AiiO-AIO6 is a quorum-sensing quenching enzyme that could decrease the virulence of pathogenic bacteria, and improve animal immunity. However, the precise regulatory mechanism of AiiO-AIO6 on intestinal immunity remains unknown. Thus, this study aimed to reduce this knowledge gap. After feeding with graded levels of AIO-AIO6 (0.0 (un-supplemented group), 2.5, 5.0, 7.5, 10.0, and 12.5 U/g) for 70 days, juvenile grass carp was selected from each group for a 6-day Aeromonas hydrophila challenge test. Meanwhile, some other fish selected from un-supplemented control group were injected with saline as un-challenged control. Results showed that A. hydrophila infection increased enteritis morbidity, and caused intestinal inflammation in grass carp compared with saline group, while AiiO-AIO6 supplementation decreased enteritis morbidity, mitigated inflammatory cell infiltration, pyroptosis, and apoptosis in the intestine after A. hydrophila infection. Furthermore, both 5.0 and 7.5 U/g AiiO-AIO6 decreased gene expressions of tumor necrosis factor-α and interleukin-1β, and elevated gene expressions of transforming growth factor-β1 and IL-10, potentially associating with decreased NF-κB p65 and increased PPARγ signaling in the intestine. Supplementing 5.0 or 7.5 U/g AiiO-AIO6 also mitigated intestinal pyroptosis, as indicated by reduced mRNA levels of NLRP3, PYCARD, caspase-1, GSDME a, and GSDME b, and decreased protein levels of N-GSDME and IL-1β. Additionally, AiiO-AIO6 alleviated intestinal apoptosis, demonstrated by reduced gene expressions of pro-apoptotic genes apoptotic protease activating factor-1, Bcl-2 associated X protein, Fas ligand, and caspase-3, as well as c-Jun N-terminal kinase and mitogen-activated protein kinase p38, and elevated gene expressions of anti-apoptotic factors, B-cell lymphoma-2, myeloid cell leukemia 1, and inhibitor of apoptosis protein. Altogether, optimal levels of AiiO-AIO6 attenuated intestinal inflammation probably relating to down-regulated NF-κB signaling, and reduced NLRP3 and GSDME-mediated pyroptosis, and finally reduced apoptosis in the intestine of grass carp.

Increased phosphorylation of TDP-43 is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the regulation and roles of TDP-43 phosphorylation remain incompletely understood. A variety of techniques have been utilized to understand TDP-43 phosphorylation, including kinase/phosphatase manipulation, phosphomimic variants, and genetic, physical, or chemical inducement in a variety of cell cultures and animal models, and via analyses of post-mortem human tissues. These studies have produced conflicting results: suggesting incongruously that TDP-43 phosphorylation may either drive disease progression or serve a neuroprotective role. In this review, we explore the roles of regulators of TDP-43 phosphorylation including the putative TDP-43 kinases c-Abl, CDC7, CK1, CK2, IKKβ, p38α/MAPK14, MEK1, TTBK1, and TTBK2, and TDP-43 phosphatases PP1, PP2A, and PP2B, in disease. Building on recent studies, we also examine the consequences of TDP-43 phosphorylation on TDP-43 pathology, especially related to TDP-43 mislocalisation, liquid-liquid phase separation, aggregation, and neurotoxicity. By comparing conflicting findings from various techniques and models, this review highlights both the discrepancies and unresolved aspects in the understanding of TDP-43 phosphorylation. We propose that the role of TDP-43 phosphorylation is site and context dependent, and includes regulation of liquid-liquid phase separation, subcellular mislocalisation, and degradation. We further suggest that greater consideration of the normal functions of the regulators of TDP-43 phosphorylation that may be perturbed in disease is warranted. This synthesis aims to build towards a comprehensive understanding of the complex role of TDP-43 phosphorylation in the pathogenesis of neurodegeneration.

Psoriasis is a chronic, immune-mediated inflammatory skin disease, and the inflammatory response plays an important role in its development and progression. Psoriasis can appear at any age and occurs around the world. The pathogenesis of psoriasis has not been fully elucidated, and there is currently no effective treatment method in clinical practice. Broussonetia papyrifera is a traditional Chinese medicine that exhibited a significant therapeutic effect on psoriasis in our previous study due to its remarkable anti-inflammatory and anti-oxidant properties. However, its mechanism of action in treating psoriasis is still unclear. The purpose of this study is to evaluate the anti-psoriasis effect of the B. papyrifera leaves extract (PLE) in vivo and to explore its potential effects. PLE effectively alleviated imiquimod (IMQ)-induced psoriasis-like lesions, reduced psoriasis lesion area and severity index, decreased epidermal hyperplasia, ameliorated the oxidative stress-induced changes in the levels of superoxide dismutase (SOD) and malondialdehyde (MDA), and reduced the levels of the inflammatory cytokines TNF-α and IL-17A. PLE can also reduce the protein expression levels of TLR4, MyD88, p-NF-κBp65, p-IκBα, p-PI3K and p-AKT induced by IMQ model. Our findings suggest that PLE is effective in improving psoriasis-like symptoms, which might be ascribed to the inhibition of the TLR4/NF-κB and PI3K/AKT inflammation pathway. Our study demonstrates the potential mechanism of a natural source of PLE for the treatment of psoriasis. However, it is important to note that these findings lack clinical validation, and further studies are required to validate these results in clinical settings. Additionally, PLE shows potential in being a cost-effective alternative compared to existing biologics, which could have broader implications for psoriasis treatment in the future.

Endogenous metabolite itaconate and its derivative Dimethyl itaconate (DMI) exhibit significant anti-inflammatory effects. Dimethyl Pent-2-Enedioate (DMP), an isomer of DMI, may possess similar properties. This study investigates the anti-inflammatory effects of DMP in LPS-induced macrophages and explores its potential regulatory mechanisms.

Inflammatory marker levels were assessed at both the mRNA and protein levels using ELISA and qRT-PCR. The activation status of macrophages was evaluated by flow cytometry, quantifying the number of CD40-positive cells. RNA sequencing was conducted to investigate the transcriptomic changes following DMP treatment. Subsequent GO and KEGG enrichment analyses were performed to identify potential mechanisms underlying DMP's effects. Western blot analysis was employed to assess the expression of p-p65, while immunofluorescence analysis was used to examine p65 nuclear translocation, providing insight into the regulatory effects of DMP on the NF-κB signaling pathway.

DMP inhibited the expression of inflammatory markers TNF-α, IL-6, and MCP-1 at both mRNA and protein levels. Flow cytometry analysis revealed a decrease in CD40-positive cells. RNA sequencing identified DEGs enriched in inflammation-related pathways. Western blotting and immunofluorescence confirmed that DMP reduced p-p65 expression and inhibited p65 nuclear translocation, suggesting a potential regulatory effect on the NF-κB signaling pathway.

DMP significantly inhibits LPS-induced inflammation in macrophages, with its underlying mechanisms being complex. Our data demonstrate that DMP exerts its anti-inflammatory effects at least in part through the downregulation of the NF-κB pathway, offering potential applications in the prevention and treatment of inflammation-related diseases.

