The impact of nanomaterials on autophagy across health and disease conditions.

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.

Expression and Clinical Significance of IRE1-XBP1s, p62, and Caspase-3 in Colorectal Cancer Patients.

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 formalin-fixed 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.

Metal-based nanoparticles in cancer therapy: Exploring photodynamic therapy and its interplay with regulated cell death pathways.

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.

Inhibition of IRE1 RNase activity modulates tumor cell progression and enhances the response to chemotherapy in colorectal cancer.

Drug resistance is one of the clinical challenges that limits the effectiveness of chemotherapy. Recent reports suggest that the unfolded protein response (UPR) and endoplasmic reticulum stress-adaptation signalling pathway, along with increased activation of its inositol-requiring enzyme 1α (IRE1α) arm, may be contributors to the pathogenesis of colorectal cancer (CRC). Here, we aimed to target the IRE1α/XBP1 pathway in order to sensitise CRC cells to the effects of chemotherapy. The CT26 colorectal cell line was treated with tunicamycin, and then was exposed to different concentrations of 5-fluorouracil (5-FU), either alone and/or in combination with the IRE1α inhibitor, 4µ8C. An MTT assay, flow cytometry and RT-PCR were performed to determine cell growth, apoptosis and IRE1α activity, respectively. In vivo BALB/c syngeneic colorectal mice received chemotherapeutic drugs. Treatment responses, tumour sizes and cytotoxicity were assessed via a range of pathological tests. 4µ8C was found to inhibit the growth of CRC, at a concentration of 10 µg/ml, without detectable cytotoxic effects and also significantly enhanced the cytotoxic potential of 5-FU, in CRC cells. In vivo experiments revealed that 4µ8C, at a concentration of 50 µM/kg prevented tumour growth without any cytotoxic or metastatic effects. Interestingly, the combination of 4µ8C with 5-FU remarkably enhanced drug responses, up to 40-60% and also lead to significantly greater inhibition of tumour growth, in comparison to monotherapy, in CRC mice. Targeting the IRE1α/XBP1 axis of the UPR could enhance the effectiveness of chemotherapy in both in vitro and in vivo models of CRC.

Exploring the Complex Link between Autophagy, Regulated Cell Death, and Cell Fate Pathways in Cancer Pathogenesis and Therapy.

Autophagy is a catabolic lysosomal-dependent pathway involved in the degradation of cellular materials, supplying precursor compounds and energy for macromolecule synthesis and metabolic needs [...].

Exosomes, autophagy and ER stress pathways in human diseases: Cross-regulation and therapeutic approaches.

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.

Exploring the role of non-coding RNAs in autophagy.

As a self-degradative mechanism, macroautophagy/autophagy has a role in the maintenance of energy homeostasis during critical periods in the development of cells. It also controls cellular damage through the eradication of damaged proteins and organelles. This process is accomplished by tens of ATG (autophagy-related) proteins. Recent studies have shown the involvement of non-coding RNAs in the regulation of autophagy. These transcripts mostly modulate the expression of ATG genes. Both long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been shown to modulate the autophagy mechanism. Levels of several lncRNAs and miRNAs are altered in this process. In the present review, we discuss the role of lncRNAs and miRNAs in the regulation of autophagy in diverse contexts such as cancer, deep vein thrombosis, spinal cord injury, diabetes and its complications, acute myocardial infarction, osteoarthritis, pre-eclampsia and epilepsy.Abbreviations: AMI: acute myocardial infarction; ATG: autophagy-related; lncRNA: long non-coding RNA; miRNA: microRNA.

Evaluation of squamous cell carcinoma antigen 1 expression in oral squamous cell carcinoma (tumor cells and peritumoral T-lymphocytes) and verrucous carcinoma and comparison with normal oral mucosa.

