Multiplex Analysis of Serum Cytokine Levels in Waldenström Macroglobulinemia Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2616-2616
Author(s):  
Sherine F. Elsawa ◽  
Anne J. Novak ◽  
Steven C. Ziesmer ◽  
Thomas E. Witzig ◽  
Vincent Rajkumar ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Elevated Serum ◽  
Fold Increase ◽  
Serum Levels ◽  
Healthy Controls ◽  
Β2 Microglobulin ◽  
Healthy Donors ◽  
Cytokine Levels

Abstract Waldenström macroglobulinemia (WM) is a monoclonal B cell disorder characterized by a circulating monoclonal IgM protein that may lead to serum hyperviscosity in association with an infiltration of lymphoplasmacytic cells into the bone marrow. Although proinflammatory and chemotactic cytokines can profoundly affect tumor cells and the tumor microenvironment, and many cytokines have been shown to have potent therapeutic efficacy in preclinical cancer models, the role of cytokine networks in WM is not fully understood. In this study, we used a high-throughput xMAP multiplex immunobead assay technology (Luminex Corp., Austin, TX) to simultaneously test 30 cytokines, chemokines, angiogenic factors as well as growth factors and soluble receptors in the sera of WM patients and compared them with other B cell malignancies including IgM monoclonal gammopathy of undetermined significance (MGUS), follicular lymphoma, chronic lymphocytic leukemia (CLL) as well as healthy controls. Using a Mann-Whitney U test to analyze the differences between the groups, 15 of the 30 cytokines tested had significantly different levels in WM compared to healthy controls. Of those 15 cytokines, 11 were elevated in WM patients and 4 were decreased. Cytokines were grouped into 3 groups; those with < 2-fold difference, 2–8 fold difference and those having > 8-fold difference in their cytokine levels compared to healthy donors. There was a greater than 8-fold increase in the serum levels of Rantes, G-CSF and IL-2R (p<0.0001) in WM patients. Furthermore, 3 cytokines had between 2–8-fold increase in WM patients including IL-4 (p<0.0001), IL-6 (p<0.0019) and IP-10 (p<0.0006). Five cytokines had statistically elevated levels in WM patients compared to healthy controls, however the fold increase was < 2 including HGF (p<0.0185), IL-10 (p<0.0002), MIP-1α (P<0.0484), IL-2 (P<0.0130) and IL-12 (P<0.0155). Of the cytokines that had significantly lower levels in the sera of WM patients, IL-8 (p<0.0001) and EGF (p<0.0001) were > 8-fold decreased, MCP-1 (p<0.0001) was 2–8 fold lower and Eotaxin (p<0.0004) was < 2-fold lower in WM patients. All of the cytokines that had the greatest fold difference (> 8-fold) in WM patients compared to healthy donors also differed significantly from the MGUS patients. Rantes, G-CSF, IL-2R and EGF had significantly different levels compared to other B cell malignancies. We tested for a correlation between the cytokines that had > 2-fold difference between the WM group and control group with clinical features of the disease and found the cytokines IL-6 and IL-2R had a significant correlation with β2-microglobulin levels (p<0.01). We analyzed cytokine levels in the bone marrow plasma of the same patients and found that high levels of IL-2R in the bone marrow microenvironment significantly correlated with anemia and elevated serum β2-microglobulin (p<0.01). In conclusion, we have simultaneously analyzed sera from WM patients for 30 cytokines and found the most significantly elevated cytokines are Rantes, G-CSF and IL-2R and the most significantly downregulated cytokines are IL-8 and EGF. Furthermore, we found that elevated serum levels of IL-6 and IL-2R correlated with β2-microglobulin levels, a measure of disease activity. Further analysis of the biological role of these cytokines in WM may offer insight into disease pathogenesis and provide a basis for novel targeted therapies.

