{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T21:41:43Z","timestamp":1791582103661,"version":"4.3.4"},"reference-count":87,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T00:00:00Z","timestamp":1574726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key Research and Development Program of China:","award":["Project No. 2017YFD0502200"],"award-info":[{"award-number":["Project No. 2017YFD0502200"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Tibial dyschondroplasia (TD) negatively affects broilers all over the world, in which the accretion of the growth plate (GP) develops into tibial proximal metaphysis. Plastrum testudinis extract (PTE) is renowned as a powerful antioxidant, anti-inflammatory, and bone healing agent. The current study was conducted to evaluate the efficacy of PTE for the treatment of thiram-induced TD chickens. Broilers (day old; n = 300) were raised for 3 days with normal feed. On the 4th day, three groups (n = 100 each) were sorted, namely, the control (normal diet), TD, and PTE groups (normal diet+ thiram 50 mg\/kg). On the 7th day, thiram was stopped in the TD and PTE group, and the PTE group received a normal diet and PTE (30 mg\/kg\/day). Plastrum testudinis extract significantly restored (p &lt; 0.05) the liver antioxidant enzymes, inflammatory cytokines, serum biochemicals, GP width, and tibia weight as compared to the TD group. The PTE administration significantly increased (p &lt; 0.05) growth performance, vascularization, AKT (serine\/threonine-protein kinase), and PI3K expressions and the number of hepatocytes and chondrocytes with intact nuclei were enhanced. In conclusion, PTE has the potential to heal TD lesions and act as an antioxidant and anti-inflammatory drug in chickens exposed to thiram via the upregulation of AKT and PI3K expressions.<\/jats:p>","DOI":"10.3390\/biom9120784","type":"journal-article","created":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T10:57:27Z","timestamp":1574765847000},"page":"784","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Plastrum Testudinis Extract Mitigates Thiram Toxicity in Broilers via Regulating PI3K\/AKT Signaling"],"prefix":"10.3390","volume":"9","author":[{"given":"Hammad","family":"Qamar","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Waqas","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China"},{"name":"Faculty of Veterinary &amp; Animal Sciences, University of the Poonch, Rawalakot, District Poonch 12350, Azad Jammu &amp; Kashmir, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aoyun","family":"Li","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mudassar","family":"Iqbal","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China"},{"name":"University College of Veterinary &amp; Animal Sciences, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalid","family":"Mehmood","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China"},{"name":"University College of Veterinary &amp; Animal Sciences, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6065-6648","authenticated-orcid":false,"given":"Jiakui","family":"Li","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China"},{"name":"College of Animals Husbandry and Veterinary Medicine, Tibet Agricultural and Animal Husbandry University, Linzhi, Tibet 860000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"25","DOI":"10.2478\/v10102-012-0005-6","article-title":"Sensitivity of some nitrogen fixers and the target pest Fusarium oxysporum to fungicide thiram","volume":"5","author":"Osman","year":"2012","journal-title":"Interdiscip. Toxicol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"312","DOI":"10.26444\/aaem\/74715","article-title":"The history of arsenical pesticides and health risks related to the use of Agent Blue","volume":"24","author":"Bencko","year":"2017","journal-title":"Ann. Agric. Environ. Med. AAEM"},{"key":"ref_3","first-page":"137","article-title":"Effect of seed coating with polymer, fungicide and insecticide on seed quality in cotton during storage","volume":"20","author":"Kunkur","year":"2007","journal-title":"Karnataka J. Agric. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Tian, W.-X., Li, J.-K., Qin, P., Wang, R., Ning, G.-B., Qiao, J.-G., Li, H.-Q., Bi, D.-R., Pan, S.-Y., and Guo, D.