Atrophic gastritis (AG) is a chronic inflammation where gastric glandular cells are replaced by intestinal-type epithelium. Gastric epithelial cell loss is often linked to multiple cell death signaling pathways. While Helicobacter pylori (H. pylori) infection is the main cause of AG, its role in inducing cell death goes beyond apoptosis and autophagy. Pyroptosis could promote development of inflammation related cancers, but its involvement in H. pylori-induced malignant transformation remains unclear.

The enrichment of pyroptosis signaling across pathological stages was assessed using immunohistochemistry and bioinformatic analysis. Gastric epithelial cells were co-cultured with VacA recombinant protein or VacA+H. pylori to investigate the role of VacA in pyroptosis, and its downstream targets. TNFAIP3 or TRAF1 was silenced/overexpressed in gastric epithelial cells to explore their impact on pyroptosis. Finally, the interaction between TNFAIP3 and TRAF1 was examined using Western Blot, immunofluorescence, co-immunoprecipitation and ubiquitin assays.

Expression of pyroptosis components and pyroptosis enrichment score were upregulated in AG and gastric cancer tissues compared to normal or non-atrophic gastritis tissues. Upon incubation with VacA recombinant protein or VacA+H. pylori, pyroptosis and TNFAIP3/TRAF1 were elevated in gastric epithelial cells. TRAF1 promoted expression of downstream pyroptosis components and release of IL-1β/IL18. TRAF1 ablation could reverse pyroptosis activation caused by VacA. Finally, we proved TNFAIP3 as deubiquitinating enzyme to increase TRAF1 stability, further inducing pyroptosis.

The VacA/TNFAIP3/TRAF1 signaling cascade facilitates pyroptosis in H. pylori- infected tissue. Overactivation of Pyroptosis caused the atrophy-like morphological changes of gastric epithelium, further inducing sustainable malignant transformation.

Coral reefs are threatened by recurrent mortality incidents in their native habitats brought on by natural and anthropogenic stressors. Elevated temperature has been indicated as a major causing factor. Although ongoing research is focused on corals, sponges are an important benthic organism on coral reefs and are often overlooked. An accurate and standardized method is needed to determine the environmental limits and thresholds of sponges commonly found on coral reefs. We established an in vitro sponge cell model and evaluated the effect of elevated temperatures on primary cell cultures of five common Florida reef sponges-Agelas clathrodes, Aplysina fulva, Cliona varians, Geodia neptuni, and Xestospongia muta. Analysis of the results revealed that the impact of increased temperatures had no significant effect at the cellular level, but there are changes at the molecular level. Shifts in the sponges' transcriptomic profiles induced by increased temperatures, trigger processes related to signal transduction, apoptosis, and cell repair pathways. Further elevation of temperature corresponding to local extremes activated the immune response and programmed cell death. The results of the present study are based on both cellular and molecular data obtained from the in vitro cell model which highlight the minimal response of all five species to thermal stress, providing an insight into the mechanisms involved in the adaptive process. Furthermore, they suggest a resilience of these sponges to the current thermal extremes, but a combination of factors could still lead to a loss of sponges on reefs. This study forms the basis for use of in vitro sponge cell models to evaluate other environmental parameters and stressors on additional sponge species.

Nuclear factor (NF) κB as a redox sensitive, anti-apoptotic and pro-inflammatory signaling molecule has been studied extensively for more than three decades. Its role in inducing antioxidant enzymes, defending against extracellular and intracellular stress and maintaining redox homeostasis in skeletal muscle has also been recognized. New research continues to explore the polytropic nature of NFκB in cellular function, especially its crosstalk with other important signaling pathways. Understanding of the broad impact of these functions has significant implications in health and disease of skeletal muscle as an organ designed for contraction and mobility. Two important aspects of muscle wellbeing, i.e., disease and aging, are not discussed in this review. This review will provide an update on the new findings related to NFκB involvement in multiple signaling pathways and refresh our knowledge of its activation in skeletal muscle with a special reference to physical exercise.

Tumor necrosis factor receptor-associated factor (TRAF) family is a critical signal transduction protein, and plays important roles in cell growth, apoptosis, and immune response, etc. In this study, molecular characteristics, expression patterns, and the role of TRAF2 in blood parrot Vieja synspila ♀ × Amphilophus citrinellus ♂, an important ornamental fish, were explored response to lipopolysaccharide (LPS) challenge. The full length of blood parrot TRAF2 was 2725 bp, with an open reading frame (ORF) of 1551 bp encoding 516 amino acids, and a molecular weight of 58.58 kDa. Blood parrot TRAF2 contained four conserved domains: RING, TRAF-type zinc finger, TRAF_BIRC3_bd, and MATH (Meprin and TRAF-C homology). Analysis of phylogenetic relationships showed that TRAF2 were conserved in different species, indicating that its role might be similar. Blood parrot TRAF2 mRNA could be detected in all of the tissues examined, and was distributed in both the cytoplasm and nucleus. The expression of blood parrot TRAF2 was up-regulated during LPS challenge. Overexpression of TRAF2 could significantly inhibit the activities of nuclear factor κB (NF-κB) and activated protein 1 (AP-1), and reduce the ratio of Bax/Bcl-2. This study indicated that the TRAF2 might play important roles in organisms during pathogen infection.

The progression and recurrence are the fatal prognostic factors in glioma patients. However, the therapeutic role and potential mechanism of TRAF7 in glioma patients remain largely unknown.

TRAF7 RNA-seq was analysed with the TCGA and CGGA databases between glioma tissues and normal brain tissues. The expression of TRAF7, cellular senescence and cell cycle arrest pathways in glioma tissues and cell lines was detected by real-time quantitative PCR (RT-qPCR), western blotting and immunohistochemistry. The interaction between TRAF7 and KLF4 was determined by Co-immunoprecipitation (Co-IP) assays. The functions of TRAF7 combined with lomustine in glioma were assessed by both in vitro, in vivo and patient-derived primary and recurrent glioma stem cell (GSC) assays.

High TRAF7 expression is closely associated with a higher recurrence rate and poorer overall survival (OS). In vitro, TRAF7 knockdown significantly inhibits glioma cell proliferation, invasion, and migration. RNA-seq analysis revealed that TRAF7 inhibition activates pathways related to cellular senescence and cell cycle arrest. In both in vitro and patient-derived GSC assays, the combination of sh-TRAF7 and lomustine enhanced therapeutic efficacy by inducing senescence and G0/G1 cell cycle arrest, surpassing the effects of lomustine or TRAF7 inhibition alone. Mechanistically, TRAF7 interacts with KLF4, and a rescue assay demonstrated that KLF4 overexpression could reverse the effects of TRAF7 depletion on proliferation and cellular senescence. In vivo, TRAF7 knockdown combined with lomustine treatment effectively suppressed glioma growth.

