Resveratrol regulates relevant genes to promote excretions of totalsterols in long-term HF fed C57BL/6J mice

2016 ◽  
Author(s):  
Xinhui Guo ◽  
Wei Xue ◽  
Yujiao Wang ◽  
Jiangang Zhang ◽  
Qinghong Meng ◽  
...  
Keyword(s):  
Small Molecule ◽  
Lipid Accumulation ◽  
Genetic Regulation ◽  
Dietary Supplementation ◽  
Fecal Excretion ◽  
Altered Expression ◽  
Beneficial Effects ◽  
Naturally Occurring

Resveratrol (RSV) as a naturally occurring small molecule has been reported to benefit the cardiovascular system through a dietary supplementation. However, the relevant genetic regulation by RSV has been uncovered. This work is solely to investigate how RSV increases a fecal excretion of total sterols of HF fed C57BL/6J mice to block lipid accumulation in vivo through regulation of PPRAa, HMG-CoA-R, CYP7A1, LDL-R and ABCG5 genes. The results showed that RSV significantly improved the excretion of total sterols through up regulation of mRNA expressions of PPARa, CYP7A1, LDL-R, ABCG5 and down regulation of HMG-CoA-R. These data indicate that beneficial effects from RSV were associated with the favorably altered expression of hepatic and large intestine genes in HF fed mice.

scholarly journals Bone Regeneration by Novel Bioactive Glasses Containing Strontium and/or Magnesium: A Preliminary In-Vivo Study

Materials ◽  
2018 ◽  
Vol 11 (11) ◽  
pp. 2223 ◽  
Author(s):  
Devis Bellucci ◽  
Valeria Cannillo ◽  
Alexandre Anesi ◽  
Roberta Salvatori ◽  
Luigi Chiarini ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Formation Processes ◽  
Complete Dissolution ◽  
In Vitro Bioactivity ◽  
Bioactive Glasses ◽  
Beneficial Effects ◽  
Glass Dissolution

In this work, a set of novel bioactive glasses have been tested in vivo in an animal model. The new compositions, characterized by an exceptional thermal stability and high in vitro bioactivity, contain strontium and/or magnesium, whose biological benefits are well documented in the literature. To simulate a long-term implant and to study the effect of the complete dissolution of glasses, samples were implanted in the mid-shaft of rabbits’ femur and analyzed 60 days after the surgery; such samples were in undersized powder form. The statistical significance with respect to the type of bioactive glass was analyzed by Kruskal–Wallis test. The results show high levels of bone remodeling, several new bone formations containing granules of calcium phosphate (sometimes with amounts of strontium and/or magnesium), and the absence of adverse effects on bone processes due to the almost complete glass dissolution. In vivo results confirming the cell culture outcomes of a previous study highlighted that these novel bioglasses had osteostimulative effect without adverse skeletal reaction, thus indicating possible beneficial effects on bone formation processes. The presence of strontium in the glasses seems to be particularly interesting.

scholarly journals B cell–intrinsic TLR signals amplify but are not required for humoral immunity

2007 ◽  
Vol 204 (13) ◽  
pp. 3095-3101 ◽  
Author(s):  
Almut Meyer-Bahlburg ◽  
Socheath Khim ◽  
David J. Rawlings
Keyword(s):  
B Cells ◽  
B Cell ◽  
Long Term Memory ◽  
Altered Expression ◽  
Intrinsic Signals ◽  
Antibody Titers ◽  
Specific Igg ◽  
B Cell Subsets

Although innate signals driven by Toll-like receptors (TLRs) play a crucial role in T-dependent immune responses and serological memory, the precise cellular and time-dependent requirements for such signals remain poorly defined. To directly address the role for B cell–intrinsic TLR signals in these events, we compared the TLR response profile of germinal center (GC) versus naive mature B cell subsets. TLR responsiveness was markedly up-regulated during the GC reaction, and this change correlated with altered expression of the key adaptors MyD88, Mal, and IRAK-M. To assess the role for B cell–intrinsic signals in vivo, we transferred MyD88 wild-type or knockout B cells into B cell–deficient μMT mice and immunized recipient animals with 4-hydroxy-3-nitrophenylacetyl (NP) chicken gamma globulin. All recipients exhibited similar increases in NP-specific antibody titers during primary, secondary, and long-term memory responses. The addition of lipopolysaccharide to the immunogen enhanced B cell-intrinsic, MyD88-dependent NP-specific immunoglobulin (Ig)M production, whereas NP-specific IgG increased independently of TLR signaling in B cells. Our data demonstrate that B cell–intrinsic TLR responses are up-regulated during the GC reaction, and that this change significantly promotes antigen-specific IgM production in association with TLR ligands. However, B cell–intrinsic TLR signals are not required for antibody production or maintenance.

