Ampakines are a class of compounds that are positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and enhance glutamatergic neurotransmission. Glutamatergic synaptic transmission and AMPA receptor activation are fundamentally important to the genesis and propagation of the neural impulses driving breathing, including respiratory motoneuron depolarization. Ampakines therefore have the potential to modulate the neural control of breathing. In this paper, we describe the influence of ampakines on respiratory motor output in health and disease. We dissect the molecular mechanisms underlying ampakine action, delineate the diverse targets of ampakines along the respiratory neuraxis, survey the spectrum of respiratory disorders in which ampakines have been tested, and culminate with an examination of how ampakines modulate respiratory function after spinal cord injury. Collectively, the studies reviewed here indicate that ampakines may be a useful adjunctive strategy to pair with conventional respiratory rehabilitation approaches in conditions with impaired neural activation of the respiratory muscles.

Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington disease (HD), and Multiple sclerosis (MS), pose a significant global health challenge due to their intricate pathology and limited therapeutic interventions. Natural products represent invaluable reservoirs for combating these neurodegenerative diseases by targeting key pathological hallmarks such as protein aggregation, synaptic dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, inflammation, and neuronal cell death. This review provides an in-depth analysis of the mechanisms and therapeutic targets of natural products for their neuroprotective effects. Furthermore, it elucidates the current progress of clinical trials investigating the potential of natural products in delaying neurodegeneration. The objective of this review is to enhance the comprehension of natural products in the prevention and treatment of neurodegenerative diseases, offering new insights and potential avenues for future pharmaceutical research.

The simultaneous targeting of neuroinflammation and cholinergic hypofunction, the key pathological changes in Alzheimer's disease (AD), is not addressed by drugs currently in clinical trials, highlighting a critical therapeutic gap. We propose that dual-acting small molecules that inhibit butyrylcholinesterase (BChE) and mitogen-activated protein kinase p38α (p38α MAPK) represent a novel strategy to combat AD. This hypothesis is supported by cellular and animal studies as well as in silico modelling showing that it is possible to act simultaneously on both enzymes. Amyloid beta (Aβ) plaques trigger a pro-inflammatory microglial response that overactivates p38α MAPK, leading to increased Aβ synthesis, tau hyperphosphorylation, and altered synaptic plasticity. Overactivated microglia exacerbate neuroinflammation and cholinergic degeneration, ultimately leading to cognitive impairment. Structural similarities between the binding sites of BChE and p38α MAPK provide a promising basis for the development of dual inhibitors that could alleviate AD symptoms and address the underlying pathology.

Cancer neuroscience, as an emerging converging discipline, provides us with new perspectives on the interactions between the nervous system and cancer progression. As the sympathetic nervous system, in particular adrenergic signaling, plays an important role in the regulation of tumor activity at every hierarchical level of life, from the tumor cell to the tumor microenvironment, and to the tumor macroenvironment, it is highly desirable to dissect its effects. Considering the far-reaching implications of drug repurposing for antitumor drug development, such a large number of adrenergic receptor antagonists on the market has great potential as one of the means of antitumor therapy, either as primary or adjuvant therapy. Therefore, this review aims to summarize the impact of adrenergic signaling on cancer development and to assess the status and prospects of intervening in adrenergic signaling as a therapeutic tool against tumors.

Natural products (NPs) have a long history as sources for drug discovery, more than half of approved drugs are related to NPs, which also exhibit multifaceted advantages in the clinical treatment of complex diseases. However, bioactivity screening of NPs, target identification, and design optimization require continuously improved strategies, the complexity of drug mechanism of action and the limitations of technological strategies pose numerous challenges to the development of new drugs. This review begins with an overview of bioactivity- and target-based drug development patterns for NPs, advances in NP screening and derivatization, and the advantages and problems of major targets such as genes and proteins. Then, target-based drugs as well as identification and validation methods are further discussed to elucidate their mechanism of action. Subsequently, the current status and development trend of the application of traditional and emerging technologies in drug discovery and development of NPs are systematically described. Finally, the collaborative strategy of multi-technology integration and multi-disciplinary intersection is emphasized for the challenges faced in the identification, optimization, activity evaluation, and clinical application of NPs. It is hoped to provide a systematic overview and inspiration for exploring new drugs from natural resources in the future.

