Crocetin ameliorates chronic restraint stress-induced depression-like behaviors in mice by regulating MEK/ERK pathways and gut microbiota

Lin, Susu; Li, Qiaoqiao; Jiang, Shanshan; Xu, Zijin; Jiang, Yu; Liu, Ling; Jiang, Jingjing; Tong, Yingpeng; Wang, Ping

doi:10.1016/j.jep.2020.113608

Cited by 60 publications

(26 citation statements)

References 79 publications

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“…Moreover, the behavioral effect of stress remained significant in mice treated after stress, whereas the two saffron-treated groups only differed by the time of saffron administration. In addition, the current results fit with compelling clinical and preclinical studies reporting its ability to improve mood and depressive symptoms [26,31,34,35,70,71], including in stressful conditions, although the number of studies is much less in this case [68,69,72]. Taken together, these findings highlight the need of investigating further the behavioral impact of saffron under stress conditions.…”

Section: Discussionsupporting

confidence: 82%

“…As expected, this is associated with HPA axis dysregulation and alterations of neurogenesis, KYN pathway activation, and monoamine neurotransmission. Exposing saffron-treated mice to the ARS procedure allowed testing whether the antidepressant-like properties of saffron previously reported in unstimulated conditions (i.e., unstressed mice) [34,35,38] extend to stress conditions, as recently reported for some of its bioactive compounds [68,69]. Interestingly, several lines of compelling evidence strongly suggest that this is the case.…”

Section: Discussionmentioning

confidence: 84%

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Prevention of Stress-Induced Depressive-like Behavior by Saffron Extract Is Associated with Modulation of Kynurenine Pathway and Monoamine Neurotransmission

et al. 2021

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Depressive disorders are a major public health concern. Despite currently available treatment options, their prevalence steadily increases, and a high rate of therapeutic failure is often reported, together with important antidepressant-related side effects. This highlights the need to improve existing therapeutic strategies, including by using nutritional interventions. In that context, saffron recently received particular attention for its beneficial effects on mood, although the underlying mechanisms are poorly understood. This study investigated in mice the impact of a saffron extract (Safr’Inside™; 6.25 mg/kg, per os) on acute restraint stress (ARS)-induced depressive-like behavior and related neurobiological alterations, by focusing on hypothalamic–pituitary–adrenal axis, inflammation-related metabolic pathways, and monoaminergic systems, all known to be altered by stress and involved in depressive disorder pathophysiology. When given before stress onset, Safr’Inside administration attenuated ARS-induced depressive-like behavior in the forced swim test. Importantly, it concomitantly reversed several stress-induced monoamine dysregulations and modulated the expression of key enzymes of the kynurenine pathway, likely reducing kynurenine-related neurotoxicity. These results show that saffron pretreatment prevents the development of stress-induced depressive symptoms and improves our understanding about the underlying mechanisms, which is a central issue to validate the therapeutic relevance of nutritional interventions with saffron in depressed patients.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 84%

Prevention of Stress-Induced Depressive-like Behavior by Saffron Extract Is Associated with Modulation of Kynurenine Pathway and Monoamine Neurotransmission

et al. 2021

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“…All the mice were fed in the SPF environment at 20–24°C with 12 h light/12 h dark under 35–50% humidity. The CRS model was established according to the previous report [ 21 ]. Briefly, mice were acclimated to 1% sucrose for 2 days before modeling.…”

Section: Methodsmentioning

confidence: 99%

Paeoniflorin ameliorates chronic stress-induced depression-like behavior in mice model by affecting ERK1/2 pathway

