Inflammatory cytokines are fundamental mediators of the organismal response to injury, infection, or other harmful stimuli. To elucidate the early and mostly direct transcriptional signatures of inflammatory cytokines, we profiled all immunologic cell types by RNAseq after systemic exposure to IL1β, IL6, and TNFα. Our results revealed a significant overlap in the responses, with broad divergence between myeloid and lymphoid cells, but with very few cell-type-specific responses. Pathway and motif analysis identified several main controllers (NF-κB, IRF8, and PU.1), but the largest portion of the response appears to be mediated by MYC, which was also implicated in the response to γc cytokines. Indeed, inflammatory and γc cytokines elicited surprisingly similar responses (∼50% overlap in NK cells). Significant overlap with interferon-induced responses was observed, paradoxically in lymphoid but not myeloid cell types. These results point to a highly redundant cytokine network, with intertwined effects between disparate cytokines and cell types.

Immune checkpoint inhibitors has opened up new avenues for cancer treatment, but serious cardiac injury has emerged in their use. A large number of data have shown that abnormal activation of cytosolic DNA-sensing cyclic GMP-AMP synthase-interferon gene activator pathway is closely related to cardiovascular inflammation and autoimmune diseases. However, the pathophysiological function of the cGAS-STING cascade in myocarditis induced by Immune checkpoint inhibitors is unclear.

In order to establish a Immune checkpoint inhibitors-associated myocarditis model, BALB/c mice were injected with mouse cardiac troponin I peptide and anti-mouse programmed death 1 antibody. Echocardiography and HE staining were then performed to assess cardiac function and inflammation. Macrophages and damaged DNA in mouse heart tissue were detected by immunofluorescence. The mitochondrial damage of macrophages was observed by electron microscope. In vitro experiments, RAW264.7 was used to detect macrophage polarization after anti-PD-1 antibody induction and STING inhibition by qPCR and flow cytometry. Mitochondrial damage was detected by immunofluorescence, and activation of the cGAS-STING signaling pathway was evaluated by protein imprinting analysis.

In the Immune checkpoint inhibitors-associated myocarditis model, DNA damage was found to activate the cGAS-STING pathway and macrophages were polarized to M1 type. In vitro experiments, anti-PD-1 antibody activate the cGAS-STING pathway through the release of damaged DNA from macrophage mitochondrial damage, causing macrophage polarization into a pro-inflammatory phenotype leading to autoimmune myocarditis.

Our results suggested that the cGAS-STING pathway played a key role in myocarditis caused by immune checkpoint inhibitors. It provided a new possibility for Immune checkpoint inhibitors to be widely used in clinic.

Podocyte injury plays a pivotal role in the pathogenesis of diabetic nephropathy (DN), leading to proteinuria formation. β-Sitosterol is a natural compound with anti-inflammatory, anti-diabetic, nephroprotective and antioxidant properties. The studyaimed to explore whether and how β-Sitosterol protected podocytes against high glucose (HG)-induced inflammatory andoxidative injury. DN cell models were established by stimulating podocytes or renal tubular epithelial cells (HK-2) cells with 25 mM glucose. Cell viability and apoptosis were evaluated using cell counting kit-8 assays and flow cytometry analyses. Westernblotting was used to quantify protein levels of genes related to podocyte injury, HK-2 cell damage, inflammation, and TLR4/NF-кB pathway. Contents of oxidative stress biomarkers were evaluated by corresponding commercial kits while proinflammatorycytokine levels were determined by enzyme-linked immunosorbent assay. Immunofluorescence staining was performed todetect intracellular levels of reactive oxygen species (ROS) and Nrf2 nuclear translocation. Experimental results revealed that HG treatment induced podocyte dysfunction by impairing cell viability while accelerating theapoptosis, and the changes were reversed by β-sitosterol treatment. Moreover, β-sitosterol repressed HG-evoked oxidative stressby reducing ROS and malondialdehyde (MDA) levels while increasing activities of antioxidant enzymes. The reduction ofproinflammatory cytokines mediated by β-sitosterol in HG-stimulated podocytes suggested the anti-inflammatory role of β-sitosterol. Additionally, the activation of the TLR4/NF-кB signaling induced by HG was inhibited by β-sitosterol in podocytes.Inactivation of the TLR4 using TAK-242 enhanced the protective effects of β-sitosterol against HG-mediated oxidative stressand inflammation. Similarly, β-sitosterol also protected HK-2 cells from HG-induced oxidative stress, inflammation, andapoptosis. In summary, β-sitosterol exerts anti-inflammatory, anti-oxidative, and anti-apoptotic activities in HG-induced podocytes or HK-2 cells by inhibiting TLR4/NF-кB signaling.

This study aimed to investigate the effects of β-glucan derived from Euglena gracilis (EGB), an edible microalga, on particulate matter (PM2.5)-induced airway inflammation in A549 cells and BALB/c mice. EGB effectively suppressed the mRNA and protein levels of inflammatory cytokines (IL-6, IL-1β, TNF-α, IL-8) and mediators (iNOS, COX-2), while inhibiting the NF-κB and MAPK signaling pathways triggered by PM2.5 exposure and reducing nuclear NF-κB levels. Additionally, EGB decreased PM2.5-induced ROS production and increased the protein levels of NRF2 and HO-1, along with genes encoding antioxidant enzymes (catalase, GPx, SOD1), associated with elevated nuclear NRF2 levels. EGB reduced immune cell infiltration and inflammatory cytokine levels in BALF and serum, both of which increased by PM2.5 exposure. EGB also significantly increased alveolar numbers while decreasing the gene expression of MMP1/9/13. Furthermore, EGB suppressed PM2.5-induced bronchial thickening and collagen-1 deposition by downregulating TGF-β1 expression, and alleviated goblet cell hyperplasia and mucin production in lung tissues. These results suggest that EGB effectively reduces PM2.5-induced airway inflammation by suppressing NF-κB and MAPK signaling pathways, lowering pro-inflammatory cytokines, and activating the NRF2-HO-1 signaling pathway to enhance antioxidant enzyme expression. This study highlights the potential of EGB as an edible functional agent for controlling PM-related airway inflammation.

The pathogenic bacterium Photobacterium damselae subsp. damselae (PDD) has the capacity to infect various mariculture fish species. The Type II secretion system is a component of PDD, facilitating the secretion of extracellular products. The gspD gene encodes the outer membrane secretory channel protein of T2SS. To investigate the role of the gspD gene in T2SS during PDD infection, we generated a gspD gene deletion mutant of PDD (ΔgspD-PDD) using a suicide plasmid-mediated homologous recombination technique and compared the biological characteristics, virulence gene expression, and pathogenicity of ΔgspD-PDD with those of the wild-type strain (WT-PDD). Our results indicated that the hemolytic activity and phospholipase activity of ΔgspD-PDD were significantly diminished compared to WT-PDD, and the complementation strain was restored to levels similar to those of the WT-PDD. The expression levels of T2SS-related genes and the virulence genes were significantly down-regulated, while the outer membrane-related gene and flagella-related genes exhibited significant up-regulation. The LD50 values of ΔgspD-PDD and its ECP in Sebastes schlegelii were 62.70-fold and 18.76-fold higher than those of WT-PDD, respectively. In summary, the mutation of the gspD gene may lead to the down-regulation of T2SS-related genes, resulting in aberrant secretion of ECPs in PDD and subsequently diminishing its pathogenicity.

