The combination of Daphnes Cortex(DC)and Liquorice Root(LR),two traditional Chinese medicinal herbs,has shown significant therapeutic effects on rheumatoid arthritis(RA),but its synergistic mechanism of action remains...The combination of Daphnes Cortex(DC)and Liquorice Root(LR),two traditional Chinese medicinal herbs,has shown significant therapeutic effects on rheumatoid arthritis(RA),but its synergistic mechanism of action remains to be elucidated.Employing a network pharmacology and molecular docking approach,this study systematically investigated the synergistic mechanism of the herb pair DC and LR in RA treatment.Active components and their corresponding targets were retrieved from the TCMSP database and relevant literature,and RA-related targets were collected from established disease databases.A total of 73 overlapping targets between DC-LR and RA were identified,among which core targets such as AKT1,TNF,and CASP3 were highlighted.GO and KEGG enrichment analyses revealed that these targets are involved in biological processes such as oxidative stress response and cell migration,and are significantly enriched in key pathways including HIF-1,TNF,and PI3K-Akt signaling pathways.Compatibility analysis further revealed that the combination of DC and LR may enhance therapeutic effects through synergistic regulation of shared targets and complementary modulation of upstream and downstream pathway components.Molecular docking confirmed strong binding affinities between core active components and key targets.This study provides a multi-dimensional“component-target-pathway”perspective on the potential synergistic anti-RA mechanism of the DC-LR herb pair,offering a theoretical basis for further experimental validation and clinical application.展开更多
Background:The analgesic effects of multiple electroacupuncture(EA)sessions and single EA sessions differ significantly in pain management.Area 24b(A24b)of the anterior cingulate cortex(ACC)is crucial in pain processi...Background:The analgesic effects of multiple electroacupuncture(EA)sessions and single EA sessions differ significantly in pain management.Area 24b(A24b)of the anterior cingulate cortex(ACC)is crucial in pain processing.EA relieves pain by targeting and modulating the neuronal activity within this subregion.However,whether the cumulative effect of EA antinociception is connected to A24b mechanisms has remained unclear.Methods:In our study,we used the Complete Freund's Adjuvant(CFA)model to induce inflammatory pain and the Spared Nerve Injury(SNI)model to induce neuropathic pain,and adult male C57BL/6,FosTRAP,and FosTRAP:Ai9 mice were used as experimental subjects to investigate the cumulative effect of EA antinociception and whether multiple EA sessions and a single EA session regulate different neuronal populations in the A24b.Results:We observed that EA effectively alleviated pain in mice,with three EA sessions yielding superior analgesic effects compared to a single session.Using chemical genetics combined with FosCreER technology to activate EA-TRAPed cells in the A24b,we found that pain relief was more pronounced with three EA sessions.Moreover,chemogenetic inhibition of EA-TRAPed cells in the A24b reversed the analgesic effects of a single EA session but not those of three EA sessions.Fluorescent in situ hybridization results indicated that three EA sessions significantly increased the number of GABAergic neurons in the A24b compared with a single session.Additionally,retrograde tracing revealed that the A24b circuit that monosynaptically innervates EA-TRAPed cells included projections from the central lateral nucleus(CL),lateral mediodorsal thalamic nucleus(MDL),lateral habenula(LHb),dorsal raphe nucleus(DR),caudal linear nucleus of the raphe(CLi),dorsal tuberomamillary nucleus(DTM),periventricular hypothalamic nucleus(Pe)and hippocampal fields CA1,CA2,and CA3.These findings suggest that multiple EA sessions and single EA sessions activated different neuronal populations in the A24b.The enhanced analgesic effect of multiple EA sessions may be attributed to an increase in the proportion of GABAergic neurons within the A24b.Conclusions:Multiple and single EA sessions recruit distinct neuronal populations in A24b,with the stronger analgesic effect of repeated EA linked to a higher proportion of GABAergic neurons in this region.展开更多
Moutan Cortex terpene glycoside is derived from the dried root bark of Paeonia suffruticosa Andr.in the Paeoniaceae family,which holds significant value as a traditional Chinese medicine.This study investigated that M...Moutan Cortex terpene glycoside is derived from the dried root bark of Paeonia suffruticosa Andr.in the Paeoniaceae family,which holds significant value as a traditional Chinese medicine.This study investigated that Moutan Cortex terpene glycoside(MCTG)improved diabetic kidney disease(DKD)by targeting sirtuin 1(SIRT1)mediated autophagy pathway.Mechanistic insights were gained using DKD model rats and human umbilical vein endothelial cells(HUVECs)to delineate how MCTG operated in the treatment of DKD.Furthermore,network pharmacology was used to identify the primary metabolic pathways affected by MCTG,with key targets being confirmed through polymerase chain reaction(PCR),Western blot,Transmission electron microscope,immunofluorescence staining and monodansylcadaverine(MDC)staining.Finally,small interfering RNA transfection testified SIRT1 in advanced glycation end-products(AGEs)-induced HUVECs injury.MCTG effectively decreased blood glucose rise in DKD rats and reduced levels of cytokines and biochemical indicators.Network pharmacology revealed that metabolism was the main pathway of Moutan Cortex,and the main targets were verified by PCR and protein experiments.Based on these results,we found that Moutan Cortex could improve DKD and SIRT1 was a potential target.Furthermore,knockdown of SIRT1 attenuated AGEs-induced the expression of Beclin 1 and microtubule-associated protein 1 light chain 3 II/I(LC3 II/I)in HUVECs.In summary,this study demonstrated that Moutan Cortex could alleviate DKD via down-regulating SIRT1-mediated autophagy pathway.展开更多
