Potential immune-related therapeutic mechanisms of multiple traditional Chinese medicines on type 2 diabetic nephropathy based on bioinformatics, network pharmacology and molecular docking.

BACKGROUND: The prevalence of type 2 diabetic nephropathy (T2DN) ranges from 20 % to 40 % among individuals with type 2 diabetes. Multiple immune pathways play a pivotal role in the pathogenesis of T2DN. This study aimed to investigate the immunomodulatory effects of active ingredients derived from 14 traditional Chinese medicines (TCMs) on T2DN. METHODS: By removing batch effect on the GSE30528 and GSE96804 datasets, we employed a combination of weighted gene co-expression network analysis, least absolute shrinkage and selection operator analysis, protein-protein interaction network analysis, and the CIBERSORT algorithm to identify the active ingredients of TCMs as well as potential hub biomarkers associated with immune cells. Functional analysis was conducted using Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and gene set variation analysis (GSVA). Additionally, molecular docking was employed to evaluate interactions between active ingredients and potential immunotherapy targets. RESULTS: A total of 638 differentially expressed genes (DEGs) were identified in this study, comprising 5 hub genes along with 4 potential biomarkers. Notably, CXCR1, CXCR2, and FOS exhibit significant associations with immune cells while displaying robust or favorable affinities towards the active ingredients kaempferol, quercetin, and luteolin. Furthermore, functional analysis unveiled intricate involvement of DEGs, hub genes and potential biomarkers in pathways closely linked to immunity and diabetes. CONCLUSION: The potential hub biomarkers and immunotherapy targets associated with immune cells of T2DN comprise CXCR1, CXCR2, and FOS. Furthermore, kaempferol, quercetin, and luteolin demonstrate potential immunomodulatory effects in modulating T2DN through the regulation of CXCR1, CXCR2, and FOS expression.

Hyperoside Suppresses Renal Inflammation by Regulating Macrophage Polarization in Mice With Type 2 Diabetes Mellitus.

Accumulating evidence reveals that both inflammation and lymphocyte dysfunction play a vital role in the development of diabetic nephropathy (DN). Hyperoside (HPS) or quercetin-3-O-galactoside is an active flavonoid glycoside mainly found in the Chinese herbal medicine Tu-Si-Zi. Although HPS has a variety of pharmacological effects, including anti-oxidative and anti-apoptotic activities as well as podocyte-protective effects, its underlying anti-inflammatory mechanisms remain unclear. Herein, we investigated the therapeutic effects of HPS on murine DN and the potential mechanisms responsible for its efficacy. We used C57BLKS/6J Lepdb/db mice and a high glucose (HG)-induced bone marrow-derived macrophage (BMDM) polarization system to investigate the potentially protective effects of HPS on DN. Our results showed that HPS markedly reduced diabetes-induced albuminuria and glomerular mesangial matrix expansion, accompanied with a significant improvement of fasting blood glucose level, hyperlipidaemia and body weight. Mechanistically, pretreatment with HPS effectively regulated macrophage polarization by shifting proinflammatory M1 macrophages (F4/80+CD11b+CD86+) to anti-inflammatory M2 ones (F4/80+CD11b+CD206+) in vivo and in bone marrow-derived macrophages (BMDMs) in vitro, resulting in the inhibition of renal proinflammatory macrophage infiltration and the reduction in expression of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF-α) and inducible nitric oxide synthase (iNOS) while increasing expression of anti-inflammatory cytokine Arg-1 and CD163/CD206 surface molecules. Unexpectedly, pretreatment with HPS suppressed CD4+ T cell proliferation in a coculture model of IL-4-induced M2 macrophages and splenic CD4+ T cells while promoting their differentiation into CD4+IL-4+ Th2 and CD4+Foxp3+ Treg cells. Taken together, we demonstrate that HPS ameliorates murine DN via promoting macrophage polarization from an M1 to M2 phenotype and CD4+ T cell differentiation into Th2 and Treg populations. Our findings may be implicated for the treatment of DN in clinic.

Tiliacora triandra extract and its major constituent attenuates diabetic kidney and testicular impairment by modulating redox imbalance and pro-inflammatory responses in rats.

