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1.
Brain Behav Immun ; 119: 84-95, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38552922

RESUMO

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that severely affects individuals' daily life and social development. Unfortunately, there are currently no effective treatments for ASD. Dexmedetomidine (DEX) is a selective agonist of α2 adrenergic receptor (α2AR) and is widely used as a first-line medication for sedation and hypnosis in clinical practice. In recent years, there have been reports suggesting its potential positive effects on improving emotional and cognitive functions. However, whether dexmedetomidine has therapeutic effects on the core symptoms of ASD, namely social deficits and repetitive behaviors, remains to be investigated. In the present study, we employed various behavioral tests to assess the phenotypes of animals, including the three-chamber, self-grooming, marble burying, open field, and elevated plus maze. Additionally, electrophysiological recordings, western blotting, qPCR were mainly used to investigate and validate the potential mechanisms underlying the role of dexmedetomidine. We found that intraperitoneal injection of dexmedetomidine in ASD model mice-BTBR T+ Itpr3tf/J (BTBR) mice could adaptively improve their social deficits. Further, we observed a significant reduction in c-Fos positive signals and interleukin-6 (IL-6) expression level in the prelimbic cortex (PrL) of the BTBR mice treated with dexmedetomidine. Enhancing or inhibiting the action of IL-6 directly affects the social behavior of BTBR mice. Mechanistically, we have found that NF-κB p65 is a key pathway regulating IL-6 expression in the PrL region. In addition, we have confirmed that the α2AR acts as a receptor switch mediating the beneficial effects of dexmedetomidine in improving social deficits. This study provides the first evidence of the beneficial effects of dexmedetomidine on core symptoms of ASD and offers a theoretical basis and potential therapeutic approach for the clinical treatment of ASD.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2 , Transtorno do Espectro Autista , Dexmedetomidina , Modelos Animais de Doenças , Interleucina-6 , NF-kappa B , Receptores Adrenérgicos alfa 2 , Comportamento Social , Animais , Dexmedetomidina/farmacologia , Camundongos , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/metabolismo , Masculino , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , NF-kappa B/metabolismo , Interleucina-6/metabolismo , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Comportamento Animal/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/tratamento farmacológico
2.
PeerJ ; 11: e15559, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37576496

RESUMO

Background: EDIL3, which contains epidermal growth factor-like repeats and discoidin I-like domains, is a secretory protein that plays an important role in embryonic development and various illnesses. However, the biological function of EDIL3 in gastric cancer (GC) is still unclear. The objective of this research was to explore the role and potential mechanism of EDIL3 in GC. Methods: In this study, we used the GEPIA, HPA, MethSurv, SMART, STRING, GeneMANIA, LinkedOmics TIMER, TIMER2.0, TISIDB, and RNAactDrug databases to comprehensively analyze the roles of EDIL3 in GC. To validate the in silico findings, EDIL3 expression was measured in our collected GC tissues. Meanwhile, several in vitro experiments were performed to test the function of EDIL3 in GC. Results: We found that EDIL3 was highly expressed in GC and associated with adverse clinical features. In vitro assays revealed that EDIL3 promoted the proliferation, migration, and invasion of GC cells. The functions of EDIL3 and co-expression genes were significantly associated with extracellular structure organization and matrix receptor interaction. EDIL3 expression was positively associated with numerous tumor-infiltrating immune cells and their biomarkers. Conclusion: This study determined that EDIL3 may function as an oncogene and is associated with immune infiltration in GC. EDIL3 could be used as a potential therapeutic target for GC.


