IL-6 Production Research Articles

Azurocidin is Associated with Dienogest-resistance in Ovarian Endometriotic Cysts.

Endometriosis and ovarian endometrioma (OMA) cause dysmenorrhea and infertility. Current hormonal therapies for OMA treatment, may exhibit limited effectiveness. Hormonal treatments function by downregulate estrogen receptors (ERs) via progesterone receptor (PR) signaling; therefore, progestins are used for the treatment of endometriosis. Dienogest (DNG), an oral progestin, is highly selective for PRs. Previously we identified the association of azurocidin with DNG resistance. Herein, we aimed to examine the effect of azurocidin on OMAs and its clinical significance. We examined the effect of azurocidin on PR or ER and the action of DNG on the inflammatory cytokines IL-6 and IL-8 in OMAs used the human immortalized endometriotic epithelial Emosis-CC/TERT1 cell line, and measured azurocidin levels in human biological samples. DNG inhibited IL-6 and IL-8 production in vitro, which was suppressed in the presence of azurocidin. Additionally, the inflammatory cytokines IL-6 and IL-8 enhanced azurocidin production. Furthermore, azurocidin induced ER expression; the proliferation of EMosis-CC/TERT1 cells increased significantly upon incubation with 17β-estradiol and azurocidin. Overall, azurocidin inhibits the action of DNG by increasing estrogen sensitivity via promoting ER expression and endometriosis. Azurocidin concentrations in the blood and urine were higher in patients resistant to DNG therapy than in other patients. Thus, azurocidin may be associated with DNG resistance in OMAs.

Human MAIT cell response profiles biased toward IL-17 or IL-10 are distinct effector states directed by the cytokine milieu

Mucosal-associated invariant T (MAIT) cells are unconventional T cells that mediate rapid antimicrobial immune responses to antigens derived from microbial riboflavin pathway metabolites presented by the evolutionarily conserved MR1 molecules. MAIT cells represent a large pre-expanded T cell subset in humans and are involved in both protective immunity and inflammatory immunopathology. However, what controls the functional heterogeneity of human MAIT cell responses is still largely unclear. Here, combining functional and transcriptomic analyses, we investigate how MAIT cell response programs are influenced by the cytokine milieu at the time of antigen recognition. Activation by MR1-presented antigen together with IL-12 induces intermediate levels of IFNγ and TNF, as well as a regulatory profile with substantial IL-10 production and elevated expression of TIM-3, LAG-3, and PD-1. Activation by the combination of antigen and IL-12 induces a c-MAF-dependent program required for IL-10 production. The MAIT cell-derived IL-10 mediates both autocrine and paracrine immune regulation. In contrast, coactivation of MAIT cells with IL-18 induces IL-17, GM-CSF, IFNγ, and TNF, without IL-10. Notably, IL-18 dominantly counteracts IL-10 expression. The activation states biased toward IL-10 or IL-17 production are reversible and do not represent stable subsets. Finally, MR1-restricted TCR-mediated activation without cytokine coactivation drives primarily granzyme B cytolytic arming. Altogether, these findings demonstrate that human MAIT cells adapt their functional effector response during antigen recognition to cytokine cues in the microenvironment, and identify programs biased toward either regulatory c-MAF-dependent IL-10 expression, or an inflammatory IL-17 and GM-CSF profile.

Regulation of IL-10 production in dendritic cells is controlled by the co-activation of TLR2 and Mincle by Lactiplantibacillus plantarum OLL2712.

