Introduction Cerebral ischemia-reperfusion (CI/R) injury is caused by blood flow recovery after ischemic stroke. Chlorogenic acid (CGA, 5-O-caffeoylquinic acid) is a major polyphenol component of Coffea canephora, Coffea arabica L. and Mate (Ilex paraguariensis A. StHil.). Previous studies have shown that CGA has a significant neuroprotective effect and can improve global CI/R injury. However, the underlying molecular mechanism of CGA in CI/R injury has not been fully revealed. Materials In this study, CI/R rat model was constructed. The rats were randomly divided into nine groups with ten in each group: Control, CGA (500 mg·kg-1), CI/R, CI/R + CGA (20 mg·kg-1), CI/R + CGA (100 mg·kg-1), CI/R + CGA (500 mg·kg-1), ML385 (30 mg·kg-1), CI/R + ML385 (30 mg·kg-1), CI/R + CGA + ML385. Cerebral infarction volume was detected by TTC staining. Brain pathological damage was detected by H&E staining. Apoptosis of cortical cells was detected by TUNEL staining. The expression of related proteins was detected by RT-qPCR and Western blotting. Results Step-down test and Y maze test showed that CGA dose-dependently mitigated CI/R-induced brain damage and enhanced learning and spatial memory. Besides, CGA promoted the expression of BDNF and NGF in a dose-dependent manner and alleviated CI/R-induced nerve injury. Moreover, CGA increased the activity of SOD and the level of GSH, as well as decreased production of ROS and LDH and the accumulation of MDA. Notably, CGA attenuated oxidative stress-induced brain injury and apoptosis and inhibited the expression of apoptosis-related proteins (cleaved caspase 3 and caspase 9). Additionally, CGA reversed CI/R induced inactivation of Nrf2 pathway and promoted Nrf2, NQO-1 and HO-1 expression. Nrf2 pathway inhibitor ML385 destroyed this promotion. Discussion All the data indicated that CGA had a neuroprotective effect on the CI/R rats by regulating oxidative stress-related Nrf2 pathway.

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Protective Effects of Chlorogenic Acid on Cerebral Ischemia/Reperfusion Injury Rats by Regulating Oxidative Stress-Related Nrf2 Pathway

It has been established, worldwide, that non-communicable diseases such as obesity, diabetes, metabolic syndrome, and cardiovascular events account for a high percentage of morbidity and mortality in contemporary societies. Several modifiable risk factors, such as sedentary activities, sleep deprivation, smoking, and unhealthy dietary habits have contributed to this increase. Healthy nutrition in terms of adherence to the Mediterranean diet (MD), rich in fruits, legumes, vegetables, olive oil, herbs, spices, and high fiber intake may contribute to the decrease in this pandemic. The beneficial effects of the MD can be mainly attributed to its numerous components rich in anti-inflammatory and antioxidant properties. Moreover, the MD may further contribute to the improvement of reproductive health, modify the risk for neurodegenerative diseases, and protect against depression and psychosocial maladjustment. There is also evidence highlighting the impact of healthy nutrition in female people on the composition of the gut microbiota and future metabolic and overall health of their offspring. It is therefore important to highlight the beneficial effects of the MD on metabolic, reproductive, and mental health, while shaping the overall health of future generations. The beneficial effects of MD can be further enhanced by increased physical activity in the context of a well-balanced healthy lifestyle.

https://www.mdpi.com/2072-6643/13/6/1951/pdf

Mediterranean Diet as an Antioxidant: The Impact on Metabolic Health and Overall Wellbeing.