Post-translational modifications (PTMs) play a crucial role in regulating protein function, and their dysregulation is frequently associated with various diseases. The emergence of epigenetic drugs targeting factors such as histone deacetylases (HDACs) and histone methyltransferase enhancers of zeste homolog 2 (EZH2) has led to a significant shift towards precision medicine, offering new possibilities to overcome the limitations of traditional therapeutics. In this review, we aim to systematically explore how small molecules modulate PTMs. We discuss the direct targeting of enzymes involved in PTM pathways, the modulation of substrate proteins, and the disruption of protein-enzyme interactions that govern PTM processes. Additionally, we delve into the emerging strategy of employing multifunctional molecules to precisely regulate the modification levels of proteins of interest (POIs). Furthermore, we examine the specific characteristics of these molecules, evaluating their therapeutic benefits and potential drawbacks. The goal of this review is to provide a comprehensive understanding of PTM-targeting strategies and their potential for personalized medicine, offering a forward-looking perspective on the evolution of precision therapeutics.

Programs for preclinical testing of targeted cancer agents in murine models of childhood cancers have been supported by the National Cancer Institute (NCI) since 2004. These programs were established to work collaboratively with industry partners to address the paucity of targeted agents for pediatric cancers compared with the large number of agents developed and approved for malignancies primarily affecting adults. The distinctive biology of pediatric cancers and the relatively small numbers of pediatric cancer patients are major challenges for pediatric oncology drug development. These factors are exacerbated by the division of cancers into multiple subtypes that are further sub-classified by their genomic properties. The imbalance between the large number of candidate agents and small patient populations requires careful prioritization of agents developed for adult cancers for clinical evaluation in children with cancer. The NCI-supported preclinical pediatric programs have published positive and negative results of efficacy testing for over 100 agents to aid the pediatric research community in identifying the most promising candidates to move forward for clinical testing in pediatric oncology. Here, we review and summarize lessons learned from two decades of experience with the design and execution of preclinical trials of antineoplastic agents in murine models of childhood cancers.

Cardioprotection is a well-established term in the scientific world. It describes the protection of various mediators on the cardiovascular system. These protective effects can also be provided by certain lipids. Since lipids are a very specific and clearly definable class of substances, we define the term lipoprotection as lipid-mediated cardioprotection. In this review, we highlight high-density lipoprotein (HDL), sphingosine-1-phosphate (S1P) and omega-3 polyunsaturated fatty acids (n-3 PUFA) as the most important lipoprotective mediators and show their beneficial impact on coronary artery disease (CAD), acute myocardial infarction (AMI) and heart failure (HF).

The transient receptor potential canonical (TRPC) channels are a group of highly homologous nonselective cation channels from the larger TRP channel family. They have the ability to form homo- and heteromers with varying degrees of calcium (Ca) permeability and signalling properties. TRPC5 is the one cold-sensitive among them and likewise facilitates the influx of extracellular Ca into cells to modulate neuronal depolarization and integrate various intracellular signalling pathways. Recent research with cryo-electron microscopy revealed its structure, along with clear insight into downstream signalling and protein-protein interaction sites. Investigations using global and conditional deficient mice revealed the involvement of TRPC5 in metabolic diseases, energy balance, thermosensation and conditions such as osteoarthritis, rheumatoid arthritis, and inflammatory pain including opioid-induced hyperalgesia and hyperalgesia following tooth decay and pulpitis. This review provides an update on recent advances in our understanding of the role of TRPC5 with focus on metabolic diseases and pain.

Natural products such as Traditional Chinese Medicines (TCMs) show great advantages in the treatment and prevention of diseases, but the unclear effective ingredients and mechanisms are key obstacles to restrict their rapid development. Under the guidance of the theoretical guidance of reductionism and the theoretical of allopathic medicine, some researches have indeed achieved some breakthrough results. However, these incomplete methods mainly limited to direct actions or indirect actions (such as the intermediated substances mediated cross-organ or cross-system regulation) mechanism of single active ingredient derived from natural products, which are often inconsistent with Systemism and Harmonizing Medicine and make it difficult to reasonably explain the pharmacodynamics and pharmacological mechanism of most natural products. Actually, effective pharmaceutical ingredients often do not exist in the form of free monomers, but prefer to assembly nanovesicles (NVs) for a combinational pharmacological effect, mainly including self-assembled nanoparticles (SANs) and exosome-like nanoparticles (ELNs). These developments of NVs-based application are a good supplement to existing pharmacological mechanism research. Hence, this review focuses on the developments and strategies of the pharmacodynamics and pharmacological mechanism of NVs-based TCMs under the combining theory of traditional Chinese and western medicine. On this basis, a novel "multidimensional combination" research approach is proposed firstly, which will provide new strategies and directions for breaking through the bottleneck of pharmacological mechanism research, and promote the clinical application of innovative natural products including TCMs.

