Administration Of Adriamycin Research Articles

Effect of intermittent fasting on adriamycin-induced nephropathy: Possible underlying mechanisms

PurposeIntermittent fasting (IF) has been shown to induce a well-organized adaptive defense against stress inside the cells, which increases the production of anti-oxidant defenses, repair of DNA, biogenesis of mitochondria, and genes that combat inflammation. So, the goal of the current investigation was to identify the effects of IF on rats with adriamycin (ADR)-induced nephropathy and any potential underlying mechanisms. MethodsFour groups of 40 mature Sprague-Dawley male rats were allocated as follow; control, fasting, ADR, and ADR plus fasting. After 8 weeks of ADR administration urine, blood samples and kidneys were taken for assessment of serum creatinine (Cr), BUN, urinary proteins, indicators of oxidative damage (malondialdehyde (MDA), reduced glutathione (GSH) and Catalase (CAT) levels), histopathological examinations, immunohistochemical examinations for caspase-3, Sirt1, aquaporin2 (AQP2) and real time PCR for antioxidant genes; Nrf2, HO-1 in kidney tissues. ResultsIF significantly improved serum creatinine, BUN and urinary protein excretion, oxidative stress (low MDA with high CAT and GSH), in addition to morphological damage to the renal tubules and glomeruli as well as caspase-3 production during apoptosis. Moreover, IF stimulates significantly the expression of Sirt1 and Nrf2/HO-1 and AQP2. ConclusionAQP2, Sirt1, Nrf2/HO-1 signaling may be upregulated and activated by IF, which alleviates ADR nephropathy. Enhancing endogenous antioxidants, reducing apoptosis and tubulointerstitial damage, and maintaining the glomerular membrane's integrity are other goals.

Effects of N-acetylcysteine on spexin immunoreactivity in kidney tissues of rats treated with adriamycin.

Due to its negative side effects, mainly nephrotoxicity, adriamycin (ADR) is used fairly infrequently. The purpose of this study is to investigate the effects of N-acetyl cysteine (NAC) on the immunoreactivity of spexin (SPX) in the kidney tissues of rats given ADR. A total of 28 male Sprague-Dawley rats were randomly assigned to four groups (n=7): control (no intervention), NAC (150 mg/kg/day, administered intraperitoneally), ADR (single dose of 15 mg/kg, administered intraperitoneally), and ADR+NAC (single dose of 15 mg/kg ADR + 150 mg/kg/day NAC, both administered intraperitoneally). The experiment was concluded on the 15th day. The administration of ADR resulted in biochemical and histopathological alterations in the kidney. It was found that ADR treatment led to elevated levels of TOS (total oxidative stress), apoptosis, and SPX. Conversely, when NAC was administered as a treatment, it effectively reduced TOS, apoptosis, and SPX levels. These findings suggest that SPX may contribute to the development of ADR-induced kidney damage. Further investigations are warranted to gain a comprehensive understanding of kidney damage, and specifically to elucidate the role of SPX in this context. Additionally, these studies can pave the way for exploring novel therapeutic strategies targeting SPX to prevent and/or treat the development of kidney damage.

Abstract 14569: Chemotherapy in Pregnancy: Assessing the Safety of Adriamycin Administration in Pregnancy Complicated by Breast Cancer

