Pub Date : 2024-08-22DOI: 10.1016/j.pharmthera.2024.108709
MicroRNAs (miRNAs) are small, non-coding RNA molecules that play a crucial role in regulating gene expression by inhibiting the translation of their specific target messenger RNAs. To date, numerous studies have demonstrated changes in the expression of miRNAs in the kidneys throughout the progression of both acute kidney injury (AKI) and chronic kidney disease (CKD) in both human patients and experimental models. The role of specific microRNAs in the pathogenesis of kidney diseases has also been demonstrated. Further studies have elucidated the regulation of these microRNAs in diseased kidneys. Besides, certain miRNAs are detected in plasma and/or urine in kidney diseases and are potential diagnostic biomarkers. In this review, we provide an overview of recent developments in our understanding of how miRNAs contribute to kidney diseases. We also explore the potential of miRNAs as both biomarkers and therapeutic targets for these conditions, and highlight future research directions.
{"title":"microRNAs in kidney diseases: Regulation, therapeutics, and biomarker potential","authors":"","doi":"10.1016/j.pharmthera.2024.108709","DOIUrl":"10.1016/j.pharmthera.2024.108709","url":null,"abstract":"<div><p>MicroRNAs (miRNAs) are small, non-coding RNA molecules that play a crucial role in regulating gene expression by inhibiting the translation of their specific target messenger RNAs. To date, numerous studies have demonstrated changes in the expression of miRNAs in the kidneys throughout the progression of both acute kidney injury (AKI) and chronic kidney disease (CKD) in both human patients and experimental models. The role of specific microRNAs in the pathogenesis of kidney diseases has also been demonstrated. Further studies have elucidated the regulation of these microRNAs in diseased kidneys. Besides, certain miRNAs are detected in plasma and/or urine in kidney diseases and are potential diagnostic biomarkers. In this review, we provide an overview of recent developments in our understanding of how miRNAs contribute to kidney diseases. We also explore the potential of miRNAs as both biomarkers and therapeutic targets for these conditions, and highlight future research directions.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":12.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-22DOI: 10.1016/j.pharmthera.2024.108710
In an aging society, unveiling new anti-aging strategies to prevent and combat aging-related diseases is of utmost importance. Mitochondria are the primary ATP production sites and key regulators of programmed cell death. Consequently, these highly dynamic organelles play a central role in maintaining tissue function, and mitochondrial dysfunction is a pivotal factor in the progressive age-related decline in cellular homeostasis and organ function.
The current review examines recent advances in understanding the interplay between mitochondrial dysfunction and organ-specific aging. Thereby, we dissect molecular mechanisms underlying mitochondrial impairment associated with the deterioration of organ function, exploring the role of mitochondrial DNA, reactive oxygen species homeostasis, metabolic activity, damage-associated molecular patterns, biogenesis, turnover, and dynamics.
We also highlight emerging therapeutic strategies in preclinical and clinical tests that are supposed to rejuvenate mitochondrial function, such as antioxidants, mitochondrial biogenesis stimulators, and modulators of mitochondrial turnover and dynamics. Furthermore, we discuss potential benefits and challenges associated with the use of these interventions, emphasizing the need for organ-specific approaches given the unique mitochondrial characteristics of different tissues.
In conclusion, this review highlights the therapeutic potential of addressing mitochondrial dysfunction to mitigate organ-specific aging, focusing on the skin, liver, lung, brain, skeletal muscle, and lung, as well as on the reproductive, immune, and cardiovascular systems. Based on a comprehensive understanding of the multifaceted roles of mitochondria, innovative therapeutic strategies may be developed and optimized to combat biological aging and promote healthy aging across diverse organ systems.
