Adipose tissue fibrosis, characterized by abnormal extracellular matrix deposition within adipose tissue, signifies a crucial indicator of adipose tissue malfunction, potentially leading to organ tissue dysfunction. Various factors, including a high-fat diet, non-alcoholic fatty liver disease, and insulin resistance, coincide with adipose tissue fibrosis. MicroRNAs (miRNAs) represent a class of small non-coding RNAs with significant influence on tissue fibrosis through diverse signaling pathways. For instance, in response to a high-fat diet, miRNAs can modulate signaling pathways such as TGF-β/Smad, PI3K/AKT, and PPAR-γ to impact adipose tissue fibrosis. Furthermore, miRNAs play roles in inhibiting fibrosis in different contexts: suppressing corneal fibrosis via the TGF-β/Smad pathway, mitigating cardiac fibrosis through the VEGF signaling pathway, reducing wound fibrosis via regulation of the MAPK signaling pathway, and diminishing fibrosis post-fat transplantation via involvement in the PDGFR-β signaling pathway. Notably, the secretome released by miRNA-transfected adipose-derived stem cells facilitates targeted delivery of miRNAs to evade host immune rejection, enhancing their anti-fibrotic efficacy. Hence, this study endeavors to elucidate the role and mechanism of miRNAs in adipose tissue fibrosis and explore the mechanisms and advantages of the secretome released by miRNA-transfected adipose-derived stem cells in combating fibrotic diseases.

This study investigated the role of RAP1B in hepatic lipid metabolism and its implications in obesity and associated metabolic disorders, focusing on the molecular mechanisms through which RAP1B influences lipid accumulation, inflammation and oxidative stress in liver tissues and hepatocyte cell lines.

Liver-specific RAP1B-knockout (LKO) and overexpression (OE) mice were generated and fed a high-fat diet for 18 weeks to evaluate systemic and hepatic metabolic changes. Comprehensive metabolic phenotyping included measurements of body weight, body fat content, activity levels, energy expenditure (EE), respiratory exchange ratio (RER), glucose tolerance test and insulin tolerance test. RAP1B-knockdown AML12 hepatocytes were used for in vitro studies. Comprehensive transcriptome and metabolome analyses identified differentially expressed genes and key metabolic shifts. Biochemical and histological analyses were performed to assess lipid accumulation, oxidative stress and inflammatory markers.

We found that LKO mice exhibited significant reductions in body weight, fat pad size and liver mass, along with decreased hepatic lipid accumulation due to enhanced lipid breakdown. These mice demonstrated improved glucose tolerance and insulin sensitivity without changes in food intake. Liver histology showed reduced F4/80-positive macrophage infiltration, indicating decreased inflammatory cell recruitment. Additionally, markers of oxidative stress were significantly lower, and molecular analysis revealed downregulation of the MAPK(p38) and NF-κB signaling pathways, further supporting an anti-inflammatory hepatic environment. In contrast, OE mice showed increased liver weight, aggravated hepatic lipid accumulation driven by enhanced lipogenesis, worsened insulin resistance and elevated inflammation.

This study highlights RAP1B's pivotal role in hepatic metabolism and positions it as a potential therapeutic target for obesity and related metabolic disorders.

Schisandra chinensis is used as a traditional Chinese medicine to treat a variety of diseases. Schisandra chinensis lignans (SCL) are one of the most active components extracted from Schisandrae chinensis fructus, exhibit a broad array of pharmacological properties, especially anti-inflammatory and hepatic lipid-lowering effects, suggesting SCL may have potential anti-nonalcoholic steatohepatitis (NASH) ability. However, the therapeutic efficacy of SCL against NASH and the underlying mechanism of this action remains unclear.

In the current study, we aimed to investigate the anti-NASH action of SCL and explore the underlying mechanism in vitro and in vivo. We also assess the involvement of the gut-liver axis in the anti-NASH effects of SCL.

Palmitic acid (PA)-treated HepG2 cells, mouse primary hepatocytes (MPHs) and methionine-choline deficient (MCD) diet-fed mice were selected as NASH models. ORO staining and qRT-PCR were performed to assess hepatic steatosis and inflammatory responses, respectively. Masson's trichrome staining was used to detect the liver fibrosis. Protein expression was detected by Western blotting or immunohistochemistry. The changes of gut microbiota were analyzed using 16S rDNA sequencing in mice. The levels of metabolites in liver and feces were measured by metabolomics.

The results showed that SCL treatment alleviated steatosis and inflammation in palmitic acid (PA)-treated HepG2 cells and mouse primary hepatocytes (MPHs). SCL treatment suppressed the phosphorylation of key components involved in NF-κB signaling and enhanced the expression of fatty acid oxidation (FAO)-related enzymes (e.g. CPT1, HMGCS2, and ACOX1) in PA-treated HepG2 cells. SCL could ameliorate hepatic steatosis and inflammation in NASH mice. SCL also ameliorated intestinal barrier injury and restructured the gut microbiota in NASH mice. SCL also modulated hepatic and colonic bile acid metabolism via FXR signaling.

These findings indicate that SCL treatment ameliorates hepatic inflammation and steatosis in NASH mice, potentially though to the suppression of NF-κB signaling and the promotion of fatty acid β-oxidation. Moreover, SCL could restore gut microbiota-mediated bile acid homeostasis via activation of FXR/FGF15 signaling. Our study presents a pharmacological rationale for using SCL in the management of NASH.

Type 2 diabetes mellitus (T2DM) represents a significant risk factor for cardiovascular disease, particularly heart failure with preserved ejection fraction (HFpEF). HFpEF predominantly affects elderly individuals and women, and is characterized by dysfunctions associated with metabolic, inflammatory, and oxidative stress pathways. Despite HFpEF being the most prevalent heart failure phenotype in patients with T2DM, its underlying pathophysiological mechanisms remain inadequately elucidated.

