Effects of total flavonoids from Oxytropis falcata Bunge on the SOCS/JAK/STAT inflammatory signaling pathway in the kidneys of diabetic nephropathy model mice

To investigate the effects of total flavonoids from Oxytropis falcata Bunge on the inflammatory signaling pathway suppressor of cytokine signaling (SOCS)/Janus kinase (JAK)/signal transducer and activator of transcription (STAT) in diabetic nephropathy KK-Ay mice. KK-Ay mice were used to establish a diabetic nephropathy model. The general condition of the mice treated with different concentrations of total flavonoids from O. falcata was monitored, respectively. Body weight, blood glucose, 24-h urinary albumin (UAlb), serum creatinine (Cre), blood urea nitrogen (BUN), and uric acid (UA) levels were measured at different time points. Hematoxylin and eosin staining quantitative reverse transcription-polymerase chain reaction and western blotting were used to detect changes in renal tissues and glomerular mesangial cells. Four weeks after model establishment, body weight, blood glucose, and 24 h UAlb significantly increased in KK-Ay mice compared with that in control C57BL/6j mice ( P < 0.05). Compared with non-treated model mice, mice treated with total flavonoids from O. falcata for 4 weeks had significantly decreased serum Cre, BUN, and UA; monocyte chemoattractant protein-1(MCP-1), nuclear factor(NF)-κB, interleukin(IL)-6, and transforming growth factor(TGF)-β1, JAK 1, STAT 3 and STAT 4 mRNA levels; and p-JAK2 and p-STAT1 protein levels and significantly increased SOCS-1 and SOCS-3 protein levels in the kidneys. The treatment effects were dose-dependent and same to in vitro. Our results reflected that total flavonoids from O. falcata relieved renal tissue inflammation in diabetic mice by reducing blood glucose levels and inhibiting JAK/STAT signaling, thereby protecting against the development of diabetic nephropathy.

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PENGARUH PEMBERIAN KOMBINASI EKSTRAK BUAH MENGKUDU (Morinda citrifolia L.) DAN KUNYIT (Curcuma longa) TERHADAP HISTOPATOLOGI GINJAL TIKUS WISTAR YANG DIINDUKSI ALLOXAN

Jurnal Ilmiah Ibnu Sina (JIIS): Ilmu Farmasi dan Kesehatan ◽

10.36387/jiis.v5i2.513 ◽

2020 ◽

Vol 5 (2) ◽

pp. 319-327

Author(s):

Pelastri Rahayu ◽

◽

Retno Hestiningsih ◽

Martini Martini ◽

Dwi Sutiningsih ◽

...

Keyword(s):

Body Weight ◽

Diabetic Nephropathy ◽

Blood Glucose ◽

Curcuma Longa ◽

Morinda Citrifolia ◽

Control Group ◽

Type I ◽

Turmeric Extract ◽

Measurement Results ◽

Diabetes Nephropathy

The prevalence of DM in Riskesdas in 2018 according to the Perkeni consensus in 2015 is higher than according to the Perkeni consensus in 2011, the prevalence was10.9%. The disease can develop into diabetes nephropathy, Increased prevalence of diabetic nephropathy directly proportional with an increase in diabetes prevalence. Diabetic nephropathy is a microvascular complication in diabetics that develops around 30% in patients with type I DM and about 40% in patients with type II DM. Turmeric extract has antioxidant and anti-inflammatory effects to prevent the bad development of diabetes nephropathy. This study looked at the effect of giving a combination of noni and turmeric extract on histopathology of alloxan-induced renal rats. A total of 25 mice were divided into 5 treatment groups, namely the PI group (250 mg / kgBB extract dose), PII group (500 mg / kgBB extract dose), PIII group (750 mg / kgBB extract dose), positive control group (glibenklamid) and negative control group (without extract and glibenklamid). The study used Post Test Only Group. The highest percentage decrease in blood glucose in the PI group was 56.11% and the lowest decrease in the PIII group was 24.12% with p = 0.012. The results of the study were not based on the number of extract doses. The measurement results of rat body weight and glomerular diameter were not affected by blood glucose level with p = 0.700 for body weight and p = 0.187 for glomerular measurement results.