We showed that Lactiplantibacillus plantarum OLL2712 (OLL2712) strongly induces interleukin (IL)-10 production in immune cells. Although beneficial effects of this strain have been observed in both mice and humans, the mechanisms underlying IL-10 induction remain unclear. In this study, we found that OLL2712 co-activates two pattern recognition receptors, leading to IL-10 production in the mouse-derived thermosensitive dendritic cell line, tsDC. We first revealed the involvement of the Toll-like receptor (TLR)2-Myeloid differentiation primary response gene (MYD) 88 pathway in OLL2712-induced IL-10 production in tsDCs. However, stimulation with the TLR2 agonist alone was insufficient to induce IL-10 production. Consequently, we explored additional signaling pathways and found that the phosphorylation of spleen tyrosine kinase (Syk) was important in response to OLL2712, which was not triggered by a TLR2 agonist alone. Notably, the activation of Syk was found to depend on macrophage-inducible C-type lectin receptor (Mincle), one of the C-type lectin receptors. However, the surface-expressed Mincle is not responsible for the IL-10 production by OLL2712. Instead, it depends on the incorporation of OLL2712 into tsDCs, suggesting that Mincle recognizes incorporated OLL2712 intracellularly. In summary, OLL2712 is initially recognized by TLR2, which subsequently induces the expression of Mincle to recognize incorporated OLL2712, ultimately inducing IL-10 production.IMPORTANCEThe objective of this study is to elucidate the mechanism by which Lactiplantibacillus plantarum OLL2712 (OLL2712), previously identified by our research group as a potent stimulator of interleukin-10 production in immune cells, exerts its immunomodulatory effects. Our findings indicate that OLL2712 acts in synergy with two pattern-recognition receptors: Toll-like receptor 2 and Macrophage inducible C-type lectin receptor (Mincle). Additionally, we observed that OLL2712 needs to be internalized intracellularly to be recognized by Mincle. These findings represent the first insights into the detailed mechanism underlying the anti-inflammatory effects of OLL2712.

Chemical Composition and Antiulcer Effects of Filipendula palmata in Mice.

Filipendula palmata (Pall) Maxim, is a wild edible herb in Northeast China. However, little is known about its constituents and bioactivities. In this study, the gastroprotective effect of the n-butanol fraction of F. palmata in mice induced by ethanol was investigated. The chemical research was performed using multiple chromatographic approaches. In addition, the active component and mechanism of action were researched. The results showed that F. palmata significantly alleviated ulcer damage in mice, prevented gastric mucosa from the lesion induced by absolute ethanol, increased superoxide dismutase and catalase levels, and decreased malondialdehyde content. Further study revealed that F. palmata downregulated the production of TNF-α and IL-6 in serum and the expression in LPS-induced RAW 264.7 cells. The chemical study led to the isolation of thirteen compounds, one of which exhibited significant anti-inflammatory activities by facilitating the polarization of macrophages. Our work revealed that F. palmata possessed gastroprotective efficacy, and anti-inflammation and antioxidation were involved in the mechanisms. The main components in the n-butanol fraction of F. palmata, flavonoids, having an anti-inflammatory effect in RAW 264.7 cells, might be related to the antiulcer activity.

Proteomic profiling of serum in cats with naturally occurring degenerative joint disease and co-morbid conditions

IntroductionDegenerative joint disease (DJD) occurs very commonly in cats and can be associated with pain. Almost 70% of cats with DJD-associated pain suffer the co-morbidity of chronic kidney disease (CKD). There are currently very limited treatment or management options. A greater understanding of the systems biology of DJD, DJD-associated pain, and CKD may contribute to identifying disease specific biomarkers and relevant targets for the development of therapeutics for the control of these conditions in cats, and help inform human pain therapeutic development.MethodsUsing mass spectrometry-based proteomic profiling of the serum of 200 highly phenotyped cats with varying burdens of DJD, pain, and CKD, we identified significant individual proteins and pathways.ResultsFunctional pathway analysis, based on differentially abundant proteins across individual disease states (DJD, pain, CKD), identified pathways playing a role in DJD and DJD-associated pain including acute phase response signaling, LXR/RXR and FXR/RXR activation and the complement system. With the added co-morbidity of CKD, similar pathways were identified, with the addition of IL-12 signaling and production in macrophages.DiscussionWe identified differentially abundant proteins associated with DJD, pain and CKD and future work should evaluate these proteins as potential biomarkers of disease (individually or as clusters). Further, these data could be leveraged to identify novel therapeutic targets to address the gap in our ability to manage DJD, pain, and CKD in cats. Given that our work was in cats with naturally occurring DJD, these results may have translational applicability to human health.