BACKGROUND: Literature has demonstrated that diabetes is associated with renal complication and testicular dysfunctions. The current study explored the potential of Tiliacora triandra extract and its major component against diabetic kidney and testicular damages in rats. METHODS: Diabetes was induced by high fat diet/streptozotocin (HFD/STZ) and treated orally with Tiliacora triandra extract (TTE, 100 and 400 mg kg-1 body weight) and its major component, 5,7-dihydroxy-6-oxoheptadecanoic acid (DHA, 25 mg kg-1 body weight) for 30 consecutive days. Testicular activities of testicular enzymes, serum levels of testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), sperm parameters and urinalysis for protein and albumin levels were evaluated. Renal and testicular biomarkers of oxidative stress and pro-inflammation were analysed along with histology. RESULTS: The experimental diabetes induced significant alterations in the levels and activities of indices evaluated compared to non-diabetic normal rats. The 28-day treatment of diabetic rats with TTE and DHA markedly improved activities of testicular enzymes, restored levels of testosterone, LH and FSH and sperm parameters compared to untreated diabetic rats. TTE and DHA abrogated proteinuria and reversed urine albumin level. Testicular and renal oxidative stress and pro-inflammation were attenuated in diabetic rats treated with TTE and DHA. The diabetes-mediated histopathological damage was alleviated in the kidney and testis. CONCLUSION: The protective effect of TTE and DHA against diabetes induced kidney and testicular damages may be related to its antioxidant and anti-inflammatory activities. © 2020 Society of Chemical Industry.

[Molecular regulative mechanisms of NLRP3 inflammasome activation in diabetic nephropathy and interventional effects of Chinese herbal medicine].

The progression of renal damage in diabetic nephropathy(DN)is closely related to Nod-like receptor protein3(NLRP3)inflammasome activation. The characteristics of NLRP3 inflammasome activation include the changed expression and combination levels of NLRP3, apoptosis-associated speck-like protein(ASC)and pro-caspase-1, the increased expression levels of caspase-1, interleukin(IL)-1ß and IL-18 and the excessive release levels of the relative inflammatory mediators. Its molecular regulative mechanisms involve the activation of multiple signaling pathways including reactive oxygen species(ROS)/thioredoxin-interacting protein(TXNIP)pathway, nuclear factor(NF)-κB pathway, nuclear factor erythroid-related factor 2(Nrf2)pathway, long non-coding RNA(lncRNA)pathway and mitogen-activated protein kinases(MAPKs)pathway. In addition, more importantly, never in mitosis aspergillus-related kinase 7(Nek7), as a kinase regulator, could target-combine with NLRP3 at upstream to activate NLRP3 inflammasome. Some extracts of Chinese herbal medicines(CHMs)such as quercetin, curcumin, cepharanthine, piperine and salidroside, as well as Chinese herbal compound prescriptions such as Wumei Pills both could treat NLRP3 inflammasome to ameliorate inflammatory renal damage in DN. Therefore, accurately clarifying the targets of anti-inflammatory CHMs and Chinese herbal compound prescriptions delaying DN progression by targeting the molecular regulative mechanisms of NLRP3 inflammasome activation will be one of the development directions in the future.

Protective effect of ginsenoside Rg5 against kidney injury via inhibition of NLRP3 inflammasome activation and the MAPK signaling pathway in high-fat diet/streptozotocin-induced diabetic mice.

Diabetic nephropathy (DN) is a common and serious complication of diabetes and causes kidney failure. Ginsenoside Rg5 (Rg5) is an important monomer in the main protopanaxadiol component of black ginseng. Rg5 has exhibited some beneficial biological effects, such as anti-cancer, neuroprotection, and anti-depression, but the effect of Rg5 on DN and its potential mechanism remains unclear. The aim of this study is to investigate the effect of Rg5 on kidney injury of C57BL/6 diabetic mice induced by high-fat diet and streptozotocin. After treatment with different concentration of Rg5 (30 and 60 mg kg-1·d-1) for 6 consecutive weeks, the fasting blood glucose, insulin levels, serum creatinine, serum urea, and serum UA in Rg5-treated DN mice were significantly reduced, while the renal histopathology was remarkably improved, compared with untreated DN mice. Moreover, ROS production, oxidative stress markers (MDA, SOD, and GSH-PX), Nox4 and TXNIP expressions of kidney in DN mice were significantly reduced after Rg5 treatment. Additionally, the expression levels of the NLRP3 inflammasome (NLRP3, ASC, and Caspase-1) and the inflammatory cytokines IL-1ß and IL-18 were significantly inhibited, and the expression of NF-kB and the phosphorylation of p38 MAPK were also decreased with Rg5 treatment compared with no treatment in DN mice. Together, our results indicate that Rg5 attenuated renal injury in diabetic mice by inhibiting oxidative stress and NLRP3 inflammasome activation to reduce inflammatory responses, indicating that Rg5 is a potential compound to prevent or control diabetic renal injury.