scholarly journals Mutations of the Igβ gene cause agammaglobulinemia in man

2007 ◽  
Vol 204 (9) ◽  
pp. 2047-2051 ◽  
Author(s):  
Simona Ferrari ◽  
Vassilios Lougaris ◽  
Stefano Caraffi ◽  
Roberta Zuntini ◽  
Jianying Yang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Transmembrane Protein ◽  
Serum Levels ◽  
Cell Development ◽  
B Cell Development ◽  
Surrogate Light Chain ◽  
Human B Cell ◽  
Homozygous Nonsense Mutation

Agammaglobulinemia is a rare primary immunodeficiency characterized by an early block of B cell development in the bone marrow, resulting in the absence of peripheral B cells and low/absent immunoglobulin serum levels. So far, mutations in Btk, μ heavy chain, surrogate light chain, Igα, and B cell linker have been found in 85–90% of patients with agammaglobulinemia. We report on the first patient with agammaglobulinemia caused by a homozygous nonsense mutation in Igβ, which is a transmembrane protein that associates with Igα as part of the preBCR complex. Transfection experiments using Drosophila melanogaster S2 Schneider cells showed that the mutant Igβ is no longer able to associate with Igα, and that assembly of the BCR complex on the cell surface is abrogated. The essential role of Igβ for human B cell development was further demonstrated by immunofluorescence analysis of the patient's bone marrow, which showed a complete block of B cell development at the pro-B to preB transition. These results indicate that mutations in Igβ can cause agammaglobulinemia in man.

Elevated Serum IL-12 Levels Attenuate Tumor Immunity Via the TIM-3/Gal-9 Axis and Worsen Patient Prognosis in Follicular B-Cell Non-Hodgkin Lymphoma (NHL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2668-2668
Author(s):  
Zhi-Zhang Yang ◽  
Steven C. Ziesmer ◽  
Anne J. Novak ◽  
Toshiro Niki ◽  
Mitsuomi Hirashima ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Cell Lymphoma ◽  
Elevated Serum ◽  
B Cell Lymphoma ◽  
Serum Levels

Abstract Abstract 2668 Poster Board II-644 Interleukin-12 (IL-12) has been demonstrated to induce IFN-g production by T and NK cells and thereby contribute to anti-tumor immunity. However, the administration of IL-12 to boost anti-tumor immunity in B-cell lymphoma has shown no clinical benefit. In fact, clinical trials of IL-12 in combination with rituximab in follicular B-cell lymphoma (FL) showed a lower response rate in patients treated with the combination than in patients treated with rituximab alone (Clin Cancer Res. 2006 15; 12:6056-63). The goal of this study was therefore to determine the role of IL-12 in the antitumor response in B-cell NHL. First, we measured serum levels of IL-12 in patients with untreated FL before treatment with rituximab and normal healthy controls. We found that serum IL-12 levels were elevated in FL patients compared to healthy individuals (median: 0.50 ng/ml, n=30 vs 0.32 ng/ml, n=22; p= 0.03) and that elevated serum IL-12 levels were associated with a poor outcome in these patients when treated with rituximab alone as initial therapy. Using 0.56 ng/ml as a cutoff, patients with serum IL-12 levels of greater than 0.56 ng/ml had a significantly shorter time to progression than patients with IL-12 levels less than 0.56 ng/ml (12 months versus 40 months; p=0.001). To determine the mechanism by which IL-12 may contribute to a poor prognosis, we investigated the role of IL-12 on induction of immune tolerance. First, we found that TIM-3, a member of the T cell immunoglobulin and mucin domain-containing protein (TIM) family that functions to terminate TH1-mediated immunity and promote tolerance, was constitutively expressed on a subset of intratumoral T cells accounting for approximately 15% and 25% of the intratumoral CD4+ and CD8+ T cells, respectively. In contrast, less than 2% of T cells from peripheral blood of normal individuals expressed TIM-3. TIM-3-expressing T cells were distinct from regulatory T cells since CD25+ and Foxp3+ T cells lacked TIM-3 expression. Secondly, we found that TIM-3-expressing CD4+ cells were unable to produce cytokines such as IL-2, IFN-g or IL-17 and that TIM-3-expressing CD8+ T cells failed to produce Granzyme B, IFN-g or IL-2. We also observed that TIM-3-expressing T cells lost the capacity to proliferate in response to TCR activation. These results suggest that TIM-3 expressing CD4+ and CD8+ T cells are functionally exhausted. Thirdly, we observed that TIM-3 expression on T cells could be induced by activation and that IL-12 was the strongest stimulus to induce TIM-3 expression on CD4+ and CD8+ T cells. Finally, we found by immunohistochemistry (IHC) that Galectin-9 (Gal-9), a ligand for TIM-3, was abundantly expressed on lymphoma B cells. In vitro incubation with a stable form of Gal-9 induced apoptosis of CD4+ and CD8+ T cells in a dose dependent fashion. Gal-9-mediated apoptosis of T cells was attenuated by a TIM-3 Fc protein and isolated TIM-3+ T cells exhibited a significantly higher apoptosis rate than TIM-3− T cells in response to Gal-9. These results indicate that, in contrast to the observations in vitro or in vivo in mice, IL-12 actually plays a detrimental role in lymphoma patients. Given the findings that IL-12 strongly induces TIM-3 expression on effector T cells and that the TIM-3/Gal-9 pathway impairs the immune response, we conclude that increased serum levels of IL-12 suppress anti-tumor immunity in follicular lymphoma patients and is associated with a poor prognosis. Disclosures: Witzig: Novartis: Research Funding.

