Malaria is an infectious disease caused by parasites of the Plasmodium genus. Its pathophysiology is highly complex, as it depends both on the host's immune response and the parasite's evasion mechanisms, which are often species-specific. This complexity has posed significant challenges to vaccine development and malaria control. Therefore, the aim of this review is to describe the host's immunological mechanisms, the parasite's evasion strategies and the available vaccines, as well as their relationship with the human immune response in controlling Plasmodium infection.

Urologic tumors are among the most common malignancies worldwide, and the association between chronic infections and the risk of developing these tumors has garnered significant attention. However, traditional observational studies are prone to confounding factors, making it challenging to establish a clear causal relationship.

This study employs a two-sample bidirectional Mendelian randomization analysis, utilizing genetic data on antibody levels and urologic tumors obtained from GWAS databases. The inverse variance weighted (IVW) method was used to estimate causal relationships, while MR-Egger and MR-PRESSO methods were applied for sensitivity analyses to assess horizontal pleiotropy and heterogeneity.

The results showed that antibody levels associated with various viral infections were significantly correlated with the risk of developing urologic tumors. For example, antibodies related to cytomegalovirus IgG and Epstein-Barr virus (EBV) were found to have complex associations with the risk of prostate cancer, bladder cancer, and testicular cancer. Some antibodies, such as those related to Varicella zoster virus, were associated with a reduced risk of clear cell renal carcinoma. Additionally, sensitivity analyses suggested the potential presence of horizontal pleiotropy in bladder and testicular cancers.

Through Mendelian randomization analysis, we revealed a potential causal relationship between antibody immune responses and urologic tumors. These findings provide new evidence for the role of chronic infections in the pathogenesis of urologic tumors, suggesting that prevention and treatment strategies targeting related pathogens, such as vaccination and antiviral therapies, could offer new avenues for the prevention and management of urologic cancers.

Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor with specificity for VEGFR, KIT, FLT3, and PDGFR, has demonstrated clinical efficacy as a first- to third-line treatment for refractory renal carcinoma. Our previous research indicated that sunitinib malate suppresses intestinal polyp proliferation by downregulating IL-6 mRNA expression, suggesting a potential analogous mechanism in colorectal carcinoma inhibition. This study aimed to elucidate the pharmacological effects and molecular mechanisms of sunitinib malate on colorectal carcinoma using HCT116, RKO, HT29, and SW480 cell lines in vitro and HCT116-derived xenografts in nude mice in vivo. We employed a comprehensive array of experimental techniques, including CCK-8/MTT assays for cell viability, Transwell and/or wound healing assays for migration, and Western blot and immunohistochemistry for protein expression analysis. Our findings demonstrate that sunitinib malate significantly inhibits colorectal cancer cell proliferation and migration in vitro. Moreover, in the xenograft model, sunitinib malate markedly suppressed colorectal tumor growth in vivo. Notably, we observed significant downregulation of c-MYC, TWIST, and MMP2 expression both in vitro and in vivo following sunitinib malate treatment. These results collectively suggest that sunitinib malate exerts its anti-colorectal carcinoma effects, at least in part, by disrupting the autocrine IL-6/STAT3/c-MYC/TWIST/MMP2 signaling axis.

Osteoarthritis (OA) is a degenerative joint disease that significantly contributes to functional disability, primarily due to inflammation and cell apoptosis. Berberine (BBR) has demonstrated notable anti-inflammatory and antiapoptotic effects in the treatment of OA. However, despite its promising pharmacological properties, the naturally occurring hydrophobic properties and limited solubility in water restrict the efficacy of BBR. Therefore, excipients are required to modify BBR. Oligomeric proanthocyanidins (OPAs) are dimers, trimers, and tetramers of proanthocyanidins (PAs). The unique interface properties of the OPAs underscore their potential as drug carriers. OPAs as natural carriers enhance medication effectiveness and significantly reduce the incidence of side effects. Herein, we developed natural self-assembled nanoparticles between BBR and the OPAs (BBR-OPAs NPs). By adopting the unification of medicines and excipients, the OPAs-based drug delivery system serves as an effective carrier and exerts therapeutic effects in OA treatment. The formation of BBR-OPAs NPs has been core-shell structure, as confirmed by transmission electron microscopy (TEM), 2D NOESY spectroscopy, and molecular dynamics (MD) simulation. The BBR-OPAs NPs exhibited good long-acting release capability due to their strong noncovalent interactions, making them competitive candidates for treating OA. Microcomputed tomography (micro-CT) scanning and histological evaluation further confirmed the efficacy of BBR-OPAs NPs in treating OA. In vivo assessments demonstrated that BBR-OPAs NPs inhibited inflammation and apoptosis, thereby preventing the progression of OA. Furthermore, treatment with BBR-OPAs NPs can inhibit synovial inflammation and protect chondrocytes. OPAs show broad prospects as drug delivery carriers and exhibit great potential in the treatment of OA.

Recent reports have shown that metabolites derived from gut microbiota play a vital role in intestinal diseases, immune regulation, and neuroinflammation. Nowadays, calycosin has been revealed the protective mechanism from different perspectives on cerebral ischemia-reperfusion injury (CIRI), while the effect of gut microbiota-bile acid-farnesoid X receptor (FXR) axis on the inflammatory protection of CIRI has not been explored. To this end, we established a middle cerebral artery occlusion (MCAO) model firstly to assess the protection of calycosin in CIRI through neurological deficit scoring, TTC staining, and HE staining. Secondly, 16s RNA sequencing, ELISA, real-time qPCR, Western blot, and total bile acid (TBA) detection kit were utilized to detect the pharmacology of calycosin on MCAO rats. Our data indicated that calycosin could significantly improve nerve function scores, reduce cerebral infarction volume, lower serum levels of IL-10, IL-17 inflammatory factors, and TBA, increase mRNA and protein levels of ZO-1 and Occludin in brain, as well as FXR, ZO-1 and Occludin levels in colon. In summary, calycosin can exert a neuroinflammatory protective effect on CIRI in rats via regulating the gut microbiota to improve bile acid metabolism.

