The Selected Traditional Chinese Medicinal Formulas for Treating Diabetic Nephropathy: Perspective of Modern Science

ABSTRACTWith the increasing patients and limited therapeutic options, diabetic nephropathy (DN) is a long-term complication of diabetic mellitus. The precise mechanism of DN is not yet fully understood and the effective blockade of the progression of nephropathy remains a therapeutic challenge. Application of traditional Chinese medicine (TCM) for diabetes and its related complications has received increasing attention due to its wide availability, low side effects, and proven therapeutic mechanisms and benefits. In the current review, we mainly focus on the recent laboratory studies of the TCM formulas including Wu-Ling-San (Poria Five Powder; 五苓散 Wǔ Líng Sǎn), Danggui-Buxue-Tang (Tangkuei and Astragalus Decoction; 當歸補血湯 Dāng Guī Bǔ Xuè Tang), and Danggui-Shaoyao-San (Tangkuei and Paeonia Formula; 當歸芍藥散 Dāng Guī Sháo Yào Sǎn), conducted by the Committee on Chinese Medicine and Pharmacy at the Department of Health of Taiwan Government, in the amelioration of DN. These selected TCM formulas have anti-diabetic properties, with antihyperglycemic activity accompanied by amelioration of advanced glycation end product–mediated renal damage in streptozotocin-induced diabetic rats. However, the renoprotective effects of the selected TCM formulas did not correlate with suppressing renal renin–angiotensin system hyperactivity in diabetic rats. These TCM formulas also have the capacity to ameliorate the defective antioxidative defense system, leading to modulation of the oxidative stress, thereby resulting in downregulation of nuclear factor-κB as well as transforming growth factor-β1 and, consequently, attenuation of extracellular matrix components such as fibronectin or type IV collagen expression in diabetic renal cortex tissue. More detailed mechanistic researches and long-term clinical evaluations, as well as evaluation of safety of the selected TCM formulas are needed for their future applications in DN therapy

Myricetin Ameliorates Defective Post-Receptor Insulin Signaling via β-Endorphin Signaling in the Skeletal Muscles of Fructose-Fed Rats

β-Endorphin plays a major role in the amelioration of insulin resistance. The present study documents that myricetin (3,5,7,3′, 4′, 5′-hexahydroxyflavone) ameliorates insulin resistance by enhancing β-endorphin production in insulin-resistant rats. The rats were induced for insulin resistance by feeding them a diet containing 60% fructose for 6 weeks. The degree of insulin resistance was measured by the homeostasis model assessment of basal insulin resistance (HOMA-IR). The plasma levels of insulin and β-endorphin were measured by an enzyme-linked immunosorbent assay. The insulin receptor-related signaling mediators in the soleus muscles of rats were evaluated by immunoprecipitation or immunoblotting. Myricetin was injected daily (1 mg kg−1 per injection, thrice daily) for 14 days. Consequently, the high-glucose plasma levels in fructose-fed rats decreased significantly concomitant with an increase in plasma β-endorphin. The reduction of the elevated HOMA-IR index following treatment with myricetin was subsequently inhibited by the administration of β-funaltrexamine hydrochloride (β-FNA) at doses sufficient to block μ-opioid receptors (MOR). The myricetin treatment was also observed to affect the phosphorylation of the insulin receptor, insulin receptor substrate-1, Akt and Akt substrate of 160 kDa, with subsequent effects on glucose-transporter subtype 4 translocation, all of which were blocked by β-FNA pretreatment. These results indicated that enhancement of β-endorphin secretion, which in turn leads to peripheral MOR activation, is involved in the action of myricetin on the amelioration of impaired signaling intermediates downstream of insulin receptors

A Chinese Herbal Decoction, Dang Gui Bu Xue Tang, Prepared from Radix Astragali and Radix Angelicae sinensis, Ameliorates Insulin Resistance Induced by A High-Fructose Diet in Rats

Dang Gui Bu Xue Tang (DBT), a Chinese medicinal decoction contains Radix Angelicae sinensis (Danggui) and Radix Astragali (Huangqi) at a ratio of 1 : 5, is used commonly for treating women's ailments. This study was conducted to explore the effects of this preparation on insulin resistance in rats fed with 6-week diet containing 60% fructose. Similar to the action of rosiglitazone (4 mg kg−1 per day by an oral administration), repeated oral administration of DBT (2.5 g kg−1 per day) for 14 days was found to significantly alleviate the hyperglycemia but made no influence on plasma lipid profiles nor weight gain in fructose chow-fed rats. Also, the higher degree of insulin resistance as measured by homeostasis model assessment of basal insulin resistance in fructose chow-fed rats was significantly decreased by repeated DBT treatment. DBT displays the characteristic of rosiglitazone by increasing the whole-body insulin sensitivity in fructose chow-fed rats after 2-week treatment, as evidenced by the marked elevation of composite whole-body insulin sensitivity index during the oral glucose tolerance test. DBT improves insulin sensitivity through increased post-receptor insulin signaling mediated by enhancements in insulin receptor substrate-1-associated phosphatidylinositol 3-kinase step and glucose transporter subtype 4 translocation in soleus muscles of animals exhibiting insulin resistance. DBT is therefore proposed as potentially useful adjuvant therapy for patients with insulin resistance and/or the patients who wish to increase insulin sensitivity

