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Exploring the Potential of Rosemary Derived Compounds (Rosmarinic and Carnosic Acids) as Cancer Therapeutics: Current Knowledge and Future Perspectives. 探索迷迭香衍生化合物(迷迭香酸和肉豆蔻酸)作为癌症治疗药物的潜力:当前知识与未来展望》。
IF 3.7 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-01 DOI: 10.4062/biomolther.2023.054
Fazila Sirajudeen, Lara J Bou Malhab, Yasser Bustanji, Moyad Shahwan, Karem H Alzoubi, Mohammad H Semreen, Jalal Taneera, Waseem El-Huneidi, Eman Abu-Gharbieh

Cancer is a global health challenge with high morbidity and mortality rates. However, conventional cancer treatment methods often have severe side effects and limited success rates. In the last decade, extensive research has been conducted to develop safe, and efficient alternative treatments that do not have the limitations of existing anticancer medicines. Plant-derived compounds have shown promise in cancer treatment for their anti-carcinogenic and anti-proliferative properties. Rosmarinic acid (RA) and carnosic acid (CA) are potent polyphenolic compounds found in rosemary (Rosmarinus officinalis) extract. They have been extensively studied for their biological properties, which include anti-diabetic, anti-inflammatory, antioxidant, and anticancer activities. In addition, RA and CA have demonstrated effective anti-proliferative properties against various cancers, making them promising targets for extensive research to develop candidate or leading compounds for cancer treatment. This review discusses and summarizes the anti-tumor effect of RA and CA against various cancers and highlights the involved biochemical and mechanistic pathways.

癌症是一项全球性的健康挑战,发病率和死亡率都很高。然而,传统的癌症治疗方法往往有严重的副作用,而且成功率有限。在过去的十年中,人们进行了广泛的研究,以开发安全、高效、不受现有抗癌药物限制的替代治疗方法。植物提取的化合物具有抗癌和抗增生的特性,因此在癌症治疗中大有可为。迷迭香酸(RA)和肉毒碱(CA)是迷迭香(Rosmarinus officinalis)提取物中的强效多酚化合物。人们对它们的生物特性进行了广泛的研究,其中包括抗糖尿病、抗炎、抗氧化和抗癌活性。此外,RA 和 CA 还对各种癌症具有有效的抗增殖特性,这使它们有望成为广泛研究的目标,以开发治疗癌症的候选或主导化合物。本综述讨论并总结了 RA 和 CA 对各种癌症的抗肿瘤作用,并重点介绍了其中涉及的生化和机理途径。
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引用次数: 0
Rosmarinic Acid Inhibits Ultraviolet B-Mediated Oxidative Damage via the AKT/ERK-NRF2-GSH Pathway In Vitro and In Vivo. 迷迭香酸通过体外和体内 AKT/ERK-NRF2-GSH 通路抑制紫外线 B 导致的氧化损伤
IF 3.7 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-01 DOI: 10.4062/biomolther.2023.179
Mei Jing Piao, Pattage Madushan Dilhara Jayatissa Fernando, Kyoung Ah Kang, Pincha Devage Sameera Madushan Fernando, Herath Mudiyanselage Udari Lakmini Herath, Young Ree Kim, Jin Won Hyun

Rosmarinic acid (RA) is a phenolic ester that protects human keratinocytes against oxidative damage induced by ultraviolet B (UVB) exposure, however, the mechanisms underlying its effects remain unclear. This study aimed to elucidate the cell signaling mechanisms that regulate the antioxidant activity of RA and confirm its cyto-protective role. To explore the signaling mechanisms, we used the human keratinocyte cell line HaCaT and SKH1 hairless mouse skin. RA enhanced glutamate-cysteine ligase catalytic subunit (GCLC) and glutathione synthetase (GSS) expression in HaCaT cells in a dose- and time-dependent manner. Moreover, RA induced nuclear factor erythroid-2-related factor 2 (NRF2) nuclear translocation and activated the signaling kinases protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, the ERK inhibitor U0126, and small interfering RNA (siRNA) gene silencing suppressed RA-enhanced GCLC, GSS, and NRF2 expression, respectively. Cell viability tests showed that RA significantly prevented UVB-induced cell viability decrease, whereas the glutathione (GSH) inhibitors buthionine sulfoximine, LY294002, and U0126 significantly reduced this effect. Moreover, RA protected against DNA damage and protein carbonylation, lipid peroxidation, and apoptosis caused by UVB-induced oxidative stress in a concentration-dependent manner in SKH1 hairless mouse skin tissues. These results suggest that RA protects against UVB-induced oxidative damage by activating AKT and ERK signaling to regulate NRF2 signaling and enhance GSH biosynthesis. Thus, RA treatment may be a promising approach to protect the skin from UVB-induced oxidative damage.

