DPP-4 inhibition by linagliptin ameliorates age-related mild cognitive impairment by regulating microglia polarization in mice.

Extensive preclinical evidence demonstrates a causative link between insulin signaling dysfunction and the pathogenesis of Alzheimer's disease (AD), and diabetic drugs may represent a promising approach to fighting AD. However, it remains to be determined which antidiabetic drugs are more effective in preventing cognitive impairment. Thus, the present study investigated the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin on cognitive impairment in middle-aged mice by comparing it with the effect of metformin. We found that DPP-4 activity increased in the hippocampus of middle-aged mice, and DPP-4 was mainly expressed by microglia rather than astrocytes and oligodendrocytes. DPP-4 directly regulated M1/M2 microglia polarization following LPS or IL-4 stimulation, while DPP-4 inhibitor, linagliptin, suppressed M1-polarized activation and induced M2-polarized activation. Both linagliptin and metformin enhanced cognitive ability, increased hippocampal synaptic plasticity and neurogenesis, and decreased age-related oxidative stress and inflammation by regulating microglia polarization in the hippocampus of middle-aged mice. The combination of linagliptin and metformin showed a maximum protective effect compared to the individual drugs alone. Loss of macrophage inflammatory protein-1α (MIP-1α), a DPP-4 substrate, abrogated the cognitive protection and anti-inflammation effects of linagliptin. Therefore, the current investigation exhibits a potential utility for DPP-4 inhibition in attenuating microglia-mediated inflammation and preventing mild cognitive impairment (MCI) in middle-aged mice, and the effect was partly mediated by MIP-1α.

CX3CL1/CX3CR1 interaction protects against lipotoxicity-induced nonalcoholic steatohepatitis by regulating macrophage migration and M1/M2 status.

BACKGROUND AND OBJECTIVES: Chemokine (C-X3-C motif) ligand 1 (CX3CL1) and its receptor CX3CR1 regulate the migration and activation of immune cells and are involved in the pathogenesis of nonalcoholic steatohepatitis (NASH), but the mechanism remains elusive. Here, the roles of CX3CL1/CX3CR1 in the macrophage migration and polarization in the livers of NASH mice were investigated. METHODS AND RESULTS: The expression of Cx3cl1 and Cx3cr1 was markedly upregulated in the livers of lipotoxicity-induced NASH mice. CX3CR1 was predominantly expressed by F4/80+ macrophages and to a lesser degree by hepatic stellate cells or endothelial cells in the livers of NASH mice. Flow cytometry analysis revealed that, compared with chow-fed mice, NASH mice exhibited a significant increase in CX3CR1+ expression by liver macrophages (LMs), particularly M1 LMs. CX3CR1 deficiency caused a significant increase in inflammatory monocyte/macrophage infiltration and a shift toward M1 dominant macrophages in the liver, thereby exacerbating the progression of NASH. Moreover, transplantation of Cx3cr1-/- bone marrow was sufficient to cause glucose intolerance, inflammation, and fibrosis in the liver. In addition, deletion of CCL2 in Cx3cr1-/- mice alleviated NASH progression by decreasing macrophage infiltration and inducing a shift toward M2 dominant LMs. Importantly, overexpression of CX3CL1 in vivo protected against hepatic fibrosis in NASH. CONCLUSION: Pharmacological therapy targeting liver CX3CL1/CX3CR1 signaling might be a candidate for the treatment of NASH.

Vitrectomy with residual internal limiting membrane covering and autologous blood for a secondary macular hole: A case report.

BACKGROUND: Myopic foveoschisis (MF) is a common complication of pathological myopia. A macular hole (MH) usually results from the natural progression of MF and is a common complication of vitrectomy. Vitrectomy combined with residual internal limiting membrane (ILM) covering and autologous blood was effective for closing a secondary MH. CASE SUMMARY: A 52-year-old woman presented to our clinic with a complaint of blurred vision in the right eye for 7 years. Her best corrected visual acuity (BCVA) was 20/100, axial length was 25.79 mm and standard equivalent refractive error was -10.5 dioptres. Preoperative optical coherence tomography revealed foveoschisis in the right eye. Vitrectomy with fovea-sparing ILM peeling was performed. An MH developed and gradually expanded 5 mo after the initial vitrectomy. Vitrectomy with residual ILM covering and autologous blood was performed. The MH closed 3 wk after the second vitrectomy. CONCLUSION: Fovea-sparing ILM peeling can provide residual ILM for the treatment of MH secondary to vitrectomy for MF. Vitrectomy combined with residual ILM covering and autologous blood is effective for closing secondary MH and improving BCVA.

