RESUMO
Ginsenoside Rb1, known as gypenoside III, exerts antidepressant-like effects in previous studies. It has also been indicated that ginsenoside Rb1 regulated neuroinflammation via inhibiting NF-κB signaling. According to the evidence that astrocytes can regulate microglia and neuroinflammation by secreting complement C3, the present study aimed to demonstrate the molecular mechanisms underlying ginsenoside Rb1-induced antidepressant-like effects from the astrocytic and microglial complement C3 pathway. The complement C3 mediated mechanism of ginsenoside Rb1 was investigated in mice exposed to chronic restraint stress (CRS). The results showed that ginsenoside Rb1 reversed the depressive-like behaviors in CRS. Treatment with ginsenoside Rb1 reduced both the number of astrocytes and microglia. In addition, ginsenoside Rb1 suppressed TLR4/NF-κB/C3 signaling in the astrocytes of the hippocampus. Furthermore, ginsenoside Rb1 attenuated the contents of synaptic protein including synaptophysin and PSD95 in microglia, suggesting the inhibition of microglia-mediated synaptic elimination caused by CRS. Importantly, ginsenoside Rb1 also maintained the dendritic spines in mice. In conclusion, our results demonstrate that ginsenoside Rb1 produces the antidepressant-like effects by inhibiting astrocyte TLR4/NF-κB/C3 signaling to covert microglia from a pro-inflammatory phenotype (amoeboid) towards an anti-inflammatory phenotype (ramified), which inhibit the synaptic pruning in the hippocampus.
Assuntos
Astrócitos , Complemento C3 , Depressão , Ginsenosídeos , Microglia , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Camundongos , Depressão/tratamento farmacológico , Depressão/metabolismo , Masculino , Complemento C3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Camundongos Endogâmicos C57BL , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Receptor 4 Toll-Like/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/tratamento farmacológico , NF-kappa B/metabolismoRESUMO
OBJECTIVE: To investigate the correlation of frailty with ED in Chinese elderly men. METHODS: This community-based study was conducted with a sample of 258 Chinese men aged 60 to 83 years old in Fuyang City, Anhui Province. All the participants completed a standard questionnaire on demographics, lifestyle, underlying diseases and medical and sexual histories. They also scored on the Chinese version of Tilburg Frailty Indicator (TFI) and International Index of Erectile Function-5 (IIEF-5). RESULTS: The incidence rates of ED and frailty in the elderly men were 85.27% and 75.58%, respectively. The ED patients, compared with the non-ED males, had a significantly older age (ï¼»71.25 ± 5.83ï¼½ vs ï¼»66.92 ± 5.44ï¼½ yr, P < 0.01) and higher body mass index (ï¼»24.37 ± 3.31ï¼½ vs ï¼»23.35 ± 2.97ï¼½ kg/m 2, P < 0.05), incidence of diabetes mellitus (38.0% vs 19.2%, P < 0.05) and TFI scores (8.61 ± 4.29 vs 5.95 ± 4.36, P < 0.05), but lower education and frequency of irregular intercourse (less than once a week) (all P<0.05). Multivariate analysis indicated that diabetes (ORï¼3.292ï¼95% CIï¼1.236ï¼8.768), irregular intercourse (ORï¼2.425ï¼95% CIï¼1.114ï¼5.279), and scores of frailty (ORï¼4.502ï¼95% CIï¼1.905ï¼10.640) were regarded as independent risk factors for ED (all P < 0.05). CONCLUSION: There is a strong correlation between ED and frailty in elderly men. Sexual health care for elderly ED patients should be more focused on the multidimensional assessment and treatment of senile frailty.
