The subnucleus reticularis dorsalis(SRD),also known as the dorsal reticular nucleus(DRt)or dorsal medullary reticular nucleus(MdD),which resides at the caudal end of the medulla,plays a pivotal role in regulating pain...The subnucleus reticularis dorsalis(SRD),also known as the dorsal reticular nucleus(DRt)or dorsal medullary reticular nucleus(MdD),which resides at the caudal end of the medulla,plays a pivotal role in regulating pain perception.Despite extensive research efforts to unravel its mechanisms,the operational intricacies of SRD remain poorly understood.Advances in experimental methodologies such as brain imaging and chemogenetics have facilitated deeper investigations into the involvement of SRD in various pain disorders.This comprehensive review aims to analyze 36 years(1989–2024)of preclinical research highlighting the critical role of SRD in diffuse noxious inhibitory control(DNIC),also known as conditioned pain modulation(CPM)in humans,and its interconnected neural circuits.Moreover,this review explores the neural circuits related to SRD,including locus coeruleus(LC)-SRD,parabrachial nucleus(PBN)-SRD,rostroventromedial medulla(RVM)-ventrolateral medulla(VLM)-SRD,anterior cingulate cortex(ACC)-SRD,medial medullary reticular formation(mMRF)-SRD,and dorsal striatum(DS)-SRD.Their activation also plays a significant role in analgesia.The pivotal roles of neurotransmitters such asμ-opioid receptor(MOR),noradrenaline,and metabotropic glutamate receptor 7(mGluR7)in modulating SRD responsiveness to pain stimuli are also discussed,as are the influences of SRD on different pain types.This review identified promising avenues for innovative analgesic treatments by shedding light on potential therapeutic strategies targeting SRD.展开更多
Precise manipulation of the catalytic spin configuration and delineation of the relationship between spin related properties and oxidation pathways remain significant challenges in Fenton-like processes.Herein,encapsu...Precise manipulation of the catalytic spin configuration and delineation of the relationship between spin related properties and oxidation pathways remain significant challenges in Fenton-like processes.Herein,encapsulated cobalt nanoparticles and cobalt-nitrogen-doped carbon moieties,endowed with confinement effects and variations in shell curvature were constructed via straightforward pyrolysis strategies,inducing alterations in magnetic anisotropy,electronic energy levels and spin polarization.The enhanced spin polarization at cobalt sites leads to a reduction in crystal field splitting energy and an increase in electronic spin density.This phenomenon facilitated electron transfer from cobalt orbitals to pz orbitals of oxygen species within peroxymonosulfate molecules,thereby promoting the formation of high-valent cobalt species.The encapsulation effectively stabilized cobalt nanoparticles,mitigating their dissolution or deactivation during reactions,which in turn enhances stability and durability in continuous flow processes.The high-valent cobalt species within the shell exhibit increased exposure and generate localized high concentrations,thereby intensifying interactions with migrating pollutants and enabling efficient and selective oxidation of emerging compounds with elevated redox potentials.This work underscores the profound impact of confined encapsulation curvature and spin polarization characteristics of metal sites on catalytic oxidation pathways and performance,opening novel avenues for spin engineering in practical environmental catalysis.展开更多
Current therapies for inflammatory bowel disease(IBD)often fail to achieve complete remission and are associated with systemic toxicity owing to their broad immunosuppressive effects.To overcome these limitations,we d...Current therapies for inflammatory bowel disease(IBD)often fail to achieve complete remission and are associated with systemic toxicity owing to their broad immunosuppressive effects.To overcome these limitations,we developed a bioengineered extracellular vesicle(EV)platform that modulates key immune signaling pathways to efficiently restore the T-cell balance in inflamed intestinal tissues.EVs derived from Wharton’s jelly mesenchymal stem cells were engineered to display PD-L1 on their surface and encapsulate miR-27a-3p.Surface PD-L1 engages the PD-1 checkpoint in activated T cells,attenuating T-cell receptor signaling via SHP2-mediated dephosphorylation of ZAP70 and AKT.In parallel,miR-27a-3p suppresses prohibitin 1(PHB1),a mitochondrial regulator of Th17 cell bioenergetics and inflammatory function,thereby reducing Th17 polarization and increasing the number of FOXP3⁺regulatory T cells.These dual-targeting EVs preferentially localized to inflamed intestinal tissues via chemokine(CCR2/CXCR4)and PD-1-dependent mechanisms.In humanized mouse models of colitis,these EVs attenuated mucosal inflammation,suppressed effector T-cell responses,and preserved epithelial integrity.In IBD patient-derived colonoid cultures,PDL1/miR-27a-3p EVs maintained epithelial viability and barrier integrity without inducing cytotoxicity or structural disruption.Transcriptomic and single-cell analyses revealed the downregulation of inflammatory and exhaustion signatures,along with the enrichment of regulatory subsets.Collectively,this study presents a cell-free immunotherapeutic approach that reprograms T cells in inflamed tissues through the PD-1 and mitochondrial signaling pathways while maintaining intestinal epithelial integrity,offering a promising therapeutic strategy for IBD and other T cell-driven inflammatory disorders.展开更多
基金funded by the Key Program of the National Natural Science Foundation of China(No.82130122).