Synaptic plasticity is essential for maintaining neuronal function in the central nervous system and serves as a critical indicator of the effects of neurodegenerative disease.Glaucoma directly impairs retinal ganglio...Synaptic plasticity is essential for maintaining neuronal function in the central nervous system and serves as a critical indicator of the effects of neurodegenerative disease.Glaucoma directly impairs retinal ganglion cells and their axons,leading to axonal transport dysfuntion,subsequently causing secondary damage to anterior or posterior ends of the visual system.Accordingly,recent evidence indicates that glaucoma is a degenerative disease of the central nervous system that causes damage throughout the visual pathway.However,the effects of glaucoma on synaptic plasticity in the primary visual cortex remain unclear.In this study,we established a mouse model of unilateral chronic ocular hypertension by injecting magnetic microbeads into the anterior chamber of one eye.We found that,after 4 weeks of chronic ocular hypertension,the neuronal somas were smaller in the superior colliculus and lateral geniculate body regions of the brain contralateral to the affected eye.This was accompanied by glial cell activation and increased expression of inflammatory factors.After 8 weeks of ocular hypertension,we observed a reduction in the number of excitatory and inhibitory synapses,dendritic spines,and activation of glial cells in the primary visual cortex contralateral to the affected eye.These findings suggest that glaucoma not only directly damages the retina but also induces alterations in synapses and dendritic spines in the primary visual cortex,providing new insights into the pathogenesis of glaucoma.展开更多
The rostral agranular insular cortex(RAIC)has been associated with pain modulation.Although the endogenous cannabinoid system(eCB)has been shown to regulate chronic pain,the roles of eCBs in the RAIC remain elusive un...The rostral agranular insular cortex(RAIC)has been associated with pain modulation.Although the endogenous cannabinoid system(eCB)has been shown to regulate chronic pain,the roles of eCBs in the RAIC remain elusive under the neuropathic pain state.Neuropathic pain was induced in C57BL/6 mice by common peroneal nerve(CPN)ligation.The roles of the eCB were tested in the RAIC of ligated CPN C57BL/6J mice,glutamatergic,or GABAergic neuron cannabinoid receptor 1(CB1R)knockdown mice with the whole-cell patch-clamp and pain behavioral methods.The E/I ratio(amplitude ratio between mEPSCs and mIPSCs)was significantly increased in layer V pyramidal neurons of the RAIC in CPN-ligated mice.Depolarization-induced suppression of inhibition but not depolarization-induced suppression of excitation in RAIC layer V pyramidal neurons were significantly increased in CPN-ligated mice.The analgesic effect of ACEA(a CB1R agonist)was alleviated along with bilateral dorsolateral funiculus lesions,with the administration of AM251(a CB1R antagonist),and in CB1R knockdown mice in GABAergic neurons,but not glutamatergic neurons of the RAIC.Our results suggest that CB1R activation reinforces the function of the descending pain inhibitory pathway via reducing the inhibition of glutamatergic layer V neurons by GABAergic neurons in the RAIC to induce an analgesic effect in neuropathic pain.展开更多
Pain is often comorbid with emotional disorders such as anxiety and depression.Hyperexcitability of the anterior cingulate cortex has been implicated in pain and pain-related negative emotions that arise from impairme...Pain is often comorbid with emotional disorders such as anxiety and depression.Hyperexcitability of the anterior cingulate cortex has been implicated in pain and pain-related negative emotions that arise from impairments in inhibitory gamma-aminobutyric acid neurotransmission.This review primarily aims to outline the main circuitry(including the input and output connectivity)of the anterior cingulate cortex and classification and functions of different gamma-aminobutyric acidergic neurons;it also describes the neurotransmitters/neuromodulators affecting these neurons,their intercommunication with other neurons,and their importance in mental comorbidities associated with chronic pain disorders.Improving understanding on their role in pain-related mental comorbidities may facilitate the development of more effective treatments for these conditions.However,the mechanisms that regulate gamma-aminobutyric acidergic systems remain elusive.It is also unclear as to whether the mechanisms are presynaptic or postsynaptic.Further exploration of the complexities of this system may reveal new pathways for research and drug development.展开更多
The visual cortex is an essential part of the brain for processing visual information.It exhibits structural and functional plasticity,which is crucial for adapting to complex visual environments.The quintessential ma...The visual cortex is an essential part of the brain for processing visual information.It exhibits structural and functional plasticity,which is crucial for adapting to complex visual environments.The quintessential manifestation of visual cortical plasticity is ocular dominance plasticity during the critical period,which involves numerous cellular and molecular events.While previous studies have emphasized the role of visual cortical neurons and their associated functional molecules in visual plasticity,recent findings have revealed that structural factors such as the extracellular matrix and glia are also involved.Investigating how these molecules interact to form a complex network that facilitates plasticity in the visual cortex is crucial to our understanding of the development of the visual system and the advancement of therapeutic strategies for visual disorders like amblyopia.展开更多
Huntington’s disease(HD)is a genetic disease characterized by the progressive degeneration of the striatum and cortex.Patients can present with a variety of symptoms that can broadly be classified into motor symptoms...Huntington’s disease(HD)is a genetic disease characterized by the progressive degeneration of the striatum and cortex.Patients can present with a variety of symptoms that can broadly be classified into motor symptoms,inclusive of choreatic movements and rigidity,mood and psychiatric symptoms,such as depression and apathy,and cognitive symptoms,such as cognitive decline.The causal mutation underlying HD results from an expansion of a CAG repeat sequence on the IT15 gene,resulting in the formation and accumulation of a mutant huntingtin protein.展开更多
