Antibiotics can significantly disrupt gut microbiota homeostasis, reducing microbial diversity and causing dysbiosis associated with health issues. Gut biofilms play a critical role in resilience and stress tolerance of the intestinal ecosystem. Mucosal microbial communities also help restore the gut microbiota after interventions like probiotics, antibiotics, or fecal transplants. Previously, we developed a core bacterial consortium with strong in vitro biofilm-forming and stress-resilient properties, but its colonization ability and in vivo function remained unclear. In this study, we first validated the in vivo biofilm formation of the microbial consortium using a germ-free (GF) mouse model, then introduced single-, dual-, and multi-strain combinations with varying biofilm-forming abilities into specific-pathogen-free mice to assess their potential for recovering antibiotic-disrupted gut microbiota. Our findings indicate that the robust, in vitro–selected consortium continued to form substantial biofilms in GF mouse intestines. 16 S rRNA sequencing showed that, compared to single- or dual-strain treatments, administering the core consortium significantly increased microbial richness and diversity. The gut microbiota of consortium-treated mice more closely resembled healthy controls, suggesting the core consortium has superior potential to restore healthy gut microbiota. Overall, our research demonstrates the core consortium markedly improves gut microbiota resilience to antibiotic-induced disruptions in mice, accelerates restoration of health-associated taxa, and reestablishes gut homeostasis. This approach could transform probiotic interventions from passive supplementation to active ecological engineering, providing a theoretical and experimental basis for next generation of engineered probiotics and microbiome restoration therapies.

Atopic dermatitis (AD) is a chronic, recurrent inflammatory skin disorder of global significance. Long-term use of conventional treatments like topical corticosteroids is associated with adverse effects and a substantial economic burden. Building on prior work demonstrating that specific probiotic strains and a tailored dietary fiber combination ameliorate AD in mice by modulating gut microbiota-derived tryptophan metabolites via the gut-skin axis, but the precise bioactive indoles and their underlying mechanisms remain elusive. Here, we induced AD in mice using 2,4-dinitrofluorobenzene and administered five representative indole derivatives via intragastric gavage. Disease amelioration was assessed through ear swelling quantification, histopathological analysis, enumeration of infiltrated mast cells, and measurement of serum IgE and cytokines by ELISA. Only indole-3acetaldehyde (IAId) and indole-3-lactic acid (ILA) markedly attenuated AD pathology, reducing ear swelling by over 30% alongside decreased skin thickness and mast cell infiltration. Immunomodulatory profiling revealed these metabolites downregulated IL-4, IL-13, and TSLP expression by 25%-40% and upregulated IFN-gamma production by 50%, thereby restoring the Th1/Th2 immune balance. To dissect the mechanism, we employed an aryl hydrocarbon receptor (AhR) inhibitor in parallel experiments, which completely abrogated the protective effects of IAId and ILA, confirming strict dependency on AhR pathway activation. Collectively, our study identifies IAId and ILA as microbiota-derived tryptophan metabolites that regulate immune homeostasis via the gutskin axis in a murine AD model. These findings provide experimental support for the potential of targeting these specific microbial metabolites, warranting further investigation into their therapeutic or nutritional applications for AD.

Insulin resistance (IR) drives obesity and type 2 diabetes, with defective skeletal muscle glucose metabolism as the primary trigger of systemic metabolic dysfunction. We previously confirmed the glycolipid-regulating activity of Chimonanthus nitens Oliv. leaves total flavonoids (CTF), yet its gut microbiota-dependent anti-insulin resistance mechanism remains unclear. In this study, five major flavonoid constituents of CTF were identified using ultra-high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UHPLC-Q-TOF MS/MS), namely rutin, isoquercitrin, kaempferol-3-O-rutinoside, astragalin and quercetin. We established a high-fat and high-fructose diet (HFFD)-induced IR mouse model to explore CTF’s protective effects and molecular mechanisms through comprehensive detection of physiological parameters, gut microbial profiles, cecal metabolites and skeletal muscle function. Microbiologically, CTF relieved glucose disorders and IR by restoring gut microbial and cecal metabolite homeostasis. Antibiotics-mediated gut microbiota depletion nearly abolished hypoglycemic and muscle-protective capacities of CTF, demonstrating gut microbiota as an indispensable mediator of CTF efficacy. Mechanistically, CTF activated adenosine monophosphate-activated protein kinase (AMPK) signaling, thereby synchronously upregulating glucose transporter 4 (GLUT4) and uncoupling protein 1 (UCP1). Specifically, CTF raised skeletal muscle glycogen accumulation and succinate dehydrogenase (SDH) activity, enhanced GLUT4 expression and its translocation onto the sarcolemma to accelerate muscular glucose uptake. Meanwhile, the upregulated UCP1 promoted thermogenesis of intermuscular fat and further alleviated lipotoxic damage. In conclusion, CTF alleviates HFFD-induced IR by regulating gut microbiota and cecal metabolism, and recovers skeletal muscle glucose homeostasis through the gut-muscle-axis-dependent AMPK/GLUT4/UCP1 pathway. This research offering a theoretical basis for CTF as natural anti-metabolic disorder dietary supplements.

