|
1
|
Ranjan G, Ranjan S, Sunita P, Pattanayak SP. Thiazolidinedione derivatives in cancer therapy: exploring novel mechanisms, therapeutic potentials, and future horizons in oncology. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:4705-4725. [PMID: 39621087 DOI: 10.1007/s00210-024-03661-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 11/20/2024] [Indexed: 04/11/2025]
Abstract
Thiazolidinedione derivatives have shown significant potential as targeted cancer therapies by leveraging their various mechanisms of action. These include suppressing cell proliferation, triggering apoptosis, and influencing signaling pathways associated with tumor development. Their multifaceted effects make them promising candidates for advancing cancer treatment strategies. They have shown significant promise as anti-cancer agents, particularly through their ability to inhibit lipogenesis pathways and apoptosis essential for cancer cell survival and proliferation. This review comprehensively examines the anti-cancer potential of thiazolidinedione derivatives by targeting key aspects of lipid metabolism, apoptosis, and various mechanistic pathways. This review provides an in-depth examination of the anti-cancer potential of TZD derivatives, focusing on their mechanisms of action, therapeutic applications, and future directions in oncology. The anti-tumor effects of TZDs primarily involve the stimulation of peroxisome proliferator-activated receptor gamma (PPAR-γ), suppressing cell proliferation, induction of apoptosis, and inhibition of angiogenesis. Moreover, recent evidence highlights their ability to modulate non-PPAR-γ pathways, such as PI3K/Akt, NF-κB, and MAPK, further expanding their role in overcoming drug resistance and enhancing therapeutic outcomes. This review explores the preclinical (in vitro and in vivo) and clinical research investigating TZD derivatives efficacy in various cancer types. The insights underscore the significance of targeting lipogenesis as a novel anti-cancer strategy, positioning thiazolidinedione derivatives as potent candidates for future cancer therapeutics. As the oncology landscape evolves, TZD derivatives (rosiglitazone, pioglitazone, inolitazone, troglitazone, and 2,4-thiazolidinedione derivatives) represent a promising class of agents with the potential to contribute meaningfully to cancer treatment. By integrating existing knowledge with recent advancements, this study provides valuable insights into the role of thiazolidinedione derivatives in cancer treatment, paving the way for further research and clinical applications.
Collapse
Affiliation(s)
- Gaurav Ranjan
- Department of Pharmacy, School of Health Sciences, Central University of South Bihar, Gaya, 824236, India
| | - Shashi Ranjan
- Department of Pharmacy, School of Health Sciences, Central University of South Bihar, Gaya, 824236, India
| | - Priyashree Sunita
- Department of Surgery, Case Comprehensive Cancer Centre, Case Western Reserve University, Wolstein Research Building 2103 Cornell Rd, Cleveland, OH, 44106, USA
| | - Shakti Prasad Pattanayak
- Department of Pharmacy, School of Health Sciences, Central University of South Bihar, Gaya, 824236, India.
- Department of Biochemistry, School of Medicine, Case Western Reserve University, Woods Building, W437, 2109 Adelbert Road, Cleaveland, OH, 44106, USA.
| |
Collapse
|
|
2
|
Lee YH, You M, Kim HA. Vaccinium oldhamii Fruit Inhibits Lipid Accumulation in 3T3-L1 Cells and Diet-Induced Obese Animals. Nutrients 2025; 17:1346. [PMID: 40284210 PMCID: PMC12030422 DOI: 10.3390/nu17081346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2025] [Revised: 04/07/2025] [Accepted: 04/11/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND/OBJECTIVES Obesity is a significant global health concern, and the natural bioactive compounds with anti-obesity effects remain challenging. This study aims to examine the anti-obesity effect and the potential mechanism of Vaccinium oldhamii fruit water extract (VOW). METHODS Lipid accumulation, AMP-activated protein kinase (AMPK) activity, and Wnt/β-catenin signaling were evaluated in 3T3-L1 cells. In high-fat and high-sucrose diet (HFHSD)-induced obese mice, body weight, food intake, fat weight, serum lipid profiles, and adipogenic transcription factors were assessed. The most effective VOW fraction was selected by Oil Red O (ORO) staining and its mechanism was studied in 3T3-L1 cells. RESULTS VOW treatment significantly inhibited cellular lipid accumulation and suppressed phosphorylation of AMPK and its downstream protein, acetyl-CoA carboxylase (ACC). VOW also decreased adipogenic-associated protein expressions such as the peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT/enhancer-binding proteins α (C/EBP α), sterol regulatory element binding protein-1c (SREBP-1c), and fatty acid synthase (FAS). The enhanced effect of VOW was abolished by the knockdown of AMPK with siRNA. The inhibitory effect of VOW on differentiation depended on the treatment period, even though VOW treatment downregulated the C/EBP β expression at the early phase of differentiation. VOW dramatically reduced activation of AMPK, thereby downregulating adipogenic-associated proteins. Furthermore, the butanol fraction (BtOH) of VOW showed the most powerful effect of VOW dose-dependently reduced lipid accumulation by suppressing the phosphorylation of AMPK. Consistent with inhibited lipid accumulation in vitro, VOW reduced body weight and white adipose tissue weight in the HFHSD-induced obese animal model. CONCLUSIONS Overall, our study suggested that the anti-adipogenesis effect of VOW and its BtOH fraction involved the activation of AMPK.
Collapse
Affiliation(s)
- Young-Hyeon Lee
- Department of Food and Nutrition, Mokpo National University, Muan-gun 58554, Republic of Korea; (Y.-H.L.); (M.Y.)
| | - Mikyoung You
- Department of Food and Nutrition, Mokpo National University, Muan-gun 58554, Republic of Korea; (Y.-H.L.); (M.Y.)
- Convergence Center for Green Anti-Aging Research, Mokpo National University, Muan-gun 58554, Republic of Korea
| | - Hyeon-A Kim
- Department of Food and Nutrition, Mokpo National University, Muan-gun 58554, Republic of Korea; (Y.-H.L.); (M.Y.)
| |
Collapse
|
|
3
|
Zhu MC, Xu MZ, Li CX, Wang JH, Li C, Gong YQ, Jin J, Lu K, Hao YM. A cross-sectional study on the correlation between fasting blood glucose and bone turnover markers in Chinese patients with osteoporotic fractures. Front Med (Lausanne) 2025; 12:1564957. [PMID: 40276745 PMCID: PMC12018312 DOI: 10.3389/fmed.2025.1564957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 03/24/2025] [Indexed: 04/26/2025] Open
Abstract
Background Recent studies suggest that metabolic factors, such as fasting blood glucose (FBG), may significantly affect bone health, influencing the risk and severity of osteoporotic fractures (OPFs). This study examined the association between FBG levels and bone turnover markers (BTMs) in patients hospitalized for OPFs requiring surgical intervention. Methods A retrospective cross-sectional analysis was conducted on 888 patients treated for OPFs at Kunshan Hospital affiliated with Jiangsu University from November 2018 to August 2023. Serum levels of FBG, procollagen type 1 N-terminal propeptide (P1NP), and β-C-terminal telopeptide of type I collagen (β-CTX) were measured, with FBG serving as an independent variable, and P1NP and β-CTX as outcome variables. Patients were stratified into tertiles based on FBG levels, and multiple regression models were adjusted for confounding variables, including age, gender, BMI, and clinical parameters. Non-linear relationships and threshold effects were analyzed. Results Adjusted regression models identified a negative association between FBG and BTMs. For each 1 mmol/L increase in FBG, β-CTX levels decreased by 0.02 ng/mL (95% CI: -0.04 to -0.01; p < 0.01), and P1NP levels decreased by 2.91 ng/mL (95% CI: -4.38 to -1.45; p < 0.01). Non-linear relationships were observed, with an inflection point at 7.93 mmol/L for both markers. Below this threshold, higher FBG levels were associated with a steeper decline in BTMs. Conclusion FBG levels exhibit a negative non-linear association with P1NP and β-CTX in patients with OPFs. Elevated FBG levels may adversely affect BTMs, potentially contributing to the progression of osteoporosis (OP). These findings underscore the importance of glycemic control in managing bone health among patients with OPFs.
Collapse
Affiliation(s)
- Meng-cheng Zhu
- Department of Orthopedics, Affiliated Kunshan Hospital of Jiangsu University, Suzhou, Jiangsu, China
- Kunshan Biomedical Big Data Innovation Application Laboratory, Suzhou, Jiangsu, China
| | - Min-zhe Xu
- Department of Orthopedics, Affiliated Kunshan Hospital of Jiangsu University, Suzhou, Jiangsu, China
- Kunshan Biomedical Big Data Innovation Application Laboratory, Suzhou, Jiangsu, China
| | - Chang-xuan Li
- Kunshan Biomedical Big Data Innovation Application Laboratory, Suzhou, Jiangsu, China
- Department of Orthopedics, The First People's Hospital of Kunshan, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China
| | - Jia-hao Wang
- Kunshan Biomedical Big Data Innovation Application Laboratory, Suzhou, Jiangsu, China
- Department of Orthopedics, The First People's Hospital of Kunshan, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China
| | - Chong Li
- Department of Orthopedics, Affiliated Kunshan Hospital of Jiangsu University, Suzhou, Jiangsu, China
- Kunshan Biomedical Big Data Innovation Application Laboratory, Suzhou, Jiangsu, China
| | - Ya-qin Gong
- Kunshan Biomedical Big Data Innovation Application Laboratory, Suzhou, Jiangsu, China
- Information Department, Affiliated Kunshan Hospital of Jiangsu University, Suzhou, Jiangsu, China
| | - Jian Jin
- Kunshan Municipal Health and Family Planning Information Center, Suzhou, Jiangsu, China
| | - Ke Lu
- Department of Orthopedics, Affiliated Kunshan Hospital of Jiangsu University, Suzhou, Jiangsu, China
- Kunshan Biomedical Big Data Innovation Application Laboratory, Suzhou, Jiangsu, China
| | - Yan-ming Hao
- Department of Orthopedics, Affiliated Kunshan Hospital of Jiangsu University, Suzhou, Jiangsu, China
- Kunshan Biomedical Big Data Innovation Application Laboratory, Suzhou, Jiangsu, China
| |
Collapse
|
|
4
|
Badralmaa Y, Natarajan V. Aberrant Wnt/β-catenin signaling in the mesenchymal stem cells of LZTFL1-depleted mice leads to increased adipogenesis, with implications for obesity. J Biol Chem 2025; 301:108057. [PMID: 39662832 PMCID: PMC11770550 DOI: 10.1016/j.jbc.2024.108057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 11/05/2024] [Accepted: 11/18/2024] [Indexed: 12/13/2024] Open
Abstract
Obesity is one of the main clinical characteristics associated with the heterogeneous genetic disorder Bardet-Biedl syndrome (BBS). Leucine zipper transcription factor like 1 (LZTFL1) is a member of the BBS gene family. Our work showed that Lztfl1knockout (LZKO) mice display the obesity phenotype as early as 3 months of age. Mesenchymal stem cells (MSCs) are multipotent stem cells that can differentiate into various cell types, including adipocytes. To understand the role of LZTFL1 in adipogenesis, we analyzed MSCs isolated from LZKO mouse compact bones (CB-MSCs). Compared to wildtype (WT), LZKO CB-MSCs had elongated primary cilia with tapered tips and increased levels of peroxisome proliferator-activated receptor γ (PPARγ), a key transcription factor that favors adipogenesis, and nuclear glucocorticoid receptor (GR), a transcription factor involved in Pparg activation. Also, LZKO CB-MSCs had a lower level of total β-catenin, a core factor of the antiadipogenic canonical Wnt/b-catenin signaling pathway involved in limiting the nuclear localization of GR. Interaction between caveolin1 (CAV1) and LRP6, the main receptor for canonical Wnt signaling, is known to be critical for Wnt pathway activation and β-catenin stabilization. Compared to WT cells, LZKO cells had elevated total, cell-surface, and lipid-raft-associated LRP6 and reduced CAV1, strongly indicating alterations in the components of the Wnt-signaling pathway. We show that in the absence of LZTFL1, adipogenesis-restraining Wnt/β-catenin signaling is inhibited, and adipogenesis-favorable factors are stimulated in CB-MSCs, leading to enhanced adipogenesis. Evidence provided here could help in understanding the mechanism and molecular basis of obesity in LZTFL1-defective patients.
Collapse
Affiliation(s)
- Yunden Badralmaa
- Laboratory of Molecular Cell Biology, Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Ven Natarajan
- Laboratory of Molecular Cell Biology, Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
| |
Collapse
|
|
5
|
Sandhu A, Rawat K, Gautam V, Kumar A, Sharma A, Bhatia A, Grover S, Saini L, Saha L. Neuroprotective effect of PPAR gamma agonist in rat model of autism spectrum disorder: Role of Wnt/β-catenin pathway. Prog Neuropsychopharmacol Biol Psychiatry 2024; 135:111126. [PMID: 39179196 DOI: 10.1016/j.pnpbp.2024.111126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 08/16/2024] [Accepted: 08/20/2024] [Indexed: 08/26/2024]
Abstract
BACKGROUND The clinical manifestation of autism spectrum disorder (ASD) is linked to the disruption of fundamental neurodevelopmental pathways. Emerging evidences claim to have an upregulation of canonical Wnt/β-catenin pathway while downregulation of PPARγ pathway in ASD. This study aims to investigate the therapeutic potential of pioglitazone, a PPARγ agonist, in rat model of ASD. The study further explores the possible role of PPARγ and Wnt/β-catenin pathway and their interaction in ASD by using their modulators. MATERIAL AND METHODS Pregnant female Wistar rats received 600 mg/kg of valproic acid (VPA) to induce autistic symptoms in pups. Pioglitazone (10 mg/kg) was used to evaluate neurobehaviors, relative mRNA expression of inflammatory (IL-1β, IL-6, IL-10, TNF-α), apoptotic markers (Bcl-2, Bax, & Caspase-3) and histopathology (H&E, Nissl stain, Immunohistochemistry). Effect of pioglitazone was evaluated on Wnt pathway and 4 μg/kg dose of 6-BIO (Wnt modulator) was used to study the PPARγ pathway. RESULTS ASD model was established in pups as indicated by core autistic symptoms, increased neuroinflammation, apoptosis and histopathological neurodegeneration in cerebellum, hippocampus and amygdala. Pioglitazone significantly attenuated these alterations in VPA-exposed rats. The expression study results indicated an increase in key transcription factor, β-catenin in VPA-rats suggesting an upregulation of canonical Wnt pathway in them. Pioglitazone significantly downregulated the Wnt signaling by suppressing the expression of Wnt signaling-associated proteins. The inhibiting effect of Wnt pathway on PPARγ activity was indicated by downregulation of PPARγ-associated protein in VPA-exposed rats and those administered with 6-BIO. CONCLUSION In the present study, upregulation of canonical Wnt/β-catenin pathway was demonstrated in ASD rat model. Pioglitazone administration significantly ameliorated these symptoms potentially through its neuroprotective effect and its ability to downregulate the Wnt/β-catenin pathway. The antagonism between the PPARγ and Wnt pathway offers a promising therapeutic approach for addressing ASD.