Bifidobacterium animalis subsp. lactis lkm512 Attenuates Obesity-Associated Inflammation and Insulin Resistance Through the Modification of Gut Microbiota in High-Fat Diet-Induced Obese Mice.

SCOPE: The impacts of longevity-promoting probiotic Bifidobacterium animalis subsp. lactis LKM512 (LKM512) on metabolic disease remain unclear. Here, the authors aim to explore the potential of LKM512 on the host physiological function and gut microbiota in high-fat diet-induced obese mice. METHODS AND RESULTS: LKM512 are orally administrated for 12 weeks, and the effects of LKM 512 on systemic inflammation and insulin resistance, as well as gut microbiota, are investigated in high-fat (HF) diet-induced obese mice. LKM512 supplementation ameliorates hepatic lipid accumulation, attenuates hepatic and adipose tissue inflammation, and improves intestinal barrier function. These results are associated with improved insulin sensitivity and metabolic endotoxemia. Furthermore, the colonization of LKM512 induces an increase in polyamine metabolism and production, together with significant alternations in the composition and function of gut microbiota in obese mice, which are correlated with these improved metabolic phenotypes in the host. CONCLUSION: The probiotic strain LKM512 may become a promising strategy to improve obesity and related metabolic disorders.

Hydrolyzed Chicken Meat Extract Attenuates Neuroinflammation and Cognitive Impairment in Middle-Aged Mouse by Regulating M1/M2 Microglial Polarization.

Aging is the most common cause of several neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. The pathological hallmarks of age-dependent neuropathology consist of chronic neuroinflammation, oxidative stress, gliosis, learning disability, and cognitive decline. A novel hydrolyzed bioactive peptide mixture extracted from chicken meat, that is, hydrolyzed chicken extract (HCE) has been previously demonstrated to exert neuroprotective effects in rodents and humans. However, the mechanism of HCE on age-related neurological disorders remains unclear. Herein, we aimed to clarify the impact and mechanism of isolated bioactive components (BCs) from HCE on age-dependent neuroinflammation and cognitive impairment in middle-aged mice. We found that both BC and HCE supplementation ameliorated age-induced memory loss, alleviated hippocampal neuroinflammation and oxidative stress, followed by promoting hippocampal neurogenesis in mice. BC and HCE treatment also ameliorated age-dependent morphological anomalies and alleviated microgliosis and astrogliosis. In parallel, BC and HCE treatment showed a significant decrease in the NF-κB p65 and p38 MAPK signaling, which were associated with the enhancement of antioxidative enzymes activities. Furthermore, BC treatment attenuated the neuroinflammatory phenotypes by the decrease in M1-polarized microglia and the increase in M2-polarized microglia in vivo and in vitro. In addition, we found that cyclo(Phe-Phe), one of the cyclopeptides purified from BC, showed notable anti-inflammatory effects in BV2 cells. Taken together, BC might be used as a dietary supplement for alleviating age-dependent neuropathology in middle-aged individuals.

Bisphenol A impairs cognitive function and 5-HT metabolism in adult male mice by modulating the microbiota-gut-brain axis.

