Inflammatory NF-κB Research Articles

Therapeutic potential and underlying mechanisms of phytoconstituents: emphasizing on resveratol, curcumin, quercetin, berberine, and hesperidin in ulcerative colitis.

Ulcerative colitis is a long-term inflammatory colon illness that significantly affects patients quality of life. Traditional medicines and therapies often come with challenges such as side effects, instability, unpredictability, and high costs. This has captured interest in natural products that have huge health benefits. Various natural compounds, including resveratrol, curcumin, quercetin, berberine, and hesperidin demonstrate immunomodulatory and oxido-inflammatory properties inside the gut epithelium, showing potential in managing ulcerative colitis. These compounds attenuate inflammatory mediators, NF-κB, and TLR4 signaling leading to a reduction in the production of inflammation-related cytokines, including TNF-α and IL-6. They also augment the activity of internal defense compounds, including superoxide radical dismutase enzyme and heme oxygenase-1, thereby alleviating oxidative damage. In addition, natural compounds have a profound effect on the endogenous microbiota and thus, support mucosal healing and intercellular barrier integrity. Both experimental and clinical analyses provide evidence that these bioactive compounds may help reduce clinical manifestations, induce and sustain remission, and improve the well-being of individuals suffering from ulcerative colitis. This review seeks to discuss various aspects of natural compounds in the management of ulcerative colitis, including mechanisms, therapeutic prospects, and hurdles, and hence the basis for future research and practice.

Unraveling the immunomodulatory and metabolic effects of bioactive glass S53P4 on macrophages in vitro

Macrophage metabolism is closely linked to their phenotype and function, which is why there is growing interest in studying the metabolic reprogramming of macrophages. Bioactive glass (BG) S53P4 is a bioactive material used especially in bone applications. Additionally, BG S53P4 has been shown to affect macrophages, but the mechanisms through which the possible immunomodulatory effects are conveyed remain unclear. According to the results presented here, the lipopolysaccharide (LPS) induced suppression in oxidative phosphorylation is rescued in macrophages cultured with BG S53P4 before the inflammatory stimulus. Additionally, BG S53P4-exposed macrophages expressed lower mRNA levels of inflammatory cytokines Il6 and Il1b, as well as demonstrated decreased activation of inflammatory interferon regulatory factor (IRF) and NF-κB pathways and nitrogen oxide secretion in response to LPS. These results did not rely on cells being in direct contact with the material as similar effects were observed in the presence of BG S53P4-conditioned medium. Our findings link the immunomodulatory properties of BG S53P4 and macrophage metabolism, which improves our understanding of the mechanisms underlying the clinical efficacy of bioactive glasses.Graphical

Anti-Inflammatory and Prebiotic Potential of Ethanol Extracts and Mucilage Polysaccharides from Korean Yams (Dioscorea polystachya and Dioscorea bulbifera).

Korean yams are abundant in bioactive compounds with significant health-promoting properties. This study evaluated the anti-inflammatory potential of ethanol and water extracts from Dioscorea polystachya and Dioscorea bulbifera in RAW 264.7 macrophage cells. Among the extracts, the 95% ethanol extract exhibited the most potent inhibition of reactive oxygen species (ROS) and nitric oxide (NO) production, warranting further exploration of its mechanisms of action. Further analysis revealed that the ethanol extract modulated key inflammatory signaling pathways, including MAPK and NF-κB, contributing to its anti-inflammatory activity. Additionally, mucilage polysaccharides, a key bioactive component of Korean yams, were extracted and characterized for their structural and functional properties. These polysaccharides demonstrated immune-enhancing effects by reducing ROS and NO production while increasing phagocytic activity in the RAW 264.7 cells. Their prebiotic potential was also assessed through microbial growth assays, which showed an enhanced proliferation of beneficial bacteria such as Lactobacillus and Bifidobacterium. Furthermore, the adhesion assays using Caco-2 intestinal epithelial cells revealed that these polysaccharides promoted probiotic adhesion while inhibiting the adhesion of pathogenic bacteria. These findings highlight the bioactive potential of ethanol extracts and mucilage polysaccharides from Korean yams, emphasizing their promising applications as anti-inflammatory, immune-modulating, and prebiotic agents for functional food and nutraceutical development.

Asperulosidic acid inhibits the PI3K/Akt/NF-κB pathway to suppress endotoxin-induced uveitis.

