Clearance of Stress-Induced Premature Senescent Cells Alleviates the Formation of Abdominal Aortic Aneurysms.

Abdominal aortic aneurysm (AAA) is a multifactorial disease characterized by various pathophysiological processes, including chronic inflammation, oxidative stress, and proteolytic activity in the aortic wall. Stress-induced premature senescence (SIPS) has been implicated in regulating these pathophysiological processes, but whether SIPS contributes to AAA formation remains unknown. Here, we detected SIPS in AAA from patients and young mice. The senolytic agent ABT263 prevented AAA development by inhibiting SIPS. Additionally, SIPS promoted the transformation of vascular smooth muscle cells (VSMCs) from a contractile phenotype to a synthetic phenotype, whereas inhibition of SIPS by the senolytic drug ABT263 suppressed VSMC phenotypic switching. RNA sequencing and single-cell RNA sequencing analysis revealed that fibroblast growth factor 9 (FGF9), secreted by stress-induced premature senescent VSMCs, was a key regulator of VSMC phenotypic switching and that FGF9 knockdown abolished this effect. We further showed that the FGF9 level was critical for the activation of PDGFRß/ERK1/2 signaling, facilitating VSMC phenotypic change. Taken together, our findings demonstrated that SIPS is critical for VSMC phenotypic switching through the activation of FGF9/PDGFRß/ERK1/2 signaling, promoting AAA development and progression. Thus, targeting SIPS with the senolytic agent ABT263 may be a valuable therapeutic strategy for the prevention or treatment of AAA.

Extracellular vesicle-derived CircWhsc1 promotes cardiomyocyte proliferation and heart repair by activating TRIM59/STAT3/Cyclin B2 pathway.

INTRODUCTION: Extracellular vesicles (EVs)-mediated cell-to-cell communication is crucial for hypoxia-induced cell proliferation and tissue repair, but its function in endogenous cardiac regeneration is still unknown. OBJECTIVES: Herein, we aimed to determine whether hypoxia-inducible circWhsc1 in endothelial EVs promoted cardiomyocyte (CM) proliferation and cardiac regeneration. METHODS: RNA-sequence data was used to identify EV circRNAs that were involved into endogenous cardiac regeneration. Quantitative polymerase chain reactions were conducted to determine circRNA expression in tissue, cells and EVs. Gain- and loss-of-function assays were performed to explore the function of EV-derived circWhsc1 during cardiac regeneration. Western blotting and RNA pulldown assays were used to investigate its underlying mechanism. RESULTS: We found that circWhsc1 was enriched in neonatal mouse hearts, particularly in cardiac ECs, and was further upregulated both in ECs and EC-derived EVs under hypoxic conditions. When cocultured with hypoxia-preconditioned neonatal ECs or their secreted EVs, both neonatal and adult CMs exhibited an increased proliferation rate and G2/M ratio, which could be attenuated by knockdown of circWhsc1 in ECs. In vivo, EC-restricted overexpression of circWhsc1 and EV-mediated delivery of circWhsc1 induced CM proliferation, alleviated cardiac fibrosis and restored cardiac function following myocardial infarction in adult mice. Mechanistic studies revealed that EV-derived circWhsc1 activated TRIM59 by enhancing its phosphorylation, thereby reinforcing the binding of TRIM59 to STAT3, phosphorylating STAT3 and inducing CM proliferation. CONCLUSION: The current study demonstrated that hypoxia-inducible circWhsc1 in EC-derived EVs induces CM proliferation and heart regeneration. EC-CM communication mediated by EV-derived circWhsc1 might represent a prospective therapeutic target for inducing cardiac repair post-myocardial infarction.

CircRNA Samd4 induces cardiac repair after myocardial infarction by blocking mitochondria-derived ROS output.