Bisphenol A (BPA) has been found to promote hepatotoxicity, reproductive toxicity, and developmental toxicity. However, the neurotoxicity and mechanism of BPA on cognitive function are still unclear. To that end, eight-week-old adult male and female C57BL/6J mice were exposed to 0.05, 0.5, 5, and 50 mg/kg BPA by dietary supplementation for 22 weeks. BPA exposure impaired learning and memory in male mice, associated with increased neuroinflammation and damaged blood-brain barrier. BPA exposure reduced the tight junctions in the colon, resulting in dysfunction of the gut barrier. The levels of neurotransmitters in the serum, hippocampus, and colon of male mice, including tryptophan, 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid, were all decreased by BPA, together with reduced expression of tryptophan and 5-HT metabolism-related genes. Cecal microbiota analysis revealed that the diversity and composition of the microbiota in male mice were markedly altered by BPA, leading to functional profile changes in the microbial community. These results suggest that the neurotoxicity of BPA in male mice may be partly regulated by the interactions of the microbiota-gut-brain axis. However, BPA has little effect on the cognitive function in female mice, which might be caused by the microbial differences and the role of estrogen receptors.

Neuroprotective effects of ProBeptigen/CMI-168 on aging-induced cognitive decline and neuroinflammation in mice: a comparison with essence of chicken.

Neuroinflammation and cognitive decline are the key pathological features in aging that bring detrimental impacts upon quality of life. However, there is no effective anti-aging pharmacological therapy thus far. Dietary supplements in particular essence of chicken (EC) has been found to be an effective remedy for alleviating mental stress and improving memory. In addition, a novel hydrolyzed chicken extract, ProBeptigen/CMI-168 (PB), showed beneficial effects on cognitive ability. However, the antiaging effect and possible mechanism of PB and EC are still unknown. Here, we investigated the antiaging effects of PB and EC on hippocampus-related cognitive decline and neuroinflammation in aged mice. PB and EC were administered for 16 weeks in 10-month-old mice. Both PB and EC treatments ameliorated age-related deterioration of learning and memory, and attenuated oxidative stress and inflammation in the hippocampus. These results were associated with decreased inflammatory cytokine levels and increased neurotransmitter levels in the hippocampus. The overall effects of improving aging-induced cognitive decline were more robust in PB-treated mice, while EC was effective in decreasing oxidative stress and inflammation. Moreover, alterations in the diversity and composition of the gut microbiota in aged mice were also regulated by both PB and EC, which induced distinguished features in the gut microbiota and their related functions. This study showed that PB exerts neuroprotective effects in aged mice, the mechanism of which might be different from that of EC. Therefore, PB has a potential as dietary supplement for ameliorating cognitive dysfunction and neuroinflammation in elderly individuals.

Preventive and Therapeutic Spermidine Treatment Attenuates Acute Colitis in Mice.

Inflammatory bowel disease (IBD) is associated with acute and chronic inflammation of the gastrointestinal tract and has emerged to be a global disease. Spermidine, a natural polyamine, plays a critical role in maintaining cellular homeostasis. Herein, we investigated the impact and mechanism of spermidine on both dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzenesulfonic acid solution (TNBS)-induced colitis in mice. We found that spermidine exerted protective effects against acute colitis, evidenced by reduced disease activity index (DAI) and colonic inflammation, increased colonic length, and upregulated tight junction proteins in these two colitis models. Importantly, spermidine exerted significant therapeutic and preventive effects against DSS-induced colitis. Pre- and post-treatment with spermidine reduced the expression of proinflammatory cytokines, phosphorylation of (nuclear factor-κB) NF-κB and (mitogen-activated protein kinase) MAPK, and the activation of F4/80 macrophages and T cells in the colon. Furthermore, spermidine upregulated M2 macrophage markers, whereas it downregulated M1 markers in the inflamed colons. In parallel, spermidine reduced M1 pro-inflammatory markers and enhanced M2 anti-inflammatory genes in RAW264.7 cells. These results revealed that spermidine-ameliorated colitis might be through the regulation of M1/M2 macrophage polarization. In addition, spermidine treatment also alleviated LPS/TNF-α-induced inflammation in Caco-2 cells. Taken together, spermidine prevented and reversed colonic inflammation in colitis mice and might be a promising candidate for IBD intervention.

Pharmacological activation of REV-ERBα improves nonalcoholic steatohepatitis by regulating intestinal permeability.

