Effects of Oriental medicines on the production of advanced glycation endproducts

Advanced glycation endproducts (AGEs) are largely involved in the pathogenesis of diabetic nephropathy. It is apparent that inhibition of AGEs formation is important in preventing the occurrence and progression of nephropathy. Therefore, to seek possible AGEs inhibitors in Oriental medicines, we began our investigation with an in vitro evaluation system. Among the 12 Oriental medical prescriptions examined, Ompi-to inhibited AGEs formation to the greatest extent, followed by Tokaku-joki-to and Keishi-bukuryo-gan and Daio-botampi-to in that order. Among the 21 component galenicals examined, Rhei Rhizoma, Cinnamomi Cortex, Moutan Cortex and Paeoniae Radix all had a potent inhibitory action, indicating that Rhei Rhizoma, vascular system disturbance -eliminating drugs and tannin-containing crude drugs can all inhibit the formation of AGEs. These Oriental prescriptions and component galenicals proved to have more potent inhibitory activity than the positive control aminoguanidine. advanced glycation endproducts(AGE)は糖尿病性腎症の成因に大きく関与しており,AGE生成の抑制が腎症発症・進展防止に重要であることが知られている。このことから,本研究ではAGE阻害薬の可能性を和漢薬に求め,in vitroの評価系で検討した。使用した漢方方剤12種類のうち,最もAGE生成を抑制した漢方方剤は温脾湯で,次いで桃核承気湯,桂枝茯苓丸,大黄牡丹皮湯の順であった。実験に供した21種類の構成生薬では大黄,桂皮,牡丹皮,芍薬に強い抑制作用を認め,大黄剤,駆〓血剤ならびにタンニン生薬がAGEの生成を抑制しているものと考えられた。またこれらは陽性対照物質のアミノグアニジンより強い活性を示した

A study of Kampo medicines in a diabetic nephropathy model

The effects of four Kampo medicines, Ompi-to, Hachimi-jio-gan, Keishi-bukuryo-gan and Sairei-to, were investigated in rats with diabetic nephropathy induced by subtotal nephrectomy and injection of streptozotocin. To evaluate their effects on the glycation reaction, excessive activity of the polyol pathway and oxidative stress (abnormal bio-chemical processes induced by persistent hyperglycemia), we determined levels of the major endproducts of these processes: advanced glycation endproducts (AGEs) and sorbitol in the kidney and lipid peroxidation in the serum. These three processes were all enhanced in rats with untreated diabetic nephropathy. Oral administration of all four medicines significantly lowered AGEs levels. The renal sorbitol concentration was significantly lowered in the Hachimi-jio-gan-, Sairei-to- and Keishi-bukuryo-gan-treated groups compared with the untreated control group. Serum lipid peroxidation was significantly lowered in the Keishi-bukuryo-gan, Ompi-to and Sairei-to groups, while creatinine clearance and urinary protein excretion (parameters of renal function) were ameliorated by Keishi-bukuryo-gan and Hachimi-jio-gan, respectively, indicating retardation of the progression of diabetic nephropathy. These results suggest the potential therapeutic usefulness of Kampo medicines as a treatment for diabetic nephropathy. It is believed that their actions may occur through different mechanisms. 漢方方剤(温脾湯,八味地黄丸,桂枝茯苓丸,柴苓湯)の糖尿病性腎症に及ぼす影響を,モデルラットを用い検討した。慢性的な高血糖状態では糖化反応,ポリオール経路,酸化ストレスの亢進をひき起こすが,これらの指標の腎組織中のadvanced glycation endproducts(AGEs)とソルビトール,血中脂質過酸化量は,いずれも糖尿病性腎症ラットで有意に増加していた。これに対し,4種類の漢方方剤を投与した群では,いずれの場合も腎組織中のAGEsレベルが有意に低下していた。しかしソルビトール含量は八味地黄丸,柴苓湯,桂枝茯苓丸投与群で,血中脂質過酸化量は桂枝茯苓丸,温脾湯,柴苓湯投与群で有意に低下していた。また腎機能パラメーターのクレアチニンクリアランスと尿蛋白排泄量は桂枝茯苓丸,八味地黄丸投与群で有意に改善していた。このことから,4種類の漢方方剤はそれぞれ異なった作用機序で,糖尿病性腎症の進展を抑制している可能性が示唆された

Immunopharmacological properties of Oren-gedoku-to (a Kampo medicine, Huang-Lian-Jie-Du-Tang) on contact hypersensitivity reaction in mice