Introduction: Treatment of Pregnancy Associated Breast Cancer (PABC) with radiation and endocrine therapy is challenging due to potential risks to the fetus. Surgical treatment is safe throughout pregnancy, and chemotherapy agents such as anthracyclines are safe during 2 nd and 3 rd trimesters. Case Presentation: A 39-year-old G4P3 female presented at 8 weeks gestation with a twin pregnancy and a right breast mass with bloody nipple discharge. Past medical history was significant for obesity and chronic hypertension. Biopsy of the mass confirmed weakly ER+/PR-/HER2-, node+, stage IIb PABC. After radical mastectomy and axillary lymph node dissection, 4 Adriamycin and Cyclophosphamide (AC) based adjuvant chemotherapy cycles q3 weeks were started at 12 weeks of gestation with a maternal and fetal echocardiogram, brain natriuretic peptide and troponin measurements after each cycle. A baseline echocardiogram revealed cardiomyopathy with an LVEF of 45% and a severely dilated left ventricle. She was New York Heart Association class II at baseline. Carvedilol 6.25 mg BID was started prior to beginning AC and titrated to 12.5 mg BID due to palpitations after 1 st AC cycle. She tolerated 4 AC cycles with no change in EF from baseline, no symptoms of heart failure, and a normal fetal echocardiogram. Weekly Paclitaxel was resumed to complete 12 cycles prior to radiation treatment. She delivered healthy male and female infants at 32 weeks with no complications (M: APGAR 5 and 7; F: APGAR 8 and 7). Postpartum EF decreased to 40%, necessitating titration of carvedilol to 25mg BID and the addition of Sacubitril/Valsartan 24/26 mg BID. Chest pain complaint after delivery prompted evaluation with computed tomography-based angiogram and cardiac magnetic resonance imaging (CMR), ruling out coronary artery disease. Despite this, no evidence of microvascular disease on CMR symptomatic relief was reported on long-acting nitrates. Discussion: This case demonstrates the importance of multidisciplinary patient management, particularly for those with low LVEF who are at higher risk of decompensation. Despite not knowing the etiology of PABC, she could be suffering from thrombotic microangiopathy of small coronary vessels, which explains relief from nitrates.

#3314 DIURETIC AND RENOPROTECTIVE EFFECTS OF GOREISAN IN A RAT MODEL OF NEPHROTIC SYNDROME

Abstract Background and Aims Goreisan, a traditional Chinese medicine composed of five herbs, is commonly used for the purpose of control of edema and gastrointestinal symptoms. However, the detailed mechanisms have not been fully elucidated. In clinical settings, nephrotic syndrome often causes edema, mainly due to hypoalbuminemia and sodium retention. Thus, we investigated the effects of Goreisan on the kidney using a rat model of nephrotic syndrome. Method A model of nephrotic syndrome was created by a right nephrectomy and subsequent administration of adriamycin using Sprague Dawley rats. Nephrotic rats were randomly divided into three groups at 10 weeks of age as follows; vehicle (control), Goreisan 0.5 g/kg (GL), and Goreisan 1.0 g/kg (GH) groups. Goreisan was administered once a day for 4 weeks. At 14 weeks of age, the rats were sacrificed for the evaluation of blood, urine, mRNA expressions, and kidney histopathology. Results Urine volume was significantly increased in the GL and GH groups than in the control group (Δurine volume: control; −1.25±2.48 mL, GL group; 9.83±4.16 mL, GH group; 10.00±2.62 mL). The GH group showed significantly lower urine osmotic pressure compared to the control group. There were no significant differences in urinary sodium excretion and serum arginine-vasopressin levels among the three groups. Subsequently, we assessed the expression of aquaporin (AQP) in kidney tissue using real-time PCR and immunohistochemical staining. The mRNA expression of AQP1, AQP2, AQP3, and AQP4 did not differ among the three groups. However, immunohistochemical staining showed that the localization of AQP2 at the apical plasma membrane of the collecting ducts was decreased by treatment with Goreisan. Furthermore, deterioration of kidney function was prevented by treatment with Goreisan. Histological analysis revealed that glomerular and tubulointerstitial damages were ameliorated in the GL and GH groups compared to the control group (glomerular damage score: control; 2.19±0.05, GL group; 1.71±0.05, GH group; 1.10±0.05, tubulointerstitial damage score: control; 2.55±0.09, GL group; 2.28±0.10, GH group; 2.12±0.10). In addition, urinary 8-OHdG, which is an oxidative stress marker, was significantly lower in the GL and GH groups than in the control group. Conclusion Our results suggested that Goreisan may have diuretic and renoprotective effects by suppressing the trafficking of AQP2 to the apical plasma membrane of the collecting ducts and possibly reducing systemic oxidative stress.

Genetic background strongly influences the transition to chronic kidney disease of adriamycin nephropathy in mice.