Tang

Chen

2021

Bioengineered

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Depression is a mental and emotional disorder that has made an opening great burden to the society. Paeoniflorin showed remarkable antidepressant-like effects in multiple animal models with depressive disorders. However, the molecule of paeoniflorin on depression is less studied. This study aims to explore the effect and the molecular mechanism of paeoniflorin on depression in a chronic restraint stress (CRS) mice model. CRS model of C57BL/6 J mice was set up. Sucrose preference test (SPT), tail suspension test (TST), open field test (OFT) and forced swimming test (FST) were used to assess depression symptoms. Immunofluorescence staining, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting were implemented to detect the expression changes of the proteins involved in extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. Results showed that paeoniflorin treatment decreased the degree of depression in the CRS mice. Further analysis showed that the expression of ERK1/2 proteins was significantly downregulated, while paeoniflorin could elevate the expression of ERK1/2 proteins in CRS mice. Finally, it showed that inhibiting signaling ERK1/2 pathway could aggravate the depressive behavior when treatment with ERK-specific inhibitor U0126, while the condition could be partially relieved when treated with paeoniflorin. In conclusion, the present study demonstrated that paeoniflorin attenuated chronic stress-induced depression-like behavior in mice by affecting the ERK1/2 pathway. These findings provided the basis for the molecular mechanism of paeoniflorin on the effect of depression, which support paeoniflorin might act as an important drug in the treatment of depression.

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“…The extraction and purification of CCT from saffron were performed as reported in our previous research, but with slight modifications ( 32 ). Ultrasonic technology was applied in the extraction of CCT and 65% ethanol was used as the extracting solvent.…”

Section: Methodsmentioning

confidence: 99%

Exploring the Protective Effects and Mechanism of Crocetin From Saffron Against NAFLD by Network Pharmacology and Experimental Validation

Lin

Gong

et al. 2021

Front. Med.

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Background: Non-alcoholic fatty liver disease (NAFLD) is a burgeoning health problem but no drug has been approved for its treatment. Animal experiments and clinical trials have demonstrated the beneficial of saffron on NAFLD. However, the bioactive ingredients and therapeutic targets of saffron on NAFLD are unclear.Purpose: This study aimed to identify the bioactive ingredients of saffron responsible for its effects on NAFLD and explore its therapy targets through network pharmacology combined with experimental tests.Methods: Various network databases were searched to identify bioactive ingredients of saffron and identify NAFLD-related targets. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were conducted to enrich functions and molecular pathways of common targets and the STRING database was used to establish a protein-protein interaction network (PPI). The effect of crocetin (CCT) on NAFLD was evaluated in a mouse model of NAFLD by measuring the biomarkers of lipid, liver and renal function, oxidative stress, and inflammation. Liver histopathology was performed to evaluate liver injury. Nuclear factor erythroid-related factor (Nrf2) and hemeoxygenase-1 (HO-1) were examined to elucidate underlying mechanism for the protective effect of saffron against NAFLD.Results: A total of nine bioactive ingredients of saffron, including CCT, with 206 common targets showed therapeutic effects on NAFLD. Oxidative stress and diabetes related signaling pathways were identified as the critical signaling pathways mediating the therapeutic effects of the active bioactive ingredients on NAFLD. Treatment with CCT significantly reduced the activities of aspartate aminotransferase (AST), alanine transaminase (ALT), and the levels of total cholesterol (TC), triglyceride (TG), malondialdehyde (MDA), blood urea nitrogen (BUN), creatinine (CR), and uric acid (UA). CCT significantly increased the activities of superoxide dismutase (SOD), and catalase (CAT). Histological analysis showed that CCT suppressed high-fat diet (HFD) induced fat accumulation, steatohepatitis, and renal dysfunctions. Results of ELISA assay showed that CCT decreased the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and increased the expression of HO-1 and Nrf2.Conclusion: This study shows that CCT is a potential bioactive ingredient of saffron that treats NAFLD. Its mechanism of action involves suppressing of oxidative stress, mitigating inflammation, and upregulating Nrf2 and HO-1 expression.

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Crocetin ameliorates chronic restraint stress-induced depression-like behaviors in mice by regulating MEK/ERK pathways and gut microbiota

Cited by 60 publications

References 79 publications

Prevention of Stress-Induced Depressive-like Behavior by Saffron Extract Is Associated with Modulation of Kynurenine Pathway and Monoamine Neurotransmission

Prevention of Stress-Induced Depressive-like Behavior by Saffron Extract Is Associated with Modulation of Kynurenine Pathway and Monoamine Neurotransmission

Paeoniflorin ameliorates chronic stress-induced depression-like behavior in mice model by affecting ERK1/2 pathway

Exploring the Protective Effects and Mechanism of Crocetin From Saffron Against NAFLD by Network Pharmacology and Experimental Validation

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