Progress in Research of Kangxianling Decoction in Delaying Renal Fibrosis / 中国实验方剂学杂志

Renal fibrosis is a common pathological change in the later stages of all kidney diseases. It is a multi-cytokine, multi-signal pathway, multi-factor driven chronic kidney disease. It includes renal interstitial fibrosis, tubular sclerosis and glomerular sclerosis, which eventually leads to chronic renal failure. From health through injury to loss of function, the disease process is closely related to the degree of deterioration of renal function and the prognosis of chronic kidney disease. There is no effective western medicine for the treatment of renal fibrosis. Professor HE Liqun from Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine has summarized the Kangxianling decoction through decades of long-term practical experience. It has the effects in strengthening the spleen and replenishing Qi, clearing away dampness and heat, promoting blood circulation and removing phlegm, and strengthening turbidity. It is composed of Salviae Miltiorrhizae Radix et Rhizoma 15 g, Persicae Semen 12 g, Angelicae Sinensis Radix 12 g, Achyranthis Bidentatae Radix 9 g, Rhei Radix et Rhizoma 15 g. Kangxianling can affect the synthesis and secretion of cytokines and inflammatory factors by expanding blood vessels, and can improve renal tubular fibrosis. It has a good multi-channel, multi-target and multi-directional protective effect on renal function. It also can delay the progress of chronic renal fibrosis by significantly alleviating such symptoms as fatigue and edema in patients with chronic renal fibrosis, and reducing serum creatinine, urea nitrogen and urine protein. In this paper, 5/6 nephrectomy, ischemia reperfusion injury, adriamycin-induced nephropathy, unilateral ureteral obstruction and other different modeling methods are listed. The mechanism of Kangxianling decoction in antagonizing renal fibrosis is discussed and summarized, which further provided new ideas and directions for future clinical and scientific research.

Huaiqihuang Granules () reduce proteinuria by enhancing nephrin expression and regulating necrosis factor κB signaling pathway in adriamycin-induced nephropathy / 中国结合医学杂志

<p><b>OBJECTIVE</b>To investigate the effects of Huaiqihuang Granules (, HQH), a mixture of Chinese herbs including Trametes robiniophila Murr, Fructus Lycii and Polygonatum sibiricum, on adriamycininduced nephropathy (ADRN) in rats and its underlying mechanisms.</p><p><b>METHODS</b>Rats with ADRN were divided into four groups: the sham group, the model group (distilled water), the low-dose HQH-treated (2 g/kg) group, and the high-dose HQH-treated (4 g/kg) group. Body weight and 24-h urinary protein (Upro) were checked every week. After 5-week intervention, at the end of the study, the rats were sacrificed and blood samples were collected for examination of biochemical parameters, including glomerular morphological makers, podocyte shape, cellular apoptosis, expressions of nephrin, inflammatory and apoptosis markers.</p><p><b>RESULTS</b>HQH ameliorated the rat's general status, proteinuria, renal morphological appearance and glomerulosclerosis. The decreased expression of nephrin in ADRN rats was increased by HQH, as well as the impaired podocyte foot process fusion. Cytosolic levels of p65 and inhibitor of nuclear factor κBα (IκBα) were decreased in ADRN rats, and recovered by the treatment of HQH. Consistently, the induced expression of tumor necrosis factor α (TNF-α), phosphorylated nuclear factor κB p65 (p-NFκB p65) and IκBα in ADRN were markedly suppressed by HQH. In addition, induction of Bax, cleaved caspase-3 and cytochrome C in ADRN rats were suppressed by HQH, indicating the amelioration of apoptosis.</p><p><b>CONCLUSION</b>HQH could ameliorate renal impairments in ADRN rats by increasing nephrin expression, inhibiting NF-κB signaling pathway via the down-regulation of p-NF-κB p65 and p-IκBα, and suppression of glomerular and tubular apoptosis.</p>

Transplant of bone marrow mesenchymal stem cells via renal artery route in experimental rats with adriamycin-induced nephropathy: comparison of the repair effect on renal function between different times of transplant / 介入放射学杂志

