scholarly journals Therapeutic efficacy and safety of a human fusion construct targeting the TWEAK receptor Fn14 and containing a modified granzyme B

2020 ◽  
Vol 8 (2) ◽  
pp. e001138
Author(s):  
Ana Alvarez de Cienfuegos ◽  
Lawrence H Cheung ◽  
Khalid A Mohamedali ◽  
Timothy G Whitsett ◽  
Jeffrey A Winkles ◽  
...  
Keyword(s):  
Granzyme B ◽  
Control Group ◽  
Target Cells ◽  
Histopathological Analysis ◽  
Efficacy And Safety ◽  
Fusion Construct ◽  
Mitochondrial Membrane Depolarization

BackgroundAntibody-drug conjugates are an exceptional and useful therapeutic tool for multiple diseases, particularly for cancer treatment. We previously showed that the fusion of the serine protease granzyme B (GrB), the effector molecule or T and B cells, to a binding domain allows the controlled and effective delivery of the cytotoxic payload into the target cell. The production of these constructs induced the formation of high molecular aggregates with a potential impact on the efficacy and safety of the protein.MethodsOur laboratory designed a new Fn14 targeted fusion construct designated GrB(C210A)-Fc-IT4 which contains a modified GrB payload for improved protein production and preserved biological activity. We assessed the construct’s enzymatic activity, as well as in vitro cytotoxicity and internalization into target cells. We also assessed pharmacokinetics, efficacy and toxicology parameters in vivo.ResultsGrB(C210A)-Fc-IT4 protein exhibited high affinity and selective cytotoxicity within the nanomolar range when tested against a panel of Fn14-positive human cancer cell lines. The construct rapidly internalized into target cells, activating the caspase cascade and causing mitochondrial membrane depolarization. Pharmacokinetic studies in mice revealed that GrB(C210A)-Fc-IT4 displayed a bi-exponential clearance from plasma with a fast initial clearance (t1/2α=0.36 hour) followed by a prolonged terminal-phase plasma half-life (t1/2β=35 hours). Mice bearing MDA-MB-231 orthotopic tumor xenografts treated with vehicle or GrB(C210A)-Fc-IT4 construct (QODx5) demonstrated tumor regression and long-term (>80 days) suppression of tumor growth. Treatment of mice bearing established, subcutaneous A549 lung tumors showed impressive, long-term tumor suppression compared with a control group treated with vehicle alone. Administration of GrB(C210A)-Fc-IT4 (100 mg/kg total dose) was well-tolerated by mice and resulted in significant reduction of tumor burden in a lung cancer patient-derived xenograft model. Toxicity studies revealed no statistically significant changes in aspartate transferase, alanine transferase or lactate dehydrogenase in treated mice. Histopathological analysis of tissues from treated mice did not demonstrate any specific drug-related changes.ConclusionGrB(C210A)-Fc-IT4 demonstrated excellent, specific cytotoxicity in vitro and impressive in vivo efficacy with no significant toxicity in normal murine models. These studies show GrB(C210A)-Fc-IT4 is an excellent candidate for further preclinical development.

scholarly journals Functional characterization of a stable, noncytolytic stage of macrophage activation in tumors.

1977 ◽  
Vol 146 (6) ◽  
pp. 1511-1520 ◽  
Author(s):  
S W Russell ◽  
W F Doe ◽  
A T McIntosh
Keyword(s):  
Macrophage Activation ◽  
Functional Characterization ◽  
Cytolytic Activity ◽  
Target Cells ◽  
Tumor Target ◽  
Total Absence

The state in which macrophages (Mphi) from regressing Moloney sarcomas could kill tumor target cells was a highly labile one which decayed rapidly in vitro. Thereafter, regressor Mphi were noncytolytic. Mphi from several different progressing sarcomas failed to kill, even when challenged with target cells immediately after explantation. Similarly, thioglycollate-induced peritoneal Mphi (TG-Mphi) did not kill. Noncytolygic Mphi derived either from progressing sarcomas or from long-term (up to 96 h) cultures of regressor Mphi were exquisitely sensitive to stimulation by bacterial lipopolysaccharide (LPS); picogram/milliliter amounts induced killing. Similar concentrations of LPS had no demonstrable effect on TG-Mphi. Thus, tumor Mphi generally appeared to have been primed in vivo, with those in regressing sarcomas having additionally acquired cytolytic activity. Inability of progressor Mphi to kill apparently stemmed from lack of, or failure to respond to, the signal needed in vivo to trigger cytolytic activity, rather than the total absence of activation.

