Trends in pharmacological sciences最新文献

Accumulating evidence highlights the pivotal role of mitochondria in cardiovascular diseases (CVDs). Understanding the molecular mechanisms underlying mitochondrial dysfunction is crucial for developing targeted therapeutics. Recent years have seen substantial advancements in unraveling mitochondrial regulatory pathways in both normal and pathological states and the development of potent drugs. However, specific delivery of drugs into the mitochondria is still a challenge. We present recent findings on regulators of mitochondrial dynamics and reactive oxygen species (ROS), critical factors influencing mitochondrial function in CVDs. We also discuss advancements in drug delivery strategies aimed at overcoming the technical barrier in targeting mitochondria for CVD treatment.

Breast cancer's tendency to metastasize poses a critical barrier to effective treatment, making it a leading cause of mortality among women worldwide. A growing body of evidence is showing that translational adaptation is emerging as a key mechanism enabling cancer cells to thrive in the dynamic tumor microenvironment (TME). Here, we systematically summarize how breast cancer cells utilize translational adaptation to drive metastasis, highlighting the intricate regulation by specific translation machinery and mRNA attributes such as sequences and structures, along with the involvement of tRNAs and other trans-acting RNAs. We provide an overview of the latest findings and emerging concepts in this area, discussing their potential implications for therapeutic strategies in breast cancer.

Navigating the ever-evolving landscape of nuclear magnetic resonance (NMR) poses challenges for the industry. This work explores promising approaches that illuminate protein-ligand interactions in the context of structural dynamics, facilitating targeted drug discovery. I acknowledge existing limitations and highlight future opportunities, which may pave the way for broader NMR integration and faster therapeutic development.

Steatotic liver diseases (SLDs) affect one-third of the population, but the pathogenesis underlying these diseases is not well understood, limiting the available treatments. A common factor in SLDs is increased hepatic mitochondrial reductive stress, which occurs as a result of excessive lipid and alcohol metabolism. Recent research has also shown that genetic risk factors contribute to this stress. This review aims to explore how these risk factors increase hepatic mitochondrial reductive stress and how it disrupts hepatic metabolism, leading to SLDs. Additionally, the review will discuss the latest clinical studies on pharmaceutical treatments for SLDs, specifically peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, thyroid hormone receptor (THR) agonists, acetyl-CoA carboxylase (ACC) inhibitors, and mitochondrial uncouplers. These treatments have a common effect of decreasing hepatic mitochondrial reductive stress, which has been largely overlooked.

The use of extracellular vesicles (EVs) for drug delivery is being widely explored by scientists from several research fields. To fully exploit their therapeutic potential, multiple methods for loading EVs have been developed. Although exogenous methods have been extensively utilized, in recent years the endogenous method has gained significant attention. This approach, based on parental cell genetic engineering, is suitable for loading large therapeutic biomolecules such as proteins and nucleic acids. We review the most commonly used EV loading methods and emphasize the inherent advantages of the endogenous method over the others. We also examine the most recent advances and applications of this innovative approach to inform on the diverse therapeutic opportunities that lie ahead in the field of EV-based therapies.

Fungal infections are a major threat to human health. The limited availability of antifungal drugs, the emergence of drug resistance, and a growing susceptible population highlight the critical need for novel antifungal agents. The enzymes involved in fungal cell wall synthesis offer potential targets for antifungal drug development. Recent studies have enhanced our focus on the enzyme Fks1, which synthesizes β-1,3-glucan, a critical component of the cell wall. These studies provide a deeper understanding of Fks1's function in cell wall biosynthesis, pathogenicity, structural biology, evolutionary conservation across fungi, and interaction with current antifungal drugs. Here, we discuss the role of Fks1 in the survival and adaptation of fungi, guided by insights from evolutionary and structural analyses. Furthermore, we delve into the dynamics of Fks1 modulation with novel antifungal strategies and assess its potential as an antifungal drug target.

Tumor-associated macrophages (TAMs) constitute an important part of the tumor microenvironment (TME) that regulates tumor progression. Tumor-derived signals, hypoxia, and competition for nutrients influence TAMs to reprogram their cellular metabolism. This altered metabolic profile creates a symbiotic communication between tumor and other immune cells to support tumor growth. In addition, the metabolic profile of TAMs regulates the expression of immune checkpoint molecules. The dynamic plasticity also allows TAMs to reshape their metabolism in response to modern therapeutic strategies. Therefore, over the years, a significant number of approaches have been implicated to reprogram cancer-promoting metabolism in TAMs. In this review, we discuss the current strategies and pitfalls, along with upcoming promising opportunities in leveraging TAM metabolism for developing better therapeutic approaches against cancer.

Alzheimer's disease (AD), similar to AD-related dementias, is characterized by impaired/lost neuronal structures and functions due to a long progression of neurodegeneration. Derailed endogenous signal pathways and disease processes have critical roles in neurodegeneration and are pharmacological targets in inducing neuroregeneration. Pharmacologically switching/shifting the brain status from neurodegeneration to neuroregeneration is emerging as a new therapeutic concept, one that is not only achievable, but also essential for effective therapy for AD. The results of the pharmacological-induced shift from neurodegeneration to neuroregeneration are twofold: arresting cognitive deterioration (and directing the brain toward cognitive recovery) in established AD, and preventing neurodegeneration through building up cognitive resilience in patients with preclinical or probable AD. In this review, we discuss these new developments in AD pharmacology and relevant clinical trials.