•Cross-talk between UPR and cancer autophagy-related signaling pathways.•UPR of ER stress in cancer is linked to oxidative stress.•The effect of UPR and inflammatory response-related signaling ...pathways in cancer.•ER stress-induced inflammatory response has two sides to cancer.
The endoplasmic reticulum (ER) acts as a moving organelle with many important cellular functions. As the ER lacks sufficient nutrients under pathological conditions leading to uncontrolled protein synthesis, aggregation of unfolded/misfolded proteins in the ER lumen causes the unfolded protein response (UPR) to be activated. Chronic ER stress produces endogenous or exogenous damage to cells and activates UPR, which leads to impaired intracellular calcium and redox homeostasis. The UPR is capable of recognizing the accumulation of unfolded proteins in the ER. The protein response enhances the ability of the ER to fold proteins and causes apoptosis when the function of the ER fails to return to normal. In different malignancies, ER stress can effectively induce the occurrence of autophagy in cells because malignant tumor cells need to re-use their organelles to maintain growth. Autophagy simultaneously counteracts ER stress-induced ER expansion and has the effect of enhancing cell viability and non-apoptotic death. Oxidative stress also affects mitochondrial function of important proteins through protein overload. Mitochondrial reactive oxygen species (ROS) are produced by calcium-enhanced ER release. The accumulation of toxic substances in ER and mitochondria in mitochondria destroys basic organelle function. It is known that sustained ER stress can also trigger an inflammatory response through the UPR pathway. Inflammatory response is thought to be associated with tumor development. This review discusses the emerging links between UPR responses and autophagy, oxidative stress, and inflammatory response signals in ER stress, as well as the potential development of targeting this multifaceted signaling pathway in various cancers.
Macrophages are essential innate immune cells that contribute to host defense during infection. An important feature of macrophages is their ability to respond to extracellular cues and to adopt ...different phenotypes and functions in response to these stimuli. The evidence accumulated in the last decade has highlighted the crucial role of metabolic reprogramming during macrophage activation in infectious context. Thus, understanding and manipulation of macrophage immunometabolism during infection could be of interest to develop therapeutic strategies. In this review, we focus on 5 major metabolic pathways including glycolysis, pentose phosphate pathway, fatty acid oxidation and synthesis, tricarboxylic acid cycle and amino acid metabolism and discuss how they sustain and regulate macrophage immune function in response to parasitic, bacterial and viral infections as well as trained immunity. At the end, we assess whether some drugs including those used in clinic and in development can target macrophage immunometabolism for potential therapy during infection with an emphasis on SARS-CoV2 infection.
Treatment strategies targeting tumor-associated macrophages (TAMs) have been proposed in cancer areas. The functional alterations of macrophages in the microenvironment during the tumorigenesis of ...human epithelial cancer remain poorly understood. Here, we explored phenotypic alteration of macrophages during the development of oral squamous cell carcinoma (OSCC).
Conditioned media (CM) and exosome supernatants were harvested from normal oral epithelium, oral leukoplakia cells and OSCC cells. We measured phenotypic alteration of macrophages using flow cytometry, luminex assays, and quantitative real-time PCR assay. Intracellular signaling pathway analysis, mass spectrometry proteomics, western blotting, enzyme-linked immunosorbent assay, immunohistochemical staining, and bioinformatics analysis were performed to uncover the underlying mechanisms.
THP-1-derived and PBMCs derived macrophages exhibited an M1-like phenotype but not M2-like phenotype, when treated with CM from OSCC cells but not with the CM from normal epithelium or leukoplakia cells. Further investigations revealed that macrophages were activated by taking up exosomes released from OSCC cells through p38, Akt, and SAPK/JNK signaling at the early phase. We further provided evidences that THBS1 derived from OSCC exosomes participated in the polarization of macrophages to an M1-like phenotype. Reciprocally, CM from exosomes induced M1-like TAMs and significantly promoted migration of OSCC cells.
We proposed a novel paracrine loop between cancer cells and macrophages based on exosomes from OSCC. Therefore, target management of M1-like TAMs polarized by exosomes shows great potential as a therapeutic target for the control of cancerous migration in OSCC.
