scholarly journals Preparation and In Vitro Evaluation of RITUXfab-Decorated Lipoplexes to Improve Delivery of siRNA Targeting C1858T PTPN22 Variant in B Lymphocytes

2021 ◽  
Vol 23 (1) ◽  
pp. 408
Author(s):  
Andrea Arena ◽  
Eugenia Belcastro ◽  
Antonella Accardo ◽  
Annamaria Sandomenico ◽  
Olivia Pagliarosi ◽  
...  
Keyword(s):  
B Lymphocytes ◽  
Tyrosine Phosphatase ◽  
Hormone Replacement ◽  
Raji Cell ◽  
Inhibitory Effect ◽  
Autoimmune Disorders ◽  
Endocrine Disorders ◽  
Gene Encoding ◽  
Autoimmune Conditions

Autoimmune endocrine disorders, such as type 1 diabetes (T1D) and thyroiditis, at present are treated with only hormone replacement therapy. This emphasizes the need to identify personalized effective immunotherapeutic strategies targeting T and B lymphocytes. Among the genetic variants associated with several autoimmune disorders, the C1858T polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, encoding for Lyp variant R620W, affects the innate and adaptive immunity. We previously exploited a novel personalized immunotherapeutic approach based on siRNA delivered by liposomes (lipoplexes) that selectively inhibit variant allele expression. In this manuscript, we improved lipoplexes carrying siRNA for variant C1858T by functionalizing them with Fab of Rituximab antibody (RituxFab-Lipoplex) to specifically target B lymphocytes in autoimmune conditions, such as T1D. RituxFab-Lipoplexes specifically bind to B lymphocytes of the human Raji cell line and of human PBMC of healthy donors. RituxFab-Lipoplexes have impact on the function of B lymphocytes of T1D patients upon CpG stimulation showing a higher inhibitory effect on total cell proliferation and IgM+ plasma cell differentiation than the not functionalized ones. These results might open new pathways of applicability of RituxFab-Lipoplexes, such as personalized immunotherapy, to other autoimmune disorders, where B lymphocytes are the prevalent pathogenic immunocytes.

scholarly journals Production of autoantibodies by CD5-expressing B lymphocytes from patients with chronic lymphocytic leukemia.

1989 ◽  
Vol 169 (1) ◽  
pp. 255-268 ◽  
Author(s):  
Z M Sthoeger ◽  
M Wakai ◽  
D B Tse ◽  
V P Vinciguerra ◽  
S L Allen ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Lymphocytes ◽  
Autoimmune Disorders ◽  
Lymphoproliferative Disorders ◽  
Lymphocytic Leukemia ◽  
Antigenic Specificity ◽  
Human B Cells ◽  
Well Differentiated

CD5-expressing B lymphocytes from patients with selected chronic lymphoproliferative disorders were used to determine whether monoclonal populations of CD5+ human B cells produce autoantibodies. CD5+ B cells from 19 patients with chronic lymphocytic leukemia (CLL) and one with diffuse well-differentiated lymphocytic lymphoma (DWDL) were cultured, with and without mitogenic stimulation, to obtain Ig from these cells. 17 of the 20 samples produced Ig in vitro. mAb from nine of the 17 patients were reactive with either IgG, ssDNA, or dsDNA. In every instance, the autoantibodies displayed monotypic L chain usage that correlated precisely with the L chain expressed on the CD5+ leukemic B cell surface. These monoclonal autoantibodies varied in their degree of antigenic specificity; some were quite specific, reacting with only one antigen, whereas others were polyspecific, reacting with two or all three autoantigens tested. Three features distinguish these autoantibodies from those observed in prior studies of CD5+ B cells. First, they are clearly the products of monoclonal populations of CD5+ cells; second, several react with dsDNA, a specificity not previously reported and often seen in association with significant autoimmune disorders; and third, two of the monoclonal autoantibodies secreted by the CD5+ clones were of the IgG class. Although not all of the Ig-producing, CD5-expressing clones elaborated mAbs reactive with the autoantigens tested, greater than 50% did. It is possible that with a broader autoantigenic panel or with larger quantities of CLL/DWDL-derived Ig, even more autoantibody-producing clones might be identified. These studies may have important implications for the antigenic specificity of subsets of human B lymphocytes as well as for lymphoproliferative and autoimmune disorders in general.

