Pub Date : 2024-11-23DOI: 10.1016/j.bcp.2024.116654
Zhiming Liu , Chi-Su Yoon , Hwan Lee , Eunae Kim , Joung Han Yim , Tai Kyoung Kim , Hyuncheol Oh , Dong-Sung Lee
Ramalin, a strong antioxidant isolated from Antarctic lichens, has been shown to have potential therapeutic effects in the treatment of Alzheimer’s disease. However, this compound is readily degraded in aqueous solutions, which restricts its development as a therapeutic agent. With a view toward addressing this problem, in this study, we modified the structure of ramalin to obtain more stable compounds and attempted to identify a derivative with the strongest neuroprotective properties. We synthesized a total of 20 ramalin derivatives, among which, RA-2 N was demonstrated to have the best neuroprotective effects, not only inhibiting inflammation in BV2 cells but also inhibiting inflammation-induced HT22 cell apoptosis in BV2–HT22 co-culture models. Moreover, we established that these effects were associated with an inhibition of the nuclear translocation of nuclear factor kappa-B (NF-κB). Our findings in this study revealed that the synthesis of ramalin derivatives is an effective approach for stabilizing this compound for therapeutic purposes. Given its modified structure, the RA-2 N derivative can inhibit inflammation and protect nerve cells, and thus indicate its potential application as a drug for treating neurodegenerative diseases.
拉玛琳是从南极地衣中分离出来的一种强抗氧化剂，已被证明对治疗阿尔茨海默氏症有潜在疗效。然而，这种化合物在水溶液中很容易降解，这限制了它作为治疗剂的发展。为了解决这一问题，在本研究中，我们改变了雷公藤苷的结构，以获得更稳定的化合物，并试图找出一种具有最强神经保护特性的衍生物。我们共合成了 20 种羊胎素衍生物，其中 RA-2 N 的神经保护效果最好，不仅能抑制 BV2 细胞的炎症反应，还能在 BV2-HT22 共培养模型中抑制炎症诱导的 HT22 细胞凋亡。此外，我们还证实这些作用与抑制核因子卡巴-B（NF-κB）的核转位有关。我们的研究结果表明，合成雷公藤苷衍生物是稳定这种化合物用于治疗目的的有效方法。鉴于 RA-2 N 衍生物的修饰结构，它可以抑制炎症和保护神经细胞，从而表明它有可能用作治疗神经退行性疾病的药物。
{"title":"The neuroprotective and anti-neuroinflammatory effects of ramalin synthetic derivatives in BV2 and HT22 cells","authors":"Zhiming Liu , Chi-Su Yoon , Hwan Lee , Eunae Kim , Joung Han Yim , Tai Kyoung Kim , Hyuncheol Oh , Dong-Sung Lee","doi":"10.1016/j.bcp.2024.116654","DOIUrl":"10.1016/j.bcp.2024.116654","url":null,"abstract":"<div><div>Ramalin, a strong antioxidant isolated from Antarctic lichens, has been shown to have potential therapeutic effects in the treatment of Alzheimer’s disease. However, this compound is readily degraded in aqueous solutions, which restricts its development as a therapeutic agent. With a view toward addressing this problem, in this study, we modified the structure of ramalin to obtain more stable compounds and attempted to identify a derivative with the strongest neuroprotective properties. We synthesized a total of 20 ramalin derivatives, among which, RA-2 N was demonstrated to have the best neuroprotective effects, not only inhibiting inflammation in BV2 cells but also inhibiting inflammation-induced HT22 cell apoptosis in BV2–HT22 co-culture models. Moreover, we established that these effects were associated with an inhibition of the nuclear translocation of nuclear factor kappa-B (NF-κB). Our findings in this study revealed that the synthesis of ramalin derivatives is an effective approach for stabilizing this compound for therapeutic purposes. Given its modified structure, the RA-2 N derivative can inhibit inflammation and protect nerve cells, and thus indicate its potential application as a drug for treating neurodegenerative diseases.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"231 ","pages":"Article 116654"},"PeriodicalIF":5.3,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142702015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-23DOI: 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.
