Biochemical pharmacology最新文献_第9页

Nanoengineered immune check point inhibitors delivery for targeted brain cancer treatment: Current status and future perspectives

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2025.116789

Juan Liu , Yichao Wang , Zhidu Song , Yukai Zhang

Brain tumors create special difficulties because of their position and the protective covering of blood brain barrier (BBB) that restricts efficient medication access. Treatment alternatives such as surgery and chemotherapy demonstrate poor performance against severe brain tumors. The use of immune checkpoint inhibitors (ICIs) hints at effective cancer therapy; however, their application to brain cancer faces challenges due to inefficient delivery through the BBB and the tumor’s suppressive environment. Nanoengineering can increase the transport of ICIs to brain tumors. Numerous nano-delivery systems such as liposomes and micelles have explored ways to avoid the BBB via transcytosis and the EPR mechanism. Functionalization of nanocarriers enhances targeting tumor cells and improves treatment accuracy. New developments involve delivering ICIs together with adjuvants to change the TME and focusing on immune cells such as TAMs and Tregs to boost immunity against tumors. Nanoengineered ICIs have shown effective improvement in animal models by reducing toxicity and enhancing efficacy. Converting these successes into real clinical trials is not easy as they face regulatory concerns and safety challenges. Clinical trials currently examine the use of nanocarriers for treating brain cancer; however, scalability’ and ’long-term safety’ continue to pose challenges. Future approaches will focus on combining customized medicine with advanced nanotechnology and AI to refine treatment methods. Despite obstacles ahead, nanotechnology-based ICIs offer a hopeful approach to enhance brain cancer efficacy and address existing therapeutic constraints.

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引用次数: 0

Gambogic acid induces GSDME dependent pyroptotic signaling pathway via ROS/P53/Mitochondria/Caspase-3 in ovarian cancer cells 藤黄酸在卵巢癌细胞中通过ROS/P53/线粒体/Caspase-3诱导GSDME依赖性热亡信号通路。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116695

Danya Zhang , Yuxin Chen , Yue Sun , Hanjie Xu , Rui Wei , Ying Zhou , Fei Li , Jie Li , Jing Wang , Pingbo Chen , Ling Xi

Gambogic acid (GA) is a naturally active compound extracted from the Garcinia hanburyi with various anticancer activities. However, whether GA induces pyroptosis (a newly discovered inflammation-mediated programmed cell death mechanism) in ovarian cancer (OC) has not yet been reported. This study revealed that GA treatment reduced cell viability by inducing pyroptosis in OC cell lines. Typical pyroptosis morphological manifestations such as cell swelling with large bubbles and loss of cell membrane integrity, were observed. Cleaved caspase-3 and GSDME-N levels increased after GA treatment, and knocking out GSDME or using a caspase-3 inhibitor could switch GA-induced cell death from pyroptosis to apoptosis, indicating GA induced caspase-3/GSDME-dependent pyroptosis. Furthermore, this research indicated that GA significantly increased reactive oxygen species (ROS) and p53 phosphorylation. OC cells pretreated with ROS inhibitor N-Acetylcysteine (NAC) and the specific p53 inhibitor pifithrin-μ could completely reverse the pyroptosis post-treatment. Elevated p53 and phosphorylated p53 reduced mitochondrial membrane potential (MMP) and Bcl-2, increase the expression of Bax, and damage mitochondria by releasing cytochrome c to activate the downstream pyroptosis pathway. Different doses of GA inhibited tumor growth in ID8 tumor-bearing mice, and high-dose GA increased in tumor-infiltrating lymphocytes CD3, CD4, and CD8 were detected in tumor tissues. Notably, the expressions of GSDME-N, cleaved caspase-3 and other proteins were increased in tumor tissues with high-dose GA groups. These findings demonstrate that GA-treated OC cells could induce GSDME-mediated pyroptosis through the ROS/p53/mitochondria signaling pathway and caspase-3/-9 activation. Thus, GA is a promising therapeutic agent for OC treatment.