Rhinacanthins-rich extract and rhinacanthin C ameliorate oxidative stress and inflammation in streptozotocin-nicotinamide-induced diabetic nephropathy.

In this present study, rhinacanthins-rich extract (RRE) and rhinacanthin C (RC) the main bioactive constituent of Rhinacanthus nasutus was investigated for their protective effect against diabetic nephropathy (DN). Diabetes was induced by administering nicotinamide (100 mg/kg, i.p.)/streptozotocin (60 mg/kg, i.p.) and diabetic rats were orally administered with RRE and RC for 4 weeks. RRE and RC significantly reduced the kidney index, renal oxidative stress markers, and pro-inflammatory cytokines. Furthermore, RRE and RC increased renal levels of glutathione, superoxide dismutase, catalase, and attenuated diabetic induced renal damages. In conclusion, RRE and RC confer protective effect against DN through the inhibition of oxidative stress and inflammation and could be a potential medicinal or nutritional supplement for the prevention of DN. PRACTICAL APPLICATIONS: Rhinacanthus nasutus is a medicinal plant that is extensively used in Thai traditional medicine as an antibacterial, antifungal, antidiabetic, and anti-inflammatory agent. The plant is rich in naphthoquinones, which confer it with several excellent bioactivities. The rich extract of the leaves was prepared with three major bioactive components and the extract was evaluated for its renoprotective effect in diabetic rats. The results from this study provides valuable pharmacological information that supports the use of the plant, especially the rich extract in the prevention and treatment of diabetes and diabetic complications.

N6 -(2-hydroxyethyl)-adenosine from Cordyceps cicadae protects against diabetic kidney disease via alleviation of oxidative stress and inflammation.

This study investigated the kidney-protective ability of N6 -(2-hydroxyethyl)-adenosine (HEA) in alloxan-induced diabetic rats. Diabetes was induced in the rats by the administration of alloxan monohydrate (150 mg/kg, i.p) and treated with HEA for 6 weeks. Diabetic rats displayed marked increase in blood glucose, serum creatinine (Scr), and blood urea nitrogen (BUN), in addition to high excretion of urinary protein and albumin. Furthermore, diabetic rats showed decreased renal levels of glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and increased malondialdehyde (MDA) as well as renal concentrations of pro-inflammatory mediators (TNF-α, IL-6, IL-1ß, and TGF-ß1). Treatment of diabetic rats with HEA (20 and 40 mg/kg) significantly increased the renal antioxidant level, reduced the levels of blood glucose, Scr, BUN, urinary protein, albumin, and pro-inflammatory mediators in a dose-dependent fashion. Histological evaluation of the kidney of diabetic rats indicated that HEA also ameliorated glomerular and tubular changes. PRACTICAL APPLICATIONS: HEA is a bioactive constituent isolated from Cordyceps cicadae and has been shown to possess antihyperglycemic, kidney protective, antioxidant, and antiinflammatory effects in diabetic rats. HEA stimulated the antioxidant enzymes' activities in the kidney tissues as well as reduced pro-inflammatory mediators, indicating its antidiabetic and renoprotective effects in diabetic models. The results showed that HEA attenuated oxidative stress and inflammation in kidney tissues.

The Effect of Iranian Propolis on Glucose Metabolism, Lipid Profile, Insulin Resistance, Renal Function and Inflammatory Biomarkers in Patients with Type 2 Diabetes Mellitus: A Randomized Double-Blind Clinical Trial.