TRAF7 could be used as a predictive biomarker and the potential therapeutic target among National Comprehensive Cancer Network (NCCN) treatment guidelines in the progression and recurrence of glioma. Lomustine, regulating cellular senescence and cell cycle could be the priority choice in glioma patients with high-level TRAF7 expression.

Investigating innate immunity and its signaling transduction is essential to understand inflammation and host defence mechanisms. Toll-like receptors (TLRs), an evolutionarily ancient group of pattern recognition receptors, are crucial for detecting microbial components and initiating immune responses. This review summarizes the mechanisms and outcomes of TLR-mediated signaling, focusing on motifs shared with other immunological pathways, which enhances our understanding of the innate immune system. TLRs recognize molecular patterns in microbial invaders, activate innate immunity and promote antigen-specific adaptive immunity, and each of them triggers unique downstream signaling patterns. Recent advances have highlighted the importance of supramolecular organizing centers (SMOCs) in TLR signaling, ensuring precise cellular responses and pathogen detection. Furthermore, this review illuminates how TLR pathways coordinate metabolism and gene regulation, contributing to adaptive immunity and providing novel insights for next-generation therapeutic strategies. Ongoing studies hold promise for novel treatments against infectious diseases, autoimmune conditions, and cancers.

MicroRNAs (miRNAs) are highly conserved endogenous non-coding RNAs that play a crucial role in fish immune response by regulating gene expression at the post-transcriptional level. In recent years, the viral diseases caused by infectious hematopoietic necrosis virus (IHNV) have caused significant economic losses in rainbow trout (Oncorhynchus mykiss) aquaculture, whereas the immune regulatory mechanisms of miRNAs involved in rainbow trout resistance to IHNV infection remains largely undefined. In this study, we analyzed the structural characteristics of Oncorhynchus mykiss tumor necrosis factor receptor-associated factor 3 (OmTRAF3) by bioinformatics software and explored the molecular mechanism of miR-203-3p in rainbow trout resistance to IHNV by regulating OmTRAF3 in vivo and in vitro. The open reading frame (ORF) of OmTRAF3 gene was 1731 bp and encoded 576 amino acids including an N-terminal RING finger domain, two zinc finger domains, a coiled-coil domain, and a C-terminal MATH domain. The expression pattern analysis showed that the expression of miR-203-3p and OmTRAF3 in immune-related tissues (head kidney, spleen, and liver) and liver cells of rainbow trout infected with IHNV varied with certain regularity and had opposite trends at key time points, and a targeting relationship between miR-203-3p and OmTRAF3 was confirmed using a dual luciferase reporter gene assay. Further, we found that in vivo and in vitro overexpression of miR-203-3p significantly reduced the expression of OmTRAF3, downstream immune-related genes (OmTANK, OmIKKε, OmIFN1, and OmISG15) and promoted IHNV copy number replication, while silencing of miR-203-3p yielded opposite results. More importantly, OmTRAF3 and downstream genes as well as IHNV copy number changed accordingly with the silencing of OmTRAF3. The above results revealed that miR-203-3p participates in the immune response against IHNV by targeting OmTRAF3, and provides a theoretical basis for the screening of antiviral drugs in rainbow trout.

Tumor necrosis factor receptor-associated factor 2 (TRAF2) is a key adaptor molecule in tumor necrosis factor receptor signaling complexes, facilitating downstream immune-related signaling cascades. This study aimed to elucidate its function in teleost fish by characterizing the TRAF2 homolog of the red-spotted grouper (Epinephelus akaara, EaTraf2). The open reading frame of EaTraf2 encodes a putative protein of 520 amino acids, containing several characteristic domains of TRAF2. These structural features of EaTraf2 are conserved across diverse organisms, with a relatively higher sequence identity to TRAF2 orthologs from other bony fish. Transcriptional analysis demonstrated that EaTraf2 was ubiquitously expressed in all examined tissues, with the highest level observed in blood. Upon immune challenge, EaTraf2 expression significantly increased in the early stages of stimulation in both blood and spleen. Subcellular localization analysis revealed that EaTraf2 is predominantly localized in the cytoplasm. Overexpression of EaTraf2 in fathead minnow (FHM) cells resulted in elevated levels of interferon and inflammation-associated genes following viral hemorrhagic septicemia virus (VHSV) infection, along with reduced viral gene expression. This provided compelling evidence that EaTraf2 possesses antiviral properties. Furthermore, EaTraf2 demonstrated the ability to promote cell death induced by oxidative stress. Additionally, luciferase reporter assays revealed that EaTraf2 activates the NF-κB signaling pathway upon poly(I:C) stimulation and the Jun N-terminal kinase (JNK) signaling pathway in response to H2O2 treatment. Overall, our study elucidated the role of EaTraf2 in regulating innate immune responses and mediating stress-induced cell death. These findings enhance our understanding of TRAF2 in fish and may contribute to improved health management strategies in finfish aquaculture.

Epstein-Barr virus is highly associated with nasopharyngeal carcinoma (NPC) with genes expressed for tumor transformation or maintenance of viral latency, but there are certain genes that can modulate immune molecules. Butyrophilin 2A1 (BTN2A1) is an important activating protein for presenting phosphoantigens for recognition by Vγ9Vδ2 T cells to achieve antitumor activities. We have previously shown that Vγ9Vδ2 T cells achieve efficacy against NPC when BTN2A1 and BTN3A1 are upregulated by stimulating EBV gene expression, particularly LMP1. While BTN3A1 can be induced by the LMP1-mediated IFN-γ/JNK/NLRC5 pathway, the viral gene that can regulate BTN2A1 remains elusive. We showed that BTN2A1 expression is directly mediated by EBV BRRF1, which can trigger the BTN2A1 promoter and downstream JAK3-STAT3 pathway in NPC43 cells, as shown by RNA-seq data and verified via inhibitor experiments. Furthermore, BRRF1 downregulated IL-22 binding protein (IL-22RA2) to complement the EBNA1-targeting probe (P4)-induced IL-22 expression. Therefore, this study elucidated a new mechanism of stimulating BTN2A1 expression in NPC cells via the EBV gene BRRF1. The JAK3-STAT3 pathway could act in concordance with IL-22 to enhance the expression of BTN2A1, which likely leads to increased tumor cell killing by Vγ9Vδ2 T cells for enhanced potential as immunotherapy against the cancer.

