Archives of Pharmacal Research最新文献

Bruton’s tyrosine kinase (BTK) is a therapeutically validated drug target. Small-molecule inhibitors of BTK have changed the treatment paradigms of multiple B-cell malignancies and evolved over three generations to overcome clinical challenges. Four drugs are now approved by the FDA, including the first-in-class drug ibrutinib and successively approved acalabrutinib, zanubrutinib, and pirtobrutinib. The third-generation drug pirtobrutinib, which binds non-covalently to BTK, is expected to overcome resistance mutations at the covalent binding Cys481 residue of the first and second-generation drugs that covalently bind to BTK. However, some newly identified non-Cys481 resistance mutations to pirtobrutinib have shown their co-resistance to some of the covalent inhibitors, and this leaves a major unmet need that is promoting the development of next-generation BTK-targeted therapeutics. More non-covalent BTK inhibitors with differentiated binding modes are under development, and the ongoing development focus of next-generation therapeutics involves new and alternative directions to target BTK using dual-binding inhibitors and degraders of BTK, as well as its allosteric inhibitors. Recent exploration of the differentiated features of BTK inhibitors in various aspects has shown the possible link between their different features and different functional and therapeutic consequences. This review summarizes the key differentiated features of the BTK inhibitors approved by the FDA and others under development to add knowledge for their therapeutic application and future development. Long-term follow-up updates of clinical outcomes of the earlier developed drugs are also included, together with direct and indirect comparisons of efficacy and safety between the different generations of drugs. The ongoing development status of next-generation BTK-targeted therapeutics is described, with a discussion on their therapeutic potential and some limitations.

Angiogenesis, the process of new blood vessel formation, is a fundamental physiological process implicated in several pathological disorders. The vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are crucial for angiogenesis and vasculogenesis. Among them, the tyrosine kinase receptor VEGFR-2 is primarily expressed in endothelial cells (ECs). These cells regulate various physiological responses, including differentiation, cell proliferation, migration, and survival, by binding to VEGF mitogens. Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) is a key regulator of this process, making it a prime target for therapeutic intervention. Several drugs targeting VEGFR-2 have been approved and are currently utilized to halt the pathological axis of VEGF-VEGFR. This review will focus on the recent developments in the molecular structure and function of VEGFR-2, the molecular mechanism of VEGFR-2 activation, and its downstream signaling pathway. It will also discuss therapies and experimental drugs approved to inhibit the function of VEGFR-2 and the resistance mechanism.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a liver manifestation of metabolic syndrome characterized by excessive hepatic lipid accumulation and lipid metabolism disorders. It has become the most common chronic liver disease worldwide. β-arrestin2 is a multifunctional scaffold protein that is among the most important regulatory molecules, and it exerts key roles in regulating various cellular processes, such as immune response, cellular collagen production, and inflammation. In the current study, we aimed to explore the function of β-arrestin2 in the development and progression of MASLD. Firstly, we observed that the expression of β-arrestin2 was upregulated in liver samples from patients with MASLD. Then, the western diet (WD) combined with CCl₄ injection-induced MASLD was established in wild-type mice, and showed that liver β-arrestin2 expression was also gradually increased, and positively correlated with the degree of lipid metabolism disorder during MASLD progression. Ulteriorly, β-arrestin2 knockout (Arrb2 KO) mice were utilized to induce the MASLD model and found that β-arrestin2 deficiency significantly ameliorated lipid accumulation and inflammatory response in the liver of MASLD mice. Furthermore, the in vitro depletion and overexpression experiments showed that increased β-arrestin2 aggravated lipid accumulation via inhibiting the activation of the TAK1/AMPK pathway, which may be mediated by competitively binding to TAB1 with TAK1. These findings suggest that β-arrestin2 is essential to regulate intrahepatic lipid metabolism. Here, we provide a novel insight in understanding of the expression and function of β-arrestin2 in MASLD, demonstrating that it may be a potential therapeutic target for MASLD treatment.