Assuntos
Diabetes Mellitus , Disfunção Erétil , Fragilidade , Idoso , Masculino , Humanos , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Disfunção Erétil/epidemiologia , Disfunção Erétil/etiologia , Fragilidade/epidemiologia , Fragilidade/complicações , Envelhecimento , Comportamento Sexual , Inquéritos e QuestionáriosRESUMO
Cisplatin, a commonly used chemotherapy drug, can increase the survival rate of cancer patients. However, it often causes various side effects, including neuronal deficit-induced cognitive impairment. Considering that curcumin is effective in neuronal protection, the action of curcumin on cognitive improvement was evaluated in cisplatin-treated C57BL/6 mice in the present study. Our results first showed that curcumin restored impaired cognitive behaviors. Consistent with this, neurogenesis and synaptogenesis were improved by curcumin. In addition, cisplatin-induced dysfunction of apoptosis-related proteins was partly reversed by curcumin. Moreover, cisplatin-induced autophagy was enhanced by curcumin. Our results also indicated that cisplatin induced autophagy through the endoplasmic reticulum (ER) stress-mediated ATF4-Akt-mTOR signaling pathway. Curcumin activated AMPK-JNK signaling, which mediated both mTOR inhibition and Bcl-2 upregulation and in turn enhanced autophagy and suppressed apoptosis, respectively. In contrast, pretreatment with the autophagy inhibitor 3-methyladenine (3-MA) completely abolished the effects of curcumin on cognitive improvement and improved neurogenesis, synaptogenesis and autophagy. Our results show that cognitive improvement induced by curcumin during chemotherapy is mediated by the enhancement of hippocampal autophagy.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antineoplásicos/toxicidade , Autofagia/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Curcumina/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Autofagia/fisiologia , Cisplatino/toxicidade , Disfunção Cognitiva/patologia , Curcumina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Distribuição AleatóriaRESUMO
OBJECTIVE: To compare two ELISA methods for the detection of the prostatic exosomal protein (PSEP) in the urine. METHODS: Using the double-antibody sandwich (DAS) method and the indirect method of ELISA, we detected PSEP in the urine samples from 100 IIIA chronic prostatitis (CP) patients and another 100 normal healthy males. Meanwhile, we examined 30 clinical urine samples using the diluent (0.1 mol/L PBS buffer) and the urine matrix standard curves to verify the consistency of the standard diluent with the sample collected. Result: The sensitivities of DAS and indirect ELISA were 89% versus 87% and their specificities 91% versus 90%, with total consistency rates of 90% versus 88.5%, with no statistically significant difference in between. The scatter plot for the results of the PBS diluent and the urine matrix standard curves showed a good linearity (R2 = 0.999). No significant difference was found in the results of detection of the clinical urine samples in different matrices. CONCLUSIONS: Considering the characteristics of PSEP, the indirect ELISA method is more practical and feasible for the clinical detection of PSEP in the urine samples of prostatitis patients.
Assuntos
Ensaio de Imunoadsorção Enzimática/métodos , Exossomos , Prostatite , Proteinúria/diagnóstico , Doença Crônica , Humanos , Masculino , Prostatite/diagnóstico , Proteínas/análiseRESUMO
OBJECTIVE: To investigate the clinical value of the prostate small extracorporeal protein (PSEP) level in the urine in evaluating the therapeutic effect on chronic prostatitis (CP). METHODS: Totally 188 CP patients were treated with minocycline and Ningmitai Capsules in our hospital and regularly returned for follow-up examination from November 2017 to November 2018. Based on the results of treatment after 4 and 8 weeks of medication, we divided the patients into a cured, an effective and an ineffective group and compared the contents of PSEP in the urine samples of the three groups of patients before and after treatment. RESULTS: Compared with the baseline, the PSEP content in the urine after 4 weeks of medication was decreased in the cured group (n = 20) (ï¼»3.63 ± 3.81ï¼½ vs ï¼»1.16 ± 0.41ï¼½ ng/ml, P < 0.05), effective group (n = 85) (ï¼»4.13 ± 4.05ï¼½ vs ï¼»2.97 ± 2.89ï¼½ ng/ml, P > 0.05) and ineffective group (n = 83) (ï¼»4.72 ± 2.98ï¼½ vs ï¼»3.74 ± 1.31ï¼½ ng/ml, P > 0.05), and so was that after 8 weeks of treatment in the cured group (n = 48) (ï¼»3.72 ± 3.51ï¼½ vs ï¼»0.89 ± 0.37ï¼½ ng/ml, P < 0.05), effective group (n = 106) (ï¼»4.37 ± 3.93ï¼½ vs ï¼»1.83 ± 0.71ï¼½ ng/ml, P < 0.05) and ineffective group (n = 34) (ï¼»4.61 ± 3.59ï¼½ vs ï¼»3.58 ± 1.15ï¼½ ng/ml, P > 0.05). CONCLUSIONS: The PSEP level in the urine can be used as an index for clinical evaluation of the therapeutic effect on chronic prostatitis.