藤黄酸（Gambogic acid， GA）是从藤黄中提取的天然活性化合物，具有多种抗癌活性。然而，GA是否在卵巢癌（OC）中诱导焦亡（一种新发现的炎症介导的程序性细胞死亡机制）尚未报道。本研究表明，GA处理通过诱导OC细胞株焦亡来降低细胞活力。观察到典型的焦亡形态学表现，如细胞肿胀伴大泡，细胞膜完整性丧失。GA处理后，裂解的caspase-3和GSDME- n水平升高，敲除GSDME或使用caspase-3抑制剂可将GA诱导的细胞死亡从焦亡转变为凋亡，表明GA诱导了caspase-3/GSDME依赖性焦亡。此外，本研究表明，GA显著增加活性氧（ROS）和p53磷酸化。用活性氧抑制剂n-乙酰半胱氨酸（NAC）和特异性p53抑制剂聚氟乙烯菊酯（pifithrin-μ）预处理OC细胞，可完全逆转处理后的焦亡。p53的升高和磷酸化降低了线粒体膜电位（MMP）和Bcl-2，增加了Bax的表达，并通过释放细胞色素c激活下游焦亡途径损伤线粒体。不同剂量GA抑制了ID8荷瘤小鼠的肿瘤生长，高剂量GA增加了肿瘤组织中肿瘤浸润淋巴细胞CD3、CD4和CD8的表达。值得注意的是，高剂量GA组肿瘤组织中GSDME-N、cleaved caspase-3等蛋白的表达增加。这些结果表明，ga处理的OC细胞可以通过ROS/p53/线粒体信号通路和caspase-3/-9活化诱导gsdme介导的凋亡。因此，GA是一种很有前途的治疗OC的药物。

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引用次数: 0

Peptide-based CAR-NK cells: A novel strategy for the treatment of solid tumors 基于肽的CAR-NK细胞：治疗实体瘤的新策略。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2025.116741

Qianqian Wang , Xin Yuan , Cuijuan Liu , Ying Huang , Lin Li , Yimin Zhu

CAR-T cell therapy has been proven to be effective on hematological tumors, although graft-versus-host disease and cytokine release syndrome(CRS) limit its application to a certain extent. However, CAR-T therapy for solid tumors met challenges, among which the lack of tumor-specific antigens (TSA) and immunosuppressive tumor microenvironment (TME) are the most important factors. CAR-NK could be a good alternative to CAR-T in some ways since they can induce mild CRS and are independent of HLA-matching, but the efficacy of CAR-NKs remains limited in solid tumors. CAR cells armed with multiple tumor targeting molecules may obtain higher therapeutic efficacy against solid tumors. Due to large molecular weight, multivalent scFvs cannot be displayed efficiently on T cells and the high affinity of scFv to the target makes it easy to cause on-target, off-tumor(OTOT) toxicity. Peptides with low molecular weight and slightly lower affinity than scFvs allow immune cells to display multiple peptides to increase killing ability and reduce OTOT toxicity. In our study, peptide-based CAR-NK cells were designed to solve the dilemma of CAR-T in solid tumors. Firstly, the peptide-based CAR-NK92MI cells with A1 peptide were constructed and their inhibitory effects on the growth of A549 tumor cells were identified. Secondly, the tri-specific CAR-NK92MI cells with peptides that simultaneously targeted PD-L1, EGFR and VEGFR2 were developed for the combinatory therapy. Tri-specific CAR-NK92MI exhibited comparable killing activities to scFv-based CAR-NK92MI. Moreover, peptide-based CAR NK92MI mitigated OTOT toxicity. Our study implied that peptide-based CAR-NKs could behave as promising tools in solid tumor.