{"title":"4-amino-3-(phenylselanyl) benzenesulfonamide attenuates intermittent cold stress-induced fibromyalgia in mice: Targeting to the Nrf2-NFκB axis.","authors":"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","doi":"10.1016/j.bcp.2024.116651","DOIUrl":"10.1016/j.bcp.2024.116651","url":null,"abstract":"<p><p>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<sup>-1</sup>) 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<sup>+</sup>, K<sup>+</sup> - 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.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116651"},"PeriodicalIF":5.3,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
SLC46A3, a transporter for lysosomal steroid conjugates and bile acids, plays a pivotal role in the pharmacological effects of noncleavable antibody–drug conjugates using maytansine as a payload. SLC46A3 may exert negative effects on various phenomena, including copper homeostasis, mitochondrial function in the liver, and the uptake of lipid-based nanoparticles (NPs) in tumor cells. Consequently, inhibiting SLC46A3 may be a promising strategy for treating hepatic disease or enhancing lipid NP delivery to tumor cells, although the underlying mechanisms remain unknown. This study investigates flavonoids, the largest subgroup of polyphenols characterized by a simple C6-C3-C6 structure, as potential SLC46A3 inhibitors and provides insights into the structural requirements for flavonoid–SLC46A3 interactions. Screening revealed several flavonoids, including dihydrochalcones, flavonols, isoflavones, flavanones, and flavones, as effective inhibitors of 5-carboxyfluorescein (5-CF) uptake in MDCKII (Mardin-Darby canine kidney type II) cells stably expressing a mutant SLC46A3 localized to the plasma membrane. Notably, apigenin and luteolin exhibited marked 5-CF uptake inhibition, with IC50 values of 10.8 and 8.7 µM, respectively. Additionally, 4′,7-dihydroxyflavone significantly inhibited 5-CF uptake, exhibiting an IC50 value of 9.3 µM, whereas acacetin and genkwanin possessing methoxy group substitutions for the hydroxy group at the 4′- or 7-position of apigenin, respectively, did not affect the uptake. Luteolin’s inhibition mechanism was found to be of a mixed type involving increased Km and decreased Vmax. These findings emphasize the importance of hydroxy groups at 4′- and 7-positions in flavone–SLC46A3 interactions.
{"title":"Exploring flavonoids as potent SLC46A3 inhibitors: Insights from the structural characteristics of flavonoid–SLC46A3 interactions","authors":"Ryuto Tomabechi , Naoki Saito , Daisuke Saito , Hisanao Kishimoto , Kei Higuchi , Katsuhisa Inoue","doi":"10.1016/j.bcp.2024.116647","DOIUrl":"10.1016/j.bcp.2024.116647","url":null,"abstract":"<div><div>SLC46A3, a transporter for lysosomal steroid conjugates and bile acids, plays a pivotal role in the pharmacological effects of noncleavable antibody–drug conjugates using maytansine as a payload. SLC46A3 may exert negative effects on various phenomena, including copper homeostasis, mitochondrial function in the liver, and the uptake of lipid-based nanoparticles (NPs) in tumor cells. Consequently, inhibiting SLC46A3 may be a promising strategy for treating hepatic disease or enhancing lipid NP delivery to tumor cells, although the underlying mechanisms remain unknown. This study investigates flavonoids, the largest subgroup of polyphenols characterized by a simple C6-C3-C6 structure, as potential SLC46A3 inhibitors and provides insights into the structural requirements for flavonoid–SLC46A3 interactions. Screening revealed several flavonoids, including dihydrochalcones, flavonols, isoflavones, flavanones, and flavones, as effective inhibitors of 5-carboxyfluorescein (5-CF) uptake in MDCKII (Mardin-Darby canine kidney type II) cells stably expressing a mutant SLC46A3 localized to the plasma membrane. Notably, apigenin and luteolin exhibited marked 5-CF uptake inhibition, with IC<sub>50</sub> values of 10.8 and 8.7 µM, respectively. Additionally, 4′,7-dihydroxyflavone significantly inhibited 5-CF uptake, exhibiting an IC<sub>50</sub> value of 9.3 µM, whereas acacetin and genkwanin possessing methoxy group substitutions for the hydroxy group at the 4′- or 7-position of apigenin, respectively, did not affect the uptake. Luteolin’s inhibition mechanism was found to be of a mixed type involving increased K<sub>m</sub> and decreased V<sub>max</sub>. These findings emphasize the importance of hydroxy groups at 4′- and 7-positions in flavone–SLC46A3 interactions.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"231 ","pages":"Article 116647"},"PeriodicalIF":5.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-22DOI: 10.1016/j.bcp.2024.116649
José Bernardo Noronha-Matos , Carlos Sousa-Soares , Paulo Correia-de-Sá
