TPCA-1作為IKKβ抑制劑在骨關(guān)節(jié)炎、炎癥損傷及干細(xì)胞等研究中的應(yīng)用
TPCA-1（AbMole，M2300）是一種選擇性IκB激酶β（IKKβ）抑制劑，通過阻斷NF-κB信號(hào)通路發(fā)揮抗炎和調(diào)控細(xì)胞功能的作用。
綜上，TPCA-1（AbMole，M2300）在多種細(xì)胞系（如豬軟骨細(xì)胞、HeLa細(xì)胞、HSPCs、小鼠巨噬細(xì)胞、成纖維細(xì)胞）及小鼠疾病模型中展現(xiàn)出穩(wěn)定的NF-κB通路抑制活性。
范例詳解
AAPS PharmSciTech. 2020 Nov 2;21(8):298.
實(shí)驗(yàn)人員構(gòu)建了一種金納米籠（AuNCs），用于負(fù)載AbMole的TPCA-1（AbMole，M2300），TPCA-1是一種選擇性IKK-2抑制劑，通過抑制NF-κB通路發(fā)揮抗炎作用。結(jié)果顯示TPCA-1與金納米籠的固有抗炎特性（通過減少TLR4和NF-κB表達(dá)）形成協(xié)同效應(yīng)，并在關(guān)節(jié)炎（AIA）小鼠模型中改善了爪部腫大和骨損傷。
參考文獻(xiàn)及鳴謝
[1] Bhatti, F. U. R.; Hasty, K. A.; Cho, H. Anti-inflammatory role of TPCA-1 encapsulated nanosomes in porcine chondrocytes against TNF-alpha stimulation. Inflammopharmacology 2019, 27 (5), 1011-1019.
[2] Tao, L.; Liu, S.; Xiong, J.; et al. IL-1beta promotes cervical cancer through activating NF-kappaB/CCL-2. International journal of clinical and experimental pathology 2021, 14 (4), 426-433.
[3] Sun, Q.; Fu, Y.; Zhu, X.; et al. Continuous NF-kappaB pathway inhibition promotes expansion of human phenotypical hematopoietic stem/progenitor cells through metabolism regulation. Experimental cell research 2021, 399 (2), 112468.
[4] Kiaei, N.; Malik, A.; Idahosa, S. O.; et al. Python-derived 16alpha-Hydroxylated Bile Acid, Pythocholic Acid is a ligand for TGR5, not farnesoid X receptors and vitamin D receptors. Biochemical and biophysical research communications 2025, 751, 151453.
[5] Jung, B.; Bhatti, F. U.; Mummareddy, H.; et al. Targeted nanosome delivery of TPCA-1 for modulating inflammation in a mouse model of post-traumatic osteoarthritis. Nanomedicine : nanotechnology, biology, and medicine 2025, 67, 102827.
[6] Zhao, J. Hyaluronic Acid-Modified and TPCA-1-Loaded Gold Nanocages Alleviate Inflammation. Pharmaceutics 2019, 11 (3).
[7] Zhao, L.; Liu, J.; Li, X.; et al. De Novo Development of Bioresponsive Nanoparticles With Antimicrobial Activity to Treat Bacterial Infections. Advanced healthcare materials 2026, e05683.
[8] Wang, B.; Bai, S.; Wang, J.; et al. TPCA-1 negatively regulates inflammation mediated by NF-kappaB pathway in mouse chronic periodontitis model. Molecular oral microbiology 2021, 36 (3), 192-201.
[9] Wang, Z.; Yang, J.; Yang, Y.; et al. Targeted and Combined TPCA-1-Gold Nanocage Therapy for In Vivo Treatment of Inflammatory Arthritis. AAPS PharmSciTech 2020, 21 (8), 298.
在細(xì)胞實(shí)驗(yàn)中，TPCA-1以10 μM的濃度顯著抑制TNF-α誘導(dǎo)的豬軟骨細(xì)胞基質(zhì)金屬蛋白酶-13（MMP-13）的表達(dá)，并阻斷p65核轉(zhuǎn)位；該濃度下還可有效提升軟骨細(xì)胞在炎癥應(yīng)激下的存活率[1]。TPCA-1在HeLa細(xì)胞中，顯著抑制IL-1β誘導(dǎo)的CCL-2釋放，并抑制NF-κB活化及p65核轉(zhuǎn)位[2]。在臍帶血來源的CD34⁺造血干細(xì)胞/祖細(xì)胞（HSPCs）培養(yǎng)體系中，100 nM 的TPCA-1（AbMole，M2300）（CAS No.：507475-17-4）處理10天可顯著促進(jìn)總細(xì)胞、CD34⁺CD38⁻及多能干性表型（CD34⁺CD38⁻CD45RA⁻CD90⁺CD49f⁺）細(xì)胞的增殖，并增強(qiáng)其二次集落形成能力，同時(shí)下調(diào)線粒體生物合成相關(guān)基因（如Pgc1α、ClpP、Hsp10、Hsp60），降低線粒體質(zhì)量與膜電位，減少線粒體ROS水平，促進(jìn)糖酵解代謝[3]。此外，TPCA-1在小鼠腹腔巨噬細(xì)胞中，能顯著降低Lipopolysaccharides（LPS，脂多糖）誘導(dǎo)的TNF-α表達(dá)[4]；在成纖維細(xì)胞中，TPCA-1預(yù)處理可抑制視黃醇（Vitamin A）誘導(dǎo)的單核細(xì)胞趨化蛋白-1（MCP-1）分泌，提示視黃醇的作用依賴于NF-κB通路。