Propolis is a natural product with many biological properties including hypoglycemic activity and modulating lipid profile. The present study was designed to evaluate the effect of Iranian propolis extract on glucose metabolism, Lipid profile, Insulin resistance, renal and liver function as well as inflammatory biomarkers in patients with type 2 diabetes mellitus (T2DM). A double-blind, placebo-controlled clinical trial was conducted. The duration of the study lasted 90 days. Patients with T2DM were recruited and randomly divided into an Iranian propolis group (1000 mg/day) (n = 50) and a placebo group (n = 44). There was a significant decrease in the serum levels of glycosylated hemoglobin (HbA1c), 2-hour post prandial (2hpp), insulin, homeostasis model assessment-insulin resistance (HOMA-IR), homeostasis model assessment of ß-cell function (HOMA-ß), High sensitive C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α). However, there was a notable elevation in the serum HDL-C in the propolis group compared with the placebo group. In addition, a notable reduction in serum liver transaminase (ALT and AST) and blood urea nitrogen (BUN) concentrations in the propolis group was observed. Iranian propolis has beneficial effects on reducing post prandial blood glucose, serum insulin, insulin resistance, and inflammatory cytokines. It is also a useful treatment for preventing the liver and renal dysfunction, as well as, elevating HDL-C concentrations in patients with T2DM.

Immunomodulatory Effects of the Nutraceutical Garlic Derivative Allicin in the Progression of Diabetic Nephropathy.

Diabetic nephropathy (DN) is presently the primary cause of chronic kidney disease and end-stage renal disease (ESRD). It has been suggested that inflammation and oxidative stress, in addition to or in concert with the metabolic changes, plays an important role in the maintenance and progression of the disease. Therefore, attenuating or blocking these mechanisms may be a therapeutic target to delay the progression of the disease. Diallyl thiosulfinate (allicin), a compound derived from garlic, inhibits free radical formation, increases glutathione synthesis and decreases the levels of proinflammatory molecules in vitro. This research aimed to assess the effect of allicin on oxidative stress and inflammation-induced diabetes. Animals were divided into control and diabetes (streptozotocin 50 mg/kg i.p.), and maintained for 30 days. After 30 days, the group of diabetic animals was subdivided into diabetes and allicin-treated diabetes (16 mg/kg/day oral gavage). The three experimental groups were maintained for another month. We analyzed the status of renal function, oxidative stress and proinflammatory cytokines. The untreated diabetic group showed hyperglycemia and increased diuresis, creatinine clearance, proteinuria, glycosuria and urinary excretion of N-acetyl-ß-d-glucosaminidase (NAG), as well as increased oxidative stress and the expression of interleukin 1ß (IL-1ß), IL-6, nuclear factor kappa beta (NFκß) and transforming growth factor-ß1 (TGF-ß1) in plasma and kidney. In contrast, the inhibitor of NFκß (Iκß) is decreased in the cortex. It has been demonstrated that the allicin treatment decreases hyperglycemia, polyuria, and NAG excretion. The oxidative stress and proinflammatory cytokines were also reduced by the allicin treatment. In conclusion, allicin delays the progression of diabetic nephropathy through antioxidant and anti-inflammatory mechanisms.

Pueraria tuberosa extract inhibits iNOS and IL-6 through suppression of PKC-α and NF-kB pathway in diabetes-induced nephropathy.

OBJECTIVES: Inflammation plays an important role in the pathogenesis of diabetic nephropathy (DN). The aim of this study was to explore the anti-inflammatory role of PTY-2r (extracted from Pueraria tuberosa), on streptozotocin (STZ)-induced DN rats. METHODS: Diabetes was induced by intraperitoneal injection of STZ (55mg/kg) in rats. After 60 days, the rats were randomly divided into three groups (n = 6/each group), namely DN control group 2, DN rats treated with PTY-2r at dose of 100 mg/100 g, group 3 and 50 mg/100 g, group 4, p.o for 20 days. The normal rats were chosen as a normal control (NC) group 1. KEY FINDINGS: In DN rats, the expression of iNOS and inflammatory cytokines (IL-6 and TNF-α) was significantly increased. Raised expression of PKC-α was also found. As NF-kB is the main transcription factor for the inflammatory response-mediated progression of DN, variation in NF-kB expression and its activated phosphorylated derivative (pNF-kB) were also evaluated and increase in expression was obtained in the kidney of DN rats. PTY-2r treatment significantly reversed these changes in dose-dependent manner. CONCLUSIONS: This study suggested that the nephroprotective effect of PTY-2r is possibly due to downregulation of PKC-α and NF-kB pathway and normalizing the expression of inflammatory cytokines and iNOS in the kidney of DN rats.