迷迭香酸(RA)是一种酚酯,可保护人类角质细胞免受紫外线 B(UVB)照射引起的氧化损伤,但其作用机制仍不清楚。本研究旨在阐明调节 RA 抗氧化活性的细胞信号传导机制,并确认其细胞保护作用。为了探索信号机制,我们使用了人类角质细胞系 HaCaT 和 SKH1 无毛小鼠皮肤。RA 能以剂量和时间依赖的方式增强 HaCaT 细胞中谷氨酸-半胱氨酸连接酶催化亚基(GCLC)和谷胱甘肽合成酶(GSS)的表达。此外,RA 还能诱导核因子红细胞-2 相关因子 2(NRF2)核转位,并激活信号激酶蛋白激酶 B(AKT)和细胞外信号调节激酶(ERK)。磷脂酰肌醇 3- 激酶(PI3K)抑制剂 LY294002、ERK 抑制剂 U0126 和小干扰 RNA(siRNA)基因沉默分别抑制了 RA 增强的 GCLC、GSS 和 NRF2 表达。细胞活力测试表明,RA 能明显阻止 UVB 诱导的细胞活力下降,而谷胱甘肽(GSH)抑制剂丁硫磺酰亚胺、LY294002 和 U0126 能明显降低这种效应。此外,在 SKH1 无毛小鼠皮肤组织中,RA 还能以浓度依赖的方式防止 UVB 诱导的氧化应激引起的 DNA 损伤、蛋白质羰基化、脂质过氧化和细胞凋亡。这些结果表明,RA 可通过激活 AKT 和 ERK 信号调节 NRF2 信号和增强 GSH 生物合成来抵御 UVB 诱导的氧化损伤。因此,RA治疗可能是一种保护皮肤免受紫外线诱导的氧化损伤的有效方法。
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引用次数: 0
Intermittent Fasting Modulates Immune Response by Generating Tregs via TGF-β Dependent Mechanisms in Obese Mice with Allergic Contact Dermatitis. 间歇性禁食通过TGF-β依赖性机制产生Tregs调节肥胖小鼠过敏性接触性皮炎的免疫反应
IF 3.7 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-01 Epub Date: 2023-07-10 DOI: 10.4062/biomolther.2023.053
Sang-Chul Han, Jung-Il Kang, Youn Kyung Choi, Hye-Jin Boo, Weon-Jong Yoon, Hee-Kyoung Kang, Eun-Sook Yoo

People with obesity maintain low levels of inflammation; therefore, their exposure to foreign antigens can trigger an excessive immune response. In people with obesity or allergic contact dermatitis (ACD), symptoms are exacerbated by a reduction in the number of regulatory T cells (Tregs) and IL-10/TGF-β-modified macrophages (M2 macrophages) at the inflammatory site. Benefits of intermittent fasting (IF) have been demonstrated for many diseases; however, the immune responses regulated by macrophages and CD4+T cells in obese ACD animal models are poorly understood. Therefore, we investigated whether IF suppresses inflammatory responses and upregulates the generation of Tregs and M2 macrophages in experimental ACD animal models of obese mice. The IF regimen relieved various ACD symptoms in inflamed and adipose tissues. We showed that the IF regimen upregulates Treg generation in a TGF-β-dependent manner and induces CD4+T cell hypo-responsiveness. IF-M2 macrophages, which strongly express TGF-β and inhibit CD4+T cell proliferation, directly regulated Treg differentiation from CD4+T cells. These results indicate that the IF regimen enhances the TGF-β-producing ability of M2 macrophages and that the development of Tregs keeps mice healthy against ACD exacerbated by obesity. Therefore, the IF regimen may ameliorate inflammatory immune disorders caused by obesity.