scholarly journals Peroxisome Proliferator-Activated Receptor-γin Thyroid Autoimmunity

PPAR Research ◽  
2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Silvia Martina Ferrari ◽  
Poupak Fallahi ◽  
Roberto Vita ◽  
Alessandro Antonelli ◽  
Salvatore Benvenga
Keyword(s):  
Inflammatory Diseases ◽  
Thyroid Autoimmunity ◽  
Thyroid Tissue ◽  
Inhibitory Effect ◽  
Autoimmune Disorders ◽  
Peroxisome Proliferator ◽  
T Helper 1 ◽  
Peroxisome Proliferator Activated Receptor ◽  
Old Patients

Peroxisome proliferator-activated receptor- (PPAR-)γexpression has been shown in thyroid tissue from patients with thyroiditis or Graves’ disease and furthermore in the orbital tissue of patients with Graves’ ophthalmopathy (GO), such as in extraocular muscle cells. An increasing body of evidence shows the importance of the (C-X-C motif) receptor 3 (CXCR3) and cognate chemokines (C-X-C motif) ligand (CXCL)9, CXCL10, and CXCL11, in the T helper 1 immune response and in inflammatory diseases such as thyroid autoimmune disorders. PPAR-γagonists show a strong inhibitory effect on the expression and release of CXCR3 chemokines,in vitro, in various kinds of cells, such as thyrocytes, and in orbital fibroblasts, preadipocytes, and myoblasts from patients with GO. Recently, it has been demonstrated that rosiglitazone is involved in a higher risk of heart failure, stroke, and all-cause mortality in old patients. On the contrary, pioglitazone has not shown these effects until now; this favors pioglitazone for a possible use in patients with thyroid autoimmunity. However, further studies are ongoing to explore the use of new PPAR-γagonists in the treatment of thyroid autoimmune disorders.

scholarly journals Inhibitory Effect of the Leaf of Psidium guajava Grown in Vietnam on α-Glucosidase and Protein Tyrosine Phosphatase 1B in vitro

2019 ◽  
Vol 35 (1) ◽  
Author(s):  
Dang Kim Thu ◽  
Le Thi Thu Huong ◽  
Tran Trong Nghia ◽  
Bui Thanh Tung
Keyword(s):  
Type 2 Diabetes ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Psidium Guajava ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine

Type 2 diabetes is a fairly common chronic disease. α-glucosidase and protein tyrosine phosphatase, as enzymes, play an important role in type 2 diabetes. This study evaluates the inhibitory effect of the two enzymes in vitro of ethanol extract and fractions of Vietnam Psidium guajava’s leaves. The leaves were collected, dried and extracted with 96% ethanol and successively fractionated with n-hexane, ethyl acetate and butanol solvents. The results show that the EtOH extract, n-nexan, EtOAc and BuOH fractions had high α-glucosidase inhibitory effect with IC50 values ​​of 2.20; 2.53; 2.24 and 2.16 µg/mL, respectively. In addition, EtOAc and BuOH fractions also show strong inhibitory PTP1B effect with IC50 at 120.22 mg/mL and 97.72 mg/mL, respectively. The study results show that Psidium guajava leaves are a potential source of material to inhibit α-glucosidase and PTP1B in the treatment of diabetes. Keywords Psidium guajava, α-glucosidase, protein tyrosine phosphatase 1B, diabetes, extraction. References [1] A. Chaudhury, C. Duvoor, R. Dendi, V. Sena, S. Kraleti, A. Chada, et al. Clinical review of antidiabetic drugs: Implications for type 2 diabetes mellitus management, Frontiers in endocrinology. 8 (2017) 6.[2] F.A. Van de Laar, P.L. Lucassen, R.P. Akkermans, E. H. Van de Lisdonk, G.E. Rutten,C. Van, Alpha - glucosidase inhibitors for type 2 diabetes mellitus. The Cochrane Library (2005).[3] J. Montalibet, B.P. Kennedy. Therapeutic strategies for targeting PTP1B in diabetes. Drug Discovery Today: Therapeutic Strategies 2(2) (2005) 129.[4] S.M. Barbalho, Farinazzi-Machado, R. De Alvares Goulart, A.C.S. Brunnati, A. Otoboni, B. Ottoboni. Psidium guajava (Guava): A plant of multipurpose medicinal applications, Med Aromat Plants. 1(104) (2012) 2167.[5] R.M.P. Gutiérrez, S. Mitchell, Solis R. V. Psidium guajava: a review of its traditional uses, phytochemistry and pharmacology. Journal of ethnopharmacology 117(1) (2008) 1.[6] B. T. Tùng, Đ.K. Thu, P.T. Hải, N.T. Hải. Đánh giá tác dụng ức chế enzym α-glucosidase của các phân đoạn dịch chiết quả Lựu (Punica granatum Linn), Tạp chí Y Dược cổ truyền Việt Nam. 5(18) (2018) 59.[7] P.H. Nguyen, J.L. Yang, M.N. Uddin, S.L. Park, S.I. Lim, D.W. Jung, et al. Protein tyrosine phosphatase 1B (PTP1B) inhibitors from Morinda citrifolia (Noni) and their insulin mimetic activity, Journal of natural products. 76(11) (2013) 2080.[8] H.B.H. Khan, D. Rajendran, M.R. Bai, Sorimuthu S. Protective effect of Psidium guajava leaf extract on altered carbohydrate metabolism in streptozotocin-induced diabetic rats, Journal of dietary supplements. 10(4) (2013) 335.[9] H. Mukhtar, S. Ansari, M. Ali, T. Naved, Z. Bhat Effect of water extract of Psidium guajava leaves on alloxan-induced diabetic rats. Die Pharmazie-An International Journal of Pharmaceutical Sciences. 59(9) (2004) 734.[10] W. K. Oh, C. H. Lee, M. S. Lee, E. Y. Bae, C. B. Sohn, H. Oh, et al. Antidiabetic effects of extracts from Psidium guajava, Journal of ethnopharmacology. 96(3) (2005) 411.[11] B. Wang, H. Liu, J. Hong, H. Li, C. Huang, Effect of Psidium guajava leaf extract on alpha-glucosidase activity in small intestine of diabetic mouse. Sichuan da xue xue bao Yi xue ban, Journal of Sichuan University Medical science edition. 38(2) (2007) 298.[12] S. C. Shen, F. C. Cheng, N. J. Wu. Effect of guava (Psidium guajava Linn.) leaf soluble solids on glucose metabolism in type 2 diabetic rats, Phytotherapy Research. 22(11) (2008) 1458.      

scholarly journals A Burkholderia cenocepacia gene encoding a non-functional tyrosine phosphatase is required for the delayed maturation of the bacteria-containing vacuoles in macrophages

Microbiology ◽  
2014 ◽  
Vol 160 (7) ◽  
pp. 1332-1345 ◽  
Author(s):  
Angel Andrade ◽  
Miguel A. Valvano
Keyword(s):  
Parental Strain ◽  
Tyrosine Phosphatase ◽  
Burkholderia Cenocepacia ◽  
Macrophage Infection ◽  
Gene Encoding ◽  
Burkholderia Multivorans ◽  
Phagosomal Maturation ◽  
Weight Protein ◽  
Delayed Maturation

