Curcumin Promotes Anti-Tumor Effect of Cisplatin and Protects Against Cisplatin-Induced Kidney Injury in Lung Cancer

2021 ◽  
Author(s):  
Miaoxin Zhao ◽  
Yue Ma ◽  
Xiangka Hu ◽  
Yuqi Sun ◽  
Zuodong Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Kidney Injury ◽  
Term Treatment ◽  
Combination Regimen ◽  
Apoptosis Pathway ◽  
Mitochondrial Apoptosis Pathway ◽  
In Vivo Experiments ◽  
Long Term Treatment

Abstract Background: Lung cancer patients will develop strong drug resistance and serious complications, especially severe renal injuries, after long-term treatment of platinum-based drugs. Curcumin (Cur) combined with cisplatin (DDP) has a synergistic and attenuating effect on lung cancer. However, the role of curcumin in protection against DDP kidney injury in lung cancer remains unknown. Methods: We conducted in vitro experiments to evaluate the anti-tumor effect of cur combined with DDP such as MTT, mitochondrial membrane potential (ΔΨm) analysis, and flow cytometry. The serology and histopathology were used to assess kidney injury induced by DDP in vivo experiments. Western blotting analysis was utilized to detect P38 levels in mouse kidneys. Results: A significant synergistic antitumor effect in A549 and LLC-1 cells based on the activation of the mitochondrial apoptosis pathway. Moreover, Cur could reduce the nephrotoxicity of DDP treatment through the P38MAPK signaling pathway. Conclusion: Cur in combination with DDP may be considered as a beneficial combination regimen for enhancing DDP sensitivity and providing a promising renoprotective effect against nephrotoxicity induced by DDP.

scholarly journals NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Zhi-Jie Xiao ◽  
Jing Liu ◽  
Si-Qi Wang ◽  
Yun Zhu ◽  
Xu-Yuan Gao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Term Treatment ◽  
Cancer Drug ◽  
Tumor Initiating Cells ◽  
Independent Manner ◽  
Lung Cancers ◽  
Novel Approach ◽  
Long Term Treatment

Tumor-initiating cells (TIC) are dynamic cancer cell subsets that display enhanced tumor functions and resilience to treatment but the mechanism of TIC induction or maintenance in lung cancer is not fully understood. In this study, we show the calcium pathway transcription factor NFATc2 is a novel regulator of lung TIC phenotypes, including tumorspheres, cell motility, tumorigenesis, as well as in vitro and in vivo responses to chemotherapy and targeted therapy. In human lung cancers, high NFATc2 expression predicted poor tumor differentiation, adverse recurrence-free and cancer-specific overall survivals. Mechanistic investigations identified NFATc2 response elements in the 3’ enhancer region of SOX2, and NFATc2/SOX2 coupling upregulates ALDH1A1 by binding to its 5’ enhancer. Through this axis, oxidative stress induced by cancer drug treatment is attenuated, leading to increased resistance in a mutation-independent manner. Targeting this axis provides a novel approach for the long-term treatment of lung cancer through TIC elimination.

scholarly journals The protective effect of klotho against contrast-associated acute kidney injury via the antioxidative effect

2019 ◽  
Vol 317 (4) ◽  
pp. F881-F889 ◽  
Author(s):  
Hyung Jung Oh ◽  
Hyewon Oh ◽  
Bo Young Nam ◽  
Je Sung You ◽  
Dong-Ryeol Ryu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Kidney Injury ◽  
Antioxidative Effect ◽  
In Vivo Experiments ◽  
Apoptotic Markers ◽  
Cytoplasmic Vacuoles ◽  
Transmission Electron ◽  
And Oxidative Stress

