Dietary inulin alleviated constipation induced depression and anxiety-like behaviors: Involvement of gut microbiota and microbial metabolite short-chain fatty acid.

Chronic constipation has been associated with depression-like behavior. Previous study identified the crucial role of gut microbiota in the development of constipation and depression. Dietary inulin (INU) could regulate gut microbiota. Whether INU treatment could ameliorate constipation induced depression was not clear. For this purpose, male CD-1 mice were administered diphenoxylate (20 mg/kg body weight/day) to induce constipation. We found that INU (10 % in standard diet) alleviated the diphenoxylate-induced constipation, manifested as the increase weight and moisture content of feces. Furthermore, the associated depression and anxiety-like behavior disorders were improved by inhibiting neuro-inflammation and preventing synaptic ultrastructure damage under INU treatment. Moreover, INU pretreatment improved the diphenoxylate-induced gut barrier damage by upregulating tight junction protein expression. INU also reshaped gut microbiota in constipation mice by increasing the relative abundance of Bacteroides and Proteobacteria and downregulating the abundance of Muribacalum and Melaminabacteria. The effects of INU on diphenoxylate-induced depression were abolished by gut microbiota depletion via antibiotic treatment. In addition, INU increased the concentration of short chain fatty acids (SCFAs) in feces contents. Meanwhile, supplementation of SCFAs could also partly improve diphenoxylate-induced depression. In conclusion, INU intake was a potential nutritional intervention strategy to prevent constipation induced depression via microbiota-gut-SCFAs axis.

The Potential Effects of Isoleucine Restricted Diet on Cognitive Impairment in High-Fat-Induced Obese Mice via Gut Microbiota-Brain Axis.

SCOPE: Obesity induced by high-fat diet (HFD) can cause lipid metabolism disorders and cognitive impairment. Isoleucine restriction can effectively alleviate lipid metabolism disorders caused by HFD but the underlying mechanisms on cognition are unknown. METHODS AND RESULTS: Thirty 3-month-old C57BL/6J mice are divided equally into the following groups: the control group, HFD group, and HFD Low Ile group (67% reduction in isoleucine in high fat feeds). Feeding for 11 weeks with behavioral testing, which shows that isoleucine restriction attenuates HFD-induced cognitive dysfunction. As observed by staining, isoleucine restriction inhibits HFD-induced neuronal damage and microglia activation. Furthermore, isoleucine restriction significantly increases the relative abundance of gut microbiota, decreases the proportion of Proteobacteria, and reduces the levels of lipopolysaccharide (LPS) in serum and brain. Isoleucine restriction reduces protein expression of TLR4/MyD88/NF-κB signaling pathway and inhibits upregulation of proinflammatory cytokine genes and protein expression in mice brain. In addition, isoleucine restriction significantly improves insulin resistance in the brain as well as synaptic plasticity impairment. CONCLUSION: Isoleucine restriction may be a potential intervention to reduce HFD-induced cognitive impairment by altering gut microbiota, reducing neuroinflammation, insulin resistance, and improving synaptic plasticity in mice brain.

Chronotoxicity of Acrylamide in Mice Fed a High-Fat Diet: The Involvement of Liver CYP2E1 Upregulation and Gut Leakage.

Acrylamide (ACR) is produced under high-temperature cooking of carbohydrate-rich foods via the Maillard reaction. It has been reported that ACR has hepatic toxicity and can induce liver circadian disorder. A high fat diet (HFD) could dysregulate liver detoxification. The current study showed that administration of ACR (100 mg/kg) reduced the survival rate in HFD-fed mice, which was more pronounced when treated during the night phase than during the day phase. Furthermore, ACR (25 mg/kg) treatment could cause chronotoxicity in mice fed a high-fat diet, manifested as more severe mitochondrial damage of liver during the night phase than during the day phase. Interestingly, HFD induced a higher CYP2E1 expressions for those treated during the night phase, leading to more severe DNA damage. Meanwhile, the expression of gut tight junction proteins also significantly decreases at night phase, leading to the leakage of LPSs and exacerbating the inflammatory response at night phase. These results indicated that a HFD could induce the chronotoxicity of ACR in mice liver, which may be associated with increases in CYP2E1 expression in the liver and gut leak during the night phase.

Lycopene attenuates oxidative stress-induced hepatic dysfunction of insulin signal transduction: involvement of FGF21 and mitochondria.