Safety and long-term maintenance of anti-HER2 immunity following booster inoculations of the E75 breast cancer vaccine.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2529-2529
Author(s):  
Raetasha Sheavette Dabney ◽  
Diane F Hale ◽  
Timothy J Vreeland ◽  
Guy T. Clifton ◽  
Alan K. Sears ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Vaccine ◽  
Peptide Vaccine ◽  
Control Group ◽  
Breast Cancer Patients ◽  
Recurrence Rates ◽  
Specific Immunity

2529 Background: We have completed accrual and are in the follow up portion of phase I/II clinical trials evaluating the E75 HER2 peptide vaccine. E75 has been proven safe, capable of stimulating HER2 immunity, and effective in decreasing breast cancer recurrence rates. During the conduct of this trial, it was noted that E75-specific immunity waned after the Primary Vaccine Series (PVS) which corresponded with late recurrences. To maintain long-term immunity, a voluntary booster program was started. Here we present analysis of the booster inoculations. Methods: The trial enrolled node-positive or high-risk, node-negative breast cancer patients (pts) with tumors expressing any level of HER2 (IHC 1-3+). HLA-A2/A3+ pts comprised the vaccine group (VG), HLA-A2/A3- pts were followed as the control group (CG). The VG received 4-6 monthly inoculations of E75+GM-CSF. Volunteer booster program pts (BG) received inoculations every 6 months after the PVS. Pts were monitored for toxicities, in vivo responses by local reactions (LR) and DTH, and in vitro responses measured by enumeration of E75 specific cytotoxic T lymphocytes. Results: 53 pts received at least 1 booster, 34 received 2, 24 three, 20 four, 12 five, and 8 at least 6. 24% of pts had no local toxicity, 73% Grade 1 (G1), 3% G2. 74% had no systemic toxicity, 35% G1, 1% G2. LRs increased significantly from the initial vaccine (R1) during PVS to each booster (B) (R1: 59.5±3.1 v B1: 89.2±3.3, p<0.001; v B2: 95.15±5, p<0.001; v B3: 86.63±5.5, p<0.001; v B4: 83.26±4.6, p=<0.001; v B5: 80.67±6.7, p=0.006; v B6: 78.75±9.4, p=0.04). Dimer values increased from the end of PVS to each post-booster value (pre B1:1.29±0.25 v post B1: 1.46±0.38; post B2: 1.41±0.4; post B3: 1.84±0.35; post B4: 2.23±0.4; post B5:1.94±0.31; post B6: 2.73±0.09, p=0.02). At median 60 months, the recurrence rate for BG was 3.8% vs 18.9% in the CG (p=0.01). Conclusions: Booster inoculations are well-tolerated and appear to assist in the maintenance of long term peptide-specific immunity. Boosted pts have improved recurrence rates. Based on the success of this program, we have incorporated the practice of booster inoculations in our current cancer vaccine trials.

T-cell redirected killing and cure of pancreatic and gastric cancer xenografts by targeting Trop-2.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 262-262
Author(s):  
David M. Goldenberg ◽  
Edmund A. Rossi ◽  
Diane L Rossi ◽  
Thomas M. Cardillo ◽  
Chien-Hsing Chang
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ex Vivo ◽  
Control Group ◽  
Calcium Signal ◽  
Target Cells ◽  
Normal Tissues

