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The authors provide evidence that simvastatin (Simva) enhances temozolomide (TMZ)-induced cell death in GBM cells through UPR-mediated autophagy flux in U251 (p53 mutant) and U87 (p53 wild type) GBM cells. There are three distinct forms of autophagy, including macroautophagy (simply referred to here as autophagy), microautophagy and chaperone-mediated autophagy (CMA) [[1]]. This review highlights four major aspects: key features of pancreatic ductal adenocarcinoma (PDAC), the role of autophagy in tumor metabolism, therapeutic approaches using autophagy inhibitors in PDAC, and autophagy-based strategies to overcome resistance in PDAC. [Extracted from the article]

Nanoparticles (NPs) are currently used in diagnosis and treatment of many human diseases, including autoimmune diseases and cancer. However, cytotoxic effects of NPs on normal cells and living organs is a severe limiting factor that hinders their use in clinic. In addition, diversity of NPs and their physico-chemical properties, including particle size, shape, surface area, dispersity and protein corona effects are considered as key factors that have a crucial impact on their safe or toxicological behaviors. Current studies on toxic effects of NPs are aimed to identify the targets and mechanisms of their side effects, with a focus on elucidating the patterns of NP transport, accumulation, degradation, and elimination, in both in vitro and in vitro models. NPs can enter the body through inhalation, skin and digestive routes. Consequently, there is a need for reliable information about effects of NPs on various organs in order to reveal their efficacy and impact on health. This review covers the existing knowledge base on the subject that hopefully prepares us better to address these challenges. [ABSTRACT FROM AUTHOR]

Diverse physiological and pathological conditions that impact on protein folding of the endoplasmic reticulum (ER) cause ER stress. The unfolded protein response (UPR) and the ER-associated degradation (ERAD) pathway are activated to cope with ER stress. In rheumatoid arthritis (RA), inflammation and ER stress work in parallel by driving inflammatory cells to release cytokines that induce chronic ER stress pathways. This chronic ER stress may contribute to the pathogenesis of RA through synoviocyte proliferation and proinflammatory cytokine production. Therefore, ER stress pathways and their constituent elements are attractive targets for RA drug development. In this review, we integrate current knowledge of the contribution of ER stress to the overall pathogenesis of RA, and suggest some therapeutic implications of these discoveries. [ABSTRACT FROM AUTHOR]

The dysregulation of autophagy is involved in the pathogenesis of a broad range of diseases, and accordingly universal research efforts have focused on exploring novel compounds with autophagy-modulating properties. While a number of synthetic autophagy modulators have been identified as promising cancer therapy candidates, autophagy-modulating phytochemicals have also attracted attention as potential treatments with minimal side effects. In this review, we firstly highlight the importance of autophagy and its relevance in the pathogenesis and treatment of cancer. Subsequently, we present the data on common phytochemicals and their mechanism of action as autophagy modulators. Finally, we discuss the challenges associated with harnessing the autophagic potential of phytochemicals for cancer therapy. [ABSTRACT FROM AUTHOR]

Nucleostemin (NS), a stem cell-abundant nucleolar protein, is critical for maintaining the self-renewal and proliferative properties of normal and cancerous stem cells. Recent data suggests that NS signaling is important for proliferation of T-cells and leukemia cells. This study was conducted to verify the role of NS in pathogenesis and treatment of T-cell acute lymphocytic leukemia (T-ALL). Our results revealed that RNA interference-mediated NS silencing primarily affected clonogenicproperty of T-ALL cells by limiting their self-renewal potential in vitro. These effects were accompanied with inhibition of proliferation and early apoptosis in Jurkat cells (p53-null) while late apoptosis in Molt-4 (p53 functional) T-ALL cells. Collectively, our results suggest that NS is a critical regulator in self-renewal and apoptosis of differentTALL cells. This suggests therapeutic potential of this gene in leukemia. [ABSTRACT FROM AUTHOR]

