Pub Date : 2023-01-16DOI: 10.1007/s12272-023-01427-4
Miso Park, Keon Wook Kang, Ji Won Kim
Gene expression is modulated through the integration of many regulatory elements and their associated transcription factors (TFs). TFs bind to specific DNA sequences and either activate or repress transcriptional activity. Through decades of research, it has been established that aberrant expression or functional abnormalities of TFs can lead to uncontrolled cell division and the development of cancer. Initial studies on transcriptional regulation in cancer have focused on TFs as transcriptional activators. However, recent studies have demonstrated several different mechanisms of transcriptional repression in cancer, which could be potential therapeutic targets for the development of specific anti-cancer agents. In the first section of this review, “Emerging roles of transcriptional repressors in cancer development,” we summarize the current understanding of transcriptional repressors and their involvement in the molecular processes of cancer progression. In the subsequent section, “Therapeutic applications,” we provide an updated overview of the available therapeutic targets for drug discovery and discuss the new frontier of such applications.
{"title":"The role and application of transcriptional repressors in cancer treatment","authors":"Miso Park, Keon Wook Kang, Ji Won Kim","doi":"10.1007/s12272-023-01427-4","DOIUrl":"10.1007/s12272-023-01427-4","url":null,"abstract":"<div><p>Gene expression is modulated through the integration of many regulatory elements and their associated transcription factors (TFs). TFs bind to specific DNA sequences and either activate or repress transcriptional activity. Through decades of research, it has been established that aberrant expression or functional abnormalities of TFs can lead to uncontrolled cell division and the development of cancer. Initial studies on transcriptional regulation in cancer have focused on TFs as transcriptional activators. However, recent studies have demonstrated several different mechanisms of transcriptional repression in cancer, which could be potential therapeutic targets for the development of specific anti-cancer agents. In the first section of this review, “Emerging roles of transcriptional repressors in cancer development,” we summarize the current understanding of transcriptional repressors and their involvement in the molecular processes of cancer progression. In the subsequent section, “Therapeutic applications,” we provide an updated overview of the available therapeutic targets for drug discovery and discuss the new frontier of such applications.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"46 1","pages":"1 - 17"},"PeriodicalIF":6.7,"publicationDate":"2023-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10581178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-06DOI: 10.1007/s12272-023-01426-5
Ga-Eun Lee, Dohyun Jeung, Weidong Chen, Jiin Byun, Joo Young Lee, Han Chang Kang, Hye Suk Lee, Dae Joon Kim, Jin-Sung Choi, Cheol-Jung Lee, Hyun-Jung An, Yong-Yeon Cho
E2F 1, 2, and 3a, (refer to as E2Fs) are a subfamily of E2F transcription factor family that play essential roles in cell-cycle progression, DNA replication, DNA repair, apoptosis, and differentiation. Although the transcriptional regulation of E2Fs has focused on pocket protein retinoblastoma protein complex, recent studies indicate that post-translational modification and stability regulation of E2Fs play key roles in diverse cellular processes. In this study, we found that FBXO1, a component of S-phase kinase-associated protein 1 (SKP1)-cullin 1-F-box protein (SCF) complex, is an E2Fs binding partner. Furthermore, FBXO1 to E2Fs binding induced K48 ubiquitination and subsequent proteasomal degradation of E2Fs. Binding domain analysis indicated that the Arg (R)/Ile (I) and R/Val (V) motifs, which are located in the dimerization domain of E2Fs, of E2F 1 and 3a and E2F2, respectively, acted as degron motifs (DMs) for FBXO1. Notably, RI/AA or RV/AA mutation in the DMs reduced FBXO1-mediated ubiquitination and prolonged the half-lives of E2Fs. Importantly, the stabilities of E2Fs were affected by phosphorylation of threonine residues located near RI and RV residues of DMs. Phosphorylation prediction database analysis and specific inhibitor analysis revealed that MEK/ERK signaling molecules play key roles in FBXO1/E2Fs’ interaction and modulate E2F protein turnover. Moreover, both elevated E2Fs protein levels by knockdown of FBXO1 and decreased E2Fs protein levels by sh-E2F3a delayed G1/S cell cycle transition, resulting in inhibition of cancer cell proliferation. These results demonstrated that FBXO1-E2Fs axis-mediated precise E2Fs stability regulation plays a key role in cell proliferation via G1/S cell cycle transition.