Osteopenia and sarcopenia are associated with adverse clinical outcomes. This study investigated the impact of osteosarcopenia on short- and long-term outcomes after gastrectomy for gastric cancer.

The present study included patients who underwent gastrectomy for gastric cancer. Osteopenia was evaluated by bone mineral density measurement in the midvertebral core of the 11th thoracic vertebra on preoperative computed tomography images. Sarcopenia was evaluated by measuring the skeletal muscle cross-sectional area at the third lumbar vertebra level. Osteosarcopenia was defined as the coexistence of osteopenia and sarcopenia. We investigated the relationship of preoperative osteosarcopenia with short- and long-term outcomes after gastrectomy for gastric cancer.

Of all 122 patients, 38 (31%) patients were diagnosed with osteosarcopenia. Multivariate logistic regression analysis revealed that osteosarcopenia (P = .008) was an independent risk factor for postoperative complications. Furthermore, multivariate Cox regression analysis revealed that male sex (P = .007), and osteosarcopenia (P = .038) were independent predictors of disease-free survival, while osteosarcopenia (P = .045) and pathological T stage ≥3 (P = .033) were independent predictors of overall survival.

Osteosarcopenia was a strong predictor of short- and long-term outcomes after gastrectomy for gastric cancer. Preoperative screening of osteosarcopenia may be helpful for better management of patients with gastric cancer.

Dietary exposure to aflatoxin B1 (AFB1) can cause acute aflatoxicosis and liver cancer, and is associated with immune suppression and growth impairment, but the molecular mechanisms of the health effects are not fully understood. A non-neoplastic human hepatocyte cell line 16 (HHL-16) was utilized to understand the effects of AFB1 on transcriptome and DNA methylation changes, identifying molecular pathways underlying toxicity and health effects. RNA sequencing and bioinformatic analysis (RNA-Seq) was applied to find the genes and pathways affected by AFB1. Bisulfite pyrosequencing was used to assess DNA methylation levels of CpG sites around promoter regions of gene of interest. RNA-sequencing revealed 280 significantly up-regulated and 296 significantly down-regulated genes in HHL-16 cells after 20 μg/ml AFB1 treatment for 24 h. KEGG pathway enrichment analysis indicated that differentially expressed genes (DEGs) were significantly enriched in the following pathways: cytokine-cytokine receptor interaction, NF-kappa B signalling pathway, TNF signalling pathway, IL-17 signalling pathway, amoebiasis, MAPK signalling pathway, and lipid and atherosclerosis. Further DNA methylation analysis found that there was significant hypomethylation at one CpG site of CCL20 after 20 μg/ml AFB1 treatment on HHL-16 cells for 24 h. In conclusion, AFB1 modulates the expression of genes related to the pathways that play important roles in inflammatory response, growth, and cancers, and demonstrates the effects of AFB1 on DNA methylation.

The ubiquitin-editing enzyme A20 is known to regulate inflammation and maintain homeostasis, but its role in self-DNA-mediated inflammation in acute kidney injury (AKI) is not well understood. Here, our study demonstrated that oxidized self-DNA accumulates in the serum of AKI mice and patients. This oxidized self-DNA exacerbates the progression of AKI by activating the cGAS-STING pathway and NLRP3 inflammasome. While inhibition of the STING pathway only slightly attenuates AKI progression, suppression of NLRP3 inflammasome-mediated pyroptosis significantly alleviates AKI progression and improves the survival of AKI mice. Subsequently, we found that Tnfaip3 (encoding A20) is significantly upregulated following oxidized self-DNA treatment. A20 significantly alleviates AKI development by dampening STING signaling pathway and NLRP3-mediated pyroptosis. Moreover, A20-derived peptide (P-II) also significantly alleviates ox-dsDNA-induced pyroptosis and improves the survival and renal injury of AKI mice. Mechanistically, A20 competitively binds with NEK7 and thus inhibiting NLRP3 inflammasome. A20 and P-II interfere with the interaction between NEK7 and NLRP3 through Lys140 of NEK7. Mutation of Lys140 effects on the interaction of NEK7 with A20 and/or NLRP3 complex. Conditional knockout of NEK7 in macrophages or pharmacological inhibition of NEK7 both significantly rescue AKI mouse models. This study reveals a new mechanism by which A20 attenuates oxidized self-DNA-mediated inflammation and provides a new therapeutic strategy for AKI.

Colorectal cancer (CRC) is among the most prevalent and lethal cancers globally, accounting for approximately 10% of all cancer cases and deaths. Regulatory T (Treg) cells, which accumulate in CRC tissue, suppress anti-tumor immune responses and facilitate tumor progression. This review discusses Treg cell origins and functions, along with the mechanisms by which Tregs influence CRC development. In addition, we highlight therapeutic strategies targeting Tregs-such as immune checkpoint inhibitors and combinatorial approaches-to enhance effector T cell responses. A deeper understanding of Treg-mediated immunosuppression in CRC may inform the design of more effective immunotherapies and precision medicine strategies.

Colorectal cancer (CRC) is a significant worldwide health issue, ranking second in women and third in men. Predictions estimate a rise to 2.5 million cases by 2035, with CRC being the fourth deadliest cancer due to delayed diagnosis and the scarcity of effective treatment options. Over 60% of CRC cases involve MAPK-activated signal pathways, particularly driven by RAS oncogene mutations, which hinder treatment responses, making them 'undruggable.' This study conducts a two-sample Mendelian randomization protein quantitative trait loci (pQTL) analysis to investigate the causal association between plasma proteins and MAPK-activated CRCs. The study indicates that four plasma proteins-MHC class I polypeptide-related sequence B (MICB), complement C4A, C4B, and interleukin-21 (IL-21) are associated with an increased risk of MAPK-activated CRCs. These findings highlight the possibility of utilizing plasma proteins as therapeutic targets and diagnostic markers to advance the fight against CRCs, indicating promising results for more effective interventions. To ascertain and expand upon these discoveries, further research is imperative to fully harness the potential of these discoveries.

