Splenomegaly induced by anemia impairs T cell movement in the spleen partially via EPO

Li, Yan; Yue, Honggang; Yang, Shouyan; Yuan, Dandi; Li, Luxia; Zhao, Jinghong; Zhao, Li

doi:10.1016/j.molimm.2019.06.021

Cited by 9 publications

(7 citation statements)

References 33 publications

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“…It was observed that body weights and food intake were relatively stable and the growth trend was consistent with the blank control. Furthermore, no obvious changes were observed after 17 treatment with respect to the organ/body weight ratio of the adrenal gland, brain, heart, kidney, liver, thymus, thymus, ovary (female), uterus with cervix (female), testes (male), and epididymis (male); however, a slight increase in the weight of the spleen (male) occurred, which may be ascribed to the pharmacological effect of the compound along with the elevation of EPO levels . Additionally, blood biochemistry studies revealed that 17 had no obvious nephrotoxicity and hepatotoxicity in SD rats compared to the control group (Figure ), as determined by kidney function indicators (urea; CRE, creatinine) and liver function indicators (AST, aspartate aminotransferase; ALT, alanine aminotransferase; A/G, albumin/globulin; GLO, globulin; ALB, albumin; TP, total protein).…”

Section: Resultsmentioning

confidence: 97%

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Discovery of Clinical Candidate (5-(3-(4-Chlorophenoxy)prop-1-yn-1-yl)-3-hydroxypicolinoyl)glycine, an Orally Bioavailable Prolyl Hydroxylase Inhibitor for the Treatment of Anemia

Zhang

Lei

et al. 2020

J. Med. Chem.

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The design and discovery of a new series of (5-alkynyl-3-hydroxypicolinoyl)glycine inhibitors of prolyl hydroxylase (PHD) are described. These compounds showed potent in vitro inhibitory activity toward PHD2 in a fluorescence polarization-based assay. Remarkably, oral administration of 17, with an IC50 of 64.2 nM toward PHD2, was found to stabilize HIF-α, elevate erythropoietin (EPO), and alleviate anemia in a cisplatin-induced anemia mouse model with an oral dose of 25 mg/kg. Rat and dog studies showed that 17 has good pharmacokinetic properties, with oral bioavailabilities of 55.7 and 54.0%, respectively, and shows excellent safety profiles even at a high dose of 200 mg/kg in these animals. Based on these results, 17 is currently being evaluated in a phase I clinical trial for anemia.

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Section: Resultsmentioning

confidence: 97%

“…4.2.1. Preparation of 3-(Benzyloxy)-5-bromopicolinonitrile (36). A solution of benzyl alcohol (59 mL, 570 mmol) in THF (1.8 L) was cooled to 0 °C.…”

Section: Methodsmentioning

confidence: 99%

Discovery of Clinical Candidate (5-(3-(4-Chlorophenoxy)prop-1-yn-1-yl)-3-hydroxypicolinoyl)glycine, an Orally Bioavailable Prolyl Hydroxylase Inhibitor for the Treatment of Anemia

Zhang

Lei

et al. 2020

J. Med. Chem.

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“…In this study, we found S. suis serotype 2 infection could cause damage to the spleen. The spleen is an important peripheral immune organ where immune cells gather and immune response occurs ( 21 , 22 ). It plays an important role in the immune response by detecting pathogens and producing white blood cells in response ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

Streptococcus suis Serotype 2 Infection Induces Splenomegaly with Splenocyte Apoptosis

Wang

Tang

et al. 2022

Microbiol Spectr

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“…The spleen is a site where innate and adaptive immune responses against pathogens are initiated ( 41 ) and this process is disturbed in splenomegaly, particularly affecting T cells ( 42 ). Macrophages are the main innate immune cells in the spleen and play a pivotal role in splenomegaly due to their responsibility for the removal of old erythrocytes and apoptotic cells.…”

Section: Discussionmentioning

confidence: 99%

“…We observed that splenomegaly is associated with more activated T cells infiltrating the liver, and that these effects were reversed by antibiotics, which also ameliorated splenomegaly, thus supporting the hypothesis that gut microbiota changes contribute to splenomegaly and possibly vice versa. The spleen is a site where innate and adaptive immune responses against pathogens are initiated (41) and this process is disturbed in splenomegaly, particularly affecting T cells (42). Macrophages are the main innate immune cells in the spleen and play a pivotal role in splenomegaly due to their responsibility for the removal of old erythrocytes and apoptotic cells.…”

Section: Effects Of Antibiotic Treatment On Histology and Immune Cellsmentioning

confidence: 99%

The gut microbiome contributes to splenomegaly and tissue inflammation in a murine model of primary biliary cholangitis

Wang¹,

Wang²,

Yao³

et al. 2022

Ann Transl Med

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Background Splenomegaly is not just a consequence of numerous chronic and acute conditions but may also contribute to their severity, due to the interaction of the spleen with the gut microbiome. This study aimed to explore the effect of the gut microbiome on splenomegaly. Methods We used p40 −/− IL-2Rα −/− mice as a murine model of primary biliary cholangitis (PBC) as per our previous study. Splenomegaly was evaluated by spleen weight. Severity of liver inflammation was evaluated by hepatic mononuclear cell (MNCs) number and pathological score. Changes of immune cells in the spleen and liver were detected by flow cytometry. The effects of the gut microbiome on splenomegaly and liver inflammation were observed by combined antibiotic treatment in p40 −/− IL-2Rα −/− mice. Results A proportion of p40 −/− IL-2Rα −/− mice developed splenomegaly. The results revealed that liver mononuclear cells infiltration, histological scores of hepatic inflammation, and bile duct damage were positively correlated with the degree of splenomegaly. Hepatic CD4 + and CD8 + T cells numbers were significantly higher in mice with splenomegaly, and this was particularly observed in activated effector memory CD4 + T and CD8 + T cells. A proportion of some other immune cells including granulocytes, B, natural killer (NK), and CD8 + T effector memory cells were also altered in the enlarged spleen. More importantly, administration of quadruple antibiotics to deplete gut microbiota relieved the splenomegaly of p40 −/− IL-2Rα −/− mice, significantly alleviated liver inflammation, and caused a significant reduction of liver and spleen T cell accumulation and activation; however, single antibiotics did not induce these changes. Conclusions Splenomegaly was associated with more severe liver inflammation in our PBC murine model, and this effect was reversed by quadruple antibiotic treatment.

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Splenomegaly induced by anemia impairs T cell movement in the spleen partially via EPO

Cited by 9 publications

References 33 publications

Discovery of Clinical Candidate (5-(3-(4-Chlorophenoxy)prop-1-yn-1-yl)-3-hydroxypicolinoyl)glycine, an Orally Bioavailable Prolyl Hydroxylase Inhibitor for the Treatment of Anemia

Discovery of Clinical Candidate (5-(3-(4-Chlorophenoxy)prop-1-yn-1-yl)-3-hydroxypicolinoyl)glycine, an Orally Bioavailable Prolyl Hydroxylase Inhibitor for the Treatment of Anemia

Streptococcus suis Serotype 2 Infection Induces Splenomegaly with Splenocyte Apoptosis

The gut microbiome contributes to splenomegaly and tissue inflammation in a murine model of primary biliary cholangitis

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