This study investigated the effects of acidifiers (ACD) supplementation level on the growth, immune response, intestinal histology and gene expression of Nile tilapia (Oreochromis niloticus). The experimental diets included three different levels of ACD concentrations: 0 g/kg (CTRL) as the control, 1 g/kg (ACD1), and 2 g/kg (ACD2). These ACD were sprayed onto the diets and fish were fed to Nile tilapia (7.12 ± 0.47 g) for 56 days. The results indicated that increasing the dietary content of ACD significantly enhanced growth performance, as reflected in higher final body weight, specific growth rate, average daily gain, and feed efficiency. The ACD2 diet showed improved outcomes compared to the CTRL diet. Fish fed ACD diets showed significantly higher antioxidant enzyme activity compared to the CTRL diet and were able to maintain their antioxidant status throughout the experiment. The activity of digestive enzymes, including protease, amylase, and lipase, was significantly increased in fish fed diets supplemented with varying levels of 1 and 2 g/kg diet compared to the CTRL diet (P < 0.05). Additionally, significant increases were observed in the thickness of the intestinal muscularis and the width of the intestinal villi in fish fed ACD at concentrations of 1 and 2 g/kg of the diet, compared to the CTRL diet (P < 0.05). Moreover, dietary supplementation with ACD at concentrations of 2 g/kg of the diet significantly upregulated the expression of immune-related genes (P < 0.05). Overall, the use of ACD in fish diets has shown improvements in growth performance, immune responses, and intestinal histology, indicating their potential as a beneficial feed additive for Nile tilapia aquaculture. To the best of our knowledge, recent evaluations of dietary ACD supplementation in practical diets also highlight the influence of ACD supplementation as a feed additive, which could benefit the aquaculture industry.

Silymarin is a natural flavonoid component isolated from the Silybum Marianum (Milk Thistle) plant with multiple pharmacological activities. We investigated its anti-fibrotic effect on the liver and demonstrated its role in activating hepatic progenitor stem cells during liver regeneration.

Hybrid polymeric protein nanoparticles were prepared by loading silymarin with an albumin-hyaluronic acid complex to achieve stem cell targeting and increase silymarin's bioavailability.

TEM, Zeta potential, DLS, UV-visible spectrophotometer, Fluorescence analysis, and FTIR verified the successful formation of nanoparticles and efficient encapsulation. In the present study, The liver fibrotic model was induced by the intraperitoneal injection of carbon tetrachloride, followed by the injection of silymarin NPs into mice twice a week for 4 weeks. We evaluated the expression of hepatic fibrosis markers such as (Collagen I, TGF-β1, SMAD3, and MMP-3) and hepatic progenitor stem cell activation markers such as (HNF1β, FOXl1, CD90, Vimentin, and CD105). The results showed that the targeted silymarin NPs caused significant suppression and downregulation of Collagen I, TGF-β, SMAD-3, and MMP-3 and upregulation of the hepatic progenitor stem cells markers HNF1β, FOXl1, CD90, Vimentin, and CD105. They also didn't induce expression of IL-6, IL-1β, and TNF-α, proving that they cause no signs of inflammation.

The novel point is that these results demonstrated that the targeted Silymarin NPs not only could efficiently alleviate CCl4-induced liver fibrosis more than using only free silymarin; by inhibiting the TGF-β/Smad-3 signaling pathway, but also could activate hepatic progenitor stem cells causing liver regeneration.

Osteogenesis of renal tubular epithelial cells (RTEC) is an important trigger for calcium oxalate (CaOx) kidney stone formation, but whether macrophages are involved in RTEC osteogenesis is unclear. The purpose of this study was to investigate the role and mechanism of macrophages in CaOx kidney stones on RTEC osteogenesis. Oxalate or ethylene glycol was used to construct in vitro and in vivo CaOx kidney stone models, respectively. Macrophage-derived conditioned medium was used to induce osteogenesis in HK-2 cells, and genetic controls and pharmacological interventions were used to investigate the underlying mechanism. The results demonstrated that macrophage-conditioned medium under oxalate intervention facilitated the increase of alkaline phosphatase and calcium salts as well as the upregulation of osteogenic marker genes (BMP2 and RUNX2) expression in HK-2 cells. On the one hand, the knockdown of the JAK2 gene in HK-2 cells reverses the role of macrophage-derived conditioned medium in promoting osteogenesis in HK-2 cells. On the other hand, inhibition of prostaglandin E2 (PGE2) generation in macrophages reverses osteogenesis in HK-2 cells. Moreover, inhibition of PGE2 generation would cure ethylene glycol-induced renal injury and calcium salt deposition, as well as osteogenesis of RTEC. This study illustrates that in the presence of oxalate, macrophages secret PGE2 to activate JAK2/STAT3 signaling in RTEC, which could trigger osteogenesis. It provides new insights into the mechanism of CaOx kidney stone formation.

The aim of this study is to explore the mechanism of benzylurea in the inflammatory injury of human periodontal ligament fibroblasts (hPDLFs).

An inflammation model of hPDLFs was established using LPS. Nuclear transport of nuclear transcription factor-κB (NF-κB), secretion of cytokines, and the morphology and distribution of F-actin were determined. Mitochondrial function was assessed by measuring mitochondrial membrane potential (MMP), mitochondrial permeability transition pore (mPTP), and reactive oxygen species (ROS) levels. The expression of mitochondrial carrier homolog 2 (MTCH2) and Cytochrome b5 type B (CYB5B) was detected.

Benzylurea alleviated the effects of lipopolysaccharide (LPS) on the proliferation and apoptosis of hPDLFs. It reduced the release of inflammatory cytokines and inhibited NF-κB nuclear translocation. Benzylurea improved mitochondrial function by regulating MMP and preventing excessive mPTP opening. Furthermore, LPS elevated the expression of MTCH2 and reduced the expression of CYB5B in hPDLFs. However, these effects can be inhibited by benzylurea. The altered expression of MTCH2 directly affected CYB5B expression, the release of inflammatory cytokines, and the activation of nuclear translocation of NF-κB.

