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1.
Neuropharmacology ; 204: 108895, 2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34813859

RESUMO

Social memory is the ability to discriminate familiar conspecific from the unknown ones. Prefrontal neurons are essentially required for social memory, but the mechanism associated with this regulation remains unknown. It is also unclear to what extent the neuronal representations of social memory formation and retrieval events overlap in the prefrontal cortex (PFC) and which event drives social memory strength. Here we asked these questions by using a repeated social training paradigm for social recognition in FosTRAP mice. We found that after 4 days' repeated social training, female mice developed stable social memory. Specifically, repeated social training activated more cells that were labeled with tdTomato during memory retrieval compared with the first day of memory encoding. Besides, combining TRAP with c-Fos immunostaining, we found about 30% of the FosTRAPed cells were reactivated during retrieval. Moreover, the number of retrieval-induced but not first-day encoding-induced tdTomato neurons correlates with the social recognition ratio in the prelimbic but not other subregions. The activated cells during the retrieval session also showed increased NMDA receptor-mediated synaptic transmission compared with that in non-labeled pyramidal neurons. Blocking NMDA receptors by MK-801 impaired social memory but not sociability. Therefore, our results reveal that repetitive training elevates mPFC involvement in social memory retrieval via enhancing NMDA receptor-mediated synaptic transmission, thus rendering stable social memory.

2.
J Neurosci ; 2021 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-34844989

RESUMO

Neuronal activity in the prefrontal cortex (PFC) controls dominance hierarchies in groups of animals. Dopamine (DA) strongly modulates PFC activity mainly through D1 receptors (D1Rs) and D2 receptors (D2Rs). Still, it is unclear how these two subpopulations of DA receptor-expressing neurons in the PFC regulate social dominance hierarchy. Here, we demonstrate distinct roles for prefrontal D1R- and D2R-expressing neurons in establishing social hierarchy, with D1R+ neurons determining dominance whereas D2R+ neurons for the subordinate. Ex vivo whole-cell recordings revealed that the dominant status of male mice correlates with rectifying AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor transmission and stronger excitatory synaptic strength onto D1R+ neurons in PFC pyramidal neurons. In contrast, the submissive status is associated with higher neuronal excitability in D2R+ neurons. Moreover, simultaneous manipulations of synaptic efficacy of D1R+ neurons in dominant male mice and neuronal excitability of D2R+ neurons of their male subordinates switch their dominant-subordinate relationship. These results reveal that prefrontal D1R+ and D2R+ neurons have distinct but synergistic functions in the dominance hierarchy, and DA-mediated regulation of synaptic strengths acts as a powerful behavioral determinant of intermale social rank.Significance StatementDominance hierarchy exists widely among animals who confront social conflict. Studies have indicated that social status largely relies on the neuronal activity in the prefrontal cortex, but how dopamine influences social hierarchy via subpopulation of prefrontal neurons is still elusive. Here, we explore the cell-type-specific role of dopamine receptor-expressing prefrontal neurons in the dominance-subordinate relationship. We found that the synaptic strength of D1 receptor-expressing neurons determines the dominant status, while hyperactive D2-expressing neurons are associated with the subordinate status. These findings highlight how social conflicts recruit distinct cortical microcircuits to drive different behaviors and reveal how D1- and D2-receptor enriched neurocircuits in the prefrontal cortex establish a social hierarchy.

3.
Nat Commun ; 12(1): 5766, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34599186

RESUMO

Engineered micro- and nanomechanical resonators with ultra-low dissipation constitute a promising platform for various quantum technologies and foundational research. Traditionally, the improvement of the resonator's performance through nanomechanical structural engineering has been driven by human intuition and insight. Such an approach is inefficient and leaves aside a plethora of unexplored mechanical designs that potentially achieve better performance. Here, we use a computer-aided inverse design approach known as topology optimization to structurally design mechanical resonators with optimized performance of the fundamental mechanical mode. Using the outcomes of this approach, we fabricate and characterize ultra-coherent nanomechanical resonators with, to the best of our knowledge, record-high Q ⋅ f products for their fundamental mode (where Q is the quality factor and f is the frequency). The proposed approach - which can also be used to improve phononic crystals and coupled-mode resonators - opens up a new paradigm for designing ultra-coherent micro- and nanomechanical resonators, enabling e.g. novel experiments in fundamental physics and extreme sensing.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34542822