Vitamin D protection from rat diabetic nephropathy is partly mediated through Klotho expression and renin-angiotensin inhibition.

OBJECTIVE: We hypothesised that vitamin D has a beneficial renal protective effect from diabetic nephropathy (DN). METHODS: Four rat groups were included: normal control (control), type 2 diabetes for eight weeks (DM), treated group with angiotensin receptor blocker losartan (DM + L), and vitamin D-treated group started from the onset of diabetes (DM + Vit D). RESULTS: In the both treated groups, we found a significant (p < .05) reduction in the renal pro-inflammatory and profibrotic markers induced by diabetes. Vitamin D caused more reduction in monocyte chemoattractant protein-1 (MCP-1), transforming growth factor (TGFß-1), and renin-angiotensin levels that gave better kidney function compared to the DM + L group. CONCLUSION: Vitamin D may have a valuable role in the renal protective effect from DN, this may occur via expression of its VDR, Klotho and blocking renin-angiotensin activation, so vitamin D should be considered as a target in renal prophylactic measures against DN.

Are the Therapeutic Effects of Huangqi (Astragalus membranaceus) on Diabetic Nephropathy Correlated with Its Regulation of Macrophage iNOS Activity?

OBJECTIVE: To investigate the correlation between the clinical effects of Huangqi (Astragalus membranaceus) on different stages of diabetic nephropathy (DN) and the pharmacological effect of Huangqi on the activity of inducible nitric oxide synthase (iNOS) in macrophages in different states. METHODS: The PubMed, China National Knowledge Infrastructure, and Wanfang databases were searched. Clinical data was sourced from papers on treatment of different stages of DN with Huangqi, and pharmacological data was from papers on the effects of Huangqi on the iNOS activity of macrophages in a resting or an activated state. RESULTS: Meta-analysis of Huangqi injections on stages III and III-IV DN and randomized controlled trials on other stages showed that Huangqi had therapeutic effects on different stages of DN and on macrophages in different states: inducing normal macrophages in a resting state to generate nitric oxide (NO), tumor necrosis factor-α, and so forth upon iNOS activation; inhibiting NO generation by normal lipopolysaccharide- (LPS-) activated macrophages; and enhancing NO generation by LPS-induced macrophages from patients with renal failure. CONCLUSIONS: Huangqi can regulate iNOS activity of macrophages in different states in vitro. These biphasic or antagonistic effects may explain why Huangqi can be used to treat different stages of DN.

Lycium barbarum Polysaccharide Mediated the Antidiabetic and Antinephritic Effects in Diet-Streptozotocin-Induced Diabetic Sprague Dawley Rats via Regulation of NF-κB.

Lycium barbarum, extensively utilized as a medicinal plant in China for years, exhibits antitumor, immunoregulative, hepatoprotective, and neuroprotective properties. The present study aims to investigate the hyperglycemic and antidiabetic nephritic effects of polysaccharide which is separated from Lycium barbarum (LBPS) in high-fat diet-streptozotocin- (STZ-) induced rat models. The reduced bodyweight and enhanced blood glucose concentration in serum were observed in diabetic rats, and they were significantly normalized to the healthy level by 100 mg/kg of metformin (Met) and LBPS at doses of 100, 250, and 500 mg/kg. LBPS inhibited albuminuria and blood urea nitrogen concentration and serum levels of inflammatory factors including IL-2, IL-6, TNF-α, IFN-α, MCP-1, and ICAM-1 compared with diabetic rats, and it indicates the protection on renal damage. Furthermore, the activities of SOD and GSH-Px in serum were enhanced strikingly by LBPS which suggests its antioxidation effects. LBPS, compared with nontreated diabetic rats, inhibited the expression of phosphor-nuclear factors kappa B (NF-κB) and inhibitor kappa B alpha in kidney tissues. Collectively, LBPS possesses antidiabetic and antinephritic effects related to NF-κB-mediated antioxidant and antiinflammatory activities.

Esculin improves dyslipidemia, inflammation and renal damage in streptozotocin-induced diabetic rats.

