It has been established that cancer can be promoted and/or exacerbated by inflammation and infections. Indeed, chronic inflammation orchestrates a tumor-supporting microenvironment that is an ...indispensable participant in the neoplastic process. The mechanisms that link infection, innate immunity, inflammation, and cancer are being unraveled at a fast pace. Important components in this linkage are the cytokines produced by activated innate immune cells that stimulate tumor growth and progression. In addition, soluble mediators produced by cancer cells recruit and activate inflammatory cells, which further stimulate tumor progression. However, inflammatory cells also produce cytokines that can limit tumor growth. Here we provide an overview of the current understanding of the role of inflammation-induced cytokines in tumor initiation, promotion, and progression.
“Maskne” is a new term coined during the 2020 COVID‐19 pandemic. It refers to a subset of acne mechanica, deserving consideration in view of widespread reusable fabric mask‐wearing to control the ...pandemic worldwide. Understanding of underlying pathophysiology directly relates to the novel skin microenvironment and textile–skin friction created by mask‐wearing, distinct from nontextile‐related acne mechanica previously linked to wearing of headgear. Specifically, the occlusive microenvironment leads to microbiome dysbiosis, which is linked to various dermatological conditions. Additional textile–skin interactions include factors such as breathability, stickiness sensations, moisture saturation, and hygiene maintenance. Increased skin temperatures can trigger sweat/heat‐related dermatoses, and ear loops potentially trigger pressure‐induced dermatoses. Important therapeutic considerations include increased skin irritation potential of conventional acne treatments under occlusion, exacerbation of chronic dermatoses, that is, perioral dermatitis, rosacea, and eczema, and susceptibility of these same patient groups to heightened discomfort with mask‐wearing. Cotton, as the traditional fabric of choice for dermatology patients, has limited benefits in the context of face masks – increased subjective discomfort relates to increased moisture saturation and stickiness, inevitable because of high biofluid load of the nasal and oral orifices. Prolonged textile–skin contact time, directly proportional to the risk of maskne, can be an opportunity for the application of biofunctional textiles.
Diabetic retinopathy (DR) and age‐related macular degeneration (AMD) are two important leading causes of acquired blindness in developed countries. As accumulation of advanced glycation end products ...(AGEs) in retinal pigment epithelial (RPE) cells plays an important role in both DR and AMD, and the methylglyoxal (MGO) within the AGEs exerts irreversible effects on protein structure and function, it is crucial to understand the underlying mechanism of MGO‐induced RPE cell death. Using ARPE‐19 as the cell model, this study revealed that MGO induces RPE cell death through a caspase‐independent manner, which relying on reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP) loss, intracellular calcium elevation and endoplasmic reticulum (ER) stress response. Suppression of ROS generation can reverse the MGO‐induced ROS production, MMP loss, intracellular calcium increase and cell death. Moreover, store‐operated calcium channel inhibitors MRS1845 and YM‐58483, but not the inositol 1,4,5‐trisphosphate (IP3) receptor inhibitor xestospongin C, can block MGO‐induced ROS production, MMP loss and sustained intracellular calcium increase in ARPE‐19 cells. Lastly, inhibition of ER stress by salubrinal and 4‐PBA can reduce the MGO‐induced intracellular events and cell death. Therefore, our data indicate that MGO can decrease RPE cell viability, resulting from the ER stress‐dependent intracellular ROS production, MMP loss and increased intracellular calcium increase. As MGO is one of the components of drusen in AMD and is the AGEs adduct in DR, this study could provide a valuable insight into the molecular pathogenesis and therapeutic intervention of AMD and DR.