RESUMO

A n ovel glycoside hydrolase (GH) family 46 chitosanase (SaCsn46A) from Streptomyces avermitilis was cloned and functionally expressed in Escherichia coli Rosetta (DE3) strains. SaCsn46A consists of 271 amino acids, which includes a 34-amino acid signal peptide. The protein sequence of SaCsn46A shows maximum identity (83.5%) to chitosanase from Streptomyces sp. SirexAA-E. Then, the mature enzyme was purified to homogeneity through Ni-chelating affinity chromatography with a recovery yield of 78% and the molecular mass of purified enzyme was estimated to be 29 kDa by SDS-PAGE. The recombinant enzyme possessed a temperature optimum of 45 °C and a pH optimum of 6.2, and it was stable at pH ranging from 4.0 to 9.0 and below 30 °C. The Km and Vmax values of this enzyme were 1.32 mg/mL, 526.32 U/mg/min, respectively (chitosan as substrate). The enzyme activity can be enhanced by Mg2+ and especially Mn2+, which could enhance the activity about 3.62-fold at a 3-mM concentration. The enzyme can hydrolyze a variety of polysaccharides which are linked by ß-1,4-glycosidic bonds such as chitin, xylan, and cellulose, but it could not hydrolyze polysaccharides linked by α-1,4-glycosidic bonds. The results of thin-layer chromatography and HPLC showed that the enzyme exhibited an endo-type cleavage pattern and could hydrolyze chitosan to glucosamine (GlcN) and (GlcN)2. This study demonstrated that SaCsn46A is a promising enzyme to produce glucosamine and chitooligosaccharides (COS) from chitosan.

5.
J Agric Food Chem ; 69(40): 11835-11846, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34590486

RESUMO

BsCsn46A, a GH46 family chitosanase from Bacillus subtilis, has great potential for industrial chitooligosaccharide production due to its high activity and stability. In this study, a special amino acid Pro121 was identified not fit in the helix structure, which was located in the opposite side of the active center in BsCsn46A, by the PoPMuSiC algorithm. Then, saturation mutagenesis was performed to explore the role of the site amino acid 121. Compared with the wild type, the specific activity of P121N, P121C, and P121V was increased by 1.69-, 1.97-, and 2.15-fold, respectively. In particular, the specific activity of P121N was increased without loss of thermostability, indicating that replacing the structural stiffness of proline in the helical structure could significantly improve the chitosanase activity. The Km values of P121N, P121C, and P121V decreased significantly, indicating that the affinity between the enzyme-substrate complex was enhanced. Through molecular docking, it was found that the increase of hydrogen bonds and van der Waals force between the enzyme-substrate complex and the removal of unfavorable bonds might be the main reason for the change of enzyme properties. In addition, the optimal temperature of the three mutants changed from 60 to 55 °C. These results indicate that the site 121 plays a critical role in the catalytic activity and enzymatic properties of chitosanase. To our knowledge, the results provide novel data on chitosanase activity and identify an excellent candidate of industrial chitosanase.


Assuntos
Bacillus subtilis , Glicosídeo Hidrolases , Bacillus subtilis/genética , Bacillus subtilis/metabolismo , Estabilidade Enzimática , Glicosídeo Hidrolases/genética , Glicosídeo Hidrolases/metabolismo , Simulação de Acoplamento Molecular , Mutagênese , Temperatura
6.
Front Neural Circuits ; 15: 716408, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34322002