BACKGROUND: Increasing studies have shown that dyslipidemia and inflammatory responses play important roles in the progression of microvascular diabetic complications. Esculin (ES), a coumarin derivative, was extracted from Fraxinus rhynchophylla. The present study was to evaluate the potential effects of ES on lipid metabolism, inflammation responses and renal damage in streptozotocin (STZ)-induced experimental diabetic rats and explore the possible mechanism. METHODS: Diabetic rat model was established by administration high-glucose-fat diet and intraperitoneal injection of STZ 45 mg/kg. ES was administrated to diabetic rats intragastrically at 10, 30 and 90 mg/kg for 10 weeks respectively. The levels of triglycerides (TG), total cholesterol (T-CHO), low density lipoproteins (LDL), and high-density-cholesterol (HDL-C) in serum were measured. IL-1, IL-6, ICAM-1, NO, NAGL, and AGEs level in serum were detected by ELISA assay. The accumulation of AGEs in kidney tissue was examined by immunohistochemistry assay. RESULTS: The results showed that ES could decrease TG, T-CHO, LDL levels in serum of diabetic rats in a dose dependent manner. ES also decreased IL-1, IL-6, ICAM-1, NO and NGAL levels in serum of diabetic rats in a dose dependent manner. Furthermore, ES at 30 and 90 mg/kg significantly decreased AGEs level in serum and alleviated AGEs accumulation in renal in diabetic rats. CONCLUSIONS: Our findings indicate that ES could improve dyslipidemia, inflammation responses, renal damage in STZ-induced diabetic rats and the possible mechanism might be associated with the inhibition of AGEs formation.

Effects of linalool on inflammation, matrix accumulation and podocyte loss in kidney of streptozotocin-induced diabetic rats.

CONTEXT: This study aimed to evaluate the renoprotective action of linalool (LIN) on streptozotocin (STZ)-induced diabetic rats. OBJECTIVE: The pathological changes in diabetic nephropathy (DN) include oxidative stress, renal injury, matrix accumulation and podocyte abnormalities. We investigated the renoprotective actions of LIN, a monoterpene alcohol, present in herbal essential oils in STZ-induced diabetic rats with renal injury. MATERIALS AND METHODS: STZ-diabetic rats were administered LIN (25 mg/kg) for 45 days, after which the activities of key enzymes of glucose metabolism, collagen content, oxidative damage and expression of glucose transporter-1 (GLUT-1), transforming growth factor-ß1 (TGF-ß1), nuclear factor-κBp65 (NF-κB p65) and nephrin were analyzed. RESULTS: Diabetic rats displayed altered glucose metabolism, collagen accumulation and increased TGF-ß1 and NF-κB expression in kidney. LIN treatment restored glucose-metabolizing enzymes, collagen content and GLUT-1 expression and also prevented nephrin loss. LIN also rescued kidney from oxidative stress and inflammation by decreasing the expression of TGF-ß1 and NF-κB. Ultrastructural changes such as basement membrane thickening, reduction in podocyte number and loss of filtration barrier integrity in diabetic rats were mitigated by LIN. DISCUSSION AND CONCLUSION: The results of this study suggest that LIN can attenuate nephropathic changes induced in kidney of diabetic rats. These findings highlight the utility of LIN as a potential drug to treat renal damage in diabetic subjects.

Reversal of the deleterious effects of chronic dietary HFCS-55 intake by PPAR-δ agonism correlates with impaired NLRP3 inflammasome activation.

Although high-fructose corn syrup (HFCS-55) is the major sweetener in foods and soft-drinks, its potential role in the pathophysiology of diabetes and obesity ("diabesity") remains unclear. Peroxisome-proliferator activated receptor (PPAR)-δ agonists have never been tested in models of sugar-induced metabolic abnormalities. This study was designed to evaluate (i) the metabolic and renal consequences of HFCS-55 administration (15% wt/vol in drinking water) for 30 weeks on male C57Bl6/J mice and (ii) the effects of the selective PPAR-δ agonist GW0742 (1 mg/kg/day for 16 weeks) in this condition. HFCS-55 caused (i) hyperlipidemia, (ii) insulin resistance, and (iii) renal injury/inflammation. In the liver, HFCS-55 enhanced the expression of fructokinase resulting in hyperuricemia and caused abnormalities in known insulin-driven signaling events. In the kidney, HFCS-55 enhanced the expression of the NLRP3 (nucleotide-binding domain and leucine-rich-repeat-protein 3) inflammasome complex, resulting in caspase-1 activation and interleukin-1ß production. All of the above effects of HFCS-55 were attenuated by the specific PPAR-δ agonist GW0742. Thus, we demonstrate for the first time that the specific PPAR-δ agonist GW0742 attenuates the metabolic abnormalities and the renal dysfunction/inflammation caused by chronic HFCS-55 exposure by preventing upregulation of fructokinase (liver) and activation of the NLRP3 inflammasome (kidney).