Objective To compare the repair effect on renal function between different times of bone marrow mesenchymal stem cells (BMSCs) transplant via renal artery route in experimental rats with adriamycininduced nephropathy.Methods Adriamycin-induced nephropathy model was established in 32 rats through injection of adriamycin though the caudal vein.Based on the scheduled times of BMSCs transplant,the experimental rats were randomly and equally divided into M0 group (zero time),M1 group (one time),M2group (2 times) and M3 group (3 times) with 8 rats in each group.Other 8 SD rats were used as normal control group (N group).Single dose of 0.5 rnl BMSC suspension (2×106 cells/ml) was transplanted to the rats of M0 group (zero time),M1 group (one time),M2 group (2 times) and M3 group (3 times),for the rats of the groups not receiving BMSC transplant a single dose of 0.5 ml L-DMEM culture medium,used as a placebo,was adopted to replace BMSC suspension.The transplant interval was one week.Before transplant as well as one and two weeks after last time of transplant,the serum urea nitrogen,serum creatinine,24 h urine protein and 24 h urine microprotein were tested,and one week after last time of transplant pathological sections were made for laser focusing microscope examination to observe renal pathological changes and the distribution of BMSC cells in the kidney.Results The values of serum urea nitrogen,serum creatinine,24 h urine protein and 24 h urine microprotein determined at each observation time point in M0 group,M1 group,M2 group and M3 group were significantly higher than those in N group (P＜0.001).The values of 24 h urine protein and 24 h urine microprotein determined at one week after last time of transplant in M2 group and M3 group were strikingly lower than those in M1 group (P＜0.05),but these differences between M2 group and M3 group were not statistically significant (P=0.063).Conclusion For the treatment of adriamycin-induced nephropathy in experimental rats,two times of using BMSCs transplant via renal artery route can achieve optimal curative effect.

Influence of infusion of mesenchymal stem cells by different routes on the expression of AQP1 and AQP2 in rats with adriamycin-induced nephropathy / 介入放射学杂志

Objective To evaluate the therapeutic effect of bone marrow mesenchymal stem cell (MSC) infusion transplantation via renal artery and via caudal vein in treating chronic kidney disease (CKD) in rats,and to compare the expressions of aquaporin1 (AQP1) and aquaporin2 (AQP2) between the two transplantation routes.Methods A total of 50 male SD rats were selected for this experiment.Two experimental rats were used to make preparation of bone marrow MSC.CKD model was established with infusion of adriamycin via caudal vein in 36 rats.The 36 CKD models were randomly divided into adriamycininduced renal failure model control group (A-C group,n=12),MSC transplantation through the right renal artery group (M-A group,n=12) and MSC transplantation through the caudal vein group (M-V group,n=12).The remaining 12 male SD rats were used as the blank control group (N group).One week after the last bone marrow MSC transplantation,the 24 h urine volume,24 h urinary protein content,serum sodium content and serum albumin level were measured,and AQP1 and AQP2 expressions in the kidney tissue were determined by immunohistochemistry.Results Compared with A-C group,the serum albumin level and 24h urine volume in both M-V group and M-A group were significantly increased (P＜0.05),while 24h urinary protein content and serum sodium content were remarkably decreased (P＜0.05).The 24h urinary protein content in the M-A group was obviously lower than that in the M-V group (P＜0.05).The AQP1 and AQP2 expressions in the kidney tissue in both M-V group and M-A group were strikingly lower than those in the A-C group (P＜ 0.05),but no statistically significant differences in AQP1 and AQP2 expressions existed between the M-V group and the M-A group (P＞0.05).Conclusion MSC transplantation can increase serum albumin,and lower urinary protein,serum sodium and the expressions of AQP1 and AQP2 in renal parenchymal cells,which has the effect on repairing renal injury of adriamycin-induced CKD rats.For a given period of time,the clinical curative effect of MSC transplantation via renal artery is better than that of MSC transplantation via peripheral vein,but the difference in curative effect between the two MSC transplantation pathways has no obvious correlation with AQP1 and AQP2 expressions.

Effects of glucocorticoids on maxillary bone mineral density in rat model of adriamycin-induced nephropathy / 天津医药