RESUMO

Prefrontal cortical GABAergic interneurons (INs) and their innervations are essential for the execution of complex behaviors such as working memory, social behavior, and fear expression. These behavior regulations are highly dependent on primary long-range afferents originating from the subcortical structures such as mediodorsal thalamus (MD), ventral hippocampus (vHPC), and basolateral amygdala (BLA). In turn, the regulatory effects of these inputs are mediated by activation of parvalbumin-expressing (PV) and/or somatostatin expressing (SST) INs within the prefrontal cortex (PFC). Here we review how each of these long-range afferents from the MD, vHPC, or BLA recruits a subset of the prefrontal interneuron population to exert precise control of specific PFC-dependent behaviors. Specifically, we first summarize the anatomical connections of different long-range inputs formed on prefrontal GABAergic INs, focusing on PV versus SST cells. Next, we elaborate on the role of prefrontal PV- and SST- INs in regulating MD afferents-mediated cognitive behaviors. We also examine how prefrontal PV- and SST- INs gate vHPC afferents in spatial working memory and fear expression. Finally, we discuss the possibility that prefrontal PV-INs mediate fear conditioning, predominantly driven by the BLA-mPFC pathway. This review will provide a broad view of how multiple long-range inputs converge on prefrontal interneurons to regulate complex behaviors and novel future directions to understand how PFC controls different behaviors.

7.
Mol Psychiatry ; 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34163013

RESUMO

The neurobiology of schizophrenia involves multiple facets of pathophysiology, ranging from its genetic basis over changes in neurochemistry and neurophysiology, to the systemic level of neural circuits. Although the precise mechanisms associated with the neuropathophysiology remain elusive, one essential aspect is the aberrant maturation and connectivity of the prefrontal cortex that leads to complex symptoms in various stages of the disease. Here, we focus on how early developmental dysfunction, especially N-methyl-D-aspartate receptor (NMDAR) development and hypofunction, may lead to the dysfunction of both local circuitry within the prefrontal cortex and its long-range connectivity. More specifically, we will focus on an "all roads lead to Rome" hypothesis, i.e., how NMDAR hypofunction during development acts as a convergence point and leads to local gamma-aminobutyric acid (GABA) deficits and input-output dysconnectivity in the prefrontal cortex, which eventually induce cognitive and social deficits. Many outstanding questions and hypothetical mechanisms are listed for future investigations of this intriguing hypothesis that may lead to a better understanding of the aberrant maturation and connectivity associated with the prefrontal cortex.

8.
Front Immunol ; 12: 682749, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34054874

RESUMO

Antibody-mediated rejection (AMR) represents a major cause of allograft dysfunction and results in allograft failure in solid organ transplantation. Cyclic helix B peptide (CHBP) is a novel erythropoietin-derived peptide that ameliorated renal allograft rejection in a renal transplantation model. However, its effect on AMR remains unknown. This study aimed to investigate the effect of CHBP on AMR using a secondary allogeneic skin transplantation model, which was created by transplanting skin from BALB/c mice to C57BL/6 mice with or without CHBP treatment. A secondary syngeneic skin transplantation model, involving transplantation from C57BL/6 mice to C57BL/6 mice, was also created to act as a control. Skin graft rejection, CD19+ B cell infiltration in the skin allograft, the percentages of splenic plasma cells, germinal center (GC) B cells, and Tfh cells, the serum levels of donor specific antibodies (DSAs), and NF-κB signaling in splenocytes were analyzed. Skin allograft survival was significantly prolonged in the CHBP group compared to the allogeneic group. CHBP treatment also significantly reduced the CD19+ B cell infiltration in the skin allograft, decreased the percentages of splenic plasma cells, GC B cells, and Tfh cells, and ameliorated the increase in the serum DSA level. At a molecular level, CHBP downregulated P100, RelB, and P52 in splenocytes. CHBP prolonged skin allograft survival by inhibiting AMR, which may be mediated by inhibition of NF-κB signaling to suppress B cell immune responses, thereby decreasing the DSA level.


Assuntos
Eritropoetina/farmacologia , Sobrevivência de Enxerto/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Aloenxertos , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Modelos Animais de Doenças , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Imuno-Histoquímica , Imunofenotipagem , Isoanticorpos , Masculino , Camundongos , Plasmócitos/imunologia , Plasmócitos/metabolismo , Transplante de Pele , Baço , Transplante Homólogo
9.
World J Clin Cases ; 9(8): 1953-1967, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33748247