肥胖症患者的炎症水平较低,因此,他们接触到外来抗原时会引发过度的免疫反应。肥胖或过敏性接触性皮炎(ACD)患者的症状会因炎症部位调节性 T 细胞(Tregs)和 IL-10/TGF-β 修饰的巨噬细胞(M2 巨噬细胞)数量减少而加剧。间歇性禁食(IF)对许多疾病的益处已得到证实;然而,人们对肥胖 ACD 动物模型中由巨噬细胞和 CD4+T 细胞调节的免疫反应却知之甚少。因此,我们研究了在肥胖小鼠的实验性 ACD 动物模型中,IF 是否能抑制炎症反应并上调 Tregs 和 M2 巨噬细胞的生成。IF 方案缓解了炎症组织和脂肪组织中的各种 ACD 症状。我们发现,IF疗法以TGF-β依赖性方式上调Treg的生成,并诱导CD4+T细胞低反应性。强烈表达 TGF-β 并抑制 CD4+T 细胞增殖的 IF-M2 巨噬细胞可直接调节 CD4+T 细胞的 Treg 分化。这些结果表明,IF疗法能增强M2巨噬细胞产生TGF-β的能力,而Tregs的发展能使小鼠健康地抵御因肥胖而加重的ACD。因此,IF疗法可改善肥胖引起的炎症性免疫紊乱。
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引用次数: 0
Effects of Corticosterone on Beta-Amyloid-Induced Cell Death in SH-SY5Y Cells. 皮质酮对β-淀粉样蛋白诱导的 SH-SY5Y 细胞死亡的影响
IF 3.7 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-01 DOI: 10.4062/biomolther.2023.133
Bo Kyeong Do, Jung-Hee Jang, Gyu Hwan Park

Alzheimer's disease (AD) is a neurodegenerative disease characterized by neuronal cell death and memory impairment. Corticosterone (CORT) is a glucocorticoid hormone produced by the hypothalamic-pituitary-adrenal axis in response to a stressful condition. Excessive stress and high CORT levels are known to cause neurotoxicity and aggravate various diseases, whereas mild stress and low CORT levels exert beneficial actions under pathophysiological conditions. However, the effects of mild stress on AD have not been clearly elucidated yet. In this study, the effects of low (3 and 30 nM) CORT concentration on Aβ25-35-induced neurotoxicity in SH-SY5Y cells and underlying molecular mechanisms have been investigated. Cytotoxicity caused by Aβ25-35 was significantly inhibited by the low concentration of CORT treatment in the cells. Furthermore, CORT pretreatment significantly reduced Aβ25-35-mediated pro-apoptotic signals, such as increased Bim/Bcl-2 ratio and caspase-3 cleavage. Moreover, low concentration of CORT treatment inhibited the Aβ25-35-induced cyclooxygenase-2 and pro-inflammatory cytokine expressions, including tumor necrosis factor-α and interleukin-1β. Aβ25-35 resulted in intracellular accumulation of reactive oxygen species and lipid peroxidation, which were effectively reduced by the low CORT concentration. As a molecular mechanism, low CORT concentration activated the nuclear factor-erythroid 2-related factor 2, a redox-sensitive transcription factor mediating cellular defense and upregulating the expression of antioxidant enzymes, such as NAD(P)H:quinone oxidoreductase, glutamylcysteine synthetase, and manganese superoxide dismutase. These findings suggest that low CORT concentration exerts protective actions against Aβ25-35-induced neurotoxicity and might be used to treat and/or prevent AD.