Capsaicin (CAP), the principal bioactive component of chili peppers (Capsicum annuum L.), is widely recognized for its anti-inflammatory properties. However, its oral bioavailability is low, likely due to extensive sulfonation metabolism. Despite the well-known pharmacological benefits of CAP, the role of sulfotransferase (SULT)-mediated sulfonation in modulating its therapeutic effects remains poorly understood. This study aims to elucidate the sulfonate metabolic profile of CAP, investigate the anti-inflammatory role of its sulfonate metabolite (CAP-S), and uncover the mechanisms underlying CAP-S's anti-inflammatory effects. In our study, the mono-sulfonate metabolite of CAP, designated as CAP-S ((E)-N-[(4-sulfo-3-methoxyphenyl)methyl]-8-methylnon-6-enamide), is identified using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) and proton nuclear magnetic resonance (1H-NMR). The metabolic profile of CAP was investigated in liver S9 fractions from human, rat, and mouse samples, with sulfonation of CAP examined using seven major recombinant SULT isoforms. The results demonstrate that CAP is primarily catalyzed by SULT1A subfamily and SULT1E1. The anti-inflammatory effects of CAP-S are evaluated in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and an acute liver injury (ALI) mouse model. CAP-S significantly reduces inflammatory mediators and nitric oxide (NO) production in LPS-induced RAW264.7 cells. In vivo, CAP-S treatment alleviates hepatocyte necrosis, inflammatory cell infiltration, and reduces aspartate aminotransferase, alanine aminotransferase, and malondialdehyde levels, while enhancing superoxide dismutase activity and decreasing NO production. Additionally, CAP-S exerts comparable anti-inflammatory effects to CAP by suppressing NF-κB p65 phosphorylation and reducing pro-inflammatory cytokines, as evidenced by network pharmacology and western blot assays. These findings underscore the role of sulfonation in modulating CAP's therapeutic potential.

Bipolar disorder is a severe mental disorder that necessitates effective long-term treatment strategies. Clinically, lithium has demonstrated favorable outcomes in managing this condition. The inflammatory theory posits that bipolar disorder is influenced by an inflammatory response, and lithium is thought to mitigate this disorder by inhibiting such responses. In terms of the pharmacodynamics of blocking inflammatory mediators, lithium mainly acts on GSK-3β. Upon interaction with GSK-3β, lithium can suppress the gene expression of inflammatory mediators, subsequently reducing their secretion. This mechanism influences multiple downstream pathways, ultimately contributing to the therapeutic effects observed in bipolar disorder. Specifically, these pathways include the arachidonic acid pathway, nitric oxide synthase pathway, neurotransmitter pathway, and so on. This article reviews the pharmacodynamic targets and mechanisms of lithium, offering insights into the appropriate clinical application of lithium and the advancement of lithium pharmacotherapies.

Stressful events are associated with impaired glutamate signaling and neuroimmune adaptations that may increase the vulnerability of individuals to cocaine addiction. We previously demonstrated that chronic stress induced reactive microglia and increased TNF-α expression in the nucleus accumbens core (NAcore), both alterations strongly linked with impaired glutamate homeostasis and the facilitation of cocaine self-administration. The nuclear factor kappa-B (NF-κB) is a critical regulator of many immune- and addiction-related genes, such as the gene coding for glutamate transporter (GLT-1), and it is considered a master regulator of inflammation, reported to be a key driver of microglia activation in psychiatric diseases. However, no studies have examined the role of NF-κB signaling within the NAcore in the neuroimmune and glutamate mechanism, underpinning stress-induced vulnerability to cocaine self-administration. Here we investigate whether viral dominant negative inhibition of I kappa B kinase (IKKdn), a signaling molecule responsible for NF-κB activation, would prevent stress-induced facilitation to cocaine self-administration and associated changes in accumbal GLT-1 and TNF-α expression. We also explore N-myc proto-oncogene protein (N-myc) levels as a link between NF-κB and stress-induced GLT-1 downregulation. For seven days (days 1-7), adult male rats were restrained for 2 h/day. Animals were administered an intra-NAcore with IKKdn or empty lentiviruses on day 14 after the first restraint stress session. Marked activation of NF-κB was detected in the NAcore of stressed subjects, along with increased NF-κB expression in astrocytes. Consistently, viral NF-κB inhibition prevented stress-induced facilitation of cocaine self-administration. Moreover, NF-κB blockade results in the restoration of stress-induced reduction in GLT-1 levels and was effective in suppressing stress-induced TNF-α within the NAcore. These findings suggest that accumbal NF-κB signaling exerts a central control over stress-altered downstream neuroimmune and glutamate function underlying vulnerability to cocaine use disorders.

Protein quality control (PQC) plays a vital role in maintaining normal heart function, as cardiomyocytes are relatively sensitive to misfolded or damaged proteins, which tend to accumulate under pathological conditions. Ubiquitin-specific protease (USP) is the largest deubiquitinating enzyme family and a key component of the ubiquitin proteasome system (UPS), which is a non-lysosomal protein degradation machinery to mediate PQC in cells. USPs regulate the stability or activity of the target proteins that involve intracellular signaling, transcriptional control of inflammation, antioxidation, and cell growth. Recent studies demonstrate that the USPs can regulate fibrosis, lipid metabolism, glucose homeostasis, hypertrophic response, post-ischemic recovery and cell death such as apoptosis and ferroptosis in cardiomyocytes. Since myocardial cell loss is an important component of cardiomyopathy, therefore, these findings suggest that the UPSs play emerging roles in cardiomyopathy. This review briefly summarizes recent literature on the regulatory roles of USPs in the occurrence and development of cardiomyopathy, giving us new insights into the molecular mechanisms of USPs in different cardiomyopathy and potential preventive strategies for cardiomyopathy.

Rutin (vitamin P or rutoside) is a citrus flavonoid glycoside that has shown beneficial health effects in different organs against various conditions including inflammation and pain. The majority of rutin therapeutic benefits are ascribed to its antioxidant and anti-inflammatory properties. This review article discusses studies that investigated pain-relieving activity of rutin and summarizes the reported mechanisms of action. Rutin pain-relieving effect has been studied in streptozotocin-induced diabetes, chronic constriction injury, and oxaliplatin-, formalin-, acetic acid- and glutamate-induced nociception in mice or rats. Based on the literature, rutin analgesic effects are induced through potentiation of antioxidant arsenal, reduction of inflammatory cytokines (e.g., Tumor necrosis factor alpha (TNF-α) and interleukin-1β) levels, suppression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions and modulation of MAPK, NF-κB and Nrf-2/HO-1 signaling. Preclinical findings on rutin pain-relieving activity are promising, however, its safety profile needs to be more thoroughly investigated and clinical trials should be conducted to assess its analgesic effects in humans.

As a synthetic rubber antioxidant, the environmental monitoring concentrations of N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine (6-PPD) have exceeded the risk threshold, attracting widespread attention. Although investigations into the harmful effects on zebrafish have commenced, a comprehensive exploration of its toxicological impacts and underlying molecular mechanisms remains to be conducted. By using zebrafish as a model, this study systematically evaluated 6-PPD-induced lipid metabolism disorders and inflammation response following environmental exposure. Bioinformatics analysis revealed that 6-PPD target genes enriched in the hepatitis B pathway, indicating potential hepatic toxicity via inflammatory pathways. Therefore, we hypothesize that 6-PPD could trigger hepatotoxicity through the crosstalk between lipid metabolism and inflammation. Further experiments substantiated this hypothesis by showing lipid accumulation in the liver following 6-PPD exposure, along with elevated triglyceride (TG) and total cholesterol (TC) levels, and imbalanced expression of lipid metabolism-related marker genes. Additionally, 6-PPD exposure induced the accumulation of reactive oxygen species (ROS) and inhibited the differentiation and maturation of immune cells, resulting in immune evasion. Most of these abnormalities were exacerbated in a dose-dependent manner with increasing concentrations of 6-PPD. The addition of the PPARγ pathway agonist puerarin (PUE) or NF-κB pathway inhibitor quinazoline (QNZ) to 6-PPD exposure group mitigated these toxic effects, validating our conjecture that lipid metabolism disorder and inflammatory responses may result from the regulation of the PPARγ/NF-κB pathway.