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2, is a worldwide pandemic. Some COVID-19 patients develop severe acute respiratory distress syndrome and progress to respiratory failure. In such cases, extracorporeal membrane oxygenation (ECMO) treatment is a necessary life-saving procedure. CASE SUMMARY: Two special COVID-19 cases-one full-term pregnant woman and one elderly (72-year-old) man-were treated by veno-venous (VV)-ECMO in the Second People's Hospital of Zhongshan, Zhongshan City, Guangdong Province, China. Both patients had developed refractory hypoxemia shortly after hospital admission, despite conventional support, and were therefore managed by VV-ECMO. Although both experienced multiple ECMO-related complications on top of the COVID-19 disease, their conditions improved gradually. Both patients were weaned successfully from the ECMO therapy. At the time of writing of this report, the woman has recovered completely and been discharged from hospital to home; the man remains on mechanical ventilation, due to respiratory muscle weakness and suspected lung fibrosis. As ECMO itself is associated with various complications, it is very important to understand and treat these complications to achieve optimal outcome. CONCLUSION: VV-ECMO can provide sufficient gas exchange for COVID-19 patients with acute respiratory distress syndrome. However, it is crucial to understand and treat ECMO-related complications.

10.
Front Behav Neurosci ; 15: 618397, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33584217

RESUMO

Abnormal social behavior, including both hypo- and hypersociability, is often observed in neurodevelopmental disorders such as autism spectrum disorders. However, the mechanisms associated with these two distinct social behavior abnormalities remain unknown. Postsynaptic density protein-95 (PSD-95) is a highly abundant scaffolding protein in the excitatory synapses and an essential regulator of synaptic maturation by binding to NMDA and AMPA receptors. The DLG4 gene encodes PSD-95, and it is a risk gene for hypersocial behavior. Interestingly, PSD-95 knockout mice exhibit hyposociability during adolescence but hypersociability in adulthood. The adolescent hyposociability is accompanied with an NMDAR hyperfunction in the medial prefrontal cortex (mPFC), an essential part of the social brain for control of sociability. The maturation of mPFC development is delayed until young adults. However, how PSD-95 deficiency affects the functional maturation of mPFC and its connection with other social brain regions remains uncharacterized. It is especially unknown how PSD-95 knockout drives the switch of social behavior from hypo- to hyper-sociability during adolescent-to-adult development. We propose an NMDAR-dependent developmental switch of hypo- to hyper-sociability. PSD-95 deficiency disrupts NMDAR-mediated synaptic connectivity of mPFC and social brain during development in an age- and pathway-specific manner. By utilizing the PSD-95 deficiency mouse, the mechanisms contributing to both hypo- and hyper-sociability can be studied in the same model. This will allow us to assess both local and long-range connectivity of mPFC and examine how they are involved in the distinct impairments in social behavior and how changes in these connections may mature over time.

11.
J Pharmacol Exp Ther ; 377(1): 189-198, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33414130

RESUMO

Previous studies identified a region on chromosome 1 associated with NG-nitro-L-arginine methyl ester (L-NAME) hypertension-induced renal disease in fawn-hooded hypertensive (FHH) rats. This region contains a mutant γ-adducin (Add3) gene that impairs renal blood flow (RBF) autoregulation, but its contribution to renal injury is unknown. The present study evaluated the hypothesis that knockout (KO) of Add3 impairs the renal vasoconstrictor response to the blockade of nitric oxide synthase and enhances hypertension-induced renal injury after chronic administration of L-NAME plus a high-salt diet. The acute hemodynamic effect of L-NAME and its chronic effects on hypertension and renal injury were compared in FHH 1Brown Norway (FHH 1BN) congenic rats (WT) expressing wild-type Add3 gene versus FHH 1BN Add3 KO rats. RBF was well autoregulated in WT rats but impaired in Add3 KO rats. Acute administration of L-NAME (10 mg/kg) raised mean arterial pressure (MAP) similarly in both strains, but RBF and glomerular filtration rate (GFR) fell by 38% in WT versus 15% in Add3 KO rats. MAP increased similarly in both strains after chronic administration of L-NAME and a high-salt diet; however, proteinuria and renal injury were greater in Add3 KO rats than in WT rats. Surprisingly, RBF, GFR, and glomerular capillary pressure were 41%, 82%, and 13% higher in L-NAME-treated Add3 KO rats than in WT rats. Hypertensive Add3 KO rats exhibited greater loss of podocytes and glomerular nephrin expression and increased interstitial fibrosis than in WT rats. These findings indicate that loss of ADD3 promotes L-NAME-induced renal injury by altering renal hemodynamics and enhancing the transmission of pressure to glomeruli. SIGNIFICANCE STATEMENT: A mutation in the γ-adducin (Add3) gene in fawn-hooded hypertensive rats that impairs autoregulation of renal blood flow is in a region of rat chromosome 1 homologous to a locus on human chromosome 10 associated with diabetic nephropathy. The present results indicate that loss of ADD3 enhanced NG-nitro-L-arginine methyl ester-induced hypertensive renal injury by altering the transmission of pressure to the glomerulus.