This study aims to investigate the effects of diabetes mellitus on myocardial inflammation, oxidative stress, and protein quality control (PQC) mechanisms in HFpEF, with particular emphasis on insulin signaling, autophagy, and chaperone-mediated stress responses.

We conducted an analysis of left ventricular myocardial tissue from HFpEF patients, both with and without diabetes, employing a range of molecular, biochemical, and functional assays. The passive stiffness of cardiomyocytes (Fpassive) was assessed in demembranated cardiomyocytes before and after implementing treatments aimed at reducing inflammation (IL-6 inhibition), oxidative stress (Mito-TEMPO), and enhancing PQC (HSP27, HSP70). Inflammatory markers (NF-κB, IL-6, TNF-α, ICAM-1, VCAM-1, NLRP3), oxidative stress markers (ROS, GSH/GSSG ratio, lipid peroxidation), and components of signaling pathways (PI3K/AKT/mTOR, AMPK, MAPK, and PKG) were evaluated using western blotting, immunofluorescence, and ELISA techniques.

Hearts from diabetic HFpEF patients exhibited significantly heightened inflammation, characterized by the upregulation of NF-κB, IL-6, and the NLRP3 inflammasome. This increase in inflammation was accompanied by elevated oxidative stress, diminished nitric oxide (NO) bioavailability, and impaired activation of the NO-sGC-cGMP-PKG signaling pathway. Notably, dysregulation of insulin signaling was observed, as indicated by decreased AKT phosphorylation and impaired autophagy regulation mediated by AMPK and mTOR. Additionally, PQC dysfunction was evidenced by reduced expression levels of HSP27 and HSP70, which correlated with increased cardiomyocyte passive stiffness. Targeted therapeutic interventions effectively reduced Fpassive, with IL-6 inhibition, Mito-TEMPO, and HSP administration leading to improvements in cardiomyocyte mechanical properties.

The findings of this study elucidate a mechanistic relationship among diabetes, inflammation, oxidative stress, and PQC impairment in the context of HFpEF. Therapeutic strategies that target these dysregulated pathways, including IL-6 inhibition, mitochondrial antioxidants, and chaperone-mediated protection, may enhance myocardial function in HFpEF patients with T2DM. Addressing these molecular dysfunctions could facilitate the development of novel interventions specifically tailored to the diabetic HFpEF population.

Radiation-induced bystander effects (RIBE) increase the complexity of radiation therapy (RT). m6A modification is implicated in ionizing radiation damage. This study aims to investigate the RIBE and the mechanism after promoting m6A modification.

Lung adenocarcinoma cells were treated to simulate a hypoxic and 0.5 Gy RT environment. The expression levels of METTL3, METTL14, and YTDHF2 were quantified by RT-qPCR. Paracellular clonogenicity and the expression of 53BP1 and γ-H2AX were assessed by immunofluorescence. The proliferative rate was evaluated by CCK-8. Probes were employed to measure ROS levels. Micronucleus formation was evaluated microscopically. m6A-mRNA/lncRNA microarrays, MERIP-PCR, RT-qPCR, and ELISA were utilized to assess m6A modification levels and the expression of inflammatory factors.

m6A modification levels were significantly diminished under hypoxic, low-dose irradiation conditions. The overexpression of METTL3 in irradiated cancer cells resulted in increased clonogenicity and proliferation of paracellular cells, suppressed the rate of micronucleus formation, and reduced DNA damage by modulating the inflammatory response. m6A-mRNA/lncRNA microarray analyses revealed a higher correlation of inflammatory molecules NF-κB and TRAF6. Further analysis demonstrated that the m6A modification levels of inflammation-related factors such as IL-6, TLR4, NF-κB2, and TRAF6 were significantly up-regulated, while their mRNA expression levels were notably decreased. Additionally, the expression of IL-10 and TGF-β was significantly reduced, with no significant changes observed in IL-1 expression.

The overexpression of METTL3 facilitated m6A modification and mitigated the inflammatory response, thereby promoting paracellular cloning and proliferation, inhibiting micronucleus formation, alleviating DNA damage, and achieving the objective of suppression of RIBE.

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.

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.

Inflammation and breast cancer are closely associated. Considering that mast cells are essential component of inflammatory cells, its relationship with breast cancer arose rising attention.

This study aims to elucidate the influence of mast cells on triple negative breast cancer (TNBC) and explore potential therapeutic interventions targeting mast cells.

The study employed proteomic analysis and molecular investigations to examine disparities between mast cells from healthy mice and those from breast tumor-bearing mice. Additionally, the natural product Ericalyxin B (Eri B) was utilized for its anti-inflammatory and anti-breast cancer properties. Ex vivo and in vivo treatments of Eri B were conducted to assess its impact on mast cell-mediated promotion of breast cancer.

The crosstalk between mast cells and TNBC cells was found to enhance proliferation, invasion, and migration of TNBC cells. Mast cells from breast tumor-bearing mice exhibited disparities compared to those from healthy mice, as confirmed by proteomic analysis. Treatment with Eri B suppressed the promoting effect of mast cells on breast cancer by inhibiting the TAK1/NF-κB signaling pathway and downregulating downstream cytokine release. In vivo treatment with Eri B also reduced mast cell numbers and tryptase levels in tumors.

This is the first study to compare disparities between mast cells derived from healthy mice and those from breast tumor-bearing mice, while also revealing the effects of the natural product Eri B on mast cells in breast cancer. Our findings highlighted the crucial role of mast cells as potential targets for triple negative breast cancer therapy and suggests that Eri B holds promise in suppressing breast cancer progression by regulating mast cells.