Lycopene (LYC) has been regarded as a nutraceutical that has powerful antioxidant and hepatoprotective bioactivities. In the present study, we aimed to investigate the beneficial effects of LYC on hepatic insulin signal transduction under oxidative stress conditions and the possible involvement of FGF21 and mitochondria pathways. Two-month-old CD-1 mice were treated by intraperitoneal injection of D-galactose (D-gal) 150 mg/kg/day for 8 weeks and received 0.03% LYC (w/w, mixed into diet). The results showed that LYC increased the expression of FGF21, alleviated mitochondrial dysfunction and improved hepatic insulin signal transduction in D-gal-treated mice. Furthermore, knockdown of FGF21 by small interfering RNA notably suppressed mitochondrial function and blunted LYC-stimulated insulin signal transduction in H2O2-treated HepG2 cells. Moreover, suppressed mitochondrial function via oligomycin also inhibited insulin signal transduction, indicating that LYC supplementation ameliorated oxidative stress-induced hepatic dysfunction of insulin signal transduction by up-regulating FGF21 and enhancing mitochondrial function.

Lycopene attenuates D-galactose-induced insulin signaling impairment by enhancing mitochondrial function and suppressing the oxidative stress/inflammatory response in mouse kidneys and livers.

Lycopene (LYC) possesses bioactivity to improve the pathogenesis of several chronic diseases via antioxidant-associated mechanisms. The purpose of this study was to investigate whether LYC could attenuate D-galactose (D-gal)-induced mitochondrial dysfunction and insulin signaling impairment in mouse kidneys and livers. Two-month-old CD-1 mice were treated by intraperitoneal injection of 150 mg kg-1 day-1D-gal for 8 weeks and received 0.03% LYC (w/w, mixed into diet). The results showed that LYC ameliorated oxidative stress triggered by D-gal by enhancing the Nrf2 antioxidant defense pathway and increasing the expression of the antioxidant response genes HO-1 and NQO1 in mouse kidneys and livers. LYC inhibited the MAPK and NFκB pathways and attenuated renal and hepatic inflammatory responses. Moreover, LYC upregulated the expression of genes related to mitochondrial biosynthesis and oxidative phosphorylation and improved insulin signal transduction through the IRS-1/AKT/GSK3ß pathway in mouse kidneys and livers.

Enhanced alleviation of insulin resistance via the IRS-1/Akt/FOXO1 pathway by combining quercetin and EGCG and involving miR-27a-3p and miR-96-5p.

Quercetin and EGCG exhibit anti-diabetic and anti-obesity activities, however, their interactive effects in anti-diabetic/anti-obesity actions and underlying mechanisms remain unclear. This study aimed to fill these knowledge gaps. Quercetin, EGCG or their combination attenuated insulin resistance and decreased hepatic gluconeogenesis in high-fat-high-fructose diet (HFFD)-fed C57BL/6 mice and in palmitic acid (PA)-treated HepG2 cells. In mice, supplementation with quercetin (0.05%w/w), EGCG (0.05%w/w) and their combination (quercetin 0.05%+EGCG 0.05%w/w) reduced weight gain and fasting blood glucose and improved serum biochemical parameters. Compare with quercetin/EGCG alone, the quercetin-EGCG combination reduced gluconeogenesis to a greater extent via IRS-1/Akt/FOXO1-mediated down-regulation of downstream PEPCK and G-6-pase. In HepG2 cells, the quercetin (5 µM)-EGCG (5 µM) co-treatment exerted greater suppression on PA-induced changes in glucose and glycogen contents and hexokinase and G-6-pase activities than quercetin/EGCG alone (each 10 µM). The quercetin-EGCG co-treatment reduced glucose production through targeting FOXO1 and inhibiting the transcription of gluconeogenic enzymes. MiR-27a-3p and miR-96-5p regulated directly FOXO1 expression and function, and co-inhibition of miR-27a-3p and miR-96-5p weakened greatly the protective effect of quercetin-EGCG combination. This is the first report on the contributions of miR-27a-3p and miR-96-5p to the synergistic and protective effect of the quercetin-EGCG co-treatment against PA-induced insulin resistance through inhibiting FOXO1 expression.

Apple phenolic extracts ameliorate lead-induced cognitive impairment and depression- and anxiety-like behavior in mice by abating oxidative stress, inflammation and apoptosis via the miR-22-3p/SIRT1 axis.