Corynebacterium pseudotuberculosis, a zoonotic intracellular bacteria, is responsible for abscesses and pyogranuloma formation of the infected host, which is essentially a chronic inflammatory response. Tripartite motif-containing protein 21 (TRIM21) negatively regulates pro-inflammatory cytokines production during C. pseudotuberculosis infection, the mechanism of which remains unclear. This study found that C. pseudotuberculosis infection in macrophages induced phosphorylation of IκB and p65. TRIM21 interacted with IκBα by PRY/SPRY domain, stabilizes IκBα and negatively regulates IκBα phosphorylation in macrophages during C. pseudotuberculosis infection. In addition, TRIM21 positively regulates the ubiquitination of IκBα via K48 linkage rather than K63 linkage in C. pseudotuberculosis-infected macrophages. In brief, our research confirmed that TRIM21 negatively regulates canonical NF-κB activation by interacting with IκBα and decreasing IκBα phosphorylation in macrophages during C. pseudotuberculosis infection. Preventing inflammation induced by C. pseudotuberculosis infection through regulation of the NF-κB pathway is a potential way to control this pathogen.

The global aging trend has posed significant challenges, rendering healthcare for older adults a crucial focus in medical research. Among the numerous health concerns related to aging, vascular aging and dysfunction are important risk factors and underlying causes of age-related diseases. Histone methylation and demethylation, which are involved in gene expression and cellular senescence, are closely associated with the occurrence and development of vascular aging. Consequently, this review aimed to identify the role of histone methylation in the pathogenesis of vascular aging and its potential for treating age-related vascular diseases and provided new insights into therapeutic strategies targeting the vascular system.

Human herpesvirus 6B (HHV-6B) belongs to the genus Roseolovirus of the betaherpesvirus subfamily, causing exanthema subitum and encephalitis. Although viral ribonucleotide reductase (RNR) is conserved in betaherpesviruses, it has lost its enzymatic activity. Human cytomegalovirus (HCMV) belongs to the other betaherpesvirus genus, Cytomegalovirus; its RNR inhibits nuclear factor-kappa B (NF-κB) signaling via interaction with the adaptor molecule RIPK1. However, the significance of enzymatically inactive RNR in roseoviruses is unclear. Here, we show that the RNRs from all three human roseoloviruses inhibit NF-κB activation. HHV-6B RNR sequesters NF-κB subunit p65 in the cytoplasm and inhibits its translocation into the nucleus. Silencing HHV-6B RNR increased the expression of inflammatory molecules in infected cells. This study reveals that inhibiting NF-κB is a conserved role of the RNR in betaherpesviruses but that the precise mechanisms responsible for these effects are different.

Bruton tyrosine kinase inhibitors (BTKi) have shown prominent clinical efficacy in patients with B cell malignancies, such as chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B cell lymphoma, and Waldenström's macroglobulinemia. Nevertheless, numerous factors contribute to BTKi resistance, encompassing genetic mutations, chromosomal aberrations, dysregulation of protein expression, tumor microenvironment, and metabolic reprogramming. Accordingly, potential therapeutic strategies have been explored to surmount BTKi resistance, including noncovalent BTKi, BTK proteolysis-targeting chimeras, and combination therapies. Herein, we summarize the mechanisms responsible for BTKi resistance as well as the current preclinical and clinical strategies to address BTKi resistance in B cell malignancies treatment.

Osteoarthritis (OA), caused by the long-term use of joints, is a representative degenerative disease in the elderly. However, recently, the age of onset has been decreasing owing to excessive activities among young people in their 20s and 30s. Gynostemma pentaphyllum (Thunb.) Makino (GP), a perennial herb of the Cucurbitaceae family, has been used since the Ming dynasty as a medicinal material to treat various ailments, such as rheumatism, liver disease, and diabetes. In this study, we investigated the anti-arthritic effects of heat-processed Gynostemma pentaphyllum extract (Actiponin (AP)) and its derivatives, damulin A (DA) and damulin B (DB), using in vitro (primary rat chondrocytes and SW1353 cells) and in vivo (destabilization of the medial meniscus (DMM)-induced OA model) systems. Histological analysis results from the in vivo study showed that the group that underwent DMM surgery induced degeneration by the loss of proteoglycan and the destruction of cartilage (OARSI score 14 ± 0.57), whereas the group that received AP daily for 8 weeks maintained an intact condition (OARSI score 5 ± 0.28 at 200 mg/kg, p < 0.001). In addition, cartilage thickness and chondrocytes were reduced in the DMM group, but were restored in the AP-administered group. Furthermore, the von Frey analysis results showed that the pain threshold of the DMM group was considerably low (54.5 g at 8 weeks), whereas that of the AP group was dose-dependently increased (65.5, 69.5, 70.3, and 71.8 at 8 weeks for 30, 50, 100, and 200 mg/kg, respectively). In vitro studies showed that AP, DA, and DB reduced the expression of interleukin-1β alone-induced nitrite; inducible nitric oxide synthase; cyclooxygenase-2; matrix metallopeptidase 1/3/13; and a disintegrin and metalloproteinase with thrombospondin motifs 4/5. They also restored the expression of collagen type II and aggrecan, which are components of the extracellular matrix. The anti-arthritic effects of AP, DA, and DB were confirmed to be mediated by the mitogen-activated protein kinase and nuclear factor kappa-light-chain-enhancer of activated B cell signaling pathways. Collectively, these results suggest that AP is a potential therapeutic agent for mitigating OA progression and chondroprotection.

High-mobility group box 1 (HMGB1) protein is a highly prevalent protein that, once it is translocated to an extracellular site, can contribute to the pathogenesis of autoimmune and inflammatory responses, including epilepsy and depression. The conditions needed for release are associated with the production of multiple isoforms, and this translocation may occur in response to both immune cell activation and cell death. HMGB1 has been shown to interact with different mediators, including exportin 1, notch receptors, mitogen-activated protein kinase, STAT, tumor protein 53, and inflammasomes. Furthermore, as a crucial inflammatory mediator, HMGB1 has demonstrated upregulated expression and a higher percentage of translocation from the nucleus to the cytoplasm, acting on downstream receptors such as toll-like receptor 4 and receptor for advanced glycation end products, thereby activating interleukin-1 beta and nuclear factor kappa-B, intensifying inflammatory responses. In this review, we aim to discuss the different molecular interactions for the secretion of HMGB1 along with its pivotal role in epilepsy and major depressive disorder.