Uveitis, a severe inflammatory disease affecting the uvea, is associated with visual impairment and irreversible blindness. Asperulosidic Acid (ASPA), derived from Hedyotis diffusa, is known for its notable anti-inflammatory and antioxidant characteristics. The present study explored the potential anti-inflammatory effects and the fundamental processes of ASPA by injecting it or a placebo into the vitreous of rats with endotoxin-induced uveitis (EIU). The severity of the disease was assessed using clinical scores obtained through slit lamp examination. The study involved the examination of protein concentrations and cell count in the aqueous humor (AqH), the detection of inflammatory mediators expressed in the retina. We evaluated the expression levels of various proteins, including the tight junction protein ZO-1, the endothelial marker VE-cadherin, and the key inflammatory mediators NF-κB and its phosphorylated form, along with the regulatory proteins IκB-a and IKK in their phosphorylated and non-phosphorylated states. ASPA treatment significantly reduced the clinical score of EIU, including inflammatory leukocyte penetration, protein accumulation, cellulose-like exudates, the expression of ICAM-1, IL-6, MCP-1, and TNF-α in the AqH; and adhesion of leukocytes. The activation of the PI3K/Akt/NF-κB pathway was observed in EIU. Nevertheless, pretreatment with ASPA significantly suppressed the release of ICAM-1, TNF-α, MCP-1, and IL-6. ASPA may play a role in suppressing LPS-induced inflammation by obstructing the activation of the PI3K/Akt/NF-κB signaling pathway. As a result, ASPA has shown the capacity to significantly reduce immune inflammation.

An Azomethine Derivative, 1-(4-nitrophenyl)-N-phenylmethanimine (BCS2) Ameliorated 7,12-dimethylbenz(a)anthracene-induced Mammary Carcinoma through Nrf2-Keap1-HO-1 Pathway.

The aim of this study is the evaluation of an Azomethine derivative, BCS2, for its antioxidant and anti-tumor activities against mammary carcinoma through the Nrf2- Keap1-HO-1 pathway. The global prevalence of breast cancer is rising at an alarming rate. The facilitation of abnormal cell proliferation in mammary carcinoma occurs due to the disruption of signaling pathways that balance pro- and antioxidant status, thereby producing oxidative stress that disrupts genomic stability. Therefore, introducing a potent antioxidant molecule with antitumor activity is of paramount importance for treating breast cancer. Synthesis, characterization, and in-vitro, in-vivo, and in-silico evaluation of an Azomethine derivative, BCS2, for its antioxidant and anti-tumor activities against chemical carcinogen- induced mammary carcinogenesis in Sprague-Dawley rats. An azomethine derivative, 1-(4-nitrophenyl)-N-phenylmethanimine (BCS2), was synthesized and characterized based on its spectral data. The cytotoxic potential was observed on breast cancer cells, MCF-7, MDA-MB-231, and MDA-MB-468. The in vivo chemotherapeutic potential of BCS2 was established on 7,12-dimethylbenz(a)anthracene (DMBA) induced breast cancer in Sprague-Dawley (SD) rats. The effect of BCS2 on kelch-like ECH-associated protein- 1 (Keap1), Nrf2, heme oxygenase-1 (HO-1), mitogen-activated protein kinase (MAPK), and nuclear factor kappa-light-chain-enhancer of activated-B (NF-κB) was evaluated through ELISA and qPCR techniques. Furthermore, the binding potential and stability of BCS2 with Keap-1, HO-1, and MAPK were predicted using in silico molecular docking and dynamics studies. Additionally, drug-likeness properties of BCS2 were evaluated using in silico ADMET tools. BCS2 showed remarkable cytotoxic activity on MCF-7 cells followed by MDA-MB- 231 and MDA-MB-468 cells having an IC50 of 2.368μM, 4.843μM and 6.472μM respectively, without affecting normal breast cells, MCF-10A. In the DMBA-induced animal model, BCS2 showed potent antitumor potential and showed protective action on endogenous-enzymatic and non-enzymatic antioxidants in cancer-bearing animals. Marked improvement in cellular architecture and ultrastructure of breast/tumor tissues excised from experimental animals was noted through histopathological and field emission scanning electron microscopy (FESEM) analyses. Significant upregulation of antioxidant proteins, Keap1 and HO-1, and downregulation of inflammatory proteins, MAPK, and NF-κB was observed after BCS2 treatment. The in silico computational studies predicted the potent binding of BCS2 with the active pockets of Keap1, HO-1, and MAPK proteins that validated the biological findings. The study revealed BCS2's potent antioxidant and antitumor potential against mammary carcinoma through the Nrf2-Keap1-HO-1 signaling pathway.