Abstract Non-alcoholic fatty liver disease (NAFLD) is a disease closely associated with metabolic dysfunction, the incidence of which is rising globally and poses a serious public health challenge. Nonetheless, current interventions have failed to achieve the desired therapeutic effects, highlighting the urgency of developing new therapies. In recent years, probiotics have gained attention for their multifaceted positive effects on human health, and a large number of studies have revealed their potential benefits in ameliorating NAFLD symptoms. This review describes the theoretical mechanisms by which probiotics intervene in NAFLD, comprehensively summarizing current research advances from the modulation of intestinal barrier function to changes in intestinal flora and their metabolites. Notably, the article provides a systematic overview of next generation probiotics (NGPs), an emerging study of probiotic intervention in NAFLD, and also combines existing theories with practical applications to discuss the key issues and challenges facing the future development of probiotics, providing direction for subsequent research.

Liver fibrosis is a pivotal stage in the progression of chronic liver disease to cirrhosis or hepatocellular carcinoma, driven by persistent activation of hepatic stellate cells (HSCs) and excessive deposition of extracellular matrix (ECM). Emerging evidence indicates that dietary flavonoids, natural bioactive compounds with broad availability and multi-target regulatory potential, exert protective effects against liver fibrosis through pleiotropic mechanisms. This review systematically describes the pharmacological mechanisms by which flavonoids mitigate liver injury, including regulation of lipid metabolism, suppression of inflammatory responses, and inhibition of fibrogenesis. Furthermore, we focus on elaborating the specific pathways by which flavonoid monomers induce cell death and regulate cell states, and further explore how these compounds regulate macrophage polarization, protect hepatic sinusoidal endothelial cells, and inhibit pathological angiogenesis. Finally, we examine recent advances in nano-delivery systems and co-administration strategies designed to address clinical challenges such as poor bioavailability and rapid metabolism. In conclusion, natural flavonoids hold promise for anti-liver fibrosis therapy. This review provides a theoretical foundation for developing effective, targeted natural therapies for hepatic fibrosis and highlights that future research requires mechanism-driven research, formulation innovation, and clinical validation to enable personalized treatment.

Hyperuricemia, characterized by increased serum uric acid (SUA) levels, correlates with renal dysfunction and gut microbiota dysbiosis. Existing therapies often exhibit limited efficacy and adverse effects, highlighting the need for safe alternatives. This study aimed to evaluate the hypouricemic effects of Cyclocarya paliurus polysaccharides (CPP), and elucidate the gut microbiota-driven mechanisms by which CPP ameliorate hyperuricemia and renal inflammation. Results revealed that CPP alleviated hyperuricemia symptoms and mitigated renal inflammation. Additionally, CPP modulated gut microbiota by enhancing microbial diversity, enriching beneficial bacteria (e.g., Parabacteroides, Roseburia), and reducing pro-inflammatory bacteria (e.g., Lachnoclostridium_B). Metabolomics analysis further revealed CPP improved uric acid homeostasis and modulated key metabolic pathways associated with hyperuricemia. Correlation analysis of heat maps and validation experiments indicated the interplay between gut microbiota, uric acid excretion, and renal function. These findings demonstrate CPP alleviates hyperuricemia by restructuring gut microbiota and modulating metabolic pathways, highlighting it as a promising dietary supplement for managing hyperuricemia and its complications.