在老龄化社会中,揭示新的抗衰老战略以预防和抗击与衰老有关的疾病至关重要。线粒体是产生 ATP 的主要场所,也是细胞程序性死亡的关键调节器。因此,这些高度动态的细胞器在维持组织功能方面发挥着核心作用,而线粒体功能障碍是与年龄相关的细胞稳态和器官功能逐渐衰退的关键因素。本综述探讨了了解线粒体功能障碍与器官特异性衰老之间相互作用的最新进展。通过探讨线粒体 DNA 的作用、活性氧平衡、代谢活动、损伤相关分子模式、生物生成、周转和动力学,我们剖析了线粒体损伤与器官功能衰退相关的分子机制。我们还重点介绍了临床前和临床试验中有望恢复线粒体功能的新兴治疗策略,如抗氧化剂、线粒体生物生成刺激剂以及线粒体更替和动态调节剂。此外,我们还讨论了与使用这些干预措施相关的潜在益处和挑战,并强调鉴于不同组织线粒体的独特性,有必要采用针对特定器官的方法。总之,本综述强调了解决线粒体功能障碍以缓解器官特异性衰老的治疗潜力,重点关注皮肤、肝脏、肺、大脑、骨骼肌和肺,以及生殖、免疫和心血管系统。在全面了解线粒体多方面作用的基础上,可以开发和优化创新的治疗策略,以对抗生物衰老,促进不同器官系统的健康衰老。
{"title":"Targeting organ-specific mitochondrial dysfunction to improve biological aging","authors":"","doi":"10.1016/j.pharmthera.2024.108710","DOIUrl":"10.1016/j.pharmthera.2024.108710","url":null,"abstract":"<div><p>In an aging society, unveiling new anti-aging strategies to prevent and combat aging-related diseases is of utmost importance. Mitochondria are the primary ATP production sites and key regulators of programmed cell death. Consequently, these highly dynamic organelles play a central role in maintaining tissue function, and mitochondrial dysfunction is a pivotal factor in the progressive age-related decline in cellular homeostasis and organ function.</p><p>The current review examines recent advances in understanding the interplay between mitochondrial dysfunction and organ-specific aging. Thereby, we dissect molecular mechanisms underlying mitochondrial impairment associated with the deterioration of organ function, exploring the role of mitochondrial DNA, reactive oxygen species homeostasis, metabolic activity, damage-associated molecular patterns, biogenesis, turnover, and dynamics.</p><p>We also highlight emerging therapeutic strategies in preclinical and clinical tests that are supposed to rejuvenate mitochondrial function, such as antioxidants, mitochondrial biogenesis stimulators, and modulators of mitochondrial turnover and dynamics. Furthermore, we discuss potential benefits and challenges associated with the use of these interventions, emphasizing the need for organ-specific approaches given the unique mitochondrial characteristics of different tissues.</p><p>In conclusion, this review highlights the therapeutic potential of addressing mitochondrial dysfunction to mitigate organ-specific aging, focusing on the skin, liver, lung, brain, skeletal muscle, and lung, as well as on the reproductive, immune, and cardiovascular systems. Based on a comprehensive understanding of the multifaceted roles of mitochondria, innovative therapeutic strategies may be developed and optimized to combat biological aging and promote healthy aging across diverse organ systems.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":12.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S016372582400130X/pdfft?md5=8f87dab5dd66f3b5f2112c8e90a66766&pid=1-s2.0-S016372582400130X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-21DOI: 10.1016/j.pharmthera.2024.108708
C-type natriuretic peptide (CNP) represents the ‘local’ member of the natriuretic peptide family, functioning in an autocrine or paracrine capacity to modulate a hugely diverse portfolio of physiological processes. Whilst the best-characterised of these regulatory roles are in the cardiovascular system, akin to its predominantly endocrine siblings atrial (ANP) and brain (BNP) natriuretic peptides, CNP governs many additional, unrelated mechanisms including bone growth, gamete maturation, auditory processing, and neuronal integrity. Furthermore, there is currently great interest in mimicking the biological activity of CNP for therapeutic gain in many of these disparate organ systems. Herein, we provide an overview of the physiology, pathophysiology and pharmacology of CNP in both cardiovascular and non-cardiovascular settings.