Characteristic Proinflammatory Serum Cytokine Profiles In Patients with B-Cell Chronic Lymphocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3595-3595
Author(s):  
James J. Harding ◽  
Raymond Yeh ◽  
Yan Nikhamin ◽  
Mark Frattini ◽  
Nicole Lamanna ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
Regulatory Role ◽  
Healthy Controls ◽  
Β2 Microglobulin ◽  
Cd38 Expression

Abstract Abstract 3595 Background: Cytokines are posited to play a critical regulatory role on the survival of the B-cell neoplastic clone in Chronic Lymphocytic Leukemia (CLL). AIM: The primary goals of this study were 1) to define additional relevant cytokines, growth factors and chemokines in CLL pathophysiology and 2) to correlate abnormal cytokine levels with disease stage, relevant hematological data and multiple prognostic factors. METHODS: A novel bead-based protein array system was employed to simultaneously measure 38 proinflammatory cytokines in the sera of CLL patients (N=116) and healthy age and sex matched controls (N=30). These results were correlated with Rai stage, β2-microglobulin level, LDH, CD38 expression and cytogenetic abnormalities. RESULTS: We first confirmed previous observations that TNFα, IL-1α, IL-1RA, IL-10, sIL-2Rα, VEGF and sCD40 ligand are significantly elevated in patients with CLL as compared with healthy controls. Expanding on the current literature, we demonstrated perturbations in an additional 15 serum cytokines in affected individuals. Compared to healthy controls, CLL patients had an increase in serum levels of IL-3 (p=0.002), IL-7 (p=0.008), INF-2α (p<0.0001), MCP-1 (p<0.0001), MIP-1β (p=0.002), MDC (p<0.0001), Fractakine (p<0.0001), EGF (p<0.0001), FGF-2 (p<0.0001), GRO (p<0.0001), Eotaxin (p<0.0001) and FLT-3 ligand (p<0.0001). Patients with CLL also exhibited significantly lower levels of INF-γ (p<0.01), IL-6 (p<0.005) and IL-8 (p<0.002) when compared to healthy individuals. Advanced Rai stage and high risk chromosomal abnormalities (del 11q and del 17p) strongly correlated with higher serum levels of TNFα, soluble IL-2Rα, IL-10, MCP-1, MIP-1α, MIP-1β and IP-10. Finally, serum levels of TNFα, MIP-1α and MIP-1β correlated with other adverse prognostic markers, including total white blood cell count, serum β2-microglobulin and LDH levels as well as CD38 expression. CONCLUSION: We have demonstrated numerous previously unrecognized cytokine abnormalities in patients with CLL and described a unique cytokine signature associated with advanced disease. Supported by the current understanding of cytokine biology and CLL pathophysiology, our observations suggest an important regulatory role for hematopoietic cytokines, such as IL-3 and IL-7, in promulgating survival of the aberrant B-cell clone. Likewise, the profoundly high levels of chemokines (i.e. MCP-1, MIP-1α, MIP-1β, IP-10) and their association with high risk prognostic factors argue for their role in sustaining the neoplastic microenvironment. Finally, the altered levels of IL-10, IL-6 and INF-γ observed in patients with CLL likely contribute to the immunosuppressive phenotype of the disease state. Disclosures: No relevant conflicts of interest to declare.