262 Background: Trop-2 [also called tumor-associated calcium signal transducer 2 (TACSTD2), EGP-1 (epithelial glycoprotein-1), GA733-1, or M1S1]is a 35 kDa transmembrane glycoprotein that is overexpressed relative to normal tissues in a variety of human cancers, including pancreatic and gastric carcinomas, where increased expression correlates with poor prognosis. Trop-2 appears to be more tumor-specific than the related molecule, EpCAM (Trop-1). MT110, the EpCAM antibody x CD3 bispecific T-cell engager (BiTE), is currently undergoing a Phase I study in various solid tumors, including lung, gastric, colorectal, breast, prostate, and ovarian cancers. We produced a similar T-cell redirecting bispecific tandem scFv, E1-3, using the variable domains of hRS7 (humanized anti-Trop-2 mAb) and Okt-3 (anti-CD3 mAb). Methods: T-cell activation, cytokine induction and cytotoxicity were evaluated ex vivo using PBMCs or purified T cells with human pancreatic (Capan-1 and BxPC3) and gastric (NCI-N87) cancer cell lines as target cells. In vivo activity was assayed with NCI-N87 xenografts that were inoculated s.c. in a mixture with twice the number of human PBMCs and matrigel. Results: In the presence of target cells and PBMCs, E1-3 potently induced T-cell activation, proliferation, and dose-dependent cytokine production of IL-2 (>2 ng/mL), IL-6 (>1 ng/mL), IL-10 (>7 ng/mL), TNF-α (>1 ng/mL) and IFN-γ (>50 ng/mL). In vitro, E1-3 mediated a highly potent T-cell lysis of BxPC3 [IC50=0.09(±0.04) pM], Capan-1 [IC50=1.2(±1.1) pM] and NCI-N87 [IC50=1.2(±1.2) pM] target cells. In vivo, two 50-µg doses of E1-3 given three days apart cured all of the mice (N=8) bearing NCI-N87 xenografts (P=0.0005; Log-Rank). Tumors in the control group (PBMCs only) reached the endpoint (TV>1 cm3) with a median of 39.5 days. All mice remained tumor-free in the E1-3 group at 78 days. Conclusions: Trop-2 is an attractive target for T-cell-mediated killing of pancreatic, gastric and other epithelial cancers.

Adipose-derived stem cells regulate fibrosis by altering CD4+ T-cell immune responses in fat grafting in a mouse model

2020 ◽  
Author(s):  
Xinyao Chen ◽  
Yunzi Chen ◽  
Zijue Wang ◽  
Ziqing Dong ◽  
Yao Yao ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Fat Grafting ◽  
Th2 Cells ◽  
Control Group ◽  
T Cell Immune Responses ◽  
Long Term Retention

Abstract Background Autologous fat grafting is becoming increasingly common worldly. However, the long-term retention of fat grafting is still unpredictable due to the inevitable fibrosis that arises during tissue repair. Fibrosis may be regulated by T-cell immune responses that are influenced by adipose-derived stem cells (ASCs). Accordingly, we hypothesized that overly abundant ASCs might promote fibrosis by promoting T-cell immune responses to adipose tissue. Methods We performed 0.3 ml fat grafts with 104/ml, 106/ml and 108/ml ASCs and control group in C57 BL/6 mice in vivo. We observed retention, fibrosis, T-cell immunity, and macrophage infiltration over 12 weeks. In addition, CD4 + T-helper 1 (Th1) cells and T-helper 2 (Th2) cells were co-cultured with ASCs or ASCs conditioned media (CM) in vitro. We detected the ratio of Th2%/Th1% after 24 and 48 hours. Results In vivo, the retention rate was higher in the 104 group, while even lower in the 108 group with significantly increased inflammation and fibrosis than the control group at week 12. There was no significance between control group and the 106 group. Also, the 108 group increased infiltration of M2 macrophages, CD4 + T-cells and Th2/Th1 ratio. In vitro, the ratio of Th2%/Th1% induced by the ASCs-transwell group was higher than the ASCs-CM group and showed concentration-dependent. Conclusions High concentrations of ASCs in adipose tissue can promote Th1–Th2 shifting, and the excess of Th2 cells might promote the persistence of M2 macrophages and increase the level of fibrosis which lead to a decrease in the long-term retention of fat grafts. In addition, we found that ASCs promoted Th1–Th2 shifting in vitro.

scholarly journals Long-Term Transgene Expression in Proliferating Cells Mediated by Episomally Maintained High-Capacity Adenovirus Vectors

2004 ◽  
Vol 78 (1) ◽  
pp. 9-22 ◽  
Author(s):  
Florian Kreppel ◽  
Stefan Kochanek
Keyword(s):  
Transgene Expression ◽  
High Capacity ◽  
Target Cells ◽  
Resting Cells ◽  
Proliferating Cells ◽  
Daughter Cells ◽  
Adenovirus Vectors