{"title":"C-type natriuretic peptide (CNP): The cardiovascular system and beyond","authors":"","doi":"10.1016/j.pharmthera.2024.108708","DOIUrl":"10.1016/j.pharmthera.2024.108708","url":null,"abstract":"<div><p>C-type natriuretic peptide (CNP) represents the ‘local’ member of the natriuretic peptide family, functioning in an autocrine or paracrine capacity to modulate a hugely diverse portfolio of physiological processes. Whilst the best-characterised of these regulatory roles are in the cardiovascular system, akin to its predominantly endocrine siblings atrial (ANP) and brain (BNP) natriuretic peptides, CNP governs many additional, unrelated mechanisms including bone growth, gamete maturation, auditory processing, and neuronal integrity. Furthermore, there is currently great interest in mimicking the biological activity of CNP for therapeutic gain in many of these disparate organ systems. Herein, we provide an overview of the physiology, pathophysiology and pharmacology of CNP in both cardiovascular and non-cardiovascular settings.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":12.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0163725824001281/pdfft?md5=a6600f580a45edf02b1283f72e0e53df&pid=1-s2.0-S0163725824001281-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-05DOI: 10.1016/j.pharmthera.2024.108700
Innovation of cancer therapy has received a dramatic acceleration over the last fifteen years thanks to the introduction of the novel immune checkpoint inhibitors (ICI). On the other hand, the conspicuous scientific knowledge accumulated in purinergic signaling since the early seventies is finally being transferred to the clinic. Several Phase I/II clinical trials are currently underway to investigate the effect of drugs interfering with purinergic signaling as stand-alone or combination therapy in cancer. This is supporting the novel concept of “purinergic immune checkpoint” (PIC) in cancer therapy.
In the present review we will address a) the basic pharmacology and cell biology of the purinergic system; b) principles of its pathophysiology in human diseases; c) implications for cell death, cell proliferation and cancer; d) novel molecular tools to investigate nucleotide homeostasis in the extracellular environment; e) recent developments in the pharmacology of P1, P2 receptors and related ecto-enzymes; f) P1 and P2 ligands as novel diagnostic tools; g) current issues in PIC-based anti-cancer therapy.
This review will provide an appraisal of the current status of purinergic signaling in cancer and will help identify future avenues of development.
{"title":"Overview of the role of purinergic signaling and insights into its role in cancer therapy","authors":"","doi":"10.1016/j.pharmthera.2024.108700","DOIUrl":"10.1016/j.pharmthera.2024.108700","url":null,"abstract":"<div><p>Innovation of cancer therapy has received a dramatic acceleration over the last fifteen years thanks to the introduction of the novel immune checkpoint inhibitors (ICI). On the other hand, the conspicuous scientific knowledge accumulated in purinergic signaling since the early seventies is finally being transferred to the clinic. Several Phase I/II clinical trials are currently underway to investigate the effect of drugs interfering with purinergic signaling as stand-alone or combination therapy in cancer. This is supporting the novel concept of “purinergic immune checkpoint” (PIC) in cancer therapy.</p><p>In the present review we will address a) the basic pharmacology and cell biology of the purinergic system; b) principles of its pathophysiology in human diseases; c) implications for cell death, cell proliferation and cancer; d) novel molecular tools to investigate nucleotide homeostasis in the extracellular environment; e) recent developments in the pharmacology of P1, P2 receptors and related ecto-enzymes; f) P1 and P2 ligands as novel diagnostic tools; g) current issues in PIC-based anti-cancer therapy.</p><p>This review will provide an appraisal of the current status of purinergic signaling in cancer and will help identify future avenues of development.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":12.0,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0163725824001207/pdfft?md5=a1daa6b93f0294c43639514fa72fb4a9&pid=1-s2.0-S0163725824001207-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141900437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-05DOI: 10.1016/j.pharmthera.2024.108699
The incidence of obesity is rapidly increasing worldwide. Obesity-associated insulin resistance has long been established as a significant risk factor for obesity-related disorders such as type 2 diabetes and atherosclerosis. Insulin plays a key role in systemic glucose metabolism, with the liver, skeletal muscle, and adipose tissue as the major acting tissues. Insulin receptors and the downstream insulin signaling-related molecules are expressed in various tissues, including vascular endothelial cells, vascular smooth muscle cells, and monocytes/macrophages. In obesity, decreased insulin action is considered a driver for associated disorders. However, whether insulin action has a positive or negative effect on obesity-related disorders depends on the tissue in which it acts. While an enhancement of insulin signaling in the liver increases hepatic fat accumulation and exacerbates dyslipidemia, enhancement of insulin signaling in adipose tissue protects against obesity-related dysfunction of various organs by increasing the capacity for fat accumulation in the adipose tissue and inhibiting ectopic fat accumulation. Thus, this “healthy adipose tissue expansion” by enhancing insulin sensitivity in adipose tissue, but not in the liver, may be an effective therapeutic strategy for obesity-related disorders. To effectively address obesity-related metabolic disorders, the mechanisms of insulin resistance in various tissues of obese patients must be understood and drugs that enhance insulin action must be developed. In this article, we review the potential of interventions that enhance insulin signaling as a therapeutic strategy for obesity-related disorders, focusing on the molecular mechanisms of insulin action in each tissue.