CYB5B may act as an effector of MTCH2, with benzylurea enhancing mitochondrial function and protecting hPDLFs from LPS-induced injury through MTCH2.

Neuroinflammation plays an important role in the pathogenesis of various central nervous system (CNS) diseases. The NLRP3 inflammasome is an important intracellular multiprotein complex composed of the innate immune receptor NLRP3, the adaptor protein ASC, and the protease caspase-1. The activation of the NLRP3 inflammasome can induce pyroptosis and the release of the proinflammatory cytokines IL-1β and IL-18, thus playing a central role in immune and inflammatory responses. Recent studies have revealed that the NLRP3 inflammasome is activated in the brain to induce neuroinflammation, leading to further neuronal damage and functional impairment, and contributes to the pathological process of various neurological diseases, such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, and stroke. In this review, we summarize the important role of the NLRP3 inflammasome in the pathogenesis of neuroinflammation and the pathological course of CNS diseases and discuss potential approaches to target the NLRP3 inflammasome for the treatment of CNS diseases.

Epithelial ovarian cancer (EOC) is a gynecological tumor with high mortality. Despite aggressive treatment, survival rates for patients with advanced EOC are low, and more effective methods of diagnosis and treatment are urgently needed. Inflammation and cancer are strongly associated; however, the mechanisms that mediate this relationship are not fully understood. In this study, we found that the expression of interleukin-1β (IL-1β), a proinflammatory cytokine, increased in an ovarian cancer tissue microarray (TMA) and inhibited A2780 and SKOV3 cell viability and metastasis. Recombinant IL-1β protein and the overexpression of IL-1β decreased the proliferation and metastasis of ovarian cancer cells. IL-1β deficiency promoted proliferation and metastasis. Moreover, transcriptome sequencing revealed that IL-1β downregulates the expression of matrix metalloproteinase 12 (MMP12). The signaling pathway involving MAPK/AP-1/MMP12 is involved in IL-1β-regulated ovarian cancer progression. Overall, we found that the proinflammatory cytokine IL-1β inhibits ovarian cancer cell viability and metastasis. These findings provided deeper insights into inflammation and cancer progression.

Tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI) combination therapy is emerging as a major therapeutic strategy for advanced clear cell renal cell carcinoma (ccRCC). To define the druggable targets for improvement of TKI and ICI combination therapy in ccRCC, we analyzed a commercial protein kinase inhibitor dataset and a public ccRCC dataset and identified LRRK2 as a potential candidate that can be targeted by a small molecule inhibitor. We demonstrated that LRRK2 was transcriptionally upregulated by HIF2A and enabled to drive proliferation of ccRCC cells in a manner independent of its kinase activity. LRRK2 inhibits the RBX1-mediated degradation of lipid metabolism modulator LPCAT1 to reducing the sensitivity to TKI and PD-1 blockade in ccRCC. Specifically, LRRK2/LPCAT1 upregulated IL-1β expression levels through AKT and also increased IL-1β shearing by activating inflammasome. To target the kinase-independent activity of LRRK2, we developed an LR-protac and showed that LR-protac decreased LRRK2 protein level and enhanced the antitumor effect of PD-1 blockade and TKI in ccRCC. These data indicate that LRRK2 is a viable target for improvement of the efficacy of PD-1 blockade and TKI in ccRCC.

Plants release extracellularly lipid bilayer-enclosed vesicles of nanometric size that can be retrieved in their fluids. Plant-derived extracellular vesicles (PDEVs) have mostly been involved in modulating host-pathogen interaction, making them a tool for cross-kingdom communication with a key role in plant immunity. In addition, PDEVs have demonstrated promising therapeutic features, not only in terms of intrinsic nutraceutical properties but also of active molecules' delivery. Transgenic plants have been developed for a variety of purposes, i.e., to improve their functional properties like crops, but also to produce therapeutic molecules. However, it is unclear whether transgenes can end up in PDEVs, thus making them a vehicle for their cross-kingdom diffusion into the environment.

Here, we investigated the association of transgenic DNA and RNA with PDEVs secreted by tobacco (Nicotiana tabacum) engineered to express the neomycine phosphotransferase II (Npt-II) gene. PDEVs were isolated from leaf apoplastic fluid by ultracentrifugation and characterized for their morphology and size. The association of DNA and RNA was assessed by qRT-PCR and their immunomodulatory properties by assaying PDEVs-induced IL1β and IL10 on THP1 monocytes.

Npt-II RNA, but not DNA, could be amplified from PDEVs, whereas no differences were observed between wt and transgenic tobacco PDEVs in terms of immunomodulatory properties.

Although a different behaviour by other types of RNAs or DNAs could still be possible, our findings indicate that in this model, PDEVs are not associated with transgenic DNA, but they can protect RNA, including transgenic RNA, from degradation, contributing to their cross-kingdom spreading.

Understanding how different contributors within the tumor microenvironment (TME) function and communicate is essential for effective cancer detection and treatment. The TME encompasses all the surroundings of a tumor such as blood vessels, fibroblasts, immune cells, signaling molecules, exosomes, and the extracellular matrix (ECM). Subsequently, effective cancer therapy relies on addressing TME alterations, known drivers of tumor progression, immune evasion, and metastasis. Immune cells and other cell types act differently under cancerous conditions, either driving or hindering cancer progression. For instance, tumor-infiltrating lymphocytes (TILs) include lymphocytes of B and T cell types that can invade malignancies, bringing in and enhancing the ability of immune system to recognize and destroy cancer cells. Therefore, TILs display a promising approach to tackling the TME alterations and have the capability to significantly hinder cancer progression. Similarly, exosomes and inflammasomes exhibit a dual effect, resulting in either tumor progression or inhibition depending on the origin of exosomes, type of inflammasome and tumor. This review will explore how cells function in the presence of a tumor, the communication between cancer cells and immune cells, and the role of TILs, exosomes and inflammasomes within the TME. The efforts in this review are aimed at garnering interest in safer and durable therapies for cancer, in addition to providing a promising avenue for advancing cancer therapy and consequently improving survival rates.