[Clinical observation on repair of lymphocyte injury in patients with diabetic nephropathy treated by regulating spleen-stomach needling].

OBJECTIVE: To explore therapeutic effect and action mechanism of regulating spleen-stomach needling on diabetic nephropathy (DN). METHODS: Using multi-centric, randomized, controlled and blind principles, 144 cases of DN were divided into an observation group and a control group according to random digital tab, 72 cases in each one. Based on regular treatment of diabetes, the regulating spleen-stomach needling was applied at Zhongwan (CV 12), Quchi (LI 11), Hegu (LI 4) and Xuehai (SP 10), etc. in the observation group while Shenshu (BL 23), Taixi (KI 3), Sanyinjiao (SP 6), Yanglingquan (GB 34), etc. were selected in the control group by reference of Acupuncture and moxibustion. The treatment was given twice a day, six days as a treatment session with interval of one day between sessions. Totally six weeks were required. Changes of clinical symptoms and signs, fast blood glucose (FBG), urinary albumin excretion rate (UAER), beta2-microglobulin (beta2-MG), monocyte chemotactic protein-1 (MCP-1), lymphocyte membrane cholesterol, propanediol (MDA), PCO, 8-hydroxydeoxy guanosine (8-OHdG), superoxide dismutase (SOD), CD3+, CD4+, CD8+, and CD4+/CD8+ were observed before and after treatment in two groups. RESULTS: As for improving clinical symptoms and signs, total effective rate was 84.29% (59/70) in the observation group and 55.56% (40/72) in the control group, which had statistical difference between two groups (P<0.01). As for regulating glycometabolism [(6.25 +/- 0.32) mmol/L vs (8.09 +/- 0.63) mmol/L], reducing UAER [(154.43 +/- 55.14) mg/24h vs (268.91 +/- 77.65) mg/24h], restraining over-expression of MCP-1 [(137.59 +/- 36.15) pg/mL vs (166.89 +/- 42.82) pg/mL], regulating level of oxidative stress, prohibiting oxidation of protein and adjusting quantity and activity of T lymphocyte subgroup, the observation group was superior to the control group (P< 0.05, P<0.01). CONCLUSION: The regulating spleen-stomach needling is an effective method for treatment of DN, which cold improve glycometabolism disturbance-induced progressive kidney injury, recover glomerular filtration, reduce urinary albumin excretion rate, restrain overexpression of MCP-1, adjust level of oxidative stress, prohibit oxidation of protein, increase protectiveness of membrane, adjust quantity and activity abnormity of T lymphocyte subgroup, leading to repairing lymphocyte damage and improving immune expression to delay kidney damage.

Purple corn anthocyanins inhibit diabetes-associated glomerular monocyte activation and macrophage infiltration.

Diabetic nephropathy (DN) is one of the major diabetic complications and the leading cause of end-stage renal disease. In early DN, renal injury and macrophage accumulation take place in the pathological environment of glomerular vessels adjacent to renal mesangial cells expressing proinflammatory mediators. Purple corn utilized as a daily food is rich in anthocyanins exerting disease-preventive activities as a functional food. This study elucidated whether anthocyanin-rich purple corn extract (PCA) could suppress monocyte activation and macrophage infiltration. In the in vitro study, human endothelial cells and THP-1 monocytes were cultured in conditioned media of human mesangial cells exposed to 33 mM glucose (HG-HRMC). PCA decreased the HG-HRMC-conditioned, media-induced expression of endothelial vascular cell adhesion molecule-1, E-selectin, and monocyte integrins-ß1 and -ß2 through blocking the mesangial Tyk2 pathway. In the in vivo animal study, db/db mice were treated with 10 mg/kg PCA daily for 8 wk. PCA attenuated CXCR2 induction and the activation of Tyk2 and STAT1/3 in db/db mice. Periodic acid-Schiff staining showed that PCA alleviated mesangial expansion-elicited renal injury in diabetic kidneys. In glomeruli, PCA attenuated the induction of intracellular cell adhesion molecule-1 and CD11b. PCA diminished monocyte chemoattractant protein-1 expression and macrophage inflammatory protein 2 transcription in the diabetic kidney, inhibiting the induction of the macrophage markers CD68 and F4/80. These results demonstrate that PCA antagonized the infiltration and accumulation of macrophages in diabetic kidneys through disturbing the mesangial IL-8-Tyk-STAT signaling pathway. Therefore, PCA may be a potential renoprotective agent treating diabetes-associated glomerulosclerosis.