{"title":"Tissue-specific activation of insulin signaling as a potential target for obesity-related metabolic disorders","authors":"","doi":"10.1016/j.pharmthera.2024.108699","DOIUrl":"10.1016/j.pharmthera.2024.108699","url":null,"abstract":"<div><p>The incidence of obesity is rapidly increasing worldwide. Obesity-associated insulin resistance has long been established as a significant risk factor for obesity-related disorders such as type 2 diabetes and atherosclerosis. Insulin plays a key role in systemic glucose metabolism, with the liver, skeletal muscle, and adipose tissue as the major acting tissues. Insulin receptors and the downstream insulin signaling-related molecules are expressed in various tissues, including vascular endothelial cells, vascular smooth muscle cells, and monocytes/macrophages. In obesity, decreased insulin action is considered a driver for associated disorders. However, whether insulin action has a positive or negative effect on obesity-related disorders depends on the tissue in which it acts. While an enhancement of insulin signaling in the liver increases hepatic fat accumulation and exacerbates dyslipidemia, enhancement of insulin signaling in adipose tissue protects against obesity-related dysfunction of various organs by increasing the capacity for fat accumulation in the adipose tissue and inhibiting ectopic fat accumulation. Thus, this “healthy adipose tissue expansion” by enhancing insulin sensitivity in adipose tissue, but not in the liver, may be an effective therapeutic strategy for obesity-related disorders. To effectively address obesity-related metabolic disorders, the mechanisms of insulin resistance in various tissues of obese patients must be understood and drugs that enhance insulin action must be developed. In this article, we review the potential of interventions that enhance insulin signaling as a therapeutic strategy for obesity-related disorders, focusing on the molecular mechanisms of insulin action in each tissue.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":12.0,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0163725824001190/pdfft?md5=e581979ebbd453ee2ff079fb7585ccff&pid=1-s2.0-S0163725824001190-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141900438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-03DOI: 10.1016/j.pharmthera.2024.108698
Melanoma is the deadliest form of skin cancer in the United States, with its incidence rates rising in older populations. As the immune system undergoes age-related changes, these alterations can significantly influence tumor progression and the effectiveness of cancer treatments. Recent advancements in understanding immune checkpoint molecules have paved the way for the development of innovative immunotherapies targeting solid tumors. However, the aging tumor microenvironment can play a crucial role in modulating the response to these immunotherapeutic approaches. This review seeks to examine the intricate relationship between age-related changes in the immune system and their impact on the efficacy of immunotherapies, particularly in the context of melanoma. By exploring this complex interplay, we hope to elucidate potential strategies to optimize treatment outcomes for older patients with melanoma, and draw parallels to other cancers.