Staphylococcus aureus induces mitophagy via the HDAC11/IL10 pathway to sustain intracellular survival.

The immune evasion and prolonged survival of Staphylococcus aureus (S. aureus) within macrophages are key factors contributing to the difficulty in curing osteomyelitis. Although macrophages play a vital role as innate immune cells, the mechanisms by which S. aureus survives within them and suppresses host immune functions remain incompletely understood. This study employed confocal microscopy, flow cytometry, ELISA, and siRNA technology to assess the survival capacity of S. aureus within macrophages and the impact of inflammatory cytokines on its persistence. Proteomics was used to investigate the potential mechanisms and differential proteins involved in S. aureus intracellular survival. Additionally, confocal microscopy, flow cytometry, Mdivi-1 intervention, and Western blot were utilized to validate the role of mitophagy in supporting S. aureus survival. The study further explored how the HDAC11/IL10 axis enhances mitophagy to promote intracellular S. aureus survival by using HDAC11 overexpression, siRNA, and rapamycin intervention combined with confocal microscopy and flow cytometry. The findings demonstrated that IL10 promotes mitophagy to clear mitochondrial reactive oxygen species (mtROS), thereby enhancing the intracellular survival of S. aureus within macrophages. Additionally, we discovered that the transcriptional repressor of IL10, HDAC11, was significantly downregulated during S. aureus infection. Overexpression of HDAC11 and the use of the autophagy activator rapamycin further validated that the HDAC11/IL10 axis regulates mitophagy via the mTOR pathway, which is essential for supporting S. aureus intracellular survival. This study reveals that S. aureus enhances IL10 production by inhibiting HDAC11, thereby promoting mitophagy and mtROS clearance, which supports its survival within macrophages. These findings offer new insights into the intracellular survival mechanisms of S. aureus and provide potential therapeutic approaches for the clinical management of osteomyelitis.

The impaired response of nasal epithelial cells to microplastic stimulation in asthma and COPD.

Microplastic particles from the air are inhaled and accumulate in the lungs, potentially causing immunological reactions and airway tissue injury. This study aimed to evaluate the biological effects of polyamide fibres on nasal epithelium co-cultivated with macrophages in control, asthma, and COPD groups. Nasal epithelial cells alone or in co-culture with monocyte-derived macrophages were exposed to polyamide fibres for 48h. We identified 8 differentially expressed genes (DEGs) in controls, 309 DEGs in asthma (including ANKRD36C, BCL2L15, FCGBP, and IL-19), and 22 DEGs in COPD (e.g., BCL2L15, IL-19, CAPN14, PGBD5, PTPRH), particularly in epithelial/moMφ co-cultures. Microplastic exposure induced inflammatory cytokine secretion only for IL-8 production in controls (epithelial/ moMφs co-culture) and asthmatic (monoculture) epithelial cells in contrast to PM2.5, which was a strong inflammatory inducer. Gene Ontology analysis revealed that microplastic exposure affected sterol and cholesterol biosynthesis, secondary alcohol metabolism, and acetyl-CoA metabolism in asthma, and cell motility, chemokine signaling, leukocyte migration, and chemotaxis in COPD. Microplastic stimulation altered the response of airway epithelial cells in obstructive lung diseases differently than in controls, linking to Th2 inflammation, stress response modulation, and carcinogenesis. Asthmatic and COPD epithelial cells are more susceptible to damage from microplastic fibre exposure.

Type-2 innate signals are dispensable for skeletal muscle regeneration and pathology linked to Duchenne muscular dystrophy.