Increased circulating CSF-1 (M-CSF) in myeloproliferative disease: association with myeloid metaplasia and peripheral bone marrow extension

Blood ◽  
1989 ◽  
Vol 74 (4) ◽  
pp. 1231-1234 ◽  
Author(s):  
HS Gilbert ◽  
V Praloran ◽  
ER Stanley
Keyword(s):  
Bone Marrow ◽  
Phenotypic Expression ◽  
Elevated Serum ◽  
Serum Levels ◽  
Myeloproliferative Disease ◽  
Myeloid Metaplasia ◽  
Macrophage Population ◽  
Agnogenic Myeloid Metaplasia ◽  
Peripheral Bone

Abstract Myeloproliferative disease (MPD) is heterogeneous in phenotypic expression and may display features consistent with expansion and activation of the monocyte/macrophage population during its course. The role of colony-stimulating factor-1 (CSF-1) in the pathophysiology of MPD was investigated by measuring circulating CSF-1 levels and examining their relationship to disease phenotype. Serum CSF-1 concentrations, measured by radioimmunoassay, were elevated in all MPD phenotypes. CSF-1 levels differed significantly between groups of patients with essential thrombocythemia, polycythemia vera, and postpolycythemic or agnogenic myeloid metaplasia (in ascending order). CSF-1 serum levels were positively correlated with spleen size and the degree of peripheral bone marrow extension, determined by scintigraphy using a macrophage-seeking isotope. There was no correlation between CSF-1 concentration and circulating levels of erythrocytes, neutrophils or platelets, or the presence of bone marrow fibrosis. Elevated serum CSF-1 levels appear to be associated with an expanded monocyte/macrophage population in MPD. In view of the known cooperativity between CSF-1 and other growth factors in regulating hematopoiesis, the finding of increased serum CSF-1 concentrations and its association with myeloid metaplasia and bone marrow extension may indicate a pathophysiologic role for CSF-1 in determining the phenotypic expression of MPD.

scholarly journals Changes in the Main Bone Marrow Cell Subpopulations May Potentially Contribute to the Initiation of Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2494-2494
Author(s):  
Shlomit Yehudai-Reshef ◽  
Rawan Sabah ◽  
Tal Gabay ◽  
Tsila Zuckerman
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Cell Viability ◽  
Myeloid Leukemia ◽  
Healthy Controls ◽  
Healthy Donors ◽  
Cluster 2 ◽  
Acute Myeloid