E2F 1、2和3a(简称E2F)是E2F转录因子家族的一个亚家族,在细胞周期进程、DNA复制、DNA修复、细胞凋亡和分化中发挥重要作用。虽然E2Fs的转录调控主要集中在口袋蛋白视网膜母细胞瘤蛋白复合物上,但最近的研究表明,E2Fs的翻译后修饰和稳定性调控在多种细胞过程中发挥关键作用。在这项研究中,我们发现FBXO1是s期激酶相关蛋白1 (SKP1)-cullin 1- f -box蛋白(SCF)复合物的一个组分,是E2Fs的结合伙伴。此外,FBXO1与E2Fs结合诱导K48泛素化和随后的E2Fs蛋白酶体降解。结合域分析表明,位于E2F二聚化结构域的Arg (R)/Ile (I)和R/Val (V)基序分别是FBXO1的脱粒基序(DMs),它们分别位于e2f1和3a和E2F2的二聚化结构域。值得注意的是,dm中的RI/AA或RV/AA突变降低了fbxo1介导的泛素化,延长了E2Fs的半衰期。重要的是,E2Fs的稳定性受到位于DMs的RI和RV残基附近的苏氨酸残基磷酸化的影响。磷酸化预测数据库分析和特异性抑制剂分析表明,MEK/ERK信号分子在FBXO1/E2Fs相互作用和调节E2F蛋白周转中发挥关键作用。此外,通过敲低FBXO1上调E2Fs蛋白水平和通过sh-E2F3a下调E2Fs蛋白水平均可延缓G1/S细胞周期转变,从而抑制癌细胞增殖。这些结果表明,FBXO1-E2Fs轴介导的精确E2Fs稳定性调控通过G1/S细胞周期转变在细胞增殖中起关键作用。
{"title":"MEKs/ERKs-mediated FBXO1/E2Fs interaction interference modulates G1/S cell cycle transition and cancer cell proliferation","authors":"Ga-Eun Lee, Dohyun Jeung, Weidong Chen, Jiin Byun, Joo Young Lee, Han Chang Kang, Hye Suk Lee, Dae Joon Kim, Jin-Sung Choi, Cheol-Jung Lee, Hyun-Jung An, Yong-Yeon Cho","doi":"10.1007/s12272-023-01426-5","DOIUrl":"10.1007/s12272-023-01426-5","url":null,"abstract":"<div><p>E2F 1, 2, and 3a, (refer to as E2Fs) are a subfamily of E2F transcription factor family that play essential roles in cell-cycle progression, DNA replication, DNA repair, apoptosis, and differentiation. Although the transcriptional regulation of E2Fs has focused on pocket protein retinoblastoma protein complex, recent studies indicate that post-translational modification and stability regulation of E2Fs play key roles in diverse cellular processes. In this study, we found that FBXO1, a component of S-phase kinase-associated protein 1 (SKP1)-cullin 1-F-box protein (SCF) complex, is an E2Fs binding partner. Furthermore, FBXO1 to E2Fs binding induced K48 ubiquitination and subsequent proteasomal degradation of E2Fs. Binding domain analysis indicated that the Arg (R)/Ile (I) and R/Val (V) motifs, which are located in the dimerization domain of E2Fs, of E2F 1 and 3a and E2F2, respectively, acted as degron motifs (DMs) for FBXO1. Notably, RI/AA or RV/AA mutation in the DMs reduced FBXO1-mediated ubiquitination and prolonged the half-lives of E2Fs. Importantly, the stabilities of E2Fs were affected by phosphorylation of threonine residues located near RI and RV residues of DMs. Phosphorylation prediction database analysis and specific inhibitor analysis revealed that MEK/ERK signaling molecules play key roles in FBXO1/E2Fs’ interaction and modulate E2F protein turnover. Moreover, both elevated E2Fs protein levels by knockdown of FBXO1 and decreased E2Fs protein levels by sh-E2F3a delayed G<sub>1</sub>/S cell cycle transition, resulting in inhibition of cancer cell proliferation. These results demonstrated that FBXO1-E2Fs axis-mediated precise E2Fs stability regulation plays a key role in cell proliferation via G<sub>1</sub>/S cell cycle transition.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"46 1","pages":"44 - 58"},"PeriodicalIF":6.7,"publicationDate":"2023-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50020123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-03DOI: 10.1007/s12272-022-01425-y
So Hee Nam, Joonhyuck Park, Heebeom Koo
Biological cell membranes are a natural barrier for living cells. In the last few decades, the cell membrane has been the main hurdle in the efficient delivery of bioactive and therapeutic agents. To increase the drug efficacy of these agents, additional mediators have been considered. Cell-penetrating peptides (CPPs), a series of oligopeptides composed of mostly hydrophobic and/or positively charged side chains, can increase the interaction with the cell membrane. CPP-based delivery platforms have shown great potential for the efficient and direct cytosol delivery of various cargos, including genes, proteins, and small molecule drugs. Bypassing endocytosis allows the CPP-based delivery systems greater defense against the degradation of protein-based drugs than other drug delivery systems. However, the delivery of CPPs exhibits intrinsically non-specific targeting, which limits their medical applications. To endow CPPs with specific targeting ability, the conjugation of pH-sensitive, enzyme-specific cleavable, and multiple targeting ligands has been reported. Optimization of the length and sequence of CPPs is still needed for various drugs of different sizes and surface charges. Toxicity issues in CPP-based delivery systems should be addressed carefully before clinical use.