Immune responses play an integral role in skeletal muscle regeneration. In the genetically inherited muscle disease Duchenne muscular dystrophy (DMD), muscle regeneration is disrupted, leading to chronic inflammation, fibrosis, and early mortality. Previously, it has been suggested that type-2 innate immune cells, particularly eosinophils and their production of IL-4, play an essential role in effective muscle regeneration after acute injury. We here re-investigate the role of eosinophils in skeletal muscle repair using mice deficient in eosinophils (ΔdblGATA), or deficient in IL-4R/IL-13R signaling through STAT6 (Stat6-/-). We show that neither deficiency has an impact on skeletal muscle regeneration in response to acute injury as quantified by fiber size, immune cell infiltration, or muscle-resident stem cell proliferation. We also investigate the role of STAT6 signaling in mdx:Stat6-/- mice, a model of DMD and, again, find that ablation of STAT6 signaling has no effect on the rate or severity of fibrotic scar formation or disease progression. In contrast to previous models, our data suggest a negligible role for eosinophils and STAT6 signaling in skeletal muscle regeneration after acute or chronic injury.

Deficiency of T follicular helper cell Tet3 DNA demethylation inhibits pathogenic IgG2c class switching and chronic GVHD.

Chronic graft-versus-host disease (cGVHD) is the leading cause of morbidity and non-relapse associated mortality following allogeneic hematopoietic cell transplantation (aHSCT). Treating steroid resistant/refractory cGVHD remains challenging. Epigenetic regulators can have global transcriptional effects that control donor T-cell responses. We previously showed that inhibiting histone lysine motifs by chromatin-modifying enzymes can ameliorate murine cGVHD. Targeting donor T-cell DNA methyltransferases reduce acute GVHD. Here, we sought to investigate the DNA demethylase Tet (ten-eleven translocase) methylcytosine dioxygenases 2 (Tet2) and Tet3 in T follicular helper cell (TFH) dependent cGVHD. In a clinically relevant model of cGVHD that recapitulates pulmonary fibrosis from bronchiolitis obliterans, recipients of Tet2 deleted donor T-cells did not have improved pulmonary function tests in contrast to the markedly improved pulmonary function in Tet3 deleted donor T-cells. Tet3 deleted donor T-cells did not impair TFH-dependent germinal center (GC) formation. Unexpectedly, TET3 deficiency resulted in elevated GATA3 expression in and IL-4 production by TFH cells. TET3 deficient TFH cells supported GC B-cell immunoglobulin (Ig) class switching to nonpathogenic IgG1 but not pathogenic IgG2c allowing mice to escape cGVHD pulmonary fibrosis. Elevated GATA3 expression and disruption of IgG2c class switching was recapitulated in an in-vitro human GC culture system. These studies provide new insights into the function of Tet3 in TFH driven Ig class switching and suggest a new approach to mitigate cGVHD.

Lactobacillus rhamnosus GG induces STING-dependent IL-10 in intestinal monocytes and alleviates inflammatory colitis in mice.

Preclinical and clinical observations indicate that the probiotic Lactobacillus rhamnosus GG (LGG) can modulate colonic inflammation. However, the underlying mechanisms have not been explored in depth. Here, we demonstrate that oral administration of live LGG alleviated inflammatory colitis by increasing IL-10 expression in intestinal Ly6C+ monocytes. Mechanistically, LGG induced IL-10 production via the stimulator of IFN genes (STING)/TBK1/NF-κB (RELA) signaling pathway in intestinal Ly6C+ monocytes, enhancing their immune-suppressive function. Elevated IL-10 subsequently activated IL-10 signaling in Ly6C+ monocytes, resulting in an IL-10-based autocrine regulatory loop and inhibition of proinflammatory cytokine production. Furthermore, LGG shifted the gut microbial community and its metabolic functions, leading to intestinal immune responses against colitis. Fecal microbiota transplantation from LGG-colonized mice alleviated immune checkpoint blockade-associated colitis. Our findings highlight the importance of STING signaling in IL-10-dependent antiinflammatory immunity and establish an empirical basis for developing oral administration of live LGG as an efficient and safe therapeutic strategy against inflammatory colitis.