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Kyungheechunggan-Tang-01, a New Herbal Medication, Suppresses LPS-Induced Inflammatory Responses through JAK/STAT Signaling Pathway in RAW 264.7 Macrophages

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/7383104 ◽

2017 ◽

Vol 2017 ◽

pp. 1-15 ◽

Cited By ~ 4

Author(s):

Hee-Soo Han ◽

Eungyeong Jang ◽

Ji-Sun Shin ◽

Kyung-Soo Inn ◽

Jang-Hoon Lee ◽

...

Keyword(s):

Signaling Pathway ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Molecular Data ◽

Mrna Levels ◽

Protein Levels ◽

Stat3 Phosphorylation ◽

Stat Signaling ◽

Cox 2 ◽

Anti Inflammatory

Medicinal plants have been used as alternative therapeutic tools to alleviate inflammatory diseases. The objective of this study was to evaluate anti-inflammatory properties of Kyungheechunggan-tang- (KCT-) 01, KCT-02, and Injinchunggan-tang (IJCGT) as newly developed decoctions containing 3–11 herbs in LPS-induced macrophages. KCT-01 showed the most potent inhibitory effects on LPS-induced NO, PGE2, TNF-α, and IL-6 production among those three herbal formulas. In addition, KCT-01 significantly inhibited LPS-induced iNOS and COX-2 at protein levels and expression of iNOS, COX-2, TNF-α, and IL-6 at mRNA levels. Molecular data revealed that KCT-01 attenuated the activation of JAK/STAT signaling cascade without affecting NF-κB or AP-1 activation. In ear inflammation induced by croton oil, KCT-01 significantly reduced edema, MPO activity, expression levels of iNOS and COX-2, and STAT3 phosphorylation in ear tissues. Taken together, our findings suggest that KCT-01 can downregulate the expression of proinflammatory genes by inhibiting JAK/STAT signaling pathway under inflammatory conditions. This study provides useful data for further exploration and application of KCT-01 as a potential anti-inflammatory medicine.

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Constitutive activation of STAT-3 and downregulation of SOCS-3 expression induced by adrenalectomy

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.281.6.r2048 ◽

2001 ◽

Vol 281 (6) ◽

pp. R2048-R2058 ◽

Cited By ~ 24

Author(s):

Abram M. Madiehe ◽

Ling Lin ◽

Christy White ◽

H. Doug Braymer ◽

George A. Bray ◽

...

Keyword(s):

Dna Binding ◽

Signaling Pathway ◽

Leptin Receptor ◽

Binding Activity ◽

Janus Kinase ◽

Adrenal Steroids ◽

Western Blots ◽

Protein Levels ◽

Dna Binding Activity ◽

Stat Signaling

Removal of adrenal steroids by adrenalectomy (ADX) slows or reverses the development of many forms of obesity in rodents, including those that are leptin or leptin receptor deficient. Obesity is associated with hyperleptinemia and leptin resistance. We hypothesized that glucocorticoids impair leptin receptor signaling and that removal thereof would activate the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling pathway. The inhibitory effect of leptin (2.5 μg icv) on food intake was enhanced in ADX rats. A combination of ribonuclease protection assays, RT-PCR, Western blots, and mobility shift assays was used to evaluate the leptin signaling pathway in whole hypothalami from sham-operated, ADX and corticosterone-replaced ADX (ADX-R) Sprague-Dawley rats that were treated acutely with either saline vehicle or leptin intracerebroventricularly. ADX increased the expression of leptin receptor mRNA, increased STAT-3 mRNA and protein levels, induced constitutive STAT-3 phosphorylation and DNA binding activity, and also reduced suppressor of cytokine signaling-3 (SOCS-3) mRNA and protein levels. ADX and leptin treatment increased STAT-3 phosphorylation, but with no concomitant increase in DNA binding activity. Leptin and ADX decreased NPY mRNA expression, but their combination did not further decrease NPY mRNA. Corticosterone supplementation of ADX rats partially reversed many of these effects. In conclusion, ADX through activation of STAT-3 and inhibition of SOCS-3 activates the JAK-STAT signaling pathway. These effects most probably explain the ability to prevent the development of obesity by removal of adrenal steroids.