{"title":"Recent advances in selective and targeted drug/gene delivery systems using cell-penetrating peptides","authors":"So Hee Nam, Joonhyuck Park, Heebeom Koo","doi":"10.1007/s12272-022-01425-y","DOIUrl":"10.1007/s12272-022-01425-y","url":null,"abstract":"<div><p>Biological cell membranes are a natural barrier for living cells. In the last few decades, the cell membrane has been the main hurdle in the efficient delivery of bioactive and therapeutic agents. To increase the drug efficacy of these agents, additional mediators have been considered. Cell-penetrating peptides (CPPs), a series of oligopeptides composed of mostly hydrophobic and/or positively charged side chains, can increase the interaction with the cell membrane. CPP-based delivery platforms have shown great potential for the efficient and direct cytosol delivery of various cargos, including genes, proteins, and small molecule drugs. Bypassing endocytosis allows the CPP-based delivery systems greater defense against the degradation of protein-based drugs than other drug delivery systems. However, the delivery of CPPs exhibits intrinsically non-specific targeting, which limits their medical applications. To endow CPPs with specific targeting ability, the conjugation of pH-sensitive, enzyme-specific cleavable, and multiple targeting ligands has been reported. Optimization of the length and sequence of CPPs is still needed for various drugs of different sizes and surface charges. Toxicity issues in CPP-based delivery systems should be addressed carefully before clinical use.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"46 1","pages":"18 - 34"},"PeriodicalIF":6.7,"publicationDate":"2023-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12272-022-01425-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10635928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-23DOI: 10.1007/s12272-022-01423-0
Chang‑Keun Cho, Ji-Young Byeon, Pureum Kang, Hye-Jung Park, Eunvin Ko, Chou Yen Mu, Choon-Gon Jang, Seok-Yong Lee, Yun Jeong Lee
Tolperisone hydrochloride is a centrally-acting muscle relaxant used for relieving spasticities of neurological origin and muscle spasms associated with painful locomotor diseases. It is metabolized to the inactive metabolite mainly by CYP2D6 and, to a lesser extent, by CYP2C19 and CYP1A2. In our previous study, the pharmacokinetics of tolperisone was significantly affected by the genetic polymorphism of CYP2D6, but the wide interindividual variation of tolperisone pharmacokinetics was not explained by genetic polymorphism of CYP2D6 alone. Thus, we studied the effects of CYP2C19 genetic polymorphism on tolperisone pharmacokinetics. Eighty-one subjects with different CYP2C19 genotypes received a single oral dose of 150 mg tolperisone with 240 mL of water, and blood samples were collected up to 12 h after dosing. The plasma concentration of tolperisone was measured by a liquid chromatography-tandem mass spectrometry system. The CYP2C19PM group had significantly higher Cmax and lower CL/F values than the CYP2C19EM and CYP2C19IM groups. The AUCinf of the CYP2C19PM group was 2.86-fold and 3.00-fold higher than the CYP2C19EM and CYP2C19IM groups, respectively. In conclusion, the genetic polymorphism of CYP2C19 significantly affected tolperisone pharmacokinetics.