Objectives: Nucleostemin (NS), a recently discovered nucleolar protein, is essential for maintaining selfrenewal and proliferation of embryonic and adult stem cells as well as cancerous cells. The aim of this study was to determine biological function of NS in MOLT-4 cells as a human T-cell acute lymphocytic leukemia (T-ALL) model. Methods: Efficacy of a specific small interference RNA on NS depletion was studied by quantitative polymerase chain reaction and western blotting. The growth rate and viability were analyzed by trypan blue exclusion test. Fluorescent microscopy was used for detecting apoptosis. Cell cycle and apoptosis were mechanistically studied by flow cytometry and western blotting. Results: Knockdown of NS inhibited proliferation, arrested the cell cycle, and induced apoptosis through p53 and p21Waf1/Cip1 pathways in MOLT-4 cells. Discussion: These findings demonstrate critical roles of NS in MOLT-4 cells and may implicate on its therapeutic potential in this human T-ALL model. [ABSTRACT FROM AUTHOR]

Abstract: Despite the depth of knowledge concerning the pathogenesis of acute myeloblastic leukemia (AML), long-term survival remains unresolved. Therefore, new agents that act more selectively and more potently are required. In that line, we have recently characterized a novel diterpene ester, called 3-hydrogenkwadaphnin (3-HK), with capability to induce both differentiation and apoptosis in various leukemia cell lines. These effects of 3-HK were mediated through inhibition of inosine 5′-monophosphate dehydrogenase, a selective up-regulated enzyme in cancerous cells, especially leukemia. However, it remains elusive to understand how cells display different fates in response to 3-HK. Here, we report the distinct molecular signaling pathways involved in forcing of 3-HK-treated U937 cells to undergo differentiation and apoptosis. After 3-HK (15 nM) treatment, a portion of U937 cells adhered to the culture plates and showed macrophage criteria while others remained in suspension and underwent apoptosis. The differentiated cells arrested in G0/G1 phase of cell cycle and showed early activation of ERK1/2 pathway (3 h) along with ERK-dependent p21Cip/WAF1 (p21) up-regulation and expression of p27Kip1 and Bcl-2. In contrast, the suspension cells underwent apoptosis through Fas/FasL and mitochondrial pathways. The occurrence of apoptosis in these cells were accompanied with caspase-8-mediated p21 cleavage and delayed activation (24 h) of JNK1/2 and p38 MAPK. Taken together, these results suggest that distinct signaling pathways play a pivotal role in fates of drug-treated leukemia cells, thus this may pave some novel therapeutical utilities. [Copyright &y& Elsevier]

Abstract: Since differentiation therapy is one of the promising strategies for treatment of leukemia, universal efforts have been focused on finding new differentiating agents. In that respect, it was recently shown that guanosine 5′-triphosphate (GTP) induced the differentiation of K562 cells, suggesting its possible efficiency in treatment of chronic myelogenous leukemia (CML). However, further investigations are required to verify this possibility. Here, the effects of GTP on activation of mitogen-activated protein kinases (MAPKs) and caspases in K562 cells were examined. Exposure of K562 cells to 100μM GTP markedly inhibited growth (4–70%) and increased percent glycophorin A positive cells after 1–6 days. GTP-induced terminal erythroid differentiation of K562 cells was accompanied with activation of three key caspases, i.e., caspase-3, -6 and -9. More detailed studies revealed that mitochondrial pathway is activated along with down-regulation of Bcl-xL and releasing of cytochrome c into cytosol. Among MAPKs, ERK1/2and p38 were modulated after GTP treatment. Western blot analyses showed that sustained phosphorylation of p38 MAPK was accompanied by a decrease in ERK1/2 activation. These modulatory effects of GTP were observed at early exposure times before the onset of differentiation (3h), and followed for 24–96h. Interestingly, inhibition of p38 MAPK pathway by SB202190 impeded GTP-mediated caspases activation and differentiation in K562 cells, suggesting that p38 MAPK may act upstream of caspases in our system. These results point to a pivotal role for p38 MAPK pathway during GTP-mediated erythroid differentiation of K562 cells and will hopefully have important impact on pharmaceutical evaluation of GTP for CML treatment in differentiation therapy approaches. [Copyright &y& Elsevier]