Myopia has become a worldwide public health problem. In this study, we constructed a form deprivation (FD) myopia mouse model and explored the potential role of NF-κB pathway and inflammatory cytokines in scleral remodeling during myopia development. Wild-type (WT) mice and C6-knockout (KO) mice were categorized into two groups: FD and normal control (NC). The right eye was covered using a translucent balloon for 4 weeks, and the left eye remained untreated which served as self-control. NC group received no treatment. Refractive error and axial length were measured at baseline, 2 weeks, 4 weeks later under normal visual conditions, and 4 weeks after FD. The mRNA and protein levels of scleral TNF-α, IL-6, IL-1β, MMP-2, collagen I, and p-NF-κB p65 were detected using quantitative PCR and western blot. Under normal visual conditions, no significant difference existed in refraction and axial length between WT and C6 KO mice. After 4 weeks of deprivation, the interocular differences of C6 KO mice were lower than those of WT mice (refraction - 2.41 ± 0.86D vs. - 4.33 ± 0.87D, P = 0.003; axial length 0.044 ± 0.028 mm vs. 0.082 ± 0.026 mm, P = 0.034). Moreover, TNF-α, IL-6, IL-1β, MMP-2, and p-NF-κB p65 levels increased, and collagen I levels decreased in deprived eyes of WT mice. Whereas these trends were weakened in C6 KO mice. Scleral C5b-9 could activate the NF-κB pathway, promoting the expression of inflammatory cytokines and MMP-2 levels, which ultimately affected scleral remodeling.

Background/Objectives: Chronic lymphocytic leukemia (CLL) remains an incurable B-cell malignancy. B-CLL cells exhibit an extended lifespan in part due to the activation of survival pathways such as NF-kB. A crosstalk between NF-kB and GSK-3β pathways has been reported. NF-kB has also been identified as a primary target of the NEDD8-activating enzyme inhibitor MLN4924. Our objective was to investigate potential synergies of MLN4924 with other NF-kB-targeting agents for the treatment of CLL and elucidate the mechanisms of action underlying this pathway regulation. Methods: To assess the cytotoxic efficacy of the combined ex vivo treatment with CHIR-99021 and MLN4924, we employed 7-AAD staining and XTT viability assays on primary samples from CLL patients. Subsequently, we conducted various analyses to identify the molecular mechanisms underlying the cytotoxic effects of this combination. Results: We discovered a discrepancy between the mRNA and protein levels of IkBɑ and provided evidence of translational control over its expression. This observation may explain why, unlike other cell types, B-CLL cells did not activate NF-kB signaling following inhibition of GSK-3ß. Furthermore, we describe a synergistic effect between a specific GSK-3ß inhibitor, CHIR-99021/Laduviglusib, and the NEDD8-activating enzyme inhibitor MLN4924/Pevonedistat, at doses that only slightly affect healthy B cell viability ex vivo. We investigated the molecular basis of this co-induction of cell death by analyzing the alterations in apoptosis-related gene expression. We found that the combinational treatment enhances a reduction in BCL2 mRNA expression levels, providing an alternative approach for BCL-2 inhibition in CLL that could have therapeutic implications for the treatment of refractory CLL cases. Conclusions: our findings revealed a unique interaction between GSK-3ß and NF-kB pathways in CLL and their regulation of BCL2 expression.

Severe acute pancreatitis (SAP) leads to systemic inflammation, resulting in multiorgan damage. Acute lung injury and acute respiratory distress syndrome develop in one-third of SAP patients, with a high mortality rate of 60% due to secondary complications. Patients with pancreatitis often have selenium deficiency, and selenium supplements may provide beneficial effects. This study examined the protective role of selenium in a model of SAP induced by caerulein + lipopolysaccharide (cae + LPS). Mice were administered selenium (1 mg/kg) before being challenged with caerulein (6 injections of 50 μg/kg) and LPS (10 mg/kg). At 3 h after the last caerulein injection, blood was collected for estimating pancreatic enzymes and cytokine levels, and the mice were euthanized. We performed morphological and histological studies, measured levels of protease and oxidative stress markers and conducted western blot, ELISA, and RT-qPCR analyses. We examined lung tissue histologically and estimated myeloperoxidase levels. Selenium pretreatment significantly reduced pancreatic enzyme levels such as amylase, lipase, and proteases (specifically MMPs) and reversed tissue injury in the pancreas and lungs caused by cae + LPS. In addition, selenium-treated mice showed decreased levels of inflammatory markers and chemokines. Examination of the downstream inflammatory pathways confirmed the protective effect of selenium, which mediates its anti-inflammatory and antioxidant action by inhibiting the major inflammatory signaling pathways (MAPKs, NF-κB, and STAT3) and activating the phosphorylation of Nrf2 via Nrf2/HO-1 pathways. These findings suggest that selenium may be a potential therapeutic option for treating SAP-associated secondary complications.

2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) exhibits a dualistic pharmacological profile, acting as both a hepatoprotective and hepatotoxic agent, which is intricately linked to its interaction with multiple signaling pathways and its stereoisomeric forms, namely, cis-SG and trans-SG. The purpose of this study is to evaluate both the hepatoprotective and hepatotoxic effects of TSG and give therapeutic guidance.

This study performed a systematic search of eight databases to identify preclinical literature up until March 2024. The CAMARADES system evaluated evidence quality and bias. STATA and Python were used for statistical analysis, including dose-effect maps, 3D maps and radar charts to show the dose-time-effect relationship of TSG on hepatoprotection and hepatotoxicity.

After a rigorous screening process, a total of 24 studies encompassing 564 rodents were selected for inclusion in this study. The findings revealed that TSG exhibited bidirectional effects on the levels of ALT and AST, while also regulating the levels of ALT, AST, TNF-α, IL-6, serum TG, serum TC, SOD, MDA, IFN-γ, and apoptosis rate. The histological analysis of liver tissue confirmed the regulatory effects of TSG, and a comprehensive analysis revealed the optimal protective dosage range was 27.27-38.81 mg/kg/d and the optimal toxic dosage range was 51.93-76.07 mg/kg/d. TSG exerts the dual effects on liver injury (LI) through the network of Keap1/Nrf2/HO-1/NQO1, NF-κB, PPAR, PI3K/Akt, JAK/STAT and TGF-β pathways.

TSG could mediate the pathways of oxidation, inflammation, and metabolism to result in hepatoprotection (27.27-38.81 mg/kg/d) and hepatotoxicity (51.93-76.07 mg/kg/d).

This study aimed to investigate whether activation of PPARγ regulates M1/M2 macrophage polarization to attenuate dextran sulfate sodium salt (DSS)-induced inflammatory bowel disease (IBD) via the STAT-1/STAT-6 pathway in vivo and in vitro. We first examined the effect of PPARγ on macrophage polarization in LPS/IFN-γ-treated M1 RAW264.7 cells and IL-4/IL-13-treated M2 RAW264.7 cells. Then, 40 male C57BL/6 mice were randomly divided into five groups: the Sham, IBD, IBD + fludarabine (FLU), IBD + IL-4, and IBD + pioglitazone (PI) groups. The mice received 2.5% DSS in their drinking water for 7 days and then received regular water for 2 days to establish the experimental IBD murine model. The mice in the IBD + FLU, IBD + IL-4, and IBD + PI groups were intraperitoneally injected with FLU, IL-4, and PI, respectively, for 9 days. Clinical symptoms, intestinal barrier function, macrophage polarization, PPARγ, and the STAT-1/STAT-6 pathway were analyzed. Activation of PPARγ decreased M1 polarization marker expression and STAT-1 phosphorylation and increased M2 polarization marker expression and STAT-6 phosphorylation in RAW264.7 cells. Activation of PPARγ attenuated disease symptoms, such as weight loss, diarrhea, and bloody stool. Histological analysis revealed that PI treatment reduced inflammatory cell infiltration, restored the mucosal architecture, and improved the expression of tight junction proteins. Moreover, the activation of PPARγ decreased the expression of iNOS and increased the expression of Arg-1, Fizz 1, and Ym 1 by inhibiting STAT-1 phosphorylation and promoting STAT-6 phosphorylation in mice with DSS-induced IBD. Activation of PPARγ regulates M1/M2 macrophage polarization to attenuate DSS-induced IBD via the STAT-1/STAT-6 pathway in vivo and in vitro.