Introduction: In acute myeloid leukemia (AML), differentiation and proliferation of early progenitors is inhibited, leading to blast accumulation in the bone marrow (BM) and in the peripheral blood (PB). Hematopoietic stem cells (HSCs) reside in specialized BM microenvironment (ME), mainly containing osteocytes and adipocytes, derived from BM mesenchymal stem cells (MSCs). Recent studies suggest a possible role of the ME in various hematological malignancies, that either serves as a potential source of an altered milieu or mediates abnormal interaction with HSCs. BM ME contributes to disease pathogenesis, chemotherapy resistance and recurrence in certain types of hematological cancers, but there is limited evidence that BM cells themselves may initiate AML. BM derived MSCs are characterized by a potential to mainly differentiate to adipocytes, osteocytes or chondrocytes. Our experiments have revealed an imbalance between osteocytes and adipocytes in the BM of AML patients that is not observed in the BM of healthy donors. We hypothesize that this imbalance could result in the development of leukemic stem cells/pre-leukemic cells, leading to leukemia initiation. The current study aimed to characterize the composition of AML BM derived adipocytes and osteocytes and evaluate the ability of these subpopulations to support AML cell viability. Methods: Secreted levels of adipogenic and osteogenic biomarkers in the BM plasma were measured using ELISA. The potential of AML MSCs to differentiate to adipocytes and osteocytes was assessed using FACS analysis. Exome sequencing was applied for genetic alteration screening in AML MSCs. Obtained adipocytes and osteocytes were separately co-cultured with AML cells and colony forming unit (CFU) assays were used to evaluate AML cell viability. ProcartaPlex immunoassay was used to evaluate levels of cytokines and other potential mediators secreted to the conditioned media. Results: The study included BM samples of 10 AML patients and 13 healthy donors. Levels of secreted FABP4 and osteocalcin biomarkers were reduced in AML plasma (279.7±164 pg/ml and 0.00057±0.017 pg/ml, respectively) compared to that of healthy controls (1230±1502 pg/ml and 0.0016±0.00052 pg/ml, respectively), with P=0.02 for FABP4 and P=0.017 for osteocalcin. According to adipocyte cell differentiation, patients were divided into two clusters. Cluster-1 demonstrated a higher expression level of FABP4 (mean 65.2±11.4%) compared to healthy controls (mean: 47.5±19.2 %; P=0.05), while cluster-2 exhibited a lower level of FABP4 expression (mean 30.78±6.1%) than healthy controls (mean 47.6±19.2%; P=0.01). A nonsynonymous somatic mutation in the AHNAK2 gene (V3209L) was found in patients' mesenchymal stromal cells. A statistically significant reduction in AML cell proliferation (P<0.01) was revealed following co-culture with adipocyte cells of cluster-1 patients. Of the 10 cytokines tested, only ANG1 levels were significantly elevated in the co-culture of adipocytes from cluster-1 (189.5±17.3pg/ml), cluster-2 (258.08±34.33pg/ml) or osteocytes (392.04±58.3pg/ml) with AML cells of the same patients compared to the levels observed in controls (0.002±0.052pg/ml for adipocytes and 168.663pg/ml for osteocytes; P<0.01). Conclusions: The current study has demonstrated that changes in the secretion of stromal specific biomarkers and in the MSC ability to differentiate to adipocytes and osteocytes indicate impaired functional properties of BM MSCs in AML. Within the adipocyte subpopulation in the AML BM, clusters with either increased or inhibited adipogenesis have been revealed. These variations in adipocyte and osteocyte cells reflect interpatient heterogeneity in AML BM subpopulations. The AHNAK2 gene mutation found in AML MSCs in our study and the previously suggested role of this gene in adipocyte differentiation regulation, may explain in part the phenotype diversity observed in AML patients. Adipocyte cells, derived from an AML patient, were found to inhibit normal hematopoiesis in HSCs of the same patient. This specific crosstalk may be related to the elevated levels of ANG1 mediating abnormal signals from adipocytes to HSCs. Overall, the findings of this study may support the contribution of abnormal composition of the main BM subpopulations to leukemogenesis and could ultimately pave the way to novel therapeutic strategies targeting the BM niche. Disclosures No relevant conflicts of interest to declare.

scholarly journals B-cell reconstitution after autologous bone marrow transplantation: increase in serum CD23 ("IgE-binding factor") precedes IgE and B-cell regeneration

Blood ◽  
1989 ◽  
Vol 73 (8) ◽  
pp. 2139-2144 ◽  
Author(s):  
M Bengtsson ◽  
J Gordon ◽  
L Flores-Romo ◽  
JA Cairns ◽  
B Smedmyr ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
B Cell ◽  
Marrow Transplantation ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
Fold Increase ◽  
Serum Levels ◽  
Cell Types ◽  
Individual Case

