scholarly journals Metabolic Rewiring by Human Placenta-Derived Mesenchymal Stem Cell Therapy Promotes Rejuvenation in Aged Female Rats

2022 ◽  
Vol 23 (1) ◽  
pp. 566
Author(s):  
Kyeoung-Hwa Kim ◽  
Kyung-Ah Lee
Keyword(s):  
Human Placenta ◽  
Vitamin B6 ◽  
Cell Function ◽  
Female Rats ◽  
Hepatocyte Proliferation ◽  
Therapeutic Effects ◽  
Mesenchymal Stem Cell Therapy ◽  
Protein Levels ◽  
Flight Mass Spectrometry ◽  
Liver Degeneration

Aging is a degenerative process involving cell function deterioration, leading to altered metabolic pathways, increased metabolite diversity, and dysregulated metabolism. Previously, we reported that human placenta-derived mesenchymal stem cells (hPD-MSCs) have therapeutic effects on ovarian aging. This study aimed to identify hPD-MSC therapy-induced responses at the metabolite and protein levels and serum biomarker(s) of aging and/or rejuvenation. We observed weight loss after hPD-MSC therapy. Importantly, insulin-like growth factor-I (IGF-I), known prolongs healthy life spans, were markedly elevated in serum. Capillary electrophoresis-time-of-flight mass spectrometry (CE-TOF/MS) analysis identified 176 metabolites, among which the levels of 3-hydroxybutyric acid, glycocholic acid, and taurine, which are associated with health and longevity, were enhanced after hPD-MSC stimulation. Furthermore, after hPD-MSC therapy, the levels of vitamin B6 and its metabolite pyridoxal 5′-phosphate were markedly increased in the serum and liver, respectively. Interestingly, hPD-MSC therapy promoted serotonin production due to increased vitamin B6 metabolism rates. Increased liver serotonin levels after multiple-injection therapy altered the expression of mRNAs and proteins associated with hepatocyte proliferation and mitochondrial biogenesis. Changes in metabolites in circulation after hPD-MSC therapy can be used to identify biomarker(s) of aging and/or rejuvenation. In addition, serotonin is a valuable therapeutic target for reversing aging-associated liver degeneration.

scholarly journals A New Symmetrical Thiazolidinedione Derivative: In Silico Design, Synthesis, and In Vivo Evaluation on a Streptozotocin- Induced Rat Model of Diabetes

Processes ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1294
Author(s):  
Samuel Álvarez-Almazán ◽  
Gabriel Navarrete-Vázquez ◽  
Itzia Irene Padilla-Martínez ◽  
José Correa-Basurto ◽  
Diana Alemán-González-Duhart ◽  
...  
Keyword(s):  
Rat Model ◽  
In Silico ◽  
Female Rats ◽  
Therapeutic Effects ◽  
Acute Oral Toxicity ◽  
Oral Toxicity ◽  
In Vivo Evaluation ◽  
Docking Simulations ◽  
Ppar Γ

By activating PPAR-γ, thiazolidinediones normalize glucose levels in animal models of type 2 diabetes and in patients with this pathology. The aim of the present study was to analyze 219 new derivatives in silico and select the best for synthesis, to be evaluated for acute oral toxicity in female rats and for control of diabetes-related parameters in a rat model of streptozotocin-induced diabetes. The best compound was chosen based on pharmacokinetic, pharmacodynamic, and toxicological parameters obtained in silico and binding orientation observed by docking simulations on PPAR-γ. Compound 1G was synthesized by a quick and easy Knoevenagel condensation. Acute oral toxicity was found at a dose greater than 2000 mg/Kg. Compound 1G apparently produces therapeutic effects similar to those of pioglitazone, decreasing glycaemia and triglyceride levels in diabetic animals, without liver damage. Moreover, it did not cause a significant weight gain and tended to reduce polydipsia and polyphagia, while diminishing systemic inflammation related to TNF-α and IL-6. It lowered the level of endogenous antioxidant molecules such as reduced glutathione and glutathione reductase. In conclusion, 1G may be a candidate for further testing as an euglycemic agent capable of preventing the complications of diabetes.

scholarly journals Comparative analysis on the anti-inflammatory/immune effect of mesenchymal stem cell therapy for the treatment of pulmonary arterial hypertension

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Seyeon Oh ◽  
Albert Y. Jang ◽  
Sehyun Chae ◽  
Seungbum Choi ◽  
Jeongsik Moon ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Ventricular Function ◽  
Right Ventricular Function ◽  
Treated Group ◽  
Therapeutic Effects ◽  
Mesenchymal Stem Cell Therapy ◽  
Adaptive Immune Cells ◽  
Pulmonary Arterial