As oxidative stress is one major factor behind contrast-associated acute kidney injury (CA-AKI), we investigated the protective effect of klotho against CA-AKI via the antioxidative effect. In in vitro experiments, cells (NRK-52E) were divided into the following three groups: control, iopamidol, or iopamidol + recombinant klotho (rKL) groups. Moreover, cell viability was measured with the Cell Counting Kit-8 assay, and oxidative stress was examined with 2',7'-dichlorodihydrofluorescein diacetate fluorescence intensity. RT-PCR and Western blot analysis were performed to assess propidium iodide klotho expression, and Bax-to-Bcl-2 and apoptosis ratios were evaluated with annexin V/Hoechst 33342 staining. Furthermore, we knocked down the klotho gene using siRNA to verify the endogenous effect of klotho. In our in vivo experiments, oxidative stress was evaluated with the thiobarbituric acid-reactive substance assay, and apoptosis was evaluated with the Bax-to-Bcl-2 ratio and cleaved caspase-3 immunohistochemistry. Additionally, cell and tissue morphology were investigated with transmission electron microscopy. In both in vitro and in vivo experiments, mRNA and protein expression of klotho significantly decreased in CA-AKI mice compared with control mice, whereas oxidative stress and apoptosis markers were significantly increased in CA-AKI mice. However, rKL supplementation mitigated the elevated apoptotic markers and oxidative stress in the CA-AKI mouse model and improved cell viability. In contrast, oxidative stress and apoptotic markers were more aggravated when the klotho gene was knocked down. Moreover, we found more cytoplasmic vacuoles in the CA-AKI mouse model using transmission electron microscopy but fewer cytoplasmic vacuoles in rKL-supplemented cells. The present study shows that klotho in proximal tubular cells can protect against CA-AKI via an antioxidative effect.

Biocompatibility of Charcoal Hemoperfusion. Effects of Long-Term Treatment on Lymphocyte Characteristics and Function

1986 ◽  
Vol 9 (5) ◽  
pp. 301-304 ◽  
Author(s):  
S. Stefoni ◽  
A. Nanni Costa ◽  
G. Liviano D'Arcangelo ◽  
M. Biavati ◽  
S. lannelli ◽  
...  
Keyword(s):  
Antigen Expression ◽  
Term Treatment ◽  
T Cell Subsets ◽  
Long Term Treatment ◽  
Circulating Lymphocytes ◽  
And Function ◽  
Charcoal Hemoperfusion

Biocompatibility of charcoal hemoperfusion was studied in a group of 15 uremic patients, evaluating the effects of long-term treatment on some structural and functional parameters of circulating lymphocytes: in vivo distribution of T-cell subsets; surface T3, T4 and T8 antigen expression, in vivo and in vitro DNA synthesis. A comparative analysis was performed with patients on conventional dialysis using cuprophan membranes.

Plasma extracellular superoxide dismutase and erythrocyte Cu, Zn-containing superoxide dismutase in alcoholics treated with disulfiram

1986 ◽  
Vol 70 (4) ◽  
pp. 365-369 ◽  
Author(s):  
Michael Öhman ◽  
Stefan L. Marklund
Keyword(s):  
Superoxide Dismutase ◽  
Chronic Alcoholism ◽  
Term Treatment ◽  
Extracellular Superoxide Dismutase ◽  
Healthy Controls ◽  
Efficient Inhibitor ◽  
Long Term Treatment

1. Disulfiram has long been used in the treatment of chronic alcoholism. It is in vivo partially reduced to diethyldithiocarbamate, which is an efficient inhibitor of Cu, Zn-containing superoxide dismutase both in vitro and in vivo. The recently described extracellular superoxide dismutase is even more sensitive to diethyldithiocarbamate than Cu, Zn-superoxide dismutase. 2. To test for the possibility that long term treatment with disulfiram leads to inhibition of the superoxide dismutases, plasma extracellular superoxide dismutase and erythrocyte Cu, Zn-superoxide dismutase were determined in 12 disulfiram-treated alcoholics, and compared with 11 non-treated alcoholics and 19 healthy controls. 3. Plasma extracellular superoxide dismutase was moderately reduced (about 20%) in the disulfiram-treated alcoholics as compared with the non-treated alcoholics and the healthy controls. No effect of disulfiram treatment on erythrocyte Cu, Zn-superoxide dismutase activity was demonstrated.