Although gemcitabine is a primary chemotherapy for pancreatic cancer, its effectiveness is limited by chemoresistance and nephrotoxicity, posing significant clinical challenges. Therefore, the development of novel therapeutic approaches to prevent pancreatic malignancy remains crucial. This study aimed to investigate the potential of melatonin in enhancing gemcitabine's anticancer efficacy while mitigating its nephrotoxic effects through modulation of the Keap1/p62 pathway. A pancreatic cancer xenograft model was established in rats, which received either gemcitabine (50 mg/kg, I.P.), melatonin (50 mg/kg, I.P.), or their combination three times per week for 2 weeks. Our findings demonstrate that melatonin potentiates gemcitabine's cancer-suppressing effects via modulation of the Kelch-like-ECH associated protein-1 (Keap1)/p62 pathway, resulting in reduced fibrosis, oxidative stress, and inflammatory markers. Additionally, melatonin significantly mitigated gemcitabine-induced nephrotoxicity. These results suggest that melatonin may serve as an adjuvant therapy in pancreatic cancer treatment, enhancing chemotherapy efficacy while reducing its adverse effects.

Research on aged individuals from developed countries show that lifestyle factors such as diet, physical activity, stress, smoking, and sleep quality impact aging. However, other relevant factors may influence aging in less-studied populations, such as Brazilian cohorts. This study aimed to analyze immunosenescence profile of individuals living in an endemic area for several infectious diseases in Brazil. We showed that these individuals exhibited accelerated epigenetic aging and increased production of IL-12p70, IL-17A, and IL-9. Production of inflammatory mediators IL-12p70, IL-6, IL-1β, IL-2, and IL-1ra in individuals with flu-like symptoms and those with COVID-19 was higher among residents in endemic areas than in residents from a control non-endemic area. Furthermore, residents of the endemic area had a more prominent inflammatory profile during viral infection and a different pattern of plasma mediators when compared to residents of a non-endemic area. Our data suggests that these two cohorts had specific immune signatures regardless of the presence or the type of infection at study. Therefore, we demonstrated that there were distinct patterns of immune responses and epigenetic aging depending on the environment the individuals live in. These observations add a layer of diversity to the studies of human aging by including individuals from less represented regions.

The pathogenesis of atopic dermatitis (AD) is closely linked to both genetic and environmental factors, with patients often exhibiting a range of immunological abnormalities, including a pronounced Th2-type overreaction, which is a key feature of the disease.

Cutibacterium acnes has been shown to induce a robust Th1 immune response through intraperitoneal injections, potentially preventing the development of AD. In this study, a novel nanoparticulate formulation of Cutibacterium acnes (NFCA) was developed with the formulation optimization for the dermal delivery.

Sponge Haliclona sp. spicules (SHS) were isolated from the explants of sponge Haliclona sp. with our proprietary method. The NFCA was prepared by high-speed grinding followed by film extrusion. The skin penetration of the model drugs in NFCA with SHS were visualized using confocal microscopy. The therapeutic effects of NFCA coupled with SHSs against AD in mice were assessed by using pathohistological examination and cytokine ELISA assay.

The NFCA particle size was 254.1±39.4 nm, with a PDI of 0.29±0.08 and a Zeta potential of -7.9±0.6 mV. SHS significantly enhanced total skin absorption of FD10K (39.6±6.7%, p=0.00076) as well as deposition in the viable epidermis (3.2±1.6%, p=0.08) and deep skin (dermis & receptor) (36.0±5.9%, p=1.82E-5) compared to the control. In vitro cytotoxicity tests showed that NFCA had low toxicity to HaCaT cells (IC50=63.8 mg/mL). The study confirmed that NFCA can activate immune signaling pathways, promoting the high expression of IL-6 and IL-8 in keratinocytes, enhancing TNF-α and IL-1β expression in macrophages, and inducing Th1 and Th17-type immune responses. Furthermore, we demonstrated that the dermal delivery of NFCA using SHS in vivo significantly reduced epidermal thickness, serum IgE levels, and tissue IL-4 levels, thereby accelerating skin repair and mitigating Th2 polarization.

SHS were employed to effectively deliver NFCA to the deeper skin layers to exert its immune functions. Moreover, the combination of SHS and NFCA can significantly cure mice with atopic dermatitis.

Chronic inflammation and oral dysbiosis are common features of oral squamous cell carcinoma (OSCC). The commensal streptococci, S. anginosus, is increased in oral diseases including OSCC. Our previous work revealed that S. anginosus promotes inflammatory responses from macrophage cell lines, however the molecular mechanism by which S. anginosus interacts with macrophages to instigate this response remains to be investigated. Here, we expand on our previous findings by investigating the effects of S. anginosus infection of primary bone marrow derived macrophages (BMMs) and during in vivo infection. We found S. anginosus activated primary BMMs, which presented an enlarged cellular area, increased NF-κB activation and downstream inflammatory cytokines TNF⍰, IL-6 and IL-1β at 24 hours post infection. S. anginosus viability was dispensable for NF-κB activation, but essential for the induction of downstream inflammatory proteins and cytokines. S. anginosus persisted intracellularly within BMMs and induced the expression of inflammasome sensors AIM2, NLRC4 and NLRP3. Further, BMMs lacking the inflammasome adapter protein ASC ( Asc -/- ) had significantly diminished IL-1β production compared to wild type BMMs, indicating that S. anginosus activated the inflammasome. S. anginosus primarily triggered the inflammasome through NLRP3 as S. anginosus -infected Nlrp3 -/- BMMs and NLRP3 inhibitor (MCC950)-treated wild type BMMs displayed diminished IL-1β production compared to wild type controls. Lastly, S. anginosus -infected Asc -/- and Nlrp3 -/- mice displayed reduced weight loss compared to C57BL/6 mice. These overall findings indicate that S. anginosus replicates within macrophages and promotes a proinflammatory response in part through activation of the NLRP3 inflammasome. brief summary sentence: S. anginosus replicates intracellularly within macrophages and is sensed by the NLRP3 inflammasome to promote proinflammatory response.

