International Journal of Drug Discovery and Pharmacology

Targeting Cancer Drug-Tolerant Persister Cells in Minimal Residual Disease

Wei Zhang — 2025-05-27

Cancer cells that survive therapeutic drug pressure are a significant cause of disease relapse and progression, impeding curative cancer treatment. Drug-triggered Darwinian selection and the emergence of subclones harbouring specific mutations that confer resistance have been well documented and extensively studied. However, these genetic alterations, while important, do not fully explain clinical observations where some patients, after a drug holiday, regain sensitivity to the same treatment despite previous disease progression. This phenomenon highlights the possibility that drug resistance may not solely rely on genetic mutations but could also involve reversible, non-genetic mechanisms. Recent studies have highlighted the existence of drug-tolerant persister cells (DTPs), a subpopulation of cancer cells that can survive short-term therapeutic pressure without acquiring resistance-associated genetic alterations. These cells exhibit a temporary yet reversible tolerance to the initial treatment while also acquiring cross-tolerance to other anti-cancer therapies. The presence of DTPs underscores a dynamic and complex plasticity in tumours, wherein cancer cells can utilise epigenetic rewiring, metabolic reprogramming, and specific signalling pathways to transit between drug-tolerant and drug-sensitive states to adapt to environmental pressures. Furthermore, this adaptive resilience enables DTPs to act as a reservoir for the development of genetically stable resistance, resulting in cancer therapy failure and eventual relapse. In this mini-review, we examine recent evidence on DTPs to provide an overview of their characteristics, development, and survival mechanisms.

Advances in Research on Tibetan Medicine for Improving Cognitive Dysfunction

Tianhao Yu — 2025-05-19

With the rapid aging of the global population, the incidence of cognitive dysfunction is on the rise. The efficacy of existing clinical medications has been less than satisfactory, leading researchers to explore traditional medicinal practices. Tibetan medicine, a vital segment of traditional medicine, has been extensively utilized for the treatment of mental, psychological, and neurological conditions. Modern clinical and experimental pharmacological studies have shown that Rhodiola L., Terminalia chebula Retz., Sibiraea laevigata (L.) Maxim., Centella asiatica (L.) Urban, Gymnadeniaconopsea (L.) R. Br., Crocus sativus L., Ganoderma lucidum (Curtis) P. Karst., Seventy Flavor Pearl Pills, Twenty-Five Flavor Coral Pills, Ruyi Treasure Pills, and Twenty-Five Flavor Pearl Pills have effects on improving cognitive dysfunction. This review meticulously examines the research progress on these Tibetan medicinal substances for their role in mitigating cognitive dysfunction, with the goal of providing valuable insights for the development of novel therapeutic approaches to cognitive deterioration.

Short QT Syndrome and Drug Treatment: A systematic Literature Review and PRISMA Analysis

Tingting You — 2025-05-12

Short QT Syndrome (SQTS) is a rare inherited myocardial ion channel disease characterized by abbreviated cardiac repolarization and shortened QT interval in ECGs, resulting to a high incidence of sudden death and malignant arrhythmias. While various gene mutations that encode subunits of K⁺, Ca²⁺, and Na⁺ channels, as well as the SLC4A3 gene mutation associated with plasma membrane anion exchange, have been implicated, targeted gene screening remains relatively low. In this review, we searched multiple databases, such as PubMed, ScienceDirect, Embase, Web of Science, and Medline, and followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) to conduct a systematic review of literatures in SQTS. We first used VOSviewer to analyze the co-authorship, co-occurrence of countries, organizations, authors, and keywords in the published literatures of SQTs, and then surveyed evidences regarding the impact of single or polygenic gene mutations identified is SQT patients on the electrophysiological properties of IKr, IKs, IK1, ICa-L, INa, and the anion exchanger AE3. Additionally, this review also surveyed current progress in the understandings of potential mechanisms underlying arrhythmogenesis of the SQT gene mutations, and possible drug therapy, unraveled by both experimental and simulation studies.

Exploring Fungi Within the Human Gut Microbiota: Obstacles, Innovations, Therapeutic Applications and Prospects Ahead

Peng Xue — 2025-04-09

Review

Exploring Fungi Within the Human Gut Microbiota: Obstacles, Innovations, Therapeutic Applications and Prospects Ahead

Peng Xue^1,†, Chao Luo^2,†, Jiashu Li³, Liang Yang^3,* and Yuanyuan Ma^1,*

¹ Nantong Key Laboratory of Environmental Toxicology, Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong 226019, China

² The People’s Hospital of Rugao, Affiliated Rugao Hospital of Xinglin College, Nantong University, Nantong 226500, China

³ School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China

* Correspondence: yangl@sustech.edu.cn (L.Y.); myycsd@ntu.edu.cn (Y.M.)