Animal models of podocytopathy and chronic kidney diseases (CKD) help elucidate these pathologies. Adriamycin (ADR)-induced nephropathy is a common rodent model of podocytopathy. BALB/c mice are sensitive to ADR, whereas C57BL/6 (B6) mice, the most commonly used strain, are resistant to ADR. Therefore, mouse strains with the B6 genetic background cannot be used as an ADR nephropathy model. We previously generated DNA-dependent protein kinase catalytic subunit (Prkdc) mutant B6 mice (B6-PrkdcR2140C) carrying the R2140C mutation that causes ADR nephropathy. However, whether ADR nephropathy in the novel strain progresses to CKD after ADR administration has not been evaluated. Therefore, we examined whether the B6-PrkdcR2140C mice develop CKD after ADR administration. We also evaluated whether differences existed in the genetic background in ADR nephropathy by comparing the B6-PrkdcR2140C mice with BALB/c mice. Our findings demonstrated that B6-PrkdcR2140C progresses to CKD and is resistant to nephropathy compared with the BALB/c mice. The B6-PrkdcR2140C and BALB/c mice differed in the expression of genes related to inflammatory mediators, and further analysis is required to identify factors that contribute to resistance to nephropathy.

The PDE5 inhibitor, vardenafil, ameliorates progressive pathological changes in a focal segmental glomerulosclerosis mouse model

AimsPhosphodiesterase 5 inhibitors (PDE5is) inhibit the hydrolysis of cyclic guanosine 5′-monophosphate in smooth muscle cells and are a widely known treatment for erectile dysfunction. Accumulating evidence also suggests that PDE5is exhibit potential benefits in cardiovascular and chronic kidney diseases. In this study, we examined the therapeutic effects of a PDE5i, vardenafil (VAR), in a focal segmental glomerulosclerosis (FSGS) mouse model. Materials and methodsFSGS was induced in BALB/c mice by the intravenous administration of Adriamycin (AD, 11 mg/kg of body weight). After 24 h, VAR (at 12.5 μg/ml) was given in drinking water ad libitum until the animals were sacrificed. At the end of the experiment, plasma and kidney samples were harvested to evaluate clinical parameters, histopathological changes, and alterations in transcriptome and protein expressions. Key findingsIn this study, VAR treatment attenuated the deterioration of proteinuria, renal dysfunction, and hypercholesterolemia in AD-induced FSGS. Treatment with VAR exhibited reductions in the severity of both glomerulosclerosis and tubulointerstitial injury in the histological analysis. In addition to relieving AD-induced podocyte loss, VAR also preserved endothelial cells in glomerular capillaries and ameliorated the accumulation of collagen fibers in the mesangial area and Bowman's capsule basement membrane. In addition, VAR showed an ability to suppress transforming growth factor-β-induced fibroblast-to-myofibroblast transdifferentiation. SignificanceOur data suggest that VAR exhibited reno-therapeutic effects via attenuating podocyte loss, preserving the integrity of the glomerular vasculature, and ameliorating fibrotic changes. These findings suggest that PDE5is might be a promising treatment modality for nephrotic syndrome.

Therapeutic Potential of Astragaloside IV Against Adriamycin-Induced Renal Damage in Rats via Ferroptosis.

Adriamycin (ADR) has been utilized to treat cancer for several decades. However, ADR-induced renal injury is one of the most common side effects accompanying ADR therapy. In the present study, we revealed that astragaloside IV (ASIV) was beneficial for renal injury caused by Adriamycin. We demonstrated that ASIV significantly ameliorated kidney injury, improved renal dysfunction, reduced oxidative stress, alleviated iron accumulation, and inhibited the induction of ferroptosis by ADR. ASIV also rescued the intracellular levels of nuclear factor-erythroid-2-related factor 2 (Nrf2) and promoted nuclear translocation of Nrf2. These protective effects of ASIV on renal injury might be attained through the ASIV-induced activation of the Pi3K/Akt signaling pathway. In vitro, the treatment of the HK-2 cells with fer-1 or deferoxamine mesylate obviously improved cell viability during Adriamycin administration. On the other hand, the protective role of ASIV can be abrogated by RSL3 to some extent. Moreover, ASIV lowered the expression of transferrin receptor 1 and divalent metal transporter 1 while enhancing the expression of ferropotin 1 and glutathione peroxidase 4 in ADR administrated cells, the effects of which were akin to those of deferoxamine mesylate. Furthermore, ASIV increased the phosphorylation of Pi3K, Akt, and the expression of Nrf2 and glutathione peroxidase 4 compared to HK-2 cells stimulated by ADR. However, Pi3K inhibitor LY294002 abrogated these activations. In conclusion, ferroptosis may involve in ADR-induced nephrotoxicity, and ASIV might protect nephrocytes against ADR-induced ferroptosis, perhaps via activations of the Pi3K/Akt and Nrf2 signaling pathways.