AbstractDespite the advancement of targeted therapy for pulmonary arterial hypertension (PAH), poor prognosis remains a reality. Mesenchymal stem cells (MSCs) are one of the most clinically feasible alternative treatment options. We compared the treatment effects of adipose tissue (AD)-, bone marrow (BD)-, and umbilical cord blood (UCB)-derived MSCs in the rat monocrotaline-induced pulmonary hypertension (PH) model. The greatest improvement in the right ventricular function was observed in the UCB-MSCs treated group. The UCB-MSCs treated group also exhibited the greatest improvement in terms of the largest decrease in the medial wall thickness, perivascular fibrosis, and vascular cell proliferation, as well as the lowest levels of recruitment of innate and adaptive immune cells and associated inflammatory cytokines. Gene expression profiling of lung tissue confirmed that the UCB-MSCs treated group had the most notably attenuated immune and inflammatory profiles. Network analysis further revealed that the UCB-MSCs group had the greatest therapeutic effect in terms of the normalization of all three classical PAH pathways. The intravenous injection of the UCB-MSCs, compared with those of other MSCs, showed superior therapeutic effects in the PH model for the (1) right ventricular function, (2) vascular remodeling, (3) immune/inflammatory profiles, and (4) classical PAH pathways.

Zoledronic acid modulates osteoclast apoptosis through activation of the NF-κB signaling pathway in ovariectomized rats

2021 ◽  
pp. 153537022110110
Author(s):  
Yu-Ting Cheng ◽  
Jian Liao ◽  
Qian Zhou ◽  
Hua Huo ◽  
Lucas Zellmer ◽  
...  
Keyword(s):  
Zoledronic Acid ◽  
Bone Mass ◽  
Mass Loss ◽  
Ovariectomized Rats ◽  
Therapeutic Effects ◽  
Bone Mass Loss ◽  
Cellular Effects ◽  
Protein Levels ◽  
Adverse Factor ◽  
Osteoclast Apoptosis

Bone mass loss (osteoporosis) seen in postmenopausal women is an adverse factor for implant denture. Using an ovariectomized rat model, we studied the mechanism of estrogen-deficiency-caused bone loss and the therapeutic effect of Zoledronic acid. We observed that ovariectomized-caused resorption of bone tissue in the mandible was evident at four weeks and had not fully recovered by 12 weeks post-ovariectomized compared with the sham-operated controls. Further evaluation with a TUNEL assay showed ovariectomized enhanced apoptosis of osteoblasts but inhibited apoptosis of osteoclasts in the mandible. Zoledronic acid given subcutaneously as a single low dose was shown to counteract both of these ovariectomized effects. Immunohistochemical staining showed that ovariectomized induced the protein levels of RANKL and the 65-kD subunit of the NF-κB complex mainly in osteoclasts, as confirmed by staining for TRAP, a marker for osteoclasts, whereas zoledronic acid inhibited these inductions. Western blotting showed that the levels of RANKL, p65, as well as the phosphorylated form of p65, and IκB-α were all higher in the ovariectomized group than in the sham and ovariectomized + zoledronic acid groups at both the 4th- and 12th-week time points in the mandible. These data collectively suggest that ovariectomized causes bone mass loss by enhancing apoptosis of osteoblasts and inhibiting apoptosis of osteoclasts. In osteoclasts, these cellular effects may be achieved by activating RANKL-NF-κB signalling. Moreover, zoledronic acid elicits its therapeutic effects in the mandible by counteracting these cellular and molecular consequences of ovariectomized.

scholarly journals THU0236 EFFICACY AND SAFETY OF NON-MITOGENIC ANTICD3 ANTIBODY ADMINISTRATION IN THE TREATMENT OF LUPUS-PRONE MICE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 345.1-345
Author(s):  
M. Morita ◽  
S. Masuyama ◽  
M. Mizui ◽  
Y. Isaka
Keyword(s):  
T Cells ◽  
Antibody Titer ◽  
Cell Function ◽  
Cell Subpopulation ◽  
Target Cells ◽  
Therapeutic Effects ◽  
Autoantibody Production ◽  
Rate Of Increase ◽  
Dsdna Antibody ◽  
The Difference