Lycii Radicis Cortex(LRC)is a medicinal and food homologous plant with various pharmacological activities,including anti-tumor effects.This study explores the anti-tumor effect of LRC on non-small cell lung cancer(NSC...Lycii Radicis Cortex(LRC)is a medicinal and food homologous plant with various pharmacological activities,including anti-tumor effects.This study explores the anti-tumor effect of LRC on non-small cell lung cancer(NSCLC)and its molecular mechanism using mice bearing Lewis lung carcinoma cells.LRC significantly suppressed the growth of NSCLC.Besides,RNA sequencing of mice tumors and hematoxylin&eosin and immunofluorescence staining revealed that LRC promoted the infiltration of T lymphocytes,specifically GZMB~+CD8~+T lymphocytes,in tumor tissues.The Gene Set Enrichment Analysis of spleen RNA indicated that LRC up-regulated PD-1-downstream pathways,suggesting that LRC exerted its effects through the PDL1/PD-1 pathway.Further experiments revealed that LRC interacted with PD-L1,blocking PD-L1/PD-1 binding and thus restoring the T cell killing activity on tumor cells.Together,these results support using LRC as healthy food to improve anti-tumor immunity in patients with NSCLC.展开更多
Objective:To anatomically and phenotypically characterize the insular cortex(IC)-nucleus tractus soli-tari(NTS)neural pathway.Methods:Adult male Sprague-Dawley rats were divided into three experimental cohorts for neu...Objective:To anatomically and phenotypically characterize the insular cortex(IC)-nucleus tractus soli-tari(NTS)neural pathway.Methods:Adult male Sprague-Dawley rats were divided into three experimental cohorts for neural circuit tracing.Anterograde labeling was achieved by injecting anterograde self-complementary adeno-associated viruses(scAAVs)into the IC.Retrograde tracing involved NTS injections of either retrograde scAAVs or FluoroGold(FG),combined with immunofluorescence histochemical staining to identify IC-originating projection neurons.For postsynaptic neurochemical phenotype characterization,IC was injected with AAV2/1-CaMKII-Cre,while a mixture of AAV2/9-Syn-DIO-mCherry and AAV2/9-VGAT1-EGFP was injected into the NTS.The rats were allowed to survive for one week following scAAVs or FG injection or four weeks after recombinase-dependent systems injection.Then the rats were sacrificed,and serial brain sections were prepared for immunofluorescence histochemical staining(brain section containing FG)and subsequent fluorescence/confocal microscopic analysis.Results:(1)Anterograde viral tracing re-vealed dense axonal terminals from the IC projecting to the medial subnucleus of the NTS,while retrograde tracing re-vealed that IC neurons projecting to the NTS were predominantly localized within the dysgranular layer;(2)IC-NTS projection neurons were exclusive glutamatergic(100%,n=3);(3)NTS neurons receiving IC inputs were mainly lo-calized in the medial subnucleus,and were predominantly GABAergic(79.8±3.2%,n=3).Conclusion:The pres-ent results indicate that a descending pathway from excitatory neurons of the IC terminates onto inhibitory neurons of the NTS,which might represent a potential neuromodulatory target for visceral pain disorders.展开更多
While multiple step saccades(MSS)are occasionally reported in the healthy population,they are more evident in patients with Parkinson’s disease(PD).Therefore,MSS has been suggested as a biological marker for the diag...While multiple step saccades(MSS)are occasionally reported in the healthy population,they are more evident in patients with Parkinson’s disease(PD).Therefore,MSS has been suggested as a biological marker for the diagnosis of PD.However,the lack of clarity on the neural mechanism underlying the generation of MSS largely impedes their application in the clinic.We have proposed recently that MSS are triggered by the discrepancy between desired and executed saccades.Accordingly,brain regions involved in saccadic planning and execution might play a role in the generation of MSS.To test this hypothesis,we explored the role of the prefrontal(PFC)and posterior parietal cortex(PPC)in generating MSS by conducting two experiments:electroencephalographic recording and single-pulse transcranial magnetic stimulation in the PFC or PPC of humans while participants were performing a gap saccade task.We found that the PFC and PPC are involved in the generation of MSS.展开更多
The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury.However,whether it is possible to stimulate ne...The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury.However,whether it is possible to stimulate neurogenesis and reconstruct cortical layers II to VI in non-neurogenic regions,such as the cortex,remains unknown.In this study,we implanted a hyaluronic acid collagen gel loaded with basic fibroblast growth factor into the motor cortex immediately following traumatic injury.Our findings reveal that this gel effectively stimulated the proliferation and migration of endogenous neural stem/progenitor cells,as well as their differentiation into mature and functionally integrated neurons.Importantly,these new neurons reconstructed the architecture of cortical layers II to VI,integrated into the existing neural circuitry,and ultimately led to improved brain function.These findings offer novel insight into potential clinical treatments for traumatic cerebral cortex injuries.展开更多
Pathological tremor is one of the cardinal symptoms in Parkinson's disease (PD).Tremor is comprised of involuntary,rhythmic,a nd oscillating movements that can vary according to the circumstances under which they ...Pathological tremor is one of the cardinal symptoms in Parkinson's disease (PD).Tremor is comprised of involuntary,rhythmic,a nd oscillating movements that can vary according to the circumstances under which they occur,the body parts that are involved,and the frequency at which they present.For example,tremors can be mild to severe,are stress sensitive,and can affect arms,legs,or the head (Dirkx and Bologna,2022).展开更多
Dear Editor,The importance of the medial entorhinal cortex(MEC)for memory and spatial navigation has been shown repeatedly in many species,including mice and humans[1,2].It is,therefore,not surprising that the connect...Dear Editor,The importance of the medial entorhinal cortex(MEC)for memory and spatial navigation has been shown repeatedly in many species,including mice and humans[1,2].It is,therefore,not surprising that the connectivity of this structure has been studied extensively over the past century,mainly using a range of anterograde and retrograde anatomical tracers[3].展开更多