{"title":"Entering the TiME machine: How age-related changes in the tumor immune microenvironment impact melanoma progression and therapy response","authors":"","doi":"10.1016/j.pharmthera.2024.108698","DOIUrl":"10.1016/j.pharmthera.2024.108698","url":null,"abstract":"<div><p>Melanoma is the deadliest form of skin cancer in the United States, with its incidence rates rising in older populations. As the immune system undergoes age-related changes, these alterations can significantly influence tumor progression and the effectiveness of cancer treatments. Recent advancements in understanding immune checkpoint molecules have paved the way for the development of innovative immunotherapies targeting solid tumors. However, the aging tumor microenvironment can play a crucial role in modulating the response to these immunotherapeutic approaches. This review seeks to examine the intricate relationship between age-related changes in the immune system and their impact on the efficacy of immunotherapies, particularly in the context of melanoma. By exploring this complex interplay, we hope to elucidate potential strategies to optimize treatment outcomes for older patients with melanoma, and draw parallels to other cancers.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":12.0,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-23DOI: 10.1016/j.pharmthera.2024.108697
Abnormal gene alternative splicing (AS) events are strongly associated with cancer progression. Here, we summarize AS events that contribute to the development of drug resistance and classify them into three categories: alternative cis-splicing (ACS), alternative trans-splicing (ATS), and alternative back-splicing (ABS). The regulatory mechanisms underlying AS processes through cis-acting regulatory elements and trans-acting factors are comprehensively described, and the distinct functions of spliced variants, including linear spliced variants derived from ACS, chimeric spliced variants arising from ATS, and circRNAs generated through ABS, are discussed. The identification of dysregulated spliced variants, which contribute to drug resistance and hinder effective cancer treatment, suggests that abnormal AS processes may together serve as a precise regulatory mechanism enabling drug-resistant cancer cell survival or, alternatively, represent an evolutionary pathway for cancer cells to adapt to changes in the external environment. Moreover, this review summarizes recent advancements in treatment approaches targeting AS-associated drug resistance, focusing on cis-acting regulatory elements, trans-acting factors, and specific spliced variants. Collectively, gaining an in-depth understanding of the mechanisms underlying aberrant alternative splicing events and developing strategies to target this process hold great promise for overcoming cancer drug resistance.
{"title":"Overcoming cancer drug-resistance calls for novel strategies targeting abnormal alternative splicing","authors":"","doi":"10.1016/j.pharmthera.2024.108697","DOIUrl":"10.1016/j.pharmthera.2024.108697","url":null,"abstract":"<div><p>Abnormal gene alternative splicing (AS) events are strongly associated with cancer progression. Here, we summarize AS events that contribute to the development of drug resistance and classify them into three categories: alternative <em>cis</em>-splicing (ACS), alternative <em>trans</em>-splicing (ATS), and alternative back-splicing (ABS). The regulatory mechanisms underlying AS processes through <em>cis-</em>acting regulatory elements and <em>trans</em>-acting factors are comprehensively described, and the distinct functions of spliced variants, including linear spliced variants derived from ACS, chimeric spliced variants arising from ATS, and circRNAs generated through ABS, are discussed. The identification of dysregulated spliced variants, which contribute to drug resistance and hinder effective cancer treatment, suggests that abnormal AS processes may together serve as a precise