Purpose Chlorogenic acid (CGA), a phenolic acid isolated from fruits and vegetables, has been established to have neuroprotective properties in relation to Alzheimer's disease (AD). However, the precise mechanism by which CGA prevents cognitive deficits in AD has not been well studied. This study aimed to explore the potential molecular mechanism of CGA action using an Aβ25-35-induced SH-SY5Y neuron injury and cogxnitive deficits model in APP/PS1 mice. Methods Three-month-old male APP/PS1 double transgenic mice and a human neuroblastoma cell line (SH-SY5Y) were used to assess the effects of CGA on AD in vivo and in vitro, respectively. Cognitive function in mice was measured using a Morris water maze (MWM) test. Hematoxylin and eosin, monodansylcadaverine fluorescence, LysoTracker Red (LTR), and immunofluorescence staining were used to evaluate the morphological changes in vivo and in vitro. The protein expressions of autophagy markers (LC3B-II/LC3B-I, p62/SQSTM, beclin1 and Atg5) and lysosomal-function-related markers (cathepsin D, mTOR, p-mTOR P70S6K, p-p70s6k and TFEB) were analyzed with Western blot analyses. Results CGA treatment significantly improved spatial memory, relieved neuron damage, and inhibited autophagy in APP/PS1 mice (P<0.05). Moreover, CGA notably suppressed autophagosome production and enhanced autophagy flux in SH-SY5Y cells induced by Aβ25-35 (P<0.05). Further analysis showed that CGA markedly promoted lysosomal activity, and this was accompanied by upregulated cathepsin D protein expression, which was induced by the mTOR/TFEB signaling pathway in APP/PS1 mice and Aβ25-35-exposed SH-SY5Y cells (P<0.05). Conclusion CGA treatment restored autophagic flux in the brain and alleviated cognitive impairments in APP/PS1 mice via enhanced activation of the mTOR/TFEB signaling pathway.

/pdf/chlorogenic-acid-alleviates-ab-25-35-induced-autophagy-and-7v3wmsb272.pdf

Chlorogenic Acid Alleviates Aβ 25-35 -Induced Autophagy and Cognitive Impairment via the mTOR/TFEB Signaling Pathway

Crocin-I alleviates the depression-like behaviors probably via modulating "microbiota-gut-brain" axis in mice exposed to chronic restraint stress.

Our previous studies have shown that chlorogenic acid (CGA) could significantly improve acute and chronic liver injury through antioxidant and anti-inflammatory activities. However, its effect on non-alcoholic fatty liver disease (NAFLD) are not entirely clear. This study aims to explore the effect of CGA on NAFLD induced by high-fat diet (HFD) and whether it regulates the gut microbiota and Glucagon-like peptide-1 (GLP-1). NAFLD mice were established by HFD and treated with or without CGA. Serum transaminase, fasting blood glucose (FBG), blood lipids, insulin, GLP-1 and lipopolysaccharide (LPS) were detected. Liver histology was evaluated with Hematoxylin-eosin staining. Toll like receptor 4 (TLR4) signaling pathway was analyzed with western blot and inflammatory cytokines were detected with real-time PCR. The content of gut microbiota were determined with real-time PCR of the bacterial 16S rRNA gene. Expressions of intestine tight junctional protein were examined with immunohistochemistry. CGA could alleviate HFD-induced hepatic steatosis and inflammation, reduce serum transaminase, FBG and blood lipids, increase insulin sensitivity. CGA also could reverse HFD-induced activation of TLR4 signaling pathway and expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in liver. Meanwhile, CGA increased the content of Bifidobacterium and reduced the content of Escherichia coli in feces. Furthermore, CGA could increase the expression of tight junction proteins Occludin and zonula occludens-1 (ZO-1) in intestinal tissue. Moreover, CGA could the level of LPS and increased the level of GLP-1 in portal vein. These results indicated that CGA protected against HFD-induced hepatic steatosis and inflammation probably through its anti-inflammatory effects associated with regulation of gut microbiota and an increase of GLP-1 secretion and thus could be used as a potential drug for prevention and treatment of NAFLD.

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Chlorogenic Acid Improves NAFLD by Regulating gut Microbiota and GLP-1.

Gut microbiota dysbiosis has been implicated as a vital element in the development or exacerbation of mental disorders, such as major depressive disorder (MDD). Based on the current interest in the gut–brain axis, we investigate the effects of chlorogenic acid (CGA) on gut microbiota in a rat model of MDD. Depression was induced by the adrenocorticotropic hormone (ACTH, 100 μg per rat) in male Wistar rats, which were intervened with using saline or CGA (500 mg kg−1). Behavioral changes and serum parameters were assessed and fecal samples were analyzed by 16S rRNA gene sequencing. Our studies demonstrated that CGA pretreatment ameliorated depression-like behavior (SPT, FST, TST, and OFT) and serum biochemical levels (5-HT, DA, IL-6, and TNF-α) in ACTH-induced depression rats. In addition, CGA ameliorated the decrease in fecal microbiota diversity in ACTH-treated rats. In particular, at the genus level, the changes in the relative abundance of some key bacteria such as Desulfovibrionales, Desulfovibrio, Klebsiella, Burkholderiales, and Bifidobacterium were modulated by CGA pretreatment. These results indicated that CGA could modify the gut microbial community structure, which may contribute to its antidepressant effects.