Nicotinic α7 receptors (α7 nAChRs) present in perisynaptic Schwann cells (PSCs) control acetylcholine (ACh) spillover from the neuromuscular synapse by transiently increasing intracellular Ca2+, which fosters adenosine release via type 1 equilibrative nucleoside transporters (ENT1) and retrograde activation of presynaptic A1 inhibitory receptors. The putative Ca2+-dependent pathways downstream α7 nAChRs involved in the sensing inhibitory drive operated by PSCs is unknown. Herein, we used phrenic nerve-hemidiaphragm preparations from Wistar rats. Time-lapse video-microscopy was instrumental to assess nerve-evoked (50-Hz bursts) transmitter exocytosis and intracellular NO oscillations in nerve terminals and PSCs loaded with FM4-64 and DAF-FM diacetate fluorescent dyes, respectively. Selective activation of α7 nAChRs with PNU 282987 reduced transmitter exocytosis (FM4-64 dye unloading) during 50-Hz bursts. Inhibition of calmodulin activity (with W-7), Ca2+/calmodulin-dependent protein kinase II (CaMKII; with KN-62) and Rho-kinase (ROCK; with H1152) all prevented the release inhibitory effect of PNU 282987. The α7 nAChR agonist transiently increased NO inside PSCs; the same occurred during phrenic nerve stimulation with 50-Hz bursts in the presence of the cholinesterase inhibitor, neostigmine. The nitric oxide synthase (NOS) inhibitor, L-NOARG, but not with the guanylylcyclase (GC) inhibitor, ODQ, prevented inhibition of transmitter exocytosis by PNU 282987. Inhibition of adenosine kinase with ABT 702 favors the intracellular accumulation and translocation of the nucleoside to the synaptic cleft, thus overcoming prevention of the PNU 282987 effect caused by H1152, but not by L-NOARG. In conclusion, the α7nAChR-mediated cholinergic inhibitory drive operated by PSCs involves two distinct Ca2+-dependent intracellular pathways: a CaMKII/ROCK cascade along with a GC-independent NO pathway with divergent end-effects concerning ADK inhibition.
{"title":"Differential participation of CaMKII/ROCK and NOS pathways in the cholinergic inhibitory drive operated by nicotinic α7 receptors in perisynaptic Schwann cells","authors":"José Bernardo Noronha-Matos , Carlos Sousa-Soares , Paulo Correia-de-Sá","doi":"10.1016/j.bcp.2024.116649","DOIUrl":"10.1016/j.bcp.2024.116649","url":null,"abstract":"<div><div>Nicotinic α7 receptors (α7 nAChRs) present in perisynaptic Schwann cells (PSCs) control acetylcholine (ACh) spillover from the neuromuscular synapse by transiently increasing intracellular Ca<sup>2+</sup>, which fosters adenosine release via type 1 equilibrative nucleoside transporters (ENT1) and retrograde activation of presynaptic A<sub>1</sub> inhibitory receptors. The putative Ca<sup>2+</sup>-dependent pathways downstream α7 nAChRs involved in the sensing inhibitory drive operated by PSCs is unknown. Herein, we used phrenic nerve-hemidiaphragm preparations from Wistar rats. Time-lapse video-microscopy was instrumental to assess nerve-evoked (50-Hz bursts) transmitter exocytosis and intracellular NO oscillations in nerve terminals and PSCs loaded with FM4-64 and DAF-FM diacetate fluorescent dyes, respectively. Selective activation of α7 nAChRs with PNU 282987 reduced transmitter exocytosis (FM4-64 dye unloading) during 50-Hz bursts. Inhibition of calmodulin activity (with W-7), Ca<sup>2+</sup>/calmodulin-dependent protein kinase II (CaMKII; with KN-62) and Rho-kinase (ROCK; with H1152) all prevented the release inhibitory effect of PNU 282987. The α7 nAChR agonist transiently increased NO inside PSCs; the same occurred during phrenic nerve stimulation with 50-Hz bursts in the presence of the cholinesterase inhibitor, neostigmine. The nitric oxide synthase (NOS) inhibitor, L-NOARG, but not with the guanylylcyclase (GC) inhibitor, ODQ, prevented inhibition of transmitter exocytosis by PNU 282987. Inhibition of adenosine kinase with ABT 702 favors the intracellular accumulation and translocation of the nucleoside to the synaptic cleft, thus overcoming prevention of the PNU 282987 effect caused by H1152, but not by L-NOARG. In conclusion, the α7nAChR-mediated cholinergic inhibitory drive operated by PSCs involves two distinct Ca<sup>2+</sup>-dependent intracellular pathways: a CaMKII/ROCK cascade along with a GC-independent NO pathway with divergent end-effects concerning ADK inhibition.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"231 ","pages":"Article 116649"},"PeriodicalIF":5.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-20DOI: 10.1016/j.bcp.2024.116643
Weiyi Li , Canyu Chen , Bo Xu , Jixiang Chen , Mingxia Yang , Lili Gao , Jiecan Zhou