CAR-T细胞疗法已被证明对血液系统肿瘤有效，但移植物抗宿主病和细胞因子释放综合征（CRS）在一定程度上限制了其应用。然而，CAR-T治疗实体肿瘤面临挑战，其中肿瘤特异性抗原（tumor-specific antigens， TSA）的缺乏和免疫抑制肿瘤微环境（immunosuppressive tumor microenvironment， TME）是最重要的因素。CAR-NK在某些方面可能是CAR-T的良好替代品，因为它们可以诱导轻度CRS并且不依赖于hla匹配，但CAR-NK在实体瘤中的疗效仍然有限。携带多种肿瘤靶向分子的CAR细胞可以获得更高的实体肿瘤治疗效果。由于分子量大，多价scFv不能在T细胞上有效展示，且scFv对靶标的高亲和力使其容易引起靶外肿瘤（OTOT）毒性。低分子量和亲和力略低于scFvs的多肽可使免疫细胞显示多肽，从而提高杀伤能力，降低OTOT毒性。在我们的研究中，我们设计了基于肽的CAR-NK细胞来解决CAR-T在实体肿瘤中的困境。首先构建含有A1肽的肽基CAR-NK92MI细胞，并鉴定其对A549肿瘤细胞生长的抑制作用。其次，开发具有同时靶向PD-L1、EGFR和VEGFR2肽的三特异性CAR-NK92MI细胞用于联合治疗。三特异性CAR-NK92MI表现出与基于scfv的CAR-NK92MI相当的杀伤活性。此外，基于肽的CAR NK92MI减轻了OTOT毒性。我们的研究表明，基于肽的CAR-NKs可以作为实体肿瘤治疗的有前途的工具。

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引用次数: 0

Erratum to “Activating transcriptional coactivator with PDZ-binding motif by (R)-PFI-2 attenuates osteoclastogenesis and prevents ovariectomized-induced osteoporosis” [Biochem. Pharmacol. 219 (2024) 115964] “通过(R)-PFI-2激活带有pdz结合基序的转录共激活因子可减弱破骨细胞的发生并预防卵巢切除引起的骨质疏松症”[Biochem]。药理学杂志，2009(5):391 - 391。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116687

Rongjian Xu , Xuewen Liu , Yufeng Zhang , Kelei Wang , Zhuolin Chen , Jiewen Zheng , Tan Zhang , Peijian Tong , Yu Qian , Wanlei Yang

引用次数: 0

Brain glucose metabolism: Role of nitric oxide 脑葡萄糖代谢：一氧化氮的作用。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116728

Asghar Ghasemi , Sajad Jeddi , Khosrow Kashfi

One possible reason for failure in achieving optimal glycemic control in patients with type 2 diabetes (T2D) is that less attention has been paid to the brain, a fundamental player in glucose homeostasis, that consumes about 25% of total glucose utilization. In addition, animal and human studies indicate that nitric oxide (NO) is a critical player in glucose metabolism. NO synthesis from L-arginine is lower in patients with T2D, and endothelial NO synthase (eNOS)-derived NO bioavailability is lower in T2D. NO in the nervous system plays a role in neurovascular coupling (NVC) and the hypothalamic control of glucose sensing and energy homeostasis, influencing glucose utilization. This review explores NO’s role in the brain’s glucose metabolism. Literature indicates that glucose metabolism is different between neurons and astrocytes. Unlike neurons, astrocytes have a higher rate of glycolysis and a greater ability for lactate production. Astrocytes produce a greater amount of NO than neurons. NO inhibits mitochondrial respiration in both neurons and astrocytes and decreases intracellular ATP. NO-induced inhibition of mitochondrial respiration in neurons is not accompanied by compensatory glycolysis because phosphofructokinase 2.3 (PFK2.3), the most potent activator of PFK1 and thus glycolysis, is subjected to ubiquitylation and proteasomal degradation by cadherin-1 (Cdh1)-activated anaphase-promoting complex/cyclosome (APC/C), which leads to a low glycolytic rate in neurons. In astrocytes, NO inhibits mitochondrial respiration, but astrocytes display compensatory glycolysis by activating the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway.