The pathogenesis of doxorubicin-induced cardiomyopathy remains unclear. This study was carried out to test our hypothesis that ADAM17 aggravates cardiomyocyte apoptosis induced by doxorubicin and inhibition of ADAM17 may ameliorate doxorubicin-induced cardiomyopathy. C57BL/6J mice were intraperitoneally injected with a cumulative dose of doxorubicin to induce cardiomyopathy. Cardiomyocyte-specific ADAM17-knockout (A17α-MHCKO) and ADAM17-overexpressing (AAV9-oeA17) mice were generated. In addition, RNA sequencing of the heart tissues in different mouse groups and in vitro experiments in neonatal rat cardiomyocytes (NRCMs) receiving different treatment were performed. Mouse tumor models were constructed in A17fl/fl and A17α-MHCKO mice. In addition, cardiomyocyte-specific TRAF3-knockdown and TRAF3-overexpressing mice were generated. ADAM17 expression and activity were markedly upregulated in doxorubicin-treated mouse hearts and NRCMs. A17α-MHCKO mice showed less cardiomyocyte apoptosis induced by doxorubicin than A17fl/fl mice, and cardiomyocyte ADAM17 deficiency did not affect the anti-tumor effect of doxorubicin. In contrast, AAV9-oeA17 mice exhibited markedly aggravated cardiomyocyte apoptosis relative to AAV9-oeNC mice after doxorubicin treatment. Mechanistically, doxorubicin enhanced the expression of transcription factor C/EBPβ, leading to increased expression and activity of ADAM17 in cardiomyocyte, which enhanced TNF-α shedding and upregulated the expression of TRAF3. Increased TRAF3 promoted TAK1 autophosphorylation, resulting in activated MAPKs pathway and cardiomyocyte apoptosis. ADAM17 acted as a positive regulator of cardiomyocyte apoptosis and cardiac remodeling and dysfunction induced by doxorubicin by upregulating TRAF3/TAK1/MAPKs signaling. Thus, targeting ADAM17/TRAF3/TAK1/MAPKs signaling holds a promising potential for treating doxorubicin-induced cardiotoxicity.

Classical swine fever (CSF) is caused by the classical swine fever virus (CSFV), which poses a threat to swine production. The activation of host innate immunity through linker proteins such as tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) is crucial for the induction of the NF-κB pathway. Recent research has revealed the involvement of mitochondrial antiviral-signaling protein (MAVS) in the interaction with TRAF2, 3, 5, and 6 to activate both the NF-κB and IRF3 pathways. This study revealed that CSFV infection led to the upregulation of TRAF1 mRNA and protein levels; moreover, TRAF1 overexpression inhibited CSFV replication, while TRAF1 knockdown promoted replication, highlighting its importance in the host response to CSFV infection. Additionally, the expression of RIG-I, MAVS, TRAF1, IRF1, and ISG15 were detected in PK-15 cells infected with CSFV, revealing that TRAF1 plays a role in regulating IRF1 and ISG15 within the RIG-I pathway. Furthermore, Co-IP, GST pull-down, and IFA analyses demonstrated that TRAF1 interacted with MAVS and co-localized in the cytoplasm during CSFV infection. Ultimately, TRAF1 acted as a novel member of the TRAF family, bound to MAVS as a linker molecule, and functioned as a mediator downstream of MAVS in the RIG-I/MAVS pathway against CSFV replication.

Tumor necrosis factor receptor-associated factors family genes play a pivotal role in tumorigenesis and metastasis, functioning as adapters or E3 ubiquitin ligases across various signaling pathways. To date, limited research has explored the association between tumor necrosis factor receptor-associated factors family genes and the clinicopathological characteristics of tumors, immunity, and the tumor microenvironment (TME). This comprehensive study investigates the relationship between tumor necrosis factor receptor-associated factors family and prognosis, TME, immune response, and drug sensitivity in a pan-cancer context.

Utilizing current public databases, this study examines the expression levels and prognostic significance of tumor necrosis factor receptor-associated factors family genes in a pan-cancer context through bioinformatic analysis. In addition, it investigates the correlation between tumor necrosis factor receptor-associated factors expression and various factors, including the TME, immune subtypes, stemness scores, and drug sensitivity in pan-cancer.

Elevated expression levels of tumor necrosis factor receptor-associated factor 2, 3, 4, and 7 were observed across various cancer types. Patients exhibiting high expression of these genes generally faced a worse prognosis. Furthermore, a significant correlation was noted between the expression of tumor necrosis factor receptor-associated factors family genes and multiple dimensions of the TME, immune subtypes, and drug sensitivity.

Intimal hyperplasia is a serious clinical problem associated with the failure of therapeutic methods in multiple atherosclerosis-related coronary heart diseases, which are initiated and aggravated by the polarization of infiltrating macrophages. The present study aimed to determine the effect and underlying mechanism by which tumor necrosis factor receptor-associated factor 5 (TRAF5) regulates macrophage polarization during intimal hyperplasia.

TRAF5 expression was detected in mouse carotid arteries subjected to wire injury. Bone marrow-derived macrophages, mouse peritoneal macrophages and human myeloid leukemia mononuclear cells were also used to test the expression of TRAF5 in vitro. Bone marrow-derived macrophages upon to LPS or IL-4 stimulation were performed to examine the effect of TRAF5 on macrophage polarization. TRAF5-knockout mice were used to evaluate the effect of TRAF5 on intimal hyperplasia.

TRAF5 expression gradually decreased during neointima formation in carotid arteries in a time-dependent manner. In addition, the results showed that TRAF5 expression was reduced in classically polarized macrophages (M1) subjected to LPS stimulation but was increased in alternatively polarized macrophages (M2) in response to IL-4 administration, and these changes were demonstrated in three different types of macrophages. An in vitro loss-of-function study with TRAF5 knockdown plasmids or TRAF5-knockout mice revealed high expression of markers associated with M1 macrophages and reduced expression of genes related to M2 macrophages. Subsequently, we incubated vascular smooth muscle cells with conditioned medium of polarized macrophages in which TRAF5 expression had been downregulated or ablated, which promoted the proliferation, migration and dedifferentiation of VSMCs. Mechanistically, TRAF5 knockdown inhibited the activation of anti-inflammatory M2 macrophages by directly inhibiting PPARγ expression. More importantly, TRAF5-deficient mice showed significantly aggressive intimal hyperplasia.

Collectively, this evidence reveals an important role of TRAF5 in the development of intimal hyperplasia through the regulation of macrophage polarization, which provides a promising target for arterial restenosis-related disease management.

