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Since nuclear factor of κ‐light chain of enhancer‐activated B cells (NF‐κB) was discovered in 1986, extraordinary efforts have been made to understand the function and regulating mechanism of NF‐κB for 35 years, which lead to significant progress. Meanwhile, the molecular mechanisms regulating NF‐κB activation have also been illuminated, the cascades of signaling events leading to NF‐κB activity and key components of the NF‐κB pathway are also identified. It has been suggested NF‐κB plays an important role in human diseases, especially inflammation‐related diseases. These studies make the NF‐κB an attractive target for disease treatment. This review aims to summarize the knowledge of the family members of NF‐κB, as well as the basic mechanisms of NF‐κB signaling pathway activation. We will also review the effects of dysregulated NF‐κB on inflammation, tumorigenesis, and tumor microenvironment. The progression of the translational study and drug development targeting NF‐κB for inflammatory diseases and cancer treatment and the potential obstacles will be discussed. Further investigations on the precise functions of NF‐κB in the physiological and pathological settings and underlying mechanisms are in the urgent need to develop drugs targeting NF‐κB for inflammatory diseases and cancer treatment, with minimal side effects. This year (2021) marks the 35th anniversary of the discovery of NF‐κB. With so many years of in‐depth research on NF‐κB, people have realized that the NF‐κB signaling pathway plays an important role in inflammation, immunity, cell survival and proliferation. This review summarizes the relevant knowledge of the NF‐κB signaling pathway, inflammation, and cancer. The progression of the translational study and drug development targeting NF‐κB for inflammatory diseases and cancer treatment and the potential obstacles will also be discussed.

At least eight types of ubiquitin chain exist, and individual linkages affect distinct cellular processes. The only distinguishing feature of differently linked ubiquitin chains is their structure, as polymers of the same unit are chemically identical. Here, we have crystallized Lys 63‐linked and linear ubiquitin dimers, revealing that both adopt equivalent open conformations, forming no contacts between ubiquitin molecules and thereby differing significantly from Lys 48‐linked ubiquitin chains. We also examined the specificity of various deubiquitinases (DUBs) and ubiquitin‐binding domains (UBDs). All analysed DUBs, except CYLD, cleave linear chains less efficiently compared with other chain types, or not at all. Likewise, UBDs can show chain specificity, and are able to select distinct linkages from a ubiquitin chain mixture. We found that the UBAN (ubiquitin binding in ABIN and NEMO) motif of NEMO (NF‐κB essential modifier) binds to linear chains exclusively, whereas the NZF (Npl4 zinc finger) domain of TAB2 (TAK1 binding protein 2) is Lys 63 specific. Our results highlight remarkable specificity determinants within the ubiquitin system.

Cellular senescence serves as a fundamental and underlying activity that drives the aging process, and it is intricately associated with numerous age-related diseases, including Alzheimer's disease (AD), a neurodegenerative aging-related disorder characterized by progressive cognitive impairment. Although increasing evidence suggests that senescent microglia play a role in the pathogenesis of AD, their exact role remains unclear. In this study, we quantified the levels of lactic acid in senescent microglia, and hippocampus tissues of naturally aged mice and AD mice models (FAD 4T and APP/PS1). We found lactic acid levels were significantly elevated in these cells and tissues compared to their corresponding counterparts, which increased the level of pan histone lysine lactylation (Kla). We aslo identified all histone Kla sites in senescent microglia, and found that both the H3K18 lactylation (H3K18la) and Pan-Kla were significantly up-regulated in senescent microglia and hippocampus tissues of naturally aged mice and AD modeling mice. We demonstrated that enhanced H3K18la directly stimulates the NFκB signaling pathway by increasing binding to the promoter of Rela (p65) and NFκB1(p50), thereby upregulating senescence-associated secretory phenotype (SASP) components IL-6 and IL-8. Our study provides novel insights into the physiological function of Kla and the epigenetic regulatory mechanism that regulates brain aging and AD. Specifically, we have identified the H3K18la/NFκB axis as a critical player in this process by modulating IL-6 and IL-8. Targeting this axis may be a potential therapeutic strategy for delaying aging and AD by blunting SASP.