Background:Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by the production of autoantibody and systemic tissue damages including glomerulonephritis. Immune responses mediated by autoreactive T-cells, as well as by autoantibody, is involved in the development and progression of end-organ damages1. Biologic agents which manipulate T-cell function such as CTLA4-Ig and anti-CD40L have been revisited and tried to treat human SLE, however, both of them failed to demonstrate efficacy.A mouse specific anti-CD3ε mAb, clone 145-2C11 (2C11) is known to be immunosuppressive by down-modulation of TCR and depletion of T-cells2. Administration of Fc-deleted 145-2C11 F(ab’)2to lupus-prone mice was reported to reduce lymphadenopathy and prolong survival, but had no significant effect on anti-DNA antibody titer3. The mechanisms by which 2C11 ameliorates lupus are still unclear.In this study, we used non-mitogenic Fc-modified silent 145-2c11 (2C11S), which disables interaction between target cells and Fc receptor-bearing cells, abolishes antibody directed cytotoxicity, and has longer half-life than F(ab’)2. 2C11S is expected to exert its effect in safe and stable as compared with functional parent-2C11 (2C11P) antibody.Objectives:The purpose of our study is to clarify the difference between 2C11S and 2C11P and to examine their therapeutic effects against murine lupus-prone (NZB/W F1) mice.Methods:20 μg of 2C11P (absolute antibody), 2C11S (absolute antibody), or isotype control immunoglobulin G1 κ (IC)(BioLegend) were administered intraperitoneally to C57BL6 mice. The difference of their action on T-cells were evaluated in a time series from peripheral blood. Plasma cytokine levels were measured within 24 hours after antibody administration.In NZB/W F1 mice from weeks 10 or 20, 2C11P, 2C11S, and IC were administered (100 μg / week, 4 times, intraperitoneally). Plasma anti-dsDNA antibody titer, spleen and kidney blood cell subpopulation, and histology of renal tissue were evaluated before and/or after treatment.Results:Duration of reduced TCR expression in 2C11S group was approximately twice as long as that in 2C11P group, and the levels of plasma TNF-α was not increased in 2C11S group while significant increase was observed in 2C11P group (IC; mean 48.3 ± SD 16.7 pg/ml, 2C11S; 57.9 ± 6.12, 2C11P; 168 ± 50.6, IC VS 2C11S; p>0.99, IC VS 2C11P; p=0.03, ANOVA).In NZB/W F1 mice, the number of follicular helper T (Tfh) cells in spleen significantly decreased in 2C11S group (IC; median 9.0*104[interquartile range 8.5*104], 2C11S; 1.8*104[1.0*104], 2C11P; 1.0*105[9.4*104], IC VS 2C11S; p=0.03, IC VS 2C11P; p>0.99, Kruskal-Wallis). The number of germinal center B (GCB) cells in spleen also decreased in 2C11S group (IC; 1.2*105[1.7*105], 2C11S; 9.0*103[2.3*104], 2C11P; 8.0*104[2.3*105], IC VS 2C11S; p=0.03, IC VS 2C11P; p>0.99). The number of infiltrating CD4+T-cells in kidney significantly reduced in 2C11S group (IC; 3.4*103[1.0*104], 2C11S; 6.4*102[8.8*102], 2C11P; 1.2*103[4.4*103], IC VS 2C11S; p=0.048, IC VS 2C11P; p=0.23). In addition, the rate of increase in anti-dsDNA IgG titers significantly decreased in 2C11S group (IC; 2.3 [1.3], 2C11S; 0.9 [1.0], 2C11P; 1.3 [1.4], IC VS 2C11S; p=0.03, IC VS 2C11P; p=0.24). Finally, glomerular hypercellularity was markedly alleviated only in 2C11S group (IC; 4.4*10 [8.4], 2C11S; 3.8*10 [1.1], 2C11P; 3.9*10 [8.2], IC VS 2C11S; p=0.02, IC VS 2C11P; p=0.57).Conclusion:2C11S did not induce cytokine release with maintaining longer effect on TCR down-modulation. 2C11S reduced autoantibody production by suppressing GCB differentiation, possibly through down-regulation of Tfh cell number. Consequently, 2C11S ameliorated lupus nephritis. On the other hand, 2C11P did not show therapeutic effect.References:[1]George C Tsokos. et al. Nat. Rev. Rheum (2016) 12: 716-730.[2]Kuhn C. et al. Immunotherapy (2016) 8: 889-906.[3]Henrickson M. et al. Arthritis Rheum (1994) 37: 587-589.Disclosure of Interests: :None declared

B74 THE EFFECTS OF ACUTE TRYPTOPHAN DEPLETION ON BDNF PROTEIN LEVELS IN BRAIN AND SERUM OF MALE AND FEMALE RATS

2005 ◽  
Vol 16 (Supplement 1) ◽  
pp. S89
Author(s):  
E.L. Van Donkelaar ◽  
L.A.W. Jans ◽  
A. Blokland ◽  
N.E.P. Deutz ◽  
G. Kenis ◽  
...  
Keyword(s):  
Female Rats ◽  
Acute Tryptophan Depletion ◽  
Tryptophan Depletion ◽  
Male And Female ◽  
Protein Levels ◽  
Male And Female Rats