The LDL Receptor-Related Protein 1(LRP1), a member of the Low-density Lipoprotein (LDL) receptor family, is a multifunctional cellular transporter and signaling receptor, this includes regulation of lipid metabolism, cell migration and signaling. Abnormal accumulation of amyloid beta (Aβ) in the brain is thought to be the main pathological change in Alzheimer’s disease. By binding to a variety of ligands, LRP1 is involved in the internalization and degradation of Aβ, thereby affecting the course of Alzheimer’s disease (AD). Here, we discuss the main mechanisms by which LRP1 mediates Aβ degradation and clearance and several current therapeutic approaches targeting LRP1. Finally, we concluded that modulating the expression level of LRP1 is an effective way to attenuate Aβ deposition and ameliorate AD.
{"title":"The LDL Receptor-Related Protein 1: Mechanisms and roles in promoting Aβ efflux transporter in Alzheimer’s disease","authors":"Weiyi Li , Canyu Chen , Bo Xu , Jixiang Chen , Mingxia Yang , Lili Gao , Jiecan Zhou","doi":"10.1016/j.bcp.2024.116643","DOIUrl":"10.1016/j.bcp.2024.116643","url":null,"abstract":"<div><div>The LDL Receptor-Related Protein 1(LRP1), a member of the Low-density Lipoprotein (LDL) receptor family, is a multifunctional cellular transporter and signaling receptor, this includes regulation of lipid metabolism, cell migration and signaling. Abnormal accumulation of amyloid beta (Aβ) in the brain is thought to be the main pathological change in Alzheimer’s disease. By binding to a variety of ligands, LRP1 is involved in the internalization and degradation of Aβ, thereby affecting the course of Alzheimer’s disease (AD). Here, we discuss the main mechanisms by which LRP1 mediates Aβ degradation and clearance and several current therapeutic approaches targeting LRP1. Finally, we concluded that modulating the expression level of LRP1 is an effective way to attenuate Aβ deposition and ameliorate AD.</div><div>Abbreviations: LRP1, LDL Receptor-Related Protein 1;LDL, Low Density Lipoprotein; Aβ, amyloid beta; AD, Alzheimer’s disease; APP, amyloid precursor protein; ApoE, apolipoprotein E; TGF, growth factor; MMP, matrix metalloproteinase;TAT, thrombin-antithrombin complex; BBB, blood–brain barrier; MMP-9,cyclophilin A (CypA)-matrix metalloproteinase-9; VMC, Vascular Mural Cell; IDE,insulin degrading enzyme; EVs, extracellular vesicles; sLRP1,shed LRP1; BDNF, brain-derived neurotrophin; IGF-1,insulin-like growth factor 1; NGF, nerve growth factor; MAPK,mitogen-activated protein kinase; ERK1/2,exogenous signal-regulated kinase1/2;JNK, c-Jun amino-terminal kinase; TLR4, toll-like receptor 4; NF-κB,nuclear factor-κB; GCAP,guanylate cyclase-activating protein; KD, ketogenic diet;KB, ketone body; BLECs,Brain-like endothelial cell; BYHWD, Buyang Huanwu decoction; LGZG, Linguizhugan decoction;P- gp, P-glycoprotein;PPARγ, Peroxisome proliferator-activated receptor γ;SP16,SERPIN peptide 16; Asx, Astaxanthin; Bex, Bexarotene;</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"231 ","pages":"Article 116643"},"PeriodicalIF":5.3,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-20DOI: 10.1016/j.bcp.2024.116646
Pankaj Garg , Siddhika Pareek , Prakash Kulkarni , David Horne , Ravi Salgia , Sharad S. Singhal
Transforming Growth Factor-beta (TGF-β) is a multifunctional cytokine that exerts its biological effects through a complex process of activation and signaling. Initially synthesized in an inactive form bound to latency-associated peptide (LAP), TGF-β requires release from the extracellular matrix via proteolytic cleavage or integrin-mediated activation to engage with its receptors. Once active, TGF-β binds to type II receptor (TβRII), which then phosphorylates and activates type I receptor (TβRI), triggering downstream signaling cascades, including both Smad-dependent and non-Smad pathways. These signaling cascades regulate key processes like cell growth, differentiation, migration, and immune response modulation, thereby influencing tumor development, progression, and treatment outcomes. This review discusses the complex signaling pathways of TGF-β in cancer, including its interactions with other signaling molecules and its involvement in epithelial-mesenchymal transition (EMT) and in evading immune surveillance. Moreover, dysregulated TGF-β signaling due to alterations in receptor expression, mutations in key signaling proteins such as TβRII and Smads, and aberrant activation of non-canonical pathways, contributes significantly to tumor aggressiveness, metastasis, and therapy resistance. The article emphasizes the potential of TGF-β as a diagnostic biomarker for cancer, highlighting its use in early detection, prognosis assessment, and monitoring treatment response. Additionally, it underscores various therapeutic strategies targeting TGF-β, such as small molecule inhibitors, monoclonal antibodies, immunotherapies, and evaluates their efficacy and limitations in preclinical and clinical settings. Finally, the review provides a comprehensive analysis of TGF-β’s role as both a diagnostic tool and a therapeutic target, while also discussing the challenges and opportunities in targeting TGF-β signaling for improving cancer treatment outcomes.