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.

There is increasing apprehension regarding the rising prevalence of microplastics (MPs) in aquatic ecosystems. Although MPs cause toxicological effect on fish via diverse pathways, the precise immunotoxicological mechanism is yet to be fully understood. Utilizing zebrafish in early developmental stages and zebrafish embryonic fibroblast (ZF4) as models, this study delved into the immune response elicited by polystyrene MPs (PS-MPs). It was observed that larvae predominantly accumulate 3 μm PS-MPs in their intestines through ingestion, leading to notable changes in locomotor behavior and histopathological alterations. Further investigation revealed that short-term exposure to PS-MPs triggers oxidative stress (OS) and inflammation in zebrafish. This is evidenced by the upregulation of OS and inflammation-related genes, increased levels of reactive oxygen species (ROS), malonaldehyde (MDA), and inflammatory cytokines, altered activities of antioxidant enzymes, along with induced recruitment of leukocyte in larvae. Cellular assays confirmed that PS-MPs elevate intracellular ROS in ZF4 cells and enhance the nuclear translocation of NF-κB P65. Notably, the activation of NF-κB and the upsurge in inflammatory cytokines can be mitigated by inhibiting ROS. This research highlights the significance of the ROS-triggered NF-κB signaling cascade in PS-MPs-mediated inflammation within zebrafish, illuminating the possible processes that underlie the innate immune system of fish toxicity caused by MPs.

Ischemia and reperfusion does damage to tissues and causes the decline of organ function though the inflammatory cascade. Noteworthy, HMGB1 possess a crucial role in promoting progression of these effects in kidney. The study aimed at ascertaining the concrete mechanism of HMGB1 triggering inflammatory cascade in renal ischemia-reperfusion injury (IRI).

IRI was induced in mice by clamping left renal arteries for 60 minutes followed by 24 hours of reperfusion with the removal of right kidney. The effects of HMGB1on IRI were evaluated by targeting creatinine, blood urea nitrogen, survival rates, renal morphology, and the translocation and secretion of HMGB1. In addition, the expression of Toll-like receptor 4, phosphorylated nuclear factor κB p65, nuclear factor κB p65, and inflammatory cascade molecules (interleukin [IL]-1β, and IL-6, and tumor necrosis factor-α) were carried out.

Our results demonstrated that antibody against HMGB1 (anti-HMGB1) can improve the survival rate; decrease the expression of creatinine, blood urea nitrogen, Toll-like receptor 4, phosphorylated nuclear factor κB p65, IL-1β, IL-6, and tumor necrosis factor-α; reduce renal pathological injury; alleviate the secretion of HMGB1; and suppress the translocation of HMGB1 from nucleus into cytoplasm in IRI. Notably, recombinant HMGB1, the agonist of HMGB1, can alleviate the noted effects of anti-HMGB1 in IRI.

HMGB1 can aggravate renal IRI by triggering the inflammatory cascade, the mechanism of which is associated with activating the Toll-like receptor 4-nuclear factor κB p65 signal pathway.

Nuclear factor-kappa B (NF-kB) plays a crucial role in numerous cellular processes, such as inflammation, immunological responses to infection, cell division, apoptosis, and the development of embryos and neurons. Cytokines, plays an important role in positive feedback loop and leads to inflammatory cell death through the release of pathogenic cytokine known to be cytokine storm which causes diseases like Acute Respiratory Disorder (ARD), multi-organ disorder, Hyperinflammation syndrome and may cause death. This cytochrome storm was identified in the people severely affected by covid-19. NF-kB presents a promising therapeutic opportunity to mitigate covid-19-induced cytokine storm and reduce the risk of severe morbidity and mortality resulting from the diseases. This paper therefore explores the modulation of the NF-kB pathway by inhibiting the binding of the transcription factor as a potential strategy to mitigate the morbidity and mortality caused by cytokine storms. To identify small molecule inhibitors of NF-kB signaling, we screened approximately 101 molecules in two identified pockets of NF-kB (p50/p65)-DNA complex. Each molecule was virtually screened in two pockets (A1 and A2). The focus library was developed starting from chemical structures obtained from the literature (Angelicin and Psolaren) which shows the inhibition of NF-kB signaling, as well as using artificial intelligence (WADDAICA) and rationally designed molecules. Among the 3 highest-scored ligands (NFAI64, NF30 and NF49) selected from the docking studies and further molecular dynamic investigations. The identified compound NF30 showed significantly higher binding affinity (ΔGbinding) in A2 pocket (60.92 ± 1.83 kJ/mol) as compared to the rest of the molecules, making it a promising molecule for the inhibition of NF-kB. The discovered novel compounds by computational studies could be of relevance to identify more potent inhibitors of NF-kB dependent biological functions beneficial to control the cytokine storm occurring in the patients affected with Covid-19.