regulatory mechanism enabling drug-resistant cancer cell survival or, alternatively, represent an evolutionary pathway for cancer cells to adapt to changes in the external environment. Moreover, this review summarizes recent advancements in treatment approaches targeting AS-associated drug resistance, focusing on <em>cis</em>-acting regulatory elements, <em>trans</em>-acting factors, and specific spliced variants. Collectively, gaining an in-depth understanding of the mechanisms underlying aberrant alternative splicing events and developing strategies to target this process hold great promise for overcoming cancer drug resistance.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":12.0,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141722806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-06DOI: 10.1016/j.pharmthera.2024.108688
Antibiotic-resistant bacteria are currently an important public health concern posing a serious threat due to their resistance to the current arsenal of antibiotics. Uropathogens Escherichia coli (UPEC), Proteus mirabilis, Klebsiella pneumoniae and Enterococcus faecalis, antibiotic-resistant gram-negative bacteria, cause serious cases of prolonged UTIs, increasing healthcare costs and potentially even leading to the death of an affected patient. This review discusses current knowledge about the increasing resistance to currently recommended antibiotics for UTI therapy, as well as novel therapeutic options. Traditional antibiotics are still a part of the therapy guidelines for UTIs, although they are often not effective and have serious side effects. Hence, novel drugs are being developed, such as combinations of β-lactam antibiotics with cephalosporins and carbapenems. Siderophoric cephalosporins, such as cefiderocol, have shown potential in the treatment of individuals with significant gram-negative bacterial infections, as well as aminoglycosides, fluoroquinolones and tetracyclines that are also undergoing clinical trials. The use of cranberry and probiotics is another potential curative and preventive method that has shown antimicrobial and anti-inflammatory effects. However, further studies are needed to assess the efficacy and safety of probiotics containing cranberry extract for UTI prevention and treatment. An emerging novel approach for UTI treatment is the use of immuno-prophylactic vaccines, as well as different nanotechnology solutions such as nanoparticles (NP). NP have the potential to be used as delivery systems for drugs to specific targets. Furthermore, nanotechnology could enable the development of nano antibiotics with improved features by the application of different NPs in their structure, such as gold and copper NPs. However, further high-quality research is required for the synthesis and testing of these novel molecules, such as safety evaluation and pharmacovigilance.
抗生素耐药细菌是当前公共卫生的一个重要问题,由于它们对现有抗生素库产生耐药性,因此构成了严重威胁。尿路病原菌大肠埃希菌(UPEC)、奇异变形杆菌、肺炎克雷伯菌和粪肠球菌是耐抗生素革兰氏阴性菌,它们会导致严重的长期UTI病例,增加医疗成本,甚至可能导致患者死亡。这篇综述讨论了有关目前推荐用于治疗尿毒症的抗生素耐药性不断增加的现有知识,以及新的治疗方案。传统抗生素仍然是尿毒症治疗指南的一部分,尽管它们往往效果不佳且有严重的副作用。因此,人们正在开发新型药物,如β-内酰胺类抗生素与头孢菌素和碳青霉烯类的复方制剂。嗜苷头孢菌素(如头孢克洛)已显示出治疗严重革兰氏阴性菌感染患者的潜力,氨基糖苷类、氟喹诺酮类和四环素类药物也正在进行临床试验。使用蔓越莓和益生菌是另一种潜在的治疗和预防方法,已显示出抗菌和消炎作用。然而,还需要进一步的研究来评估含有蔓越莓提取物的益生菌在预防和治疗 UTI 方面的有效性和安全性。一种新出现的治疗尿毒症的新方法是使用免疫预防疫苗以及不同的纳米技术解决方案,如纳米颗粒(Nanoparticles)。纳米颗粒有可能被用作向特定靶点输送药物的系统。此外,通过在纳米抗生素的结构中应用不同的纳米粒子(如金和铜纳米粒子),纳米技术还能开发出功能更强的纳米抗生素。不过,这些新型分子的合成和测试,如安全性评估和药物警戒,还需要进一步的高质量研究。