Evaluation of the Preventive Effect of Regional Cooling Nursing on Hand Foot Syndrome Caused by Doxorubicin Hydrochloride Liposome

Purpose: To explore the preventive effect of Regional cooling comprehensive nursing on hand foot syndrome caused by pegylated liposomal doxorubicin (PLD). Method: Adopt overall sampling method. Patients who used the same adjuvant drugs from January to December 2020 were randomly divided into an intervention group and a control group. The patients in the two groups received routine nursing guidance and drug prevention for the use of amygdalin. The patients in the intervention group were required to take protective measures of Regional cooling during chemotherapy. The occurrence of hand foot syndrome during adriamycin liposome administration was compared between the two groups. Results: By comparing the adverse reactions of cases during Adriamycin Administration, the incidence rates of grade I, II and III hand foot syndrome in the control group were 28.8%, 7.6% and 27.5% respectively, and the incidence rates of grade I, II and III hand foot syndrome in the intervention group were 42.1%, 12.3% and 7.0% respectively, with statistical significance (P < 0.05). Conclusion: Regional cooling nursing and preventive behavior guidance can effectively reduce the severity of hand foot syndrome caused by adriamycin.

Oxidative Stress and Cognitive Alterations Induced by Cancer Chemotherapy Drugs: A Scoping Review.

Cognitive impairment is one of the most deleterious effects of chemotherapy treatment in cancer patients, and this problem sometimes remains even after chemotherapy ends. Common classes of chemotherapy-based regimens such as anthracyclines, taxanes, and platinum derivatives can induce both oxidative stress in the blood and in the brain, and these effects can be reproduced in neuronal and glia cell cultures. In rodent models, both the acute and repeated administration of doxorubicin or adriamycin (anthracyclines) or cisplatin impairs cognitive functions, as shown by their diminished performance in different learning and memory behavioural tasks. Administration of compounds with strong antioxidant effects such as N-acetylcysteine, gamma-glutamyl cysteine ethyl ester, polydatin, caffeic acid phenethyl ester, and 2-mercaptoethane sulfonate sodium (MESNA) counteract both oxidative stress and cognitive alterations induced by chemotherapeutic drugs. These antioxidant molecules provide the scientific basis to design clinical trials in patients with the aim of reducing the oxidative stress and cognitive alterations, among other probable central nervous system changes, elicited by chemotherapy in cancer patients. In particular, N-acetylcysteine and MESNA are currently used in clinical settings and are therefore attracting scientific attention.

Accuracy of echocardiography for detecting cancer therapeutics-related cardiac dysfunction

The survival rate of breast cancer patients has been improved thanks to the progress accomplished in chemotherapy therapeutics and targeted therapies. However, cardiovascular side effects have increased. Cancer therapeutics-related cardiac dysfunction (CTRCD) is a serious side effect of anti-cancer treatment. The aim of our study was to determinate the role of echocardiography in the detection of CTRCD. This was a longitudinal, prospective and monocentric study. Eighty female patients diagnosed with breast cancer and addressed to the echocardiography lab of Ariana hospital, were enrolled between 2017 and 2019. An echocardiographic monitoring were realised according to the chemotherapy protocol. CTRCD is defined as a drop of left ventricular ejection fraction (LVEF) by > 10 percentage points from baseline to a value < 50%. A new entity named subclinical systolic dysfunction, is defined by drop of global longitudinal strain (GLS) by > 15% from baseline, however, LVEF remains > 50%. The average age of our patients was 49.9 ± 10.8 years. The mean LVEF was at 64 ± 4.4%. The incidence of CTRCD was 6% (5 patients). It was reversible in 3 cases after the initiation of a cardioprotective treatment. The incidence of subclinical cardiac dysfunction was 25%. Cardioprotective treatment was administered in this case and none of them evolved to CTRCD. At univariate analysis, baseline LVEF between 50 and 55% (P < 0.001), GLS decrease (P < 0.001) and adriamycin administration (P = 0.01) were predictive factors of cardiotoxicity. At multivariate analysis, only borderline baseline LVEF between 50% and 50% was a predictive factor of CTRCD (P = 0.002). Echocardiographic monitoring of breast cancer patients revealed a CTRCD in 5 cases (6%). GLS allowed the diagnosis of a subclinical cardiac dysfunction in 25% of cases. In breast cancer patients, both Simpson biplane LVEF and GLS should be assessed.