2型糖尿病（T2D）患者未能达到最佳血糖控制的一个可能原因是对大脑的关注较少，大脑是葡萄糖稳态的基本参与者，消耗约25%的总葡萄糖利用。此外，动物和人体研究表明，一氧化氮（NO）在葡萄糖代谢中起着关键作用。T2D患者l -精氨酸合成NO较低，内皮NO合成酶（eNOS）产生的NO生物利用度较低。神经系统中的NO参与神经血管耦合（NVC）和下丘脑对葡萄糖感知和能量稳态的控制，影响葡萄糖的利用。这篇综述探讨了NO在大脑葡萄糖代谢中的作用。文献表明，葡萄糖代谢在神经元和星形胶质细胞之间是不同的。与神经元不同，星形胶质细胞具有更高的糖酵解速率和更大的乳酸生成能力。星形胶质细胞比神经元产生更多的NO。NO抑制神经元和星形胶质细胞的线粒体呼吸并降低细胞内ATP。no诱导的神经元线粒体呼吸抑制不伴有代偿性糖酵解，因为磷酸果糖激酶2.3 （PFK2.3）是PFK1最有效的激活剂，因此糖酵解会被钙凝素-1 （Cdh1）激活的后期促进复合物/环体（APC/C）泛素化和蛋白酶体降解，导致神经元糖酵解率低。在星形胶质细胞中，NO抑制线粒体呼吸，但星形胶质细胞通过激活单磷酸腺苷（AMP）激活的蛋白激酶（AMPK）途径进行代偿性糖酵解。

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引用次数: 0

The PROTAC selectively degrading BCL-XL inhibits the growth of tumors and significantly synergizes with Paclitaxel PROTAC选择性降解BCL-XL抑制肿瘤生长，并与紫杉醇显著协同作用。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116731

Fenglan Qiu , Yachuan Tao , Yue Chen , Zhuqin Shen , Xuan Huang , Wenfu Tan , Taomin Huang , Xin Cao

B-cell lymphoma extra large (BCL-X_L) is an important anti-apoptotic protein of BCL-2 family. It is frequently overexpressed in various hematologic and solid tumors, often positively correlated with chemotherapy resistance in tumors. However, the clinical development of the small molecule BCL-X_L inhibitor ABT-263 has been challenged on account of its on-target and dose-limiting toxicity. We have previously reported that SIAIS361034, a Proteolysis Targeting Chimera (PROTAC) specifically targeting BCL-X_L to cereblon (CRBN) E3 ligase for degradation, represents a novel Hedgehog (Hh) inhibitor and inhibits tumors addiction to the Hh pathway activity with little influence on platelets. However, the inhibitory effect of SIAIS361034 on tumors independent on Hh pathway remains to be fully elucidated. In the present study, we explored its inhibitory effect on the growth of hematologic malignancies and small cell lung cancer (SCLC). Our results showed that SIAIS361034 selectively and efficiently degraded BCL-X_L in tumor cells via a CRBN- and proteasome-dependent manner, with the half-maximal degradation concentration (DC₅₀) of below 10 nM. Moreover, SIAIS361034 effectively killed BCL-X_L-dependent MOLT-4 acute lymphoblastic leukemia (ALL) cells in vitro, with the half-maximal effective concentration (EC₅₀) of 16.09 nM, and triggered apoptosis of MOLT-4 cells. SIAIS361034 obviously inhibited the growth of MOLT-4 xenografts with tumor growth inhibition rate (TGI) of 96.1 %, and did not induce acute and severe thrombocytopenia at therapeutic dosages. Furthermore, SIAIS361034 potently boosted the response of SCLC cells to Paclitaxel (PTX) and yielded more apoptosis in vitro by concurrently reduced the expression of BCL-X_L and myeloid cell leukemia 1 (MCL-1), respectively. Meanwhile, we observed that SIAIS361034 significantly synergized with PTX to inhibit the growth of SCLC xenografts in vivo, without causing exacerbating PTX-induced neutropenia. Taken together, SIAIS361034, shows great potentiality in killing tumors cells, both as a monotherapy and in combination with PTX.