阿尔茨海默病(AD)是一种神经退行性疾病,以神经元细胞死亡和记忆受损为特征。皮质酮(CORT)是一种糖皮质激素,由下丘脑-垂体-肾上腺轴在应激状态下产生。众所周知,过度应激和高水平的 CORT 会导致神经中毒并加重各种疾病,而轻度应激和低水平的 CORT 则会在病理生理条件下发挥有益的作用。然而,轻度应激对AD的影响尚未明确阐明。本研究探讨了低浓度(3 nM和30 nM)CORT对Aβ25-35诱导的SH-SY5Y细胞神经毒性的影响及其分子机制。低浓度 CORT 对 Aβ25-35 引起的细胞毒性有明显抑制作用。此外,CORT 预处理能明显减少 Aβ25-35 介导的促凋亡信号,如 Bim/Bcl-2 比值升高和 caspase-3 裂解。此外,低浓度 CORT 还能抑制 Aβ25-35 诱导的环氧化酶-2 和促炎细胞因子(包括肿瘤坏死因子-α 和白细胞介素-1β)的表达。Aβ25-35 导致细胞内活性氧积累和脂质过氧化,而低浓度 CORT 能有效减少活性氧积累和脂质过氧化。作为一种分子机制,低浓度 CORT 激活了核因子-红细胞 2 相关因子 2,这是一种对氧化还原反应敏感的转录因子,可介导细胞防御并上调 NAD(P)H:醌氧化还原酶、谷氨酰半胱氨酸合成酶和锰超氧化物歧化酶等抗氧化酶的表达。这些研究结果表明,低浓度 CORT 对 Aβ25-35 诱导的神经毒性具有保护作用,可用于治疗和/或预防注意力缺失症。
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引用次数: 0
Bortezomib Is Toxic but Induces Neurogenesis and Inhibits TUBB3 Degradation in Rat Neural Stem Cells. 硼替佐米有毒,但能诱导神经发生并抑制大鼠神经干细胞中 TUBB3 的降解
IF 3.7 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-01 Epub Date: 2023-12-11 DOI: 10.4062/biomolther.2023.134
Seung Yeon Sohn, Thin Thin San, Junhyung Kim, Hyun-Jung Kim

Bortezomib (BTZ) is a proteasome inhibitor used to treat multiple myeloma (MM). However, the induction of peripheral neuropathy is one of the major concerns in using BTZ to treat MM. In the current study, we have explored the effects of BTZ (0.01-5 nM) on rat neural stem cells (NSCs). BTZ (5 nM) induced cell death; however, the percentage of neurons was increased in the presence of mitogens. BTZ reduced the B-cell lymphoma 2 (Bcl-2)/Bcl-2 associated X protein ratio in proliferating NSCs and differentiated cells. Inhibition of βIII-tubulin (TUBB3) degradation was observed, but not inhibition of glial fibrillary acidic protein degradation, and a potential PEST sequence was solely found in TUBB3. In the presence of growth factors, BTZ increased cAMP response element-binding protein (CREB) phosphorylation, brain-derived neurotrophic factor (Bdnf) transcription, BDNF expression, and Tubb3 transcription in NSCs. However, in the neuroblastoma cell line, SH-SY5Y, BTZ (1-20 nM) only increased cell death without increasing CREB phosphorylation, Bdnf transcription, or TUBB3 induction. These results suggest that although BTZ induces cell death, it activates neurogenic signals and induces neurogenesis in NSCs.

硼替佐米(BTZ)是一种蛋白酶体抑制剂,用于治疗多发性骨髓瘤(MM)。然而,诱发周围神经病变是使用硼替佐米治疗多发性骨髓瘤的主要问题之一。在本研究中,我们探讨了BTZ(0.01-5 nM)对大鼠神经干细胞(NSCs)的影响。BTZ(5 nM)可诱导细胞死亡;然而,在有丝分裂原存在的情况下,神经元的比例会增加。BTZ 降低了增殖的 NSCs 和分化细胞中 b 细胞淋巴瘤 2(Bcl-2)/Bcl-2 相关 X 蛋白的比率。观察到βⅢ-tubulin(TUBB3)降解受到抑制,但胶质纤维酸性蛋白降解未受抑制,而且仅在TUBB3中发现了潜在的PEST序列。在有生长因子存在的情况下,BTZ 可增加 NSCs 中的 cAMP 反应元件结合蛋白(CREB)磷酸化、脑源性神经营养因子(Bdnf)转录、BDNF 表达和 Tubb3 转录。然而,在神经母细胞瘤细胞系 SH-SY5Y 中,BTZ(1-20 nM)只会增加细胞死亡,而不会增加 CREB 磷酸化、Bdnf 转录或 TUBB3 诱导。这些结果表明,虽然 BTZ 能诱导细胞死亡,但它能激活神经源信号并诱导 NSCs 的神经发生。
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引用次数: 0
Antiproliferative Activity of Piceamycin by Regulating Alpha-Actinin-4 in Gemcitabine-Resistant Pancreatic Cancer Cells. 通过调节吉西他滨耐药胰腺癌细胞中的α-Actinin-4,皮塞霉素具有抗增殖活性
IF 3.7 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-01 DOI: 10.4062/biomolther.2023.109
Jee-Hyung Lee, Jin Ho Choi, Kyung-Min Lee, Min Woo Lee, Ja-Lok Ku, Dong-Chan Oh, Yern-Hyerk Shin, Dae Hyun Kim, In Rae Cho, Woo Hyun Paik, Ji Kon Ryu, Yong-Tae Kim, Sang Hyub Lee, Sang Kook Lee