Abstract: 3-Hydrogenkwadaphnin (3-HK) is a recently characterized daphnane-type compound isolated from Dendrostellera lessertii with high anti-tumor activity in animal models. Herein, we report on time- and dose-dependent effects of this compound on growth, differentiation, IMPDH inhibition, cell cycle and apoptosis of a panel of human leukemia cell lines (HL-60, K562 and Molt4). The drug decreased the growth of leukemia cells in less than 24h of treatment. However, longer exposure times and/or higher concentrations were required to promote cell apoptosis. Cell cycle analysis revealed the accumulation of cells in their G1 phase as early as 12h after drug exposure but sub-G1 population was recorded after 24h. Occurrence of apoptosis was constantly accompanied by morphological (staining with DNA-binding dyes) and biochemical (DNA fragments) variations among drug-treated cells. Despite these observations, non-activated normal human PBL were insensitive to the drug action. In addition, treatment of PHA-activated PBL, K562, Molt4 and HL-60 cells with a single dose of the drug for 24h led to the inhibition of IMPDH activity by almost 37, 38, 44 and 50%, respectively. In contrast, no difference in IMPDH activities were seen between normal PBL and the drug treated PBL cells. Restoration of the depleted GTP concentration by exogenous addition of guanosine (25–50μM) reversed the drug effects on cell growth, DNA fragmentation and apoptosis. Furthermore, the drug effects were potentiated by exogenous addition of hypoxanthine to the drug-treated cells. Reduction of the drug potency on the non-proliferative (retinoic acid treated) HL-60 cells by almost 40%, compared to the proliferative cells, clearly shows type II IMPDH as one of the main targets of the drug. These results suggest that 3-HK may be a powerful candidate for treatment of leukemia. [Copyright &y& Elsevier]

Autophagy is one of the main cellular catabolic pathways controlling a variety of physiological processes, including those involved in self-renewal, differentiation and death. While acute promyelocytic leukemia (APL) cells manifest low levels of expression of autophagy genes associated with reduced autophagy activity, the introduction of all-trans retinoid acid (ATRA)—a differentiating agent currently used in clinical settings—restores autophagy in these cells. ATRA-induced autophagy is involved in granulocytes differentiation through a mechanism that involves among others the degradation of the PML-RARα oncoprotein. Arsenic trioxide (ATO) is another anti-cancer agent that promotes autophagy-dependent clearance of promyelocytic leukemia retinoic acid receptor alpha gene (PML-RARα) in APL cells. Hence, enhancing autophagy may have therapeutic benefits in maturation-resistant APL cells. However, the role of autophagy in response to APL therapy is not so simple, because some autophagy proteins have been shown to play a pro-survival role upon ATRA and ATO treatment, and both agents can activate ETosis, a type of cell death mediated by the release of neutrophil extracellular traps (ETs). This review highlights recent findings on the impact of autophagy on the mechanisms of action of ATRA and ATO in APL cells. We also discuss the potential role of autophagy in the development of resistance to treatment, and of differentiation syndrome in APL. [ABSTRACT FROM AUTHOR]

Background: Three main cell signaling pathways including the endoplasmic reticulum stress (ERS) response, autophagy, and apoptosis play critical roles in both cell survival and death. They were found to crosstalk with one another during tumorigenesis and cancer progression. This study aimed to investigate the expression of the spliced form of X-box binding protein 1 (XBP1s), p62, and caspase-3, as the essential biomarkers of ERS, autophagy, and apoptosis in patients with colorectal cancer (CRC), as well as the correlation between their expression and clinicopathological data. Methods: This retrospective study was conducted on formalinfixed paraffin-embedded (FFPE) blocks, which were collected from patients and their tumor margins, from the tumor bank of Imam Khomeini Hospital (Tehran, Iran) from 2017 to 2019. Tissue microarray (TMA) was used to measure the XBP1s, p62, and caspase-3 biomarkers. Data were analyzed using SPSS software version 20, and P≤0.05 was considered statistically significant. Results: Evaluating the total of 91 patients, a significant relationship was found between XBP1s expression and TNM stage (P=0.003), primary tumor (pT) (P=0.054), and the degree of differentiation (P=0.006); and between caspase-3 with pT (P=0.004), and lymphovascular invasion (P=0.02). However, no significant correlation was found between p62 and clinicopathological data. Furthermore, a positive relationship between XBP1s and p62 was confirmed (correlation coefficient: 22.2% and P=0.05). Conclusion: Our findings indicated that XBP1s could be considered as a target for therapy in personalized medicine. [ABSTRACT FROM AUTHOR]

