The effects of honey on pro- and anti-inflammatory cytokines: A narrative review.

Honey contains flavonoids and phenolic acids, and because of their antioxidant and anti-inflammatory properties, they may play an important role in human health. The purpose of this review was to synthesize the effects of natural honey on pro- and anti-inflammatory cytokines. The effects of honey on wound healing and immunity appear to be inconsistent. The available databases )PubMed and Scopus) were searched and 42 studies were assessed. In patients with cancer, honey has been reported to inhibit the effects of pro-inflammatory factors such as TNF-α and IL-6. In patients with neuro-inflammatory disorders honey has been shown to inhibit the expression of pro-inflammatory markers. It has also been reported that honey can reduce TNF-α expression in conditions associated with liver injury, by suppressing TNF-α converting enzyme activity. Honey inhibits APAP-induced hepatocellular necrosis by modulating the expression of IL-10 and IL-1ß. Animal studies have shown that honey can reduce serum IL-1ß, IL-6 and TNF-α concentration and increase IL-10 concentrations in a model of gastric ulcer. Some studies in diabetics have shown that honey can reduce serum TNF-α, IL-6, IL-1ß and TGF-ß by inhibiting NF-Kß. The source and type of honey and its component have not been indicated in various clinical and practical studies, which are a limitation of these studies, in relation to reproducing them. Sigma, Manuka, Gelam and Tulang honey have been used in most of the in vitro and animal studies. The animal studies have demonstrated similar effects on pro-inflammatory factors, which include reducing serum TNF-α, IL-6 and IL-1ß as well as increasing IL-10. There are few human RCTs investigating the effects of honey on inflammatory cytokines. Only one RCT has reported the type of honey that they have used. Tulang honey has been reported to increase serum TNF-α and decrease hs-CRP, which is therefore controversial. Further high-quality studies are needed to firmly establish the clinical efficacy of honey. Because most studies had used different duration, type of honey and dosage, which make them difficult to contextualize, as the phytochemical content of a honey may depend on its source. Furthermore, it is unclear whether honey's anti-inflammatory effects are related to its phenolic or tocopherol compounds, and whether its effects are greater than these individual components.

Altered IFN-γ Levels after Treatment of Epileptic Patients with Omega-3 Fatty Acids.

Epilepsy is a frequent chronic disorder of the brain characterized by intermittent epileptic seizures caused by hypersynchronous discharge of neurons in the brain. Studies have reported the role of cytokines in the pathogenesis of epilepsy, and a number of investigations have shown decreased levels of omega-3 fatty acids in epileptic patients. We investigated differences in serum levels of two cytokines, transforming growth factor (TGF)-ß and interferon (IFN)-γ, in 40 epileptic cases prior to and after treatment with omega-3 fatty acids. IFN-γ levels were significantly increased after the 16-week treatment period (P < 0.001). However, TGF-ß levels remained unchanged (P = 0.14). Omega-3 fatty acid treatment may alter the immune response in epileptic patients. This should be considered in prescription of omega-3 fatty acid supplements in these patients. Future studies with larger sample sizes should verify the results of the current study.

Effects of ozone autohemotherapy on blood VEGF, TGF-ß and PDGF levels after finger replantation.

BACKGROUND: The study aimed to confirm the important role of ozone autologous blood therapy (autohemotherapy) in promoting successful finger replantation and its possible influence mechanism. METHODS: A total of 150 patients with severed finger replantation admitted to our hospital from March 2018 to March 2019 were selected. Patients were divided into observation group and control group according to different treatment methods. The observation group received additional ozone autologous blood treatment in the control group. We compared the number of white blood cells, visual analogue scale (VAS) scores, and the expression levels of vascular endothelial growth factor (VEGF), transforming growth factor-ß (TGF-ß), and platelet-derived growth factor (PDGF) in the two groups of patients before and after intervention. We also assessed the hospitalization time and survival time of the replanted finger in the two groups, as well as blood flow values (Vbcf). RESULTS: Compared with the observation group on the 1st day after the operation and the control group on the 7th day after the operation, the average white blood cell count of the observation group on the 7th day after the operation was significantly increased (P<0.05), and the VAS score was significantly decreased (P<0.05).48 hours after the operation, the average Vbcf value of the replanted finger was lower than that of the contralateral healthy finger (P<0.05). Compared with the control group, the Vbcf value of the replanted fingers in the observation group was higher, and the hospitalization time and finger survival time were shorter (P<0.05). At 7 days after operation, the serum VEGF, TGF-ß and PDGF levels in the observation group were significantly higher than the 1 day after operation, before the operation and the control group (P<0.05). CONCLUSIONS: Intervention with ozone autohemotherapy after severed finger replantation can significantly increase the number of white blood cells, relieve postoperative pain, and improve the survival rate of the finger body. Ozone autohemotherapy also improves the microcirculation after anastomosis of the severed finger by up-regulating the expression of VEGF, TGF-ß and PDGF in blood.