Heart failure with preserved left ventricular ejection fraction (HFpEF) is a disease that affects multiple organs throughout the body, accounting for over 50% of heart failure cases. HFpEF has a significant impact on individuals' life expectancy and quality of life, but the exact pathogenesis remains unclear. Emerging evidence implicates low-grade systemic inflammation as a crucial role in the onset and progression of HFpEF. Gut microbiota dysregulation and associated metabolites alteration, including short-chain fatty acids, trimethylamine N-oxides, amino acids, and bile acids can exacerbate chronic systemic inflammatory responses and potentially contribute to HFpEF. In light of these findings, we propose the hypothesis of a "gut microbiota-inflammation-HFpEF axis", positing that the interplay within this axis could be a crucial factor in the development and progression of HFpEF. This review focuses on the role of gut microbiota dysregulation-induced inflammation in HFpEF's etiology. It explores the potential mechanisms linking dysregulation of the gut microbiota to cardiac dysfunction and evaluates the therapeutic potential of restoring gut microbiota balance in mitigating HFpEF severity. The objective is to offer novel insights and strategies for the management of HFpEF.

Accumulation of regulatory T (Treg) cells, an immunosuppressive population, limits the efficacy of immunotherapy in NSCLC. C-C motif chemokine receptor 8 (CCR8) is selectively expressed in tumor-infiltrating Treg cells and is, therefore, considered an ideal target.

The efficacy and safety of anti-CCR8 monotherapy and its combination with programmed cell death protein-1 (PD1) inhibitor were evaluated in four NSCLC-bearing mice models. To track the dynamic changes in tumor microenvironment, we performed the single-cell RNA sequencing, the single-cell T-cell receptor sequencing analysis, the flow cytometry, the multi-color immunofluorescence, and the Luminex assay on tumors after three, seven, 14, and 21 days of different treatment regimens. Then, in vitro and in vivo experiments were applied to validate our findings and explore molecular mechanisms of the synergistic effects.

Across four NSCLC-bearing mice models, the combination of CCR8 antibody and PD1 inhibitor significantly reduced tumor growth (p < 0.05) without obvious mouse body weight drops and systemic cytokine storm. The anti-CCR8 therapy synergizes with PD1 blockade by remodeling the tumor microenvironment and disrupting CCR8+Treg-C-C motif chemokine ligand 5 (CCL5)+ dendritic cells (DC) interaction. Mechanistically, therapeutic depletion of CCR8+Treg cells combined with PD1 inhibitor extremely increased interleukin-12 secretion by the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway activation on CCL5+ DCs, thereby promoting cytotoxic activity of CD8+ T cells. The therapeutic potential of the CCR8 antibody LM-108 in combination with immunotherapy was observed in clinical patients with advanced NSCLC.

Overall, CCR8 expression on tumor-infiltrating Treg cells is correlated with immunosuppressive function on DCs and CD8+ T cells, thus impeding antitumor immunity.

Rheumatoid arthritis (RA) is a prevalent and debilitating autoimmune disease. Numerous studies have demonstrated promising results regarding the use of probiotics as a therapeutic approach to alleviate RA symptoms. This study isolated monocytes from the PBMCs of RA patients and healthy donors. These monocytes were then differentiated into macrophages and divided into five groups: untreated, LPS-treated, L. delbrueckii (Del)-treated, L. rhamnosus (Ram)-treated, and a mixed treatment group. Three macrophage subpopulations-M0, M1, and M2-were identified in all treatment groups, with variations observed in the population percentages of each subpopulation and the expression levels of CD14, CD80, and HLA-DR. Flow cytometry results indicated that, compared to the untreated and LPS-treated groups, treatment with probiotic bacteria (Del, Ram, and Mix) stimulated the polarization of macrophages toward the M2 phenotype while suppressing the percentage of the M1 population. Additionally, the expression of CD14, a Pathogen-Associated Molecular Pattern (PAMP) and phagocytosis-inducing receptor, was significantly reduced in the probiotic-treated groups. Probiotic treatment also profoundly influenced antigen presentation by suppressing CD80, a ligand for the CD28 co-stimulatory marker on T cells, and HLA-DR, which presents antigens to the T cell receptors of Th4 cells. Interestingly, quantitative real-time PCR results indicated that probiotic treatment of macrophages significantly increased the expression of IL-10 and TGF-β, both anti-inflammatory cytokines, while significantly decreasing the expression of inflammatory cytokines, including IL-12, IL-1β, and TNF-α, in both healthy controls and RA patients. It seems that these probiotics may have a regulatory effect on macrophages, affecting their polarization, antigen presentation patterns, phagocytosis, and cytokine secretion profiles. This suggests that these probiotics may have therapeutic and prophylactic effects on RA.

Breast cancer is one of the most common cancers worldwide, 30-50 % of patients with advanced breast cancer develop brain metastasis, causing severe damage to their life quality. Due to the existence of the blood-brain barrier (BBB), brain lesions were recognized to be a unique microenvironment with limited infiltration of circulating immune cells and drugs. However, emerging studies reported the immunology of the brain tumor microenvironment (TME) and indicated the potential of immunotherapy against brain metastases. Therefore, it is of great value to comprehensively investigate the TME and identify the pro-tumoral mechanisms facilitating brain metastases and the crucial molecules involved in this process. In this research, we re-analyzed public data on three brain surgical specimens of breast cancer metastases and identified the immunosuppressive roles of macrophages in the metastatic TME. Then, we conducted the first single-cell RNA sequencing on a murine model of breast cancer brain metastasis. In the brain TME, immune cells showed prominent heterogeneity, especially the mononuclear phagocyte system (MPS). We identified the alteration of macrophage subclusters in the central nerve system (CNS) after breast cancer invasion and found that metastatic cancer cells re-shaped the TME cellular interactions for immune evasion and nutrition supply. Finally, this research could serve as a reference for further analysis of new therapies against brain metastatic lesions.

