scholarly journals OSTEOPOROSIS: CELLULAR AND MOLECULAR MECHANISMS OF DEVELOPMENT AND TARGET MOLECULES IN SEARCH FOR NEW TREATMENTS OF THE DISEASE

2012 ◽  
Vol 15 (1) ◽  
pp. 15-22
Author(s):  
S Sagalovski
Keyword(s):  
Bone Formation ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Development Process ◽  
Molecular Mechanisms ◽  
New Drugs ◽  
Review Of The Literature ◽  
Target Molecules ◽  
Mechanisms Of Development ◽  
New Treatments

In a review of the literature reflects the modern understanding of the cellular-molecular mechanism development of osteoporosis. Reflects the importance of cytokine RANKL-RANK-OPG sistem and Wnt/β-catenin signaling pathway in the development process of osteoblasto- and osteoclastogenesis. Noting the key role in the process of bone formation a number of molecules of cell signaling pathway and their antagonists are of interest as a target molecule to search for new drugs treatment for osteoporosis.

scholarly journals Uvaol Exerts Anti-Proliferative and Pro-Apoptotic Effects on Human Hepatocarcinoma Cells by Modulating AKT/PI3K Signaling Pathway

2020 ◽  
Author(s):  
Gloria C. Bonel-Pérez ◽  
Amalia Pérez-Jiménez ◽  
Isabel Gris-Cárdenas ◽  
Alberto M. Parra-Pérez ◽  
José Antonio Lupiáñez ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Morphological Changes ◽  
New Drugs ◽  
Pi3k Signaling ◽  
Apoptotic Effect ◽  
Anticancer Mechanism ◽  
Pi3k Signaling Pathway ◽  
Hepatocarcinoma Cells ◽  
New Treatments ◽  
Apoptotic Effects

Natural products have a significant role in the development of new drugs, being relevant the pentacyclic triterpenes extracted from Olea europaea. Anticancer effect of uvaol, a natural triterpene, has been scarcely studied. The aim of this study was to understand the anticancer mechanism of uvaol in HepG2 cell line. Cytotoxicity results showed a selectivity effect of uvaol with higher influence in HepG2 than WRL68 cells used as control. Uvaol presented anti-migratory capacity in HepG2, supported by the morphological changes and higher HSP-60 expression. This compound also induced arrest in G0/G1 phase and an increase in apoptosis rate. These results are supported by decreased Bcl-2 expression and down-regulation of AKT/PI3K signaling pathway. A reduction in reactive oxygen species levels in HepG2 cells was observed. Altogether, results showed anti-proliferative and pro-apoptotic effect of uvaol on hepatocellular carcinoma, constituting an interesting challenge in the development of new treatments against this type of cancer.

scholarly journals Enhancing Activity of Pleurotus sajor-caju (Fr.) Sing β-1,3-Glucanoligosaccharide (Ps-GOS) on Proliferation, Differentiation, and Mineralization of MC3T3-E1 Cells through the Involvement of BMP-2/Runx2/MAPK/Wnt/β-Catenin Signaling Pathway

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 190
Author(s):  
Thanintorn Yodthong ◽  
Ureporn Kedjarune-Leggat ◽  
Carl Smythe ◽  
Pannawich Sukprasirt ◽  
Aratee Aroonkesorn ◽  
...  
Keyword(s):  
Bone Formation ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Integration Site ◽  
Biological Activities ◽  
Mitogen Activated Protein Kinase ◽  
Bone Morphogenetic Protein 2 ◽  
World Health ◽  
Wide Range ◽  
Pleurotus Sajor Caju