Beneficial Effect of Traditional Chinese Medicinal Formula Danggui-Shaoyao-San on Advanced Glycation End-Product-Mediated Renal Injury in Streptozotocin-Diabetic Rats

The present study was undertaken to characterize the effects of Danggui-Shaoyao-San (DSS), a famous traditional Chinese medicine formula consisting of six herbal medicines, on diabetic nephropathy. Streptozotocin-induced diabetic rats were orally administrated DSS (2.8 g kg−1 per day) for 12 consecutive weeks. DSS partially decreased the high plasma glucose level in diabetic rats. Diabetic-dependent alterations in urinary albumin, 24-hour urinary albumin excretion rate, and creatinine clearance as well as the kidney hypertrophy (kidney weight/body weight ratio) and glomerular mesangial matrix expansion were ameliorated after 12 weeks of DSS treatment. The increased expression of nuclear factor-κB as well as transforming growth factor-β1 and the progressive accumulation of type IV collagen in kidney of diabetic rats were also attenuated by DSS. Not only the elevated levels of advanced glycation end products (AGEs) and Nε-(carboxymethyl)lysine but also the higher levels of lipid peroxidation products in kidney of diabetic rats were ameliorated by DSS. Decreased activity of superoxide diamutase and glutathione peroxidase in kidney of diabetic rats was enhanced by DSS. These data demonstrated that the renoprotective effects of DSS in STZ-diabetic rats not only were attributable to regulate plasma glucose to attenuate AGEs expression in diabetic glomeruli but also likely reflected its antioxidant activity

Myricetin Increases Hepatic Peroxisome Proliferator-Activated Receptor α Protein Expression and Decreases Plasma Lipids and Adiposity in Rats

The aim of this study was to investigate the antiobesity and antihyperlipidaemic effects of myricetin. Myricetin exhibited a significant concentration-dependent decrease in the intracellular accumulation of triglyceride in 3T3-L1 adipocytes. The high-fat diet (HFD)-fed rats were dosed orally with myricetin or fenofibrate, once daily for eight weeks. Myricetin (300 mg kg−1 per day) displayed similar characteristics to fenofibrate (100 mg kg−1 per day) in reducing lowered body weight (BW) gain, visceral fat-pad weights and plasma lipid levels of HFD-fed rats. Myricetin also reduced the hepatic triglyceride and cholesterol contents, as well as lowered hepatic lipid droplets accumulation and epididymal adipocyte size in HFD-fed rats. Myricetin and fenofibrate reversed the HFD-induced down-regulation of the hepatic peroxisome proliferator activated receptor (PPAR)α. HFD-induced decreases of the hepatic protein level of acyl-CoA oxidase and cytochrome P450 isoform 4A1 were up-regulated by myricetin and fenofibrate. The elevated expressions of hepatic sterol regulatory element binding proteins (SREBPs) of HFD-fed rats were lowered by myricetin and fenofibrate. These results suggest that myricetin suppressed BW gain and body fat accumulation by increasing the fatty acid oxidation, which was likely mediated via up-regulation of PPARα and down-regulation of SREBP expressions in the liver of HFD-fed rats

Emodin, a Naturally Occurring Anthraquinone Derivative, Ameliorates Dyslipidemia by Activating AMP-Activated Protein Kinase in High-Fat-Diet-Fed Rats

The aim of this study was to investigate the antiobesity and antihyperlipidaemic effects of emodin on high-fat diet (HFD)-induced obese rats, and on the regulation of the expression of the genes involved in lipid metabolism to elucidate the mechanisms. After being fed HFD for two weeks, Wistar rats were dosed orally with emodin (40 and 80 mg kg−1) or pioglitazone (20 mg kg−1), once daily for eight weeks. Emodin (80 mg kg−1 per day) displayed similar characteristics to pioglitazone (20 mg kg−1 per day) in reducing body weight gain, plasma lipid levels as well as coronary artery risk index and atherogenic index of HFD-fed rats. Emodin also caused dose related reductions in the hepatic triglyceride and cholesterol contents and lowered hepatic lipid droplets accumulation in HFD-fed rats. Emodin and pioglitazone enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and its primary downstream targeting enzyme, acetyl-CoA carboxylase, up-regulated gene expression of carnitine palmitoyl transferase 1, and down-regulated sterol regulatory element binding protein 1 and fatty acid synthase protein levels in hepatocytes of HFD-fed rats. Our findings suggest emodin could attenuate lipid accumulation by decreasing lipogenesis and increasing mitochondrial fatty acid β-oxidation mediated by activation of the AMPK signaling pathway