Is clinical effect of autologous conditioned serum in spontaneously occurring equine articular lameness related to ACS cytokine profile?

BACKGROUND: Biologic' therapies, such as autologous conditioned serum (ACS), are gaining popularity in treating orthopaedic conditions in equine veterinary medicine. Evidence is scarce regarding ACS constituents, and large inter-individual differences in cytokine and growth factor content have been demonstrated. The objective of the current study was to investigate the potential association between cytokine and growth factor content of ACS and clinical effect in harness racehorses with spontaneously occurring low-grade articular lameness. Horses received 3 intra-articular injections of ACS administered at approximately 2-week intervals. Lameness evaluation consisting of a trot-up with subsequent flexions tests was performed at inclusion and approximately 2 weeks after the last treatment (re-evaluation); horses were classified as responders when there was no detectable lameness on trot-up and a minimum of 50% reduction in flexion test scores at re-evaluation. Association between clinical outcome (responders vs. non-responders) and age, lameness grades at inclusion (both initial trot-up and after flexion tests), treatment interval, follow-up time and the ACS content of IL-1Ra, IGF-1 and TGF-ß was determined by regression modelling. RESULTS: Outcome analysis was available for 19 of 20 included horses; 11 responded to treatment whereas 8 did not. There was considerable inter-individual variability in cytokine/growth factor content of ACS, and in the majority of the horses, the level of IL-10, IL-1ß and TNF-α was below the detection limit. In the final multivariate logistic regression model, ACS content of IGF-1 and IL-1Ra was significantly associated with clinical response (P = 0.01 and P = 0.03, respectively). No association with clinical response was found for the other tested variables. CONCLUSIONS: The therapeutic benefit of ACS may be related to higher levels of IL-1Ra and IGF-1. Our study corroborates previous findings of considerable inter-individual variability of cytokine- and growth factor content in ACS.

Serum proteins TGFBI, PCSK9, and CCL14 are potential biomarkers for different traditional Chinese medicine syndromes of multidrug-resistant tuberculosis.

Patients with multidrug-resistant tuberculosis (MDR-TB) tend to have a long course of anti-TB treatment and severe side effects. Traditional Chinese Medicine (TCM) has a synergistic effect in attenuation of MDR-TB. However, the lack of objective biological standards to classify and diagnose MDR-TB TCM syndromes could result in less effective TCM treatment. Therefore, in this study, we identified differentially expressed proteins (DEPs) in serum of individuals with MDR-TB TCM syndromes by applying isobaric tags for relative and absolute quantification coupled with two-dimensional liquid chromatography-tandem mass spectrometry (iTRAQ-2DLC-MS/MS) method and bioinformatics analysis. The functional analysis of DEPs was also performed. Additionally, DEPs among three different TCM syndromes of MDR-TB were validated by enzyme-linked immunosorbent assay (ELISA). Finally, a receiver operating characteristic (ROC) curve was performed to estimate the diagnostic ability of DEPs. A total of 71 DEPs were identified in the three different MDR-TB TCM syndrome groups such as the pulmonary Yin deficiency (PYD) syndrome group, the Hyperactivity of Fire due to Yin deficiency (HFYD) syndrome group, and the deficiency of Qi and Yin (DQY) syndrome group. The results showed that the expression level of transforming growth factor-beta-induced protein ig-h3 (TGFBI) was lower in the PYD syndrome group (p = .002), the proprotein convertase subtilisin/kexin type 9 (PCSK9) was overexpressed in the HFYD syndrome group (p < .0001), and the C-C motif chemokine ligand 14 (CCL14) expression level was reduced in the DQY syndrome group (p = .004). Our study demonstrated that serum TGFBI, PCSK9, and CCL14 may serve as potential novel biomarkers for PYD syndrome, HFYD syndrome and DQY syndrome of MDR-TB, respectively. The study provides a biological basis for MDR-TB TCM syndromes classification and can be of great significance for the treatment of different TCM syndromes.