A single amino acid substitution in PRKDC is a determinant of sensitivity to Adriamycin-induced renal injury in mouse

Adriamycin (ADR)-induced nephropathy is frequently utilized in rodent models of podocytopathy. However, the application of this model in mice is limited to a few strains, such as BALB/c mice. The most commonly used mouse strain, C57BL/6 (B6), is resistant to ADR-induced nephropathy, as are all mouse strains with a B6 genetic background. Reportedly, the R2140C variant of the Prkdc gene is the cause of susceptibility to ADR-induced nephropathy in mice. To verify this hypothesis, we produced Prkdc mutant B6 mice, termed B6-PrkdcR2140C, that possess the R2140C mutation. After administration of ADR, B6-PrkdcR2140C mice exhibited massive proteinuria and glomerular and renal tubular injuries. In addition, there was no significant difference in the severity between B6-PrkdcR2140C and BALB/c. These findings demonstrated that B6-PrkdcR2140C show ADR-induced nephropathy susceptibility at a similar level to BALB/c, and that the PRKDC R2140C variant causes susceptibility to ADR-induced nephropathy. In future studies, ADR-induced nephropathy may become applicable to various kinds of genetically modified mice with a B6 background by mating with B6-PrkdcR2140C.

P-Coumaric acid alleviates adriamycin-induced hepatotoxicity in rats

Objective: To evaluate the effect of p-coumaric acid against adriamycin-induced hepatotoxicity in rats. Methods: The rats were divided into 4 groups. The control group received solvent; the p-coumaric acid group was treated with 100 mg/kg of p-coumaric acid orally for five consecutive days; the adriamycin group was administered with a single dose of adriamycin (15 mg/kg, i.p.), and the p-coumaric acid + adriamycin group was given p-coumaric acid five days before adriamycin administration. Twenty-four hours after the last administration, blood samples were collected for biochemical analysis, and liver tissues were removed for histopathological and immunohistochemistrical studies. Moreover, the levels of tissue lipid peroxidation and enzyme activities of glutathione peroxidase, superoxide dismutase, and catalase in liver tissue were measured. Results: Treatment with p-coumaric acid protected the liver from the toxicity of adriamycin by attenuating the increase in alkaline phosphatase, alanine transaminase, aspartate transaminase, total bilirubin, total cholesterol, triglyceride, and low-density lipoprotein cholesterol and lessening the decrease in high-density lipoprotein cholesterol and albumin. p-Coumaric acid also raised the levels of glutathione peroxidase, superoxide dismutase, and catalase, as well as decreased lipid peroxidation in liver tissue and hepatic IL- 1β expression. Additionally, histopathological study confirmed the protective effect of p-coumaric acid against liver damage. Conclusions: p-Coumaric acid can alleviate adriamycin-induced hepatotoxicity.

(Pro)renin receptor decoy peptide PRO20 protects against adriamycin-induced nephropathy by targeting the intrarenal renin-angiotensin system.

