scholarly journals Therapeutic Effects of HIF-1α on Bone Formation around Implants in Diabetic Mice Using Cell-Penetrating DNA-Binding Protein

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 760 ◽  
Author(s):  
Sang-Min Oh ◽  
Jin-Su Shin ◽  
Il-Koo Kim ◽  
Jung-Ho Kim ◽  
Jae-Seung Moon ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Repair ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Bioinformatic Analysis ◽  
Treated Group ◽  
Diabetic Patients ◽  
Therapeutic Effects ◽  
Diabetic Mice ◽  
The Right

Patients with uncontrolled diabetes are susceptible to implant failure due to impaired bone metabolism. Hypoxia-inducible factor 1α (HIF-1α), a transcription factor that is up-regulated in response to reduced oxygen during bone repair, is known to mediate angiogenesis and osteogenesis. However, its function is inhibited under hyperglycemic conditions in diabetic patients. This study thus evaluates the effects of exogenous HIF-1α on bone formation around implants by applying HIF-1α to diabetic mice and normal mice via a protein transduction domain (PTD)-mediated DNA delivery system. Implants were placed in the both femurs of diabetic and normal mice. HIF-1α and placebo gels were injected to implant sites of the right and left femurs, respectively. We found that bone-to-implant contact (BIC) and bone volume (BV) were significantly greater in the HIF-1α treated group than placebo in diabetic mice (p < 0.05). Bioinformatic analysis showed that diabetic mice had 216 differentially expressed genes (DEGs) and 21 target genes. Among the target genes, NOS2, GPNMB, CCL2, CCL5, CXCL16, and TRIM63 were found to be associated with bone formation. Based on these results, we conclude that local administration of HIF-1α via PTD may boost bone formation around the implant and induce gene expression more favorable to bone formation in diabetic mice.

scholarly journals Therapeutic effects of Hypoxia-Inducible Factor-1α (HIF-1α) on bone formation around implants in diabetic mice

2018 ◽  
Author(s):  
Sang-Min Oh ◽  
Jin-Su Shin ◽  
Il-Koo Kim ◽  
Jae-Seung Moon ◽  
Jung-Ho Kim ◽  
...  
Keyword(s):  
Bone Formation ◽  
Rna Sequencing ◽  
Normal Mouse ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Diabetic Mouse ◽  
Differentially Expressed ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Hypoxia Inducible Factor 1Α

AbstractPatients with uncontrolled diabetes are susceptible to implant failure due to impaired bone metabolism. Hypoxia-Inducible Factor 1α (HIF-1α), a transcription factor that is up-regulated in response to reduced oxygen condition during the bone repair process after fracture or osteotomy, is known to mediate angiogenesis and osteogenesis. However, its function is inhibited under hyperglycemic conditions in diabetic patients. The aim of this study is to evaluate the effects of exogenous HIF-1α on bone formation around implants by applying HIF-1α to diabetic mice via a novel PTD-mediated DNA delivery system. Smooth surface implants (1mm in diameter; 2mm in length) were placed in the both femurs of diabetic and normal mice. HIF-1α and placebo gels were injected to implant sites of the right and left femurs, respectively: Normal mouse with HIF-1α gel (NH), Normal mouse with placebo gel (NP), Diabetic mouse with HIF-1α gel (DH), and Diabetic mouse with placebo gel (DP). RNA sequencing was performed 4 days after surgery. Based on RNA sequencing, Differentially Expressed Genes (DEGs) were identified and HIF-1α target genes were selected. Histologic and histomorphometric results were evaluated 2 weeks after the surgery. The results showed that bone-to-implant contact (BIC) and bone volume (BV) were significantly greater in the DH group than the DP group (p < 0.05). A total of 216 genes were differentially expressed in DH group compared to DP group. On the other hand, there were 95 DEGs in the case of normal mice. Twenty-one target genes of HIF-1α were identified in diabetic mice through bioinformatic analysis of DEGs. Among the target genes, NOS2, GPNMB, CCL2, CCL5, CXCL16 and TRIM63 were manually found to be associated with wound healing-related genes. In conclusion, local administration of HIF-1α via PTD may help bone formation around the implant and induce gene expression more favorable to bone formation in diabetic mice.