Autophagy, a catabolic process integral to cellular homeostasis, is constitutively active under physiological and stress conditions. The role of autophagy as a cellular defense response becomes particularly evident upon exposure to nanomaterials (NMs), especially environmental nanoparticles (NPs) and nanoplastics (nPs). This has positioned autophagy modulation at the forefront of nanotechnology-based therapeutic interventions. While NMs can exploit autophagy to enhance therapeutic outcomes, they can also trigger it as a pro-survival response against NP-induced toxicity. Conversely, a heightened autophagy response may also lead to regulated cell death (RCD), in particular autophagic cell death, upon NP exposure. Thus, the relationship between NMs and autophagy exhibits a dual nature with therapeutic and environmental interventions. Recognizing and decoding these intricate patterns are essential for pioneering next-generation autophagy-regulating NMs. This review delves into the present-day therapeutic potential of autophagy-modulating NMs, shedding light on their status in clinical trials, intervention of autophagy in the therapeutic applications of NMs, discusses the potency of autophagy for application as early indicator of NM toxicity. [ABSTRACT FROM AUTHOR]

[Display omitted] • Nanoparticles caused toxicity to the reproductive tract in females and males. • Nanoparticles have a toxicity effect on the implantation pathway. • The use of nanomaterials should be monitored due to potential health implications. Over the past two decades, nanotechnology has been involved in an array of applications in various fields, including diagnostic kits, disease treatment, drug manufacturing, drug delivery, and gene therapy. But concerns about the toxicity of nanoparticles have greatly hindered their use; also, due to their increasing use in various industries, all members of society are exposed to the toxicity of these nanoparticles. Nanoparticles have a negative impact on various organs, including the reproductive system. They also can induce abortion in women, reduce fetal growth and development, and can damage the reproductive system and sperm morphology in men. In some cases, it has been observed that despite the modification of nanoparticles in composition, concentration, and method of administration, there is still damage to the reproductive organs. Therefore, understanding how nanoparticles affect the reproductive system is of very importance. In several studies, the nanoparticle toxicity effect on the genital organs has been investigated at the clinical and molecular levels using the in vivo and in vitro models. This study reviews these investigations and provides important data on the toxicity, hazards, and safety of nanoparticles in the reproductive system to facilitate the optimal use of nanoparticles in the industry. [ABSTRACT FROM AUTHOR]

Schematic illustration of various uses of metal-based NPs in PDT for cancer treatment. PDT can trigger ACD (accidental cell death), RCD (regulated cell death) and ICD (immunologic cell death) and result in tumor destruction. (DAMPs: Damage associated molecular patterns, NPs: nanoparticles, PDT: photodynamic therapy, PS: photosensitizer, ROS: reactive oxygen species). Created with BioRender.com [Display omitted] • We explored the distinctive contributions of various metal-based nanoparticles in enhancing the efficiency of photodynamic therapy. • We unveiled the combined power of nanotechnology and PDT in targeted cancer treatment, with a focus on metal-based NPs. • We delved deep into the influence of metal NPs on diverse cell death pathways during PDT. • We highlighted the safety concerns and potential toxicities associated with the use of metal-based nanoparticles in PDT. • We discussed the emerging multi-modal treatment strategies integrating PDT, MHT, and other therapeutic methods using metal NPs for enhanced cancer therapy. Photodynamic therapy (PDT) represents a non-invasive treatment strategy currently utilized in the clinical management of selected cancers and infections. This technique is predicated on the administration of a photosensitizer (PS) and subsequent irradiation with light of specific wavelengths, thereby generating reactive oxygen species (ROS) within targeted cells. The cellular effects of PDT are dependent on both the localization of the PS and the severity of ROS challenge, potentially leading to the stimulation of various cell death modalities. For many years, the concept of regulated cell death (RCD) triggered by photodynamic reactions predominantly encompassed apoptosis, necrosis, and autophagy. However, in recent decades, further explorations have unveiled additional cell death modalities, such as necroptosis, ferroptosis, cuproptosis, pyroptosis, parthanatos, and immunogenic cell death (ICD), which helps to achieve tumor cell elimination. Recently, nanoparticles (NPs) have demonstrated substantial advantages over traditional PSs and become important components of PDT, due to their improved physicochemical properties, such as enhanced solubility and superior specificity for targeted cells. This review aims to summarize recent advancements in the applications of different metal-based NPs as PSs or delivery systems for optimized PDT in cancer treatment. Furthermore, it mechanistically highlights the contribution of RCD pathways during PDT with metal NPs and how these forms of cell death can improve specific PDT regimens in cancer therapy. [ABSTRACT FROM AUTHOR]