Spinal cord injury typically causes corticospinal tract disruption.Although the disrupted corticospinal tract can self-regenerate to a certain degree,the underlying mechanism of this process is still unclear.N6-methyl...Spinal cord injury typically causes corticospinal tract disruption.Although the disrupted corticospinal tract can self-regenerate to a certain degree,the underlying mechanism of this process is still unclear.N6-methyladenosine(m^(6)A)modifications are the most common form of epigenetic regulation at the RNA level and play an essential role in biological processes.However,whether m^(6)A modifications participate in corticospinal tract regeneration after spinal cord injury remains unknown.We found that expression of methyltransferase 14 protein(METTL14)in the locomotor cortex was high after spinal cord injury and accompanied by elevated m^(6)A levels.Knockdown of Mettl14 in the locomotor cortex was not favorable for corticospinal tract regeneration and neurological recovery after spinal cord injury.Through bioinformatics analysis and methylated RNA immunoprecipitation-quantitative polymerase chain reaction,we found that METTL14 regulated Trib2 expression in an m^(6)A-regulated manner,thereby activating the mitogen-activated protein kinase pathway and promoting corticospinal tract regeneration.Finally,we administered syringin,a stabilizer of METTL14,using molecular docking.Results confirmed that syringin can promote corticospinal tract regeneration and facilitate neurological recovery by stabilizing METTL14.Findings from this study reveal that m^(6)A modification is involved in the regulation of corticospinal tract regeneration after spinal cord injury.展开更多
[Objectives]This study was conducted to investigate the alleviating effect of Phellodendri Chinensis Cortex extract on the phytotoxicity of pretilachlor in rice.[Methods]In addition to CK,Phellodendri Chinensis Cortex...[Objectives]This study was conducted to investigate the alleviating effect of Phellodendri Chinensis Cortex extract on the phytotoxicity of pretilachlor in rice.[Methods]In addition to CK,Phellodendri Chinensis Cortex extract and pretilachlor with different gradients were added to the culture medium,and rice seeds with the same bud length were evenly placed in the culture medium.After 10 and 15 d of culture,the plant height and fresh weight of rice seedlings were measured and the alleviation rate was calculated.[Results]Ten days after application,the plant height of treatment 8(pretilachlor:extract concentration ratio of 25:200)was alleviated with an alleviation rate of 21.72%,and the fresh weight of treatment 9(pretilachlor:extract concentration ratio of 25:400)was alleviated with an alleviation rate of 31.04%.Fifteen days after treatment,the plant height of treatment 6(pretilachlor:extract concentration ratio of 25:50)showed a better alleviating effect,and the fresh weight of treatment 8(pretilachlor:extract concentration ratio of 25:200)exhibited a better alleviating effect,with an alleviation rate of 22.39%.Meanwhile,it was found that the extract of Phellodendri Chinensis Cortex could alleviate the increase of POD activity in rice leaves caused by pretilachlor.Meanwhile,it was found that the extract of Phellodendri Chinensis Cortex promoted the expression of CAT in rice seedlings,thus significantly increasing its activity and alleviating the toxicity of pretilachlor to rice.[Conclusions]This study can provide technical support for the screening and field application of plant-derived safeners.展开更多
The anterior cingulate cortex(ACC)has recently been proposed as a key player in the representation of itch stimuli.However,to date,little is known about the contribution of specific ACC interneuron populations to itch...The anterior cingulate cortex(ACC)has recently been proposed as a key player in the representation of itch stimuli.However,to date,little is known about the contribution of specific ACC interneuron populations to itch processing.Using c-Fos immunolabeling and in vivo Ca2+imaging,we reported that both histamine and chloroquine stimuli-induced acute itch caused a marked enhancement of vasoactive intestinal peptide(VIP)-expressing interneuron activity in the ACC.Behavioral data indicated that optogenetic and chemogenetic activation of these neurons reduced scratching responses related to histaminergic and non-histaminergic acute itch.Similar neural activity and modulatory role of these neurons were seen in mice with chronic itch induced by contact dermatitis.Together,this study highlights the importance of ACC VIP+neurons in modulating itch-related affect and behavior,which may help us to develop novel mechanism-based strategies to treat refractory chronic itch in the clinic.展开更多
Objective:To elucidate the specific mechanisms by which electroacupuncture(EA)alleviates anxiety and fear behaviors associated with posttraumatic stress disorder(PTSD),focusing on the role of lipocalin-2(Lcn2).Methods...Objective:To elucidate the specific mechanisms by which electroacupuncture(EA)alleviates anxiety and fear behaviors associated with posttraumatic stress disorder(PTSD),focusing on the role of lipocalin-2(Lcn2).Methods:The PTSD mouse model was subjected to single prolonged stress and shock(SPS&S),and the animals received 15 min sessions of EA at Shenmen acupoint(HT7).Behavioral tests were used to investigate the effects of EA at HT7 on anxiety and fear.Western blotting and enzyme-linked immunosorbent assay were used to quantify Lcn2 and inflammatory cytokine levels in the prefrontal cortex(PFC).Additionally,the activity of PFC neurons was evaluated by immunofluorescence and in vivo electrophysiology.Results:Mice subjected to SPS&S presented increased anxiety-and fear-like behaviors.Lcn2 expression in the PFC was significantly upregulated following SPS&S,leading to increased expression of the proinflammatory cytokines tumor necrosis factor-a and interleukin-6 and suppression of PFC neuronal activity.However,EA at HT7 inhibited Lcn2 release,reducing neuroinflammation and hypoexcitability in the PFC.Lcn2 overexpression mitigated the effects of EA at HT7,resulting in anxiety-and fear-like behaviors.Conclusion:EA at HT7 can ameliorate PTSD-associated anxiety and fear,and its mechanism of action appears to involve the inhibition of Lcn2-mediated neural activity and inflammation in the PFC.展开更多
基金supported by National Training Program of Innovation and Entrepreneurship for Undergraduates(202510163044).