{"title":"Effects of CYP2C19 genetic polymorphism on the pharmacokinetics of tolperisone in healthy subjects","authors":"Chang‑Keun Cho, Ji-Young Byeon, Pureum Kang, Hye-Jung Park, Eunvin Ko, Chou Yen Mu, Choon-Gon Jang, Seok-Yong Lee, Yun Jeong Lee","doi":"10.1007/s12272-022-01423-0","DOIUrl":"10.1007/s12272-022-01423-0","url":null,"abstract":"<div><p>Tolperisone hydrochloride is a centrally-acting muscle relaxant used for relieving spasticities of neurological origin and muscle spasms associated with painful locomotor diseases. It is metabolized to the inactive metabolite mainly by CYP2D6 and, to a lesser extent, by CYP2C19 and CYP1A2. In our previous study, the pharmacokinetics of tolperisone was significantly affected by the genetic polymorphism of <i>CYP2D6</i>, but the wide interindividual variation of tolperisone pharmacokinetics was not explained by genetic polymorphism of <i>CYP2D6</i> alone. Thus, we studied the effects of <i>CYP2C19</i> genetic polymorphism on tolperisone pharmacokinetics. Eighty-one subjects with different <i>CYP2C19</i> genotypes received a single oral dose of 150 mg tolperisone with 240 mL of water, and blood samples were collected up to 12 h after dosing. The plasma concentration of tolperisone was measured by a liquid chromatography-tandem mass spectrometry system. The CYP2C19PM group had significantly higher C<sub>max</sub> and lower CL/F values than the CYP2C19EM and CYP2C19IM groups. The AUC<sub>inf</sub> of the CYP2C19PM group was 2.86-fold and 3.00-fold higher than the CYP2C19EM and CYP2C19IM groups, respectively. In conclusion, the genetic polymorphism of <i>CYP2C19</i> significantly affected tolperisone pharmacokinetics.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"46 2","pages":"111 - 116"},"PeriodicalIF":6.7,"publicationDate":"2022-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10762271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-21DOI: 10.1007/s12272-022-01422-1
Chang‑Keun Cho, Ji-Young Byeon, Pureum Kang, Jung-In Park, Choon-Gon Jang, Seok-Yong Lee, Chang-Ik Choi, Jung‑Woo Bae, Yun Jeong Lee
Tolperisone, a muscle relaxant used for post-stroke spasticity, has been reported to have a very wide interindividual pharmacokinetic variability. It is metabolized mainly by CYP2D6 and, to a lesser extent, by CYP2C19 and CYP1A2. CYP2D6 is a highly polymorphic enzyme, and CYP2D6*wt/*wt, CYP2D6*wt/*10 and CYP2D6*10/*10 genotypes constitute more than 90% of the CYP2D6 genotypes in the Korean population. Thus, effects of the CYP2D6*10 on tolperisone pharmacokinetics were investigated in this study to elucidate the reasons for the wide interindividual variability. Oral tolperisone 150 mg was given to sixty-four healthy Koreans, and plasma concentrations of tolperisone were measured by liquid chromatography-tandem mass spectrometry (LC–MS/MS). The CYP2D6*10/*10 and CYP2D6*wt/*10 groups had significantly higher Cmax and lower CL/F values than the CYP2D6*wt/*wt group. The AUCinf of CYP2D6*10/*10 and CYP2D6*wt/*10 groups were 5.18-fold and 2.25-fold higher than the CYP2D6*wt/*wt group, respectively. There were considerable variations in the Cmax and AUC values within each genotype group, and the variations were greater as the activity of CYP2D6 decreased. These results suggest that the genetic polymorphism of CYP2D6 significantly affected tolperisone pharmacokinetics and factor(s) other than CYP2D6 may also have significant effects on the pharmacokinetics of tolperisone.