Received: 15 September 2024; Revised: 23 October 2024; Accepted: 23 October 2024; Published: 9 April 2025

Abstract: Fungi in the human gut microbiota participate in the maintenance of health and regulation of physiological processes. This review examines the complex role of gut fungi, highlighting challenges such as diverse fungal populations, cultivation difficulties, and knowledge gaps in their functional roles. Recent advancements in metagenomics and metabolomics have enabled innovative investigations into fungal communities, revealing their influence on host metabolism and immune responses. Future research should address the existing knowledge gaps and explore the therapeutic applications of gut fungi. Interdisciplinary collaborations and new methodologies are proposed to enhance the current understanding of fungi-host interactions, ultimately improving health outcomes and guide the development of novel treatment strategies. This review emphasizes the need to integrate fungal research into microbiome studies to provide a comprehensive understanding of gut health.

Comparison of Thromboelastography, Conventional Coagulation Tests and Clotting Time in Preclinical Investigations of Anticoagulant Drugs in Rodents

Xinrong Yang — 2025-04-22

Article

Comparison of Thromboelastography, Conventional Coagulation Tests and Clotting Time in Preclinical Investigations of Anticoagulant Drugs in Rodents

Xinrong Yang, Boning Huang, Ping Tang, Liuqing Lin and Baoqin Lin^*

The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Clinical Research Academy of Chinese Medicine, Guangdong Engineering Research Center of Commercialization of Medical Institution Preparations and Traditional Chinese Medicines, Guangdong Engineering Technology Research Center of Commercialization of Linnan Special Medical Institution Preparations, Guangzhou, 510405; China

* Correspondence: linbaoqin@gzucm.edu.cn

Received: 11 September 2024; Revised: 24 October 2024; Accepted: 28 October 2024; Published: 22 April 2025

Abstract: Background This aimed to compare thromboelastography (TEG), conventional coagulation tests (CCTs) and clotting time (CT) during the detection of coagulation in rodents. Methods The TEG, CCTs and CT were detected in blood samples from the abdominal aorta to assess the coagulation system in rodents administered with anticoagulants. Similarly, the CT test was performed on blood samples from the retro-orbital venous plexus of mice. Subsequently, the sensitivity of CT to detect coagulation changes in mice administered with different anticoagulants was assessed. Finally, factors influencing the clotting time were investigated, including the sources of blood samples, laparotomy, fasting, irrigation, gender, and different technicians. Results TEG failed to detect rivaroxaban-induced changes in the coagulation system of rats. In contrast, APTT, PT, and CT were significantly prolonged following rivaroxaban administration in rats. APTT and PT exhibited higher sensitivity compared to the clotting time. Furthermore, the clotting time of mice was more sensitive relative to that of rats. Moreover, laparotomy, fasting, irrigation, and gender did not influence the clotting time, however, different technicians did. Conclusion In summary, TEG may not be an appropriate method for assessing the impact of drug-induced prolongation of clotting time in rodents. CCTs and CT are effective screening methods for anticoagulant agents. Besides, the CT appears to be ideal for application in the primary screening of anticoagulant drugs in mice, while CCTs are suitable for rats.

Analyzing the Structure-Activity Relationship of Necrostain-1 and Its Analogues as RIPK1 Inhibitors on Necroptosis

Huilin Liu — 2025-06-20

Necroptosis is a type of programmed cell death mediated by the RIPK1-RIPK3-MLKL axis. Receptor-interacting serine/threonine-protein kinase 1(RIPK1), the key upstream regulator of necroptosis, has been implicated in the pathogenesis of various diseases, and its inhibitors are being tested in clinical trials. Necrostatin-1 (Nec-1), the firstly identified RIPK1 inhibitor, effectively prevents necroptosis by specifically inhibiting the kinase activity of RIPK1. In our study, we compared the inhibitory efficiency of Nec-1 and its analogues on RIPK1 by using the TBZ-induced necroptosis model in HT29 cells and analyzing their structure-activity relationship (SAR). The results showed that Nec-1, Nec-1s, Nec-a1, Nec-a2, Nec-a3, Nec-a4, and Nec-a5 exhibited potent inhibition of TBZ-induced necroptosis and phosphorylation of RIPK1, RIPK3, MLKL. Molecular docking showed that there were two potential binding pockets between Nec-1 and its analogues with RIPK1. SAR analysis showed that the type and size of a substituent at the nitrogen atom in the 3-position of the imidazolidine ring markedly influenced the activity, indicating that a substituent at this position is essential for maintaining the biological function. This study helps to further elucidate how Nec-1 works and could lead to the development of more effective analogues.