Gel-based meat products have appealing market potential due to their unique texture, elasticity, and tender taste. Sodium chloride (NaCl) is commonly used in these products to enhance flavor, improve texture, ensure food safety, and extend shelf life. However, excessive long-term NaCl intake is connected with health issues such as hypertension and cardiovascular diseases, raising concerns about its impact on human health. As a result, the reduction of NaCl in these products, while maintaining their flavor and texture, has become a key area in the food industry. Salt reduction strategies often compromise product quality, limiting the search for substitutes. Consequently, there is growing interest in developing new salt substitutes. Recently, basic amino acids (BAA) have emerged as a viable alternative to NaCl in low-salt gel-based meat products. Studies have shown that BAAs not only enhance the solubility, gelation, and emulsification properties of salt-soluble proteins but also reduce protein and lipid oxidation in low-salt conditions, improving sensory characteristics and texture. When combined with chloride salts, BAAs can further lower salt content while improving the quality of the products. In addition, adding modern processing techniques (such as ultrasound, pulsed electric fields) has indicated positive effects on the taste and texture of low-salt meat products. Future studies should deploy advanced tools to dissect the micro-/macro-level impacts of BAAs on low-salt gel products. Furthermore, integrating modern food processing and information technologies could lead to the development of personalized, intelligent low-salt meat products that satisfy consumer demands for both health and taste.

To reduce the sodium content in beef patties without compromising their quality, the impact of three salt additions (T1: 0.6 M NaCl, T2: 0.3 M NaCl +0.3 M KCl, T3: 0.3 M NaCl +0.1 M KCl + 0.2 M L-Arg) on the gel properties, antioxidant capacity, and microbial community profiles in beef patties was evaluated. Scanning electron microscopy analysis confirmed that the T3 treatment induced a denser, more homogeneous network, directly enhancing water holding capacity (81.29 %), product yield (87.04 %). T2 group exhibited the highest total sulfhydryl content and lowest total carbonyl content, indicating reduced protein oxidation. According to E-nose/tongue data, T1 and T2 had similar taste attributes and volatile flavor compositions, T3 reduced off-flavors while enhancing saltiness and umami. Salt reduction altered microbial communities: T2/T3 displayed greater community diversity. Moreover, T3's flavor-associated microbes included Corynebacterium, Kocuria, Staphylococcus, and Macrococcus. Thus, T3 achieved salt reduction while maintaining saltiness and improving product quality. This study provides a reference for the application of L-Arg salt reduction in beef products.

Bioactive dietary fiber has been proven to confer numerous health benefits against metabolic diseases based on the modification of gut microbiota. The metabolic protective effects of glucomannan have been previously reported in animal experiments and clinical trials. However, critical microbial signaling metabolites and the host targets associated with the metabolic benefits of glucomannan remain elusive. The results of this study revealed that glucomannan supplementation alleviated high-fat diet (HFD)-induced insulin resistance in mice and that its beneficial effects were dependent on the gut microbiota. Administration of glucomannan to mice promoted the growth of Bacteroides ovatus. Moreover, colonization with B. ovatus in HFD-fed mice resulted in a decrease in insulin resistance, accompanied by improved intestinal barrier integrity and reduced systemic inflammation. Furthermore, B. ovatus-derived indoleacetic acid (IAA) was established as a key bioactive metabolite that fortifies intestinal barrier function via activation of intestinal aryl hydrocarbon receptor (AhR), leading to an amelioration in insulin resistance. Thus, we conclude that glucomannan acts through the B. ovatus-IAA-intestinal AhR axis to relieve insulin resistance.