-Z. (2013). Screening of differentially expressed genes in the growth plate of broiler chickens with tibial dyschondroplasia by microarray analysis. BMC Genom., 14.","DOI":"10.1186\/1471-2164-14-276"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.jcpa.2005.01.005","article-title":"Changes in the tibial growth plates of chickens with thiram-induced dyschondroplasia","volume":"133","author":"Rath","year":"2005","journal-title":"J. Comp. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"28264","DOI":"10.1007\/s11356-018-2824-2","article-title":"Effect of tetramethyl thiuram disulfide (thiram) in relation to tibial dyschondroplasia in chickens","volume":"25","author":"Zhang","year":"2018","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1177\/030098589403100401","article-title":"Avian tibial dyschondroplasia: A morphological and biochemical review of the growth plate lesion and its causes","volume":"31","author":"Orth","year":"1994","journal-title":"Vet. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1093\/ps\/83.2.266","article-title":"Comparative efficacy of different dithiocarbamates to induce tibial dyschondroplasia in poultry 1","volume":"83","author":"Rath","year":"2004","journal-title":"Poult. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1080\/03079457.2016.1141170","article-title":"Hsp90 inhibitor celastrol reinstates growth plate angiogenesis in thiram-induced tibial dyschondroplasia","volume":"45","author":"Nabi","year":"2016","journal-title":"Avian Pathol."},{"key":"ref_10","first-page":"224","article-title":"Gambogic acid inhibits Hsp90 expressions in thiram-induced tibial dyschondroplasia","volume":"36","author":"Nabi","year":"2016","journal-title":"Pak. Vet. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/S0925-4439(00)00020-X","article-title":"Expression patterns of chondrocyte genes cloned by differential display in tibial dyschondroplasia","volume":"1501","author":"Jefferies","year":"2000","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_12","first-page":"545","article-title":"Hsp-90 inhibitor geldanamycin attenuates liver oxidative stress and toxicity in thiram-induced tibial dyschondroplasia","volume":"34","author":"Shahzad","year":"2014","journal-title":"Pak. Vet. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.3382\/ps.2012-02207","article-title":"The effect of inhibition of heat-shock proteins on thiram-induced tibial dyschondroplasia","volume":"91","author":"Genin","year":"2012","journal-title":"Poult. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2390","DOI":"10.3382\/ps.2007-00219","article-title":"Thiram-induced changes in the expression of genes relating to vascularization and tibial dyschondroplasia","volume":"86","author":"Rath","year":"2007","journal-title":"Poult. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1007\/s002239900568","article-title":"Development of avian tibial dyschondroplasia: Gene expression and protein synthesis","volume":"63","author":"Pines","year":"1998","journal-title":"Calcif. Tissue Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1002\/art.39816","article-title":"Review: Novel Insights Into Tumor Necrosis Factor Receptor, Death Receptor 3, and Progranulin Pathways in Arthritis and Bone Remodeling","volume":"68","author":"Williams","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/0167-5699(92)90116-O","article-title":"Two TNF receptors","volume":"13","author":"Tartaglia","year":"1992","journal-title":"Immunol. Today"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1111\/j.1742-4658.2011.08017.x","article-title":"Tumor necrosis factor receptor cross-talk","volume":"278","author":"Naude","year":"2011","journal-title":"FEBS J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1530\/JOE-11-0175","article-title":"The skeleton: A multi-functional complex organ: New insights into osteoblasts and their role in bone formation: The central role of PI3Kinase","volume":"211","author":"Guntur","year":"2011","journal-title":"J. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"640","DOI":"10.3109\/10799893.2015.1041647","article-title":"The PI3K\/AKT cell signaling pathway is involved in regulation of osteoporosis","volume":"35","author":"Xi","year":"2015","journal-title":"J. Recept. Signal Transduct. Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kawamura, N., Kugimiya, F., Oshima, Y., Ohba, S., Ikeda, T., Saito, T., Shinoda, Y., Kawasaki, Y., Ogata, N., and Hoshi, K. (2007). Akt1 in osteoblasts and osteoclasts controls bone remodeling. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0001058"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/S0092-8674(00)80595-4","article-title":"Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor","volume":"96","author":"Brunet","year":"1999","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1128\/MCB.01401-09","article-title":"Selective Signaling by Akt2 Promotes Bone Morphogenetic Protein 2-Mediated Osteoblast Differentiation","volume":"30","author":"Mukherjee","year":"2010","journal-title":"Mol. Cell. Biol."},{"key":"ref_24","first-page":"951","article-title":"Neural Beginnings for the Turtle\u2019s Shell","volume":"303","author":"Pennisi","year":"2004","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1111\/j.1365-2184.2007.00431.x","article-title":"Extracts from Plastrum testudinis promote proliferation of rat bone-marrow-derived mesenchymal stem cells","volume":"40","author":"Chen","year":"2007","journal-title":"Cell Prolif."},{"key":"ref_26","first-page":"1357","article-title":"Effects of dexamethasone on proliferation, differentiation and apoptosis of adult human osteoblasts in vitro","volume":"116","author":"Yang","year":"2003","journal-title":"Chin. Med. J."},{"key":"ref_27","first-page":"1139","article-title":"p21Waf1\/Cip1 is a common target induced by short-chain fatty acid HDAC inhibitors (valproic acid, tributyrin and sodium butyrate) in neuroblastoma cells","volume":"13","author":"Rocchi","year":"2005","journal-title":"Oncol. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1038\/sj.ejcn.1602132","article-title":"The effects of conjugated linoleic acid supplementation on immune function in healthy volunteers","volume":"59","author":"Nugent","year":"2005","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1111\/j.1753-4887.2010.00292.x","article-title":"Intestinal alkaline phosphatase: Multiple biological roles in maintenance of intestinal homeostasis and modulation by diet","volume":"68","year":"2010","journal-title":"Nutr. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.4049\/jimmunol.1302944","article-title":"Regulation of intestinal IgA responses by dietary palmitic acid and its metabolism","volume":"193","author":"Kunisawa","year":"2014","journal-title":"J. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.freeradbiomed.2011.04.019","article-title":"ROS-activated p38 MAPK\/ERK-Akt cascade plays a central role in palmitic acid-stimulated hepatocyte proliferation","volume":"51","author":"Wang","year":"2011","journal-title":"Free Radic. Biol. Med."},{"key":"ref_32","first-page":"217","article-title":"Improvement of liver cell therapy in rats by dietary stearic acid","volume":"20","author":"Goradel","year":"2016","journal-title":"Iran. Biomed. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1016\/j.bbrc.2009.12.119","article-title":"Stearic acid attenuates cholestasis-induced liver injury","volume":"391","author":"Pan","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1002\/hep.510300402","article-title":"Activation of nuclear factor kappa B and cytokine imbalance in experimental alcoholic liver disease in the rat","volume":"30","author":"Nanji","year":"1999","journal-title":"Hepatology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1111\/j.1745-7254.2007.00512.x","article-title":"Stearic acid protects primary cultured cortical neurons against oxidative stress 4","volume":"28","author":"Wang","year":"2007","journal-title":"Acta Pharm. Sin."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.1002\/jcp.27635","article-title":"A dual role of cholesterol in osteogenic differentiation of bone marrow stromal cells","volume":"234","author":"Li","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1590\/0001-3765201720160908","article-title":"Antifungal and antioxidant activity of fatty acid methyl esters from vegetable oils","volume":"89","author":"Pinto","year":"2017","journal-title":"An. Acad. Bras. Ci\u00eancias"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"10617","DOI":"10.1038\/s41598-017-10614-5","article-title":"Promotion effect of extracts from plastrum testudinis on alendronate against glucocorticoid-induced osteoporosis in rat spine","volume":"7","author":"Ren","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1159\/000491541","article-title":"Plastrum Testudinis Extracts Promote BMSC Proliferation and Osteogenic Differentiation by Regulating Let-7f-5p and the TNFR2\/PI3K\/AKT Signaling Pathway","volume":"47","author":"Shen","year":"2018","journal-title":"Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharm."},{"key":"ref_40","unstructured":"Council, N.R. (1994). Nutrient Requirements of Poultry, National Academies Press."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"143","DOI":"10.29261\/pakvetj\/2018.034","article-title":"Healing of Growth Plate Cartilage by Hypoxia Inducible Factor-1a Inhibitor Apigenin on Thiram Induced Tibial Dyschondroplasia","volume":"38","author":"Iqbal","year":"2018","journal-title":"Pak. Vet. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.biopha.2016.04.068","article-title":"Extracts from plastrum testudinis reverse glucocorticoid-induced spinal osteoporosis of rats via targeting osteoblastic and osteoclastic markers","volume":"82","author":"Liang","year":"2016","journal-title":"Biomed. Pharm."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Zhang, J., Huang, S., Tong, X., Zhang, L., Jiang, X., Zhang, H., Mehmood, K., and Li, J. (2019). Chlorogenic Acid Alleviates Thiram-Induced Tibial Dyschondroplasia by Modulating Caspases, BECN1 Expression and ECM Degradation. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20133160"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1038\/s41598-018-20562-3","article-title":"Effect of tetramethylpyrazine on tibial dyschondroplasia incidence, tibial angiogenesis, performance and characteristics via HIF-1alpha\/VEGF signaling pathway in chickens","volume":"8","author":"Mehmood","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Waqas, M., Wang, Y., Li, A., Qamar, H., Yao, W., Tong, X., Zhang, J., Iqbal, M., Mehmood, K., and Li, J. (2019). Osthole: A Coumarin Derivative Assuage Thiram-Induced Tibial Dyschondroplasia by Regulating BMP-2 and RUNX-2 Expressions in Chickens. Antioxidants, 8.","DOI":"10.3390\/antiox8090330"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Rajput, S.A., Sun, L., Zhang, N.-Y., Khalil, M.M., Ling, Z., Chong, L., Wang, S., Rajput, I.R., Bloch, D.M., and Khan, F.A. (2019). Grape Seed Proanthocyanidin Extract Alleviates AflatoxinB1-Induced Immunotoxicity and Oxidative Stress via Modulation of NF-\u03baB and Nrf2 Signaling Pathways in Broilers. Toxins, 11.","DOI":"10.3390\/toxins11010023"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.ecoenv.2018.10.080","article-title":"Ligustrazine recovers thiram-induced tibial dyschondroplasia in chickens: Involvement of new molecules modulating integrin beta 3","volume":"168","author":"Mehmood","year":"2019","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Rajput, S., Sun, L., Zhang, N., Khalil, M., Gao, X., Ling, Z., Zhu, L., Khan, F., Zhang, J., and Qi, D. (2018). Ameliorative Effects of Grape Seed Proanthocyanidin Extract on Growth Performance, Immune Function, Antioxidant Capacity, Biochemical Constituents, Liver Histopathology and Aflatoxin Residues in Broilers Exposed to Aflatoxin B1. Toxins, 10.","DOI":"10.3390\/toxins10090366"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s12575-018-0080-y","article-title":"Icariin: A Potential Compound for the Recovery of Tibial Dyschondroplasia Affected Chicken Via Up-Regulating BMP-2 Expression","volume":"20","author":"Iqbal","year":"2018","journal-title":"Biol. Proced. Online"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"16210","DOI":"10.1007\/s11356-019-05032-1","article-title":"Protective effect of Astragaloside IV to inhibit thiram-induced tibial dyschondroplasia","volume":"26","author":"Mehmood","year":"2019","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_51","unstructured":"Levene, H. (1960). Contributions to Probability and Statistics: Essays in Honor of Ingram Olkin, Springer Science & Business Media."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1093\/biomet\/52.3-4.591","article-title":"An analysis of variance test for normality (complete samples)","volume":"52","author":"Shapiro","year":"1965","journal-title":"Biometrika"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1093\/toxsci\/kfq169","article-title":"Dithiocarbamates induce craniofacial abnormalities and downregulate sox9a during zebrafish development","volume":"117","author":"Pieterse","year":"2010","journal-title":"Toxicol. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"93","DOI":"10.2131\/jts.38.93","article-title":"Effect of thiram on avian growth plate chondrocytes in culture","volume":"38","author":"Rasaputra","year":"2013","journal-title":"J. Toxicol. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1637\/11641-032817-RegR","article-title":"In Vitro effect of apigenin and danshen in tibial dyschondroplasia through inhibition of heat-shock protein 90 and vascular endothelial growth factor expressions in avian growth plate cells","volume":"61","author":"Mehmood","year":"2017","journal-title":"Avian Dis."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1637\/10781-012614-ResNote.1","article-title":"Expression of genes encoding matrilin-3 and cyclin-I during the impairment and recovery of chicken growth plate in tibial dyschondroplasia","volume":"58","author":"Shahzad","year":"2014","journal-title":"Avian Dis."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1080\/03079457.2014.987210","article-title":"Differential expression of extracellular matrix metalloproteinase inducer (EMMPRIN\/CD147) in avian tibial dyschondroplasia","volume":"44","author":"Shahzad","year":"2015","journal-title":"Avian Pathol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1111\/jvp.12692","article-title":"Clinical efficiency and safety of Hsp90 inhibitor Novobiocin in avian tibial dyschondroplasia","volume":"41","author":"Nabi","year":"2018","journal-title":"J. Vet. Pharm."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.jcpa.2010.12.008","article-title":"Expression of genes encoding extracellular matrix macromolecules and metalloproteinases in avian tibial dyschondroplasia","volume":"145","author":"Velada","year":"2011","journal-title":"J. Comp. Pathol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"62","DOI":"10.3382\/ps.2011-01599","article-title":"The effects of broiler chicken growth rate on valgus, varus, and tibial dyschondroplasia","volume":"91","author":"Shim","year":"2012","journal-title":"Poult. Sci."},{"key":"ref_61","first-page":"6796271","article-title":"Effect of Icariin on Tibial Dyschondroplasia Incidence and Tibial Characteristics by Regulating P2RX7 in Chickens","volume":"2018","author":"Zhang","year":"2018","journal-title":"Biomed Res. Int."},{"key":"ref_62","first-page":"89","article-title":"FK228 recovers thiram-induced tibial dyschondroplasia in chicken via hypoxia inducible factor-1alpha","volume":"32","author":"Iqbal","year":"2018","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.3382\/ps.2008-00124","article-title":"Hypoxia, hypoxia-inducible factor-1alpha (HIF-1alpha), and heat-shock proteins in tibial dyschondroplasia","volume":"87","author":"Genin","year":"2008","journal-title":"Poult. Sci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1111\/j.1747-0285.2012.01361.x","article-title":"Chemical components in extracts from Plastrum testudinis with proliferation-promoting effects on rat mesenchymal stem cells","volume":"79","author":"Wang","year":"2012","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1080\/01926230600611836","article-title":"Review of the effects of anti-angiogenic compounds on the epiphyseal growth plate","volume":"34","author":"Hall","year":"2006","journal-title":"Toxicol. Pathol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/j.pharep.2017.02.016","article-title":"Icariin protects against thioacetamide-induced liver fibrosis in rats: Implication of anti-angiogenic and anti-autophagic properties","volume":"69","author":"Algandaby","year":"2017","journal-title":"Pharm. Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1038\/sj.bjc.6600078","article-title":"Thiram inhibits angiogenesis and slows the development of experimental tumours in mice","volume":"86","author":"Marikovsky","year":"2002","journal-title":"Br. J. Cancer"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.bbapap.2009.11.004","article-title":"The structural biochemistry of the superoxide dismutases","volume":"1804","author":"Perry","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"76","DOI":"10.29261\/pakvetj\/2018.015","article-title":"Tetramethylpyrazine mitigates toxicity and liver oxidative stress in tibial dyschondroplasia chickens","volume":"38","author":"Mehmood","year":"2018","journal-title":"Pak. Vet. J."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.3892\/ijmm.2013.1338","article-title":"Plastrum testudinis induces gamma-globin gene expression through epigenetic histone modifications within the gamma-globin gene promoter via activation of the p38 MAPK signaling pathway","volume":"31","author":"Qian","year":"2013","journal-title":"Int. J. Mol. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1007\/s11914-012-0109-0","article-title":"Signaling pathways affecting skeletal health","volume":"10","author":"Marie","year":"2012","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1089\/ten.teb.2012.0672","article-title":"The key regulatory roles of the PI3K\/Akt signaling pathway in the functionalities of mesenchymal stem cells and applications in tissue regeneration","volume":"19","author":"Chen","year":"2013","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1159\/000479605","article-title":"Alpha-Lipoic Acid Alleviates High-Glucose Suppressed Osteogenic Differentiation of MC3T3-E1 Cells via Antioxidant Effect and PI3K\/Akt Signaling Pathway","volume":"42","author":"Dong","year":"2017","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"981","DOI":"10.3892\/mmr.2015.3514","article-title":"Gene expression changes in human mesenchymal stem cells from patients with osteoporosis","volume":"12","author":"Liu","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_75","first-page":"433","article-title":"Expression profile analysis of new candidate genes for the therapy of primary osteoporosis","volume":"20","author":"Zhang","year":"2016","journal-title":"Eur. Rev. Med. Pharm. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.3892\/ijmm.2016.2794","article-title":"Bergapten exerts inhibitory effects on diabetes-related osteoporosis via the regulation of the PI3K\/AKT, JNK\/MAPK and NF-kappaB signaling pathways in osteoprotegerin knockout mice","volume":"38","author":"Li","year":"2016","journal-title":"Int. J. Mol. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1101\/gad.10.13.1580","article-title":"Bone morphogenetic proteins: Multifunctional regulators of vertebrate development","volume":"10","author":"Hogan","year":"1996","journal-title":"Genes Dev."},{"key":"ref_78","first-page":"3149","article-title":"(-)-Epigallocatechin gallate but not chlorogenic acid suppresses EGF-stimulated migration of osteoblasts via attenuation of p38 MAPK activity","volume":"42","author":"Kawabata","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Thouverey, C., and Caverzasio, J. (2015). Focus on the p38 MAPK signaling pathway in bone development and maintenance. Bonekey Rep., 4.","DOI":"10.1038\/bonekey.2015.80"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1159\/000343393","article-title":"Enhanced FGF23 serum concentrations and phosphaturia in gene targeted mice expressing WNK-resistant SPAK","volume":"36","author":"Pathare","year":"2012","journal-title":"Kidney Blood Press. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"44005","DOI":"10.1074\/jbc.M208265200","article-title":"Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization","volume":"277","author":"Zhang","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"6815620","DOI":"10.1155\/2019\/6815620","article-title":"Effect of Plastrum Testudinis Extracts on the Proliferation and Osteogenic Differentiation of rBMSCs by Regulating p38 MAPK-Related Genes","volume":"2019","author":"Shang","year":"2019","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/nri3495","article-title":"Mitogen-activated protein kinases in innate immunity","volume":"13","author":"Arthur","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1111\/j.1365-2222.2006.02606.x","article-title":"Regulation of the T cell response","volume":"36","author":"Romagnani","year":"2006","journal-title":"Clin. Exp. Allergy"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1016\/j.molmed.2017.09.007","article-title":"TNFR2: A Novel Target for Cancer Immunotherapy","volume":"23","author":"Vanamee","year":"2017","journal-title":"Trends Mol. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/nrd3030","article-title":"TNF receptor 2 pathway: Drug target for autoimmune diseases","volume":"9","author":"Faustman","year":"2010","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/nrd3669","article-title":"Inflammatory bone loss: Pathogenesis and therapeutic intervention","volume":"11","author":"Redlich","year":"2012","journal-title":"Nat. Rev. Drug Discov."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/9\/12\/784\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:37:39Z","timestamp":1760189859000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/9\/12\/784"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,26]]},"references-count":87,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["biom9120784"],"URL":"https:\/\/doi.org\/10.3390\/biom9120784","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,26]]}}}