Collapse
Affiliation(s)
- Arushi Sandhu
- Department of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh 160012, India
| | - Kajal Rawat
- Department of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh 160012, India
| | - Vipasha Gautam
- Department of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh 160012, India
| | - Anil Kumar
- Department of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh 160012, India
| | - Antika Sharma
- Department of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh 160012, India
| | - Alka Bhatia
- Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India
| | - Sandeep Grover
- Department of Psychiatry, Post Graduate Institute ofMedical Education and Research (PGIMER), Chandigarh 160012, India
| | - Lokesh Saini
- Department of Paediatrics, All India Institute of Medical Sciences (AIIMS), Jodhpur, Rajasthan 342001, India
| | - Lekha Saha
- Department of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh 160012, India.
| |
Collapse
|
|
6
|
Simao JDJ, Bispo AFDS, Plata VTG, Abel ABM, Saran RJ, Barcella JF, Alonso JCC, Santana AV, Armelin-Correa LM, Alonso-Vale MIC. The Activation of the NF-κB Pathway in Human Adipose-Derived Stem Cells Alters the Deposition of Epigenetic Marks on H3K27 and Is Modulated by Fish Oil. Life (Basel) 2024; 14:1653. [PMID: 39768360 PMCID: PMC11678231 DOI: 10.3390/life14121653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 11/27/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Chronic low-grade inflammation in obesity is linked to white adipose tissue (WAT) dysfunction. Plasma lipopolysaccharide (LPS) activates Toll-like receptor 4 (TLR4), triggering NF-κB and worsening these disturbances. Previously, we showed that histone H3 lysine 27 (H3K27) epigenetic modifications affect WAT gene expression in high-fat-diet mice, identifying key pathways in adipose-derived stem cells (ASCs). This study explores whether NF-κB influences H3K27 modifiers in human ASCs and evaluates fish oil (FO) as a modulator. METHODS Human visceral WAT ASCs were stimulated with LPS and treated with FO enriched with eicosapentaenoic acid (EPA). Flow cytometry, PCR array, RT-PCR, and Western blot assays were used. RESULTS LPS increased NF-κB activity, elevating KDM6B demethylase levels and H3K27 acetylation. These epigenetic modifications in LPS-stimulated ASCs were associated with persistent changes in the expression of genes involved in adipogenesis, metabolic regulation, and inflammation, even after LPS removal and cell differentiation. FO mitigated these effects, reducing H3K27 acetylation and promoting methylation. CONCLUSIONS FO demonstrates potential in modulating inflammation-induced epigenetic changes and preserving adipocyte function.
Collapse
Affiliation(s)
- Jussara de Jesus Simao
- Post-Graduate Program in Chemical Biology, Institute of Environmental Sciences, Chemical and Pharmaceutical, Federal University of São Paulo—UNIFESP, Diadema 09913-030, Brazil; (J.d.J.S.); (A.F.d.S.B.); (V.T.G.P.); (L.M.A.-C.)
| | - Andressa França de Sousa Bispo
- Post-Graduate Program in Chemical Biology, Institute of Environmental Sciences, Chemical and Pharmaceutical, Federal University of São Paulo—UNIFESP, Diadema 09913-030, Brazil; (J.d.J.S.); (A.F.d.S.B.); (V.T.G.P.); (L.M.A.-C.)
| | - Victor Tadeu Gonçalves Plata
- Post-Graduate Program in Chemical Biology, Institute of Environmental Sciences, Chemical and Pharmaceutical, Federal University of São Paulo—UNIFESP, Diadema 09913-030, Brazil; (J.d.J.S.); (A.F.d.S.B.); (V.T.G.P.); (L.M.A.-C.)
| | - Ana Beatriz Marques Abel
- Post-Graduate Program in Nutrition, Paulista School of Medicine, Federal University of São Paulo—UNIFESP, Sao Paulo 04023-062, Brazil;
| | - Raphael Justa Saran
- Department of Biological Sciences, Institute of Environmental Sciences, Chemical and Pharmaceutical, Federal University of São Paulo—UNIFESP, Diadema 09913-030, Brazil; (R.J.S.); (J.F.B.)
| | - Júlia Fernandes Barcella
- Department of Biological Sciences, Institute of Environmental Sciences, Chemical and Pharmaceutical, Federal University of São Paulo—UNIFESP, Diadema 09913-030, Brazil; (R.J.S.); (J.F.B.)
| | | | - André Valente Santana
- Post-Graduate Program in Interdisciplinary Surgical Science, Paulista School of Medicine, Federal University of São Paulo—UNIFESP, Sao Paulo 04023-062, Brazil;
| | - Lucia Maria Armelin-Correa
- Post-Graduate Program in Chemical Biology, Institute of Environmental Sciences, Chemical and Pharmaceutical, Federal University of São Paulo—UNIFESP, Diadema 09913-030, Brazil; (J.d.J.S.); (A.F.d.S.B.); (V.T.G.P.); (L.M.A.-C.)
- Department of Biological Sciences, Institute of Environmental Sciences, Chemical and Pharmaceutical, Federal University of São Paulo—UNIFESP, Diadema 09913-030, Brazil; (R.J.S.); (J.F.B.)
| | - Maria Isabel Cardoso Alonso-Vale
- Post-Graduate Program in Chemical Biology, Institute of Environmental Sciences, Chemical and Pharmaceutical, Federal University of São Paulo—UNIFESP, Diadema 09913-030, Brazil; (J.d.J.S.); (A.F.d.S.B.); (V.T.G.P.); (L.M.A.-C.)
- Post-Graduate Program in Nutrition, Paulista School of Medicine, Federal University of São Paulo—UNIFESP, Sao Paulo 04023-062, Brazil;
- Department of Biological Sciences, Institute of Environmental Sciences, Chemical and Pharmaceutical, Federal University of São Paulo—UNIFESP, Diadema 09913-030, Brazil; (R.J.S.); (J.F.B.)
| |
Collapse
|
|
7
|
Galigniana NM, Ruiz MC, Piwien-Pilipuk G. FK506 binding protein 51: Its role in the adipose organ and beyond. J Cell Biochem 2024; 125:e30351. [PMID: 36502528 DOI: 10.1002/jcb.30351] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 11/04/2022] [Accepted: 11/15/2022] [Indexed: 02/17/2024]
Abstract
There is a great body of evidence that the adipose organ plays a central role in the control not only of energy balance, but importantly, in the maintenance of metabolic homeostasis. Interest in the study of different aspects of its physiology grew in the last decades due to the pandemic of obesity and the consequences of metabolic syndrome. It was not until recently that the first evidence for the role of the high molecular weight immunophilin FK506 binding protein (FKBP) 51 in the process of adipocyte differentiation have been described. Since then, many new facets have been discovered of this stress-responsive FKBP51 as a central node for precise coordination of many cell functions, as shown for nuclear steroid receptors, autophagy, signaling pathways as Akt, p38 MAPK, and GSK3, as well as for insulin signaling and the control of glucose homeostasis. Thus, the aim of this review is to integrate and discuss the recent advances in the understanding of the many roles of FKBP51 in the adipose organ.
Collapse
Affiliation(s)
- Natalia M Galigniana
- Laboratory of Nuclear Architecture, Instituto de Biología y Medicina Experimental (IBYME)-CONICET, Buenos Aires, Argentina
- Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Marina C Ruiz
- Laboratory of Nuclear Architecture, Instituto de Biología y Medicina Experimental (IBYME)-CONICET, Buenos Aires, Argentina
| | - Graciela Piwien-Pilipuk
- Laboratory of Nuclear Architecture, Instituto de Biología y Medicina Experimental (IBYME)-CONICET, Buenos Aires, Argentina
| |
Collapse
|
|
8
|
Saxena S, Dagar N, Shelke V, Puri B, Gaikwad AB. Wnt/beta-catenin modulation: A promising frontier in chronic kidney disease management. Fundam Clin Pharmacol 2024; 38:1020-1030. [PMID: 39102849 DOI: 10.1111/fcp.13031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 07/03/2024] [Accepted: 07/22/2024] [Indexed: 08/07/2024]
Abstract
BACKGROUND Being amongst the leading factors of death and distress, chronic kidney disease (CKD) has affected around 850 million people globally. The Wnt/β-catenin axis is vital for maintaining kidney homeostasis, from nephron generation to overall management. The β-catenin growth factor is typically not expressed in the adult kidney; however, its expression is found to increase under stress and injury conditions. It is categorised as canonical and non-canonical based on β-catenin availability, which mounts promising targets for ameliorating CKD. Hence, modulation of the Wnt/β-catenin signalling for CKD management is of utmost relevance. OBJECTIVES The primary aim of this review is to highlight the significance of targeting Wnt/β-catenin signalling for CKD management. METHODS The literature review regarding the role of Wnt/β-catenin signalling and therapies modulating it in CKD was conducted using PubMed, Scopus, Science Direct and Google Scholar. RESULTS The current review summarises the pharmacological therapies modulating the Wnt/β-catenin axis in CKD, building upon promising preclinical studies to establish a foundation for clinical studies in the future. CONCLUSION Wnt/β-catenin signalling is the evolution's most conserved pathway, which plays a pivotal role in CKD progression. Therapies modulating Wnt/β-catenin signalling have emerged as effective means for alleviating CKD.
Collapse
Affiliation(s)
- Shubhangi Saxena
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Pilani Campus, Pilani, Rajasthan, India
| | - Neha Dagar
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Pilani Campus, Pilani, Rajasthan, India
| | - Vishwadeep Shelke
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Pilani Campus, Pilani, Rajasthan, India
| | - Bhupendra Puri
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Pilani Campus, Pilani, Rajasthan, India
| | - Anil Bhanudas Gaikwad
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Pilani Campus, Pilani, Rajasthan, India
| |
Collapse
|
|
9
|
Guo G, Wang W, Tu M, Zhao B, Han J, Li J, Pan Y, Zhou J, Ma W, Liu Y, Sun T, Han X, An Y. Deciphering adipose development: Function, differentiation and regulation. Dev Dyn 2024; 253:956-997. [PMID: 38516819 DOI: 10.1002/dvdy.708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 03/02/2024] [Accepted: 03/10/2024] [Indexed: 03/23/2024] Open
Abstract
The overdevelopment of adipose tissues, accompanied by excess lipid accumulation and energy storage, leads to adipose deposition and obesity. With the increasing incidence of obesity in recent years, obesity is becoming a major risk factor for human health, causing various relevant diseases (including hypertension, diabetes, osteoarthritis and cancers). Therefore, it is of significance to antagonize obesity to reduce the risk of obesity-related diseases. Excess lipid accumulation in adipose tissues is mediated by adipocyte hypertrophy (expansion of pre-existing adipocytes) or hyperplasia (increase of newly-formed adipocytes). It is necessary to prevent excessive accumulation of adipose tissues by controlling adipose development. Adipogenesis is exquisitely regulated by many factors in vivo and in vitro, including hormones, cytokines, gender and dietary components. The present review has concluded a comprehensive understanding of adipose development including its origin, classification, distribution, function, differentiation and molecular mechanisms underlying adipogenesis, which may provide potential therapeutic strategies for harnessing obesity without impairing adipose tissue function.
Collapse
Affiliation(s)
- Ge Guo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Wanli Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Mengjie Tu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Binbin Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Jiayang Han
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Jiali Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Yanbing Pan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Jie Zhou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Wen Ma
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Yi Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Tiantian Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Xu Han
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Yang An
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| |
Collapse
|
|
10
|
Bose GS, Kalakoti G, Kulkarni AP, Mittal S. AP-1/C-FOS and AP-1/FRA2 differentially regulate early and late adipogenic differentiation of mesenchymal stem cells. J Cell Biochem 2024; 125:e30543. [PMID: 38440920 DOI: 10.1002/jcb.30543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 02/01/2024] [Accepted: 02/15/2024] [Indexed: 03/06/2024]
Abstract
Obesity is defined as an abnormal accumulation of adipose tissue in the body and is a major global health problem due to increased morbidity and mortality. Adipose tissue is made up of adipocytes, which are fat-storing cells, and the differentiation of these fat cells is known as adipogenesis. Several transcription factors (TFs) such as CEBPβ, CEBPα, PPARγ, GATA, and KLF have been reported to play a key role in adipogenesis. In this study, we report one more TF AP-1, which is found to be involved in adipogenesis. Human mesenchymal stem cells were differentiated into adipocytes, and the expression pattern of different subunits of AP-1 was examined during adipogenesis. It was observed that C-FOS was predominantly expressed at an early stage (Day 2), whereas FRA2 expression peaked at later stages (Days 6 and 8) of adipogenesis. Chromatin immunoprecipitation-sequencing analysis revealed that C-FOS binds mainly to the promoters of WNT1, miR-30a, and ANAPC7 and regulates their expression during mitotic clonal expansion. In contrast, FRA2 binds to the promoters of CIDEA, NOTCH1, ARAF, and MYLK, regulating their expression and lipid metabolism. Data obtained clearly indicate that the differential expression of C-FOS and FRA2 is crucial for different stages of adipogenesis. This also raises the possibility of considering AP-1 as a therapeutic target for treating obesity and related disorders.
Collapse
Affiliation(s)
- Ganesh Suraj Bose
- Department of Biotechnology, Savitribai Phule Pune University, Pune, India
| | - Garima Kalakoti
- Bioinformatics Center, Savitribai Phule Pune University, Pune, India
| | | | - Smriti Mittal
- Department of Biotechnology, Savitribai Phule Pune University, Pune, India
| |
Collapse
|
|
11
|
Okumuş EB, Böke ÖB, Turhan SŞ, Doğan A. From development to future prospects: The adipose tissue & adipose tissue organoids. Life Sci 2024; 351:122758. [PMID: 38823504 DOI: 10.1016/j.lfs.2024.122758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 05/22/2024] [Accepted: 05/27/2024] [Indexed: 06/03/2024]
Abstract
Living organisms store their energy in different forms of fats including lipid droplets, triacylglycerols, and steryl esters. In mammals and some non-mammal species, the energy is stored in adipose tissue which is the innervated specialized connective tissue that incorporates a variety of cell types such as macrophages, fibroblasts, pericytes, endothelial cells, adipocytes, blood cells, and several kinds of immune cells. Adipose tissue is so complex that the scope of its function is not only limited to energy storage, it also encompasses to thermogenesis, mechanical support, and immune defense. Since defects and complications in adipose tissue are heavily related to certain chronic diseases such as obesity, cardiovascular diseases, type 2 diabetes, insulin resistance, and cholesterol metabolism defects, it is important to further study adipose tissue to enlighten further mechanisms behind those diseases to develop possible therapeutic approaches. Adipose organoids are accepted as very promising tools for studying fat tissue development and its underlying molecular mechanisms, due to their high recapitulation of the adipose tissue in vitro. These organoids can be either derived using stromal vascular fractions or pluripotent stem cells. Due to their great vascularization capacity and previously reported incontrovertible regulatory role in insulin sensitivity and blood glucose levels, adipose organoids hold great potential to become an excellent candidate for the source of stem cell therapy. In this review, adipose tissue types and their corresponding developmental stages and functions, the importance of adipose organoids, and the potential they hold will be discussed in detail.
Collapse
Affiliation(s)
- Ezgi Bulut Okumuş
- Faculty of Engineering, Genetics and Bioengineering Department, Yeditepe University, İstanbul, Turkey
| | - Özüm Begüm Böke
- Faculty of Engineering, Genetics and Bioengineering Department, Yeditepe University, İstanbul, Turkey
| | - Selinay Şenkal Turhan
- Faculty of Engineering, Genetics and Bioengineering Department, Yeditepe University, İstanbul, Turkey
| | - Ayşegül Doğan
- Faculty of Engineering, Genetics and Bioengineering Department, Yeditepe University, İstanbul, Turkey.
| |
Collapse
|
|
12
|
Flores-Opazo M, Kopinke D, Helmbacher F, Fernández-Verdejo R, Tuñón-Suárez M, Lynch GS, Contreras O. Fibro-adipogenic progenitors in physiological adipogenesis and intermuscular adipose tissue remodeling. Mol Aspects Med 2024; 97:101277. [PMID: 38788527 PMCID: PMC11692456 DOI: 10.1016/j.mam.2024.101277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 04/27/2024] [Accepted: 05/13/2024] [Indexed: 05/26/2024]
Abstract
Excessive accumulation of intermuscular adipose tissue (IMAT) is a common pathological feature in various metabolic and health conditions and can cause muscle atrophy, reduced function, inflammation, insulin resistance, cardiovascular issues, and unhealthy aging. Although IMAT results from fat accumulation in muscle, the mechanisms underlying its onset, development, cellular components, and functions remain unclear. IMAT levels are influenced by several factors, such as changes in the tissue environment, muscle type and origin, extent and duration of trauma, and persistent activation of fibro-adipogenic progenitors (FAPs). FAPs are a diverse and transcriptionally heterogeneous population of stromal cells essential for tissue maintenance, neuromuscular stability, and tissue regeneration. However, in cases of chronic inflammation and pathological conditions, FAPs expand and differentiate into adipocytes, resulting in the development of abnormal and ectopic IMAT. This review discusses the role of FAPs in adipogenesis and how they remodel IMAT. It highlights evidence supporting FAPs and FAP-derived adipocytes as constituents of IMAT, emphasizing their significance in adipose tissue maintenance and development, as well as their involvement in metabolic disorders, chronic pathologies and diseases. We also investigated the intricate molecular pathways and cell interactions governing FAP behavior, adipogenesis, and IMAT accumulation in chronic diseases and muscle deconditioning. Finally, we hypothesize that impaired cellular metabolic flexibility in dysfunctional muscles impacts FAPs, leading to IMAT. A deeper understanding of the biology of IMAT accumulation and the mechanisms regulating FAP behavior and fate are essential for the development of new therapeutic strategies for several debilitating conditions.