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Oleuropein alleviates gestational diabetes mellitus by activating AMPK signaling

Endocrine Connections ◽

10.1530/ec-20-0466 ◽

2020 ◽

Author(s):

Zhiwei Zhang ◽

Hui Zhao ◽

Aixia Wang

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Body Weight ◽

Blood Glucose ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Signaling Pathway ◽

Hepatic Glycogen ◽

Ampk Signaling ◽

Tnf Α

Background: Gestational diabetes mellitus (GDM) has a high incidence rate among pregnant women. The objective of the study was to assess the effect of plant-derived oleuropein in attenuating inflammatory and oxidative stress of GDM. Methods: Oleuropein was administered to GDM mice at the doses of 5 or 10 mg/kg/day. Body weight, blood glucose, insulin and hepatic glycogen levels were recorded. To evaluate the effect of oleuropein in reducing oxidative stress, enzyme-linked immunosorbent assay (ELISA) was used to measure the hepatic oxidative stress markers. The inflammation levels of GDM mice were evaluated by measuring serum levels of IL-6 and TNF-α by ELISA, and mRNA levels of IL-1β, TNF-α and IL-6 by real-time PCR (RT-PCR). The AMP-activated protein kinase (AMPK) signaling pathway was assessed by Western blot. Gestational outcome was analyzed through comparing litter size and birth weight. Results: Oleuropein attenuated the elevated body weight of GDM mice, and efficiently reduced blood glucose, insulin and hepatic glycogen levels. Oxidative stress and inflammation were alleviated by oleuropein treatment. The AMPK signaling was activated by oleuropein in GDM mice. Gestational outcome was markedly improved by oleuropein treatment. Conclusions: Our study suggests that oleuropein is effective in alleviating symptoms of GDM and improving gestational outcome in the mouse model. This effect is achieved by attenuating oxidative stress and inflammation, which is mediated by the activation of the AMPK signaling pathway.

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The expression of POMC and AgRP in brain and kidney tissues at different stages of diabetic nephropathy rats

Diabetic Nephropathy ◽

10.2478/dine-2021-0008 ◽

2021 ◽

Vol 1 (1) ◽

pp. 43-49

Author(s):

Shasha Liu ◽

Jingjing Da ◽

Jiayu Li ◽

Rong Dong ◽

Jing Yuan ◽

...

Keyword(s):

Body Weight ◽

Diabetic Nephropathy ◽

Blood Glucose ◽

Urinary Albumin Excretion ◽

Excretion Rate ◽

Kidney Tissue ◽

Albumin Excretion Rate ◽

Urinary Albumin ◽

Urinary Albumin Excretion Rate ◽

Albumin Excretion

Abstract Objective To explore the changes of proopiomelanocortin (POMC) and Agouti-Related Peptide (AgRP) expression in brain and kidney tissues under insulin intervention at different stages of diabetic nephropathy (DN) rats. Methods The male Sprague-Dawley (SD) rats of DN were treated with high-fat diet for 8 weeks and induced by intraperitoneally injection of streptozotocin (30 mg/kg) for one time. Then DN rats were also injected insulin subcutaneously at 2–5 U/(kg·24 h) from initiation of the streptozotocin. Kidney tissue, blood sample, and 24 h-urine were collected to detect the ratio of kidney/body weight, blood glucose and 24-h urinary albumin excretion rate at different stages (4, 8, 12, and 16 weeks). Immunohistochemistry assay was used to measure the expression of POMC and AgRP at different stages of DN rats. Results The DN rats were established successfully. With the progression of DN, blood glucose, 24-h urinary albumin excretion rate and kidney body weight ratio increased significantly, while decreased when insulin was injected. Immunohistochemistry showed that the expression levels of POMC were decreased gradually in brain and kidney tissues. Conversely, the expression of AgRP in kidney was highest at week 8 and then decreased gradually. The effect of insulin on normalizing POMC and AgRP expression in brain and renal tissues was also observed in DKD rats. Conclusion With the progression of DN, the expression of POMC and AgRP in kidney tissues was observed at different stages of disease, and their expressions were significantly normalized by insulin. The mechanism of in situ expression of POMC and AGRP in kidney to the progression of DN needs further investigations.