Abstract The serum levels of IgE and the soluble cleavage product of CD23 (sCD23) were prospectively monitored for up to 1 year after transplantation in 34 patients who underwent autologous (n = 33) or syngeneic (n = 1) bone marrow transplantation (BMT). In 25 patients (74%), a transient IgE peak (two- to 2,750-fold increase) appeared in the serum 3 to 4 weeks after BMT. In 18 patients (51%), a two- to 125- fold increase in sCD23 coincided with the IgE peak. In only three patients was a sCD23 peak observed without a concomitant increase in IgE. The sCD23 increment preceded the IgE peak in each individual case. During the period of increased sCD23 serum levels, the absolute numbers of circulating B cells and other cell types expressing surface CD23 were extremely low. The biologic significance of these findings is discussed in light of present knowledge of regulation of B-cell growth and differentiation with special reference to the role of sCD23 as a multifunctional cytokine.

scholarly journals Increased circulating CSF-1 (M-CSF) in myeloproliferative disease: association with myeloid metaplasia and peripheral bone marrow extension

Blood ◽  
1989 ◽  
Vol 74 (4) ◽  
pp. 1231-1234
Author(s):  
HS Gilbert ◽  
V Praloran ◽  
ER Stanley
Keyword(s):  
Bone Marrow ◽  
Phenotypic Expression ◽  
Elevated Serum ◽  
Serum Levels ◽  
Myeloproliferative Disease ◽  
Myeloid Metaplasia ◽  
Macrophage Population ◽  
Agnogenic Myeloid Metaplasia ◽  
Peripheral Bone

Myeloproliferative disease (MPD) is heterogeneous in phenotypic expression and may display features consistent with expansion and activation of the monocyte/macrophage population during its course. The role of colony-stimulating factor-1 (CSF-1) in the pathophysiology of MPD was investigated by measuring circulating CSF-1 levels and examining their relationship to disease phenotype. Serum CSF-1 concentrations, measured by radioimmunoassay, were elevated in all MPD phenotypes. CSF-1 levels differed significantly between groups of patients with essential thrombocythemia, polycythemia vera, and postpolycythemic or agnogenic myeloid metaplasia (in ascending order). CSF-1 serum levels were positively correlated with spleen size and the degree of peripheral bone marrow extension, determined by scintigraphy using a macrophage-seeking isotope. There was no correlation between CSF-1 concentration and circulating levels of erythrocytes, neutrophils or platelets, or the presence of bone marrow fibrosis. Elevated serum CSF-1 levels appear to be associated with an expanded monocyte/macrophage population in MPD. In view of the known cooperativity between CSF-1 and other growth factors in regulating hematopoiesis, the finding of increased serum CSF-1 concentrations and its association with myeloid metaplasia and bone marrow extension may indicate a pathophysiologic role for CSF-1 in determining the phenotypic expression of MPD.

scholarly journals B-cell reconstitution after autologous bone marrow transplantation: increase in serum CD23 ("IgE-binding factor") precedes IgE and B-cell regeneration

Blood ◽  
1989 ◽  
Vol 73 (8) ◽  
pp. 2139-2144
Author(s):  
M Bengtsson ◽  
J Gordon ◽  
L Flores-Romo ◽  
JA Cairns ◽  
B Smedmyr ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
B Cell ◽  
Marrow Transplantation ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
Fold Increase ◽  
Serum Levels ◽  
Cell Types ◽  
Individual Case

The serum levels of IgE and the soluble cleavage product of CD23 (sCD23) were prospectively monitored for up to 1 year after transplantation in 34 patients who underwent autologous (n = 33) or syngeneic (n = 1) bone marrow transplantation (BMT). In 25 patients (74%), a transient IgE peak (two- to 2,750-fold increase) appeared in the serum 3 to 4 weeks after BMT. In 18 patients (51%), a two- to 125- fold increase in sCD23 coincided with the IgE peak. In only three patients was a sCD23 peak observed without a concomitant increase in IgE. The sCD23 increment preceded the IgE peak in each individual case. During the period of increased sCD23 serum levels, the absolute numbers of circulating B cells and other cell types expressing surface CD23 were extremely low. The biologic significance of these findings is discussed in light of present knowledge of regulation of B-cell growth and differentiation with special reference to the role of sCD23 as a multifunctional cytokine.