Tumor necrosis factor receptor-associated factor (TRAF) proteins play pivotal roles in a multitude of cellular signaling pathways, encompassing immune response, cell fate determination, development, and thrombosis. Their involvement in these processes hinges largely on their ability to interact directly with diverse receptors via the TRAF domain. Given the limited binding interface, understanding how specific TRAF domains engage with various receptors and how structurally similar binding interfaces of TRAF family members adapt their distinct binding partners has been the subject of extensive structural investigations over several decades. This review presents an in-depth exploration of the current insights into the structural and molecular diversity exhibited by the TRAF domain and TRAF-binding motifs across a range of receptors, with a specific focus on TRAF1.

A sphingolipid metabolite regulator, sphingosine kinase 1 (SPHK1), plays a critical role in the development of colorectal cancer (CRC). Studies have demonstrated that invasion and metastasis of CRC are promoted by SPHK1-driven autophagy. However, the exact mechanism of SPHK1 drives autophagy to promote tumor progression remains unclear. Here, immunohistochemical detection showed the expression of SPHK1 and tumor necrosis factor receptor-associated factor-6 (TRAF6) in human CRC tissues was stronger than in adjacent normal tissues, they were both associated with distance metastasis. It was discovered that knockdown of SPHK1 reduced the expression of TRAF6, inhibited autophagy, and inhibited the growth and metastasis of CRC cells in vitro. Moreover, the effects of SPHK1-downregulating were reversed by overexpression of TRAF6 in CRC cells transfected by double-gene. Overexpression of SPHK1 and TRAF6 promoted the expression of autophagy protein LC3 and Vimentin, while downregulated the expression of autophagy protein P62 and E-cadherin. The expression of autophagy-related ubiquitination protein ULK1 and Ubiquitin protein were significantly upregulated in TRAF6-overexpressed CRC cells. In addition, autophagy inhibitor 3-methyladenine (3MA) significantly inhibited the metastasis-promoting effect of SPHK1 and TRAF6, suppressed the expression of LC3 and Vimentin, and promoted the expression of P62 and E-cadherin, in CRC cells. Immunofluorescence staining showed SPHK1 and TRAF6 were co-localized in HT29 CRC cell membrane and cytoplasm. Immunoprecipitation detection showed SPHK1 was efficiently combined with the endogenous TRAF6, and the interaction was also detected reciprocally. Additionally, proteasome inhibitor MG132 treatment upregulated the expression of TRAF6 and the level of Ubiquitin protein, in SPHK1-downregulating CRC cells. These results reveal that SPHK1 potentiates CRC progression and metastasis via regulating autophagy mediated by TRAF6-induced ULK1 ubiquitination. SPHK1-TRAF6-ULK1 signaling axis is critical to the progression of CRC and provides a new strategy for the therapeutic control of CRC.

Current studies have indicated that insufficient trophoblast epithelial-mesenchymal transition (EMT), migration and invasion are crucial for spontaneous abortion (SA) occurrence and development. Exosomal miRNAs play significant roles in embryonic development and cellular communication. Hereon, we explored the roles of serum exosomes derived from SA patients on trophoblast EMT, migration and invasion. Exosomes were isolated from normal control (NC) patients with abortion for unplanned pregnancy and SA patients, then characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blotting. Exosomal miRNA profiles were identified by miRNA sequencing. The effects of serum exosomes on trophoblast migration and invasion were detected by scratch wound healing and transwell assays, and other potential mechanisms were revealed by quantitative real-time PCR (RT-PCR), western blotting and dual-luciferase reporter assay. Finally, animal experiments were used to explore the effects of exosomal miR-410-3p on embryo absorption in mice. The serum exosomes from SA patients inhibited trophoblast EMT and reduced their migration and invasion ability in vitro. The miRNA sequencing showed that miR-410-3p was upregulated in SA serum exosomes. The functional experiments showed that SA serum exosomes restrained trophoblast EMT, migration and invasion by releasing miR-410-3p. Mechanistically, SA serum exosomal miR-410-3p inhibited trophoblast cell EMT, migration and invasion by targeting TNF receptor-associated factor 6 (TRAF6) at the post-transcriptional level. Besides, SA serum exosomal miR-410-3p inhibited the p38 MAPK signalling pathway by targeting TRAF6 in trophoblasts. Moreover, milk exosomes loaded with miR-410-3p mimic reached the maternal-fetal interface and aggravated embryo absorption in female mice. Clinically, miR-410-3p and TRAF6 expression were abnormal and negatively correlated in the placental villi of SA patients. Our findings indicated that exosome-derived miR-410-3p plays an important role between SA serum and trophoblasts in intercellular communication, suggesting a novel mechanism by which serum exosomal miRNA regulates trophoblasts in SA patients.

The Tat proteins of HIV-1 and simian immunodeficiency virus (SIV) are essential for activating viral transcription. In addition, Tat stimulates nuclear factor κB (NF-κB) signaling pathways to regulate viral gene expression although its molecular mechanism is unclear. Here, we report that Tat directly activates NF-κB through the interaction with TRAF6, which is an essential upstream signaling molecule of the canonical NF-κB pathway. This interaction increases TRAF6 oligomerization and auto-ubiquitination, as well as the synthesis of K63-linked polyubiquitin chains to further activate the NF-κB pathway and HIV-1 transcription. Moreover, ectopic expression of TRAF6 significantly activates HIV-1 transcription, whereas TRAF6 knockdown inhibits transcription. Furthermore, Tat-mediated activation of NF-κB through TRAF6 is conserved among HIV-1, HIV-2, and SIV isolates. Our study uncovers yet another mechanism by which HIV-1 subverts host transcriptional pathways to enhance its own transcription.

Menopause causes a reduction in estradiol (E2) and may be associated with neuromuscular degeneration. Compared to pre-menopausal (PRE-M) women, this study sought to determine dietary protein intake and whether lower levels of circulating E2 in post-menopausal women (POST-M) were occurring alongside increased levels of biomarkers of axonal and neuromuscular junction degeneration (NMJ), inflammation, muscle protein degradation, and reduced indices of muscle quality and performance. Employing a cross-sectional design, PRE-M (n = 6) and POST-M (n = 6) dietary analysis data were collected and participants then donated a blood and urine sample followed by assessments for body composition, motor unit activation, and muscle performance. Independent group t-tests were performed to determine differences between groups (p ≤ 0.05). In POST-M women, E2, motor unit activity, muscle quality, and muscle performance were significantly less than those for PRE-M women; however, the levels of c-terminal fragment of agrin, tumor necrosis factor-α, and urinary titin were significantly greater (p < 0.05). POST-M women were also shown to be ingesting fewer total calories and less protein than PRE-M (p < 0.05). Reduced E2 and dietary protein intake in POST-M women occurs in conjunction with increased levels of biomarkers of NMJ degradation, inflammation, and muscle proteolysis, which may be associated with reduced motor unit activation and muscle quality.

