Expert Opinion on Therapeutic Targets最新文献

Introduction: Lysine-specific histone demethylase 1A (KDM1A/LSD1) has emerged as an important therapeutic target in various cancer types. LSD1 regulates a wide range of biological processes that influence cancer development, progression, metastasis, and therapy resistance. However, recent studies have revealed novel aspects of LSD1 biology, shedding light on its involvement in immunogenicity, antitumor immunity, and DNA damage response. These emerging findings have the potential to be leveraged in the design of effective LSD1-targeted therapies.

Areas covered: This paper discusses the latest developments in the field of LSD1 biology, focusing on its role in regulating immunogenicity, antitumor immunity, and DNA damage response mechanisms. The newfound understanding of these mechanisms has opened possibilities for the development of novel LSD1-targeted therapies for cancer treatment. Additionally, the paper provides an overview of LSD1 inhibitor-based combination therapies for the treatment of cancer.

Expert opinion: Exploiting LSD1 role in antitumor immunity and DNA damage response provides cues to not only understand the LSD1-resistant mechanisms but also rationally design new combination therapies that are more efficient and less toxic than monotherapy. The exploration of LSD1 biology and the development of LSD1-targeted therapies hold great promise for the future of cancer treatment.

Introduction: Brain metastasis is a highly traumatic event in the progression of malignant tumors, often symbolizing higher mortality. Metabolic alterations are hallmarks of cancer, and the mask of lipid metabolic program rearrangement in cancer progression is gradually being unraveled.

Areas covered: In this work, we reviewed clinical and fundamental studies related to lipid expression and activity changes in brain metastases originating from lung, breast, and cutaneous melanomas, respectively. Novel roles of lipid metabolic reprogramming in the development of brain metastasis from malignant tumors were identified and its potential as a therapeutic target was evaluated. Published literature and clinical studies in databases consisting of PubMed, Embase, Scopus and www.ClinicalTrials.gov from 1990 to 2022 were searched.

Expert opinion: Lipid metabolic reprogramming in brain metastasis is involved in de novo lipid synthesis within low lipid availability environments, regulation of lipid uptake and storage, metabolic interactions between brain tumors and the brain microenvironment, and membrane lipid remodeling, in addition to being a second messenger for signal transduction. Although some lipid metabolism modulators work efficiently in preclinical models, there is still a long way to go from laboratory to clinic. This area of research holds assurance for the organ-targeted treatment of brain metastases through drug-regulated metabolic targets and dietary interventions.

Introduction: Although there are several FDA-approved treatments for Alzheimer's disease (AD), only recently have disease-modifying therapies received approval for use in patients. In this narrative review, we examine the history of aquaporin-4 (AQP4) as a therapeutic target for NMOSD (neuromyelitis optica spectrum disorder) and as a potential therapeutic target for AD.

Areas covered: We review the basic science and discovery of AQP4, a transmembrane water-channel essential to regulating water balance in the central nervous system (CNS). We also review the pathogenesis of NMOSD, an autoimmune disease characterized by the destruction of cells that express AQP4. Then, we review how AQP4 is likely involved in the pathogenesis of Alzheimer's disease (AD). Finally, we discuss future challenges with drug design that would modulate AQP4 to potentially slow AD development. The literature search for this article consisted of searching Google Scholar and PubMed for permutations of the keywords 'Alzheimer's disease,' 'aquaporin-4,' 'neuromyelitis optica,' and their abbreviations.

Expert opinion: We place research into AQP4 into context with other recent developments in AD research. A major difficulty with drug development for Alzheimer's is the lack of strategies to cleanly target the early pathogenesis of the disease. Targeting AQP4 may provide such a strategy.

Introduction: Influenza A virus (IAV) is highly contagious and causes respiratory diseases in birds, mammals, and humans. Some strains of IAV, whether from human or avian sources, have developed resistance to existing antiviral drugs. Therefore, the discovery of new influenza antiviral drugs and therapeutic approaches is crucial. Recent studies have shown that galectins (Gal), a group of β-galactose-binding lectins, play a role in regulating various viral infections, including IAVs.

Areas covered: This review provides an overview of the roles of different galectins in IAV infection. We discuss the characteristics of galectins, their impact on IAV infection and spread, and highlight their positive or negative regulatory functions and potential mechanisms during IAV infection. Furthermore, we explore the potential application of galectins in IAV therapy.

Expert opinion: Galectins were first identified in the mid-1970s, and currently, 15 mammalian galectins have been identified. While all galectin members possess the carbohydrate recognition domain (CRD) that interacts with β-galactoside, their regulatory functions vary in different DNA or RNA virus infections. Certain galectin members have been found to regulate IAV infection through diverse mechanisms. Therefore, a comprehensive understanding of their roles in IAV infection is essential, as it may pave the way for novel therapeutic strategies.

Introduction: Understanding the role of efflux pumps in biofilm resistance provides valuable insights for developing effective therapeutic strategies. Drugs designed for targeting efflux pumps in drug design holds promise for combating biofilm-related infections. Nanoparticles offer unparalleled advantages in designing drugs targeting efflux pumps.

Areas covered: This review rigorously examines the existing body of knowledge on the prospective targeting of efflux pumps using metal-based nanoparticles. It includes and analyses the pertinent research findings sourced from the PubMed and SciFinder databases. It covers the experimental studies on efflux inhibition by nanoparticles and provides detailed analyses of their mechanisms of action, elucidating their interactions with the efflux system and their influence on biofilm formation and persistence.