Adriamycin (ADR) administration in susceptible rodents such as the BALB/c mouse strain produces injury to the glomerulus mimicking human chronic kidney disease due to primary focal segmental glomerulosclerosis. The goal of the present study was to use this model to investigate antiproteinuric actions of the (pro)renin receptor decoy inhibitor PRO20. BALB/c mice were pretreated for 1 day with PRO20 at 500 μg·kg-1·day-1 via an osmotic minipump followed by a single injection of vehicle or ADR (10 mg/kg) via the tail vein. Albuminuria and renal function were analyzed at the fourth week post-ADR administration. ADR-treated mice exhibited severe proteinuria, hypoalbuminemia and hyperlipidemia, glomerulosclerosis, podocyte loss, tubulointerstitial fibrosis, and oxidative stress, accompanied by elevated urinary neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, all of which were significantly attenuated by PRO20. Urinary and renal renin activity and angiotensin II were elevated by ADR and suppressed by PRO20. In parallel, urinary and renal H2O2 levels and renal NADPH oxidase 4 (Nox4) and transient receptor potential channel C6 (TRPC6) expression in response to ADR were all similarly suppressed. Taken together, the results of the present study provide the first evidence that PRO20 can protect against podocyte damage and interstitial fibrosis in ADR nephropathy by preventing activation of the intrarenal renin-angiotensin system and upregulation of Nox4 and TRPC6 expression. PRO20 may have a potential application in the treatment of ADR nephropathy.

Regenerated nephrons in kidney cortices ameliorate exacerbated serum creatinine levels in rats with adriamycin nephropathy

Kidney regeneration could be classified into 2 groups: kidney generation and kidney repair. We have attempted in vivo nephron generation for kidney repair, as a therapy for chronic renal failure (CRF), by exploiting cellular interactions via conditioned media. In the previous report, we demonstrated the generation of rich nephrons in rat intact kidney cortices through percapsular injection of mesenchymal stem cell (MSC)-differentiated tubular epithelial cells (TECs) after pretreatment of 3-dimensional culture using a small amount of gel complex and condensed medium. In this study, to verify the amelioration of serum creatinine (sCr) levels by regenerated nephrons in rats with CRF, we first created damaged kidneys through systemic administration of adriamycin, and implanted the pretreated MSC-differentiated TECs into unilateral kidney cortices 2 weeks after adriamycin administration (A-2W, that is I–0W). After recovery of acute kidney injury, the control rats without cell implantation showed re-exacerbation of sCr levels, resulting in death within A-12W. Alternatively, the cell-implanted rats had a formation of mature nephrons in I–3W, and showed significant amelioration of sCr levels in I–7W. As a result, these rats could live until euthanization in I–12W or I–16W, indicating the utility of cell injection therapy into a kidney (K-CIT) for CRF. We expect that our K-CIT or the refined methods will be applied to patients with CRF.

Cytoprotective and antioxidant effects of aged garlic extract against adriamycin-induced cardiotoxicity in adult male rats.

Adriamycin (ADR) efficacy in cancer chemotherapy is well-established. However, ADR-induced cardiotoxicity remains a significant challenge. Aged garlic extract (AGE) is a natural polyphenol with high antioxidant potential. This study was planned to determine the cytoprotective and antioxidant actions of AGE against the cardiotoxic effect of ADR in rats. Six equal groups, control, ADR-treated (single dose of 10 mg/kg on day 8); AGE-treated (one dose of 250 mg/kg for 14 days); AGE plus ADR-treated (one dose of 250 mg/kg AGE for one week plus ADR injection of 10 mg/kg on day 8); ADR plus AGE-treated (single ADR injection of 10 mg/kg on day 8 plus AGE of 250 mg/kg once from 8th to 14th day); combined AGE plus ADR plus AGE-treated (one dose of 250 mg/kg AGE for 14 days plus single ADR injection of 10 mg/kg on day 8). Sera and cardiac samples were collected on day 15 and prepared for histological, ultrastructural and biochemical study. Disorganization, focal degeneration and necrosis with apoptotic changes of the cardiac myofibrils were observed in ADR-treated rats. Also, reduction in level of total creatine kinase, lactic dehydrogenase, alkaline phosphatase enzymes, glutathione, glutathione- peroxidase, superoxide dismutase, and catalase activities and elevation in malondialdehyde concentration were detected in ADR-treated rats. However, combination of AGE attenuated most of the histopathological, ultrastructural, and biochemical changes induced by ADR. Combination of AGE attenuated the cardiotoxic effects-induced by ADR through its antioxidant and cytoprotective potentials. Therefore, AGE can use as adjunct during administration of ADR in cancer therapy.