scholarly journals A small molecule HIF-1α stabilizer that accelerates diabetic wound healing

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Guodong Li ◽  
Chung-Nga Ko ◽  
Dan Li ◽  
Chao Yang ◽  
Wanhe Wang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Small Molecule ◽  
Hypoxia Inducible Factor ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Impaired Wound Healing ◽  
Von Hippel Lindau ◽  
Design And Synthesis

AbstractImpaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design and synthesis of a cyclometalated iridium(III) metal complex 1a as a stabilizer of hypoxia-inducible factor-1α (HIF-1α). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL–HIF-1α interaction. Furthermore, the compound accumulates HIF-1α levels in cellulo and activates HIF-1α mediated gene expression, including VEGF, GLUT1, and EPO. In in vivo mouse models, the compound significantly accelerates wound closure in both normal and diabetic mice, with a greater effect being observed in the diabetic group. We also demonstrate that HIF-1α driven genes related to wound healing (i.e. HSP-90, VEGFR-1, SDF-1, SCF, and Tie-2) are increased in the wound tissue of 1a-treated diabetic mice (including, db/db, HFD/STZ and STZ models). Our study demonstrates a small molecule stabilizer of HIF-1α as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1α interaction.

scholarly journals PPARβ/δ Agonist Alleviates Diabetic Osteoporosis via Regulating M1/M2 Macrophage Polarization

2021 ◽  
Vol 9 ◽  
Author(s):  
Miao Chen ◽  
Weimin Lin ◽  
Rui Ye ◽  
Jianru Yi ◽  
Zhihe Zhao
Keyword(s):  
Therapeutic Target ◽  
Macrophage Polarization ◽  
Osteoclast Differentiation ◽  
Diabetic Patients ◽  
M2 Macrophage ◽  
Therapeutic Effects ◽  
Peroxisome Proliferator ◽  
Diabetic Mice ◽  
Diabetic Osteoporosis

Diabetic osteoporosis is a common complication in diabetic patients, leading to increased fracture risk and impaired bone healing. As a member of the peroxisome proliferator-activated receptor (PPAR) family, PPARβ/δ agonist is suggested as a therapeutic target for the treatment of metabolic syndrome, and has been reported to positively regulate bone turnover by improving osteogenesis. However, its regulatory role in diabetic osteoporosis has not been reported yet. Here, we explored the therapeutic effects and potential mechanisms of PPARβ/δ agonist to the osteoporotic phenotypes of diabetic mice. Our results indicated that the osteoporotic phenotypes could be significantly ameliorated in diabetic mice by the administration of PPARβ/δ agonists. In vitro experiments suggested that PPARβ/δ agonist treatment could alleviate the abnormal increase of osteoclast activity in diabetic mice by rectifying high glucose-mediated macrophage dysfunction instead of directly inhibiting osteoclast differentiation. Mechanistically, Angptl4 may act as a downstream target of PPARβ/δ to regulate macrophage polarization. In conclusion, our study demonstrates the potential of PPARβ/δ agonist as a therapeutic target for the treatment of osteoporosis and immune homeostasis disorder in diabetic patients.

Abstract 14365: Identification of MicroRNAs and Their Target Genes in Microvascular Disease in Diabetes

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Lei Gao ◽  
Atsumi Tsuji Hosokawa ◽  
Jody Tori O Cabrera ◽  
Tong Zhou ◽  
Ayako Makino
Keyword(s):  
Molecular Mechanisms ◽  
Target Genes ◽  
Obstructive Coronary Artery Disease ◽  
Microvascular Disease ◽  
Diabetic Patients ◽  
Transcriptional Level ◽  
Diabetic Mice ◽  
Mirna Array ◽  
Patients With Diabetes ◽  
Artery Disease

