Receptor tyrosine kinases (RTKs) are known to perform versatile roles in disease landscapes, which determine the fate of the cell. Although much has been discussed from the perspective of proliferation, this review focuses on the impact of RTK-mediated signaling and its role in cytoskeletal degradation, the penultimate stage of cellular degeneration. In the case of degenerative diseases such as Alzheimer’s disease (AD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), age-related macular degeneration (AMD), and type 2 diabetes mellitus (T2DM), RTK signaling has been reported to be perturbed in several studies. The implications of downstream signaling via these receptors through canonical and noncanonical pathways alter the status of actin filaments that provide structural integrity to cells. Degenerative signaling leads to the altered status of rat sarcoma (Ras), Ras homologous (Rho), Ras-related C3 botulinum toxin substrate (Rac), and cell division control protein 42 (Cdc42), the best-characterized components of the cytoskeleton remodeling machinery. RTKs, along with their diverse adaptor partners and other membrane receptors, affect the functionality of Rho family guanosine triphosphate hydrolases (GTPases), which are discussed in this review. To conclude, this review focuses on therapeutic strategies targeting RTKs and Rho GTPase-mediated pathways that can be more effective due to their combined multifactorial impact on neurodegenerative cascades.
Proprioception provides important sensory feedback regarding the position of an animal’s body and limbs in space. This interacts with a central pattern generator responsible for rhythmic movement, to adapt locomotion to the demands that an animal’s environment places on it. The mechanisms by which this feedback is enabled are poorly understood, which belies its importance: dysfunctional proprioception is associated with movement disorder and improving it can help reduce the severity of symptoms. Similarly, proprioception is important for guiding accurate robotic movement and for understanding how sensory systems capture and process information to guide action selection. It is therefore important to interpret research that investigates mechanisms of proprioception, to ask: what type of information do proprioceptive sensors capture, and how do they capture it? Work in mammalian models has made important progress towards answering this question. So too, has research conducted Drosophila. Fruit fly proprioceptors are more accessible than mammalian equivalents and can be manipulated using a unique genetic toolkit, so experiments conducted in the invertebrate can make a significant contribution to overall understanding. It can be difficult, however, to relate work conducted in different models, to draw general conclusions about proprioception. This review, therefore, explores what research in the fruit fly has revealed about proprioceptor function, to highlight its potential translation to mammals. Specifically, the present text presents evidence that differential expression of mechanoelectrical transducers contributes to tuning of fly proprioceptors and suggests that the same mechanism may play a role in tuning mammalian proprioceptors.
Aim: The ability of synthetic 1,4-naphthoquinones (1,4-NQs) to prevent adenosine triphosphate (ATP)-induced and purinergic P2X7 receptor (P2X7R) mediated inflammation in macrophage and neurodegeneration of neuronal cells in vitro was previously established. The aim of the present study was to investigate analgesic-like and anti-inflammatory activity of 1,4-NQs thioglucoside derivatives, compounds U-286 and U-548, in in vivo experiments.
Methods: Spectrofluorimetry approach and YO-PRO-1 fluorescent dye uptake determination were applied to study the effect of 1,4-NQs upon ATP-induced P2X7R mediated macropore formation in mouse neuroblastoma Neuro-2a cells and macrophages RAW 264.7 cells. An acetic acid-induced writhing test, hot plate test, and carrageenan-induced paw edema test were used as an in vivo mouse models to study the ability of 1,4-NQs to inhibit pain and inflammation. In the in vivo experiments, compounds were administered to mice intraperitoneally at dosages of 0.1 mg/kg, 1.0 mg/kg and 10.0 mg/kg. A group of animals that received injections of sterile water was used as a control. Each dosage group and the control group consisted of 6 mice.
