Neurosteroid allopregnanolone attenuates high glucose-induced apoptosis and prevents experimental diabetic neuropathic pain: In vitro and in vivo studies

Abstract Background Previous study has been reported that braykinin B2 receptor (Bdkrb2) involves in high glucose-induced renal and podocytes injuries. However, there have been some studies with contradictory results that Bdkrb2 has a protective effect on hyperglycemia-induced injuries in vivo and in vitro. The purpose of the present study was carried out to further investigate the post-transcriptional regulatory mechanism of microRNA (miR) in high glucose-treated podocytes by targeting Bdkrb2 signaling in vitro. Methods The CCK-8 and flow cytometry were performed to measure the cell viability and apoptosis. Gene and protein expression were assayed by RT-qPCR and western blotting, respectively. Results High glucose treatment decreased cell viability and induced membrane and DNA damage, as well as apoptosis in podocytes. High glucose treatment also increased the expression of Bdkrb2, which was blocked by miR-204-3p mimics transfection in podocytes. Bioinformatics and luciferase reporter activity showed that miR-204-3p was directly targeted to the 3′-untranslated region (3′-UTR) of Bdkrb2. High glucose-induced apoptosis and dysfunction in podocytes were reserved by miR-204-3p mimics transfection, while the effects of miR-204-3p mimics in high glucose-treated podocytes were neutralized by overexpressed Bdkrb2. Conclusions These findings suggested that miR-204-3p may play a protective role in high glucose-induced apoptosis and dysfunction in podocytes through down-regulation of Bdkrb2.

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In vitro neuroprotective activities of two distinct probiotic consortia

Beneficial Microbes ◽

10.3920/bm2018.0105 ◽

2019 ◽

Vol 10 (4) ◽

pp. 437-447 ◽

Cited By ~ 2

Author(s):

D.R. Michael ◽

T.S. Davies ◽

K.E. Loxley ◽

M.D. Allen ◽

M.A. Good ◽

...

Keyword(s):

Cell Model ◽

Neuronal Cell ◽

In Vivo Studies ◽

Intact Cells ◽

Bacterial Consortia ◽

Differentiated Cells ◽

Genes Encoding ◽

Induced Apoptosis

Neurodegeneration has been linked to changes in the gut microbiota and this study compares the neuroprotective capability of two bacterial consortia, known as Lab4 and Lab4b, using the established SH-SY5Y neuronal cell model. Firstly, varying total antioxidant capacities (TAC) were identified in the intact cells from each consortia and their secreted metabolites, referred to as conditioned media (CM). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Crystal Violet (CV) assays of cell viability revealed that Lab4 CM and Lab4b CM could induce similar levels of proliferation in SH-SY5Y cells and, despite divergent TAC, possessed a comparable ability to protect undifferentiated and retinoic acid-differentiated cells from the cytotoxic actions of rotenone and undifferentiated cells from the cytotoxic actions of 1-methyl-4-phenylpyridinium iodide (MPP+). Lab4 CM and Lab4b CM also had the ability to attenuate rotenone-induced apoptosis and necrosis with Lab4b inducing the greater effect. Both consortia showed an analogous ability to attenuate intracellular reactive oxygen species accumulation in SH-SY5Y cells although the differential upregulation of genes encoding glutathione reductase and superoxide dismutase by Lab4 CM and Lab4b CM, respectively, implicates the involvement of consortia-specific antioxidative mechanisms of action. This study implicates Lab4 and Lab4b as potential neuroprotective agents and justifies their inclusion in further in vivo studies.

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Angiostatin regulates the expression of antiangiogenic and proapoptotic pathways via targeted inhibition of mitochondrial proteins

Blood ◽

10.1182/blood-2008-12-197236 ◽

2009 ◽

Vol 114 (9) ◽

pp. 1987-1998 ◽

Cited By ~ 27

Author(s):

Tong-Young Lee ◽

Stefan Muschal ◽

Elke A. Pravda ◽

Judah Folkman ◽

Amir Abdollahi ◽

...

Keyword(s):

Molecular Mechanisms ◽

Antiangiogenic Therapy ◽

Krebs Cycle ◽

In Vivo Studies ◽

Antitumor Effects ◽

Down Regulation ◽

Proteolytic Fragment ◽

Induced Apoptosis

Angiostatin, a proteolytic fragment of plasminogen, is a potent endogenous antiangiogenic agent. The molecular mechanisms governing angiostatin's antiangiogenic and antitumor effects are not well understood. Here, we report the identification of mitochondrial compartment as the ultimate target of angiostatin. After internalization of angiostatin into the cell, at least 2 proteins within the mitochondria bind this molecule: malate dehydrogenase, a member of Krebs cycle, and adenosine triphosphate synthase. In vitro and in vivo studies revealed differential regulation of key prosurvival and angiogenesis-related proteins in angiostatin-treated tumors and tumor-endothelium. Angiostatin induced apoptosis via down-regulation of mitochondrial BCL-2. Angiostatin treatment led to down-regulation of c-Myc and elevated levels of another key antiangiogenic protein, thrombospondin-1, reinforcing its antitumor and antiangiogenic effects. Further evidence is provided for reduced recruitment and infiltration of bone marrow–derived macrophages in angiostatin-treated tumors. The observed effects of angiostatin were restricted to the tumor site and were not observed in other major organs of the mice, indicating unique tumor specific bioavailability. Together, our data suggest mitochondria as a novel target for antiangiogenic therapy and provide mechanistic insights to the antiangiogenic and antitumor effects of angiostatin.