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), an intracellular signaling molecule, is widely expressed during inflammatory responses. To investigate the immune function of AjMALT1 in Apostichopus japonicus, the full length of AjMALT1 gene was cloned using transcriptome data and RACE technology. The results showed that AjMALT1 was distributed in all tissues, with higher expression found in coelomocytes and intestine. The expression of AjMALT1 was significantly upregulated in Vibrio splendidus-challenged sea cucumbers, as well as in coelomocytes exposed to inactive V. splendidus, and was positively correlated with the expression of the pro-inflammatory cytokine AjIL17 and the inflammasome component AjNLRP3. Further investigation using specific siRNA to silence AjMALT1 for 48 h revealed that the expression of AjIL17 and AjNLRP3 was reduced under V. splendidus stimulation. Additionally, histological observations showed a decrease in intestinal inflammation. Interference with AjMALT1 also led to downregulation of AjTRAF6 and AjRel expression, as well as inhibited nuclear translocation of AjRel. These findings suggest AjMALT1 exacerbates intestinal and coelomic inflammation by activating the AjTRAF6-dependent NF-κB pathway in A. japonicus.

Nuclear factor-κB (NF-κB)/p65, a vital signaling molecule in the NF-κB pathway, participates in diverse physiological functions and host-virus interactions. However, the involvement of NF-κB/p65 in fish virus infection remains poorly understood. In this study, we explored the role of the p65 in virus infection and its impact on IL-18 regulation in largemouth bass (Micropterus salmoides). Bioinformatics analysis showed that the ORF sequence of Msp65 spanned 1941 bp, encoding 646 amino acids with two conserved functional domains, including RHD and IPT domain. Msp65 mRNA was presented in various tissues, with higher levels detected in the liver and gill. After exposure to largemouth bass virus (LMBV), red grouper nervous necrosis virus, lipopolysaccharide and poly (I:C), Msp65 expression was activated in vivo. In addition, the antiviral role of Msp65 were explored. In vitro, Msp65 overexpression hindered LMBV replication and formation of viral assembly site. In vivo, we found that disruption of Msp65 by using maslinic acid (MA) notably promoted the infectivity of LMBV, indicating its antiviral capabilities in largemouth bass. Besides, the downregulation of Msp65 suppressed the expression of inflammatory and interferon signaling molecules. Conversely, Msp65 overexpression boosted the activities of IFN-I, IFN-III and ISRE promoters, suggesting the positive regulation of Msp65 on interferon immune pathway. Furthermore, to unveil the regulatory role of Msp65 on MsIL-18, a promoter investigation was conducted. The luciferase reporter assay demonstrated that Msp65 positively influenced the expression of MsIL-18. Subsequent analysis suggested that the putative binding sites for MsIL-18 could potentially reside within the -228 to -203 bp of the MsIL-18 promoter. These findings illustrated that Msp65 involved in LMBV infection by modulating immune responses, presenting a novel insight into the antiviral mechanisms of p65 in bony fish.

Oxidative stress plays a crucial role in the pathogenesis of acute kidney injury (AKI), chronic kidney disease (CKD), and the AKI-to-CKD transition. This review examines the intricate relationship between oxidative stress and kidney pathophysiology, emphasizing the potential therapeutic role of nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of cellular redox homeostasis. In diverse AKI and CKD models, diminished NRF2 activity exacerbates oxidative stress, whereas genetic and pharmacological NRF2 activation alleviates kidney damage induced by nephrotoxic agents, ischemia-reperfusion injury, fibrotic stimuli, and diabetic nephropathy. The renoprotective effects of NRF2 extend beyond antioxidant defense, encompassing its anti-inflammatory and anti-fibrotic properties. The significance of NRF2 in renal fibrosis is further underscored by its interaction with the transforming growth factor-β signaling cascade. Clinical trials using bardoxolone methyl, a potent NRF2 activator, have yielded both encouraging and challenging outcomes, illustrating the intricacy of modulating NRF2 in human subjects. In summary, this overview suggests the therapeutic potential of targeting NRF2 in kidney disorders and highlights the necessity for continued research to refine treatment approaches.

Sepsis, a common clinical complication, leads to multi-organ damage due to systemic infection and currently lacks effective therapeutic drugs. Polysaccharide derived from Tetrastigma hemsleyanum Diels et Gilg (TH), abbreviated as THP, is a water-soluble component extracted from TH, exhibiting anti-inflammatory and immunomodulatory properties. This study aims to investigate the effects and mechanisms of THP in sepsis. Results demonstrated that THP reduced neutrophils in the peripheral blood of mice established by cecal ligation and puncture (CLP), and inhibited IL-6 and MCP-1 in plasma, thereby improving systemic inflammation. THP ameliorated pulmonary edema, mitigated lung and liver histopathological injuries, reduced infiltration of neutrophils and macrophages in the lung and liver, and inhibited the TNF-α, IL-6, IL-1β, and MCP-1 transcription in both organs. Additionally, THP decreased myeloid cells, neutrophils, monocytes, and Tregs in the spleens of septic mice, while increasing T cells, CD4+ T cells, and CD8+ T cells, thereby restoring immune imbalance. Mechanistically, THP attenuated sepsis by inhibiting the overactivation of the TLR4/NF-κB/COX-2 pathway, and reducing PD-1, PD-L1, IDO1 in the lung, and PD-1, PD-L1 in the liver of septic mice. In conclusion, this study provides theoretical support for the potential application of THP in sepsis treatment.

Deleterious molecules or factors produced by pathogens can hinder the normal physiological functioning of organisms. In response to these survival challenges, organisms rely on innate immune signaling as their first line of defense, which regulates immune-responsive genes and antimicrobial peptides to protect against pathogenic infections. These genes are under the control of transcription factors, which are known to regulate the transcriptional activity of genes after binding to their regulatory sequences. Previous studies have employed Caenorhabditis elegans as a host-pathogen interaction model to demonstrate the essential role of different transcription factors in the innate immunity of worms. In this review, we summarize the advances made regarding the functioning of distinct transcription factors in the innate immune response upon pathogen infection. Finally, we discuss the open questions in the field, whose resolutions have the potential to expand our understanding of the mechanisms underlying the innate immunity of organisms.

Human periodontal ligament (hPDL) is continuously exposed to mechanical forces that can induce inflammatory responses in resident stem cells (hPDLSCs). Here, we review the impact of mechanical force on hPDLSCs, focusing on the activation of inflammatory cytokines and related signalling pathways, which subsequently influence periodontal tissue remodelling. The effects of various mechanical forces, including compressive, shear, and tensile forces, on hPDLSCs are discussed. The review highlights the role of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α in mediating inflammatory responses, as well as the counteracting effects of anti-inflammatory cytokines like IL-4 and IL-10. Additionally, we underscore the involvement of toll-like receptors (TLRs), particularly TLR4, in transducing mechanical stress signals and modulating cytokine production. This review demonstrates that hPDLSCs respond to different mechanical forces with specific gene expression changes that direct inflammatory and bone remodelling signals, leading to increased osteoblast and osteoclast activity. Moreover, hPDLSCs, together with contiguous hPDL cells, respond to various mechanical forces by regulating the immune function of several immune cells. This complex relationship between the mechanical force stress, inflammation, and the cellular response in hPDLSCs warrants further research to develop therapeutic strategies for periodontal and related diseases.