ABSTRACT High-capacity “gutless” adenovirus vectors (HC-AdV) mediate long-term transgene expression in resting cells in vitro and in vivo because of low toxicity and immunogenicity. However, in proliferating cells, expression is transient since HC-AdV genomes do not possess elements that allow for replication and segregation of the replicated genomes to daughter cells. We developed a binary HC-AdV system that, under certain conditions, allows for significantly prolonged episomal maintenance of HC-AdV genomes in proliferating tissue culture cells, resulting in sustained transgene expression. After transduction of target cells the linear HC-AdV genomes were circularized by the DNA recombinase FLPe, which was expressed from the second HC-AdV. The oriP/EBNA-1 replication system derived from Epstein-Barr virus, as well as the human replication origin from the lamin B2 locus, were used as cis elements to test for replication of the 28-kb circular vector genomes with or without selective pressure. Depending on the system, up to 98% of the circularized genomes were replicated and segregated to daughter cells, as demonstrated by Southern assays and as confirmed by monitoring EGFP transgene expression. Surprisingly, in the absence of FLPe recombinase, a small but significant number of HC-AdV genomes spontaneously circularized after transduction of target cells. These circles, found to contain end-to-end joined adenovirus termini, replicated with increased efficiency compared to vectors circularized by FLPe. After further improvements, this HC-AdV system might be suitable for gene therapy applications requiring long-term transgene expression.

scholarly journals Efficacy and Safety of Hydroxychloroquine and Chloroquine for Treating COVID-19: A Rapid Review

2020 ◽  
Author(s):  
Nor Asiah Muhamad ◽  
Chandrika Jeevananthan ◽  
Nor Soleha Mohd Dali ◽  
Mohammed Faizal Bakhtiar ◽  
Tahir Aris ◽  
...  
Keyword(s):  
Randomized Study ◽  
In Vivo Studies ◽  
Rapid Review ◽  
Severe Illness ◽  
Control Group ◽  
Symptom Duration ◽  
Efficacy And Safety ◽  
Clinical Trial Registry

Abstract Background: Since its emergence, COVID-19 has affected more than one million people with over 100,000 deaths globally as of early April 2020. In this review, we evaluated the efficacy and safety of hydroxychloroquine and chloroquine on patients with COVID-19. Methods: PubMed, CENTRAL, Google Scholar, Chinese Clinical Trial Registry and Trial Registers: ISRCTN; UMIN-CTR (Japan's Trial Register); and the WHO portal up were searched for the in vitro and in vivo studies of hydroxychloroquine and chloroquine.Results: Moderate-certainty evidence from a single published RCT to-date showed that after a five-days treatment, patients on hydroxychloroquine may have shorter symptom duration compared to the control group, including fever (MD-1.0 day (95% CI -1.48, -0.52), cough (MD -1.1 day (95% CI -1.63, -0.57) and higher likelihood of having improved chest CT appearance (RR 1.47 (95% CI 1.02, 2.11), no clear differences was observed in the risk of progressing to severe illness and risk of adverse effects. A single non-randomized study showed marked decreased in the number with positive viral load at day 6, but due to several flaws in the study, the certainty of evidence for the outcome was very low.Conclusion: Despite the evidence on possible effects of hydroxychloroquine and chloroquine, given the paucity of available evidence especially in relation to the number on-going RCTs, conclusion on the effectiveness and safety of hydroxychloroquine cannot yet be made.

Inhibition of diacylglycerol kinase alpha to augment antitumor effector T cells in tumor-bearing host.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 293-293
Author(s):  
Naoki Okada ◽  
Ko Sugiyama ◽  
Hidemitsu Kitamura ◽  
Akinobu Taketomi
Keyword(s):  
T Cells ◽  
Cancer Cells ◽  
Granzyme B ◽  
Diacylglycerol Kinase ◽  
Effector T Cells ◽  
Control Group ◽  
Antigen Stimulation ◽  
Tumor Bearing