超大型b细胞淋巴瘤（BCL-XL）是BCL-2家族重要的抗凋亡蛋白。它在各种血液学和实体肿瘤中经常过表达，常与肿瘤化疗耐药呈正相关。然而，小分子BCL-XL抑制剂ABT-263的临床开发由于其靶向性和剂量限制性毒性而受到挑战。我们之前报道过SIAIS361034，一种靶向BCL-XL to cereblon (CRBN) E3连接酶降解的蛋白水解靶向嵌合体（PROTAC），是一种新型的Hedgehog （Hh）抑制剂，可以抑制肿瘤对Hh通路的依赖性，对血小板的影响很小。然而，SIAIS361034对不依赖Hh通路的肿瘤的抑制作用仍有待完全阐明。在本研究中，我们探讨了其对血液恶性肿瘤和小细胞肺癌（SCLC）生长的抑制作用。结果表明，SIAIS361034通过依赖于CRBN和蛋白酶体的方式选择性有效地降解肿瘤细胞中的BCL-XL，其半最大降解浓度（DC50）低于10 nM。此外，SIAIS361034在体外有效杀伤bcl - xl依赖性MOLT-4急性淋巴细胞白血病（ALL）细胞，其半最大有效浓度（EC50）为16.09 nM，并引发MOLT-4细胞凋亡。SIAIS361034明显抑制MOLT-4异种移植物的生长，肿瘤生长抑制率（TGI）为96.1 %，且在治疗剂量下不诱导急性和重度血小板减少。此外，SIAIS361034通过同时降低BCL-XL和骨髓细胞白血病1 （MCL-1）的表达，在体外有效地促进SCLC细胞对紫杉醇（PTX）的反应，并导致更多的细胞凋亡。同时，我们观察到SIAIS361034与PTX在体内显著协同抑制SCLC异种移植物的生长，而不会加重PTX诱导的中性粒细胞减少症。综上所述，SIAIS361034无论是单独使用还是与PTX联合使用，都显示出杀灭肿瘤细胞的巨大潜力。

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引用次数: 0

Protective effects of cannabinoid receptor 2 on annulus fibrosus degeneration by upregulating autophagy via AKT-mTOR-p70S6K signal pathway 大麻素受体2通过AKT-mTOR-p70S6K信号通路上调自噬对纤维环变性的保护作用。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116734

Yubo Mao , Pengfei Zhu , Jiale Wang , Chunyang Fan , Zilin Yu , Lingye Yao , Wei He , Xinyun Li , Feng Zhou , Minfeng Gan , Xiexing Wu , Dechun Geng

As an important pathological process, annulus fibrosus (AF) degeneration contributes greatly to intervertebral disc degeneration (IVDD). Moreover, extracellular matrix (ECM) degradation and AF cell (AFC) autophagy are of utmost importance. The involvement of cannabinoid receptor type 2 (CB2) in the pathological mechanisms underlying different diseases has been demonstrated due to its capacity to regulate autophagy. The objective of this study was to explore the impact of CB2-induced autophagy on AF degeneration and its underlying mechanism. First, the expression of CB2 in human degenerative AF tissues decreased with increasing degeneration degree, whereas its expression in rat AFCs increased in a concentration- and time-dependent manner following H₂O₂ intervention. Activation of CB2 increased collagen Ⅰ and Ⅱ expression while decreasing MMP3 and MMP13 expression. In addition, p62 expression decreased, whereas beclin-1 and LC3-Ⅱ/LC3-Ⅰ expression increased after JWH133 intervention. After CB2 activation, the addition of 3-MA impeded the synthesis of collagen Ⅰ and Ⅱ while preserving the elevated levels of MMP3 and MMP13. The activation of CB2 greatly suppressed the protein levels of the AKT/mTOR/p70S6K signaling pathway. In vivo, the JWH133 group exhibited elevated disk height index (DHI) and MRI signals, along with a comparatively intact structure of the intervertebral disc in contrast to the vehicle group. In general, CB2 activation could modulate apoptosis and autophagy in rat AFCs, thereby mitigating the advancement of IVDD. Moreover, the AKT/mTOR/p70S6K signaling pathway plays a role in the development of AF degeneration through the regulation of autophagy. The findings suggest that CB2 is a potentially effective therapeutic target for IVDD.