Epidermal growth factor (EGF) is recognized for its role in regulating keratinocyte proliferation and differentiation, thereby facilitating the restoration of impaired skin barriers. Nevertheless, challenges related to the penetration and safety of EGF remain to be resolved. In this study, we evaluated the efficacy of TDP1, a transdermal peptide, in enhancing the penetration of EGF through murine skin, utilizing EGF expressed in A. thaliana. The coding sequences of the TDP1 and EGF genes were cloned as a fusion construct into a plant expression vector. The resulting plasmid, pGM3301-TDP1-EGF, was introduced into A. thaliana via the floral dip method. Positive clones were identified using polymerase chain reaction (PCR). High-expression strains were selected through Western-blot analysis and enzyme-linked immunosorbent assay (ELISA). Homozygotes plants were obtained through self-pollination. The impact of the TDP1-EGF fusion protein on the restoration of a compromised epidermal barrier was assessed using dermatoscopy. Keratinocyte (KC) proliferation was examined via hematoxylin and eosin (H&E) staining, while KC differentiation, lipid synthesis, and inflammatory factors were analyzed using reverse transcription quantitative PCR (RT-qPCR) and immunohistochemistry. Compared to other expression systems, the A. thaliana system utilized for TDP1-EGF expression offers the advantages of being devoid of toxicity from endogenous plant substances, rendering it both safe and suitable for scalable production of the recombinant protein. The yield of the TDP1-EGF fusion protein expressed in A. thaliana accounted for 0.0166% of the total soluble protein. EGF conjugated with TDP1 displayed enhanced transdermal activity compared to unconjugated EGF, as evidenced by the Franz diffusion cell assay. Furthermore, the biological efficacy of the TDP1-EGF fusion protein surpassed that of EGF alone in ameliorating epidermal barrier damage in a murine skin injury model. This research has the potential to revolutionize the development and delivery of skincare products and establishes a foundation for the application of molecular farming in skin health.

To elucidate the relationship between circulating cytokines and the prognosis of microsatellite-stable(MSS) colorectal cancer (CRC) patients, we examined the correlation between circulating cytokine levels and tumor immune infiltration microenvironment in this patient population. By conducting a preliminary analysis of the GEO database, we identified five core genes associated with colorectal cancer and further analyzed their impact on immune infiltration. We measured serum cytokine levels and validated the immune infiltration results through immunohistochemical staining of common inflammatory cell markers, including CD3, CD4, CD8, CD163, and FOXP3. Our findings indicate that serum cytokine levels significantly influence immune infiltration in colorectal cancer, particularly IL6 and IFNγ, which play crucial roles. Specifically, the infiltration of M2-type macrophages and CD8 + T cells is correlated with serum levels of IL6 and IFNγ. MSS CRC patients with elevated IL6 expression exhibit improved prognosis.

Bile acids promote the progression of colon adenocarcinoma (COAD), and ursodeoxycholic acid (UDCA) is a key drug in promoting bile acid excretion, but its role in COAD unclear. Our study aims to investigate the relationship between COAD and bile acid metabolism and to assess the feasibility of UDCA for the treatment of COAD.

Firstly, biological targets closely related to COAD were identified: Based on the cancer genome atlas (TCGA) database, the core genes of COAD were obtained by differential expression analysis and weighted gene-coexpression network analysis (WGCNA), and subjected to gene ontology (GO) function annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Secondly, finding a drug by target, after identifying UDCA as a candidate drug, the feasibility of UDCA in treating COAD was verified in reverse: Using databases to collect potential targets for COAD and UDCA, and the intersecting genes were the potential targets for UDCA to exert anti-tumor effects. Then Autodock was used for molecular docking to analyze the interaction between UDCA and core target proteins. Finally, experimental validation was performed: MTT assay, wound healing, transwell migration, and angiogenesis assays were used to detect the effects of UDCA on cell proliferation, migration, invasion, and neovascularization.

2064 differential genes were screened from TCGA. WGCNA obtained the module most relevant to CRC, containing 493 genes. KEGG analysis found that overlapping genes were mainly concentrated in bile acid metabolic pathways. A total of 26 UDCA anti-tumor targets were obtained in database, and 5 core targets were selected by STRING database and Cytoscape software: TNF, CYP27B1, MDM2, MMP2, CASP3. Molecular docking results showed that UDCA had good binding activity with the core targets. In vitro experiment showed UDCA effectively inhibited the proliferation, migration, invasion and neovascularization in colon cancer cells.

The antitumor activity of ursodeoxycholic acid may be related to cell apoptosis, proliferation, migration and vascular neogenesis.

Chronic inflammation of the intestine is a significant risk factor in the development of colorectal cancer. The emergence of colitis and colorectal cancer is a complex, multifactorial process involving chronic inflammation, immune regulation, and tumor microenvironment remodeling. Macrophages represent one of the most prevalent cells in the colorectal cancer microenvironment and play a pivotal role in maintaining intestinal health and the development of colitis-associated colon cancer (CAC). Macrophages are activated mainly in two ways and resulted in three phenotypes: classically activated macrophages (M1), alternatively activated macrophages (M2). The most characteristic of these cells are the pro-inflammatory M1 and anti-inflammatory M2 types, which play different roles at different stages of the disease. During chronic inflammation progresses to cancer, the proportion of M2 macrophages gradually increases. The M2 macrophages secrete cytokines such as IL-10 and TGF-β, which promote angiogenesis and matrix remodeling, and create the favorable conditions for cancer cell proliferation, infiltration, and migration. Therefore, macrophage polarization has a dual effect on the progression of colitis to CAC. The combination of immunotherapy with reprogrammed macrophages and anti-tumor drugs may provide an effective means for enhancing the therapeutic effect. It may represent a promising avenue for developing novel treatments for CAC. In this review, we focus on the process of intestinal macrophage polarization in CAC and the role of intestinal macrophage polarization in the progression of colitis to colon cancer, and review the immunotherapy targets and relevant drugs targeting macrophages in CAC.