Autophagy functions as the primary cellular mechanism for clearing unwanted intracellular contents. Emerging evidence suggests that the selective elimination of intracellular organelles through autophagy, compared to the increased bulk autophagic flux, is crucial for the pathological progression of central nervous system (CNS) disorders. Notably, autophagic removal of mitochondria, known as mitophagy, is well-understood in an unhealthy brain. Accumulated data indicate that selective autophagy of other substrates, including protein aggregates, liposomes, and endoplasmic reticulum, plays distinctive roles in various pathological stages. Despite variations in substrates, the molecular mechanisms governing selective autophagy can be broadly categorized into two types: ubiquitin-dependent and -independent pathways, both of which can be subjected to regulation by small-molecule compounds. Notably, natural products provide the remarkable possibility for future structural optimization to regulate the highly selective autophagic clearance of diverse substrates. In this context, we emphasize the selectivity of autophagy in regulating CNS disorders and provide an overview of chemical compounds capable of modulating selective autophagy in these disorders, along with the underlying mechanisms. Further exploration of the functions of these compounds will in turn advance our understanding of autophagic contributions to brain disorders and illuminate precise therapeutic strategies for these diseases.

Secreted proteins have gained more and more attentions, since they can become therapeutic targets, drugs and biomarkers for prevention, diagnosis and treatment of disease and aging. In 2014, Metrnl (also named Meteorin-like, Cometin, Subfatin, Interleukin-39, Interleukin-41, Meteorin-β, and Metrn-β/Metrnβ), as a novel secreted protein released from a certain tissue, was reported by us and others. During the past decade, the number of articles on Metrnl has continued to increase. Different sources of Metrnl have been described with different functions, including Metrnl as an adipokine for insulin sensitization, a cardiokine against cardiac hypertrophy and dysfunction, an endothelium-derived factor against endothelial dysfunction and atherosclerosis, etc. Especially, we show that endothelial Metrnl is a major source for circulating Metrnl levels. Meanwhile, lots of clinical studies have investigated the relationship between blood Metrnl levels and metabolic, inflammatory and cardiovascular diseases. Metrnl appears a protective factor and a promising therapeutic target and/or drug against these diseases, given the relatively consistent conclusion from the preclinical studies. In addition to graphically demonstrating the role of Metrnl in various organs and diseases, this review will mainly describe the discovery of Metrnl, summarize the role of Metrnl in cardiovascular system that is a recently major progress in Metrnl research, and highlight several perspectives for future basic and translational research. Also, we suggest using one name Metrnl instead of other multiple names for the same protein.

In the landscape of proteins controlled by membrane voltage (V), like voltage-gated ionotropic channels, the emergence of the voltage sensitivity within the vast family of G-protein coupled receptors (GPCRs) marked a significant milestone at the onset of the 21st century. Since its discovery, extensive research has been devoted to understanding the intricate relationship between V and GPCRs. Approximately 30 GPCRs out of a family comprising more than 800 receptors have been implicated in V-dependent positive and negative regulation. GPCRs stand out as the quintessential regulators of synaptic transmission in neurons, where they encounter substantial variations in V. However, the molecular mechanism underlying the V sensor of GPCRs remains enigmatic, hindered by the scarcity of mutant GPCRs insensitive to V yet functionally intact, impeding a comprehensive understanding of this unique property in physiology. Nevertheless, two decades of dedicated research have furnished numerous insights into the molecular aspects of GPCR V-sensing, accompanied by recently proposed physiological roles as well as pharmacological potential, which we encapsulate in this review. The V sensitivity of GPCRs emerges as a pivotal attribute, shedding light on previously unforeseen roles in synaptic transmission and extending beyond, underscoring its significance in cellular signaling and physiological processes.