文摘The combination of Daphnes Cortex(DC)and Liquorice Root(LR),two traditional Chinese medicinal herbs,has shown significant therapeutic effects on rheumatoid arthritis(RA),but its synergistic mechanism of action remains to be elucidated.Employing a network pharmacology and molecular docking approach,this study systematically investigated the synergistic mechanism of the herb pair DC and LR in RA treatment.Active components and their corresponding targets were retrieved from the TCMSP database and relevant literature,and RA-related targets were collected from established disease databases.A total of 73 overlapping targets between DC-LR and RA were identified,among which core targets such as AKT1,TNF,and CASP3 were highlighted.GO and KEGG enrichment analyses revealed that these targets are involved in biological processes such as oxidative stress response and cell migration,and are significantly enriched in key pathways including HIF-1,TNF,and PI3K-Akt signaling pathways.Compatibility analysis further revealed that the combination of DC and LR may enhance therapeutic effects through synergistic regulation of shared targets and complementary modulation of upstream and downstream pathway components.Molecular docking confirmed strong binding affinities between core active components and key targets.This study provides a multi-dimensional“component-target-pathway”perspective on the potential synergistic anti-RA mechanism of the DC-LR herb pair,offering a theoretical basis for further experimental validation and clinical application.
基金The National Natural Science Fund of China(82374561,82174490,81873360)the Research Project of Zhejiang Chinese Medical University(2022JKZKTS44,2022FSYYZZ07)the Zhejiang Medical and Health Science and Technology Program(2021RC098)。
文摘Background:The analgesic effects of multiple electroacupuncture(EA)sessions and single EA sessions differ significantly in pain management.Area 24b(A24b)of the anterior cingulate cortex(ACC)is crucial in pain processing.EA relieves pain by targeting and modulating the neuronal activity within this subregion.However,whether the cumulative effect of EA antinociception is connected to A24b mechanisms has remained unclear.Methods:In our study,we used the Complete Freund's Adjuvant(CFA)model to induce inflammatory pain and the Spared Nerve Injury(SNI)model to induce neuropathic pain,and adult male C57BL/6,FosTRAP,and FosTRAP:Ai9 mice were used as experimental subjects to investigate the cumulative effect of EA antinociception and whether multiple EA sessions and a single EA session regulate different neuronal populations in the A24b.Results:We observed that EA effectively alleviated pain in mice,with three EA sessions yielding superior analgesic effects compared to a single session.Using chemical genetics combined with FosCreER technology to activate EA-TRAPed cells in the A24b,we found that pain relief was more pronounced with three EA sessions.Moreover,chemogenetic inhibition of EA-TRAPed cells in the A24b reversed the analgesic effects of a single EA session but not those of three EA sessions.Fluorescent in situ hybridization results indicated that three EA sessions significantly increased the number of GABAergic neurons in the A24b compared with a single session.Additionally,retrograde tracing revealed that the A24b circuit that monosynaptically innervates EA-TRAPed cells included projections from the central lateral nucleus(CL),lateral mediodorsal thalamic nucleus(MDL),lateral habenula(LHb),dorsal raphe nucleus(DR),caudal linear nucleus of the raphe(CLi),dorsal tuberomamillary nucleus(DTM),periventricular hypothalamic nucleus(Pe)and hippocampal fields CA1,CA2,and CA3.These findings suggest that multiple EA sessions and single EA sessions activated different neuronal populations in the A24b.The enhanced analgesic effect of multiple EA sessions may be attributed to an increase in the proportion of GABAergic neurons within the A24b.Conclusions:Multiple and single EA sessions recruit distinct neuronal populations in A24b,with the stronger analgesic effect of repeated EA linked to a higher proportion of GABAergic neurons in this region.
基金supported by grants from the National Natural Science Foundation of China(82474093,81973536)Jiangsu Province“Blue and Green Project”(184080H10240)+2 种基金Graduate Research Innovation Program of Jiangsu(KYCX23_0871)the National Natural Science Foundation of the Youth Science Fund Project(81703775)Health Research Program of Wuxi Municipal Health Commission(Q202107).
文摘Moutan Cortex terpene glycoside is derived from the dried root bark of Paeonia suffruticosa Andr.in the Paeoniaceae family,which holds significant value as a traditional Chinese medicine.This study investigated that Moutan Cortex terpene glycoside(MCTG)improved diabetic kidney disease(DKD)by targeting sirtuin 1(SIRT1)mediated autophagy pathway.Mechanistic insights were gained using DKD model rats and human umbilical vein endothelial cells(HUVECs)to delineate how MCTG operated in the treatment of DKD.Furthermore,network pharmacology was used to identify the primary metabolic pathways affected by MCTG,with key targets being confirmed through polymerase chain reaction(PCR),Western blot,Transmission electron microscope,immunofluorescence staining and monodansylcadaverine(MDC)staining.Finally,small interfering RNA transfection testified SIRT1 in advanced glycation end-products(AGEs)-induced HUVECs injury.MCTG effectively decreased blood glucose rise in DKD rats and reduced levels of cytokines and biochemical indicators.Network pharmacology revealed that metabolism was the main pathway of Moutan Cortex,and the main targets were verified by PCR and protein experiments.Based on these results,we found that Moutan Cortex could improve DKD and SIRT1 was a potential target.Furthermore,knockdown of SIRT1 attenuated AGEs-induced the expression of Beclin 1 and microtubule-associated protein 1 light chain 3 II/I(LC3 II/I)in HUVECs.In summary,this study demonstrated that Moutan Cortex could alleviate DKD via down-regulating SIRT1-mediated autophagy pathway.
基金supported by the National Natural Science Foundation of China,No.82271115(to MY).
