scholarly journals The Effects of Inorganic Arsenic On Apoptosis and Autophagy in Human Hepatic Sellate Cells

2022 ◽  
Author(s):  
Fei Huang ◽  
Yu Hui ◽  
Ang Li ◽  
Rishalaiti Tayier ◽  
Dilinaer Yaermaimaiti ◽  
...  
Keyword(s):  
Smooth Muscle Actin ◽  
Mammalian Target Of Rapamycin ◽  
Inorganic Arsenic ◽  
B Cell Lymphoma ◽  
Beclin 1 ◽  
Effector Protein ◽  
Laser Confocal Microscopy ◽  
Ubiquitin Binding ◽  
Key Issues ◽  
Apoptotic Pathways

Abstract Endemic arsenism is a major disease concern in China, with arsenic poisoning and induced potential lesions key issues on a global level. The liver is the main target organ where arsenic is metabolized; chronic exposure to arsenic-induced liver fibrosis is also closely related to autophagy, however, the exact mechanisms are remain unclear. In this study, we explored the effects of NaAsO2 on apoptosis and autophagy in human hepatic stellate cells(HSC). We established a fibrosis model in the HSC line, LX-2 which was exposed to NaAsO2 for 24h, 48h, and 72h. Cells were then transfected using an autophagy double-labeled RFP-GFP-LC3 adenoviral plasmid. Laser confocal microscopy indicated significant infection efficiencies and autophagy in LX-2. Flow cytometry was also used to investigate the effects of different NaAsO2 doses on apoptosis. NaAsO2 treatment upregulated the expression of autophagic markers, including microtubule-associated protein light chain A/B(LC3), ubiquitin binding protein(SQSTM-1/P62), autophagy related genes(ATGs), recombinant human autophagy effector protein (Beclin-1), and B cell lymphoma-2(BCL-2), but downregulated mammalian target of rapamycin(mTOR). Also, α-smooth muscle actin(α-SMA) expression was significantly upregulated in all NaAsO2 groups. Furthermore, mTOR silencing via 3-methyladenine(3-MA) altered NaAsO2 induced autophagy, LC3, Beclin-1, and SQSTM-1/P62 expression were all upregulated in both NaAsO2 and 3-MA-iAs groups. Altogether, NaAsO2 induced HSC autophagy via apoptotic pathways. 3-MA inhibited LX-2 activity and reduced NaAsO2-induced autophagy which may inhibit fibrosis progression caused by this toxin.

scholarly journals The AP-1 Transcription Factor Fosl-2 Regulates Autophagy in Cardiac Fibroblasts during Myocardial Fibrogenesis

2021 ◽  
Vol 22 (4) ◽  
pp. 1861
Author(s):  
Jemima Seidenberg ◽  
Mara Stellato ◽  
Amela Hukara ◽  
Burkhard Ludewig ◽  
Karin Klingel ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Smooth Muscle Actin ◽  
Beclin 1 ◽  
Type I ◽  
Alpha Smooth Muscle Actin