{"title":"Effects of CYP2D6*10 allele on the pharmacokinetics of tolperisone","authors":"Chang‑Keun Cho, Ji-Young Byeon, Pureum Kang, Jung-In Park, Choon-Gon Jang, Seok-Yong Lee, Chang-Ik Choi, Jung‑Woo Bae, Yun Jeong Lee","doi":"10.1007/s12272-022-01422-1","DOIUrl":"10.1007/s12272-022-01422-1","url":null,"abstract":"<div><p>Tolperisone, a muscle relaxant used for post-stroke spasticity, has been reported to have a very wide interindividual pharmacokinetic variability. It is metabolized mainly by CYP2D6 and, to a lesser extent, by CYP2C19 and CYP1A2. CYP2D6 is a highly polymorphic enzyme, and <i>CYP2D6*wt</i>/<i>*wt</i>, <i>CYP2D6*wt/*10</i> and <i>CYP2D6*10/*10</i> genotypes constitute more than 90% of the <i>CYP2D6</i> genotypes in the Korean population. Thus, effects of the <i>CYP2D6*10</i> on tolperisone pharmacokinetics were investigated in this study to elucidate the reasons for the wide interindividual variability. Oral tolperisone 150 mg was given to sixty-four healthy Koreans, and plasma concentrations of tolperisone were measured by liquid chromatography-tandem mass spectrometry (LC–MS/MS). The <i>CYP2D6*10/*10</i> and <i>CYP2D6*wt/*10</i> groups had significantly higher C<sub>max</sub> and lower CL/F values than the <i>CYP2D6*wt/*wt</i> group. The AUC<sub>inf</sub> of <i>CYP2D6*10/*10</i> and <i>CYP2D6*wt/*10</i> groups were 5.18-fold and 2.25-fold higher than the <i>CYP2D6*wt/*wt</i> group, respectively. There were considerable variations in the C<sub>max</sub> and AUC values within each genotype group, and the variations were greater as the activity of CYP2D6 decreased. These results suggest that the genetic polymorphism of <i>CYP2D6</i> significantly affected tolperisone pharmacokinetics and factor(s) other than CYP2D6 may also have significant effects on the pharmacokinetics of tolperisone.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"46 1","pages":"59 - 64"},"PeriodicalIF":6.7,"publicationDate":"2022-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12272-022-01422-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10657760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-03DOI: 10.1007/s12272-022-01421-2
Hyung-Ook Kim
Although atopic dermatitis (AD) is primarily a Th2-driven disease, it shows high heterogeneity with additional variable contributions of the Th22, Th17, and Th1 pathways, depending on the subtype of the disease. Expanding knowledge and understanding of AD pathogenesis has promoted the development of numerous novel therapeutics that target cytokines and their signaling molecules, representatively, Janus kinases, involved in the underlying immune pathways, resulting in therapeutic success and failure. The first FDA approval was for the targeted biologic dupilumab. Although this proved the therapeutic relevance of targeting Th2 cytokines in moderate-to-severe forms of AD, it did not treat all patients, necessitating additional targeted therapeutics that modulate other cytokine pathways to resolve AD in all subtypes. Three more recently FDA-approved targeted therapeutics and several others that have been developed represent different targeted approaches directed to the Th2, Th22, Th17, or Th1 pathways. This review summarizes the main features and clinical outcomes of various approaches targeting cytokines and signaling molecules in these different pathways in view of both successful and failed cases, with a discussion of their therapeutic implications. In future, AD should be treated with more specific treatments reflecting the disease heterogeneity, but the current development of targeted therapeutics has faced some challenges in this context, which is also discussed.