The Effect of Moderate Vitamin B6 Deficiency on Immunological and Hematological Parameters of Adult Female Rats

1990 ◽  
Vol 587 (1) ◽  
pp. 292-293
Author(s):  
D. S. KELLEY ◽  
M. C. SCHAEFFER ◽  
D. A. SAMPSON ◽  
P. C. TAYLOR ◽  
Y. M. RIVERA
Keyword(s):  
Adult Female ◽  
Vitamin B6 ◽  
Hematological Parameters ◽  
Female Rats ◽  
Vitamin B6 Deficiency

Abstract P472: Prorenin Independently Causes Hypertension And Renal and Cardiac Fibrosis In Cyp1a1-Prorenin Transgenic Rats

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Yufeng Huang ◽  
Guangyu Zhou ◽  
Jie Wu ◽  
Chunyan Gu ◽  
Alfred Cheung
Keyword(s):  
Cardiac Fibrosis ◽  
Heart Tissue ◽  
Female Rats ◽  
Organ Injury ◽  
Heart Weight ◽  
Diabetic Patients ◽  
Transgenic Rats ◽  
Protein Levels ◽  
Male And Female Rats ◽  
Pai 1

Plasma prorenin is commonly elevated in diabetic patients and appears to predict the development of diabetic nephropathy. However, the pathological role of prorenin is unclear. In this study, a transgenic, inducible, hepatic prorenin-overexpressing rat model was generated and the effect of prorenin in organ injury was examined. Four groups of rats (Cyp1a1 prorenin transgenic male and female rats and nontransgenic littermates) were assigned to receive a diet containing 0.3% of the transgene inducer indole-3-carbinol (I3C) for 4 weeks. Plasma prorenin concentration rose from 23±6 to 208±44 (μg/ml) and MAP increased from 77±5 to 138±17 (mmHg), whereas renal prorenin/renin protein expression was unchanged, in transgenic rats fed with I3C diet. The intact prorenin, not renin, in plasma and urine samples was further observed by western blot analysis. Importantly, transgenic rats with high levels of prorenin developed albuminuria, glomerular and tubulointerstitial fibrosis associated with increased expression of TGFß1, PAI-1, collagen and fibronectin. These rats also exhibited cardiac hypertrophy determined by echocardiography, with elevated ratio of heart weight to body weight. Cardiac collagen in interstitial and perivascular area was prominent, accompanied by the increases in mRNA contents of ANP, BNP, ß-MHC, TGFß1 and PAI-1 in the heart tissue. Furthermore, renal protein levels of phosphor-NF-kB-p65 and MCP-1, NAPDH oxidase and MDA, phospho-ß-catenin and phospho-Akt were dramatically increased in prorenin overexpressed rats. These results indicate that prorenin, without being converted to renin, causes arterial hypertension, renal and cardiac fibrosis independently via the induction of inflammation, oxidative stress and the ß-catenin and Akt-mediated signals.

scholarly journals Expression, Localization, and Activity of the Aryl Hydrocarbon Receptor in the Human Placenta

2018 ◽  
Vol 19 (12) ◽  
pp. 3762 ◽  
Author(s):  
Anaïs Wakx ◽  
Margaux Nedder ◽  
Céline Tomkiewicz-Raulet ◽  
Jessica Dalmasso ◽  
Audrey Chissey ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Human Placenta ◽  
Target Genes ◽  
Environmental Pollutants ◽  
Cell Fractionation ◽  
Protein Levels ◽  
Aryl Hydrocarbon ◽  
Epithelial Barriers ◽  
Expression And Activity

The human placenta is an organ between the blood of the mother and the fetus, which is essential for fetal development. It also plays a role as a selective barrier against environmental pollutants that may bypass epithelial barriers and reach the placenta, with implications for the outcome of pregnancy. The aryl hydrocarbon receptor (AhR) is one of the most important environmental-sensor transcription factors and mediates the metabolism of a wide variety of xenobiotics. Nevertheless, the identification of dietary and endogenous ligands of AhR suggest that it may also fulfil physiological functions with which pollutants may interfere. Placental AhR expression and activity is largely unknown. We established the cartography of AhR expression at transcript and protein levels, its cellular distribution, and its transcriptional activity toward the expression of its main target genes. We studied the profile of AhR expression and activity during different pregnancy periods, during trophoblasts differentiation in vitro, and in a trophoblast cell line. Using diverse methods, such as cell fractionation and immunofluorescence microscopy, we found a constitutive nuclear localization of AhR in every placental model, in the absence of any voluntarily-added exogenous activator. Our data suggest an intrinsic activation of AhR due to the presence of endogenous placental ligands.

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