Background: Pathological activation of cardiac fibroblasts is a key step in development and progression of cardiac fibrosis and heart failure. This process has been associated with enhanced autophagocytosis, but molecular mechanisms remain largely unknown. Methods and Results: Immunohistochemical analysis of endomyocardial biopsies showed increased activation of autophagy in fibrotic hearts of patients with inflammatory cardiomyopathy. In vitro experiments using mouse and human cardiac fibroblasts confirmed that blockade of autophagy with Bafilomycin A1 inhibited fibroblast-to-myofibroblast transition induced by transforming growth factor (TGF)-β. Next, we observed that cardiac fibroblasts obtained from mice overexpressing transcription factor Fos-related antigen 2 (Fosl-2tg) expressed elevated protein levels of autophagy markers: the lipid modified form of microtubule-associated protein 1A/1B-light chain 3B (LC3BII), Beclin-1 and autophagy related 5 (Atg5). In complementary experiments, silencing of Fosl-2 with antisense GapmeR oligonucleotides suppressed production of type I collagen, myofibroblast marker alpha smooth muscle actin and autophagy marker Beclin-1 in cardiac fibroblasts. On the other hand, silencing of either LC3B or Beclin-1 reduced Fosl-2 levels in TGF-β-activated, but not in unstimulated cells. Using a cardiac hypertrophy model induced by continuous infusion of angiotensin II with osmotic minipumps, we confirmed that mice lacking either Fosl-2 (Ccl19CreFosl2flox/flox) or Atg5 (Ccl19CreAtg5flox/flox) in stromal cells were protected from cardiac fibrosis. Conclusion: Our findings demonstrate that Fosl-2 regulates autophagocytosis and the TGF-β-Fosl-2-autophagy axis controls differentiation of cardiac fibroblasts. These data provide a new insight for the development of pharmaceutical targets in cardiac fibrosis.

scholarly journals Oxidative Stress and Apoptotic Responses Elicited by Nostoc-Synthesized Silver Nanoparticles against Different Cancer Cell Lines

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2099 ◽  
Author(s):  
Reham Samir Hamida ◽  
Gadah Albasher ◽  
Mashael Mohammed Bin-Meferij
Keyword(s):  
Oxidative Stress ◽  
Silver Nanoparticles ◽  
Cancer Cells ◽  
Hepg2 Cells ◽  
Caspase 3 ◽  
Mammalian Target Of Rapamycin ◽  
B Cell Lymphoma ◽  
Phosphorylated Akt ◽  
Hct 116 ◽  
Mcf 7

Green nanoparticles represent a revolution in bionanotechnology, providing opportunities to fight life-threatening diseases, such as cancer, with less risk to the environment and to human health. Here, for the first time, we systematically investigated the anticancer activity and possible mechanism of novel silver nanoparticles (N-SNPs) synthesized by Nostoc Bahar M against the MCF-7 breast cancer cells, HCT-116 colorectal adenocarcinoma cells, and HepG2 liver cancer cells, using cell viability assays, morphological characterization with inverted light and transmission electron microscopy, antioxidants and enzymes (glutathione peroxidase (GPx), glutathione (GSH), adenosine triphosphatase (ATPase), and lactate dehydrogenase (LDH)), and western blotting (protein kinase B (Akt), phosphorylated-Akt (p-Akt), mammalian target of rapamycin (mTOR), B-cell lymphoma 2 (Bcl-2), tumor suppressor (p53), and caspase 3). N-SNPs decreased the viability of MCF-7, HCT-116, and HepG2 cells, with half-maximal inhibitory concentrations of 54, 56, and 80 µg/mL, respectively. They also significantly increased LDH leakage, enhanced oxidative stress via effects on antioxidative markers, and caused metabolic stress by significantly decreasing ATPase levels. N-SNPs caused extensive ultrastructural alterations in cell and nuclear structures, as well as in various organelles. Furthermore, N-SNPs triggered apoptosis via the activation of caspase 3 and p53, and suppressed the mTOR signaling pathway via downregulating apoptosis-evading proteins in MCF-7, HCT-116, and HepG2 cells. Ultrastructural analysis, together with biochemical and molecular analyses, revealed that N-SNPs enhanced apoptosis via the induction of oxidative stress and/or through direct interactions with cellular structures in all tested cells. The cytotoxicity of Nostoc-mediated SNPs represents a new strategy for cancer treatment via targeting various cell death pathways. However, the potential of N-SNPs to be usable and biocompatible anticancer drug will depend on their toxicity against normal cells.

scholarly journals Genetic Events Inhibiting Apoptosis in Diffuse Large B Cell Lymphoma