BACKGROUND: Squamous cell carcinoma antigen (SCCA) is used as a prognostic marker for recurrence of squamous cell carcinoma in various sites, including head and neck. Studies suggest that its high serum levels are correlated to some clinical features, such as nodal metastasis. However, it is still unknown if high SCCA in patients with SCCA tissue expression in tumor cells are related to peripheral T-lymphocytes. Therefore, we did this study to evaluate SCCA expression in squamous cell carcinoma and verrucous carcinoma and to compare it with normal oral mucosa, also investigating the correlation between serum-based and tissue-based antigen levels. METHODOLOGY: In this study, the immunohistochemistry (IHC) technique was used to determine the SCCA1 expression pattern in 81 specimens divided into 3 groups, including oral squamous cell carcinoma, verrucous carcinoma, and normal oral mucosa. Serum-based and tissue-based antigen levels of 20 oral squamous cell carcinoma cases were compared by the western blot assay. SCCA expression was also evaluated and compared in both tumor cells and peripheral T-lymphocytes by the immunofluorescence assay. RESULTS: Our results showed that the SCCA levels in SCC specimens were significantly lower than in verrucous carcinoma and normal and hyperplastic oral mucosa specimens. We found no correlation between the IHC expression of SCCA and serum levels. SCCA was well expressed in both tumor cells and peripheral T-lymphocytes. CONCLUSION: Decreasing SCCA in SCC specimens suggested that SCC tumor cells may affect more than the serum levels of SCCA in some patients. In addition, expression of SCCA in peripheral T-lymphocytes showed that both tumor cells and T-lymphocytes may cause serum SCCA.

Potential toxicity of nanoparticles on the reproductive system animal models: A review.

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.

TRAIL Triggers CRAC-Dependent Calcium Influx and Apoptosis through the Recruitment of Autophagy Proteins to Death-Inducing Signaling Complex.

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.

Effects of different autophagy inhibitors on sensitizing KG-1 and HL-60 leukemia cells to chemotherapy.

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.

Evaluation of squamous cell carcinoma antigen 1 expression in oral squamous cell carcinoma (tumor cells and peritumoral T-lymphocytes) and verrucous carcinoma and comparison with normal oral mucosa

Abstract Background: Squamous cell carcinoma antigen (SCCA) is used as a prognostic marker for recurrence of squamous cell carcinoma in various sites, including head and neck. Studies suggest that its high serum levels are correlated to some clinical features, such as nodal metastasis. However, it is still unknown if high SCCA in patients with SCCA tissue expression in tumor cells are related to peripheral T-lymphocytes. Therefore, we did this study to evaluate SCCA expression in squamous cell carcinoma and verrucous carcinoma and to compare it with normal oral mucosa, also investigating the correlation between serum-based and tissue-based antigen levels. Methodology: In this study, the immunohistochemistry (IHC) technique was used to determine the SCCA1 expression pattern in 81 specimens divided into 3 groups, including oral squamous cell carcinoma, verrucous carcinoma, and normal oral mucosa. Serum-based and tissue-based antigen levels of 20 oral squamous cell carcinoma cases were compared by the western blot assay. SCCA expression was also evaluated and compared in both tumor cells and peripheral T-lymphocytes by the immunofluorescence assay. Results: Our results showed that the SCCA levels in SCC specimens were significantly lower than in verrucous carcinoma and normal and hyperplastic oral mucosa specimens. We found no correlation between the IHC expression of SCCA and serum levels. SCCA was well expressed in both tumor cells and peripheral T-lymphocytes. Conclusion: Decreasing SCCA in SCC specimens suggested that SCC tumor cells may affect more than the serum levels of SCCA in some patients. In addition, expression of SCCA in peripheral T-lymphocytes showed that both tumor cells and T-lymphocytes may cause serum SCCA.

New insights on the role of autophagy in the pathogenesis and treatment of melanoma.

Despite the depth of knowledge concerning the pathogenesis of melanoma, the most aggressive type of skin cancer, the prognosis and survival of patients still remain a challenge. In addition, responses to chemotherapy and immunotherapy are still poor, which underscore an urgent need in the development of new therapeutic strategies for the treatment of melanoma. Recently, the dynamic role of autophagy has gained considerable interest in the pathogenesis and treatment of melanoma. Whereas a decrease in autophagy activity promotes melanoma formation by increasing oncogene-induced tumorigenesis and DNA damage accumulation, an enhanced level of autophagy sustains melanoma cell viability and contributes to drug resistance. Obviously, the understanding of autophagy regulation may lead to a better defining melanoma pathogenesis and the progression toward new treatment options. In this review, we present new insights into a dual role of autophagy during melanoma tumorigenesis. In addition to summarizing current therapeutics for treating melanoma, we discuss how autophagy manipulation may improve the patients' outcome. Finally, autophagy-modulating drugs and nanoparticles, alone or in combination with current therapeutics, are proposed for possible clinical use in melanoma management.