Absence of Genotoxic and Mutagenic Effects of Zingiber zerumbet

The present study evaluated the potential genotoxicity of the ethanol extracts from the rhizome of Zingiber zerumbet (L.) Smith (EEZZR) using a standard battery of tests. Chemical analysis with liquid chromatography-tandem mass spectrometry revealed that EEZZR contained Zerumbone (200.3±0.37 μg/g) and 6-gingerol (102.5±0.28 μg/g). There were no increases in the number of revertant colonies with EEZZR at concentrations of 150–5000 μg per plate, regardless of the metabolic activation system (S-9 mix) used in the histidine-dependent auxotrophic mutants of Salmonella typhimurium (strains TA97, TA98, TA100, TA102, and TA1535) compared to the vehicle control. Furthermore, EEZZR at doses of 150–5000 μg mL-1 did not increase the number of structural aberrations in Chinese hamster lung cells in the presence or absence of S-9 mix. An oral administration of EEZZR to ICR mice, with doses of up to 2000 mg/kg, caused no significant increases in the number of micronucleated polychromatic erythrocytes (MNPCEs) and mean ratio of polychromatic erythrocytes to total erythrocytes. Lastly, RZZEE did not increase the incidence of MNPCEs in bone marrow. Based on these findings, it may be concluded that the use of EEZZR in traditional medicine poses no risk of genotoxicity

Acute and 28-Day Subchronic Oral Toxicity of an Ethanol Extract of Zingiber zerumbet

The objective of this study was to evaluate the acute and subacute toxicity (28 days) of the ethanol extract of Z. zerumbet rhizomes (EEZZ) via the oral route in Wistar rats of both sexes. In the acute toxicity study, Wistar rats were administered a single dose of 15 g kg−1 of body weight by gavage, and were monitored for 14 days. EEZZ did not produce any toxic signs or deaths; the 50% lethal dose must be higher than 15 g kg−1. In the subchronic toxicity study, EEZZ was administered by gavage at doses of 1000, 2000 and 3000 mg/kg daily for 4 weeks to Wistar rats. The subacute treatment with EEZZ did not alter either the body weight gain or the food and water consumption. The hematological and biochemical analysis did not show significant differences in any of the parameters examined in female or male groups. Necropsy and histopathological examination, did not reveal any remarkable and treatment related changes. A no-observed adverse-effect level for EEZZ is 3000 mg kg−1 for rats under the conditions of this study. Hence, consumption of EEZZ for various medicinal purposes is safe

Antioxidant-Rich Extract from Plantaginis Semen Ameliorates Diabetic Retinal Injury in a Streptozotocin-Induced Diabetic Rat Model

Plantaginis semen, the dried ripe seed of Plantago asiatica L. or Plantago depressa Willd. (Plantaginaceae), has been traditionally used to treat blurred vision in Asia. The aim of this work was to investigate the effect of plantaginis semen ethanol extract (PSEE) on the amelioration of diabetic retinopathy (DR) in streptozotocin (STZ)-diabetic rats. PSEE has abundant polyphenols with strong antioxidant activity. PSEE (100, 200 or 300 mg/kg) was oral administrated to the diabetic rats once daily consecutively for 8 weeks. Oral administration of PSEE resulted in significant reduction of hyperglycemia, the diameter of the retinal vessels, and retinal vascular permeability and leukostasis in diabetic rats. In addition, PSEE administration increased the activities of superoxidase dismutase (SOD) and catalase (CAT), and glutathione peroxidase (GSH) level in diabetic retinae. PSEE treatment inhibited the expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) and the phosphorylation of Akt without altering the Akt protein expression in diabetic retinae. PSEE not only down-regulated the gene expression of hypoxia-inducible factor-1α (TNF-α) and interleukin-1β (IL-1β), but also reduced ICAM-1 and VCAM-1 expression in diabetic retinae. Moreover, PSEE reduced the nuclear factor-κB (NF-κB) activation and corrected imbalance between histone deacetylases (HDAC) and histone acetyltransferases (HAT) activities in diabetic retinae. In conclusion, phenolic antioxidants extract from plantaginis semen has potential benefits in the prevention and/or progression of DR