Cancer cells grow and survive in the tumor microenvironment, which is a complicated process. As a key part of how colorectal cancer (CRC) progresses, tumor-associated macrophages (TAMs) exhibit a double role. Through angiogenesis, this TAM can promote the growth of cancers. Although being able to modify and adjust immune cells is a great advantage, these cells can also exhibit anti-cancer properties including direct killing of cancer cells, presenting antigens, and aiding T cell-mediated responses. The delicate regulatory mechanisms between the immune system and tumors are composed of a complex network of pathways regulated by several factors including hypoxia, metabolic reprogramming, cytokine/chemokine signaling, and cell interactions. Decoding and figuring out these complex systems become significant in building targeted treatment programs. Targeting TAMs in CRC involves disrupting chemokine signaling or adhesion molecules, reprogramming them to an anti-tumor phenotype using TLR agonists, CD40 agonists, or metabolic modulation, and selectively removing TAM subsets that promote tumor growth. Multi-drug resistance, the absence of an accurate biomarker, and drug non-specificity are also major problems. Combining macrophage-targeted therapies with chemotherapy and immunotherapy may revolutionize treatment. Macrophage studies will advance with new technology and multi-omics methodologies to help us understand CRC and build specific and efficient treatments.

Colorectal cancer (CRC) ranks among the most prevalent cancers globally. Some studies have found that arthritis could reduce the risk of CRC through inflammatory immune mediation. However, there have been no reports on whether arthritis is related to CRC. Therefore, the correlation between arthritis and CRC was investigated to provide some theoretical support for understanding the prevention and diagnosis of CRC.

This study utilized data from the National Health and Nutrition Examination Survey (NHANES) to investigate the relationship between arthritis and CRC among Americans. A total of 300,106 adults participated in the study, and through a questionnaire survey, they were categorized into the control group and the CRC group. In this study, arthritis was considered the exposure variable, and 17 covariates were included. The relationship between the variables and CRC was then revealed through baseline characteristic analysis, association analysis, and stratified analysis. The predictive efficiency of arthritis for the CRC was assessed using the receiver operating characteristic curve (ROC) analysis. Finally, nomogram was created to evaluate the predictive capacity.

A total of 297,681 control subjects and 2,425 CRC subjects within this survey. Significant disparities were observed between the two groups for all variables except for drink and poverty income ratio (PIR). Three models demonstrated a clear association between arthritis and CRC (model 1: odds ratio (OR) = 3.57, 95% confidence interval (CI) = 2.5-5.1, P = 0.00000000025; model 2: OR = 1.71, 95% CI = 1.15-2.53, P = 0.008; model 3: OR = 1.56, 95% CI = 1.03-2.38, P = 0.0369), indicating that the effect of arthritis on CRC was not significantly confounded by other covariates across the three models. Stratified analysis showed that arthritis was positively associated with CRC, and the area under the curve (AUC) was 0.818, indicating that arthritis was more effective in the prognosis of CRC. Finally, the decision curve and calibration curve indicated that the nomogram could effectively predict CRC.

This study found that arthritis had a strong association with the occurrence of CRC, providing ideas and strategies for its early detection.

Early diagnosis and disease management based on risk stratification have a very positive impact on colon adenocarcinoma (COAD) prognosis. It is of positive significance to further explore risk stratification of COAD patients and identify predictive molecular biomarkers. PANoptosis is defined as a form of inflammatory cell death regulated by PANoptosome, with common features of pyroptosis, apoptosis and necroptosis. The role of PANoptosis in COAD has not been fully studied. In this study, we analyzed significant differences in the expression of PANoptosis-related gene (PRG) features in COAD. Subsequently, the PANoptosis associated lncRNAs (PALs) associated with PRGs were analyzed by LASSO algorithm and multivariate Cox analysis, and PALs related to the prognosis of COAD were selected. Based on the expression patterns of prognostic PAL features, we performed unsupervised consensus cluster analysis to categorize COAD samples into distinct PAL molecular subtypes and investigate their associated immune infiltration characteristics. We subsequently constructed PAL score model based on prognostic characteristics and verified its independent prognostic value for COAD. The nomogram diagnostic model was established to confirm the prognostic value of PAL scoring system again. Pathway enrichment analysis, somatic mutation profiling, and drug sensitivity analysis were employed to comprehensively assess the clinical value of the PAL score. Additionally, qRT-PCR was used to further validate the abnormal expression of the selected targets in COAD. Our results provide a new idea for clinical risk stratification and new evidence for the role of PANoptosis in COAD.

Colon inflammation plays an essential role in the development and progression of colorectal cancer. Emerging evidence from clinical and animal studies indicates that metformin may reduce the risk of colorectal cancer through its anti-inflammatory effects.

To investigate the efficacy of metformin in reducing the risk of colorectal cancer and the possible pathways and mechanisms.

The Enterotoxigenic Bacteroides Fragilis (ETBF)/azoxymethane (AOM)/dextran sulfate sodium (DSS) mouse model was established and low-dose metformin (125 mg/kg) or high-dose metformin (250 mg/kg) was administered daily by gavage. Colon tumors were counted, and colon tissue was stained with hematoxylin and eosin (HE) and Periodic Acid-Schiff's and Alcian Blue (PAS-AB). Colon Ki67, ZO-1 Muc2, Claudin-1, Occludin, MPO, reactive oxygen species (ROS), E-cadherin, CD206 and Arg-1 expression were detected by immunohistochemistry or immunofluorescence staining. NF-κB pathway-related protein expression was assessed by Western blot. Fecal short-chain fatty acid (SCFA) levels were also examined.