Reactive oxygen species (ROS) derived from oxygen-dependent mitochondrial metabolism are the essential drivers of cardiomyocyte (CM) cell-cycle arrest in adulthood. Mitochondria-localized circular RNAs (circRNAs) play important roles in regulating mitochondria-derived ROS production, but their functions in cardiac regeneration are still unknown. Herein, we investigated the functions and underlying mechanism of mitochondria-localized circSamd4 in cardiac regeneration. We found that circSamd4 was selectively expressed in fetal and neonatal CMs. The transcription factor Nrf2 controlled circSamd4 expression by binding to the promoter of circSamd4 host gene. CircSamd4 overexpression reduced while circSamd4 silenced increased mitochondrial oxidative stress and subsequent oxidative DNA damage. Moreover, circSamd4 overexpression induced CM proliferation and prevented CM apoptosis, which reduced the size of the fibrotic area and improved cardiac function after myocardial infarction (MI). Mechanistically, circSamd4 reduced oxidative stress generation and maintained mitochondrial dynamics by inducing the mitochondrial translocation of the Vcp protein, which downregulated Vdac1 expression and prevented the mitochondrial permeability transition pore (mPTP) from opening. Our findings suggest that circSamd4 is a novel therapeutic target for heart failure after MI.

Circular RNA Cdyl promotes abdominal aortic aneurysm formation by inducing M1 macrophage polarization and M1-type inflammation.

Macrophage polarization plays a crucial role in regulating abdominal aortic aneurysm (AAA) formation. Circular RNAs (circRNAs) are important regulators of macrophage polarization during the development of cardiovascular diseases. How-ever, the roles of circRNAs in regulating AAA formation through modulation of macrophage polarization remain unknown. In the present study, we compared circRNA microarray data under two distinct polarizing conditions (M1 and M2 macrophages) and identified an M1-enriched circRNA, circCdyl. Loss- and gain-of-function assay results demonstrated that circCdyl overexpression accelerated angiotensin II (Ang II)- and calcium chloride (CaCl2)-induced AAA formation by promoting M1 polarization and M1-type inflammation, while circCdyl deficiency showed the opposite effects. RNA pulldown, mass spectrometry analysis, and RNA immunoprecipitation (RIP) assays were conducted to elucidate the underlying mechanisms by which circCdyl regulates AAA formation and showed that circCdyl promotes vascular inflammation and M1 polarization by inhibiting interferon regulatory factor 4 (IRF4) entry into the nucleus, significantly inducing AAA formation. In addition, circCdyl was shown to act as a let-7c sponge, promoting C/EBP-δ expression in macrophages to induce M1 polarization. Our results indicate an important role for circCdyl-mediated macrophage polarization in AAA formation and provide a potent therapeutic target for AAA treatment.

LncRNA Snhg1-driven self-reinforcing regulatory network promoted cardiac regeneration and repair after myocardial infarction.

Rationale: Most current cardiac regeneration approaches result in very limited cell division and little new cardiomyocyte (CM) mass. Positive feedback loops are vital for cell division, but their role in CM regeneration remains unclear. We aimed to determine whether the lncRNA small nucleolar RNA host gene 1 Snhg1 (Snhg1) could form a positive feedback loop with c-Myc to induce cardiac regeneration. Methods: Quantitative PCR and in situ hybridization experiments were performed to determine the Snhg1 expression patterns in fetal and myocardial infarction (MI) hearts. Gain- and Loss-of-function assays were conducted to explore the effect of Snhg1 on cardiomyocyte (CM) proliferation and cardiac repair following MI. We further constructed CM-specific Snhg1 knockout mice to confirm the proliferative effect exerted by Snhg1 using CRISPR/Cas9 technology. RNA sequencing and RNA pulldown were performed to explore how Snhg1 mediated cardiac regeneration. Chromatin immunoprecipitation and luciferase reporter assays were used to demonstrate the positive feedback loop between Snhg1 and c-Myc. Results: Snhg1 expression was increased in human and mouse fetal and myocardial infarction (MI) hearts, particularly in CMs. Overexpression of Snhg1 promoted CM proliferation, angiogenesis, and inhibited CM apoptosis after myocardial infarction, which further improved post-MI cardiac function. Antagonism of Snhg1 in early postnatal mice inhibited CM proliferation and impaired cardiac repair after MI. Mechanistically, Snhg1 directly bound to phosphatase and tensin homolog (PTEN) and induced PTEN degradation, activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway to promote CM proliferation. The c-Myc protein, one of downstream targets of PI3K/AKT signaling, functioned as a transcription factor by binding to the promoter regions of Snhg1. Perturbation of the positive feedback between Snhg1 and c-Myc by mutation of the binding sequence significantly affected Snhg1-induced CM proliferation. Conclusions: Snhg1 effectively elicited CM proliferation and improved cardiac function post-MI by forming a positive feedback loop with c-Myc to sustain PI3K/Akt signaling activation, and thus may be a promising cardiac regeneration strategy in treating heart failure post-MI.