A little number of current autophagy inhibitors may have beneficial effects on the acute myeloid leukemia (AML) patients. However, there is a strong need to figure out which settings should be activated or inhibited in autophagy pathway to prevail drug resistance and also to improve current treatment options in leukemia. Therefore, this study aimed to compare the effects of well‐known inhibitors of autophagy (as 3‐MA, BafA1, and HCQ) in leukemia KG‐1 and HL‐60 cells exposed to arsenic trioxide (ATO) and/or all‐trans retinoic acid (ATRA). Cell proliferation and cytotoxicity of cells were examined by MTT assay. Autophagy was studied by evaluating the development of acidic vesicular organelles, and the autophagosomes formation was investigated by acridine orange staining and transmission electron microscopy. Moreover, the gene and protein expressions levels of autophagy markers (ATGs, p62/SQSTM1, and LC‐3B) were also performed by qPCR and western blotting, respectively. The rate of apoptosis and cell cycle were evaluated using flow cytometry. We compared the cytotoxic and apoptotic effects of ATO and/or ATRA in both cell lines and demonstrated that some autophagy markers upregulated in this context. Also, it was shown that autophagy blockers HCQ and/or BafA1 could potentiate the cytotoxic effects of ATO/ATRA, which were more pronounced in KG‐1 cells compared to HL‐60 cell line. This study showed the involvement of autophagy during the treatment of KG‐1 and HL‐60 cells by ATO/ATRA. This study proposed that therapy of ATO/ATRA in combination with HCQ can be considered as a more effective strategy for targeting leukemic KG‐1 cells. [ABSTRACT FROM AUTHOR]

Purpose: Despite recent advances in the diagnosis and treatment of rheumatoid arthritis (RA), this inflammatory disease remains a challenge to patients and physicians. Recent evidence highlights the contribution of endoplasmic reticulum (ER) stress in the pathogenesis and treatment of RA. Herein, we study the expression of the ER stress sensor inositol-requiring enzyme 1α (IRE1α), as well as XBP1 splicing and the regulated IRE1-dependent decay (RIDD), in peripheral blood mononuclear cells (PBMCs) from patients with RA compared with healthy controls. Methods: The PBMCs from blood samples of RA patients and healthy volunteers were isolated by a density gradient centrifugation method using Ficoll. The gene expression levels of GRP78/Bip, IRE1, XBP1s, micro-RNAs (miRNAs) were evaluated by real-time PCR. Results: The expression of GRP78, IRE1, and XBP1s were increased in PBMCs of RA patients compared with healthy controls. We further show that the RIDD targets (miRNA-17, -34a, -96, and -125b) were downregulated in RA samples. Conclusion: This study can expand our knowledge on the importance of RNase activity of IRE1α in RA and may offer new potentials for developing novel diagnostic and/or therapeutic biomarkers. [ABSTRACT FROM AUTHOR]

Here, we report that targeting Nucleostemin (NS) , a recently discovered stem cells-enriched gene, by a specific small interference RNA (siNS), decreases the rate of proliferation of acute promyelocytic leukemia (APL) NB4 cells and induces differentiation and autophagy. In addition, NS silencing promotes the effects of all- trans -retinoic acid (ATRA)-based differentiation therapy in NB4 cells. Autophagy inhibitors 3-methyladenine and bafilomycin block the effect of NS targeting on differentiation, indicating a new functional link between NS and autophagy as an important regulator of differentiation in NB4 cells. The capability of NS in modulating autophagy and differentiation, alone or in combination with ATRA, may help to broaden the range of treatment options available to treat leukemia. [ABSTRACT FROM AUTHOR]