Modulating immune function is a critical strategy in cancer and atherosclerosis treatments. For cancer, boosting or maintaining the immune system is crucial to prevent tumor growth. However, in vascular disease, mitigating immune responses can decrease inflammation and slow atherosclerosis progression. Anti-inflammatory therapy, therefore, presents a unique dilemma for cancer survivors: while it may decrease cardiovascular risk, it might also promote cancer growth and metastasis by suppressing the immune response. Senescence presents a potentially targetable solution to this challenge; senescence increases the risk of both cancer therapy resistance and vascular disease. Exercise, notably, shows promise in delaying this premature senescence, potentially improving cancer outcomes and lowering vascular disease risk post-treatment. This review focuses on the long-term impact of cancer therapies on vascular health. We underscore the importance of modulating senescence to balance cancer treatment's effectiveness and its vascular impact, and we emphasize investigating the role of exercise-mediated suppression of senescence in improving cancer survivorship.

Thrombosis is a critical complication in lymphomas, driven by chronic inflammation. To observe this systemic mechanism, we evaluated inflammatory cytokines, neutrophil and monocyte activation, and platelet function in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Hodgkin lymphoma (HL), with and without thrombosis using ELISA and flow cytometry according to laboratory and clinical data. Interleukin-1β was elevated across lymphomas and inversely correlated with the Khorana score for venous thromboembolism, while increased tumor necrosis factor-alpha (TNF-α) was inversely associated with the International Prognostic Index (IPI) in thrombosis-associated lymphomas. Neutrophil activation was increased in DLBCL, while elevated neutrophil extracellular traps (NETs) biomarkers were inversely consistent with thrombosis and the ThroLy score. NETs were elevated in HL. Classical monocytes were increased in all lymphoma subtypes, with intermediate and tissue factor (TF)-carrying monocytes elevated in DLBCL and HL. Platelet activation was pronounced, with platelet-monocyte aggregates and platelet-associated TF elevated in DLBCL and FL but not HL. P-selectin was increased in lymphomas with thrombosis, aligned with Khorana and ThroLy scores, and reflected clinical stage while inversely correlating with IPI in non-thrombotic lymphomas. These findings highlight distinct thromboinflammatory mechanisms across lymphoma subtypes, providing insights into biomarkers for thrombosis risk and therapeutic targets in lymphoma management.

Currently, the number of e-cigarette and heated tobacco product (HTP) users are steadily increasing, while the number of classic cigarette users are decreasing. The effects of smoking classic cigarettes on human health have been thoroughly described in the literature, but the negative health effects of e-cigarettes and HTPs on the human body are not clearly defined. Among users of different forms of tobacco, those at a particularly high risk of developing particular disease entities should be identified, allowing for the faster implementation of potential treatments, including psychotherapeutic ones. Biomarkers are used for this purpose. This paper summarizes the potential of these compounds from the different exposure groups of classic cigarettes, e-cigarettes, and HTPs, and presents changes in their concentrations in the body fluids of different tobacco users. This review discusses the impact of tobacco use in relation to levels of the following biomarkers: TNF-α, IL-1β, IL-6, IL-8, IL-17, IFN-γ, IL-10, IL-4, Il-13, TGF-β, VEGF EGF, HGF, BDNF, MMP-9, CRP, microplastics, and selected parameters of oxidative stress. This review also includes suggested forms of treatment, including Tobacco Product Use Reduction Programs, to minimize the potential negative effects of the above-mentioned products.

Astragali Radix (AR), a traditional food and medicinal herb used for thousands of years, is widely recognized for its role in enhancing immunity, particularly when combined with adjuvant chemotherapy. The two primary types of AR available in the market are imitation wild AR (grown for seven years) and cultivated AR (grown for two years). However, whether differences exist in their immune-enhancing effects and chemical constituents remains unclear. In this study, a comparative analysis was performed to evaluate the immune activity and chemical composition of cultivated and imitation wild AR. Immune activity was assessed through in vivo animal studies, while metabolomic analysis was used to characterize their chemical profiles. The results demonstrate that AR possesses significant antitumor and immune-enhancing activities, with imitation wild AR showing superior efficacy compared with cultivated AR. Following 16 days of daily AR treatment, both the thymus and spleen coefficients were significantly increased, effectively reversing the immune dysfunction induced by cyclophosphamide (CTX). Moreover, the administration of AR showed no significant toxicity, as evidenced by the stable liver and kidney function indicators, including ALT, UREA, and CRE levels. To investigate chemical differences, a customized chemotaxonomic-based in-house library containing 215 compounds was developed and integrated with the Progenesis QI informatics platform for metabolite annotation. Using multivariate analysis, 48 constituents were identified in total: 46 unique to the imitation wild AR and 45 specific to the cultivated AR. The correlation between chemical constituents and the pharmacological effects of AR was evaluated. Based on orthogonal partial least-squares discriminant analysis (OPLS-DA) and S-plot analysis, five potential biomarkers were identified, including Calycosin-7-glucoside, Rhamnocitrin-3-O-β-D-glucopyranoside, Ononin, 3,5-Dicaffeoylquinic acid, and Acetylastragaloside I. These biomarkers likely account for the differences in immune-enhancing effects between the two AR types. This study provides a scientific foundation for the rational use of Astragali Radix.