Although gemcitabine-based regimens are widely used as an effective treatment for pancreatic cancer, acquired resistance to gemcitabine has become an increasingly common problem. Therefore, a novel therapeutic strategy to treat gemcitabine-resistant pancreatic cancer is urgently required. Piceamycin has been reported to exhibit antiproliferative activity against various cancer cells; however, its underlying molecular mechanism for anticancer activity in pancreatic cancer cells remains unexplored. Therefore, the present study evaluated the antiproliferation activity of piceamycin in a gemcitabine-resistant pancreatic cancer cell line and patient-derived pancreatic cancer organoids. Piceamycin effectively inhibited the proliferation and suppressed the expression of alpha-actinin-4, a gene that plays a pivotal role in tumorigenesis and metastasis of various cancers, in gemcitabine-resistant cells. Long-term exposure to piceamycin induced cell cycle arrest at the G0/G1 phase and caused apoptosis. Piceamycin also inhibited the invasion and migration of gemcitabine-resistant cells by modulating focal adhesion and epithelial-mesenchymal transition biomarkers. Moreover, the combination of piceamycin and gemcitabine exhibited a synergistic antiproliferative activity in gemcitabine-resistant cells. Piceamycin also effectively inhibited patient-derived pancreatic cancer organoid growth and induced apoptosis in the organoids. Taken together, these findings demonstrate that piceamycin may be an effective agent for overcoming gemcitabine resistance in pancreatic cancer.

尽管以吉西他滨为基础的治疗方案被广泛用作胰腺癌的有效治疗手段,但吉西他滨获得性耐药性已成为一个日益普遍的问题。因此,迫切需要一种新的治疗策略来治疗吉西他滨耐药的胰腺癌。据报道,皮卡霉素对多种癌细胞具有抗增殖活性;然而,其在胰腺癌细胞中抗癌活性的潜在分子机制仍有待探索。因此,本研究评估了皮卡霉素在吉西他滨耐药胰腺癌细胞系和患者胰腺癌器官组织中的抗增殖活性。皮卡霉素能有效抑制吉西他滨耐药细胞的增殖,并抑制α-肌动蛋白-4的表达。长期暴露于皮卡霉素可诱导细胞周期停滞在 G0/G1 期,并导致细胞凋亡。皮卡霉素还能通过调节病灶粘附和上皮-间质转化生物标志物,抑制吉西他滨耐药细胞的侵袭和迁移。此外,皮卡霉素和吉西他滨的联合疗法对吉西他滨耐药细胞具有协同抗增殖活性。皮卡霉素还能有效抑制患者胰腺癌器官组织的生长,并诱导器官组织凋亡。综上所述,这些研究结果表明,皮卡霉素可能是克服胰腺癌吉西他滨耐药性的有效药物。
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引用次数: 0
Licochalcone C Inhibits the Growth of Human Colorectal Cancer HCT116 Cells Resistant to Oxaliplatin. 甘草查尔酮 C 可抑制对奥沙利铂耐药的人类结直肠癌 HCT116 细胞的生长。
IF 3.7 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-01 DOI: 10.4062/biomolther.2023.167
Seung-On Lee, Sang Hoon Joo, Jin-Young Lee, Ah-Won Kwak, Ki-Taek Kim, Seung-Sik Cho, Goo Yoon, Yung Hyun Choi, Jin Woo Park, Jung-Hyun Shim