Osteoporosis is a leading world health problem that results from an imbalance between bone formation and bone resorption. β-glucans has been extensively reported to exhibit a wide range of biological activities, including antiosteoporosis both in vitro and in vivo. However, the molecular mechanisms responsible for β-glucan-mediated bone formation in osteoblasts have not yet been investigated. The oyster mushroom Pleurotus sajor-caju produces abundant amounts of an insoluble β-glucan, which is rendered soluble by enzymatic degradation using Hevea glucanase to generate low-molecular-weight glucanoligosaccharide (Ps-GOS). This study aimed to investigate the osteogenic enhancing activity and underlining molecular mechanism of Ps-GOS on osteoblastogenesis of pre-osteoblastic MC3T3-E1 cells. In this study, it was demonstrated for the first time that low concentrations of Ps-GOS could promote cell proliferation and division after 48 h of treatment. In addition, Ps-GOS upregulated the mRNA and protein expression level of bone morphogenetic protein-2 (BMP-2) and runt-related transcription factor-2 (Runx2), which are both involved in BMP signaling pathway, accompanied by increased alkaline phosphatase (ALP) activity and mineralization. Ps-GOS also upregulated the expression of osteogenesis related genes including ALP, collagen type 1 (COL1), and osteocalcin (OCN). Moreover, our novel findings suggest that Ps-GOS may exert its effects through the mitogen-activated protein kinase (MAPK) and wingless-type MMTV integration site (Wnt)/β-catenin signaling pathways.

Phosphocreatine Promotes Osteoblastic Activities in H2O2-induced MC3T3-E1 Cells by Regulating SIRT1/FOXO1/PGC-1α Signaling Pathway

2020 ◽  
Vol 21 ◽  
Author(s):  
Zheng Jing ◽  
Changyuan Wang ◽  
Shijie Wen ◽  
Yue Jin ◽  
Qiang Meng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Bone Formation ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Sirtuin 1 ◽  
Peroxisome Proliferator ◽  
Expression Levels ◽  
Positive Effects ◽  
Osteogenic Markers ◽  
Atp Generation

Background: Osteoporosis, characterized by bone loss, usually occurs with the increased bone resorption and the decreased bone formation. H2O2-induced MC3T3-E1 cells are commonly used for the study of osteoblastic activities which play a crucial role in bone formation. Objective: This study aimed to investigate the effects of Phosphocreatine (PCr) on the osteoblastic activities in H2O2- induced MC3T3-E1 cells and to elaborate the possible molecular mechanism. Method: The osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) ratio and osteogenic markers were detected to investigate the effects of PCr on osteoblastic activities, and the osteoblastic apoptosis was detected using Hochest staining. Moreover, oxidative stress, adenosine triphosphate (ATP) generation and the expression of Sirtuin 1 (SIRT1), forkhead box O 1 (FOXO1) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) were also examined to uncover the possible molecular mechanism in H2O2-induced MC3T3-E1 cells. Result: The results showed that PCr promoted the osteoblastic differentiation by increasing the expression levels of osteogenic markers of alkaline phosphatase (ALP) and Runt-related transcription factor 2 (Runx2), as well as increased the OPG/RANKL ratio and suppressed the osteoblastic apoptosis in H2O2-induced MC3T3-E1 cells. Moreover, treatment with PCr suppressed reactive oxygen species (ROS) over-generation and promoted the ATP production as well as increased the PGC-1α, FOXO1 and SIRT1 protein expression levels in H2O2-induced MC3T3-E1 cells. Conclusion: PCr treatment could promote osteoblastic activities via suppressing oxidative stress and increasing the ATP generation in H2O2-induced MC3T3-E1 cells. In addition, the positive effects of PCr on osteoblasts might be regulated by SIRT1/FOXO1/ PGC-1α signaling pathway.

scholarly journals Molecular Mechanism of Epidermal Barrier Dysfunction as Primary Abnormalities

2020 ◽  
Vol 21 (4) ◽  
pp. 1194 ◽  
Author(s):  
Ai-Young Lee
Keyword(s):  
Molecular Mechanism ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
Early Time ◽  
Skin Disorders ◽  
Barrier Dysfunction ◽  
Epidermal Barrier ◽  
Skin Lipids ◽  
Target Molecules ◽  
Differentiation And Proliferation