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Astragali Radix Contributes to the Inhibition of Liver Fibrosis via High-Mobility Group Box 1-Mediated Inflammatory Signaling Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/5574010 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Jianxia Wen ◽

Dan Wang ◽

Jian Wang ◽

Ruilin Wang ◽

Shizhang Wei ◽

...

Keyword(s):

Liver Fibrosis ◽

Signaling Pathway ◽

Type I Collagen ◽

Oral Treatment ◽

High Mobility ◽

High Mobility Group ◽

Type I ◽

Mrna Levels ◽

Inflammatory Signaling ◽

Astragali Radix

Astragali Radix (AR), the dried root of Astragali Radix membranaceus (Fisch.) Bge. or Astragali Radix membranaceus (Fisch.) Bge. var. mongholicus (Bge) Hsiao, is a commonly used traditional Chinese medicine for the treatment of liver diseases. This study aimed to comprehensively evaluate the pharmacological action and explore the potential mechanism of AR on liver fibrosis. Rats were administered with carbon tetrachloride for eight weeks, followed by oral treatment with AR for six weeks. The efficacy was confirmed by measuring liver function and liver fibrosis levels. The underlying mechanisms were explored by detecting the expression of related proteins. AR significantly decreased the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), collagen IV (COL-IV), hyaluronic acid (HA), laminin (LN), and precollagen type III (PCIII). In addition, AR inhibited the deposition of collagen and the activation of hepatic stellate cells. Those data strongly demonstrated that AR alleviated liver fibrosis by CCl4. In order to illustrate the potential inflammatory, the mRNA levels of IL-6, TNF-α, and IL-1β were detected. Subsequently, immunohistochemistry analysis was performed to further verify the expression of type I collagen. Finally, the expression of key proteins in the inflammatory signaling pathway was detected. AR significantly reduced the expression of high-mobility group box 1 (HMGB1), TLR4, Myd88, RAGE, and NF-κ B p65 genes and proteins. In addition, western blotting showed AR decreased the protein expression of RAGE, p-MEK1/2, p-ERK1/2, and p-c-Jun. Taken together, our data reveal that AR significantly inhibits liver fibrosis by intervening in the HMGB1-mediated inflammatory signaling pathway and secretion signaling pathway. This study will provide valuable references for the in-depth research and development of Astragali Radix against liver fibrosis.

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Abstract P207: Role of (Pro)Renin Receptor in the Pathogenesis of Colon Cancer

Hypertension ◽

10.1161/hyp.66.suppl_1.p207 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Akira Nishiyama ◽

Juan Wang ◽

Shinichi Yachida ◽

Genevieve Nguyen ◽

Takuo Hirose ◽

...

Keyword(s):