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2167
Author(s):  
Etienne Leveille ◽  
Nathalie Johnson
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Point Mutations ◽  
B Cell Lymphoma ◽  
Malignant Cells ◽  
Large B Cell Lymphoma ◽  
Apoptotic Proteins ◽  
Apoptotic Pathways ◽  
Genetic Events ◽  
Large B Cell

Diffuse large B cell lymphoma (DLBCL) is curable with chemoimmunotherapy in ~65% of patients. One of the hallmarks of the pathogenesis and resistance to therapy in DLBCL is inhibition of apoptosis, which allows malignant cells to survive and acquire further alterations. Inhibition of apoptosis can be the result of genetic events inhibiting the intrinsic or extrinsic apoptotic pathways, as well as their modulators, such as the inhibitor of apoptosis proteins, P53, and components of the NF-kB pathway. Mechanisms of dysregulation include upregulation of anti-apoptotic proteins and downregulation of pro-apoptotic proteins via point mutations, amplifications, deletions, translocations, and influences of other proteins. Understanding the factors contributing to resistance to apoptosis in DLBCL is crucial in order to be able to develop targeted therapies that could improve outcomes by restoring apoptosis in malignant cells. This review describes the genetic events inhibiting apoptosis in DLBCL, provides a perspective of their interactions in lymphomagenesis, and discusses their implication for the future of DLBCL therapy.

scholarly journals Aromadendrin Protects Neuronal Cells from Methamphetamine-Induced Neurotoxicity by Regulating Endoplasmic Reticulum Stress and PI3K/Akt/mTOR Signaling Pathway

2021 ◽  
Vol 22 (5) ◽  
pp. 2274
Author(s):  
Hyun-Su Lee ◽  
Eun-Nam Kim ◽  
Gil-Saeng Jeong
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Signaling Pathway ◽  
Neuronal Cells ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Irreversible Damage ◽  
Pre Treatment ◽  
Apoptotic Pathways

Methamphetamine (METH) is a highly addictive drug that induces irreversible damage to neuronal cells and pathological malfunction in the brain. Aromadendrin, isolated from the flowers of Chionanthus retusus, has been shown to have anti-inflammatory or anti-tumor activity. Nevertheless, it has been reported that METH exacerbates neurotoxicity by inducing endoplasmic reticulum (ER) stress via the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in neuronal cells. There is little evidence that aromadendrin protects cells from neurotoxicity induced by METH. In this study, we found that aromadendrin partially suppressed the METH-induced cell death in SH-SY5y cells without causing cytotoxicity. Aromadendrin regulated METH-induced ER stress by preserving the phosphorylation of the PI3K/Akt/mTOR signaling pathway in METH-exposed SH-SY5y cells. In addition, aromadendrin mitigated METH-induced autophagic and the apoptotic pathways in METH-exposed SH-SY5y cells. Mechanistic studies revealed that pre-treatment with aromadendrin restored the expression of anti-apoptotic proteins in METH-exposed conditions. The inhibitor assay confirmed that aromadendrin-mediated restoration of mTOR phosphorylation protected cells from autophagy and apoptosis in METH-exposed cells. Therefore, these findings suggest that aromadendrin relatively has a protective effect on SH-SY5y cells against autophagy and apoptosis induced by METH via regulation of ER stress and the PI3K/Akt/mTOR signaling pathway.

Aucubin Protects against TGFβ1-Induced Cardiac Fibroblasts Activation by Mediating the AMPKα/mTOR Signaling Pathway

Planta Medica ◽  
2017 ◽  
Vol 84 (02) ◽  
pp. 91-99 ◽  
Author(s):  
Yang Xiao ◽  
Wei Chang ◽  
Qing-Qing Wu ◽  
Xiao-Han Jiang ◽  
Ming-Xia Duan ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Smooth Muscle Actin ◽  
Mammalian Target Of Rapamycin ◽  
Transforming Growth Factor Β1 ◽  
Neonatal Rat ◽  
Cell Counting ◽  
Compound C ◽  
Underlying Mechanisms