Assuntos
Prostatite , Proteínas/análise , Urinálise , Doença Crônica , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Masculino , Minociclina/uso terapêutico , Prostatite/tratamento farmacológico , Prostatite/urinaRESUMO
Syzygium aromaticum has been widely used in traditional medicine. Our study investigated the safety and antidepressant-like effects of the essential oil of S. aromaticum after acute or long-term treatment. Using GC-MS, a total of eight volatile constituents were identified in the essential oil of S. aromaticum. The single LD50 was approximately 4500 mg/kg based on a 24-h acute oral toxicity study. In a long-term repeated toxicity study of this essential oil (100, 200, and 400 mg/kg, p.âo.), only 400 mg/kg induced a significant decrease in body weight. In addition, no significant changes in relative organ weights and histopathological analysis were observed in all doses of essential oil-treated mice compared with the control group. Furthermore, acute S. aromaticum essential oil administration by gavage exerted antidepressant-like effects in the forced swimming test (200 mg/kg, p < 0.05) and tail suspension test (100 and 200 mg/kg, p < 0.05). Long-term S. aromaticum essential oil treatment via gavage significantly increased sucrose preference (50 mg/kg, p < 0.05; 100 and 200 mg/kg, p < 0.01) as well as elevated the protein levels of hippocampal p-ERK, p-CREB, and brain-derived neurotrophic factor in mice exposed to chronic unpredictable mild stress. These results confirmed the safety of the essential oil of S. aromaticum and suggested that its potent antidepressant-like property might be attributed to the improvement in the hippocampal pERK1/2-pCREB-BDNF pathway in rats exposed to chronic unpredictable mild stress.
Assuntos
Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Óleos Voláteis/uso terapêutico , Fitoterapia , Estresse Psicológico/tratamento farmacológico , Syzygium/química , Animais , Antidepressivos/farmacologia , Proteína de Ligação a CREB , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Preferências Alimentares , Elevação dos Membros Posteriores , Masculino , Camundongos Endogâmicos ICR , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos Sprague-Dawley , Sacarose/administração & dosagem , NataçãoRESUMO
OBJECTIVE: To systematically review the role of two common prostheses(metal on metal and metal on polythene)in total hip replacement. METHODS: Studies on two prostheses(metal on metal and metal on polythene)in total hip replacement were searched in databases including PubMed, EMBASE, the Cochrane library, CNKI database, WANFANG database, and VIP database using key words including"metal on metal", "metal on polythene", and "total hip replacement". Meta-analysis was performed using RevMan 5.2 software. RESULTS: Metal on metal group was superior to metal on polythene group in terms of Harris function evaluation(WMDï¼4.40, 95%CI: 3.50-5.31, P<0.01), operation time(WMDï¼6.82, 95%CI: 4.50-9.13, P<0.01), whereas other indicators showed no significant difference between these two groups. CONCLUSIONS: Compared with the prosthesis, metal on metal is better than metal on polythene in improving the Harris function when applied for total hip replacement. However, more high-quality large-scale randomized controlled trials are required to further verify it.
