جستجوی مقالات مرتبط با کلیدواژه "unfolded protein response" در نشریات گروه "پزشکی"

This study investigated modulating the G protein-coupled estrogen receptor (GPER) on the IRE1α/TXNIP pathway and its role in drug resistance in MDA-MB231 cells.

Experimental approach: 

To determine the optimal concentrations of G1 and 4-hydroxytamoxifen (TAM), GPER expression and ERK1/2 phosphorylation were analyzed using qRT-PCR and western blotting, respectively. Cells were treated with individual concentrations of G1 (1000 nM), G15 (1000 nM), and TAM (2000 nM), as well as combinations of these treatments (G1 + G15, TAM + G15, and G1 + TAM) for 24 and 48 h. The expression levels of GPER, IRE1α, miR-17-5p, TXNIP, ABCB1, and ABCC1 genes and TXNIP protein expression were evaluated. Finally, apoptosis and cell migration were examined using flow cytometry and the wound-healing assay, respectively.

Activating GPER with its specific agonist G1 and TAM significantly increased IRE1α levels in MDA-MB231 cells. IRE1α through splicing XBP1 led to unfolded protein response. In addition, decreased TXNIP gene and protein expression reduced apoptosis, increased migration, and upregulated the genes associated with drug resistance.

Conclusion and implication: 

Our investigation revealed that blocking the GPER/IRE1α/TXNIP pathway in MDA-MB231 cells could enhance treatment efficacy and improve chemotherapy responsiveness. The distinct unfolded protein response observed in MDA-MB231 cells may stem from the unique characteristics of these cells, which lack receptors for estrogen, progesterone, and HER2/neu hormones, possessing only the GPER receptor (ER-/PR-/HER2-/GPER+). This study introduced a new pathway in TNBC cells, indicating that targeting GPER could be crucial in comprehensive therapeutic strategies in TNBC cells.

The potential anticancer effect of melittin has motivated scientists to find its exact molecular mechanism of action. There are few data on the effect of melittin on the UPR and autophagy as two critical pathways involved in tumorigenesis of colorectal and drug resistance. This study aimed to investigate the effect of melittin on these pathways in the CRC HCT116 cells.

MTT method was carried out to assess the cytotoxicity of melittin on the HCT116 cell line for 24, 48, and 72 h. After selecting the optimal concentrations and treatment times, the gene expression of autophagy flux markers (LC3-βII and P62) and UPR markers (CHOP and XBP-1s) were determined using qRT-PCR. The protein level of autophagy initiation marker (Beclin1) was also determined by Western blotting.

MTT assay showed a cytotoxic effect of melittin on the HCT116 cells. The increase in LC3-βII and decrease in P62 mRNA expression levels, along with the elevation in the Beclin1 protein level, indicated the stimulatory role of melittin on the autophagy. Melittin also significantly enhanced the CHOP and XBP-1s expressions at mRNA level, suggesting the positive role of the melittin on the UPR activation.

This study shows that UPR and autophagy can potentially be considered as two key signaling pathways in tumorigenesis, which can be targeted by the BV melittin in the HCT116 cells. Further in vivo evaluations are recommended to verify the obtained results.

Purinergic receptors stimulation by adenosine triphosphate (ATP) contributes significantly to macrophage activation, and also macrophage cell death. Upon the macrophage activation, the protein load of the endoplasmic reticulum is increased which is resulted in the activation of unfolded protein response (UPR). In the current study, we aimed to evaluate the connection between prototypic P2X7 receptor agonist, extracellular 2ʹ(3ʹ)-O-(4-Benzoylbenzoyl)-ATP (BzATP), and the UPR pathway in macrophages. The monocyte-derived macrophages from blood samples of 14 healthy volunteers were skewed toward M1 macrophages after incubation with LPS and IFN-γ. M1 macrophages were treated with 200 µM BzATP. The expression levels of UPR genes, including CHOP, HERP, GADD34, XBP1, and ATF6 in macrophages before and after treatment were measured using real-time polymerase chain reaction. The results demonstrated that the expression of CHOP, HERP, and ATF6 is significantly decreased and the expression level of GADD34 and XBP1 is significantly increased after M1 polarization. BzATP not only significantly increased the expression levels of CHOP, GADD34, ATF6, and HERP but also significantly decreases the XBP1 expression level in M1 macrophages. The present study showed that BzATP induces cellular stress in M1 macrophages by elevating the expression levels of UPR genes including CHOP, GADD34, ATF6, and reducing cell viability.