Objective To evaluate effects of glucocorticoids on maxillary bone mineral density in rats with acute adriamycin-induced nephrotoxicity (ADR). Methods Forty rats were randomly divided into four groups, control group, glucocorticoids- treated group, ADR group and ADR + glucocorticoids- treated group. ADR group and ADR +glucocorticoids-treated group were given 4 mg/kg adriamycin injection via tail vein to establish ADR model. Control group and glucocorticoids-treated group were given 4 mg/kg saline injection via tail vein. After establishment of ADR model, glucocorticoids-treated group and ADR + glucocorticoids-treated group were intragastric administration of 30 mg/(kg · d) methylprednisolone for 10 weeks, and control group and ADR group were given the same volumes of normal saline. Values of bone calcium pigment (BGP), type Ⅰ collagen, N-terminal pro-peptide (PINP), β-Ⅰ type collagen C-terminal cross-linked telopeptide (CTX) were detected by ELISA. The micro-CT scan was used to measure Tb.Th, Tb.Sp, Tb.N, BVF and bone mineral density (BMD). Results Compared with other three groups, the levels of BGP and PINP were significantly decreased, and CTX were significantly increased in ADR + glucocorticoids-treated group (P<0.05). Micro-CT analysis showed that there was significant maxillae osteoporosis, including changes of porous micro architecture, lower BMD, decreased BVF, lower Tb.Th and widening Tb.Sp in ADR + glucocorticoids-treated group (P<0.05). There was no significant difference in Tb.N between four groups. Conclusion There is imbalanced bone metabolism in rat model of ADR. High-dose hormone therapy can accelerate the occurrence of osteoporosis, decrease bone metabolism, and affect bone structure.

Pregnancy in breast cancer survivor with anthracycline induced cardiomyopathy.

With earlier diagnosis and improved treatment modalities and management of breast cancer patients, survival is improving. An increasing number of survivors are in the reproductive age group; however a neglected medical area is contraceptive advice, failure of which can result in unwanted pregnancy and further medical complications. An undiagnosed pregnancy in a breast cancer survivor with known anthracycline- induced cardiomyopathy is presented here.

Total glucosides of paeony inhibits adriamycin-induced nephropathy in rats through blocking TLR4/NF-κB/TGF-β1 signaling / 中国生化药物杂志

Objective To study effect and its possible mechanism of total glucosides of paeony ( TGP ) on adriamycin-induced nephropathy rats.Methods Thirty male SD rats were randomly divided into normal group ( CON) , adriamycin-induced nephropathy group ( ADRN) and TGP-treated ADRN group (TGP).The rat nephropathy model was established by adriamycin injection.At the end of the 8th week after treatment, ELISA was used to detect the level of Cr and BUN.The values of 24 urine protein was determined by urinary protein kit.Masson staining was used to observe the fibrosis.RT-PCR was used to detect the mRNA levels of TLR4/NF-κB/TGF-β1 .Immunohistochemical method was used to detect the content of TLR4/NF-κB/TGF-β1.ResuIts Compared with the CON group, the level of Cr, BUN, 24 urine protein of ADRN group rised(P<0.01), the degree of fibrosis of ADRN group were aggravated(P<0.01), and the expressions of TLR4/NF-κB/TGF-β1 of ADRN group increased significantly.However, compared with ADRN group, the(P<0.01) level of Cr, BUN, 24 urine protein of TGP-treated rats reduced(P<0.01), the degree of fibrosis of TGP-treated rats eased(P<0.05), and the expressions of TLR4/NF-κB/TGF-β1 of TGP-treated rats decreased significantly.ConcIusion TGP retards the process of fibrosis and reduces the pathological damage in adriamycin-induced rats by down-regulating the expression of TLR4/NF-κB/TGF-β1 signaling.

Effect of reinforcing spleen and kidney on the p21 and TGF-β1 in renal tissue of adriamycin-induced CKD in rats / 国际中医中药杂志

Objective To investigate the effect of reinforcing spleen and kidney method on adriamycin-induced CKD in rats and to explore its possible mechanism.Methods Totally 36 Sprague-Dawley rats were randomly divided into a Adriamycin-induced model group and a control group.The model group was further divided into five groups:the Adriamycin-induced model control group,bennazepril-treated group,and TCM treated low,moderate,and high dose groups.The level of serum creatinine,urea nitrogen,24hours urine protein and urine creatinine were measured at 14,28,42 days after establishing the model rats.And the protein expression of transforming growth factor-β1 (TGF-β1) and cyclin-dependent kinase inhibitor p21cip1 (p21)were detected by immunohistochemistry.Results The proteinuria was observed on the seventh day after injection of adriamycin in adriamycin nephropathy model group,and reached summit on the fourteenth day.Both TCM treated groups and benazepril group reduced the level of urine protein within 24 hours (P＜0.05),the reduction was most remarkable in the TCM high dose group.The expression of p21 and TGF-β1 (p21 288627.66±97021.65,TGF-β1 98405.14± 19216.89) in kidney increased in the model groups,while the TCM treated high dose group (p21 518886.35±6810.89,TGF-β1 222012.95± 50484.73) was significantly lower than the model control group (P＜ 0.05).Conclusion Reinforcing spleen and kidney method could decrease the level of urine protein within 24 hours by regulating the expression of p21 and TGF-β1,so thus to protect renal function and delay progress of kidney disease.