纤维环（AF）变性是椎间盘退变的重要病理过程。此外，细胞外基质（ECM）降解和AF细胞（AFC）自噬是至关重要的。大麻素受体2型（CB2）由于其调节自噬的能力而参与不同疾病的病理机制已被证明。本研究的目的是探讨cb2诱导的自噬对房颤变性的影响及其潜在机制。首先，CB2在人退行性房颤组织中的表达随着退行性程度的增加而降低，而在H2O2干预后，其在大鼠房颤组织中的表达呈浓度和时间依赖性增加。激活CB2增加了胶原Ⅰ和Ⅱ的表达，同时降低了MMP3和MMP13的表达。此外，JWH133干预后，p62表达降低，而beclin-1和LC3-Ⅱ/LC3-Ⅰ表达升高。CB2激活后，3-MA的加入阻碍了胶原Ⅰ和Ⅱ的合成，同时保持了MMP3和MMP13的升高水平。CB2的激活极大地抑制了AKT/mTOR/p70S6K信号通路的蛋白水平。在体内，与载药组相比，JWH133组表现出较高的椎间盘高度指数（DHI）和MRI信号，同时椎间盘结构相对完整。总的来说，CB2激活可以调节大鼠AFCs的凋亡和自噬，从而减缓IVDD的进展。此外，AKT/mTOR/p70S6K信号通路通过调控自噬在房颤变性的发生发展中发挥作用。研究结果表明，CB2是IVDD的潜在有效治疗靶点。

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引用次数: 0

CMAP prediction and experimental validation of Forskolin as a podocyte protective and anti-proteinuric drug for nephrotoxic serum-treated mice 福斯可林作为肾毒性血清处理小鼠足细胞保护和抗蛋白尿药物的CMAP预测和实验验证。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116727

Weijun Huang , Peng Yu , Xi Zhao , Jingsong Shi , Xi Jin , Runbing Jin , Shihui Dong , Wen Xia , Xiaodong Zhu , Jingjing Wang , Haitao Zhang , Lu Ren , Shaolin Shi

Podocyte injury leads to proteinuria and glomerular diseases. Different podocyte injuries have distinct mechanisms. It is desirable to use a regimen that targets the mechanism of a given podocyte injury for a specific and improved result. However, the mechanisms of the most podocyte injuries are largely elusive, preventing optimal drug choices. Here, we test the feasibility of combining kidney single-cell RNA-seq databases and the Connectivity Map database (CMAP) to predict drugs for a specific podocyte injury. We downloaded glomerular single-cell RNA-seq dataset of nephrotoxic serum (NTS)-treated and control mice from the GEO, and compared their podocyte gene expression, resulting in identification of genes with altered expression in NTS-treated podocytes. GO and KEGG enrichment of them revealed activations of podocyte injurious NFκB, TNFα, AGE-RAGE, apoptosis, cellular senescence, MAPK, and p53 pathways, and dedifferentiation. CMAP analysis of the genes ranked Forskolin top 3. Indeed, we found that NTS-treated mice developed massive proteinuria, which was prevented by Forskolin, accompanied by pathological improvement of podocytes. In treating overdose NTS-induced severe podocyte injury, Forskolin exhibited a comparable efficacy as glucocorticoids (methylprednisolone). In vitro, Forskolin prevented NTS-induced cellular injury in cultured podocytes as shown by cell viability and cytoskeletal integrity assays. Mechanistically, Forskolin inhibited STAT3, p53, NFκB, FAK, and TGF-β pathways, while upregulated podocyte essential genes, WT1, SYNPO, and VEGFA, independently of NTS. In conclusion, Forskolin protects podocytes by directly inhibiting harmful pathways and the associated genes while enhancing podocyte essential gene expression independently of insults, resulting in an efficacy comparable with that of glucocorticoids in NTS-treated mice.

足细胞损伤可导致蛋白尿和肾小球疾病。不同的足细胞损伤有不同的机制。我们希望使用一种针对特定足细胞损伤机制的治疗方案，以获得特定的改善结果。然而，大多数足细胞损伤的机制在很大程度上是难以捉摸的，这阻碍了最佳药物的选择。在这里，我们测试了结合肾脏单细胞RNA-seq数据库和连接图数据库（CMAP）来预测特定足细胞损伤药物的可行性。我们下载了来自GEO的肾毒性血清（NTS）处理和对照小鼠的肾小球单细胞RNA-seq数据集，并比较了它们的足细胞基因表达，从而鉴定了NTS处理的足细胞表达改变的基因。GO和KEGG的富集揭示了足细胞损伤nf - κ b、tnf - α、AGE-RAGE、凋亡、细胞衰老、MAPK和p53通路的激活以及去分化。CMAP分析将Forskolin基因排在前3位。事实上，我们发现nts治疗的小鼠出现了大量蛋白尿，这是由Forskolin预防的，并伴有足细胞的病理改善。在治疗过量nts诱导的严重足细胞损伤时，Forskolin表现出与糖皮质激素（甲基强的松龙）相当的疗效。体外培养足细胞的细胞活力和细胞骨架完整性显示，Forskolin可预防nts诱导的细胞损伤。在机制上，Forskolin抑制STAT3、p53、NFκB、FAK和TGF-β通路，同时上调足细胞必需基因WT1、SYNPO和VEGFA，而不依赖于NTS。综上所述，Forskolin通过直接抑制有害通路和相关基因来保护足细胞，同时不受损伤地增强足细胞必需基因的表达，从而在nts处理的小鼠中具有与糖皮质激素相当的功效。