Cardiovascular disease is the leading cause of death in patients with diabetes. Among coronary vascular defects, obstructive coronary artery disease (CAD) is the primary cause of cardiac mortality. However, there is growing evidence that patients with coronary microvascular disease (CMD, also known as non-obstructive coronary disease) also experience chest pain and occasional heart attack. Furthermore, recent studies show that diabetes is the risk factor of CMD. However, the molecular mechanisms by which diabetes develops CMD is not fully understood. MicroRNAs (miRNAs) are a non-coding small RNA that regulates gene expression at the post-transcriptional level, and the change of miRNA profile is implicated in many diseases. In this study, we identified the core miRNAs which are involved in the development of coronary endothelial dysfunction in diabetes. We used an inducible type 2 diabetic (T2D) mouse model generated by high-fat diet and a single injection of low-dose streptozotocin. Our T2D mice did not show detectable atherosclerotic plaque, but developed CMD evidenced by reduced coronary flow velocity reserve. We conducted a miRNA array using mouse coronary endothelial cells (MCECs) isolated from diabetic and control mice, and selected seven miRNAs based on the result. Next, real-time PCR assays were carried out with seven miRNAs and found that miR210 and miR342-5p were downregulated, and miR378 was upregulated in MCECs of diabetic mice compared to the control. To identify the target genes of miR342-5p and miR378, we inhibited miR342-5p or overexpressed miR378 in MCECs. After testing 93 genes that are involved in endothelial functions, we found that inhibition of miR342-5p decreased the levels of Atp2a3 , Opa1 , Sod3 , and Vegfb , whereas miR378 overexpression significantly decreased Aggf1, HK1, Mapk3, Pak1, Panx1, Stim1, Stim2, Vcam1, and Vegfb and increased Casp2 and Gja1 . Western blotting data revealed that the expression levels of Affg1, Opa1, and Pak1 were significantly decreased in the MCECs from diabetic mice compared to the control. In summary, these data suggest that miR342-5p and miR378 could be a potential therapeutic target for CMD in diabetic patients, and Affg1 Opa1 and Pak1 are the downstream mRNAs of miR342-5p or miR378.

scholarly journals Platelet-rich plasma in bone repair of irradiated tibiae of Wistar rats

2010 ◽  
Vol 25 (3) ◽  
pp. 257-263 ◽  
Author(s):  
Emne Hammoud Gumieiro ◽  
Márcio Abrahão ◽  
Ricardo Schmitutz Jahn ◽  
Helena Segretto ◽  
Maria Tereza de Seixas Alves ◽  
...  
Keyword(s):  
Bone Formation ◽  
Wistar Rats ◽  
Bone Repair ◽  
Platelet Rich Plasma ◽  
Control Group ◽  
Regeneration Period ◽  
Male Wistar Rats ◽  
Cellular Regeneration ◽  
Histological Processing ◽  
The Right

PURPOSE: To evaluate the influence of PRP addition on bone repair of circular defects created in irradiated tibiae of rats by histometric analysis. METHODS: Sixty male Wistar rats had the right tibiae irradiated with 30 Gy. After 30 days monocortical defects were created and platelet-rich plasma was applied in 30 rats. In the control group defects were created but not filled. The animals were desanguinated after 4, 7, 14, 21, 56 and 84 days and the tibiae removed for histological processing. RESULTS: There was a tendency in the PRP group to increased bone neoformation from 14-days to 84-days; in the control group increased bone neoformation was not seen after 21 days or later. CONCLUSION: The addition of platelet-rich plasma had a beneficial effect in the initial cellular regeneration period and enhanced bone formation in later periods when compared to control.