Nonenzymatic lysine d-lactylation induced by glyoxalase II substrate SLG dampens inflammatory immune responses

Immunometabolism is critical in the regulation of immunity and inflammation; however, the mechanism of preventing aberrant activation-induced immunopathology remains largely unclear. Here, we report that glyoxalase II (GLO2) in the glycolysis branching pathway is specifically downregulated by NF-κB signaling during innate immune activation via tristetraprolin (TTP)-mediated mRNA decay. As a result, its substrate S-D-lactoylglutathione (SLG) accumulates in the cytosol and directly induces d-lactyllysine modification of proteins. This nonenzymatic lactylation by SLG is greatly facilitated by a nearby cysteine residue, as it initially reacts with SLG to form a reversible S-lactylated thiol intermediate, followed by SN-transfer of the lactyl moiety to a proximal lysine. Lactylome profiling identifies 2255 lactylation sites mostly in cytosolic proteins of activated macrophages, and global protein structure analysis suggests that proximity to a cysteine residue determines the susceptibility of lysine to SLG-mediated d-lactylation. Furthermore, lactylation is preferentially enriched in proteins involved in immune activation and inflammatory pathways, and d-lactylation at lysine 310 (K310) of RelA attenuates inflammatory signaling and NF-κB transcriptional activity to restore immune homeostasis. Accordingly, TTP-binding site mutation or overexpression of GLO2 in vivo blocks this feedback lactylation in innate immune cells and promotes inflammation, whereas genetic deficiency or pharmacological inhibition of GLO2 restricts immune activation and attenuates inflammatory immunopathology both in vitro and in vivo. Importantly, dysregulation of the GLO2/SLG/d-lactylation regulatory axis is closely associated with human inflammatory phenotypes. Overall, our findings uncover an immunometabolic feedback loop of SLG-induced nonenzymatic d-lactylation and implicate GLO2 as a promising target for combating clinical inflammatory disorders.

Prognostic value and clinical significance of IL-33 expression in patients with uterine corpus endometrial carcinoma.

Uterine corpus endometrial carcinoma (UCEC) is one of the most common malignant tumours of the female genital tract. In the occurrence, progression and prognosis of UCEC, chronic inflammation plays an important role, making it pivotal to identify inflammatory response-related endometrial diseases. The cytokine interleukin-33 (IL-33) plays significant roles in immune responses, and has been associated with inappropriate allergic reactions, autoimmune diseases, and cancer pathology. In the past decade, studies have begun to uncover the pivotal roles of IL-33 in shaping tumour microenvironment (TME), where it may promote or inhibit tumorigenesis and development depending on the specific tumour types. However, the association between IL-33 expression and UCEC remains unclear. Here we investigated the expression profiles of IL-33 in pan-cancer based on TCGA database. Then, differential gene expression analysis and correlation analysis of IL-33 was investigated in UCEC. In addition, functional enrichment analysis and Kaplan-Meier survival analysis were performed to predict the potential function of IL-33 and its role in the prognosis of UCEC patients. Also, a nomogram model was constructed to predict the prognosis of UCEC. The expression of the inflammatory factor NF-κB p65 and the IL-33, along with its receptor ST2, was analyzed in UCEC tumour tissues and normal tissues of clinical specimens through immunohistochemical staining. Meanwhile, we used toluidine blue staining and methanol Congo red staining to observe the infiltration of mast cells and eosinophils in the endometrial tissue. The results of Kaplan-Meier plotter data indicated that patients with lower IL-33 expression had poorer progression-free interval than those with higher expression. Based on the results of multifactor Cox regression, a nomogram was generated to predict UCEC occurrence risk and prognosis. Clinical specimen characteristics also confirmed a negative correlation between IL-33 expression and UCEC staging and grading. This comprehensive analysis of IL-33, based on bioinformatics and immunohistochemistry, revealed that IL-33 has the function of inhibiting UCEC occurrence and progression and can be served as a beneficial prognostic marker in the clinic.

Daptomycin alleviates collagen-induced arthritis via suppressing inflammatory cytokines and NF-κB pathway.

