Abstract
Tibial dyschondroplasia (TD) is a developmental cartilaginous disease due to thiram toxicity. The abnormity of chondrocytes and insufficient angiogenesis within the growth plate are the major factors leading to the occurrence of TD in most cases. In the current study, we evaluated the beneficial effects of ginsenoside (Rg1) against thiram-induced TD for knowing the possible underlying mechanisms in broiler chickens through in vivo and in vitro assessment. Arbor acres broilers (1-day-old, n = 120) were randomly divided for the in vivo evaluation. The control broilers were fed under normal conditions during the whole experiment cycle (18 days). The TD broilers were fed with 50 mg/kg thiram, while the treatment group was given 40 mg/kg of Rg1. According to our findings, thiram caused a decrease in production performance and tibia parameters (p < 0.05), which were significantly reversed by Rg1 administration. In addition, the results from the histological evaluation showed that the proliferative zone had a smaller number of blood vessels, surrounded by inviable chondrocytes, proving apoptosis during the occurrence of TD, while Rg1 treatment significantly increased blood vessels and decreased apoptotic cells. Furthermore, it was found that Rg1 effectively ameliorated the angiogenesis by regulation of HIF-1α/VEGFA/VEGFR2 signaling pathway and the chondrocytes’ apoptosis via the mitochondrial pathway. Hence, these findings suggest that Rg1 might be a perfect choice in the prevention and treatment of TD via regulating chondrocytes apoptosis and angiogenesis. Also, it might be a potential therapeutic drug for humans to overcome different bone disorders, involving chondrocytes.
Graphical Abstract
Similar content being viewed by others
Data availability
The data used to support the findings of the study are available from the corresponding author upon request.
Abbreviations
- AA:
-
Arbor acres
- Apaf-1:
-
Apoptotic protease activating factor-1
- BMD:
-
Bone mineral density
- Cyt c:
-
Cytochrome c
- FBS:
-
Fetal bovine serum
- HIF-1α:
-
Hypoxia inducible factor-1α
- IF:
-
Immunofluorescence
- PBS:
-
Phosphate-buffered saline
- RT:
-
Room temperature
- TD:
-
Tibial dyschondroplasia
- TH:
-
Thiram
- TUNEL:
-
Terminal deoxy-nucleotidyl transferase-mediated nick end labeling
- VEGF:
-
Vascular endothelial growth factor
- VEGFR1:
-
Vascular endothelial growth factor receptor 1
- VEGFR2:
-
Vascular endothelial growth factor receptor 2
- WB:
-
Western blotting
References
Cao HQ, Wei W, Xu RR, Cui X (2021) Ginsenoside Rg1 can restore hematopoietic function by inhibiting Bax translocation-mediated mitochondrial apoptosis in aplastic anemia. Sci Rep 11:12742
Chen CF, Chiou WF, Zhang JT (2008) Comparison of the pharmacological effects of Panax ginseng and Panax quinquefolium. Acta Pharmacol Sin 29:1103–1108
Chen J, Zhang X, Liu X, Zhang C, Shang W, Xue J, Chen R, Xing Y, Song D, Xu R (2019) Ginsenoside Rg1 promotes cerebral angiogenesis via the PI3K/Akt/mTOR signaling pathway in ischemic mice. Eur J Pharmacol 856:172418
Cheng W, Jing J, Wang Z, Wu D, Huang Y (2017) Chondroprotective effects of ginsenoside Rg1 in human osteoarthritis chondrocytes and a rat model of anterior cruciate ligament transection. Nutrients 9:263
Cheung LWT, Leung KW, Wong CKC, Wong RNS, Wong AST (2011) Ginsenoside-Rg1 induces angiogenesis via non-genomic crosstalk of glucocorticoid receptor and fibroblast growth factor receptor-1. Cardiovasc Res 89:419–425
Czabotar PE, Lessene G, Strasser A, Adams JM (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15:49–63
Ding Y, Yao W, Kulyar MF-e-A, Mo Q, Pan H, Zhang Y, Ma B, He Y, Zhang M, Hong J (2021) Taurine is an effective therapy against thiram induced tibial dyschondroplasia via HIF-1α/VEGFA and β-catenin/GSK-3β pathways in broilers. Ecotoxicol Environ Saf 228:112981
Fan C, Song Q, Wang P, Li Y, Yang M, Yu SY (2018) Neuroprotective effects of Ginsenoside-Rg1 against depression-like behaviors via suppressing glial activation, synaptic deficits, and neuronal apoptosis in rats. Front Immunol 9:2889
Gerber H-P, Ferrara N (2000) Angiogenesis and bone growth. Trends Cardiovasc Med 10:223–228
Hasky-Negev M, Simsa S, Tong A, Genina O, Ornan EM (2008) Expression of matrix metalloproteinases during vascularization and ossification of normal and impaired avian growth plate. J Anim Sci 86:1306–1315