Lead can lead to neurotoxicity and cognitive impairment. In this study, for the first time, the protective effects and working mechanisms of apple phenolic extracts (APEs) against lead acetate (Pb(Ac)2)-induced cognitive impairment and depression- and anxiety-like behavior were examined in vivo. Forty male mice were administered daily (via gastric gavage; 8 weeks) with 0.9% normal saline (control), Pb(Ac)2 (20 ppm), APE (200 ppm) or Pb(Ac)2 (20 ppm) + APE (200 ppm). The APE contained five major phenolic compounds: chlorogenic acid, proanthocyanidin B2, epicatechin, phloridzin and phloretin. Behavioral tests, histopathological examinations and biochemical analyses revealed that Pb(Ac)2-treated mice exhibited cognitive and behavioral deficits (i.e. a reduced percentage of spontaneous alternation, prolonged duration of immobility and decreased open field test scores compared with the control. Pb(Ac)2 exposure significantly increased cellular oxidative damage and the levels of pro-inflammatory cytokines (interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α (TNF-α), ionized calcium binding adaptor molecule 1 (Iba1) and pro-apoptotic proteins (caspase 3, caspase 9 and Bax), while downregulating the expression of Bcl-2 in the brain. APE administration alleviated these Pb(Ac)2-induced changes through regulating oxidative stress, neuroinflammation and apoptosis via the miR-22-3p/Sirtuin 1 (SIRT1) signaling pathway. Taken together, the APE has the potential to treat lead-induced neurotoxicity and neurodegenerative disorders via antioxidant, anti-inflammatory and anti-apoptotic actions.

Secoisolariciresinol diglucoside mitigates benzo[a]pyrene-induced liver and kidney toxicity in mice via miR-101a/MKP-1-mediated p38 and ERK pathway.

Benzo[a]pyrene (BaP) can cause hepatorenal toxicity. Secoisolariciresinol diglucoside (SDG), a polyphenolic compound present in flaxseed, has shown a variety of biological activities including antioxidant, anti-inflammatory, anti-apoptotic effects. This study aimed to investigate the protective effects and working mechanisms of SDG against BaP-induced hepatorenal injury. Forty male mice were administrated daily (via gastric gavage; 4 weeks) with 0.9% saline (control), BaP (75 mg/kg body weight (b.w.)), SDG (100 mg/kg b.w.), SDG (100 mg/kg b.w.)+BaP (75 mg/kg b.w.). Results showed that the mice treated with SDG + BaP had significantly (P < 0.05) higher body weight, lower organ-to-body weight ratio, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) activities, and less levels of serum creatinine (CRE) and blood urea nitrogen (BUN) than those treated with BaP alone. SDG administration alleviated BaP-induced oxidative damages, inflammation and apoptosis. Furthermore, it significantly (P < 0.05) downregulated phosphor-p38 (p-p38) and phosphor-extracellular regulated protein kinases (p-ERK) levels, upregulated mitogen-activated protein kinase phosphatase-1 (MKP-1) level, and suppressed miR-101a expression compared with BaP alone group. Taken together, these results showed for the first time that SDG has protective effects against BaP-induced liver and kidney toxicity in mice through regulating oxidative stress, inflammation and apoptosis via miR-101a/MKP-1-mediated p38 and ERK pathway.

Synthetic coded aperture snapshot spectral imaging based on coprime sub-aperture sampling.

The imaging of a large area scene is difficult to achieve for a single camera. Alternatively, a virtual large aperture can be synthesized by sub-aperture cooperation. We propose a solution through the combination of a coded aperture snapshot spectral imager and coprime array. This method reduces the amount of data by using a smaller sub-aperture for sampling. The position of the sub-aperture is determined according to the element distribution of the coprime array, so that the data obtained from each sampling are about the target object and its adjacent area, which can ensure high reconstruction accuracy. The feasibility of coprime sub-aperture sampling is verified by numerical simulation.

MiR-34a/Sirt1/p53 signaling pathway contributes to cadmium-induced nephrotoxicity: A preclinical study in mice.