We investigated the effects of Oren-gedoku-to (Huang-Lian-Jie-Du-Tang), a Kampo medicine, on DNFB-induced contact hypersensitivity (CHS) response in mice in order to further clarify the immunopharmacological properties of this formulation. 1) Administration of Oren-gedoku-to decreased the magnitude of ear swelling in the CHS response and shortened the affected period. The inhibitory effect on ear swelling was observed even when Oren-gedoku-to was given orally with different timing schedules. 2) The expressions of mRNAs for CD8, IFN-7 and TNF-α in the ear of Oren-gedoku-to-treated mice were markedly decreased 24 h after the challenge. 3) The number of skin-draining regional lymph node cells (LNCs), CD4^+ T cells and CD8^+ T cells was decreased without affecting the ratio of CD8^+/CD4^+ T cells. 4) Oren-gedoku-to resulted in a marked impairment of the hapten-specific development of LNCs. These results suggest that the suppressive effect of Oren-gedoku-to on ear swelling was partly caused by the suppression of lymphocyte proliferation. 接触過敏反応(CHS)に対する黄連解毒湯の抑制効果について検討した。1g/kgの黄連解毒湯を感作日より連続投与することで,DNFB塗布による耳介の腫脹は軽減し,その持続時間も短縮した。また,黄連解毒湯の投与期間を変更(感作後0-2日間あるいは4-6日間の投与)しても抑制効果が認められた。耳介局所では,黄連解毒湯の連続投与により,CD8,IFN-γおよびTNF-αのmRNA発現は減弱した。所属リンパ節では,全リンパ節細胞,CD8^+T細胞,CD4^+T細胞の数が減少したが,CD8/CD4比に変化はみられなかった。さらに,リンパ節細胞のハプテン特異的な増殖能は抑制された。以上の結果より,黄連解毒湯のCHSの抑制効果にハプテン特異的リンパ球の増殖抑制が関与していると考えられた

A report of three cases of diabetic nephropathy satisfactorily treated with traditional herbal medicine

We reported that three cases of diabetic nephropathy, who had overt proteinuria, were treated satisfactorily not only for their symptoms but also renal nephropathy with traditional herbal medicine over the long term. In Case 1, the level of S-Cr had changed from 1.2 to 2.0 mg/dl over 98 months, in Case 2 from 0.9 to 1.9 mg/dl over 70 months, and in Case 3 from 1.1 to 2.9 mg/dl over 81 months, acceptably moderate increases, meaning that the progression of their renal insufficiency was controlled over the long term. At the same time, the symptoms of hotness, numbness and edema were improved. Diabetic nephropathy with overt proteinuria is known to develop into renal failure after several years. In these cases, traditional herbal medicine was considered responsible for improving their QOL and prolonging the pre-dialysis period of diabetic nephropathy. 顕性蛋白尿期にある糖尿病性腎症の患者に漢方治療を施行した。その結果,随伴する諸症状の改善のみならず長期問,腎機能低下の進行を抑制した3症例を経験したので報告した。症例lでは,98ケ月の観察でS-Cr値はl.2から2.0mg/dl,症例2では70ケ月の観察で,S-Cr値は0.9から1.9mg/dl,症例3では81ケ月の観察で,S-Cr値は1.1から2.9mg/dl,と長期間腎機能低下の進行を抑制した。同時に,手足の火照りやしぴれ感,下肢の浮腫などの症状の軽快も認めた。持続的に蛋白尿を認める顕牲腎症期に至った糖尿病性腎症は数年の経過で,末期腎不全から血液透析に至ると言われている。今回の症例から和漢薬は,糖尿病性腎症における腎機能障害に対して腎機能障害の進行抑制作用を有する可能性が示唆された。このことから,和漢薬は糖尿病に随伴する諸症状を緩和し,QOLを改善するのみでなく,血液透析導人までの期間を延長し,予後を改善したと考えられた

Evaluation of Keishi-bukuryo-gan in a diabetic nephropathy model by comparison with aminoguanidine, butylated hydroxytoluene and captopril

