Modulation Of Cytokine Levels Research Articles

Annona muricata ethanolic extract protects BALB/c mice against colitis-associated colon cancer through modulation of cytokine levels and KRAS and APC expression

Annona muricata ethanolic extract protects BALB/c mice against colitis-associated colon cancer through modulation of cytokine levels and KRAS and APC expression

Multiplex array analysis of circulating cytokines and chemokines in COVID-19 patients during the first wave of the SARS-CoV-2 pandemic in Milan, Italy

BackgroundThe systemic inflammatory syndrome called “cytokine storm” has been described in COVID-19 pathogenesis, contributing to disease severity. The analysis of cytokine and chemokine levels in the blood of 21 SARS-CoV-2 positive patients throughout the phases of the pandemic has been studied to understand immune response dysregulation and identify potential disease biomarkers for new treatments. The present work reports the cytokine and chemokine levels in sera from a small cohort of individuals primarily infected with SARS-CoV-2 during the first wave of the COVID-19 pandemic in Milan (Italy).ResultsAmong the 27 cytokines and chemokines investigated, a significant higher expression of Interleukin-9 (IL-9), IP-10 (CXCL10), MCP-1 (CCL2) and RANTES (CCL-5) in infected patients compared to uninfected subjects was observed. When the change in cytokine/chemokine levels was monitored over time, from the hospitalization day to discharge, only IL-6 and IP-10 showed a significant decrease. Consistent with these findings, a significant negative correlation was observed between IP-10 and anti-Spike IgG antibodies in infected individuals. In contrast, IL-17 was positively correlated with the production of IgG against SARS-CoV-2.ConclusionsThe cytokine storm and the modulation of cytokine levels by SARS-CoV-2 infection are hallmarks of COVID-19. The current global immunity profile largely stems from widespread vaccination campaigns and previous infection exposures. Consequently, the immunological features and dynamic cytokine profiles of non-vaccinated and primarily-infected subjects reported here provide novel insights into the inflammatory immune landscape in the context of SARS-CoV-2 infection, and offer valuable knowledge for addressing future viral infections and the development of novel treatments.

Cytokine levels in Type-2 Diabetes Mellitus (T2DM) Patients with Asymptomatic Bacteriuria (ASB) in Northern Andhra Pradesh

Diabetes is a systemic inflammatory condition. The modulation of cytokine levels caused by Asymptomatic Bacteriuria (ASB) infection can lead to altered inflammatory status in various tissues and may affect their homeostasis and function. We aim to estimate the cytokine (IL-6, TNF-α and IL-10) levels in serum of diabetic individuals with and without ASB to study their clinical significance. The current study evaluates the role of cytokines in inflammation caused due to ASB in T2DM patients. Increase in IL-6 and TNF-α levels may indicate renal tissue damage caused due to inflammation by ASB. Whereas increased IL-10 levels is a possible indicator of persistent infection with bacteria which may lead to diabetic renal disease.

Evaluating the Efficacy of a Polyherbal Formulation in Ameliorating Arthritis Induced by Complete Freund’s Adjuvant

Background: This study investigates the antiarthritic potential of a polyherbal formulation (PHF) comprising extracts from Tinospora cordifolia, Rosa damescena, and Acacia leucoploea in a rat model of rheumatoid arthritis (RA). RA is a chronic autoimmune disorder with debilitating consequences. PHF's impact on joint inflammation, bone degradation, and cartilage preservation were evaluated. Methods: Arthritis was induced using complete Freund’s adjuvant (CFA), and animals were treated with PHF (200 and 400 mg/kg), prednisolone, or control treatments for 28 days. Parameters including body weight, paw volume, arthritis severity score, hematological parameters, serum markers (creatinine, ALP, total proteins), cytokine levels (IL-1β, IL-6, TNF-α, IL-10), and radiographic changes were assessed. Results: CFA-treated rats exhibited significant body weight loss, paw edema, increased arthritis severity scores, altered hematological parameters, and elevated serum markers compared to normal controls. PHF treatment at both doses mitigated body weight loss, reduced paw edema, and improved arthritis severity scores. Hematological changes induced by CFA were also attenuated by PHF treatment. Serum creatinine, ALP, and total protein levels, elevated in CFA-treated rats, were significantly improved by PHF. Furthermore, PHF modulated cytokine levels, decreasing IL-6, IL-1β, and TNF-α while increasing IL-10. Radiographic analysis displayed reduced joint damage in PHF-treated rats compared to CFA controls. Conclusion: This comprehensive investigation highlights PHF's potential to mitigate the inflammatory processes associated with RA, as evidenced by improved clinical, hematological, and biochemical parameters. The study underscores the promise of traditional botanical compounds in managing RA and suggests PHFs as novel therapeutic options. Further mechanistic studies are warranted to elucidate the exact pathways involved.