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 include 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 act as barriers 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 highlight the the role of UPR and its mediators in cancerous cells fate and then discuss their potential opportunities in cancer therapy. [ABSTRACT FROM AUTHOR]

Previous studies have suggested that quinazolinone derivatives are potent apoptosis-inducing agents in various cancer cell lines. In the present study, we have investigated cytotoxic, apoptosis induction, and molecular docking activities of the spiroquinazolinone benzamide derivatives family on MCF-7 human breast cancer cells. The MTT cytotoxicity assays and docking studies showed that 4t-CHQB was the most active compound among the prepared spiroquinazolinone benzamide compounds with IC50 of 50 ± 1.2 μM and was selected for further assessments. Apoptosis, as the mechanism of cell death, was assessed morphologically by acridine orange/ethidium bromide (AO/EtBr) double staining, evaluation of the cell surface phosphatidylserine (PS) expression through annexin V/PI technique and, the formation of DNA ladder. Down regulation of survivin was evaluated in protein level after cell treatment with 4t-CHQB using western blotting method. Molecular modeling experiments involving 4t-CHQB binding site of survivin showed several strong hydrogen bonds and hydrophobic interactions between many important amino acid residues. Overall, the obtained data suggest that the assessed spiroquinazolinone benzamide compounds may provide a novel therapeutic approach for further evaluation, as an effective chemotherapeutic family acting through down regulation of survivin and apoptosis induction in breast cancer. [ABSTRACT FROM AUTHOR]

In this study, the catalase-like activity of monomeric tau protein was reported in the presence of of zinc (Zn(II)) ions at low pH value. Monomeric tau protein contains two SH groups that are a target of disulfide bond formation. However these SH groups are able to interact with Zn(II) ion at pH 7.2 which creates a thiol bond as a mimetic model of chloroperoxidase active site which performs catalase like activity at low pH. Zn(II)/tau protein complex decomposed H 2 O 2 with a high rate (V m ) as well as an efficient turn oven number (k cat ) at pH 3. This remarkable catalase like activity is may be attributed to the conformational reorientation of protein at low pH. Circular dichroism (CD) studies did not demonstrate any secondary structural changes of tau protein after addition of Zn(II) ions at pH 7.2. In addition, tau protein shows identical CD bands at pH 7.2 and 3. Moreover, fluorescence quenching of tau by Zn(II) at pH 7.2 was initiated by complex formation rather than by dynamic collision. A significant red shift (6 nm) was observed in the emission maximum of the fluorescence spectra when the protein was dissolved at pH 3 compared to pH 7.2. This conformational change can provide information regarding the rearrangements of the protein structure and exposure of Cys-Zn(II) group to the solvent which induces easy access of active site to H2O2 molecules and corresponding enhanced catalytic activity of Zn(II)/tau protein complex. This study introduces tau protein as a bio-inspired high performing scaffold for transition metal encapsulation and introducing an engineered apoprotein-induced biomimetic enzyme. [ABSTRACT FROM AUTHOR]