Evidence linking Faecalibacterium prausnitzii abundance to nonalcoholic fatty liver disease (NAFLD) is accumulating; however, the causal relationship remains obscure. In this study, 12 F. prausnitzii strains were orally administered to high fat diet fed C57BL/6J mice for 12 weeks to evaluate the protective effects of F. prausnitzii on NAFLD. We found that five F. prausnitzii strains, A2-165, LB8, ZF21, PL45, and LC49, significantly restored serum lipid profiles and ameliorated glucose intolerance, adipose tissue dysfunction, hepatic steatosis, inflammation, and oxidative stress in a mouse model of NAFLD. Moreover, two strains, LC49 and LB8, significantly enhanced short-chain fatty acid (SCFA) production and modulated the gut microbiota. Based on the combined analysis of linear discriminant analysis effect size and microbial communities, the core microbiome related to NAFLD comprised Odoribacter, Roseburia, Erysipelatoclostridium, Tyzzerella, Faecalibaculum, Blautia, and Acetatifactor, and the last five genera can be reversed by treatment with the LC49 and LB8 strains. Additionally, the LC49 and LB8 strains enriched Lactobacillus, Ileibacterium, Faecalibacterium, Dubosiella, and Bifidobacterium and downregulated pathways involving carbohydrate metabolism, amino acid metabolism, and fatty acid biosynthesis. Interestingly, LC49 supplementation also upregulated tryptophan metabolism, glutathione metabolism, and valine, leucine, and isoleucine degradation, which might be related to NAFLD prevention. Collectively, F. prausnitzii LC49 and LB8 exerted considerable anti-NAFLD and microbiota-regulating effects, indicating their potential as probiotic agents for NAFLD treatment.

Faecalibacterium prausnitzii is prevalent in the human gut and is a potential candidate for next-generation probiotics (NGPs) or biotherapeutics. However, the biodiversity and physiological characteristics of Faecalibacterium prausnitzii remain unclear. This study isolated 26 novel F. prausnitzii strains from human feces using a combination of negative screening and prime-specific PCR amplification (NSPA). Based on a 16S rRNA gene analysis, F. prausnitzii strains can be classified into two main phylogroups (phylogroups I and II), which were further clustered into five subgroups (I-A, II-B, II-C, II-D, and II-E). The ultrastructure, colony morphology, growth performance, and short-chain fatty acids (SCFAs)-producing ability were found to be variable among these F. prausnitzii isolates. The optimal pH for the isolates growth ranged between 6.0 and 7.0, while most isolates were inhibited by 0.1% of bile salts. Antimicrobial resistance profiles showed that all F. prausnitzii isolates were susceptible to vancomycin, whereas >80% were kanamycin and gentamicin resistant. Additionally, all strains can utilize maltose, cellulose, and fructose but not xylose, sorbose, and 2′-FL. Overall, our work provides new insights into the biodiversity and physiological characteristics of F. prausnitzii, as well as the choices of strains suitable for NGPs.

BACKGROUND Asthma is increasingly prevalent worldwide, and novel strategies to prevent or treat this disease are needed. Probiotic intervention has recently been reported to be effective for asthma prevention. Here, we explored the effects of Faecalibacterium prausnitzii on the development of allergic airway inflammation in a murine model of house dust mite (HDM)-induced allergic asthma. RESULTS Supplementation with living and dead F. prausnitzii blocked eosinophils, neutrophil, lymphocytes, and macrophages influx and alleviated the pathological changes. Moreover, both living and dead F. prausnitzii administration decreased the levels of IL-4, IL-5, IL-13, and IgG1, elevated the regulatory T cells (Tregs) ratio, improved the microbial dysbiosis, and enhanced SCFAs production. The network correlation analysis revealed that the immune indicators were strongly associated with SCFAs production. Based on the linear discriminant analysis effect size (LEfSe), Turicibacter was found as the core genus related to HDM-induced asthma. Living F. prausnitzii treatment enriched Faecalibaculum, Dubosiella, and Streptococcus, while dead F. prausnitzii treatment increased Muribaculaceae and Parabacteroides. Interestingly, both living and dead F. prausnitzii administration enriched Lachnoclostridium and normalized the pathways involving carbohydrate and lipid metabolisms, which might be related to SCFAs production. CONCLUSION F. prausnitzii exerts an anti-asthmatic effect partly by gut microbiota modulation and SCFAs production, suggesting its promising potential as a probiotic agent for allergic asthma prevention. This article is protected by copyright. All rights reserved.

•The procedures for separation, extraction and purification of CPP-3 were improved.•CPP-3 (600 mg/kg) significantly increased the spleen and thymus index.•CPP-3 enhanced the activities of SOD, T-AOC, GSH-Px and CAT.•CPP-3 enhanced iNOS, IFN-γ, TNF-α, IL-12 and IL-18 mRNA expression levels.