scholarly journals Oral delivery of xenon for cardiovascular protection

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Xing Yin ◽  
Melanie R. Moody ◽  
Valeria Hebert ◽  
Melvin E. Klegerman ◽  
Yong-Jian Geng ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Oral Delivery ◽  
Noble Gas ◽  
Left Ventricular ◽  
Beneficial Effects ◽  
Normal Left Ventricular ◽  
Term Administration ◽  
Apoe Knockout Mice

Abstract Cardiac hypertrophy often causes impairment of cardiac function. Xenon (Xe), a naturally occurring noble gas, is known to provide neurological and myocardial protection without side effects. The conventional method of Xe delivery by inhalation is not feasible on a chronic basis. We have developed an orally deliverable, effective Xe formulation for long-term administration. We employed 2-hydroxypropyl)-β-cyclodextrin (HPCD), which was dissolved in water to increase the Xe concentration in solution. The beneficial effects of long-term oral administration of Xe-enriched solutions on cardiovascular function were evaluated in vivo. HPCD increased Xe solubility from 0.22 mM to 0.67 mM (3.8-fold). Aged ApoE knockout mice fed high-fat diet for 6 weeks developed hypertension, and myocardial hypertrophy with impaired cardiac function. Oral Xe prevented this ischemic damage, preserving normal blood pressure, while maintaining normal left ventricular mass and wall thickness. This novel formulation allows for gastrointestinal delivery and cardiovascular stabilization.

scholarly journals A Novel Small Molecule CXCR4 Antagonist Potently Mobilizes Hematopoietic Stem Cells in Mice and Monkeys

2020 ◽  
Author(s):  
Xiao Fang ◽  
Xiong Fang ◽  
Yujia Mao ◽  
Aaron Ciechanover ◽  
Yan Xu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Small Molecule ◽  
Cxcr4 Antagonist ◽  
Hematopoietic Stem ◽  
Stromal Microenvironment ◽  
Stromal Cell Derived Factor ◽  
Hsc Transplantation

Abstract Background Hematopoietic stem cell (HSC) transplantation is an effective treatment strategy for many types of diseases. Peripheral blood (PB) is the most commonly used source of bone marrow (BM)-derived stem cells for current HSC transplantation. However, PB usually contains very few HSCs under normal conditions, as these cells are normally retained within the BM. This retention depends on the interaction between the CXC chemokine receptor 4 (CXCR4) expressed on the HSCs and its natural chemokine ligand, stromal cell-derived factor (SDF)-1α (also named CXCL12) present in the BM stromal microenvironment. In clinical practice, blocking this interaction with a CXCR4 antagonist can induce the rapid mobilization of HSCs from the BM into the PB.Methods C3H/HEJ, DBA/2, CD45.1+, CD45.2+ mice and monkeys were employed in colony-forming unit (CFU) assays, flow cytometry assays, and competitive/non-competitive transplantation assays, to assess the short-term mobilization efficacy of HF51116 and the long-term repopulating (LTR) ability of HSCs. Kinetics of different blood cells and the concentration of HF51116 in PB were also explored by blood routine examinations and pharmacokinetic assays. Results In this paper, we report that a novel small molecule CXCR4 antagonist, HF51116, which was designed and synthesized by our laboratory, can rapidly and potently mobilize HSCs from BM to PB in mice and monkeys. HF51116 not only mobilized HSCs when used alone but also synergized with the mobilizing effects of granulocyte-colony stimulating factor (G-CSF) after co-administration. Following mobilization by HF51116 and G-CSF, the long-term repopulating (LTR) and self-renewing HSCs were sufficiently engrafted in primary and secondary lethally irradiated mice and were able to rescue and support long-term mouse survival. In monkeys, HF51116 exhibited strong HSC mobilization activity and quickly reached the highest in vivo blood drug concentration. Conclusions These results demonstrate that HF51116 is a new promising stem cell mobilizer which specifically targets CXCR4 and merits further preclinical and clinical studies.

scholarly journals A novel small molecule CXCR4 antagonist potently mobilizes hematopoietic stem cells in mice and monkeys