Current research primarily focuses on the pathological mechanisms of spinal cord injury (SCI), seeking to promote spinal cord repair and restore motorial and sensory functions by elucidating mechanisms of cell death or axonal regeneration. However, SCI is almost irreversible, and patients often struggle to regain mobility or self-care abilities after injuries. Consequently, there has been significant interest in modulating systemic symptoms following SCI to improve patients' quality of life. Neuron axonal disconnection and substantial apoptotic events following SCI result in signal transmission loss, profoundly impacting various organ and systems, including the gastrointestinal tract. Dysbiosis can lead to severe bowel dysfunction in patients, substantially lowering their quality of life and significantly reducing life expectancy of them. Therefore, researches focusing on the restoration of the gut microbiota hold promise for potential therapeutic strategies aimed at rehabilitation after SCI. In this paper, we explore the regulatory roles that dietary fiber, short-chain fatty acids (SCFAs), probiotics, and microbiota transplantation play in patients with SCI, summarize the potential mechanisms of post-SCI dysbiosis, and discuss possible strategies to enhance long-term survival of SCI patients. We aim to provide potential insights for future research aimed at ameliorating dysbiosis in SCI patients.

Genistein (4',5,7-trihydroxyisoflavone) is a phytoestrogen belonging to a subclass of natural flavonoids that exhibits a wide range of pharmacological functions, including antioxidant and anti-inflammatory properties. These characteristics make genistein a valuable phytochemical compound for the prevention and/or treatment of cancer. Genistein effectively inhibits tumor growth and dissemination by modulating key cellular mechanisms. This includes the suppression of angiogenesis, the inhibition of epithelial-mesenchymal transition, and the regulation of cancer stem cell proliferation. These effects are mediated through pivotal signaling pathways such as JAK/STAT, PI3K/Akt/mTOR, MAPK/ERK, NF-κB, and Wnt/β-catenin. Moreover, genistein interferes with the function of specific cyclin/CDK complexes and modulates the activation of Bcl-2/Bax and caspases, playing a critical role in halting tumor cell division and promoting apoptosis. The aim of this review is to discuss in detail the key cellular and molecular mechanisms underlying the pleiotropic anticancer effects of this flavonoid.

Acute kidney injury (AKI) is a common critical clinical disease that is linked to significant morbidity, recurrence, and mortality. It is characterized by a fast and prolonged loss in renal function arising from numerous etiologies and pathogenic pathways. Renal fibrosis, defined as the excessive accumulation of collagen and proliferation of fibroblasts within renal tissues, contributes to the structural damage and functional decline of the kidneys, playing a pivotal role in the advancement of Chronic Kidney Disease (CKD). Until now, while continuous renal replacement therapy (CRRT) has been utilized in the management of severe AKI, there remains a dearth of effective targeted therapies for AKI stemming from diverse etiologies. Similarly, the identification of specific biomarkers and pharmacological targets for the treatment of renal fibrosis remains a challenge. Baicalin, a naturally occurring compound classified within the flavonoid group and commonly found in the Chinese herb Scutellaria baicalensis, has shown a range of pharmacological characteristics, such as antioxidant, anti-inflammatory, antifibrotic, antitumor and antiviral effects, as evidenced by research studies. Research shows that Baicalin has potential in treating kidney diseases like AKI and renal fibrosis. This review aims to summarize Baicalin's progress in these areas, including its molecular mechanism, application in treatment, and absorption, distribution, metabolism, and excretion. Baicalin's therapeutic effects are achieved through various pathways, including antioxidant, anti-inflammatory, antifibrosis, and regulation of apoptosis and cell proliferation. Besides, we also hope this review may give some enlightenment for treating AKI and renal fibrosis in clinical practice.

Oncogenes are typically overexpressed in tumor tissues and often linked to poor prognosis. However, recent advancements in bioinformatics have revealed that many highly expressed genes in tumors are associated with better patient outcomes. These genes, which act as tumor suppressors, are referred to as "paradoxical genes." Analyzing The Cancer Genome Atlas (TCGA) confirmed the widespread presence of paradoxical genes, and KEGG analysis revealed their role in regulating tumor metabolism. Mechanistically, discrepancies between gene and protein expression-affected by pre- and post-transcriptional modifications-may drive this phenomenon. Mechanisms like upstream open reading frames and alternative splicing contribute to these inconsistencies. Many paradoxical genes modulate the tumor immune microenvironment, exerting tumor-suppressive effects. Further analysis shows that the stage- and tumor-specific expression of these genes, along with their environmental sensitivity, influence their dual roles in various signaling pathways. These findings highlight the importance of paradoxical genes in resisting tumor progression and maintaining cellular homeostasis, offering new avenues for targeted cancer therapy.

Aging and age-related disease are among the most common and challenging issues worldwide. During the aging process, the accumulation of oxidative stress, DNA damage, telomere dysfunction, and other related changes lead to cellular dysfunction and the development of diseases such as neurodegenerative and cardiovascular conditions. Curcumin is a widely-used dietary supplement against various diseases such as cancer, diabetes, cardiovascular diseases and aging. This agent mediates its effects through several mechanisms, including the reduction of reactive oxygen species (ROS) and oxidative stress-induced damage, as well as the modulation of subcellular signaling pathways such as AMPK, AKT/mTOR, and NF-κB. These pathways are involved in cellular senescence and inflammation, and their modulation can improve cell function and help prevent disease. In cancer, Curcumin can induce apoptosis in a variety of different tumor cell lines. Curcumin also activates redox reactions within cells inducing ROS production that leads to the upregulation of apoptosis receptors on the tumor cell membrane. Curcumin can also upregulate the expression and activity of p53 that inhibits tumor cell proliferation and increases apoptosis. Furthermore, curcumin has a potent inhibitory effect on the activity of nuclear factor kappa B (NF-κB) and cyclooxygenase-2 (COX-2), which are involved in the overexpression of antiapoptosis genes such as Bcl-2. It can also attenuate the regulation of antiapoptosis phosphoinositide 3-kinases (PI3K) signaling and increase the expression of mitogen-activated protein kinases (MAPKs) to induce endogenous production of ROS. Therefore, herein, we aim to summarize how curcumin affect different epigenetic processes (such as apoptosis and oxidative stress) in order to change aging-related mechanisms. Furthermore, we discuss its roles in age-related diseases, such as Alzheimer, Parkinson, osteoporosis, and cardiovascular diseases.