Rheumatoid arthritis (RA) is a chronic autoimmune disease, and its pathogenic factors include bacterial infection and immune inflammation. Daptomycin (DAP) is a cyclic lipopeptide that has been approved to treat skin infections, bacteremia and right-sided endocarditis due to its effective antibacterial effects against most Gram-positive pathogenic bacteria. Herein, we focus on whether DAP exerts anti-inflammatory activity on RA to expand DAP drug indications. Our studies are first time to evaluate anti-inflammatory effect and reveal its molecular pharmacological mechanism of DAP on lipopolysaccharide-activated macrophage and collagen-induced arthritis (CIA) mice. In vitro cytological studies show that 10µg/mL DAP inhibits secretion of IL-1β, IL-6 and TNF-α to alleviate cell inflammation, and the phosphorylation level of p65 (p-p65) of RAW 264.7 cells is decreased under DAP exposure. Administration with 10mg/kg/2d DAP via intravenous injection on CIA mice significantly reduces arthritis symptom by inhibiting p-p65 level and decreasing serum level of IL-6, IL-1β and TNF-α. Moreover, our study is the first time to reveal new immunomodulatory effects of DAP on RA, which provides a pharmacological basis for new clinical applications of DAP for other immune-related diseases except to bacterial infections.

Mechanism of Liraglutide Regulating the Expression of PI3K/AKT/NF-KB Pathway-related Proteins on Nonalcoholic Fatty Liver Disease

Background and Objective: GLP-1RAs can effectively prevent hepatic steatosis. It was to investigate the mechanism by which the GLP-1RA Liraglutide ameliorates non-alcoholic fatty liver disease (NAFLD) and its impact on PI3K/AKT/NF-κB pathway. Materials and Methods: eight-week-old, clean-grade male C57BL/6J mice were assigned to Normal group (NG, fed standard chow), NAFLD group (high-calorie, high-cholesterol), and Liraglutide group (LG, high-calorie, high-cholesterol for 12 weeks + Liraglutide treatment at 1 mg/kg). Serum samples were collected from the mice to assess changes in glucose and lipid metabolism and liver function (LF) indicators. Histopathological changes in liver tissues (LTs) were visualized. Real-time quantitative PCR measured expression levels (ELs) of inflammatory genes in LTs. Western blotting was conducted to detect EL of proteins related to PI3K/AKT/NF-κB pathway in LTs. Results: NAFLD group exhibited markedly elevated levels of blood glucose (BG), blood lipids, and LF indicators relative to NG. Histopathological examination revealed increased scores for steatosis, lobular inflammation, and hepatocellular ballooning. The ELs of inflammatory genes IL-1β, TNF-α, and NF-κB p65 in LTs, were greatly elevated (P<0.05). In contrast, relative to NAFLD group, LG showed notably reduced levels of BG, blood lipids, and LF indicators, along with decreased histopathological scores. Furthermore, the ELs of inflammatory genes and protein ELs of p-PI3K, p-AKT, and p-NF-κBp65 in LTs were drastically lowered (P<0.05). Conclusion: Liraglutide ameliorates glucose and lipid metabolism disorders and suppresses inflammatory responses in liver by inhibiting PI3K/AKT/NF-κB signaling, thereby improving NAFLD in mice.

Piperazine ferulate impact on diabetes-induced testicular dysfunction: unveiling genetic insights, MAPK/ERK/JNK pathways, and TGF-β signaling.

Diabetic testicular dysfunction (DTD) poses a significant threat to male reproductive health. This study delves into the potential of piperazine ferulate (PF), a natural phenolic compound, in alleviating DTD and sheds light on its underlying mechanisms in rats. Animals were divided into the control, PF, diabetic, and diabetic plus PF groups. Diabetes was induced in rats with a single intraperitoneal (i.p.) injection of streptozotocin (STZ) at 50mg/kg. PF was administered at 50mg/kg/day via i.p. injection for four weeks. Significant changes in sexual behavior were observed in diabetic rats, which additionally revealed lower serum levels of testosterone, FSH, and LH. The abnormalities in sperm count, viability, motility, and morphology occurred along with the demonstrated suppression of genes and protein expression related to spermatogenesis. Atrophy of the seminiferous tubules and extensive degeneration and necrosis of the germ and Leydig cells were highlighted by histopathological examination. The testicular function of diabetic rats was significantly improved after PF administration, evidenced by normalized testicular histology, increased testosterone levels, and enhanced sperm quality. In addition to reducing inflammatory cytokines, COX2, and NF-κB expression, pf administration elevated the antioxidant levels and Nrf2/HO-1 expression. Furthermore, key signaling pathways involved in testicular degeneration are regulated by PF. It promoted cell survival and tissue repair by activating the protective TGF-β signaling pathway and attenuating the MAPK/ERK/JNK signaling cascade, which in turn reduced inflammation and apoptosis. PF suppressed the expression of INSL3, SPHK1, CD62E, ANGPTL2, and miR-148a-5p, while increasing the expression of testicular genes like HSD17B1, DAZL, and S1P, addressing DTD. This study highlights the potential of PF to restore testicular function and fertility in diabetic males by modulating genetic and signaling pathways.