{"title":"Exploring the potential of TGFβ as a diagnostic marker and therapeutic target against cancer","authors":"Pankaj Garg , Siddhika Pareek , Prakash Kulkarni , David Horne , Ravi Salgia , Sharad S. Singhal","doi":"10.1016/j.bcp.2024.116646","DOIUrl":"10.1016/j.bcp.2024.116646","url":null,"abstract":"<div><div>Transforming Growth Factor-beta (TGF-β) is a multifunctional cytokine that exerts its biological effects through a complex process of activation and signaling. Initially synthesized in an inactive form bound to latency-associated peptide (LAP), TGF-β requires release from the extracellular matrix via proteolytic cleavage or integrin-mediated activation to engage with its receptors. Once active, TGF-β binds to type II receptor (TβRII), which then phosphorylates and activates type I receptor (TβRI), triggering downstream signaling cascades<strong>,</strong> including both Smad-dependent and non-Smad pathways. These signaling cascades regulate key processes like cell growth, differentiation, migration, and immune response modulation, thereby influencing tumor development, progression, and treatment outcomes. This review discusses the complex signaling pathways of TGF-β in cancer, including its interactions with other signaling molecules and its involvement in epithelial-mesenchymal transition (EMT) and in evading immune surveillance. Moreover, dysregulated TGF-β signaling due to alterations in receptor expression, mutations in key signaling proteins such as TβRII and Smads, and aberrant activation of non-canonical pathways, contributes significantly to tumor aggressiveness, metastasis, and therapy resistance. The article emphasizes the potential of TGF-β as a diagnostic biomarker for cancer, highlighting its use in early detection, prognosis assessment, and monitoring treatment response. Additionally, it underscores various therapeutic strategies targeting TGF-β, such as small molecule inhibitors, monoclonal antibodies, immunotherapies, and evaluates their efficacy and limitations in preclinical and clinical settings. Finally, the review provides a comprehensive analysis of TGF-β’s role as both a diagnostic tool and a therapeutic target, while also discussing the challenges and opportunities in targeting TGF-β signaling for improving cancer treatment outcomes.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"231 ","pages":"Article 116646"},"PeriodicalIF":5.3,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-20DOI: 10.1016/j.bcp.2024.116644
Jessica A.O. Rodrigues , Neelakanta S. Kiran , Ankita Chatterjee , Bhupendra G. Prajapati , Namdev Dhas , Adenilson O. dos Santos , Francisco F. de Sousa , Eliana B. Souto
As a multifactorial and heterogeneous disease, cancer has a high mortality rate, and the search for more effective treatments is an enormous challenge. Metal coordination compounds open a range of possibilities that conventional organic and biological molecules can no longer fulfil due to increasing drug resistance. Metallodrugs still have tremendous potential to help overcome drug resistance and find new cures in medicine, considering that at least 25 metallic elements participate in healthy functioning of the human body. Transition metal ions, such as copper, zinc and iron, are incorporated into catalytic proteins, the so-called metalloenzymes, which participate in various chemical reactions necessary for life. The interaction of metal complexes in different pathways with the structural richness of deoxyribonucleic acid encouraged to seek to understand the mechanisms of action and overcome the obstacles encountered for a promising future of these drugs. The success of platinum-based metallodrugs is one of the great inspirations for the search of new metallodrugs, although the approval of these molecules has been slow in recent years due to the risk of systemic toxicity and insufficient understanding of their mechanisms. To overcome the clinical limitations encountered in some metallodrugs, nanoencapsulation has been proposed as a new approach to improve therapeutic index in chemotherapy. The remarkable selectivity of nanoencapsulated metallodrugs and their enhanced capacity to bypass various biological barriers allow site-specific targeting. In this review, we present the advances in the development and use of the most relevant metallodrugs, and new delivery approaches, in the fight against cancer.