Assuntos
Artroplastia de Quadril , Próteses e Implantes , HumanosRESUMO
BACKGROUND: Diosgenin is a well-known steroid saponin possessing neuroprotective activities. However, it is unknown whether diosgenin could alleviate depression-like symptoms. METHODS: The antidepressant-like effect of diosgenin was investigated in mice induced by chronic restraint stress. The effects of diosgenin on behaviors, inflammation, neuroendocrine, neurotrophic function, and gut microbiota were evaluated. RESULTS: The results showed that diosgenin alleviated the depressive-like behaviors in mice. In addition, diosgenin was found to reduce serum concentrations of proinflammatory cytokines and the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Besides, diosgenin could activate hippocampal brain-derived neurotrophic factor (BDNF)/TrkB/ERK/CREB signaling pathway and improve the expression of postsynaptic protein PSD95. Meanwhile, the neurogenesis which was inhibited by chronic restraint stress, was totally reversed by diosgenin. Moreover, diosgenin increased the abundance of phylum Firmicutes and the genus Lactobacillus in stressed mice. The results further showed that diosgenin caused a strong correlation between gut microbiota composition and inflammation, the HPA axis activity, or hippocampus neurotrophic function. LIMITATIONS: Only male mice were used for evaluation in the present study, which limits the understanding of effects of diosgenin on the both sexes. In addition, the results only indicate microbiota at the phylum or genus mediate the regulation of neuroinflammation, neuroendocrine, and neurotrophic function, but does not elucidate how microbiota modulate the systems via their primary or secondary metabolites. CONCLUSIONS: The present study shows that diosgenin exerts the antidepressant activity, which is associated with the enhancement of neurotrophic function and the inhibition of inflammatory and neuroendocrine activities via the regulation of gut microbiota.
Assuntos
Diosgenina , Microbioma Gastrointestinal , Masculino , Feminino , Camundongos , Animais , Diosgenina/farmacologia , Diosgenina/uso terapêutico , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Inflamação/tratamento farmacológico , Antidepressivos/farmacologia , Antidepressivos/uso terapêuticoRESUMO
Depression is a multifaceted psychiatric disorder that affects a significant number of individuals worldwide, and its pathophysiology encompasses a variety of mechanisms, including the induction of endoplasmic reticulum (ER) stress, which has been correlated with depressive-like behaviors in animal models. Yamogenin, a bioactive compound derived from traditional Chinese medicine Dioscorea species, possesses diverse pharmacological properties. This investigation aimed to explore the antidepressant-like effects of yamogenin and the underlying mechanisms involved. By utilizing a murine model of lipopolysaccharide (LPS)-induced depressive-like behavior, we demonstrated that yamogenin enhanced sucrose preference and reduced immobility time in the forced swimming test. These effects were observed alongside the attenuation of ER stress through modulation of the PERK/eIF2α/ATF4/CHOP signaling pathway in the prefrontal cortex. Moreover, yamogenin augmented the expression of the antiapoptotic protein Bcl-2 while diminishing the expression of the proapoptotic protein caspase-3. Additionally, yamogenin exhibited inhibitory effects on microglial activation but did not elicit the promotion of brain-derived neurotrophic factor (BDNF) signaling. Collectively, our findings propose that yamogenin exerts antidepressant-like effects in LPS-induced mice by inhibiting ER stress and microglial activation. This study contributes novel insights into the potential utilization of yamogenin as a natural antidepressant agent.
Assuntos
Diosgenina , Lipopolissacarídeos , Camundongos , Animais , Lipopolissacarídeos/farmacologia , Microglia , Antidepressivos/farmacologia , Diosgenina/farmacologia , Estresse do Retículo Endoplasmático , Depressão/metabolismoRESUMO
BACKGROUND: Inflammatory bowel disease (IBD) is a chronic, life-threatening inflammatory disease of gastrointestinal tissue characterized by inflammation of the gut. Recent studies have shown that gut microbiota is involved in the pathophysiology of IBD. However, it is unknown whether direct inhibition of NLR family pyrin domain containing 3 (NLRP3) inflammasome regulates IBD and alters gut microbiota. METHODS: Here, the NLRP3 expression was evaluated in the colon of IBD subjects. Then, we investigated the effects of NLRP3 inhibition by MCC950 on the gut microbiota and IBD-like symptoms induced by dextran sulfate sodium (DSS). RESULTS: Firstly, NLRP3 and IL-1ß levels were increased in patients with IBD as compared with healthy individuals. Then, the animal experiment showed that NLRP3 inhibition by MCC950 significantly attenuated IBD-like symptoms such as diarrhea and colonic inflammation in DSS-induced mice. In addition, NLRP3 inhibition inhibited NLRP3/ASC/caspase-1/IL-1ß signaling pathway in the colon, which was over-activated by DSS. Furthermore, MCC950 increased the abundance of phylum Firmicutes, decreased the abundance of phylum Bacteroidetes, and increased the Firmicutes/Bacteroidetes ratio, indicating that the inhibition of NLRP3 inflammasome could regulate the abundance of intestinal flora. According to correlation analysis, NLRP3 might produce its functional role in the regulation of oxidation indicators by changing the gut microbiota composition, especially the phylum Bacteroidota, genus Lactobacillus and species Lactobacillus reuteri. CONCLUSIONS: This study suggests that NLRP3 inflammasome inhibition attenuates IBD-like symptoms by regulating gut microbiota, and provides a basis for the clinical application of NLRP3 as a target for the treatment of IBD.