The CCL5/CCR5/SHP2 axis sustains Stat1 phosphorylation and activates NF-κB signaling promoting M1 macrophage polarization and exacerbating chronic prostatic inflammation

Background and objectiveChronic prostatitis (CP) is a condition markered by persistent prostate inflammation, yet the specific cytokines driving its progression remain largely undefined. This study aims to identify key cytokines involved in CP and investigate their role in driving inflammatory responses through mechanistic and therapeutic exploration.MethodsA 48-cytokine panel test was conducted to compare the plasma cytokine profiles between participants with CP-like symptoms (CP-LS) and healthy controls. Experimental autoimmune prostatitis (EAP) models were used for functional validation, with further mechanistic studies performed through in vivo and in vitro assays. Pharmacological inhibition was applied using maraviroc, and pathway inhibitors to assess therapeutic potential.ResultsOur analysis identified CCL5 as one of the most prominently elevated cytokines in CP-LS patients. Further validation in the EAP model mice confirmed elevated CCL5 levels, highlighting its role in driving prostatic inflammation. Mechanistic studies revealed that CCL5 interacts with the CCR5 receptor, promoting M1 macrophage polarization and activating key inflammatory signaling pathways, including Stat1 and NF-κB, as indicated by increased phosphorylation of Stat1 and p65. In vitro, CCL5 combined with LPS stimulation amplified these effects, further promoting M1 polarization. CCL5 also sustained Stat1 activation by inhibiting its dephosphorylation through reduced interaction with SHP2, leading to prolonged inflammatory signaling. Single-cell transcriptomics confirmed high CCR5 expression in macrophages, correlating with inflammatory pathways. Pharmacological inhibition of CCR5, or its downstream signaling, significantly reduced macrophage-driven inflammation both in vivo and in vitro.ConclusionThese findings establish the CCL5/CCR5 axis as a critical driver of persistant prostatic inflammation and present it as a potential therapeutic target for CP.Graphic The graphic abstract illustrates the central role of the CCL5/CCR5 axis in promoting chronic prostatitis progression. CCL5 binds to the CCR5 receptor on macrophages, enhancing M1 polarization and activating key inflammatory pathways, including Stat1 and NF-κB, as shown by the increased phosphorylation of Stat1 and p65. The interaction also inhibits SHP2-mediated Stat1 dephosphorylation, sustaining prolonged inflammatory signaling. Pharmacological inhibition of CCR5 or its downstream pathways attenuates macrophage-driven inflammation, highlighting this axis as a critical driver and potential therapeutic target for chronic prostatitis.

Exploring the anti-inflammatory and antiapoptotic properties of phloroglucinol on pancreatic cells in diabetic models: In silico and in vivo study.

Pancreatic cell damage in diabetes mellitus is closely linked to inflammation and apoptosis. This study aimed to investigate the protective effects of phloroglucinol on pancreatic cells in a streptozotocin-induced diabetic model by assessing its anti- inflammatory and anti-apoptotic mechanisms. Phloroglucinol ligand and the structures of Bax, Bcl-2, and caspase-3 proteins were sourced from the PubChem database. Molecular docking was performed using Autodock Tools and docking results were analyzed with PyRx software. In addition, during the in vivo study, the BALB/c mice were grouped into four categories: healthy control, untreated streptozotocin-induced diabetic, and streptozotocin-induced diabetic treated with two doses of oral phloroglucinol at 100 mg/kg and 200 mg/kg body weight. After 28 days, pancreatic tissues were collected for flow cytometric analysis of NF-κB, IL-6, TNF-α, and apoptotic markers (Bax, Bcl-2, and caspase-3). The docking simulations revealed specific binding interactions: phloroglucinol interacted with Bcl-2 via amino acid residues of ALA90 and TYR139, with Bax via ALA42, LEU45, ALA46, LEU47, PRO130, and ILE133, and with caspase-3 through ARG64, SER120, GLN161, CYS163, and ARG207. The binding affinities for Bax, Bcl-2, and caspase-3 were -5.0, -4.7, and -4.9 kcal/mol, respectively. In vivo, results showed that streptozotocin significantly elevated inflammatory cytokines NF-κB, TNF-α, and IL-6, along with apoptotic markers in pancreatic cells (p<0.05) compared to healthy controls. Phloroglucinol administration at 200 mg/kg significantly reduced TNF-α, NF-κB and IL- 6 levels. Phloroglucinol also prevented streptozotocin-induced pancreatic cell damage through anti-apoptotic effects by downregulating Bax and caspase-3 and upregulating Bcl-2. These findings suggest that phloroglucinol may offer protective benefits in diabetic conditions by modulating apoptotic and inflammatory pathways.