Endoplasmic reticulum (ER) stress triggers the unfolded protein response (UPR), which has been correlated with enhancedproduction of inflammatory cytokines. Given the important pathogenic roles of macrophages and inflammatory responses in theetiopathogenesis of Behcet’s disease (BD), this study aimed to assess the mRNA expression pattern of genes involved in theUPR pathway in macrophages from smoker and non-smoker BD patients. This case-control study was conducted between 2015and 2016 in Shariati Hospital, Tehran, Iran. Monocytes were enriched from obtained whole blood samples of 10 smokers and 10non-smoker BD patients as well as 10 healthy individuals. Using macrophage-colony stimulating factor (M-CSF), separatedmonocytes were differentiated into macrophages. After total RNA purification and cDNA synthesis, quantification analysis ofUPR genes, including activating transcription factor (ATF) 4, ATF6, X-box binding protein 1 (XBP1), binding immunoglobulinprotein (BIP), C/EBP homologous protein (CHOP), homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1 (HERP), and growth arrest and DNA damage-inducible protein (GADD34), was performed using SYBRgreen master mix and real-time PCR. Among the measured genes, HERP mRNA was overexpressed in macrophages from BDpatients in comparison with healthy macrophages. HERP and GADD34 genes were upregulated in smoker BD patients comparedwith non-smoker BD patients as well as healthy subjects. Cigarette smoke can induce UPR gene expression in BD patients. Thealtered UPR gene expression in BD macrophages may contribute to BD pathogenesis.

Perturbation of endoplasmic reticulum (ER) homeostasis leads to a stress condition described as “ER stress” which can induce the well-regulated program termed as unfolded protein response (UPR). The principal purpose of UPR is to reestablish the ER homeostasis. Some of the physiological and pathological situations that disrupt the homeostasis including hypoxia, glucose limitations, nutrient deprivation, low pH, genomic instability, and some cytotoxic compounds are frequently observed during the core formation and progression of tumors. These stressful microenvironments around the tumors affect the innate and adaptive immune responses. In Addition, different immunoregulatory myeloid populations, like dendritic cells, myeloid-derived suppressor cells (MDSCs) and macrophages, accumulate in the tumor milieu and are barrier to cancer immunotherapy. In these stressful situations, ER stress is usually induced to activate the UPR. Although the UPR mechanism is primarily a pro-survival process, preserved and/or prolonged excessive stress may induce cell apoptosis. Cancer and sustained ER stress may have modifications in ER stress mediated cell apoptosis and facilitate chronic inflammation and immune suppression within tumors. In this mini review, at first, we discuss the role of UPR and its mediators in cancerous cells fate and their potential opportunities in cancer therapy.

Recently, it has been revealed that tyrosine kinase inhibitors (TKIs) act through inducing both oxidative and endoplasmic reticulum (ER) stress in chronic myeloid leukemia cells. However, ER stress signaling triggers both apoptotic and survival processes within cells. Nevertheless, mechanisms by which TKIs avoid the pro-survival effects are not clear. The aim of this study was to evaluate the potential role of oxidative stress in activity of unfolded protein response (UPR) survival pathway within K562 cell line. The expression of UPR survival target genes, Xbp1, and Grp94 (glucose requiring protein 94) was studied in single and combined exposure to oxidative and ER stress in K562 cell line by quantitative and qualitative PCR. The expression of UPR-related survival gene Grp94 was hampered by exposing to oxidative stress in cell induced with ER stress. Interaction of oxidative and ER stress may role as a mediator influencing UPR signaling activity.

Asthma is one the fastest growing syndromes in many countries and is adding a huge cost to the health care system. Increasing reports have linked airway infectious diseases to asthma. Influenza is one the most serious airway infectious diseases and in recent years there havebeen some serious influenza virus pandemics which caused increased fatality in numerous different populations. Diverse host response pathways during virus infection have been identified, including different cell death and survival pathways. These pathways include 1) programmed cell death I (apoptosis), 2) programmed cell death II (autophagy), and 3) endoplasmic reticulum stress with subsequent unfolded protein (UPR) response. There has been extensive research on the regulatory roles of these pathways during the influenza virus life cycle. These studies address the benefits of enhancing or inhibiting these pathways on viral replication. Here we review the most recent and significant knowledge in this area for possible benefits to clinicians and basic scientist researchers in different areas of the respiratory and virology sciences.