Abstract
The coronavirus disease 2019 (COVID-19) pandemic has caused large-scale economic and social losses and worldwide deaths. Although most COVID-19 patients have initially complained of ...respiratory insufficiency, the presence of neuropsychiatric manifestations is also reported frequently, ranging from headache, hyposmia/anosmia, and neuromuscular dysfunction to stroke, seizure, encephalopathy, altered mental status, and psychiatric disorders, both in the acute phase and in the long term. These neuropsychiatric complications have emerged as a potential indicator of worsened clinical outcomes and poor prognosis, thus contributing to mortality in COVID-19 patients. Their etiology remains largely unclear and probably involves multiple neuroinvasive pathways. Here, we summarize recent animal and human studies for neurotrophic properties of severe acute respiratory syndrome coronavirus (SARS-CoV-2) and elucidate potential neuropathogenic mechanisms involved in the viral invasion of the central nervous system as a cause for brain damage and neurological impairments. We then discuss the potential therapeutic strategy for intervening and preventing neuropsychiatric complications associated with SARS-CoV-2 infection. Time-series monitoring of clinical–neurochemical–radiological progress of neuropsychiatric and neuroimmune complications need implementation in individuals exposed to SARS-CoV-2. The development of a screening, intervention, and therapeutic framework to prevent and reduce neuropsychiatric sequela is urgently needed and crucial for the short- and long-term recovery of COVID-19 patients.
Spinal cord injury (SCI) is a severely disabling central nervous system injury with complex pathological mechanisms that leads to sensory and motor dysfunction. The current treatment for SCI is aimed ...at symptomatic symptom relief rather than the pathological causes. Several studies have reported that signaling pathways play a key role in SCI pathological processes and neuronal recovery mechanisms. The PI3K/Akt signaling pathway is an important pathway closely related to the pathological process of SCI, and activation of this pathway can delay the inflammatory response, prevent glial scar formation, and promote neurological function recovery. Activation of this pathway can promote the recovery of neurological function after SCI by reducing cell apoptosis. Based on the role of the PI3K/Akt pathway in SCI, it may be a potential therapeutic target. This review highlights the role of activating or inhibiting the PI3K/Akt signaling pathway in SCI-induced inflammatory response, apoptosis, autophagy, and glial scar formation. We also summarize the latest evidence on treating SCI by targeting the PI3K/Akt pathway, discuss the shortcomings and deficiencies of PI3K/Akt research in the field of SCI, and identify potential challenges in developing these clinical therapeutic SCI strategies, and provide appropriate solutions.
•This paper reviews the recent literature on PI3K/Akt signaling pathway and spinal cord injury.•According to the role of PI3K/Akt pathway in spinal cord injury, the role of PI3K/Akt pathway on SCI field was summarized.•It is concluded that PI3K/Akt pathway may be a potential therapeutic target for spinal cord injury.
An eco-friendly, sustainable and practical method for the synthesis of various 5-organylselanyl uracils via the electrochemical selenylation of uracils and diorganyl diselenides at ambient ...temperature under oxidant- and external electrolyte-free conditions was developed.
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An eco-friendly, sustainable and practical method for the efficient preparation of 5-organylselanyl uracils through the electrochemical selenylation of uracils and diorganyl diselenides at room temperature under oxidant- and external electrolyte-free conditions was developed.
Spinal opioid-induced itch, a prevalent side effect of pain management, has been proposed to result from pain inhibition. We now report that the μ-opioid receptor (MOR) isoform MOR1D is essential for ...morphine-induced scratching (MIS), whereas the isoform MOR1 is required only for morphine-induced analgesia (MIA). MOR1D heterodimerizes with gastrin-releasing peptide receptor (GRPR) in the spinal cord, relaying itch information. We show that morphine triggers internalization of both GRPR and MOR1D, whereas GRP specifically triggers GRPR internalization and morphine-independent scratching. Providing potential insight into opioid-induced itch prevention, we demonstrate that molecular and pharmacologic inhibition of PLCβ3 and IP3R3, downstream effectors of GRPR, specifically block MIS but not MIA. In addition, blocking MOR1D-GRPR association attenuates MIS but not MIA. Together, these data suggest that opioid-induced itch is an active process concomitant with but independent of opioid analgesia, occurring via the unidirectional cross-activation of GRPR signaling by MOR1D heterodimerization.