Repurposing Aprepitant: Can it protect against doxorubicin-induced Chemobrain beyond its antiemetic role?

The substance P (SP) and neurokinin-1 receptor (NK-1R) axis is crucial in numerous pathological processes, including inflammation, stress responses, pain perception, and vomiting. Consequently, aprepitant, an NK-1R blocker, is used as an antiemetic in chemotherapy, including the use of doxorubicin (DOX), but whether aprepitant can also assuage DOX-mediated chemobrain remains to be unveiled. Here, we scrutinized the potential neuroprotective effect and underlying mechanisms of aprepitant using DOX-induced chemobrain model, where rats were allocated into 4 groups (control, aprepitant, DOX, and DOX+ aprepitant). Cognitive deficits were assessed through behavioral tests and hippocampal structural alterations were determined by H&E and toluidine blue staining. Biochemical measurements were performed using ELISA, real-time quantitative PCR, western blotting, and immunohistochemical methods. Aprepitant improved cognitive responses, and hippocampal morphology, enhancing the presence of intact neurons. At the molecular tier, aprepitant significantly reduced hippocampal contents of SP and the inflammatory markers NF-κB and IL-1β. Additionally, it signified its antioxidant and antiapoptotic capacities by downregulating cleaved caspase-3 protein expression and curbing the content of malondialdehyde but boosted those of glutathione and Bcl-2. Aprepitant also downregulated the expression of miR-146a and turned off the endoplasmic reticulum (ER) stress cascade PERK/eIF-2α/ATF-4/CHOP. To recapitulate, aprepitant demonstrates a neuroprotective effect against DOX-mediated chemobrain by alleviating inflammatory, oxidative, and apoptotic responses, partly by reducing SP, ER stress, and miR-146a. These findings not only underscore the potential of aprepitant as a neuroprotective agent but also offer new understanding of the mechanisms behind chemobrain, leading to better therapeutic strategies for cancer patients.

The role of ischaemia-modified albumin in the prognosis of acute pancreatitis and its correlation with the NF-κB-mediated inflammatory response.

To investigate the correlation between the serum levels of ischaemia-modified albumin (IMA) and disease severity in rats with acute pancreatitis (AP). A rat AP model was established and blood samples from each group were analysed at different time points. After the experiment, the pancreatic tissues of the rats were collected for pathological examination and the measurement of protein levels of NF-κB and NF-κB p65. Serum levels of amylase (α-AMY), tumour necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-8 were also compared between groups of rats. The serum IMA concentration in the severe acute pancreatitis (SAP) group was greater than that in the mild acute pancreatitis (MAP) group. The levels of the NF-κB and NF-κB p65 proteins were increased in the MAP and SAP groups in a time-dependent manner. α-AMY, TNF-α and IL-6 were increased at all time points in the MAP and SAP groups. The increases were greatest at 24 h in the SAP group. In terms of pathological changes in the pancreas, renal and lung tissues, the damage in the SAP group was more obvious than that in the MAP group. Serum IMA level was associated with inflammatory markers and NF-κB p65 in rats with AP.

Bifidobacterium regulates premature infant gut metabolites, reducing serum inflammatory factors: a randomised controlled trial.

Analyse the effects of Bifidobacterium BB-12 on intestinal metabolites and serum inflammatory factors in premature infants. 71 premature infants at gestational age of ≤32 weeks were randomly divided into the probiotic (n = 36) and control (n = 35) groups. Faecal and blood samples were collected from the two groups of premature infants at the 2nd and 4th week of life for intestinal metabolite detection and assessment of the level of the serum inflammatory markers TLR4, NF- κ B, IL-1β, and TNF- α. Compared to the control group, the probiotic group contained more amino acids, these elements were enriched on multiple amino acid metabolic pathways, and the probiotic group showed significantly lower levels of the serum inflammatory markers TLR4, NF-κB, IL-1β, and TNF-α. Finally, the probiotic group showed a lower incidence of feeding intolerance. The administration of Bifidobacterium BB-12 is associated with increasing the levels of glutamine, glutamic acid, and kynurenine in the gut of premature infants, and associated with reducing the levels of TLR4 and NF-κB in the serum, further decreasing the secretion of the pro-inflammatory factors IL-1β and TNF-α, and alleviating systemic inflammatory reactions, thereby reducing the incidence of feeding intolerance. 1. The use of Bifidobacterium BB-12 in premature infants can increase the levels of amino acids in the intestine. 2. Increases in Bifidobacterium BB-12 may decrease the serum levels of TLR4, NF-κB, IL-1β, and TNF-α. 3. Kynurenine may improve the prognosis of preterm infants by reducing inflammation. 4. Bifidobacterium BB-12 may improve the feeding tolerance of premature infants, thus reducing the incidence of feeding intolerance.