Every year, prostate cancer is diagnosed in millions of men. The androgen receptor's (AR) unchecked activation is crucial in causing the development and progression of prostate cancer. Second-generation anti-androgen therapies, which primarily focus on targeting the Ligand Binding Domain (LBD) of AR, are effective for most patients. However, the adverse effects pose significant challenges in managing the disease. Furthermore, genetic mutations or the emergence of AR splice variants create an even more complex tumor environment, fostering resistance to these treatments. Natural compounds and their analogs, while showing a lower toxicity profile and a potential for selective AR splice variants inhibition, are constrained by their bioavailability and therapeutic efficacy. Nonetheless, recent breakthroughs in using natural derivatives to target AR and its splice variants have shown promise in treating chemoresistant castration-resistant prostate cancer (CRPC). This review will discuss the role of AR variants, particularly androgen receptor splice variant 7 (AR-V7), in CRPC and investigate the latest findings on how natural compounds and their derivatives target AR and AR splice variants.

This review summarizes findings presented at the 19th World Congress of Basic & Clinical Pharmacology 2023 (Glasgow, Scotland, July 3rd to 7th, 2023) from 8 speakers in the field of resolution of inflammation, resolution pharmacology and resolution biology. It is now accepted that the acute inflammatory response is protective to defend the host against infection or tissue injury. Acute inflammation is self-limited and programmed to be limited in space and time: this is achieved through endogenous resolution processes that ensure return to homeostasis. Resolution is brought about by agonist mediators that include specialized pro-resolving lipid mediators (SPMs) and pro-resolving proteins and peptides such as annexin A1 and angiotensin-(1-7), all acting to initiate anti-inflammatory and pro-resolving processes. If the inflammatory reaction remains unchecked through dysfunctional resolution mechanism, it can become chronic and contribute to a plethora of human diseases, including respiratory, cardiovascular, metabolic, allergic diseases, and arthritis. Herein, we discuss how non-resolving inflammation plays a role in the pathogenesis of these diseases. In addition to SPMs, we highlight the discovery, biosynthesis, biofunctions, and latest research updates on innovative therapeutics (including annexin-A1 peptide-mimetic RTP-026, small molecule FPR2 agonist BM-986235/LAR-1219, biased agonist for FPR1/FPR2 Cmpd17b, lipoxin mimetics AT-01-KG and AT-02-CT, melanocortin receptor agonist AP1189, gold nanoparticles, angiotensin-(1-7), and CD300a) that can promote resolution of inflammation directly or through modulation of SPMs production. Drug development strategies based on the biology of the resolution of inflammation can offer novel therapeutic means and/or add-on therapies for the treatment of chronic diseases.

Oral administration of Chinese Herbal Medicine (CHM) faces various challenges in reaching the target organs including absorption and conversion in the gastrointestinal tract, hepatic metabolism via the portal vein, and eventual systemic circulation. During this process, factors such as gut microbes, physical or chemical barriers, metabolic enzymes, and transporters play crucial roles. Particularly, interactions between different herbs in CHM have been observed both in vitro and in vivo. In vitro, interactions typically manifest as detectable physical or chemical changes, such as facilitating solubilization or producing precipitates when decoctions of multiple herbs are administered. In vivo, such interactions cause alterations in the ADME (absorption, distribution, metabolism, and excretion) profile on metabolic enzymes or transporters in the body, leading to competition, antagonism, inhibition, or activation. These interactions ultimately contribute to differences in the therapeutic and pharmacological effects of multi-herb formulas in CHM. Over the past two thousand years, China has cultivated profound expertise and solid theoretical frameworks over the scientific use of herbs. The combination of multiple herbs in one decoction has been frequently employed to synergistically enhance therapeutic efficacy or mitigate toxic and side effects in clinical settings. Additionally combining herbs with increased toxicity or decreased effect is also regarded as a remedy, a practice that should be approached with caution according to Traditional Chinese Medicine (TCM) physicians. Such historical records and practices serve as a foundation for predicting favorable multi-herb combinations and their potential risks. However, systematic data that are available to support the clinical practice and the exploration of novel herbal formulas remain limited. Therefore, this review aims to summarize the pharmacokinetic interactions and mechanisms of herb-herb or herb-drug combinations from existing works, and to offer guidance as well as evidence for optimizing CHM and developing new medicines with CHM characteristics.