Modulation of gut microbiota by chlorogenic acid pretreatment on rats with adrenocorticotropic hormone induced depression-like behavior.

Adrenocorticotrophic hormone (ACTH)-treatment rat model has been utilized as a widely accepted model of treatment-resistant depression. Metabolomic signatures represent the pathophysiological phenotype of diseases. Recent studies in gut microbiota and metabolomics analysis revealed the dramatic role of microbiome in psychoneurological system diseases, but still, the mechanisms underlying gut microbiome–host interaction remain unclear. Male Wistar rats were s.c. injection of ACTH fragment 1–24 for 14 days to induce treatment-resistant depression. Depression-related behavioral tests, analysis of serum monoamine neurotransmitters and hypothalamic–pituitary–adrenal (HPA) axis-related hormones were determined for assessment of ACTH-induced depression rat model. A gas chromatography-time-of-flight mass spectrometer based urinary metabolomic signatures integrated 16S rRNA sequence analysis based gut microbial profiling was performed, as well as Spearman’s correlation coefficient analysis was used to manifest the covariation between the differential urinary metabolites and gut microbiota of genus level. Chronic injection of ACTH-induced depression-like phenotype (increased immobility time in forced swimming test and tail suspension test) was accompanied by peripheral serotonin down-regulation and HPA axis overactivation (ACTH and corticosterone up-regulation). Urinary metabolomics analysis indicated that pyruvic acid, l-threonine, mannitol, d-gluconic acid, 4-hydroxybenzoic acid, d-arabitol, myo-inositol and ascorbic acid levels were reduced in ACTH-treated rats’ urine, while hippurate level was elevated. In addition, microbial community profiling revealed bacterial enrichment (e.g. Ruminococcus, Klebsiella) and reduction (e.g. Akkermansia, Lactobacillus) in the ACTH-induced depression rat model. Correlation analysis showed that Akkermansia and Lactobacillus were closely relevant to metabolites myo-inositol and hippurate, which were included in host inositol phosphate metabolism, and phenylalanine, tyrosine and tryptophan biosynthesis. Depression rat model induced by ACTH is associated with disturbance of pyruvate metabolism, ascorbate and aldarate metabolism, inositol phosphate metabolism, glycine, serine and threonine metabolism, and glycolysis or gluconeogenesis, as well as changes in microbial community structure. Gut microbiota may participate in the mediation of systemic metabolomic changes in ACTH-induced depression model. Therefore, integrated metabolomic signatures and gut microbial community profiling would provide a basis for further studies on the pathogenesis of depression.

/pdf/metabolomic-signatures-and-microbial-community-profiling-of-co45n8lcml.pdf

Metabolomic signatures and microbial community profiling of depressive rat model induced by adrenocorticotrophic hormone.

Polyphenols, present in a broad range of plants, have been thought to be responsible for many beneficial health effects, such as an antidepressant. Despite that polyphenols can be absorbed in the small intestine directly, most of them have low bioavailability and reach the large intestine without any modifications due to their complex structures. The interaction between microbial communities and polyphenols in the intestine is important for the latter to exert antidepressant effects. Gut microbiota can improve the bioavailability of polyphenols; in turn, polyphenols can maintain the intestinal barrier as well as the community of the gut microbiota in normal status. Furthermore, gut microbita catabolize polyphenols to more active, better-absorbed metabolites, further ameliorating depression through the microbial-gut-brain (MGB) axis. Based on this evidence, the review illustrates the potential role of gut microbiota in the processes of polyphenols or their metabolites acting as antidepressants and further envisions the gut microbiota as therapeutic targets for depression.

Xinyi Gu

Papers

Modulation of gut microbiota by chlorogenic acid pretreatment on rats with adrenocorticotropic hormone induced depression-like behavior.

Metabolomic signatures and microbial community profiling of depressive rat model induced by adrenocorticotrophic hormone.

Gut Microbiota: A Pivotal Hub for Polyphenols as Antidepressants

Hepatoprotection and hepatotoxicity of Chinese herb Rhubarb (Dahuang): How to properly control the "General (Jiang Jun)" in Chinese medical herb.

Energy metabolism in major depressive disorder: Recent advances from omics technologies and imaging.