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Objective: Diabetic nephropathy (DN) is a serious complication that may occur during the later stages of diabetes, and can be further exacerbated by podocyte damage. Piperazine ferulate (PF) has well-defined nephroprotective effects and is used clinically in the treatment of chronic nephritis and other kidney diseases. However, the renoprotective effects and mechanisms of PF on DN are not clear. This study aims to investigate the protective effect of PF on DN and its mechanism of action, to inform the clinical application of PF in DN treatment. Methods: Network pharmacology was performed to predict themechanism of action of PF in DN. Male Sprague Dawley rats were intraperitoneally injected with STZ (60 mg/kg) to establish a DN model, and then assessed for renal injury after 12 weeks of administration. In vitro, rat podocytes were treated with 25 mmol/L glucose and cultured for 24 h, followed by an assessment of cell injury. Results: Our results showed that PF significantly improved renal function, reduced renal pathological changes, decreased inflammatory response, and alleviated podocyte damage in DN rats. PF also attenuated glucose-induced podocyte injury in vitro. Regarding molecular mechanisms, our study demonstrated that PF downregulated the expression of genes and proteins related to AGE-RAGE-mediated inflammatory signaling. Conclusion: In summary, PF exerts its renoprotective effects by decreasing inflammation and protecting against podocyte injury through the inhibition of the AGE/RAGE/NF-κB/NLRP3 pathway. Overall, these data support the clinical potential of PF as a renoprotective agent in DN. [ABSTRACT FROM AUTHOR]

Abstract Background Prostate cancer (PCa) is becoming the most common malignancy in men worldwide. We investigated the effect of astragaloside IV combined with PESV on the gut microbiota and metabolite of PCa mice and the process of treating PCa. Methods Nude mice were genetically modified to develop tumors characteristic of PCa. The treatment of PCa mice involved the administration of a combination of astragaloside IV and peptides derived from scorpion venom (PESV). Feces were collected for both 16 S rDNA and metabolic analysis. Fecal supernatant was extracted and used for fecal transplantation in PCa mice. Tumor development was observed in both PCa mice and nude mice. Tumor histopathology was examined, and the expression of inflammatory factors and the AGE-RAGE axis in PCa tissues were analyzed. Results PCa mice treated with Astragaloside IV in combination with PESV showed a significant reduction in tumor volume and weight, and stabilization of gut microbiota and metabolites. At the Genus level, significant differences were observed in Porphyromonas, Corynebacterium, Arthromitus and Blautia, and the differential metabolites were PA16_016_0, Astragaloside+, Vitamin A acid, Nardosinone, a-Nortestoster, D-Pantethine, Hypoxanthine, Pregnenolone, cinnamic acid, Pyridoxa, Cirtruline and Xanthurenate. There was a correlation between gut microbiota and metabolites. After the fecal transplantation, tumor growth was effectively suppressed in the PCa mice. Notably, both the mRNA and protein levels of the receptor for advanced glycation end products (RAGE) were significantly decreased. Furthermore, the expression of inflammatory factors, namely NF-κB, TNF-α, and IL-6, in the tumor tissues was significantly attenuated. Conversely, upregulation of RAGE led to increased inflammation and reversed tumor growth in the mice. Conclusion Astragaloside IV combined with PESV could treat PCa by intervening in gut microbiota composition and metabolite by targeting RAGE.

Background: Prostate cancer (PCa) is becoming the most common malignancy in men worldwide. We investigated the effect of astragaloside IV combined with PESV on the gut microbiota and metabolite of PCa mice and the process of treating PCa. Methods: Nude mice were genetically modified to develop tumors characteristic of PCa. The treatment of PCa mice involved the administration of a combination of astragaloside IV and peptides derived from scorpion venom (PESV). Feces were collected for both 16 S rDNA and metabolic analysis. Fecal supernatant was extracted and used for fecal transplantation in PCa mice. Tumor development was observed in both PCa mice and nude mice. Tumor histopathology was examined, and the expression of inflammatory factors and the AGE-RAGE axis in PCa tissues were analyzed. Results: PCa mice treated with Astragaloside IV in combination with PESV showed a significant reduction in tumor volume and weight, and stabilization of gut microbiota and metabolites. At the Genus level, significant differences were observed in Porphyromonas, Corynebacterium, Arthromitus and Blautia, and the differential metabolites were PA16_016_0, Astragaloside+, Vitamin A acid, Nardosinone, a-Nortestoster, D-Pantethine, Hypoxanthine, Pregnenolone, cinnamic acid, Pyridoxa, Cirtruline and Xanthurenate. There was a correlation between gut microbiota and metabolites. After the fecal transplantation, tumor growth was effectively suppressed in the PCa mice. Notably, both the mRNA and protein levels of the receptor for advanced glycation end products (RAGE) were significantly decreased. Furthermore, the expression of inflammatory factors, namely NF-κB, TNF-α, and IL-6, in the tumor tissues was significantly attenuated. Conversely, upregulation of RAGE led to increased inflammation and reversed tumor growth in the mice. Conclusion: Astragaloside IV combined with PESV could treat PCa by intervening in gut microbiota composition and metabolite by targeting RAGE. [ABSTRACT FROM AUTHOR]