文摘Synaptic plasticity is essential for maintaining neuronal function in the central nervous system and serves as a critical indicator of the effects of neurodegenerative disease.Glaucoma directly impairs retinal ganglion cells and their axons,leading to axonal transport dysfuntion,subsequently causing secondary damage to anterior or posterior ends of the visual system.Accordingly,recent evidence indicates that glaucoma is a degenerative disease of the central nervous system that causes damage throughout the visual pathway.However,the effects of glaucoma on synaptic plasticity in the primary visual cortex remain unclear.In this study,we established a mouse model of unilateral chronic ocular hypertension by injecting magnetic microbeads into the anterior chamber of one eye.We found that,after 4 weeks of chronic ocular hypertension,the neuronal somas were smaller in the superior colliculus and lateral geniculate body regions of the brain contralateral to the affected eye.This was accompanied by glial cell activation and increased expression of inflammatory factors.After 8 weeks of ocular hypertension,we observed a reduction in the number of excitatory and inhibitory synapses,dendritic spines,and activation of glial cells in the primary visual cortex contralateral to the affected eye.These findings suggest that glaucoma not only directly damages the retina but also induces alterations in synapses and dendritic spines in the primary visual cortex,providing new insights into the pathogenesis of glaucoma.
基金This work was supported by the National Natural Science Foundation of China(32271056,81671081,and 81701095)University Science and Technology Fund Planning Projects(2022XC002 and 2019XB006).
文摘The rostral agranular insular cortex(RAIC)has been associated with pain modulation.Although the endogenous cannabinoid system(eCB)has been shown to regulate chronic pain,the roles of eCBs in the RAIC remain elusive under the neuropathic pain state.Neuropathic pain was induced in C57BL/6 mice by common peroneal nerve(CPN)ligation.The roles of the eCB were tested in the RAIC of ligated CPN C57BL/6J mice,glutamatergic,or GABAergic neuron cannabinoid receptor 1(CB1R)knockdown mice with the whole-cell patch-clamp and pain behavioral methods.The E/I ratio(amplitude ratio between mEPSCs and mIPSCs)was significantly increased in layer V pyramidal neurons of the RAIC in CPN-ligated mice.Depolarization-induced suppression of inhibition but not depolarization-induced suppression of excitation in RAIC layer V pyramidal neurons were significantly increased in CPN-ligated mice.The analgesic effect of ACEA(a CB1R agonist)was alleviated along with bilateral dorsolateral funiculus lesions,with the administration of AM251(a CB1R antagonist),and in CB1R knockdown mice in GABAergic neurons,but not glutamatergic neurons of the RAIC.Our results suggest that CB1R activation reinforces the function of the descending pain inhibitory pathway via reducing the inhibition of glutamatergic layer V neurons by GABAergic neurons in the RAIC to induce an analgesic effect in neuropathic pain.
基金supported by the National Natural Science Foundation of China,Nos.82374561(to JD),82174490(to JF)the Medical and Health Science and Technology Program of Zhejiang Province,No.2021RC098(to JD)the Research Project of Zhejiang Chinese Medical University,Nos.2022JKZKTS44(to JD),2022FSYYZZ07(to JF).
文摘Pain is often comorbid with emotional disorders such as anxiety and depression.Hyperexcitability of the anterior cingulate cortex has been implicated in pain and pain-related negative emotions that arise from impairments in inhibitory gamma-aminobutyric acid neurotransmission.This review primarily aims to outline the main circuitry(including the input and output connectivity)of the anterior cingulate cortex and classification and functions of different gamma-aminobutyric acidergic neurons;it also describes the neurotransmitters/neuromodulators affecting these neurons,their intercommunication with other neurons,and their importance in mental comorbidities associated with chronic pain disorders.Improving understanding on their role in pain-related mental comorbidities may facilitate the development of more effective treatments for these conditions.However,the mechanisms that regulate gamma-aminobutyric acidergic systems remain elusive.It is also unclear as to whether the mechanisms are presynaptic or postsynaptic.Further exploration of the complexities of this system may reveal new pathways for research and drug development.
基金supported by the National Natural Science Foundation of China(81770956,81371049,32471055 and 82171090)Project of Tianjin 131 Innovative Talent Team(201936)+4 种基金the Science and Technology Planning Project of Tianjin(21JCYBJC00780)the Science and Technology Fund for Health of Tianjin(TJWJ2023ZD008)Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)ZJLab,Shanghai Center for Brain Science and Brain-Inspired Technology,the Lingang Laboratory(LG-QS-202203-12)Tianjin Key Medical Discipline(Specialty)Construction Project(TJYXZDXK‑016A).
文摘The visual cortex is an essential part of the brain for processing visual information.It exhibits structural and functional plasticity,which is crucial for adapting to complex visual environments.The quintessential manifestation of visual cortical plasticity is ocular dominance plasticity during the critical period,which involves numerous cellular and molecular events.While previous studies have emphasized the role of visual cortical neurons and their associated functional molecules in visual plasticity,recent findings have revealed that structural factors such as the extracellular matrix and glia are also involved.Investigating how these molecules interact to form a complex network that facilitates plasticity in the visual cortex is crucial to our understanding of the development of the visual system and the advancement of therapeutic strategies for visual disorders like amblyopia.
文摘Huntington’s disease(HD)is a genetic disease characterized by the progressive degeneration of the striatum and cortex.Patients can present with a variety of symptoms that can broadly be classified into motor symptoms,inclusive of choreatic movements and rigidity,mood and psychiatric symptoms,such as depression and apathy,and cognitive symptoms,such as cognitive decline.The causal mutation underlying HD results from an expansion of a CAG repeat sequence on the IT15 gene,resulting in the formation and accumulation of a mutant huntingtin protein.