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引用次数: 0

Identification of a dual JAK3/TEC family kinase inhibitor for atopic dermatitis therapy 双重JAK3/TEC家族激酶抑制剂治疗特应性皮炎的鉴定。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2025.116740

Yiwen Du , Longling Wang , Jingmei Zhou , Wenxiang Hong , Xuanyan Cai , Hongbo Ma , Zonghui Wei , Wenwen Nie , Hong Zhu , Bo Yang , Qiaojun He , Binhui Chen , Jiajia Wang , Qinjie Weng

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by recurrent eczematous lesions and severe itching, for which clinical treatments are limited. Selectively inhibiting Janus Kinase 3 (JAK3) and tyrosine kinase expressed in hepatocellular carcinoma (TEC) family kinases is proposed as a promising strategy to treat AD with possible reduced side effects and enhanced efficacy. In this study, we developed a dual JAK3/TEC family kinase inhibitor ZZB, which demonstrated potent inhibitory activity with IC₅₀ values of 0.89 nM against JAK3 and 11.56 nM against TEC kinase interleukin-2-inducible T-cell kinase (ITK). Docking studies revealed that ZZB forms a covalent bond with the unique cysteine residue at position 909 (Cys⁹⁰⁹) in JAK3 and Cys⁴⁴² in ITK. Utilizing human peripheral blood mononuclear cells, we discovered ZZB selectively inhibits JAK3-dependent cytokines signaling and ITK-mediated CD4⁺ T cell activation. Moreover, in vitro studies indicated ZZB significantly suppresses the proliferation and differentiation of CD4⁺ T cells, as well as the cytolytic function of CD8⁺ T cells and NK cells. We then conducted a pharmacokinetic study in mice and observed a favorable pharmacokinetic profile for ZZB. In a mouse model of AD induced by repeated application of 2,4-dinitrochlorobenzene to the shaved dorsal skin, oral administration of ZZB (100 mg/kg) markedly improved skin condition and reduced immune cell infiltration, matching the efficacy of the positive drug dexamethasone. We conclude that the JAK3/TEC kinase inhibitor ZZB is a highly promising candidate for the treatment of AD.

特应性皮炎（AD）是一种慢性炎症性皮肤疾病，其特征是反复发作的湿疹病变和严重的瘙痒，临床治疗有限。选择性抑制Janus Kinase 3 （JAK3）和酪氨酸激酶在肝细胞癌（TEC）家族激酶中的表达，被认为是治疗AD的一种有希望的策略，可能减少副作用并提高疗效。在本研究中，我们开发了JAK3/TEC家族双激酶抑制剂ZZB，对JAK3和TEC激酶的IC50值分别为0.89 nM和11.56 nM。对接研究发现，ZZB与JAK3中909位（Cys909）和ITK中Cys442位独特的半胱氨酸残基形成共价键。利用人外周血单个核细胞，我们发现ZZB选择性地抑制jak3依赖性细胞因子信号和itk介导的CD4+ T细胞活化。此外，体外研究表明，ZZB显著抑制CD4+ T细胞的增殖和分化，以及CD8+ T细胞和NK细胞的细胞溶解功能。然后，我们在小鼠身上进行了药代动力学研究，并观察到ZZB具有良好的药代动力学特征。2,4-二硝基氯苯反复应用于剃除的背侧皮肤诱导的AD小鼠模型中，口服ZZB （100 mg/kg）可显著改善皮肤状况，减少免疫细胞浸润，其疗效与阳性药物地塞米松相当。我们得出结论，JAK3/TEC激酶抑制剂ZZB是治疗AD的极有希望的候选药物。