2020 ◽  
Author(s):  
Xiao Fang ◽  
Xiong Fang ◽  
Yujia Mao ◽  
Aaron Ciechanover ◽  
Yan Xu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Small Molecule ◽  
Cxcr4 Antagonist ◽  
Hematopoietic Stem ◽  
Stromal Microenvironment ◽  
Stromal Cell Derived Factor ◽  
Hsc Transplantation

Abstract Background Hematopoietic stem cell (HSC) transplantation is an effective treatment strategy for many types of diseases. Peripheral blood (PB) is the most commonly used source of bone marrow (BM)-derived stem cells for current HSC transplantation. However, PB usually contains very few HSCs under normal conditions, as these cells are normally retained within the BM. This retention depends on the interaction between the CXC chemokine receptor 4 (CXCR4) expressed on the HSCs and its natural chemokine ligand, stromal cell-derived factor (SDF)-1α (also named CXCL12) present in the BM stromal microenvironment. In clinical practice, blocking this interaction with a CXCR4 antagonist can induce the rapid mobilization of HSCs from the BM into the PB.Methods C3H/HEJ, DBA/2, CD45.1+, CD45.2+ mice and monkeys were employed in colony-forming unit (CFU) assays, flow cytometry assays, and competitive/non-competitive transplantation assays, to assess the short-term mobilization efficacy of HF51116 and the long-term repopulating (LTR) ability of HSCs. Kinetics of different blood cells and the concentration of HF51116 in PB were also explored by blood routine examinations and pharmacokinetic assays. Results In this paper, we report that a novel small molecule CXCR4 antagonist, HF51116, which was designed and synthesized by our laboratory, can rapidly and potently mobilize HSCs from BM to PB in mice and monkeys. HF51116 not only mobilized HSCs when used alone but also synergized with the mobilizing effects of granulocyte-colony stimulating factor (G-CSF) after co-administration. Following mobilization by HF51116 and G-CSF, the long-term repopulating (LTR) and self-renewing HSCs were sufficiently engrafted in primary and secondary lethally irradiated mice and were able to rescue and support long-term mouse survival. In monkeys, HF51116 exhibited strong HSC mobilization activity and quickly reached the highest in vivo blood drug concentration. Conclusions These results demonstrate that HF51116 is a new promising stem cell mobilizer which specifically targets CXCR4 and merits further preclinical and clinical studies.

Discovery and Validation of a Novel Class of Small Molecule Inhibitors of the CDC7 Kinase: Modulation of Tumor Cell Growth in Vitro and In Vivo.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3771-3771
Author(s):  
Mark G. Frattini ◽  
David Shum ◽  
Kristen M O'Dwyer ◽  
Renier J. Brentjens ◽  
Peter Maslak ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Lines ◽  
Small Molecule ◽  
Caspase 3 ◽  
S Phase ◽  
Leukemia Cell Line ◽  
Naturally Occurring ◽  
Cdc7 Kinase

Abstract Abstract 3771 Poster Board III-707 High throughput screening of compounds comprising the Memorial Sloan Kettering chemical library resulted in several confirmed hits against the recombinant Cdc7:Dbf4 heterodimeric kinase, a key regulator in the initiation of DNA replication and the G1 to S phase transition. Chemoinformatic analysis of the hits revealed an enrichment in one chemical cluster made up of several naturally occurring compounds, of which the most potent compound, CKI-7, was selected for further investigation. First, CKI-7 was found to be a non competitive inhibitor for ATP and prompted us to prolife it against a panel of 200 known kinases in order to assess its selectivity profile. The results were as predicted and very few kinases were specifically affected. Second, CKI-7 cytotoxic activity was assessed against a panel of well established cancer cell lines representing both hematopoietic and solid tumor malignancies as well as against a panel of primary hematopoietic cells derived from leukemia patients (both chemotherapy naïve and relapsed/refractory samples) and was found to be a very effective agent with potencies in the low nanomolar range. Subsequent studies using an isogenic pair of cell lines with one over expressing the Bcl_xL anti-apoptotic protein further confirmed the induction of the intrinsic apoptotic pathway via caspase-3 activation in the absence and attenuation of the activity in the presence of Bcl_xL. This was further demonstrated through standard cell cycle synchronization studies revealing that exposure to the Cdc7 inhibitor results in an S phase arrest, cell cycle dependent caspase-3 activation, and apoptotic cell death. This cell death is the direct result of Cdc7 kinase inhibition by CKI-7 as demonstrated using a Cdc7 substrate biomarker assay. Third, the physicochemical properties of this class of naturally occurring compounds also prompted us to investigate their effect on several multidrug resistence (MDR) over-expressing cell lines. We found that CKI-7 was not a substrate for the efflux pumps demonstrating that this novel compound can overcome a major mechanism of chemotherapy resistence in human tumor cells. Based of the above observations, in vivo dose-dependent anti-tumor activity of CKI-7 was subsequently demonstrated in a SCID-Beige mouse systemic tumor model utilizing a recently isolated Philadelphia chromosome positive acute lymphoblastic leukemia cell line (PhALL3.1). Taken together, our data confirm that Cdc7 is a new promising target for cancer therapy, and that the newly discovered inhibitor CKI-7, a naturally occurring selective small molecule inhibitor of this enzyme, is an equally promising novel cancer therapeutic agent. Disclosures: No relevant conflicts of interest to declare.