Ectopic olfactory receptors are expressed in nonolfactory tissues and perform diverse roles including regulation of glucose homeostasis. We explored the effect of citronellal treatment on olfactory receptor 4M1 subtype (OR4M1) signaling in insulin resistance and Type II diabetes in rats. We aimed to validate the anti-diabetic effect of citronellal through Asprosin/OR4M1 modulation. Exploring new antidiabetics and pharmacological targets is important to improve quality of life and limit complications. The model was established in Sprague-Dawley rats by a high-fat diet for 4 weeks followed by a single low-dose streptozotocin (STZ) (35 mg/kg/ip). One week after STZ injection, oral citronellal (100 mg/kg) was administered for 4 weeks. Citronellal lowered serum glucose and triglycerides and ameliorated OGTT and HOMA-IR results. Docking results revealed that citronellal blocked the Asprosin binding site at OR4M1. The hepatic expression of OR4M1 and Asprosin was reduced. Citronellal lowered cAMP levels causing attenuated levels of protein kinase A and downstream gluconeogenic enzymes: glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. Citronellal also inhibited the expression of hepatic TLR-4 and inhibited JNK phosphorylation. Citronellal attenuated hepatic levels of NF-κB, p-NF-κB, and downstream proteins MCP-1 and TNF-α. These results suggest that citronellal alleviates insulin resistance by mitigating Asprosin/OR4M1 and Asprosin/TLR4/JNK signaling.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to joint deformity and ultimately disability. The metabolite of quercetin, 4-Methylcatechol (4-MC), has been acknowledged for its anti-inflammatory and antioxidant properties; however, the protective effects of 4-MC on RA and its underlying mechanisms remain incompletely elucidated. In a collagen-induced arthritis (CIA) model, we observed that 4-MC effectively mitigated joint inflammation and bone destruction in CIA mice. Additionally, it significantly suppressed the upregulated expression of inflammatory cytokines in synovial tissues. Mechanistically, upon lipopolysaccharide (LPS) stimulation, 4-MC inhibited M1 polarization of macrophages and induced a phenotypic switch from M1 to M2 phenotype, thereby reducing the release of pro-inflammatory cytokines by M1 macrophages while increasing the release of anti-inflammatory cytokines by M2 macrophages. Furthermore, it attenuated LPS/adenosine triphosphate (ATP)-induced pyroptosis in macrophages by downregulating NLRP3 expression levels along with cleaved caspase-1, cleaved IL-1β, and GSDMD-NT expression levels. Notably, our findings revealed that 4-MC exerted inhibitory effects on the NF-κB signaling pathway through specific modulation of the NF-κB complex as well as phosphorylation of the upstream IKK kinase complex. Collectively, these results highlight significant therapeutic potential for utilizing 4-MC in RA treatment.

Natural products are valuable medicinal resources in the field of anti-inflammation due to their significant bioactivity and low antibiotic resistance. Research has demonstrated that many natural products exert notable anti-inflammatory effects by modulating the Toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB) signaling pathways. The research on related signal transduction mechanisms and pharmacological mechanisms is increasingly being discovered and validated. However, there is currently a lack of comprehensive reviews focusing on the pharmacological mechanisms of natural products targeting the TLR4/NF-κB pathway for anti-inflammatory effects. In light of these considerations, this review comprehensively synthesizes recent research findings concerning the TLR4/NF-κB signaling pathway, including the translocation of TLR4 activation to lysosomes within the cytoplasm, the assembly of protein complexes mediated by ubiquitin chains K63 and K48, and the deacetylation modification of p65. These discoveries are integrated into the classical TLR4/NF-κB pathway to systematically elucidate the latest mechanisms among various targets. Additionally, we summarize the pharmacological mechanisms by which natural products exert anti-inflammatory effects through the TLR4/NF-κB pathway. This aims to elucidate the multitarget advantages of natural products in the treatment of inflammation and their potential applications, thereby providing theoretical support for molecular pharmacology research on inflammation and the development of novel natural anti-inflammatory drugs.

This study investigates the role of NIK in activating specific inflammatory genes in macrophages, focusing on the effect of a mutation in NIK found in alymphoplasia (aly/aly) mice. Mouse peritoneal macrophages from aly/aly mice showed a severe defect in the production of some pro-inflammatory cytokines, such as IL-12. This effect seemed to take place at the transcriptional level, as shown by the reduced transcription of Il12b and Il12a in aly/aly macrophages after exposure to the TLR4 agonist LPS. Immunoprecipitation studies showed that the binding of NIK to c-Rel was not efficient in RAW 264.7 cells over-expressing the aly/aly mutation. In addition, the shuttling of c-Rel to the nucleus was shown to be impaired in aly/aly macrophages in response to LPS. When looking more specifically at the regulation of the Il12b promoter, we found that c-Rel bound to the NF-kB consensus sequence in macrophages from WT mice 1 hr. after LPS challenge, whereas in aly/aly macrophages, the transcription factor bound to the promoter was p65. These findings indicate that NIK is essential for efficient c-Rel activation and proper inflammatory responses. NIK dysfunction could lead to weakened immune responses, and targeting this pathway may help in developing therapies for immune-related conditions.

Advances in adaptive immunity have greatly contributed to the development of cancer immunotherapy. However, its over-low efficacy and insufficient invasion of immune cells in the tumor tissue, and safety problems caused by cytokine storm, have seriously impeded further clinical application for solid tumor immunotherapy. Notably, the immune microenvironment of the lungs is naturally enriched with alveolar macrophages (AMs). Herein, we introduce a novel nebulized magnetothermal immunotherapy strategy to treat orthotopic lung cancer by using magnetothermal nanomaterial (Zn-CoFe2O4@Zn-MnFe2O4-PEG, named ZCMP), which can release iron ions via an acid/thermal-catalytic reaction to maximize the use of lung's immune environment through the cascade activations of AMs and natural killer (NK) cells. Nebulized administration greatly enhance drug bioavailability by localized drug accumulation at the lesion site. Upon mild magnetic hyperthermia, the released iron ions catalyze endogenous H2O2 decomposition to produce reactive oxygen species (ROS), which triggers the M1 polarization of AMs, and the resultant inflammatory cytokine IFN-β, IL-1β and IL-15 releases to activate c-Jun, STAT5 and GZMB related signaling pathways, promoting NK cells proliferation and activation. This innovative strategy optimally utilizes the lung's immune environment and shows excellent immunotherapeutic outcomes against orthotopic lung cancer.

Wnt and Notch signaling pathways play crucial roles in the development and homeostasis of the cardiovascular system. These pathways regulate important cellular processes in cardiomyocytes, endothelial cells, and smooth muscle cells, which are the key cell types involved in the structure and function of the heart and vasculature. During embryonic development, Wnt and Notch signaling coordinate cell fate specification, proliferation, differentiation, and morphogenesis of the heart and blood vessels. In the adult cardiovascular system, these pathways continue to maintain tissue homeostasis and arrange adaptive responses to various physiological and pathological stimuli. Dysregulation of Wnt and Notch signaling has been involved in the pathogenesis of numerous cardiovascular diseases, including atherosclerosis, hypertension, myocardial infarction, and heart failure. Abnormal activation or suppression of these pathways in specific cell types can contribute to endothelial dysfunction, vascular remodeling, cardiomyocyte hypertrophy, impaired cardiac contractility and dead. Understanding the complex interplay between Wnt and Notch signaling in the cardiovascular system has led to the investigation of these pathways as potential therapeutic targets in clinical trials. In conclusion, this review summarizes the current knowledge on the roles of Wnt and Notch signaling in the development and homeostasis of cardiomyocytes, endothelial cells, and smooth muscle cells. It further discusses the dysregulation of these pathways in the context of major cardiovascular diseases and the ongoing clinical investigations targeting Wnt and Notch signaling for therapeutic intervention.