Assuntos
Proteínas de Ligação a Calmodulina/metabolismo , Hipertensão Renal/metabolismo , Insuficiência Renal Crônica/metabolismo , Animais , Pressão Sanguínea , Proteínas de Ligação a Calmodulina/genética , Inibidores Enzimáticos/toxicidade , Deleção de Genes , Taxa de Filtração Glomerular , Homeostase , Hipertensão Renal/etiologia , Hipertensão Renal/fisiopatologia , Masculino , NG-Nitroarginina Metil Éster/toxicidade , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Ratos , Circulação Renal , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/fisiopatologia , Vasoconstrição
12.
J Spec Pediatr Nurs ; 26(3): e12318, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33159385

RESUMO

PURPOSE: To develop the Chinese version of the Pediatric Patient-Reported Outcome Measurement Information System (PROMIS)-Emotional Distress item bank version 2.0-both conceptually equivalent to the original and relevant in the Chinese culture. DESIGN AND METHODS: The Pediatric PROMIS-Emotional Distress item bank was translated, following the standard Functional Assessment of Chronic Illness Therapy (FACIT) translation methodology, by a translation team. Eight children aged 8-17 years from the general population were cognitively interviewed. RESULTS: Most items were well understood by children, and some revisions were made after the cognitive interviewing based on the suggestions of the interviewees. The Chinese version of the Pediatric PROMIS-Emotional Distress-v2.0 item bank was conceptually and semantically equivalent to the original. PRACTICE IMPLICATIONS: The Chinese version of the Pediatric PROMIS-Emotional Distress item bank is now available for further studies to develop computer adaptive tests (CATs). Future CAT version measures may become a new standard measure for children in the general population and those living with a chronic condition in China.

13.
Biol Psychiatry ; 89(5): 521-531, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33190846

RESUMO

BACKGROUND: The medial prefrontal cortex (mPFC) is essential for social behaviors, yet whether and how it encodes social memory remains unclear. METHODS: We combined whole-cell patch recording, morphological analysis, optogenetic/chemogenetic manipulation, and the TRAP (targeted recombination in active populations) transgenic mouse tool to study the social-associated neural populations in the mPFC. RESULTS: Fos-TRAPed prefrontal social-associated neurons are excitatory pyramidal neurons with relatively small soma sizes and thin-tufted apical dendrite. These cells exhibit intrinsic firing features of dopamine D1 receptor-like neurons, show persisting firing pattern after social investigation, and project dense axons to nucleus accumbens. In behaving TRAP mice, selective inhibition of prefrontal social-associated neurons does not affect social investigation but does impair subsequent social recognition, whereas optogenetic reactivation of their projections to the nucleus accumbens enables recall of a previously encountered but "forgotten" mouse. Moreover, chemogenetic activation of mPFC-to-nucleus accumbens projections ameliorates MK-801-induced social memory impairments. CONCLUSIONS: Our results characterize the electrophysiological and morphological features of social-associated neurons in the mPFC and indicate that these Fos-labeled, social-activated prefrontal neurons are necessary and sufficient for social memory.