{"title":"Targeting cytokines and signaling molecules related to immune pathways in atopic dermatitis: therapeutic implications and challenges","authors":"Hyung-Ook Kim","doi":"10.1007/s12272-022-01421-2","DOIUrl":"10.1007/s12272-022-01421-2","url":null,"abstract":"<div><p>Although atopic dermatitis (AD) is primarily a Th2-driven disease, it shows high heterogeneity with additional variable contributions of the Th22, Th17, and Th1 pathways, depending on the subtype of the disease. Expanding knowledge and understanding of AD pathogenesis has promoted the development of numerous novel therapeutics that target cytokines and their signaling molecules, representatively, Janus kinases, involved in the underlying immune pathways, resulting in therapeutic success and failure. The first FDA approval was for the targeted biologic dupilumab. Although this proved the therapeutic relevance of targeting Th2 cytokines in moderate-to-severe forms of AD, it did not treat all patients, necessitating additional targeted therapeutics that modulate other cytokine pathways to resolve AD in all subtypes. Three more recently FDA-approved targeted therapeutics and several others that have been developed represent different targeted approaches directed to the Th2, Th22, Th17, or Th1 pathways. This review summarizes the main features and clinical outcomes of various approaches targeting cytokines and signaling molecules in these different pathways in view of both successful and failed cases, with a discussion of their therapeutic implications. In future, AD should be treated with more specific treatments reflecting the disease heterogeneity, but the current development of targeted therapeutics has faced some challenges in this context, which is also discussed.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"45 12","pages":"894 - 908"},"PeriodicalIF":6.7,"publicationDate":"2022-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10374383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-11-28DOI: 10.1007/s12272-022-01419-w
Muhammad Sohaib Khan, Choongho Lee, Sang Geon Kim
Metabolism of carbohydrates and lipids and protein degradation occurs in the liver and contributes to the body's homeostasis by secreting a variety of mediators. Any imbalance in this homeostasis due to excess fat consumption and the pathologic events accompanying lipotoxicity, autophagy dysregulation, endoplasmic reticulum stress, and insulin resistance may cause disturbances in the secretion of the proteins from the liver and their physiologic modifications and interactions with others. Since the liver secretome plays a role in the regulation of fuel metabolism and inflammation not only in the liver per se but also in other organs, the proteins belong to the utmost targets for treating metabolic and inflammatory diseases (e.g., COVID-19), depending on the available and feasible approaches to controlling their biological effects. However, in this era, we still come across new liver-derived proteins but are yet unable to entirely understand the pathologic basis underlying disease progression. This review aims to provide an updated overview of liver secretome biology with explanatory mechanisms with regard to the progression of metabolic and inflammatory liver diseases.
{"title":"Non-alcoholic fatty liver disease and liver secretome","authors":"Muhammad Sohaib Khan, Choongho Lee, Sang Geon Kim","doi":"10.1007/s12272-022-01419-w","DOIUrl":"10.1007/s12272-022-01419-w","url":null,"abstract":"<div><p>Metabolism of carbohydrates and lipids and protein degradation occurs in the liver and contributes to the body's homeostasis by secreting a variety of mediators. Any imbalance in this homeostasis due to excess fat consumption and the pathologic events accompanying lipotoxicity, autophagy dysregulation, endoplasmic reticulum stress, and insulin resistance may cause disturbances in the secretion of the proteins from the liver and their physiologic modifications and interactions with others. Since the liver secretome plays a role in the regulation of fuel metabolism and inflammation not only in the liver per se but also in other organs, the proteins belong to the utmost targets for treating metabolic and inflammatory diseases (e.g., COVID-19), depending on the available and feasible approaches to controlling their biological effects. However, in this era, we still come across new liver-derived proteins but are yet unable to entirely understand the pathologic basis underlying disease progression. This review aims to provide an updated overview of liver secretome biology with explanatory mechanisms with regard to the progression of metabolic and inflammatory liver diseases.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"45 12","pages":"938 - 963"},"PeriodicalIF":6.7,"publicationDate":"2022-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12272-022-01419-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10747603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-11-28DOI: 10.1007/s12272-022-01420-3