The global burden of chronic kidney disease will increase during the next century. As NFκB, first described more than 30 years ago, plays a major role in immune and non-immune-mediated diseases and in inflammatory and metabolic disorders, this review article summarizes current knowledge on the role of NFκB in kidney injury and describes the new and so far not completely understood crosstalk between canonical and non-canonical NFκB pathways in T-lymphocyte activation in renal disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). Genetic predisposition and immune dysfunction are involved in the pathogenesis of PD. Notably, peripheral inflammatory disorders and neuroinflammation are associated with PD neuropathology. Type 2 diabetes mellitus (T2DM) is associated with inflammatory disorders due to hyperglycaemia‐induced oxidative stress and the release of pro‐inflammatory cytokines. Particularly, insulin resistance (IR) in T2DM promotes the degeneration of dopaminergic neurons in the substantia nigra (SN). Thus, T2DM‐induced inflammatory disorders predispose to the development and progression of PD, and their targeting may reduce PD risk in T2DM. Therefore, this narrative review aims to find the potential link between T2DM and PD by investigating the role of inflammatory signalling pathways, mainly the nuclear factor kappa B (NF‐κB) and the nod‐like receptor pyrin 3 (NLRP3) inflammasome. NF‐κB is implicated in the pathogenesis of T2DM, and activation of NF‐κB with induction of neuronal apoptosis was also confirmed in PD patients. Systemic activation of NLRP3 inflammasome promotes the accumulation of α‐synuclein and degeneration of dopaminergic neurons in the SN. Increasing α‐synuclein in PD patients enhances NLRP3 inflammasome activation and the release of interleukin (IL)‐1β followed by the development of systemic inflammation and neuroinflammation. In conclusion, activation of the NF‐κB/NLRP3 inflammasome axis in T2DM patients could be the causal pathway in the development of PD. The inflammatory mechanisms triggered by activated NLRP3 inflammasome lead to pancreatic β‐cell dysfunction and the development of T2DM. Therefore, attenuation of inflammatory changes by inhibiting the NF‐κB/NLRP3 inflammasome axis in the early T2DM may reduce future PD risk.

The non-canonical NF-κB pathway is an important arm of NF-κB signaling that predominantly targets activation of the p52/RelB NF-κB complex. This pathway depends on the inducible processing of p100, a molecule functioning as both the precursor of p52 and a RelB-specific inhibitor. A central signaling component of the non-canonical pathway is NF-κB-inducing kinase (NIK), which integrates signals from a subset of TNF receptor family members and activates a downstream kinase, IκB kinase-α (IKKα), for triggering p100 phosphorylation and processing. A unique mechanism of NIK regulation is through its fate control: the basal level of NIK is kept low by a TRAF-cIAP destruction complex and signal-induced non-canonical NF-κB signaling involves NIK stabilization. Tight control of the fate of NIK is important, since deregulated NIK accumulation is associated with lymphoid malignancies.

Increased osteoclast (OC) differentiation and activity is the critical event that results in bone loss and joint destruction in common pathological bone conditions, such as osteoporosis and rheumatoid arthritis (RA). RANKL and its decoy receptor, osteoprotegerin (OPG), control OC differentiation and activity. However, there is a specific concern of a rebound effect of denosumab discontinuation in treating osteoporosis. TNFα can induce OC differentiation that is independent of the RANKL/RANK system. In this review, we discuss the factors that negatively and positively regulate TNFα induction of OC formation, and the mechanisms involved to inform the design of new anti-resorptive agents for the treatment of bone conditions with enhanced OC formation. Similar to, and being independent of, RANKL, TNFα recruits TNF receptor-associated factors (TRAFs) to sequentially activate transcriptional factors NF-κB p50 and p52, followed by c-Fos, and then NFATc1 to induce OC differentiation. However, induction of OC formation by TNFα alone is very limited, since it also induces many inhibitory proteins, such as TRAF3, p100, IRF8, and RBP-j. TNFα induction of OC differentiation is, however, versatile, and Interleukin-1 or TGFβ1 can enhance TNFα-induced OC formation through a mechanism which is independent of RANKL, TRAF6, and/or NF-κB. However, TNFα polarized macrophages also produce anabolic factors, including insulin such as 6 peptide and Jagged1, to slow down bone loss in the pathological conditions. Thus, the development of novel approaches targeting TNFα signaling should focus on its downstream molecules that do not affect its anabolic effect.