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► Unique isoforms of the μ-opioid receptor (MOR) separate itch from analgesia ► Heterodimers of MOR1D and gastrin-releasing peptide receptor (GRPR) form ► Molecular basis for opioid-induced itch relies on MOR1D activation of GRPR ► PLCβ3 and IP3R3 signal downstream of MOR1D-GRPR to trigger itch response
Itching is an unwanted side effect of opioid-mediated pain relief. This study reveals how distinct populations of spinal cord neurons differentially respond to morphine, producing either itch or analgesia.
Chronic itch, or pruritus, is associated with a wide range of skin abnormalities. The mechanisms responsible for chronic itch induction and persistence remain unclear. We developed a mouse model in ...which a constitutively active form of the serine/threonine kinase BRAF was expressed in neurons gated by the sodium channel Nav1.8 (BRAF(Nav1.8) mice). We found that constitutive BRAF pathway activation in BRAF(Nav1.8) mice results in ectopic and enhanced expression of a cohort of itch-sensing genes, including gastrin-releasing peptide (GRP) and MAS-related GPCR member A3 (MRGPRA3), in nociceptors expressing transient receptor potential vanilloid 1 (TRPV1). BRAF(Nav1.8) mice showed de novo neuronal responsiveness to pruritogens, enhanced pruriceptor excitability, and heightened evoked and spontaneous scratching behavior. GRP receptor expression was increased in the spinal cord, indicating augmented coding capacity for itch subsequent to amplified pruriceptive inputs. Enhanced GRP expression and sustained ERK phosphorylation were observed in sensory neurons of mice with allergic contact dermatitis– or dry skin–elicited itch; however, spinal ERK activation was not required for maintaining central sensitization of itch. Inhibition of either BRAF or GRP signaling attenuated itch sensation in chronic itch mouse models. These data uncover RAF/MEK/ERK signaling as a key regulator that confers a subset of nociceptors with pruriceptive properties to initiate and maintain long-lasting itch sensation.
Monosodium urate (MSU) crystals, the etiological agent of gout, are formed in joints and periarticular tissues due to long-lasting hyperuricemia. Although MSU crystal-triggered NLRP3 inflammasome ...activation and interleukin 1β (IL-1β) release are known to have key roles in gouty arthritis, recent studies revealed that MSU crystal-induced necrosis also plays a critical role in this process. However, it remains unknown what forms of necrosis have been induced and whether combined cell death inhibitors can block such necrosis. Here, we showed that MSU crystal-induced necrosis in murine macrophages was not dependent on NLRP3 inflammasome activation, as neither genetic deletion nor pharmacological blockade of the NLRP3 pathway inhibited the necrosis. Although many cell death pathways (such as ferroptosis and pyroptosis) inhibitors or reactive oxygen species inhibitors did not have any suppressive effects, necroptosis pathway inhibitors GSK'872 (RIPK3 inhibitor), and GW806742X (MLKL inhibitor) dose-dependently inhibited MSU crystal-induced necrosis. Moreover, a triple combination of GSK'872, GW806742X, and IDN-6556 (pan-caspase inhibitor) displayed enhanced inhibition of the necrosis, which was further fortified by the addition of MCC950 (NLRP3 inhibitor), suggesting that multiple cell death pathways might have been triggered by MSU crystals. Baicalin, a previously identified inhibitor of NLRP3, inhibited MSU crystal-induced inflammasome activation and suppressed the necrosis in macrophages. Besides, baicalin gavage significantly ameliorated MSU crystal-induced peritonitis in mice. Altogether, our data indicate that MSU crystals induce NLRP3-independent necrosis, which can be inhibited by combined inhibitors for multiple signaling pathways, highlighting a new avenue for the treatment of gouty arthritis.
•LaFe11.8Si1.2/La65Co35 bulk composites were prepared by spark plasma sintering and diffusion annealing technologies.•Diffusion characteristics in LaFe11.8Si1.2/La65Co35 bulk composites before and ...after annealing was clarified.•The Co atoms diffusion behavior was a key factor for the property set of LaFe11.8Si1.2/La65Co35 bulk composites.