The increasing incidence of metabolic diseases, including obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD), in the past decade is a serious concern worldwide. Disruption of cellular protein homeostasis has been considered as a crucial contributor to the pathogenesis of metabolic diseases. To maintain protein homeostasis, cells have evolved multiple dynamic and self-regulating quality control processes to adapt new environmental conditions and prevent prolonged damage. Among them, the ubiquitin proteasome system (UPS), the primary proteolytic pathway for degradation of aberrant proteins via ubiquitination, has an essential role in maintaining cellular homeostasis in response to intracellular stress. Correspondingly, accumulating evidences have shown that dysregulation of ubiquitination can aggravate various metabolic derangements in many tissues, including the liver, skeletal muscle, pancreas, and adipose tissue, and is involved in the initiation and progression of diverse metabolic diseases. In this part, we will summarize the role of ubiquitination in the pathogenesis of metabolic diseases, including obesity, T2DM and NAFLD, and discuss its potential as a therapeutic target.

Soluble epoxide hydrolase (sEH) is an enzyme involved in the metabolism of bioactive lipid signaling molecules. sEH converts epoxyeicosatrienoic acids (EET) to virtually inactive dihydroxyeicosatrienoic acids (DHET). The first acids are "medicinal" molecules, the second increase the inflammatory infiltration of cells. Mitogen-activated protein kinases (p38 MAPKs) are key protein kinases involved in the production of inflammatory mediators, including tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2). p38 MAPK signaling plays an important role in the regulation of cellular processes, especially inflammation. The proto-oncogenic serine/threonine protein kinase Raf (c-Raf) is a major component of the mitogen-activated protein kinase (MAPK) pathway: ERK1/2 signaling. Normal cellular Raf genes can also mutate and become oncogenes, overloading the activity of MEK1/2 and ERK1/2. The development of multitarget inhibitors is a promising strategy for the treatment of socially dangerous diseases. We synthesized 1,3-disubstituted ureas and diureas containing a dichloroadamantyl moiety. The results of computational methods show that soluble epoxide hydrolase inhibitors can act on two more targets in different signaling pathways of mitogen-activated protein kinases p38 MAPK and c-Raf. The two chlorine atoms in the adamantyl moiety may provide additional Cl-π interactions in the active site of human sEH. Molecular dynamics studies have shown that the stability of ligand-protein complexes largely depends on the "spacer effect." The compound containing a bridge between the chloroadamantyl fragment and the ureide group forms more stable ligand-protein complexes with sEH and p38 MAPK, which indicates a better conformational ability of the molecule in the active sites of these targets. In turn, a compound containing two chlorine atoms forms a more stable complex with c-Raf, probably due to the presence of additional halogen bonds of chlorine atoms with amino acid residues.

Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammatory disease associated with CD4+ Th1 and Th17 cell immune responses. Tumour necrosis factor-associated factor 5 (TRAF5) deficiency has been shown to aggravate DSS-induced colitis. However, the potential role of TRAF5 in regulating CD4+ T cell immune responses in the pathogenesis of IBD remains unclear. TRAF5-/- CD4+ CD45RBhigh T cells and WT CD4+ CD45RBhigh T cells were transferred to Rag2-/- mice via intravenous (i.v.) tail injection, respectively, to establish a chronic colitis model. Adeno-associated virus (AAV)-mediated gene knockout technique was used to knock out runt-associated transcription factor 1 (Runx1) expression in vivo. Specific cytokines of Th1 and Th17 cells were detected by quantitative RT-PCR, immunohistochemistry, ELISA, and flow cytometry. In T-cell transfer colitis mice, the Rag2-/- mice reconstituted with TRAF5-/- CD4+ CD45RBhigh T cells showed more severe intestinal inflammation than the WT control group, which was characterised by increased expression of INF-γ, TNF-α, IL-17a. Furthermore, we found that the INF-γ+ CD4+ , IL17a+ CD4+ , and INF-γ+ IL17a+ CD4+ T cells in the intestinal mucosa of Rag2-/- mice reconstituted with TRAF5-/- CD4+ CD45RBhigh T cells were significantly higher than those of the WT control group by flow cytometry. Mechanistically, knockout Runx1 inhibited the differentiation of TRAF5-/- CD4+ T cells into Th1 and Th17 cells in the intestinal mucosa of T-cell transfer colitis mice. TRAF5 regulates Th1 and Th17 cell differentiation and immune response through Runx1 to participate in the pathogenesis of colitis. Thus targeting TRAF5 in CD4+ T cells may be a novel treatment for IBD.

Tumor necrosis factor receptor-associated factors (TRAFs) are a protein family with a wide variety of roles and binding partners. Among them, TRAF6, a ubiquitin ligase, possesses unique receptor binding specificity and shows diverse functions in immune system regulation, cellular signaling, central nervous system, and tumor formation. TRAF6 consists of an N-terminal Really Interesting New Gene (RING) domain, multiple zinc fingers, and a C-terminal TRAF domain. TRAF6 is an important therapeutic target for various disorders and structural studies of this protein are crucial for the development of next-generation therapeutics. Here, we presented a TRAF6 N-terminal structure determined at the Turkish light source "Turkish DeLight" to be 3.2 Å resolution at cryogenic temperature (PDB ID: 8HZ2). This structure offers insight into the domain organization and zinc-binding, which are critical for protein function. Since the RING domain and the zinc fingers are key targets for TRAF6 therapeutics, structural insights are crucial for future research. Separately, we rationally designed numerous new compounds and performed molecular docking studies using this template (PDB ID:8HZ2). According to the results, 10 new compounds formed key interactions with essential residues and zinc ion in the N-terminal region of TRAF6. Molecular dynamic (MD) simulations were performed for 300 ns to evaluate the stability of three docked complexes (compounds 256, 322, and 489). Compounds 256 and 489 was found to possess favorable bindings with TRAF6. These new compounds also showed moderate to good pharmacokinetic profiles, making them potential future drug candidates as TRAF6 inhibitors.