Colon Cancer ◽

Signaling Pathway ◽

Western Blotting ◽

Cell Number ◽

Ductal Adenocarcinoma ◽

Mrna Levels ◽

Protein Levels ◽

Colon Cancer Cell Lines ◽

Cancer Tissues

(Pro)renin receptor ((P)RR) is a component of the Wnt receptor complex (Science, 2010). We have recently demonstrated that (P)RR plays an important role in the tumorigenesis of pancreatic ductal adenocarcinoma via the activation of Wnt/β-catenin signaling pathway (Shibayama et al. Sci Rep. 2015). Since the patients with colon cancer often show aberrantly activated Wnt/β-catenin-dependent signaling pathway by the mutations of its components, we investigated the possible role of (P)RR and Wnt/β-catenin signaling pathway in carcinogenesis of colon cancer. Real-time PCR was used for measuring mRNA levels of (P)RR. Protein levels of (P)RR was determined by Western blotting and immunohistochemistry. Activated β-catenin levels were determined by Western blotting. Cell proliferative ability was evaluated by counting the cell number in cultured colon cancer cell lines, HCT116 and DLD-1 cells. As compared to normal colon tissues (n=6), mRNA and protein levels of (P)RR were increased by 2.6- and 2.2-fold, respectively, in colon cancer tissues (n=9), which were associated with increased activated β-catenin levels (by 2.8-fold, P<0.05). However, plasma soluble (P)RR levels were not changed in patients with colon cancer (n=9). (P)RR and activated β-catenin levels were also increased in HCT116 (by 2.2- and 2.7-fold, n=5, respectively) and DLD-1 cells (by 1.9- and 2.8-fold, n=5, respectively). In these cells, inhibiting (P)RR with an siRNA attenuated the activity of β-catenin and reduced the proliferative abilities (n=5, P<0.05, respectively). These data suggest that (P)RR contributes to the tumorigenesis of colon cancer through the activation of Wnt/β-catenin signaling pathway.

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Expression of Notch–Hif-1α signaling pathway in liver regeneration of rats

Journal of International Medical Research ◽

10.1177/0300060520943790 ◽

2020 ◽

Vol 48 (9) ◽

pp. 030006052094379

Author(s):

Yanshan Li ◽

Yunxiuxiu Xu ◽

Ruomei Wang ◽

Wenxin Li ◽

Wenguang He ◽

...

Keyword(s):

Cell Proliferation ◽

Body Weight ◽

Protein Expression ◽

Liver Regeneration ◽

Signaling Pathway ◽

Western Blotting ◽

Saline Control ◽

Control Group ◽

Mrna Levels ◽

Ki 67

Objective To investigate whether the Notch–Hif-1α signaling pathway is involved in liver regeneration. Methods Rats were divided into two groups and treated with daily intraperitoneal injections of saline (control) or the gamma-secretase inhibitor, Fli-06, for 2 days. Two-thirds of the rat livers were resected and rats were later euthanized at specific time points post-resection to analyze the remnant livers. Each group's liver/body weight ratio was calculated, and immunostaining and western blotting were used to determine the cell proliferation marker, PCNA and Ki-67 expression. Real-time PCR and western blotting were used to compare the mRNA expression of Notch homolog-1 ( Notch1), hairy and enhancer of split-1 ( Hes1), and vascular endothelial growth factor ( Vegf), and the protein expression of NICD and HIF-1α, respectively. Results The liver/body weight ratios and number of Ki-67- and PCNA-positive cells were significantly lower in the experimental group than the control group, indicating lower levels of liver regeneration following the disruption of Notch signaling by Fli-06. The Hes1 and Vegf mRNA levels and NICD and HIF-1α protein expression levels were all down-regulated by Fli-06 treatment. Conclusion Notch–Hif-α signaling pathway activation plays an important role in liver regeneration, where it may contribute toward liver cell proliferation.

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Synergistic reduction in albuminuria in type 2 diabetic mice by esaxerenone (CS-3150), a novel nonsteroidal selective mineralocorticoid receptor blocker, combined with an angiotensin II receptor blocker

Hypertension Research ◽

10.1038/s41440-020-0495-0 ◽

2020 ◽

Vol 43 (11) ◽

pp. 1204-1213

Author(s):

Kiyoshi Arai ◽

Yuka Morikawa ◽

Naoko Ubukata ◽

Kotaro Sugimoto

Keyword(s):