Hydrogen sulfide-loaded microbubbles combined with ultrasound mediate thrombolysis and simultaneously mitigate ischemia-reperfusion injury in a rat hindlimb model.

BACKGROUND: Thromboembolism and subsequent ischemia/reperfusion injury (IRI) remain major clinical challenges. OBJECTIVES: To investigate whether hydrogen sulfide (H2 S)-loaded microbubbles (hs-Mbs) combined with ultrasound (US) radiation (hs-Mbs+US) dissolve thrombi and simultaneously alleviate tissue IRI through local H2 S release. METHODS: hs-Mbs were manufactured and US-triggered H2 S release was recorded. White and red thromboembolisms were established ex vivo and in rats left iliac artery. All subjects randomly received control, US, Mbs+US, or hs-Mbs+US treatment for 30 minutes. RESULTS: H2 S was released from hs-Mbs+US both ex vivo and in vivo. Compared with control and US, hs-Mbs+US and Mbs+US showed comparable substantial decreases in thrombotic area, clot mass, and flow velocity increases for both ex vivo macrothrombi. In vivo, hs-Mbs+US and Mbs+US caused similarly increased recanalization rates, blood flow velocities, and hindlimb perfusion for both thrombi compared with the other treatments, with no obvious influence on hemodynamics, respiration, and macrophage vitality. More importantly, hs-Mbs+US substantially alleviated skeletal muscle IRI by reducing reactive oxygen species, cellular apoptosis, and proapoptotic Bax, caspase-3, and caspase-9 and increasing antiapoptotic Bcl-2 compared with other treatments. In vitro, hypoxia/reoxygenation-predisposed skeletal muscle cells and endothelial cells treated with normal saline solution exhibited similar trends, which were largely reversed by an H2 S scavenger or an inhibitor of Akt phosphorylation. CONCLUSION: hs-Mbs+US effectively dissolved both white and red macrothrombi and simultaneously alleviated skeletal muscle IRI through the US-triggered, organ-specific release of H2 S. This integrated therapeutic strategy holds promise for treating thromboembolic diseases and subsequent IRI.

circRNA Hipk3 Induces Cardiac Regeneration after Myocardial Infarction in Mice by Binding to Notch1 and miR-133a.