Huang S-c, Rehman MU, Lan Y-f, Qiu G, Zhang H, Iqbal MK, Luo H-q, Mehmood K, Zhang L-h, Li J-k (2017) Tibial dyschondroplasia is highly associated with suppression of tibial angiogenesis through regulating the HIF-1α/VEGF/VEGFR signaling pathway in chickens. Sci Rep 7:9089
Huang SC, Zhang LH, Zhang JL, Rehman MU, Tong XL, Qiu G, Jiang X, Iqbal M, Shahzad M, Shen YQ, Li JK (2018) Role and regulation of growth plate vascularization during coupling with osteogenesis in tibial dyschondroplasia of chickens. Sci Rep 8:3680
Jahejo AR, Bukhari SAR, Rajput N, Kalhoro NH, Leghari IH, Raza SHA, Li Z, Liu WZ, Tian WX (2022) Transcriptome-based biomarker gene screening and evaluation of the extracellular fatty acid-binding protein (Ex-FABP) on immune and angiogenesis-related genes in chicken erythrocytes of tibial dyschondroplasia. BMC Genomics 23:323
Kulyar MF-e-A, Mo Q, Yao W, Ding Y, Yan Z, Du H, Pan H, Li K, Gao J, Shahzad M, Mansoor MK, Iqbal M, Waqas M, Akhtar M, Bhutta ZA, Li J (2022) Chlorogenic acid suppresses miR-460a in the regulation of Bcl-2, causing interleukin-1β reduction in thiram exposed chondrocytes via caspase-3/caspase-7 pathway. Phytomedicine 104:154296. https://doi.org/10.1016/j.phymed.2022.154296
Kulyar MFEA, Yao WY, Ding YM, Du HT, Li K, Zhang LH, Li AY, Huachun P, Waqas M, Mehmood K, Li JK (2021) Cluster of differentiation 147 (CD147) expression is linked with thiram induced chondrocyte’s apoptosis via Bcl-2/Bax/Caspase-3 signalling in tibial growth plate under chlorogenic acid repercussion. Ecotoxicol Environ Saf 213:112059. https://doi.org/10.1016/j.ecoenv.2021.112059
Kulyar MF, Yao W, Mo Q, Ding Y, Zhang Y, Gao J, Li K, Pan H, Nawaz S, Shahzad M, Mehmood K, Iqbal M, Akhtar M, Bhutta ZA, Waqas M, Li J, Qi D (2022) Regulatory role of apoptotic and inflammasome related proteins and their possible functional aspect in thiram associated tibial dyschondroplasia of poultry. Animals (Basel) 12(16):2028. https://doi.org/10.3390/ani12162028
Leung KW, Ng HM, Tang MKS, Wong CCK, Wong RNS, Wong AST (2011) Ginsenoside-Rg1 mediates a hypoxia-independent upregulation of hypoxia-inducible factor-1 alpha to promote angiogenesis. Angiogenesis 14:515–522
Li JK, Bi DR, Pan SY, Zhang YH, Zhou DH (2008) Effects of high dietary vitamin A supplementation on tibial dyschondroplasia, skin pigmentation and growth performance in avian broilers. Res Vet Sci 84:409–412
Li H, Xu JM, Wang X, Yuan GX (2014) Protective effect of ginsenoside Rg1 on lidocaine-induced apoptosis. Mol Med Rep 9:395–400
Lin J, Huang HF, Yang SK, Duan J, Qu SM, Yuan B, Zeng Z (2020) The effect of Ginsenoside Rg1 in hepatic ischemia reperfusion (I/R) injury ameliorates ischemia-reperfusion-induced liver injury by inhibiting apoptosis. Biomed Pharmacother 129:110398
Liu K, Li Y, Iqbal M, Tang Z, Zhang H (2022) Thiram exposure in environment: a critical review on cytotoxicity. Chemosphere 295:133928
Lushchak VI, Matviishyn TM, Husak VV, Storey JM, Storey KB (2018) Pesticide toxicity: a mechanistic approach. EXCLI J 17:1101–1136
Maes C, Araldi E, Haigh K, Khatri R, Van Looveren R, Giaccia AJ, Haigh JJ, Carmeliet G, Schipani E (2012) VEGF-independent cell-autonomous functions of HIF-1α regulating oxygen consumption in fetal cartilage are critical for chondrocyte survival. J Bone Miner Res 27:596–609
Majno G, Joris I (1995) Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol 146:3–15
Martins SE, Fillmann G, Lillicrap A, Thomas KV (2018) Review: ecotoxicity of organic and organo-metallic antifouling co-biocides and implications for environmental hazard and risk assessments in aquatic ecosystems. Biofouling 34:34–52
Nabi F, Shahzad M, Liu J, Li K, Han Z, Zhang D, Iqbal MK, Li J (2016) Hsp90 inhibitor celastrol reinstates growth plate angiogenesis in thiram-induced tibial dyschondroplasia. Avian Pathol 45:187–193
Nnadi PA, George SO (2010) A cross-sectional survey on parasites of chickens in selected villages in the subhumid zones of South-eastern Nigeria. J Parasitol Res 2010:141826
Porter AG, Janicke RU (1999) Emerging roles of caspase-3 in apoptosis. Cell Death Differ 6:99–104
Praul CA, Ford BC, Gay CV, Pines M, Leach RM (2000) Gene expression and tibial dyschondroplasia. Poult Sci 79:1009–1013
Qi LW, Wang CZ, Yuan CS (2011) Ginsenosides from American ginseng: chemical and pharmacological diversity. Phytochemistry 72:689–699