Major depressive disorder (MDD) is a common mental disorder that severely disrupts psychosocial function and decreases the quality of life. Although the pathophysiological mechanism underlying MDD is complex and remains unclear, emerging evidence suggests that autophagy dysfunction plays a role in MDD occurrence and progression. Natural products serve as a major source of drug discovery and exert tremendous potential in developing antidepressants. Recently published reports are paying more attention on the autophagy regulatory effect of antidepressant natural products. In this review, we comprehensively discuss the abnormal changes occurred in multiple autophagy stages in MDD patients, and animal and cell models of depression. Importantly, we emphasize the regulatory mechanism of antidepressant natural products on disturbed autophagy, including monomeric compounds, bioactive components, crude extracts, and traditional Chinese medicine formulae. Our comprehensive review suggests that enhancing autophagy might be a novel approach for MDD treatment, and natural products restore autophagy homeostasis to facilitate the renovation of mitochondria, impede neuroinflammation, and enhance neuroplasticity, thereby alleviating depression.

Epigenetic modifications are chemical groups in our DNA (and chromatin) that determine which genes are active and which are shut off. Importantly, they integrate environmental signals to direct cellular function. Upon chronic environmental exposures, the epigenetic signature of lung cells gets altered, triggering aberrant gene expression programs that can lead to the development of chronic lung diseases. In addition to driving disease, epigenetic marks can serve as attractive lung disease biomarkers, due to early onset, disease specificity, and stability, warranting the need for more epigenetic research in the lung field. Despite substantial progress in mapping epigenetic alterations (mostly DNA methylation) in chronic lung diseases, the molecular mechanisms leading to their establishment are largely unknown. This review is meant as a guide for clinicians and lung researchers interested in epigenetic regulation with a focus on DNA methylation. It provides a short introduction to the main epigenetic mechanisms (DNA methylation, histone modifications and non-coding RNA) and the machinery responsible for their establishment and removal. It presents examples of epigenetic dysregulation across a spectrum of chronic lung diseases and discusses the current state of epigenetic therapies. Finally, it introduces the concept of epigenetic editing, an exciting novel approach to dissecting the functional role of epigenetic modifications. The promise of this emerging technology for the functional study of epigenetic mechanisms in cells and its potential future use in the clinic is further discussed.

This manuscript reviews recent work on oxytocin and its use in neurodevelopmental disorders including spectrum disorder (ASD) and Prader-Willi syndrome (PWS). Oxytocin is involved in social recognition, bonding, maternal behaviors, anxiety, food motivation, and hyperphagia. While the pathophysiology of ASD and PWS involve abnormalities in the oxytocin system, clinical trials have shown discrepant results in the effectiveness of oxytocin as a treatment for core symptoms associated with these disorders. In this review, we outline oxytocin's clinical pharmacology, safety considerations, and results in recent clinical trials. We propose that oxytocin may be most beneficial in these populations if dosed in a dynamic regimen (PRN) and paired with social interventions.

The rise of antibiotic resistance and the decrease in the discovery of new antibiotics have caused a global health crisis. Of particular concern is the fact that despite efforts to develop new antibiotics, drug discovery is unable to keep up with the rapid development of resistance. This ongoing crisis highlights the fact that single-target drugs may not always exhibit satisfactory therapeutic effects and are prone to target mutations and resistance due to the complexity of bacterial mechanisms. Retrospective studies have shown that most successful antibiotics have multiple targets. Compared with single-target drugs, successfully designed multitarget drugs can simultaneously regulate multiple targets to reduce resistance caused by single-target mutations or expression changes. In addition to a lower risk of drug-drug interactions, multitarget drugs show superior pharmacokinetics and higher patient compliance compared with combination therapies. Therefore, to reduce resistance, many efforts have been made to discover and design multitarget drugs with different chemical structures and functions. Although there have been numerous studies on how to develop drugs and slow down the development of drug resistance, the reduction of bacterial resistance by multitarget antibacterial drugs has not received widespread attention and is rarely mentioned in the peer-reviewed literature. This review summarises the development of antibiotic resistance and the mechanisms proposed for its emergence, examines the potential of multitarget drugs as an effective strategy to slow the development of resistance, and discusses the rationale for multitarget drug therapy. We also describe multitarget antibacterial compounds with the potential to reduce drug resistance and the available strategies to develop multitarget drugs.