Objective: Baicalin (BC) is a flavonoid reported to have various pharmacological activities, including antioxidant, anti-cancer, anti-inflammatory, anti-allergy, immune regulation, and anti-diabetic. This study examines the probable mechanism for gestational diabetes mellitus (GDM) brought on by streptozotocin (STZ) and the impact of BC on fetal development via AGEs (advanced serum glycation end products) and RAGE (the role of advanced glycation end products). Material and Method: STZ has been used in the current experimental study to induce diabetes mellitus in pregnant animals (gestational diabetes mellitus). GDM pregnant animals were separated into five groups and were treated with BC in a dose-dependent pattern for 19 days. At the end of the experiment, the fetus and blood samples were drawn from all the pregnant rats to assess the biochemical parameter as well as AGE-RAGE. Result: Administration of BC at varying doses leads to enhancement in the weight of the fetus body and placenta while gestational diabetic pregnant animals induced by STZ had a lower weight of the fetus body and placenta. The dose-dependent pattern of BC also enhanced fasting insulin (FINS), high-density lipoprotein (HDL), serum insulin, and hepatic glycogen. It also significantly enhanced the content of the antioxidant profile and pro-inflammatory cytokines and modulated the gene expression (VCAM- 1, p65, EGFR, MCP-1, 1NOX2, and RAGE) in various tissues in gestational diabetes mellitus pregnant rats. Conclusion: Baicalin demonstrated the potential impact on the embryo's development via the AGE-RAGE signaling pathway in STZ-induced GDM pregnant animals. [ABSTRACT FROM AUTHOR]

Cannabidiol (CBD), the most abundant nonpsychoactive constituent of Cannabis sativa plant, is a promising potential pharmacotherapy for the treatment of diabetes and associated comorbidities. Previous studies have shown the potential of CBD to prevent diabetes in mice, the precise mechanisms of action remain unclear. The purpose of this study was to explore the mechanism of CBD alleviating hyperglycemia. The results demonstrated that CBD reduced blood glucose of STZ‐induced diabetic mice without causing hypoglycemia. To elucidate the possible mechanisms of CBD effect, RNA‐seq analysis was performed on high glucose‐induced human mesangial cells (HMCs). By cluster analysis of differential genes, the results showed that advanced glycation end products‐receptor of advanced glycation endproducts (AGE‐RAGE) pathway‐related genes CCL2 and interleukin‐1β (IL‐1β) play an important role in the biological of CBD. The expression of CCL2 and IL‐1β were significantly increased in HMCs. Whereas, treatment with CBD decreased the expression of CCL2 and IL‐1β. In addition, CBD significantly reduced AGE‐RAGE levels in high glucose‐induced HMCs. Similar results were confirmed in diabetic mice. In conclusion, we discovered for the first time that CBD ameliorates hyperglycemia partly through AGE‐RAGE mediated CCL2/IL‐1β pathway. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are critical antigen-presenting cells which are the initiators and regulators of the immune response. Numerous studies support the idea that dietary sugars influence DC functions. Increased consumption of fructose has been thought to be the leading cause of metabolic disorders. Although evidence supports their association with immune dysfunction, the specific mechanisms are not well understood. Fructose is one of the main dietary sugars in our diet. Therefore, here we compared the effect of fructose and glucose on the functions of human DCs. High levels of D-fructose compared to D-glucose led to activation of DCs in vitro by promoting interleukin (IL)-6 and IL-1β production. Moreover, fructose exposed DCs also induced interferon (IFN)-γ secretion from T cells. Proinflammatory response of DCs in high fructose environment was found to be independent of the major known metabolic regulators or glycolytic control. Instead, DC activation on acute exposure to fructose was via activation of receptor for advanced glycation end product (RAGE) in response to increased accumulation of advanced glycation end products (AGE). However, chronic exposure of DCs to high fructose environment induced a shift towards glycolysis compared to glucose cultured DCs. Further investigations revealed that the AGEs formed by fructose induced increased levels of inflammatory cytokines in DCs compared to AGEs from glucose. In summary, understanding the link between metabolic changes and fructose-induced DC activation compared to glucose has broad implications for immune dysfunction associated with metabolic disorders.

