R Monteiro Ana, Barbosa Daniel José, Remião Fernando, Silva Renata
Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases that affect millions of people worldwide, with both prevalence and incidence increasing with age. It is characterized by cognitive decline associated, specifically, with degeneration of cholinergic neurons. The problem of this disease is even more fundamental as the available therapies remain fairly limited and mainly focused on symptoms' relief. Although the aetiology of the disease remains elusive, two main pathological hallmarks are described: i) presence of neurofibrillary tangles formed by unfolded protein aggregates (hyperphosphorylated Tau protein) and ii) presence of extracellular aggregates of amyloid-beta peptide...
March 28, 2023: Biochemical Pharmacology
Yuping Yang, Xiaoxiao Fan, Yongjian Liu, Danyang Ye, Cen Liu, Hongliu Yang, Zhijun Su, Yuanyuan Zhang, Yonggang Liu
Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is an evolutionarily conserved protein kinase and the most studied member of the Dual-specificity tyrosine-regulated kinase (DYRK) family. It has been shown that it participates in the development of plenty of diseases, and both the low or high expression of DYRK1A protein could lead to disorder. Thus, DYRK1A is recognized as a key target for the therapy for these diseases, and the studies on natural or synthetic DYRK1A inhibitors have become more and more popular...
March 27, 2023: Biochemical Pharmacology
Yingying Tian, Longyan Wang, Xiaonan Chen, Yanan Zhao, Ailin Yang, Huiming Huang, Lishan Ouyang, Daoran Pang, Jinxin Xie, Dongxiao Liu, Pengfei Tu, Jun Li, Zhongdong Hu
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and is extremely malignant in nature. It is an important way to discover anti-cancer drugs from natural products at present. (R)-7,3'-dihydroxy-4'-methoxy-8-methylflavane (DHMMF), a natural flavonoid, was isolated from Resina Draconis which is the red resin from Dracaena cochinchinensis (Lour.) S. C. Chen. However, the anti-hepatoma effect and underlying mechanisms of DHMMF remain unclear. Herein, we demonstrated that DHMMF treatment significantly inhibited the proliferation of human hepatoma HepG2 and SK-HEP-1 cells...
March 24, 2023: Biochemical Pharmacology
Xiaodi Zhang, Zhengfang Sun, Ying Zhang, Liuzhu Pan, Wei Jiang, Hui Dong, Zhengxin Jin, Jianning Kang, Ronghan Liu, Bin Ning
Osteoporosis is a common inflammaging-related condition, where long-term accumulation of pro-inflammatory cytokines causes massive bone loss. Periplocin, a cardiotonic steroid isolated from Periploca forrestii, has been proved to reduce inflammation in several inflammatory diseases, such as rheumatoid arthritis. However, its effect and mechanism of inflammation in osteoporosis, in which pro-inflammatory factors accelerate bone loss, has not been well demonstrated. In this study, periplocin attenuated receptor activator of nuclear factor-κB (RANKL)-induced osteoclast differentiation of bone marrow-derived macrophages (BMMs) and RAW264...
March 24, 2023: Biochemical Pharmacology
Tuling Li, Xiaomeng Li, Yixian Hao, Jinpeng Liu, Bo Bao, Zhaohui Yang, Mengxian Zhou, Huixia Wei, Ruixue Zhang, Jiawen Hao, Wenjun Jiang, Hongsheng Bi, Dadong Guo
Myopia is one of the most common eye diseases in children and adolescents worldwide. Currently, there is no effective treatment in clinical practice. Ocular tissue fibrosis is involved in the development of myopia and this study aimed to investigate the effect of miR-138-5p on choroidal fibrosis in myopic guinea pigs via regulating the HIF-1α signaling pathway. First, guinea pigs were randomly divided into a normal control (NC) group, a lens-induced myopia (LIM) group, a LIM + miR-138-5p-carried Lentivirus treatment (LV) group, and a LIM + miR-138-5p-Vector treatment (VECTOR) group...