293 Background: Diacylglycerol kinases (DGKs), lipid kinases transforming diacylglycerol to phosphatidic acid, play important roles in intracellular signal transduction. Diacylglycerol kinase alpha (DGKa), an isozyme of DGKs, is well-known to promote proliferation of cancer cells by suppression of the apoptosis. Additionally, a previous report demonstrated that activation of DGKa induced anergy state of T lymphocytes in vivo. In this study, we investigated whether inhibition of DGKa not only suppress the tumorigenesis of cancer cells but also activate anti-tumor immunity. Methods: We first investigated the effect of DGKa inhibitor on in vitro proliferation of murine hepatoma cell lines (Hepa1-6) by cell proliferation assay. Cytokine and Granzyme B productions by CD8+ T cells from OT-1 mice after the OVA antigen stimulation were evaluated by ELISA and flowcytometry, respectively. Next, we established a tumor-bearing mice model by injection of mCherry-transfected Hepa1-6 cells into spleen. Tumorigenesis and tumor-infiltrating T cells in the liver were evaluated by in vivo imaging system, HE staining, and immunohistochemistry. CD8+ T cells were collected from the liver and stimulated with PMA and Ca2+ ionophore and the IFN-g production levels were evaluated by flowcytometry. Results: Proliferation of Hepa1-6 cells were suppressed in the presence of DGKa inhibitor in vitro. IL-2 production levels of OT-1 CD8 T cells in control group was augmented by the addition of DGKa inhibitor (246 vs 579 pg/ml, p < 0.05). Granzyme B-positive cells in OT-1 CD8+ T cells were increased by the treatment with DGKa inhibitor compared to the control group (4.4 vs 8.9 %, P < 0.05) after the antigen stimulation. In vivo administration of DGKa inhibitor significantly suppressed the tumor size (fluorescence (AU) 2.0x1010 vs 6.3x109, area (μm2) 1.5x107 vs 0.9x107, p < 0.05) in the liver of tumor bearing mice. Then, the number of tumor-infiltrating T cells (582 vs 1506, 5 HPF, p < 0.05) and the IFN-g-producing cells (9.2 vs 16.0 %) in CD8+ T cells were elevated by the DGKa treatment. Conclusions: Inhibition of DGKa not only suppressed the proliferation of hepatoma but also activated anti-tumor effector T cells in vivo.

scholarly journals Cholesterol Synthesis Increased in the MMI-Induced Subclinical Hypothyroidism Mice Model

2017 ◽  
Vol 2017 ◽  
pp. 1-6
Author(s):  
Yongfeng Song ◽  
Xiujuan Zhang ◽  
Wenbin Chen ◽  
Ling Gao
Keyword(s):  
Subclinical Hypothyroidism ◽  
Cholesterol Synthesis ◽  
Cholesterol Metabolism ◽  
Thyroid Stimulating Hormone ◽  
Normal Serum ◽  
Control Group ◽  
Mice Model

Subclinical hypothyroidism (SCH) is defined as increased serum thyroid-stimulating hormone (TSH) concentrations and normal serum thyroid hormone (TH) levels as well as an increased serum cholesterol level, which is an important cause of secondary hypercholesterolemia and cardiovascular diseases. Some studies have demonstrated a direct effect of TSH on cholesterol metabolism via in vivo and in vitro experiments. However, because no suitable SCH model has been established until now, the changes in cholesterol synthesis that occur in SCH patients remain unknown. Here, we establish an SCH mouse model by using long-term low-dose MMI administered in drinking water. Compared with the control group, the MMI-treated mice had elevated circulating TSH levels, but the serum FT3 levels in these mice did not change. Additionally, the TC levels increased in both the serum and liver of the experimental mice. Both the protein expression and activity of hepatic HMGCR, the rate-limiting enzyme for cholesterol synthesis in the liver, increased in these mice. We also found that the SCH mice had decreased phospho-HMGCR and phospho-AMPK expression, while the expression of AMPK showed no change. In conclusion, we established a suitable SCH model in which cholesterol synthesis is increased.

Orphan Granzymes Downstream from Granzyme B Are Important for Tumor Clearance In Vivo and in Vitro.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2653-2653
Author(s):  
Xuefang Cao ◽  
Paula A. Revell ◽  
William J. Grossman ◽  
Dori A. Thomas ◽  
Zhi Hong Lu ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Serine Proteases ◽  
Granzyme B ◽  
Lak Cells ◽  
Target Cells ◽  
Cytotoxic Lymphocytes ◽  
Cytotoxic Lymphocyte ◽  
Deficient Mice