Endogenous retroviruses (ERVs) shape human genome functionality and influence disease pathogenesis, including cancer. ERVK-7, a significant ERV, acts as an immune modulator and prognostic marker in lung adenocarcinoma (LUAD). Although ERVK-7 overexpression has been linked to the amplification of the 1q22 locus in approximately 10% of LUAD cases, it predominantly arises from alternative regulatory mechanisms. Our findings indicate that the canonical 5' long terminal repeat (LTR) of ERVK-7 is methylated and inactive, necessitating the use of alternative upstream promoters. We identified two novel transcripts, ERVK-7.long and ERVK-7.short, arising from distinct promoters located 2.8 kb and 13.8 kb upstream of the 5'LTR of ERVK-7, respectively. ERVK-7.long is predominantly overexpressed in LUAD. Through comprehensive epigenetic mapping and single-cell transcriptomics, we demonstrate that ERVK-7.long activation is predetermined by cell lineage, specifically in small airway epithelial cells (SAECs), where its promoter displays tumor-specific H3K4me3 modifications. Single-cell RNA sequencing further reveals a distinct enrichment of ERVK-7.long in LUAD tumor cells and alveolar type 2 epithelial cells, underscoring a cell-type-specific origin. Additionally, inflammatory signaling significantly influences ERVK-7 expression; TNF-α enhances ERVK-7.long, while interferon signaling preferentially augments ERVK-7.short by differential recruitment of NF-κB/RELA and IRF to their respective promoters. This differential regulation clarifies the elevated ERVK-7 expression in LUAD compared to lung squamous cell carcinoma (LUSC). Our study elucidates the complex regulatory mechanisms governing ERVK-7 in LUAD and proposes these transcripts as potential biomarkers and therapeutic targets, offering new avenues to improve patient outcomes.

Multiple sclerosis is a chronic autoimmune demyelinating disorder predominantly affecting the white matter of the central nervous system, with experimental autoimmune encephalomyelitis (EAE) serving as its classical animal model. Irisin, a glycosylated protein derived from the proteolytic cleavage of fibronectin type III domain-containing protein 5, plays a significant role in metabolic regulation and inflammatory modulation within the organism.

In this study, we systematically investigated the therapeutic effects and underlying mechanism of Irisin on EAE and BV2 microglial cells through comprehensive methodologies including quantitative real-time polymerase chain reaction, immunofluorescence staining and western blot.

Irisin exerts neuroprotective effects in EAE mice, significantly ameliorating both clinical and pathological manifestations of the disease. Mechanistically, Irisin attenuated inflammatory response and reduced the number of microglia through NF-κBp65 signaling pathway.

In conclusion, these results collectively suggest that Irisin alleviates EAE progression by suppressing microglia activation via the NF-κBp65 pathway, highlighting its potential as a promising therapeutic target for multiple sclerosis treatment.

The advent of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, offering life-saving benefits to tumor patients. However, the utilize of ICI agents is often accompanied by immune-related adverse events (irAEs), among which cardiovascular toxicities have attracted more and more attention. ICI induced cardiovascular toxicities predominantly present as acute myocarditis and chronic atherosclerosis, both of which are driven by excessive immune activation. Reprogramming of T cells and macrophages has been demonstrated as a pivotal factor in the pathogenesis of these complications. Therapeutic strategies targeting glycolysis, fatty acid oxidation, reactive oxygen species (ROS) production and some other key signaling have shown promise in mitigating immune hyperactivation and inflammation. In this review, we explored the intricate mechanisms underlying ICI-induced cardiovascular toxicities and highlighted the protective potential of immune reprogramming. We emphasize the roles of T cell and macrophage reprogramming in the heart and vasculature, showcasing their contributions to both short-term and long-term regulation of cardiovascular health. Ultimately, a deeper understanding of these processes will not only enhance the safety of ICIs but also pave the way for innovative strategies to manage immune-related toxicities in cancers therapy.

Acute myeloid leukemia (AML) is a lethal hematologic malignancy caused by leukemic blasts that fail to mature normally. AML has a high relapse rate, primarily due to a small subset known as leukemic stem cells (LSCs). In this work, we investigated the ability of a Ru(II)-thymine complex (RTC) with the formula [Ru(PPh3)2(Thy)(bipy)]PF6 (where PPh3 = triphenylphosphine, Thy = thymine, and bipy = 2,2'-bipyridine) to suppress AML LSCs. RTC exhibited potent cytotoxicity toward both solid and hematologic malignancies and suppressed primary AML LSCs, as observed by the reduction in the CD34 +CD38- cell population. In the AML cell line KG-1a, which has an LSC-like population, RTC reduced the number of CD34 + and CD123 + cells. A reduction in leukemic blasts was detected in the bone marrow of RTC-treated NSG mice bearing KG-1a xenografts. Increased DNA fragmentation, YO-PRO-1 staining, active caspase-3 and cleaved PARP (Asp 214) levels, and mitochondrial superoxide levels were detected in RTC-treated KG-1a cells. The pancaspase inhibitor Z-VAD-(OMe)-FMK, but not the antioxidant N-acetylcysteine, partially prevented RTC-induced cell death in KG-1a cells, indicating that RTC induces caspase-mediated apoptosis in KG-1a cells via an oxidative stress-independent pathway. In molecular mechanism studies, transcripts of the NF-κB inhibitor NFKBIA were upregulated, and the level of NF-κB p65 phosphorylated at the Ser529 residue was reduced in RTC-treated KG-1a cells, indicating that RTC may inhibit NF-κB signaling. Overall, these results indicate the anti-AML potential of RTC in AML LSCs via the suppression of NF-κB signaling.

Macrophages are pivotal in osteoarthritis (OA) pathogenesis, as their dysregulated polarization can contribute to chronic inflammatory processes. This review explores the molecular and metabolic mechanisms that influence macrophage polarization and identifies potential strategies for OA treatment. Currently, non-surgical treatments for OA focus only on symptom management, and their efficacy is limited; thus, mesenchymal stem/stromal cells (MSCs) have gained attention for their anti-inflammatory and immunomodulatory capabilities. Emerging evidence suggests that small extracellular vesicles (sEVs) derived from MSCs can modulate macrophage function, thus offering potential therapeutic benefits in OA. Additionally, the transfer of mitochondria from MSCs to macrophages has shown promise in enhancing mitochondrial functionality and steering macrophages toward an anti-inflammatory M2-like phenotype. While further research is needed to confirm these findings, MSC-based strategies, including the use of sEVs and mitochondrial transfer, hold great promise for the treatment of OA and other chronic inflammatory diseases.