{"title":"Metallodrugs: Synthesis, mechanism of action and nanoencapsulation for targeted chemotherapy","authors":"Jessica A.O. Rodrigues , Neelakanta S. Kiran , Ankita Chatterjee , Bhupendra G. Prajapati , Namdev Dhas , Adenilson O. dos Santos , Francisco F. de Sousa , Eliana B. Souto","doi":"10.1016/j.bcp.2024.116644","DOIUrl":"10.1016/j.bcp.2024.116644","url":null,"abstract":"<div><div>As a multifactorial and heterogeneous disease, cancer has a high mortality rate, and the search for more effective treatments is an enormous challenge. Metal coordination compounds open a range of possibilities that conventional organic and biological molecules can no longer fulfil due to increasing drug resistance. Metallodrugs still have tremendous potential to help overcome drug resistance and find new cures in medicine, considering that at least 25 metallic elements participate in healthy functioning of the human body. Transition metal ions, such as copper, zinc and iron, are incorporated into catalytic proteins, the so-called metalloenzymes, which participate in various chemical reactions necessary for life. The interaction of metal complexes in different pathways with the structural richness of deoxyribonucleic acid encouraged to seek to understand the mechanisms of action and overcome the obstacles encountered for a promising future of these drugs. The success of platinum-based metallodrugs is one of the great inspirations for the search of new metallodrugs, although the approval of these molecules has been slow in recent years due to the risk of systemic toxicity and insufficient understanding of their mechanisms. To overcome the clinical limitations encountered in some metallodrugs, nanoencapsulation has been proposed as a new approach to improve therapeutic index in chemotherapy. The remarkable selectivity of nanoencapsulated metallodrugs and their enhanced capacity to bypass various biological barriers allow site-specific targeting. In this review, we present the advances in the development and use of the most relevant metallodrugs, and new delivery approaches, in the fight against cancer.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"231 ","pages":"Article 116644"},"PeriodicalIF":5.3,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-20DOI: 10.1016/j.bcp.2024.116645
Ryoiti Kiyama, Yuko Wada-Kiyama
This comprehensive review of estrogenic alkaloids reveals that although the number is small, they exhibit a wide range of structures, biosynthesis pathways, mechanisms of action, and applications. Estrogenic alkaloids belong to different classes, different biosynthetic pathways, different estrogenic actions (estrogenic/synergistic, anti-estrogenic/antagonistic, biphasic, and acting as a selective estrogen receptor modulator or SERM), different receptor-initiated signaling pathways, different ways of modulations of estrogen action, and different applications. The future applications of estrogenic alkaloids, such as those for diagnostics, drug development, and therapeutics, are considered with the help of new databases containing comprehensive descriptions of their relationships and more elaborate artificial intelligence-based prediction technologies. Structure-activity studies reveal the significance of the nitrogen atom for their structural and functional diversity, which may help support their broader applications. Based on the summary of previous reports, estrogenic alkaloids have significant potential for future applications.