Decoy receptor 3 (DcR3), also known as tumor necrosis factor receptor (TNFR) superfamily member 6b (TNFRSF6B), is a soluble decoy receptor which can neutralize the biological functions of three ...members of tumor necrosis factor superfamily (TNFSF): Fas ligand (FasL), LIGHT, and TL1A. In addition to 'decoy' function, recombinant DcR3.Fc is able to modulate the activation and differentiation of dendritic cells (DCs) and macrophages via 'non-decoy' action. DcR3-treated DCs skew T cell differentiation into Th2 phenotype, while DcR3-treated macrophages behave M2 phenotype. DcR3 is upregulated in various cancer cells and several inflammatory tissues, and is regarded as a potential biomarker to predict inflammatory disease progression and cancer metastasis. However, whether DcR3 is a pathogenic factor or a suppressor to attenuate inflammatory reactions, has not been discussed comprehensively yet. Because mouse genome does not have DcR3, it is not feasible to investigate its physiological functions by gene-knockout approach. However, DcR3-mediated effects in vitro are determined via overexpressing DcR3 or addition of recombinant DcR3.Fc fusion protein. Moreover, CD68-driven DcR3 transgenic mice are used to investigate DcR3-mediated systemic effects in vivo. Upregulation of DcR3 during inflammatory reactions exerts negative-feedback to suppress inflammation, while tumor cells hijack DcR3 to prevent apoptosis and promote tumor growth and invasion. Thus, 'switch-on' of DcR3 expression may be feasible for the treatment of inflammatory diseases and enhance tissue repairing, while 'switch-off' of DcR3 expression can enhance tumor apoptosis and suppress tumor growth in vivo.
Although prior research underscores the benefits of external collaboration for a firm's innovative output, little research has examined the role that collaboration plays across the different stages ...of the innovation process. Drawing from organizational learning theory, this article examines (1) how collaboration with domestic partners assists in the formation of collaborations with foreign partners, (2) how knowledge from these collaborations is associated with product innovation at different levels of novelty, and (3) how the relationship between the level of innovation novelty and firm growth is influenced by whether the focal firm engages in open or closed innovation and the origin of the collaborator (foreign or domestic). Three key findings emerge from the econometric analysis of a sample of 1684 Taiwanese firms. First, domestic collaborations assist in the formation of foreign collaborations when the partner type is the same. Second, the level of innovation novelty is associated with the type and geographic location of partners. This study differentiates among noninnovating firms, incremental innovators, and radical innovators and demonstrates that the role of partners changes as the number of countries in which a firm collaborates with each partner type increases. Third, only radical innovation is relevant to firm growth, regardless of whether it is developed internally or through collaboration with domestic or foreign partners.
Syk increases NLRP3 inflammasome formation through phosphorylation of ASC and enhancement of ASC oligomerization.
NLRP3 is the most crucial member of the NLR family, as it detects the existence of ...pathogen invasion and self‐derived molecules associated with cellular damage. Several studies have reported that excessive NLRP3 inflammasome‐mediated caspase‐1 activation is a key factor in the development of diseases. Recent studies have reported that Syk is involved in pathogen‐induced NLRP3 inflammasome activation; however, the detailed mechanism linking Syk to NLRP3 inflammasome remains unclear. In this study, we showed that Syk mediates NLRP3 stimuli‐induced processing of procaspase‐1 and the consequent activation of caspase‐1. Moreover, the kinase activity of Syk is required to potentiate caspase‐1 activation in a reconstituted NLRP3 inflammasome system in HEK293T cells. The adaptor protein ASC bridges NLRP3 with the effector protein caspase‐1. Herein, we find that Syk can associate directly with ASC and NLRP3 by its kinase domain but interact indirectly with procaspase‐1. Syk can phosphorylate ASC at Y146 and Y187 residues, and the phosphorylation of both residues is critical to enhance ASC oligomerization and the recruitment of procaspase‐1. Together, our results reveal a new molecular pathway through which Syk promotes NLRP3 inflammasome formation, resulting from the phosphorylation of ASC. Thus, the control of Syk activity might be effective to modulate NLRP3 inflammasome activation and treat NLRP3‐related immune diseases.