Macrophages are highly variable immune cells that are important in controlling inflammation and maintaining tissue balance. The ability to polarize into two major types-M1, promoting inflammation, and M2, resolving inflammation and contributing to tissue repair-determines their specific roles in health and disease. M2 macrophages are particularly important for reducing inflammation and promoting tissue regeneration, but their function is shaped mainly by surrounding cells. This is evident in obesity, diabetes, and chronic inflammation. Although many cytokines regulate macrophage polarization, interleukin-6 (IL-6) and interleukin-1β (IL-1β) are major players, but their effects on M2 macrophage behavior under metabolic stress remain unclear. This study describes the intricacies within M2 macrophages concerning IL-6 and IL-1β signaling when under metabolic stress. Though, more frequently than not, IL-6 is labelled as pro-inflammatory, it can also behave as an anti-inflammatory mediator. On the other hand, IL-1β is the main pro-inflammatory agent, particularly in metabolic disorders. The relationship between these cytokines and the macrophages is mediated through important pathways such as JAK/STAT and NFκB, which get perturbed by metabolic stress. Therefore, metabolic stress also alters the functional parameters of macrophages, including alterations in mitochondrial metabolism, glycolytic and oxidative metabolism. Phosphorylation alters the kinetics involved in energy consumption and affects their polarization and their function. However, it has been suggested that IL-6 and IL-1β may work in concert or competition when inducing M2 polarization and, importantly, implicate cytokine release, phagocytic activity, and tissue repair processes. In this review, we discuss the recent literature on the participation of IL-6 and IL-1β cytokines in macrophage polarization and how metabolic stress changes cytokine functions and synergistic relations. A better understanding of these cytokines would serve as an important step toward exploring alternative antiviral strategies directed against metabolic disturbance and, hence, approve further endeavors.

Background: Canakinumab, a humanized anti-IL-1β monoclonal antibody, is known for its ability to suppress IL-1β-mediated inflammation. However, continuous monitoring of its safety remains essential. Thus, we comprehensively evaluated the safety signals of canakinumab by data mining from FAERS. Methods: We used a disproportionate analysis to quantify canakinumab-related adverse events (AEs) using four algorithms. Clinical prioritization of the detected signals was assessed with a semiquantitative score method. Serious and non-serious outcomes were compared by statistical methods. Additionally, a stratification analysis of serious infections was conducted at the system organ class (SOC) level. Results: A total of 28,496 canakinumab-related AEs were collected, and 71 suspicious signals detected. Among these, 19 preferred terms (PTs) were identified as unexpected signals, including deafness, appendicitis, brain oedema, cushingoid, cellulitis, and papilledema. Of the AEs, 16 were more likely reported as serious outcomes, such as pneumonia, abdominal pain, deafness, and infection. Based on clinical priority score, 44 PTs were classified as weak, 27 as moderate, and none as strong. Furthermore, 30 PTs demonstrated a high level of evidence, primarily derived from FDA prescribing information, randomized controlled trials, and systematic reviews. Stratification analysis of infections and infestations (serious outcomes) revealed a stronger association of severe infections with canakinumab in older or heavier individuals. All positive signals followed an early failure pattern, with the incidence of canakinumab-associated AEs decreasing over time. Conclusions: We found that most of the suspicious signals were associated with infections. More attention should be paid to serious infections, particularly in males, individuals aged ≥60 years, or those weighing >100 kg, who demonstrated the highest risk of serious infections.

The first part of this review highlighted the evolving landscape of atherosclerosis, noting emerging cardiometabolic risk factors, the growing impact of exposomes, and social determinants of health. The prominent role of atherosclerosis in the bidirectional relationship between cardiovascular disease and cancer was also discussed. In this second part, we examine the complex interplay between multimorbid cardio-oncologic patients, cardiometabolic risk factors, and the harmful environments that lend a "syndemic" nature to these chronic diseases. We summarize management strategies targeting disordered cardiometabolic factors to mitigate cardiovascular disease and explore molecular mechanisms enabling more tailored therapies. Importantly, we emphasize the early interception of atherosclerosis through multifactorial interventions that detect subclinical signs (via biomarkers and imaging) to treat modifiable risk factors and prevent clinical events. A concerted preventive effort-referred to by some as a "preventome"-is essential to reduce the burden of atherosclerosis-driven chronic diseases, shifting from mere chronic disease management to the proactive promotion of "chronic health".

Targeting the TGF-β pathway in tumor therapy has proven challenging due to the highly context-dependent functions of TGF-β. Integrin αvβ8, a pivotal activator of TGF-β, has been implicated in TGF-β signaling within tumors, as demonstrated by the significant anti-tumor effects of anti-αvβ8 antibodies. Nevertheless, the expression profile of αvβ8 remains a subject of debate, and the precise mechanisms underlying the anti-tumor effects of anti-αvβ8 antibodies are not yet fully elucidated.

We utilized single-cell RNA sequencing to assess αvβ8 expression across various human tumors. An anti-αvβ8 antibody was developed and characterized for its binding and blocking properties in vitro. Cryo-EM single-particle analysis was employed to study the detailed interaction between αvβ8 and the antibody Fab fragment. The anti-tumor efficacy of the antibody was evaluated in syngeneic mouse models with varying levels of αvβ8 expression, both as a monotherapy and in combination with PD-1 antibodies. Human PBMCs were isolated to investigate αvβ8 expression in myeloid cells, and macrophages were exposed to the antibody to study its impact on macrophage polarization. Pharmacokinetic studies of the αvβ8 antibody were conducted in cynomolgus monkeys.

Integrin αvβ8 is notably expressed in certain tumor types and tumor-infiltrating macrophages. The specific αvβ8 antibody 130H2 demonstrated high affinity, specificity, and blocking potency in vitro. Cryo-EM analysis further revealed that 130H2 interacts exclusively with the β8 subunit, without binding to the αv subunit. In vivo studies showed that this antibody significantly inhibited tumor growth and alleviated immunosuppression by promoting immune cell infiltration. Furthermore, combining the antibody with PD-1 inhibition produced a synergistic anti-tumor effect. In human PBMCs, monocytes exhibited high αvβ8 expression, and the antibody directly modulated macrophage polarization. Tumors with elevated αvβ8 expression were particularly responsive to 130H2 treatment. Additionally, favorable pharmacokinetic properties were observed in cynomolgus monkeys.