Assuntos
Colite , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Humanos , Animais , Camundongos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR , Sulfato de Dextrana/efeitos adversos , Inflamassomos , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Inflamação , Modelos Animais de DoençasRESUMO
CONTEXT: The fruit of the Prunus mume Sieb. et Zucc (Rosaceae) is used as a health food or medicinal material in traditional herb medicine for a long time in Eastern Asian countries. OBJECTIVE: Our present study investigated the hypouricemic effect of the methanol extract from P. mume fruit (MPMF) in mice with potassium oxonate-induced hyperuremia. MATERIALS AND METHODS: Effect of MPMF (35, 70 and 140 mg/kg, p.o.) administrated for 7 days on the serum, liver, urinary uric acid levels and liver xanthine oxidase (XO) activity were assessed in mice. RESULTS: Hyperuricemic mice induced by potassium oxonate demonstrated an elevation in serum and liver uric acid levels (11.0 mg/dL and 0.52 mg/g tissue) and a reduction in urinary uric acid levels (49.9 mg/dL). Oral administration of 140 mg/kg MPMF for 7 days reversed the abnormalities in serum, liver and urinary uric acid levels (7.1 mg/dL, 0.37 mg/g tissue and 69.7 mg/dL, respectively). In addition, 70 and 140 mg/kg MPMF (3.1 and 2.9 nmol/min per mg protein) inhibited liver XO activity compared with hyperuricemic mice (3.9 nmol/min per mg protein). DISCUSSION AND CONCLUSION: The results indicated that the beneficial hypouricaemic effect of MPMF may be mediated, at least in part, by inhibiting XO activity in the liver. Our study suggests that P. mume and its extracts may have a considerable potential for development as an anti-gout agent for clinical application.
Assuntos
Hiperuricemia/tratamento farmacológico , Extratos Vegetais/farmacologia , Prunus/química , Xantina Oxidase/antagonistas & inibidores , Administração Oral , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Frutas , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Medicina Tradicional do Leste Asiático , Metanol/química , Camundongos , Ácido Oxônico/toxicidade , Extratos Vegetais/administração & dosagem , Ácido Úrico/sangue , Ácido Úrico/metabolismo , Ácido Úrico/urinaRESUMO
Major depressive disorder is characterized by the deficiencies of monoamine neurotransmitters, neurotrophic factors and persistent neuroinflammation. Microglial activation has been associated with neuroinflammation-related mental diseases, accompanied by NLR family pyrin domain containing 3 (NLRP3) inflammasome. Here, we investigated the effect of NLRP3 inhibition by its small molecular inhibitor MCC950 on inflammatory activity and depressive-like mice induced by chronic unpredictable mild stress (CUMS), followed by the behavioral tests including sucrose preference test and forced swimming test. NLRP3/caspase-1/IL-1ß signaling and microglial morphology in the prefrontal cortex were measured. The results showed that CUMS caused a decrease in sucrose preference and an increase in immobility time, which were reversed by NLRP3 inhibitor MCC950. In addition, NLRP3 inhibition decreased the number of microglia and changed the activated state of microglia to a resting state by morphology 3D reconstruction. Moreover, NLRP3 inhibition inactivated NLRP3/caspase-1/IL-1ß signaling in the prefrontal cortex. The results from immunofluorescence demonstrated that NLRP3 and IL-1ß expression was decreased in microglia in response to MCC950 treatment. Accordingly, proinflammatory cytokines were also decreased by NLRP3 inhibition. In conclusion, this study demonstrates that microglial NLRP3 inhibition prevents stress-induced neuroinflammation in the prefrontal cortex and suggests that microglial NLRP3 could be one of the potential therapeutic targets for depression treatment.