Karine Lino Rodrigues,1 Vivian Vieira Dias Da Silva,1 Evelyn Nunes Goulart da Silva Pereira,1 Raquel Rangel Silvares,1 Beatriz Peres de Araujo,1 Edgar Eduardo Ilaquita Flores,1 Isalira Peroba Ramos,2 Juliana Pereira Borges,3 Caroline Fernandes-Santos,1,4 Anissa Daliry1 1Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, RJ, Brazil; 2National Center of Structural Biology and Bio-imaging, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; 3Laboratory of Physical Activity and Health Promotion, University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; 4Department of Basic Sciences, Federal Fluminense University, Nova Friburgo, RJ, BrazilCorrespondence: Anissa Daliry, Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, FIOCRUZ, Pavilhão Ozorio de Almeida Av. Brasil, 4365 (Room 14), Manguinhos, Rio de Janeiro, RJ, CEP: 21040-900, Brazil, Tel +55 212562-1312, Email daliry@ioc.fiocruz.brPurpose: Type 2 diabetic (T2D) patients have liver and adipose tissue microcirculation disturbances associated with metabolic dysfunction and disease progression. However, the potential role of aerobic training on hepatic and white adipose tissue (WAT) microcirculation and the underlying mechanisms have not been elucidated to date. Therefore, we investigated the role of aerobic training on liver and WAT microcirculation and AGE-RAGE modulation in T2D mice.Methods: The control group (CTL) was fed standard chow, and T2D was induced by feeding male C57BL/6 a high-fat, high-carbohydrate diet for 24 weeks. In the following 12 weeks, mice underwent aerobic training (CTL EX and T2D EX groups), or were kept sedentary (CTL and T2D groups). We assessed metabolic parameters, biochemical markers, oxidative damage, the AGE-RAGE axis, hepatic steatosis, hepatic stellate cells activation (HSC) and liver and WAT microcirculation.Results: Hepatic microcirculation was improved in T2D EX mice which were associated with improvements in body, liver and fat mass, blood pressure, hepatic steatosis and fibrosis, and decreased HSC and AGE-RAGE activation. In contrast, improvement in WAT microcirculation, that is, decreased leukocyte recruitment and increased perfusion, was associated with increased catalase antioxidant activity.Conclusion: Physical training improves hepatic and adipose tissue microcirculatory dysfunction associated with T2D, likely due to downregulation of AGE-RAGE axis, decreased HSC activation and increased antioxidant activity.Keywords: microcirculation, physical training, AGE-RAGE, hyperglycemia

Adipose tissue is a complex organ composed of various cell types and an extracellular matrix (ECM). The visceral adipose tissue (VAT) is dynamically altered in response to nutritional regimens that lead to local cues affecting the cells and ECM. The adipocytes are in conjunction with the surrounding ECM that maintains the tissue's niche, provides a scaffold for cells and modulates their signaling. In this study, we provide a better understanding of the crosstalk between nutritional regimens and the ECM's stiffness. Histological analyses showed that the adipocytes in mice fed a high-fat diet (HFD) were increased in size, while the ECM was also altered with changes in mass and composition. HFD-fed mice exhibited a decrease in elastin and an increase in collagenous proteins. Rheometer measurements revealed a stiffer ECM in whole tissue (nECM) and decellularized (deECM) in HFD-fed animals. These alterations in the ECM regulate cellular activity and influence their metabolic function. HFD-fed mice expressed high levels of the receptor for advanced-glycation-end-products (RAGE), indicating that AGEs might play a role in these processes. The cells also exhibited an increase in phosphoserine332 of IRS-1, a decrease in the GLUT4 transporter levels at the cells' membrane, and a consequent reduction in insulin sensitivity. These results show how alterations in the stiffness of ECM proteins can affect the mechanical cues transferred to adipocytes and, thereby, influence the adipocytes' functionality, leading to metabolic disorders. [ABSTRACT FROM AUTHOR]