BACKGROUND AND OBJECTIVES: The gut-liver axis plays an important role in the pathogenesis of nonalcoholic steatohepatitis (NASH), and increased intestinal permeability causes transfer of endotoxin to the liver, which activates the immune response, ultimately leading to hepatic inflammation. Nuclear receptor Rev-erbα is a critical regulator of circadian rhythm, cellular metabolism, and inflammatory responses. However, the role and mechanism of Rev-erbα in gut barrier function and NASH remain unclear. In the present study, we investigated the involvement of Rev-erbα in the regulation of intestinal permeability and the treatment of NASH. METHODS AND RESULTS: The expression of tight junction-related genes and Rev-erbs decreased in the jejunum, ileum and colon of mice with high cholesterol, high fat diet (CL)-induced NASH. Chromatin immunoprecipitation analysis indicated that REV-ERBα directly bound to the promoters of tight junction genes to regulate intestinal permeability. Pharmacological activation of REV-ERBα by SR9009 protected against lipopolysaccharide-induced increased intestinal permeability both in vitro and in vivo, and these effects were associated with the activation of autophagy and decreased apoptotic signaling of epithelial cells. In addition, the chronopharmacological effects of SR9009 were more potent at Zeitgeber time 0 (ZT0) than at ZT12, which was contrary to the rhythm of Rev-erbs in the gastrointestinal tract. The administration of SR9009 attenuated hepatic lipid accumulation, insulin resistance, inflammation, and fibrosis in mice with CL diet-induced NASH, which might be partly attributed to the enhancement of intestinal barrier function. CONCLUSION: Chronopharmacological activation of REV-ERBα might be a potential strategy to treat intestinal barrier dysfunction-related disorders and NASH.

Spermidine ameliorates high-fat diet-induced hepatic steatosis and adipose tissue inflammation in preexisting obese mice.

AIMS: The therapeutic effects of spermidine on preexisting obese mice have been not fully elucidated. In this study, we assessed the anti-obesity impact of spermidine on high-fat diet (HFD)-induced obese mice. MAIN METHODS: C57BL/6J mice were fed a HFD for 16 weeks to induce obesity, and then treated with or without spermidine via drinking water for additional 8 weeks. The contributions of spermidine in regulating obesity phenotypes and metabolic syndrome were further evaluated. KEY FINDINGS: Spermidine administration lowered fat mass and plasma lipid profile in HFD-induced obese mice without affecting body weight. In addition, spermidine attenuated hepatic steatosis by regulating lipid metabolism and enhancing antioxidant capacity. Moreover, spermidine reduced adipose tissue inflammation by decreasing inflammatory cytokine and chemokines expression, and these results might contributed to the enhanced thermogenic gene expression in brown adipose tissue. Furthermore, spermidine treatment enhanced gut barrier function by up-regulating tight junction- and mucin-related gene expression. SIGNIFICANCE: Spermidine-mediated protective impacts involve the regulation of lipid metabolism, inflammation response, gut barrier function and thermogenesis. These findings demonstrate that spermidine has potentials in treating obesity.

Spermidine improves gut barrier integrity and gut microbiota function in diet-induced obese mice.

Obesity is associated with impaired intestinal barrier function and dysbiosis of the gut microbiota. Spermidine, a polyamine that acts as an autophagy inducer, has important benefits in patients with aging-associated diseases and metabolic dysfunction. However, the mechanism of spermidine on obesity remains unclear. Here, we show that spermidine intake is negatively correlated with obesity in both humans and mice. Spermidine supplementation causes a significant loss of weight and improves insulin resistance in diet-induced obese (DIO) mice. These effects are associated with the alleviation of metabolic endotoxemia and enhancement of intestinal barrier function, which might be mediated through autophagy pathway and TLR4-mediated microbial signaling transduction. Moreover, spermidine causes the significant alteration of microbiota composition and function. Microbiota depletion compromises function, while transplantation of spermidine-altered microbiota confers protection against obesity. These changes might partly be driven by an SCFA-producing bacterium, Lachnospiraceae NK4A136 group, which was decreased in obese subjects and subsequently increased by spermidine. Notably, the change of Lachnospiraceae NK4A136 group is significantly correlated with enhanced gut barrier function induced by spermidine. Our results indicate that spermidine supplementation may serve as a viable therapy for obesity.