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引用次数: 0

4-amino-3-(phenylselanyl) benzenesulfonamide attenuates intermittent cold stress-induced fibromyalgia in mice: Targeting to the Nrf2-NFκB axis 4-amino-3-(phenylselanyl) benzenesulfonamide 可减轻间歇性冷应激诱发的小鼠纤维肌痛：靶向 Nrf2-NFκB 轴。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116651

Carolina C. Martins , Angélica S. Reis , Ketlyn P. da Motta , Eduardo B. Blödorn , William Domingues , Manoela do Sacramento , Juliano A. Roehrs , Diego Alves , Vinicius F. Campos , Márcia F. Mesko , Cristiane Luchese , Ethel A. Wilhelm

Stress is widely recognized as the primary environmental factor associated with chronic pain conditions, including fibromyalgia. A recent study demonstrated the potential antinociceptive effects of 4-amino-3-(phenylselanyl) benzenesulfonamide (4-APSB) in acute nociceptive animal models due to its antioxidant and anti-inflammatory properties. However, the efficacy of 4-APSB in managing chronic painful conditions, such as fibromyalgia, has not been explored so far. This study investigated the pharmacological effects of 4-APSB in an experimental model of fibromyalgia induced by intermittent cold stress (ICS). Male and female mice were divided into Control, ICS, 4-APSB, and ICS + 4-APSB. After the ICS, the animals were treated with 4-APSB (1 mg kg⁻¹) or vehicle by the intragastric route until the tenth day. The behavioral tasks were performed on days 5, 8, and 10. The findings showed a negative correlation between paw withdrawal threshold and Nrf2 or NFκB mRNA expression levels caused by ICS exposure. The 4-APSB suppressed the nociceptive signs and a depressive like-phenotype in male and female mice exposed to ICS. 4-APBS normalized the elevated levels of TBARS and the up-regulation of Nrf2 and NFκB expression in the cerebral cortex of ICS-exposed mice. This compound also modulated the oxidative stress in the spinal cord of female mice. The 4-APSB attenuated the inhibition of Na⁺, K⁺ − ATPase activity in the central nervous system (CNS) of female mice exposed to ICS. 4-APSB attenuated behavioral and redox imbalance triggered by the ICS model in male and female mice, suggesting its beneficial effects for treating fibromyalgia in both sexes.

压力被广泛认为是与纤维肌痛等慢性疼痛相关的主要环境因素。最近的一项研究表明，4-氨基-3-（苯基苯丙氨酰）苯磺酰胺（4-APSB）具有抗氧化和抗炎特性，因此在急性痛觉动物模型中具有潜在的抗痛觉作用。然而，迄今为止，4-APSB 在治疗纤维肌痛等慢性疼痛病症方面的疗效尚未得到探讨。本研究调查了 4-APSB 在间歇性冷应激（ICS）诱导的纤维肌痛实验模型中的药理作用。雌雄小鼠被分为对照组、ICS 组、4-APSB 组和 ICS + 4-APSB 组。间歇性冷应激（ICS）后，动物通过胃内途径接受 4-APSB（1 毫克/千克-1）或药物治疗，直至第十天。行为任务分别在第 5、8 和 10 天进行。研究结果表明，ICS暴露导致的爪退缩阈值与Nrf2或NFκB mRNA表达水平呈负相关。4-ABS抑制了暴露于ICS的雌雄小鼠的痛觉症状和类似抑郁的表型。4-APSB 使暴露于 ICS 的小鼠大脑皮层中升高的 TBARS 水平以及 Nrf2 和 NFκB 表达的上调恢复正常。这种化合物还能调节雌性小鼠脊髓中的氧化应激。4-APSB 可减轻对暴露于 ICS 的雌性小鼠中枢神经系统（CNS）中 Na+、K+-ATPase 活性的抑制。4-APSB 可减轻 ICS 模型在雌雄小鼠中引发的行为和氧化还原失衡，这表明它对治疗雌雄小鼠的纤维肌痛都有益处。

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引用次数: 0