Yes-associated protein regulates podocyte cell cycle re-entry and dedifferentiation in adriamycin-induced nephropathy

Podocytes are terminally differentiated cells with little proliferative capacity. The high expression levels of cell cycle inhibitory proteins, including p21, p27, and p57, play an important role in maintaining the low level of proliferation of mature podocytes. In the present study, we aimed to explore the role of yes-associated protein (YAP) signalling in adriamycin-induced podocyte re-entry into the cell cycle and dedifferentiation. Proliferating cell nuclear antigen (PCNA)-, cyclin-dependent kinase 4 (CDK4)-, and Cyclin D1-positive podocytes were found in mice with adriamycin-induced nephropathy. In vitro, adriamycin administration increased the percentage of cells in S phase and the upregulation of mesenchymal-related marker proteins. CDK4 and cyclin D1 were significantly up-regulated after incubation with adriamycin. Overexpression of YAP in podocytes promoted their entry into the cell cycle; up-regulated cyclin D1, desmin, and snail2 expression and down-regulated Wilms’ tumour 1 (WT1) and nephrin production. Recombinant murine FGF-basic induced podocytes to re-enter the cell cycle, inhibited WT1 and nephrin, and increased desmin and snail2 expression. Pretreating podocytes with verteporfin, an inhibitor of YAP/ TEA domain transcription factor (TEAD), decreased the adriamycin-induced overexpression of cyclin D1 and reduced the ratio of S-phase podocytes. This result was further verified by knocking down YAP expression using RNA interference. In conclusion, adriamycin induced podocytes to re-enter the cell cycle via upregulation of CDK4 and cyclin D1 expression, which was at least partly mediated by YAP signalling. Re-entry into the cell cycle induced the over-expression of mesenchymal markers in podocytes.

Ameliorative effect of rosiglitazone, a peroxisome proliferator gamma agonist on adriamycin-induced cardio toxicity via suppressing oxidative stress and apoptosis.

We investigated the rosiglitazone (RSG) effect on adriamycin (ADM)-induced cardio toxicity in experimental animals. Forty adult Wistar male rats were separated into four groups as follows: normal control; RSG (10 mg/kg)-treated; ADM (10 mg/kg)-administered; and ADM (10 mg/kg) + RSG (10 mg/kg)-treated. Serum lipid level, different biochemical biomarkers, histological analysis, and nuclear factor erythroid 2-related factor/heme oxygenase-1 (Nrf2/HO-1), Caspase 3, B-cell lymphoma 2 (Bcl-2), and Bax gene expression were assessed in serum and cardiac tissue samples. Our results show that RSG treatment in ADM-administered animals significantly diminished low-density lipoprotein cholesterol, triglyceride, and total cholesterol, and increases high-density lipoprotein cholesterol (HDL-c) in comparison with the ADM group. RSG treatment reduced the effect of ADM administration on cardiac dysfunction markers such as cardiac troponin T Creatine Kinase-MB, aspartate aminotransferase, and lactate dehydrogenase, showing the amelioration of cardio toxicity in ADM-administered rats. Additionally, RSG treatment significantly decreased the level of malondialdehyde and nitric oxide in cardiovascular tissue. RSG-treated rats in combination with ADM likewise showed a significant increase in reduced glutathione, superoxide dismutase, catalase content, and the activity of glutathione peroxidase (GPx) as compared with ADM group. Moreover, RSG treatment in ADM rats significantly increased an Nrf2 and HO-1 expression in comparison with ADM group. While in apoptosis parameters, RSG treatment in ADM rats significantly diminished a cleaved caspase-3 and Bax expression as well as expanded Bcl-2 expression when contrasted with ADM group of rats. In conclusion, RSG is capable of protecting heart toxicity in ADM-treated animals through defensive effects on oxidative stress and biochemical markers.

Inhibition of the ERK1/2-mTORC1 axis ameliorates proteinuria and the fibrogenic action of transforming growth factor-β in Adriamycin-induced glomerulosclerosis