Collapse
Affiliation(s)
| | - Daniel Kopinke
- Department of Pharmacology and Therapeutics, University of Florida, Gainesville, 32610, FL, USA; Myology Institute, University of Florida College of Medicine, Gainesville, FL, USA.
| | | | - Rodrigo Fernández-Verdejo
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA; Laboratorio de Fisiología Del Ejercicio y Metabolismo (LABFEM), Escuela de Kinesiología, Facultad de Medicina, Universidad Finis Terrae, Chile.
| | - Mauro Tuñón-Suárez
- Laboratorio de Fisiología Del Ejercicio y Metabolismo (LABFEM), Escuela de Kinesiología, Facultad de Medicina, Universidad Finis Terrae, Chile.
| | - Gordon S Lynch
- Centre for Muscle Research, Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Parkville 3010, Australia.
| | - Osvaldo Contreras
- Developmental and Regenerative Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, 2010, Australia; School of Clinical Medicine, UNSW Sydney, Kensington, NSW 2052, Australia.
| |
Collapse
|
|
13
|
González-Sánchez GD, Granados-López AJ, López-Hernández Y, Robles MJG, López JA. miRNAs as Interconnectors between Obesity and Cancer. Noncoding RNA 2024; 10:24. [PMID: 38668382 PMCID: PMC11055034 DOI: 10.3390/ncrna10020024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 03/21/2024] [Accepted: 04/04/2024] [Indexed: 04/29/2024] Open
Abstract
Obesity and cancer are a concern of global interest. It is proven that obesity may trigger the development or progression of some types of cancer; however, the connection by non-coding RNAs has not been totally explored. In the present review, we discuss miRNAs and lncRNAs dysregulation involved in obesity and some cancers, shedding light on how these conditions may exacerbate one another through the dysregulation of ncRNAs. lncRNAs have been reported as regulating microRNAs. An in silico investigation of lncRNA and miRNA interplay is presented. Our investigation revealed 44 upregulated and 49 downregulated lncRNAs in obesity and cancer, respectively. miR-375, miR-494-3p, miR-1908, and miR-196 were found interacting with 1, 4, 4 and 4 lncRNAs, respectively, which are involved in PPARγ cell signaling regulation. Additionally, miR-130 was found to be downregulated in obesity and reported as modulating 5 lncRNAs controlling PPARγ cell signaling. Similarly, miR-128-3p and miR-143 were found to be downregulated in obesity and cancer, interacting with 5 and 4 lncRNAs, respectively, associated with MAPK cell signaling modulation. The delicate balance between miRNA and lncRNA expression emerges as a critical determinant in the development of obesity-associated cancers, presenting these molecules as promising biomarkers. However, additional and deeper studies are needed to reach solid conclusions about obesity and cancer connection by ncRNAs.
Collapse
Affiliation(s)
- Grecia Denisse González-Sánchez
- Doctorate in Biosciences, University Center of Los Altos, University of Guadalajara, Tepatitlán de Morelos C.P. 47620, Mexico;
| | - Angelica Judith Granados-López
- Laboratory of microRNAs and Cancer, Academic Unit of Biological Sciences, Autonomous University of Zacatecas “Francisco García Salinas”, Zacatecas C.P. 98066, Mexico;
| | - Yamilé López-Hernández
- Laboratory of Proteomics and Metabolomics, Cátedras-CONACYT, Academic Unit of Biological Sciences, Autonomous University of Zacatecas “Francisco García Salinas”, Zacatecas C.P. 98066, Mexico;
| | - Mayra Judith García Robles
- Biotechnology Department of the Polytechnic, University of Zacatecas, Fresnillo, Zacatecas C.P. 99059, Mexico
| | - Jesús Adrián López
- Laboratory of microRNAs and Cancer, Academic Unit of Biological Sciences, Autonomous University of Zacatecas “Francisco García Salinas”, Zacatecas C.P. 98066, Mexico;
| |
Collapse
|
|
14
|
Jia Y, Liu Y, Liu S, Chang Y, Xu L, Li H. Wnt10b knockdown promotes UCP1 expression in brown adipose tissue in mice. Genes Cells 2023; 28:764-775. [PMID: 37691290 DOI: 10.1111/gtc.13064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 08/15/2023] [Accepted: 08/23/2023] [Indexed: 09/12/2023]
Abstract
The effect of Wnt10b overexpression on adipose tissue development has been reported. However, the impact of Wnt10b knockdown on the function of brown adipose tissue (BAT) is yet largely unknown. Here, we used the CRISPR/Cas9 technique to generate Wnt10b-knockdown (Wnt10b+/- ) mice. We compared the development and thermogenic gene expression of interscapular BAT (iBAT) between Wnt10b+/- and Wnt10b+/+ mice under a chow diet, high-fat diet (HFD), and cold exposure conditions. Moreover, the effect of Wnt10b knockdown on brown adipocyte function was tested via in vitro experiments. Results indicated that Wnt10b knockdown decreased the iBAT mass and the brown adipocyte size and enhanced thermogenic gene expression, including UCP1, under chow diet conditions. In addition, Wnt10b+/- mice appeared to be able to maintain their body temperature better than the control in a cold environment, accompanied by higher UCP1 protein expression. Intriguingly, even under HFD conditions, Wnt10b+/- mice still showed higher UCP1 expression, which was associated with an alleviated obesity phenotype. In vitro studies further evidenced the Wnt10b knockdown stimulation of UCP1 expression and suppression of the adipogenic program. This study indicates that Wnt10b knockdown enhances UCP1 expression and inhibits the adipogenic differentiation of brown adipocytes, providing a novel option for therapeutic interventions in adiposity.
Collapse
Affiliation(s)
- Yanxin Jia
- State Key Laboratory of Crop Biology, College of Life Sciences, Shandong Agricultural University, Tai'an, China
| | - Yan Liu
- State Key Laboratory of Crop Biology, College of Life Sciences, Shandong Agricultural University, Tai'an, China
| | - Shuang Liu
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an, China
| | - Yaxin Chang
- State Key Laboratory of Crop Biology, College of Life Sciences, Shandong Agricultural University, Tai'an, China
| | - Longfei Xu
- State Key Laboratory of Crop Biology, College of Life Sciences, Shandong Agricultural University, Tai'an, China
| | - Haifang Li
- State Key Laboratory of Crop Biology, College of Life Sciences, Shandong Agricultural University, Tai'an, China
| |
Collapse
|
|
15
|
Podinić T, Werstuck G, Raha S. The Implications of Cannabinoid-Induced Metabolic Dysregulation for Cellular Differentiation and Growth. Int J Mol Sci 2023; 24:11003. [PMID: 37446181 DOI: 10.3390/ijms241311003] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/27/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
The endocannabinoid system (ECS) governs and coordinates several physiological processes through an integrated signaling network, which is responsible for inducing appropriate intracellular metabolic signaling cascades in response to (endo)cannabinoid stimulation. This intricate cellular system ensures the proper functioning of the immune, reproductive, and nervous systems and is involved in the regulation of appetite, memory, metabolism, and development. Cannabinoid receptors have been observed on both cellular and mitochondrial membranes in several tissues and are stimulated by various classes of cannabinoids, rendering the ECS highly versatile. In the context of growth and development, emerging evidence suggests a crucial role for the ECS in cellular growth and differentiation. Indeed, cannabinoids have the potential to disrupt key energy-sensing metabolic signaling pathways requiring mitochondrial-ER crosstalk, whose functioning is essential for successful cellular growth and differentiation. This review aims to explore the extent of cannabinoid-induced cellular dysregulation and its implications for cellular differentiation.
Collapse
Affiliation(s)
- Tina Podinić
- The Department of Pediatrics and the Graduate Program in Medical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada
| | - Geoff Werstuck
- Department of Medicine and the Thrombosis and Atherosclerosis Research Institute, David Braley Research Institute, McMaster University, Hamilton, ON L8L 2X2, Canada
| | - Sandeep Raha
- The Department of Pediatrics and the Graduate Program in Medical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada
| |
Collapse
|
|
16
|
Fu C, Chin-Young B, Park G, Guzmán-Seda M, Laudier D, Han WM. WNT7A suppresses adipogenesis of skeletal muscle mesenchymal stem cells and fatty infiltration through the alternative Wnt-Rho-YAP/TAZ signaling axis. Stem Cell Reports 2023; 18:999-1014. [PMID: 37001514 PMCID: PMC10147829 DOI: 10.1016/j.stemcr.2023.03.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 02/28/2023] [Accepted: 03/01/2023] [Indexed: 04/03/2023] Open
Abstract
Intramuscular fatty infiltration in muscle injuries and diseases, caused by aberrant adipogenesis of fibro-adipogenic progenitors, negatively impacts function. Intramuscular delivery of wingless-type MMTV integration site family 7a (WNT7A) offers a promising strategy to stimulate muscle regeneration, but its effects on adipogenic conversion of fibro-adipogenic progenitors remain unknown. Here, we show that WNT7A decreases adipogenesis of fibro-adipogenic progenitors (FAPs) by inducing nuclear localization of Yes-associated protein (YAP) through Rho in a β-CATENIN-independent manner and by promoting nuclear retention of YAP and transcriptional co-activator with PDZ-binding motif (TAZ) in differentiating FAPs. Furthermore, intramuscular injection of WNT7A in vivo effectively suppresses fatty infiltration in mice following glycerol-induced injury. Our results collectively suggest WNT7A as a potential protein-based therapeutic for diminishing adipogenesis of FAPs and intramuscular fatty infiltration in pathological muscle injuries or diseases.
Collapse
Affiliation(s)
- Chengcheng Fu
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Britney Chin-Young
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - GaYoung Park
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Mariana Guzmán-Seda
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Biomedical Engineering, Polytechnic University of Puerto Rico, San Juan, PR, USA
| | - Damien Laudier
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Woojin M Han
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| |
Collapse
|
|
17
|
Li Y, Wang X, Lu J. Interleukin-35 Promote Osteogenesis and Inhibit Adipogenesis: Role of Wnt/β-Catenin and PPARγ Signaling Pathways. Inflammation 2023; 46:522-533. [PMID: 36380113 DOI: 10.1007/s10753-022-01749-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 09/23/2022] [Accepted: 09/30/2022] [Indexed: 11/16/2022]
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells that are able to differentiate into several cell types, including cartilage, fat, and bone. It has been reported that the decision process of MSCs into fat and bone cells is competing and reciprocal. Interleukin (IL)-35 is an important effector protein in the Wnt/β-catenin signaling pathway that acts as a bone metabolism regulator. However, it is unclear whether IL-35 is also important for regulating MSC differentiation to fat and bone. In the current study, we evaluated the role of IL-35 in C3H10T1/2 cells, which are a good cell model for investigating osteogenesis and adipogenesis in bone marrows. The role of IL-35 on osteoblast proliferation and apoptosis was assessed using cell counting kit-8 assay and flow cytometry, respectively. Extracellular matrix mineralization and lipid accumulation were measured by Alizarin Red S staining and Oil Red O staining, respectively. The most important transcription factor of the process of osteogenesis Runx2 and Wnt/β-catenin signaling pathway components β-catenin and Axin2 were investigated in response to IL-35 treatment. Furthermore, the adipogenic markers PPAR-γ and C/EBPα were also investigated. Our observations showed that IL-35 could promote the proliferation of MSCs and inhibit the apoptosis of MSCs. We found that IL-35 treatment resulted in a dramatic stimulation of osteogenesis and inhibition of adipogenesis. Moreover, IL-35 enhanced Wnt/β-catenin pathway key component β-catenin as well as Axin2 expression during MSCs differentiated to osteoblasts. Our findings suggested that IL-35 might control the balance between osteogenic and adipogenic differentiation of progenitor cells through the Wnt/β-catenin-PPARγ signaling pathway, suggesting its potential application in providing an intervention in osteoporosis and obesity.
Collapse
Affiliation(s)
- Yuxuan Li
- Department of Rheumatology and Immunology, Shengjing Hospital of China Medical University, No. 36 San Hao Street, Heping District, Shenyang, 110004, People's Republic of China
| | - Xiaofei Wang
- Department of Rheumatology and Immunology, Shengjing Hospital of China Medical University, No. 36 San Hao Street, Heping District, Shenyang, 110004, People's Republic of China
| | - Jing Lu
- Department of Rheumatology and Immunology, The First Affiliated Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, People's Republic of China.
| |
Collapse
|
|
18
|
Guo L, Chang Y, Sun Z, Deng J, Jin Y, Shi M, Zhang J, Miao Z. Effects of Chinese Yam Polysaccharide on Intramuscular Fat and Fatty Acid Composition in Breast and Thigh Muscles of Broilers. Foods 2023; 12:foods12071479. [PMID: 37048300 PMCID: PMC10094610 DOI: 10.3390/foods12071479] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/21/2023] [Accepted: 03/29/2023] [Indexed: 04/03/2023] Open
Abstract
The purpose of this study is to evaluate the influences of Chinese yam polysaccharide (CYP) dietary supplementation on the composition of intramuscular fat (IMF) and fatty acids (FA) in thigh and breast muscles of broilers. Three hundred and sixty healthy one-day-old broilers (the breed of Crossbred chicken is named 817) with gender-balanced and similar body weight (39 ± 1 g) were randomly allocated into four groups (control, CYP1, CYP2, and CYP3 groups). Broilers in the control group were only fed a basal diet, and broilers in CYP1 group were fed the same diets further supplemented with 250 mg/kg CYP, the CYP2 group was fed the same diets further supplemented with 500 mg/kg CYP, and the CYP3 group was fed the same diets further supplemented with 1000 mg/kg CYP, respectively. Each group consisted of three replicates and each replicate consisted of 30 birds. The feeding days were 48 days. The results observed that the CYP2 group (500 mg/kg) can up-regulate the mRNA expression levels of β-catenin in thigh muscle compared to the control group. At the same time, all CYP groups (CYP1, CYP2, and CYP3 groups) can up-regulate mRNA expression of Wnt1 and β-catenin in breast muscle, while mRNA expression of PPARγ and C/EBPα in breast and thigh muscles could be down-regulated (p < 0.05). In summary, 500 mg/kg of CYP dietary supplementation can reduce IMF content and improve the FAs composition, enhancing the nutritional value of chicken meat.