Does Scheduled Low-Dose Short-Term NSAID (Ketorolac) Modulate Cytokine Levels After Orthopaedic Polytrauma? A Secondary Analysis of a Randomized Clinical Trial.

To determine whether scheduled low-dose, short-term ketorolac modulates cytokine concentrations in orthopaedic polytrauma patients. Secondary analysis of a double-blinded, randomized controlled trial. Single Level I trauma center from August 2018 to October 2022. Orthopaedic polytrauma patients between 18 and 75 years with a New Injury Severity Score greater than 9 were enrolled. Participants were randomized to receive 15 mg of intravenous ketorolac every 6 hours for up to 5 inpatient days or 2 mL of intravenous saline similarly. Daily concentrations of prostaglandin E2 and interleukin (IL)-1a, IL-1b, IL-6, and IL-10. Clinical outcomes included hospital and intensive care unit length of stay, pulmonary complications, and acute kidney injury. Seventy orthopaedic polytrauma patients were enrolled, with 35 participants randomized to the ketorolac group and 35 to the placebo group. The overall IL-10 trend over time was significantly different in the ketorolac group ( P = 0.043). IL-6 was 65.8% higher at enrollment compared to day 3 ( P < 0.001) when aggregated over both groups. There was no significant treatment effect for prostaglandin E2, IL-1a, or IL-1b ( P > 0.05). There were no significant differences in clinical outcomes between groups ( P > 0.05). Scheduled low-dose, short-term, intravenous ketorolac was associated with significantly different mean trends in IL-10 concentration in orthopaedic polytrauma patients with no significant differences in prostaglandin E2, IL-1a, IL-1b, or IL-6 levels between groups. The treatment did not have an impact on clinical outcomes of hospital or intensive care unit length of stay, pulmonary complications, or acute kidney injury. Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Modulation of T Cell Differentiation in Mice with COPD Combined with Lung Cancer Through Key Targets of PD-1 by Tao Hong Si Wu Tang.

The objective is to assess the anti-inflammatory effect of Tao Hong Si Wu Tang combined with anti-PD-1 in a mouse model of COPD combined with lung cancer, elucidating its mechanism through modulation of PD-1/PD-L binding, regulation of Th1/Th2 and Th17/Treg balance, inhibition of IL-4 and IL-17, and promotion of IFN-γ and TGF-β levels in peripheral blood. One hundred male C57/BL6 mice were randomly allocated to five groups: A (blank control), B (model control), C (THSW), D (anti-PD-1), and E (THSW + anti-PD-1), with 20 mice in each group. The COPD model was induced using fumigation and LPS intra-airway drip, followed by the establishment of lung cancer by Lewis cell inoculation. Treatment groups received Tao Hong Si Wu Tang or/and PD-1 monoclonal antibody. Various indicators were assessed, including macroscopic observation, HE staining of lung tissue, ELISA for cytokines, flow cytometry for cell proportions, and immunohistochemistry/western blotting for protein expression. Lung tissue analysis revealed significant differences between groups, with marked tumor formation observed in groups B-E. Serum levels of IL-4, IFN-γ, IL-17, and TGF-β were significantly altered, along with changes in CD4 + T/CD8 + T ratio and cytokine-producing cell populations. Expression levels of key proteins were also significantly affected across treatment groups. Tao Hong Si Wu Tang demonstrated anti-inflammatory effects comparable to anti-PD-1, potentially through modulation of PD-1/PD-L binding, correction of Th1/Th2 and Th17/Treg imbalance, and modulation of cytokine levels. These findings suggest a role for Tao Hong Si Wu Tang in ameliorating inflammation and immune dysregulation in COPD combined with lung cancer.