Abstract Cytotoxic lymphocytes (Natural Killer cells and Cytotoxic T lymphocytes) can utilize the perforin/granzyme pathway as a major mechanism to kill pathogen-infected cells and tumor cells. Perforin is responsible for delivering and/or trafficking the granzymes (a family of neutral serine proteases) to the target cells. In the target cell cytoplasm and nucleus, the granzymes deliver the lethal hits. Granzymes A and B are the best characterized granzymes, and they can cleave a variety of important protein substrates to execute the target cells. However, some tumors and viruses have developed potent granzyme inhibitors that may allow them to evade cytotoxic lymphocyte-induced death. Interestingly, additional granzyme genes downstream from granzyme B (C, F, G, and D) on murine chromosome 14 are also expressed in cytotoxic lymphocytes, and are referred to as “orphans” since their functions have not been defined. We have developed two kinds of granzyme B knockout mice in the 129/SvJ background (H-2b) and examined their expression of granzyme B and orphan granzymes using quantitative RT-PCR and Western Blotting. In the first mouse (Gzm B−/−/+PGK-neo) a PGK-neo cassette was retained in the granzyme B gene, which caused a neighborhood effect, with significantly reduced expression of orphan granzymes C and F in cytotoxic lymphocytes (this mouse is referred to as “B cluster” deficient); In the second mouse (Gzm B−/−/ΔPGK-neo) the PGK-neo cassette was removed by Cre/loxP technology, which restored expression of granzymes C and F in cytotoxic lymphocytes (referred to as “B only” deficient). Both mutations completely abolish granzyme B expression. Using a Flow-based Killing Assay (FloKA), we have examined the cytotoxic functions of lymphocytes derived from mixed lymphocyte reactions (MLR) and 10-day lymphokine activated killer (LAK) cultures. We have found that granzyme B cluster-deficient cytotoxic lymphocytes (H-2b) generated by MLR kill allogeneic P815 or TA-3 tumor cells (H-2d) less efficiently than those deficient for granzyme B only (e.g. P815 killing at 3 hours, WT: 35%±1%, B only-deficient: 24%±5%, B cluster-deficient: 14%±3%, p&lt;0.001). The reduction in granzyme B cluster-deficient killing is also seen with LAK cells against YAC-1 and RMA-S target cells (e.g. RMA-S killing at 4 hours, WT: 26%±1%, B only-deficient: 24%±1%, B cluster-deficient: 18%±1%, p&lt;0.001). These results suggest that both allogeneic CTL and LAK cells require orphan granzymes (C and/or F) for optimal tumor cell killing. The defects in cytotoxicity detected by the FloKA assay have been confirmed to be biologically relevant (Revell et al, Blood2003, 102 (11): 1022) since granzyme B cluster-deficient mice cleared P815 cells less efficiently than either WT or granzyme B only-deficient mice (p&lt;0.02). These studies suggest that the orphan granzymes are important for cytotoxic lymphocyte functions, and that they may provide a source of functional redundancy that would help protect from pathogens or tumor cells that express inhibitors of granzyme A or B.

Protective Effects of Low Dose Vorinostat on Cisplatin-induced Nephrotoxicity in Rats

2020 ◽  
Vol 13 ◽  
Author(s):  
Omnyah M. O. Bashraf ◽  
Ahmed S. Ali ◽  
Hala S. A. Eweis ◽  
Soad S. Ali
Keyword(s):  
Single Dose ◽  
Therapeutic Potential ◽  
Control Group ◽  
Histopathological Analysis ◽  
Protective Effects ◽  
Necrosis Factor Alpha ◽  
In Vivo Models ◽  
Pre Treatment

Background and Aim: Cisplatin (cis-diamminedichloroplatinum [II]; CDDP) is the most widely used drug in cancer chemotherapy. The nephrotoxicity of CDDP is one of its major side effects. Vorinostat (VST) has been reported to have antioxidant and anti-inflammatory effects in both in-vitro and in vivo models. The present study aimed to explore the potential protective effects of VST against CDDP-induced nephrotoxicity in rats. Materials and Methods: The rats were randomly divided into 4 groups; control group, CDDP group (received CDDP 7.5 mg/kg IP single dose 5 days before the end of the experiment), VST group, (received VST 15 mg/kg/day by gastric gavage for 28 days), and CDDP + VST group (received CDDP + VST as above). Blood and kidney samples were collected on the 28th day for biochemical and histopathological examinations. Results : Administration of CDDP single dose (7.5 mg/kg IP) 5 days before the end of the experiment (at day 23) produced a significant decrease in renal glutathione levels and a significant increase in serum urea nitrogen, creatinine, renal malondialdehyde, tumor necrosis factor-alpha, tumor suppressor protein (p53) and nuclear factor kappa B levels compared to the control group. Pre-treatment with VST for 28 days significantly attenuated all unfavorable changes of these parameters. Histopathological analysis showed that VST significantly decreased kidney inflammatory and degenerative changes induced by CDDP. VST also significantly increased Bcl-2 and decreased Caspas-3 immunoexpression in renal tissues. Conclusion: These results suggest that VST alleviates CDDP-induced nephrotoxicity in rats showing a novel therapeutic potential for the management of nephrotoxicity induced by CDDP.

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