Licochalcone C (LCC; PubChem CID:9840805), a chalcone compound originating from the root of Glycyrrhiza inflata, has shown anticancer activity against skin cancer, esophageal squamous cell carcinoma, and oral squamous cell carcinoma. However, the therapeutic potential of LCC in treating colorectal cancer (CRC) and its underlying molecular mechanisms remain unclear. Chemotherapy for CRC is challenging because of the development of drug resistance. In this study, we examined the antiproliferative activity of LCC in human colorectal carcinoma HCT116 cells, oxaliplatin (Ox) sensitive and Ox-resistant HCT116 cells (HCT116-OxR). LCC significantly and selectively inhibited the growth of HCT116 and HCT116-OxR cells. An in vitro kinase assay showed that LCC inhibited the kinase activities of EGFR and AKT. Molecular docking simulations using AutoDock Vina indicated that LCC could be in ATP-binding pockets. Decreased phosphorylation of EGFR and AKT was observed in the LCC-treated cells. In addition, LCC induced cell cycle arrest by modulating the expression of cell cycle regulators p21, p27, cyclin B1, and cdc2. LCC treatment induced ROS generation in CRC cells, and the ROS induction was accompanied by the phosphorylation of JNK and p38 kinases. Moreover, LCC dysregulated mitochondrial membrane potential (MMP), and the disruption of MMP resulted in the release of cytochrome c into the cytoplasm and activation of caspases to execute apoptosis. Overall, LCC showed anticancer activity against both Ox-sensitive and Ox-resistant CRC cells by targeting EGFR and AKT, inducing ROS generation and disrupting MMP. Thus, LCC may be potential therapeutic agents for the treatment of Ox-resistant CRC cells.

甘草查尔酮 C(LCC;PubChem CID:9840805)是一种源自甘草根部的查尔酮化合物,对皮肤癌、食道鳞状细胞癌和口腔鳞状细胞癌具有抗癌活性。然而,LCC 在治疗结直肠癌(CRC)方面的治疗潜力及其潜在的分子机制仍不清楚。由于耐药性的产生,对 CRC 的化疗具有挑战性。在这项研究中,我们检测了 LCC 在人类结直肠癌 HCT116 细胞、奥沙利铂(Ox)敏感和奥沙利铂耐药 HCT116 细胞(HCT116-OxR)中的抗增殖活性。LCC 能明显且选择性地抑制 HCT116 和 HCT116-OxR 细胞的生长。体外激酶试验表明,LCC 可抑制表皮生长因子受体和 AKT 的激酶活性。使用 AutoDock Vina 进行的分子对接模拟表明,LCC 可能位于 ATP 结合口袋中。经 LCC 处理的细胞中表皮生长因子受体和 AKT 的磷酸化程度降低。此外,LCC 通过调节细胞周期调节因子 p21、p27、细胞周期蛋白 B1 和 cdc2 的表达,诱导细胞周期停滞。LCC诱导CRC细胞产生ROS,ROS诱导伴随着JNK和p38激酶的磷酸化。此外,LCC 还能使线粒体膜电位(MMP)失调,MMP 失调会导致细胞色素 c 释放到细胞质中,并激活 caspases 以执行细胞凋亡。总之,LCC 通过靶向表皮生长因子受体和 AKT、诱导 ROS 生成和破坏 MMP,对氧化敏感和氧化耐药的 CRC 细胞都显示出抗癌活性。因此,LCC 可能是治疗耐氧化 CRC 细胞的潜在治疗药物。
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引用次数: 0
Therapeutic Effects of (+)-Afzelechin on Particulate Matter-Induced Pulmonary Injury. (+)-Afzelechin 对微粒物质引起的肺损伤的治疗作用
IF 3.7 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-01 DOI: 10.4062/biomolther.2023.187
Sanghee Cho, Yun Jin Park, Jong-Sup Bae