Our results showed that low- or high-dose metformin ameliorates colonic mucosal damage, reduces colonic inflammation, and eventually inhibits colorectal tumorigenesis in the ETBF/AOM/DSS mouse model. Our further research found that metformin suppresses the expression of TLR4/MyD88/NFκB/MAPK pathway-related proteins, modulates macrophage M2 polarization and increases SCFA levels in colon contents, which may be the mechanisms by which metformin exerts a protective effect against colon carcinogenesis.

Metformin inhibited colorectal tumorigenesis by suppressing the TLR4/MyD88/NFκB/MAPK pathway, modulating macrophage M2 polarization and increasing SCFA levels. It holds promise as a potentially effective treatment for colorectal cancer.

Cardiovascular diseases (CVDs) include atherosclerosis, which is an inflammatory disease of large and medium vessels that leads to atherosclerotic plaque formation. The key factors contributing to the onset and progression of atherosclerosis include the pro-inflammatory cytokines interferon (IFN)α and IFNγ and the pattern recognition receptor (PRR) Toll-like receptor 4 (TLR4). Together, they trigger the activation of IFN regulatory factors (IRFs) and signal transducer and activator of transcription (STAT)s. Based on their promoting role in atherosclerosis, we hypothesized that the inhibition of pro-inflammatory target gene expression through multi-IRF inhibitors may be a promising strategy to treat CVDs. Using comparative in silico docking of multiple IRF-DNA-binding domain (DBD) models on a multi-million natural compound library, we identified the novel multi-IRF inhibitor, ALEKSIN. This compound targets the DBD of IRF1, IRF2, and IRF8 with the same affinity and simultaneously inhibits the expression of multiple IRF target genes in human microvascular endothelial cells (HMECs) in response to IIFNα and IFNγ. Under the same conditions, ALEKSIN also inhibited the phosphorylation of STATs, potentially through low-affinity STAT-SH2 binding but with lower potency than the known multi-STAT inhibitor STATTIC. This was in line with the common inhibition of ALEKSIN and STATTIC observed on the genome-wide expression of pro-inflammatory IRF/STAT/NF-κB target genes, as well as on the migration of HMECs. Finally, we identified a novel signature of 46 ALEKSIN and STATTIC commonly inhibited pro-atherogenic target genes, which was upregulated in atherosclerotic plaques in the aortas of high-fat diet-fed ApoEKO mice and associated with inflammation, proliferation, adhesion, chemotaxis, and response to lipids. Interestingly, the majority of these genes could be linked to macrophage subtypes present in aortic plaques in HFD-fed LDLR-KO mice. Together, this suggests that ALEKSIN represents a novel class of multi-IRF inhibitors, which inhibits IRF-, STAT-, and NF-κB-mediated transcription and could offer great promise for the treatment of CVDs. Furthermore, the ALEKSIN and STATTIC commonly inhibited pro-inflammatory gene signature could help monitor plaque progression during experimental atherosclerosis.

We aim to explore the immunomodulatory properties of T cells on different titanium nanotubes and the key immunological factors involved in this process.

Transcriptome data from GEO database of healthy people and healthy implants were used to analyze cell infiltration and factor distribution of adaptive immune using bioinformatics tools. T cells from activated rat were cultured on titanium nanotubes that were prepared by anodization with different diameters (P-0, NT15-30 nm, NT40-100 nm, NT70-200 nm). The proliferation and expressions of the main transcription factors and cytokines of T-cells were detected. Magnetic bead sorting of CD3+ T cells and transcriptome sequencing were performed to explore the signaling pathways and key immune factors that may influence the related immune responses.

Bioinformatics analysis showed that healthy peri-implant tissues were enriched by the most of T-cell subtypes. T-cell-mediated adaptive immunological responses involved IL-17A. On the third day, the NT15 and NT40 groups showed significantly higher pro-proliferative effects than the NT70 group (P<0.05). Notably, the NT40 group exhibited the lowest T-bet expression (P<0.05) along with the highest levels of Rorγt, Gata3, and Foxp3(P<0.05), followed by the NT15 group. Additionally, the NT40 group demonstrated reduced RANKL, TNF-α, and IL-6 (P<0.05) and increased OPG and IL-10 (P<0.05). Meanwhile, the NT15 group had lower IFN-γ expression(P>0.05) but higher IL-4, and TGF-β1 expressions(P<0.05). Differential expressed genes (DGEs) of T-cell related to the morphologies of titanium nanotubes were mostly enriched in the IL-17 signaling pathway mediated by IL-17A/F. Gene and protein expressions indicated that the NT40 group had the highest secretion in IL-17A of T cells.

Titanium nanotube morphologies in medium (100 nm) and small (30 nm) sizes significantly influence T cell differentiation and immune factor secretion, with T-cell-derived IL-17A likely playing a key regulatory role.

Increased entropy is a common cause of disease and aging. Lifespan entropy is the overall increase in disorder caused by a person over their lifetime. Aging leads to the excessive production of reactive oxygen species (ROS), which damage the antioxidant system and disrupt redox balance. Organ aging causes chronic inflammation, disrupting the balance of proinflammatory and anti-inflammatory factors. Inflammaging, which is a chronic low-grade inflammatory state, is activated by oxidative stress and can lead to immune system senescence. During this process, entropy increases significantly as the body transitions from a state of low order to high disorder. However, the connection among inflammation, aging, and immune system activity is still not fully understood. This review introduces the idea of the ROS-inflammation-immune balance for the first time and suggests that this balance may be connected to aging and the development of age-related diseases. We also explored how the balance of these three factors controls and affects age-related diseases. Moreover, imbalance in the relationship described above disrupts the regular structures of cells and alters their functions, leading to cellular damage and the emergence of a disorganized state marked by increased entropy. Maintaining a low entropy state is crucial for preventing and reversing aging processes. Consequently, we examined the current preclinical evidence for antiaging medications that target this balance. Ultimately, comprehending the intricate relationships between these three factors and the risk of age-related diseases in organisms will aid in the development of clinical interventions that promote long-term health.