Anti-Inflammatory Effects of Anthocyanin-Enriched Black Soybean Seed Coat (BSSC) Crude Extract on LPS-Induced Acute Liver Injury in Mice.

Soybeans rank among the top five globally produced crops. Black soybeans contain anthocyanins in their seed coat, offering strong antioxidant and anti-inflammatory benefits. This study explores the protective effects of black soybean seed coat (BSSC) against acute liver injury (ALI) in mice. Mice pretreated with BSSC crude extract showed reduced liver damage, inflammation, and apoptosis. High doses (300 mg/kg) of the extract decreased levels of proinflammatory cytokines (IL-6, IFN-γ) and increased levels of anti-inflammatory ones (IL-4, IL-10), alongside mitigating liver pathological damage. Additionally, it influenced the Nrf2/HO-1 pathway and reduced levels of apoptosis-related proteins. In vitro, the compounds delphinidin-3-O-glucoside (D3G) and cyanidin-3-O-glucoside (C3G) in BSSC were found to modulate cytokine levels, suggesting their role in ALI protection. The study concludes that BSSC extract, particularly due to D3G and C3G, effectively protects against LPS-induced ALI in mice by inhibiting inflammation, oxidative stress, and apoptosis.

M1 cholinergic signaling in the brain modulates cytokine levels and splenic cell sub-phenotypes following cecal ligation and puncture.

The contribution of the central nervous system to sepsis pathobiology is incompletely understood. In previous studies, administration of endotoxin to mice decreased activity of the vagus anti-inflammatory reflex. Treatment with the centrally-acting M1 muscarinic acetylcholine (ACh) receptor (M1AChR) attenuated this endotoxin-mediated change. We hypothesize that decreased M1AChR-mediated activity contributes to inflammation following cecal ligation and puncture (CLP), a mouse model of sepsis. In male C57Bl/6 mice, we quantified basal forebrain cholinergic activity (immunostaining), hippocampal neuronal activity, serum cytokine/chemokine levels (ELISA) and splenic cell subtypes (flow cytometry) at baseline, following CLP and following CLP in mice also treated with the M1AChR agonist xanomeline. At 48h. post-CLP, activity in basal forebrain cells expressing choline acetyltransferase (ChAT) was half of that observed at baseline. Lower activity was also noted in the hippocampus, which contains projections from ChAT-expressing basal forebrain neurons. Serum levels of TNFα, IL-1β, MIP-1α, IL-6, KC and G-CSF were higher post-CLP than at baseline. Post-CLP numbers of splenic macrophages and inflammatory monocytes, TNFα+ and ILβ+ neutrophils and ILβ+ monocytes were higher than baseline while numbers of central Dendritic Cells (cDCs), CD4+ and CD8+ T cells were lower. When, following CLP, mice were treated with xanomeline activity in basal forebrain ChAT-expressing neurons and in the hippocampus was significantly higher than in untreated animals. Post-CLP serum concentrations of TNFα, IL-1β, and MIP-1α, but not of IL-6, KC and G-CSF, were significantly lower in xanomeline-treated mice than in untreated mice. Post-CLP numbers of splenic neutrophils, macrophages, inflammatory monocytes and TNFα+ neutrophils also were lower in xanomeline-treated mice than in untreated animals. Percentages of IL-1β+ neutrophils, IL-1β+ monocytes, cDCs, CD4+ T cells and CD8+ T cells were similar in xanomeline-treated and untreated post-CLP mice. Our findings indicate that M1AChR-mediated responses modulate CLP-induced alterations in serum levels of some, but not all, cytokines/chemokines and affected splenic immune response phenotypes.