Epidermal barrier integrity could be influenced by various factors involved in epidermal cell differentiation and proliferation, cell–cell adhesion, and skin lipids. Dysfunction of this barrier can cause skin disorders, including eczema. Inversely, eczema can also damage the epidermal barrier. These interactions through vicious cycles make the mechanism complicated in connection with other mechanisms, particularly immunologic responses. In this article, the molecular mechanisms concerning epidermal barrier abnormalities are reviewed in terms of the following categories: epidermal calcium gradients, filaggrin, cornified envelopes, desquamation, and skin lipids. Mechanisms linked to ichthyoses, atopic dermatitis without exacerbation or lesion, and early time of experimental irritation were included. On the other hand, the mechanism associated with epidermal barrier abnormalities resulting from preceding skin disorders was excluded. The molecular mechanism involved in epidermal barrier dysfunction has been mostly episodic. Some mechanisms have been identified in cultured cells or animal models. Nonetheless, research into the relationship between the causative molecules has been gradually increasing. Further evidence-based systematic data of target molecules and their interactions would probably be helpful for a better understanding of the molecular mechanism underlying the dysfunction of the epidermal barrier.

scholarly journals Nanog/NFATc1/Osterix signaling pathway-mediated promotion of bone formation at the tendon-bone interface after ACL reconstruction with De-BMSCs transplantation

2021 ◽  
Author(s):  
Kai Tie ◽  
Jinghang Cai ◽  
Jun Qin ◽  
Hao Xiao ◽  
Yangfan Shangguan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Formation ◽  
Osteogenic Differentiation ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Bone Healing ◽  
Osteogenic Potential ◽  
Differentiation Potential ◽  
Bone Interface ◽  
Biomechanical Strength

Abstract Background: Bone formation plays an important role in early tendon-bone healing after anterior cruciate ligament reconstruction (ACLR). Dedifferentiated osteogenic bone marrow mesenchymal stem cells (De-BMSCs) have enhanced osteogenic potential. This study aimed to investigate the effect of De-BMSCs transplantation on the promotion of bone formation at the tendon-bone interface after ACLR and to further explore the molecular mechanism of the enhanced osteogenic potential of De-BMSCs.Methods: BMSCs from the femurs and tibias of New Zealand White rabbits were subjected to osteogenic induction and then cultured in medium without osteogenic factors; the obtained cell population was termed De-BMSCs. De-BMSCs were induced to undergo osteo-, chondro- and adipo-differentiation in vitro to examine the characteristics of primitive stem cells. An ACLR model with a semitendinosus tendon was established in rabbits, and the animals were divided into a control group, BMSCs group and De-BMSCs group. At 12 weeks after surgery, the rabbits in each group were sacrificed to evaluate tendon-bone healing by histologic staining, micro–computed tomography (micro-CT) examination, and biomechanical testing. During osteogenic differentiation of De-BMSCs, an siRNA targeting nuclear factor of activated T cells 1 (NFATc1) was used to verify the molecular mechanism of the enhanced osteogenic potential of De-BMSCs.Results: De-BMSCs exhibited some properties similar to BMSCs, including multiple differentiation potential and cell surface markers. Bone formation at the tendon-bone interface in the De-BMSCs group was significantly increased, and biomechanical strength was significantly improved. During the osteogenic differentiation of De-BMSCs, the expression of Nanog and NFATc1 was synergistically increased, which promoted the interaction of NFATc1 and Osterix, resulting in increased expression of osteoblast marker genes such as COL1A, OCN, and OPN.Conclusions: De-BMSCs transplantation could promote bone formation at the tendon-bone interface after ACLR and improve the biomechanical strength of the reconstruction. The Nanog/NFATc1/Osterix signaling pathway mediated the enhanced osteogenic differentiation efficiency of De-BMSCs.