Ramasamy SK, Kusumbe AP, Adams RH (2014) Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature 507:376–380
Rath NC, Richards MP, Huff WE, Huff GR, Balog JM (2005) Changes in the tibial growth plates of chickens with thiram-induced dyschondroplasia. J Comp Pathol 133:41–52
Rath NC, Huff WE, Huff GR (2007) Thiram-induced changes in the expression of genes relating to vascularization and tibial dyschondroplasia. Poult Sci 86:2390–2395
Salam S, Iqbal Z, Khan AA, Mahmood R (2021) Oral administration of thiram inhibits brush border membrane enzymes, oxidizes proteins and thiols, impairs redox system and causes histological changes in rat intestine: a dose dependent study. Pestic Biochem Physiol 178:104915
Sharma VK, Aulakh JS, Malik AK (2003) Thiram: degradation, applications and analytical methods. J Environ Monit 5:717–723
Singh B, Sharma DK, Gupta A (2009) A study towards release dynamics of thiram fungicide from starch-alginate beads to control environmental and health hazards. J Hazard Mater 161:208–216
Tao T, Chen F, Bo L, Xie Q, Yi W, Zou Y, Hu B, Li J, Deng X (2014) Ginsenoside Rg1 protects mouse liver against ischemia–reperfusion injury through anti-inflammatory and anti-apoptosis properties. J Surg Res 191:231–238
Tian WX, Li JK, Qin P, Wang R, Ning GB, Qiao JG, Li HQ, Bi DR, Pan SY, Guo DZ (2013) Screening of differentially expressed genes in the growth plate of broiler chickens with tibial dyschondroplasia by microarray analysis. BMC Genomics 14:276
Van Delft MF, Huang D (2006) How the Bcl-2 family of proteins interact to regulate apoptosis. Cell Res 16:203–213
Waqas M, Qamar H, Zhang JL, Yao WY, Li AY, Wang YP, Iqbal M, Mehmood K, Jiang X, Li JK (2020) Puerarin enhance vascular proliferation and halt apoptosis in thiram-induced avian tibial dyschondroplasia by regulating HIF-1 alpha, TIMP-3 and BCL-2 expressions. Ecotoxicol Environ Saf 190:110126. https://doi.org/10.1016/j.ecoenv.2019.110126
Yue PY, Wong DY, Ha W-Y, Fung M, Mak NK, Yeung H, Leung HW, Chan K, Liu L, Fan T (2005) Elucidation of the mechanisms underlying the angiogenic effects of ginsenoside Rg1 in vivo and in vitro. Angiogenesis 8:205–216
Zhang JP, Deng YF, Zhou ZL, Hou JF (2013) Expression and identification of recombinant chicken vascular endothelial growth factor in Pichia pastoris and its role in the pathogenesis of tibial dyschondroplasia. Poult Sci 92:3214–3227
Zhang H, Mehmood K, Jiang X, Yao W, Iqbal M, Waqas M, Rehman MU, Li A, Shen Y, Li J (2018) Effect of tetramethyl thiuram disulfide (thiram) in relation to tibial dyschondroplasia in chickens. Environ Sci Pollut Res Int 25:28264–28274
Zhang H, Mehmood K, Jiang X, Li ZX, Yao WY, Zhang JL, Tong XL, Wang YP, Li AY, Waqas M, Iqbal M, Li JK (2019) Identification of differentially expressed MiRNAs profile in a thiram-induced tibial dyschondroplasia. Ecotoxicol Environ Saf 175:83–89
Zhang J, Luo B, Liu J, Waqas M, Kulyar MF-e-A, Guo K, Li J (2021) Chlorogenic acid inhibits apoptosis in thiram-induced tibial dyschondroplasia via intrinsic pathway. EnEnviron Sci Pollut Res Int 28:68288–68299
Funding
The study was supported by the National Natural Science Foundation of China (grant nos. 32172929 and 31873031).
Author information
Authors and Affiliations
Contributions
Huaisen Zhu: methodology, conceptualization, data curation, and writing—original draft; Muhammad Fakhar-e-Alam Kulyar: software and writing—review and editing; Yanmei Ding: methodology and formal analysis; Wangyuan Yao: data curation; Mo Quan: writing—review and editing; Jiakui Li: writing—review and editing, project administration, and funding acquisition.
Corresponding author
Ethics declarations
Ethics approval
All maintenance, handling, and procedures of the experimental animals were performed in accordance with the ethics committee of Huazhong Agricultural University (approval no. 31273519).
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Additional information
Responsible Editor: Mohamed M. Abdel-Daim
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Zhu, H., Kulyar, M.FeA., Ding, Y. et al. Ginsenoside Rg1 regulates thiram-induced chondrocytes’ apoptosis and angiogenesis in broiler chickens. Environ Sci Pollut Res 30, 34188–34202 (2023). https://doi.org/10.1007/s11356-022-24598-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11356-022-24598-x