Collapse
Affiliation(s)
- Liping Guo
- School of Food Science and Technology, Henan Institute of Science and Technology, Xinxiang 453003, China
| | - Yadi Chang
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang 453003, China
| | - Zhe Sun
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang 453003, China
| | - Jiahua Deng
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang 453003, China
| | - Yan Jin
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang 453003, China
| | - Mingyan Shi
- College of Life Science, Luoyang Normal University, Jiqing Road, Luoyang 471022, China
| | - Jinzhou Zhang
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang 453003, China
| | - Zhiguo Miao
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang 453003, China
- Correspondence: ; Tel.: +86-373-3040718; Fax: +86-373-3040718
| |
Collapse
|
|
19
|
Perna A, Carleo MA, Mascolo S, Guida A, Contieri M, Sellitto C, Hay E, De Blasiis P, Lucariello A, Guerra G, Baldi A, De Luca A, Maggi P, Esposito V. Adipocyte differentiation of 3T3-L1 cells under tenofovir alafenamide, tenofovir disoproxil fumarate, and integrase strand transfer inhibitors selective challenge: an in-vitro model. AIDS 2023; 37:561-570. [PMID: 36504092 PMCID: PMC9994803 DOI: 10.1097/qad.0000000000003455] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 11/24/2022] [Accepted: 11/29/2022] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral therapy (ART) medications with a good tolerability profile and a high genetic barrier to HIV drug resistance. However, several studies report significant weight gain among persons receiving INSTI-based ART regimens compared with other regimens. DESIGN In-vitro model of adipogenesis. METHODS We used 3T3-L1 cells to investigate the effects of the nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), alone or in combination with INSTIs: raltegravir (RAL), elvitegravir (ELV), dolutegravir (DTG), and bictegravir (BIC) on adipose differentiation. To monitor adipocyte differentiation, expression levels of PPARɣ and C/EBPα and the intracellular lipid accumulation by Red Oil staining were used. Furthermore, we evaluated the immunohistochemical expression of ER-TR7, a fibroblastic marker, after INSTIs treatment. RESULTS Compared with control, INSTIs were able to increase adipogenesis, especially RAL and ELV. TAF and TDF inhibited adipogenesis alone and in combination with INSTIs. This ability was more evident when TAF was used in combination with DTG and BIC. Finally, INSTIs increased the expression of ER-TR7 compared with control and cells treated with TAF or TDF. CONCLUSION Our data support the evidence that in-vitro challenge of 3T3-L1 cells with INSTIs is able to increase adipocytic differentiation and to drive a number of these cells toward the expression of fibroblastic features, with a different degree according to the various drugs used whereas TAF and TDF have an antagonistic role on this phenomenon.
Collapse
Affiliation(s)
- Angelica Perna
- Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, Campobasso
| | - Maria A. Carleo
- Infectious Diseases and Gender Medicine Unit, Cotugno Hospital, AO dei Colli
| | - Silvia Mascolo
- Infectious Diseases and Gender Medicine Unit, Cotugno Hospital, AO dei Colli
| | - Alessandra Guida
- Infectious Diseases and Gender Medicine Unit, Cotugno Hospital, AO dei Colli
| | - Marcella Contieri
- Department of Mental and Physical Health and Preventive Medicine, Section of Human Anatomy, University of Campania “Luigi Vanvitelli”
| | - Carmine Sellitto
- Department of Mental and Physical Health and Preventive Medicine, Section of Human Anatomy, University of Campania “Luigi Vanvitelli”
| | - Eleonora Hay
- Department of Mental and Physical Health and Preventive Medicine, Section of Human Anatomy, University of Campania “Luigi Vanvitelli”
| | - Paolo De Blasiis
- Department of Mental and Physical Health and Preventive Medicine, Section of Human Anatomy, University of Campania “Luigi Vanvitelli”
| | - Angela Lucariello
- Department of Sport Sciences and Wellness, University of Naples “Parthenope”, Naples
| | - Germano Guerra
- Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, Campobasso
| | - Alfonso Baldi
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, Caserta, Italy
| | - Antonio De Luca
- Department of Mental and Physical Health and Preventive Medicine, Section of Human Anatomy, University of Campania “Luigi Vanvitelli”
| | - Paolo Maggi
- Department of Mental and Physical Health and Preventive Medicine, Section of Human Anatomy, University of Campania “Luigi Vanvitelli”
| | - Vincenzo Esposito
- Infectious Diseases and Gender Medicine Unit, Cotugno Hospital, AO dei Colli
| |
Collapse
|
|
20
|
Bomkamp C, Musgrove L, Marques DMC, Fernando GF, Ferreira FC, Specht EA. Differentiation and Maturation of Muscle and Fat Cells in Cultivated Seafood: Lessons from Developmental Biology. MARINE BIOTECHNOLOGY (NEW YORK, N.Y.) 2023; 25:1-29. [PMID: 36374393 PMCID: PMC9931865 DOI: 10.1007/s10126-022-10174-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 10/10/2022] [Indexed: 06/16/2023]
Abstract
Cultivated meat, also known as cultured or cell-based meat, is meat produced directly from cultured animal cells rather than from a whole animal. Cultivated meat and seafood have been proposed as a means of mitigating the substantial harms associated with current production methods, including damage to the environment, antibiotic resistance, food security challenges, poor animal welfare, and-in the case of seafood-overfishing and ecological damage associated with fishing and aquaculture. Because biomedical tissue engineering research, from which cultivated meat draws a great deal of inspiration, has thus far been conducted almost exclusively in mammals, cultivated seafood suffers from a lack of established protocols for producing complex tissues in vitro. At the same time, fish such as the zebrafish Danio rerio have been widely used as model organisms in developmental biology. Therefore, many of the mechanisms and signaling pathways involved in the formation of muscle, fat, and other relevant tissue are relatively well understood for this species. The same processes are understood to a lesser degree in aquatic invertebrates. This review discusses the differentiation and maturation of meat-relevant cell types in aquatic species and makes recommendations for future research aimed at recapitulating these processes to produce cultivated fish and shellfish.
Collapse
Affiliation(s)
- Claire Bomkamp
- Department of Science & Technology, The Good Food Institute, Washington, DC USA
| | - Lisa Musgrove
- University of the Sunshine Coast, Sippy Downs, Queensland Australia
| | - Diana M. C. Marques
- Department of Bioengineering and Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal
- Associate Laboratory i4HB—Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal
| | - Gonçalo F. Fernando
- Department of Science & Technology, The Good Food Institute, Washington, DC USA
| | - Frederico C. Ferreira
- Department of Bioengineering and Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal
- Associate Laboratory i4HB—Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal
| | - Elizabeth A. Specht
- Department of Science & Technology, The Good Food Institute, Washington, DC USA
| |
Collapse
|
|
21
|
Yu D, Xin L, Qing X, Hao Z, Yong W, Jiangjiang Z, Yaqiu L. Key circRNAs from goat: discovery, integrated regulatory network and their putative roles in the differentiation of intramuscular adipocytes. BMC Genomics 2023; 24:51. [PMID: 36707755 PMCID: PMC9883971 DOI: 10.1186/s12864-023-09141-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 01/17/2023] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND The procession of preadipocytes differentiation into mature adipocytes involves multiple cellular and signal transduction pathways. Recently. a seirces of noncoding RNAs (ncRNAs), including circular RNAs (circRNAs) were proved to play important roles in regulating differentiation of adipocytes. RESULT In this study, we aimed to identificate the potential circRNAs in the early and late stages of goat intramuscular adipocytes differentiation. Using bioinformatics methods to predict their biological functions and map the circRNA-miRNA interaction network. Over 104 million clean reads in goat intramuscular preadipocytes and adipocytes were mapped, of which16 circRNAs were differentially expressed (DE-circRNAs). Furthermore, we used real-time fluorescent quantitative PCR (qRT-PCR) technology to randomly detect the expression levels of 8 circRNAs among the DE-circRNAs, and our result verifies the accuracy of the RNA-seq data. From the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the DE-circRNAs, two circRNAs, circ_0005870 and circ_0000946, were found in Focal adhesion and PI3K-Akt signaling pathway. Then we draw the circRNA-miRNA interaction network and obtained the miRNAs that possibly interact with circ_0005870 and circ_0000946. Using TargetScan, miRTarBase and miR-TCDS online databases, we further obtained the mRNAs that may interact with the miRNAs, and generated the final circRNA-miRNA-mRNA interaction network. Combined with the following GO (Gene Ontology) and KEGG enrichment analysis, we obtained 5 key mRNAs related to adipocyte differentiation in our interaction network, which are FOXO3(forkhead box O3), PPP2CA (protein phosphatase 2 catalytic subunit alpha), EEIF4E (eukaryotic translation initiation factor 4), CDK6 (cyclin dependent kinase 6) and ACVR1 (activin A receptor type 1). CONCLUSIONS By using Illumina HiSeq and online databases, we generated the final circRNA-miRNA-mRNA interaction network that have valuable functions in adipocyte differentiation. Our work serves as a valuable genomic resource for in-depth exploration of the molecular mechanism of ncRNAs interaction network regulating adipocyte differentiation.
Collapse
Affiliation(s)
- Du Yu
- grid.412723.10000 0004 0604 889XKey Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China ,grid.412723.10000 0004 0604 889XKey Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu, China ,grid.412723.10000 0004 0604 889XCollege of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, China
| | - Li Xin
- grid.412723.10000 0004 0604 889XKey Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China ,grid.412723.10000 0004 0604 889XKey Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu, China ,grid.412723.10000 0004 0604 889XCollege of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, China
| | - Xu Qing
- grid.412723.10000 0004 0604 889XKey Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China ,grid.412723.10000 0004 0604 889XKey Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu, China ,grid.412723.10000 0004 0604 889XCollege of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, China
| | - Zhang Hao
- grid.412723.10000 0004 0604 889XKey Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China ,grid.412723.10000 0004 0604 889XKey Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu, China ,grid.412723.10000 0004 0604 889XCollege of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, China
| | - Wang Yong
- grid.412723.10000 0004 0604 889XKey Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China ,grid.412723.10000 0004 0604 889XKey Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu, China ,grid.412723.10000 0004 0604 889XCollege of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, China
| | - Zhu Jiangjiang
- grid.412723.10000 0004 0604 889XKey Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China ,grid.412723.10000 0004 0604 889XKey Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu, China
| | - Lin Yaqiu
- grid.412723.10000 0004 0604 889XKey Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu, China ,grid.412723.10000 0004 0604 889XKey Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu, China ,grid.412723.10000 0004 0604 889XCollege of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, China
| |
Collapse
|
|
22
|
Elgamal MA, Khodeer DM, Abdel-Wahab BA, Ibrahim IAA, Alzahrani AR, Moustafa YM, Ali AA, El-Sayed NM. Canagliflozin alleviates valproic acid-induced autism in rat pups: Role of PTEN/PDK/PPAR-γ signaling pathways. Front Pharmacol 2023; 14:1113966. [PMID: 36909191 PMCID: PMC9992196 DOI: 10.3389/fphar.2023.1113966] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 02/09/2023] [Indexed: 02/24/2023] Open
Abstract
Autism is complex and multifactorial, and is one of the fastest growing neurodevelopmental disorders. Canagliflozin (Cana) is an antidiabetic drug that exhibits neuroprotective properties in various neurodegenerative syndromes. This study investigated the possible protective effect of Cana against the valproic acid (VPA)-induced model of autism. VPA was injected subcutaneously (SC) into rat pups at a dose of 300 mg/kg, twice daily on postnatal day-2 (PD-2) and PD-3, and once on PD-4 to induce an autism-like syndrome. Graded doses of Cana were administered (5 mg/kg, 7.5 mg/kg, and 10 mg/kg, P.O.) starting from the first day of VPA injections and continued for 21 days. At the end of the experiment, behavioral tests and histopathological alterations were assessed. In addition, the gene expression of peroxisome proliferator-activated receptor γ (PPAR γ), lactate dehydrogenase A (LDHA), pyruvate dehydrogenase kinase (PDK), cellular myeloctomatosis (c-Myc) with protein expression of glucose transporter-1 (GLUT-1), phosphatase and tensin homolog (PTEN), and level of acetylcholine (ACh) were determined. Treatment with Cana significantly counteracted histopathological changes in the cerebellum tissues of the brain induced by VPA. Cana (5 mg/kg, 7.5 mg/kg, and 10 mg/kg) improved sociability and social preference, enhanced stereotypic behaviors, and decreased hyperlocomotion activity, in addition to its significant effect on the canonical Wnt/β-catenin pathway via the downregulation of gene expression of LDHA (22%, 64%, and 73% in cerebellum tissues with 51%, 60%, and 75% in cerebrum tissues), PDK (27%, 50%, and 67% in cerebellum tissues with 34%, 66%, and 77% in cerebrum tissues), c-Myc (35%, 44%, and 72% in cerebellum tissues with 19%, 58%, and 79% in cerebrum tissues), protein expression of GLUT-1 (32%, 48%, and 49% in cerebellum tissues with 30%, 50%, and 54% in cerebrum tissues), and elevating gene expression of PPAR-γ (2, 3, and 4 folds in cerebellum tissues with 1.5, 3, and 9 folds in cerebrum tissues), protein expression of PTEN (2, 5, and 6 folds in cerebellum tissues with 6, 6, and 10 folds in cerebrum tissues), and increasing the ACh levels (4, 5, and 7 folds) in brain tissues. The current study confirmed the ameliorating effect of Cana against neurochemical and behavioral alterations in the VPA-induced model of autism in rats.
Collapse
Affiliation(s)
- Mariam A Elgamal
- Egypt Healthcare Authority, Comprehensive Health Insurance, Port-Said, Egypt
| | - Dina M Khodeer
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
| | - Basel A Abdel-Wahab
- Department of Pharmacology, College of Pharmacy, Najran University, Najran, Saudi Arabia
| | - Ibrahim Abdel Aziz Ibrahim
- Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Abdullah R Alzahrani
- Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Yasser M Moustafa
- Dean of Faculty of Pharmacy, Badr University in Cairo, Badr City, Egypt.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
| | - Azza A Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
| | - Norhan M El-Sayed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
| |
Collapse
|
|
23
|
Simão JJ, Cruz MM, Abdala FM, Bolsoni-Lopes A, Armelin-Correa L, Alonso-Vale MIC. Palmitoleic Acid Acts on Adipose-Derived Stromal Cells and Promotes Anti-Hypertrophic and Anti-Inflammatory Effects in Obese Mice. Pharmaceuticals (Basel) 2022; 15:1194. [PMID: 36297306 PMCID: PMC9609051 DOI: 10.3390/ph15101194] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/16/2022] [Accepted: 09/19/2022] [Indexed: 04/16/2024] Open
Abstract
Adipose tissue (AT) secretes adipokines, modulators of low-grade chronic inflammation in obesity. Molecules that induce the emergence of new and functional adipocytes in AT can alleviate or prevent inflammatory and metabolic disorders. The objective of this study was to investigate the role of palmitoleic acid (n7) in 3T3-L1 and primary pre-adipocyte differentiation and AT inflammation. C57BL/6j mice were submitted to a control or high-fat diet (HFD) for 8 weeks, and treated with n7 for 4 weeks. Mice consuming a HFD presented an increase in body weight, epididymal (Epi) fat mass, and Epi adipocytes size. N7 treatment attenuated the body weight gain and completely prevented the hypertrophy of Epi adipocytes, but not the increment in Epi mass induced by the HFD, suggesting a greater adipocytes hyperplasia in animals treated with n7. It was agreed that n7 increased 3T3-L1 proliferation and differentiation, as well as the expression of genes involved in adipogenesis, such as Cebpa, Pparg, aP2, Perilipin, and Scl2a4. Furthermore, n7 decreased the inflammatory cytokines Mcp1, Tnfa, Il6, Cxcl10, and Nos2 genes in Epi vascular stromal cells, but not in the whole AT. These findings show that n7 exerts anti-hypertrophic effects in adipocytes which influence the surrounding cells by attenuating the overexpression of pro-inflammatory cytokines triggered by a HFD.