scholarly journals Transcriptomics‐based analysis of the mechanism by which Wang-Bi capsule alleviates joint destruction in rats with collagen‐induced arthritis

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Haiyang Shu ◽  
Hanxiao Zhao ◽  
Yingjie Shi ◽  
Cheng Lu ◽  
Li Li ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Protective Effect ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Joint Destruction ◽  
Micro Ct ◽  
Collagen Induced Arthritis ◽  
Cartilage Development ◽  
And Cartilage

Abstract Background Rheumatoid arthritis (RA) is a chronic autoimmune disease accompanied with joint destruction that often leads to disability. Wang-Bi capsule (WB), a traditional Chinese medicine-based herbs formula, has exhibited inhibition effect on joint destruction of collagen-induced arthritis (CIA) animal model in our previous study. But its molecular mechanisms are still obscure. Methods CIA rats were treated intragastrical with WB for eight weeks, and the effect of joints protection were evaluated by hematoxylin and eosin (H&E) staining, safranin O fast green staining, tartrate-resistant acid phosphatase (TRAP) staining and micro‑CT scanning analysis. The transcriptomic of tarsal joints were used to investigate how WB alleviated joint destruction. Results The histological examination of ankle joints showed WB alleviated both cartilage damage and bone destruction of CIA rats. This protective effect on joints were further evidenced by micro-CT analysis. The transcriptomic analysis showed that WB prominently changed 12 KEGG signaling pathways (“calcium signaling pathway”, “cAMP signaling pathway”, “cell adhesion molecules”, “chemokine signaling pathway”, “complement and coagulation cascades”, “MAPK signaling pathway”, “NF-kappa B signaling pathway”, “osteoclast differentiation”, “PI3K-Akt signaling pathway”, “focal adhesion”, “Gap junction” and “Rap1 signaling pathway”) associated with bone or cartilage. Several genes (including Il6, Tnfsf11, Ffar2, Plg, Tnfrsf11b, Fgf4, Fpr1, Siglec1, Vegfd, Cldn1, Cxcl13, Chad, Arrb2, Fgf9, Egfr) regulating bone resorption, bone formation and cartilage development were identified by further analysis. Meanwhile, these differentially expressed genes were validated by real-time quantitative PCR. Conclusions Overall, the protective effect of WB treatment on joint were confirmed in CIA rats, and its basic molecular mechanisms may be associated with regulating some genes (including Il6, Tnfsf11, Ffar2 and Plg etc.) involved in bone resorption, bone formation and cartilage development.

scholarly journals Nanog/NFATc1/Osterix signaling pathway-mediated promotion of bone formation at the tendon–bone interface after ACL reconstruction with De-BMSCs transplantation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kai Tie ◽  
Jinghang Cai ◽  
Jun Qin ◽  
Hao Xiao ◽  
Yangfan Shangguan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Formation ◽  
Osteogenic Differentiation ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Bone Healing ◽  
Osteogenic Potential ◽  
Differentiation Potential ◽  
Bone Interface ◽  
Biomechanical Strength