Introduction Sciatica causes intense pain. No satisfactory therapeutic drugs exist to treat sciatica. This study aimed to probe the potential mechanism of ferulic acid in sciatica treatment. Methods Thirty‐two SD rats were randomly divided into 4 groups: sham operation, chronic constriction injury (CCI), mecobalamin, and ferulic acid. We conducted RNA sequencing, behavioral tests, ELISA, PCR, western blotting, and immunofluorescence analysis. TAK‐242 and JSH23 were administered to RSC96 and GMI‐R1 cells to explore whether ferulic acid can inhibit apoptosis and alleviate inflammation. Results RNA sequencing showed that TLR4/NF‐κB pathway is involved in the mechanism of sciatica. CCI induced cold and mechanical hyperalgesia; destroyed the sciatic nerve structure; increased IL‐1β, IL‐6, TNF‐α, IL‐8, and TGF‐β protein levels and IL‐1β, IL‐6, TNF‐α, TGF‐β, TLR4, and IBA‐1 mRNA levels; and decreased IL‐10 and INF‐γ protein levels and IL‐4 mRNA levels. Immunohistochemistry showed that IBA‐1, CD32, IL‐1β, iNOS, nNOS, COX2, and TLR4 expression was increased while S100β and Arg‐1 decreased. CCI increased TLR4, IBA‐1, IL‐1β, iNOS, Myd88, p‐NF‐κB, and p‐p38MAPK protein levels. Treatment with mecobalamin and ferulic acid reversed these trends. Lipopolysaccharide (LPS) induced RSC96 cell apoptosis by reducing Bcl‐2 and Bcl‐xl protein and mRNA levels and increasing Bax and Bad mRNA and IL‐1β, TLR4, Myd88, p‐NF‐κB, and p‐p38MAPK protein levels, while ferulic acid inhibited cell apoptosis by decreasing IL‐1β, TLR4, Myd88, p‐NF‐κB, and p‐p38MAPK levels and increasing Bcl‐2 and Bcl‐xl levels. In GMI‐R1 cells, Ferulic acid attenuated LPS‐induced M1 polarization by decreasing the M1 polarization markers IL‐1β, IL‐6, iNOS, and CD32 and increasing the M2 polarization markers CD206, IL‐4, IL‐10 and Arg‐1. After LPS treatment, IL‐1β, iNOS, TLR4, Myd88, p‐p38MAPK, and p‐NF‐κB levels were obviously increased, and Arg‐1 expression was reduced, while ferulic acid reversed these changes. Conclusion Ferulic acid can promote injured sciatic nerve repair by reducing neuronal cell apoptosis and inflammatory infiltration though the TLR4/NF‐κB pathway. Ferulic acid promotes sciatic nerve repair by inhibiting Schwann cell apoptosis and promoted the transformation of M1 GMI‐R1 microglia to M2 microglia to relieve inflammatory infiltration though the TLR4/NF‐κB pathway.

The regulation of bone mass relies on a dynamic interplay between bone-forming osteoblasts and bone-resorbing osteoclasts. Imbalances in this regulatory system favor bone resorption and are implicated in the development of osteolytic disorders such as osteoporosis. Although current treatments targeting osteoclast activity are effective, safety concerns remain a notable limitation. As a multifunctional adipokine, apelin (APLN) serves a role in angiogenesis and metabolic regulation. However, to the best of our knowledge, its involvement in osteoclast differentiation has not yet been characterized. The present study thus examined the effects of APLN on osteoclastogenesis using a murine-macrophage model stimulated with receptor activator of NF-κB ligand (RANKL). The results revealed that APLN augmented RANKL-induced osteoclast differentiation, promoting the formation of tartrate-resistant acid phosphatase-positive multinucleated cells and the development of organized F-actin rings. Transcriptome analyses of a public dataset confirmed the temporal upregulation of osteoclast-related genes under RANKL stimulation. It was further discovered that co-treatment with APLN and RANKL significantly enhanced the expression of these osteoclast-specific markers. APLN co-treatment with RANKL upregulated the ERK, JNK, p38 and NF-κB signaling pathways, and this activation was effectively attenuated by specific pathway inhibitors. In conclusion, these findings identified APLN as an enhancer of RANKL-dependent osteoclast differentiation and signaling, suggesting that the modulation of APLN activity may provide a promising strategy for controlling excessive bone resorption in skeletal diseases.

Decreased adult neurogenesis, or the gradual depletion of neural stem cells in adult neurogenic niches, is considered a hallmark of brain aging. This review provides a comprehensive overview of the intricate relationship between aging, adult neurogenesis, and the potential neuroregenerative properties of astaxanthin, a carotenoid principally extracted from the microalga Haematococcus pluvialis. The unique chemical structure of astaxanthin enables it to cross the blood–brain barrier and easily reach the brain, where it may positively influence adult neurogenesis. Astaxanthin can affect molecular pathways involved in the homeostasis, through the activation of FOXO3-related genetic pathways, growth, and regeneration of adult brain neurons, enhancing cell proliferation and the potency of stem cells in neural progenitor cells. Furthermore, astaxanthin appears to modulate neuroinflammation by suppressing the NF-κB pathway, reducing the production of pro-inflammatory cytokines, and limiting neuroinflammation associated with aging and chronic microglial activation. By modulating these pathways, along with its potent antioxidant properties, astaxanthin may contribute to the restoration of a healthy neurogenic microenvironment, thereby preserving the activity of neurogenic niches during both normal and pathological aging.