Longitudinal Patient Analysis Suggests a Positive Correlation of IL-10/IL-6 and FVIII Inhibitor Amount

Hemophilia A (HA) is the most common X-linked bleeding disorder caused by a deficiency in coagulation factor VIII (FVIII). Inhibitor development in up to 30% of HA patients is the most challenging complication in HA treatment and has been associated with several patient-related risk factors such as gene mutation and residual plasma factor VIII concentrations. Treatment related risk factors are under debate. However, HCV infections were recently shown to correlate with low level inhibitor abundance, potentially as a result of chemokine and cytokine regulation. Therefore, the aim of this study was to evaluate a potential connection between proinflammatory cytokine levels and FVIII-specific B cell responses in HA patients without infections, but with other comorbidities that might modulate cytokine levels. Thus, several clinical parameters and concentrations of plasmatic proinflammatory cytokines (IL-1ß, IL-6, IL-8, IL-10, IL-12p70, TNF, IFNa, IFNg, TNFa, MCP-,1 IL-17A, IL-18, IL-23 and IL-33) were quantified from different patient samples. At first, the influence of proinflammatory cytokines on inhibitor development was assessed in a HA patient, who had an intron 22 inversion and was also diagnosed with type 1 diabetes. Prophylactic treatment began at the age of 9 months with 30IU/kg Octanate, and after four days of exposure, the formation of inhibitors was initially detected. Longitudinal cytokine analysis in plasma samples of that patient revealed differential regulation patterns of cytokines. IL-1b, IFNg, TNFa, IL-6, IL-10 and IL-12p70 tended to increase upon inhibitor occurrence, whereas other cytokines remained unchanged (MCP-1, IL-8, IL-17A, IL-18 and IL-23) or decreased (IFNa2 and IL-33). Next, a correlation analysis was performed, assuming that proinflammatory cytokines might stimulate B cells to produce antibodies. This analysis involved all cytokines that were found to be elevated upon inhibitor formation. The comparison of clinical and laboratory data from that patient revealed a strong association of inhibitor levels and IL-10 expression (Pearson r = 0,9391; R squared = 0,8818) as well as with IL-6 (Pearson r = 0,9290; R squared = 0,8630). Furthermore, a modest correlation was observed for IL-1b (Pearson r = 0,5277; R squared = 0,2785), IFNg (Pearson r = 0,3413; R squared = 0,1165), IL-12p70 (Pearson r = 0,3547; R squared = 0,1258), and TNFa (Pearson r = 0,3070; R squared = 0,09422). Other proinflammatory cytokines with a rather stable profile upon inhibitor initiation like MCP-1 (Pearson r = -0,06810; R squared = 0,004638) and IL-18 (Pearson r = 0,2245; R squared = 0,05042) seemed not to be directly correlated with inhibitor occurrence. Finally, we aim to investigate the potential impact of IL-10 and IL-6 on inhibitor production and/or FVIII immune tolerization across various patient groups and conditions. Therefore, we will compare patients with detectable inhibitor titers, those who have successfully eradicated inhibitors, and individuals without inhibitor titers (with normal recovery). Preliminary data suggest a positive correlation between both cytokines and active inhibitor presence. However, to reach a definitive conclusion, the sample size will be/should be increased.

Efficacy of TurmiZn, a Metallic Complex of Curcuminoids-Tetrahydrocurcumin and Zinc on Bioavailability, Antioxidant, and Cytokine Modulation Capability

Complexes of curcumin with metals have shown much-improved stability, solubility, antioxidant capability, and efficacy when compared to curcumin. The present research investigates the relative bioavailability, antioxidant, and ability to inhibit inflammatory cytokine production of a curcuminoid metal chelation complex of tetrahydrocurcumin-zinc-curcuminoid termed TurmiZn. In vitro uptake assay using pig intestinal epithelial cells showed that TurmiZn has an ~3-fold increase (p ≤ 0.01) in uptake compared to curcumin and a ~2-fold increase (p ≤ 0.01) over tetrahydrocurcumin (THC). In a chicken model, an oral 1-g dose of TurmiZn showed a ~2.5-fold increase of a specific metabolite peak compared to curcumin (p = 0.004) and a ~3-fold increase compared to THC (p = 0.001). Oral doses (5 g/Kg) of TurmiZn in rats also showed the presence of curcumin and THC metabolites in plasma, indicating bioavailability across cell membranes in animals. Determination of the antioxidant activity by a 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) radical scavenging assay indicated that TurmiZn was about 13x better (p ≤ 0.0001) than curcumin and about 4X better (p ≤ 0.0001) than THC, in reducing free radicals. In vitro experiments further showed significant (p ≤ 0.01) reductions of lipopolysaccharide (LPS)-induced proinflammatory cytokines such as interleukin (IL) IL-6, IL-8, IL-15, IL-18, and tumor necrosis factor (TNF)-alpha, while showing a significant (p ≤ 0.01) increase of granulocyte-macrophage colony-stimulating factor (GM-CSF) in dog kidney cells. In vivo cytokine modulations were also observed when TurmiZn was fed for 6 weeks to newborn chickens. TurmiZn reduced IL-1 and IL-6, but significantly reduced (p ≤ 0.01) IL-10 levels while there was a concurrent significant (p = 0.02) increase in interferon gamma compared to controls. Overall, these results indicate that TurmiZn has better bioavailability and antioxidant capability than curcumin or THC and has the ability to significantly modulate cytokine levels. Thus, TurmiZn could be an excellent candidate for a novel ingredient that can be incorporated into food and supplements to help overall health during the aging process.