Therapeutic Effects of Hab Shabyar on Open-Angle Glaucoma: A Double-Blinded, Randomized, Placebo-Controlled Trial

2019 ◽  
Vol 8 ◽  
pp. 1218
Author(s):  
Ebrahim Khalil BaniHabib ◽  
Ali Mostafai ◽  
Seyyed Mohammad Bagher Fazljou ◽  
Ghadir Mohammdi
Keyword(s):  
Placebo Group ◽  
Intraocular Pressure ◽  
Open Angle Glaucoma ◽  
Controlled Trial ◽  
Intervention Group ◽  
Therapeutic Effects ◽  
Open Angle ◽  
The Mean ◽  
The Right ◽  
Double Blinded

Background: Open-angle glaucoma (OAG) is one of the leading causes of blindness worldwide. This study evaluates the therapeutic effects of hab shabyar in patients with open-angle glaucoma. Materials and Methods: In this clinical randomized controlled trial, 50 patients with OAG were randomized into two groups. The intervention group was received a drop of timolol plus 500 mg of hab shabyar every 12 hours. The placebo group was received a drop of timolol every 12 hours plus 500 mg of wheat germ as a placebo. The intraocular pressure in patients with OAG was measured in each group and compared at before the intervention (t1), one month (t2), and two months (t3) after the intervention. Results: The mean decrease in intraocular pressure for the right eye at three times in the intervention group was statistically significant, but the mean decrease in the placebo group was not significant. Similar results were obtained for the left eye at t1 when compared to t3. The patients in the intervention group expressed more satisfaction than the patients in the placebo group (P≤0.001). Conclusion: Our study demonstrated that consumption of timolol plus hab shabyar instead of consuming of timolol alone was probably more effective for reducing intraocular pressure in patients with OAG.[GMJ.2019;In press:e1218]

ATF4, DLX3, FRA1, MSX2, C/EBP-ζ, and C/EBP-α Shape the Molecular Basis of Therapeutic Effects of Zoledronic Acid in Bone Disorders

2020 ◽  
Vol 20 (18) ◽  
pp. 2274-2284
Author(s):  
Faroogh Marofi ◽  
Jalal Choupani ◽  
Saeed Solali ◽  
Ghasem Vahedi ◽  
Ali Hassanzadeh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Zoledronic Acid ◽  
Mrna Expression ◽  
Promoter Methylation ◽  
Methylation Level ◽  
Target Genes ◽  
Osteoblastic Differentiation ◽  
Therapeutic Effects ◽  
Significant Difference ◽  
Scheduled Time

Objective: Zoledronic Acid (ZA) is one of the common treatment choices used in various boneassociated conditions. Also, many studies have investigated the effect of ZA on Osteoblastic-Differentiation (OSD) of Mesenchymal Stem Cells (MSCs), but its clear molecular mechanism(s) has remained to be understood. It seems that the methylation of the promoter region of key genes might be an important factor involved in the regulation of genes responsible for OSD. The present study aimed to evaluate the changes in the mRNA expression and promoter methylation of central Transcription Factors (TFs) during OSD of MSCs under treatment with ZA. Materials and Methods: MSCs were induced to be differentiated into the osteoblastic cell lineage using routine protocols. MSCs received ZA during OSD and then the methylation and mRNA expression levels of target genes were measured by Methylation Specific-quantitative Polymerase Chain Reaction (MS-qPCR) and real.time PCR, respectively. The osteoblastic differentiation was confirmed by Alizarin Red Staining and the related markers to this stage. Results: Gene expression and promoter methylation level for DLX3, FRA1, ATF4, MSX2, C/EBPζ, and C/EBPa were up or down-regulated in both ZA-treated and untreated cells during the osteodifferentiation process on days 0 to 21. ATF4, DLX3, and FRA1 genes were significantly up-regulated during the OSD processes, while the result for MSX2, C/EBPζ, and C/EBPa was reverse. On the other hand, ATF4 and DLX3 methylation levels gradually reduced in both ZA-treated and untreated cells during the osteodifferentiation process on days 0 to 21, while the pattern was increasing for MSX2 and C/EBPa. The methylation pattern of C/EBPζ was upward in untreated groups while it had a downward pattern in ZA-treated groups at the same scheduled time. The result for FRA1 was not significant in both groups at the same scheduled time (days 0-21). Conclusion: The results indicated that promoter-hypomethylation of ATF4, DLX3, and FRA1 genes might be one of the mechanism(s) controlling their gene expression. Moreover, we found that promoter-hypermethylation led to the down-regulation of MSX2, C/EBP-ζ and C/EBP-α. The results implicate that ATF4, DLX3 and FRA1 may act as inducers of OSD while MSX2, C/EBP-ζ and C/EBP-α could act as the inhibitor ones. We also determined that promoter-methylation is an important process in the regulation of OSD. However, yet there was no significant difference in the promoter-methylation level of selected TFs in ZA-treated and control cells, a methylation- independent pathway might be involved in the regulation of target genes during OSD of MSCs.