This study aimed to describe Enzymolysis-ultrasonic assisted extraction of flavanoid from Cyclocarya paliurus (Batal) Iljinskaja: HPLC profile, antimicrobial and antioxidant activity. An enzymolysis-ultrasonic assisted extraction (EUAE) method was developed and optimized for the extraction of Cyclocarya paliurus flavonoids in liquid form (CPF). The key factor influencing the extraction yield of Cyclocarya paliurus flavonoids was identified by two-level Plackett-Burman Design (PBD) with eight factors. Plackett-Burman Design determined the following four key factors as significant for the extraction yield of Cyclocarya paliurus flavonoids viz. Enzymatic temperature, enzymatic pH, complex enzyme concentration and ultrasonic power. The Box-Behnken Design (BBD) was subsequently applied to optimize the four key factors identified from Box-Behnken Design. Chemical composition of Cyclocarya paliurus flavonoids was investigated by high performance liquid chromatography (HPLC). Antimicrobial activity was carried out with the disc diffusion method. Antioxidant activities were investigated by DPPH assays, O-2 center dot(-) assays, ABTS(+) assays and the reducing power. The optimal extraction conditions were as follow: enzymatic temperature of 50.71 degrees C, enzymatic pH of 5.08, complex enzyme concentration of 3.23% and ultrasonic power of 108.03 W. Under the optimal extraction conditions, the extraction yield of Cyclocarya paliurus flavonoids was 34.24 +/- 0.32 mg/g, which was well-matched with the predicted value (34.47 mg/g). Isoquercetin, quercetin-3-O-alpha-L-rhamnoside, kaempferol-3-O-alpha-L-rhamnoside, quercetin and kaempferol were identified from Cyclocarya paliurus flavonoids with the content of 2.37%, 1.94%, 15.77%, 4.86% and 2.64%, respectively. The inhibition zones diameters of Cyclocarya paliurus flavonoids at the concentration of 80 mu g/mL against Staphylococcus aureus, Salmonella and Escherichia coil were 21.5 +/- 0.45, 17.5 +/- 0.35 and 13.5 +/- 0.25 mm, respectively. Results also showed a dose dependent scavenging activity as evidenced by IC50 values for superoxide (0.152 mg/mL) and ABTS(+) (0.185 mg/mL) radicals. These results indicated that Cyclocarya paliurus flavonoids could be used as antimicrobial and antioxidant agents applying in pharmaceutical, functional foods and natural cosmetics.

为研究干酪乳杆菌LC01对肠道的益生功能,本实验探讨了不同剂量干酪乳杆菌LC01小鼠肠道菌群及转运的影响.基于MiSeq高通量平台进行扩增子测序,比较LC01菌对正常小鼠、青霉素诱导的菌群失调小鼠的肠道菌群调节作用;并利用墨汁推进率评价LC01菌对便秘小鼠肠道转运的影响.结果表明,LC01菌可明显提高正常小鼠肠道中Lactobacillus属和Bacteroides属的相对丰度,降低条件性致病菌Prevotella属、Helicobacter属的相对丰度,对小鼠肠道菌群具有显著的调节作用.相对于模型组,菌群失调小鼠灌胃LC01菌两周后,能够显著增加拟杆菌属、梭菌属和乳杆菌属的丰度,并可改善肠道转运速率,且600亿活菌效果均优于300亿活菌.综上表明,干酪乳杆菌LC01对小鼠肠道菌群具有一定的调节作用,并且对肠道转运有着良好的促进作用,说明LC01菌具有潜在的益生作用和应用价值.

This study aimed to investigate the chemical composition and hepatoprotective effect of flavonoid fraction from Cyclocarya paliurus leaves (CPF) on the lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced acute liver failure (ALF). UPLC-MS analysis revealed that CPF mainly contained quercetin-3-O-glycoside, quercetin-3-O-rhamnoside, kaempferol-3-O-rhamnoside, quercetin and kaempferol. CPF treatment (100, 200, and 400 mg/kg) effectively prevented LPS/D-GalN-induced ALF by lessening the mortality; improving hepatic morphological structures and oxidative stress; decreasing the ALT and AST levels and inflammatory cytokines. Additionally, CPF alleviated hepatocyte apoptosis and mitochondrial dysfunction, which could be attributed to the activation of nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase (HO)-1 pathway and the regulation of caspse-3, reactive oxygen species modulator 1 (Romo1) and B-cell lymphoma-extra large (Bcl-XL) expressions. Moreover, CPF dose-dependently inhibited the activation of NF-κB pathway and downregulated the expression of CD14 and TNF-R1. These results indicate that CPF could be developed as a promising functional food for the prevention of ALF.