Vitamin D3 improves spatial memory and modulates cytokine levels in aged rats.

Vitamin D3 deficiency is associated with an increased risk of dementia. An association between vitamin D3 deficiency and subjective cognitive complaints in geriatric patients has been previously reported. This study aimed to evaluate the effects of two doses of vitamin D3 on spatial memory (using the Radial Maze) and cytokine levels [tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-10 (IL-10)] on 2-, 6-, 13-, 22-, and 31-month-old male Wistar rats. Animals were supplemented with vitamin D3 at doses of 42IU/kg and 420IU/kg for 21days. A radial maze test was performed to evaluate spatial memory. After the behavioral test, the frontal cortex and hippocampus were dissected for enzyme immunoassay analyses to measure the cytokine levels (TNFα, IL-1β, IL-6, and IL-10). Our results showed that vitamin D3 supplementation reversed spatial memory impairment at the supplemented doses (42 and 420IU/kg) in 6-, 13-, and 22-month-old animals and at a dose of 420IU/kg in 31-month-old animals. The lower dose (42IU/kg) regulates both pro- and anti-inflammatory cytokines mainlyin the frontal cortex. Our results suggest that vitamin D3 has a modulatory action on pro- and anti-inflammatory cytokines, since older animals showed increased cytokine levels compared to 2-month-old animals, and that vitamin D3 may exert an immunomodulatory effect on aging.

Pseudomonas quinolone signal induces organelle stress and dysregulates inflammation in human macrophages

Pseudomonas quinolone signal (PQS) is a quorum-sensing molecule associated with Pseudomonas aeruginosa that regulates quorum sensing, extracellular vesicle biogenesis, iron acquisition, and the secretion of virulence factors. PQS has been shown to have immunomodulatory effects on the host. It induces oxidative stress, modulates cytokine levels, and activates regulated cell death in the host. In this study, we investigated the effects of PQS (10 μM) on host organelle dynamics and dysfunction in human macrophages at the interphase of endoplasmic reticulum (ER), mitochondria, and lysosome. This study showed that PQS increases cytosolic Ca+2 levels and elevates ER stress, as evidenced by increased expression of BiP and activation of the PERK-CHOP axis of unfolded protein response (UPR). Moreover, PQS also negatively affects mitochondria by disrupting mitochondrial membrane potential and increasing mitochondrial ROS generation (mROS). Additionally, PQS stimulation decreased the number of acridine orange-positive lysosomes, indicating lysosomal destabilization. Furthermore, PQS-induced lysosomal destabilization also induces overexpression of the lysosomal stress-responsive gene TFEB. Besides organelle dysfunction, PQS dysregulates inflammation-related genes by upregulating NLRC4, TMS1, and Caspase 1 while downregulating NLRP3 and IL-1β. Also, PQS increases gene expression of pro-inflammatory cytokines (IL-6, TNF-α, and IFN-γ). In conclusion, our findings suggest that PQS negatively affects human macrophages by interfering with organelle function and dysregulating inflammatory response. Consequently, this study provides crucial insight into PQS-driven macrophage dysfunction and may contribute to a better understanding of Pseudomonas aeruginosa-associated infections.

PBPK modelling to predict drug-biologic interactions with cytokine modulators: Are these relevant and is IL-6 enough?