scholarly journals Combined Inhibition of Epigenetic Readers and Transcription Initiation Targets the EWS-ETS Transcriptional Program in Ewing Sarcoma

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 304 ◽  
Author(s):  
Günther H.S. Richter ◽  
Tim Hensel ◽  
Oxana Schmidt ◽  
Vadim Saratov ◽  
Kristina von Heyking ◽  
...  
Keyword(s):  
Ewing Sarcoma ◽  
Transcription Initiation ◽  
Combined Treatment ◽  
Term Treatment ◽  
Transcriptional Elongation ◽  
Transcriptional Program ◽  
Development Of Resistance ◽  
Long Term Treatment

Background: Previously, we used inhibitors blocking BET bromodomain binding proteins (BRDs) in Ewing sarcoma (EwS) and observed that long term treatment resulted in the development of resistance. Here, we analyze the possible interaction of BRD4 with cyclin-dependent kinase (CDK) 9. Methods: Co-immunoprecipitation experiments (CoIP) to characterize BRD4 interaction and functional consequences of inhibiting transcriptional elongation were assessed using drugs targeting of BRD4 or CDK9, either alone or in combination. Results: CoIP revealed an interaction of BRD4 with EWS-FLI1 and CDK9 in EwS. Treatment of EwS cells with CDKI-73, a specific CDK9 inhibitor (CDK9i), induced a rapid downregulation of EWS-FLI1 expression and block of contact-dependent growth. CDKI-73 induced apoptosis in EwS, as depicted by cleavage of Caspase 7 (CASP7), PARP and increased CASP3 activity, similar to JQ1. Microarray analysis following CDKI-73 treatment uncovered a transcriptional program that was only partially comparable to BRD inhibition. Strikingly, combined treatment of EwS with BRD- and CDK9-inhibitors re-sensitized cells, and was overall more effective than individual drugs not only in vitro but also in a preclinical mouse model in vivo. Conclusion: Treatment with BRD inhibitors in combination with CDK9i offers a new treatment option that significantly blocks the pathognomonic EWS-ETS transcriptional program and malignant phenotype of EwS.

CARD8/BCL-2 cascade in early adaptive drug resistant tumor escape against targeted inhibitors in NSCLC.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22032-e22032
Author(s):  
Rakesh K. Bagai ◽  
Wei Zhang ◽  
Patrick Leahy ◽  
Lihong Yin ◽  
Patrick C. Ma
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Expression Analysis ◽  
Xenograft Model ◽  
Tumor Escape ◽  
Apoptosis Pathway ◽  
Egfr Tki ◽  
Resistant Cells

e22032 Background: Lung cancer targeted therapy is largely limited by inevitable recurrent resistant disease after initial response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), typically accompanied with divergent late acquired resistance mechanisms. We now focused on studying the emergence of early adaptive resistance to uncover attractive therapeutic targets to overcome drug resistance. Methods: HCC827 cells were treated with EGFR-TKI (0-9 days) with apoptosis pathway-specific QPCR array and TLVM analysis performed. MTS and crystal violet assays were performed. Western blot analysis was performed to examine prosurvival signaling developed against erlotinib, alone or in combination with MET inhibitor SU11274. IHC was performed on lung cancer tumor microarray (TMA) using BCL-2 and caspase-recruitment domain-containing protein 8 (CARD8) antibodies and graded (4 tier scoring system). NSCLC cell lines and murine xenograft models (HCC827, H1975) were developed for resistance biomarkers expression analysis in pre-/post-TKI treatment using anti-human CARD8, p-STAT3 and BCL-2 antibodies. Results: We characterized the emergence of early resistant lung cancer cells in escape against targeted TKIs with 100-fold higher IC50 in adaptive drug resistance. The resistant cells that evaded EGFR-TKI based targeted inhibition exhibited MET-independent induction of CARD8 and STAT3/BCL-2 mitochondrial prosurvival signaling in cellular quiescence, and inhibited cytoskeletal functions. Expression analysis studies demonstrated common tumor-associated expression of CARD8 but relatively low BCL-2 level in NSCLC. In vitro cell line studies suggest that CARD8 induction was preceded by a resurgence of STAT3 activation. In vivo xenograft model (HCC827/erlotinib; H1975/erlotinib+ SU11274) also verified upregulated CARD8/BCL-2 activation within early resistant cells. Conclusions: Resistant tumor cells that evaded EGFR inhibitors, alone or in combination with MET inhibitors, exhibited increased expression of CARD8-STAT3/BCL-2 prosurvival signaling cascade. Further studies to define the mechanism of CARD8 in promoting adaptive tumor drug resistance would be warranted.