Polydatin (PD), a glucoside derivative of resveratrol (RES), is extracted as a monomer compound from the dried rhizome of Polygonum cuspidatum. Our laboratory synthesized PD via the biotransformation of resveratrol. To assess the reproductive protective effects of PD, an oligozoospermia mouse model was induced by administering 30 mg/kg busulfan (BUS) via intraperitoneal injection. Initially, mice were categorized into groups based on PD concentrations of 10, 50, and 100 mg/kg. Subsequently, the optimal concentration of 10 mg/kg was ascertained based on testis weight and spermatological parameters. Additionally, a 10 mg/kg resveratrol group was included as a control. The findings revealed that exposure to BUS resulted in a reduction of testicular weight, diminished spermatogenic cells and epididymal sperm counts, increased sperm deformity, disordered testicular cytoskeleton, compromised blood-testis barrier integrity, and a significant decrease in serum sex hormone levels, notably testosterone. This resulted in decreased expression of androgen receptors and other testosterone-related proteins, increased levels of malondialdehyde and reactive oxygen species, and promoted testicular ferroptosis. However, PD could successfully reverse these injuries. High-throughput sequencing data demonstrated that polydatin significantly downregulated the expression of inflammatory and metabolic genes, including PRKCQ and CARD11. These proteins are pivotal in the activation of the NF-κB pathway during the inflammatory response. Molecular docking studies showed that PD could interact with PRKCQ and CARD11 to reduce the level of inflammation. Additionally, PD was shown to interact with the ferroptosis-promoting gene ACSL4, modulating ferroptosis. In summary, PD facilitates the reversal of BUS-induced oligozoospermia through the mitigation of oxidative stress and inflammation, the inhibition of ferroptosis, and the modulation of hormonal levels.

We investigated the involvement of FOXO3a in lipopolysaccharide (LPS)-induced inflammation in primary human dental pulp cells (HDPCs).

HDPCs that were isolated from donors undergoing tooth extraction for orthodontic purposes were cultured with or without 1 μg/mL LPS at various intervals. The FOXO3a localization in the HDPCs was verified using immunofluorescence. Proinflammatory cytokines, such as interleukin (IL) 1β, IL6, and IL8, as well as their underlying mechanisms were assessed by observing gene and protein expressions through quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analyses.

LPS treatment enhanced the expressions of IL1β, IL6, and IL8 in HDPCs, concurrently activating nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). Furthermore, FOXO3a expression was higher in the LPS-stimulated HDPCs, as confirmed by immunofluorescence localization. The results of loss-/gain-of-function approaches confirmed the regulatory role of FOXO3a in inflammatory HDPCs. FOXO3a knockdown attenuated proinflammatory cytokine expression; FOXO3a overexpression augmented their expression levels. FOXO3a inhibited retinoic acid receptor-related orphan receptor alpha (RORα) expression, thereby inactivating NFκB.

Our findings suggest that FOXO3a contributes to homeostasis in HDPCs through modulating the expression of proinflammatory cytokines under inflammatory conditions.

Cells orchestrate their processes through complex interactions, precisely organizing biomolecules in space and time. Recent discoveries have highlighted the crucial role of biomolecular condensates-membrane-less assemblies formed through the condensation of proteins, nucleic acids, and other molecules-in driving efficient and dynamic cellular processes. These condensates are integral to various physiological functions, such as gene expression and intracellular signal transduction, enabling rapid and finely tuned cellular responses. Their ability to regulate cellular signaling pathways is particularly significant, as it requires a careful balance between flexibility and precision. Disruption of this balance can lead to pathological conditions, including neurodegenerative diseases, cancer, and viral infections. Consequently, biomolecular condensates have emerged as promising therapeutic targets, with the potential to offer novel approaches to disease treatment. In this review, we present the recent insights into the regulatory mechanisms by which biomolecular condensates influence intracellular signaling pathways, their roles in health and disease, and potential strategies for modulating condensate dynamics as a therapeutic approach. Understanding these emerging principles may provide valuable directions for developing effective treatments targeting the aberrant behavior of biomolecular condensates in various diseases.

Hypoxia-inducible factors (HIFs) are essential transcription factors that orchestrate cellular responses to oxygen deprivation. HIF-1α, as an unstable subunit of HIF-1, is usually hydroxylated by prolyl hydroxylase domain enzymes under normoxic conditions, leading to ubiquitination and proteasomal degradation, thereby keeping low levels. Instead of hypoxia, sometimes even in normoxia, HIF-1α translocates into the nucleus, dimerizes with HIF-1β to generate HIF-1, and then activates genes involved in adaptive responses such as angiogenesis, metabolic reprogramming, and cellular survival, which presents new challenges and insights into its role in cellular processes. Thus, the review delves into the mechanisms by which HIF-1 maintains its stability under normoxia including but not limited to giving insights into transcriptional, translational, as well as posttranslational regulation to underscore the pivotal role of HIF-1 in cellular adaptation and malignancy. Moreover, HIF-1 is extensively involved in cancer and cardiovascular diseases and potentially serves as a bridge between them. An overview of HIF-1-related drugs that are approved or in clinical trials is summarized, highlighting their potential capacity for targeting HIF-1 in cancer and cardiovascular toxicity related to cancer treatment. The review provides a comprehensive insight into HIF-1's regulatory mechanism and paves the way for future research and therapeutic development.

Lysosomes are the major cellular organelles responsible for nutrient recycling and degradation of cellular material. Maintenance of lysosomal integrity is essential for cellular homeostasis and lysosomal membrane permeabilization (LMP) sensitizes toward cell death. Damaged lysosomes are repaired or degraded via lysophagy, during which glycans, exposed on ruptured lysosomal membranes, are recognized by galectins leading to K48- and K63-linked poly-ubiquitination (poly-Ub) of lysosomal proteins followed by recruitment of the macroautophagic/autophagic machinery and degradation. Linear (M1) poly-Ub, catalyzed by the linear ubiquitin chain assembly complex (LUBAC) E3 ligase and removed by OTULIN (OTU deubiquitinase with linear linkage specificity) exerts important functions in immune signaling and cell survival, but the role of M1 poly-Ub in lysosomal homeostasis remains unexplored. Here, we demonstrate that L-leucyl-leucine methyl ester (LLOMe)-damaged lysosomes accumulate M1 poly-Ub in an OTULIN- and K63 Ub-dependent manner. LMP-induced M1 poly-Ub at damaged lysosomes contributes to lysosome degradation, recruits the NFKB (nuclear factor kappa B) modulator IKBKG/NEMO and locally activates the inhibitor of NFKB kinase (IKK) complex to trigger NFKB activation. Inhibition of lysosomal degradation enhances LMP- and OTULIN-regulated cell death, indicating pro-survival functions of M1 poly-Ub during LMP and potentially lysophagy. Finally, we demonstrate that M1 poly-Ub also occurs at damaged lysosomes in primary mouse neurons and induced pluripotent stem cell-derived primary human dopaminergic neurons. Our results reveal novel functions of M1 poly-Ub during lysosomal homeostasis, LMP and degradation of damaged lysosomes, with important implications for NFKB signaling, inflammation and cell death.Abbreviation: ATG: autophagy related; BafA1: bafilomycin A1; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CRISPR: clustered regularly interspaced short palindromic repeats; CHUK/IKKA: component of inhibitor of nuclear factor kappa B kinase complex; CUL4A-DDB1-WDFY1: cullin 4A-damage specific DNA binding protein 1-WD repeat and FYVE domain containing 1; DGCs: degradative compartments; DIV: days in vitro; DUB: deubiquitinase/deubiquitinating enzyme; ELDR: endo-lysosomal damage response; ESCRT: endosomal sorting complex required for transport; FBXO27: F-box protein 27; GBM: glioblastoma multiforme; IKBKB/IKKB: inhibitor of nuclear factor kappa B kinase subunit beta; IKBKG/NEMO: inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; IKK: inhibitor of NFKB kinase; iPSC: induced pluripotent stem cell; KBTBD7: kelch repeat and BTB domain containing 7; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LCD: lysosomal cell death; LGALS: galectin; LMP: lysosomal membrane permeabilization; LLOMe: L-leucyl-leucine methyl ester; LOP: loperamide; LUBAC: linear ubiquitin chain assembly complex; LRSAM1: leucine rich repeat and sterile alpha motif containing 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NBR1: NBR1 autophagy cargo receptor; NFKB/NF-κB: nuclear factor kappa B; NFKBIA/IĸBα: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; OPTN: optineurin; ORAS: OTULIN-related autoinflammatory syndrome; OTULIN: OTU deubiquitinase with linear linkage specificity; RING: really interesting new gene; RBR: RING-in-between-RING; PLAA: phospholipase A2 activating protein; RBCK1/HOIL-1: RANBP2-type and C3HC4-type zinc finger containing 1; RNF31/HOIP: ring finger protein 31; SHARPIN: SHANK associated RH domain interactor; SQSTM1/p62: sequestosome 1; SR-SIM: super-resolution-structured illumination microscopy; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1; TH: tyrosine hydroxylase; TNF/TNFα: tumor necrosis factor; TNFRSF1A/TNFR1-SC: TNF receptor superfamily member 1A signaling complex; TRIM16: tripartite motif containing 16; Ub: ubiquitin; UBE2QL1: ubiquitin conjugating enzyme E2 QL1; UBXN6/UBXD1: UBX domain protein 6; VCP/p97: valosin containing protein; WIPI2: WD repeat domain, phosphoinositide interacting 2; YOD1: YOD1 deubiquitinase.