Bergapten attenuates sepsis-induced acute lung injury in mice by regulating Th17/Treg balance

Background The abnormality of the immune system caused by infection is a contributor to the organ dysfunctions associated with sepsis. The balance between Th17/Treg cells is essential for maintaining immune homeostasis. Bergapten is a natural furocoumarin and has been reported to alleviate the Th17/Treg imbalance. Here, we explored the effects of bergapten on the inflammation and immune state in mouse models of sepsis. Methods The model was established using the cecal ligation and puncture method. Mice were administered 30 mg/kg bergapten. Histological examination, RT-qPCR, enzyme-linked immunosorbent assay, immunoblotting, immunofluorescence, immunohistochemistry, and flow cytometry were used to evaluate the effects of bergapten in vivo. Results Bergapten ameliorated lung damage, reduced lung wet/dry weight ratio, inhibited myeloperoxidase activity, and reduced inflammatory cell infiltration. Bergapten also restrained sepsis-induced inflammation via inhibition of inflammatory cytokines and NF-κB signaling. These effects were accompanied by the restored Th17/Treg balance induced by bergapten. Bergapten decreased the number of Th17 cells and elevated the number of Tregs, and this effect was mediated by the signal transducer and activator of transcription 5 (STAT5)/Forkhead box P3 (Foxp3) and STAT3/retinoid-related orphan receptor-γt (RORγt) pathways. Conclusions Bergapten exerted anti-inflammatory effects in acute lung injury by improving the Th17/Treg balance, which suggested a potential of bergapten as an immunomodulatory drug treating sepsis-associated diseases.

DJ-X-013 reduces LPS-induced inflammation, modulates Th17/ myeloid-derived suppressor cells, and alters NF-κB expression to ameliorate experimental colitis

ScopeInflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition of unknown etiology, although recent evidence suggests that it is caused by an excessive immune response to mucosal antigens. We determined the anti-inflammatory properties of novel compound DJ-X-013 in vitro in lipopolysaccharide (LPS)-induced macrophages and in an in vivo dextran sodium sulfate (DSS)-induced model of colitis. Methods and resultsTo evaluate the anti-inflammatory properties of DJ-X-013, we used LPS-activated RAW 264.7 macrophages in vitro and a DSS-induced experimental model of colitis in vivo. We examine cellular morphology, and tissue architecture by histology, flow cytometry, RT-qPCR, multiplex, and immunoblot analysis to perform cellular and molecular studies. DJ-X-013 treatment altered cell morphology and expression of inflammatory cytokines in LPS-activated macrophages as compared to cells treated with LPS alone. DJ-X-013 also impeded the migration of RAW 264.7 macrophages by modulating cytoskeletal organization and suppressed the expression of NF-κB and inflammatory markers as compared to LPS alone. DJ-X-013 treatment improved body weight, and colon length and attenuated inflammation in the colon of DSS-induced colitis. Intriguingly, DSS-challenged mice treated with DJ-X-013 induced the numbers of myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), and natural killer T cells (NKT) in the colon lamina propria (LP) relative to DSS. DJ-X-013 also reduced the influx of neutrophils, TNF-α producing macrophages, restricted the number of Th17 cells, and suppressed inflammatory cytokines and NF-κB in the LP relative to DSS. ConclusionDJ-X-013 is proposed to be a therapeutic strategy for ameliorating inflammation and experimental colitis.

Glutamic-Alanine Rich Glycoprotein from Undaria pinnatifida: A Promising Natural Anti-Inflammatory Agent.

This study aimed to assess the anti-inflammatory properties of a bioactive glutamic-alanine rich glycoprotein (GP) derived from Undaria pinnatifida on both LPS-stimulated RAW264.7 cells, peritoneal macrophages, and mouse models of carrageenan- and xylene-induced inflammation, investigating the underlying molecular mechanisms. In both in-vitro and in-vivo settings, GP was found to reduce the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) while also inhibiting the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in response to lipopolysaccharide (LPS) stimulation. GP treatment significantly impeded the nuclear translocation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway by blocking the phosphorylation of IKKα and IκBα, leading to a reduction in proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Additionally, GP effectively inhibited the activation of mitogen-activated protein kinases (MAPKs), with specific inhibitors of p38 and extra-cellular signal regulated kinase (ERK) enhancing GP's anti-inflammatory efficacy. Notably, GP administration at 10 mg/kg/day (p.o.) markedly reduced carrageenan-induced paw inflammation and xylene-induced ear edema by preventing the infiltration of inflammatory cells into targeted tissues. GP treatment also downregulated key inflammatory markers, including iNOS, COX-2, IκBα, and NF-κB, by suppressing the phosphorylation of p38 and ERK, thereby improving the inflammatory index in both carrageenan- and xylene-induced mouse models. These findings suggest that marine resources, particularly seaweeds like U. pinnatifida, could serve as valuable sources of natural anti-inflammatory proteins for the effective treatment of inflammation and related conditions.