Assuntos
Proteínas de Ligação ao Cálcio , Neoplasias Gástricas , Humanos , Proteínas de Ligação ao Cálcio/metabolismo , Neoplasias Gástricas/genética , Prognóstico , Moléculas de Adesão Celular/metabolismo
3.
Neurochem Res ; 48(8): 2350-2359, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36947308

RESUMO

Sympathetic axonal sprouting into dorsal root ganglia is a major phenomenon implicated in neuropathic pain, and sympathetic ganglia blockage may relieve some intractable chronic pain in animal pain models and clinical conditions. These suggest that sympathetic ganglia participated in the maintenance of chronic pain. However, the molecular mechanism underlying sympathetic ganglia-mediated chronic pain is not clear. Here, we found that spared nerve injury treatment upregulated the expression of ADAMTS4 and AP-2α protein and mRNA in the noradrenergic neurons of sympathetic ganglia during neuropathic pain maintenance. Knockdown the ADAMTS4 or AP-2α by injecting specific retro scAAV-TH (Tyrosine Hydroxylase)-shRNA ameliorated the mechanical allodynia induced by spared nerve injury on day 21 and 28. Furthermore, chromatin immunoprecipitation and coimmunoprecipitation assays found that spared nerve injury increased the recruitment of AP-2α to the ADAMTS4 gene promoter, the interaction between AP-2α and histone acetyltransferase p300 and the histone H4 acetylation on day 28. Finally, knockdown the AP-2α reduced the acetylation of H4 on the promoter region of ADAMTS4 gene and suppressed the increase of ADAMTS4 expression induced by spared nerve injury. Together, these results suggested that the enhanced interaction between AP-2α and p300 mediated the epigenetic upregulation of ADAMTS4 in sympathetic ganglia noradrenergic neurons, which contributed to the maintenance of spared nerve injury induced neuropathic pain.


Assuntos
Dor Crônica , Neuralgia , Traumatismos do Sistema Nervoso , Ratos , Animais , Regulação para Cima , Dor Crônica/metabolismo , Ratos Sprague-Dawley , Neuralgia/genética , Neuralgia/metabolismo , Gânglios Simpáticos , Gânglios Espinais/metabolismo , Traumatismos do Sistema Nervoso/metabolismo , Epigênese Genética
4.
BMC Complement Altern Med ; 17(1): 288, 2017 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-28577538

RESUMO

BACKGROUND: Dai-Huang-Fu-Zi-Tang (DHFZT) is a famous traditional Chinese prescription with intestinal obstruction, acute pancreatitis and cholecystalgia for thousands of years. Our previous work found that DHFZT could act against pulmonary and intestinal pathological injury in rats with severe acute pancreatitis (SAP). But the underlying mechanism has not been fully elucidated. The aim of present study was to investigate whether DHFZT could relieve pulmonary and intestinal injury by regulating aquaporins after SAP induced by sodium taurocholate in rats. METHODS: Forty of SD rats were used for dose dependant experiments of DHFZT.Accurate-mass Time-of-flight liquid chromatography-mass spectrometry was used for qualitative screening of chemical compositions of DHFZT. Twenty-four rats were randomly divided into 3 groups: sham group (n = 8), model group (SAP, n = 8), DHFZT group (SAP with DHFZT treatment, n = 8). SAP models were established by retrograde injections of 5% sodium taurocholate solutions into rat pancreaticobiliary ducts. Blood samples were taken at 0, 12, 24, 48 h post-operation for detecting serum amylase, lipase, endotoxin, TNF-α, IL-6 and IL-10. Protein expression and location of aquaporin (AQP)1, 5, 8 and 9 were assessed by immunohistochemistry, western blot and immunofluorescence respectively. RESULTS: The study showed that 27 kinds of chemical composition were identified, including 10 kinds in positive ion mode and 17 kinds in negative ion mode. The results showed that AQP1, AQP5 of lung, and AQP1, AQP5, AQP8 of intestine in model group were significantly lower than that of sham group (P < 0.05), and which were obviously reversed by treatment with DHFZT. In addition, protein levels of pro-inflammatory cytokines such as TNF-α, IL-6 and endotoxin in peripheral blood were significantly suppressed by DHFZT, and that anti-inflammatory cytokine like IL-10 was just opposite. Finally, we also noted that DHFZT reduced serum levels of amylase, lipase and endotoxin, and also improved edema and pathological scores of lung and intestine after SAP. CONCLUSIONS: DHFZT ameliorated the pulmonary and intestinal edema and injury induced by SAP via the upregulation of different AQPs in lung and intestine, and suppressed TNF-α, IL-6 expression and enhanced IL-10 expression.