Collapse
Affiliation(s)
- Jussara J. Simão
- Post-Graduate Program in Chemical Biology, Institute of Environmental Sciences, Chemical and Pharmaceutical, Federal University of Sao Paulo, Diadema 09913-030, SP, Brazil
| | - Maysa M. Cruz
- Post-Graduate Program in Chemical Biology, Institute of Environmental Sciences, Chemical and Pharmaceutical, Federal University of Sao Paulo, Diadema 09913-030, SP, Brazil
| | - Fernanda M. Abdala
- Department of Biological Sciences, Institute of Environmental Sciences, Chemical and Pharmaceutical, Federal University of Sao Paulo, Diadema 09913-030, SP, Brazil
| | - Andressa Bolsoni-Lopes
- Department of Nursing, Health Sciences Center, Federal University of Espirito Santo, Vitoria 29075-910, ES, Brazil
| | - Lucia Armelin-Correa
- Post-Graduate Program in Chemical Biology, Institute of Environmental Sciences, Chemical and Pharmaceutical, Federal University of Sao Paulo, Diadema 09913-030, SP, Brazil
- Department of Biological Sciences, Institute of Environmental Sciences, Chemical and Pharmaceutical, Federal University of Sao Paulo, Diadema 09913-030, SP, Brazil
| | - Maria Isabel C. Alonso-Vale
- Post-Graduate Program in Chemical Biology, Institute of Environmental Sciences, Chemical and Pharmaceutical, Federal University of Sao Paulo, Diadema 09913-030, SP, Brazil
- Department of Biological Sciences, Institute of Environmental Sciences, Chemical and Pharmaceutical, Federal University of Sao Paulo, Diadema 09913-030, SP, Brazil
| |
Collapse
|
|
24
|
Zhang M, Gao Y, Li Q, Cao H, Yang J, Cai X, Xiao J. Downregulation of DNA methyltransferase-3a ameliorates the osteogenic differentiation ability of adipose-derived stem cells in diabetic osteoporosis via Wnt/β-catenin signaling pathway. Stem Cell Res Ther 2022; 13:397. [PMID: 35927735 PMCID: PMC9351106 DOI: 10.1186/s13287-022-03088-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 07/23/2022] [Indexed: 02/06/2023] Open
Abstract
Background Diabetes-related osteoporosis (DOP) is a chronic disease caused by the high glucose environment that induces a metabolic disorder of osteocytes and osteoblast-associated mesenchymal stem cells. The processes of bone defect repair and regeneration become extremely difficult with DOP. Adipose-derived stem cells (ASCs), as seed cells in bone tissue engineering technology, provide a promising therapeutic approach for bone regeneration in DOP patients. The osteogenic ability of ASCs is lower in a DOP model than that of control ASCs. DNA methylation, as a mechanism of epigenetic regulation, may be involved in DNA methylation of various genes, thereby participating in biological behaviors of various cells. Emerging evidence suggests that increased DNA methylation levels are associated with activation of Wnt/β-catenin signaling pathway. The purpose of this study was to investigate the influence of the diabetic environment on the osteogenic potential of ASCs, to explore the role of DNA methylation on osteogenic differentiation of DOP-ASCs via Wnt/β-catenin signaling pathway, and to improve the osteogenic differentiation ability of ASCs with DOP. Methods DOP-ASCs and control ASCs were isolated from DOP C57BL/6 and control mice, respectively. The multipotency of DOP-ASCs was confirmed by Alizarin Red-S, Oil Red-O, and Alcian blue staining. Real-time polymerase chain reaction (RT-PCR), immunofluorescence, and western blotting were used to analyze changes in markers of osteogenic differentiation, DNA methylation, and Wnt/β-catenin signaling. Alizarin Red-S staining was also used to confirm changes in the osteogenic ability. DNMT small interfering RNA (siRNA), shRNA-Dnmt3a, and LVRNA-Dnmt3a were used to assess the role of Dnmt3a in osteogenic differentiation of control ASCs and DOP-ASCs. Micro-computed tomography, hematoxylin and eosin staining, and Masson staining were used to analyze changes in the osteogenic capability while downregulating Dnmt3a with lentivirus in DOP mice in vivo. Results The proliferative ability of DOP-ASCs was lower than that of control ASCs. DOP-ASCs showed a decrease in osteogenic differentiation capacity, lower Wnt/β-catenin signaling pathway activity, and a higher level of Dnmt3a than control ASCs. When Dnmt3a was downregulated by siRNA and shRNA, osteogenic-related factors Runt-related transcription factor 2 and osteopontin, and activity of Wnt/β-catenin signaling pathway were increased, which rescued the poor osteogenic potential of DOP-ASCs. When Dnmt3a was upregulated by LVRNA-Dnmt3a, the osteogenic ability was inhibited. The same results were obtained in vivo. Conclusions Dnmt3a silencing rescues the negative effects of DOP on ASCs and provides a possible approach for bone tissue regeneration in patients with diabetic osteoporosis.
Collapse
Affiliation(s)
- Maorui Zhang
- Department of Oral Implantology, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, 646000, China.,State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Yujin Gao
- Department of Oral Implantology, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, 646000, China.,Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Qing Li
- Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Huayue Cao
- Department of Oral Implantology, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Jianghua Yang
- Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Xiaoxiao Cai
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
| | - Jingang Xiao
- Department of Oral Implantology, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, 646000, China. .,Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China. .,Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, 646000, China.
| |
Collapse
|
|
25
|
Fung CW, Zhou S, Zhu H, Wei X, Wu Z, Wu AR. Cell fate determining molecular switches and signaling pathways in Pax7-expressing somitic mesoderm. Cell Discov 2022; 8:61. [PMID: 35764624 PMCID: PMC9240041 DOI: 10.1038/s41421-022-00407-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 03/28/2022] [Indexed: 11/09/2022] Open
Abstract
During development, different cell types originate from a common progenitor at well-defined time points. Previous lineage-tracing of Pax7+ progenitors from the somitic mesoderm has established its developmental trajectory towards the dermis, brown adipocytes, and skeletal muscle in the dorsal trunk; yet the molecular switches and mechanisms guiding the differentiation into different lineages remain unknown. We performed lineage-tracing of Pax7-expressing cells in mouse embryos at E9.5 and profiled the transcriptomes of Pax7-progenies on E12.5, E14.5, and E16.5 at single-cell level. Analysis of single-cell transcriptomic data at multiple time points showed temporal-specific differentiation events toward muscle, dermis, and brown adipocyte, identified marker genes for putative progenitors and revealed transcription factors that could drive lineage-specific differentiation. We then utilized a combination of surface markers identified in the single-cell data, Pdgfra, Thy1, and Cd36, to enrich brown adipocytes, dermal fibroblasts, and progenitors specific for these two cell types at E14.5 and E16.5. These enriched cell populations were then used for further culture and functional assays in vitro, in which Wnt5a and Rgcc are shown to be important factors that could alter lineage decisions during embryogenesis. Notably, we found a bipotent progenitor population at E14.5, having lineage potentials towards both dermal fibroblasts and brown adipocytes. They were termed eFAPs (embryonic fibro/adipogenic progenitors) as they functionally resemble adult fibro/adipogenic progenitors. Overall, this study provides further understanding of the Pax7 lineage during embryonic development using a combination of lineage tracing with temporally sampled single-cell transcriptomics.
Collapse
|
|
26
|
Idelfonso-García OG, Alarcón-Sánchez BR, Vásquez-Garzón VR, Baltiérrez-Hoyos R, Villa-Treviño S, Muriel P, Serrano H, Pérez-Carreón JI, Arellanes-Robledo J. Is Nucleoredoxin a Master Regulator of Cellular Redox Homeostasis? Its Implication in Different Pathologies. Antioxidants (Basel) 2022; 11:antiox11040670. [PMID: 35453355 PMCID: PMC9030443 DOI: 10.3390/antiox11040670] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/26/2022] [Accepted: 03/28/2022] [Indexed: 01/27/2023] Open
Abstract
Nucleoredoxin (NXN), an oxidoreductase enzyme, contributes to cellular redox homeostasis by regulating different signaling pathways in a redox-dependent manner. By interacting with seven proteins so far, namely disheveled (DVL), protein phosphatase 2A (PP2A), phosphofructokinase-1 (PFK1), translocation protein SEC63 homolog (SEC63), myeloid differentiation primary response gene-88 (MYD88), flightless-I (FLII), and calcium/calmodulin-dependent protein kinase II type alpha (CAMK2A), NXN is involved in the regulation of several key cellular processes, including proliferation, organogenesis, cell cycle progression, glycolysis, innate immunity and inflammation, motility, contraction, protein transport into the endoplasmic reticulum, neuronal plasticity, among others; as a result, NXN has been implicated in different pathologies, such as cancer, alcoholic and polycystic liver disease, liver fibrogenesis, obesity, Robinow syndrome, diabetes mellitus, Alzheimer’s disease, and retinitis pigmentosa. Together, this evidence places NXN as a strong candidate to be a master redox regulator of cell physiology and as the hub of different redox-sensitive signaling pathways and associated pathologies. This review summarizes and discusses the current insights on NXN-dependent redox regulation and its implication in different pathologies.
Collapse
Affiliation(s)
- Osiris Germán Idelfonso-García
- Laboratory of Liver Diseases, National Institute of Genomic Medicine–INMEGEN, Mexico City 14610, Mexico; (O.G.I.-G.); (B.R.A.-S.); (J.I.P.-C.)
- Department of Health Sciences, Metropolitan Autonomous University-Iztapalapa Campus, Mexico City 09340, Mexico;
| | - Brisa Rodope Alarcón-Sánchez
- Laboratory of Liver Diseases, National Institute of Genomic Medicine–INMEGEN, Mexico City 14610, Mexico; (O.G.I.-G.); (B.R.A.-S.); (J.I.P.-C.)
- Department of Cell Biology, Center for Research and Advanced Studies of the National Polytechnic Institute–CINVESTAV-IPN, Mexico City 07360, Mexico;
| | - Verónica Rocío Vásquez-Garzón
- Laboratory of Fibrosis and Cancer, Faculty of Medicine and Surgery, ‘Benito Juárez’ Autonomous University of Oaxaca–UABJO, Oaxaca 68020, Mexico; (V.R.V.-G.); (R.B.-H.)
- Directorate of Cátedras, National Council of Science and Technology–CONACYT, Mexico City 03940, Mexico
| | - Rafael Baltiérrez-Hoyos
- Laboratory of Fibrosis and Cancer, Faculty of Medicine and Surgery, ‘Benito Juárez’ Autonomous University of Oaxaca–UABJO, Oaxaca 68020, Mexico; (V.R.V.-G.); (R.B.-H.)
- Directorate of Cátedras, National Council of Science and Technology–CONACYT, Mexico City 03940, Mexico
| | - Saúl Villa-Treviño
- Department of Cell Biology, Center for Research and Advanced Studies of the National Polytechnic Institute–CINVESTAV-IPN, Mexico City 07360, Mexico;
| | - Pablo Muriel
- Laboratory of Experimental Hepatology, Department of Pharmacology, Center for Research and Advanced Studies of the National Polytechnic Institute–CINVESTAV-IPN, Mexico City 07360, Mexico;
| | - Héctor Serrano
- Department of Health Sciences, Metropolitan Autonomous University-Iztapalapa Campus, Mexico City 09340, Mexico;
| | - Julio Isael Pérez-Carreón
- Laboratory of Liver Diseases, National Institute of Genomic Medicine–INMEGEN, Mexico City 14610, Mexico; (O.G.I.-G.); (B.R.A.-S.); (J.I.P.-C.)
| | - Jaime Arellanes-Robledo
- Laboratory of Liver Diseases, National Institute of Genomic Medicine–INMEGEN, Mexico City 14610, Mexico; (O.G.I.-G.); (B.R.A.-S.); (J.I.P.-C.)
- Directorate of Cátedras, National Council of Science and Technology–CONACYT, Mexico City 03940, Mexico
- Correspondence: ; Tel.: +52-55-5350-1900 (ext. 1218)
| |
Collapse
|
|
27
|
Chen H, Peng T, Shang H, Shang X, Zhao X, Qu M, Song X. RNA-Seq Analysis Reveals the Potential Molecular Mechanisms of Puerarin on Intramuscular Fat Deposition in Heat-Stressed Beef Cattle. Front Nutr 2022; 9:817557. [PMID: 35387191 PMCID: PMC8978796 DOI: 10.3389/fnut.2022.817557] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 02/10/2022] [Indexed: 11/13/2022] Open
Abstract
To investigate the effect of Puerarin on intramuscular fat deposition in heat-stressed beef cattle and its underlying mechanism. Thirty-two healthy Jinjiang bulls were randomly divided into four groups and dietary with 0 (Control), 200 (Pue200), 400 (Pue400), and 800 (Pue800) mg/kg Puerarin in the feed concentrate. The results showed that Puerarin treatment enhanced the concentration of crude fat, fatty acid (C14:1 and C17:1), and the activity of fatty acid synthase in Longissimus thoracis (LT), but decreased the levels of blood leptin (P < 0.05). High-throughput sequencing of mRNA technology (RNA-Seq) was used and the analysis showed that 492 genes were down-regulated and 341 genes were up-regulated in LT, and these genes were significantly enriched to the pathways related to lipid metabolism. These results indicated that dietary supplemental with Puerarin enhanced intramuscular fat deposition by regulating lipid metabolism of heat-stressed beef cattle.
Collapse
|
|
28
|
Vallée A. Neuroinflammation in Schizophrenia: The Key Role of the WNT/β-Catenin Pathway. Int J Mol Sci 2022; 23:ijms23052810. [PMID: 35269952 PMCID: PMC8910888 DOI: 10.3390/ijms23052810] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/24/2022] [Accepted: 02/27/2022] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia is a very complex syndrome involving widespread brain multi-dysconnectivity. Schizophrenia is marked by cognitive, behavioral, and emotional dysregulations. Recent studies suggest that inflammation in the central nervous system (CNS) and immune dysfunction could have a role in the pathogenesis of schizophrenia. This hypothesis is supported by immunogenetic evidence, and a higher incidence rate of autoimmune diseases in patients with schizophrenia. The dysregulation of the WNT/β-catenin pathway is associated with the involvement of neuroinflammation in schizophrenia. Several studies have shown that there is a vicious and positive interplay operating between neuroinflammation and oxidative stress. This interplay is modulated by WNT/β-catenin, which interacts with the NF-kB pathway; inflammatory factors (including IL-6, IL-8, TNF-α); factors of oxidative stress such as glutamate; and dopamine. Neuroinflammation is associated with increased levels of PPARγ. In schizophrenia, the expression of PPAR-γ is increased, whereas the WNT/β-catenin pathway and PPARα are downregulated. This suggests that a metabolic-inflammatory imbalance occurs in this disorder. Thus, this research’s triptych could be a novel therapeutic approach to counteract both neuroinflammation and oxidative stress in schizophrenia.
Collapse
Affiliation(s)
- Alexandre Vallée
- Department of Clinical Research and Innovation (DRCI), Foch Hospital, 92150 Suresnes, France
| |
Collapse
|
|
29
|
Shull LC, Lencer ES, Kim HM, Goyama S, Kurokawa M, Costello JC, Jones K, Artinger KB. PRDM paralogs antagonistically balance Wnt/β-catenin activity during craniofacial chondrocyte differentiation. Development 2022; 149:274527. [PMID: 35132438 PMCID: PMC8918787 DOI: 10.1242/dev.200082] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 01/13/2022] [Indexed: 12/20/2022]
Abstract
Cranial neural crest cell (NCC)-derived chondrocyte precursors undergo a dynamic differentiation and maturation process to establish a scaffold for subsequent bone formation, alterations in which contribute to congenital birth defects. Here, we demonstrate that transcription factor and histone methyltransferase proteins Prdm3 and Prdm16 control the differentiation switch of cranial NCCs to craniofacial cartilage. Loss of either paralog results in hypoplastic and disorganized chondrocytes due to impaired cellular orientation and polarity. We show that these proteins regulate cartilage differentiation by controlling the timing of Wnt/β-catenin activity in strikingly different ways: Prdm3 represses whereas Prdm16 activates global gene expression, although both act by regulating Wnt enhanceosome activity and chromatin accessibility. Finally, we show that manipulating Wnt/β-catenin signaling pharmacologically or generating prdm3-/-;prdm16-/- double mutants rescues craniofacial cartilage defects. Our findings reveal upstream regulatory roles for Prdm3 and Prdm16 in cranial NCCs to control Wnt/β-catenin transcriptional activity during chondrocyte differentiation to ensure proper development of the craniofacial skeleton.