In summary, integrin αvβ8 is highly expressed in certain tumors and tumor-infiltrating macrophages. Targeting αvβ8 with a blocking antibody significantly inhibits tumor growth by modulating macrophage polarization and enhancing immune cell infiltration. Combining αvβ8 targeting with PD-1 treatment markedly increases the sensitivity of immune-excluded tumors. These results support further clinical evaluation of αvβ8 antibodies.

Human papillomavirus (HPV) infection is closely related to upper respiratory mucosal lesions, and the most common disease is adult upper respiratory papilloma, which has a certain probability of cancer transformation.This study conducted in vitro tissue and cell experiments to explore the inflammatory mechanisms associated with HPV + adult laryngeal papilloma.

We compared differential expression of AIM2 and IL-1β between HPV (High-risk) negative and positive adult laryngeal papilloma patients. In vitro experiments were conducted to investigate the differences in expression of AIM2, Caspase-1, and IL-1β in HPV- and HPV+ upper respiratory mucosal cells.

The expression level of AIM2 and IL-1β was higher in HPV (High-risk) positive papilloma tissue than HPV (High-risk) negative papilloma tissue. The expression of AIM2, Caspase-1, and IL-1β in HPV+ cells was also significantly higher than in HPV- cells.

The expression of IL-1β mediated by AIM2 was associated with chronic inflammation of upper respiratory mucosal tissue caused by HPV infection, and it may yet be associated with further pathological changes.

Viral infections are a significant factor in the etiology of various cancers, with the tumor microenvironment (TME) playing a crucial role in disease progression. This review delves into the complex interactions between viruses and the TME, highlighting how these interactions shape the course of viral cancers. We explore the distinct roles of immune cells, including T-cells, B-cells, macrophages, and dendritic cells, within the TME and their influence on cancer progression. The review also examines how viral oncoproteins manipulate the TME to promote immune evasion and tumor survival. Unraveling these mechanisms highlights the emerging paradigm of targeting the TME as a novel approach to cancer treatment. Our analysis provides insights into the dynamic interplay between viruses and the TME, offering a roadmap for innovative treatments that leverage the unique characteristics of viral cancers.

Head and neck squamous cell carcinoma (HNSCC) is a very aggressive disease characterized by a heterogeneous tumor immune microenvironment (TIME). Tumor-associated macrophages (TAMs) constitute the major innate immune population in the TIME where they facilitate crucial regulatory processes that participate in malignant tumor progression. SPP1 + macrophages (SPP1 + Macs) are found in many cancers, but their effects on HNSCC remain unknown. This study aimed to identify and validate the role and function of SPP1 + Macs in the malignant progression of HNSCC.

In this study, we applied single-cell RNA sequencing (scRNA-seq) analyses of paired tumor and normal tissues from 5 HNSCC patients to identify tumor-specific SPP1 + Macs. RT-qPCR and multiplex immunohistochemical and multiplex immunofluorescence staining were used to verify the presence of SPP1 + Macs in the clinical samples. Gene set variation analysis suggested that SPP1 + Macs were actively involved in cytokine production. Thus, we constructed SPP1-OE macrophages and SPP1-KD macrophages (both differentiated from THP-1 cells), performed a Luminex liquid suspension chip detection assay to detect differential cytokines, and further assessed their biological functions and mechanisms in several HNSCC cell lines and adjacent macrophages. An in vivo experiment was used to verify the function of SPP1 + Macs in HNSCC progression.

The scRNA-seq results revealed that myeloid cells were heterogeneous and strongly correlated with tumor cells in the TIME in HNSCC and identified tumor-specific SPP1 + Macs, which were positively correlated with poor prognosis of HNSCC patients. Gene set variation analysis (GSVA) suggested that SPP1 + Macs were actively involved in cytokine production. Luminex liquid suspension chip detection assay indicated that SPP1 + Mac-derived TNF-α and IL-1β played important roles. Both in vitro and in vivo experiments and the use of VGX-1027, an inhibitor of macrophage-derived TNF-α and IL-1β, confirmed that SPP1 + Mac-derived TNF-α and IL-1β promoted HNSCC progression by supporting tumor cell proliferation and migration. Mechanistically, we found that TNF-α and IL-1β were upregulated due to NF-kappa B signaling pathway activation in SPP1 + Macs. Moreover, SPP1 + Mac-derived TNF-α and IL-1β promoted the expression of OPN in both tumor cells and other adjacent macrophages through different signaling pathways.

SPP1 + Macs increase the secretion of TNF-α and IL-1β via the NF-kappa B pathway to promote HNSCC cell proliferation, and TNF-α and IL-1β in turn upregulate the expression of OPN in tumor cells and macrophages; thus, SPP1 + Macs may be a candidate target through which antitumor efficacy can be enhanced.

Chemotherapy is often combined with immune checkpoint inhibitor (ICIs) to enhance immunotherapy responses. Despite the approval of chemo-immunotherapy in multiple human cancers, many immunologically cold tumors remain unresponsive. The mechanisms determining the immunogenicity of chemotherapy are elusive. Here, we identify the ER stress sensor IRE1α as a critical checkpoint that restricts the immunostimulatory effects of taxane chemotherapy and prevents the innate immune recognition of immunologically cold triple-negative breast cancer (TNBC). IRE1α RNase silences taxane-induced double-stranded RNA (dsRNA) through regulated IRE1-dependent decay (RIDD) to prevent NLRP3 inflammasome-dependent pyroptosis. Inhibition of IRE1α in Trp53-/- TNBC allows taxane to induce extensive dsRNAs that are sensed by ZBP1, which in turn activates NLRP3-GSDMD-mediated pyroptosis. Consequently, IRE1α RNase inhibitor plus taxane converts PD-L1-negative, ICI-unresponsive TNBC tumors into PD-L1high immunogenic tumors that are hyper-sensitive to ICI. We reveal IRE1α as a cancer cell defense mechanism that prevents taxane-induced danger signal accumulation and pyroptotic cell death.

Many countries use commercial foot-and-mouth disease (FMD) vaccines to prevent FMD pandemics, but these vaccines have disadvantages, such as repeated vaccinations due to the short persistence of antibody (Ab) titers and incomplete host defense despite high Ab titers. To address these shortcomings, we aimed to develop a novel FMD vaccine containing furfurman as an adjuvant.