Sodium orthovanadate protects against ulcerative colitis and associated liver damage in mice: insights into modulations of Nrf2/Keap1 and NF-κB pathways.

Ulcerative colitis (UC) is a prominent category of disease that is associated with bowel inflammation, it can occur at any period of life and is prevalently rising on a global scale. Dextran sulfate sodium (DSS) has been extensively used to develop colitis due to its ability to mimic human UC, providing consistent and reproducible inflammation, ulceration, and disruption of the epithelial barrier in the colon. Chronic inflammation in the gut can lead to alterations in the gut-liver axis, potentially impacting liver function over time, while direct evidence linking diversion colitis to liver damage is limited. Thus, the present study aims to assess the gut and liver damage against DSS and the possible molecular mechanisms. Forty-seven animals were randomly assigned to six groups. Ulcerative colitis was induced using 2.5% w/v DSS in three alternate cycles, each lasting 7 days, with 1-week remission periods in between. SOV (5 and 10 mg/kg, orally) and the standard drug 5-aminosalicylic acid (100 mg/kg, orally) were administered from the start of the 2nd DSS cycle until the end of the experiment. Biochemical parameters, ELISA, histopathological, and immunohistochemical analyses have been conducted to assess damage in the colon and liver. SOV significantly reduced colitis severity by lowering the DAI score, oxidative stress markers (LPS, IL-1β, MPO, nitrite), and restoring liver biomarkers (SGPT, SGOT). Histopathological findings supported these protective benefits in the liver and gut. Moreover, immunohistochemical analysis showed SOV enhanced the expression of the cytoprotective mediator Nrf2/Keap-1 and reduced the expression of inflammatory mediators NF-κB and IL-6. Present findings concluded that SOV demonstrated a dose-dependent effect against UC through anti-inflammatory and antioxidant pathways, with the highest dose of SOV 10 mg/kg having more significant (p < 0.001) results than the low dose of 5 mg/kg.

Protective Effects of Carvacrol on Mercuric Chloride-Induced Lung Toxicity Through Modulating Oxidative Stress, Apoptosis, Inflammation, and Autophagy.

Mercuric chloride (HgCl2) is extremely toxic to both humans and animals. It could be absorbed via ingestion, inhalation, and skin contact. Exposure to HgCl2 can cause severe health effects, including damages to the gastrointestinal, respiratory, and central nervous systems. The purpose of this work was to explore if carvacrol (CRV) could protect rats lungs from damage caused by HgCl2. Intraperitoneal injections of HgCl2 at a dose of 1.23 mg/kg body weight were given either alone or in conjunction with oral CRV administration at doses of 25 and 50 mg/kg body weight for 7 days. The study included biochemical and histological techniques to examine the lung tissue's oxidative stress, apoptosis, inflammation, and autophagy processes. HgCl2-induced reductions in GSH levels and antioxidant enzymes (SOD, CAT, and GPx) activity were enhanced by CRV co-administration. Furthermore, MDA levels were lowered by CRV. The inflammatory mediators NF-κB, IκB, NLRP3, TNF-α, IL-1β, IL6, COX-2, and iNOS were all reduced by CRV. When exposed to HgCl2, the levels of apoptotic Bax, caspase-3, Apaf1, p53, caspase-6, and caspase-9 increased, but the levels of antiapoptotic Bcl-2 reduced after CRV treatment. CRV decreased levels of Beclin-1, LC3A, and LC3B, which in turn decreased HgCl2-induced autophagy damage. After HgCl2 treatment, higher pathological damage was observed in terms of alveolar septal thickening, congestion, edema, and inflammatory cell infiltration compared to the control group while CRV ameliorated these effects. Consequently, by preventing HgCl2-induced increases in oxidative stress and the corresponding inflammation, autophagy, apoptosis, and disturbance of tissue integrity in lung tissues, CRV might be seen as a useful therapeutic alternative.