ACS Pharmacology and Translational Science最新文献

Glioma is the primary malignant tumor with the highest incidence rate in the adult central nervous system. The application of bioinformatics methods to analyze the RNA sequences of multiple gliomas revealed that the CDT1 gene has a significant impact on the cell cycle of glioma cells. Subsequently, we comprehensively and systematically investigated the expression of CDT1 in gliomas through bioinformatics analysis, clinical tissue specimens, and in vitro functional experiments. Our study is the first to report the expression of CDT1 in glioma. Our findings demonstrate that CDT1 plays a crucial role in the proliferation and invasion of glioma. Additionally, our bioinformatics analysis identified several other genes and signaling pathways that are dysregulated in multifocal gliomas, providing potential targets for further research and drug development.

Increasing evidence substantiates the role of mitochondrial dysfunction, inflammation, fibrosis, and cell senescence in the onset and progression of acute kidney injury (AKI) to chronic kidney disease . The underlying governing cellular and transcriptional events, however, are not fully understood. Recently, the key factors that regulate successful and failed repair states in the proximal tubule have been identified at a single-cell resolution following bilateral ischemia-reperfusion (I/R) in a mouse model of AKI. Previously, our group showed that treatment with the FDA-approved selective 5-hydroxytryptamine receptor 1F agonist lasmiditan following AKI induces mitochondrial biogenesis , restores renal mitochondrial function, and increases renal and vascular recovery in vivo. Here, we assessed the effect of lasmiditan on transcriptional and translational changes that are responsible for successful repair, injury, and failed repair states in the renal cortex following I/R-induced AKI. Increased levels of successful repair genes such as acyl-coA synthase medium-chain family member 2a, low-density lipoprotein receptor-related protein 2, solute carrier family 5 member 12, and hepatocyte nuclear factor 4 alpha were observed with 6 and 12 days of lasmiditan treatment following AKI compared to vehicle control. While 6 days of lasmiditan treatment had no effect on failed repair genes, the administration of lasmiditan for 12 days decreased the levels of vascular cell adhesion protein 1, tumor necrosis factor α, and interleukin-1β, which drive maladaptive repair. These data reveal that lasmiditan treatment post-AKI differentially regulates successful and failed repair gene expression in the renal cortex, likely contributing to the restoration of renal function and providing a potential targeted therapeutic pathway for the treatment of AKI.

Neuropathic pain (NP) is one of the debilitating pain phenotypes that leads to the progressive degeneration of the central as well as peripheral nervous system. NP is often associated with hyperalgesia, allodynia, paresthesia, tingling, and burning sensations leading to disability, motor dysfunction, and compromised psychological state of the patients. Most of the conventional pharmacological agents are unable to improve the devastating conditions of pain because of their limited efficacy, undesirable side effects, and multifaceted pathophysiology of the diseased condition. A rapid rise in new cases of NP warrants further research for identifying the potential novel therapeutic modalities for treating NP. Recently, small interfering RNA (siRNA) approach has shown therapeutic potential in many disease conditions including NP. Delivery of siRNAs led to potential and selective downregulation of target mRNA and abolished the pain-related behaviors/pathophysiological pain response. The crucial role of siRNA in the treatment of NP by considering all of the pathways associated with NP that could be managed by siRNA therapeutics has been discussed. However, their therapeutic use is limited by several hurdles such as instability in systemic circulation due to their negative charge and membrane impermeability, off-target effects, immunogenicity, and inability to reach the intended site of action. This review also emphasizes several strategies and techniques to overcome these hurdles for translating these therapeutic siRNAs from bench to bedside by opening a new avenue for obtaining a potential therapeutic approach for treating NP.

Diabetic foot ulcers (DFUs) pose a significant challenge in wound care due to their chronic nature and impaired healing processes. This study examines the biogenic amines and small molecule metabolites present in DFU wound exudates to identify their potential roles in wound healing. Under an IRB-approved protocol, wound fluid samples were collected from 25 diabetic patients and analyzed using ultrahigh-pressure liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry. The analysis identified 721 metabolites, with 402 confirmed through stringent criteria. Key metabolites significantly contributing to the wound exudates include betaine, lactic acid, carnitine, choline, creatine, and metformin (a widely used first-line treatment for type 2 diabetes). These molecules are known to influence wound healing processes, such as collagen synthesis, angiogenesis, inflammation modulation, and energy metabolism. Notably, the presence of drugs such as metformin and beclomethasone in the exudates suggests significant pharmacodynamic interactions that could influence wound healing. Specifically, we discovered that the combined use of insulin and metformin administered systemically significantly increased the concentration of metformin in the wound exudates (from 0.3% ± 0.0 to 3.1% ± 3.4; p = 0.00 49). This study highlights the complexity of DFU exudate composition and underscores the potential for targeted metabolic profiling to develop personalized wound care strategies.