Cadmium (Cd), as an environmental pollutant, can lead to nephrotoxicity. However, its nephrotoxicological mechanisms have not been fully elucidated. In this study, Cd (1.5 mg/kg body weight, gavaged for 4 weeks) was found to induce the renal damage in mice, based on indicators including Cd concentration, kidney index, serum creatinine and blood urea nitrogen levels, pro-inflammatory cytokines and their mRNA expressions, levels of Bcl-2, Bax and caspase9, and histopathological changes of the kidneys. Furthermore, Cd-caused detrimental changes through inducing inflammation and apoptosis via the miR-34a/Sirt1/p53 axis. This is the first report on the role of miR-34a/Sirt1/p53 axis in regulating Cd-caused apoptosis and nephrotoxicity in mice. The findings obtained in this study provide new insights into miRNA-based regulation of heavy metal induced-nephrotoxicity.

Caffeic acid phenethyl ester reversed cadmium-induced cell death in hippocampus and cortex and subsequent cognitive disorders in mice: Involvements of AMPK/SIRT1 pathway and amyloid-tau-neuroinflammation axis.

Exposure to nonbiodegradable cadmium (Cd) causes many health problems including the damage to the nervous system. This study aimed to increase knowledge about its neurotoxic effects and the neuroprotective potential of caffeic acid phenethyl ester (CAPE, a polyphenol abundant in honeybee propolis). In mice, CAPE (10 µmol/kg/day body weight) attenuated significantly learning and memory deficits induced by CdCl2 (1.5 mg/kg/day body weight). For the CdCl2-treated mice, CAPE increased crossing number in open field test, decreased the alternation in Y-maze test, and increased the latency time and error number in step down test. CAPE also inhibited CdCl2-initiated Aß accumulation and activation of pro-inflammatory factors and microglia in the brains. Therefore, CAPE could be a food-derived neuroprotective agent against Cd-induced neurotoxicity and neurodegenerative disorders, through attenuating neuronal apoptosis and neuroinflammation via the AMPK/SIRT1 pathway and amyloid-tau-neuroinflammation axis.

Caffeic acid phenethyl ester against cadmium induced toxicity mediated by CircRNA modulates autophagy in HepG2 cells.

Cadmium pollution and poisoning are serious environmental and pharmacological concerns, and effective drugs can alleviate or offset cadmium-induced toxicity are badly needed. In this study, Caffeic acid phenethyl ester (CAPE), a major active component of propolis, showed protective effect against CdCl2-induced toxicology by suppressing autophagy in HepG2 cells. CircRNAs are increasingly perceived as vital regulators in the process of autophagy. However, it remain unclear whether circRNAs are involved in CAPE's protection against CdCl2-induced autophagy. Under this context, the roles of CircRNA (hsa_circ_0040768) in CAPE's protection against CdCl2-induced damage were investigated by PCR and Western blot. Results showed that CAPE significantly (P < 0.05) increased cell viability via inhibiting CdCl2-induced autophagy, and this process was regulated by hsa_circ_0040768/MAP1LC3B axis. Overexpressing hsa_circ_0040768 led to reduced cell viability and increased autophagy in CAPE-treated HepG2 cells exposed to CdCl2. In contrast, silencing hsa_circ_0040768 showed similar protective effect to CAPE. These results show for the first time the involvement of the hsa_circ_0040768/MAP1LC3B axis in the CAPE's protection against CdCl2-induced autophagy, and provide novel insights into the pathogenesis and potential prevention/treatment of cadmium-associated diseases.

Lycopene Alleviates DSS-Induced Colitis and Behavioral Disorders via Mediating Microbes-Gut-Brain Axis Balance.

Gut microbes play significant roles in colitis development. The current study was aimed to uncover the preventive effects of lycopene (LYC), a functional carotenoid component, on colitis and the accompanied behavior disorders. The current study demonstrated that LYC treatment (50 mg/kg body weight/day) for 40 days prevented the dextran sulfate sodium (DSS)-induced gut barrier damages and inflammatory responses in male mice. LYC improved DSS-induced depression and anxiety-like behavioral disorders by suppressing neuroinflammation and prevented synaptic ultrastructure damages by upregulating the expressions of neurotrophic factor and postsynaptic-density protein. Moreover, LYC reshaped the gut microbiome in colitis mice by decreasing the relative abundance of proteobacteria and increasing the relative abundance of Bifidobacterium and Lactobacillus. LYC also elevated the generation of short-chain fatty acids and inhibited the permeability of lipopolysaccharide in colitis mice. In conclusion, LYC ameliorate DSS-induced colitis and behavioral disorders via mediating microbes-gut-brain axis balance.

Gut microbiota mediates intermittent-fasting alleviation of diabetes-induced cognitive impairment.