Transforming growth factor-β (TGF-β) plays crucial roles in the development of focal segmental glomerulosclerosis, but key molecular pathways remain unknown. Here, we identified the regulation of mammalian target of rapamycin complex1 (mTORC1) by TGF-β via ERK1/2 in the Adriamycin-induced murine model of focal segmental glomerulosclerosis. Adriamycin administration elicited early activation of TGF-β-ERK1/2-mTORC1 in podocytes, which persisted at later stages of albuminuria and glomerulosclerosis. Phosphorylation of the TGF-β receptor-I (TGF-βRI), Smad3, ERK1/2 and ribosomal protein S6 were evident in the glomeruli of adriamycin-treated mice. Targeting TGFβ-RI and mTORC1 with pharmacological inhibitors suppressed TGF-β signaling in glomeruli and significantly reduced albuminuria, glomerulosclerosis, protein levels of collagen 4α3, plasminogen activator inhibitor-1, and vimentin and restored mRNA levels of podocyte markers. Low dose US Food and Drug Administration (FDA)-approved MEK/ERK inhibitor trametinib/GSK1120212 blunted TGF-β1-induced mTORC1 activation in podocytes, ameliorated up-regulation of TGF-β, plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, fibronectin and α-smooth muscle actin and prevented albuminuria and glomerulosclerosis with improved serum albumin. In cultured podocytes, this pathway was found to be associated with translation of fibrogenic collagen 4α3 and plasminogen activator inhibitor-1, without influencing their transcription. Notably, rapamycin suppressed upstream p-TGF-βRI, p-Smad3 and p-ERK1/2, and trametinib down-regulated upstream p-Smad3 in exvivo and invivo studies, indicating that harmful paracrine signaling among glomerular cells amplified the TGF-β-ERK1/2-mTORC1 axis by forming a positive feedback loop. Thus, an accentuated TGF-β-ERK1/2-mTORC1 pathway is suggested as a central upstream mediator to develop proteinuria and glomerulosclerosis. Hence, preventing activation of this vicious loop by trametinib may offer a new therapeutic strategy for glomerular disease treatment.

Plectin protects podocytes from adriamycin-induced apoptosis and F-actin cytoskeletal disruption through the integrin α6β4/FAK/p38 MAPK pathway.

Podocyte injury is an early pathological change characteristic of various glomerular diseases, and apoptosis and F‐actin cytoskeletal disruption are typical features of podocyte injury. In this study, we found that adriamycin (ADR) treatment resulted in typical podocyte injury and repressed plectin expression. Restoring plectin expression protected against ADR‐induced podocyte injury whereas siRNA‐mediated plectin silencing produced similar effects as ADR‐induced podocyte injury, suggesting that plectin plays a key role in preventing podocyte injury. Further analysis showed that plectin repression induced significant integrin α6β4, focal adhesion kinase (FAK) and p38 MAPK phosphorylation. Mutating Y1494, a key tyrosine residue in the integrin β4 subunit, blocked FAK and p38 phosphorylation, thereby alleviating podocyte injury. Inhibitor studies demonstrated that FAK Y397 phosphorylation promoted p38 activation, resulting in podocyte apoptosis and F‐actin cytoskeletal disruption. In vivo studies showed that administration of ADR to rats resulted in significantly increased 24‐hour urine protein levels along with decreased plectin expression and activated integrin α6β4, FAK, and p38. Taken together, these findings indicated that plectin protects podocytes from ADR‐induced apoptosis and F‐actin cytoskeletal disruption by inhibiting integrin α6β4/FAK/p38 pathway activation and that plectin may be a therapeutic target for podocyte injury‐related glomerular diseases.

JNK pathway inhibition enhances chemotherapeutic sensitivity to Adriamycin in nasopharyngeal carcinoma cells.

The role of c-Jun N-terminal kinases (JNKs) in the pathogenesis of cancer is well-known due to their involvement in carcinogenesis. Although previous studies have discussed different functions of JNKs depending on cell type, the present study aimed to investigate the function of JNKs in nasopharyngeal carcinoma (NPC) cells, as well as their involvement in chemotherapy sensitivity to Adriamycin. The present results showed that Adriamycin administration reduced cell viability and led to elevated expressions of c-Jun, phosphorylated JNK and phosphorylated c-Jun, indicating an activated JNK pathway. Notably, JNK inhibition by SP600125 also reduced cell growth. Thus, Adriamycin treatment combined with SP600125 was more effective on cell growth inhibition than each agent alone. The apoptosis analysis confirmed the reduction in cell growth. Therefore, these data provide evidence that the JNK pathway activity is negatively associated with cell viability, and its decline could sensitize NPC cells to Adriamycin.