Shenfu injection (SFI) is a traditional Chinese medicine (TCM) for treating sepsis. The purpose of this study was to evaluate the protective effect of SFI on lipopolysaccharide (LPS)-induced liver injury in septic mice. The results showed that SFI intervention reduced liver/body weight and significantly improved the survival rate of septic mice. SFI could relieve the apoptosis of liver cells and ameliorate liver function in LPS-induced septic mice. SFI also diminished the serum and liver levels of the inflammatory factors IL-1β, IL-6, IL-18, IL-12, and TNF-α in a dose-dependent manner. SFI enhanced the mitochondrial membrane potential and alleviated the mitochondrial damage of liver in septic mice. Western blot revealed that the phosphorylation levels of IκB and NF-κB p65 increased significantly in the liver of LPS-induced septic mice. After SFI intervention, the phosphorylation levels of IκB and NF-κB p65 gradually recovered, especially at high concentration. SFI treatment reduced nuclear transduction, thus reducing transcriptional activity, which indicated that NF-κB p65 signal pathway might contribute to the anti-inflammatory and anti-apoptotic activities of SFI in the liver of LPS-induced septic mice. In addition, the metabolic profile of liver tissue in the model group was different from that in the control group, and SFI significantly regulated liver purine metabolism. These valuable findings suggested that SFI could improve mitochondrial function and mitigate inflammation and apoptosis, and thus alleviate LPS-induced liver injury in septic mice. SFI may be a promising drug to treat septic liver injury.

Angiogenesis, a crucial process in tumor growth and metastasis, necessitates targeted therapeutic intervention. This review reviews the latest knowledge of anti-angiogenesis targets in tumors, with emphasis on the molecular mechanisms and signaling pathways that regulate this process. We emphasize the tumor microenvironment's role in angiogenesis, examine endothelial cell metabolic changes, and evaluated potential therapeutic strategies targeting the tumor vascular system. At the same time, we analyzed the signaling pathway and molecular mechanism of tumor angiogenesis in detail. In addition, this paper also looks at the development trend of tumor anti-angiogenesis drugs, including their future development direction and challenges, aiming to provide prospective insight into the development of this field. Despite their potential, anti-angiogenic therapies encounter challenges like drug resistance and side effects, necessitating ongoing research to enhance cancer treatment strategies and the efficacy of these therapies.

The current definition of a postbiotic is a "preparation of inanimate microorganisms and/or their components that confers a health benefit on the host". Postbiotics can be mainly classified as metabolites, derived from intestinal bacterial fermentation, or structural components, as intrinsic constituents of the microbial cell. Secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA) are bacterial metabolites generated by the enzymatic modifications of primary bile acids by microbial enzymes. Secondary bile acids function as receptor ligands modulating the activity of a family of bile-acid-regulated receptors (BARRs), including GPBAR1, Vitamin D (VDR) receptor and RORγT expressed by various cell types within the entire human body. Secondary bile acids integrate the definition of postbiotics, exerting potential beneficial effects on human health given their ability to regulate multiple biological processes such as glucose metabolism, energy expenditure and inflammation/immunity. Although there is evidence that bile acids might be harmful to the intestine, most of this evidence does not account for intestinal dysbiosis. This review examines this novel conceptual framework of secondary bile acids as postbiotics and how these mediators participate in maintaining host health.

Tire wear particles (TWPs), as a pervasive environmental pollutant, pose significant risks to aquatic ecosystems. This study investigates the effects of small (HS) and large (HL) TWPs produced by heavy vehicles on zebrafish, focusing on physiological, microbial, and transcriptomic levels, as well as their intergenerational consequences, under short-term (15 days) and long-term (90 days) exposure. Short-term exposure to small particles (HS15) significantly reduced body width and triggered widespread oxidative stress, while long-term exposure to large particles (HL90) increased gut weight and decreased gill weight, reflecting respiratory and digestive disruptions. Tissue-level analyses revealed that smaller particles accumulated more readily in internal organs, whereas larger particles caused localized physiological stress. Gut microbiota profiling indicated a marked decline in microbial diversity, compositional shifts, and network simplification, with HL15 enriched in Acinetobacter and xenobiotic metabolism pathways, and HS15 exhibiting Proteobacteria-dominated dysbiosis and enrichment of LPS biosynthesis genes. Liver transcriptomics revealed group-specific responses: HL15 exposure activated innate immunity via the NOD-MAPK axis, while HS15 induced atypical PI3K-NF-κB signaling, potentially linked to microbial LPS. Notably, all TWP-exposed groups showed enrichment of the herpes simplex virus 1 (HSV-1) infection pathway, suggesting a conserved antiviral-like host response. Transgenerational effects were evidenced by impaired growth and significant downregulation of GH/IGF signaling and upregulation of apoptotic genes in offspring, despite only subtle transcriptomic changes in long-term exposed parents. These findings underscore the importance of particle size, exposure duration, and microbiota-gut-liver axis interactions in mediating TWP toxicity and highlight potential transgenerational risks associated with environmental microplastic exposure.

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.

