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

CD206+ M2-like macrophages regulate systemic glucose metabolism by inhibiting proliferation of adipocyte progenitors

Adipose tissue resident macrophages have important roles in the maintenance of tissue homeostasis and regulate insulin sensitivity for example by secreting pro-inflammatory or anti-inflammatory cytokines. Here, we show that M2-like macrophages in adipose tissue regulate systemic glucose homeostasis by inhibiting adipocyte progenitor proliferation via the CD206/TGFβ signaling pathway. We show that adipose tissue CD206+ cells are primarily M2-like macrophages, and ablation of CD206+ M2-like macrophages improves systemic insulin sensitivity, which was associated with an increased number of smaller adipocytes. Mice genetically engineered to have reduced numbers of CD206+ M2-like macrophages show a down-regulation of TGFβ signaling in adipose tissue, together with up-regulated proliferation and differentiation of adipocyte progenitors. Our findings indicate that CD206+ M2-like macrophages in adipose tissues create a microenvironment that inhibits growth and differentiation of adipocyte progenitors and, thereby, control adiposity and systemic insulin sensitivity

A MORPHOLOGICAL STUDY ON PULMONARY VASCULAR RESPONSE TO UNILATERAL HYPOXIA IN GUINEA PIG

この論文は国立情報学研究所の学術雑誌公開支援事業により電子化されました。In 1946,Euler reported pulmonary arterial hypertension occurred through induction of alveolar hypoxia in cats. In his report, Euler attributed the pressure rise to constriction of pulmonary vascular bed. Although a large number of studies have been done on this problem since then, no clear-cut evidence for pulmonary vascular constriction have been obtained so far, mainly due to lack of proper experimental methods. In 1962,Staub reported rapid freezing method of the lung with liquid propane or liquid nitrogen for the purpose of visualizing the pulmonary circulatory hemodynamics on morphological base. Utilizing his method, we designed an experiment to solve a few problems on the reactivity of pulmonary vascular bed of guinea pig as follows. -1) Whether hypoxic stimulus can actually induce constriction of pulmonary vascular bed or not? 2) Site of constriction within the vascular bed, if the constriction can be induced by hypoxia. 3) The mechanism of constriction

EFFECT OF UNILATERAL HYPOXIA ON THE DISTRIBUTION OF PULMONARY BLOOD FLOW IN MAN

この論文は国立情報学研究所の学術雑誌公開支援事業により電子化されました。1) We induced unilateral pulmonary hypoxia in human subjects by means of divided ventilation using Carlens tube. Decrease in pulmonary blood flown in hypoxic lung was demonstrated by lung scanning method using I^ MAA. 2) The response occurred without accompanying systemic hypoxia or pulmonary arterial pressure rise. 3) The response occurred only when P_> is lower than P_>. 4) The flow reduction is the result of pulmonary blood flow shift from hypoxic to hyperoxic lung area due to regional vasoconstriction in hypoxic lung area

SYMPATHETIC NERVOUS CONTROL OF THE PULMONARY VESSELS IN EXPERIMENTAL PULMONARY EMBOLISM

この論文は国立情報学研究所の学術雑誌公開支援事業により電子化されました。In the acute stage of the pulmonary embolism, so-called Bezold-Jarisch-like reflexes are brought about which include bradycardia, systemic hypotension, pulmonary hypertension and hyperventilation following hypoventilation. There have been many works which dealt with pulmonary hypertension induced by experimental pulmonary embolism that are ascribed to the mechanical obstruction of the pulmonary vascular beds. But recently many investigators have revealed the possibility of concomitant pulmonary vasoconstriction along with the mechanical obstruction. Dexter et al showed in 1963 that arteriolar embolization caused active vasoconstriction in opposition to prearteriolar embolization by comparing the embolized vascular areas with grades of pulmonary hypertension when different sizes of emboli were injected into the pulmonary arteries. Bernthal and Aviado utilized the perfusion technique with constant pressure and constant flow respectively in order to measure the active vasoconstriction and emphasized that an intrinsic or sympathetic regulation of the vasoconstriction plays an important role in pulmonary embolism. The possibility of vasoconstriction in pulmonary embolism has been re-examined in this study by the method of constant flow perfusion of the left lower lobe and the rapid freezing method

Long-term outcomes after percutaneous coronary intervention for chronic total occlusion (from the CREDO-Kyoto registry cohort-2).

Despite improving success rate of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) lesions, the clinical benefit of recanalization of CTO is still a matter of debate. Of 13, 087 patients who underwent PCI in the CREDO-Kyoto registry cohort-2, 1, 524 patients received PCI for CTO (CTO-PCI). Clinical outcomes were compared between 1, 192 patients with successful CTO-PCI and 332 patients with failed CTO-PCI. In-hospital death tended to occur less frequently in the successful CTO-PCI group than in the failed CTO-PCI group (1.4% vs 3.0%, p = 0.053). Through 3-year follow-up, the cumulative incidence of all-cause death was not significantly different between the successful and failed CTO-PCI groups (9.0% vs 13.1%, p = 0.18), whereas the cumulative incidence of cardiac death was significantly less in the successful CTO-PCI group than in the failed CTO-PCI group (4.5% vs 8.4%, p = 0.03). However, after adjusting confounders, successful CTO-PCI was associated with lesser risk for neither all-cause death (hazard ratio 0.93, 95% confidence interval 0.64 to 1.37, p = 0.69) nor cardiac death (hazard ratio 0.71, 95% confidence interval 0.44 to 1.16, p = 0.16). The cumulative incidence of coronary artery bypass grafting (CABG) was remarkably less in patients with successful PCI compared with those with failed PCI (1.8% vs 19.6%, p <0.0001). In conclusion, successful CTO-PCI compared with failed PCI was not associated with lesser risk for 3-year mortality. However, successful CTO-PCI was associated with significantly less subsequent CABG