scholarly journals Functional Cereal Products in the Diet for Type 2 Diabetes Patients

2019 ◽  
Vol 2019 ◽  
pp. 1-7
Author(s):  
Ada Krawęcka ◽  
Aldona Sobota ◽  
Emilia Sykut-Domańska
Keyword(s):  
Type 2 Diabetes ◽  
Nutritional Value ◽  
Glycaemic Index ◽  
Modern World ◽  
Diabetic Patients ◽  
Therapeutic Effects ◽  
Major Health ◽  
Cereal Products

Type 2 diabetes has become one of the major health problems of the modern world. It is assumed that environmental factors have a significant impact on the development of the disease, and great importance is ascribed to the diet, which can be modified accordingly. The diet can exert prophylactic and therapeutic effects; changes in the diet in advanced disease can improve the quality of life of diabetic patients and minimise the risk of complications, which are the direct cause of diabetes-related death. Functional food, which has a potentially health-enhancing effect in addition to its nutritional value, has been increasingly recognised and required. Cereal products are crucial in diabetic nutrition. Their function can additionally be enhanced by fortification with compounds with proven hypoglycaemic effects. Pasta has a low glycaemic index and is a good carrier of fortifying substances; hence, it can be highly recommended in diets for diabetic patients.

scholarly journals Activation of the S100A7/RAGE Pathway by IGF-1 Contributes to Angiogenesis in Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 621
Author(s):  
Maria Grazia Muoio ◽  
Marianna Talia ◽  
Rosamaria Lappano ◽  
Andrew H. Sims ◽  
Veronica Vella ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Bioinformatic Analysis ◽  
Tube Formation ◽  
Endothelial Cell Proliferation ◽  
Diabetic Patients ◽  
Obesity And Diabetes ◽  
Er Positive

Background: Breast cancer (BC) mortality is increased among obese and diabetic patients. Both obesity and diabetes are associated with dysregulation of both the IGF-1R and the RAGE (Receptor for Advanced Glycation End Products) pathways, which contribute to complications of these disorders. The alarmin S100A7, signaling through the receptor RAGE, prompts angiogenesis, inflammation, and BC progression. Methods: We performed bioinformatic analysis of BC gene expression datasets from published studies. We then used Estrogen Receptor (ER)-positive BC cells, CRISPR-mediated IGF-1R KO BC cells, and isogenic S100A7-transduced BC cells to investigate the role of IGF-1/IGF-1R in the regulation of S100A7 expression and tumor angiogenesis. To this aim, we also used gene silencing and pharmacological inhibitors, and we performed gene expression and promoter studies, western blotting analysis, ChIP and ELISA assays, endothelial cell proliferation and tube formation assay. Results: S100A7 expression correlates with worse prognostic outcomes in human BCs. In BC cells, the IGF-1/IGF-1R signaling engages STAT3 activation and its recruitment to the S100A7 promoter toward S100A7 increase. In human vascular endothelial cells, S100A7 activates RAGE signaling and prompts angiogenic effects. Conclusions: In ER-positive BCs the IGF-1 dependent activation of the S100A7/RAGE signaling in adjacent endothelial cells may serve as a previously unidentified angiocrine effector. Targeting S100A7 may pave the way for a better control of BC, particularly in conditions of unopposed activation of the IGF-1/IGF-1R axis.

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