Microglia are the most important immune cells in the central nervous system (CNS), which can defend against external pathogens and stimuli. Dysregulation of microglia releases excessive proinflammatory cytokines and leads to neuroinflammation, which is fundamental to the pathophysiology of multiple neurological diseases. However, the molecular mechanisms underlying the regulation of proinflammatory cytokines in microglia are still not well-understood. Here, we identified that inhibitor of DNA binding protein 2 (Id2) was a negative regulator of tumor necrosis factor-α (TNFα) in cultured microglia. Knockdown of Id2 significantly increased the expression of TNFα in microglia, while overexpression of Id2 inhibited TNFα expression. Furthermore, by interacting with the p65 subunit of nuclear factor kappa-B (NF-κB), Id2 suppressed the transcription activation of NF-κB and inhibited TNFα expression. Interestingly, in lipopolysaccharides (LPS)-treated microglia, Id2 increased and underwent a cytoplasmic relocation. Immunoprecipitation and immunostaining results showed that by binding to the LIM domain of Id2, a scaffold protein PDZ and LIM 5 (PDLIM5) involved in the Id2 cytoplasmic relocation, which inactivated Id2 and resulted in higher TNFα expression in LPS-treated microglia. Collectively, our data delineate a novel effect of Id2 on TNFα regulation in microglia, which may shed a light on the proinflammatory cytokines regulating in microglia associated neuroimmune disorders.

Osteoclasts derived from hematopoietic stem cells express immunoreceptors on their cell surface. Previously, we showed that the β-glucan curdlan suppressed osteoclastogenesis via binding to dectin-1, a pattern recognition receptor. Curdlan negatively regulates osteoclast differentiation and bone resorption capacity by suppressing the expression of nuclear factor of activated T cells 1 (NFATc1), a master factor for osteoclast differentiation, in a dectin-1-dependent manner; however, the mechanism involved in this process has not yet been fully elucidated. In this study, we aimed to elucidate the molecular mechanism involved in the suppression of RANKL-induced osteoclast differentiation by curdlan. Real-time RT-qPCR results showed that curdlan suppressed the expression of NFATc1 in cells of the osteoclast progenitor cell line RAW264.7 overexpressing dectin-1 (d-RAW cells), without altering the expression of negative regulators. Therefore, we examined the effect of curdlan on the NF-κB pathway, which is important for the induction of NFATc1 expression. Western blot analysis results showed that curdlan addition suppressed RANKL-induced NF-κB activation in the vector control line (c-RAW) cells with low expression of dectin-1, in d-RAW cells, and the parental RAW264.7 (RAW) cells. The results of tartrate-resistant alkaline phosphatase staining and real-time RT-qPCR showed that curdlan addition suppressed osteoclast differentiation in RAW cells, suggesting the presence of a dectin-1-independent modification system. Finally, we focused on the complement receptor 3 (CR3), which binds β-glucan, and revealed that blocking the binding of β-glucan to the CD11b molecule, a component of CR3, by neutralizing antibody, recovered the suppression of IκBα degradation by curdlan. These results suggest that the suppression of osteoclast differentiation by curdlan involves not only the dectin-1-dependent pathway but also the negative regulation of NFATc1 via modification of the NF-κB pathway via CR3 recognition. The results of this study may aid to establish treatment methods for metabolic bone diseases and inflammatory bone destruction and to clarify their pathogenesis.

The main causes of failure for cartilage tissue engineering implants are tissue integration, inflammation, and infection. The development of biomaterials with antiforeign body response (FBR) is of particular importance. Herein, we developed a hydrogel loaded with anti-inflammatory drugs to reduce the inflammatory response that follows implantation. The human chondrocytes were used for in vitro study, and cell-laden hydrogel samples were implanted with the backs of rabbits for in vivo study. Soyasaponin Bb (SsBb) as a traditional Chinese medicine could significantly (P < 0.05) downregulate the expression levels of inflammation-related markers including iNOS, COX-2, and IL-6 in chondrocytes induced by IL-1β through the NF-κB signaling pathway. The in vitro experiments demonstrated that a gelatin-methacryloyl (GelMA) hydrogel loaded with SsBb (SsBb/GelMA) could similarly reduce the gene and protein expression levels of inflammation-related markers (iNOS, COX-2, and IL-6). The in vivo anti-inflammatory effects of the SsBb/GelMA hydrogels were assessed by immunohistochemical staining. The results demonstrated that SsBb/GelMA hydrogels inhibited the inflammatory response and downregulated the expression of the inflammatory cytokine IL-6. Therefore, SsBb/GelMA hydrogels are promising candidates for promoting anti-inflammation and cartilage tissue regeneration of implant surfaces.

Background/Objectives: In addition to oncological applications, poly(ADP-ribose) polymerase (PARP) inhibitors have potential as anti-inflammatory agents. Colon-targeted delivery of PARP inhibitors has been evaluated as a pharmaceutical strategy to enhance their safety and therapeutic efficacy against gut inflammation. Methods: Colon-targeted PARP inhibitors 5-aminoisoquinoline (5-AIQ) and 3-aminobenzamide (3-AB) were designed and synthesized by azo coupling with salicylic acid (SA), yielding 5-AIQ azo-linked with SA (AQSA) and 3-AB azo-linked with SA (ABSA). Additional conjugation of AQSA with acidic amino acids yielded glutamic acid-conjugated AQSA (AQSA-Glu) and aspartic acid-conjugated AQSA, which further increased the hydrophilicity of AQSA. Results: The distribution coefficients of PARP inhibitors were lowered by chemical modifications, which correlated well with drug permeability via the Caco-2 cell monolayer. All derivatives were effectively converted to their corresponding PARP inhibitors in the cecal contents. Compared with observations in the oral administration of PARP inhibitors, AQSA-Glu and ABSA resulted in the accumulation of much greater amounts of each PARP inhibitor in the cecum. ABSA accumulated mesalazine (5-ASA) in the cecum to a similar extent as sulfasalazine (SSZ), a colon-targeted 5-ASA prodrug. In the DNBS-induced rat colitis model, AQSA-Glu enhanced the anticolitic potency of 5-AIQ. Furthermore, ABSA was more effective against rat colitis than SSZ or AQSA-Glu, and the anticolitic effects of AQSA-Glu were augmented by combined treatment with a colon-targeted 5-ASA prodrug. In addition, the colon-targeted delivery of PARP inhibitors substantially reduced their systemic absorption. Conclusions: Colon-targeted PARP inhibitors may improve the therapeutic and toxicological properties of inhibitors and synergize the anticolitic effects of 5-ASA.