Diabetes nephropathy (DN) is a severe diabetic chronic microvascular complication and the major cause of end-stage renal disease (ESRD). Our study aimed to investigate the effects of isoliquiritigenin (ISL) a natural flavonoid compound on DN and to explore the underlying mechanisms. The db/db mice were received intragastric treatments of ISL (5, 10, or 20 mg/kg), vehicle or positive drug metformin (300 mg/kg) once a day for 12 weeks, and the db/m mice treated with vehicle were used as controls. ISL significantly ameliorated pathological changes and functional injury in the kidneys of db/db mice in a dose-dependent manner. The administration of 20 mg/kg ISL reduced the levels of serum creatinine (Scr; 49.0 ± 1.7 vs. 56.9 ± 2.9 μmol/L; p < 0.01), blood urine nitrogen (BUN; 9.6 ± 1.3 vs. 12.0 ± 1.1 mmol/L; p < 0.05), albumin to creatinine ratio (ACR; 1925.8 ± 798.1 vs. 4269.4 ± 925.6 μg/mg; p < 0.01) and urinary albumin (276.2 ± 39.9 vs. 576.9 ± 108.9 μg; p < 0.05). Further study identified advanced glycation end product (AGE)-receptor for AGE (RAGE) axis as a target of ISL. ISL (20 mg/kg) lowered renal AGE level (2.5 ± 0.5 vs. 3.8 ± 0.6 μg/mg; p < 0.01) and RAGE expression, leading to improvements in renal fibrosis, oxidative stress, and inflammation. To sum up, our study demonstrated that ISL displayed preventive effects on the experimental model of DN through suppressing AGE-RAGE pathway, and provided some insights into the application of ISL in DN treatment., (© 2025 Wiley Periodicals LLC.)

Purpose: Type 2 diabetic (T2D) patients have liver and adipose tissue microcirculation disturbances associated with metabolic dysfunction and disease progression. However, the potential role of aerobic training on hepatic and white adipose tissue (WAT) microcirculation and the underlying mechanisms have not been elucidated to date. Therefore, we investigated the role of aerobic training on liver and WAT microcirculation and AGE-RAGE modulation in T2D mice. Methods: The control group (CTL) was fed standard chow, and T2D was induced by feeding male C57BL/6 a high-fat, high-carbohydrate diet for 24 weeks. In the following 12 weeks, mice underwent aerobic training (CTL EX and T2D EX groups), or were kept sedentary (CTL and T2D groups). We assessed metabolic parameters, biochemical markers, oxidative damage, the AGE-RAGE axis, hepatic steatosis, hepatic stellate cells activation (HSC) and liver and WAT microcirculation. Results: Hepatic microcirculation was improved in T2D EX mice which were associated with improvements in body, liver and fat mass, blood pressure, hepatic steatosis and fibrosis, and decreased HSC and AGE-RAGE activation. In contrast, improvement in WAT microcirculation, that is, decreased leukocyte recruitment and increased perfusion, was associated with increased catalase antioxidant activity. Conclusion: Physical training improves hepatic and adipose tissue microcirculatory dysfunction associated with T2D, likely due to downregulation of AGE-RAGE axis, decreased HSC activation and increased antioxidant activity. [ABSTRACT FROM AUTHOR]

The present study involves the integrated network pharmacology and phytoinformatics-based investigation of phytocompounds from Ocimum tenuiflorum against diabetes mellitus-linked Alzheimer's disease. It aims to investigate the mechanism of the Ocimum tenuiflorum phytocompounds in the amelioration of diabetes mellitus-linked Alzheimer's disease through network pharmacology, druglikeness and pharmacokinetics, molecular docking simulations, GO analysis, molecular dynamics simulations, and binding free energy analyses. A total of 14 predicted genes of the 26 orally bioactive compounds were identified. Among these 14 genes, GAPDH and AKT1 were the most significant. The network analysis revealed the AGE-RAGE signaling pathway to be a prominent pathway linked to GAPDH with 50.53% probability. Upon the molecular docking simulation with GAPDH, isoeugenol was found to possess the most significant binding affinity (−6.0 kcal/mol). The molecular dynamics simulation and binding free energy calculation results also predicted that isoeugenol forms a stable protein–ligand complex with GAPDH, where the phytocompound is predicted to chiefly use van der Waal's binding energy (−159.277 kj/mol). On the basis of these results, it can be concluded that isoeugenol from Ocimum tenuiflorum could be taken for further in vitro and in vivo analysis, targeting GAPDH inhibition for the amelioration of diabetes mellitus-linked Alzheimer's disease. [ABSTRACT FROM AUTHOR]