Consequences of differential effects of ADH and other peptide hormones on thick ascending limb of mammalian kidney

1991 ◽  
Vol 260 (6) ◽  
pp. R1023-R1035 ◽  
Author(s):  
C. De Rouffignac ◽  
A. Di Stefano ◽  
M. Wittner ◽  
N. Roinel ◽  
J. M. Elalouf
Keyword(s):  
Term Treatment ◽  
Thick Ascending Limb ◽  
Adenylate Cyclase System ◽  
Nacl Transport ◽  
Differential Effects ◽  
Physiological Relevance ◽  
Long Term Treatment ◽  
Nephron Segment

Several hormones stimulate the adenylate cyclase system of the thick ascending limb (TAL). There are, however, some species differences concerning the cyclase sensitivity and the hormonal response in this nephron segment. In the mouse, antidiuretic hormone (ADH), parathyroid hormone, glucagon, calcitonin, and isoproterenol stimulate Na+, Cl-, Mg2+, and Ca2+ transports in the cortical TAL, whereas ADH, glucagon, and isoproterenol stimulate NaCl transport only in the medullary TAL. Many of these effects are different from those previously described for the corresponding segments of the rabbit nephron. The close similarity of the cyclase responsiveness to hormones of the mouse and rat TALs makes it possible to interpret the micropuncture data obtained in vivo in the rat superficial (S) and juxtamedullary (JM) nephrons, in the light of the in vitro data obtained in the mouse. Long-term treatment of Brattleboro rats with ADH also elicits differential effects along the TAL. Their consequences on the function of the S and JM nephrons are also examined. There are several indications supporting the view that the newly described hormonal effects in the mouse and rat are of physiological relevance.

scholarly journals Unraveling Natural Products’ Role in Osteoarthritis Management—An Overview

Antioxidants ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 348 ◽  
Author(s):  
Georgia-Eirini Deligiannidou ◽  
Rafail-Efraim Papadopoulos ◽  
Christos Kontogiorgis ◽  
Anastasia Detsi ◽  
Eugenia Bezirtzoglou ◽  
...  
Keyword(s):  
Natural Products ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Meta Analysis ◽  
Term Treatment ◽  
Naturally Occurring ◽  
Long Term Treatment ◽  
Living Organisms

The natural process of aging gradually causes changes in living organisms, leading to the deterioration of organs, tissues, and cells. In the case of osteoarthritis (OA), the degradation of cartilage is a result of both mechanical stress and biochemical factors. Natural products have already been evaluated for their potential role in the prevention and treatment of OA, providing a safe and effective adjunctive therapeutic approach. This review aimed to assess the therapeutic potential of natural products and their derivatives in osteoarthritis via a systematic search of literature after 2008, including in vitro, in vivo, ex vivo, and animal models, along with clinical trials and meta-analysis. Overall, 170 papers were obtained and screened. Here, we presented findings referring to the preventative and therapeutic potential of 17 natural products and 14 naturally occurring compounds, underlining, when available, the mechanisms implicated. The nature of OA calls to initially focus on the management of symptoms, and, in that context, several naturally occurring compounds have been utilized. Underlying a global need for more sustainable natural sources for treatment, the evidence supporting their chondroprotective potential is still building up. However, arriving at that kind of solution requires more clinical research, targeting the implications of long-term treatment, adverse effects, and epigenetic implications.