Particulate matter (PM) constitutes a hazardous blend of organic and inorganic particles that poses health risks. Inhalation of fine airborne PM with a diameter of ≤ 2.5 μm (PM2.5) can lead to significant lung impairments. (+)-afzelechin (AZC), a natural compound sourced from Bergenia ligulata, boasts a range of attributes, including antioxidant, antimicrobial, anticancer, and cardiovascular effects. However, knowledge about the therapeutic potential of AZC for patients with PM2.5-induced lung injuries remains limited. Thus, in this study, we investigated the protective attributes of AZC against lung damage caused by PM2.5 exposure. AZC was administered to the mice 30 min after intratracheal instillation of PM2.5. Various parameters, such as changes in lung tissue wet/dry (W/D) weight ratio, total protein/total cell ratio, lymphocyte counts, levels of inflammatory cytokines in bronchoalveolar lavage fluid (BALF), vascular permeability, and histology, were evaluated in mice exposed to PM2.5. Data demonstrated that AZC mitigated lung damage, reduced W/D weight ratio, and curbed hyperpermeability induced by PM2.5 exposure. Furthermore, AZC effectively lowered plasma levels of inflammatory cytokines produced by PM2.5 exposure. It reduced the total protein concentration in BALF and successfully alleviated PM2.5-induced lymphocytosis. Additionally, AZC substantially diminished the expression levels of Toll-like receptors 4 (TLR4), MyD88, and autophagy-related proteins LC3 II and Beclin 1. In contrast, it elevated the protein phosphorylation of the mammalian target of rapamycin (mTOR). Consequently, the anti-inflammatory attribute of AZC positions it as a promising therapeutic agent for mitigating PM2.5-induced lung injuries by modulating the TLR4-MyD88 and mTOR-autophagy pathways.

微粒物质(PM)是一种有害的有机和无机颗粒混合体,对健康构成威胁。吸入空气中直径≤ 2.5 μm(PM2.5)的细颗粒物会导致严重的肺部损伤。(+)-阿夫儿茶素(AZC)是一种天然化合物,来源于岩白菜(Bergenia ligulata),具有一系列特性,包括抗氧化、抗菌、抗癌和心血管作用。然而,有关AZC对PM2.5引起的肺损伤患者的治疗潜力的知识仍然有限。因此,在本研究中,我们研究了 AZC 对 PM2.5 暴露引起的肺损伤的保护特性。在小鼠气管内灌入 PM2.5 30 分钟后给其注射 AZC。对暴露于 PM2.5 的小鼠的各种参数进行了评估,如肺组织湿/干(W/D)重量比、总蛋白/总细胞比、淋巴细胞计数、支气管肺泡灌洗液(BALF)中炎症细胞因子水平、血管通透性和组织学的变化。数据显示,AZC 可减轻 PM2.5 暴露引起的肺损伤、降低 W/D 重量比并抑制高渗透性。此外,AZC 还能有效降低 PM2.5 暴露所产生的血浆炎症细胞因子水平。它降低了 BALF 中的总蛋白浓度,并成功缓解了 PM2.5 诱导的淋巴细胞增多。此外,AZC 还大大降低了 Toll 样受体 4(TLR4)、MyD88 以及自噬相关蛋白 LC3 II 和 Beclin 1 的表达水平。因此,AZC 的抗炎特性使其成为一种有前途的治疗药物,可通过调节 TLR4-MyD88 和 mTOR 自噬途径来减轻 PM2.5 引起的肺损伤。
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引用次数: 0
Biased Dopamine D2 Receptors Exhibit Distinct Intracellular Trafficking Properties and ERK Activation in Different Subcellular Domains. 有偏向的多巴胺 D2 受体在不同的亚细胞区表现出不同的胞内贩运特性和 ERK 激活。
IF 3.7 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-01 Epub Date: 2023-07-19 DOI: 10.4062/biomolther.2023.033
Shujie Wang, Lulu Peng, Kyeong-Man Kim