Effect of an aqueous extract of Averrhoa carambola L. on endothelial function in rats with ventricular remodelling.

Ventricular remodelling leads to cardiomyocyte hypertrophy, myocardial fibrosis, endothelial vasoactive substance changes and endothelial dysfunction. Our purpose was to research the effect of an aqueous extract of Averrhoa carambola L. (AEA) on endothelial function in rats with ventricular remodelling induced by isoprenaline. Rats were subjected to injection of isoprenaline and administration of various drugs. Vasoactive substances were measured, and the ventricular remodelling index was detected by the weighing method. Immunohistochemical analysis, pathological examination, Western blot and Masson's trichrome staining were performed. After AEA administration, the levels of transforming growth factor-ß (TGF-ß), angiotensin II (AngII), inducible NO synthase (iNOS), endothelin-converting enzyme (ECE), and endothelin 1 (ET-1); the ventricular remodelling index; and the collagen volume fraction were decreased, while the levels of total NO synthase (tNOS) and endothelial NO synthase (eNOS) were increased. The pathological examination results showed that apoptosis, fibrosis, necrosis and inflammatory infiltration of myocardial tissue were attenuated by AEA treatment. AEA might alleviate ventricular remodelling in rats by maintaining the balance of vasoactive substances and the function of the vascular endothelium.

Paricalcitol regulatory effect on inflammatory, fibrotic and anticalcificating parameters in renal patiente. Far beyond mineral bone disease regulation. / Efecto regulador de paricalcitol sobre parámetros inflamatorios, fibróticos y anticalcificantes en el paciente con enfermedad renal crónica. Más allá de la regulación de la enfermedad óseo-mineral.

BACKWARD: Cardiovascular events are the major cause of morbidity and mortality in patients with chronic kidney disease (CKD). Inflammation and mineral-bone disorder are pathological conditions that have been associated with an increased cardiovascular risk. OBJECTIVE: Show paricalcitol regulation overinflammatory, fibrotic and mineral disorder parameters in CKD. MATERIAL AND METHODS: Prospective Study in 46 CKD stages III-V patients without dialysis patients whith elevated parathormone in which we introduced paricalcitol. We evaluated classic and newest mineral and bone metabolism serum parameters (calcium, phosphorus, parathormone, fibroblast growth factor-23 [FGF-23], Klotho, calcidiol), inflammatory-fibrosis and anticalcifying parameters (interleukin-6 and 10, tumor necrosis factor-a [TNF- α], transforming growth factor-b [TGF-ß],bone morphogenic protein-7 [BMP-7] and fetuin-A) for four months. RESULTS: At the end of study soluble Klotho increased (p=.001), FGF-23 remained stable, calcium and phosphorus levels were not increased, calcidiol increased (p=.010) and PTH decreased (p=.002). Inflammation-fibrosis and calcification parameters showed positive regulation after paricalcitol treatment: interleukin-6 decreased significantly (p=.001) and also TNF-α did (p=.005), on the contrary, interleukin-10 and fetuin-A increased (p=.001 for both). Anti-fibrosis marker BMP-7 increased (p=.001) and TGF-b decreased (p=.001). We did not find significant changes in renal function. CONCLUSIONS: Paricalcitol treatment might be profitable in regulating inflammatory and anticalcificant parameters, unmodified calcium or phosphorus seric levels and preserving kidney function in renal patients with no dialysis. Our selected parameters could indicate paricalcitol effects in mineral and endothelial disorder related to renal disease.