The Influence of Different Infusion Methods of Bone Marrow Mesenchymal Stem Cells in Adriamycin Nephropathy Rat Model / 天津医药

Objective To investigate the effectiveness of bone marrow mesenchymal stem cell (MSC) and different transplantation methods of MSC on adriamycin (ADR) model of nephropathy in rats. Methods The ADR model of nephrop-athy was induced by left nephrectomy plus injection of ADR (2.5 mg/kg) in Sprague-Dawley (SD) rats, once a week for two weeks. The model rats with nephropathy were randomly divided into three groups: adriamycin nephropathic model control group (ADR, n=12), MSCs transplantation through right renal artery group (M-A, n=12) and MSCs transplantation through peripheral veins group (M-V, n=12). Another 12 SD rats were served as normal controls (N, n=12). MSCs were cultured, transplanted via right renal artery (2×106/mL) to rats in M-A group, and were transplanted via peripheral veins 2×106/mL) to rats in M-V group. The same procedure was repeated in two weeks. The blood urea nitrogen, serum creatinine, 24 h urine protein and 24 h uromicroprotein were detected before transplantation and in one and two weeks after the second transplanta-tion. The renal morphology and labeled cells were examined in the kidney one week after the second transplantation. Results The values of blood urea nitrogen, serum creatinine, 24 h urine protein and 24 h uromicroprotein were significant-ly higher in M-A group, M-V group and ADR group than those of N group (P<0.01). The level of 24 h uromicroprotein was significantly lower before the second transplantation in M-A group than that of ADR group (P<0.01). The serum level of cre-atinine was significantly decreased in M-A group than that of ADR group and M-V group (P<0.01). The levels of 24 h urine protein and 24 h uromicroprotein were significantly lower after one week transplantation in M-A group than those of M-V group (P<0.01). The serum level of creatinine was significantly lower two weeks after the second transplantation in M-A group than that of ADR group and M-V group (P<0.01), but no significant differences in the levels of urine protein and uro-microprotein between M-A group and M-V group. Conclusion Transplantation of MSCs can alleviate renal damage of chronic ADR-induced nephropathy, which is more effective in rats with MSCs transplantation via renal artery than that in rats with MSCs transplantation via peripheral vein.

Effect of prednisone on expression of Ezrin and NEPH1 in rats with Adriamycin-induced nephrosis / 中华实用儿科临床杂志

Objective To explore the mechanism of proteinuria and renal protection of prednisone by observing the expressions of Ezrin and NEPH1 in rats with Adriamycin (ADR)-induced nephrosis.Methods The 24 rats were divided into 3 groups,which were control group,model group and prednisone group.ADR model was induced by a tail intravenous injection of ADR for 2 times.Serum index and 24 h urinary protein were measured in 4 and 8 weeks.The expressions of Ezrin and NEPH1 in glomerulus were evaluated by using two-step immunohistochemistry respectively.Results Compared with control group,heavy proteinuria,hypoalbuminemia,hyperlipemia were observed in 4 weeks in the model group and the prednisone group which indicated that the models were successfully established.Compared with model group,in 8 weeks,24 h urinary protein,total cholesterol and serum creatinine in prednisone group were significantly decreased(all P ＜ 0.0 l),while albumin,total protein and endogenous creatinine clearance rate were significantly increased(all P ＜ 0.05) ;The expressions of Ezrin and NEPH1 in model group were significantly decreased compared with control group(all P ＜ 0.01).The expressions of Ezrin and NEPH1 in prednisone group were significantly increased compared with model group(all P ＜0.01).The expressions of Ezrin and NEPH1 were negatively related to proteinuria(r =-0.838,-0.884,all P ＜ 0.01).Conclusions The declined expressions of Ezrin and NEPH1 in rats with ADR-induced nephrosis may be one of mechanisms of proteinuria.Prednisone can reduce the proteinuria and relieve the renal pathological damage by improving the expression of Ezrin and NEPH1.