Hepatocellular carcinoma (HCC) is a highly fatal form of malignancy that seriously threatens patient survival. The global 5-year survival rate for HCC patients ranges from 15% to 19%, and nearly 80% of patients are diagnosed at an advanced stage. Therefore, exploring the mechanism of HCC development and identifying biomarkers and therapeutic targets for HCC are vital. MicroRNAs (miRNAs), a class of noncoding single-stranded RNAs, are 20-24 nucleotides (nt) long. They play pivotal roles in modulating the progression of diverse diseases. The specific role of miR-32-5p in the development of HCC remains unclear. In this study, qRT-PCR is utilized to precisely determine the downregulated expression levels of miR-32-5p in HCC. Subsequently, functional analysis reveals the suppressive role of miR-32-5p in modulating the proliferative and migratory capabilities of HCC cells. Glycogen synthase kinase 3β (GSK3β) has emerged as a potential target of miR-32-5p, which is confirmed through a dual-luciferase reporter assay. Notably, the expression of GSK3β in HCC tissue specimens is negatively correlated with the abundance of miR-32-5p, and patients with high GSK3β expression have shorter survival time. Furthermore, the targeted downregulation of GSK3β remarkably impedes the proliferation and migration of tumor cells. This study suggests that miR-32-5p inhibits the proliferation and migration of HCC through regulating the GSK3β/NF-κB signaling pathway. Therefore, this study reveals that miR-32-5p exerts its suppressive effect on HCC progression, suggesting that it is a promising target for both diagnostic and targeted therapeutic interventions against HCC.

The pathological hallmarks of various neurodegenerative diseases including Parkinson's disease and Alzheimer's disease prominently feature the accumulation of misfolded proteins and neuroinflammation. Chaperone-mediated autophagy (CMA) has emerged as a distinct autophagic process that coordinates the lysosomal degradation of specific proteins bearing the pentapeptide motif Lys-Phe-Glu-Arg-Gln (KFERQ), a recognition target for the cytosolic chaperone HSC70. Beyond its role in protein quality control, recent research underscores the intimate interplay between CMA and immune regulation in neurodegeneration. In this review, we illuminate the molecular mechanisms and regulatory pathways governing CMA. We further discuss the potential roles of CMA in maintaining neuronal proteostasis and modulating neuroinflammation mediated by glial cells. Finally, we summarize the recent advancements in CMA modulators, emphasizing the significance of activating CMA for the therapeutic intervention in neurodegenerative diseases.

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.

Bisphenol A (BPA), a common endocrine-disrupting chemical, is found in a wide range of home plastics. Early-life BPA exposure has been linked to neurodevelopmental disorders; however, the link between neuroinflammation, pyroptosis, and the development of psychiatric disorders is rarely studied. The current study attempted to investigate the toxic effect of BPA on inflammatory and microglial activation markers, as well as behavioral responses, in the brains of male rats in a dose- and age-dependent manner. Early BPA exposure began on postnatal day (PND) 18 at dosages of 50 and 125 mg/kg/day. We started with a battery of behavioral activities, including open field, elevated plus- and Y-maze tests, performed on young PND 60 rats and adult PND 95 rats. BPA causes anxiogenic-related behaviors, as well as cognitive and memory deficits. The in vivo and in silico analyses revealed for the first time that BPA is a substantial activator of nuclear factor kappa B (NF-κB), interleukin (IL)-1β, -2, -12, cyclooxygenase-2, and the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, with higher beclin-1 and LC3B levels in BPA rats' PFC and hippocampus. Furthermore, BPA increased the co-localization of caspase-1 immunoreactive neurons, as well as unique neurodegenerative histopathological hallmarks. In conclusion, our results support the hypothesis that neuroinflammation and microglial activation are involved with changes in the brain after postnatal BPA exposure and that these alterations may be linked to the development of psychiatric conditions later in life. Collectively, our findings indicate that BPA triggers anxiety-like behaviors and pyroptotic death of nerve cells via the NF-κB/IL-1β/NLRP3/Caspase-1 pathway.

Acetaminophen (N-acetyl-p-aminophenol [APAP]) toxicity is a common cause of acute liver failure. Innate immune signaling and specifically NFκB activation play a complex role in mediating the hepatic response to toxic APAP exposures. While inflammatory innate immune responses contribute to APAP-induced injury, these same pathways play a role in regeneration and repair. Previous studies have shown that attenuating IκBβ/NFκB signaling downstream of TLR4 activation can limit injury, but whether this pathway contributes to APAP-induced hepatic injury is unknown. We hypothesized that the absence of IκBβ/NFκB signaling in the setting of toxic APAP exposure would attenuate APAP-induced hepatic injury. To test this, we exposed adult male WT and IκBβ-/- mice to APAP (280 mg/kg, IP) and evaluated liver histology at early (2-24 hr) and late (48-72 hr) time points. Furthermore, we interrogated the hepatic expression of NFκB inflammatory (Cxcl1, Tnf, Il1b, Il6, Ptgs2, and Ccl2), anti-inflammatory (Il10, Tnfaip3, and Nfkbia), and Nrf2/antioxidant (Gclc, Hmox, and Nqo1) target genes previously demonstrated to play a role in APAP-induced injury. Conflicting with our hypothesis, we found that hepatic injury was similar in WT and IκBβ-/- mice. Acutely, the induced expression of some target genes was similar in WT and IκBβ-/- mice (Tnfaip3, Nfkbia, and Gclc), while others were either not induced (Cxcl1, Tnf, Ptgs2, and Il10) or significantly attenuated (Ccl2) in IκBβ-/- mice. At later time points, APAP-induced hepatic expression of Il1b, Il6, and Gclc was significantly attenuated in IκBβ-/- mice. Based on these findings, the therapeutic potential of targeting IκBβ/NFκB signaling to treat toxic APAP-induced hepatic injury is likely limited.