Phosphorylation of Ser32 and Ser36 controls the degradation of IκBα is the conserved cascade mechanisms of immune core signaling pathway, NF-κB pathway in metazoans, but it's response to abiotic stress and the presence of novel phosphorylation mechanisms in other species remain unclear. Herein, we reported a novel heat-induced phosphorylation site (Ser74) at oysters' major IκBα, which independently regulated ubiquitination-proteasome degradation without the requirement of phosphorylation at S32 and S36. And this site was phosphorylated by ERK/MAPK pathway, which then promoted REL nuclear translocation to activate cell survival related genes to defend heat-stress. The MAPK-NF-κB cascade exhibited divergent thermal responses and adaptation patterns between two congeneric oyster species with differential habitat temperatures, indicating its involvement in shaping temperature adaptation. This study demonstrated that the existence of complex and unique phosphorylation-mediated signaling transduction mechanism in marine invertebrates, and expanded our understanding of the evolution and function of established classical pathway crosstalk mechanisms.

Metabolic diseases that include obesity and metabolic-associated fatty liver disease (MAFLD) are a rapidly growing worldwide public health problem. The pathogenesis of MAFLD includes abnormally increased lipogenesis, chronic inflammation, and mitochondrial dysfunction. Mounting evidence suggests that hydrogen sulfide (H2S) is an important player in the liver, regulating lipid metabolism and mitochondrial function. However, direct delivery of H2S to mitochondria has not been investigated as a therapeutic strategy in obesity-related metabolic disorders. Therefore, our aim was to comprehensively evaluate the influence of prolonged treatment with a mitochondria sulfide delivery molecule (AP39) on the development of fatty liver and obesity in a high fat diet (HFD) fed mice. Our results demonstrated that AP39 reduced hepatic steatosis in HFD-fed mice, which was corresponded with decreased triglyceride content. Furthermore, treatment with AP39 downregulated pathways related to biosynthesis of unsaturated fatty acids, lipoprotein assembly and PPAR signaling. It also led to a decrease in hepatic de novo lipogenesis by downregulating mTOR/SREBP-1/SCD1 pathway. Moreover, AP39 administration alleviated obesity in HFD-fed mice, which was reflected by reduced weight of mice and adipose tissue, decreased leptin levels in the plasma and upregulated expression of adipose triglyceride lipase in epididymal white adipose tissue (eWAT). Finally, AP39 reduced inflammation in the liver and eWAT measured as the expression of proinflammatory markers (Il1b, Il6, Tnf, Mcp1), which was due to downregulated mTOR/NF-κB pathway. Taken together, mitochondria-targeted sulfide delivery molecules could potentially provide a novel therapeutic approach to the treatment/prevention of obesity-related metabolic disorders.

The Complement System is composed of more than 40 proteins that act in innate and adaptive immunity. C3 is the most abundant one and C3-deficient patients are more susceptible to recurrent and severe infections. Several studies have demonstrated the importance of C3 in controlling infections. However, its role in leukocyte biology is still poorly understood. This study aimed to evaluate several cellular parameters in macrophages from C3-deficient mice and compare them to similar cells from wild-type counterparts. We observed that in the absence of C3, the population of F4/80low macrophages in the peritoneal cavity of thioglycolate-treated mice is diminished, probably due to the lack of chemotactic factors like C3a and low levels of C5a. Using fluorescence microscopy analysis, we observed that macrophages from C3-deficient mice exhibited morphological alterations when compared to similar cells from wild-type mice. We observed a significant increase in the expression of CD11c, which is part of CR4 (CD11c/CD18), in macrophages from C3-deficient compared to cells from wild-type mice. Treatment with 12-o-tetradecanoylphorbol-13-acetate, stimulated ROS production and MAPK activation by macrophages. However, these parameters were lower in macrophages from C3-deficient mice when compared to wild-type counterparts. In addition, the phagocytosis of iC3b-opsonized Zymosan particles was diminished in macrophages from C3-deficient mice. Our results suggest that C3 deficiency in C57Black/6 mice may influence specific morphological and functional parameters of macrophages, cells of fundamental importance for both the innate and acquired immune responses.

Bile acid homeostasis is crucial for the normal physiological functioning of the liver. Disruptions in bile acid profiles are closely linked to the occurrence of cholestatic liver injury. As part of our diagnostic and therapeutic approach, we aimed to investigate the disturbance in bile acid profiles during cholestasis and its correlation with cholestatic liver injury. Before the occurrence of liver injury, alterations in bile acid profiles were detected in both plasma and liver between 8 and 16 h, persisting up to 96 h. TCA, TCDCA, and TUDCA in the plasma, as well as TCA, TUDCA, TCDCA, TDCA, TLCA, and THDCA in the liver, emerged as early sensitive and potential markers for diagnosing ANIT-induced cholestasis at 8-16 h. The distinguishing features of ANIT-induced liver injury were as follows: T-BAs exceeding G-BAs and serum biochemical indicators surpassing free bile acids. Notably, plasma T-BAs, particularly TCA, exhibited higher sensitivity to cholestatic hepatotoxicity compared with serum enzyme activity and liver histopathology. Further investigation revealed that TCA exacerbated ANIT-induced liver injury by elevating liver function enzyme activity, inflammation, and bile duct proliferation and promoting the migration of bile duct epithelial cell. Nevertheless, no morphological changes or alterations in transaminase activity indicative of liver damage were observed in the rats treated with TCA alone. Additionally, there were no changes in bile acid profiles or inflammatory responses under physiological conditions with maintained bile acid homeostasis. In summary, our findings suggest that taurine-conjugated bile acids in both plasma and liver, particularly TCA, can serve as early and sensitive markers for predicting intrahepatic cholestatic drugs and can act as potent exacerbators of cholestatic liver injury progression. However, exogenous TCA does not induce liver injury under physiological conditions where bile acid homeostasis is maintained.

Pancreatic ductal adenocarcinoma (PDAC) is a digestive system malignancy characterized by challenging early detection, limited treatment alternatives, and generally poor prognosis. Although there have been significant advancements in immunotherapy for hematological malignancies and various solid tumors in recent decades, with impressive outcomes in recent preclinical and clinical trials, the effectiveness of these therapies in treating PDAC continues to be modest. The unique immunological microenvironment of PDAC, especially the abnormal distribution, complex composition, and variable activation states of tumor-infiltrating immune cells, greatly restricts the effectiveness of immunotherapy. Undoubtedly, integrating data from both preclinical models and human studies helps accelerate the identification of reliable molecules and pathways responsive to targeted biological therapies and immunotherapies, thereby continuously optimizing therapeutic combinations. In this review, we delve deeply into how PDAC cells regulate the immune microenvironment through complex signaling networks, affecting the quantity and functional status of immune cells to promote immune escape and tumor progression. Furthermore, we explore the multi-modal immunotherapeutic strategies currently under development, emphasizing the transformation of the immunosuppressive environment into an anti-tumor milieu by targeting specific molecular and cellular pathways, providing insights for the development of novel treatment strategies.

Humans are exposed to different types of toxic agents, which may directly induce organ malfunction or indirectly alter gene expression, leading to carcinogenic and teratogenic effects, and eventually death. Ginseng (Panax ginseng) is the most valuable of all medicinal herbs. Nevertheless, specific data on the antidotal mechanisms of this golden herb are currently unavailable. Based on the findings of in vitro, in vivo, and clinical studies, this review focused on the probable protective mechanisms of ginseng and its major components, such as protopanaxadiols, protopanaxatriols, and pentacyclic ginsenosides against various chemical toxic agents. Relevant articles from 2000 to 2023 were gathered from PubMed/Medline, Scopus, and Google Scholar. This literature review shows that P. ginseng and its main components have protective and antidotal effects against the deteriorative effects of pesticides, pharmaceutical agents, including acetaminophen, doxorubicin, isoproterenol, cyclosporine A, tacrolimus, and gentamicin, ethanol, and some chemical agents. These improvements occur through multi-functional mechanisms. They exhibit antioxidant activity, induce anti-inflammatory action, and block intrinsic and extrinsic apoptotic pathways. However, relevant clinical trials are necessary to validate the mentioned effects and translate the knowledge from basic science to human benefit, fulfilling the fundamental goal of all toxicologists.