The Gut Microbiota and Its Metabolites, Novel Targets for Treating and Preventing Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent metabolic disorders worldwide, along with obesity and type 2 diabetes. NAFLD involves a series of liver abnormalities from simple hepatic steatosis to non-alcoholic steatohepatitis, which can ultimately lead to liver cirrhosis and cancer. The gut-liver axis plays an important role in the development of NAFLD, which depends mainly on regulation of the gut microbiota and its bacterial products. These intestinal bacterial species and their metabolites, including bile acids, tryptophan catabolites, and branched-chain amino acids, regulate adipose tissue and intestinal homeostasis and contribute to the pathogenesis of NAFLD/non-alcoholic steatohepatitis. In this review, the current evidence regarding the key role of the gut microbiota and its metabolites in the pathogenesis and development of NAFLD is highlighted, and the advances in the progression and applied prospects of gut microbiota-targeted dietary and exercise therapies is also discussed.

Adipose Tissue Macrophage Phenotypes and Characteristics: The Key to Insulin Resistance in Obesity and Metabolic Disorders.

Obesity is one of the most serious global health problems, with an incidence that increases yearly and coincides with the development of a variety of associated comorbidities (e.g., type 2 diabetes, nonalcoholic fatty liver disease, some immune-related disorders). Although many studies have investigated the pathogenesis of overweight and obesity, multiple regulatory factors underlying the onset of obesity-related metabolic disorders remain elusive. Macrophages contribute to modulation of obesity-related inflammation and insulin resistance (IR); adipose tissue macrophages are particularly important in this context. Based on newly identified links between the chemokine system and obesity, macrophage polarization has become an essential target of new therapies for obesity-related IR. The findings of multiple studies imply that variations in gut microbiota and its metabolites might contribute to the regulation of obesity and related metabolic disorders. Recently, several novel antidiabetic drugs, applied as treatment for weight loss, were shown to be effective for obesity-induced IR and other comorbidities. The present review will discuss the properties and functions of macrophages in adipose tissue under conditions of obesity from three perspectives: the chemokine system, the gut microbiota, and antidiabetic drug application. It is proposed that macrophages might be a key therapeutic target for obesity-induced complications.

Preliminary clinical investigation of cataract surgery with a noncontact femtosecond laser system.

BACKGROUND AND OBJECTIVE: Femtosecond laser-assisted cataract surgery (FLACS) is rapidly gaining popularity due to the improved consistency and predictability for capsulorhexis. This study aimed to investigate the preliminary clinical outcomes of FLACS with a noncontact femtosecond laser system. PATIENTS AND METHODS: This prospective study enrolled 25 eyes in the trial group underwent FLACS (LLS-fs 3D, LENSAR, USA), and 29 eyes in the control group underwent conventional cataract surgery (Stellaris, Bausch & Lomb, USA). The phacoemulsification time, energy, and complications during operation were recorded. Postoperative refraction at 1 day, 1 week, 1 and 3 months, the capsulorhexis size and corneal endothelial density at 1 and 3 months were also measured. RESULTS: Compared to the control group, reduction in phacoemulsification time was 51.5% (P = 0.02), and in overall energy, 65.1% (P = 0.02) in the trial group. In the trial group and the control group, total time of cataract procedure was 10.04 ± 1.37 minutes, 10.52 ± 1.92 minutes, respectively (P = 0.31); the absolute difference between attempted and achieved capsulorhexis diameter at 1 month was 192.9 ± 212.0 µm, 626.9 ± 656.6 µm, respectively (P = 0.04), and at 3 months, 256.6 ± 181.9 µm, 572.1 ± 337.0 µm, respectively (P= 0.03); the absolute difference between attempted and achieved spherical equivalent at 3 months was 0.16 ± 0.16 D, 0.74 ± 0.65 D, respectively (P < 0.01); mean corneal endothelial cell loss at 1 month was 15.6% and 14.2%, respectively (P = 0.77), and at 3 months, 2.9%, 4.2%, respectively (P = 0.50). CONCLUSIONS: With the noncontact femtosecond laser system, FLACS can significantly improve the accuracy and repeatability of capsulorhexis, reduce the phacoemulsification time and overall energy, and enhance the predictability and stability of postoperative refraction.