshore LNG storage tanks under different loads. This paper presents a numerical investigation of the dynamic behaviour of an LNG-tank interaction system subject to impact and earthquake to assess its safety. The coupling system is modelled by a mixed finite element approach where pressure and shell elements are adopted for LNG and the tank wall respectively. The natural characteristics of the dry tank, LNG sloshing in the rigid tank and the coupling system are calculated. The displacement / stress responses of the system are obtained. In the analysis, the multi-layered tank wall is idealised using shell elements with equivalent mechanical properties. An available earthquake data and empirical formula for the impact loads are used. The influence of the fluid-structure interactions is studied for various filling levels of the tank and the different loading conditions. Some conclusions for engineering applications are drawn from the outcome of the simulations

A numerical investigation of a wave energy harness device-water interaction system subject to the wave maker excitation in a towing tank

This paper investigates numerically a wave energy harness device-water interaction system excited by a wave maker motion in order to extract maximum wave energy. The model of the energy harness device consists of a moving coil connected to a magnetic body floating on the water surface of the towing tank. At one end of the towing tank, a wave maker produces waves to excite the device-water interaction system. The motion of the coil relative to the magnetic body produces an electromagnetic induction voltage added to an energy collection circuit, so that the kinetic energy of the coil motion is transformed to electric energy. To extract maximum energy from the wave requires a large relative motion between the coil and the magnetic body of the energy harness device. To this end, the natural frequency of the wave energy harness device should be so close to the wave frequency that a resonance of the wave energy device can be reached. Since the wave energy device floats on the water surface, its dynamic behaviour is affected by the water motion. Therefore, it is necessary to consider fluid-structure interactions to design an effective wave energy device. This problem is addressed in this paper. In this numerical simulation, the water is considered as a compressible fluid satisfying a wave equation in the water domain in association with the boundary conditions on the free surface, wall and bottom of the towing tank. The wave maker motion is simulated by a given boundary acceleration on the wet interface of the wave maker. The energy harness device is treated as a two masses connected by four springs between them. The spring stiffness can be adjusted to obtain an effective energy extraction device. On the interface between the magnetic body and the water, the equilibrium and motion consistent conditions are required. The governing equations describing the fluid-structure interaction dynamics of the integrated system are presented. A corresponding variational principle is formulated and a mixed finite element model is established. The developed computer program-FSIAP is used to complete the numerical simulations. Suitable parameters of the energy harness device are obtained. The dynamic responses of the integrated fluid-structure interaction system excited by the wave maker motions are calculated. It is shown that the designed energy harness device can extract maximum wave energy using the resonance principle. The results obtained are compared and discussed. Some guidelines for engineering applications are provided

A viral caspase contributes to modified apoptosis for virus transmission

The Spodoptera frugiperda ascovirus, a DNA virus that attacks lepidopterans, codes for an executioner caspase synthesized by 9 h after infection of Sf21 cells. This caspase alone induces apoptosis in insect cells and, during viral replication in vivo, contributes to a novel cell cleavage process in which developing apoptotic bodies are rescued by the virus and differentiate to form large vesicles in which virions assemble. These viral vesicles disseminate to the blood, where they are acquired during egg-laying by parasitic wasps that transmit the virus. No other viruses encode caspases or form such modified apoptotic bodies, suggesting this caspase plays a direct role in cell partitioning that facilitates viral reproduction and transmission

Ascovirus P64 Homologs: A Novel Family of Large Cationic Proteins That Condense Viral Genomic DNA for Encapsidation

Eukaryotic dsDNA viruses use small basic protamine-like proteins or histones, typically &lt;15 kDa, to condense and encapsidate their genomic (g)DNAs during virogenesis. Ascoviruses are large dsDNA (~100&ndash;200 kbp) viruses that are pathogenic to lepidopteran larvae. Little is known about the molecular basis for condensation and encapsidation of their gDNAs. Previous proteomic analysis showed that Spodoptera frugiperda ascovirus (SfAV-1a) virions contain a large unique DNA-binding protein (P64; 64 kDa, pI = 12.2) with a novel architecture proposed to condense its gDNA. Here we used physical, biochemical, and transmission electron microscopy techniques to demonstrate that P64&rsquo;s basic C-terminal domain condenses SfAV-1a gDNA. Moreover, we demonstrate that only P64 homologs in other ascovirus virions are unique in stably binding DNA. As similar protein families or subfamilies were not identified in extensive database searches, our collective data suggest that ascovirus P64 homologs comprise a novel family of atypical large viral gDNA condensing proteins