Assuntos
Transtorno Depressivo Maior , Microglia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Camundongos , Caspase 1/metabolismo , Doenças Neuroinflamatórias , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Sulfonamidas/farmacologia , Estresse PsicológicoRESUMO
BACKGROUND: Major depressive disorder is characterized by not only monoamine neurotransmitters deficiencies but also persistent neuroinflammation. The complement system is an attractive therapeutic target for various inflammation-related diseases due to its early activation in inflammatory processes. RESULTS: In the present study, the dynamic alteration of complement C3 and its receptor C3aR during the occurrence of depression and the mechanism of astrocyte-microglia IL-1R/C3/C3aR on synaptic pruning were investigated. The proteomic analysis firstly showed that chronic stress caused an elevation of C3. GO analysis indicated that complement system-mediated synaptic pruning signaling was involved in depression. The dynamic observation indicated that C3/C3aR was activated in the early onset and throughout the course of depression induced by lipopolysaccharide (LPS) and chronic stress. In contrast, C3aR blockade inhibited the hyperactivation of microglial APT2/DHHC7 palmitoylation cycle, which mediated the translocation of STAT3 and the expression of proinflammatory cytokines. Meanwhile, C3aR blockade also attenuated the synaptic pruning and enhanced the synaptogenesis in the prefrontal cortex of mice. Moreover, the blockade of IL-1R/NF-κB signaling pathway reduced the release of C3 from astrocyte. CONCLUSIONS: The current study demonstrates that astrocyte-microglia IL-1R/C3/C3aR activation causes the abnormal synaptic pruning in depression, and suggests that the activation of complement C3/C3aR may be particularly helpful in predicting the onset stage of depression.
RESUMO
Depression is a serious mental illness, mainly characterized as large mood swings and sleep, diet, and cognitive function disorders. NLPR3, one of the inflammasomes that can be activated by a variety of stimuli to promote the maturation and secretion of pro-inflammatory cytokines, has been considered to be involved in the pathophysiology of depression. In this study, the putative role of CY-09, a selective and direct inhibitor of NLRP3, was evaluated in the lipopolysaccharide (LPS)-induced mice. The results of the study indicated that CY-09 significantly decreased the levels of NLRP3 in the hippocampus of LPS-induced mice. In addition, CY-09 increased the sucrose preference and shortened the immobility time in LPS-induced mice, suggesting the antidepressant-like effects of inhibiting NLRP3 inflammasome. Biochemical analysis showed that LPS significantly activated the NLRP3/ASC/cytokine signaling pathway and caused microglial activation, while CY-09 prevented the changes. Moreover, CY-09 increased the brain-derived neurotrophic factor (BDNF) only in microglia but not in the whole hippocampus. Meanwhile, CY-09 did not promote neurogenesis in the hippocampus of LPS mice. In conclusion, the results of the study showed that the antidepressant-like effects of NLRP3 inhibitor CY-09 were mediated by alleviating neuroinflammation in microglia and independent of the neurotrophic function in the hippocampus.