{"title":"Estrogenic actions of alkaloids: Structural characteristics and molecular mechanisms.","authors":"Ryoiti Kiyama, Yuko Wada-Kiyama","doi":"10.1016/j.bcp.2024.116645","DOIUrl":"10.1016/j.bcp.2024.116645","url":null,"abstract":"<p><p>This comprehensive review of estrogenic alkaloids reveals that although the number is small, they exhibit a wide range of structures, biosynthesis pathways, mechanisms of action, and applications. Estrogenic alkaloids belong to different classes, different biosynthetic pathways, different estrogenic actions (estrogenic/synergistic, anti-estrogenic/antagonistic, biphasic, and acting as a selective estrogen receptor modulator or SERM), different receptor-initiated signaling pathways, different ways of modulations of estrogen action, and different applications. The future applications of estrogenic alkaloids, such as those for diagnostics, drug development, and therapeutics, are considered with the help of new databases containing comprehensive descriptions of their relationships and more elaborate artificial intelligence-based prediction technologies. Structure-activity studies reveal the significance of the nitrogen atom for their structural and functional diversity, which may help support their broader applications. Based on the summary of previous reports, estrogenic alkaloids have significant potential for future applications.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116645"},"PeriodicalIF":5.3,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-19DOI: 10.1016/j.bcp.2024.116641
Xue Zhang , Hongling Liu , Chao Wan , Yijian Li , Chunge Ren , Jia Lu , Yong Liu , Yuli Yang
Corneal endothelial cells (CECs) dysfunction frequently results in a hazy, edematous cornea due to corneal endothelial decompensation and is a major cause of corneal blindness. Drug interventions provide a less invasive alternative to corneal transplantation surgery. However, endothelial-to-mesenchymal transition (EndMT) limits CECs function. Rho-kinase (ROCK) inhibitors, shown in numerous studies to be an adjunctive therapy for CECs dysfunction, cannot completely reverse pathological EndMT caused by inflammatory environmental damage. Verteporfin (VP) is an inhibitor of Yes-associated protein (YAP) and has significant inhibitory effects on cell fibrosis and mesenchymal transition. Here, we explored VP’s utility in mitigating EndMT during ROCK inhibitors treatment of corneal endothelial dysfunction. We surgically constructed a rat model of CECs injury and studied VP and ROCK inhibitors’ effects on EndMT, cell proliferation, and corneal edema using RNA-Seq sequencing, immunofluorescence, optical coherence tomography, and qPCR. The results indicated that YAP expression in human fetal CECs was higher than in adults and decreased with age in rats. Moreover, YAP expression in human CECs was negatively correlated with functional genes, such as AQP1 and ATP1A1. VP effectively reversed EndMT and accelerated corneal hydration regression. However, it inhibited CECs proliferation. We also confirmed that the optimal ratio of VP combined with Y-27632 (ROCK inhibitor) was 1:1, promoting CECs proliferation and reversing EndMT by down-regulating transcription factors downstream of TGF-β signaling, thereby increasing CECs functional and intercellular adhesion proteins. These combined effects promote corneal endothelial damage repair, providing a new treatment strategy.
{"title":"Verteporfin combined with ROCK inhibitor promotes the restoration of corneal endothelial cell dysfunction in rats","authors":"Xue Zhang , Hongling Liu , Chao Wan , Yijian Li , Chunge Ren , Jia Lu , Yong Liu , Yuli Yang","doi":"10.1016/j.bcp.2024.116641","DOIUrl":"10.1016/j.bcp.2024.116641","url":null,"abstract":"<div><div>Corneal endothelial cells (CECs) dysfunction frequently results in a hazy, edematous cornea due to corneal endothelial decompensation and is a major cause of corneal blindness. Drug interventions provide a less invasive alternative to corneal transplantation surgery. However, endothelial-to-mesenchymal transition (EndMT) limits CECs function. Rho-kinase (ROCK) inhibitors, shown in numerous studies to be an adjunctive therapy for CECs dysfunction, cannot completely reverse pathological EndMT caused by inflammatory environmental damage. Verteporfin (VP) is an inhibitor of Yes-associated protein (YAP) and has significant inhibitory effects on cell fibrosis and mesenchymal transition. Here, we explored VP’s utility in mitigating EndMT during ROCK inhibitors treatment of corneal endothelial dysfunction. We surgically constructed a rat model of CECs injury and studied VP and ROCK inhibitors’ effects on EndMT, cell proliferation, and corneal edema using