LaFe11.8Si1.2/16wt%La65Co35 samples were prepared by spark plasma sintering (SPS) and subsequent annealing. The La65Co35 binder increased the desired 1:13 phase content in these samples during annealing at 1323 K. Interestingly, the α-Fe phase formed between the LaFe11.8Si1.2 particles and the La65Co35 binder and then disappeared as the annealing time extended. The sample annealed for 0.5 h had a distinct core-shell structure with Co in the shell, a desirable table-like (−∆SM)−T curve was obtained and its RC (153 J·kg−1) was 107% higher compared to the sample before annealing. The diffusion of Co from La3Co to the 1:13 phase was hampered by the growth of La5Si3 phase. Relatively large (−∆SM)max of 8.51 J·kg−1·K−1 (Δμ0H=2 T) and (σbc)max of 374 MPa for the sample annealed for 24 h were obtained. These results indicated that the method combining SPS and diffusion annealing is promising to prepare La-Fe-Si based magnetocaloric composites with good properties.
Display omitted (a) Schematic diagram of diffusion of Co atoms during annealing; (b) Co maps of samples after annealing; (c) Magnetic and magnetocaloric properties of La-Fe-Si/La-Co composites after annealing.
We previously showed that gastrin-releasing peptide receptor (GRPR) in the spinal cord is important for mediating nonhistaminergic itch. Neuromedin B receptor (NMBR), the second member of the ...mammalian bombesin receptor family, is expressed in a largely nonoverlapping pattern with GRPR in the superficial spinal cord, and its role in itch transmission remains unclear. Here, we report that Nmbr knock-out (KO) mice exhibited normal scratching behavior in response to intradermal injection of pruritogens. However, mice lacking both Nmbr and Grpr (DKO mice) showed significant deficits in histaminergic itch. In contrast, the chloroquine (CQ)-evoked scratching behavior of DKO mice is not further reduced compared with Grpr KO mice. These results suggest that NMBR and GRPR could compensate for the loss of each other to maintain normal histamine-evoked itch, whereas GRPR is exclusively required for CQ-evoked scratching behavior. Interestingly, GRPR activity is enhanced in Nmbr KO mice despite the lack of upregulation of Grpr expression; so is NMBR in Grpr KO mice. We found that NMB acts exclusively through NMBR for itch transmission, whereas GRP can signal through both receptors, albeit to NMBR to a much lesser extent. Although NMBR and NMBR(+) neurons are dispensable for histaminergic itch, GRPR(+) neurons are likely to act downstream of NMBR(+) neurons to integrate NMB-NMBR-encoded histaminergic itch information in normal physiological conditions. Together, we define the respective function of NMBR and GRPR in itch transmission, and reveal an unexpected relationship not only between the two receptors but also between the two populations of interneurons in itch signaling.
Al2O3/Ba-β-Al2O3/ZrO2 composites were fabricated by solid-state reaction sintering of Al2O3, BaZrO3, and yttria stabilized zirconia (YSZ) powders. The effects of YSZ addition on microstructure and ...mechanical properties have been investigated. The incorporation of YSZ promoted the densification of the composites and formation of tetragonal ZrO2 phase. The microstructure of the composites was characterized by elongated Ba-β-Al2O3 phase and equiaxed ZrO2 particles including added YSZ and reaction-formed ZrO2. The Al2O3/Ba-β-Al2O3/ZrO2 composites with YSZ addition exhibited improved fracture toughness, as a result of multiple toughening effects including crack deflection, crack bridging, crack branching, and martensitic transformation of ZrO2 formed by the reactions between Al2O3 and BaZrO3. Moreover, owing to the grain refinement of Al2O3 matrix, dispersion strengthening of the added YSZ particles, and an increase in density of the composites, the Vickers hardness and flexural strength of Al2O3/Ba-β-Al2O3/ZrO2 composites were dramatically enhanced in comparison with the composites without YSZ addition.
Gut microbiota influences nutrient metabolism and immunity of animal hosts. Better understanding of the composition and diversity of gut microbiota contributes to conservation and management of ...threatened animals both in situ and ex situ. In this study, we applied 16S rRNA gene amplicon sequencing to evaluate the composition and diversity of the fecal bacterial community of four gibbon genera (Family Hylobatidae) at four Chinese zoos. The results showed that the dominant bacterial phyla were Bacteroidetes, Firmicutes, and Proteobacteria and dominant families were Prevotellaceae (Bacteroidetes), Spirochaetaceae (Spirochaetes) and Ruminococcaceae (Firmicutes) in the gut of all gibbons. Both captive site and host genus had significant effects on the relative abundance of dominant bacteria and structure of gut bacterial community. We found that captive site and host genus did not solely impact gut bacterial diversity, but the interaction between them did. This study provides basic knowledge for gut microbiota of all four gibbon genera and contributes to management and conservation of captive gibbons.
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