The cytokine, transforming growth factor beta (TGF-β), has a history of more than 40 years. TGF-β is secreted by many tumor cells and is associated with tumor growth and cancer immunity. The ...canonical TGF-β signaling pathway, SMAD, controls both tumor metastasis and immune regulation, thereby regulating cancer immunity. TGF-β regulates multiple types of immune cells in tumor microenvironment, including T cells, natural killer (NK) cells, and macrophages. One of the main roles of TGF-β in the tumor microenvironment is the generation of regulatory T cells, which contribute to the suppression of anti-tumor immunity. Because cancer is one of the highest causes of death globally, the discovery of immune checkpoint inhibitors by Honjo and Allison in cancer immunotherapy earned a Nobel Prize in 2018. TGF-β also regulates the levels of immune checkpoints inhibitory receptors on immune cells. Immune checkpoints inhibitors are now being developed along with anti-TGF-β antibody and/or TGF-β inhibitors. More recently, chimeric antigen receptors (CARs) were applied to cancer immunity and tried to combine with TGF-β blockers.
High frequency and high efficiency operation is one of the premier interests in the signal and energy conversion applications. The wide bandgap GaN based devices possess superior properties and have ...demonstrated exceeding performance than Si or GaAs devices. In order to further exploit the potential of GaN electronics, monolithic power integration is proposed. Firstly, this paper discusses the structure and properties of GaN power devices to explain the choice of lateral integration in the view of GaN power ICs. Then the state-of-the-art performance of GaN power integration in two major application areas is reviewed, which are the microwave power amplification and DC-DC power conversion. The GaN power integration technologies in MMIC platforms are summarized in terms of the gate length, operation frequency and power added efficiency of ICs. On the other hand, the smart GaN power IC platforms have boosted the development of DC-DC power converters. Demonstrations of high frequency (>1 MHz) and high efficiency (>95 %) converters with various kinds of integration technology and topology are reviewed. Lastly novel integration schemes and methods are introduced to stimulate new thoughts on GaN power integration road.
Traditional wisdom holds that intact immune responses, such as immune surveillance or immunoediting, are required for preventing and inhibiting tumor development; but recent evidence has also ...indicated that unresolved immune responses, such as chronic inflammation, can promote the growth and progression of cancer. Within the immune system, cytotoxic CD8(+) and CD4(+) Th1 T cells, along with their characteristically produced cytokine IFN-γ, function as the major anti-tumor immune effector cells, whereas tumor associated macrophages (TAM) or myeloid-derived suppressive cells (MDSC) and their derived cytokines IL-6, TNF, IL-1β and IL-23 are generally recognized as dominant tumor-promoting forces. However, the roles played by Th17 cells, CD4(+) CD25(+) Foxp3(+) regulatory T lymphocytes and immunoregulatory cytokines such as TGF-β in tumor development and survival remain elusive. These immune cells and the cellular factors produced from them, including both immunosuppressive and inflammatory cytokines, play dual roles in promoting or discouraging cancer development, and their ultimate role in cancer progression may rely heavily on the tumor microenvironment and the events leading to initial propagation of carcinogenesis.
Regulatory T cells (Tregs) in the tumor microenvironment regulate tumor immunity. Programmed cell death protein 1 (PD‐1) is known to be expressed on Tregs and plays crucial roles in suppressing tumor ...immunity. However, the immune checkpoint inhibitor, anti‐PD‐1 antibody, is known to promote the proliferation of the Treg population in tumor‐infiltrating lymphocytes, thereby restricting the efficacy of cancer immunotherapy. In this study, we focused on the curcumin analog GO‐Y030, an antitumor chemical. GO‐Y030 inhibited the immune‐suppressive ability of Tregs via metabolic changes in vitro, even in the presence of immune checkpoint inhibitors. Mechanistically, GO‐Y030 inhibited the mTOR‐S6 axis in Tregs, which plays a pivotal role in their immune‐suppressive ability. GO‐Y030 also controlled the metabolism in cultured CD4+ T cells in the presence of TGF‐β + IL‐6; however, it did not prevent Th17 differentiation. Notably, GO‐Y030 significantly inhibited IL‐10 production from Th17 cells. In the tumor microenvironment, L‐lactate produced by tumors is known to support the suppressive ability of Tregs, and GO‐Y030 treatment inhibited L‐lactate production via metabolic changes. In addition, experiments in the B16‐F10 melanoma mouse model revealed that GO‐Y030 helped inhibit the anti‐PD‐1 immune checkpoint and reduce the Treg population in tumor‐infiltrating lymphocytes. Thus, GO‐Y030 controls the metabolism of both Tregs and tumors and could serve as a booster for anti‐immune checkpoint inhibitors.