Collapse
Affiliation(s)
- Lomeli C. Shull
- Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Ezra S. Lencer
- Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Hyun Min Kim
- Department of Pharmacology and University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Susumu Goyama
- Division of Cellular Therapy, The University of Tokyo, Tokyo, 108-8639, Japan
| | - Mineo Kurokawa
- Department of Hematology and Oncology, The University of Tokyo, Tokyo, 113-8655, Japan
| | - James C. Costello
- Department of Pharmacology and University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Kenneth Jones
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Kristin B. Artinger
- Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA,Author for correspondence ()
| |
Collapse
|
|
30
|
Wang H, Zhang R, Wu X, Chen Y, Ji W, Wang J, Zhang Y, Xia Y, Tang Y, Yuan J. The Wnt Signaling Pathway in Diabetic Nephropathy. Front Cell Dev Biol 2022; 9:701547. [PMID: 35059392 PMCID: PMC8763969 DOI: 10.3389/fcell.2021.701547] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 12/06/2021] [Indexed: 12/17/2022] Open
Abstract
Diabetic nephropathy (DN) is a serious kidney-related complication of both type 1 and type 2 diabetes mellitus (T1DM, T2DM) and the second major cause of end-stage kidney disease. DN can lead to hypertension, edema, and proteinuria. In some cases, DN can even progress to kidney failure, a life-threatening condition. The precise etiology and pathogenesis of DN remain unknown, although multiple factors are believed to be involved. The main pathological manifestations of DN include mesangial expansion, thickening of the glomerular basement membrane, and podocyte injury. Eventually, these pathological manifestations will lead to glomerulosclerosis, thus affecting renal function. There is an urgent need to develop new strategies for the prevention and treatment of DN. Existing evidence shows that the Wnt signaling cascade plays a key role in regulating the development of DN. Previous studies focused on the role of the Wnt canonical signaling pathway in DN. Subsequently, accumulated evidence on the mechanism of the Wnt non-canonical signaling indicated that Wnt/Ca2+ and Wnt/PCP also have essential roles in the progression of DN. In this review, we summarize the specific mechanisms of Wnt signaling in the occurrence and development of DN in podocyte injury, mesangial cell injury, and renal fibrosis. Also, to elucidate the significance of the Wnt canonical pathway in the process of DN, we uncovered evidence supporting that both Wnt/PCP and Wnt/Ca2+ signaling are critical for DN development.
Collapse
Affiliation(s)
- Haiying Wang
- Department of Physiology, Jining Medical University, Jining, China
| | - Ran Zhang
- Basic Medical School, Jining Medical University, Jining, China
| | - Xinjie Wu
- Basic Medical School, Jining Medical University, Jining, China
| | - Yafen Chen
- Basic Medical School, Jining Medical University, Jining, China
| | - Wei Ji
- Basic Medical School, Jining Medical University, Jining, China
| | - Jingsuo Wang
- Basic Medical School, Jining Medical University, Jining, China
| | - Yawen Zhang
- Basic Medical School, Jining Medical University, Jining, China
| | - Yong Xia
- Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of Precision Medicine, Jining Medical University, Jining, China
| | - Yiqun Tang
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jinxiang Yuan
- Collaborative Innovation Center, Jining Medical University, Jining, China
| |
Collapse
|
|
31
|
Yang Y, Xu Y, Zhao C, Zhang L, Nuerbol A, Wang L, Jiao Y. Pronounced Enhancement in Radiosensitization of Esophagus Cancer Cultivated in Docosahexaenoic Acid via the PPAR -γ Activation. Front Med (Lausanne) 2022; 9:922228. [PMID: 37153924 PMCID: PMC10155814 DOI: 10.3389/fmed.2022.922228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 06/22/2022] [Indexed: 05/10/2023] Open
Abstract
Docosahexaenoic acid (DHA) has been reported to suppress the tumor growth and improve prognosis and has been used to cooperate with many other chemotherapy medicines. Up to now, surveys focused on the Interaction between DHA and radiation are relatively modest. Our study sought to evaluate the radiosensitivity changes caused by DHA on esophageal cancer cells. We selected TE-1 and TE-10 esophagus cancer cells as models and performed routine cell proliferation assay and cloning assay to detect the impact of DHA combined with X-ray. We used cell cycle assay, lipid peroxidation assay, comet assay, and apoptosis assay to unearth the potential causes. We also launched a mouse transplanted tumor experiment to verify the synergetic effect of DHA and irradiation. Finally, a western blot assay was used to find a novel mechanism. As a result, DHA improved TE-1 and TE-10 radiosensitivity in vivo and in vitro. What's more, PPAR-γ expression increased due to the DHA supplement. Inhibiting PPAR-γ could attenuate benefits brought out by DHA somehow. Due to its explicit usage and convenience, DHA would serve as an adjuvant therapy before radiotherapy if the clinical trials indicated positive.
Collapse
Affiliation(s)
- Ying Yang
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Ying Xu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Congzhao Zhao
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Lirong Zhang
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Aslibek Nuerbol
- Department of Ultrasound Diagnosis, Gaochun Peoples' Hospital, Affiliated Hospital of Nanjing Drum Tower Hospital, Nanjing, China
| | - Lili Wang
- Department of Radiotherapy, Second Hospital of Soochow University, Suzhou, China
| | - Yang Jiao
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, China
- *Correspondence: Yang Jiao
| |
Collapse
|
|
32
|
Geraniol protects against cyclosporine A-induced renal injury in rats: Role of Wnt/β-catenin and PPARγ signaling pathways. Life Sci 2021; 291:120259. [PMID: 34968469 DOI: 10.1016/j.lfs.2021.120259] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 12/09/2021] [Accepted: 12/17/2021] [Indexed: 11/24/2022]
Abstract
AIMS The nephrotoxicity of cyclosporine A (CsA) limits its use as an immunosuppressant. Wnt/β-catenin signaling is involved in the pathogenesis of both acute and chronic kidney disease, and it is inhibited by peroxisome proliferator-activated receptor gamma (PPARγ). We aimed to evaluate if geraniol, which can modulate both PPARγ and Wnt signaling, could protect against CsA-induced nephrotoxicity. MATERIALS AND METHODS Rats (6 groups) received the vehicle or a combination of CsA (30 mg/kg) with the vehicle, geraniol (50, 100, or 200 mg/kg), or the PPARγ agonist pioglitazone for 4 weeks. Blood pressure (BP), markers of renal injury (serum urea, serum creatinine, blood urea nitrogen, and urinary NAG), oxidative stress (glutathione peroxidase), inflammation (ICAM-1, IL-18, and NF-κB), apoptosis (caspase-3), extracellular matrix remodeling [matrix metalloproteinase-9 (MMP-9)], and fibrosis (TGF-β1, Smad3, and Smad7) were assessed. Renal histological analysis, Wnt signaling components (Wnt-4/β-catenin and E-cadherin), and PPARγ expression were evaluated. KEY FINDINGS CsA group had renal injury, as well as increased BP, renal oxidative stress, inflammation, and fibrosis. The latter changes were associated with altered renal architecture, active Wnt signaling (higher Wnt-4 and β-catenin expression and E-cadherin down-regulation), and lower PPARγ levels. Geraniol protected against kidney damage and the associated biochemical and histomorphological changes in a dose-dependent manner. The latter effects were comparable or superior to those of pioglitazone. SIGNIFICANCE The down-regulation of Wnt/β-catenin and the increase in PPARγ by geraniol suggest that both pathways are involved in its renoprotective potential. The study highlights geraniol as a valuable protective asset against chemically induced nephrotoxicity.
Collapse
|
|
33
|
Das B, Das M, Kalita A, Baro MR. The role of Wnt pathway in obesity induced inflammation and diabetes: a review. J Diabetes Metab Disord 2021; 20:1871-1882. [PMID: 34900830 PMCID: PMC8630176 DOI: 10.1007/s40200-021-00862-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 07/17/2021] [Indexed: 02/06/2023]
Abstract
Diabetes has become a major killer worldwide and at present, millions are affected by it. Being a chronic disease it increases the risk of other diseases ranging from pulmonary disorders to soft tissue infections. The loss of insulin-producing capacity of the pancreatic β-cells is the main reason for the development of the disease. Obesity is a major complication that can give rise to several other diseases such as cancer, diabetes, etc. Visceral adiposity is one of the major factors that play a role in the development of insulin resistance. Obesity causes a chronic low-grade inflammation in the tissues that further increases the chances of developing diabetes. Several pathways have been associated with the development of diabetes due to inflammation caused by obesity. The Wnt pathway is one such candidate pathway that is found to have a controlling effect on the development of insulin resistance. Moreover, the pathway has also been linked to obesity and inflammation. This review aims to find a connection between obesity, inflammation, and diabetes by taking the wnt pathway as the connecting link.
Collapse
Affiliation(s)
- Bhabajyoti Das
- Department of Zoology, Animal Physiology and Biochemistry Laboratory, Gauhati University, Guwahati, 781014 Assam India
| | - Manas Das
- Department of Zoology, Animal Physiology and Biochemistry Laboratory, Gauhati University, Guwahati, 781014 Assam India
| | - Anuradha Kalita
- Department of Zoology, Animal Physiology and Biochemistry Laboratory, Gauhati University, Guwahati, 781014 Assam India
| | - Momita Rani Baro
- Department of Zoology, Animal Physiology and Biochemistry Laboratory, Gauhati University, Guwahati, 781014 Assam India
| |
Collapse
|
|
34
|
Li J, Lu L, Liu Y, Yu X. Bone marrow adiposity during pathologic bone loss: molecular mechanisms underlying the cellular events. J Mol Med (Berl) 2021; 100:167-183. [PMID: 34751809 DOI: 10.1007/s00109-021-02164-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 10/09/2021] [Accepted: 11/03/2021] [Indexed: 02/05/2023]
Abstract
Bone marrow (BM) is a heterogeneous niche where bone marrow stromal cells (BMSCs), osteoblasts, osteoclasts, adipocytes, hematopoietic cells, and immune cells coexist. The cellular composition of BM changes with various pathophysiological states. A reduction in osteoblast number and a concomitant increase in adipocyte number in aging and pathological conditions put bone marrow adipose tissue (BMAT) into spotlight. Accumulating evidence strongly supports that an overwhelming production of BMAT is a major contributor to bone loss disorders. Therefore, BMAT-targeted therapy can be an efficient and feasible intervention for osteoporosis. However, compared to blocking bone-destroying molecules produced by BMAT, suppressing BMAT formation is theoretically a more effective and fundamental approach in treating osteoporotic bone diseases. Thus, a deep insight into the molecular basis underlying increased BM adiposity during pathologic bone loss is critical to formulate strategies for therapeutically manipulating BMAT. In this review, we comprehensively summarize the molecular mechanisms involved in adipocyte differentiation of BMSCs as well as the interaction between bone marrow adipocytes and osteoclasts. More importantly, we further discuss the potential clinical implications of therapeutically targeting the upstream of BMAT formation in bone loss diseases.
Collapse
Affiliation(s)
- Jiao Li
- Department of Endocrinology and Metabolism, Laboratory of Endocrinology and Metabolism, Rare Disease Center, West China Hospital, Sichuan University, No.37 Guoxue Alley, Wuhou District, Chengdu, 610041, Sichuan Province, China
| | - Lingyun Lu
- Department of Endocrinology and Metabolism, Laboratory of Endocrinology and Metabolism, Rare Disease Center, West China Hospital, Sichuan University, No.37 Guoxue Alley, Wuhou District, Chengdu, 610041, Sichuan Province, China
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yi Liu
- Department of Rheumatology and Immunology, Rare Disease Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xijie Yu
- Department of Endocrinology and Metabolism, Laboratory of Endocrinology and Metabolism, Rare Disease Center, West China Hospital, Sichuan University, No.37 Guoxue Alley, Wuhou District, Chengdu, 610041, Sichuan Province, China
| |
Collapse
|
|
35
|
Steinman JB, Salomao MA, Pajvani UB. Zonation in NASH - A key paradigm for understanding pathophysiology and clinical outcomes. Liver Int 2021; 41:2534-2546. [PMID: 34328687 DOI: 10.1111/liv.15025] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 07/23/2021] [Accepted: 07/26/2021] [Indexed: 12/11/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) exists as a spectrum ranging from simple steatosis to histologically defined hepatocyte injury and inflammatory changes that define steatohepatitis (NASH), and increase risk for fibrosis. Although zonal differences in NASH have not been systematically studied, periportal involvement has been associated with worse metabolic outcomes and more hepatic fibrosis as compared to pericentral disease. These data suggest that hepatic zonation of disease may influence the diversity of clinical presentations. Similarly, several randomized clinical trials suggest a differential response based on zonation of disease, with preferential effects on periportal (cysteamine) or pericentral disease (obeticholic acid, pioglitazone). Intriguingly, morphogenic pathways known to affect zonal development and maintenance - WNT/β-Catenin, Hedgehog, HIPPO/Yap/TAZ and Notch - have been implicated in NASH pathogenesis, and nuclear hormone receptors downstream of potential NASH therapeutics show zonal preferences. In this review, we summarize these data and propose that patient-specific activation of these pathways may explain the variability in clinical presentation, and the zone-specific response observed in clinical trials.
Collapse
Affiliation(s)
| | - Marcela A Salomao
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, USA
| | - Utpal B Pajvani
- Department of Medicine, Columbia University, New York, NY, USA
| |
Collapse
|
|
36
|
Luo Y, Ji H, Cao Y, Ding X, Li M, Song H, Li S, WaTableng C, Wu H, Meng J, Du H. miR-26b-5p/TCF-4 Controls the Adipogenic Differentiation of Human Adipose-derived Mesenchymal Stem Cells. Cell Transplant 2021; 29:963689720934418. [PMID: 32579400 PMCID: PMC7563810 DOI: 10.1177/0963689720934418] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
In this study, we assessed the ability of miR-26b-5p to regulate T cell factor 4 (TCF-4) expression and thereby control human adipose-derived mesenchymal stem cell (hADMSC) adipogenic differentiation. Adipogenic medium was used to induce hADMSC differentiation over a 6-d period. The ability of miR-26b-5p to interact with the TCF-4 mRNA was confirmed through both predictive bioinformatics analyses and luciferase reporter assays. Immunofluorescent staining was used to visualize the impact of miR-26b-5p inhibition or overexpression on TCF-4 and β-catenin levels in hADMSCs. Further functional analyses were conducted by transfecting these cells with siRNAs specific for TCF-4 and β-catenin. Adipogenic marker and Wnt/β-catenin pathway gene expression levels were assessed via real-time polymerase chain reaction and western blotting. β-catenin localization was assessed via immunofluorescent staining. As expected, our adipogenic media induced the adipocytic differentiation of hADMSCs. In addition, we confirmed that TCF-4 is an miR-26b-5p target gene in these cells, and that protein levels of both TCF-4 and β-catenin were reduced when these cells were transfected with miR-26b-5p mimics. Overexpression of this microRNA also enhanced hADMSC adipogenesis, whereas TCF-4 and β-catenin overexpression inhibited this process. The enhanced hADMSC adipogenic differentiation that was observed following TCF-4 or β-catenin knockdown was partially reversed when miR-26b-5p expression was inhibited. We found that miR-26b-5p serves as a direct negative regulator of TCF-4 expression within hADMSCs, leading to inactivation of the Wnt/β-catenin pathway and thereby promoting the adipogenic differentiation of these cells in vitro.