Serine incorporator 5 (SER5) can be incorporated into HIV-1 virions to block viral entry by disrupting the envelope glycoprotein-mediated viral fusion to the plasma membrane. Recent studies suggest that SER5 also inhibits HIV-1 mRNA transcription and the subsequent progeny virion biogenesis. However, the underlying mechanisms through which SER5 antagonizes the viral transcription remain poorly understood. Here, we demonstrate that SER5 inhibits HIV-1 transcription by negatively regulating NF-κB signaling, which is mediated by the retinoic acid-inducible gene I-like receptors, MDA5 and RIG-I. By recruiting TRIM40 as the E3 ubiquitination ligase to promote K48-linked polyubiquitination and proteasomal degradation of MDA5 and RIG-I, SER5 impedes nuclear translocation of the p50/p65 dimer, resulting in repression of HIV-1 LTR-driven gene expression. Hence, our findings strongly support a role for SER5 in restricting HIV-1 replication through inhibition of NF-κB-mediated viral gene expression.

Recent research has underscored the pivotal role of chronic inflammation in cancer development. Investigations have elucidated key molecular mechanisms underpinning inflammation-related cancer. Extrinsic pathway, driven by inflammatory conditions and intrinsic pathway, propelled by genetic events, emerged as critical links between inflammation and carcinogenesis. The persistent inflammation exacerbates genomic instability, providing a mechanistic link between inflammation and cancer. Targeting crucial inflammatory pathways such as NFκB, JAK-STAT, MAPK/ERK, PI3K/AKT, Wnt and TGF-β, holds promise for advancing cancer treatment modalities. Hence, understanding the key signalling pathways will highlight the intricate interplay between inflammation and cancer recognizing it as a potential target for interventions.

Three new monoterpenes compounds (5S, 8S)-5-(2E-butenyl)-8-methyl propionate-cyclopentanone (1), 1-Oxy, 10-keto-α-myrcene hydroxide (2), (3R,4R)-3-hydroxy-4-isobutenyl-cyclopentyl ester (3), along with eleven known small molecular compounds such as monoterpenes (1-7, 14), coumarin (10), and other small molecular compounds (8, 9, 11-13) were isolated from Seriphidium terrae-albae. The structures were elucidated by NMR, HRESIMS, ECD calculations, and X-ray crystallography. Anti-inflammatory activity test results showed that 9 compounds were detected to inhibit NO secretion by mouse macrophage Raw 264.7. Among them, the IC50 value of compound 1 (9.56 ± 0.66 μM) was relatively close to the positive control drug Andrographolide (AG) (2.70 ± 0.39 μM). Molecular docking predicted that the target of compound 1 may be the STAT3 proteins. Further mechanism studies have revealed that compound 1 acted on the STAT3 target in the JAK/STAT signaling pathway, indicating the activation of M2 macrophages, exerted anti-inflammatory effects. Additionally, it could also reduce the cytoplasmic NF-κB content achieve the anti-inflammatory effect. Therefore, compound 1 has the potential to become an anti-inflammatory lead compound. This study provides reference value for the research and development of small-molecule natural product anti-inflammatory drugs.

Inflammation is a vital and normal physiological response; however, excessive inflammation can contribute to the development of various diseases. Artemisia sieversiana, a traditional Chinese medicinal plant, contains a variety of chemical compounds. One such compound, 3-oxo-11αH-germacra-1(10)E,4Z-dien-12,6α-olide, a germacranolide sesquiterpenoid (germacranolide, GMO), has not been thoroughly investigated regarding its potential anti-inflammatory properties. In this study, the anti-inflammatory and antioxidant properties of GMO were investigated for the lipopolysaccharide (LPS)-induced inflammation in RAW264.7 cells. It was demonstrated that GMO effectively suppressed the production of inflammatory mediators, decreased the phosphorylation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) in RAW264.7 cells. Additionally, GMO exhibited the capacity to mitigate oxidative damage induced by LPS, as indicated by assessments of reactive oxygen species and mitochondrial membrane potential. In summary, GMO possesses significant anti-inflammatory effects by modulating the NF-κB/MAPK pathway and antioxidant effects by regulating ROS production.

Cancer stem cells (CSCs) play a key role in non-small cell lung cancer (NSCLC) chemoresistance and metastasis. In this study, we used two NSCLC cell lines to investigate the regulating effect of hypoxia in the induction and maintenance of CSC traits. Our study demonstrated hypoxia-induced stemness and chemoresistance at levels comparable to those in typical CSC sphere culture. Activation of the NF-κB pathway (by transfection of NF-κB-p65) plays a key role in NSCLC CSCs and chemoresistance. Disulfiram (DS), an anti-alcoholism drug, showed a strong in vitro anti-CSC effect. It blocked cancer cell sphere reformation and clonogenicity, synergistically enhanced the cytotoxicity of four anti-NSCLC drugs (doxorubicin, gemcitabine, oxaliplatin and paclitaxel) and reversed hypoxia-induced resistance. The effect of DS on CSCs is copper-dependent. A very short half-life in the bloodstream is the major limitation for the translation of DS into a cancer treatment. Our team previously developed a poly lactic-co-glycolic acid (PLGA) nanoparticle encapsulated DS (DS-PLGA) with a long half-life in the bloodstream. Intra venous injection of DS-PLGA in combination with the oral application of copper gluconate has strong anticancer efficacy in a metastatic NSCLC mouse model. Further study may be able to translate DS-PLGA into cancer applications.