Anti-inflammatory activity of the sesquiterpene lactone diacethylpiptocarphol in dextransulfate sodium-induced colitis in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Sesquiterpene lactones are organic compounds derived mainly from plants that exhibit anti-inflammatory and antitumor activities being one of the key mechanism of action of NF-kB pathway and synthesis of cytokines such as IL-1 and TNF- α. AIM OF THE STUDY: The overall objective of the present study was to evaluate the anti-inflammatory action of a sesquiterpene lactone diacethylpiptocarphol (DPC) from Vernonia scorpioides (Lam.) Pers. and parthenolide (PTH) in Balb-c mice with DSS-induced colitis. MATERIALS AND METHODS: The anti-inflammatory effects of Intraperitonial administration of DPC (5 mg/kg/day) were evaluated in Balb/c mice with DSS-induced colitis, and further the body weight measurement, TNF-α and TGF-ß level was determined. RESULTS: After intraperitoneal treatment for one week, DSS-induced colitis was significantly reduced in mice treated with either of both sesquiterpenes lactones, as witnessed by reduced cellular infiltration, tissue damage, TNF-α production, and enhanced production of TGF-ß. CONCLUSIONS: Sesquiterpene lactone DPC, isolated from Vernonia scorpioides showed anti-inflammatory activity, in this experimental model of colitis the sesquiterpene lactones DPC and PTH exhibit equal anti-inflammatory activity.

Ang-(1-7) treatment attenuates lipopolysaccharide-induced early pulmonary fibrosis.

Early pulmonary fibrosis is the leading cause of poor prognosis in patients with acute respiratory distress syndrome (ARDS). However, whether the renin-angiotensin system (RAS) can serve as a therapeutic target is unknown. In this study, an animal model of early pulmonary fibrosis was established via the LPS three-hit regimen. Afterwards, the animals were treated with intraperitoneal injections of Ang-(1-7), AVE0991, or A779 once per day for 20 days. The plasma and BALF AngII levels of the animals were increased, while there were no significant changes in Ang-(1-7) levels in lung tissue after LPS treatment. Furthermore, the AT1R protein levels were significantly increased and the Mas levels were significantly decreased on days 14 and 21. Administration of Ang-(1-7) downregulated LPS-induced AT1R mRNA expression, which was upregulated by A779. The expression of Mas mRNA responded in the opposite direction relative to AT1R. Moreover, LPS caused decreased levels of Mas and E-cadherin and increased AT1R, Vimentin, and Src phosphorylation levels. Ang-(1-7) or AVE0991 blocked these effects but was counteracted by A779 treatment. Our findings suggested that AngII and AT1R levels exhibit opposite dynamic trends during LPS-induced early pulmonary fibrosis, as do Ang-(1-7) and Mas. Ang-(1-7) exerts protective effects against early pulmonary fibrosis, mainly by regulating the balance between AngII and AT1R and between Ang-(1-7) and Mas and by inhibiting Src kinase activation.

Dianthus superbus Improves Glomerular Fibrosis and Renal Dysfunction in Diabetic Nephropathy Model.

Glomerular fibrosis is caused by an accumulation of intercellular spaces containing mesangial matrix proteins through either diffused or nodular changes. Dianthus superbus has been used in traditional medicine as a diuretic, a contraceptive, and an anti-inflammatory agent. The aim of this study was to investigate the effects of Dianthus superbus-EtOAc soluble fraction (DS-EA) on glomerular fibrosis and renal dysfunction, which has been implicated in diabetic nephropathy in human renal mesangial cells and db/db mice. DS-EA was administered to db/db mice at 10 or 50 mg/kg/day for 8 weeks. DS-EA treatment significantly ameliorated blood glucose, insulin, the homeostasis model assessment of insulin resistance (HOMA-IR) index, and HbA1c in diabetic mice. DS-EA decreased albumin excretion, creatinine clearance (Ccr), and plasma creatinine levels. DS-EA also ameliorated the levels of kidney injury molecules-1 (KIM-1) and C-reactive protein. DS-EA reduced the periodic acid-Schiff (PAS) staining intensity and basement membrane thickening in glomeruli of the diabetic nephropathy model. In addition, DS-EA suppressed transforming growth factor-ß (TGF-ß)/Smad signaling. Collagen type IV, a glomerular fibrosis biomarker, was significantly decreased upon DS-EA administration. DS-EA pretreatment attenuated levels of inflammation factors such as intracellular cell adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1). DS-EA inhibited the translocation of nuclear factor kappa B (NF-κB) in Angiotensin II (Ang II)-stimulated mesangial cells. These findings suggest that DS-EA has a protective effect against renal inflammation and fibrosis. Therefore, DS-EA may serve as a potential therapeutic agent targeting glomerulonephritis and glomerulosclerosis, which lead to diabetic nephropathy.