The Role of Immune Defense in Serratia marcescens Nosocomial Infections

Developing resistance mechanisms leads to various nosocomial infections caused by opportunistic bacteria. Serratia marcescens are well known to be opportunistic and are equipped with an armory of virulence factors against host immune response. The study aims to detect the immune defense in patients infected with multidrug-resistant S. marcescens. The study includes 132 clinical samples, including burn, wound, otitis media, and urinary tract infection (UTI) at several hospitals in Baghdad, Iraq. All isolates are identified by cultivation on MacConkey agar, nutrient agar, and blood agar, followed by biochemical tests and assessment with the VITEK 2 compact system. The isolates are tested for antibiotic susceptibility tests, interleukin-12 (IL12) levels, neutrophil ability to phagocytosis, and complement C3 and C4 levels. Out of 120 positive cultures, six isolates are identified as S. marcescens. The urine samples are the most isolated source and a higher level of antibiotic resistance was noticed in ampicillin and cefotaxime (100%), whereas a lower level is in imipenem. Stimulation (p ꞊ 0.005) provided a significant increase in IL-12 production. The infection with the S. marcescens stimulated the neutrophil’s phagocytosis process compared with the control. The interplay role of virulence factors in S. marcescens influences its pathogenesis, antibiotic resistance, and immune response, particularly involving neutrophils and IL-12. Understanding these interactions is crucial for developing effective therapeutic strategies.

Impairment of the T cell memory response in chronic lymphocytic leukemia patients after SARS-CoV-2 vaccination.

CLL patients face increased vulnerability to COVID-19 because of weakened immune systems from comorbidities and treatments. Therefore, the need for these patients of vaccination is of outermost importance. In our study we have evaluated T cell-mediated responses to COVID19 vaccines by performing the activation-induced markers (AIM) assay which allows to determine spike-specific CD4+ and CD8+ T cell responses. A CD4+T cell memory response was registered in all healthy control (HC) (responders), while 28.60% of CLL patients did not respond to the stimulation (non-responders). CD8+T cell memory response was impaired in 61.90% of CLL patients and in 33.33% of HC. In addition, CLL responders showed a significant impairment of the magnitude of memory response in CD8 subset. Interestingly, impairment of the CD4+ AIM+ memory was associated to a more severe COVID-19 infection. Ibrutinib therapy had negative impact on IL-2 production by CD8+ cells, while the duration of the treatment positively affected the memory response. The majority of CLL patients don't respond well to vaccination, leaving clinicians in need of a reliable way to identify non-responders and assess the protection levels of those who do. Our findings suggest the AIM test as a promising method for screening and categorizing patients, potentially addressing this need.

Exercise-induced cytosolic calcium oscillations: mechanisms and modulation of T-cell function.

This study investigated time-dependent changes in intracellular Ca2⁺ levels in T cells, regulatory mechanisms, and functional effects after acute exercise. Male C57BL/6 mice were assigned to control and exercise groups, with the latter sacrificed at different intervals post-exercise. Murine splenic lymphocytes were isolated, and cytosolic Ca2⁺ levels were measured using Fluo-3/AM. T-cell proliferation was assessed by flow cytometry and CFSE labeling, apoptosis by Annexin V/PI staining, and cytokine levels by CBA. RNA sequencing results were validated by qRT-PCR. The findings revealed that exercise significantly altered intracellular calcium oscillations in CD3+ cells, leading to reduced mitogen-stimulated proliferation, increased IL-6, IL-5, and IL-13 production, and decreased IL-2 secretion. Additionally, there was an increase in the apoptotic fraction of CD3+ cells, with upregulated expression of Cav1.1, Cav3.2, Cav3.3, SERCA2B, PKCθ, Bcl-xL, and FADD, and downregulated Ryr3 (p<0.05). Transcriptomic analysis identified 607 differentially expressed genes involved in calcium ion binding and related pathways, including calcium signaling and cytokine-cytokine receptor interactions. Thus, acute exercise induces specific calcium oscillation patterns in T cells, mediated by PKCθ, affecting proliferation, apoptosis, and cytokine production. These changes are attributed to increased calcium influx through Cav1.1, Cav3.2, and Cav3.3 channels, decreased calcium reuptake via SERCA2B, and reduced calcium release through Ryr3. This research provides novel insights into how exercise modulates immune cell function by altering calcium levels, potential implications for enhancing immune responses or reducing inflammation.