AbstractFibrosis is a key feature of various cardiovascular diseases and compromises cardiac systolic and diastolic performance. The lack of effective anti-fibrosis drugs is a major contributor to the increasing prevalence of heart failure. The present study was performed to investigate whether the iridoid aucubin alleviates cardiac fibroblast activation and its underlying mechanisms. Neonatal rat cardiac fibroblasts were incubated with aucubin (1, 10, 20, 50 µM) followed by transforming growth factor β1 (TGFβ1, 10 ng/mL) stimulation for 24 h. Fibrosis proliferation was measured by cell counting kit-8 assay. The differentiation of fibroblasts into myofibroblasts was determined by measuring the expression of α-smooth muscle actin. Then, the expressions levels of cardiac fibrosis-related proteins in myofibroblasts were analyzed by western blot and real-time PCR to confirm the anti-fibrosis effect of aucubin. As a result, aucubin suppressed TGFβ1-induced proliferation in fibroblasts and inhibited the TGFβ1-induced activation of fibroblasts to myofibroblasts. In addition, aucubin further attenuated fibrosis-related protein expression in myofibroblasts. Furthermore, this protective effect was related to increased adenosine 5′-monophosphate-activated protein kinase (AMPK) phosphorylation and decreased mammalian target of rapamycin (mTOR) phosphorylation, which was confirmed by an mTOR inhibitor (rapamycin), an AMPK agonist (AICAR) and an AMPKα inhibitor compound C. Collectively, our findings suggest that aucubin protects against TGFβ1-induced fibroblast proliferation, activation and function by regulating the AMPKα/mTOR signal axis.

scholarly journals Prodigiosin-Emerged PI3K/Beclin-1-Independent Pathway Elicits Autophagic Cell Death in Doxorubicin-Sensitive and -Resistant Lung Cancer

2018 ◽  
Vol 7 (10) ◽  
pp. 321 ◽  
Author(s):  
Wei-Jun Chiu ◽  
Shian-Ren Lin ◽  
Yu-Hsin Chen ◽  
May-Jwan Tsai ◽  
Max Leong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Mammalian Target Of Rapamycin ◽  
Underlying Mechanism ◽  
Beclin 1 ◽  
Class Iii ◽  
Microtubule Associated Proteins ◽  
Associated Proteins ◽  
Anti Tumor Activity

Prodigiosin (PG) belongs to a family of prodiginines isolated from gram-negative bacteria. It is a water insoluble red pigment and a potent proapoptotic compound. This study elucidates the anti-tumor activity and underlying mechanism of PG in doxorubicin-sensitive (Dox-S) and doxorubicin-resistant (Dox-R) lung cancer cells. The cytotoxicity and cell death characteristics of PG in two cells were measured by MTT assay, cell cycle analysis, and apoptosis/autophagic marker analysis. Then, the potential mechanism of PG-induced cell death was evaluated through the phosphatidylinositol-4,5-bisphosphate 3-kinase-p85/Protein kinase B /mammalian target of rapamycin (PI3K-p85/Akt/mTOR) and Beclin-1/phosphatidylinositol-4,5-bisphosphate 3-kinase-Class III (Beclin-1/PI3K-Class III) signaling. Finally, in vivo efficacy was examined by intratracheal inoculation and treatment. There was similar cytotoxicity with PG in both Dox-S and Dox-R cells, where the half maximal inhibitory concentrations (IC50) were all in 10 μM. Based on a non-significant increase in the sub-G1 phase with an increase of microtubule-associated proteins 1A/1B light chain 3B-phosphatidylethanolamine conjugate (LC3-II), the cell death of both cells was categorized to achieve autophagy. Interestingly, an increase in cleaved-poly ADP ribose polymerase (cleaved-PARP) also showed the existence of an apoptosis-sensitive subpopulation. In both Dox-S and Dox-R cells, PI3K-p85/Akt/mTOR signaling pathways were reduced, which inhibited autophagy initiation. However, Beclin-1/PI3K-Class III downregulation implicated non-canonical autophagy pathways were involved in PG-induced autophagy. At completion of the PG regimen, tumors accumulated in the mice trachea and were attenuated by PG treatment, which indicated the efficacy of PG for both Dox-S and Dox-R lung cancer. All the above results concluded that PG is a potential chemotherapeutic agent for lung cancer regimens regardless of doxorubicin resistance.