Burkholderia cenocepacia infects patients with cystic fibrosis. We have previously shown that B. cenocepacia can survive in macrophages within membrane vacuoles [B. cenocepacia-containing vacuoles (BcCVs)] that preclude fusion with the lysosome. The bacterial factors involved in B. cenocepacia intracellular survival are not fully elucidated. We report here that deletion of BCAM0628, encoding a predicted low molecular weight protein tyrosine phosphatase (LMW-PTP) that is restricted to B. cenocepacia strains of the transmissible ET-12 clone, accelerates the maturation of the BcCVs. Compared to the parental strain and deletion mutants in other LMW-PTPs that are widely conserved in Burkholderia species, a greater proportion of BcCVs containing the ΔBCAM0628 mutant were targeted to the lysosome. Accelerated BcCV maturation was not due to reduced intracellular viability since ΔBCAM0628 survived and replicated in macrophages similarly to the parental strain. Therefore, BCAM0628 was referred to as dpm (delayed phagosome maturation). We provide evidence that the Dpm protein is secreted during growth in vitro and upon macrophage infection. Dpm secretion requires an N-terminal signal peptide. Heterologous expression of Dpm in Burkholderia multivorans confers to this bacterium a similar phagosomal maturation delay to that found with B. cenocepacia. We demonstrate that Dpm is an inactive phosphatase, suggesting that its contribution to phagosomal maturation arrest must be unrelated to tyrosine phosphatase activity.

scholarly journals Expression and catalytic activity of the tyrosine phosphatase PTP1C is severely impaired in motheaten and viable motheaten mice.

1993 ◽  
Vol 178 (6) ◽  
pp. 2157-2163 ◽  
Author(s):  
M Kozlowski ◽  
I Mlinaric-Rascan ◽  
G S Feng ◽  
R Shen ◽  
T Pawson ◽  
...  
Keyword(s):  
Tyrosine Phosphatase ◽  
Critical Role ◽  
Sh2 Domain ◽  
Loss Of Function ◽  
Phosphotyrosine Phosphatase ◽  
Gene Encoding ◽  
Phosphatase Domain ◽  
Sh2 Domains ◽  
Src Homology

Mutations in the gene encoding the phosphotyrosine phosphatase PTP1C, a cytoplasmic protein containing a COOH-terminal catalytic and two NH2-terminal Src homology 2 (SH2) domains, have been identified in motheaten (me) and viable motheaten (mev) mice and are associated with severe hemopoietic dysregulation. The me mutation is predicted to result in termination of the PTP1C polypeptide within the first SH2 domain, whereas the mev mutation creates an insertion or deletion in the phosphatase domain. No PTP1C RNA or protein could be detected in the hemopoietic tissues of me mice, nor could PTP1C phosphotyrosine phosphatase activity be isolated from cells homozygous for the me mutation. In contrast, mice homozygous for the less severe mev mutation expressed levels of full-length PTP1C protein comparable to those detected in wild type mice and the SH2 domains of mev PTP1C bound normally to phosphotyrosine-containing ligands in vitro. Nevertheless, the mev mutation induced a marked reduction in PTP1C activity. These observations provide strong evidence that the motheaten phenotypic results from loss-of-function mutations in the PTP1C gene and imply a critical role for PTP1C in the regulation of hemopoietic differentiation and immune function.

scholarly journals Polyglandular autoimmune syndromes

2009 ◽  
Vol 161 (1) ◽  
pp. 11-20 ◽  
Author(s):  
George J Kahaly
Keyword(s):  
Cytotoxic T Lymphocyte ◽  
Wide Spectrum ◽  
Tyrosine Phosphatase ◽  
Immunological Tolerance ◽  
Autoimmune Disorders ◽  
Chromosome 21 ◽  
Endocrine Disorders ◽  
Type I ◽  
Adult Type ◽  
Testing Management