Abstract Background Bone formation plays an important role in early tendon–bone healing after anterior cruciate ligament reconstruction (ACLR). Dedifferentiated osteogenic bone marrow mesenchymal stem cells (De-BMSCs) have enhanced osteogenic potential. This study aimed to investigate the effect of De-BMSCs transplantation on the promotion of bone formation at the tendon–bone interface after ACLR and to further explore the molecular mechanism of the enhanced osteogenic potential of De-BMSCs. Methods BMSCs from the femurs and tibias of New Zealand white rabbits were subjected to osteogenic induction and then cultured in medium without osteogenic factors; the obtained cell population was termed De-BMSCs. De-BMSCs were induced to undergo osteo-, chondro- and adipo-differentiation in vitro to examine the characteristics of primitive stem cells. An ACLR model with a semitendinosus tendon was established in rabbits, and the animals were divided into a control group, BMSCs group, and De-BMSCs group. At 12 weeks after surgery, the rabbits in each group were sacrificed to evaluate tendon–bone healing by histologic staining, micro-computed tomography (micro-CT) examination, and biomechanical testing. During osteogenic differentiation of De-BMSCs, an siRNA targeting nuclear factor of activated T-cells 1 (NFATc1) was used to verify the molecular mechanism of the enhanced osteogenic potential of De-BMSCs. Results De-BMSCs exhibited some properties similar to BMSCs, including multiple differentiation potential and cell surface markers. Bone formation at the tendon–bone interface in the De-BMSCs group was significantly increased, and biomechanical strength was significantly improved. During the osteogenic differentiation of De-BMSCs, the expression of Nanog and NFATc1 was synergistically increased, which promoted the interaction of NFATc1 and Osterix, resulting in increased expression of osteoblast marker genes such as COL1A, OCN, and OPN. Conclusions De-BMSCs transplantation could promote bone formation at the tendon–bone interface after ACLR and improve the biomechanical strength of the reconstruction. The Nanog/NFATc1/Osterix signaling pathway mediated the enhanced osteogenic differentiation efficiency of De-BMSCs.

scholarly journals Integrated bioinformatics and network pharmacology to identify the therapeutic target and molecular mechanisms of Huangqin decoction on ulcerative Colitis

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Yi Wu ◽  
Xinqiao Liu ◽  
Guiwei Li
Keyword(s):  
Ulcerative Colitis ◽  
Molecular Docking ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Molecular Mechanisms ◽  
Topological Analysis ◽  
Therapeutic Targets ◽  
Venn Diagram ◽  
Network Pharmacology ◽  
Active Components

AbstractHuangqin decoction (HQD) is a Traditional Chinese Medicine formula for ulcerative colitis. However, the pharmacology and molecular mechanism of HQD on ulcerative colitis is still unclear. Combined microarray analysis, network pharmacology, and molecular docking for revealing the therapeutic targets and molecular mechanism of HQD against ulcerative colitis. TCMSP, DrugBank, Swiss Target Prediction were utilized to search the active components and effective targets of HQD. Ulcerative colitis effective targets were obtained by microarray data from the GEO database (GSE107499). Co-targets between HQD and ulcerative colitis are obtained by Draw Venn Diagram. PPI (Protein–protein interaction) network was constructed by the STRING database. To obtain the core target, topological analysis is exploited by Cytoscape 3.7.2. GO and KEGG enrichment pathway analysis was performed to Metascape platform, and molecular docking through Autodock Vina 1.1.2 finished. 161 active components with 486 effective targets of HQD were screened. 1542 ulcerative colitis effective targets were obtained with |Log2FC|> 1 and adjusted P-value < 0.05. The Venn analysis was contained 79 co-targets. Enrichment analysis showed that HQD played a role in TNF signaling pathway, IL-17 signaling pathway, Th17 cell differentiation, etc. IL6, TNF, IL1B, PTGS2, ESR1, and PPARG with the highest degree from PPI network were successfully docked with 19 core components of HQD, respectively. According to ZINC15 database, quercetin (ZINC4175638), baicalein (ZINC3871633), and wogonin (ZINC899093) recognized as key compounds of HQD on ulcerative colitis. PTGS2, ESR1, and PPARG are potential therapeutic targets of HQD. HQD can act on multiple targets through multi-pathway, to carry out its therapeutic role in ulcerative colitis.

scholarly journals Antiproliferative and Pro-Apoptotic Effect of Uvaol in Human Hepatocarcinoma HepG2 Cells by Affecting G0/G1 Cell Cycle Arrest, ROS Production and AKT/PI3K Signaling Pathway