{"title":"Current state and novel outlook on prevention and treatment of rising antibiotic resistance in urinary tract infections","authors":"","doi":"10.1016/j.pharmthera.2024.108688","DOIUrl":"10.1016/j.pharmthera.2024.108688","url":null,"abstract":"<div><p>Antibiotic-resistant bacteria are currently an important public health concern posing a serious threat due to their resistance to the current arsenal of antibiotics. Uropathogens <em>Escherichia coli (UPEC), Proteus mirabilis, Klebsiella pneumoniae</em> and <em>Enterococcus faecalis</em>, antibiotic-resistant gram-negative bacteria, cause serious cases of prolonged UTIs, increasing healthcare costs and potentially even leading to the death of an affected patient. This review discusses current knowledge about the increasing resistance to currently recommended antibiotics for UTI therapy, as well as novel therapeutic options. Traditional antibiotics are still a part of the therapy guidelines for UTIs, although they are often not effective and have serious side effects. Hence, novel drugs are being developed, such as combinations of β-lactam antibiotics with cephalosporins and carbapenems. Siderophoric cephalosporins, such as cefiderocol, have shown potential in the treatment of individuals with significant gram-negative bacterial infections, as well as aminoglycosides, fluoroquinolones and tetracyclines that are also undergoing clinical trials. The use of cranberry and probiotics is another potential curative and preventive method that has shown antimicrobial and anti-inflammatory effects. However, further studies are needed to assess the efficacy and safety of probiotics containing cranberry extract for UTI prevention and treatment. An emerging novel approach for UTI treatment is the use of immuno-prophylactic vaccines, as well as different nanotechnology solutions such as nanoparticles (NP). NP have the potential to be used as delivery systems for drugs to specific targets. Furthermore, nanotechnology could enable the development of nano antibiotics with improved features by the application of different NPs in their structure, such as gold and copper NPs. However, further high-quality research is required for the synthesis and testing of these novel molecules, such as safety evaluation and pharmacovigilance.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":12.0,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0163725824001086/pdfft?md5=04c16e2d669acf095ccda39eb8fb74ad&pid=1-s2.0-S0163725824001086-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141553851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-06DOI: 10.1016/j.pharmthera.2024.108685
Azizah Ugusman , Nur Syahidah Nor Hisam , Nur Syakirah Othman , Nur Najmi Mohamad Anuar , Adila A. Hamid , Jaya Kumar , Maisarah Md Razmi , Amilia Aminuddin
Advanced atherosclerosis is linked to plaque instability, which can result in rupture and the onset of a heart attack. Evidence gathered from human atheroma plaques indicates that intraplaque neovascularization poses a risk to plaque stability and may lead to plaque hemorrhage. Hence, targeting the neovascularization within the atheroma plaque has the potential to mitigate the plaque's vulnerability. While neovascularization has been extensively explored in the context of cancer, research on pharmacological inhibition of this phenomenon in atherosclerosis remains limited. This systematic review aimed to comprehensively assess current and emerging pharmacological interventions for inhibiting intraplaque neovascularization in preclinical settings. Electronic databases (Web of Science, PubMed, Scopus, and Ovid) were searched from January 2013 until February 1, 2024. Preclinical studies reporting the effect of any pharmacological interventions targeting intraplaque neovascularization were included. A total of 10 articles involving in vivo animal studies were eligible for inclusion, with five of them incorporating in vitro experiments to complement their in vivo findings. The pharmacological interventions studied were axitinib, ghrelin, K5, rosuvastatin, atorvastatin, 3PO, everolimus, melatonin, Si-Miao-Yong-A, and protocatechuic aldehyde. All the interventions showed a positive impact in inhibiting intraplaque neovascularization in various atherosclerotic animal models through various signaling pathways. This review provides valuable insights into pharmacological approaches to attenuate intraplaque neovascularization that could serve as a promising therapeutic avenue to enhance plaque stability.