Collapse
Affiliation(s)
- Yadong Luo
- Department of Stomatology, Central Hospital of Xuzhou, the Xuzhou Clinical College of Xuzhou Medical University, Xuzhou, Jiangsu Province, PR China.,These authors contributed equally to this article
| | - Huan Ji
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.,Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, Jiangsu Province, PR China.,These authors contributed equally to this article
| | - Yan Cao
- Nanjing Maternity and Child Health Care Institute, Women's Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.,These authors contributed equally to this article
| | - Xu Ding
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.,Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, Jiangsu Province, PR China
| | - Meng Li
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.,Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, Jiangsu Province, PR China
| | - Haiyang Song
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.,Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, Jiangsu Province, PR China
| | - Sheng Li
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.,Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, Jiangsu Province, PR China
| | - Chenxing WaTableng
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.,Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, Jiangsu Province, PR China
| | - Heming Wu
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.,Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, Jiangsu Province, PR China
| | - Jian Meng
- Department of Stomatology, Central Hospital of Xuzhou, the Xuzhou Clinical College of Xuzhou Medical University, Xuzhou, Jiangsu Province, PR China.,Both authors are co-corresponding authors
| | - Hongming Du
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.,Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, Jiangsu Province, PR China.,Both authors are co-corresponding authors
| |
Collapse
|
|
37
|
Cataldi S, Costa V, Ciccodicola A, Aprile M. PPARγ and Diabetes: Beyond the Genome and Towards Personalized Medicine. Curr Diab Rep 2021; 21:18. [PMID: 33866450 DOI: 10.1007/s11892-021-01385-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/25/2021] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW Full and partial synthetic agonists targeting the transcription factor PPARγ are contained in FDA-approved insulin-sensitizing drugs and used for the treatment of metabolic syndrome-related dysfunctions. Here, we discuss the association between PPARG genetic variants and drug efficacy, as well as the role of alternative splicing and post-translational modifications as contributors to the complexity of PPARγ signaling and to the effects of synthetic PPARγ ligands. RECENT FINDINGS PPARγ regulates the transcription of several target genes governing adipocyte differentiation and glucose and lipid metabolism, as well as insulin sensitivity and inflammatory pathways. These pleiotropic functions confer great relevance to PPARγ in physiological regulation of whole-body metabolism, as well as in the etiology of metabolic disorders. Accordingly, PPARG gene mutations, nucleotide variations, and post-translational modifications have been associated with adipose tissue disorders and the related risk of insulin resistance and type 2 diabetes (T2D). Moreover, PPARγ alternative splicing isoforms-generating dominant-negative isoforms mainly expressed in human adipose tissue-have been related to impaired PPARγ activity and adipose tissue dysfunctions. Thus, multiple regulatory levels that contribute to PPARγ signaling complexity may account for the beneficial as well as adverse effects of PPARγ agonists. Further targeted analyses, taking into account all these aspects, are needed for better deciphering the role of PPARγ in human pathophysiology, especially in insulin resistance and T2D. The therapeutic potential of full and partial PPARγ synthetic agonists underlines the clinical significance of this nuclear receptor. PPARG mutations, polymorphisms, alternative splicing isoforms, and post-translational modifications may contribute to the pathogenesis of metabolic disorders, also influencing the responsiveness of pharmacological therapy. Therefore, in the context of the current evidence-based trend to personalized diabetes management, we highlight the need to decipher the intricate regulation of PPARγ signaling to pave the way to tailored therapies in patients with insulin resistance and T2D.
Collapse
Affiliation(s)
- Simona Cataldi
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", CNR, Via P. Castellino 111, 80131, Naples, Italy
| | - Valerio Costa
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", CNR, Via P. Castellino 111, 80131, Naples, Italy
| | - Alfredo Ciccodicola
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", CNR, Via P. Castellino 111, 80131, Naples, Italy.
- Department of Science and Technology, University of Naples "Parthenope", 80131, Naples, Italy.
| | - Marianna Aprile
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", CNR, Via P. Castellino 111, 80131, Naples, Italy
| |
Collapse
|
|
38
|
Vallée A, Lecarpentier Y, Vallée JN. Interplay of Opposing Effects of the WNT/β-Catenin Pathway and PPARγ and Implications for SARS-CoV2 Treatment. Front Immunol 2021; 12:666693. [PMID: 33927728 PMCID: PMC8076593 DOI: 10.3389/fimmu.2021.666693] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 03/26/2021] [Indexed: 02/06/2023] Open
Abstract
The Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), has quickly reached pandemic proportions. Cytokine profiles observed in COVID-19 patients have revealed increased levels of IL-1β, IL-2, IL-6, and TNF-α and increased NF-κB pathway activity. Recent evidence has shown that the upregulation of the WNT/β-catenin pathway is associated with inflammation, resulting in a cytokine storm in ARDS (acute respire distress syndrome) and especially in COVID-19 patients. Several studies have shown that the WNT/β-catenin pathway interacts with PPARγ in an opposing interplay in numerous diseases. Furthermore, recent studies have highlighted the interesting role of PPARγ agonists as modulators of inflammatory and immunomodulatory drugs through the targeting of the cytokine storm in COVID-19 patients. SARS-CoV2 infection presents a decrease in the angiotensin-converting enzyme 2 (ACE2) associated with the upregulation of the WNT/β-catenin pathway. SARS-Cov2 may invade human organs besides the lungs through the expression of ACE2. Evidence has highlighted the fact that PPARγ agonists can increase ACE2 expression, suggesting a possible role for PPARγ agonists in the treatment of COVID-19. This review therefore focuses on the opposing interplay between the canonical WNT/β-catenin pathway and PPARγ in SARS-CoV2 infection and the potential beneficial role of PPARγ agonists in this context.
Collapse
Affiliation(s)
- Alexandre Vallée
- Department of Clinical Research and Innovation, Foch Hospital, Suresnes, France
| | - Yves Lecarpentier
- Centre de Recherche Clinique, Grand Hôpital de l'Est Francilien (GHEF), Meaux, France
| | - Jean-Noël Vallée
- University Hospital Center (CHU) Amiens Picardie, University of Picardie Jules Verne (UPJV), Amiens, France.,Laboratory of Mathematics and Applications (LMA), Unité Mixte de Recherche (UMR) Centre National de la Recherche Scientifique (CNRS) 7348, University of Poitiers, Poitiers, France
| |
Collapse
|
|
39
|
He HP, Gu S. The PPAR-γ/SFRP5/Wnt/β-catenin signal axis regulates the dexamethasone-induced osteoporosis. Cytokine 2021; 143:155488. [PMID: 33814272 DOI: 10.1016/j.cyto.2021.155488] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 02/20/2021] [Accepted: 02/22/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND The inhibition of glucocorticoid (GC) on osteoblastic differentiation of bone marrow stromal stem cells (BMSC) is an important pathway for GC to reduce bone formation. Recent studies implicated an important role of peroxisome proliferator-activated receptor-gamma (PPAR-γ) in GC-mediated cell proliferation and differentiation. Thus, our purpose is to investigate the role of PPAR-γ in regulating rat BMSC (rBMSC) osteoblastic differentiation. METHODS The rBMSC treated with dexamethasone (Dex) was used to construct an in vitro cell model of GC-induced osteoporosis. The expressions of PPAR-γ, RUNX2, ALP, OPN and SFRP5 in cells were detected by RT-qPCR and western blot assays. Osteogenic differentiation of rBMSC was measured by Alizarin Red S (ARS) staining analysis. Lentivirus-delivered shRNA was used to knock down PPAR-γ or SFRP5, and lentivirus-delivered constructs were used to overexpress SFRP5 in rBMSC to verify the effect of PPAR-γ or SFRP5 on cell osteogenic differentiation. RESULTS Dex significantly reduced rBMSC osteoblastic differentiation. The expression of PPAR-γ was enhanced in Dex treated rBMSC. PPAR-γ down-regulation improved Dex inhibition of rBMSC osteogenic differentiation. Moreover, PPAR-γ knockdown promoted protein levels of RUNX2, ALP, OPN and Dex-decreased rBMSC osteogenic differentiation. The expression of SFRP5 was reduced while Wnt and β-catenin were increased in PPAR-γ knockdown and Dex treated rBMSC. Moreover, the up-regulation of SFRP5 reversed the osteogenic differentiation of rBMSC induced by PPAR-γ knockdown. CONCLUSION These data indicated that in GC-induced osteoporosis, PPAR-γ/SFRP5 affects osteogenic differentiation by regulating the Wnt/β-catenin signaling pathway.
Collapse
Affiliation(s)
- Hai-Peng He
- Shenzhen Institute of ENT & Longgang ENT Hospital, Shenzhen 518172, China
| | - Shan Gu
- Shenzhen Institute of ENT & Longgang ENT Hospital, Shenzhen 518172, China.
| |
Collapse
|
|
40
|
Goel D, Vohora D. Liver X receptors and skeleton: Current state-of-knowledge. Bone 2021; 144:115807. [PMID: 33333244 DOI: 10.1016/j.bone.2020.115807] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 11/26/2020] [Accepted: 12/11/2020] [Indexed: 12/25/2022]
Abstract
The liver X receptors (LXR) is a nuclear receptor that acts as a prominent regulator of lipid homeostasis and inflammatory response. Its therapeutic effectiveness against various diseases like Alzheimer's disease and atherosclerosis has been investigated in detail. Emerging pieces of evidence now reveal that LXR is also a crucial modulator of bone remodeling. However, the molecular mechanisms underlying the pharmacological actions of LXR on the skeleton and its role in osteoporosis are poorly understood. Therefore, in the current review, we highlight LXR and its actions through different molecular pathways modulating skeletal homeostasis. The studies described in this review propound that LXR in association with estrogen, PTH, PPARγ, RXR hedgehog, and canonical Wnt signaling regulates osteoclastogenesis and bone resorption. It regulates RANKL-induced expression of c-Fos, NFATc1, and NF-κB involved in osteoclast differentiation. Additionally, several studies suggest suppression of RANKL-induced osteoclast differentiation by synthetic LXR ligands. Given the significance of modulation of LXR in various physiological and pathological settings, our findings indicate that therapeutic targeting of LXR might potentially prevent or treat osteoporosis and improve bone quality.
Collapse
Affiliation(s)
- Divya Goel
- Department of Pharmacology, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi 110062, India
| | - Divya Vohora
- Department of Pharmacology, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi 110062, India.
| |
Collapse
|
|
41
|
Epo receptor signaling in macrophages alters the splenic niche to promote erythroid differentiation. Blood 2021; 136:235-246. [PMID: 32350523 DOI: 10.1182/blood.2019003480] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 04/04/2020] [Indexed: 12/27/2022] Open
Abstract
Anemic stress induces stress erythropoiesis, which rapidly generates new erythrocytes to restore tissue oxygenation. Stress erythropoiesis is best understood in mice where it is extramedullary and occurs primarily in the spleen. However, both human and mouse stress erythropoiesis use signals and progenitor cells that are distinct from steady-state erythropoiesis. Immature stress erythroid progenitors (SEPs) are derived from short-term hematopoietic stem cells. Although the SEPs are capable of self-renewal, they are erythroid restricted. Inflammation and anemic stress induce the rapid proliferation of SEPs, but they do not differentiate until serum erythropoietin (Epo) levels increase. Here we show that rather than directly regulating SEPs, Epo promotes this transition from proliferation to differentiation by acting on macrophages in the splenic niche. During the proliferative stage, macrophages produce canonical Wnt ligands that promote proliferation and inhibit differentiation. Epo/Stat5-dependent signaling induces the production of bioactive lipid mediators in macrophages. Increased production of prostaglandin J2 (PGJ2) activates peroxisome proliferator-activated receptor γ (PPARγ)-dependent repression of Wnt expression, whereas increased production of prostaglandin E2 (PGE2) promotes the differentiation of SEPs.
Collapse
|
|
42
|
Zuo Q, He J, Zhang S, Wang H, Jin G, Jin H, Cheng Z, Tao X, Yu C, Li B, Yang C, Wang S, Lv Y, Zhao F, Yao M, Cong W, Wang C, Qin W. PPARγ Coactivator-1α Suppresses Metastasis of Hepatocellular Carcinoma by Inhibiting Warburg Effect by PPARγ-Dependent WNT/β-Catenin/Pyruvate Dehydrogenase Kinase Isozyme 1 Axis. Hepatology 2021; 73:644-660. [PMID: 32298475 DOI: 10.1002/hep.31280] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 01/23/2020] [Accepted: 04/03/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator-1α (PGC1α) is a key regulator of mitochondrial biogenesis and respiration. PGC1α is involved in the carcinogenesis, progression, and metabolic state of cancer. However, its role in the progression of hepatocellular carcinoma (HCC) remains unclear. APPROACH AND RESULTS In this study, we observed that PGC1α was down-regulated in human HCC. A clinical study showed that low levels of PGC1α expression were correlated with poor survival, vascular invasion, and larger tumor size. PGC1α inhibited the migration and invasion of HCC cells with both in vitro experiments and in vivo mouse models. Mechanistically, PGC1α suppressed the Warburg effect through down-regulation of pyruvate dehydrogenase kinase isozyme 1 (PDK1) mediated by the WNT/β-catenin pathway, and inhibition of the WNT/β-catenin pathway was induced by activation of PPARγ. CONCLUSIONS Low levels of PGC1α expression indicate a poor prognosis for HCC patients. PGC1α suppresses HCC metastasis by inhibiting aerobic glycolysis through regulating the WNT/β-catenin/PDK1 axis, which depends on PPARγ. PGC1α is a potential factor for predicting prognosis and a therapeutic target for HCC patients.
Collapse
Affiliation(s)
- Qiaozhu Zuo
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Jia He
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Shu Zhang
- Liver Cancer InstituteZhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education)Fudan UniversityShanghaiChina
| | - Hui Wang
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Guangzhi Jin
- Department of PathologyEastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghaiChina
| | - Haojie Jin
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Zhuoan Cheng
- Shanghai Jiao Tong University School of Biomedical EngineeringShanghaiChina
| | - Xuemei Tao
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Chengtao Yu
- Shanghai Jiao Tong University School of Biomedical EngineeringShanghaiChina
| | - Botai Li
- Shanghai Jiao Tong University School of Biomedical EngineeringShanghaiChina
| | - Chen Yang
- Shanghai Medical College of Fudan UniversityShanghaiChina
| | - Siying Wang
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yuanyuan Lv
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Fangyu Zhao
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Ming Yao
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Wenming Cong
- Department of PathologyEastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghaiChina
| | - Cun Wang
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Wenxin Qin
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| |
Collapse
|
|
43
|
LINC complex regulation of genome organization and function. Curr Opin Genet Dev 2021; 67:130-141. [PMID: 33524904 DOI: 10.1016/j.gde.2020.12.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 11/25/2020] [Accepted: 12/11/2020] [Indexed: 12/28/2022]
Abstract
The regulation of genomic function is in part mediated through the physical organization and architecture of the nucleus. Disruption to nuclear organization and architecture is increasingly being recognized by its contribution to many diseases. The LINC complexes - protein structures traversing the nuclear envelope, that physically connect the nuclear interior, and hence the genome, to cytoplasmic cytoskeletal networks are an important component in the physical organization of the genome and its function. This connection, potentially allows for the constant detection of environmental mechanical stimuli, resulting in altered regulation of nuclear architecture and genome function, either directly or via the process of mechanotransduction. Here, we review the influences LINC complexes exert on genome functions and their impact on cellular/organismal health.
Collapse
|
|
44
|
Gomart A, Vallée A, Lecarpentier Y. Necrotizing Enterocolitis: LPS/TLR4-Induced Crosstalk Between Canonical TGF-β/Wnt/β-Catenin Pathways and PPARγ. Front Pediatr 2021; 9:713344. [PMID: 34712628 PMCID: PMC8547806 DOI: 10.3389/fped.2021.713344] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 09/13/2021] [Indexed: 12/13/2022] Open
Abstract
Necrotizing enterocolitis (NEC) represents one of the major causes of morbidity and mortality in premature infants. Several recent studies, however, have contributed to a better understanding of the pathophysiology of this dreadful disease. Numerous intracellular pathways play a key role in NEC, namely: bacterial lipopolysaccharide (LPS), LPS toll-like receptor 4 (TLR4), canonical Wnt/β-catenin signaling and PPARγ. In a large number of pathologies, canonical Wnt/β-catenin signaling and PPARγ operate in opposition to one another, so that when one of the two pathways is overexpressed the other is downregulated and vice-versa. In NEC, activation of TLR4 by LPS leads to downregulation of the canonical Wnt/β-catenin signaling and upregulation of PPARγ. This review aims to shed light on the complex intracellular mechanisms involved in this pathophysiological profile by examining additional pathways such as the GSK-3β, NF-κB, TGF-β/Smads, and PI3K-Akt pathways.