Novel anti-inflammatory actions of amlodipine in a rat model of arteriosclerosis induced by long-term inhibition of nitric oxide synthesis

2004 ◽  
Vol 286 (2) ◽  
pp. H768-H774 ◽  
Author(s):  
Chu Kataoka ◽  
Kensuke Egashira ◽  
Minako Ishibashi ◽  
Shujiro Inoue ◽  
Weihua Ni ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Rat Model ◽  
Vascular Inflammation ◽  
Monocyte Chemoattractant Protein 1 ◽  
Beneficial Effects ◽  
Pressure Lowering ◽  
Anti Inflammatory ◽  
Synthase Inhibitor

Amlodipine (a new class of calcium channel antagonist) has been shown to limit the progression of arteriosclerosis and decrease the incidence of cardiovascular events. The mechanisms underlying the beneficial effects of amlodipine, however, remain unclear. Therefore, we hypothesized that amlodipine attenuates the development of arteriosclerosis through the inhibition of inflammation in vivo. Long-term inhibition of nitric oxide (NO) by administration of a NO synthase inhibitor, Nω-nitro-l-arginine methyl ester (l-NAME), to rats induces coronary vascular inflammation [monocyte infiltration, monocyte chemoattractant protein-1 (MCP-1) expression, increased activity of angiotensin-converting enzyme (ACE)], and arteriosclerosis. Here, we used the rat model to investigate the anti-inflammatory effects of amlodipine in vivo. Treatment with amlodipine markedly inhibited the l-NAME-induced increase in vascular inflammation, oxidative stress, and local ACE and Rho activity and prevented arteriosclerosis. Interestingly, amlodipine prevented the l-NAME-induced increase in MCP-1 receptor CCR2 expression in circulating monocytes. Amlodipine markedly attenuated the high mortality rate at 8 wk of treatment. These data suggest that amlodipine attenuated arteriosclerosis through inhibiting inflammatory disorders in the rat model of long-term inhibition of NO synthesis. The anti-inflammatory effects of amlodipine seem to be mediated not only by the inhibition of local factors such as MCP-1 but also by the decrease in CCR2 in circulating monocytes. Inhibition of the MCP-1 to CCR2 pathway may represent novel anti-inflammatory actions of amlodipine beyond blood pressure lowering.

Nano-soldiers Ameliorate Silibinin Delivery: A Review Study

2020 ◽  
Vol 17 (1) ◽  
pp. 15-22 ◽  
Author(s):  
Milad Ashrafizadeh ◽  
Zahra Ahmadi ◽  
Reza Mohammadinejad ◽  
Tahereh Farkhondeh ◽  
Saeed Samarghandian
Keyword(s):  
Beneficial Effects ◽  
Naturally Occurring ◽  
Bioactive Component ◽  
Daily Diet ◽  
Clinical Disorders ◽  
Health Promoting ◽  
Therapeutic Activities ◽  
Significant Attention

: Flavonoids are a large group of naturally occurring compounds, which are of interest due to their great pharmacological effects and health-promoting impacts. These properties have led to their extensive application in a variety of pathological conditions, particularly cancer. Flavonoids are used in large quantities in a human's daily diet and a high amount of flavonoids are found in the intestine after oral usage. However, flavonoid concentrations in tissue/plasma are low because of their low bioavailability, the leading to the low efficacy of flavonoids in different clinical disorders. For this reason, nanotechnology application for delivering flavonoids to tumor sites has recently received significant attention. Silibinin is a key member of flavonoids and a bioactive component of silymarin, which is widely isolated from Silybum marianum. This plant-derived chemical has a number of valuable biological and therapeutic activities such as antioxidant, anti-inflammatory, neuroprotective, anti-tumor, hepatoprotective, cardioprotective and anti-diabetic. These beneficial effects have been demonstrated in in vivo and in vitro experiments. However, it seems that silibinin has a variety of limitations and poor bioavailability is the most important factor restricting its wide application. Hence, there have been attempts to improve the bioavailability of silibinin and it has been suggested that nano-soldiers are potential candidates for this aim. In the present review, we describe the different drug delivery systems for improving the bioavailability of silibinin.