Assuntos
Memória , Córtex Pré-Frontal , Animais , Camundongos , Neurônios , Núcleo Accumbens , Comportamento Social
14.
Am J Physiol Heart Circ Physiol ; 320(2): H549-H562, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33306445

RESUMO

Diabetes mellitus (DM) is one of the primary pathological factors that contributes to aging-related cognitive impairments, but the underlying mechanisms remain unclear. We recently reported that old DM rats exhibited impaired myogenic responses of the cerebral arteries and arterioles, poor cerebral blood flow autoregulation, enhanced blood-brain barrier (BBB) leakage, and cognitive impairments. These changes were associated with diminished vascular smooth muscle cell contractile capability linked to elevated reactive oxygen species (ROS) and reduced ATP production. In the present study, using a nonobese T2DN DM rat, we isolated parenchymal arterioles (PAs), cultured cerebral microvascular pericytes, and examined whether cerebrovascular pericyte in DM is damaged and whether pericyte dysfunction may play a role in the regulation of cerebral hemodynamics and BBB integrity. We found that ROS and mitochondrial superoxide production were elevated in PAs isolated from old DM rats and in high glucose (HG)-treated α-smooth muscle actin-positive pericytes. HG-treated pericytes displayed decreased contractile capability in association with diminished mitochondrial respiration and ATP production. Additionally, the expression of advanced glycation end products, transforming growth factor-ß, vascular endothelial growth factor, and fibronectin were enhanced, but claudin 5 and integrin ß1 was reduced in the brain of old DM rats and HG-treated pericytes. Further, endothelial tight junction and pericyte coverage on microvessels were reduced in the cortex of old DM rats. These results demonstrate our previous findings that the impaired cerebral hemodynamics and BBB leakage and cognitive impairments in the same old DM model are associated with hyperglycemia-induced cerebrovascular pericyte dysfunction.NEW & NOTEWORTHY This study demonstrates that the loss of contractile capability in pericytes in diabetes is associated with enhanced ROS and reduced ATP production. Enhanced advanced glycation end products (AGEs) in diabetes accompany with reduced pericyte and endothelial tight junction coverage in the cortical capillaries of old diabetic rats. These results suggest our previous findings that the impaired cerebral hemodynamics, BBB leakage, and cognitive impairments in old DM model are associated with hyperglycemia-induced cerebrovascular pericyte dysfunction.


Assuntos
Envelhecimento/metabolismo , Diabetes Mellitus/metabolismo , Junções Comunicantes/metabolismo , Hiperglicemia/complicações , Pericitos/metabolismo , Trifosfato de Adenosina/metabolismo , Envelhecimento/patologia , Animais , Arteríolas/citologia , Arteríolas/metabolismo , Arteríolas/fisiopatologia , Encéfalo/irrigação sanguínea , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento , Células Cultivadas , Diabetes Mellitus/etiologia , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Masculino , Pericitos/fisiologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Vasoconstrição
15.
J Ethnopharmacol ; 269: 113745, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33359859

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ephedrae Herba (EH, Ephedra sinica Stapf.) and Armeniacae Semen Amarum (ASA, Prunus armeniaca L. var. ansu Maxim.) have been used to treat asthma, cold, fever, and cough in China for thousands of years. AIM OF THE STUDY: In this study, we aimed to investigate the optimal ratio of EH and ASA compatibility (EAC) to reduce airway injury in asthmatic rats and its possible mechanism. METHODS: Rats were sensitized with a mixture of acetylcholine chloride and histamine bisphosphate 1 h before sensitization by intragastric administration of EAC or dexamethasone or saline for 7 days. Subsequently, the ultrastructure of rat airway epithelial tissue changes, apoptosis of the airway epithelial cells, and the expression of mRNA and protein of EGRF and Bcl-2 were detected. RESULTS: Transmission electron microscope: EAC (groups C and E) had the most prominent effect on repairing airway epithelial cells' ultrastructural changes in asthmatic rats. TUNEL: dexamethasone and EAC (groups B、C、E and F) inhibited the apoptosis of airway epithelial cells in asthmatic rats (P < 0.05). In situ hybridization: EAC (group E) inhibited the overexpression of EGFR and Bcl-2 mRNA (P < 0.05).Western Blotting: EAC (groups A、B、C、E and F) inhibited the upregulation of airway epithelial EGFR and Bcl-2 protein expression (P < 0.01). CONCLUSIONS: Our findings indicate that EAC can inhibit abnormal changes in airway epithelial structure and apoptosis of airway epithelial cells, thereby alleviating airway injury. In this study, the best combination of EH and ASA to alleviate airway epithelial injury in asthmatic rats was group E (EH: ASA = 8: 4.5).