Exosomal release pathway and autophagy together maintain homeostasis and survival of cells under stressful conditions. Autophagy is a catabolic process through which cell entities, such as malformed biomacromolecules and damaged organelles, are degraded and recycled via the lysosomal-dependent pathway. Exosomes, a sub-type of extracellular vesicles (EVs) formed by the inward budding of multivesicular bodies (MVBs), are mostly involved in mediating communication between cells. The unfolded protein response (UPR) is an adaptive response that is activated to sustain survival in the cells faced with the endoplasmic reticulum (ER) stress through a complex network that involves protein synthesis, exosomes secretion and autophagy. Disruption of the critical crosstalk between EVs, UPR and autophagy may be implicated in various human diseases, including cancers and neurodegenerative diseases, yet the molecular mechanism(s) behind the coordination of these communication pathways remains obscure. Here, we review the available information on the mechanisms that control autophagy, ER stress and EV pathways, with the view that a better understanding of their crosstalk and balance may improve our knowledge on the pathogenesis and treatment of human diseases, where these pathways are dysregulated. [Display omitted] • Autophagy, ER stress and exosomes are related pathways that maintain cells homeostasis. • Disruption of crosstalk between exosomes, UPR and autophagy implicates in human diseases. • Fine tuning autophagy, ER stress and exosomal pathway hold therapeutic potential in pathological conditions. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively kills various cancer cell types, but also leads to the activation of signaling pathways that favor resistance to cell death. Here, we investigated the as yet unknown roles of calcium signaling and autophagy regulatory proteins during TRAIL-induced cell death in leukemia cells. Taking advantage of the Gene Expression Profiling Interactive Analysis (GEPIA) project, we first found that leukemia patients present a unique TRAIL receptor gene expression pattern that may reflect their resistance to TRAIL. The exposure of NB4 acute promyelocytic leukemia cells to TRAIL induces intracellular Ca2+ influx through a calcium release-activated channel (CRAC)-dependent mechanism, leading to an anti-apoptotic response. Mechanistically, we showed that upon TRAIL treatment, two autophagy proteins, ATG7 and p62/SQSTM1, are recruited to the death-inducing signaling complex (DISC) and are essential for TRAIL-induced Ca2+ influx and cell death. Importantly, the treatment of NB4 cells with all-trans retinoic acid (ATRA) led to the upregulation of p62/SQSTM1 and caspase-8 and, when added prior to TRAIL stimulation, significantly enhanced DISC formation and the apoptosis induced by TRAIL. In addition to uncovering new pleiotropic roles for autophagy proteins in controlling the calcium response and apoptosis triggered by TRAIL, our results point to novel therapeutic strategies for sensitizing leukemia cells to TRAIL. [ABSTRACT FROM AUTHOR]

Nanoparticles (NPs)-based drugs have been recently introduced to improve the efficacy of current therapeutic strategies for the treatment of cancer; however, the molecular mechanisms by which a NP interacts with cellular systems still need to be delineated. Here, we utilize the autophagic potential of TiO 2 NPs for improving chemotherapeutic effects of 5-fluorouracil (5-FU) in human AGS gastric cells. Cell growth and viability were determined by trypan blue exclusion test and MTT assay, respectively. Vesicular organelles formation was evaluated by acridine orange staining of cells. Cell cycle and apoptosis were monitored by flow cytometry. Reactive oxygen species (ROS) level were measured by DCHF-DA staining. Autophagy was examined by q-PCR and western blotting. Molecular docking was used for studying NP interaction with autophagic proteins. TiO 2 NPs increase ROS production, impair lysosomal function and subsequently block autophagy flux in AGS cells. In addition, the autophagy blockade induced by non-toxic concentrations of TiO 2 NPs (1 μg/ml) can promote cytotoxic and apoptotic effects of 5-FU in AGS cells. These results confirm the beneficial effects of TiO 2 NPs in combination with chemotherapy in in vitro model of gastric cancer, which may pave the way to develop a possible solution to circumvent chemoresistance in cancer. [ABSTRACT FROM AUTHOR]

• His-GQDs synthesized via pyrolysis green-synthesis route. • His-GQDs were used for cellular imaging of ACHN cell lines as a novel bright green fluorescence probe. • This is the first reported of label-free, selective and non-toxic fluorescence probe for cellular imaging of ACHN cell lines. • Cellular imaging was achieved successfully show that His-GQDs can be easily penetrated into cytoplasm. In this study, bright green-luminescent probe (His-GQDs) were synthesized using a new one-pot "bottom-up" pyrolysis green-synthesis route, without consuming any water and chemical reagent. Citric acid as carbon source and Histidine as amino-functionalized agent, with optimized ratios, were used for fabricating His-GQDs as a novel, label-free, and selective probe. His-GQDs can be then used for cellular imaging of human ACHN cell lines that are composed of graphene sheets with the average size of 2.0 nm. Obtained His-GQDs probe has ultra-small size, low toxicity, chemical stability, biocompatibility, anti-photo bleaching and excellent optical properties with a rather high quantum yield of 62.8%. The detailed structural studies were confirmed by FT-IR, HR-TEM and powdered X-ray diffraction analysis respectively. In this project, the His-GQDs were utilized for cellular imaging of human ACHN cell lines for the first time. This probe indicated the presence desired biocompatibility of His-GQDs in human ACHN cell lines even at high their concentration (1800 µg mL−1) at 24 h post-treatment and their distribution in ACHN cell lines cytoplasm. [ABSTRACT FROM AUTHOR]