ACS Pharmacology and Translational Science最新文献

Antenatal depression, or depression during pregnancy, is a common psychiatric disorder and poses significant risks to both the mother and the fetus. Despite these risks, it is frequently left untreated due to fears of side effects caused by antidepressant medications which cross through the placental barrier. It is therefore desirable to develop formulation strategies to mitigate systemic exposure to psychotropics while maintaining their efficacy. In this work, we develop formulations of sertraline, a common antidepressant, to target delivery to the brain through intranasal administration. Formulation engineering enables successful solubilization of sertraline at high concentrations over months at room temperature. Using mice, we compare sertraline biodistribution following intranasal administration and standard oral administration. Intranasal administration of our candidate formulation provides comparable brain exposure at half the dose compared to oral treatment and lowers the maximum plasma exposure. These findings suggest that intranasal administration may provide selectivity for drug exposure in the central nervous system over systemic exposure.

In many autoimmune pathologies, including Rheumatoid Arthritis (RA), only a small percentage of the total B cell population is autoreactive and sustain disease. Yet, current immunotherapy treatments often eliminate the entire B-cell population, leading to immune deficiency. We developed an approach to selectively eliminate autoreactive B cells with targeted photodynamic therapy (tPDT). We designed a construct containing a dimeric peptidic antigen (diCCP4) that selectively binds a patient-derived autoreactive B cell receptor (BCR) and additionally included the photosensitizer IRDye700DX. We tested the construct on a modified Ramos B-cell line (Ramos 3F3), expressing this specific autoreactive BCR sequence. After brief exposure to 689 nm light, the photosensitizer selectively eliminates the modified Ramos cells, while the construct is not cytotoxic to cells lacking the autoreactive BCR. In a 3D coculture of the Ramos autoreactive B cell line with peripheral blood mononuclear cells (PBMCs) we observed only a minimal response of the untargeted cells. These results highlight the potential of tPDT against autoreactive B cells in autoimmune disease.

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic pathology currently treated with two antifibrotic drugs, nintedanib and pirfenidone; however, more effective and safer cell-specific therapeutic agents are needed to overcome their limited efficacy and tolerability. αvβ6 integrin is a clinically validated fibrosis biomarker, and several αvβ6-targeted small molecules and positron emission tomography (PET) tracers have recently proven their therapeutic and diagnostic potential in IPF. Surprisingly, αvβ6-targeted and fibrosis-related drug conjugates are still lacking. Two molecular conjugates, namely the previously reported peptide–drug conjugate (PDC) 1 and the novel fluorescent probe 2, were developed here, where a αvβ6-targeted cyclopeptide is covalently linked to either nintedanib or the near-infrared (NIR) ZW800-1 fluorescent tag via robust linkers. Chemical synthesis of the two compounds, molecular docking studies of 1 in complex with αvβ6, mouse and human plasma stability measurement, binding affinity evaluation toward the isolated αvβ6 receptor, and in vitro human IPF-derived fibroblast cell internalization and antifibrotic studies were performed. Then, in vivo and ex vivo assessments of the antifibrotic efficacy of 1 and the diagnostic potential of 2 were carried out in a bleomycin (BLM)-induced lung fibrosis mouse model. Conjugate 1 demonstrated superior antifibrotic efficacy as compared to the separated peptide and drug components, and probe 2 specifically accumulated in the fibrotic lesions of mice lungs. The molecular conjugates 1 and 2 represent a promising theranostic couple for lung fibrosis and αvβ6-related pathologies and a useful proof-of-principle tool testifying how the simultaneous cell-targeted inhibition of multiple fibrosis-related receptors could be more impactful than the inhibition of one sole receptor.