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

Colorectal cancer (CRC) is currently ranked as the third most common type of cancer, contributing significantly to mortality and morbidity worldwide. Epigenetic and genetic changes occurred during CRC progression resulted in the cell proliferation, cancer progression, angiogenesis, and invasion. Angiogenesis is one of the crucial steps during cancer progression required for the delivery of essential nutrients to cancer cells and removes metabolic waste. During angiogenesis, different molecules are secreted from tumoral cells to trigger vascular formation including epidermal growth factor and the vascular endothelial growth factor (VEGF). The production and regulation of the secretion of these molecules are modulated by different subcellular pathways such as NF-κB. NF-κB is involved in regulation of different homeostatic pathways including apoptosis, cell proliferation, inflammation, differentiation, tumor migration, and angiogenesis. Investigation of different aspects of this pathway and its role in angiogenesis could provide a comprehensive overview about the underlying mechanisms and could be used for development of further therapeutic targets. In this review of literature, we comprehensively reviewed the current understanding and potential of NF-κB-related angiogenesis in CRC. Moreover, we explored the treatments that are based on the NF-κB pathway.

Background/Objectives: Chronic inflammation and psychosocial factors significantly influence cancer progression and patient behavior in seeking medical care. Understanding their interplay is essential for enhancing early detection and developing personalized treatment strategies. This study aims to develop a comprehensive patient profiling model by comparing non-melanoma skin cancer (NMSC) and colorectal cancer (CRC). The goal is to identify common and distinct patterns in inflammation and psychosocial factors that affect disease progression and clinical presentation. Methods: We conducted a comparative analysis of patients diagnosed with NMSC and CRC, integrating clinical data with sociodemographic and psychological assessments. Advanced neural network algorithms were employed to detect subtle patterns and interactions among these factors. Based on the analysis, a cancer risk assessment questionnaire was developed to stratify patients into low-, moderate-, and high-risk categories. Results: Patients with low systemic inflammation and adequate vagal tone, supported by a stable family environment, demonstrated heightened sensitivity to subclinical symptoms, enabling earlier diagnosis and timely intervention. Conversely, patients with high systemic inflammation and reduced vagal tone, often influenced by chronic stress and unstable family environments, presented at more advanced disease stages. The developed risk assessment tool effectively classified patients into distinct risk categories, facilitating targeted preventive measures and personalized therapeutic strategies. Neural network profiling revealed significant interactions between biological and psychosocial factors, enhancing our understanding of their combined impact on cancer progression. Conclusions: The integrated profiling approach and the newly developed risk assessment questionnaire have the potential to transform cancer management by improving early detection, personalizing treatment strategies, and addressing psychosocial factors. This model not only enhances clinical outcomes and patient quality of life but also offers a framework adaptable to other cancer types, promoting a holistic and patient-centered approach in oncology.

Dysregulation of intestinal homeostasis, characterized by imbalanced immunological proteins, contributes to the pathogenesis of common intestinal diseases, e.g., irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and colorectal cancer (CRC). However, the potential causal relationships between specific immunological proteins and these diseases remain to be fully elucidated. In this study, we employed the bidirectional two-sample Mendelian randomization analysis to infer potential causal relationships between representative immunological proteins and these intestinal diseases. Genome-wide association study (GWAS) summary statistics of IBS, IBD, and CRC were obtained from public databases and utilized in MR analysis. Multiple sensitivity analyses were performed to evaluate the robustness, with p-values adjusted using the Benjamini-Hochberg method for multiple comparisons. Our findings revealed a significant association between IL-1β (OR = 0.783, 95 % CI: 0.676 to 0.908, adjusted P = 0.048) and a decreased risk of IBS. Furthermore, genetic predisposition to IBS was related to the reduced levels of IL-25 (β =  - 0.233, 95 % CI: -0.372 to -0.094, adjusted P = 0.047). Additionally, genetic predisposition to IBD was correlated with elevated levels of IL-6 (β = 0.046, 95 % CI: 0.022-0.069, adjusted P = 0.010). The levels of TNF-α (OR = 1.252, 95 % CI: 1.102 to 1.423, adjusted P = 0.047) were associated with an increased risk of CRC. Our study suggests associations between specific immunological proteins and intestinal diseases, which would provide valuable insights for developing targeted immunomodulation therapies for these conditions. Further investigation into underlying mechanisms remains a research priority in the future.

Defense of the human body against damaging and pathogenic insults is a heavily regulated affair. A primary mechanism of defense at sites of insult are soluble mediators whose defensive maneuvers increase barrier integrity and promote pro-reparative and resolution processes. IL-22 is a cytokine in the IL-10 cytokine family that has garnered increased attention in recent years due to its intimate link in promoting resolution of inflammatory insults, while simultaneously being over expressed in certain fibrotic and chronic inflammatory-skewed diseases. The spatial action of IL-22 centers around the barrier sites of the body, including the skin, lungs, and gut mucosa. As such, a detailed understanding of the role of this cytokine, the producers and responders, and the diseases resulting from over- or under-expression have prominent impacts on a variety of disease outcomes. Herein we present a comprehensive review of IL-22; from historical perspectives and initial discovery, as well as more recent data that dramatically expands on the cellular sources and impact of this cytokine. We aim to showcase the duality of IL-22 and highlight addressable gaps in the field of IL-22 crosstalk and impacts at the ever-important mucosal and tissue barrier sites.