March 24, 2023: Biochemical Pharmacology
Hye-Young Min, Yijae Lim, Hyukjin Kwon, Hye-Jin Boo, Seung Yeob Hyun, Junhwa Hong, Suckchang Hong, Ho-Young Lee
The heat shock protein (HSP) system is essential for the conformational stability and function of several proteins. Therefore, the development of efficacious HSP-targeting anticancer agents with minimal toxicity is required. We previously demonstrated that evodiamine is an anticancer agent that targets HSP70 in non-small cell lung cancer (NSCLC) cells. In this study, we synthesized a series of evodiamine derivatives with improved efficacy and limited toxicity. Among the 14 evodiamine derivatives, EV408 (10-hydroxy-14-methyl-8,13,13b,14-tetrahydroindolo [2',3':3,4]pyrido[2,1-b]quinazolin-5(7H)-one) exhibited the most potent inhibitory effects on viability and colony formation under anchorage-dependent and -independent culture conditions in various human NSCLC cells, including those that are chemoresistant, by inducing apoptosis...
March 21, 2023: Biochemical Pharmacology
Jiahui Zhu, Guihong Li, Qiang Huang, Jikai Wen, Yiqun Deng, Jun Jiang
T-2 toxin is a hazardous environmental pollutant that poses a risk to both farm animals and humans. Our previous research has reported that T-2 toxin highly induced the expression of human cytochrome P450 1A1 (CYP1A1), which may be a representative inducible marker of T-2 toxin and mediate the toxicity of T-2 toxin. In this study, we found that T-2 toxin decreased the DNA methylation levels of the CpG islands on the CYP1A1 promoter by inducing the expression of eleven translocation family protein 3 (TET3) and facilitating its binding to the promoter...
March 20, 2023: Biochemical Pharmacology
Zahra Alimardan, Maryam Abbasi, Farshid Hasanzadeh, Mahmud Aghaei, Ghadamali Khodarahmi, Khosrow Kashfi
Heat shock proteins (Hsp) and FoxM1 have significant roles in carcinogenesis. According to their relative molecular weight, Hsps are divided into Hsp110, Hsp90, Hsp70, Hsp60, Hsp40, and small Hsps. Hsp70 can play essential functions in cancer initiation and is overexpressed in several human cancers. Hsp70, in combination with cochaperones HIP and HOP, refolds partially denatured proteins and acts as a cochaperone for Hsp90. Also, Hsp70, in combination with BAG3, regulates the FoxM1 signaling pathway. FoxM1 protein is a transcription factor of the Forkhead family that is overexpressed in most human cancers and is involved in many cancers' development features, including proliferation, migration, invasion, angiogenesis, metastasis, and resistance to apoptosis...
March 15, 2023: Biochemical Pharmacology
Jing-Ting Chiou, Chia-Chi Hsu, Ying-Chung Hong, Yuan-Chin Lee, Long-Sen Chang
Although cytarabine (Ara-C) is the mainstay of treatment for acute myeloid leukemia (AML), its cytotoxic mechanisms for inducing apoptosis are poorly understood. Therefore, we investigated the Ara-C-induced cell death pathway in human AML U937 cells. Ara-C-induced downregulation of MCL1 is associated with the induction of mitochondrial depolarization and apoptosis. Ara-C triggered NOX4-mediated ROS production, which in turn activated p38 MAPK but inactivated AKT. Ara-C-induced DNA damage modulates p38 MAPK activation without affecting AKT inactivation in U937 cells...
March 14, 2023: Biochemical Pharmacology
Huihui Chen, Chongqing Tan, Zhiruo Wang, Jie Zha, Hong Liu, Zheng Dong, Guochun Chen
Conventional glucocorticoid (GC) treatment has a long-term influence on T-cell immunity, resulting in an increased risk of opportunistic infection after drug withdrawal. The underlying mechanisms remain ambiguous. This study demonstrated that long-term GC treatment induced persistent lymphopenia in patients with primary glomerular disease. GCs continuously suppressed the proportion of CD4+ T cells even after the daily dose was tapered down to the physiologic equivalences, leading to a significant decline of the CD4/CD8 ratio...