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The Predictive Role of the Biomarker Kidney Molecule-1 (KIM-1) in Acute Kidney Injury (AKI) Cisplatin-Induced Nephrotoxicity

International Journal of Molecular Sciences ◽

10.3390/ijms20205238 ◽

2019 ◽

Vol 20 (20) ◽

pp. 5238 ◽

Cited By ~ 12

Author(s):

Daniela Maria Tanase ◽

Evelina Maria Gosav ◽

Smaranda Radu ◽

Claudia Florida Costea ◽

Manuela Ciocoiu ◽

...

Keyword(s):

Acute Kidney Injury ◽

Kidney Injury ◽

In Vivo Studies ◽

Renal Tubular Cells ◽

Renal Tubular ◽

Induced Apoptosis ◽

Kidney Injury Molecule 1

Acute kidney injury (AKI) following platinum-based chemotherapeutics is a frequently reported serious side-effect. However, there are no approved biomarkers that can properly identify proximal tubular injury while routine assessments such as serum creatinine lack sensitivity. Kidney-injury-molecule 1 (KIM-1) is showing promise in identifying cisplatin-induced renal injury both in vitro and in vivo studies. In this review, we focus on describing the mechanisms of renal tubular cells cisplatin-induced apoptosis, the associated inflammatory response and oxidative stress and the role of KIM-1 as a possible biomarker used to predict cisplatin associated AKI.

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The Anticancer Effect of Sanguinarine: A Review

Current Pharmaceutical Design ◽

10.2174/1381612824666180829100601 ◽

2018 ◽

Vol 24 (24) ◽

pp. 2760-2764 ◽

Cited By ~ 7

Author(s):

Chenxing Fu ◽

Guiping Guan ◽

Hongbing Wang

Keyword(s):

Tumor Cell ◽

In Vivo Studies ◽

Inhibitory Effects ◽

Anticancer Effect ◽

Growth Inhibitory ◽

Cell Proliferation Inhibition ◽

Anti Cancer ◽

Induced Apoptosis

In vitro and in vivo studies have revealed that Sanguinarine has antioxidant, anti-inflammatory, proapoptotic, and growth inhibitory effects on tumor cells of a variety of cancers. Previous research showed that sanguinarine induced apoptosis (cell death) and/or antiproliferative while reducing tumor cell antiangiogenic and anti-invasive properties. This paper describes various sanguinarine anti-cancer mechanisms, including inhibition of erroneously-activated signal transduction pathways, apoptosis, and tumor cell proliferation inhibition.

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Inhibition of Src and insulin/insulin-like growth factor-1 receptor (IR/IGF-1R) on tumors and bone turnover in prostate cancer (PCa) models in vivo compared with inhibition of either kinase alone.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.61 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 61-61

Author(s):

Farshid Dayyani ◽

Nila Parikh ◽

Jian H. Song ◽

John C. Araujo ◽

Joan M. Carboni ◽

...

Keyword(s):

Bone Turnover ◽

Tumor Growth ◽

Bone Turnover Markers ◽

Bone Destruction ◽

In Vivo Studies ◽

Pc3 Cells ◽

Turnover Markers ◽

Induced Apoptosis

61 Background: The Src and IGF-1R axes are aberrantly activated in both PCa and the microenvironment of bone metastases. Dasatinib and BMS-754807 are clinically promising small molecule inhibitors with high potency against Src family kinases (SFK) and IR/IGF-1R, respectively. Based on a phase I/II clinical trial in which 9/19 pts treated with docetaxel + dasatinib were increased in serum IGF-1 levels after one cycle, the aim of this study was to establish potential antitumor cooperativity of inhibiting both IGF-1R and Src in experimental PCa models in vitro and in mice. Methods: Inhibition of Src and IGF-1R pathways was accomplished by pharmacologic agents (dasatinib against Src and BMS-754807 against IR/IGF-1R) as well as by shRNA, in PC3 and LNCaP cells. In vivo studies were done after orthotopic and intratibial injection of PC3 cells in nude mice. Results: SFK inhibition decreased proliferation and migration of PCa cells whereas IGF-1R blockade induced apoptosis. All anti-tumor effects were enhanced by dual blockade. IGF-1 induced phosphorylation of Akt1 and 2. Only Akt 1 phosphorylation was decreased by dasatinib; whereas Akt 1 and 2 phosphorylation were completely abrogated by the combination. Dasatinib and BMS-754807 inhibited orthotopic in vivo tumor growth of PC3 cells more potently than either inhibitor alone. Similarly, intratibial tumor growth and bone destruction was significantly reduced with the drug combination, accompanied by a decrease in serum bone turnover markers alkaline phosphatase and N-telopeptide. Conclusions: Dual inhibition of Src and IGF-1R has greater anti-tumor effect in PCa cells compared to inhibiting either alone. In the presence of IGF-1, dasatinib and BMS-754807 are necessary to inhibit IGF-1-induced phosphorylation of Akt1 and 2 in tumor cells in culture. In intratibial models, decreased bone turnover markers in serum support the concept of targeting both the epithelial and bone microenvironment. The combination of dasatinib and BMS-754807 may be a rational therapeutic approach in PCa by blocking complementary processes of tumor growth and progression.