This manuscript describes a novel unconventional secretory pathway that facilitates EGF receptor (EGFR) signaling from apical membranes in polarized epithelial cells responding to immune cell mediators. Epithelial tissues provide a physical barrier between our bodies and the external environment and share an intimate relationship with circulating and local immune cells. Our studies describe an unexpected connection between the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) and EGFR typically localized to basolateral membranes in polarized epithelial cells. These two molecules sit atop complex biological networks with a long history of shared investigative interest from the vantage point of signaling pathway interactions. We have discovered that TNF-α alters the functional landscape of fully polarized epithelial cells by changing the speed and direction of EGFR secretion. Our results show apical EGFR delivery occurs within minutes of de novo synthesis likely via a direct route from the endoplasmic reticulum without passage through the Golgi complex. Additionally, our studies have revealed that apical cellular compartmentalization constitutes an important mechanism to specify EGFR signaling via phosphatidylinositol-4,5-bisphosphate 3-kinase/protein-kinase-B pathways. Our study paves the way for a better understanding of how inflammatory cytokines fine-tune local homeostatic and inflammatory responses by altering the spatial organization of epithelial cell signaling systems.

The vascular endothelium plays a central role in the maintenance of vascular homeostasis. Inflammation of vascular endothelial cells has been closely related to the development of a wide range of cardiovascular diseases, including atherosclerosis. Bupleuri Radix (BR) possesses several biological properties, including anticancer, antimicrobial, antiviral, immunomodulatory, and anti-inflammatory properties. Furthermore, it can prevent and cure several diseases, such as the common cold, hepatitis, menoxenia, and hyperlipidemia. However, it is unclear whether BR can regulate vascular endothelial function under inflammatory conditions induced by interleukin-1β (IL-1β), a key proinflammatory cytokine. Therefore, in this study, we aimed to investigate the effect of BR on endothelial cell function using human umbilical vein endothelial cells (HUVECs) with IL-1β-induced inflammation.

The effects of BR on cell migration, angiogenesis, and monocyte adhesion were determined using scratch wound-healing assay, tube-formation assay, cell adhesion assay, fluorescein isothiocyanate-dextran Transwell assay, and transepithelial electrical resistance assay. The expression of tight junction (TJ) protein and adhesion molecules was estimated using western blotting and immunofluorescence assay. The generation of reactive oxygen species was assessed using flow cytometry.

BR significantly suppressed the proliferation, migration, and tube-formation ability of IL-1β-stimulated HUVECs, and the expression of adhesion molecules, especially intracellular adhesion molecule-1. BR also regulated TJ protein expression, thereby restoring the transepithelial electrical resistance value to a level comparable to that of IL-1β-treated HUVECs. Moreover, BR decreased the production of intracellular reactive oxygen species and the nuclear translocation of the nuclear factor-kappa-B p65 subunit.

These findings revealed for the first time that BR prevents IL-1β-induced inflammation of blood vessel. Therefore, BR has the potential to protect the damage of vascular endothelial cells and prevent the progression of cardiovascular diseases.

Inflammation contributes to the onset and development of many diseases, including neurodegenerative diseases, caused by the activation of microglia, leading to neurological deterioration. Nuclear factor-κB (NF-κB) is one of the most relevant pathways for identifying anti-inflammatory molecules. In this study, polygodial and isotadeonal, two drimane sesquiterpene dialdehydes, were isolated from Drimys winteri, a medicinal tree of the Mapuche people in Chile. Isotadeonal, or epi-polygodial, was obtained from polygodial by epimerization in basic media (60% yield, Na2CO3, r/t, 24 h). Both sesquiterpenoids were evaluated on the NF-κB pathway, with the result that isotadeonal inhibited the phosphorylation of IκB-α at 10 μM with higher potency by Western blotting. The final inhibition of the pathway was evaluated using a SEAP reporter (secreted alkaline phosphatase) on THP-1 cells. Isotadeonal inhibited SEAP with higher potency than polygodial, quercetin, and CAPE (phenethyl ester of caffeic acid). In silico analysis suggests that the α-aldehyde of isotadeonal adopts a more stable conformation in the active pocket of IκB-α than polygodial.

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.

Low-level laser therapy (LLLT) has been shown to influence cellular and molecular processes in irradiated tissues and cells. By altering gene expression and activating specific laser-induced signaling pathways, LLLT can impact key cellular activities such as proliferation, differentiation, migration, and metabolism. This review focuses on exploring the molecular-level effects of LLLT, examining how different wavelengths interact with various cell lines, including stem cells, to induce these changes in gene expression and signaling pathways. A comprehensive review was performed by analyzing relevant literature published between 2003 and 2024. The search utilized databases such as PubMed, Scopus, MEDLINE, EMBASE, and Google Scholar. Selection criteria were based on the presence of keywords including "gene expression," "signaling pathways," "molecular mechanisms," "photobiomodulation," and "LLLT." Among the 150 recent studies on low-level laser therapy and its molecular and cellular effects on irradiated cells, articles related to changes in gene expression and laser-induced signaling pathways were reviewed. Low-level laser therapy exhibits varying effects based on the parameters and wavelengths used. Red and infrared lasers are particularly effective for promoting cell proliferation, differentiation, reducing inflammation, and enhancing wound healing. Blue lasers tend to inhibit cell proliferation, while green lasers are effective in reducing inflammation and aiding in conditions such as intervertebral disc (IVD) degeneration. These effects are linked to changes in gene expression and laser-induced signaling pathways, highlighting the importance of selecting the appropriate laser type for specific therapeutic goals.