Impact of Vitamin D Supplementation on Influenza Vaccine Response and Immune Functions in Deficient Elderly Persons: A Randomized Placebo-Controlled Trial.

Background: Immunosenescence contributes to reduced vaccine response in elderly persons, and is worsened by deficiencies in nutrients such as Vitamin (Vit-D). The immune system is a well-known target of Vit-D, which can both potentiate the innate immune response and inhibit the adaptive system, and so modulate vaccination response. Objective: This randomized placebo-controlled double-blind trial investigated whether Vit-D supplementation in deficient elderly persons could improve influenza seroprotection and immune response. Design: Deficient volunteers (Vit-D serum <30 ng/mL) were assigned (V1) to receive either 100,000 IU/15 days of cholecalciferol (D, n = 19), or a placebo (P, n = 19), over a 3 month period. Influenza vaccination was performed at the end of this period (V2), and the vaccine response was evaluated 28 days later (V3). At each visit, serum cathelicidin, immune response to vaccination, plasma cytokines, lymphocyte phenotyping, and phagocyte ROS production were assessed. Results: Levels of serum 25-(OH)D increased after supplementation (D group, V1 vs. V2: 20.7 ± 5.7 vs. 44.3 ± 8.6 ng/mL, p < 0.001). No difference was observed for serum cathelicidin levels, antibody titers, and ROS production in D vs. P groups at V3. Lower plasma levels of TNFα (p = 0.040) and IL-6 (p = 0.046), and higher ones for TFGß (p = 0.0028) were observed at V3. The Th1/Th2 ratio was lower in the D group at V2 (D: 0.12 ± 0.05 vs. P: 0.18 ± 0.05, p = 0.039). Conclusions: Vit-D supplementation promotes a higher TGFß plasma level in response to influenza vaccination without improving antibody production. This supplementation seems to direct the lymphocyte polarization toward a tolerogenic immune response. A deeper characterization of metabolic and molecular pathways of these observations will aid in the understanding of Vit-D's effects on cell-mediated immunity in aging. This clinical trial was registered at clinicaltrials.gov as NCT01893385.

Icaritin Improves Antibody-Induced Thrombocytopenia in a Mouse Model by Regulating T-cell Polarization.

Previous studies have shown that icaritin (ICT) has significant protective effects on immune thrombocytopenia (ITP), and the present study aimed to discuss the mechanism of this protective effect from the aspect of regulating T-cell polarization by an antibody-induced ITP mice model. Mice were given rat anti-mouse CD41 antibody (MWReg30) by intraperitoneal injection for 7 d to produce ITP model. At the same time, ICT was administrated at 10 mg/kg/d orally for 9 d. Peripheral blood platelets were counted by hematology analyzer. Spleen index was also tested. Spleen T-helper cell (Th), cytotoxic T-cell (CTL), Th1, Th2, Th17, regulatory T-cell (Treg), and follicular helper T-cell (Tfh) were quantified by flow cytometry. Serum Th1/Th2/Th17 cytokines were tested by mouse Th1/Th2/Th17 cytometric bead array (CBA) kit and transforming growth factor beta (TGF-ß) were analyzed by enzyme-linked immunosorbent assay (ELISA) kit. The results indicated that ICT (10 mg/kg) protected against MWReg30-induced ITP, as evidenced by increased blood platelets and decreased spleen index. In addition, the imbalance of Th/CTL in ITP mice spleen was regulated by ICT. Meanwhile, ICT inhibited Th1, Th17, and Tfh and improved Th2 and Treg in ITP mice spleen. Furthermore, the results of CBA and ELISA suggested that ICT decreased serum Th1- and Th17-related cytokines and increased Th2 cytokines, as well as promoted the release of TGF-ß. These results demonstrated that the protective effect of ICT on ITP was mediated by regulating T-cell polarization.