The polyglandular autoimmune syndromes (PAS) comprise a wide spectrum of autoimmune disorders and are divided into a very rare juvenile (PAS type I) and a relatively common adult type with (PAS II) or without adrenal failure (PAS III). First clinical manifestation of PAS I usually occurs in childhood, whereas PAS II mostly occurs during the third and fourth decades. PAS I is caused by mutations in the autoimmune regulatory (AIRE) gene on chromosome 21 and is inherited in an autosomal recessive manner. Mutations in the AIRE gene result in defect proteins which cause autoimmune destruction of target organs by disturbing the immunological tolerance of the patients. Genetic testing may identify patients with PAS I, but not those with PAS II/III. For PAS II/III, susceptibility genes are known which increase the risk for developing autoimmune disorders, but must not be causative. These are certain HLA genes, the cytotoxic T lymphocyte antigen gene, and the protein tyrosine phosphatase non-receptor type 22 gene on chromosomes 6, 2 and 1 respectively. Actual diagnosis of PAS involves serological measurement of organ-specific autoantibodies and subsequent functional testing. Management of patients with PAS including their family relatives is best performed in centres with special expertise in autoimmune endocrine disorders.

Effect of Dipyridamole on Spontaneous Platelet Aggregation in Whole Blood Decreases with the Time After Venepuncture: Evidence for the Role of ADP

1987 ◽  
Vol 58 (02) ◽  
pp. 744-748 ◽  
Author(s):  
A R Saniabadi ◽  
G D O Lowe ◽  
J C Barbenel ◽  
C D Forbes
Keyword(s):  
Platelet Aggregation ◽  
Correlation Coefficient ◽  
Whole Blood ◽  
Blood Platelet ◽  
Inhibitory Effect ◽  
Time Interval ◽  
Adp Receptor ◽  
Spontaneous Platelet Aggregation

SummarySpontaneous platelet aggregation (SPA) was studied in human whole blood at 3, 5, 10, 20, 30, 40 and 60 minutes after venepuncture. Using a whole blood platelet counter, SPA was quantified by measuring the fall in single platelet count upon rollermixing aliquots of citrated blood at 37° C. The extent of SPA increased with the time after venepuncture, with a correlation coefficient of 0.819. The inhibitory effect of dipyridamole (Dipy) on SPA was studied: (a) 10 μM at each time interval; (b) 0.5-100 μM at 3 and 30 minutes and (c) 15 μM in combination with 100 μM adenosine, 8 μM 2-chloroadenosine (2ClAd, an ADP receptor blocker) and 50 μM aspirin. There was a rapid decrease in the inhibitory effect of Dipy with the time after venepuncture; the correlation coefficient was -0.533. At all the concentrations studied, Dipy was more effective at 3 minutes than at 30 minutes after venepuncture. A combination of Dipy with adenosine, 2ClAd or aspirin was a more effective inhibitor of SPA than either drug alone. However, when 15 μM Dipy and 10 μM Ad were added together, the inhibitory effect of Dipy was not increased significantly, suggesting that Dipy inhibits platelet aggregation independent of Ad. The increase in SPA with the time after venepuncture was abolished when blood was taken directly into the anticoagulant containing 5 μM 2ClAd. It is suggested that ADP released from the red blood cells is responsible for the increased platelet aggregability with the time after venepuncture and makes a serious contribution to the artifacts of in vitro platelet function studies.

In Vitro Effects of Ethanol on Rabbit Platelet Aggregation, Secretion of Granule Contents, and Cyclic AMP Levels in the Presence of Prostacyclin

1989 ◽  
Vol 61 (02) ◽  
pp. 254-258 ◽  
Author(s):  
Margaret L Rand ◽  
Peter L Gross ◽  
Donna M Jakowec ◽  
Marian A Packham ◽  
J Fraser Mustard
Keyword(s):  
Cyclic Amp ◽  
Inhibitory Effect ◽  
Rabbit Platelet ◽  
Inhibitory Effects ◽  
Low Concentrations ◽  
Rabbit Platelets ◽  
High Concentrations ◽  
In Vitro Effects ◽  
Aggregation Of Platelets