To demonstrate the efficacy of the test vaccine, adaptive immunity was evaluated by measuring Ab and neutralizing Ab titers and host defense against viral infections in experimental and target animals. In addition, the expression levels of cytokines [interferon (IFN)α, IFNβ, IFNγ, interleukin (IL)-1β, IL-2, and IL-12p40] were evaluated at the early stages of vaccination to confirm the simultaneous induction of cellular and humoral immune responses induced by the test vaccine.

The groups that received vaccine containing furfurman showed a strong early, mid-term, and long-term immune response and host defense against viral infections compared to the control groups. The significant upregulation observed in cytokine levels in the furfurman group compared to those in the control groups strongly suggest that the test vaccine strengthens cellular immune response and effectively induces a humoral immune response.

Our study demonstrated that furfurman, as an FMD vaccine adjuvant, achieves long-lasting immunity and host defense against viral infections by eliciting potent cellular and humoral immune responses. Therefore, our findings contribute to the design of next-generation FMD vaccines and highlight the potential application of furfurman as an adjuvant for other viral diseases.

Interleukin 1 (IL-1) is a pro-inflammatory cytokine that plays a key role in the development and regulation of nonspecific defense and specific immunity. However, its regulatory influence extends beyond inflammation and impacts a range of immune and non-immune processes. The involvement of IL-1 in numerous biological processes, including modulation of inflammation, necessitates strict regulation at multiple levels. This review focuses on these regulatory processes and discusses their underlying mechanisms. IL-1 activity is controlled at various levels, including receptor binding, gene transcription, expression as inactive proforms, and regulated post-translational processing and secretion. Regulation at the level of the receptor expression - alternative splicing, tissue-specific isoforms, and gene polymorphism - is also crucial to IL-1 functional activity. Understanding these regulatory features of IL-1 will not only continue to shape future research directions but will also highlight promising therapeutic strategies to modulate the biological effects of IL-1.

Ovarian cancer (OvCa) is the most lethal gynaecology malignancies worldwide. Neutrophil extracellular traps (NETs), net-like protein structures produced by activated neutrophils and DNA-histone complexes, have a central role in tumours, though haven't been fully explored in OvCa. We obtained transcriptome data from TCGA-OvCa database (n = 376) as training, ICGC-OvCa database (n = 111) as validation and GTEx database (n = 180) as controls. Through LASSO-COX Regression analysis, we identified an eight-gene signature among 87 NETs-related genes, which was significantly related to poor prognosis in both TCGA-OvCa and ICGC-OvCa cohorts (Log-rank p-value = 0.0003 and 0.0014). Next, we constructed and validated a prognostic nomogram, consist of NETs-related signature and clinical features (C-index = 0.82). We evaluated 22 typical immune cell infiltration through CIBERSORT analysis, which implied upregulation of memory CD4 + T cells, follicular helper T cells and neutrophils in high-risk group. Additionally, we predicted therapy sensitivity through TIDE algorithm, indicating that high NETs-riskscore exhibited more sensitivity towards Sorafenib and less sensitivity towards immunotherapy. We initially reported that RAC2 upregulation was associated with NETs formation and poor prognosis (p-value < 0.05) through IHC analysis of tissue microarrays (n = 125). Conclusively, NETs-related signature was reliable for OvCa prognosis prediction and therapy assessment. Especially, RAC2 was predominantly related to NETs formation, thus providing hints towards anti-tumour mechanism of NETs in OvCa.

6-hydroxy-L-nicotine (6HLN) is a nicotine (NIC) derivative with proven therapeutic potential in neurodegenerative disorders. Here, the impact of 6HLN on cell growth, migratory behavior, and inflammatory status of three different cancer cell lines (A549, MCF7, and U87) and two normal cell lines (16HBE14o and MCF10A) was investigated. In silico analyses were conducted to evaluate the binding affinity of 6HLN to nicotinic receptors (nAChRs) containing α9 and α5 subunits. The obtained in silico data revealed that 6HLN might act on the cholinergic system. Interestingly, the in vitro data showed the compound has cancer-stimulatory effects in U87 glioblastoma cells and cancer-inhibitory effects in MCF7 breast cancer cells. In A549 lung cancer cells, no changes were detected upon 6HLN administration. More importantly, 6HLN appears not to be deleterious for normal cells, with the viability of 16HBE14o pulmonary cells and MCF10A mammary cells remaining unchanged.

Surgery, chemotherapy, and radiation often have limited utility for advanced metastatic disease in the liver, and despite its promising activity in select cancers, PD-1 blockade therapy similarly has minimal benefit in this setting. Curaxin, CBL0137, is an experimental anti-cancer drug that disrupts the binding of DNA to histones, destabilizes chromatin, and induces Z-DNA formation which may stimulate anti-tumor immune responses.

Murine cell lines of colon (CT26) and breast (4T1) cancer were interrogated for survival and CBL0137-associated DNA changes in vitro. Immunocompetent models of liver metastases followed by CBL0137 hepatic arterial infusion (HAI) were used to examine in vivo tumor cell DNA alterations, treatment responses, and the immune contexture associated with CBL0137, both alone and in combination with anti-PD-1 therapy.

CBL0137 induced immediate changes to favor tumor cell death in vitro and in vivo with an efficient tumor uptake via the HAI route. Toxicity to CBL0137 was minimal and anti-tumor treatment effects were more efficient with HAI compared to intravenous delivery. Immune effects were pronounced with CBL0137 HAI with concurrent depletion of a specific population of myeloid-derived suppressor cells and maintenance of effector T cell populations.

Combination of CBL0137 HAI with PD-1 blockade improved survival in 4T1 tumors but not in CT26 tumors, and therapeutic efficacy relies on the finding of simultaneous and targeted depletion of myeloid-derived suppressor cells and skewing of T cell populations to produce synergy with PD-1 blockade therapy.