scholarly journals Myricitrin Protects against Doxorubicin-Induced Cardiotoxicity by Counteracting Oxidative Stress and Inhibiting Mitochondrial Apoptosis via ERK/P53 Pathway

2016 ◽  
Vol 2016 ◽  
pp. 1-16 ◽  
Author(s):  
Jing Sun ◽  
Guibo Sun ◽  
Xiaolan Cui ◽  
Xiangbao Meng ◽  
Meng Qin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Damage ◽  
Mitochondrial Apoptosis ◽  
Mechanism Study ◽  
Apoptosis Pathway ◽  
Mitochondrial Apoptosis Pathway ◽  
Myocardial Apoptosis ◽  
Underlying Mechanisms

Doxorubicin (Dox) is one of the most effective and widely used anthracycline antineoplastic antibiotics. Unfortunately, the use of Dox is limited by its cumulative and dose-dependent cardiac toxicity. Myricitrin, a natural flavonoid which is isolated from the ground bark ofMyrica rubra, has recently been found to have a strong antioxidative effect. This study aimed to evaluate the possible protective effect of myricitrin against Dox-induced cardiotoxicity and the underlying mechanisms. An in vivo investigation in SD rats demonstrated that myricitrin significantly reduced the Dox-induced myocardial damage, as indicated by the decreases in the cardiac index, amelioration of heart pathological injuries, and decreases in the serum cardiac enzyme levels. In addition, in vitro studies showed that myricitrin effectively reduced the Dox-induced cell toxicity. Further study showed that myricitrin exerted its function by counteracting oxidative stress and increasing the activities of antioxidant enzymes. Moreover, myricitrin suppressed the myocardial apoptosis induced by Dox, as indicated by decreases in the activation of caspase-3 and the numbers of TUNEL-positive cells, maintenance of the mitochondrial membrane potential, and increase in the Bcl-2/Bax ratio. Further mechanism study revealed that myricitrin-induced suppression of myocardial apoptosis relied on the ERK/p53-mediated mitochondrial apoptosis pathway.

In vivo administration of a GnRH antagonist to male mice: effects on pituitary gonadotropin secretion in vitro

1989 ◽  
Vol 120 (3) ◽  
pp. 308-314
Author(s):  
A. M. Ultee-van Gessel ◽  
G.J. van Steenbrugge ◽  
F. G. Leemborg ◽  
F. H. Schroeder ◽  
F. H. de Jong
Keyword(s):  
Gnrh Antagonist ◽  
Term Treatment ◽  
Plasma Testosterone ◽  
High Dose ◽  
Male Mice ◽  
Short Term Treatment ◽  
Gonadotropin Secretion ◽  
Long Term Treatment

Abstract. The potent luteinizing hormone-releasing hormone antagonist [N-Ac-D-p-Cl-Phe1,2,D-Trp3,D-Arg6,D-Ala10]GnRH (4 mg/kg) was administered sc once or daily for 21 days to immune-deficient (nude) and normal immune-competent (NIC) male mice derived from the same genetic background. Effects of in vivo pretreatment with the antagonist on gonadotropin secretion from hemipituitary glands from both types of mice were studied in vitro in the presence or absence of synthetic GnRH. Treatment with the GnRH antagonist caused differential effects on release of FSH and LH from and amounts of FSH and LH in hemipituitary glands. Pituitary FSH secretion was effectively inhibited, whereas effects on pituitary LH were less evident or nonsignificant under these experimental conditions. Long-term treatment with the antagonist caused larger effects on pituitary secretion and content of FSH, when compared with short-term treatment. No significant effects of duration of treatment on secretion or pituitary content of LH were detected. Addition of synthetic GnRH to the incubation medium caused stimulation of gonadotropin release. Therefore, it was concluded that the high doses of this GnRH antagonist were not able to block GnRH receptors effectively in the pituitary glands of nude and NIC male mice. The incomplete suppression of LH secretion by this high dose of the GnRH antagonist may partly explain the inability of the antagonist to suppress plasma testosterone levels and the growth of androgen-dependent tumours in male mice.

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