Effect and mechanism of Qishen Yiqi Pills on adriamycin- induced cardiomyopathy in mice / 中国天然药物

AIM@#To study the effect and probable mechanism of Qishen Yiqi Pills on adriamycin (ADR)-induced cardiomyopathy in mice.@*METHODS@#Sixty-four mice were randomly divided into (1) the ADR group: saline (1 mL/100 g) administered every day by intragavage, ADR (4 mg·kg(-1)) administered to each mouse by intraperitoneal injection twice a week for four weeks; (2) the ADR + Qishen Yiqi Pills I group: ADR (4 mg·kg(-1)) administered to each mouse by intraperitoneal injection twice a week for four weeks, and at the beginning of the third week Qishen Yiqi Pills (3.5 mg/100 g) administered by intragavage every day for four weeks; (3) the ADR + Qishen Yiqi Pills II group: ADR (4 mg·kg(-1)) administered to each mouse by intraperitoneal injection twice a week for four weeks, and at the same time Qishen Yiqi Pills (3.5 mg/100 g) administered by intragavage every day for four weeks; (4) the control group: saline (1 mL/100 g) administered every day by intragavage, saline (1 mL·kg(-1)) administered to each mouse by intraperitoneal injection twice a week for four weeks. Six weeks later, cardiac function, myocardial pathology, and expression of Bcl-2 and Bax were evaluated.@*RESULTS@#1. The left ventricular diastolic diameter and the left ventricular systolic diameter were significantly increased (P < 0.05) and the left ventricular ejection fraction was significantly decreased (P < 0.05) in the ADR group, and the cardiac function of both the ADR + Qishen Yiqi Pills I group and the ADR + Qishen Yiqi Pills II group improved. 2. Myocardial morphologic observation showed that the myocardial fibers were disordered, there was cell edema, and gap widening in the ADR group. The degree of myocardial cell injury was reduced in the ADR + Qishen Yiqi Pills I group and ADR + Qishen Yiqi Pills II group compared with the ADR group. 3. The expression of Bax in the ADR group was significantly up-regulated, and the expression of Bcl-2 was significantly downregulated in the ADR group compared with the ADR + Qishen Yiqi Pills I group, the ADR + Qishen Yiqi Pills II group, and the control group (P < 0.05).@*CONCLUSIONS@#Qishen Yiqi Pills can effectively improve the cardiac function of ADR-induced cardiomyopathy, and the earlier it is used is better. The probable mechanism of action may be the inhibition of the apoptosis of myocardial cells.

Efficacy research of immune inhibitors sequential therapy according to the cell cycle for the adriamYcin-induced nephropathy rats / 中华肾脏病杂志

Objective To assess the efficacy of different sequential therapy regimens according to the theory of cell cycle on adriamycin-induced nephropathy (AIN) rats. Methods SD rats were randomly divided into five groups:control group (n=8),AIN model group (n=8),MP+ CsA+MMF group (n=8),MP+CsA+CTX treated group (n=8) and MP+FK506+Rapa group (n=8).The levels of 24-hour urinary protein,serum total protein (TP),albumin (Alb),cholesterin (Chol),triglyeride (TG),serum urea nitrogen (BUN),serum creatinine (Scr) were measured.The renal pathological changes were observed by light microscope.The expressions of nephrin and podocin were analyzed by immunohistochemistry and real-time PCR.The expression of CTGF was detected by Western blotting. Results (1)Compared with control group,the levels of 24-hour urinary protein in AIN model group were obviously increased at 2nd,4th,8th and 12th week (all P＜0.01).The level of 24-hour urinary protein were obviously decreased in treatment groups at 8th and 12th week than those in AIN model group (all P＜0.05). (2)The levels of TP and Alb were significantly lower in AIN model group than those in control group (all P＜0.01),and the levels of TG and Chol were significantly higher in AIN model group than that in control group (all P＜0.01).The levels of TP and Alb were significantly higher and the levels of TG and Chol were significantly lower in treatment groups than those in AIN model group (all P ＜0.05). (3)The results of immunohistochemistry indicated the expressions of nephrin and podocin in treatment group rats were obviously higher than those in AIN model group (all P＜0.01). (4)The results of Western blotting indicated the expression of CTGF in treatment group rats was higher than that in AIN model group (P＜0.05).The effect of inhibitting fibrous degeneration in MP +FK506 +Rapa group was more greater than other treatment groups. Conclusions Sequential combined regimens according to the cell cycle can improve the pathological change in adriamycin-induced nephropathy rats,reduce the urine protein,increase the levels of TP and Alb,decrease the levels of TG and Chol,increase the expression of nephrin and podocin,and ameliorate kidney fibrosis.