Expert opinion: The potential of nanoparticles to act as potent antibacterial agents through efflux pump inhibition remains tantalizing, although hindered by limited mechanistic understanding. From the burgeoning research landscape nanoparticles emerge as a novel direction for shaping antimicrobial drug design. Notably, beyond their contribution to drug resistance, efflux pumps play a pivotal role in biofilm development. The deliberate disruption of these pumps can effectively reduce biofilm adhesion and maturation. More details however are needed to exploit this potential.

Introduction: When collected in a standardized fashion, oral fluid analysis can refine the diagnosis of periodontal and peri-implant disease. In practice, dental professionals can perform active matrix metalloproteinase (aMMP-8) analysis chairside.

Areas covered: Periodontal tissues are mainly made up of type I collagen, and collagen breakdown is one of the main events in periodontal and peri-implantitis destructive lesions. In addition to traditional measurements, their diagnosis can be refined with tests utilizing oral fluids. The active matrix metalloproteinase-8 (aMMP-8) is possible to be determined from the gingival crevicular fluid (GCF), peri-implant sulcus fluid (PISF), and other oral fluids such as mouth rinse and saliva. We also investigated the applicability of aMMP-8 chair-side test kits in the evaluation of oral health benefits of different adjunctive host-modulating periodontal therapies including fermented lingonberry mouthwash (FLJ) and antibacterial photodynamic therapy (aPDT).

Expert opinion: The aMMP-8 levels can more reliably detect early activation of periodontal and peri-implant disease as compared to traditional diagnostic methods that assess the experienced health status or past disease, rather than the present or future pathology. Novel therapies like, fermented lingonberry juice as a mouthrinse or aPDT, are potential host-modulating adjunctive treatments to reduce the signs of oral inflammation and infection.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, but underlying mechanisms are not fully understood. In recent years, a growing body of evidence has emphasized the therapeutic role of vitamin D in NAFLD, but the specific mechanism remains to be investigated.

Areas covered: This review summarized the roles of vitamin D/VDR (vitamin D receptor) pathway in different types of liver cells (such as hepatocytes, hepatic stellate cells, liver macrophages, T lymphocytes, and other hepatic immune cells) in case of NAFLD. Meanwhile, the effects of pathways in the gut-liver axis, adipose tissue-liver axis, and skeletal muscle-liver axis on the development of NAFLD were further reviewed. Relevant literature was searched on PubMed for the writing of this review.

Expert opinion: The precise regulation of regional vitamin D/VDR signaling pathway based on cell-specific or tissue-specific function will help clarify the potential mechanism of vitamin D in NAFLD, which may provide new therapeutic targets to improve the safety and efficacy of vitamin D based drugs.

Introduction: Recent neuroscience breakthroughs have shed light on the sophisticated relationship between calcium channelopathies and movement disorders, exposing a previously undiscovered tale focusing on the Ryanodine Receptor (RyR) and the Sarco/Endoplasmic Reticulum Calcium ATPase (SERCA). Calcium signaling mainly orchestrates neural communication, which regulates synaptic transmission and total network activity. It has been determined that RyR play a significant role in managing neuronal functions, most notably in releasing intracellular calcium from the endoplasmic reticulum.

Areas covered: It highlights the involvement of calcium channels such as RyR and SERCA in physiological and pathophysiological conditions.

Expert opinion: Links between RyR and SERCA activity dysregulation, aberrant calcium levels, motor and cognitive dysfunction have brought attention to the importance of RyR and SERCA modulation in neurodegenerative disorders. Understanding the obscure function of these proteins will open up new therapeutic possibilities to address the underlying causes of neurodegenerative diseases. The unreported RyR and SERCA narrative broadens the understanding of calcium channelopathies in movement disorders and calls for more research into cutting-edge therapeutic approaches.

Background: Drug repurposing is an attractive strategy for extending the arsenal of oncology therapies. Tolperisone is an old centrally acting muscle relaxant used for treatment of chronic pain conditions. In this study, we investigated the therapeutic effect and mechanism of tolperisone in human cancers and explored the combination strategy with proteasome inhibitor and immunotherapy.

Research design and methods: The antitumor effect of tolperisone was evaluated by measuring half maximal inhibitory concentration, cell death, and cell growth. RNA sequencing, western blotting, molecular docking, enzyme activity assay, and ChIP-qPCR were performed to reveal the underlying mechanism. Xenograft models were used to evaluate the efficacy of tolperisone alone or in combination with proteasome inhibitor or immunotherapy.

Results: Tolperisone inhibited cell growth and induced cell death in human cancer cell lines. Unfolded protein responses (UPR) pathway was hyperactivated in tolperisone-treated cells. We further identified histone lysine-specific demethylase 1 (LSD1) as a potential target of tolperisone, which directly demethylates UPR-related genes in H3K4me2. Tolperisone synergistically improved the efficacy of MG132 by enhancing UPR and sensitized tumors to immunotherapy by reprogramming M2 macrophages into M1 phenotype.

Conclusions:

Tolperisone inhibits human cancer by targeting LSD1. Repurposing tolperisone in cancer therapy by a combination strategy implies clinical potential.