Faezeh Almasi, Wen Dang, Fatemeh Mohammadipanah, Ning Li
In addition to the typical respiratory manifestations, various disorders including involvement of the nerve system have been detected in COVID-19 ranging from 22 to 36%. Although growing records are focusing on neurological aspects of COVID-19, the pathophysiological mechanisms and related therapeutic methods remain obscure. Considering the increased concerns of SARS-CoV-2 potential for more serious neuroinvasion conditions, the present review attempts to focus on the neuroprotective effects of natural compounds as the principle source of therapeutics inhibiting multiple steps of the SARS-CoV-2 infection cycle. The great majority of the natural products with anti-SARS-CoV-2 activity mainly inhibit the attachment, entry and gene expression rather than the replication, assembly, or release. Although microbial-derived natural products comprise 38.5% of the known natural products with neuroprotective effects following viral infection, the neuroprotective potential of the majority of microorganisms is still undiscovered. Among natural products, chrysin, huperzine A, ginsenoside Rg1, pterostilbene, and terrein have shown potent in vitro neuroprotective activity and can be promising for new or repurpose drugs for neurological complications of SARS-CoV-2.
{"title":"Neurological disorders of COVID-19: insights to applications of natural products from plants and microorganisms","authors":"Faezeh Almasi, Wen Dang, Fatemeh Mohammadipanah, Ning Li","doi":"10.1007/s12272-022-01420-3","DOIUrl":"10.1007/s12272-022-01420-3","url":null,"abstract":"<div><p>In addition to the typical respiratory manifestations, various disorders including involvement of the nerve system have been detected in COVID-19 ranging from 22 to 36%. Although growing records are focusing on neurological aspects of COVID-19, the pathophysiological mechanisms and related therapeutic methods remain obscure. Considering the increased concerns of SARS-CoV-2 potential for more serious neuroinvasion conditions, the present review attempts to focus on the neuroprotective effects of natural compounds as the principle source of therapeutics inhibiting multiple steps of the SARS-CoV-2 infection cycle. The great majority of the natural products with anti-SARS-CoV-2 activity mainly inhibit the attachment, entry and gene expression rather than the replication, assembly, or release. Although microbial-derived natural products comprise 38.5% of the known natural products with neuroprotective effects following viral infection, the neuroprotective potential of the majority of microorganisms is still undiscovered. Among natural products, chrysin, huperzine A, ginsenoside Rg1, pterostilbene, and terrein have shown potent in vitro neuroprotective activity and can be promising for new or repurpose drugs for neurological complications of SARS-CoV-2.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"45 12","pages":"909 - 937"},"PeriodicalIF":6.7,"publicationDate":"2022-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12272-022-01420-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10747604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-11-28DOI: 10.1007/s12272-022-01417-y
S. Swathi Krishna, Beena Briget Kuriakose, P. K. Lakshmi
Phytoestrogens are non-steroidal, polyphenolic compounds that are derived from plants and have biological properties similar to those of human estrogens. Their bioactivity, which is based on the core ring system, is caused by their structural resemblance to estrogen. Flavonoids, coumestans, lignans, and stilbenes are the four major categories into which they can be divided. They are structurally and functionally related to ovarian and placental estrogens, which are essential in female reproductive processes. Phytoestrogens are present in numerous dietary supplements and find application in hormone replacement therapy as an alternative to synthetic hormones. In addition, they provide health benefits for osteoporosis, heart disease, breast cancer, and prostate cancer. There is a growing interest in using phytoestrogen as preventative medicine in the form of nutraceuticals. This literature provides comprehensive information about the types, sources, and biological actions of phytoestrogens in the reproductive system.