Homeobox A5 (HOXA5), a homeodomain transcription factor, is considered a tumor suppressor in cancer progression; however, its function in prostate cancer (PCa) remains unclear. This study focused on the relevance of HOXA5 in PCa progression. We identified the downregulation of HOXA5 in PCa tissues based on the TCGA database and further verified in 30-paired PCa and adjacent normal tissues. Functional studies revealed that HOXA5 upregulation impaired the stem-like characteristics and malignant behaviors of PCa cells in vitro and in vivo. Mechanistically, HOXA5 was found to be regulated by tumor necrosis factor receptor-associated factor 7 (TRAF7), a putative E3-ubiquitin ligase. We observed that TRAF7 was overexpressed in PCa and subsequently enhanced the degradation of HOXA5 protein via its ubiquitin ligase activity, contributing to the acquisition of an aggressive PCa phenotype. For its downstream mechanism, we demonstrated that sprouty RTK signaling antagonist 2 (SPRY2) served as a downstream target of HOXA5. HOXA5 could directly bind to the SPRY2 promoter, thereby regulating the SPRY2-mediated MEK/ERK signaling pathway. Silencing SPRY2 largely compromised the tumor-suppressive effect of HOXA5 in PCa progression and cancer stemness. Our findings highlight the previously-underappreciated signaling axis of TRAF7-HOXA5-SPRY2, which provides a novel prognostic and therapeutic target for PCa treatment.

Posttranslational modification of proteins via ubiquitination determines their activation, translocation, dysregulation, or degradation. This process targets a large number of cellular proteins, affecting all biological pathways involved in the cell cycle, development, growth, and differentiation. Thus, aberrant regulation of ubiquitination is likely associated with several diseases, including various types of metabolic diseases. Among the ubiquitin enzymes, E3 ubiquitin ligases are regarded as the most influential ubiquitin enzymes due to their ability to selectively bind and recruit target substrates for ubiquitination. Continued research on the regulatory mechanisms of E3 ligases and their adaptors in metabolic diseases will further stimulate the discovery of new targets and accelerate the development of therapeutic options for metabolic diseases. In this review, based on recent discoveries, we summarize new insights into the roles of E3 ubiquitin ligases and their adaptors in the pathogenesis of metabolic diseases by highlighting recent evidence obtained in both human and animal model studies.

Tumor necrosis factor (TNF) binding to endothelial TNF receptor-I (TNFR-I) facilitates monocyte recruitment and chronic inflammation, leading to the development of atherosclerosis. In vitro data show a heightened inflammatory response and atherogenic potential in endothelial cells (ECs) from African American (AA) donors. High laminar shear stress (HSS) can mitigate some aspects of racial differences in endothelial function at the cellular level. We examined possible racial differences in TNF-induced monocyte adhesion and TNFR1 signaling complex expression/activity, along with the effects of HSS. Tohoku Hospital Pediatrics-1 (THP-1) monocytes were used in a co-culture system with human umbilical vein ECs (HUVECs) from Caucasian American (CA) and AA donors to examine racial differences in monocyte adhesion. An in vitro exercise mimetic model was applied to investigate the potential modulatory effect of HSS. THP-1 adherence to ECs and TNF-induced nuclear factor kappa B (NF-κB) DNA binding were elevated in AA ECs compared to CA ECs, but not significantly. We report no significant racial differences in the expression of the TNFR-I signaling complex. Application of HSS significantly increased the expression and shedding of TNFR-I and the expression of TRAF3, and decreased the expression of TRAF5 in both groups. Our data does not support TNF-induced NF-κB activation as a potential mediator of racial disparity in this model. Other pathways and associated factors activated by the TNFR1 signaling complex are recommended targets for future research.

Targeting costimulatory receptors of the tumor necrosis factor receptor (TNFR) superfamily with agonistic antibodies is a promising approach in cancer immuno therapy. It is known that their efficacy strongly depends on FcγR cross-linking.

In this study, we made use of a Jurkat-based reporter platform to analyze the influence of individual FcγRs on the costimulatory activity of the 41BB agonists, Urelumab and Utomilumab, and the CD27 agonist, Varlilumab.

We found that Urelumab (IgG4) can activate 41BB-NFκB signaling without FcγR cross-linking, but the presence of the FcγRs (CD32A, CD32B, CD64) augments the agonistic activity of Urelumab. The human IgG2 antibody Utomilumab exerts agonistic function only when crosslinked via CD32A and CD32B. The human IgG1 antibody Varlilumab showed strong agonistic activity with all FcγRs tested. In addition, we analyzed the costimulatory effects of Urelumab, Utomilumab, and Varlilumab in primary human peripheral blood mononuclear cells (PBMCs). Interestingly, we observed a very weak capacity of Varlilumab to enhance cytokine production and proliferation of CD4 and CD8 T cells. In the presence of Varlilumab the percentage of annexin V positive T cells was increased, indicating that this antibody mediated FcγR-dependent cytotoxic effects.

Collectively, our data underscore the importance to perform studies in reductionist systems as well as in primary PBMC samples to get a comprehensive understanding of the activity of costimulation agonists.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor has been demonstrated to exert a great cardioprotection in cardiometabolic impairments, including atherosclerosis. However, its underlying mechanism remains not fully understood. This study focuses on uncovering the actions of PCSK9 inhibitor on the connection between atherosclerosis and vascular smooth muscle cell (VSMC) behaviors. qRT-PCR was utilized to detect the expression of SNHG16. Proliferation and migration of VSMC were characterized by Cell Counting Kit-8 and wound healing assays. The intracellular lipids and foam cell formation were assessed by Oil Red O staining, fluorescence image, and cholesterol quantification kit. Atherosclerosis in vivo was evaluated by imaging the atherosclerotic lesions, hematoxylin-eosin staining, Oil Red O staining and Masson staining. The interaction between SNHG16 with EZH2 and histone H3 lysine 27 trimethylation (H3K27me3) were investigated by fluorescence in situ hybridization, RNA immunoprecipitation, and chromatin immunoprecipitation assays. A ApoE-/- mice model was used to validate the role of PCSK9 inhibitor and SNHG16 for atherosclerosis. The protective regulation of PCSK9 inhibitor was observed both in high-fat diet (HFD)-fed mice and oxidized low-density lipoprotein (ox-LDL)-treated VSMC, as manifested in the decreased the atherosclerotic lesions in vivo, as well as the weakened cell proliferation, migration, and formation of foam cells in vitro. SNHG16 was identified to be a downstream effector of PCSK9 inhibitor-mediated biological functions, of which knockdown also significantly ox-LDL-treated VSMC proliferation, migration, and foam cell formation abilities. SNHG16 epigenetically suppressed TRAF5 via recruiting EZH2. Silencing of TRAF5 abolished the protective effects of SNHG16 knockdown on the pathogenesis of atherosclerosis. Collectively, PCSK9 inhibitor attenuated atherosclerosis by regulating SNHG16/EZH2/TRAF5 axis to impair the proliferation, migration, and foam cell formation of VSMC.