SummaryEthanol, at physiologically tolerable concentrations, inhibits platelet responses to low concentrations of collagen or thrombin, but does not inhibit responses of washed rabbit platelets stimulated with high concentrations of ADP, collagen, or thrombin. However, when platelet responses to high concentrations of collagen or thrombin had been partially inhibited by prostacyclin (PGI2), ethanol had additional inhibitory effects on aggregation and secretion. These effects were also observed with aspirin- treated platelets stimulated with thrombin. Ethanol had no further inhibitory effect on aggregation of platelets stimulated with ADP, or the combination of ADP and epinephrine. Thus, the inhibitory effects of ethanol on platelet responses in the presence of PGI2 were very similar to its inhibitory effects in the absence of PGI2, when platelets were stimulated with lower concentrations of collagen or thrombin. Ethanol did not appear to exert its inhibitory effects by increasing cyclic AMP above basal levels and the additional inhibitory effects of ethanol in the presence of PGI2 did not appear to be brought about by further increases in platelet cyclic AMP levels.

The Effect of Barbituric Acid Derivatives on Platelet Function in Vitro and in Vivo

1973 ◽  
Vol 30 (02) ◽  
pp. 315-326
Author(s):  
J. Heinz Joist ◽  
Jean-Pierre Cazenave ◽  
J. Fraser Mustard
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Barbituric Acid ◽  
Platelet Rich Plasma ◽  
Inhibitory Effect ◽  
Primary Response ◽  
Sodium Pentobarbital ◽  
Barbituric Acid Derivatives

SummarySodium pentobarbital (SPB) and three other barbituric acid derivatives were found to inhibit platelet function in vitro. SPB had no effect on the primary response to ADP of platelets in platelet-rich plasma (PRP) or washed platelets but inhibited secondary aggregation induced by ADP in human PRP. The drug inhibited both phases of aggregation induced by epinephrine. SPB suppressed aggregation and the release reaction induced by collagen or low concentrations of thrombin, and platelet adherence to collagen-coated glass tubes. The inhibition by SPB of platelet aggregation was readily reversible and isotopically labeled SPB did not become firmly bound to platelets. No inhibitory effect on platelet aggregation induced by ADP, collagen, or thrombin could be detected in PRP obtained from rabbits after induction of SPB-anesthesia.

Inhibition of Human and Animal Platelet Adhesiveness to Glass Bead Columns by Adenosine, Dipyridamole, Chlorpromazine and Acetylsalicylic Acid

1976 ◽  
Vol 36 (02) ◽  
pp. 401-410 ◽  
Author(s):  
Buichi Fujttani ◽  
Toshimichi Tsuboi ◽  
Kazuko Takeno ◽  
Kouichi Yoshida ◽  
Masanao Shimizu
Keyword(s):  
Guinea Pig ◽  
Acetylsalicylic Acid ◽  
Guinea Pigs ◽  
Glass Bead ◽  
Animal Species ◽  
Inhibitory Effect ◽  
Rabbit Platelet ◽  
Platelet Adhesiveness

SummaryThe differences among human, rabbit and guinea-pig platelet adhesiveness as for inhibitions by adenosine, dipyridamole, chlorpromazine and acetylsalicylic acid are described, and the influence of measurement conditions on platelet adhesiveness is also reported. Platelet adhesiveness of human and animal species decreased with an increase of heparin concentrations and an increase of flow rate of blood passing through a glass bead column. Human and rabbit platelet adhesiveness was inhibited in vitro by adenosine, dipyridamole and chlorpromazine, but not by acetylsalicylic acid. On the other hand, guinea-pig platelet adhesiveness was inhibited by the four drugs including acetylsalicylic acid. In in vivo study, adenosine, dipyridamole and chlorpromazine inhibited platelet adhesiveness in rabbits and guinea-pigs. Acetylsalicylic acid showed the inhibitory effect in guinea-pigs, but not in rabbits.

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