{"title":"Pharmacological interventions for intraplaque neovascularization in atherosclerosis","authors":"Azizah Ugusman , Nur Syahidah Nor Hisam , Nur Syakirah Othman , Nur Najmi Mohamad Anuar , Adila A. Hamid , Jaya Kumar , Maisarah Md Razmi , Amilia Aminuddin","doi":"10.1016/j.pharmthera.2024.108685","DOIUrl":"10.1016/j.pharmthera.2024.108685","url":null,"abstract":"<div><p>Advanced atherosclerosis is linked to plaque instability, which can result in rupture and the onset of a heart attack. Evidence gathered from human atheroma plaques indicates that intraplaque neovascularization poses a risk to plaque stability and may lead to plaque hemorrhage. Hence, targeting the neovascularization within the atheroma plaque has the potential to mitigate the plaque's vulnerability. While neovascularization has been extensively explored in the context of cancer, research on pharmacological inhibition of this phenomenon in atherosclerosis remains limited. This systematic review aimed to comprehensively assess current and emerging pharmacological interventions for inhibiting intraplaque neovascularization in preclinical settings. Electronic databases (Web of Science, PubMed, Scopus, and Ovid) were searched from January 2013 until February 1, 2024. Preclinical studies reporting the effect of any pharmacological interventions targeting intraplaque neovascularization were included. A total of 10 articles involving in vivo animal studies were eligible for inclusion, with five of them incorporating in vitro experiments to complement their in vivo findings. The pharmacological interventions studied were axitinib, ghrelin, K5, rosuvastatin, atorvastatin, 3PO, everolimus, melatonin, Si-Miao-Yong-A, and protocatechuic aldehyde. All the interventions showed a positive impact in inhibiting intraplaque neovascularization in various atherosclerotic animal models through various signaling pathways. This review provides valuable insights into pharmacological approaches to attenuate intraplaque neovascularization that could serve as a promising therapeutic avenue to enhance plaque stability.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":12.0,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141557701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-05DOI: 10.1016/j.pharmthera.2024.108689
Chemotherapy has allowed an increase in cancer survivorship, but it causes important adverse effects. Mucositis affecting the gastrointestinal tract is one of the main problems acutely caused by many antineoplastic drugs, such as 5-fluorouracil or methotrexate. Mucositis may cause pain, diarrhea, anorexia, weight loss, systemic infections and even death. This narrative review focuses on intestinal mucositis and the role that some nutraceuticals, namely vitamins (both lipid- and water-soluble) as well as fatty acids (FAs) and lipid-based products, can have in it. In preclinical (cell cultures, animal models) and/or human studies, vitamins A, D, E, B2, B9 and C, omega-3 long-chain FAs (eicosapentaenoic, docosahexaenoic, conjugated linoleic acid), short-chain FAs (mainly butyrate), medium-chain FAs (capric acid), and different lipid-based products (emu oil, extra-virgin olive oil, lipid replacement therapy), enriched in beneficial FAs and natural antioxidants, were shown to exert beneficial effects (both preventative and palliative) against chemotherapy-induced intestinal mucositis. Although the exact mechanisms of action involved in these effects are not yet well known, our review highlights the interest of investigating on diet and nutrition to implement scientifically robust strategies to improve protection of cancer patients against chemotherapy-induced adverse effects.
{"title":"Vitamins and fatty acids against chemotherapy-induced intestinal mucositis","authors":"","doi":"10.1016/j.pharmthera.2024.108689","DOIUrl":"10.1016/j.pharmthera.2024.108689","url":null,"abstract":"<div><p>Chemotherapy has allowed an increase in cancer survivorship, but it causes important adverse effects. Mucositis affecting the gastrointestinal tract is one of the main problems acutely caused by many antineoplastic drugs, such as 5-fluorouracil or methotrexate. Mucositis may cause pain, diarrhea, anorexia, weight loss, systemic infections and even death. This narrative review focuses on intestinal mucositis and the role that some nutraceuticals, namely vitamins (both lipid- and water-soluble) as well as fatty acids (FAs) and lipid-based products, can have in it. In preclinical (cell cultures, animal models) and/or human studies, vitamins A, D, E, B2, B9 and C, omega-3 long-chain FAs (eicosapentaenoic, docosahexaenoic, conjugated linoleic acid), short-chain FAs (mainly butyrate), medium-chain FAs (capric acid), and different lipid-based products (emu oil, extra-virgin olive oil, lipid replacement therapy), enriched in beneficial FAs and natural antioxidants, were shown to exert beneficial effects (both preventative and palliative) against chemotherapy-induced intestinal mucositis. Although the exact mechanisms of action involved in these effects are not yet well known, our review highlights the interest of investigating on diet and nutrition to implement scientifically robust strategies to improve protection of cancer patients against chemotherapy-induced adverse effects.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":12.0,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0163725824001098/pdfft?md5=ffd1117625949a41758bb70bcd328b2a&pid=1-s2.0-S0163725824001098-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141553852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}