Highlights • Increased activation of spinal GSK3β is associated with the genesis of taxol-induced pain. • This is accompanied by increased GFAP, IL-1β expression and a decreased expression of GLT-1. ...• Lithium (a GSK3β inhibitor) treatment prevents and attenuates taxol-induced neuropathic pain. • Lithium attenuates GSK3β activities, GFAP, IL-1β expression and improves the expression of GLT-1.
Partial reprogramming by expression of reprogramming factors (Oct4, Sox2, Klf4 and c-Myc) for short periods of time restores a youthful epigenetic signature to aging cells and extends the life span ...of a premature aging mouse model. However, the effects of longer-term partial reprogramming in physiologically aging wild-type mice are unknown. Here, we performed various long-term partial reprogramming regimens, including different onset timings, during physiological aging. Long-term partial reprogramming lead to rejuvenating effects in different tissues, such as the kidney and skin, and at the organismal level; duration of the treatment determined the extent of the beneficial effects. The rejuvenating effects were associated with a reversion of the epigenetic clock and metabolic and transcriptomic changes, including reduced expression of genes involved in the inflammation, senescence and stress response pathways. Overall, our observations indicate that partial reprogramming protocols can be designed to be safe and effective in preventing age-related physiological changes. We further conclude that longer-term partial reprogramming regimens are more effective in delaying aging phenotypes than short-term reprogramming.
Present studies suggested that cultural and religious factors, as well as law and policy, may have impeded the advancement of palliative care in the Middle East. Little is known about health care ...providers' perceptions of palliative care and the barriers to its development in the Gulf Cooperation Council.
To understand health care professionals' attitudes and beliefs regarding palliative care and highlight current practice barriers in Bahrain.
Semistructured interviews with 16 health care providers (physicians and nurses) were conducted. Thematic analysis was then performed after interviews were transcribed verbatim.
Health care professionals perceived palliative care as a service only delivered to patients at the end of life. Palliative care was only offered to patients who have been diagnosed with cancer and had exhausted all curative treatments. Do-not-resuscitate orders and code status discussions are not currently practiced. Palliative care decisions are usually decided by patients' families. Middle Eastern culture, health care law and policy, conservative interpretations of Islam, and a lack of professional expertise were identified as barriers.
This study unveiled the perceptions of palliative care among health care professionals in a Gulf Cooperation Council country. Six major barriers that hindered palliative care practice were identified. Future health care policy in the region needs to address these barriers within the current health care system while taking culture, religion, and social factors into consideration.
Glutamate is a primary excitatory neurotransmitter in the mammalian CNS. Glutamate released from presynaptic neurons is cleared from the synaptic cleft passively by diffusion and actively by ...glutamate transporters. In this study, the role of glutamate transporters in sensory processing in the spinal cord has been investigated in behavioral, in vivo and in vitro experiments. Intrathecal application of a non-selective glutamate transport inhibitor, l-trans-pyrrolidine-2,4-dicarboxylic acid (10μl of 100μM solution) induced hypersensitivity to peripheral mechanical and thermal stimuli. Topical application of l-trans-pyrrolidine-2,4-dicarboxylic acid (100μM) onto the dorsal surface of the L3–L6 spinal cord increased spontaneous activities, innocuous and noxious stimulus-evoked responses and after-discharges of wide dynamic range neurons in the L4–5 spinal segments. Whole cell recordings made from superficial dorsal horn neurons in an isolated whole spinal cord from newborn rats (2–3 weeks old) revealed that bath-applied l-trans-pyrrolidine-2,4-dicarboxylic acid (100μM) produced partial membrane depolarization, increased spontaneous action potentials with decreased neuronal membrane resistance and time constant, but without significant changes of capacitance. Finally, the amplitude and duration of primary afferent evoked-excitatory postsynaptic currents recorded from neurons in the substantia gelatinosa in the spinal slices from young adult rats (6–8 weeks old) were increased in the presence of l-trans-pyrrolidine-2,4-dicarboxylic acid (100μM). This study indicates that glutamate transporters regulate baseline excitability and responses of dorsal horn neurons to peripheral stimulation, and suggests that dysfunction of glutamate transporters may contribute to certain types of pathological pain.
Abstract Activation of glutamate receptors and glial cells in the spinal dorsal horn are two fundamental processes involved in the pathogenesis of various pain conditions, including neuropathic pain ...induced by injury to the peripheral or central nervous systems. Numerous studies have demonstrated that minocycline treatment attenuates allodynic and hyperalgesic behaviors induced by tissue inflammation or nerve injury. However, the synaptic mechanisms by which minocycline prevents hyperalgesia are not fully understood. We recently reported that deficient glutamate uptake by glial glutamate transporters (GTs) is key for the enhanced activation of N-methyl- d -aspartate (NMDA) receptors in the spinal sensory synapses of rats receiving partial sciatic nerve ligation (pSNL). In this study, we investigated how minocycline affects activation of NMDA receptors in the spinal sensory synapses in rats with pSNL by whole cell recordings of NMDA currents in spinal laminea I and II neurons from spinal slices. The effects of minocycline treatments on the dorsal horn expression of glial GTs and astrocyte marker glial fibrillary acidic protein (GFAP) were analyzed by immunohistochemistry. We demonstrated that normalized activation of NMDA receptors in synapses activated by both weak and strong peripheral input in the spinal dorsal horn is temporally associated with attenuated mechanical allodynia in rats with pSNL receiving intraperitoneal injection of minocycline. Minocycline ameliorated both the downregulation of glial GT expression and the activation of astrocytes induced by pSNL in the spinal dorsal horn. We further revealed that preventing deficient glial glutamate uptake at the synapse is crucial for preserving the normalized activation of NMDA receptors in the spinal sensory synapses in pSNL rats treated with minocycline. Our studies suggest that glial GTs may be a potential target for the development of analgesics.