Dendritic cells (DCs) are uniquely capable of transporting tumor antigens to tumor-draining lymph nodes (tdLNs) and interact with effector T cells in the tumor microenvironment (TME) itself, mediating both natural antitumor immunity and the response to checkpoint blockade immunotherapy. Using LIPSTIC (Labeling Immune Partnerships by SorTagging Intercellular Contacts)-based single-cell transcriptomics, we identified individual DCs capable of presenting antigen to CD4+ T cells in both the tdLN and TME. Our findings revealed that DCs with similar hyperactivated transcriptional phenotypes interact with helper T cells both in tumors and in the tdLN and that checkpoint blockade drugs enhance these interactions. These findings show that a relatively small fraction of DCs is responsible for most of the antigen presentation in the tdLN and TME to both CD4+ and CD8+ tumor-specific T cells and that classical checkpoint blockade enhances CD40-driven DC activation at both sites.

There is ongoing exploration into herbal treatments to identify adjunct therapies with minimal side effects. One such treatment involves curcumin from turmeric (Curcuma longa). This study aims to review the efficacy of curcumin as an anti-inflammatory agent for periodontitis along with the mechanisms of action involved.

A systematic review of pre-clinical and clinical studies published on Scopus, PubMed, ScienceDirect, and Google Scholar up to May 2024 was employed following the PRISMA guidelines. Three tools were used for risk of bias assessment, namely the QUIN tool for in vitro studies, the SYRCLE's RoB for in vivo studies, and the Cochrane RoB 2 for RCTs. Finally, nineteen studies were included for review.

This study highlights curcumin's efficacy in addressing periodontitis through diverse mechanisms. Curcumin demonstrated efficacy in attenuating inflammation within periodontal tissue by inhibiting several pro-inflammatory cytokines and mediators such as interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, matrix metalloproteinases (MMPs), prostaglandin E2 (PGE2), cyclooxygenase (COX)-2, while concurrently increasing IL-4 and IL-10. In addition, several transcription factors such as nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 1 (STAT1) were also inhibited by curcumin. Administration of curcumin has additionally been demonstrated to reduce other biomarkers of periodontitis, including C-reactive protein (CRP), alkaline phosphatase (ALP), and procalcitonin (PCT).

Curcumin has been shown to be effective as an adjunct therapeutic agent for periodontitis due to its anti-inflammatory effects by reducing the inflammatory response through a diverse range of mechanisms of action.

Low-grade inflammation in people living with HIV (PWH) has become a significant contributor to the development of non-communicable diseases (NCDs) such as heart disease, stroke, and renal dysfunction. Though antiretroviral therapy (ART) has dramatically reduced mortality by limiting the emergence of opportunistic infections, it has not been successful in eliminating the remaining chronic, low-grade inflammation and activation that persists in the infected despite viral suppression and better CD4+ T cell count. Nonetheless, this relatively asymptomatic and subclinical chronic inflammation remains poorly understood and has become a major contributor to mortality in PWH. Another important component involved in this step is the Nuclear Factor kappa B (NF-κB) which is a central transcription factor in the immune system to respond to infection. Specifically, the p65/RELA subunit attaches to the HIV LTR (long terminal repeat) gene and consequently initiates the synthesis of genes related to inflammation and immune reactions. Persistent low-level chronic inflammation contributes to the pathophysiology of metabolic-inflammatory NCDs. Therefore, this review aims to assess the complex contextual function of NF-κB p65 during HIV-1 disease, particularly among individuals on ART who achieve viral suppression. As much as ART has helped to arrest the progression of the virus, immune function, and chronic inflammation have not been reversed in most PWH. It is, therefore, pertinent to know how the NF-κB p65 molecule remains involved in those with persistent immune inflammation concerns to enhance strategies on the same. This review will also discuss the possible variation in NF-κB p65 activity in particular population groups such as MSM (men who have sex with men) to acquire additional information that could potentially enhance the treatment.

The pyroptosis of cardiomyocytes has become an essential topic in heart failure research. The abnormal accumulation of these biological factors, including angiotensin II, advanced glycation end products, and various growth factors (such as connective tissue growth factor, vascular endothelial growth factor, transforming growth factor beta, among others), activates the nuclear factor-κB (NF-κB) signaling pathway in cardiovascular diseases, ultimately leading to pyroptosis of cardiomyocytes. Therefore, exploring the underlying molecular biological mechanisms is essential for developing novel drugs and therapeutic strategies. However, our current understanding of the precise regulatory mechanism of this complex signaling pathway in cardiomyocyte pyroptosis is still limited. Given this, this study reviews the milestone discoveries in the field of pyroptosis research since 1986, analyzes in detail the similarities, differences, and interactions between pyroptosis and other cell death modes (such as apoptosis, necroptosis, autophagy, and ferroptosis), and explores the deep connection between pyroptosis and heart failure. At the same time, it depicts in detail the complete pathway of the activation, transmission, and eventual cardiomyocyte pyroptosis of the NF-κB signaling pathway in the process of heart failure. In addition, the study also systematically summarizes various therapeutic approaches that can inhibit NF-κB to reduce cardiomyocyte pyroptosis, including drugs, natural compounds, small molecule inhibitors, gene editing, and other cutting-edge technologies, aiming to provide solid scientific support and new research perspectives for the prevention and treatment of heart failure.

While immune checkpoint blockade (ICB) has shown promise for clinical cancer therapy, its efficacy has only been observed in a limited subset of patients and the underlying mechanisms regulating innate and acquired resistance to ICB of tumor cells remain poorly understood. Here, we identified ependymin-related protein 1 (EPDR1) as an important tumor-intrinsic regulator of PD-L1 expression and tumor immune evasion. Aberrant expression of EPDR1 in hepatocellular carcinoma is associated with immunosuppression. Mechanistically, EPDR1 binds to E3 ligase TRIM21 and disrupts its interaction with IkappaB kinase-b, suppressing its ubiquitylation and autophagosomal degradation and enhancing NF-κB-mediated transcriptional activation of PD-L1. Further, we validated through a mouse liver cancer model that EPDR1 mediates exhaustion of CD8+ T cells and promotes tumor progression. In addition, we observed a positive correlation between EPDR1 and PD-L1 expression in both human and mouse liver cancer samples. Collectively, our study reveals a previously unappreciated role of EPDR1 in orchestrating tumor immune evasion and cancer progression.

Protein aggregation is a common pathological occurrence in neurodegenerative diseases. This often leads to neuroinflammation, which exacerbates the aggregation and progression of diseases like Parkinson's and Alzheimer's. Here, we focus on immune responses and neurotoxicity in a Parkinson's disease model in Drosophila. Mutations in the SNCA gene that encodes the alpha (α)-Synuclein protein have been linked to familial Parkinson's disease, disrupting autophagy regulation in neuronal cells and promoting the formation of Lewy bodies, a hallmark of Parkinson's pathology. This results in the loss of dopaminergic neurons, manifesting as movement disorders. α-Synuclein aggregation triggers innate immune responses by activating microglial cells, leading to phagocytic activity and the expression of neuroprotective antimicrobial peptides (AMPs). However, sustained AMP expression or chronic inflammation resulting from inadequate microglial phagocytosis can induce neuronal toxicity and apoptosis, leading to severe dopaminergic neuron loss. This review underscores the mechanistic connection between immune response pathways and α-Synuclein-mediated neurodegeneration using Drosophila models. Furthermore, we extensively explore factors influencing neuroinflammation and key immune signaling pathways implicated in neurodegenerative diseases, particularly Parkinson's disease. Given the limited success of traditional treatments, recent research has focused on therapies targeting inflammatory signaling pathways. Some of these approaches have shown promising results in animal models and clinical trials. We provide an overview of current therapeutic strategies showing potential in treating neurodegenerative diseases, offering new avenues for future research and treatment development.