SMEPPI: An indenone derivative that selectively inhibits M1 macrophage activation and enhances phagocytic activity.

SMEPPI is a small molecule synthesized as a derivative of KR-62980 that has anti-diabetic and anti-inflammatory activities. Despite the established physiological effects of KR-62980, the effects and benefits of SMEPPI remain largely unexplored. This study investigated the immunomodulatory functions of SMEPPI on macrophages and inflammatory diseases. SMEPPI did not affect the differentiation and maturation of bone marrow-derived monocytes into macrophages, nor did it affect the proliferation of M1 or M2 macrophages. Although SMEPPI did not affect M2 macrophage polarization, it significantly inhibited IL-1β and IL-6 cytokine production in both M1 macrophages and activated RAW264.7 macrophages. Importantly, SMEPPI inhibited the expression and phosphorylation of NF-κB p65 through inhibition of Akt expression, preventing its translocation to the nucleus. It also promoted p65 degradation through the stimulation of the proteasomal degradation pathway by inducing the expression of proteasome-related genes, thereby inhibiting p65 transcriptional activity. SMEPPI also enhanced the expression of various molecules associated with macrophage phagocytosis, including CD68, CD33, and lectins, thereby increasing phagocytic activity. Moreover, SMEPPI mitigated lipopolysaccharides-induced acute lung injury by suppressing IL-1β and IL-6 production in M1 macrophages and reduced mortality related to severe lung injury. These findings indicate that SMEPPI effectively regulates inflammatory diseases by impeding p65-induced cytokine production and enhancement of phagocytosis by M1 macrophages.

A glucan from the stems of Acanthopanax senticosus: Structure and anticolorectal cancer activity.

ASPN-1, a novel glucan with a molecular weight of 33.31kDa, was purified from Acanthopanax senticosus stems, characterized in structure, and evaluated for antitumor potential. The analysis of the structure of ASPN-1 revealed that it consisted of a backbone constructed from →4)-α-D-Glcp-(1→glucosyls, branched at the O-3 position by an α-D-Glcp-(1→residue and at the O-6 positions with α-D-Glcp-(1→6)-α-D-Glcp-(1→and/or α-D-Glcp-(1→residues. Surface morphological analysis revealed that ASPN-1 is an archetypal amorphous powder with an irregular network architecture composed of lamellar thin layers, filaments, and spherical particles. In vivo anti-tumor experiments indicated that ASPN-1 exerted inhibitory effects on CT26.WT mouse tumors by preserving immune function, elevating the production of IL-2, IFN-γ and TNF-α, and reducing production of TGF-β and IL-10. These findings indicated that ASPN-1, derived from A. senticosus, could potentially be used to treat colorectal carcinomas, acting through its immunomodulatory actions.