Collapse
Affiliation(s)
- Alexia Gomart
- Département de Pédiatrie et Médecine de l'adolescent, Centre Hospitalier Intercommunal de Créteil, Créteil, France
| | - Alexandre Vallée
- Department of Clinical Research and Innovation, Foch Hospital, Suresnes, France
| | - Yves Lecarpentier
- Centre de Recherche Clinique, Grand Hôpital de l'Est Francilien, Meaux, France
| |
Collapse
|
|
45
|
Gomes PS, Resende M, Fernandes MH. Doxycycline restores the impaired osteogenic commitment of diabetic-derived bone marrow mesenchymal stromal cells by increasing the canonical WNT signaling. Mol Cell Endocrinol 2020; 518:110975. [PMID: 32758627 DOI: 10.1016/j.mce.2020.110975] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/21/2020] [Accepted: 07/31/2020] [Indexed: 01/09/2023]
Abstract
Diabetes mellitus comprehends a group of chronic metabolic disorders, associated with damage and dysfunction of distinct tissues, including bone. At the cellular level, an impaired osteoblastogenesis has been reported, affecting the viability, proliferation and functionality of osteoblasts and precursor populations, hampering the bone metabolic activity, remodeling and healing. Tetracyclines embrace a group of broad-spectrum antibacterial compounds with potential anabolic effects on the bone tissue, through antibacterial-independent mechanisms. Accordingly, this study aims to address the modulatory capability and associated molecular signaling of a low dosage doxycycline - a semi-synthetic tetracycline, in the functional activity of osteoblastic progenitor cells (bone marrow-derived mesenchymal stromal cells), established from a translational diabetic experimental model. Bone marrow-derived mesenchymal stromal cells were isolated from streptozotocin-induced diabetic Wistar rat with proven osteopenia. Cultures were characterized, in the presence of doxycycline (1 μg ml-1) for proliferation, metabolic activity, apoptosis, collagen synthesis and relevant gene expression with the osteogenic and adipogenic program. The activation of the Wnt/β-catenin pathway was further detailed. Doxycycline normalized the viability, proliferation and metabolic activity of the established cultures, further decreasing cell apoptosis, to levels similar to control. The addition of this drug to the culture environment further increased the osteogenic activation, upregulating the expression of osteogenic markers and collagen synthesis, at the same time that a decreased adipogenic priming was attained. These processes were found to me mediated, at least in part, by the restoration of the signaling through the Wnt/β-catenin pathway.
Collapse
Affiliation(s)
- Pedro Sousa Gomes
- BoneLab - Laboratory for Bone Metabolism and Regeneration, Faculty of Dental Medicine, U. Porto, R. Dr. Manuel Pereira da Silva, 4200-393, Porto, Portugal; LAQV/REQUIMTE, U. Porto, Porto, 4160-007, Portugal.
| | - Marta Resende
- Faculty of Dental Medicine, U. Porto, R. Dr. Manuel Pereira da Silva, 4200-393, Porto, Portugal
| | - Maria Helena Fernandes
- BoneLab - Laboratory for Bone Metabolism and Regeneration, Faculty of Dental Medicine, U. Porto, R. Dr. Manuel Pereira da Silva, 4200-393, Porto, Portugal; LAQV/REQUIMTE, U. Porto, Porto, 4160-007, Portugal
| |
Collapse
|
|
46
|
Ahluwalia A, Hoa N, Ge L, Blumberg B, Levin ER. Mechanisms by Which Membrane and Nuclear ER Alpha Inhibit Adipogenesis in Cells Isolated From Female Mice. Endocrinology 2020; 161:5911730. [PMID: 32976570 DOI: 10.1210/endocr/bqaa175] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 09/23/2020] [Indexed: 12/21/2022]
Abstract
Mesenchymal stem cells can differentiate into mature chondrocytes, osteoblasts, and adipocytes. Excessive and dysfunctional visceral adipocytes increase upon menopause and importantly contribute to altered metabolism in postmenopausal women. We previously showed both plasma membrane and nuclear estrogen receptors alpha (ERα) with endogenous estrogen are required to suppress adipogenesis in vivo. Here we determined mechanisms by which these liganded ER pools collaborate to inhibit the peroxisome proliferator-activated gamma (PPARγ) gene and subsequent progenitor differentiation. In 3T3-L1 pre-adipocytes and adipose-derived stem cells (ADSC), membrane ERα signaled through phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) to enhance ERα nuclear localization, importantly at the PPARγ gene promoter. AKT also increased overall abundance and recruitment of co-repressors GATA3, β-catenin, and TCF4 to the PPARγ promoter. Membrane ERα signaling additionally enhanced wingless-integrated (Wnt)1 and 10b expression. The components of the repressor complex were required for estrogen to inhibit rosiglitazone-induced differentiation of ADSC and 3T3-L1 cells to mature adipocytes. These mechanisms whereby ER cellular pools collaborate to inhibit gene expression limit progenitor differentiation to mature adipocytes.
Collapse
Affiliation(s)
- Amrita Ahluwalia
- Division of Endocrinology, Department of Veterans Affairs Medical Center, Long Beach, Long Beach, California, USA
| | - Neil Hoa
- Division of Endocrinology, Department of Veterans Affairs Medical Center, Long Beach, Long Beach, California, USA
| | - Lisheng Ge
- Division of Endocrinology, Department of Veterans Affairs Medical Center, Long Beach, Long Beach, California, USA
| | - Bruce Blumberg
- Department of Developmental Biology, University of California, Irvine, Irvine, California, USA
- Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, California, USA
| | - Ellis R Levin
- Division of Endocrinology, Department of Veterans Affairs Medical Center, Long Beach, Long Beach, California, USA
- Department of Medicine, University of California, Irvine, Irvine, California, USA
- Department of Biochemistry, University of California, Irvine, Irvine, California, USA
| |
Collapse
|
|
47
|
Enhancing insulin sensitivity by dual PPARγ partial agonist, β-catenin inhibitor: Design, synthesis of new αphthalimido-o-toluoyl2-aminothiazole hybrids. Life Sci 2020; 259:118270. [PMID: 32814067 DOI: 10.1016/j.lfs.2020.118270] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/28/2020] [Accepted: 08/10/2020] [Indexed: 01/03/2023]
Abstract
AIMS Partial PPARγ agonists attracted substantially heightened interest as safer thiazolidinediones alternatives. On the other hand, Wnt/β-catenin antagonists have been highlighted as promising strategy for type 2 diabetes management via up-regulating PPARγ gene expression. We aimed at synthesizing novel partial PPARγ agonists with β-catenin inhibitory activity which could enhance insulin sensitivity and avoid the side effects of full PPARγ agonists. MAIN METHODS We synthesized novel series of α-phthlimido-o-toluoyl-2-aminothiazoles hybrids for evaluating their antidiabetic activity and discovering its mechanistic pathway. We assessed effect of the new hybrids on PPARγ activation using a luciferase reporter assay system. Moreover, intracellular triglyceride levels, gene levels of c/EBPα, PPARγ and PPARγ targets including GLUT4, adiponectin, aP2 were measured in 3T3-L1 cells. Uptake of 2-DOG together with PPARγ and β-catenin protein levels were evaluated in 3T3-L1cells. In addition, molecular docking studies with PPARγ LBD, physicochemical properties and structure activity relationship of the novel hybrids were also studied. KEY FINDINGS Three of the synthesized hybrids showed partial PPARγ agonistic activity and distinct PPARγ binding pattern. These compounds modulated PPARγ gene expression and PPARγ target genes; and increased glucose uptake in 3T3-L1 and slightly induced adipogenesis compared to rosiglitazone. Moreover, these compounds reduced β-catenin protein level which reflected in increased both PPARγ gene and protein levels that leads to improved insulin sensitivity and increased GLUT4 and adiponectin gene expression. SIGNIFICANCE Our synthesized compounds act as novel partial PPARγ agonists and β-catenin inhibitors that have potent insulin sensitizing activity and mitigate the lipogenic side effects of TZDs.
Collapse
|
|
48
|
Bagchi DP, Nishii A, Li Z, DelProposto JB, Corsa CA, Mori H, Hardij J, Learman BS, Lumeng CN, MacDougald OA. Wnt/β-catenin signaling regulates adipose tissue lipogenesis and adipocyte-specific loss is rigorously defended by neighboring stromal-vascular cells. Mol Metab 2020; 42:101078. [PMID: 32919095 PMCID: PMC7554252 DOI: 10.1016/j.molmet.2020.101078] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 08/14/2020] [Accepted: 09/06/2020] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE Canonical Wnt/β-catenin signaling is a well-studied endogenous regulator of mesenchymal cell fate determination, promoting osteoblastogenesis and inhibiting adipogenesis. However, emerging genetic evidence in humans links a number of Wnt pathway members to body fat distribution, obesity, and metabolic dysfunction, suggesting that this pathway also functions in adipocytes. Recent studies in mice have uncovered compelling evidence that the Wnt signaling pathway plays important roles in adipocyte metabolism, particularly under obesogenic conditions. However, complexities in Wnt signaling and differences in experimental models and approaches have thus far limited our understanding of its specific roles in this context. METHODS To investigate roles of the canonical Wnt pathway in the regulation of adipocyte metabolism, we generated adipocyte-specific β-catenin (β-cat) knockout mouse and cultured cell models. We used RNA sequencing, ChIP sequencing, and molecular approaches to assess expression of Wnt targets and lipogenic genes. We then used functional assays to evaluate effects of β-catenin deficiency on adipocyte metabolism, including lipid and carbohydrate handling. In mice maintained on normal chow and high-fat diets, we assessed the cellular and functional consequences of adipocyte-specific β-catenin deletion on adipose tissues and systemic metabolism. RESULTS We report that in adipocytes, the canonical Wnt/β-catenin pathway regulates de novo lipogenesis (DNL) and fatty acid monounsaturation. Further, β-catenin mediates effects of Wnt signaling on lipid metabolism in part by transcriptional regulation of Mlxipl and Srebf1. Intriguingly, adipocyte-specific loss of β-catenin is sensed and defended by CD45-/CD31- stromal cells to maintain tissue-wide Wnt signaling homeostasis in chow-fed mice. With long-term high-fat diet, this compensatory mechanism is overridden, revealing that β-catenin deletion promotes resistance to diet-induced obesity and adipocyte hypertrophy and subsequent protection from metabolic dysfunction. CONCLUSIONS Taken together, our studies demonstrate that Wnt signaling in adipocytes is required for lipogenic gene expression, de novo lipogenesis, and lipid desaturation. In addition, adipose tissues rigorously defend Wnt signaling homeostasis under standard nutritional conditions, such that stromal-vascular cells sense and compensate for adipocyte-specific loss. These findings underscore the critical importance of this pathway in adipocyte lipid metabolism and adipose tissue function.
Collapse
Affiliation(s)
- Devika P Bagchi
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Akira Nishii
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Ziru Li
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Jennifer B DelProposto
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Callie A Corsa
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Hiroyuki Mori
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Julie Hardij
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Brian S Learman
- Department of Microbiology and Immunology, University of Buffalo, Buffalo, NY, USA.
| | - Carey N Lumeng
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Ormond A MacDougald
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
| |
Collapse
|
|
49
|
Bagchi DP, Li Z, Corsa CA, Hardij J, Mori H, Learman BS, Lewis KT, Schill RL, Romanelli SM, MacDougald OA. Wntless regulates lipogenic gene expression in adipocytes and protects against diet-induced metabolic dysfunction. Mol Metab 2020; 39:100992. [PMID: 32325263 PMCID: PMC7264081 DOI: 10.1016/j.molmet.2020.100992] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 03/27/2020] [Accepted: 04/02/2020] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVE Obesity is a key risk factor for many secondary chronic illnesses, including type 2 diabetes and cardiovascular disease. Canonical Wnt/β-catenin signaling is established as an important endogenous inhibitor of adipogenesis. This pathway is operative in mature adipocytes; however, its roles in this context remain unclear due to complexities of Wnt signaling and differences in experimental models. In this study, we used novel cultured cell and mouse models to investigate functional roles of Wnts secreted from adipocytes. METHODS We generated adipocyte-specific Wntless (Wls) knockout mice and cultured cell models to investigate molecular and metabolic consequences of disrupting Wnt secretion from mature adipocytes. To characterize Wls-deficient cultured adipocytes, we evaluated the expression of Wnt target and lipogenic genes and the downstream functional effects on carbohydrate and lipid metabolism. We also investigated the impact of adipocyte-specific Wls deletion on adipose tissues and global glucose metabolism in mice fed normal chow or high-fat diets. RESULTS Many aspects of the Wnt signaling apparatus are expressed and operative in mature adipocytes, including the Wnt chaperone Wntless. Deletion of Wntless in cultured adipocytes results in the inhibition of de novo lipogenesis and lipid monounsaturation, likely through repression of Srebf1 (SREBP1c) and Mlxipl (ChREBP) and impaired cleavage of immature SREBP1c into its active form. Adipocyte-specific Wls knockout mice (Wls-/-) have lipogenic gene expression in adipose tissues and isolated adipocytes similar to that of controls when fed a normal chow diet. However, closer investigation reveals that a subset of Wnts and downstream signaling targets are upregulated within stromal-vascular cells of Wls-/- mice, suggesting that adipose tissues defend loss of Wnt secretion from adipocytes. Interestingly, this compensation is lost with long-term high-fat diet challenges. Thus, after six months of a high-fat diet, Wls-/- mice are characterized by decreased adipocyte lipogenic gene expression, reduced visceral adiposity, and improved glucose homeostasis. CONCLUSIONS Taken together, these studies demonstrate that adipocyte-derived Wnts regulate de novo lipogenesis and lipid desaturation and coordinate the expression of lipogenic genes in adipose tissues. In addition, we report that Wnt signaling within adipose tissues is defended, such that a loss of Wnt secretion from adipocytes is sensed and compensated for by neighboring stromal-vascular cells. With chronic overnutrition, this compensatory mechanism is lost, revealing that Wls-/- mice are resistant to diet-induced obesity, adipocyte hypertrophy, and metabolic dysfunction.
Collapse
Affiliation(s)
- Devika P Bagchi
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Ziru Li
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Callie A Corsa
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Julie Hardij
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Hiroyuki Mori
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Brian S Learman
- Department of Microbiology and Immunology, University of Buffalo, Buffalo, NY, USA.
| | - Kenneth T Lewis
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Rebecca L Schill
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Steven M Romanelli
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Ormond A MacDougald
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
| |
Collapse
|
|
50
|
Hu Y, Wang C, Ha S, Zhu N, Cao Z, Song Y. Peroxisome proliferator activated receptor γ promotes mineralization and differentiation in cementoblasts via inhibiting Wnt/β-catenin signaling pathway. J Cell Biochem 2020; 121:3700-3710. [PMID: 31709625 DOI: 10.1002/jcb.29509] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 10/10/2019] [Indexed: 01/24/2023]
Abstract
Peroxisome proliferator activated receptor γ (PPARγ) is a member of the nuclear receptor family of transcription factors, which involved in inflammation regulating and bone remodeling. Rare studies explored the effects of PPARγ on mineralization and differentiation in cementoblasts. To explore the potential approaches to repair the damaged periodontal tissues especially for cementum, the present study aims to investigate the effects and the regulating mechanism of PPARγ on mineralization and differentiation in cementoblasts. Murine cementoblast cell lines (OCCM-30) were cultured in basic medium for 24 hours/48 hours or in mineralization medium for 3/7/10 days, respectively at addition of dimethyl sulphoxide, rosiglitazone (PPARγ agonist), GW9662 (PPARγ antagonist), lithium chloride (LiCl), tumor necrosis factor-α (TNF-α), or respective combination. Expression of mineralization genes alkaline phosphatase (ALP), runt related transcription factors 2 (RUNX2), and osteocalcin (OCN) were detected by quantitative real-time polymerase chain reaction or/and Western blot. ALP staining and alizarin red staining were used to evaluate the mineralization in OCCM-30 cells. The change of β-catenin expression and translocation in cytoplasm/nucleus was analyzed by Western blot and immunofluorescence. The results showed that PPARγ agonist rosiglitazone improved the expression of ALP, RUNX2, and OCN, deepened ALP staining, increased mineralized nodules formation, and decreased β-catenin expression in the nucleus. LiCl, an activator of the Wnt signaling pathway, inhibited the expression of mineralization genes and reversed the upregulated expression of mineralization genes resulted from rosiglitazone. Under inflammatory microenvironment, rosiglitazone not only suppressed the expression of interleukin-1β caused by TNF-α, but improved the expression of mineralization genes in OCCM-30 cells. In conclusion, PPARγ could promote mineralization and differentiation in cementoblasts via inhibiting the Wnt/β-catenin signaling pathway, which would shed new light on the treatment of periodontitis and periodontal tissue regeneration.
Collapse
Affiliation(s)
- Yingying Hu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, Hubei, China
| | - Changning Wang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, Hubei, China
| | - Shanshan Ha
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, Hubei, China
| | - Ningjing Zhu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, Hubei, China
| | - Zhengguo Cao
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, Hubei, China
| | - Yaling Song
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, Hubei, China
| |
Collapse
|