The synergism between cardiomyogenesis and angiogenesis is essential for cardiac regeneration. Circular RNAs (circRNAs) play pivotal roles in cell growth and angiogenesis, but their functions in cardiac regeneration are not yet known. In this study, we investigated the role and underlying mechanisms of circRNA Hipk3 (circHipk3) in both cardiomyogenesis and angiogenesis during cardiac regeneration. We found that circHipk3 was overexpressed in the fetal or neonatal heart of mice. The transcription factor Gata4 bound to the circHipk3 promoter and increased circHipk3 expression. Cardiomyocyte (CM) proliferation in vitro and in vivo was inhibited by circHipk3 knockdown and increased by circHipk3 overexpression. Moreover, circHipk3 overexpression promoted coronary vessel endothelial cell proliferation, migration, and tube-forming capacity and subsequent angiogenesis. More importantly, circHipk3 overexpression attenuated cardiac dysfunction and decreased fibrotic area after myocardial infarction (MI). Mechanistically, circHipk3 promoted CM proliferation by increasing Notch1 intracellular domain (N1ICD) acetylation, thereby increasing N1ICD stability and preventing its degradation. In addition, circHipk3 acted as a sponge for microRNA (miR)-133a to promote connective tissue growth factor (CTGF) expression, which activated endothelial cells. Our findings suggested that circHipk3 might be a novel therapeutic target for preventing heart failure post-MI.

Intestinal epithelial chemokine (C-C motif) ligand 7 overexpression protects against high fat diet-induced obesity and hepatic steatosis in mice.

BACKGROUND: We previously found that the intestinal epithelial chemokine (C-C motif) ligand 7 (CCL7) plays an important role in the development of toxin-induced acute liver damage. The detailed effects of intestinal epithelial CCL7 on chronic diseases; however, are still unclear. Here, we aimed to investigate the impact of intestinal epithelial CCL7 overexpression on high-fat diet (HFD)-induced obesity and steatohepatitis in mice. METHODS: Intestinal epithelial CCL7 overexpression (CCL7) mice and their wild-type (WT) littermates were fed with normal chow or HFD for 16 weeks to induce obesity and non-alcoholic fatty liver disease. Body weight gain, as well as adipose tissue index were assessed. Liver injury was monitored by histological analysis and real time polymerase chain reaction. Gut microbial composition was analyzed by 16S rRNA gene sequencing. RESULTS: We found that the CCL7 mice on a HFD had markedly decreased weight gain (8.9 vs. 17.0 g, P < 0.05) and a lower adipose tissue index that include mesenteric fat (1.0% vs. 1.76%, P < 0.05), gonadal fat (2.1% vs. 6.1%, P < 0.05), subcutaneous fat (1.0% vs. 2.8%, P < 0.05) compared to WT animals. HFD-induced glucose intolerance and insulin resistance were also significantly improved in CCL7 mice compared to WT. Furthermore, HFD-fed CCL7 mice displayed less hepatic lipid accumulation and lower expression of inflammatory factors than WT mice. 16S rRNA gene sequencing demonstrated that CCL7 overexpression in intestinal epithelial cells improved HFD-induced gut microbial dysbiosis. CONCLUSIONS: Our study revealed that CCL7 overexpression in the intestinal epithelium protects mice against the progression of diet-induced obesity, hepatic steatosis, and enteric dysbiosis.

Correction to: L-Fucose ameliorates high-fat diet-induced obesity and hepatic steatosis in mice.

An amendment to this paper has been published and can be accessed via the original article.

Itaconate prevents abdominal aortic aneurysm formation through inhibiting inflammation via activation of Nrf2.

BACKGROUND: Identifying effective drugs to suppress vascular inflammation is a promising strategy to delay the progression of abdominal aortic aneurysm (AAA). Itaconate has a vital role in regulating inflammatory activation in various inflammatory diseases. However, the role of itaconate in the progression of AAA is unknown. In this study, we explored the inhibitory effect of itaconate on AAA formation and its underlying mechanisms. METHODS: Quantitative PCR, western blotting and immunohistochemistry were used to determine Irg1 and downstream Nrf2 expression in human and mouse AAA samples. Liquid chromatograph-mass spectrometry (LC-MS) analysis was performed to measure the abundance of itaconate. OI treatment and Irg1 knockdown were performed to study the role of OI in AAA formation. Nrf2 intervention in vivo was performed to detect the critical role of Nrf2 in the beneficial effect of OI on AAA. FINDINGS: We found that itaconate suppressed the formation of angiotensin II (Ang II)-induced AAA in apolipoprotein E-deficient (Apoe-/-) mice, while Irg1 deficiency exerted the opposite effect. Mechanistically, itaconate inhibited vascular inflammation by enabling Nrf2 to function as a transcriptional repressor of downstream inflammatory genes via alkylation of Keap1. Moreover, Nrf2 deficiency significantly aggravated inflammatory factor expression and promoted AAA formation. In addition, Keap1 overexpression significantly promoted Ang II-induced AAA formation, which was inhibited by itaconate. INTERPRETATION: Itaconate inhibited AAA formation by suppressing vascular inflammation, and therapeutic approaches to increase itaconate are potentially beneficial for preventing AAA formation. FUNDING: National Natural Science Foundations of China and Guangzhou regenerative medicine and Health Laboratory of Guangdong.