RNA-Seq sequencing, immunofluorescence, optical coherence tomography, and qPCR. The results indicated that YAP expression in human fetal CECs was higher than in adults and decreased with age in rats. Moreover, YAP expression in human CECs was negatively correlated with functional genes, such as <em>AQP1</em> and <em>ATP1A1</em>. VP effectively reversed EndMT and accelerated corneal hydration regression. However, it inhibited CECs proliferation. We also confirmed that the optimal ratio of VP combined with Y-27632 (ROCK inhibitor) was 1:1, promoting CECs proliferation and reversing EndMT by down-regulating transcription factors downstream of TGF-β signaling, thereby increasing CECs functional and intercellular adhesion proteins. These combined effects promote corneal endothelial damage repair, providing a new treatment strategy.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"231 ","pages":"Article 116641"},"PeriodicalIF":5.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-19DOI: 10.1016/j.bcp.2024.116638
Zhiying Liu , Qianyu Zhou , Jinjing Xue , Minhe Cui , Lei Xu , Tianqi Fang , Zhongmei Wen , Dan Li , Jianfeng Wang , Xuming Deng , Yonglin Zhou
Propyl gallate (PG), an approved food additive, can be added to different foods and drugs to provide health benefits with minimal danger. However, no clinical application of PG as an antibacterial agent for the treatment of antimicrobial resistance (AMR) has been documented. The aim of this study was to elucidate the effects and mechanisms by which PG inhibits the activity of Tet(X4). Enzyme activity inhibition assay, antimicrobial tests, scanning electron microscopy (SEM) assay, molecular docking and dynamics simulation assays, and animal infection models were used to confirm the synergistic efficacy and mechanism. Here, we found that PG efficiently inhibited Tet(X4) enzyme activity (IC50 = 34.83 μg/mL) while affecting the expression of tet(X4). PG has a synergistic effect with tigecycline (fractional inhibitory concentration index (FICI) < 0.5) against tet(X4)-positive Escherichia coli (E. coli) isolates of animal origin. The survival rates of G. mellonella larvae and the mouse systemic infection model increased by 60 % and 39 %, respectively. The combination of PG and tigecycline showed remarkable treatment benefits in terms of the bacterial load and inflammatory factors in mice. Our results indicate that PG is a valuable adjuvant with tetracyclines and can be considered to address the inevitable infection caused by tet(X4)-positive bacteria, which is a feasible way to extend the lifespan of existing antibiotics.
{"title":"Recent discoveries of propyl gallate restore the antibacterial effect of tigecycline against tet(X4)-positive Escherichia coli","authors":"Zhiying Liu , Qianyu Zhou , Jinjing Xue , Minhe Cui , Lei Xu , Tianqi Fang , Zhongmei Wen , Dan Li , Jianfeng Wang , Xuming Deng , Yonglin Zhou","doi":"10.1016/j.bcp.2024.116638","DOIUrl":"10.1016/j.bcp.2024.116638","url":null,"abstract":"<div><div>Propyl gallate (PG), an approved food additive, can be added to different foods and drugs to provide health benefits with minimal danger. However, no clinical application of PG as an antibacterial agent for the treatment of antimicrobial resistance (AMR) has been documented. The aim of this study was to elucidate the effects and mechanisms by which PG inhibits the activity of Tet(X4). Enzyme activity inhibition assay, antimicrobial tests, scanning electron microscopy (SEM) assay, molecular docking and dynamics simulation assays, and animal infection models were used to confirm the synergistic efficacy and mechanism. Here, we found that PG efficiently inhibited Tet(X4) enzyme activity (IC<sub>50</sub> = 34.83 μg/mL) while affecting the expression of <em>tet</em>(X4). PG has a synergistic effect with tigecycline (fractional inhibitory concentration index (FICI) < 0.5) against <em>tet</em>(X4)-positive <em>Escherichia coli</em> (<em>E. coli</em>) isolates of animal origin. The survival rates of <em>G. mellonella</em> larvae and the mouse systemic infection model increased by 60 % and 39 %, respectively. The combination of PG and tigecycline showed remarkable treatment benefits in terms of the bacterial load and inflammatory factors in mice. Our results indicate that PG is a valuable adjuvant with tetracyclines and can be considered to address the inevitable infection caused by <em>tet</em>(X4)-positive bacteria, which is a feasible way to extend the lifespan of existing antibiotics.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"231 ","pages":"Article 116638"},"PeriodicalIF":5.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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