Rhodiola decreases the expression of ?-smooth muscle actin in tuhulointerstitial of adriamycin-induced nephropathy rats / 基础医学与临床

Objective To find the effect of Rhodiola herb on the phenotypic transfer of epithelial cell in renal tubule of adriamycin-induced nephropathy rats.Methods The rat nephropathy model is established by adriamycin.For Rhodiola herb treated group,feed with Rhodiola herb 0.672 g/kg?d from the 4th week,for the control group and neohropathy group,feed with water [3 mL/(kg?d)].Kill the rats per batch at the week of 4th,8th,12th,16thand 20th week,observe the pathological change of nephridial tissue,test the expression of ?-SMA-protein of myofibroblast in the tuhulointerstitial.Results A semi-quantitative analysis of ?-SMA of rats at the 16th week in the nephropathy group is 6.24?0.57,which is obviously higher than that of Rhodiola herb treated group,3.84?0.28(P

Effect of hydrogen sulfide on myocardial structure and function of rats with adriamycin-induced dilated cardiomyopathy / 基础医学与临床

Objective This study was designed to investigate the importance of H2S in rats with adriamycin-induced dilated cardiomyopathy.Methods Weight-matched adult male Wistar rats were randomly divided into 5 groups as follows:(1)the ADR group(n=12)where adriamycin(2.5 mg/kg)was given once a week;(2)ADR + small-dose NaHS group(n=12)where NaHS solution [2.8 ?mol/(kg?d)] was given;(3)ADR+large-dose NaHS group(n=12)where NaHS solution [14 ?mol/(kg?d)] was given;(4)the control group(n=9)where physiological saline was administered instead of adriamycin.(5)NaHS group(n=9)where NaHS solution [14 ?mol/(kg?d)]was given.Hemodynamic and echocardiographic measurements were carried out after treatment.Histological examination was implemented at the 10th week after the rats were sacrificed.Meanwhile,H2S concentrations in serum and myocardial tissues were evaluated by modified sulfide electrode method.Results The heart function of ADR rats decreased obviously.Pathological examination demonstrated that characteristics consistentwith cardiomyopathy were found in ADR group.H2S concentrations in serum and myocardial tissues of the rats in ADR group were both significantly decreased as compared with those in the control group(both P

The role of hydrogen sulfide in adriamycin-induced dilated cardiomyopathy in rats / 中国药理学通报

Aim To investigate the effect of hydrogen sulfide(H2S) on apoptosis of myocardial tissues of adriamycin-induced dilated cardiomyopathy in rats and to explore the underlying mechanisms.Methods Weight-matched male Wistar rats were randomly divided into 5 groups as follows:(1) ADR group(n=12),2.5 mg?kg-1 of adriamycin was injected intraperitoneally once a week for 10 weeks(total dose of 25 mg?kg-1);(2) ADR+small-dose-NaHS group(n=12),the dosage and use of adriamycin were as mentioned above,while NaHS solution was injected to rats at a dosage of 2.8 ?mol?kg-1?d-1 at the same time;(3) ADR+large-dose-NaHS group(n=12),the dosage and use of adriamycin were as mentioned above,while NaHS solution was injected to rats at a dosage of 14 ?mol?kg-1?d-1 at the same time;(4) ADR+PPG group(n=12),in which the dosage and use of adriamycin were as mentioned above,while PPG solution was injected to rats at a dosage of 30 mg?kg-1?d-1;(5) control group(n=9),an equivalent volume of physiological saline was administered weekly for 10 weeks.(6) NaHS group(n= 9),14 ?mol?kg-1 of NaHS solution was injected to rats intraperitoneally for 10 weeks.Hemodynamic and echocardiographic measurements were obtained 10 weeks after treatment.Histological examination was implemented at the 10th week after sacrificed.And apoptotic index,Fas and Bcl-2 expressions in myocardiocytes were analyzed semiquantitatively by TUNEL or immunohistochemical analysis.Meanwhile,H2S concentrations in serum and myocardial tissues were evaluated by a modified sulfide electrode-based method.Results Left ventricular systolic pressure(LVSP),difference of left ventricular pressure(△LVP=left ventricular systolic pressure minus left ventricular diastolic pressure) and ventricular peak rate of contraction(+LV dp/dtmax),peak rate of relaxation(-LV dp/dtmax) were significantly reduced in the group of ADR rats(P0.05).Conclusion H2S might play an important role in the development of adriamycin-induced dilated cardiomyopathy.Administration of exogenous H2S could protect the cardiac function and myocardial pathological lesions via the down-regulation of augmented myocardiocyte apoptosis.