Drugs that modulate cytokine levels are often used for the treatment of cancer as well as inflammatory or immunological disorders. Pharmacokinetic drug-biologic interactions (DBI) may arise from suppression or elevation of cytochrome P450 (CYP) enzymes caused by the increase or decrease in cytokine levels following administration of these therapies. There is in vitro and in vivo evidence that demonstrates a clear link between raised interleukin (IL)-6 levels and CYP suppression, in particular CYP3A4. However despite this, the changes in IL-6 levels in vivo rarely lead to significant drug interactions (AUC and Cmax ratios < 2-fold). The clinical significance of such interactions therefore remains questionable and is dependent on the therapeutic index of the small molecule therapy. Physiologically-based pharmacokinetic (PBPK) modelling has been used successfully to predict the impact of raised IL-6 on CYP activities. Beyond IL-6, published data show little evidence that IL-8, IL-10, and IL-17 suppress CYP enzymes. I n vitro data suggest that IL-1β, IL-2, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ can cause suppression of CYP enzymes. Despite in vivo there being a link between IL-6 levels and CYP suppression, the evidence to support a direct effect of IL-2, IL-8, IL-10, IL-17, IFN-γ, TNF-α or vascular endothelial growth factor (VEGF) on CYP activity is inconclusive. This commentary will discuss the relevance of such drug-biologic interactions and whether current PBPK models considering only IL-6 are sufficient. Significance Statement This commentary summarizes the current in vitro and in vivo literature regarding cytokine-mediated CYP suppression and compares the relative suppressive potential of different cytokines in reference to IL-6. It also discusses the relevance of drug-biologic interactions to therapeutic use of small molecule drugs and whether current PBPK models considering only IL-6 are sufficient to predict the extent of drug-biologic interactions.

Importance of gut microbiome regulation for the prevention and recovery process after SARS-CoV-2 respiratory viral infection (Review).

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported to affect organs other than the lungs, including the liver, brain, kidneys and intestine, and gastrointestinal symptoms, such as nausea, vomiting, diarrhea and abdominal discomfort, have also been reported. Thus, SARS-CoV-2 could potentially directly or indirectly regulate the gut microbiome profile and its homeostasis. The abundance of Coprobacillus, Clostridium ramosum and Clostridium are associated with the severity of COVID-19, and Firmicutes, Bacteriodetes, Proteobacteria and Actinobacteria are also related to COVID-19 infection. The four phyla are correlated with the severity of COVID-19 infection in patients. The modulation of factors that control the physiological growth of the gut microbiome will determine the proportionate ratio of microbiome types (profile). Taken together, gut microbiome profile alterations in COVID-19 patients may have a cross effect with the modulation of cytokine levels in COVID-19 infection. With these findings, several factors that regulate gut microbiome homeostasis may support the degree of the clinical symptoms and hasten the recovery process after COVID-19 infection.

Anti-S100A4 Antibody Therapy Is Efficient in Treating Aggressive Prostate Cancer and Reversing Immunosuppression: Serum and Biopsy S100A4 as a Clinical Predictor.

S100A4 oncoprotein plays a critical role during prostate cancer progression and induces immunosuppression in host tissues. We hypothesized that S100A4-regulated oncogenic activity in immunosuppressed prostate tumors promotes growth of neoplastic cells, which are likely to become aggressive. In the current study, we investigated whether biopsy-S100A4 gene alteration independently predicts the outcome of disease in patients and circulatory-S100A4 is druggable target for treating immunosuppressive prostate cancer. Aided by DECIPHER-genomic test, we show biopsy-S100A4 overexpression as predictive of (i) poor ADT response and (ii) high risk of mortality in 228 radical prostatectomy-treated patients. Furthermore, analysis of tumor genome data of more than 1,000 patients with prostate cancer (PRAD/SU2C/FHCRC studies) validated the association of S100A4-alteration to poor survival and metastasis. We show that increased serum-S100A4 levels are associated to the prostate cancer progression in patients. The prerequisite for metastasis is the escape of tumor cells via vascular system. We show that extracellular-S100A4 protein as a growth factor induces vascular transmigration of prostate cancer cells and bone demineralization thus forms an ideal target for therapies for treating prostate cancer. By employing surface plasmon resonance and isothermal titration calorimetry, we show that mab6B12 antibody interacts with and neutralizes S100A4 protein. When tested for therapeutic efficacy, the mab6B12 therapy reduced the (i) osteoblastic demineralization of bone-derived MSCs, (ii) S100A4-target (NFκB/MMP9/VEGF) levels in prostate cancer cells, and (iii) tumor growth in a TRAMPC2 syngeneic mouse model. The immuno-profile analysis showed that mAb6B12-therapy (i) shifted Th1/Th2 balance (increased Stat4+/T-bet+ and decreased GATA2+/CD68+/CD45+/CD206+ cells); (ii) modulated cytokine levels in CD4+ T cells; and (iii) decreased levels of IL5/6/12/13, sTNFR1, and serum-RANTES. We suggest that S100A4-antibody therapy has clinical applicability in treating immunosuppressive prostate cancer in patients.