文摘The subnucleus reticularis dorsalis(SRD),also known as the dorsal reticular nucleus(DRt)or dorsal medullary reticular nucleus(MdD),which resides at the caudal end of the medulla,plays a pivotal role in regulating pain perception.Despite extensive research efforts to unravel its mechanisms,the operational intricacies of SRD remain poorly understood.Advances in experimental methodologies such as brain imaging and chemogenetics have facilitated deeper investigations into the involvement of SRD in various pain disorders.This comprehensive review aims to analyze 36 years(1989–2024)of preclinical research highlighting the critical role of SRD in diffuse noxious inhibitory control(DNIC),also known as conditioned pain modulation(CPM)in humans,and its interconnected neural circuits.Moreover,this review explores the neural circuits related to SRD,including locus coeruleus(LC)-SRD,parabrachial nucleus(PBN)-SRD,rostroventromedial medulla(RVM)-ventrolateral medulla(VLM)-SRD,anterior cingulate cortex(ACC)-SRD,medial medullary reticular formation(mMRF)-SRD,and dorsal striatum(DS)-SRD.Their activation also plays a significant role in analgesia.The pivotal roles of neurotransmitters such asμ-opioid receptor(MOR),noradrenaline,and metabotropic glutamate receptor 7(mGluR7)in modulating SRD responsiveness to pain stimuli are also discussed,as are the influences of SRD on different pain types.This review identified promising avenues for innovative analgesic treatments by shedding light on potential therapeutic strategies targeting SRD.
文摘Precise manipulation of the catalytic spin configuration and delineation of the relationship between spin related properties and oxidation pathways remain significant challenges in Fenton-like processes.Herein,encapsulated cobalt nanoparticles and cobalt-nitrogen-doped carbon moieties,endowed with confinement effects and variations in shell curvature were constructed via straightforward pyrolysis strategies,inducing alterations in magnetic anisotropy,electronic energy levels and spin polarization.The enhanced spin polarization at cobalt sites leads to a reduction in crystal field splitting energy and an increase in electronic spin density.This phenomenon facilitated electron transfer from cobalt orbitals to pz orbitals of oxygen species within peroxymonosulfate molecules,thereby promoting the formation of high-valent cobalt species.The encapsulation effectively stabilized cobalt nanoparticles,mitigating their dissolution or deactivation during reactions,which in turn enhances stability and durability in continuous flow processes.The high-valent cobalt species within the shell exhibit increased exposure and generate localized high concentrations,thereby intensifying interactions with migrating pollutants and enabling efficient and selective oxidation of emerging compounds with elevated redox potentials.This work underscores the profound impact of confined encapsulation curvature and spin polarization characteristics of metal sites on catalytic oxidation pathways and performance,opening novel avenues for spin engineering in practical environmental catalysis.
基金supported by the Basic Research Laboratory Program(Advanced Type)through the National Research Foundation of Korea(NRF),funded by the Korean Government(RS-2023-00218476)Image created with BioRender.com with permission.
文摘Current therapies for inflammatory bowel disease(IBD)often fail to achieve complete remission and are associated with systemic toxicity owing to their broad immunosuppressive effects.To overcome these limitations,we developed a bioengineered extracellular vesicle(EV)platform that modulates key immune signaling pathways to efficiently restore the T-cell balance in inflamed intestinal tissues.EVs derived from Wharton’s jelly mesenchymal stem cells were engineered to display PD-L1 on their surface and encapsulate miR-27a-3p.Surface PD-L1 engages the PD-1 checkpoint in activated T cells,attenuating T-cell receptor signaling via SHP2-mediated dephosphorylation of ZAP70 and AKT.In parallel,miR-27a-3p suppresses prohibitin 1(PHB1),a mitochondrial regulator of Th17 cell bioenergetics and inflammatory function,thereby reducing Th17 polarization and increasing the number of FOXP3⁺regulatory T cells.These dual-targeting EVs preferentially localized to inflamed intestinal tissues via chemokine(CCR2/CXCR4)and PD-1-dependent mechanisms.In humanized mouse models of colitis,these EVs attenuated mucosal inflammation,suppressed effector T-cell responses,and preserved epithelial integrity.In IBD patient-derived colonoid cultures,PDL1/miR-27a-3p EVs maintained epithelial viability and barrier integrity without inducing cytotoxicity or structural disruption.Transcriptomic and single-cell analyses revealed the downregulation of inflammatory and exhaustion signatures,along with the enrichment of regulatory subsets.Collectively,this study presents a cell-free immunotherapeutic approach that reprograms T cells in inflamed tissues through the PD-1 and mitochondrial signaling pathways while maintaining intestinal epithelial integrity,offering a promising therapeutic strategy for IBD and other T cell-driven inflammatory disorders.