Protective Roles of Adenosine A1 Receptor Agonist and KATP Channel Opener in Adriamycin induced Cardiac Toxicity / 체질인류학회지

Although adriamycin is a potent chemotherapeutic agent, it elicits serious adverse effects, including cardiac toxicity. Evidence suggests that congestive heart failure induced by adriamycin is mediated by oxidative stress. We investigated whether regulators of adenosine A1 receptor and KATP channel, which have been demonstrated to mediate protective effects of ischemic -preconditioning in myocardium, are able to modulate adriamicin -induced impairment of cardiomyocyte. To study the effect of antioxidant, adenosine A1 receptor agonist & antagonist and KATP channel agonist & antagonist, ICR mice were pretreated with Cu,Zn -SOD, dimethyl thiourea, RPIA (R (-)N6 -(2 -Phenylisopropropyl)- adenosine, adenosine A1 receptor agonist), 8 -CPDPX (8 -Cyclopentyl -1, 3 -dipropylxanthine, adenosine A1 receptor antagonist), Pinacidil (KATP channel opener) and glibenclamide (KATP channel closer), followed by i.p injection with adriamycin. Mice were sacrificed day 1 or day 4 after adriamycin injection and cardiac toxicity was accessed by measurement of creatine phosphokinase (CK) levels in serum, immunohistochemistry using anti -Bcl -2 antibody and TUNEL histochemical assay. As expected, pretreatment of mice with Cu, Zn -SOD and DMTU reduced the frequency of TUNEL positive cells, indicating antioxidants protected cardiocytes from adriamycin -induced apoptosis. Interestingly, pretreatment with RPIA and pinacidil induced a significant decrease in adriamycin -induced cytotoxicity, whereas 8 -CPDPX and glibenclamide generated the opposite results. In Bcl -2 immunohistochemistry, an increased expression of Bcl -2 was found in all ADR treated groups, especially in glibenclamide pretreated group, and 8 -CPDPX pretreated groups, but Bcl -2 failed to protect myocytes from apoptosis. All ADR treated groups exhibited elevated levels of serum CK, compared with nomal controls, especially mice sacrificed at day 4 than those at day 1, and showed similar patterns of TUNNEL assay, reflecting heart tissue damages. This observation implicated cytoprotective roles of RPIA and pinacidil against adriamycin -induced cardiac toxicity. In conclusion, these results demonstrated that adriamycin -induced cardiotoxicity was associated with the generation of reactive oxygen species and that regulators including SOD, DMTU, RPIA and pinacidil elicited protective effects on this toxicity. In particular, pinacidil, the KATP channel opener, was more effective than RPIA, the adenosine A, receptor agonist, to attenate the adriamycin -induced cardiac toxicity.

Transthoracic Echocardiographic Assessment of Adriamycin-induced Cardiomyopathy in Rats with a 15 MHz Transducer

BACKGROUND: Adriamycin (doxorubicin) is one of the widely used drugs in the treatment of a variety of solid and hematologic malignancies. However, the adriamycin-induced cardiomyopathy limits the prolonged use of this effective drug. Transthoracic echocardiography is the excellent tool in early detection and follow-up studies of adriamycin-induced cardiomyopathy. The aim of this study was to assess the cardiac function and morphology using a 15 MHz high-frequency imaging in rats. METHODS: Adriamycin was administrated intraperitoneally by six equal injections at a dose of 2.5 mg/kg over a period of 2 weeks for total cumulative dose of 15 mg/kg body weight in 12 male Sprague-Dawley rats (weight 367+/-39 g). Transthoracic echocardiography with a 15 MHz linear-array transducer was performed at baseline and additionally at 3 weeks to measure the left ventricular wall thickness and dimension from the parasternal short axis view with 2D guided M-mode and pulsed Doppler signals of mitral inflow. Within 2 days of echocardiography, the heart was harvested for electron microscopic evaluation after potassium-induced cardiac arrest. RESULTS: 1) The mortality rate during the experimental period was 0%. 2) Transthoracic echocardiography provided adequate 2D guided M-mode images and pulsed Doppler signals of mitral inflow in all rats. 3) In follow-up echocardiography, pericardial effusion was detected in 7out of 12 rats (58%). 4) Compared to baseline, end-diastolic dimensions were increased from 7.01+/-0.69 to 7.74+/-1.25 mm (p<0.001), end-systolic dimensions were increased from 4.13+/-0.69 to 5.22+/-1.12 mm (p<0.05), and interventricular septal and posterior wall thickness at end-systole and end-diastole were significantly decreased (p<0.05, respectively). 5) Fractional shortening was decreased from 43.0+/-6.8 to 32.7+/-8.0%, compared to baseline (p<0.05). 6) E/A ratio of mitral inflow changed significantly from 1.63+/-0.36 to 2.78+/-1.0, compared to baseline (p<0.05). CONCLUSION: Adriamycin administration at total cumulative dose of 15 mg/kg body weight over 2 weeks creates a reliable model of non-ischemic dilated cardiomyopathy in rats with a high success rate. Transthoracic echocardiography using a 15 MHz transducer provides adequate images for assessing the cardiac function and morphology in follow-up studies in adriamycin-induced cardiomyopathy of rats. These results suggest that transthoracic echocardiography using a 15 MHz Transducer is a promising tool for an assessment of adriamycin-induced cardiomyopathy in small animals.