Macrophages represent primary players of the innate immune system. Macrophage activation triggers several signaling pathways and is tightly associated with metabolic changes, which drive different immune subsets. Recent studies unveil the role of various metabolic enzymes in macrophage activation. Here, we show that malic enzyme 1 (ME1) is overexpressed in LPS-induced macrophages. Through chromatin immunoprecipitation, we demonstrate that ME1 transcriptional regulation is under control of NF-κB. Furthermore, ME1 activity is also increased in activated human PBMC-derived macrophages. Notably, ME1 gene silencing decreases nitric oxide as well as reactive oxygen species and prostaglandin E2 inflammatory mediators. Therefore, modulating ME1 provides a potential approach for immunometabolic regulation and in turn macrophage function.

Lead (Pb) is a major environmental pollutant that can cause nephrotoxicity, hepatotoxicity, encephalopathy, and even death. Smilax glabra Roxb. has been used to treat heavy metal poisoning in China for over 500 years. We hypothesized that the Smilax glabra flavonoid extract (SGF) can ameliorate lead poisoning and investigated the possible mechanisms using network pharmacology. In total, 13 active compounds of Smilax glabra Roxb. and 71 overlapping potential targets were identified. The drug-compound-target-disease network analysis revealed that oxidative stress, inflammation, and apoptosis were mainly involved in the treatment of lead poisoning. Gene Ontology (GO) enrichment analysis showed that the biological processes involved in the therapeutic effect of Smilax glabra Roxb. against lead poisoning included biological processes, cellular components, and molecular functions. Additionally, 112 Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathways were obtained with the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways showing strong associations with lead poisoning by KEGG enrichment. The results of target pathway analysis showed that NF-κB was the most relevant gene involved in the therapeutic effect of Smilax glabra Roxb. against lead poisoning and was closely related to the MAPK signaling pathway. In vivo experiments confirmed that SGF treatment alleviated the pathological damage caused by lead-induced nephrotoxicity in weaning rats. Furthermore, SGF treatment markedly inhibited the expression of key proteins involved in the NF-κB/MAPK signaling pathway, highlighting the strong therapeutic effect of SGF against lead-induced nephrotoxicity. Results from network pharmacology and experimental verification indicated that SGF mitigated Pb-induced nephrotoxicity by downregulating the NF-κB/MAPK signaling pathway.

A sedentary lifestyle and physical inactivity leads to metabolic syndrome-associated comorbidities involving abdominal obesity, type 2 diabetes, hyperlipidaemia associated Cardiovascular Diseases (CVDs), and Metabolic dysfunction-associated fatty liver disease (MAFLD). In this study, we evaluated the novel hepato/cardio/adipo-protective role of Quercetin via Vitamin D Receptor, and elucidated its underlying mechanisms in reducing lipotoxicity, inflammation and fibrosis in high calorie diet induced metabolic syndrome. Male Swiss albino mice were fed with western diet and sugar water for multiple time intervals. Anti-lipotoxicity, anti-inflammatory, and anti-fibrotic effect of Quercetin was assessed by Oil Red O, H&E and TMS staining at different time points. The lipid profile, mRNA expression of inflammatory markers (TNF- α, IL-1β, IL-6 and MCP-1), fibrotic markers (α-SMA, COL1A1, COL1A2), adiponectin, AdipoR2, and VDR expression levels were measured from RNA pools of adipose, liver and heart tissues. Also, lipid-lowering and anti-steatohepatitic effects of Quercetin was assessed using mouse 3T3-L1 adipocytes, rat H9c2 cardiac cells, and human HepG2 hepatocytes. Our results indicate that, western diet fed mice with Quercetin ameliorated lipid profile and lipotoxicity. Histopathological examination and gene expression data revealed that Quercetin reduced hepatic and cardiac inflammation and fibrosis-associated markers. Interestingly, Quercetin treatment increased the serum levels of adiponectin and mRNA expressions of AdipoR2 and VDR. In-vitro experiments revealed the reduction in lipid accumulation of 3T3-L1 and fatty-acid-treated hepatic and cardiac cells following Quercetin treatment. These findings indicate that Quercetin exhibits a protective role on multiple organs through VDR activation and subsequent Adipo/AdipoR2 signaling in metabolic syndrome associated obesity, hepatic injury, and cardiac dysfunction.

In recent times, space flights receive continued interest. Humankind's next two goals are to return to the Moon and, a few years later, to land on the surface of Mars. Although technology will improve enough to enable long voyages, there are still some unresolved questions about the effects of the space environment on human health, including the effects of such long voyages on organs. Specifically, there is no information on the effects of radiation in space on the human cardiovascular system. To better understand the adaptation of the cardiovascular system to radiation exposure, the physical properties of radiation and the cellular and molecular mechanisms underlying tissue changes are essential. To this end, this article aims to provide an overview of the effects of radiation on the cardiovascular system by analyzing the physical properties of radiation and their relationship to cellular and molecular mechanisms and potential changes. Each type of radiation triggers different responses in the cardiovascular system. Radiation plays a relevant role in altering endothelial function and arterial wall stiffness by inducing vascular changes that accelerate atherosclerosis and affect endothelial adhesiveness. Clinical studies have shown that vascular changes due to radiation depend on the delayed manifestations of early radiation damage. To reduce the effects of radiation in space, some pharmacological treatments that seem to be able to counteract oxidative stress during flight are being used. At the same time, new shielding systems that can reduce or eliminate radiation exposure must be developed. Future studies should aim to replicate flights in the deep space environment to study in more detail the harmful effects of radiation on the whole cardiovascular system.

Phillygenin (PHI) is an active ingredient derived from the leaf of Forsythia suspensa that has been found to alleviate inflammation and peroxidation response. Avian infectious bronchitis (IB) is a major threat to poultry industry viral respiratory tract disease that infected with infectious bronchitis virus (IBV). This study investigated the protection of PHI to CEK cell and broiler's tracheal injury triggered by avian infectious bronchitis virus (IBV). The results showed that IBV infection did not cause serious clinical symptoms and slowing-body weight in PHI-treated broilers. The expression of virus loads, pro-inflammation factors (IL-6, TNF-α, and IL-1β) in CEK cell, and tracheas were decreased compared to the IBV group, exhibiting its potent anti-inflammation. Mechanistically, the study demonstrated that the inhibition of TLR7/MyD88/NF-κB pathway was mainly involved in the protection effect of PHI to inflammation injury. Interestingly, a higher abundance of Firmicutes and Lactobacillus in respiratory tract was observed in PHI-treated broilers than in the IBV group. Significant differences were observed between the IBV group and PHI-treated group in the Ferroptosis, Tryptophan metabolism, and Glutathione metabolism pathways. PHI exhibited potent protection effect on IBV infection and alleviated inflammation injury, mainly through inhibiting TLR7/MyD88/NF-κB pathway. The study encourages further development of PHI, paving the way to its clinical use as a new candidate drug to relieve IBV-induced respiratory symptoms.