Prior research has determined that music plays a central role in psychedelic assisted therapy (PAT). While there is a general consensus of the importance of music during PAT, there are only three empirical studies published to date that directly investigate which type of music might best support PAT. Importantly, no review to date has critically analyzed these studies and identified the gaps. Careful examination reveals these studies have important limitations and the findings lack alignment with other publications and existing recommendations. Additionally, our understanding of guidelines seems to be not much different from when this research started in 1970. This paper summarizes the common impacts of music during PAT, reviews what we know about music selection and guidelines for PAT, and makes suggestions of priorities for future research.

p-Cresol (pC) is a phenolic compound to which humans can be exposed through both environmental sources, such as a pollutant, and endogenous production by the gut microbiota. Among microbial contributors, Clostridioides difficile appears to be a major source of pC within the body. Once absorbed, pC is highly protein-bound in plasma and predominantly circulates in its hepatic conjugated forms: p-cresyl sulfate (pCS) and p-cresol glucuronide (pCG), which are mainly excreted in urine. Accumulation of these metabolites, particularly pCS, classified as a protein-bound uremic toxin, has been associated with the progression of chronic kidney disease (CKD) and related complications, due to its pro-oxidant, pro-inflammatory, and pro-apoptotic properties. CKD patients are at increased risk for cognitive impairment, affective disorders, and central nervous system (CNS) dysfunctions. In recent years, increasing evidence has suggested a potential role of pC and its metabolites in CNS diseases. Here, we summarize current knowledge on the involvement of these compounds in the pathogenesis and progression of autism spectrum disorder, Parkinson’s disease, Alzheimer’s disease, and post-traumatic stress disorder. We also discuss how modulating systemic levels of pC may represent a promising strategy to improve pathological phenotypes in the context of neurodevelopmental and neurodegenerative disorders.

Glioblastoma multiforme (GBM) is the most aggressive and prevailing form of primary brain tumor, illustrated by its rapid growth and invasive nature. GBM continues to be highly incurable despite advancements in treatment due to its complex tumor microenvironment (TME) and the unique characteristics of tumor-associated macrophages (TAMs). This review explores the function of macrophages within the TME of GBM, specifically emphasizing the impact of colony-stimulating Factor-1 (CSF-1) and its receptor CSF1R in macrophage biology. The progression, survival, and differentiation of TAMs, which often rely on immunosuppressive properties that contribute to tumor growth and treatment resistance, are facilitated by elevated CSF-1 levels in GBM. The inhibition of CSF1R presents a promising therapeutic strategy, as it selectively targets tumor-promoting macrophages while sparing antitumor macrophages. Preclinical evidence demonstrates improved survival outcomes through CSF1R inhibition in mouse models, highlighting its potential for clinical application. Ongoing clinical trials further investigate this approach, aiming to enhance treatment efficacy for patients with GBM. This review concludes by emphasizing the significance of repolarizing macrophages as a novel therapeutic opportunity in GBM management, alongside emerging trends and future research directions that could lead to breakthroughs in treatment strategies.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID (LC) are increasingly recognized as debilitating postinfectious conditions that impact both individuals and society. Recent research highlights the potential of metformin, an antidiabetic agent, as a treatment for these syndromes by targeting their underlying mechanisms. This review assesses the effectiveness of metformin in ME/CFS and LC, which involve complex dysfunctions related to cytokines, glycolysis, ATP generation, oxidative stress, gastrointestinal microbiomes, and vascular endothelial function. Metformin, traditionally known for its antihyperglycemic properties may offer broader therapeutic benefits by influencing these pathological pathways. It works by inhibiting complexes I and IV of the electron transport chain, which reduces the strain on malfunctioning complex V and decreases the production of harmful free radicals. Additionally, metformin’s impact on mTOR signaling could improve energy metabolism in ME/CFS and LC by downregulating an overactive but underperforming protein, thereby alleviating symptoms. Beyond the impact on cellular metabolism, metformin has shown to have anti-inflammatory, vascular, gastrointestinal, neuroprotective and epigenetic effects. We explore this impact of metformin and the potential role it could play to help people with ME/CFS. While metformin shows promise, it is unlikely to be a stand-alone solution. Instead, it may be part of a broader treatment strategy that includes other therapies targeting neurocognitive and autonomic impairments.