Microneedles (MN) have emerged as a promising transdermal drug delivery technology that offers advantages such as minimal invasiveness, high biocompatibility, and biodegradability. Gelatin methacryloyl (GelMA)-based MNs have gained attention because of their flexibility, mechanical strength, and modification capabilities, which support controlled drug release. The synthesis process of GelMA involves crosslinking using UV light, resulting in a stable hydrogel structure that supports therapeutic applications, such as wound healing, cancer therapy, and glucose monitoring. However, challenges such as skin penetration strength, drug-loading capacity, and regulatory standards still require solutions. Material and design innovations, particularly the combination of GelMA with nanomaterials and natural polymers, have the potential to enhance the MN efficiency and expand its applications in various medical fields. This review explores the latest developments in GelMA-based MN design and their future potential as reliable therapeutic devices.

The growth factor-mediated mitogen-activated protein kinase (MAPK) signaling pathways in cancer development have become increasingly important in the discovery of therapeutic agents for the treatment of cancer. RSK2 has been historically overlooked in studies regarding its involvement in physiology and signaling pathways related to human diseases, except for Coffin-Lowry syndrome, because it is located downstream of ERKs. For the last 25 years, the authors’ laboratory has made groundbreaking discoveries regarding the role of RSK2, especially by elucidating its binding partners, signaling network, and crosstalk. RSK2 is an important emerging target for developing anticancer drugs. Nevertheless, further studies on the detailed mechanism and signaling network are necessary to avoid the unexpected effects of RSK2 inhibitors. This paper describes a new paradigm of RSK2, where it works as a signaling node to modulate diverse cellular processes, including cell proliferation and transformation, cell cycle regulation, chromatin remodeling, and immune response and inflammation regulation.

Endothelial dysfunction plays a pivotal role in the pathogenesis of various cardiovascular diseases (CVDs), including atherosclerosis, hypertension, heart failure, stroke, and peripheral artery disease. It disrupts vascular homeostasis, leading to reduced nitric oxide (NO) bioavailability, increased oxidative stress, and chronic inflammation, all of which collectively drive vascular damage, atherosclerotic plaque formation, and thrombosis. Additionally, shear stress-induced alterations in blood flow patterns, particularly disturbed flow (d-flow), aggravate endothelial dysfunction. Furthermore, the endothelial-to-mesenchymal transition (EndMT), a process in which endothelial cells acquire mesenchymal-like properties, contributes to vascular remodeling and accelerates CVD progression.

This review explores the significant role of epigenetic mechanisms, such as DNA methylation, histone modifications, and noncoding RNAs (ncRNAs), which serve as critical regulators of endothelial function in response to shear stress in endothelial dysfunction and the development of atherosclerosis. Furthermore, we discuss the pivotal role of endothelial dysfunction in cardiovascular and metabolic diseases, emphasizing the need for innovative therapeutic strategies beyond conventional treatments. In particular, we highlight the endothelial-protective mechanisms of emerging pharmacological agents, including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors, along with supporting clinical evidence demonstrating their efficacy in improving endothelial function and reducing cardiovascular risk.

Abnormal α-synuclein aggregation is a key neuropathological hallmark of α-synucleinopathies, such as Parkinson’s disease (PD), multiple system atrophy (MSA), and several other neurological disorders, and closely contributes to pathogenesis. The primary characteristics of α-synucleinopathies are selective targeted neurodegeneration and the accumulation of Lewy pathologies. Specifically, α-synuclein positron emission tomography (PET) radiotracers target the fibrillar forms of the protein, thus enhancing early diagnosis and the evaluation of treatment effectiveness for various α-synucleinopathies. Therefore, in vivo detection of α-synuclein aggregates using targeted radiolabeled probes would aid in drug development, early diagnosis, and ongoing disease monitoring. As such, no promising α-synuclein biomarkers suitable for clinical applications have been reported. PET is a valuable non-invasive technique for imaging drug distribution in tissues and receptor occupancy at target sites in living animals and humans. Advances in PET biomarkers have significantly enhanced our understanding of the mechanisms underlying PD. This review summarizes recent ongoing efforts in the development of selective PET tracers for α-synuclein and discusses future perspectives.