March 14, 2023: Biochemical Pharmacology
HaiShan Li, Wei Deng, QiuLi Qin, YueWei Lin, Teng Liu, GuoYe Mo, Yang Shao, YongChao Tang, Kai Yuan, LiangLiang Xu, YongXian Li, ShunCong Zhang
Osteoporosis, an immune disease characterized by bone mass loss and microstructure destruction, is often seen in postmenopausal women. Isoimperatorin (ISO), a bioactive, natural furanocoumarin isolated from many traditional Chinese herbal medicines, has therapeutic effects against various diseases; however, its effect on bone homeostasis remains unclear. In this study, we investigated the effect of ISO on the differentiation and activation of osteoclast and its molecular mechanism in vitro, and evaluated the effect of ISO on bone metabolism by ovariectomized (OVX) rat model...
March 13, 2023: Biochemical Pharmacology
Riccardo V Mancuso, Gisbert Schneider, Marianne Hürzeler, Martin Gut, Jonas Zurflüh, Werner Breitenstein, Jamal Bouitbir, Felix Reisen, Kenneth Atz, Claus Ehrhardt, Urs Duthaler, Daniel Gygax, Albrecht G Schmidt, Stephan Krähenbühl, Gabriele Weitz-Schmidt
Integrins are a family of cell surface receptors well-recognized for their therapeutic potential in a wide range of diseases. However, the development of integrin targeting medications has been impacted by unexpected downstream effects, reflecting originally unforeseen interference with the bidirectional signalling and cross-communication of integrins. We here selected one of the most severely affected target integrins, the integrin lymphocyte function-associated antigen-1 (LFA-1, αL β2 , CD11a/CD18), as a prototypic integrin to systematically assess and overcome these known shortcomings...
March 13, 2023: Biochemical Pharmacology
Yinfeng Lyu, Meishu Tan, Meng Xue, Wenjing Hou, Chengyi Yang, Anshan Shan, Wensheng Xiang, Baojing Cheng
Antimicrobial peptides, as an integral part of the innate immune system, kill bacteria through a special mechanism of action, making them less susceptible to drug resistance. However, Lipopolysaccharide (LPS) as the permeation barrier on the bacterial membrane, inhibits the antibacterial activity of antimicrobial peptides and triggers the inflammatory response. GWKRKRFG is an LPS binding sequence with a β-boomerang motif that can be linked to antimicrobial peptides to enhance their LPS affinity and reduce the possibility of LPS-induced inflammatory responses...
March 13, 2023: Biochemical Pharmacology
Takuma Isshiki, Megan Vierhout, Safaa Naiel, Pareesa Ali, Parichehr Yazdanshenas, Vaishnavi Kumaran, Zi Yang, Anna Dvorkin-Gheva, Anthony F Rullo, Martin R J Kolb, Kjetil Ask
Idiopathic pulmonary fibrosis (IPF) is the representative phenotype of interstitial lung disease where severe scarring develops in the lung interstitium. Although antifibrotic treatments are available and have been shown to slow the progression of IPF, improved therapeutic options are still needed. Recent data indicate that macrophages play essential pro-fibrotic roles in the pathogenesis of pulmonary fibrosis. Historically, macrophages have been classified into two functional subtypes, "M1" and "M2," and it is well described that "M2" or "alternatively activated" macrophages contribute to fibrosis via the production of fibrotic mediators, such as TGF-β, CTGF, and CCL18...
March 13, 2023: Biochemical Pharmacology
Runhong Zhou, Jianan Hu, Jingnan Qiu, Shengsheng Lu, Haixing Lin, Ruifeng Huang, Shaofen Zhou, Guoqing Huang, Jian He
Influenza A virus (IAV) is one of the leading causes of respiratory illness and continues to cause pandemics around the world. Against this backdrop, drug resistance poses a challenge to existing antiviral drugs, and hence, there is an urgent need for developing new antiviral drugs. In this study, we obtained a phenolic compound SG-7, a derivative of natural compound 2-hydroxymethyl-1,4-hydroquinone, which exhibits inhibitory activity toward a panel of influenza viruses and has low cellular toxicity. Mechanistic studies have shown that SG-7 exerts its anti-IAV properties by acting on the virus itself and modulating host signaling pathways...