TiO2 nanoparticles enhance the chemotherapeutic effects of 5-fluorouracil in human AGS gastric cancer cells via autophagy blockade.

AIMS: 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 TiO2 NPs for improving chemotherapeutic effects of 5-fluorouracil (5-FU) in human AGS gastric cells. MATERIALS AND METHODS: 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. KEY FINDINGS: TiO2 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 TiO2 NPs (1 µg/ml) can promote cytotoxic and apoptotic effects of 5-FU in AGS cells. SIGNIFICANCE: These results confirm the beneficial effects of TiO2 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.

The Increased RNase Activity of IRE1α in PBMCs from Patients with Rheumatoid Arthritis.

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.

Anti-oxidant and Selective Anti-proliferative Effects of the Total Cornicabra Olive Polyphenols on Human Gastric MKN45 Cells.

BACKGROUND: According to the epidemiological studies, consuming olive products can decrease the incidence of the different types of cancers mostly due to the high anti-oxidant properties of their polyphenolic compounds. OBJECTIVES: To evaluate the anti-oxidant and anti-proliferative potentials of the olive fruits total polyphenols on the gastric adenocarcinoma MKN45 cells in comparison to the normal Hu02 cells. MATERIALS AND METHODS: The total phenolic content of the olive fruits and radical scavenging activity were determined by Folin and 2,2-diphenyl-1-picrylhydrazyl (DPPH) tests respectively. MTT assay was performed for the evaluation of the cell viability. Intracellular reactive oxygen species (ROS) level was measured using DCFH-DA. Statistical analysis was performed using SPSS 16 statistical software. RESULTS: Treatment of the MKN45 cells with the phenolic compounds extracted from olive fruits decreased growth and viability of the cells in a dose- and time-dependent manner. In addition, treatment of the MKN45 cells with a combination of the phenolic compounds extracts and cytarabine further decreased cell compared to monotherapy of the cells with each compound alone. Mechanistically, we showed that the anti-cancer effects of the olive polyphenols in the MKN45 cells are mediated through depletion of ROS. Similarly, polyphenolic extracts were found to decrease ROS level in the normal cells at the concentrations of 500 and 1000 µg.mL-1 and short treatment times (6 h), but the viability of these cells did not significantly change. At high concentrations (2000 µg.mL-1) of the phenolic extracts or at longer times of incubation (12 h), however, both ROS levels and the viability of the cells were significantly decreased in the normal cells. CONCLUSIONS: The olive fruits polyphenolic extract modulates ROS levels and selectively targets cancerous cells at low concentrations. Also, the effects of cytarabine could be potentiated by the olive fruits polyphenols. Thus, for a combined protocol of cancer cell therapy, olive fruit polyphenolic compound could be proposed as a proper candidate.

Autophagy: New Insights into Mechanisms of Action and Resistance of Treatment in Acute Promyelocytic leukemia.

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.

Necrotic, apoptotic and autophagic cell fates triggered by nanoparticles.

Nanomaterials have gained a rapid increase in use in a variety of applications that pertain to many aspects of human life. The majority of these innovations are centered on medical applications and a range of industrial and environmental uses ranging from electronics to environmental remediation. Despite the advantages of NPs, the knowledge of their toxicological behavior and their interactions with the cellular machinery that determines cell fate is extremely limited. This review is an attempt to summarize and increase our understanding of the mechanistic basis of nanomaterial interactions with the cellular machinery that governs cell fate and activity. We review the mechanisms of NP-induced necrosis, apoptosis and autophagy and potential implications of these pathways in nanomaterial-induced outcomes. Abbreviations: Ag, silver; CdTe, cadmium telluride; CNTs, carbon nanotubes; EC, endothelial cell; GFP, green fluorescent protein; GO, graphene oxide; GSH, glutathione; HUVECs, human umbilical vein endothelial cells; NP, nanoparticle; PEI, polyethylenimine; PVP, polyvinylpyrrolidone; QD, quantum dot; ROS, reactive oxygen species; SiO2, silicon dioxide; SPIONs, superparamagnetic iron oxide nanoparticles; SWCNT, single-walled carbon nanotubes; TiO2, titanium dioxide; USPION, ultra-small super paramagnetic iron oxide; ZnO, zinc oxide.

Health Concerns of Various Nanoparticles: A Review of Their in Vitro and in Vivo Toxicity.

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.

ER Stress: A Therapeutic Target in Rheumatoid Arthritis?

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.