Besides the negative longitudinal magnetoresistance (MR), planar Hall effect (PHE) is a newly emerging experimental tool to test the chiral anomaly or nontrivial Berry curvature in Weyl semimetals ...(WSMs). However, the origins of PHE in various systems are not fully distinguished and understood. Here we perform a systematic study on the PHE and anisotropic MR (AMR) of Td-MoTe2, a type-II WSM. Although the PHE and AMR curves can be well fitted by the theoretical formulas, we demonstrate that the anisotropic resistivity arises from the orbital MR (OMR), instead of the negative MR as expected in the chiral anomaly effect. In contrast, the positive MR indicates that the large OMR dominates over the chiral anomaly effect. This explains why it is difficult to measure negative MR in type-II WSMs. We argue that the measured PHE can be related with the chiral anomaly only when the negative MR is simultaneously observed.
Abnormal sensation and pain are major dose-limiting factors in cancer chemotherapy with vincristine. In this study, we have adapted a model of this condition by using repeated daily intraperitoneal ...injections of vincristine in rats. Mechanical allodynia and hyperalgesia without change in responses to thermal stimuli were first observed following 5-8 days of vincristine treatment (0.1mg/kg/day) and then persisted throughout the remainder of the treatment interval (2-3 weeks). Electrophysiological recording from wide dynamic range (WDR) neurons in the lumbar (L4-L5) spinal dorsal horn in hyperalgesic rats demonstrated significantly increased spontaneous activity and after-discharges to noxious mechanical stimuli (von Frey filaments with a bending force greater than 58.02mN, skin compression 1.3 and 3N, 1mm(2)), increased acute A- and C-fiber responses, after-discharges and abnormal 'wind-up' to electrical stimuli (5mA, 2ms) at 0.1Hz applied across the receptive field. These results suggest a state of central sensitization develops in spinal WDR neurons with repeated vincristine treatment that contributes to the spontaneous pain and hyperalgesia seen in patients and the hyperresponsiveness to sensory stimuli seen in animals treated with vincristine.
Lysophospholipids are bioactive signaling molecules derived from cell membrane glycerophospholipids or sphingolipids and are highly regulated under normal physiological conditions. Lysophosphatidic ...acids (LPAs) are a class of lysophospholipids that act on G-protein-coupled receptors to exert a variety of cellular functions. Dysregulation of phospholipase activity and consequently LPA synthesis in serum have been linked to inflammation, such as seen in chronic obstructive pulmonary disease (COPD). The accurate measurement of phospholipids is critical for evaluating their dysregulation in disease. In this study, we optimized experimental parameters for the sensitive measurement of LPAs. We validated the method based on matrix, linearity, accuracy, precision, and stability. An investigation into sample extraction processes emphasized that the common practice of including low concentration of hydrochloric acid in the extraction buffer causes an overestimation of lipid recovery. The liquid chromatography gradient was optimized to separate various lysophospholipid classes. After optimization, detection limits of LPA were sufficiently sensitive for subsequent analysis, ranging from 2 to 8 nM. The validated workflow was applied to a cohort of healthy donor and COPD patient sera. Eight LPA species were identified, and five unique species of LPA were quantified. Most LPA species increased significantly in COPD patients compared to healthy donors. The correlation between LPAs and other demographic parameters was further investigated in a sample set of over 200 baseline patient sera from a COPD clinical trial. For the first time, LPAs other than the two most abundant and readily detectable moieties are quantified in COPD patients using validated methods, opening the door to downstream biomarker evaluation in respiratory disease.
γδ T cells are a distinct subgroup of T cells that bridge the innate and adaptive immune system and can attack cancer cells in an MHC-unrestricted manner. Trials of adoptive γδ T cell transfer in ...solid tumors have had limited success. Here, we show that DNA methyltransferase inhibitors (DNMTis) upregulate surface molecules on cancer cells related to γδ T cell activation using quantitative surface proteomics. DNMTi treatment of human lung cancer potentiates tumor lysis by ex vivo-expanded Vδ1-enriched γδ T cells. Mechanistically, DNMTi enhances immune synapse formation and mediates cytoskeletal reorganization via coordinated alterations of DNA methylation and chromatin accessibility. Genetic depletion of adhesion molecules or pharmacological inhibition of actin polymerization abolishes the potentiating effect of DNMTi. Clinically, the DNMTi-associated cytoskeleton signature stratifies lung cancer patients prognostically. These results support a combinatorial strategy of DNMTis and γδ T cell-based immunotherapy in lung cancer management.
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