One of the proposed mechanisms for the development of diabetic nephropathy (DN) is the increase of end products of advanced glycosylation (AGEs), which bind to its receptor (RAGE), favoring nephron cellular damage. An isoform of this receptor is soluble RAGE (sRAGE), which can antagonize AGE-altered intracellular signaling. It has known that green tea extract (GTE) increases the expression of sRAGE, but it is unknown whether this could improve kidney function. The objective of this study was to evaluate the effect of the administration of GTE on the concentrations of sRAGE, renal function, and metabolic profile in patients with type 2 diabetes mellitus (T2DM) and DN. A randomized, double-blinded, placebo-controlled clinical trial was carried out in 39 patients who received GTE (400 mg every 12 h) or placebo for 3 months. sRAGE levels, renal function, and metabolic parameters were determined before and after the intervention. In the GTE group, there were statistically significant increase on sRAGE (320.55 ± 157.63 pg/mL vs. 357.59 ± 144.99 pg/mL; P = .04) and glomerular filtration rate (GFR; 66.44 ± 15.17 mL/min/1.73 m2 vs. 71.70 ± 19.33 mL/min/1.73 m2; P = .04), and a statistically significant decrease in fasting serum glucose (7.62 ± 3.00 mmol/L vs. 5.86 ± 1.36 mmol/L; P ≤ .01) and triacylglycerols (1.91 ± 0.76 mmol/L vs. 1.58 ± 0.69; P = .02). Administration of GTE increases the serum concentration of sRAGE and the GFR and decreases the concentration of fasting serum glucose and triacylglycerols. The study was registered in ClinicalTrials.gov with the identifier NCT03622762. [ABSTRACT FROM AUTHOR]

Ferroptosis is a new way of cell death, and stimulating the process of cell ferroptosis is a new strategy to treat breast cancer. NGR1 has good anti-cancer activity and is able to slow the progression of breast cancer. However, NGR1 has not been reported in the field related to ferroptosis. By searching the online database for potential targets of NGR1 and the breast cancer disease database, among 11 intersecting genes we focused on Runt-related transcription factor 2 (RUNX2), which is highly expressed in breast cancer, and KEGG pathway enrichment showed that the intersecting genes were mainly enriched in the AGE (advanced glycosylation end products)-RAGE (receptor of AGEs) signaling pathway. After that, we constructed overexpression and down-regulation breast cancer cell lines of RUNX2 in vitro , and tested whether NGR1 treatment induced ferroptosis in breast cancer cells by regulating RUNX2 to inhibit the AGE-RAGE signaling pathway through phenotyping experiments of ferroptosis, Western blot experiments, QPCR experiments, and electron microscopy observation. The results showed that NGR1 was able to inhibit the expression level of RUNX2 and suppress the AGE/PAGE signaling pathway in breast cancer cells. NGR1 was also able to promote the accumulation of Fe 2+ and oxidative damage in breast cancer cells by regulating RUNX2 and then down-regulating the expression level of GPX4, FIH1 and up-regulating the expression level of ferroptosis-related proteins such as COX2, ACSL4, PTGS2 and NOX1, which eventually led to the ferroptosis of breast cancer cells.