{"title":"Effects of phytoestrogens on reproductive organ health","authors":"S. Swathi Krishna, Beena Briget Kuriakose, P. K. Lakshmi","doi":"10.1007/s12272-022-01417-y","DOIUrl":"10.1007/s12272-022-01417-y","url":null,"abstract":"<div><p>Phytoestrogens are non-steroidal, polyphenolic compounds that are derived from plants and have biological properties similar to those of human estrogens. Their bioactivity, which is based on the core ring system, is caused by their structural resemblance to estrogen. Flavonoids, coumestans, lignans, and stilbenes are the four major categories into which they can be divided. They are structurally and functionally related to ovarian and placental estrogens, which are essential in female reproductive processes. Phytoestrogens are present in numerous dietary supplements and find application in hormone replacement therapy as an alternative to synthetic hormones. In addition, they provide health benefits for osteoporosis, heart disease, breast cancer, and prostate cancer. There is a growing interest in using phytoestrogen as preventative medicine in the form of nutraceuticals. This literature provides comprehensive information about the types, sources, and biological actions of phytoestrogens in the reproductive system.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"45 12","pages":"849 - 864"},"PeriodicalIF":6.7,"publicationDate":"2022-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10733665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-11-24DOI: 10.1007/s12272-022-01418-x
Md. Emranul Karim, Sheikh Tanzina Haque, Hamed Al-Busaidi, Athirah Bakhtiar, Kyi Kyi Tha, Mark M. Banaszak Holl, Ezharul Hoque Chowdhury
Messenger RNA (mRNA) recently emerged as an appealing alternative to treat and prevent diseases ranging from cancer and Alzheimer’s disease to COVID-19 with significant clinical outputs. The in vitro-transcribed mRNA has been engineered to mimic the structure of natural mRNA for vaccination, cancer immunotherapy and protein replacement therapy. In past decades, significant progress has been noticed in unveiling the molecular pathways of mRNA, controlling its translatability and stability, and its evolutionary defense mechanism. However, numerous unsolved structural, biological, and technical difficulties hamper the successful implementation of systemic delivery of mRNA for safer human consumption. Advances in designing and manufacturing mRNA and selecting innovative delivery vehicles are mandatory to address the unresolved issues and achieve the full potential of mRNA drugs. Despite the substantial efforts made to improve the intracellular delivery of mRNA drugs, challenges associated with diverse applications in different routes still exist. This study examines the current progress of mRNA therapeutics and advancements in designing biomaterials and delivery strategies, the existing translational challenges of clinical tractability and the prospects of overcoming any challenges related to mRNA.
{"title":"Scope and challenges of nanoparticle-based mRNA delivery in cancer treatment","authors":"Md. Emranul Karim, Sheikh Tanzina Haque, Hamed Al-Busaidi, Athirah Bakhtiar, Kyi Kyi Tha, Mark M. Banaszak Holl, Ezharul Hoque Chowdhury","doi":"10.1007/s12272-022-01418-x","DOIUrl":"10.1007/s12272-022-01418-x","url":null,"abstract":"<div><p>Messenger RNA (mRNA) recently emerged as an appealing alternative to treat and prevent diseases ranging from cancer and Alzheimer’s disease to COVID-19 with significant clinical outputs. The in vitro-transcribed mRNA has been engineered to mimic the structure of natural mRNA for vaccination, cancer immunotherapy and protein replacement therapy. In past decades, significant progress has been noticed in unveiling the molecular pathways of mRNA, controlling its translatability and stability, and its evolutionary defense mechanism. However, numerous unsolved structural, biological, and technical difficulties hamper the successful implementation of systemic delivery of mRNA for safer human consumption. Advances in designing and manufacturing mRNA and selecting innovative delivery vehicles are mandatory to address the unresolved issues and achieve the full potential of mRNA drugs. Despite the substantial efforts made to improve the intracellular delivery of mRNA drugs, challenges associated with diverse applications in different routes still exist. This study examines the current progress of mRNA therapeutics and advancements in designing biomaterials and delivery strategies, the existing translational challenges of clinical tractability and the prospects of overcoming any challenges related to mRNA.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"45 12","pages":"865 - 893"},"PeriodicalIF":6.7,"publicationDate":"2022-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12272-022-01418-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10402808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}