Psoriasis and psoriatic arthritis are chronic inflammatory conditions that constitute a significant global health burden due to their prevalence and impact on quality of life. A deeper comprehension of psoriasis and psoriatic arthritis pathogenesis has recently led to the emergence of novel classes of biologics targeting the IL-23/Th17 pathway. The specific role of interleukin-12, -23, and -17 in cancer as either promoters or inhibitors is under investigation in various studies. Here, we explore the potential role of interleukin-12, -23, and -17 in the development of skin tumours as well as the safety of using their inhibitors in the treatment of psoriasis and psoriatic arthritis, particularly in relation to the risk of melanoma and non-melanoma skin cancer (NMSC) development.

Ammonia, a common toxic gas, posed a hazard to both human and chickens. The Golgi apparatus, an essential organelle, helped maintain the internal environment of the organism and supported the protein foundation for the endoplasmic reticulum to be involved in pyroptosis. Thus, the Golgi apparatus has garnered significant attention. The purpose of our research was to explore the mechanisms of Golgin A7 (Golga7) involved in pyroptosis after chicken exposure to ammonia. To reach our goal, we first created an in vitro ammonia model to study the effect of ammonia on chicken splenic lymphocyte pyroptosis. Then, leveraging this model, we established Golga7 and miR-32-5p knockdown and overexpression models to investigate their roles in ammonia-induced pyroptosis. We found the ultrastructural changes in the nucleus, Golgi apparatus, and mitochondria of chicken splenic lymphocytes exposure to ammonia. The damage of mitochondria increased the level of Reactive Oxygen Species (ROS), which caused the down-regulation of miR-32-5p. The miR-32-5p inhibitor increased the expression of Golga7 and pyroptosis-related genes (NOD-like receptor protein 3 (NLRP3), Cysteine aspartase-1 (Caspase-1), Golgin A3 (Golga3), Nuclear Factor-kappa B (NF-κB), and Tumor Necrosis Factor-alpha (TNF-α)), which induced the pyroptosis, but when miR-32-5p mimic/si-Golga7 (Golga7 inhibitor) was utilized, these effects were reduced. Our research demonstrated that miR-32-5p/Golga7 regulated NLRP3 involving in the pyroptosis of chicken splenic cells exposed to ammonia. Our study provided a valuable foundation for the prevention and treatment chickens ammonia poisoning in the livestock production.

SIGLEC9 (sialic acid-binding Ig-like lectin 9) is a molecule thought to have a significant influence on the immune properties of the colorectal cancer (CRC) tumor microenvironment (TME). In our study, we assessed the expression of the SIGLEC9 protein in CRC tissue and the surgical margin tissue. Using RT-PCR, we analyzed mutations in the KRAS, NRAS, BRAF, PIK3CA, and AKT genes. We observed a significantly elevated expression of the SIGLEC9 protein in CRC tissue compared to the control group. No significant differences were observed in SIGLEC9 protein expression depending on mutations in the KRAS, NRAS, BRAF, PIK3CA, and AKT genes or microsatellite instability (MSI) status. However, we found a significantly higher expression of the SIGLEC9 protein in high-grade tumors compared to the low-grade tumors group. SIGLEC9 expression was significantly associated with the expression of multiple cytokines, chemokines, and growth factors in the CRC TME. These associations suggest the significant potential of SIGLEC9 as a molecule that plays a crucial role in shaping the immune properties of the CRC TME, as well as its potential therapeutic relevance, particularly in the group of high-grade CRC tumors.

Huangqin Tang (HQT), a traditional Chinese medicine formula, is commonly used in clinical practice for the treatment of inflammatory bowel diseases. It has been reported that HQT exerts antitumor effects on colitis-associated colorectal cancer (CAC). However, the mechanism by which HQT interferes with the inflammation-to-cancer transformation remains unclear.

The purpose of this study was to dynamically evaluate the efficacy of HQT in alleviating or delaying CAC and to reveal the underlying mechanism.

We established a mouse model of CAC using azoxymethane combined with 1.5% dextran sodium sulphate. The efficacy of HQT was evaluated based on pathological sections and serum biochemical indices. Subsequently, amino acids (AAs) metabolism analyses were performed using ultra-performance liquid chromatography-tandem mass spectrometry, and the phosphatidylinositol 3 kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) pathway was detected by western blotting.

The data demonstrated that HQT could alleviate the development of CAC in the animal model. HQT effectively reduced the inflammatory response, particularly interleukin-6 (IL-6), in the inflammation induction stage, as well as in the stages of proliferation initiation and tumorigenesis. During the proliferation initiation and tumorigenesis stages, immunohistochemistry staining showed that the expression of the proliferation marker Ki67 was reduced, while apoptosis was increased in the HQT group. Accordingly, HQT substantially decreased the levels of specific AAs in the colon with CAC, including glutamic acid, glutamine, arginine, and isoleucine. Furthermore, HQT significantly inhibited the activated PI3K/AKT/mTOR pathway, which may contribute to suppression of cell proliferation and enhancement of apoptosis.

HQT is effective in alleviating and delaying the colon "inflammation-to-cancer". The mechanism of action may involve HQT maintained AAs metabolism homeostasis and regulated PI3K/AKT/mTOR pathway, so as to maintain the balance between proliferation and apoptosis, and then interfere in the occurrence and development of CAC.