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Targeting cancer stem cells with a pan-BCL-2 inhibitor in preclinical and clinical settings in patients with gastroesophageal carcinoma

Gut ◽

10.1136/gutjnl-2020-321175 ◽

2021 ◽

pp. gutjnl-2020-321175

Author(s):

Shumei Song ◽

Qiongrong Chen ◽

Yuan Li ◽

Guang Lei ◽

Ailing Scott ◽

...

Keyword(s):

Clinical Trial ◽

Stem Cells ◽

Cancer Stem Cells ◽

Antitumour Activity ◽

Clinical Specimen ◽

Therapy Resistance ◽

In Vivo Studies ◽

Induced Apoptosis

ObjectiveGastro-oesophageal cancers (GEC) are resistant to therapy and lead to poor prognosis. The cancer stem cells (CSCs) and antiapoptotic pathways often confer therapy resistance. We sought to elucidate the antitumour action of a BCL-2 inhibitor, AT101 in GEC in vitro, in vivo and in a clinical trial.MethodsExtensive preclinical studies in vitro and in vivo were carried out to establish the mechanism action of AT101 on targeting CSCs and antiapoptotic proteins. A pilot clinical trial in patients with GEC was completed with AT-101 added to standard chemoradiation.ResultsOverexpression of BCL-2 and MCL-1 was noted in gastric cancer tissues (GC). AT-101 induced apoptosis, reduced proliferation and tumour sphere formation in MCL-1/BCL-2 high GC cells. Interestingly, AT101 dramatically downregulated genes (YAP-1/Sox9) that control CSCs in GEC cell lines regardless of BCL-2/MCL-1 expression. Addition of docetaxel to AT-101 amplified its antiproliferation and induced apoptosis effects. In vivo studies confirmed the combination of AT101 and docetaxel demonstrated stronger antitumour activity accompanied with significant decrease of CSCs biomarkers (YAP1/SOX9). In a pilot clinical trial, 13 patients with oesophageal cancer (EC) received AT101 orally concurrently with chemoradiation. We observed dramatic clinical complete responses and encouraging overall survival in these patients. Clinical specimen analyses revealed that AT-101 dramatically reduced the expression of CSCs genes in treated EC specimens indicating antitumour activity of AT101 relies more on its anti-CSCs activity.ConclusionsOur preclinical and clinical data suggest that AT-101 overcomes resistance by targeting CSCs pathways suggesting a novel mechanism of action of AT101 in patients with GEC.

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High glucose promotes nascent nephron apoptosis via NF-κB and p53 pathways

AJP Renal Physiology ◽

10.1152/ajprenal.00361.2010 ◽

2011 ◽

Vol 300 (1) ◽

pp. F147-F156 ◽

Cited By ~ 16

Author(s):

Yun-Wen Chen ◽

Isabelle Chenier ◽

Shiao-Ying Chang ◽

Stella Tran ◽

Julie R. Ingelfinger ◽

...

Keyword(s):

High Glucose ◽

Nuclear Translocation ◽

Dominant Negative ◽

In Vivo Studies ◽

Ros Generation ◽

Small Interfering Rnas ◽

Kidney Size ◽

P53 Signaling

A hyperglycemic environment in utero reduces kidney size and nephron number due to nascent nephron apoptosis. However, the underlying mechanisms are incompletely understood. The present study investigated whether the nascent nephron apoptosis promoted by high glucose is mediated via the transcription factor NF-κB and p53 signaling pathways. Neonatal mouse kidneys from the offspring of nondiabetic, diabetic, and insulin-treated diabetic dams were used for in vivo studies, and MK4 cells, an embryonic metanephric mesenchymal (MM) cell line, were used for in vitro studies. Neonatal kidneys of the offspring of diabetic mothers exhibited an increased number of apoptotic cells and reactive oxygen species (ROS) generation, enhanced NF-κB activation, and nuclear translocation of its subunits (p50 and p65 subunits) as well as phosphorylation (Ser 15) of p53 compared with kidneys of offspring of nondiabetic mothers. Insulin treatment of diabetic dams normalized these parameters in the offspring. In vitro, high-glucose (25 mM) induced ROS generation and significantly increased MK4 cell apoptosis and caspase-3 activity via activation of NF-κB pathway, with p53 phosphorylation and nuclear translocation compared with normal glucose (5 mM). These changes in a high-glucose milieu were prevented by transient transfection of small interfering RNAs for dominant negative IκBα or IKK or p53. Our data demonstrate that high glucose-induced nascent nephron apoptosis is mediated, at least in part, via ROS generation and the activation of NF-κB and p53 pathways.

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