Cognitive decline is one of the complications of type 2 diabetes (T2D). Intermittent fasting (IF) is a promising dietary intervention for alleviating T2D symptoms, but its protective effect on diabetes-driven cognitive dysfunction remains elusive. Here, we find that a 28-day IF regimen for diabetic mice improves behavioral impairment via a microbiota-metabolites-brain axis: IF enhances mitochondrial biogenesis and energy metabolism gene expression in hippocampus, re-structures the gut microbiota, and improves microbial metabolites that are related to cognitive function. Moreover, strong connections are observed between IF affected genes, microbiota and metabolites, as assessed by integrative modelling. Removing gut microbiota with antibiotics partly abolishes the neuroprotective effects of IF. Administration of 3-indolepropionic acid, serotonin, short chain fatty acids or tauroursodeoxycholic acid shows a similar effect to IF in terms of improving cognitive function. Together, our study purports the microbiota-metabolites-brain axis as a mechanism that can enable therapeutic strategies against metabolism-implicated cognitive pathophysiologies.

Resveratrol Prevents Acrylamide-Induced Mitochondrial Dysfunction and Inflammatory Responses via Targeting Circadian Regulator Bmal1 and Cry1 in Hepatocytes.

Acrylamide, mainly formed in Maillard browning reaction during food processing, causes defects in liver circadian clock and mitochondrial function by inducing oxidative stress. Resveratrol is a polyphenol that has powerful antioxidant and anti-inflammatory activity. However, the preventive effects of resveratrol on acrylamide-triggered oxidative damage and circadian rhythm disorders are unclear at the current stage. The present research revealed that resveratrol pretreatment prevented acrylamide-induced cell death, mitochondrial dysfunction, and inflammatory responses in HepG2 liver cells. Acrylamide significantly triggered disorders of circadian genes transcription and protein expressions including Bmal1 and Cry 1 in primary hepatocytes, which were prevented by resveratrol pretreatment. Moreover, we found that the beneficial effects of resveratrol on stimulating Nrf2/NQO-1 pathway and mitochondrial respiration complex expressions in acrylamide-treated cells were Bmal1-dependent. Similarly, the inhibitory effects of resveratrol on inflammation signaling NF-κB were Cry1-dependent. In conclusion, these results demonstrated resveratrol could be a promising compound in suppressing acrylamide-induced hepatotoxicity and balancing the circadian clock.

Role of Food Phytochemicals in the Modulation of Circadian Clocks.

The circadian clock is an intrinsic mechanism of biological adaptation to the cyclical changes of the environment. The circadian rhythm disorders affect the life activities of organisms. A variety of phytochemicals (e.g., polyphenols, flavonoids, alkaloids, and melatonin) reportedly can regulate the expression and rhythm of circadian clock genes and stabilize the internal environment. This perspective focuses on the relationship of circadian clock genes with oxidative stress, inflammatory response, and metabolic disorders and emphasizes the regulation of phytochemicals on the circadian clock. Potential mechanisms and applications of supplemental phytochemicals to improve metabolic disorders and circadian rhythm disorders are also discussed.

Lycopene supplementation attenuates western diet-induced body weight gain through increasing the expressions of thermogenic/mitochondrial functional genes and improving insulin resistance in the adipose tissue of obese mice.

This passive overconsumption of western diet has precipitated a steep rise in obesity and its comorbidities, and obesity has become one of the main threats to health worldwide. Thus, deciphering the molecular mechanisms leading to obesity is therefore of utmost importance to guide the search for novel therapeutic and preventive strategies. Lycopene (LYC), a major carotenoid present in tomato, has been regarded as a nutraceutical that has powerful anti-oxidant and anti-obesity bioactivities. Even though substantial progress has been made in deciphering the mechanism of how LYC affects obesity in recent years, whether thermogenic genes, mitochondrial function and insulin resistance are involved in the anti-obesity effect of LYC is yet to be elucidated. In the current study, we demonstrated that LYC remarkably suppressed HFFD-elevated mice body weight gain. LYC blocked lipid accumulation in adipose tissue by decreasing the expressions of lipogenesis genes and increasing the expressions of lipidolysis related genes, including thermogenic and mitochondrial functional genes. Moreover, LYC improved HFFD-induced insulin resistance in WATs via inhibiting the inflammation responses in WATs, decreasing circulating proinflammatory cytokines, suppressing gut leak and intestinal inflammation. Our study indicating that the supplementation of LYC might be a nutritional preventive strategy to combat obesity.