Effects of S100B neutralization on the long-term cognitive impairment and neuroinflammatory response in an animal model of sepsis

The nervous system is one of the first systems to be affected during sepsis. Sepsis not only has a high risk of mortality, but could also lead to cerebral dysfunction and cognitive impairment in long-term survival patients. The receptor for advanced glycation end products (RAGE) can interact with several ligands, and its activation triggers a series of cell signaling events, resulting in the hyperinflammatory condition related to sepsis. Recent studies show that elevated levels of S100B (RAGE ligand) are associated with the pathophysiology of neurodegenerative disorders. They also participate in inflammatory brain diseases and may lead to an increased activation of microglia and astrocytes, leading to neuronal death. This study aimed to determine the effect of S100B inhibition on the neuroinflammatory response in sepsis. Sepsis was induced in Wistar rats by cecal ligation and perforation (CLP). There were three groups: Sham, CLP, and CLP +10 μg/kg of monoclonal antibody (Anti-S100B) administered intracerebroventricularly. The animals were killed 30 days after sepsis following behavioral evaluation by open field, novel object recognition, and splash test. The hippocampus, prefrontal cortex, and amydgala were used for the determination of S100B and RAGE proteins by western blotting and for the evaluation of cytokine levels and verification of the number of microglial cells by immunohistochemistry. On day 30, both the Sham and CLP + anti-S100B groups were capable of recovering the habitual memory in the open field task. Regarding novel object recognition, Sham and CLP + anti-S100B groups increased the recognition index during the test session in comparison to the training session. There was a significant increase in the time of grooming in CLP + anti-S100B in comparison to the CLP group. There was a modulation of cytokine levels and immunohistochemistry showed that the CLP + anti-S100B group had a decrease in the number of microglial cells only in the hippocampus. These results helped to understand the role of S100B protein in the pathophysiology of sepsis-associated encephalopathy and could be helpful to further experimental studies regarding this subject.

The Role and Impact of Extracellular Vesicles in the Modulation and Delivery of Cytokines during Autoimmunity.

Cytokines and extracellular vesicles are two methods of initiating and maintaining cellular crosstalk. The role of cytokines in the initiation, progression, and resolution of inflammation has been well studied and more so, their pathophysiological role in the development of autoimmune disease. In recent years, the impact of extracellular vesicles on the progression of autoimmunity has become more widely appreciated. In this review, we discuss the mechanisms that allow extracellular vesicles of various sources to modulate cytokine production, and release, and how extracellular vesicles might be involved in the direct delivery and modulation of cytokine levels. Moreover, we explore what challenges are faced by current therapies and the promising future for extracellular vesicles as therapeutic agents in conditions driven by immune dysregulation.

Sulforaphane Modulates Cytokine Levels in Cell Culture Media of Triple-Negative Breast Cancer Cells Grown with Macrophages

