Targeting epigenetic and post-translational modifications regulating pyroptosis for the treatment of inflammatory diseases.

Inflammatory diseases, including infectious diseases, diabetes-related diseases, arthritis-related diseases, neurological diseases, digestive diseases, and tumor, continue to threaten human health and impose a significant financial burden despite advancements in clinical treatment. Pyroptosis, a pro-inflammatory programmed cell death pathway, plays an important role in the regulation of inflammation. Moderate pyroptosis contributes to the activation of native immunity, whereas excessive pyroptosis is associated with the occurrence and progression of inflammation. Pyroptosis is complicated and tightly controlled by various factors. Accumulating evidence has confirmed that epigenetic modifications and post-translational modifications (PTMs) play vital roles in the regulation of pyroptosis. Epigenetic modifications, which include DNA methylation and histone modifications (such as methylation and acetylation), and post-translational modifications (such as ubiquitination, phosphorylation, and acetylation) precisely manipulate gene expression and protein functions at the transcriptional and post-translational levels, respectively. In this review, we summarize the major pathways of pyroptosis and focus on the regulatory roles and mechanisms of epigenetic and post-translational modifications of pyroptotic components. We also illustrate these within pyroptosis-associated inflammatory diseases. In addition, we discuss the effects of novel therapeutic strategies targeting epigenetic and post-translational modifications on pyroptosis, and provide prospective insight into the regulation of pyroptosis for the treatment of inflammatory diseases.

Pathway network of pyroptosis and its potential inhibitors in acute kidney injury.

Acute kidney injury (AKI) is a worldwide problem, and there is no effective drug to eliminate AKI. The death of renal cells is an important pathological basis of intrinsic AKI. At present, targeted therapy for TEC death is a research hotspot in AKI therapy. There are many ways of cell death involved in the occurrence and development of AKI, such as apoptosis, necrosis, ferroptosis, and pyroptosis. This article mainly focuses on the role of pyroptosis in AKI. The assembly and activation of NLRP3 inflammasome is a key event in the occurrence of pyroptosis, which is affected by many factors, such as the activation of the NF-κB signaling pathway, mitochondrial instability and excessive endoplasmic reticulum (ER) stress. The activation of NLRP3 inflammasome can trigger its downstream inflammatory cytokines, which will lead to pyroptosis and eventually induce AKI. In this paper, we reviewed the possible mechanism of pyroptosis in AKI and the potential effective inhibitors of various key targets in this process. It may provide potential therapeutic targets for novel intrinsic AKI therapies based on pyroptosis, so as to develop better therapeutic strategies.

NLRP3 inflammasome and IL-1ß pathway in type 2 diabetes and atherosclerosis: Friend or foe?

Type 2 diabetes and atherosclerosis have gradually garnered great attention as inflammatory diseases. Previously, the fact that Interleukin-1ß (IL-1ß) accelerates the development of type 2 diabetes and atherosclerosis has been proved in animal experiments and clinical trials. However, the continued studies found that the effect of IL-1ß on type 2 diabetes and atherosclerosis is much more complicated than the negative impact. Nucleotide-binding oligomerization domain and leucine-rich repeat pyrin 3 domain (NLRP3) inflammasome, whose activation and assembly significantly affect the release of IL-1ß, is a crucial effector activated by a variety of metabolites. The diversity of NLRP3 activation mode is one of the fundamental reasons for the intricate effects on the progression of type 2 diabetes and atherosclerosis, providing many new insights for us to intervene in metabolic diseases. This review focuses on how NLRP3 inflammasome affects the progression of type 2 diabetes and atherosclerosis and what opportunities and challenges it can bring us.

Tranilast inhibits interleukin-33 production by macrophages.

Tranilast is an anti-allergy medication that inhibits the release of chemical mediators such as histamine. However, the mechanisms underlying its anti-allergy effects are not fully understood. Interleukin (IL)-33, a novel member of the IL-1 cytokine family, promotes T helper type 2 immune responses and plays a pathogenic role in allergic disorders. In the present study, we examined the effects of tranilast on IL-33 production by RAW264.7 macrophages. Lipopolysaccharide (LPS) increased both IL-33 mRNA expression and IL-33 protein synthesis. Tranilast significantly inhibited LPS-induced IL-33 protein production by RAW264.7 macrophages in a dose-dependent manner; these same effects were observed on IL-33 mRNA levels in RAW264.7 macrophages and a primary culture of macrophages. LPS markedly activated Akt in RAW264.7 macrophages, whereas tranilast suppressed LPS-induced Akt activation. The effects of tranilast on Akt activation appeared to be responsible for the decrease in IL-33 production. Our present findings suggest that the inhibition of IL-33 production by tranilast might contribute to the anti-allergy effects of this medication.

Eyelid skin as a potential site for drug delivery to conjunctiva and ocular tissues.

The feasibility of topical application onto the (lower) eyelid skin to deliver hydrophilic and lipophilic compounds into the conjunctiva and ocular tissues was evaluated by comparing with conventional eye drop application. Skin permeation and the concentration of several model compounds, and skin impedance were determined utilizing eyelid skin from hairless rats, as well as abdominal skin in the same animals for comparison. In vitro static diffusion cells were used to assess the skin permeation in order to provide key insights into the relationship between the skin sites and drugs. The obtained results revealed that drug permeation through the eyelid skin was much higher than that through abdominal skin regardless of the drug lipophilicity. Specifically, diclofenac sodium salt and tranilast exhibited approximately 6-fold and 11-fold higher permeability coefficients, respectively, through eyelid skin compared with abdominal skin. Histomorphological evaluation and in vivo distribution of model fluorescent dyes were also examined in the conjunctiva and skin after eyelid administration by conventional microscope and confocal laser scanning microscope analyses. The result revealed that eyelid skin has a thinner stratum corneum, thereby showing lower impedance, which could be the reason for the higher drug permeation through eyelid skin. Comparative evaluation of lipophilic and hydrophilic model compounds administered via the eyelid skin over 8h revealed stronger fluorescence intensity in the skin and surrounding tissues compared with eye drop administration. These results suggested that the (lower) eyelid skin is valuable as a prospective site for ophthalmic medicines.

From dioxin toxicity to putative physiologic functions of the human Ah receptor in homeostasis of stem/progenitor cells.

Despite decades of intensive research physiologic Ah receptor (AHR) functions are not yet elucidated. Challenges include marked species differences and dependence of AHR function on the cell type and cellular context. Hints to physiologic functions may be derived (i) from feedback loops between endogenous ligands and substrates of major target enzymes such as CYP1A1 and UGT1A1, and (ii) from dioxin toxicity in human individuals. For example, dioxin-mediated chloracne is probably due to dysregulated homeostasis of sebocyte stem/progenitor cells. Dioxin-mediated inflammatory responses may be due to complex dysregulation of hematopoiesis. Comparison of AHR functions with those of PXR and its target enzyme CYP3A4 may be helpful to emphasize AHR functions in specialized cells: PXR is known to be mainly involved in regulation of systemic metabolism of endo- and xenobiotics. However, AHR may be mostly controlling local homeostasis of signals in specialized cells such as stem/progenitor cells. Accumulating evidence suggests that knowledge about physiologic AHR functions may stimulate drug development.