Identification of plasma interleukins as biomarkers for deflazacort and omega-3 based Duchenne muscular dystrophy therapy.

Duchenne muscular dystrophy (DMD) is a progressive and fatal disease, characterized by the absence of dystrophin, muscle degeneration and cardiorespiratory failure. Creatine kinase is the classic marker to screen for DMD. However, other markers are needed to follow disease progression and to evaluate the response to therapy over longer periods. In the present study, we aim to identify interleukins in the plasma of the mdx mice model of DMD that could serve as biomarkers to monitor dystrophy progression, at distinct stages of the disease (1, 3 and 8 months of age). We used deflazacort and omega-3 therapies to validate the biomarkers studied. Plasma levels of TNF-α and TGF-ß were increased in mdx mice in relation to control, at all times studied. Differences in IFN-γ and IL-10 contents, comparing mdx x CTRL, were detected only at the early stage (1 month). IL-6 decreased at 3 and 8 months and IL-13 increased at 8 months in the mdx compared to control. Deflazacort and omega-3 reduced the plasma levels of the pro-inflammatory (TNF-α, INF-γ, IL-6) and pro-fibrotic (IL-13 and TGF-ß) interleukins and increased the plasma levels of IL-10. It is suggested that TNF-α and TGF-ß in plasma would be the best markers to follow disease progression. IL-6, INF-γ and IL-10 would be suitable markers to the earlier stages of dystrophy and IL-13 a suitable marker to the later stages of dystrophy.

Effect of Qianghuo Erhuang Decoction on T Regulatory and T Helper 17 Cells in Treatment of Adjuvant-induced Arthritis in Rats.

QianghuoErhuang Decoction (QED) is an effective recipe in treating rheumatoid arthritis. The present study aimed to explore the effects of QED on Treg and Th17 in adjuvant arthritis (AA) model. The study included 6 group rats: normal control group, AA group, AA + methotrexate (MTX) group, AA + high, moderate, and low dose QED groups. The arthritis score was significantly decreased in the MTX and high-dose QED groups compared with the AA group on days 24 and 28 (P < 0.01), respectively. The synovial tissue inflammation was attenuated by histological observation, and the proliferation of splenocytes was significantly inhibited in MTX and high-dose QED groups (P < 0.01). High-dose QED can up-regulated the percentage of Treg cells (P < 0.01) and down-regulated the percentage of Th17 cells (P < 0.05). Notably, the serum levels of IL-6, IL-17 and TNF-α were significantly decreased, while TGF-ß levels were apparently elevated compared with AA group (P < 0.05, P < 0.01). Interestingly, moderate and low-dose QED had no such similar effects. In summary, high-dose QED had a therapeutic effect against adjuvant arthritis and regulated the related cytokine levels in serum. The underlying mechanism might be mediated via restoration of the imbalance in CD4+ T lymphocyte subsets, Treg/Th17.

Metabolomics reveals the mechanisms for the cardiotoxicity of Pinelliae Rhizoma and the toxicity-reducing effect of processing.