Tripartite motif (TRIM) family proteins, distinguished by their N-terminal region that includes a Really Interesting New Gene (RING) domain with E3 ligase activity, two B-box domains, and a coiled-coil region, have been recognized as significant contributors in carcinogenesis, primarily via the ubiquitin-proteasome system (UPS) for degrading proteins. Mechanistically, these proteins modulate a variety of signaling pathways, including Wnt/β-catenin, PI3K/AKT, and TGF-β/Smad, contributing to cellular regulation, and also impact cellular activities through non-signaling mechanisms, including modulation of gene transcription, protein degradation, and stability via protein-protein interactions. Currently, growing evidence indicates that TRIM proteins emerge as potential regulators in gastric cancer, exhibiting both tumor-suppressive and oncogenic roles. Given their critical involvement in cellular processes and the notable challenges of gastric cancer, exploring the specific contributions of TRIM proteins to this disease is necessary. Consequently, this review elucidates the roles and mechanisms of TRIM proteins in gastric cancer, emphasizing their potential as therapeutic targets and prognostic factors.

Mesenchymal stem cells (MSCs) are widely applied in the treatment of various clinical diseases and in the field of medical aesthetics. However, MSCs exhibit greater heterogeneity limited stability, and more complex molecular and mechanistic characteristics compared to conventional drugs, making rapid and precise monitoring more challenging.

Surface-enhanced Raman spectroscopy (SERS) is an ultrasensitive, tractable and low-cost fingerprinting technique capable of identifying a wide range of molecules related to biological processes. Here, we employed SERS for reproducible quantification of ultralow concentrations of molecules and utilized spectral sets, termed SERSomes, for robust and comprehensive intracellular multi-metabolite profiling.

We revealed that with increasing passage number, there is a gradual decline in cell expansion efficiency, accompanied by significant changes in intracellular amino acids, purines, and pyrimidines. By integrating these metabolic features detected by SERS with transcriptomic data, we established a correlation between SERS signals and biological changes, as well as differentially expressed genes.

In this study, we explore the application of SERS technique to provide robust metabolic characteristics of MSCs across different passages and donors. These results demonstrate the effectiveness of SERSome in reflecting biological characteristics. Due to its sensitivity, adaptability, low cost, and feasibility for miniaturized instrumentation throughout pretreatment, measurement, and analysis, the label-free SERSome technique is suitable for monitoring MSC expansion and offers significant advantages for large-scale MSC manufacturing.

Malignant pleural effusion (MPE) is one of the most difficult complications of cancer to cure, usually indicating poor prognosis in late-stage cancer patients. Due to the presence of a large number of tumor-associated immune cells with the tumor promoting phenotype in MPE and pleural tumors, current clinical therapy offers limited effectiveness. Here, a mild magnetothermal regulation strategy is proposed based on a magnetic nanocatlytic nanoplatform ZCMF@PEG-AF (ZCMF-AF) constructed by surface-modifying anti-F4/80 antibody (AF) on ZnCoFe2O4@ZnMnFe2O4 magnetic nanoparticles (ZCMF) to target and polarize tumor-associated macrophages. Under alternating magnetic field-induced hyperthermia (41-42 °C), ZCMF-AF exhibits in situ nanocatalytic production of hydroxyl radicals via released iron ions under acidic cellular environment, which induces repolarization from the immunosuppressed M2 phenotype to the M1 phenotype. More importantly, the tumor cell damage induced by M1 macrophages and magnetic hyperthermia promote the maturation of dendritic cells, which subsequently awakens cytotoxic T lymphocytes to combat tumor cells. The integrated innate and adaptive immunity activations based on ZCMF-AF nano-immunomedicine through intrapleural administration elicit substantially regulated immune microenvironment of MPE and pleural tumors. Moreover, the interpleural magnetic nanoparticle-based immunotherapy effectively reduced the MPE volume and inhibited tumor growth in the pleural cavity, significantly prolonging the survival of the MPE-bearing mice.

Type 2 diabetes mellitus (T2D) is defined by chronic hyperglycemia due to insufficient insulin secretion or activity and decreased insulin sensitivity, known as insulin resistance (IR). This condition leads to oxidative stress and inflammation, increasing the risk of systemic inflammatory diseases. Obesity and a sedentary lifestyle are major risk factors for IR and T2D. Various metabolites act as mediators of IR by disrupting communication between organs. Lipids, including free fatty acids and short-chain fatty acids, along with intracellular lipotoxins, impair insulin function and mitochondrial activity, contributing to IR through direct and indirect mechanisms such as oxidative stress and inflammation. Our research explores the role of TNFα and CXCR1/2 in IR conditions, emphasizing their interactions and potential as therapeutic targets. In this study we selected two models of IR, adipocytes and hepatocytes, since are key players in glucose and lipid metabolism. To develop IR model, TNFα was used as challenge and we focused on investigating the role of CXCR1/2 inhibition. We assessed glucose uptake, insulin signaling pathways, and gene expression related to IR. Cells treated with TNFα showed reduced p-Akt and increased p-JNK levels, indicative of IR. In contrast, CXCR1/2 inhibition restored p-Akt levels and reduced p-JNK levels, suggesting improvements in insulin signaling and glucose uptake. Furthermore, CXCR1/2 inhibition counteracted the TNFα-induced decrease in IGF expression and restored GLUT2 expression, indicating enhanced insulin sensitivity. These results underscore the pivotal role of CXCR1/2 in modulating the inflammatory response and insulin signaling in IR conditions in both IR models. CXCR1/2 inhibition can mitigate IR and improve glucose metabolism. Thus, targeting the TNFα-CXCR1/2 pathway presents a promising therapeutic approach for managing IR and T2D. Further investigation is necessary to understand the clinical implications of these findings and develop effective treatments for patients with IR and T2D.

Thyroid cancer has an overwhelming incidence in the population. Thus, there is an urgent need to understand the underlying mechanism of its occurrence and development, which may provide new insights into therapeutic strategies. The role and mechanism of TFCP2L1 in regulating the progression of thyroid cancer remains unclear.

Public databases and clinical samples were used to detect the expression of TFCP2L1 in cancer and non-cancer tissues. Kaplan-Meier and Cox regression analyses were used to compare the differences in survival probability of the TFCP2L1 highly expressing group and the TFCP2L1 lowly expressing group. Functional assays were used to evaluate the biological effect of TFCP2L1 on thyroid cancer cells. RNA sequencing and enrichment analyses were used to find out pathways that were activated or inactivated by TFCP2L1.

We demonstrated that TFCP2L1 was significantly downregulated in thyroid cancer. Decreased expression of TFCP2L1 was associated with malignant clinicopathological characteristics. Kaplan-Meier and Cox regression analyses indicated that thyroid tumor patients with low TFCP2L1 expression presented shorter disease-free interval and progression-free interval. Additionally, TFCP2L1 expression was positively correlated with thyroid differentiation degree. Overexpression of TFCP2L1 in thyroid cancer cells inhibited cell growth and motility in vitro, and tumorigenicity and metastasis in vivo. Mechanistically, the NF-κB signaling pathway was found inactivated by overexpressing TFCP2L1.

Our results suggest that TFCP2L1 is a tumor suppressor and potential differentiation regulator, and might be a potential therapeutic target in thyroid cancer.