Immunotherapy strategy for treating inflammatory bowel disease based on a nanozyme/total glucosides of paeony hybrid materials

Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammatory condition that has long plagued patients. Herein, an innovative oral treatment strategy for IBD is proposed, which utilizes calcium alginate hydrogel as a carrier to deliver Co3O4 nanocages loaded with total glucosides of paeony (TGP) into the body. This design ingeniously exploits the protective properties of the alginate outer layer to ensure that the enzyme is not prematurely degraded when passing through acidic gastric juice. However, upon reaching the inflamed intestinal site, the overexpressed H2O2 there mixes with a specific solution, causing the hydrogel to degrade and release Co3O4@TGP. These negatively charged nanozymes can precisely recognize and accumulate in the inflamed colonic tissue, achieving targeted therapy through their unique charge characteristics. More importantly, Co3O4 itself possesses excellent catalytic activity, effectively consuming excess H2O2 at the site of inflammation and degrading into 10 nm small particles in the process, while simultaneously releasing TGP. Together, they exert dual effects of scavenging reactive oxygen species (ROS) and anti-inflammation. Its therapeutic mechanism involves fine regulation of the expression of key proteins such as TLR7, MYD88, and GAPDH, as well as effective inhibition of the NF-κB signaling pathway. This series of actions not only reduces the release of various pro-inflammatory cytokines (such as TNF-α, IL-18, IL-1β, IL-6, and HMGB1) but also promotes the production of the anti-inflammatory cytokine IL-10, thereby effectively maintaining the integrity of the intestinal barrier. This research achievement opens up a novel path for the treatment of colitis.

Interleukin-13 partly induced by the NLRP3 inflammasome promotes Trichinella spiralis encapsulation in infected mice.

Trichinella spiralis infection is a serious parasitic zoonosis in which a collagenous capsule surrounding the larva is developed in the striated muscle cells. However, the mechanism of T. spiralis encapsulation is currently poorly understood. It has been reported that T. spiralis infection can induce the production of IL-13 via the NLRP3 inflammasome, and it has also been suggested IL-13 thus produced may be involved in T. spiralis encapsulation. This research aimed to clarify the involvement of NLRP3 and IL-13 in the T. spiralis capsule formation process. IL-13 and NLRP3 inhibitors were used in a T. spiralis infected mouse model and in C2C12 cells to analyze the role of IL-13 and NLRP3 in encapsulation. The results showed that T. spiralis infection significantly increased the expression levels of IL-13 and collagen IV and VI. The production of collagen around the T. spiralis encapsulation zone was significantly inhibited when an IL-13 inhibitor was applied. Moreover, the expression levels of IL-13 and collagen IV and VI were significantly decreased by the NLRP3 inhibitor in vitro and in vivo. The above results indicated that NLRP3 can participate in the development of T. spiralis encapsulation by regulating IL-13 expression and stimulating collagen IV and VI synthesis during T. spiralis infection.

Multi-organ toxicity caused by PM2.5 in mice with cardiovascular diseases: The role of PAHs played from the most polluted episodes in China.

PAHs pollutants, as the key toxic components in PM2.5, have been proved to be closely related to the morbidity and mortality of people with cardiovascular diseases, however, their effects on organs and tissues other than cardiovascular/lung systems have not been deeply discussed. Here we collected PM2.5 samples from 2017 to 2020 in Xi'an, the city with one of the highest PM2.5 level in China, investigated the effects of PM2.5-bound PAHs on lung, spleen, liver and kidney by using the ApoE-/- mice model with high-fat diet. Firstly, six key toxic components in PAHs were screened to determine their relative importance in pollutants. The results showed that PAHs had the most significant toxicity in lung, followed by liver, kidney and spleen. In addition, PAHs activated systemic inflammation by enhancing the production of IL-6, particularly through strong protein interactions, mainly via van der Waals forces. This process exacerbated cardiovascular damage and led to elevated levels of pro-inflammatory cytokines circulating in the bloodstream, thereby increasing multi-organ toxicity. The results of this study deepened the understanding of comprehensive impacts of PAHs on cardiovascular patients, and suggest more strict emission source-control strategies on PAHs prevention especially for the susceptible population with cardiovascular diseases.

Period circadian clock 3 is crucial for regulation of IL-22-producing type 3 innate lymphoid cells by flavonoids from Shen Ling Bai Zhu San to alleviate colitis.