Pinelliae Rhizoma (PR) is a commonly used Chinese medicinal herb, but it has been frequently reported about its toxicity. According to the traditional Chinese medicine theory, processing can reduce the toxicity of the herbs. Here, we aim to determine if processing reduces the toxicity of raw PR, and to explore the underlying mechanisms of raw PR-induced toxicities and the toxicity-reducing effect of processing. Biochemical and histopathological approaches were used to evaluate the toxicities of raw and processed PR. Rat serum metabolites were analyzed by LC-TOF-MS. Ingenuity pathway analysis of the metabolomics data highlighted the biological pathways and network functions involved in raw PR-induced toxicities and the toxicity-reducing effect of processing, which were verified by molecular approaches. Results showed that raw PR caused cardiotoxicity, and processing reduced the toxicity. Inhibition of mTOR signaling and activation of the TGF-ß pathway contributed to raw PR-induced cardiotoxicity, and free radical scavenging might be responsible for the toxicity-reducing effect of processing. Our data shed new light on the mechanisms of raw PR-induced cardiotoxicity and the toxicity-reducing effect of processing. This study provides scientific justifications for the traditional processing theory of PR, and should help in optimizing the processing protocol and clinical combinational application of PR.

Preclinical rationale for TGF-ß inhibition as a therapeutic target for the treatment of myelofibrosis.

To assess the role of abnormal transforming growth factor-beta (TGF-ß) signaling in the pathogenesis of primary myelofibrosis (PMF), the effects of the TGF-ß receptor-1 kinase inhibitor SB431542 on ex vivo expansion of hematopoietic cells in cultures from patients with JAK2V617+-polycythemia vera (PV) or PMF (JAK2V617F+, CALRpQ365f+, or unknown) and from normal sources (adult blood, AB, or cord blood, CB) were compared. In cultures of normal sources, SB431542 significantly increased by 2.5-fold the number of progenitor cells generated by days 1-2 (CD34+) and 6 (colony-forming cells) (CB) and that of precursor cells, mostly immature erythroblasts, by days 14-17 (AB and CB). In cultures of JAK2V617F+-PV, SB431542 increased by twofold the numbers of progenitor cells by day 10 and had no effect on that of precursors cells by days 12-17 (∼fourfold increase in all cases). In contrast, SB431542 had no effect on the number of either progenitor or precursor cells in cultures of JAK2V617F+ and CALR pQ365fs+ PMF. These ontogenetic- and disease-specific effects were associated with variegation in the ability of SB431542 to induce CD34+ cells from AB (increased), CB (decreased), or PV and PMF (unaffected) into cycle and erythroblasts in proliferation (increased for AB and PV and unaffected for CB and PMF). Differences in expansion of erythroblasts from AB, CB, and PV were associated with differences in activation of TGF-ß signaling (SHCY317, SMAD2S245/250/255, and SMAD1S/S/SMAD5S/S/SMAD8S/S) detectable in these cells by phosphoproteomic profiling. In conclusion, treatment with TGF-ß receptor-1 kinase inhibitors may reactivate normal hematopoiesis in PMF patients, providing a proliferative advantage over the unresponsive malignant clone.

Glutamine promotes intestinal SIgA secretion through intestinal microbiota and IL-13.

SCOPE: Glutamine supplementation enhances secretory IgA (SIgA) production in the intestine, but the mechanism is largely unknown. We examined this issue using a mouse model. METHODS AND RESULTS: In mouse model, glutamine supplementation increased both SIgA abundance in intestinal luminal contents and IgA(+) plasma cell numbers in the mouse ileum, and decreased bacterial loads in mouse mesenteric lymph nodes. Glutamine supplementation increased mouse ileal expression of cytokines associated with T cell-dependent and T cell-independent pathways of SIgA induction, including IL-5, IL-6, IL-13, transforming growth factor (TGF-ß), a proliferation-inducing ligand (APRIL), B cell-activating factor (BAFF), vasoactive intestinal peptide (VIP) receptor, and retinal dehydrogenases. Injecting an IL-13 antibody during glutamine supplementation reduced J-chain expression in the mouse ileum. Glutamine supplementation increased bacterial invasion into the mouse ileal wall, while disrupting the mouse intestinal microbiota abrogated the influence of glutamine supplementation on SIgA secretion. CONCLUSION: Glutamine supplementation appears to enhance SIgA secretion in the mouse intestine through the intestinal microbiota and subsequently through T cell-dependent and T cell-independent pathways.

Vitamin A supplementation reduces the Th17-Treg - Related cytokines in obese and non-obese women.