mTOR inhibition as a possible pharmacological target in the management of systemic inflammatory response and associated neuroinflammation by lipopolysaccharide challenge in rats

2021 ◽  
Author(s):  
Demet Sinem Guden ◽  
Meryem Temiz-Resitoglu ◽  
Sefika Pınar Senol ◽  
Deniz Kibar ◽  
Sakir Necat Yilmaz ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Microglial Activation ◽  
Critical Role ◽  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
B Cell Lymphoma ◽  
Nuclear Factor Κb ◽  
Systemic Inflammatory Response ◽  
Mtor Inhibition ◽  
Factor Α

Neuroinflammation plays a critical role during sepsis triggered by microglial activation. Mammalian target of rapamycin (mTOR) has gained attraction in neuroinflammation, however, the mechanism remains unclear. Our goal was to assess the effects of mTOR inhibition by rapamycin on inflammation, microglial activation, oxidative stress, and apoptosis associated with the changes in the inhibitor-κB (IκB)-α/nuclear factor-κB (NF-κB)/hypoxia-inducible factor-1α (HIF-1α) pathway activity following a systemic challenge with lipopolysaccharide (LPS). Rats received saline (10 ml/kg), LPS (10 mg/kg), and/or rapamycin (1 mg/kg) via intraperitoneally. Inhibition of mTOR by rapamycin blocked phosphorylated form of ribosomal protein S6, NF-κB p65 activity by increasing degradation of IκB-α in parallel with HIF-1α expression increased by LPS in the kidney, heart, lung, and brain tissues. Rapamycin attenuated the increment in the expression of tumor necrosis factor-α and interleukin-1β, the inducible nitric oxide synthase, gp91<sup>phox</sup>, and p47<sup>phox</sup> in addition to nitrite levels elicited by LPS in tissues or sera. Concomitantly, rapamycin treatment reduced microglial activation, brain expression of caspase-3, and Bcl-2-associated X protein while increased expression of B-cell lymphoma 2 induced by LPS. Overall, this study supports the hypothesis that mTOR contributes to the detrimental effect of LPS-induced systemic inflammatory response associated with neuroinflammation via IκB-α/NF-κB/HIF-1α signaling pathway.

scholarly journals Targeting Apoptotic Pathways in Acute Myeloid Leukaemia

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1660 ◽  
Author(s):  
Jonathan R. Sillar ◽  
Anoop K. Enjeti
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
B Cell Lymphoma ◽  
Clinical Work ◽  
Biological Research ◽  
Apoptotic Pathways ◽  
Molecular Landscape ◽  
Early Phase Clinical Trials ◽  
Acute Myeloid

Acute Myeloid Leukaemia is a devastating disease that continues to have a poor outcome for the majority of patients. In recent years, however, a number of drugs have received FDA approval, following on from successful clinical trial results. This parallels the characterization of the molecular landscape of Acute Myeloid Leukaemia (AML) over the last decade, which has led to the development of drugs targeting newly identified recurring mutations. In addition, basic biological research into the pathobiology of AML has identified aberrant programmed cell death pathways in AML. Following on from successful outcomes in lymphoid malignancies, drugs targeting the B Cell Lymphoma 2 (BCL-2) family of anti-apoptotic proteins have been explored in AML. In this review, we will outline the preclinical and clinical work to date supporting the role of drugs targeting BCL-2, with Venetoclax being the most advanced to date. We will also highlight rationale combinations using Venetoclax, ongoing clinical trials and biomarkers of response identified from the early phase clinical trials performed.