Antioxidants are organic molecules that scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS), thereby maintaining cellular redox balance in living organisms. The human body synthesizes endogenous antioxidants, whereas humans obtain exogenous antioxidants from other organisms such as plants, animals, fungi, and bacteria. This review primarily focuses on the antioxidant potential of natural metabolites and extracts from five major bacterial phyla, including the well-studied Actinobacteria and Cyanobacteria, as well as less-studied Bacteroides, Firmicutes, and Proteobacteria. The literature survey revealed that the metabolites and the extracts with antioxidant activity can be obtained from bacterial cells and their culture supernatants. The metabolites with antioxidant activity include pigments, phycobiliproteins, polysaccharides, mycosporins-like amino acids, peptides, phenolic compounds, and alkaloids. Both metabolites and extracts demonstrate in vitro antioxidant capacity through radical-scavenging, metal-reducing, and metal-chelating activity assays. In in vivo models, they can scavenge ROS and RNS directly and/or indirectly eliminate them by enhancing the activities of antioxidant enzymes, such as catalase, superoxide dismutase, and glutathione peroxidase. Due to their antioxidant activities, they may find applications in the cosmetic industry as anti-aging agents for the skin and in medicine as drugs or supplements for combating oxidative stress-related disorders, such as neurodegenerative diseases and diabetes. The literature survey also elucidated that some metabolites and extracts with antioxidant activity also exhibited strong antimicrobial properties. Therefore, we consider that they may have future applications in the treatment of infectious diseases, the preparation of pathogen-free healthy foods, and the extension of food shelf life.

Macrophages are crucial to innate immunity, eliminating pathogens and damaged tissues through phagocytosis and modulating immune responses. Recently, macrophage extracellular traps (METs) have been identified as chromatin-based structures composed of DNA and various immune-related proteins. While METs play a defensive role in trapping and neutralizing pathogens, they are also implicated in disease pathology, contributing to chronic inflammation, tissue damage, and immune dysregulation. The precise mechanisms regulating MET formation are still under investigation, but emerging evidence indicates the involvement of various regulatory factors. Dysregulated MET activity has been associated with various diseases, including autoimmune disorders, cancer, and neurological conditions. A deeper understanding of MET mechanisms and their pathological impact may offer novel therapeutic strategies. Given the limited number of reviews and articles on METs, this review provides valuable insights into MET formation, regulatory pathways, and their role in disease progression.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapeutics; however limited patient responses necessitate combination strategies to improve therapeutic efficacy. Among potential combination partners, drugs targeting DLL4-NOTCH1 signaling pathway—a critical regulator of vascular function—show promise as angiogenesis modulators, but their clinical development have been hindered by safety concerns. To address this challenge, we adopted a novel approach by screening natural compounds with a long history of human consumption. Building upon our earlier findings, we identified three inhibitors of DLL4-NOTCH1 signaling: steppogenin, sanggenon F, and dehydrovomifoliol. Steppogenin inhibited both DLL4 and NOTCH1 activities, while sanggenon F and dehydrovomifoliol selectively suppressed DLL4 and NOTCH1 activity, respectively. We assessed their impact on key angiogenic processes, including endothelial cell migration, sprouting, and proliferation, and elucidated the relative contributions of selective DLL4 or NOTCH1 inhibition to the anti-angiogenic effect. By comparing structurally similar compounds, we identified the 2'-hydroxyflavanone moiety as a key element for DLL4 inhibition. Notably, combining steppogenin with an ICI demonstrated that a nature-derived angiogenesis inhibitor can boost the anti-cancer effect of ICI in a mouse melanoma allograft model. This comprehensive analysis of structure–activity relationships and in vivo therapeutic evaluation provides valuable insights into the development of novel anti-angiogenic compounds for combination therapy with ICIs in cancer treatment.