桂枝茯苓丸の糖尿病性腎症に対する作用を,モデルラットを用い検討した。腎機能パラメーター,病理組織学的検討に加え,advanced glycation end products(AGEs)の蓄積,酸化ストレスに及ぼす影響を,アミノグアニジン(AGEs阻害薬),カプトプリル(アンジオテンシン変換酵素阻害薬),buthylated hydroxytoluene(BHT)(抗酸化剤)とで比較検討した。桂枝茯苓丸では腎機能(血清Cr,尿蛋白排泄量)と病理所見の有意な改善作用が認められ,糖尿病性腎症の進展を抑制することが実験的に明らかとなったが,このような腎保護作用はカプトプリルよりは弱く,アミノグアニジンと同程度であった。BHTには腎保護作用は認められなかった。腎組織中のAGEsの蓄積に対しては,桂枝茯苓丸,カプトプリル,BHTがいずれも有意に低下していたが,アミノグアニジンの作用よりは弱かった。腎組織中の脂質過酸化量はBHTで最も低下し,桂枝茯苓丸,カプトプリルでも有意に低下していた。一方,血中脂質過酸化に対しては,すべてにおいて有意な低下作用が認められたが,カプトプリルで最も強かった。このことから,桂枝茯苓丸はカプトプリルやアミノグアニジンとは異なった機序で糖尿病性腎症の進展を抑制している可能性が示された。 A study was done to investigate whether Keishi-bukuryo-gan can delay the progression of diabetic nephropathy in an experimentally induced diabetic nephropathy model. The efficacy of Keishi-bukuryo-gan against renal functional and structural changes and its influence on accumulation of advanced glycation end-products (AGEs) and oxidative stress were also examined by comparison with aminoguanidine (an AGEs inhibitor), butylated hydroxytoluene (BHT; an antioxidant) and captopril (an angiotensin converting enzyme inhibitor). Treatment with Keishi-bukuryo-gan for 10 weeks preserved renal function, as assessed in terms of proteinuria and serum creatinine, and prevented the morphological changes peculiar to diabetic nephropathy. However, its renoprotective activity was inferior to that of captopril and comparable to that of aminoguanidine. BHT lacked any of these effects. On the other hand, renal AGEs accumulation and oxidative stress were significantly enhanced in rats with untreated diabetic nephropathy compared with normal rats. Keishi-bukuryo-gan, captopril and BHT showed significant reduction of AGEs levels, but not to the extent shown by aminoguanidine. Renal lipid peroxidation levels were significantly lowered in the groups given Keishi-bukuryo-gan and captopril, but not to the extent shown in the rats given BHT. The reduction of serum lipid peroxidation levels by captopril was stronger than that by BHT. The effects of Keishi-bukuryo-gan and aminoguanidine on serum lipid peroxidation levels were similar to those of BHT. These results suggest that the pharmaceutical characteristics of Keishi-bukuryo-gan may differ from those of the other three medicines examined

Effects of Keishi-bukuryo-gan (Gui-Zhi-Fu-Ling-Wan) on endothelial function in spontaneously hypertensive rats

We examined the protective effect of Keishi-bukuryo-gan (Gui-Zhi-Fu-Ling-Wan) (KB) against vascular endothelial disorder in spontaneously hypertensive rats (SHR). We administered KB extract (400 mg/kg/day, p.o.) to SHR for 14 weeks. Blood pressure and plasma viscosity in the KB group were significantly lower than in the SHR control group without KB, and the endothelium-dependent relaxation rate by acetylcholine in the KB group was significantly higher than that in the SHR control group. The rate of endothelium-dependent contraction induced by oxygen-derived free radicals produced by the xanthine-xanthine oxidase system was significantly lower in the KB group than in the SHR control group, and plasma lipid peroxide concentration was also significantly lower in the KB group than in the SHR control group. These results suggest the possibility that KB prevents vascular complications due to hypertension. 自然発症高血圧ラット(SHR)における血管内皮障害に対する桂枝茯苓丸(KB)の保護作用について検討した。KBエキス(400mg/kg/day)は,経口で14週間SHRに投与した。KB群の血圧と血漿粘度は,SHR対照群と比較して有意に低下した。内皮依存性血管弛緩作用はSHR対照群と比較してKB群で有意に増加した。キサンチン-キサンチンオキシダーゼ系による内皮依存性血管収縮作用はSHR対照群と比較してKB群で有意に減少し,血漿過酸化脂質はKB群で有意に低下した。このことから,桂枝茯苓丸が,高血圧症による血管合併症を予防する可能性が示唆された

Effects of Choto-san (Diao-Teng-San) on microcirculation of bulbar conjunctiva and hemorheological factors in patients with asymptomatic cerebral infarction

In this study, the effects of Choto-san ( 釣藤散 ) on the microcirculation of bulbar conjunctiva in 16 patients with asymptornatic cerebral infarction were investigated with a video-microscopic system. After the administration of Choto-san for four weeks, variables of microcirculatory flow of the bulbar conjunctiva, that is, the internal diameter of vessels, flow velocity and flow volume rate were increased (p<0.05) . Erythrocyte aggregability, evaluated by measuring the maximum diameter of a column of intravascular erythrocyte aggregation, was also improved (p<0.05) . Simultaneously, hemorheological factors such as whole blood viscosity, plasrna viscosity, erythrocyte deformability and leukocyte deformability were examined. Choto-san improved deformability of both erythrocytes and leukocytes (p<0.05) , but not blood viscosity. These results suggest that Choto-san may have favorable effects on cerebrovascular disorders through changes in microcirculatory flow, erythrocyte aggregability and blood cell deformability. 今回,無症候性脳梗塞患者16名を対象に,眼球結膜微小循環に及ぼす釣藤散の効果をビデオ顕徴鏡システムを用いて検討した。釣藤散を4週間投与後,眼球結膜微小循環の血管内径,血流速度,血流量が増加した(p<0.05)。血管内赤血球集合現象を認める血管の最大内径で評価ざれる赤血球集合能も改善した(p<0.05)。同時に,血液レオロジー因子である全血粘度,血漿粘度,赤血球変形能,白血球変形能も検討したところ,釣藤散は赤血球と白血球の変形能を改善したが(p<0.05),血液粘度は改善しなかった。以上の結果から,釣藤散は徴小循環血流や赤血球集合能,血球変形能を改善することで,脳血管障害に好影響を与える可能性が示唆された