Background Inflammation is generally suppressed during hibernation, but select tissues (e.g. lung) have been shown to activate both antioxidant and pro-inflammatory pathways, particularly during arousal from torpor when breathing rates increase and oxidative metabolism fueling the rewarming process produces more reactive oxygen species. Brown and white adipose tissues are now understood to be major hubs for the regulation of immune and inflammatory responses, yet how these potentially damaging processes are regulated by fat tissues during hibernation has hardly been studied. The advanced glycation end-product receptor (RAGE) can induce pro-inflammatory responses when bound by AGEs (which are glycated and oxidized proteins, lipids, or nucleic acids) or damage associated molecular pattern molecules (DAMPs, which are released from dying cells). Methods Since gene expression and protein synthesis are largely suppressed during torpor, increases in AGE-RAGE pathway proteins relative to a euthermic control could suggest some role for these pro-inflammatory mediators during hibernation. This study determined how the pro-inflammatory AGE-RAGE signaling pathway is regulated at six major time points of the torpor-arousal cycle in brown and white adipose from a model hibernator, Ictidomys tridecemlineatus. Immunoblotting, RT-qPCR, and a competitive ELISA were used to assess the relative gene expression and protein levels of key regulators of the AGE-RAGE pathway during a hibernation bout. Results The results of this study revealed that RAGE is upregulated as animals arouse from torpor in both types of fat, but AGE and DAMP levels either remain unchanged or decrease. Downstream of the AGE-RAGE cascade, nfat5 was more highly expressed during arousal in brown adipose. Discussion An increase in RAGE protein levels and elevated mRNA levels of the downstream transcription factor nfat5 during arousal suggest the pro-inflammatory response is upregulated in adipose tissue of the hibernating ground squirrel. It is unlikely that this cascade is activated by AGEs or DAMPs. This research sheds light on how a fat-but-fit organism with highly regulated metabolism may control the pro-inflammatory AGE-RAGE pathway, a signaling cascade that is often dysregulated in other obese organisms.

Background: Fuzi-Gancao herb couple is one of the most common herb couples involved in the TCM formula, which was used for the treatment of chronic diseases. The herb couple has a hepatoprotective effect. However, its main components and therapeutic mechanism are not yet clear. This study aims to elucidate the therapeutic effect and mechanism of the Fuzi-Gancao herb couple on NAFLD from animal experiments, network pharmacology, and molecular docking., Methods: 60 Male C57BL/6 mice (20 g ± 2 g) were randomly divided into six groups including the blank group (n=10) and NALFD group (n=50). The mice of the NALFD group were fed with a high-fat diet for 20 weeks to establish the NAFLD model and the NALFD mice were randomly divided into five groups including positive group (berberine), model group and F-G groups with three dosages (0.257, 0.514, 0.771 g/kg) (n=10). After 10 weeks of administration, the serum was collected for the analysis of ALT, AST, LDL-c, HDL-c, and TC, and liver tissues were collected for pathological analysis. The TCMAS database was used to collect the main components and targets of the Fuzi-Gancao herb couple. The GeneCards database was used to collect NAFLD-related targets, and the key targets were obtained by intersecting with herbal targets. The diseasecomponent- target relationship diagram was constructed by Cytoscape 3.9.1. The obtained key targets were imported into the String database to obtain the PPI network, and imported into the DAVID database for KEGG pathway analysis and GO analysis. Finally, the key targets and key gene proteins were imported into Discovery Studio 2019 for molecular docking verification., Results: In this study, H-E staining indicated the pathological changes of liver tissue in Fuzi- Gancao groups were significantly improved, and the levels of AST, ALT, TC, HDL-c, and LDL-c in serum of Fuzi-Gancao groups decreased in a dose-dependent manner, compared with the model group. 103 active components and 299 targets in the Fuzi-Gancao herb couple were confirmed in the TCMSP database and 2062 disease targets in NAFLD were obtained. 142 key targets and 167 signal pathways were screened, such as the AGE-RAGE signaling pathway in diabetic complications, HIF-1 signaling pathway, IL-17 signaling pathway, TNF signaling pathway, and so on. The main bioactive ingredients of Fuzi-Gancao herb couple in the treatment of NAFLD are quercetin, kaempferol, naringenin, inermine, (R)-norcoclaurine, isorhamnetin, ignavine, 2,7-Dideacetyl-2,7- dibenzoyl-taxayunnanine F, glycyrol mainly involving IL6, AKT1, TNF, TP53, IL1B, VEGFA and other core targets. Molecular docking analysis indicated that there is a good affinity between the key components and the key targets., Conclusion: This study preliminarily explained the main components and mechanism of the Fuzi- Gancao herb couple in the treatment of NAFLD and provided an idea for subsequent research., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background. Inflammation is generally suppressed during hibernation, but select tissues (e.g. lung) have been shown to activate both antioxidant and pro-inflammatory pathways, particularly during arousal from torpor when breathing rates increase and oxidative metabolism fueling the rewarming process produces more reactive oxygen species. Brown and white adipose tissues are now understood to be major hubs for the regulation of immune and inflammatory responses, yet how these potentially damaging processes are regulated by fat tissues during hibernation has hardly been studied. The advanced glycation end-product receptor (RAGE) can induce pro-inflammatory responses when bound by AGEs (which are glycated and oxidized proteins, lipids, or nucleic acids) or damage associated molecular pattern molecules (DAMPs, which are released from dying cells). Methods. Since gene expression and protein synthesis are largely suppressed during torpor, increases in AGE-RAGE pathway proteins relative to a euthermic control could suggest some role for these pro-inflammatory mediators during hibernation. This study determined how the pro-inflammatory AGE-RAGE signaling pathway is regulated at six major time points of the torpor-arousal cycle in brown and white adipose from a model hibernator, Ictidomys tridecemlineatus. Immunoblotting, RT-qPCR, and a competitive ELISA were used to assess the relative gene expression and protein levels of key regulators of the AGE-RAGE pathway during a hibernation bout. Results. The results of this study revealed that RAGE is upregulated as animals arouse from torpor in both types of fat, but AGE and DAMP levels either remain unchanged or decrease. Downstream of the AGE-RAGE cascade, nfat5 was more highly expressed during arousal in brown adipose. Discussion. An increase in RAGE protein levels and elevated mRNA levels of the downstream transcription factor nfat5 during arousal suggest the pro-inflammatory response is upregulated in adipose tissue of the hibernating ground squirrel. It is unlikely that this cascade is activated by AGEs or DAMPs. This research sheds light on how a fat-but-fit organism with highly regulated metabolism may control the pro- inflammatory AGE-RAGE pathway, a signaling cascade that is often dysregulated in other obese organisms. [ABSTRACT FROM AUTHOR]