Results: In the present work the analgesic-like and anti-inflammatory activity of 1,4-NQs, U-286 and U-548, was demonstrated. Compound U-548 showed a significant inhibitory effect in antinociceptive tests reducing the number of mouse writhings and eliminating the latent time of mouse hind paw licking, correspondingly. Selected compounds were able to almost completely reduce the size of carrageenan-induced paw edema 24 h after injection and had a potent anti-inflammatory activity. Observed effects were accompanied with aptitude of studied 1,4-NQs to inhibit the formation of purinergic P2X7R macropore associated with inflammation and nociceptive pain.
Conclusions: The results obtained allow to consider compounds U-286 and U-548 and as a pharmacological basis for the development of new analgesic-like and anti-inflammatory drugs.
The ubiquity of circadian rhythms in living organisms has generally been accepted by researchers over the last century. Indeed, morphology and molecular biology of the circadian clock were described during the last fifty years. This main biological clock is located in the suprachiasmatic nucleus of the hypothalamus. This nucleus is connected with the retina by the retinohypothalamic tract. This way, light regulates the functioning of the biological clock and biological rhythms such as the sleep-wake cycle and other cyclic functions by releasing melatonin from the pineal body (PB) into the general circulation. Melatonin reaches the retina via the bloodstream as humoral feedback. More than a hundred years ago a reverse neuronal connection between the central nervous system and the retina was hypothesized. This so-called centrifugal visual or retinopetal system has been explored in detail in birds, but less information is available in mammals. In this work, the morphology and physiology of mammalian centrifugal visual pathways are reviewed. It is generally accepted that the centrifugal (retinopetal) fibers terminate mainly on the amacrine cells of the retina. Histaminergic fibers terminate on dopaminergic amacrine cells. Serotoninergic synapses were identified on ganglion cells. In addition, serotoninergic fibers were also associated with photoreceptor terminals. Luteinizing hormone releasing hormone fibers have been observed in birds, but not in mammalian retinas. In summary, based on the data available in the literature, it seems that the retinopetal system has a mandatory role in lower vertebrates, but a modulatory role in mammals. There is currently no adequate way to eliminate the centrifugal visual system that would better explain its true function.
Stroke is among the leading causes of mortality and disability; therefore, it constitutes a relevant health problem. Cuban policosanol presents lipid-lowering, antiplatelet, antioxidant and vascular endothelium protective properties, all of which give it a comprehensive anti-atherosclerotic effect. This review is aimed to show, analyze and discuss the main preclinical and clinical evidence of the effects of Cuban policosanol on ischemic stroke. Preclinical studies evidenced the anti-ischemic effects of preventive and therapeutic oral treatment with Cuban policosanol in Mongolian gerbils with cerebral ischemia induced by unilateral and permanent ligation of a carotid artery, and in global cerebral ischemia induced by bilateral clamping and recirculation of both carotids; being similar or superior to other anti-ischemic agents. Also, combination therapy with aspirin produced greater anti-stroke efficacy compared with aspirin monotherapy, but being similar to policosanol plus atorvastatin combination. This anti-stroke effect was associated to a serum thromboxane A2 (TxA2) concentrations reduction and prostacyclin (PgI2) increase, leading to a favorable TxA2/PgI2 balance, and also to the malondialdehyde (MDA) and sulfhydryl groups (SHG, lipid peroxidation and protein oxidation markers, respectively) reduction. Cuban policosanol combined with aspirin (standard therapy) improved and benefited patients with prior ischemic stroke in terms of functional and neurological outcomes, in open-label studies and in randomized, double-blind, controlled studies. These beneficial effects on stroke patients were associated with antioxidant and antiplatelet effects of policosanol. Also, the combinations of Cuban policosanol plus aspirin and atorvastatin plus aspirin compared in a clinical study significantly and similarly improved the neurological recovery of patients with ischemic stroke. Cuban policosanol was safe and well tolerated, with no serious adverse events occurring during the trials. In conclusion, Cuban policosanol is a safe and effective natural drug for ischemic stroke treatment, which is supported by preclinical and clinical evidences.