Bovine lactoferrin is a natural iron-binding glycoprotein known for its antimicrobial, antiviral, antitumor, anti-inflammatory, and immunomodulatory properties. In this study, we artificially recombined a fragment of bovine lactoferrin with immunomodulatory and antimicrobial properties to create a novel peptide named LF-MQL. The primary objective was to investigate the effects of LF-MQL on the intestinal tract and immune cells in animals. First, we assessed the in vitro activation effects of LF-MQL on mouse peritoneal macrophages. The results indicated that LF-MQL enhanced the macrophage phagocytic activity and increased IL-1β mRNA expression without significantly affecting IL-6 mRNA levels. Next, we examined the effects of LF-MQL on mucosal immunity by administering LF-MQL orally at doses of 300 mg/kg, 30 mg/kg, and 3 mg/kg to mice. The results demonstrated that different doses of LF-MQL modulated IL-6 and IL-10 mRNA levels in the small intestine. Low doses enhanced the intestinal immune response, while higher doses reduced the inflammatory response. In conclusion, LF-MQL exerts immunomodulatory effects rather than simply boosting immune activity in animal models.

The metabolism of long-chain polyunsaturated fatty acids (LCPUFAs) is closely associated with the risk and progression of colorectal cancer (CRC). This paper aims to investigate the role of LCPUFA in the crosstalk between intestinal microflora and macrophages, as well as the effects of these three parties on the progression of CRC. The metabolism and function of LCPUFA play important roles in regulating the composition of the human gut microflora and participating in the regulation of inflammation, ultimately affecting macrophage function and polarization, which is crucial in the tumor microenvironment. The effects of LCPUFA on cellular interactions between the two species can ultimately influence the progression of CRC. In this review, we explore the molecular mechanisms and clinical applications of LCPUFA in the interactions between intestinal microflora and intestinal macrophages, as well as its significance for CRC progression. Furthermore, we reveal the role of LCPUFA in the construction of the CRC microenvironment and explore the key nodes of the interactions between intestinal flora and intestinal macrophages in the environment. It provides potential targets for the metabolic diagnosis and treatment of CRC.

In the colorectal cancer (CRC) niche, the transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB) are hyperactivated in both malignant cells and tumor-infiltrating leukocytes (TILs) and cooperate to maintain cancer cell proliferation/survival and drive protumor inflammation. Through drug repositioning studies, the anthelmintic drug rafoxanide has recently emerged as a potent and selective antitumor molecule for different types of cancer, including CRC. Here, we investigate whether rafoxanide could negatively modulate STAT3/NF-κB and inflammation-associated CRC. The antineoplastic effect of rafoxanide was explored in a murine model of CRC resembling colitis-associated disease. Cell proliferation and/or STAT3/NF-κB activation were evaluated in colon tissues taken from mice with colitis-associated CRC, human CRC cells, and CRC patient-derived explants and organoids after treatment with rafoxanide. The STAT3/NF-κB activation and cytokine production/secretion were assessed in TILs isolated from CRC specimens and treated with rafoxanide. Finally, we investigated the effects of TIL-derived supernatants cultured with or without rafoxanide on CRC cell proliferation and STAT3/NF-κB activation. The results showed that rafoxanide restrains STAT3/NF-κB activation and inflammation-associated colon tumorigenesis in vivo without apparent effects on normal intestinal cells. Rafoxanide markedly reduces STAT3/NF-κB activation in cultured CRC cells, CRC-derived explants/organoids, and TILs. Finally, rafoxanide treatment impairs the ability of TILs to produce protumor cytokines and promote CRC cell proliferation. We report the novel observation that rafoxanide negatively affects STAT3/NF-κB oncogenic activity at multiple levels in the CRC microenvironment. Our data suggest that rafoxanide could potentially be deployed as an anticancer drug in inflammation-associated CRC.

Although the association between Alzheimer's disease (AD) and constipation is controversial, its causality and underlying mechanisms remain unknown.

To investigate the potential association between slow gut transit and AD using epidemiological data and a murine model.

We conducted a bi-national cohort study in South Korea (discovery cohort, N=3,130,193) and Japan (validation cohort, N=4,379,285) during the pre-observation period to determine the previous diagnostic history (2009-2010) and the follow-up period (2011-2021). To evaluate the causality, we induced slow gut transit using loperamide in 5xFAD transgenic mice. Changes in amyloid-beta (Aβ) and other markers were examined using ELISA, qRT-PCR, RNA-seq, and behavioral tests.

Constipation was associated with an increased risk of AD in the discovery cohort (hazard ratio, 2.04; 95% confidence interval [CI], 2.01-2.07) and the validation cohort (hazard ratio; 2.82; 95% CI, 2.61-3.05). We found that loperamide induced slower gut transit in 5xFAD mice, increased Aβ and microglia levels in the brain, increased transcription of genes related to norepinephrine secretion and immune responses, and decreased the transcription of defense against bacteria in the colonic tissue.

Impaired gut transit may contribute to AD pathogenesis via the gut-brain axis, thus suggesting a cyclical relationship between intestinal barrier disruption and Aβ accumulation in the brain. We propose that gut transit or motility may be a modifiable lifestyle factor in the prevention of AD, and further clinical investigations are warranted.

Maternal immune activation (MIA) is critical for imparting neuropathology and altered behaviors in offspring; however, maternal-fetal immune cell populations have not been thoroughly investigated in MIA-induced autism spectrum disorders (ASDs). Here, we report the single-cell transcriptional landscape of placental cells in both PBS- and poly(I:C)-induced MIA dams. We observed a decrease in regulatory T (Treg) cells but an increase in the M1 macrophage population at the maternal-fetal interface in MIA dams. Based on the Treg-targeting approach, we investigate an immunoregulatory protein, the helminth-derived heat shock protein 90α (Sjp90α), that induces maternal Treg cells and subsequently rescues the autism-like behaviors in adult offspring. Furthermore, in vivo depletion of maternal macrophages attenuates placental inflammatory reaction and reverses behavioral abnormalities in adult offspring. Notably, Sjp90α induces CD4+ T cell differentiation via scavenger receptor A (SR-A) on the macrophage in vitro. Our findings suggest a maternal Treg-targeted approach to alleviate MIA-induced autism-like behavior in adult offspring.