Diabetic Nephropathy ◽

Blood Glucose ◽

Mineralocorticoid Receptor ◽

Antihypertensive Effect ◽

Urinary Albumin ◽

Receptor Blocker ◽

Angiotensin Ii Receptor Blocker ◽

Angiotensin Ii Receptor ◽

Ay Mice

AbstractEsaxerenone is a novel selective mineralocorticoid receptor (MR) blocker that was recently approved in Japan to treat hypertension. In phase II and III studies, esaxerenone plus a renin–angiotensin system inhibitor markedly reduced the urinary albumin-to-creatinine ratio (UACR) in hypertensive patients with diabetic nephropathy. To evaluate a direct renoprotective effect by MR blockade independent of an antihypertensive effect in the context of diabetic nephropathy, esaxerenone (3 mg/kg), olmesartan (an angiotensin II receptor blocker; 1 mg/kg), or both were orally administered to KK-Ay mice, a type 2 diabetes model, once daily for 56 days. Urinary albumin (Ualb), UACR, and markers, such as podocalyxin, monocyte chemoattractant protein-1 (MCP-1), and 8-hydroxy-2′-deoxyguanosine (8-OHdG), were measured, along with systolic blood pressure (SBP), fasting blood glucose, and serum K+ levels. Prior to the initiation of drug administration, KK-Ay mice showed higher blood glucose, insulin, Ualb excretion, and UACR levels than C57BL/6 J mice, a nondiabetic control, indicating the development of diabetic renal injury. Combined treatment with esaxerenone and olmesartan significantly reduced the change in UACR from baseline compared with the change associated with vehicle at week 8 (−1.750 vs. 0.339 g/gCre; P < 0.002) and significantly inhibited the change in Ualb from baseline compared with the change associated with vehicle at week 8 (P < 0.002). The combination treatment also reduced urinary excretion of podocalyxin and MCP-1, but did not influence 8-OHdG excretion, SBP, blood glucose, or serum K+ levels. Overall, esaxerenone plus olmesartan treatment ameliorated diabetic nephropathy in KK-Ay mice without affecting SBP, suggesting that the renoprotective effects of esaxerenone could be exerted independently of its antihypertensive effect.

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Ameliorative Potentials of Cocoyam (Colocasia esculentaL.) and Unripe Plantain (Musa paradisiacaL.) on the Relative Tissue Weights of Streptozotocin-Induced Diabetic Rats

Journal of Diabetes Research ◽

10.1155/2013/160964 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 12

Author(s):

C. O. Eleazu ◽

M. Iroaganachi ◽

K. C. Eleazu

Keyword(s):

Body Weight ◽

Diabetic Nephropathy ◽

Blood Glucose ◽

Chemical Composition ◽

Growth Rates ◽

Diabetic Control ◽

Diabetic Rats ◽

Musa Paradisiaca ◽

Urine Assay ◽

Standard Techniques

Aim. To investigate the ameliorating potentials of cocoyam (Colocasia esculentaL.) and unripe plantain (Musa paradisiacaL.) incorporated feeds on the renal and liver growths of diabetic rats, induced with 55 and 65 mg/kg body weight of Streptozotocin.Method. The blood glucose level of the rats was measured with a glucometer, the protein and glucose and specific gravity (SPGR) in the urine samples of the rats were measured using urine assay strips and urinometer respectively. The chemical composition and antioxidant screening of the test feeds were carried out using standard techniques.Results. Administration of the test feeds for 21 days to the diabetic rats of groups 4 and 5, resulted in 58.75% and 38.13% decreases in hyperglycemia and amelioration of their elevated urinary protein, glucose, SPGR, and relative kidney weights. The diabetic rats administered cocoyam incorporated feeds, had 2.71% and 19.52% increases in weight and growth rates, the diabetic rats administered unripe plantain incorporated feeds had 5.12% and 29.52% decreases in weight and growth rates while the diabetic control rats had 28.69%, 29.46%, 248.9% and 250.14% decreases in weights and growth rates. The cocoyam incorporated feeds contained higher antioxidants, minerals and phytochemicals except alkaloids than unripe plantain feed.Conclusion. Cocoyam and unripe plantain could be useful in the management of diabetic nephropathy.

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