Hepatoprotective Role of Berberine on Doxorubicin Induced Hepatotoxicity - Involvement of Cyp

2020 ◽  
Vol 21 (7) ◽  
pp. 541-547
Author(s):  
Bao Sun ◽  
Yue Yang ◽  
Mengzi He ◽  
Yanan Jin ◽  
Xiaoyu Cao ◽  
...  
Keyword(s):  
Drug Metabolism ◽  
Cardiac Tissue ◽  
Liver Toxicity ◽  
Elevated Serum ◽  
Similar Response ◽  
Wide Range ◽  
Cytokine Levels ◽  
Major Organ ◽  
Anti Oxidant

Background: The liver is one of the major organ involved in drug metabolism. Cytochrome P450s are predominantly involved in drug metabolism. A wide range of CYPs have been reported in the liver which have been involved in its normal as well as in diseased conditions. Doxorubicin, one of the most potent chemotherapeutic drugs, although highly efficacious, also has adverse side effects, with its targets being liver and cardiac tissue. Objective: The study aims to evaluate the reversal potentials of berberine on Doxorubicin induced cyp conversion. Methodology: In the present study, the interplay between anti-oxidants, cytochrome and inflammatory markers in DOX induced liver toxicity and its possible reversal by berberine was ascertained. Results: DOX administration significantly elevated serum as well as tissue stress, which was reverted by berberine treatment. A similar response was observed in tissue inflammatory mediators as well as in serum cytokine levels. Most profound reduction in the cytochrome expression was found in Cyp 2B1, 2B2, and 2E1. However, 2C1, 2C6, and 3A1 although showed a decline, but it did not revert the expression back to control levels. Conclusion: It could be concluded that berberine may be an efficient anti-oxidant and immune modulator. It possesses low to moderate cytochrome modulatory potentials.

scholarly journals The Role of Butyric Acid in Treatment Response in Drug-Naïve First Episode Schizophrenia

2021 ◽  
Vol 12 ◽  
Author(s):  
Xue Li ◽  
Xiaoduo Fan ◽  
Xiuxia Yuan ◽  
Lijuan Pang ◽  
Shaohua Hu ◽  
...  
Keyword(s):  
Treatment Response ◽  
Butyric Acid ◽  
Serum Levels ◽  
First Episode ◽  
Healthy Controls ◽  
Significant Difference ◽  
Drug Naïve ◽  
First Episode Schizophrenia ◽  
Risperidone Treatment

Background: Butyric acid, a major short-chain fatty acid (SCFA), has an important role in the microbiota–gut–brain axis and brain function. This study investigated the role of butyric acid in treatment response in drug-naïve first episode schizophrenia.Methods: The study recruited 56 Chinese Han schizophrenia inpatients with normal body weight and 35 healthy controls. Serum levels of butyric acid were measured using Gas Chromatography-Mass Spectrometer (GC-MS) analysis at baseline (for all participants) and 24 weeks after risperidone treatment (for patients). Clinical symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) for patients at both time points.Results: At baseline, there was no significant difference in serum levels of butyric acid between patients and healthy controls (p = 0.206). However, there was a significant increase in serum levels of butyric acid in schizophrenia patients after 24-week risperidone treatment (p = 0.030). The PANSS total and subscale scores were decreased significantly after 24-week risperidone treatment (p's &lt; 0.001). There were positive associations between baseline serum levels of butyric acid and the reduction ratio of the PANSS total and subscale scores after controlling for age, sex, education, and duration of illness (p's &lt; 0.05). Further, there was a positive association between the increase in serum levels of butyric acid and the reduction of the PANSS positive symptoms subscale scores (r = 0.38, p = 0.019) after controlling for potential confounding factors.Conclusions: Increased serum levels of butyric acid might be associated with a favorable treatment response in drug-naïve, first episode schizophrenia. The clinical implications of our findings were discussed.

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