TNF receptor-associated factors (TRAFs) are signaling adaptor proteins that play a crucial role in regulating cellular receptors' signaling transduction to downstream pathways and exert multifaceted roles in regulating signaling pathways, cell survival, and carcinogenesis. The 13-cis-retinoic acid (RA), an active metabolite of vitamin A, exhibits anti-cancer properties, but the development of retinoic acid resistance poses a challenge in clinical application. This study aimed to investigate the relationship between TRAFs and retinoic acid sensitivity in various cancers. Here, we revealed that TRAFs' expression varied significantly across The Cancer Genome Atlas (TCGA) cancer cohorts and human cancer cell lines. Additionally, inhibiting TRAF4, TRAF5, or TRAF6 improved retinoic acid sensitivity and reduced colony formation in ovarian cancer and melanoma cells. Mechanistically, knocking down TRAF4, TRAF5, or TRAF6 in retinoic acid-treated cancer cell lines increased the levels of procaspase 9 and induced cell apoptosis. Further in vivo studies using the SK-OV-3 and MeWo xenograft models confirmed the anti-tumor effects of TRAF knockdown combined with retinoic acid treatment. These findings support that combination therapy with retinoic acid and TRAF silencing may offer significant therapeutic advantages in treating melanoma and ovarian cancers.

Excessive inflammation is a postulated cause of severe disease and death in respiratory virus infections. In response to severe influenza virus infection, adoptively transferred naïve hemagglutinin-specific CD4⁺ T cells from CD4⁺ TCR-transgenic 6.5 mice drive an IFN-γ-producing Th1 response in wild-type mice. It helps in virus clearance but also causes collateral damage and disease aggravation. The donor 6.5 mice have all the CD4⁺ T cells with TCR specificity toward influenza hemagglutinin. Still, the infected 6.5 mice do not suffer from robust inflammation and grave outcome. The initial Th1 response wanes with time, and a prominent Th17 response of recent thymic emigrants alleviates inflammation and bestows protection in 6.5 mice. Our results suggest that viral neuraminidase-activated TGF-β of the Th1 cells guides the Th17 evolution, and IL-17 signaling through the non-canonical IL-17 receptor EGFR activates the scaffold protein TRAF4 more than TRAF6 during alleviation of lung inflammation in severe influenza.

Accumulating evidence suggests that Interleukin-33 (IL-33), a member of the IL-1 family, has crucial roles in tissue homeostasis and repair, type 2 immunity, inflammation, and viral infection. IL-33 is a novel contributing factor in tumorigenesis and plays a critical role in regulating angiogenesis and cancer progression in a variety of human cancers. The partially unraveled role of IL-33/ST2 signaling in gastrointestinal tract cancers is being investigated through the analysis of patients' samples and by studies in murine and rat models. In this review, we discuss the basic biology and mechanisms of release of the IL-33 protein and its involvement in gastrointestinal cancer onset and progression.

Many studies in mice have demonstrated that cardiac-specific innate immune signaling pathways can be reprogrammed to modulate inflammation in response to myocardial injury and improve outcomes. While the echocardiography standard parameters of left ventricular (LV) ejection fraction, fractional shortening, end-diastolic diameter, and others are used to assess cardiac function, their dependency on loading conditions somewhat limits their utility in completely reflecting the contractile function and global cardiovascular efficiency of the heart. A true measure of global cardiovascular efficiency should include the interaction between the ventricle and the aorta (ventricular-vascular coupling, VVC) as well as measures of aortic impedance and pulse wave velocity.

We measured cardiac Doppler velocities, blood pressures, along with VVC, aortic impedance, and pulse wave velocity to evaluate global cardiac function in a mouse model of cardiac-restricted low levels of TRAF2 overexpression that conferred cytoprotection in the heart.

While previous studies reported that response to myocardial infarction and reperfusion was improved in the TRAF2 overexpressed mice, we found that TRAF2 mice had significantly lower cardiac systolic velocities and accelerations, diastolic atrial velocity, aortic pressures, rate-pressure product, LV contractility and relaxation, and stroke work when compared to littermate control mice. Also, we found significantly longer aortic ejection time, isovolumic contraction and relaxation times, and significantly higher mitral early/atrial ratio, myocardial performance index, and ventricular vascular coupling in the TRAF2 overexpression mice compared to their littermate controls. We found no significant differences in the aortic impedance and pulse wave velocity.

While the reported tolerance to ischemic insults in TRAF2 overexpression mice may suggest enhanced cardiac reserve, our results indicate diminished cardiac function in these mice.

Adaptor proteins represent key signalling molecules involved in regulating immune responses. The host's innate immune system recognizes pathogens via various surface and intracellular receptors. Adaptor molecules are centrally involved in different receptor-mediated signalling pathways, acting as bridges between the receptors and other molecules. The presence of adaptors in major signalling pathways involved in the pathogenesis of various chronic inflammatory diseases has drawn attention toward the role of these proteins in such diseases. In this review, we summarize the importance and roles of different adaptor molecules in macrophage-mediated signalling in various chronic disease states. We highlight the mechanistic roles of adaptors and how they are involved in protein-protein interactions (PPI) via different domains to carry out signalling. Hence, we also provide insights into how targeting these adaptor proteins can be a good therapeutic strategy against various chronic inflammatory diseases.

TRAF2 (Tumor necrosis factor receptor-associated factor 2) is a dual function protein, acting as an adaptor protein and a ubiquitin E3 ligase, which plays an essential role in mediating the TNFα-NFκB signal pathway. Dysregulated expression of TRAF2 has been reported in a variety of human cancers. Whether and how TRAF2 regulates the growth of liver cancer cells remains elusive. The goal of this study is to investigate potential dysregulation of TRAF2 and its biological function in liver cancer, and to elucidate the underlying mechanism, leading to validation of TRAF2 as an attractive liver cancer target. Here, we reported TRAF2 is up-regulated in human liver cancer cell lines and tissues, and high TRAF2 expression is associated with a poor prognosis of HCC patients. Proteomics profiling along with Co-immunoprecipitation analysis revealed that p62 is a new substrate of TRAF2, which is subjected to TRAF2-induced polyubiquitination via the K63 linkage at the K420 residue. A strong negative correlation was found between the protein levels of p62 and TRAF2 in human HCC samples. TRAF2 depletion inhibited growth and survival of liver cancer cells both in vitro and in vivo by causing p62 accumulation, which is partially rescued by simultaneous p62 knockdown. Mechanistically, TRAF2-mediated p62 polyubiquitylation activates the mTORC1 by forming the p62-mTORC1-Rag complex, which facilitates the lysosome localization of mTORC1. TRAF2 depletion inhibited mTORC1 activity through the disruption of interaction between p62 and the mTORC1 complex. In conclusion, our study provides the proof-of-concept evidence that TRAF2 is a valid target for liver cancer.