Assuntos
Depressão , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Doenças Neuroinflamatórias , Tiazolidinas , Tionas , Animais , Camundongos , Inflamassomos/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Tionas/farmacologia , Tionas/uso terapêutico , Tiazolidinas/farmacologia , Tiazolidinas/uso terapêutico , Doenças Neuroinflamatórias/complicações , Depressão/tratamento farmacológico , Depressão/etiologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismoRESUMO
Gynostemma pentaphyllum is a herbal medicine widely used in Asian countries, and its saponin extracts have been shown to possess potent anti-inflammatory effects. Gypenoside XVII, an active ingredient isolated from Gynostemma pentaphyllum, has been found to alleviate the inflammation induced by LPS in the BV2 microglia, according to our preliminary study. This study aims to evaluate whether Gypenoside XVII could attenuate depression-like symptoms in vivo and tries to demonstrate the involvement of the complement regulation in its antidepressant-like effect. The results showed that Gypenoside XVII significantly attenuated depression-like behaviors in the forced swimming test, tail suspension test and sucrose preference test. It also alleviated the acute stress-induced hyperactivity of serum corticosterone levels. Additionally, Gypenoside XVII significantly inhibited the activation of microglia and the expression of C3 in mice exposed to chronic unpredictable mild stress (CUMS). Meanwhile, the activation of C3aR/STAT3 signaling and the expression of proinflammatory cytokines was reversed by Gypenoside XVII. Moreover, CUMS induced excessive synaptic pruning by activating microglia, while Gypenoside XVII restored it in the prefrontal cortex. Our data demonstrated that Gypenoside XVII, the active ingredient of Gynostemma pentaphyllum, produced the antidepressant-like effects in mice, which was mediated by the inhibition of complement C3/C3aR/STAT3/cytokine signaling in the prefrontal cortex.
Assuntos
Gynostemma , Saponinas , Animais , Antidepressivos/farmacologia , Citocinas/metabolismo , Camundongos , Plasticidade Neuronal , Extratos Vegetais/metabolismo , Extratos Vegetais/farmacologia , Saponinas/farmacologiaRESUMO
Objective: Berberine, a cationic alkaloid first isolated in 1917, has been approved by the China Drug Administration for decades. Accumulating evidence demonstrated its antidepressant-like activities in vivo. Our previous study has shown that chronic stress leads to the upregulation of miR-34a in the hippocampus of mice. This study aims to evaluate the underlying miR-34a mediated mechanism of berberine in chronic stress-induced depression in mice. Methods: In the present study, mice were administered with berberine during chronic stress. Levels of miR-34a, dendritic density, mitochondrial morphology, and neurogenesis were assessed in the hippocampus. Subsequently, miR-34a agomir was used as a pharmacological intervention for the investigation of berberine. Results: The results showed that berberine reversed the decrease in sucrose preference and the increase in latency to feed without altering total food consumption. Furthermore, chronic stress-induced overexpression of miR-34a decreased synaptotagmin-1 and Bcl-2 levels, thereby impairing spinal morphology, mitochondria and neurogenesis. Berberine inhibited miR-34a expression, in turn restored synaptotagmin-1 and Bcl-2 levels, and thus improved spinal morphology, mitochondria and neurogenesis in the hippocampus. However, the improvements induced by berberine were totally blocked by the pretreatment of miR-34a agomir, which caused the elevation of miR-34a levels in the hippocampus. Conclusion: This finding demonstrated that miR-34a downregulation was involved in the antidepressant-like effects of berberine in mice exposed to chronic stress.
RESUMO
Ethnopharmacological relevance Paeonia lactiflora is a famous Traditional Chinese medicine widely used for immunological regulation. Paeoniflorin, the main component of Paeonia lactiflora, exerts neuroprotective and antidepressant-like effects in rodents. AIM OF THE STUDY: Fibroblast growth factor 2 (FGF-2) is essentially required in the central nervous system as it acts as both a neurotrophic factor and an anti-inflammatory factor participating in the regulation of proliferation, differentiation and apoptosis of neurons in the brain. However, it is unclear whether paeoniflorin could exert antidepressant effects via regulating FGF-2. MATERIALS AND METHODS: In the present study, the effects of paeoniflorin were evaluated in depressive mice induced by the endotoxin lipopolysaccharide (LPS) injection. RESULTS: The results showed that paeoniflorin markedly increased sucrose preference and reduced immobility time in LPS mice, indicating antidepressant effects. Consistent with the results from molecular docking showing paeoniflorin antagonizes TLR4, NF-κB and NLRP3, the biochemical analysis also indicated paeoniflorin inhibited TLR4/NF-κB/NLRP3 signaling, decreased proinflammatory cytokine levels and microglial activation in the hippocampus of LPS induced mice. In addition, the levels of neuronal FGF-2 and the density of dendritic spine were improved by paeoniflorin. More importantly, the FGFR1 inhibitor SU5402 prevented the antidepressant effects of paeoniflorin and blocked the neuroinflammatory and neurogenic regulatory effects of paeoniflorin, indicating that FGF-2/FGFR1 activation was required for the effects of paeoniflorin. CONCLUSION: Taken together, the results demonstrate that paeoniflorin exhibits neuroprotective and antidepressant effects in mice, which may be mediated by activating neuronal FGF-2/FGFR1 signaling via the inhibition of microglial activation in the hippocampus.