OBJECTIVE: The objective of the present study was to investigate the effect of vitamin A supplementation on serum Th17 (IL-6, IL-17, IFNγ) and Treg (TGF-ß, IL-10) related cytokines in obese and non-obese women. SUBJECTS AND METHODS: In a randomized double blind placebo controlled design, 56 obese women were randomly assigned to receive either an oral dose of 25,000 IU retinyl palmitate or placebo per day for 4 months. Twenty eight ages matched non-obese women were also received vitamin A. At the study entry, anthropometric variables were measured and serum Th17 and Treg related cytokine profile were determined at baseline and 4 months after intervention. RESULTS: Significantly higher baseline concentrations of IL-6 were observed in obese compared with non-obese women (P < 0.05). However, the initial concentrations of other cytokines were not significantly different between groups. The mean concentrations of IL-17 and TGF-ß were significantly decreased after vitamin A supplementation in non-obese and obese women respectively. Positive relationships between IL-17 and IL-10 (r = 0.42, P < 0.001), TGF-ß and IL-17 (r = 0.35, P < 0.001) and between IL-10 and IFN-γ (r = 0.41, P = 0.002) in total participants were also observed. CONCLUSIONS: The results of the present study showed for the first time that vitamin A supplementation reduces serum concentrations of IL-17 and TGF-ß in reproductive age women. Further studies are needed to explore the possible underlying mechanisms.

Vitamin A supplementation reduces the Th17-Treg – Related cytokines in obese and non-obese women

ABSTRACT Objective The objective of the present study was to investigate the effect of vitamin A supplementation on serum Th17 (IL-6, IL-17, IFNγ) and Treg (TGF-β, IL-10) related cytokines in obese and non-obese women. Subjects and methods In a randomized double blind placebo controlled design, 56 obese women were randomly assigned to receive either an oral dose of 25,000 IU retinyl palmitate or placebo per day for 4 months. Twenty eight ages matched non-obese women were also received vitamin A. At the study entry, anthropometric variables were measured and serum Th17 and Treg related cytokine profile were determined at baseline and 4 months after intervention. Results Significantly higher baseline concentrations of IL-6 were observed in obese compared with non-obese women (P < 0.05). However, the initial concentrations of other cytokines were not significantly different between groups. The mean concentrations of IL-17 and TGF-β were significantly decreased after vitamin A supplementation in non-obese and obese women respectively. Positive relationships between IL-17 and IL-10 (r = 0.42, P < 0.001), TGF-β and IL-17 (r = 0.35, P < 0.001) and between IL-10 and IFN-γ (r = 0.41, P = 0.002) in total participants were also observed. Conclusions The results of the present study showed for the first time that vitamin A supplementation reduces serum concentrations of IL-17 and TGF-β in reproductive age women. Further studies are needed to explore the possible underlying mechanisms.

Effect of Probiotic Supplement on Cytokine Levels in HIV-Infected Individuals: A Preliminary Study.

UNLABELLED: Inflammation persists in patients infected with HIV. Reduction of inflammatory cytokines and microbial translocation might be one way that this could be managed. PURPOSE: The anti-inflammatory properties of certain probiotic strains prompted us to investigate whether a probiotic could reduce the inflammatory index of HIV-infected patients. METHODS: The study involved 30 HIV+ males on antiretroviral therapy, who were given one bottle of fermented milk Yakult Light® containing Lactobacillus casei Shirota (LcS) twice a day for four weeks. RESULTS: The probiotic LcS was associated with an increase of T lymphocytes and a significant increase of CD56+ cells (p = 0.04). There was also a significant decrease of mRNA levels of TGFß, IL-10 and IL-12 (p < 0.001) and IL-1ß expression (p < 0.001) and an increase of serum IL-23 (p = 0.03). In addition, decreased inflammation and cardiovascular risk were observed, as shown by a reduction of cystatin C (p < 0.001). CONCLUSIONS: These data provide preliminary evidence that probiotic supplementation may modulate certain immunological parameters and some of the cytokines that were analyzed. Thus, we propose that LcS may be an inexpensive and practical strategy to support the immune function of HIV+ patients.