Morphine-induced analgesia and antinociceptive tolerance are known to be modulated by interaction between δ-opioid receptors (DORs) and μ-opioid receptors (MORs) in the pain pathway. However, evidence for expression of DORs in nociceptive small-diameter neurons in dorsal root ganglia (DRG) and for coexistence of DORs with MORs and neuropeptides has recently been challenged. We now report, using in situ hybridization, single-cell PCR, and immunostaining, that DORs are widely expressed not only in large DRG neurons but in small ones and coexist with MORs in peptidergic small DRG neurons, with protachykinin-dependent localization in large dense-core vesicles. Importantly, both DOR and MOR agonists reduce depolarization-induced Ca
2+
currents in single small DRG neurons and inhibit afferent C-fiber synaptic transmission in the dorsal spinal cord. Thus, coexistence of DORs and MORs in small DRG neurons is a basis for direct interaction of opioid receptors in modulation of nociceptive afferent transmission and opioid analgesia.
Cobalt sulfide materials have attracted enormous interest as low‐cost alternatives to noble‐metal catalysts capable of catalyzing both oxygen reduction and oxygen evolution reactions. Although recent advances have been achieved in the development of various cobalt sulfide composites to expedite their oxygen reduction reaction properties, to improve their poor oxygen evolution reaction (OER) activity is still challenging, which significantly limits their utilization. Here, the synthesis of Fe3O4‐decorated Co9S8 nanoparticles in situ grown on a reduced graphene oxide surface (Fe3O4@Co9S8/rGO) and the use of it as a remarkably active and stable OER catalyst are first reported. Loading of Fe3O4 on cobalt sulfide induces the formation of pure phase Co9S8 and highly improves the catalytic activity for OER. The composite exhibits superior OER performance with a small overpotential of 0.34 V at the current density of 10 mA cm−2 and high stability. It is believed that the electron transfer trend from Fe species to Co9S8 promotes the breaking of the Co–O bond in the stable configuration (Co–O–O superoxo group), attributing to the excellent catalytic activity. This development offers a new and effective cobalt sulfide‐based oxygen evolution electrocatalysts to replace the expensive commercial catalysts such as RuO2 or IrO2.
Mesenchymal stem cell-derived exosomes (MSC-Exo) have robust anti-inflammatory effects in the treatment of neurological diseases such as epilepsy, stroke, or traumatic brain injury. While astrocytes are thought to be mediators of these effects, their precise role remains poorly understood. To address this issue, we investigated the putative therapeutic effects and mechanism of MSC-Exo on inflammation-induced alterations in astrocytes.Methods: Lipopolysaccharide (LPS)-stimulated hippocampal astrocytes in primary culture were treated with MSC-Exo, which were also administered in pilocarpine-induced status epilepticus (SE) mice. Exosomal integration, reactive astrogliosis, inflammatory responses, calcium signaling, and mitochondrial membrane potentials (MMP) were monitored. To experimentally probe the molecular mechanism of MSC-Exo actions on the inflammation-induced astrocytic activation, we inhibited the nuclear factor erythroid-derived 2, like 2 (Nrf2, a key mediator in neuroinflammation and oxidative stress) by sgRNA (in vitro) or ML385 (Nrf2 inhibitor) in vivo.Results: MSC-Exo were incorporated into hippocampal astrocytes as well as attenuated reactive astrogliosis and inflammatory responses in vitro and in vivo. Also, MSC-Exo ameliorated LPS-induced aberrant calcium signaling and mitochondrial dysfunction in culture, and SE-induced learning and memory impairments in mice. Furthermore, the putative therapeutic effects of MSC-Exo on inflammation-induced astrocytic activation (e.g., reduced reactive astrogliosis, NF-κB deactivation) were weakened by Nrf2 inhibition.Conclusions: Our results show that MSC-Exo ameliorate inflammation-induced astrocyte alterations and that the Nrf2-NF-κB signaling pathway is involved in regulating astrocyte activation in mice. These data suggest the promising potential of MSC-Exo as a nanotherapeutic agent for the treatment of neurological diseases with hippocampal astrocyte alterations.
Mesenchymal stem cells have been at the forefront of regenerative medicine for many years. Exosomes, which are nanovesicles involved in intercellular communication and the transportation of genetic material transportation that can be released by mesenchymal stem cells, have been recently reported to play a role in cell-free therapy of many diseases, including myocardial infarction, drug addiction, and status epilepticus. They are also thought to help ameliorate inflammation-induced preterm brain injury, liver injury, and various types of cancer. This review highlights recent advances in the exploration of mesenchymal stem cell-derived exosomes in therapeutic applications. The natural contents, drug delivery potency, modification methods, and drug loading methods of exosomes are also discussed.
Angiotensin II stimulates the formation of reactive oxygen species by increased NADPH oxidase activity, which contributes to proapoptotic and profibrotic mechanisms critical in renal injury. Here we determine if apocynin, an inhibitor of NADPH oxidase, interferes with the action of the intrarenal renin-angiotensin system to minimize the progression of renal disease. Transgenic mice that overexpress rat angiotensinogen in their proximal tubule cells were given either apocynin, perindopril, or hydralazine while untreated or apocynin-treated non-transgenic littermates served as controls. Untreated transgenic mice had significant elevations of their systolic blood pressure, albuminuria, reactive oxygen species production, NADPH oxidase activity, tubular apoptosis, active caspase-3, Bax, transforming growth factor-beta1, plasminogen activator inhibitor-1, extracellular matrix proteins, collagen type IV, and phosphorylated p47phox expression compared to untreated non-transgenic mice. Apocynin and perindopril blunted these changes; however, apocynin had no effect on the systolic blood pressure whereas hydralazine prevented hypertension and tubulointerstitial fibrosis but not proximal tubule cell apoptosis. Our study shows that the intrarenal renin-angiotensin system stimulates proximal tubule cell apoptosis and tubulointerstitial fibrosis, in part, by enhanced NADPH oxidase activity and reactive oxygen species generation independent of systemic hypertension.
The third vesicular glutamate transporter, VGLUT3, is distributed in cell bodies of neocortical neurons and axon terminals mainly in the superficial part of layer II/III of the cerebral cortex. We examined the chemical characteristics of VGLUT3-expressing neurons by immunohistochemistry in the rat neocortex. Since the vast majority of VGLUT3-immunoreactive neurons showed immunoreactivities for GABA, preprotachykinin B (PPTB) and cholecystokinin, VGLUT3-immunoreactive neocortical neurons were considered to constitute a subgroup of GABAergic interneurons. VGLUT3-immunoreactive axon terminals were immunopositive for either vesicular GABA transporter (VGAT) or serotonin. These results together with anterograde tracer injection and chemical lesion experiments in the dorsal and median raphe nuclei revealed that the neocortex contains at least two kinds of VGLUT3-laden axon terminals: one is serotonergic and derived from the raphe nuclei, and the other is GABAergic and intrinsic in the neocortex. Furthermore, many VGLUT3/VGAT-immunoreactive terminals formed axon baskets and made axosomatic symmetric synapses on neocortical neurons, most of which were immunoreactive for PPTB. VGLUT3-immunopositive axon baskets surrounded about a half of PPTB-positive and almost all VGLUT3-positive neurons. Thus, VGLUT3-expressing GABAergic interneurons form a chemically specific circuit within the PPTB-producing interneuron group and it is likely that glutamate is used within the chemically specific circuit.
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