scholarly journals E47 regulates hematopoietic stem cell proliferation and energetics but not myeloid lineage restriction

Blood ◽  
2011 ◽  
Vol 117 (13) ◽  
pp. 3529-3538 ◽  
Author(s):  
Qi Yang ◽  
Brandt Esplin ◽  
Lisa Borghesi
Keyword(s):  
Energy Metabolism ◽  
Myeloid Differentiation ◽  
Short Term ◽  
Hematopoietic Stem ◽  
Altered Expression ◽  
Helix Loop Helix ◽  
Multipotent Progenitors

Abstract The immune system is replenished by self-renewing hematopoietic stem cells (HSCs) that produce multipotent progenitors (MPPs) with little renewal capacity. E-proteins, the widely expressed basic helix-loop-helix transcription factors, contribute to HSC and MPP activity, but their specific functions remain undefined. Using quantitative in vivo and in vitro approaches, we show that E47 is dispensable for the short-term myeloid differentiation of HSCs but regulates their long-term capabilities. E47-deficient progenitors show competent myeloid production in short-term assays in vitro and in vivo. However, long-term myeloid and lymphoid differentiation is compromised because of a progressive loss of HSC self-renewal that is associated with diminished p21 expression and hyperproliferation. The activity of E47 is shown to be cell-intrinsic. Moreover, E47-deficient HSCs and MPPs have altered expression of genes associated with cellular energy metabolism, and the size of the MPP pool but not downstream lymphoid precursors in bone marrow or thymus is rescued in vivo by antioxidant. Together, these observations suggest a role for E47 in the tight control of HSC proliferation and energy metabolism, and demonstrate that E47 is not required for short-term myeloid differentiation.

scholarly journals A novel small molecule CXCR4 antagonist potently mobilizes hematopoietic stem cells in mice and monkeys

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiao Fang ◽  
Xiong Fang ◽  
Yujia Mao ◽  
Aaron Ciechanover ◽  
Yan Xu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Small Molecule ◽  
Cxcr4 Antagonist ◽  
Hematopoietic Stem ◽  
Stromal Microenvironment ◽  
Stromal Cell Derived Factor ◽  
Hsc Transplantation

Abstract Background Hematopoietic stem cell (HSC) transplantation is an effective treatment strategy for many types of diseases. Peripheral blood (PB) is the most commonly used source of bone marrow (BM)-derived stem cells for current HSC transplantation. However, PB usually contains very few HSCs under normal conditions, as these cells are normally retained within the BM. This retention depends on the interaction between the CXC chemokine receptor 4 (CXCR4) expressed on the HSCs and its natural chemokine ligand, stromal cell-derived factor (SDF)-1α (also named CXCL12) present in the BM stromal microenvironment. In clinical practice, blocking this interaction with a CXCR4 antagonist can induce the rapid mobilization of HSCs from the BM into the PB. Methods C3H/HEJ, DBA/2, CD45.1+, and CD45.2+ mice and monkeys were employed in colony-forming unit (CFU) assays, flow cytometry assays, and competitive/noncompetitive transplantation assays, to assess the short-term mobilization efficacy of HF51116 and the long-term repopulating (LTR) ability of HSCs. Kinetics of different blood cells and the concentration of HF51116 in PB were also explored by blood routine examinations and pharmacokinetic assays. Results In this paper, we report that a novel small molecule CXCR4 antagonist, HF51116, which was designed and synthesized by our laboratory, can rapidly and potently mobilize HSCs from BM to PB in mice and monkeys. HF51116 not only mobilized HSCs when used alone but also synergized with the mobilizing effects of granulocyte colony-stimulating factor (G-CSF) after co-administration. Following mobilization by HF51116 and G-CSF, the long-term repopulating (LTR) and self-renewing HSCs were sufficiently engrafted in primary and secondary lethally irradiated mice and were able to rescue and support long-term mouse survival. In monkeys, HF51116 exhibited strong HSC mobilization activity and quickly reached the highest in vivo blood drug concentration. Conclusions These results demonstrate that HF51116 is a new promising stem cell mobilizer which specifically targets CXCR4 and merits further preclinical and clinical studies.

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