The tumor necrosis factor receptor-related factor (TRAF) family has been reported to be involved in many immune pathways, such as TNFR, TLR, NLR, and RLR in animals. However, little is known about the roles of TRAF genes in the innate immune of Argopecten scallops. In this study, we first identified five TRAF genes, including TRAF₂, TRAF₃, TRAF₄, TRAF₆ and TRAF₇, but not TRAF₁ and TRAF₅, from both the bay scallop A. irradians (Air) and the Peruvian scallop A. purpuratus (Apu). The phylogenetic analysis showed that the TRAF genes in Argopecten scallops (AiTRAF) belong to the branch of molluscan TRAF family, which lacks TRAF₁ and TRAF₅. Since TRAF₆ is a key bridge factor in the tumor necrosis factor superfamily and plays an important role in innate and adaptive immunity, we cloned the ORFs of the TRAF₆ gene in both A. irradians and A. purpuratus, as well as in two reciprocal hybrids (Aip for the hybrid Air × Apu and Api for the hybrid Apu × Air). Differences in conformational and post-translational modification resulted from the variation in amino acid sequences may cause differences in activity among them. Analysis of conserved motifs and protein structural domains revealed that AiTRAF contains typical structural domains similar to those of other mollusks and has the same conserved motifs. Tissue expression of TRAF in Argopecten scallops challenged by Vibrio anguillarum was examined by qRT-PCR. The results showed that AiTRAF were higher in gill and hepatopancreas. When challenged by Vibrio anguillarum, the expression of AiTRAF was significantly increased compared with the control group, indicating that AiTRAF may play an important role in the immunity of scallops. In addition, the expression of TRAF was higher in Api and Aip than in Air when challenged by Vibrio anguillarum, suggesting that TRAF may have contributed to the high resistance of Api and Aip to Vibrio anguillarum. The results of this study may provide new insights into the evolution and function of TRAF genes in bivalves and ultimately benefit scallop breeding.

TRAF6 has emerged as a key regulator of breast cancer (BCa). However, the TRAF family constitutes of seven members that exhibit distinct and overlapping functions. To explore which TRAF represents a potential druggable target for BCa treatment, we searched Medline, Web of Science and Scopus for relevant studies from inception to June 27, 2021. We identified 14 in vitro, 11 in vivo and 4 human articles. A meta-analysis of pharmacological studies showed that in vitro inhibition of TRAF2/4 (mean difference (MD): - 57.49, 95% CI: - 66.95, - 48.02, P < 0.00001) or TRAF6 (standard(Std.)MD: - 4.01, 95% CI: - 5.75, - 2.27, P < 0.00001) is associated with reduction in BCa cell migration. Consistently, inhibition of TRAF2/4 (MD: - 51.08, 95% CI: - 64.23, - 37.94, P < 0.00001) and TRAF6 (Std.MD: - 2.80, 95% CI: - 4.26, - 1.34, P = 0.0002) is associated with reduced BCa cell invasion, whereas TRAF2/4 inhibition (MD: - 40.54, 95% CI: - 52.83, - 28.26, P < 0.00001) is associated with reduced BCa cell adhesion. Interestingly, only inhibition of TRAF6 (MD: - 21.46, 95% CI: - 30.40, - 12.51, P < 0.00001) is associated with reduced cell growth. In animal models of BCa, administration of pharmacological inhibitors of TRAF2/4 (Std.MD: - 3.36, 95% CI: - 4.53, - 2.18, P < 0.00001) or TRAF6 (Std.MD: - 4.15, 95% CI: - 6.06, - 2.24, P < 0.0001) in mice is associated with reduction in tumour burden. In contrast, TRAF6 inhibitors (MD: - 2.42, 95% CI: - 3.70, - 1.14, P = 0.0002) reduced BCa metastasis. In BCa patients, high expression of TRAF6 (Hazard Ratio: 1.01, CI: 1.01, 1.01, P < 0.00001) is associated with poor survival rate. Bioinformatics validation of clinical and pathway and process enrichment analysis in BCa patients confirmed that gain/amplification of TRAF6 is associated with secondary BCa in bone (P = 0.0079), and poor survival rate (P < 0.05). Overall, TRAF6 inhibitors show promise in the treatment of metastatic BCa. However, low study number and scarcity of evidence from animal and human studies may limit the translation of present findings into clinical practice.

Seven tumor necrosis factor receptor- (TNFR-) associated factors (TRAFs) have been found in mammals, which are primarily involved in the signal translation of the TNFR superfamily, the Toll-like receptor (TLR) family, and the retinoic acid-inducible gene I- (RIG-I-) like receptor (RLR) family. TRAF3 is one of the most diverse members of the TRAF family. It can positively regulate type I interferon production while negatively regulating signaling pathways of classical nuclear factor-κB, nonclassical nuclear factor-κB, and mitogen-activated protein kinase (MAPK). This review summarizes the roles of TRAF3 signaling and the related immune receptors (e.g., TLRs) in several preclinical and clinical diseases and focuses on the roles of TRAF3 in immune responses, the regulatory mechanisms, and its role in disease.

Follicle selection is an important step in the laying process of chicken, which is closely related to the laying performance and fecundity of hens. Follicle selection mainly depends on the regulation of follicle-stimulating hormone (FSH) secreted by pituitary gland and the expression of follicle stimulation hormone receptor. To uncover the role of FSH in chicken follicle selection, in this study, we analyzed the changes in the mRNA transcriptome profiles of FSH-treated chicken granulosa cells from prehierarchical follicles by long-read sequencing Oxford Nanopore Technologies (ONT) approach. Among the 10,764 genes detected, 31 differentially expressed (DE) transcripts of 28 DE genes were significantly upregulated by FSH treatment. These DE transcripts (DETs) were mainly related to the steroid biosynthetic process by GO analysis and enriched in pathways of ovarian steroidogenesis and aldosterone synthesis and secretion by KEGG analysis. Among these genes, the mRNA and protein expression of TNF receptor associated factor 7 (TRAF7) was upregulated after FSH treatment. Further study revealed that TRAF7 stimulated the mRNA expression of steroidogenic enzymes steroidogenic acute regulatory protein (StAR) and cytochrome P450 family 11 subfamily A member 1 (CYP11A1) genes and the proliferation of granulosa cells. This is the first study to investigate differences in chicken prehierarchical follicular granulosa cells before and after FSH treatment by using ONT transcriptome sequencing, which provides a reference for a more comprehensive understanding of the molecular mechanism of follicle selection in chicken.