Correction to: CCR2 and CCR5 promote diclofenac-induced hepatotoxicity in mice.

After re-read our published article, the authors found a mistake and would like to make correction: Fig. 4a, b, 0h groups, we mistakenly placed wrong representative staining pictures in the original figure, the correct figures are showed as follow.

Long noncoding RNA GAS5 induces abdominal aortic aneurysm formation by promoting smooth muscle apoptosis.

Objective: Long noncoding RNAs (lncRNAs) may serve as specific targets for the treatment of abdominal aortic aneurysms (AAAs). LncRNA GAS5, functionally associated with smooth muscle cell (SMC) apoptosis and proliferation, is likely involved in AAA formation, but the exact role of GAS5 in AAA is unknown. We thus explored the contribution of GAS5 to SMC-regulated AAA formation and its underlying mechanisms. Methods: Human specimens were used to verify the diverse expression of GAS5 in normal and AAA tissues. The angiotensin II (Ang II)-induced AAA model in ApoE-/- mice and the CaCl2-induced AAA model in wild-type C57BL/6 mice were used. RNA pull-down and luciferase reporter gene assays were performed in human aortic SMCs to detect the interaction between GAS5 and its downstream targets of protein or microRNA (miR). Results: GAS5 expression was significantly upregulated in human AAA specimens and two murine AAA models compared to human normal aortas and murine sham-operated controls. GAS5 overexpression induced SMC apoptosis and repressed its proliferation, thereby promoting AAA formation in two murine AAA models. Y-box-binding protein 1 (YBX1) was identified as a direct target of GAS5 while it also formed a positive feedback loop with GAS5 to regulate the downstream target p21. Furthermore, GAS5 acted as a miR-21 sponge to release phosphatase and tensin homolog from repression, which blocked the activation and phosphorylation of Akt to inhibit proliferation and promote apoptosis in SMCs. Conclusion: The LncRNA GAS5 contributes to SMC survival during AAA formation. Thus, GAS5 might serve as a novel target against AAA.

Magnetic Targeting Improves the Therapeutic Efficacy of Microbubble-Mediated Obstructive Thrombus Sonothrombolysis.

BACKGROUND: Magnetic targeting may help microbubbles (MBs) reach obstructive thrombi and improve the efficacy of MB-mediated sonothrombolysis, but the role of magnetic targeting in MB-mediated sonothrombolysis remains elusive. OBJECTIVES: We investigate the feasibility and efficacy of magnetically targeted MB-mediated sonothrombolysis for the treatment of obstructive thrombi. MATERIALS AND METHODS: Red and white thromboembolic models were established in vitro and in vivo. The models were randomly assigned to the control, ultrasound plus control MB (US + C-MB), ultrasound plus magnetic MB (US + M-MB), or US + M-MB + recombinant tissue-type plasminogen activator (r-tPA) groups and treated for 30 minutes. The recanalization rate, average blood flow velocity, hindlimb perfusion, and skeletal muscle injury marker levels were recorded. RESULTS: The recanalization rate, average blood flow velocity, and hindlimb perfusion in the red and white thromboembolic models were all significantly higher in the US + M-MB and US + M-MB + r-tPA groups than in the control and US + C-MB groups both in vitro and in vivo. Moreover, the levels of the skeletal muscle injury markers were all significantly lower in the US + M-MB and US + M-MB + r-tPA groups than in the other two groups in vivo for both thromboembolic models. However, the thrombolytic effects of red thrombi performed better than those of white thrombi in the US + M-MB + r-tPA group. CONCLUSION: M-MB-mediated sonothrombolysis improves the efficacy of thrombolysis both in vitro and in vivo, and reduces tissue damage in clogging model; thus, this method may serve as a promising approach for treating thrombus-occlusive diseases.