Effect of Haikun Shenxi Capsule on Endothelin-1 and mRNA Expression in Kidney Tissue of Rats with Adriamycin-induced Nephrosis and Proliferation of Glomerular Mesanglal Cells / 中医杂志

Objective To study the effect of Haikun Shenxi Capsule(HSC)on endothelin-1(ET-1)and mRNA expression of rats with adriamyein-induced nephrosis and proliferation of glomerular mesangial cells(GMCs)cultured in vitro.Methods The rats were randomized into 6 groups,normal group,sham operation group,model group,benazepril group,HSC low-and high-dose groups.Ten weeks after treatment,ET-1 and mRNA expression were measured with immunohistochemical and hybridization in situ method.Tak- ing the Benazepril group as the control group,the proliferation of GMCs was detected with MTT method.Results In the model group,ET-1 and mRNA expression presented a strong positive,compared with which,that of the HSC low-and high-dose groups was remarkably reduced(P

Modification of adriamycin-induced cytotoxicity by recombinant human interferon-gamma and/or verapamil in human stomach cancer cells

Recombinant human-interferon-gamma (rH-IFN-gamma) and verapamil (VRP), either alone or in combination, were evaluated in MTT assay for their modification effects on adriamycin-induced cytotoxicity against MKN-45, human stomach adenocarcinoma cells. VRP as a single agent did not inhibit the survival of MKN-45 at doses of up to 5.0 micrograms/ml. The survival of MKN-45 was inhibited by rH-IFN-gamma dose-dependently and further inhibited by the addition of VRP. However, the maximum growth inhibition of MKN-45 in any combination treatment with rH-IFN-gamma and VRP was less than 50% except in the highest concentration combinations (% survival: 47.9% at 10(4) U/ml of rH-IFN-gamma and 3.0 micrograms/ml of VRP). Adriamycin caused a concentration-dependent cytotoxicity and its cytotoxicity was significantly enhanced by the addition of rH-IFN-gamma and further enhanced by the combined use of rH-IFN-gamma and VRP. The modification effects of rH-IFN-gamma and VRP on adriamycin-induced cytotoxicity were evaluated in terms of modification index (MI), demonstrating that rH-IFN-gamma significantly increased in adriamycin-induced cytotoxicity and that the combined use of rH-IFN-gamma and VRP enhanced the adriamycin-induced cytotoxicity to a greater extent than did rH-IFN-gamma alone: MI values at 10(2) U/ml and 10(3) U/ml of rH-IFN-gamma were 1.7 and 3.1, respectively; those at 1.5 micrograms/ml and 3.0 micrograms/ml of VRP in the presence of 10(3) U/ml of rH-IFN-gamma were 4.4 and 6.0, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Study on the expression of ?-SMA in rats with adriamycin-induced nephrothy and intervention of Valsartan on it / 中国药理学通报

Aim To observe the changes on the expression of ?-SMA in rats with adriamycin-induced nephrothy and intervention of Valsartan. Methods The model group were made by unilateral nephrectomy with twice-adriamycin injections by caudal vein. Immunohistochemical method, flow cytometry and pathologic image analysis were used to observe the expression of ?-SMA, FN and LN in rats. Results The expression of ?-SMA was positive in the model group. Rates of positive cell and protein semi-quantitative analysis were more higher than the sham group(P