There is growing evidence that chronic hyperglycemia leads to the formation of advanced glycation end products (AGEs) which exerts its effect via interaction with the receptor for advanced glycation end products (RAGE). AGE-RAGE activation results in oxidative stress and inflammation. It is well known that this mechanism is involved in the pathogenesis of cardiovascular disease in diabetes. Kaempferol, a dietary flavonoid, is known to possess antioxidant, anti-apoptotic, and anti-inflammatory activities. However, little is known about the effect of kaempferol on myocardial ischemia-reperfusion (IR) injury in diabetic rats. Diabetes was induced in male albino Wistar rats using streptozotocin (70 mg/kg; i.p.), and rats with glucose level >250 mg/dL were considered as diabetic. Diabetic rats were treated with vehicle (2 mL/kg; i.p.) and kaempferol (20 mg/kg; i.p.) daily for a period of 28 days and on the 28th day, ischemia was produced by one-stage ligation of the left anterior descending coronary artery for 45 min followed by reperfusion for 60 min. After completion of surgery, rats were sacrificed and the heart tissue was processed for biochemical, morphological, and molecular studies. Kaempferol pretreatment significantly reduced hyperglycemia, maintained hemodynamic function, suppressed AGE-RAGE axis activation, normalized oxidative stress, and preserved morphological alterations. In addition, there was decreased level of inflammatory markers (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and NF-κB), inhibition of active c-Jun N-terminal kinase (JNK) and p38 proteins, and activation of Extracellular signal regulated kinase 1/2 (ERK1/2) a prosurvival kinase. Furthermore, it also attenuated apoptosis by reducing the expression of pro-apoptotic proteins (Bax and Caspase-3), Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells, and increasing the level of anti-apoptotic protein (Bcl-2). In conclusion, kaempferol attenuated myocardial ischemia-reperfusion injury in diabetic rats by reducing AGE-RAGE/ mitogen activated protein kinase (MAPK) induced oxidative stress and inflammation. [ABSTRACT FROM AUTHOR]