Loss of Super-Enhancer-Regulated circRNA Nfix Induces Cardiac Regeneration After Myocardial Infarction in Adult Mice.

BACKGROUND: circRNAs (circular RNAs) are emerging as powerful regulators of cardiac development and disease, but their roles in cardiac regeneration are still unknown. This study used superenhancers to distinguish key circRNAs in the regulation of cardiac regeneration and explored the mechanisms underlying circRNA functions. METHODS: We used integrated bioinformatics analysis of RNA sequencing data and superenhancer catalogs to identify superenhancer-associated circRNAs. Quantitative polymerase chain reactions and in situ hybridization were performed to determine the circRNA expression patterns in hearts. Gain- and loss-of-function assays were conducted to detect the role of circRNAs in cardiomyocyte proliferation and cardiac repair after myocardial infarction. Chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assays were used to determine the binding of Meis1 (Meis homeobox 1) on circNfix-associated superenhancers. RNA pulldown and luciferase reporter assays were used to study circRNA interactions with proteins and miRNAs (micro RNAs). RESULTS: We identified a circRNA, Nfix circRNA (circNfix), that was regulated by a superenhancer and overexpressed in the adult heart in humans, rats, and mice. The transcription factor Meis1 bound to the superenhancer at the circNfix locus, and increased its expression. In vitro and in vivo, cardiomyocyte proliferation was increased by knockdown of circNfix, whereas it was inhibited by circNfix overexpression. Moreover, circNfix downregulation promoted cardiomyocyte proliferation and angiogenesis and inhibited cardiomyocyte apoptosis after myocardial infarction, attenuating cardiac dysfunction and improving the prognosis. Mechanistically, circNfix reinforced the interaction of Ybx1 (Y-box binding protein 1) with Nedd4l (an E3 ubiquitin ligase), and induced Ybx1 degradation through ubiquitination, repressing cyclin A2 and cyclin B1 expression. In addition, circNfix acted as a sponge for miR-214 to promote Gsk3ß (glycogen synthase kinase 3 ß) expression and repress ß-catenin activity. CONCLUSIONS: Loss of superenhancer-regulated circNfix promotes cardiac regenerative repair and functional recovery after myocardial infarction by suppressing Ybx1 ubiquitin-dependent degradation and increasing miR-214 activity and thus may be a promising strategy for improving the prognosis after MI.

Granisetron protects polymicrobial sepsis-induced acute lung injury in mice.

Sepsis is a serious condition with a high mortality rate worldwide. Granisetron is an anti-nausea drug for patients undergoing chemotherapy. Here we aimed to identify the novel effect of granisetron on sepsis-induced acute lung injury (ALI). Our results showed that mice treated with granisetron displayed less severe lung damage than controls. Granisetron administration reduced pulmonary neutrophil recruitment after CLP. Moreover, the expressions of Cxcl1 and Cxcl2 were diminished in the presence of granisetron in THP-1 macrophages after lipopolysaccharide exposure. Additionally, granisetron could inhibit the activation of p38 MAPK and NLRP3 inflammasome both in vivo and in vitro. Collectively, granisetron protects against sepsis-induced ALI by suppressing macrophage Cxcl1/Cxcl2 expression and neutrophil recruitment in the lung.