Tissue fibrosis represents an aberrant repair process, occurring because of prolonged injury, sustained inflammatory response, or metabolic disorders. It is characterized by an excessive accumulation of extracellular matrix (ECM), resulting in tissue hardening, structural remodeling, and loss of function. This pathological phenomenon is a common feature in the end stage of numerous chronic diseases. Despite the advent of novel therapeutic modalities, including antifibrotic agents, these have only modest efficacy in reversing established fibrosis and are associated with adverse effects. In recent years, a growing body of research has demonstrated that exercise has significant benefits and potential in the treatment of tissue fibrosis. The anti-fibrotic effects of exercise are mediated by multiple mechanisms, including direct inhibition of fibroblast activation, reduction in the expression of pro-fibrotic factors such as transforming growth factor-β (TGF-β) and slowing of collagen deposition. Furthermore, exercise has been demonstrated to assist in maintaining the dynamic equilibrium of tissue repair, thereby indirectly reducing tissue damage and fibrosis. It can also help maintain the dynamic balance of tissue repair by improving metabolic disorders, exerting anti-inflammatory and antioxidant effects, regulating cellular autophagy, restoring mitochondrial function, activating stem cell activity, and reducing cell apoptosis, thereby indirectly alleviating tissue. This paper presents a review of the therapeutic potential of exercise and its underlying mechanisms for the treatment of a range of tissue fibrosis, including cardiac, pulmonary, renal, hepatic, and skeletal muscle. It offers a valuable reference point for non-pharmacological intervention strategies for the comprehensive treatment of fibrotic diseases.

Inflammation appears to play a crucial role in the development and progression of penile cancer (PeCa). Two molecular pathways of PeCa are currently described: HPV-dependent and HPV-independent. The tumor immune microenvironment (TIME) of PeCa is characterized by the presence of tumor-associated macrophages, cancer-associated fibroblasts, and tumor-infiltrating lymphocytes. The components of the TIME produce pro-inflammatory cytokines and chemokines, which have been found to be overexpressed in PeCa tissues and are associated with tumor progression and unfavorable prognoses. Additionally, the nuclear factor kappa B (NF-κB) pathway and secreted phosphoprotein 1 (SPP1) have been implicated in PeCa pathogenesis. Elevated C-reactive protein (CRP) levels and the neutrophil-to-lymphocyte ratio (NLR) have been identified as potential prognostic biomarkers in PeCa. This overview presents the complex contribution of the inflammatory process and collates projects aimed at modulating TIME in PeCa.

Infection with Porphyromonas gingivalis (Pg), which is a major periodontal pathogen, causes a large number of systemic diseases based on chronic inflammation such as diabetes and Alzheimer's disease (AD). However, it is not yet fully understood how Pg can augment local systemic immune and inflammatory responses during progression of AD. There is a strong association between depression and elevated levels of inflammation. Noradrenaline (NA) is a key neurotransmitter that modulates microglial activation during stress conditions. In this study, we have thus investigated the regulatory mechanisms of NA on the production of interleukin-1β (IL-1β) by microglia following stimulation with Pg virulence factors, lipopolysaccharide (LPS), and outer membrane vesicles (OMVs). NA (30-1000 nM) significantly enhanced the mRNA level, promoter activity, and protein level of IL-1β up to 20-fold in BV-2 microglia following treatment with Pg LPS (10 μg/mL) and OMVs (150 μg of protein/mL) in a dose-dependent manner. Pharmacological studies have suggested that NA synergistically augments the responses induced by Pg LPS and OMVs through different mechanisms. AP-1 is activated by the β2 adrenergic receptor (Aβ2R)-mediated pathway. NF-κB, which is activated by the Pg LPS/toll-like receptor 2-mediated pathway, is required for the synergistic effect of NA on the Pg LPS-induced IL-1β production by BV-2 microglia. Co-immunoprecipitation combined with Western blotting and the structural models generated by AlphaFold2 suggested that cross-coupling of NF-κB p65 and AP-1 c-Fos transcription factors enhances the binding of NF-κB p65 to the IκB site, resulting in the synergistic augmentation of the IL-1β promoter activity. In contrast, OMVs were phagocytosed by BV-2 microglia and then activated the TLR9/p52/RelB-mediated pathway. The Aβ2R/Epac-mediated pathway, which promotes phagosome maturation, may be responsible for the synergistic effect of NA on the OMV-induced production of IL-1β in BV-2 microglia. Our study provides the first evidence that NA synergistically enhances the production of IL-1β in response to Pg LPS and OMVs through distinct mechanisms.

Major depressive disorder is a significant global cause of disability, particularly among adolescents. The dopamine system and nearby neuroinflammation, crucial for regulating mood and processing rewards, are central to the frontostriatal circuit, which is linked to depression. This study aimed to investigate the effect of post-weaning isolation (PWI) on depression in adolescent mice, with a focus on exploring the involvement of microglia and dopamine D1 receptor (D1R) in the frontostriatal circuit due to their known links with mood disorders.

Adolescent mice underwent 8 weeks of PWI before evaluating their depression-like behaviors and the activation status of microglia in the frontostriatal regions. Selective D1-like dopamine receptor agonist SKF-81,297 was administered into the medial prefrontal cortex (mPFC) of PWI mice to assess its antidepressant and anti-microglial activation properties. The effects of SKF-81,297 on inflammatory signaling pathways were examined in BV2 microglial cells. After 8 weeks of PWI, female mice exhibited more severe depression-like behaviors than males, with greater microglial activation in the frontostriatal regions. Microglial activation in mPFC was the most prominent among the three frontostriatal regions examined, and it was positively correlated with the severity of depression-like behaviors. Female PWI mice exhibited increased expression of dopamine D2 receptors (D2R). SKF-81,297 treatment alleviated depression-like behaviors and local microglial activation induced by PWI; however, SKF-81,297 induced these alterations in naïve mice. In vitro, SKF-81,297 decreased pro-inflammatory cytokine release and phosphorylations of JNK and ERK induced by lipopolysaccharide, while in untreated BV2 cells, SKF-81,297 elicited inflammation.

This study highlights a sex-specific susceptibility to PWI-induced neuroinflammation and depression. While targeting the D1R shows potential in alleviating PWI-induced changes, further investigation is required to evaluate potential adverse effects under normal conditions.