在動(dòng)物模型方面，TPCA-1（AbMole，M2300）被廣泛用于小鼠疾病模型研究：在創(chuàng)傷后骨關(guān)節(jié)炎小鼠（PTOA）模型中，通過循環(huán)機(jī)械負(fù)荷法誘導(dǎo)小鼠的關(guān)節(jié)損傷，隨后在其關(guān)節(jié)內(nèi)給予100 μM TPCA-1溶液或負(fù)載TPCA-1的靶向納米囊泡（nanosomes），結(jié)果顯示能顯著降低MMP13、IL1β、HIF-2α等炎癥與分解代謝相關(guān)基因表達(dá)，減少血清NO和LDH水平，并通過IVIS成像（一種活體成像技術(shù)）與組織學(xué)評(píng)估證實(shí)了TPCA-1對(duì)軟骨結(jié)構(gòu)與功能的保護(hù)作用[5]；在膠原（Collagenase）誘導(dǎo)的關(guān)節(jié)炎（AIA）小鼠模型中，將TPCA-1（AbMole，M2300）負(fù)載于透明質(zhì)酸修飾的金納米籠（HA-AuNCs/T/P）后，有效劑量可從20 mg/kg大幅降至0.016 mg/kg，顯著抑制關(guān)節(jié)腫脹及軟骨骨破壞，并有效降低TNF-α和IL-6水平[6]；在急性肺損傷和腹膜炎小鼠模型中，TPCA-1被包載于表面修飾抗ICAM-1抗體的pH響應(yīng)型納米顆粒（TPCA-1@NPs-anti-ICAM-1），經(jīng)靜脈注射后可靶向炎癥部位，在酸性微環(huán)境中釋放藥物，顯著減少炎癥細(xì)胞浸潤(rùn)[7]；在慢性牙周炎小鼠模型中，采用結(jié)扎法誘導(dǎo)疾病，靜脈注射TPCA-1可抑制牙齦組織中促炎因子表達(dá)及NF-κB信號(hào)活化[8]。
綜上，TPCA-1（AbMole，M2300）在多種細(xì)胞系（如豬軟骨細(xì)胞、HeLa細(xì)胞、HSPCs、小鼠巨噬細(xì)胞、成纖維細(xì)胞）及小鼠疾病模型中展現(xiàn)出穩(wěn)定的NF-κB通路抑制活性。
范例詳解
AAPS PharmSciTech. 2020 Nov 2;21(8):298.
實(shí)驗(yàn)人員構(gòu)建了一種金納米籠（AuNCs），用于負(fù)載AbMole的TPCA-1（AbMole，M2300），TPCA-1是一種選擇性IKK-2抑制劑，通過抑制NF-κB通路發(fā)揮抗炎作用。結(jié)果顯示TPCA-1與金納米籠的固有抗炎特性（通過減少TLR4和NF-κB表達(dá)）形成協(xié)同效應(yīng)，并在關(guān)節(jié)炎（AIA）小鼠模型中改善了爪部腫大和骨損傷。
Targeted and Combined TPCA-1-Gold Nanocage Therapy for In Vivo Treatment of Inflammatory Arthritis[9]
參考文獻(xiàn)及鳴謝
[1] Bhatti, F. U. R.; Hasty, K. A.; Cho, H. Anti-inflammatory role of TPCA-1 encapsulated nanosomes in porcine chondrocytes against TNF-alpha stimulation. Inflammopharmacology 2019, 27 (5), 1011-1019.
[2] Tao, L.; Liu, S.; Xiong, J.; et al. IL-1beta promotes cervical cancer through activating NF-kappaB/CCL-2. International journal of clinical and experimental pathology 2021, 14 (4), 426-433.
[3] Sun, Q.; Fu, Y.; Zhu, X.; et al. Continuous NF-kappaB pathway inhibition promotes expansion of human phenotypical hematopoietic stem/progenitor cells through metabolism regulation. Experimental cell research 2021, 399 (2), 112468.
[4] Kiaei, N.; Malik, A.; Idahosa, S. O.; et al. Python-derived 16alpha-Hydroxylated Bile Acid, Pythocholic Acid is a ligand for TGR5, not farnesoid X receptors and vitamin D receptors. Biochemical and biophysical research communications 2025, 751, 151453.
[5] Jung, B.; Bhatti, F. U.; Mummareddy, H.; et al. Targeted nanosome delivery of TPCA-1 for modulating inflammation in a mouse model of post-traumatic osteoarthritis. Nanomedicine : nanotechnology, biology, and medicine 2025, 67, 102827.
[6] Zhao, J. Hyaluronic Acid-Modified and TPCA-1-Loaded Gold Nanocages Alleviate Inflammation. Pharmaceutics 2019, 11 (3).
[7] Zhao, L.; Liu, J.; Li, X.; et al. De Novo Development of Bioresponsive Nanoparticles With Antimicrobial Activity to Treat Bacterial Infections. Advanced healthcare materials 2026, e05683.
[8] Wang, B.; Bai, S.; Wang, J.; et al. TPCA-1 negatively regulates inflammation mediated by NF-kappaB pathway in mouse chronic periodontitis model. Molecular oral microbiology 2021, 36 (3), 192-201.
[9] Wang, Z.; Yang, J.; Yang, Y.; et al. Targeted and Combined TPCA-1-Gold Nanocage Therapy for In Vivo Treatment of Inflammatory Arthritis. AAPS PharmSciTech 2020, 21 (8), 298.
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