CCR2 and CCR5 promote diclofenac-induced hepatotoxicity in mice.

Liver injury, one of the major side effects of diclofenac (DIC), plagues thousands of patients who treated with it. Although involvements of metabolic factors, oxidative stress, and mitochondrial injury have been characterized, the exact immunomolecular mechanism of the hepatotoxicity of DIC still remains ambiguous. In this study, we investigated the role of chemokine receptors CCR2 and CCR5 in this progression. Ccr2, Ccr5, and Tnfr1/2-deficient mice, as well as wild type littermates, were administrated DIC or vehicle for 24 h, receptively. Hepatic expression of CCR2, CCR5, and their ligands were upregulated after DIC treatment. DIC-induced liver injury was augmented in Ccr2+/+ mice than Ccr2-/- mice, a similar phenotype was observed in Ccr5-deficient mice. In addition, antagonists of CCR2 or CCR5 protected liver damage caused by diclofenac. Besides, the number of neutrophils present in the liver was gradually increased from 0 to 12 h after drug administration. However, the recruitment of neutrophils was dramatically lessened after blocking CCR2 or CCR5 signaling. Furthermore, TNF-α level in the liver was decreased in Ccr2-/- mice compared with Ccr2+/+ mice. Intriguingly, in line with this, TNF receptor 1 and 2 double knockout mice showed markedly attenuated hepatotoxicity of DIC. These suggested that CCR2 and CCR5 mediated hepatotoxicity induced by diclofenac, TNF-α was responsible, at least in part, for it, and the pharmacological inhibition of CCR2 or CCR5 might serve as a novel therapeutic approach for DIC-induced hepatotoxicity.

L-Fucose ameliorates high-fat diet-induced obesity and hepatic steatosis in mice.

BACKGROUND: L-Fucose (Fuc), a six-deoxy hexose monosaccharide, is present endogenously in humans and animals and has a wide range of biological functions. In the present study, we aimed to examine the effect of Fuc on obesity and hepatic steatosis in mice fed a high-fat diet (HFD). METHODS: C57BL/6 mice were fed a normal chow (NC) or HFD for 18 weeks to induce obesity and fatty liver. Fuc was administered intragastrically from the 8th week to the end of the experiment (18 weeks). RESULTS: Metagenomic analysis showed that HFD altered the genomic profile of gut microbiota in the mice; specifically, expression of alpha-L-fucosidase, the gene responsible for Fuc generation, was markedly reduced in the HFD group compared with that in the NC group. Fuc treatment decreased body weight gain, fat accumulation, and hepatic triglyceride elevation in HFD-fed mice. In addition, Fuc decreased the levels of endotoxin-producing bacteria of the Desulfovibrionaceae family and restored HFD-induced enteric dysbiosis at both compositional and functional levels. CONCLUSION: Our findings suggest that Fuc might be a novel strategy to treat HFD-induced obesity and fatty liver.

Light exposure influences the diurnal oscillation of gut microbiota in mice.

The gut microbiota exhibit diurnal compositional and functional oscillations that influence the host homeostasis. However, the upstream factors that affect the microbial oscillations remain elusive. Here, we focused on the potential impact of light exposure, the main factor that affects the host circadian oscillation, on the diurnal oscillations of intestinal microflora to explore the upstream factor that governs the fluctuations of the gut microbes. The gut microbiota of the mice that were underwent regular light/dark (LD) cycles exhibited a robust rhythm at both compositional and functional level, in all parts of the intestine. Comparably, constant darkness (Dark-Dark, DD) led to the loss of the rhythmic oscillations in almost all parts of the intestine. Additionally, the abundance of Clostridia in DD conditions was dramatically enhanced in the small intestine. Our data indicated light exposure is the upstream factor that governs the regular diurnal fluctuations of gut microbiota in vivo.