UV irradiation can injure the epidermis, resulting in sunburn, inflammation, and cutaneous tissue disorders. Previous studies demonstrate that EGFR in keratinocytes can be activated by UVB and ...contributes to inflammation. Poly (ADP‐ribose) polymerase‐1 (PARP‐1) is a nuclear enzyme and plays an essential role in DNA repair under moderate stress. In this study, we set out to understand how PARP‐1 regulates UVB irradiation‐induced skin injury and interplays with EGFR to mediate the inflammation response. We found that PARP‐1 deficiency exacerbated the UVB‐induced inflammation, water loss, and back skin damage in mice. In human primary keratinocytes, UVB can activate PARP‐1 and enhance DNA damage upon PARP‐1 gene silencing. Moreover, PARP‐1 silencing and PARP inhibitor olaparib can suppress UVB‐induced COX‐2 and MMP‐1 expression, but enhance TNF‐α and IL‐8 expression. In addition, EGFR silencing or EGFR inhibition by gefitinib can decrease UVB‐induced COX‐2, TNF‐α, and IL‐8 expression, suggesting EGFR activation via paracrine action can mediate UVB‐induced inflammation responses. Immunoblotting data revealed that PARP‐1 inhibition decreases UVB‐induced EGFR and p38 activation. Pharmacological inhibition of p38 also dramatically led to the attenuation of UVB‐induced inflammatory gene expression. Of note, genetic ablation of PARP‐1 or EGFR can attenuate UVB‐induced ROS production, and antioxidant NAC can attenuate UVB‐induced EGFR‐p38 signaling axis and PARP‐1 activation. These data suggest the regulatory loops among EGFR, PARP‐1, and ROS upon UVB stress. PARP‐1 not only serves DNA repair function but also orchestrates interactions to EGFR transactivation and ROS production, leading to p38 signaling for inflammatory gene expression in keratinocytes.
The mechanisms by which a T cell detects antigen using its T cell antigen receptor (TCR) are crucial to our understanding of immunity and the harnessing of T cells therapeutically. A hallmark of the ...T cell response is the ability of T cells to quantitatively respond to antigenic ligands derived from pathogens while remaining inert to similar ligands derived from host tissues. Recent studies have revealed exciting properties of the TCR and the behaviors of its signaling effectors that are used to detect and discriminate between antigens. Here we highlight these recent findings, focusing on the proximal TCR signaling molecules Zap70, Lck, and LAT, to provide mechanistic models and insights into the exquisite sensitivity and specificity of the TCR.
The interface of a T cell and an APC is thought to exert force on the TCR and increasing evidence indicates the TCR is mechanosensitive. During antigen detection, mechanical force may be important for antigen discrimination.
Lck is basally active and phosphorylates the TCR complex and Zap70 on pMHC binding. Active Lck abundance and its coupling to the TCR during antigen encounter are able to influence affinity discrimination.
A hallmark of TCR signaling is its sensitivity and specificity. How the strict TCR signaling hierarchy is enforced is continuing to emerge through structural insight into the substrate selectivity of Lck and Zap70 and how the activation of Zap70 is controlled.
The emerging properties of the LAT signalosome include its assembly into liquid-like phase-separated clusters that contain phospho-LAT and its binding partners, which can enhance actin polymerization. These emerging properties reveal how LAT can function as foci of TCR signaling.
Oxidative stress is a major factor in retinal pigment epithelium (RPE) cells injury that contributes to age-related macular degeneration (AMD). NaIO3 is an oxidative toxic agent and its selective RPE ...cell damage makes it as a reproducible model of AMD. Although NaIO3 is an oxidative stress inducer, the roles of ROS in NaIO3-elicited signaling pathways and cell viability have not been elucidated, and the effect of NaIO3 on autophagy in RPE cells remains elusive.
In human ARPE-19 cells, we used Annexin V/PI staining to determine cell viability, immunoblotting to determine protein expression and signaling cascades, confocal microscopy to determine mitochondrial dynamics and mitophagy, and Seahorse analysis to determine mitochondrial oxidative phosphorylation.
We found that NaIO3 can dramatically induce cytosolic but not mitochondrial ROS production. NaIO3 can also activate ERK, p38, JNK and Akt, increase LC3II expression, induce Drp-1 phosphorylation and mitochondrial fission, but inhibit mitochondrial respiration. Confocal microscopic data indicated a synergism of NaIO3 and bafilomycin A1 on LC3 punctate formation, indicating the induction of autophagy. Using cytosolic ROS antioxidant NAC, we found that p38 and JNK are downstream signals of ROS and involve in NaIO3-induced cytotoxicity but not in mitochondrial dynamics, while ROS is also involved in LC3II expression. Unexpectedly NAC treatment upon NaIO3 stimulation leads to an enhancement of mitochondrial fragmentation and cell death. Moreover, inhibition of autophagy and Akt further enhances cell susceptibility to NaIO3.
We conclude that NaIO3-induced oxidative stress and cytosolic ROS production exert multiple signaling pathways that coordinate to control cell death in RPE cells. ROS-dependent p38 and JNK activation lead to cytotoxicity, while ROS-mediated autophagy and mitochondrial dynamic balance counteract the cell death mechanisms induced by NaIO3 in RPE cells.
PDF