Assuntos
Asma/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Ephedra sinica/química , Prunus armeniaca/química , Sistema Respiratório/efeitos dos fármacos , Acetilcolina/toxicidade , Animais , Apoptose/efeitos dos fármacos , Asma/induzido quimicamente , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/uso terapêutico , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Células Epiteliais/ultraestrutura , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/biossíntese , Receptores ErbB/genética , Histamina/análogos & derivados , Histamina/toxicidade , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , Ratos Sprague-Dawley , Sistema Respiratório/lesões , Sistema Respiratório/patologia , Sistema Respiratório/ultraestrutura , Traqueia/efeitos dos fármacos , Traqueia/lesões , Traqueia/patologia , Traqueia/ultraestrutura
16.
Physiol Rep ; 9(1): e14688, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33377622

RESUMO

Hypertension is the second leading cause of end-stage renal disease (ESRD) after diabetes mellitus. The significant differences in the incidence of hypertensive ESRD between different patient populations worldwide and patients with and without family history indicate that genetic determinants play an important role in the onset and progression of this disease. Recent studies have identified genetic variants and pathways that may contribute to the alteration of renal function. Mechanisms involved include affecting renal hemodynamics (the myogenic and tubuloglomerular feedback responses); increasing the production of reactive oxygen species in the tubules; altering immune cell function; changing the number, structure, and function of podocytes that directly cause glomerular damage. Studies with hypertensive animal models using substitution mapping and gene knockout strategies have identified multiple candidate genes associated with the development of hypertension and subsequent renal injury. Genome-wide association studies have implicated genetic variants in UMOD, MYH9, APOL-1, SHROOM3, RAB38, and DAB2 have a higher risk for ESRD in hypertensive patients. These findings provide genetic evidence of potential novel targets for drug development and gene therapy to design individualized treatment of hypertension and related renal injury.

18.
Am J Physiol Renal Physiol ; 320(1): F97-F113, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33308016

RESUMO

We recently reported that the enhanced susceptibility to chronic kidney disease (CKD) in the fawn-hooded hypertensive (FHH) rat is caused, at least in part, by a mutation in γ-adducin (ADD3) that attenuates renal vascular function. The present study explored whether Add3 contributes to the modulation of podocyte structure and function using FHH and FHH.Add3 transgenic rats. The expression of ADD3 on the membrane of primary podocytes isolated from FHH was reduced compared with FHH.Add3 transgenic rats. We found that F-actin nets, which are typically localized in the lamellipodia, replaced unbranched stress fibers in conditionally immortalized mouse podocytes transfected with Add3 Dicer-substrate short interfering RNA (DsiRNA) and primary podocytes isolated from FHH rats. There were increased F/G-actin ratios and expression of the Arp2/3 complexes throughout FHH podocytes in association with reduced synaptopodin and RhoA but enhanced Rac1 and CDC42 expression in the renal cortex, glomeruli, and podocytes of FHH rats. The expression of nephrin at the slit diaphragm and the levels of focal adhesion proteins integrin-α3 and integrin-ß1 were decreased in the glomeruli of FHH rats. Cell migration was enhanced and adhesion was reduced in podocytes of FHH rats as well as in immortalized mouse podocytes transfected with Add3 DsiRNA. Mean arterial pressures were similar in FHH and FHH.Add3 transgenic rats at 16 wk of age; however, FHH rats exhibited enhanced proteinuria associated with podocyte foot process effacement. These results demonstrate that reduced ADD3 function in FHH rats alters baseline podocyte pathophysiology by rearrangement of the actin cytoskeleton at the onset of proteinuria in young animals.