Abstract Objectives Triple negative breast cancer (TNBC) makes up approximately 10–20% of all breast cancer cases and is more common in younger women and in Hispanic and African American populations. It is particularly difficult to treat, exhibiting high-metastasis rates, poor prognosis, and limited treatment options. Mortality from TNBC is largely due to the tumor cells high invasive capacity and rapid progression to metastasis. Evidence suggests that macrophages in the breast tumor microenvironment release cytokines that increase tumor cell proliferation, invasion and metastasis. Sulforaphane (SFN) is a broccoli phytochemical that has been identified to slow the progression of breast cancer as well as alter cytokine secretion from macrophages and breast cancer cells grown in single culture. SFN effects on cytokine secretion in the breast tumor microenvironment remain unclear. This study is investigating the effect of SFN on cytokine levels in cell culture media of TNBC cells grown with and without macrophages. Our hypothesis is that cytokine levels differ in media from cocultured cells versus singly cultured cells, and SFN treatment further alters cytokine levels in media. Methods In this study, TNBC cells (MDA-MB-231) were grown in transwell plates with and without macrophages (THP-1 cells differentiated with phorbol-myristate acetate). Cell cultures (n = 3) were treated with either 15 µM SFN, DMSO (vehicle-control), or a non-treatment control. We evaluated the levels of 44 individual cytokines in cell culture media at 24 and 48 hours after treatment using a multi-plex (BioPlex) assay. Control groups included single-cultured MDA-MB-231 and differentiated THP-1 cells. Results Preliminary analyses revealed that cytokine levels differed in the media of single versus cocultured cells and among treatment groups after 24 and 48 hours of treatment. Conclusions The profile of cytokines in the media of TNBC cells grown with macrophages was influenced by SFN treatment. This information may help establish mechanisms underlying SFN effects on TNBC behavior and identify new treatment strategies. Funding Sources California State University Program for Education and Research in Biotechnology, California State University-Chico.

Effect of vitiligo treatment using compound glycyrrhizin combined with fractional carbon dioxide laser and topical triamcinolone acetonide on serum interleukin-17 and tissue growth factor-β levels

ObjectiveVitiligo is a common pigmentation disorder of the skin, and its pathogenesis remains unclear. We evaluated the effectiveness of compound glycyrrhizin combined with fractional carbon dioxide (CO2) laser and triamcinolone acetonide solution in patients with vitiligo.MethodsPatients with stable vitiligo treated at our hospital between May 2016 and August 2017 were randomized to a control group or an observation group. Both groups were treated with fractional CO2 laser and triamcinolone acetonide solution, while the observation group also received compound glycyrrhizin. Clinical effectiveness, serum IL-17 and TGF-β levels, and adverse drug reactions were compared between the groups.ResultsFollowing treatment, the clinical effective rate was significantly higher in the observation group than in the control group (75.00% vs. 52.50%). Furthermore, IL-17 decreased in both groups but was significantly lower in the observation group, while TGF-β increased in both groups but was significantly higher in the observation group. The incidence of adverse drug reactions was not significantly different between the groups.ConclusionCompound glycyrrhizin in combination with fractional CO2 laser and triamcinolone acetonide solution can be used to treat vitiligo and appears to modulate cytokine levels.Trial registration: Hebei Provincial Administration of Traditional Chinese Medicine (no. 2019366; http://www.hebwst.gov.cn/index.do?templet=cs_zyj)

Eugenol attenuates concanavalin A-induced hepatitis through modulation of cytokine levels and inhibition of mitochondrial oxidative stress

Therapeutic management of hepatitis with conventional drugs alone worsens hepatic functioning in the long term because of sustained oxidative stress. Active compounds from several plant sources have been investigated to counteract this. Eugenol, a phytochemical abundant in various plants, is known for its wide range of pharmacological effects. There is a lacuna in the deeper understanding of its hepatoprotective activity at the molecular level. Our present study aimed to determine the effects of eugenol on the changes in antioxidant components, inflammatory cytokines and modulation of mitochondrial oxidative stress in immune-mediated hepatitis. We employed a model that mimics viral hepatitis using concanavalin A (ConA) to induce T-cell-mediated acute hepatitis. Eugenol increased (P&lt;0.01) antioxidant enzyme activities, including reduced glutathione (GSH)-regenerating enzyme, glutathione reductase, and glucose-6-phosphate dehydrogenase. Its antiinflammatory and antifibrogenic effects were evident from the reduction (P&lt;0.01) in interleukin and tumor necrosis factor levels. Eugenol was found to decrease mitochondrial oxidative stress, which was elevated in hepatitis. The hepatoprotective effects of eugenol were confirmed by histological findings. The current investigation shows that eugenol exerts a hepatoprotective effect through the modulation of different pathways which include restoration of mitochondrial oxidative stress. Eugenol could be a promising candidate for human hepatitis management, warranting preclinical studies.