The present study aimed to explore the potent molecular mechanisms behind the hypoglycemic effect of Chimonanthus nitens Oliv. leaf extract (COE) in combination with a high-glucose-fat diet-fed and streptozotocin-induced diabetic mouse model. COE (50 and 200 mg per kg body weight per day) was given to the diabetic-model mice by intragastric administration for 4 weeks. It was found that the fasting blood glucose level (FBG), serum insulin level (FINS), and insulin sensitivity index (ISI) were significantly improved in the COE-treated diabetic-model mice. Glucose metabolism genes expression analysis of the skeletal muscle showed that COE exerted a glucose-lowering effect through the following two ways: on the one hand, COE enhanced insulin sensitivity by upregulating the transcription level of GLUT4, and in addition, it enhanced the insulin signaling pathway to promote the translocation of GLUT4 and upregulated thermogenesis genes expression, including PGC-1α and UCP-1; while on the other hand, GLUT1 expression was also increased in both the transcription and translation levels in the presence of COE. These two ways may result in promoting glucose uptake in skeletal muscle, thus leading to the reduction of the blood glucose level. The results suggested that COE ameliorated hyperglycemia in the diabetic-model mice through regulating glucose transporters, and then was likely to increase glucose uptake, which provided more evidence for applying COE to treat anti-hyperglycemia.

The ethanol extracts of Chimonanthus nitens Oliv. leaves were prepared sequentially by ethanol gradient elution and tested for their α-glucosidase inhibitory. The fraction of 50% ethanol eluate (EE) exhibited the notable inhibition with IC50 of 0.376mg/mL. Also, 50% EE was chemically characterized by liquid chromatography–mass spectrometry (LC–MS) analysis. Eight compounds including rutin (1), hyperin (2), isoquercitrin (3), luteoloside (4), astragalin (6), quercetin (13), naringenin (14), kaempferol (15) were identified by compared with standard substances as well as proper luteolin-5-O-glucoside (5), kaempferol-7-O-rhamnoside (9), 5,7,8-trihydroxy-2-methoxyl-flavone-7-O-glucoside (10), kaempferol-7-O-acetyl-galactoside (11). The experiments of ultra-filtration combined with liquid chromatography–mass spectrometry (UF-LC–MS) guided quercetin and kaempferol as the key factors for 50% EE showing highly inhibitory activity on α-glucosidase. Quercetin and kaempferol inhibited yeast α-glucosidase in a mixed-type manner with IC50 of 66.8 and 109μg/mL, respectively. These results would provide theoretical underpinning for the C. nitens Oliv. leaves ethanol extracts used as nutraceutical health supplement in the management of type 2 diabetes.

The paper investigated the antihyperglycemic and antihyperlipidemic efficacy and antioxidant capacity of Chimonanthus nitens Oliv. leaf extract (COE) in combination of high-glucose-fat diet-fed and streptozotocin-induced diabetic model mice. Various physiological indexes in diabetic model mice were well improved especially by oral administration of high dose of COE; the results were listed as follows. Fast blood glucose (FBG) level and serum triglyceride (TC), total cholesterol (TG), low-density lipoprotein cholesterol (LDLC), and malondialdehyde (MDA) as well as MDA in liver were significantly reduced; fasting serum insulin (FINS) and insulin sensitivity index (ISI) were both increased; high-density lipoprotein cholesterol (HDLC) in serum was significantly increased; total antioxidant capacity (T-AOC), activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in serum and liver were apparently enhanced; liver coefficient (LC), liver transaminase, and alkaline phosphatase (ALP) were decreased. Furthermore, pancreas islets and liver in diabetic model mice showed some extend of improvement in morphology and function after 4 weeks of COE treatment. In consequence, COE was advantageous to regulate glycolipid metabolism and elevate antioxidant capacity in diabetic model mice. Thus, the present study will provide a scientific evidence for the use of COE in the management of diabetes and its related complications.