Assuntos
Citoesqueleto de Actina/metabolismo , Proteínas de Ligação a Calmodulina/metabolismo , Hipertensão/metabolismo , Podócitos/metabolismo , Proteinúria/metabolismo , Insuficiência Renal Crônica/metabolismo , Citoesqueleto de Actina/patologia , Animais , Pressão Arterial , Proteínas de Ligação a Calmodulina/genética , Adesão Celular , Linhagem Celular , Movimento Celular , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Adesões Focais/metabolismo , Adesões Focais/patologia , Hipertensão/genética , Hipertensão/patologia , Hipertensão/fisiopatologia , Integrinas/metabolismo , Masculino , Camundongos , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Podócitos/patologia , Proteinúria/genética , Proteinúria/patologia , Proteinúria/fisiopatologia , Ratos Endogâmicos , Ratos Transgênicos , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/fisiopatologia , Transdução de Sinais
19.
Front Behav Neurosci ; 14: 598469, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33192373

RESUMO

The paraventricular nucleus of the thalamus (PVT) has for decades been acknowledged to be an important node in the limbic system, but studies of emotional processing generally fail to incorporate it into their investigational framework. Here, we propose that the PVT should be considered as an integral part of the emotional processing network. Through its distinct subregions, cell populations, and connections with other limbic nuclei, the PVT participates in both major features of emotion: arousal and valence. The PVT, particularly the anterior PVT, can through its neuronal activity promote arousal, both as part of the sleep-wake cycle and in response to novel stimuli. It is also involved in reward, being both responsive to rewarding stimuli and itself affecting behavior reflecting reward, likely via specific populations of cells distributed throughout its subregions. Similarly, neuronal activity in the PVT contributes to depression-like behavior, through yet undefined subregions. The posterior PVT in particular demonstrates a role in anxiety-like behavior, generally promoting but also inhibiting this behavior. This subregion is also especially responsive to stressors, and it functions to suppress the stress response following chronic stress exposure. In addition to participating in unconditioned or primary emotional responses, the PVT also makes major contributions to conditioned emotional behavior. Neuronal activity in response to a reward-predictive cue can be detected throughout the PVT, and endogenous activity in the posterior PVT strongly predicts approach or seeking behavior. Similarly, neuronal activity during conditioned fear retrieval is detected in the posterior PVT and its activation facilitates the expression of conditioned fear. Much of this involvement of the PVT in arousal and valence has been shown to occur through the same general afferents and efferents, including connections with the hypothalamus, prelimbic and infralimbic cortices, nucleus accumbens, and amygdala, although a detailed functional map of the PVT circuits that control emotional responses remains to be delineated. Thus, while caveats exist and more work is required, the PVT, through its extensive connections with other prominent nuclei in the limbic system, appears to be an integral part of the emotional processing network.

20.
Neuropharmacology ; 179: 108277, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-32818520

RESUMO

Postsynaptic Density Protein-95 (PSD-95) is a major scaffolding protein in the excitatory synapses in the brain and a critical regulator of synaptic maturation for NMDA and AMPA receptors. PSD-95 deficiency has been linked to cognitive and learning deficits implicated in neurodevelopmental disorders such as autism and schizophrenia. Previous studies have shown that PSD-95 deficiency causes a significant reduction in the excitatory response in the hippocampus. However, little is known about whether PSD-95 deficiency will affect gamma-aminobutyric acid (GABA)ergic inhibitory synapses. Using a PSD-95 transgenic mouse model (PSD-95+/-), we studied how PSD-95 deficiency affects GABAA receptor expression and function in the medial prefrontal cortex (mPFC) during adolescence. Our results showed a significant increase in the GABAA receptor subunit α1. Correspondingly, there are increases in the frequency and amplitude in spontaneous inhibitory postsynaptic currents (sIPSCs) in pyramidal neurons in the mPFC of PSD-95+/- mice, along with a significant increase in evoked IPSCs, leading to a dramatic shift in the excitatory-to-inhibitory balance in PSD-95 deficient mice. Furthermore, PSD-95 deficiency promotes inhibitory synapse function via upregulation and trafficking of NLGN2 and reduced GSK3ß activity through tyr-216 phosphorylation. Our study provides novel insights on the effects of GABAergic transmission in the mPFC due to PSD-95 deficiency and its potential link with cognitive and learning deficits associated with neuropsychiatric disorders.


Assuntos
Proteína 4 Homóloga a Disks-Large/deficiência , Potenciais Pós-Sinápticos Inibidores/fisiologia , Inibição Neural/fisiologia , Córtex Pré-Frontal/metabolismo , Receptores de GABA/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Proteína 4 Homóloga a Disks-Large/genética , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Inibição Neural/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacologia
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