Stroke is one of the leading causes of death worldwide. Hemorrhagic transformation (HT) is a common serious complication of ischemic stroke (IS) and is related to poor prognosis. Hyperglycemia after stroke is associated with the occurrence of HT and seriously affects the clinical treatment of stroke. Our previous experiments demonstrated that the Xiao-Xu-Ming decoction effective components group (XXMD), which is a Chinese medicine formula reconstituted by active ingredients, has multiple pharmacological effects in the treatment of IS. However, the effects of XXMD on HT after IS remain unclear. Thus, we investigated the preventive effects of XXMD on hyperglycemia-induced HT and further explored the underlying mechanism. Acute hyperglycemia combined with the electrocoagulation cerebral ischemia model was used to establish the HT model. XXMD (37.5, 75, 150 mg/kg/d) was given by gavage for 5 days. Network pharmacology was used to predict potential targets and pathways of XXMD in HT occurrence, and further studies confirmed the related targets. The results showed that hyperglycemia aggravated neurological deficits and blood-brain barrier (BBB) disruption, leading to intracerebral hemorrhage. Pretreatment with XXMD improved neurological function and BBB integrity and inhibited HT occurrence. Network pharmacology revealed that AGE-RAGE-mediated neuroinflammation may be associated with hyperglycemia-induced HT. Further studies confirmed that hyperglycemia activated the AGE-RAGE signaling pathway, increased the expression of HMGB1, TLR4 and p-p65, and induced the release of inflammatory factors and neutrophil infiltration, leading to HT. XXMD could inhibit AGE-RAGE-mediated neuroinflammation. These findings indicated that pretreatment with XXMD alleviated hyperglycemia-induced HT, which may be associated with the inhibition of AGE-RAGE-mediated neuroinflammation. Therefore, XXMD may be a potential therapeutic drug for HT. [Display omitted] • HT is a common and serious complication after ischemic stroke. • Hyperglycemia promotes the occurrence of HT and worsens prognosis of stroke. • Pretreatment with XXMD alleviates BBB disruption and the incidence of HT. • Pretreatment with XXMD inhibits AGE-RAGE-mediated neuroinflammation. [ABSTRACT FROM AUTHOR]

• T2D rats received HFD, 25 % w/v fructose water and a single STZ injection. • PCA reduced fasting glycemia, AUC OGTT , AUC ITT , and HOMA-IR index in T2D rats. • PCA ameliorated hepatic function, oxidative stress and hepatosteatosis in T2D rats. • PCA enhanced hepatic levels of P-AKTser473, IRS1, (PI3K)-p85 and AKT2 in T2D rats. • PCA reduced serum AGEs and vascular expression of RAGE and NOX4 in T2D rats. This work explored influences of protocatechuic acid (PCA) on type 2 diabetes (T2D)-associated hepatic insulin resistance and other metabolic, hepatic and vascular irregularities using the rat model of high fat diet (HFD)+high fructose+low dose streptozotocin (STZ). Twenty-four male Wister rats were used. Twelve rats were ad libitum supplied with HFD and high fructose drinking water (25 % w/v) for 60 days. On day 30, they received a single injection of STZ (35 mg/kg, i.p). On day 32, they were divided into two subgroups (n = 6/each): T2D + PCA , received PCA (100 mg/kg/day, orally) and T2D , received PCA vehicle till the end of experiment. Rats provided with regular diet and fructose-free drinking water, with or without PCA treatment, served as PCA and control groups (n = 6/each), respectively. PCA treatment significantly reduced the elevated levels of fasting glycemia and insulin, AUC OGTT , AUC ITT , and HOMA-IR index, while it boosted HOMA-β and insulinogenic index values in T2D rats. PCA ameliorated serum lipid levels and hepatic function parameters and mitigated hepatosteatosis in T2D rats. Mechanistically, PCA mitigated hepatic lipid peroxidation and restored reduced glutathione (GSH) and superoxide dismutase (SOD) to near-normal levels. Moreover, PCA enhanced hepatic protein levels of P-AKT ser473 and hepatic mRNA expression of insulin receptor substrate 1 (IRS1), phosphatidylinositol 3 kinase (PI3K)-p85 and AKT2. Furthermore, PCA ameliorated aortic oxidative stress in T2D rats, possibly via reducing serum levels of advanced glycation end products (AGEs) and diminishing vascular expression of RAGE and NOX4 mRNA. Collectively, PCA may improve hepatic insulin resistance and vascular oxidative status by modulating IRS1/PI3K/AKT2 and AGE-RAGE-NOX4 pathways, respectively. [ABSTRACT FROM AUTHOR]