Lung adenocarcinoma (LUAD) is the most dominant histological subtype of lung cancer and one of the most lethal malignancies. The identification of novel therapeutic targets is required for the treatment of LUAD. Here, we showed that MYC-associated zinc-finger protein (MAZ) is upregulated in LUAD tissues. MAZ expression levels are inversely correlated with patient survival. Silencing of MAZ decreased tumor proliferation and the expression of pro-tumorigenic chemokines and Galectin-9 (Gal-9), an immune checkpoint molecule. The pro-tumorigenic chemokines and Gal-9 induce immune suppression by recruitment of myeloid cells and inhibition of T cell activation, respectively. Mechanistically, MAZ transcriptionally regulates KRAS expression and activates its downstream AKT-NF-κB signaling pathway, which is crucial for tumor progression and immune evasion. Additionally, in vivo animal models and bioinformatic analyses indicated that MAZ suppression could enhance the efficacy of immune checkpoint blockade (ICB) therapy for LUAD. Overall, our results suggest that MAZ plays an important role in regulating cell proliferation and immune evasion via KRAS/AKT/NF-κB signaling in LUAD. Our findings offer a candidate molecular target for LUAD therapy, with implications for improving the efficacy of ICB therapy.

The interleukin-33/interleukin-1 receptor-like-1 (IL-33/IL1RL1) signalling pathway is implicated in asthma pathogenesis, with IL1RL1 nonsynonymous genetic polymorphisms associated with disease risk. We aimed to determine these variants' effect on IL1RL1 signalling induced by different IL33 isoforms thought to be elevated in the asthmatic airway.

In a project funded by GSK plc, which has developed an IL-33 receptor inhibitor for asthma treatment, human embryonic kidney 293 (HEK293) cells expressing secreted embryonic alkaline phosphatase (SEAP) driven by a nuclear factor kappa-beta (NF-κB) promoter, were transiently transfected with IL1RL1, containing one of four extracellular and Toll/interleukin 1 receptor (TIR) domain haplotypes. Cells were stimulated with seven different splice and proteolytic-generated IL-33 isoforms (0.001-50 ng/mL) for 24 h. Supernatant SEAP activity and interleukin-8 (IL-8) levels were determined. Primary human bronchial epithelial cells (HBECs) representing different genotype carriers were stimulated with IL-33112-270 (50 ng/mL) and induced IL-8 mRNA expression measured.

HEK293 cells carrying both asthma extracellular and TIR domain IL1RL1 risk haplotypes presented maximal IL33-driven signalling, with minimal signalling after IL-33 activation in other protective haplotypes. All IL-33 isoforms activated IL1RL1 but with differing magnitudes. Proteolytically cleaved IL3395-270 and IL33106-270 had the greatest effect and the IL33113-270, and Exon 3,4 deletion isoform exhibited the lowest. The effect of extracellular and TIR domain genetic variants on receptor signalling was replicated in primary HBECs. Maximal IL1RL1 signalling was observed in cells carrying both extracellular and TIR signalling domain risk haplotypes.

Overall, our study suggests asthma patients carrying the extracellular and TIR domain risk haplotype and have a lung microenvironment that promotes elevated levels of cleaved IL33, particularly where IL3395-270 and IL33106-270 may be more amenable to IL33/IL1RL1 targeting.

This study was designed to observe the effect of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway activity on sepsis-associated acute kidney injury (SA-AKI), thereby providing new considerations for the prevention and treatment of SA-AKI.

The rats were divided into Sham, cecal ligation and puncture (CLP), CLP + vehicle, and CLP + TAK-242 groups. Except the Sham group, a model of CLP-induced sepsis was established in other groups. After 24 h, the indicators related to kidney injury in blood samples were detected. The pathological changes in the kidneys were observed by hematoxylin-eosin staining, and tubular damage was scored. Oxidative stress-related factors, mitochondrial dysfunction-related indicators in each group were measured; the levels of inflammatory factors in serum and kidney tissue of rats were examined. Finally, the expression of proteins related to the TLR4/NF-κB signaling pathway was observed by western blot.

Compared with the CLP + vehicle and CLP + TAK-242 groups, the CLP + TAK-242 group reduced blood urea nitrogen (BUN), creatinine (Cr), cystatin-C (Cys-C), reactive oxygen species (ROS), malondialdehyde (MDA), and inflammatory factors levels (p < 0.01), as well as increased superoxide dismutase (SOD) activity of CLP rats (p < 0.01). Additionally, TAK-242 treatment improved the condition of CLP rats that had glomerular and tubular injuries and mitochondrial disorders (p < 0.01). Further mechanism research revealed that TAK-242 can inhibit the TLR4/NF-κB signaling pathway activated by CLP (p < 0.01). Above indicators after TAK-242 treatment were close to those of the Sham group.

TAK-242 can improve oxidative stress, mitochondrial dysfunction, and inflammatory response by inhibiting the activity of TLR4/NF-κB signaling pathway, thereby preventing rats from SA-AKI.

Human health is endangered by the occurrence and progression of urological cancers, including renal cell carcinoma, prostate cancer and bladder cancer, which are usually associated with the activation of oncogenic factors and inhibition of cancer suppressors. The primary mechanism for protein breakdown in cells is the ubiquitin-proteasome system, whilst deubiquitinases contribute to the reversal of this process. However, both are important for protein homeostasis. Deubiquitination may also be involved in the control of the cell cycle, proliferation and apoptosis, and dysregulated deubiquitination is associated with the malignant transformation, invasion and metastasis of urologic malignancies. Therefore, a comprehensive summary of the mechanisms underlying deubiquitination in urological cancers may provide novel strategies and insights for diagnosis and treatment. The present review aimed to methodically clarify the role of deubiquitinating enzymes in urinary system cancers as well as their prospective application prospects for clinical treatment.

As a pattern recognition receptor, Toll-like receptor 4 (TLR4) is crucial for the development and progression of acute kidney injury (AKI). This study aims to explore whether the deubiquitinase Usp9x influences the TLR4/NF-B pathway to cause sepsis-induced acute kidney injury (S-AKI). The model of AKI was established in Sprague-Dawley rats using the cecal ligation and puncture (CLP) method, while renal tubular epithelial cell NRK-52E was stimulated with lipopolysaccharide (LPS) in vitro. All plasmids were transfected into NRK-52E cells according to the indicated group. The deubiquitinase of TLR4 was predicted by the online prediction software Ubibrowser. Subsequently, Western blot and Pearson correlation analysis identified Usp9x protein as a potential candidate. Co-IP analysis verified the interaction between TLR4 and Usp9x. Further research revealed that overexpression of Usp9x inhibited degradation of TLR4 protein by downregulating its ubiquitination modification levels. Both in vivo and in vitro experiments observed that interference with Usp9x effectively alleviated the inflammatory response and apoptosis of renal tubular epithelial cells (RTECs) induced by CLP or LPS, whereas overexpression of TLR4 reversed this situation. Transfection with sh-Usp9x in NRK-52E cells suppressed the expression of proteins associated with the TLR4/NF-κB pathway induced by LPS. Moreover, the overexpression of TLR4 reversed the effect of sh-Usp9x transfection. Therefore, the deubiquitinase Usp9x interacts with TLR4, leading to the upregulation of its expression through deubiquitination modification, and the activation of the TLR4/NF-κB signaling pathway, thereby promoting inflammation and apoptosis in renal tubular epithelial cells and contributing to sepsis-induced acute kidney injury.