Biased signaling or functional selectivity refers to the ability of an agonist or receptor to selectively activate a subset of transducers such as G protein and arrestin in the case of G protein-coupled receptors (GPCRs). Although signaling through arrestin has been reported from various GPCRs, only a few studies have examined side-by-side how it differs from signaling via G protein. In this study, two signaling pathways were compared using dopamine D2 receptor (D2R) mutants engineered via the evolutionary tracer method to selectively transduce signals through G protein or arrestin (D2G and D2Arr, respectively). D2G mediated the inhibition of cAMP production and ERK activation in the cytoplasm. D2Arr, in contrast, mediated receptor endocytosis accompanied by arrestin ubiquitination and ERK activation in the nucleus as well as in the cytoplasm. D2Arr-mediated ERK activation occurred in a manner dependent on arrestin3 but not arrestin2, accompanied by the nuclear translocation of arrestin3 via importin1. D2R-mediated ERK activation, which occurred in both the cytosol and nucleus, was limited to the cytosol when cellular arrestin3 was depleted. This finding supports the results obtained with D2Arr and D2G. Taken together, these observations indicate that biased signal transduction pathways activate distinct downstream mechanisms and that the subcellular regions in which they occur could be different when the same effectors are involved. These findings broaden our understanding on the relation between biased receptors and the corresponding downstream signaling, which is critical for elucidating the functional roles of biased pathways.

偏向信号传导或功能选择性是指激动剂或受体选择性激活子集传导因子的能力,如 G 蛋白和 G 蛋白偶联受体(GPCR)中的捕获素。尽管各种 GPCR 都报道了通过 arrestin 发出信号的情况,但只有少数研究并列研究了它与通过 G 蛋白发出信号的不同之处。在本研究中,通过进化示踪法设计的多巴胺 D2 受体(D2R)突变体选择性地通过 G 蛋白或 arrestin(分别为 D2G 和 D2Arr)传递信号,比较了两种信号传递途径。D2G 可抑制细胞质中 cAMP 的产生和 ERK 的激活。与此相反,D2Arr 介导的受体内吞伴随着 arrestin 泛素化以及细胞核和细胞质中的 ERK 激活。D2Arr 介导的 ERK 激活是以依赖于 arrestin3 而非 arrestin2 的方式发生的,同时伴随着 arrestin3 通过导入素 1 的核转位。D2R介导的ERK活化同时发生在细胞质和细胞核中,但当细胞抑制素3被耗尽时,ERK活化仅限于细胞质。这一发现支持了 D2Arr 和 D2G 的研究结果。综上所述,这些观察结果表明,有偏向的信号转导途径会激活不同的下游机制,而且当涉及相同的效应因子时,它们发生作用的亚细胞区域也可能不同。这些发现拓宽了我们对偏倚受体与相应下游信号转导之间关系的理解,这对阐明偏倚途径的功能作用至关重要。
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引用次数: 0
Anti-Inflammatory Herbal Extracts and Their Drug Discovery Perspective in Atopic Dermatitis. 抗炎草药提取物及其在特应性皮炎中的药物发现前景。
IF 3.7 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-01 DOI: 10.4062/biomolther.2023.102
Jae-Won Lee, Eun-Nam Kim, Gil-Saeng Jeong

Atopic dermatitis (AD) is an allergic disorder characterized by skin inflammation. It is well known that the activation of various inflammatory cells and the generation of inflammatory molecules are closely linked to the development of AD. There is accumulating evidence demonstrating the beneficial effects of herbal extracts (HEs) on the regulation of inflammatory response in both in vitro and in vivo studies of AD. This review summarizes the anti-atopic effects of HEs and its associated underlying mechanisms, with a brief introduction of in vitro and in vivo experiment models of AD based on previous and recent studies. Thus, this review confirms the utility of HEs for AD therapy.

特应性皮炎(AD)是一种以皮肤炎症为特征的过敏性疾病。众所周知,各种炎症细胞的活化和炎症分子的产生与特应性皮炎的发生密切相关。越来越多的证据表明,草药提取物(HEs)在体外和体内研究中对调节 AD 的炎症反应均有益处。本综述总结了草药提取物的抗变应性作用及其相关的内在机制,并根据以往和近期的研究简要介绍了 AD 的体外和体内实验模型。因此,这篇综述证实了 HEs 在治疗 AD 方面的实用性。
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引用次数: 0
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Biomolecules & Therapeutics
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