基金supported by Natural Science Foundation of Guangdong Province,China(2022A1515011575)National Natural Science Foundation of China,China(81873154)President Foundation of Integrated Hospital of Traditional Chinese Medicine,Southern Medical University,China(1202103010)。
文摘Lycii Radicis Cortex(LRC)is a medicinal and food homologous plant with various pharmacological activities,including anti-tumor effects.This study explores the anti-tumor effect of LRC on non-small cell lung cancer(NSCLC)and its molecular mechanism using mice bearing Lewis lung carcinoma cells.LRC significantly suppressed the growth of NSCLC.Besides,RNA sequencing of mice tumors and hematoxylin&eosin and immunofluorescence staining revealed that LRC promoted the infiltration of T lymphocytes,specifically GZMB~+CD8~+T lymphocytes,in tumor tissues.The Gene Set Enrichment Analysis of spleen RNA indicated that LRC up-regulated PD-1-downstream pathways,suggesting that LRC exerted its effects through the PDL1/PD-1 pathway.Further experiments revealed that LRC interacted with PD-L1,blocking PD-L1/PD-1 binding and thus restoring the T cell killing activity on tumor cells.Together,these results support using LRC as healthy food to improve anti-tumor immunity in patients with NSCLC.
文摘Objective:To anatomically and phenotypically characterize the insular cortex(IC)-nucleus tractus soli-tari(NTS)neural pathway.Methods:Adult male Sprague-Dawley rats were divided into three experimental cohorts for neural circuit tracing.Anterograde labeling was achieved by injecting anterograde self-complementary adeno-associated viruses(scAAVs)into the IC.Retrograde tracing involved NTS injections of either retrograde scAAVs or FluoroGold(FG),combined with immunofluorescence histochemical staining to identify IC-originating projection neurons.For postsynaptic neurochemical phenotype characterization,IC was injected with AAV2/1-CaMKII-Cre,while a mixture of AAV2/9-Syn-DIO-mCherry and AAV2/9-VGAT1-EGFP was injected into the NTS.The rats were allowed to survive for one week following scAAVs or FG injection or four weeks after recombinase-dependent systems injection.Then the rats were sacrificed,and serial brain sections were prepared for immunofluorescence histochemical staining(brain section containing FG)and subsequent fluorescence/confocal microscopic analysis.Results:(1)Anterograde viral tracing re-vealed dense axonal terminals from the IC projecting to the medial subnucleus of the NTS,while retrograde tracing re-vealed that IC neurons projecting to the NTS were predominantly localized within the dysgranular layer;(2)IC-NTS projection neurons were exclusive glutamatergic(100%,n=3);(3)NTS neurons receiving IC inputs were mainly lo-calized in the medial subnucleus,and were predominantly GABAergic(79.8±3.2%,n=3).Conclusion:The pres-ent results indicate that a descending pathway from excitatory neurons of the IC terminates onto inhibitory neurons of the NTS,which might represent a potential neuromodulatory target for visceral pain disorders.
基金supported by North Sichuan Medical College(CBY23-QDA14)the National Natural Science Foundation of China(32030045 and 82071454)+4 种基金Nanchong Federation of Social Science Associations(NC24C145)the Sichuan Science and Technology Program(2024NSFSC2017,2024ZYD0086)the Sichuan Students'Platform for Innovation Training Program(S202410634035)the Health Commission of Sichuan Province(24WSXT044)funded by the Open Research Fund of the State Key Laboratory of Cognitive Neuroscience and Learning(CNLYB2403).
文摘While multiple step saccades(MSS)are occasionally reported in the healthy population,they are more evident in patients with Parkinson’s disease(PD).Therefore,MSS has been suggested as a biological marker for the diagnosis of PD.However,the lack of clarity on the neural mechanism underlying the generation of MSS largely impedes their application in the clinic.We have proposed recently that MSS are triggered by the discrepancy between desired and executed saccades.Accordingly,brain regions involved in saccadic planning and execution might play a role in the generation of MSS.To test this hypothesis,we explored the role of the prefrontal(PFC)and posterior parietal cortex(PPC)in generating MSS by conducting two experiments:electroencephalographic recording and single-pulse transcranial magnetic stimulation in the PFC or PPC of humans while participants were performing a gap saccade task.We found that the PFC and PPC are involved in the generation of MSS.
基金supported by the National Natural Science Foundation of China,Nos.82272171(to ZY),82271403(to XL),81941011(to XL),31971279(to ZY),31730030(to XL)the Natural Science Foundation of Beijing,No.7222004(to HD).
文摘The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury.However,whether it is possible to stimulate neurogenesis and reconstruct cortical layers II to VI in non-neurogenic regions,such as the cortex,remains unknown.In this study,we implanted a hyaluronic acid collagen gel loaded with basic fibroblast growth factor into the motor cortex immediately following traumatic injury.Our findings reveal that this gel effectively stimulated the proliferation and migration of endogenous neural stem/progenitor cells,as well as their differentiation into mature and functionally integrated neurons.Importantly,these new neurons reconstructed the architecture of cortical layers II to VI,integrated into the existing neural circuitry,and ultimately led to improved brain function.These findings offer novel insight into potential clinical treatments for traumatic cerebral cortex injuries.
基金supported by the German Research Foundation (SFB-TR 295)(to MM)。
文摘Pathological tremor is one of the cardinal symptoms in Parkinson's disease (PD).Tremor is comprised of involuntary,rhythmic,a nd oscillating movements that can vary according to the circumstances under which they occur,the body parts that are involved,and the frequency at which they present.For example,tremors can be mild to severe,are stress sensitive,and can affect arms,legs,or the head (Dirkx and Bologna,2022).
文摘Dear Editor,The importance of the medial entorhinal cortex(MEC)for memory and spatial navigation has been shown repeatedly in many species,including mice and humans[1,2].It is,therefore,not surprising that the connectivity of this structure has been studied extensively over the past century,mainly using a range of anterograde and retrograde anatomical tracers[3].