Serotonergic psychedelics have shown promise in clinical trials for treating an array of mental health disorders, including depression, anxiety, and post-traumatic stress disorder. Despite these findings, our understanding of how these drugs mechanistically exert their therapeutic effects remains incomplete. While researchers have regularly employed rodent preclinical models to assess such mechanisms, many of these findings arise from stress-naïve animals. Given that prior environmental stress is a critical component for the mental health disorders being studied in clinical trials of psychedelics, understanding the performance of these drugs in animals previously exposed to acute or chronic stress is of strong translational relevance. In this study, we examined the effects of psilocybin in male mice that were stress-naïve, as well as in those that underwent either single-prolonged stress (SPS) or chronic restraint stress (CRS). The effects of these treatments on corticosterone release, extinction of freezing behavior, and recall of extinction in Pavlovian fear conditioning were examined for each group. We observed that psilocybin challenge transiently increased serum corticosterone in stress-naïve mice relative to saline; however, this effect was not observed in SPS and CRS animals. Interestingly, psilocybin treatment enhanced fear extinction and promoted extinction recall 24 h later not only in stress-naïve animals but also in stressed animals. These findings indicate psilocybin’s ability to acutely enhance fear extinction and promote enhanced extinction recall across animals with diverse environmental stress experiences prior to exposure.

Limb-girdle muscular dystrophy R3 (LGMDR3), a rare genetic disorder characterized by progressive impairment of limb, diaphragmatic, and respiratory muscles, is caused by loss-of-function mutations in the α-sarcoglycan gene (SGCA) and aggravated by immune-mediated damage and fibrotic tissue replacement. Pharmacological inhibition of purinergic receptor P2X7 (P2X7R) reduced inflammation and fibrosis in Sgca^–/– mice. To further define the role of P2X7R, we generated a double knockout mouse model Sgca^–/–P2rx7^-/-. We compared diaphragms isolated from 24-week-old Sgca^–/–P2rx7^+/+ and Sgca^–/–P2rx7^–/–mice since the diaphragmatic muscle is early and severely damaged by Sgca genetic loss-of-function. Unexpectedly, Sgca^–/–P2rx7^–/– mice displayed increased extracellular matrix deposition and augmented cellularity in fibrotic areas, in particular, a higher number of CD3⁺ lymphocytes and Iba1⁺ macrophages compared to Sgca^–/–P2rx7^+/+ mice. Moreover, intense P2X4R signal colocalized with CD3⁺ and Iba1⁺ cells, confirming its expression by these infiltrating immune cells. Absence of an improvement of the dystrophic phenotype was histologically confirmed in Sgca^–/–P2rx7^–/– quadriceps, although the fibrotic reaction was milder than that in diaphragms, suggesting a differential influence of the tissue microenvironment on the receptor functions. Flow cytometric analysis of limb muscle-infiltrating immune cells revealed a decrease in NK cells. Motor performance tests did not reveal any difference between the two genotypes. In conclusion, this study identified a divergent outcome of genetic deletion of the P2rx7 gene as compared to P2X7R blockade in α-sarcoglycan dystrophic tissue, suggesting that pharmacological interventions targeting the P2X7R in dystrophic immune-mediated damage require careful definition of a precise time window and dosage.

Epidermal growth factor receptors, such as human epidermal growth factor receptors (EGFR, HER1) and HER2, HER3, are essential in cell growth and differentiation. EGFR, HER2, and HER3 dimerize to generate signaling for cell growth, and in cancer cells, these receptors are either overexpressed or harbor mutations, resulting in uncontrolled signaling. The dimerization of these receptors is required for signaling and can be inhibited by peptides and antibodies. We have designed a grafted peptide, SFTI-G5, that targets the HER2 protein and inhibits dimerization of both EGFR:HER2 and HER2:HER3. To develop the grafted peptide as an orally bioavailable peptide, we evaluated the stability of the peptide against enzymatic degradation. Oral administration of SFTI-G5 at 50 mg/kg suppressed the growth of lung cancer cell lines that overexpress the HER2 protein in a mouse xenograft model. To evaluate the specificity of the peptide for the HER2 protein, a patient-derived xenograft (PDX) model of mice with low HER2 expression was used. The peptide did not have any effect on tumor growth in the low HER2 expression model, suggesting the specificity of the peptide for the HER2 protein. Pharmacokinetic studies via the IV route indicated that the peptide is stable in serum, with a terminal half-life of more than 40 h. These studies suggest that stable grafted cyclic peptides can be designed to target protein–protein interactions and that these peptides can be made orally bioavailable.