Anti-Fatigue Activity of Aqueous Extracts of Sonchus arvensis L. in Exercise Trained Mice.

Sonchus arvensis L. is a nutritious vegetable and herbal medicine that is consumed worldwide. The aim of this study was to evaluate the anti-fatigue effects and underlying effects of aqueous extract of Sonchus arvensis L. (SA). Male C57BL/6 mice from four groups designated vehicle, exercise, exercise with low dose (250 mg/kg) or high dose of SA (500 mg/kg), were trained by swimming exercise and orally administrated with SA every other day for 28 days. The anti-fatigue activity was determined by exhaustive swimming test, as well as the muscle structure, levels of blood hemoglobin, and metabolites including lactate and urea nitrogen. SA alleviated mice fatigue behaviors by eliminating metabolites, while improving muscle structure and hemoglobin levels. Moreover, SA enhanced glycogen synthesis of liver but not muscle via increasing GCK and PEPCK gene expressions. Importantly, SA improved antioxidant enzymes expression and activities in both liver and muscle, which was possibly related to its primary components polysaccharides and the antioxidant components including chlorogenic acid, luteolin, and chicoric acid. Taken together, the anti-fatigue effects of SA could be partly explained by its antioxidant activity and mediating effects on glycogen synthesis and metabolites elimination. Therefore, SA could be a potential nutraceutical for improving exercise performance and alleviating physical fatigue.

Lycopene ameliorates systemic inflammation-induced synaptic dysfunction via improving insulin resistance and mitochondrial dysfunction in the liver-brain axis.

Systemic inflammation is an important determinant of synaptic dysfunction, but the underlying molecular mechanisms remain elusive. Lycopene (LYC), a major carotenoid present in tomato, is regarded as a nutraceutical that has significant antioxidant and anti-obesity bioactivities. In the current study, we randomly divided 3-month-old C57BL/6J mice into 3 groups: the control, LPS and LPS + LYC groups (LYC, 0.03% w/w, mixed with normal chow) for 5 weeks, and then mice were intraperitoneally injected with LPS (0.25 mg kg-1) for 9 days. Our results demonstrated that LYC supplementation effectively attenuated LPS-elicited neuronal damage and synaptic dysfunction through increasing the expressions of neurotrophic factors and the synaptic proteins SNAP-25 and PSD-95. LYC ameliorated LPS-induced insulin resistance and mitochondrial dysfunction in the mouse brain and liver. LYC alleviated the neuroinflammation and hepatic inflammation. Furthermore, LYC decreased the circulating levels of insulin and proinflammatory mediators LPS, TNF-α, IL-1ß and IL-6. In conclusion, these results indicated that the supplementation of LYC might be a nutritional preventive strategy in systemic inflammation-induced synaptic dysfunction.

Acrylamide aggravates cognitive deficits at night period via the gut-brain axis by reprogramming the brain circadian clock.

Imbalance of the circadian rhythm leads to pathologies including obesity, neurodegenerative diseases, and even cancer. Acrylamide (ACR) is a chronic neurotoxin which can lead to carcinogenicity, reproduction toxicity, teratogenicity, and neurotoxicity. The aim of this study was to reveal a potential mechanism of ACR-triggered neurotoxicity related to circadian clock in mice brain. For this purpose, 80 3-month-old C57/BL6J mice were randomly divided into two groups (n = 40/group): the control group was fed a standard diet (AIN-93M) with pure water, and the ACR group was fed a standard diet (AIN-93M) with 0.003% ACR in drinking water for 16 weeks. In the current study, ACR treatment induced circadian disorder and suppressed the circadian-related protein expressions in mice brain. Furthermore, ACR diet aggravated the cognitive dysfunction and spatial memory loss at night phase. Consistent with these results, ACR caused cognitive defects in the night period by down-regulating the ERK/cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling pathways and the expression of synaptosomal-related protein SNAP-25 and PSD-95. Moreover, excessive autophagy phenomenon also occurred in mice hippocampus in the night phase under ACR administration. Of note, ACR stimulated the brain inflammatory reaction via affecting the intestinal barrier integrity and increasing the levels of circulating LPS, IL-1ß and TNF-α. Above all, the present research discovered that ACR is a potential circadian-depressing compound that influences cognitive function in mice brain.