基金supported by the National Natural Science Foundation of China,Nos.82030071(to JH),82272495(to YC)Science and Technology Major Project of Changsha,No.kh2103008(to JH)Graduate Students’Independent Innovative Projects of Hunan Province,No.CX20230311(to YJ)。
文摘Spinal cord injury typically causes corticospinal tract disruption.Although the disrupted corticospinal tract can self-regenerate to a certain degree,the underlying mechanism of this process is still unclear.N6-methyladenosine(m^(6)A)modifications are the most common form of epigenetic regulation at the RNA level and play an essential role in biological processes.However,whether m^(6)A modifications participate in corticospinal tract regeneration after spinal cord injury remains unknown.We found that expression of methyltransferase 14 protein(METTL14)in the locomotor cortex was high after spinal cord injury and accompanied by elevated m^(6)A levels.Knockdown of Mettl14 in the locomotor cortex was not favorable for corticospinal tract regeneration and neurological recovery after spinal cord injury.Through bioinformatics analysis and methylated RNA immunoprecipitation-quantitative polymerase chain reaction,we found that METTL14 regulated Trib2 expression in an m^(6)A-regulated manner,thereby activating the mitogen-activated protein kinase pathway and promoting corticospinal tract regeneration.Finally,we administered syringin,a stabilizer of METTL14,using molecular docking.Results confirmed that syringin can promote corticospinal tract regeneration and facilitate neurological recovery by stabilizing METTL14.Findings from this study reveal that m^(6)A modification is involved in the regulation of corticospinal tract regeneration after spinal cord injury.
基金Supported by Hunan Provincial Postgraduate Scientific Research Innovation Project(CX20231270).
文摘[Objectives]This study was conducted to investigate the alleviating effect of Phellodendri Chinensis Cortex extract on the phytotoxicity of pretilachlor in rice.[Methods]In addition to CK,Phellodendri Chinensis Cortex extract and pretilachlor with different gradients were added to the culture medium,and rice seeds with the same bud length were evenly placed in the culture medium.After 10 and 15 d of culture,the plant height and fresh weight of rice seedlings were measured and the alleviation rate was calculated.[Results]Ten days after application,the plant height of treatment 8(pretilachlor:extract concentration ratio of 25:200)was alleviated with an alleviation rate of 21.72%,and the fresh weight of treatment 9(pretilachlor:extract concentration ratio of 25:400)was alleviated with an alleviation rate of 31.04%.Fifteen days after treatment,the plant height of treatment 6(pretilachlor:extract concentration ratio of 25:50)showed a better alleviating effect,and the fresh weight of treatment 8(pretilachlor:extract concentration ratio of 25:200)exhibited a better alleviating effect,with an alleviation rate of 22.39%.Meanwhile,it was found that the extract of Phellodendri Chinensis Cortex could alleviate the increase of POD activity in rice leaves caused by pretilachlor.Meanwhile,it was found that the extract of Phellodendri Chinensis Cortex promoted the expression of CAT in rice seedlings,thus significantly increasing its activity and alleviating the toxicity of pretilachlor to rice.[Conclusions]This study can provide technical support for the screening and field application of plant-derived safeners.
基金supported by grants from the National Natural Science Foundation of China(82271243 and 82101318)Shaanxi Province Key Research and Development Plan(2024SF-ZDCYL-01-13)+1 种基金the support funding from Fourth Military Medical University(2024JC005,2020AXJHHJ,and XJZT24JC27)Liaoning Provincial Joint Science and Technology Program(2023-MSLH-345).
文摘The anterior cingulate cortex(ACC)has recently been proposed as a key player in the representation of itch stimuli.However,to date,little is known about the contribution of specific ACC interneuron populations to itch processing.Using c-Fos immunolabeling and in vivo Ca2+imaging,we reported that both histamine and chloroquine stimuli-induced acute itch caused a marked enhancement of vasoactive intestinal peptide(VIP)-expressing interneuron activity in the ACC.Behavioral data indicated that optogenetic and chemogenetic activation of these neurons reduced scratching responses related to histaminergic and non-histaminergic acute itch.Similar neural activity and modulatory role of these neurons were seen in mice with chronic itch induced by contact dermatitis.Together,this study highlights the importance of ACC VIP+neurons in modulating itch-related affect and behavior,which may help us to develop novel mechanism-based strategies to treat refractory chronic itch in the clinic.
基金supported by the Anhui Provincial Department of Education Outstanding Young Teachers Cultivation Key Project(No.YQZD2023046)the Anhui University of Traditional Chinese Medicine School Talent Support Program Project(Nos.DT2400000222 and DT2100000545)。
文摘Objective:To elucidate the specific mechanisms by which electroacupuncture(EA)alleviates anxiety and fear behaviors associated with posttraumatic stress disorder(PTSD),focusing on the role of lipocalin-2(Lcn2).Methods:The PTSD mouse model was subjected to single prolonged stress and shock(SPS&S),and the animals received 15 min sessions of EA at Shenmen acupoint(HT7).Behavioral tests were used to investigate the effects of EA at HT7 on anxiety and fear.Western blotting and enzyme-linked immunosorbent assay were used to quantify Lcn2 and inflammatory cytokine levels in the prefrontal cortex(PFC).Additionally,the activity of PFC neurons was evaluated by immunofluorescence and in vivo electrophysiology.Results:Mice subjected to SPS&S presented increased anxiety-and fear-like behaviors.Lcn2 expression in the PFC was significantly upregulated following SPS&S,leading to increased expression of the proinflammatory cytokines tumor necrosis factor-a and interleukin-6 and suppression of PFC neuronal activity.However,EA at HT7 inhibited Lcn2 release,reducing neuroinflammation and hypoexcitability in the PFC.Lcn2 overexpression mitigated the effects of EA at HT7,resulting in anxiety-and fear-like behaviors.Conclusion:EA at HT7 can ameliorate PTSD-associated anxiety and fear,and its mechanism of action appears to involve the inhibition of Lcn2-mediated neural activity and inflammation in the PFC.