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4254 ◽  
Author(s):  
Gloria C. Bonel-Pérez ◽  
Amalia Pérez-Jiménez ◽  
Isabel Gris-Cárdenas ◽  
Alberto M. Parra-Pérez ◽  
José Antonio Lupiáñez ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Hepg2 Cells ◽  
New Drugs ◽  
Pi3k Signaling ◽  
Apoptotic Protein ◽  
Apoptotic Effect ◽  
Anticancer Mechanism ◽  
Pi3k Signaling Pathway ◽  
Cell Arrest ◽  
New Treatments

Natural products have a significant role in the development of new drugs, being relevant the pentacyclic triterpenes extracted from Olea europaea L. Anticancer effect of uvaol, a natural triterpene, has been scarcely studied. The aim of this study was to understand the anticancer mechanism of uvaol in the HepG2 cell line. Cytotoxicity results showed a selectivity effect of uvaol with higher influence in HepG2 than WRL68 cells used as control. Our results show that uvaol has a clear and selective anticancer activity in HepG2 cells supported by a significant anti-migratory capacity and a significant increase in the expression of HSP-60. Furthermore, the administration of this triterpene induces cell arrest in the G0/G1 phase, as well as an increase in the rate of cell apoptosis. These results are supported by a decrease in the expression of the anti-apoptotic protein Bcl2, an increase in the expression of the pro-apoptotic protein Bax, together with a down-regulation of the AKT/PI3K signaling pathway. A reduction in reactive oxygen species (ROS) levels in HepG2 cells was also observed. Altogether, results showed anti-proliferative and pro-apoptotic effect of uvaol on hepatocellular carcinoma, constituting an interesting challenge in the development of new treatments against this type of cancer.

scholarly journals Network Pharmacology-Based Approach to Investigate the Mechanisms of Piwei-Peiyuan Decoction in the Treatment of Gastric Carcinoma

2021 ◽  
Author(s):  
Bei Pei ◽  
Zi'ang Wen ◽  
Yanmin Zheng ◽  
Xuejun Li
Keyword(s):  
Gastric Carcinoma ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Interaction Network ◽  
Mapk Signaling ◽  
New Drugs ◽  
Network Pharmacology ◽  
Ras Signaling ◽  
Active Chemical ◽  
Promising Treatment

Abstract Purpose Piwei-Peiyuan Decoction is a traditional Chinese medicine decoction, which has shown promising treatment in gastric carcinoma. However, the molecular mechanisms of gastric carcinoma (GC) have not been systematically revealed yet. In this work, a network pharmacology research was conducted to analyze mechanisms of Piwei-Peiyuan Decoction, aiming to provide a basis for the development and application of new drugs in treatment of GC. Methods In this study, a network pharmacology approach was used to predict targets, construct network maps and analyze relevant signaling pathways. We discovered active chemical ingredients and their targets in the Piwei-Peiyuan Decoction by the TCMSP and ADME database. Then we found main targets of GC by GeneCards (https://www.genecards.org), OMIM (http://www.omim.org) and DRUGBANK (https://go.drugbank.com) databases. According to the information of ingredients and GC, a PPI network was performed by the String (https://string-db.org) database. And a targets-pathways interaction network was constructed by Cytoscape (version 3.7.2), a bioinformatics software used for data visualization and integration. Results Our result indicated that the main active ingredients of Piwei-Peiyuan Decoction in treating GC are Isorhamnetin, Kaempferol, Quercetin and Luteolin, and main active targets are CASP-3, MAPK1, MYC, AKT1, P53. We found the mechanism of Piwei-Peiyuan Decoction for treating GC is mainly to regulate PI3K-Akt signaling pathway, MAPK signaling pathway, Ras signaling pathway, IL-17 signaling pathway, HIF-1α signaling pathway to inhibit cell proliferation, promote apoptosis and then exert anti-cancer effects. Conclusion This study preliminarily analyzed the multi-component, multi-target and multi-path mechanism of Peiwei-Peiyuan Decoction in the treatment of gastric carcinoma, providing a theoretical basis for its clinical application.

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