Type 3 Innate lymphoid cells (ILC3s) functions bear complex response during Inflammatory bowel diseases (IBD). Here, our study first analyzed the main pharmacological components in Shen Ling Bai Zhu San n-butanol extracts (S-Nb), and then explored whether S-Nb administrated immune response of ILC3s, and how it regulates ILC3s. Shen Ling Bai Zhu San (SLBZS) or S-Nb were administrated for 7days to analyze the frequency of ILC3s and their produced cytokine. Using siRNA technology to knock down the expression of period circadian clock 2 (Per2) and period circadian clock 3 (Per3) and Anti-IL-22 antibody was supplied to mice, then detecting the moderator effect of S-Nb on colitis. The most class of S-Nb is flavonoids, with a content of approximately 48%. Oral administration of S-Nb enhanced the production of NCR+ILC3s and IL-22 produced by ILC3s, but did not alter IL-17A. Surprisingly, knocking down the expression of Per3 instead of Per2 inhibited the modulation effect of S-Nb on colitis and reduced IL-22 production, whether originating from NCR+ILC3s or NCR-ILC3s. After neutralizing the expression of IL-22 in mice, S-Nb was deprived of ability to alleviate colitis. The reason why S-Nb alleviates colitis is by enhancing the expression of Per3 via flavonoids, which in turn promotes the secretion of IL-22+ILC3s in intestine.

A Comparative Effect of 12-Week Dietary Intervention of Policosanol (Raydel®) and Red Yeast Rice (RYR, Kobayashi) in Managing Dyslipidemia and Organ Damage in Hyperlipidemic Zebrafish

Background: A comparative 12-week dietary intervention of red yeast rice (RYR, Beni-koji, Kobayashi, Japan) and Cuban policosanol (PCO, Raydel®, Thornleigh, Australia) was assessed for dyslipidemia, antioxidant status, and vital organ functionality in hyperlipidemic zebrafish. Methods: Hyperlipidemic zebrafish were supplemented with a high-cholesterol diet (HC, final 4%, w/w) infused with either a powdered RYR tablet (final 1.0%, w/w), a PCO tablet (final 1.0%, w/w), or a combination of 0.5% (w/w) each of RYR and PCO powder for 12 weeks. Subsequently, blood and organs were collected and processed for biochemical and histological examination. Results: RYR and PCO consumption showed a substantial effect against HC-induced hyperlipidemia by reducing the total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C). Exclusively, PCO supplementation revealed a significant elevation in the HC-diminished high-density lipoprotein cholesterol (HDL-C). In addition, PCO supplementation showed a significant elevation in plasma ferric ion-reducing ability (FRA) and sulfhydryl content, as well as alleviating the blood glucose level of hyperlipidemic zebrafish. The most noteworthy impact, with a significant two-fold (p &lt; 0.001) augmentation of HC-diminished plasma paraoxonase (PON) activity, was observed in response to PCO. In contrast, the RYR supplementation failed to establish curative effects against HC-disturbed plasma antioxidant variables and blood glucose levels. The histological outcome revealed a severe toxicological impact of the RYR on the liver, reflected by fatty liver changes and three-fold heightened IL-6 production compared to HC control. Contrastingly, PCO exhibited significant hepatoprotection and effectively neutralized the hepatic toxicity triggered by HC and RYR. Also, RYR showed kidney atrophy, intense ROS generation, apoptosis, and senescence. Conversely, the PCO supplementation protected the kidney from HC- and RYR-induced toxicity. Likewise, PCO supplementation notably alleviated histological alterations and oxidative stress in the brain, ovary, and testis of hyperlipidemic zebrafish. Conclusions: This comparative study establishes PCO’s therapeutic effect against the challenges posed by HC, while RYR emerged with serious toxicological concerns towards the liver, kidney, and other organs of hyperlipidemic zebrafish.