Podocyte as a potential target of inflammation: role of pioglitazone hydrochloride in patients with type 2 diabetes.

OBJECTIVE: To observe the effects of pioglitazone hydrochloride on urinary sediment podocalyxin and monocyte chemoattractant protein-1 (MCP-1) excretion in patients with type 2 diabetes and to explore its possible renoprotective mechanisms. METHODS: Ninety-eight patients with uncontrolled type 2 diabetes, who were previously prescribed metformin, acarbose, or both, were randomly assigned to a DP group (add-on pioglitazone; n = 49) or a DS group (add-on sulfonylurea; n = 49). RESULTS: After 12 weeks of treatment, both add-on pioglitazone therapy (the DP group) and add-on sulfonylurea therapy (the DS group) demonstrated a similar improvement in fasting blood glucose and hemoglobin A1c, but systolic and diastolic blood pressure declined significantly in only the DP group. Moreover, the DP group showed significantly better efficacy in reducing urinary MCP-1 excretion in comparison with the DS group. Furthermore, both urinary albumin and urinary sediment podocalyxin excretion decreased significantly in the DP group but not in the DS group. The urinary sediment podocalyxin to creatinine ratio had a positive correlation with urinary albumin to creatinine ratio (r = 0.624; P<.01) and urinary MCP-1 to creatinine ratio (r = 0.346; P<.01). CONCLUSION: Pioglitazone treatment revealed a podocyte-protective capacity in patients with type 2 diabetes, and the underlying mechanisms may be partly attributed to its effective suppression of excessive local renal inflammation.

Inhibition of high glucose-induced inflammatory response and macrophage infiltration by a novel curcumin derivative prevents renal injury in diabetic rats.

BACKGROUND AND PURPOSE: Inflammation is involved in the development and/or progression of many diseases including diabetic complications. Investigations on novel anti-inflammatory agents may offer new approaches for the prevention of diabetic nephropathy. Our previous bioscreening of synthetic analogues of curcumin revealed C66 as a novel anti-inflammatory compound against LPS challenge in macrophages. In this study, we hypothesized that C66 affects high glucose (HG)-induced inflammation profiles in vitro and in vivo and then prevents renal injury in diabetic rats via its anti-inflammatory actions. EXPERIMENTAL APPROACH: Primary peritoneal macrophages (MPM), prepared from C57BL/6 mice, were treated with HG in the presence or absence of C66. Diabetes was induced in Sprague-Dawley rats with streptozotocin, and the effects of C66 (0.2, 1.0 or 5.0 mg·kg(-1) ), administered daily for 6 weeks, on plasma TNF-α levels and expression of inflammatory genes in the kidney were assessed. KEY RESULTS: Pretreatment of MPMs with C66 reduced HG-stimulated production of TNF-α and NO, inhibited HG-induced IL-1ß, TNF-α, IL-6, IL-12, COX-2 and iNOS mRNA transcription, and the activation of JNK/NF-kB signalling. In vivo, C66 inhibited the increased plasma TNF-α levels and renal inflammatory gene expression, improved histological abnormalities and fibrosis of diabetic kidney, but did not affect the hyperglycaemia in these diabetic rats. CONCLUSIONS AND IMPLICATIONS: The anti-inflammatory effects of C66 are mediated by inhibiting HG-induced activation of the JNK/NF-κB pathway, rather than by reducing blood glucose in diabetic rats. This novel compound is a potential anti-inflammatory agent and might be beneficial for the prevention of diabetic nephropathy.