Assuntos
Aquaporinas/genética , Medicamentos de Ervas Chinesas/administração & dosagem , Enteropatias/tratamento farmacológico , Lesão Pulmonar/tratamento farmacológico , Pancreatite/complicações , Animais , Aquaporinas/metabolismo , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Enteropatias/etiologia , Enteropatias/genética , Enteropatias/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/lesões , Lesão Pulmonar/etiologia , Lesão Pulmonar/genética , Lesão Pulmonar/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
5.
J Surg Res ; 193(1): 368-76, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25088371

RESUMO

BACKGROUND: To investigate protective effects of pyruvate-enriched peritoneal dialysis solution (P-PDS), compared with lactate-PDS (L-PDS), on the intestinal mucosal barrier in peritoneal resuscitation (PR) from severe hemorrhagic shock (HS) in rats. MATERIALS AND METHODS: Fifty male SD rats were randomly divided into five groups (n = 10): group sham, group control (HS without fluid resuscitation), group intravenous resuscitation (IVR) (HS with IVR only), group L-PDS (HS with i.v. infusion plus PR with L-PDS), and group P-PDS (HS with i.v. infusion plus PR with P-PDS). HS was induced by hemorrhage with mean arterial pressure 40 mm Hg for 60 min. In three groups with fluid rehydration, IVR included shed blood and dl-lactate Ringer solution equal to two times the volume of shed blood during 60 min; in two groups with PR, 20 mL of L-PDS, or P-PDS were infused when i.v. infusion started after HS into the peritoneal cavity in 20 min, respectively. Blood samples were taken for determinations of pH, base excess, PaCO2, PaO2, and D-LA 60 min post fluid resuscitation. After rats were sacrificed, a segment of intestine was harvested for the detection of expressions of intestinal barrier proteins: zonula occludens-1 (ZO-1) and phosphorylated vasodilator-stimulated phosphoprotein (p-VASP) by Western blot and immunohistochemistry. Intestinal morphologic alterations were also observed. RESULTS: Blood pH, base excess, and PaO2 were higher, whereas PaCO2 and D-LA were lower in group P-PDS than in other three HS groups (P < 0.05 and P < 0.01, respectively). Severe acidosis was nearly corrected in group P-PDS. Intestinal barrier proteins ZO-1 and p-VASP were significantly preserved in group P-PDS than in group L-PDS (P < 0.05) although they were improved in group L-PDS in comparison with other two HS groups (P < 0.05 or P < 0.01). Expressions of barrier proteins by Western blotting in group P-PDS were reversed to normal. The score of intestinal epithelial damage index was reduced in group L-PDS, compared with other two HS groups (P < 0.05), however, it was significantly lower in group P-PDS than in group L-PDS (P < 0.05). CONCLUSIONS: Pyruvate was superior to lactate in PDS in the correction of severe acidosis with PR. P-PDS was more preservative of expressions of intestinal ZO-1 and p-VASP and mucosal barrier function, compared with L-PDS in PR from severe HS in rats.


Assuntos
Soluções para Diálise/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Diálise Peritoneal/métodos , Ácido Pirúvico/farmacologia , Ressuscitação/métodos , Choque Hemorrágico/tratamento farmacológico , Animais , Pressão Sanguínea/efeitos dos fármacos , Moléculas de Adesão Celular/metabolismo , Modelos Animais de Doenças , Mucosa Intestinal/fisiologia , Ácido Láctico/farmacologia , Masculino , Proteínas dos Microfilamentos/metabolismo , Fosfoproteínas/metabolismo , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Ratos Sprague-Dawley , Choque Hemorrágico/metabolismo , Choque Hemorrágico/fisiopatologia , Proteína da Zônula de Oclusão-1/metabolismo
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