Assuntos
Anti-Inflamatórios/uso terapêutico , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Glucosídeos/uso terapêutico , Monoterpenos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Antidepressivos/farmacologia , Proteínas de Ligação ao Cálcio/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Depressão/induzido quimicamente , Depressão/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Glucosídeos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Lipopolissacarídeos , Antígeno 96 de Linfócito/metabolismo , Masculino , Camundongos Endogâmicos ICR , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Simulação de Acoplamento Molecular , Monoterpenos/farmacologia , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Receptor 4 Toll-Like/metabolismoRESUMO
INTRODUCTION: Degraded porphyran is a bioactive polysaccharide extracted from Porphyra haitanensis (P. haitanensis). According to the previous studies, it produced anti-inflammatory activity, but little is known about its effects on depression. METHODS AND RESULTS: As inflammation is one of the critical factors involved in the development of depression, this study aims to elucidate the potential antidepressant-like effects of degraded porphyran. The results show that acute porphyran treatment decreased the immobility time in despair tests. In addition, subchronic porphyran administration reverses depressive-like behaviors in lipopolysaccharide (LPS)-treated mice. Meanwhile, porphyran inhibits NF-κB/NLRP3 signaling, proinflammatory cytokine release, and microglial activation in the hippocampus. Moreover, chronic porphyran treatment activates hippocampal brain derived neurotrophic factor (BDNF)/TrkB/ERK/CREB signaling pathway in chronic unpredictable mild stress (CUMS) in mice. As a result, neurogenesis and spinogenesis are maintained. CONCLUSIONS: The findings of the present study indicate that degraded porphyran intake provides a potential strategy for depression treatment, which is mediated by the inhibition of neuroinflammation and the enhancement of neurogenesis and spinogenesis in the central nervous systems.
Assuntos
Antidepressivos/farmacologia , Porphyra/química , Sefarose/análogos & derivados , Animais , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Simulação de Acoplamento Molecular , Neurogênese/efeitos dos fármacos , Doenças Neuroinflamatórias/tratamento farmacológico , Sefarose/farmacologia , Receptor 4 Toll-Like/fisiologiaRESUMO
MicroRNAs (miRNAs) are noncoding RNAs that participate in the pathophysiology of depression by targeting many functional genes. As shown in our previous study, chronic stress up-regulates miR-34a in the hippocampus. However, little is known about the mechanism by which miR-34a regulates the process of depression or its functions as an antidepressant by regulating its targets. In the present study, the dynamic alterations in miR-34a expression and the mechanism underlying miR-34a regulation were assessed after the administration of the antidepressant fluoxetine to mice exposed to chronic stress. In addition, the effects of miR-34a inhibition on mice were directly evaluated. Both lipopolysaccharide (LPS) and corticosterone treatment caused depression-like symptoms and increased miR-34a expression. Additionally, the expression of miR-34a, which was regulated by tropomyosin receptor kinase B (TrkB)/MEK1/ERK signaling, was consistent with the onset of action of fluoxetine. A luciferase reporter assay identified synaptotagmin-1 and Bcl-2 as the targets of miR-34a. Moreover, a miR-34a antagomir exerted antidepressant-like effects, activated TrkB/MEK1/ERK signaling and improved spine morphology in the hippocampus. In conclusion, hippocampal miR-34a overexpression was a typical feature in depression-like animals, and miR-34a downregulation exerts antidepressant-like effects by restoring the spine morphology through its target synaptotagmin-1.