Curcumin analog GO‐Y030 boosts cancer immunotherapy via metabolic changes.
Systemic infusion of bone marrow mesenchymal stem cells (BMMSCs) yields therapeutic benefit for a variety of autoimmune diseases, but the underlying mechanisms are poorly understood. Here we show ...that in mice systemic infusion of BMMSCs induced transient T cell apoptosis via the FAS ligand (FASL)-dependent FAS pathway and could ameliorate disease phenotypes in fibrillin-1 mutated systemic sclerosis (SS) and dextran-sulfate-sodium-induced experimental colitis. FASL−/− BMMSCs did not induce T cell apoptosis in recipients, and could not ameliorate SS and colitis. Mechanistic analysis revealed that FAS-regulated monocyte chemotactic protein 1 (MCP-1) secretion by BMMSCs recruited T cells for FASL-mediated apoptosis. The apoptotic T cells subsequently triggered macrophages to produce high levels of TGFβ, which in turn led to the upregulation of CD4+CD25+Foxp3+ regulatory T cells and, ultimately, immune tolerance. These data therefore demonstrate a previously unrecognized mechanism underlying BMMSC-based immunotherapy involving coupling via FAS/FASL to induce T cell apoptosis.
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► Bone marrow MSCs induce transient T cell apoptosis in autoimmune disease models ► FASL is required in the BMMSCs to generate this effect ► MCP-1 secretion by BMMSCs recruits T cells for FASL-mediated apoptosis ► Apoptotic T cells trigger macrophages to produce TGFβ and thus upregulate Tregs
Under the background of the quick development of lightweight, flexible, and wearable electronic devices in our society, a flexible and highly efficient energy management strategy is needed for their ...counterpart energy-storage systems. Among them, flexible electrochemical capacitors (ECs) have been considered as one of the most promising candidates because of their significant advantages in power and energy densities, and unique properties of being flexible, lightweight, low-cost, and environmentally friendly compared with current energy storage devices. In a common EC, carbon materials play an irreplaceable and principal role in its energy-storage performance. Up till now, most progress towards flexible ECs technologies has mostly benefited from the continuous development of carbon materials. As a result, in view of the dual remarkable highlights of ECs and carbon materials, a summary of recent research progress on carbon-based flexible EC electrode materials is presented in this review, including carbon fiber (CF, consisting of carbon microfiber-CMF and carbon nanofiber-CNF) networks, carbon nanotube (CNT) and graphene coatings, CNT and/or graphene papers (or films), and freestanding three-dimensional (3D) flexible carbon-based macroscopic architectures. Furthermore, some promising carbon materials for great potential applications in flexible ECs are introduced. Finally, the trends and challenges in the development of carbon-based electrode materials for flexible ECs and their smart applications are analyzed.
Allogeneic mesenchymal stem cells (MSCs) exhibit immunoregulatory function in human autoimmune diseases such as systemic lupus erythematosus (SLE), but the underlying mechanisms remain incompletely ...understood. Here we show that the number of peripheral tolerogenic CD1c
dendritic cells (DCs) and the levels of serum FLT3L are significantly decreased in SLE patients especially with lupus nephritis, compared to healthy controls. Transplantation of allogeneic umbilical cord-derived MSCs (UC-MSCs) significantly up-regulates peripheral blood CD1c
DCs and serum FLT3L. Mechanistically, UC-MSCs express FLT3L that binds to FLT3 on CD1c
DCs to promote the proliferation and inhibit the apoptosis of tolerogenic CD1c
DCs. Conversely, reduction of FLT3L with small interfering RNA in MSCs abolishes the up-regulation of tolerogenic CD1c
DCs in lupus patients treated with MSCs. Interferon-γ induces FLT3L expression in UC-MSCs through JAK/STAT signaling pathway. Thus, allogeneic MSCs might suppress inflammation in lupus through up-regulating tolerogenic DCs.
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