March 12, 2023: Biochemical Pharmacology
Xue-Xia Yuan, You-Fa Duan, Chunxiang Luo, Lu Li, Meng-Jie Yang, Ting-Yu Liu, Zhi-Rui Cao, Wenlin Huang, Xianzhang Bu, Xin Yue, Ran-Yi Liu
Despite the use of targeted therapy in non-small cell lung cancer (NSCLC) patients, cisplatin (DDP)-based chemotherapy is still the main option. However, DDP resistance is the major factor contributing to the failure of chemotherapy. In this study, we tried to screen DDP sensitizers from an FDA-approved drug library containing 1374 small-molecule drugs to overcome DDP resistance in NSCLC. As a result, disulfiram (DSF) was identified as a DDP sensitizer: DSF and DDP had synergistic anti-NSCLC effects, which are mainly reflected in inhibiting tumor cell proliferation, plate colony formation and 3D spheroidogenesis and inducing apoptosis in vitro, as well as the growth of NSCLC xenografts in mice...
March 11, 2023: Biochemical Pharmacology
Miao Cheng, Juan-Juan Li, Xue-Ni Niu, Lin Zhu, Jin-Yu Liu, Peng-Cheng Jia, Sai Zhu, Hong-Wu Meng, Xiong-Wen Lv, Cheng Huang, Jun Li
Hepatic fibrosis (HF) is a reversible wound-healing response characterized by excessive extracellular matrix (ECM) deposition and secondary to persistent chronic injury. Bromodomain protein 4 (BRD4) commonly functions as a "reader" to regulate epigenetic modifications involved in various biological and pathological events, but the mechanism of HF remains unclear. In this study, we established a CCl4 -induced HF model and spontaneous recovery model in mice and found aberrant BRD4 expression, which was consistent with the results in human hepatic stellate cells (HSCs)- LX2 cells in vitro...
March 10, 2023: Biochemical Pharmacology
Sabiya Samim Khan, Sushmita Janrao, Saurabh Srivastava, Shashi Bala Singh, Lalitkumar Vora, Dharmendra Kumar Khatri
Neuroinflammation is a critical degradative condition affecting neurons in the brain. Progressive neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease (PD) have been strongly linked to neuroinflammation. The trigger point for inflammatory conditions in the cells and body is the physiological immune system. The immune response mediated by glial cells and astrocytes can rectify the physiological alterations occurring in the cell for the time being but prolonged activation leads to pathological progression...
March 10, 2023: Biochemical Pharmacology
Na Li, Shanru Yang, Yan Ren, Risheng Tai, Hua Liu, Yixuan Wang, Jianing Li, Fuyan Wang, Jingjun Xing, Yanru Zhang, Xiaoxia Zhu, Suling Xu, Xin Hou, Geng Wang
Tumor cells can evade the innate and adaptive immune systems, which play important roles in tumor recurrence and metastasis. Malignant tumors that recur after chemotherapy are more aggressiveciscis, suggesting an increased ability of the surviving tumor cells to evade innate and adaptive immunity. Therefore, in order to reduce patient mortality, it is important to discover the mechanisms by which tumor cells develop resistance to chemotherapeutics. In the present study we focused on the tumor cells that survived chemotherapy...
March 8, 2023: Biochemical Pharmacology
Yongxia Zhu, Lidan Zhang, Xuejiao Song, Qiangsheng Zhang, Ting Wang, Hongtao Xiao, Luoting Yu
The incidence and mortality rate of malignant melanoma are increasing worldwide. Metastasis reduces the efficacy of current melanoma therapies and leads to poor prognosis for patients. EZH2 is a methyltransferase that promotes the proliferation, metastasis, and drug resistance of tumor cells by regulating transcriptional activity. EZH2 inhibitors could be effective in melanoma therapies. Herein, we aimed to investigate whether the pharmacological inhibition of EZH2 by ZLD1039, a potent and selective S-adenosyl-l-methionine-EZH2 inhibitor, suppresses tumor growth and pulmonary metastasis in melanoma cells...
March 8, 2023: Biochemical Pharmacology
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