A Study of the Expression of the LMP1 Oncoprotein in Low-Grade B Cell Lymphomas and Correlation with the Levels of Oxidative Stress

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4833-4833
Author(s):  
Panagiotis Theodorou Diamantopoulos ◽  
Vasiliki Papadopoulou ◽  
Aikaterini Polonyfi ◽  
Athanasios G. Galanopoulos ◽  
Fani Kalala ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Low Grade ◽  
B Cell Lymphomas ◽  
Ebv Infection ◽  
Lmp1 Expression ◽  
Apoptotic Pathways

Abstract Abstract 4833 Introduction. The Epstein-Barr virus has been implicated in the pathogenesis of certain human B-cell neoplasms, such as Burkitt's lymphoma, Hodgkin's disease and post-transplant lympho-proliferative disorders. Persistent latent EBV infection is, however, frequent and therefore its role is of interest in all types of B cell malignancies. In low-grade B cell lymphomas there are few reports for its potential role in higher grade transformation and its association with stereotypic BCRs in CLL. The mechanisms of EBV-associated B cell transformation are probably associated with its proteins expressed during latency; one of the most studied is the LMP1 oncoprotein, which is considered as an anti-apoptotic factor (activator of NF-êB). Recent studies, however, show evidence of coexisting apoptotic properties of LMP1. The level of oxidative stress reflects activation of caspase-mediated apoptotic pathways. Aims and methods. We measured the levels of oxidative stress in low-grade B cell lymphoma patient samples and correlated them with the expression of the LMP1 oncoprotein in order to study apoptotic functions of LMP1. Whole blood samples from 48 patients aged 51–87 (median age 74 years, 25 males, 23 females) without treatment in the previous six months were examined (chronic lymphocytic leukemia: 27, marginal zone lymphoma: 12, mantle cell lymphoma: 4, hairy cell leukemia: 2, follicular lymphoma: 2, lymphoplasmacytic lymphoma: 1). Latent EBV infection was detected with RT-PCR for the viral BXLF1 gene. LMP1 expression was quantitated with Real-Time PCR in EBV-positive patients. The levels of oxidative stress were quantitated in the sera of all patients with the use of a peroxide measuring kit (PerOx TOS/TOC kit by Immundiagnostik) and compared between the LMP1-positive (13) and LMP1-negative (35) group of patients with the use of 2-tailed Mann-Whitney test. Results. Of the fourty-eight (48) patients tested, nineteen (19) were EBV-positive. Thirteen (13) of the nineteen (19) EBV-positive ones expressed LMP1. Oxidative stress was found to be significantly higher in LMP1-negative vs LMP1-positive patients (372.3 vs 261.4 micromol/L, p=0.014). Discussion. The role of LMP1 expression is under investigation in the non EBV-related low grade B cell lymphomas. In the present study we examined a potential effect of LMP1 expression on oxidative stress and found that levels of oxidative stress were lower in LMP1-positive vs LMP1-negative patients with low-grade B cell lymphomas, reflecting an anti-apoptotic function of LMP1. In accordance with this result, LMP1 has been shown to upregulate BCL-2 using the NF-êB pathway. BCL-2 is a major inhibitor of the initiation of caspase-related apoptotic pathways and BCL-2 upregulation inhibits apoptosis resulting in lower levels of oxidative stress. However, in a study of sixty-four patients with low grade B cell lymphomas, we recently showed that LMP1 expression increases the levels of the apoptotic marker survivin, confirming that LMP1 may also possess an apoptotic function, as has been shown by another recent study on cell lines. Conclusion. The lower oxidative stress in the LMP1-expressing low grade B cell lymphoma samples shows evidence of an apoptotic function of the oncoprotein in this group of diseases. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document