Ubiquitin (Ub) is often considered a structurally conserved protein. Ubiquitination plays a prominent role in the regulation of physiological pathways. Since the first mention of Ub in protein degradation pathways, a plethora of nonproteolytic functions of this post-translational modification have been identified and investigated in detail. In addition, several other structurally and functionally related proteins have been identified and investigated for their Ub-like structures and functions. Ubiquitination and Ub-like modifications play vital roles in modulating the pathways involved in crucial biological processes and thus affect the global proteome. In this Review, we provide a snapshot of pathways, substrates, diseases, and novel therapeutic targets that are associated with ubiquitination or Ub-like modifications. In the past few years, a large number of proteomic studies have identified pools of ubiquitinated proteins (ubiquitylomes) involved or induced in healthy or stressed conditions. These comprehensive studies involving identification of new ubiquitination substrates and sites contribute enormously to our understanding of ubiquitination in more depth. However, with the current tools, there are certain limitations that need to be addressed. We review recent technological advancements in ubiquitylomic studies and their limitations and challenges. Overall, large-scale ubiquitylomic studies contribute toward understanding global ubiquitination in the contexts of normal and disease conditions.

Metastasis stands as a prime contributor to triple-negative breast cancer (TNBC) associated mortality worldwide, presenting heightened severity and significant challenges due to limited treatment options. Addressing TNBC metastasis necessitates innovative approaches and novel therapeutics to specifically target its propensity for dissemination to distant organs. Targeted therapies capable of reversing epithelial-to-mesenchymal transition (EMT) play a crucial role in suppressing metastasis and enhancing the treatment response. Beauvericin, a promising fungal secondary metabolite, exhibits significant potential in diminishing the viability of EMT-induced TNBC cells by triggering intracellular oxidative stress, as evidenced by an enhanced reactive oxygen species level and reduced mitochondrial transmembrane potential. In monolayer cultures, it has exhibited an IC₅₀ of 2.3 μM in both MDA-MB-468 and MDA-MB-231 cells, while in 3D spheroids, the IC₅₀ values are 9.7 and 7.1 μM, respectively. Beauvericin has also reduced the migratory capability of MDA-MB-468 and MDA-MB-231 cells by 1.5- and 1.7-fold, respectively. Both qRT-PCR and Western blot analysis have shown significant upregulation in the expression of epithelial marker (E-cadherin) and downregulation in the expression of mesenchymal markers (N-cadherin, vimentin, Snail, Slug, and β-catenin), following treatment, indicating reversal of EMT. Furthermore, beauvericin has suppressed the Notch signaling pathway by substantially downregulating Notch-1, Notch-3, Hes-1, and cyclinD3 expression and induced autophagy as observed by elevated expression of autophagy markers LC3 and Beclin-1. In conclusion, beauvericin has successfully downregulated TNBC cell survival by inducing oxidative stress and suppressed their migratory potential by reversing EMT through the inhibition of Notch signaling and activation of autophagy.

Thin-layer chromatography (TLC) is commonly employed to screen technetium-99m labeled polymer nanoparticle batches for unreduced pertechnetate and radio-colloidal impurities. Although this method is widely accepted, our findings applying radiolabeled PLGA/PLA–PEG nanoparticles underscore its lack of transferability between different settings and its limitations as a standalone quality control tool. While TLC profiles may appear similar for purified and radiocolloid containing nanoparticle formulations, their in vivo behavior can vary significantly, as demonstrated by discrepancies between TLC results and single-photon emission computed tomography (SPECT) and biodistribution data. This highlights the urgent need for a case-by-case evaluation of TLC methods for each specific nanoparticle type. Our study revealed that polymeric nanoparticles cannot be considered analytically uniform entities in the context of TLC analysis, emphasizing the complex interplay between nanoparticle composition, radiolabeling conditions, and subsequent biological behavior.

The melanocortin receptors are a centrally and peripherally expressed family of Class A GPCRs with physiological roles, including pigmentation, steroidogenesis, energy homeostasis, and others yet to be fully characterized. There are five melanocortin receptor subtypes that, apart from the melanocortin-2 receptor (MC2R), are stimulated by a shared set of endogenous agonists. Until 2020, X-ray crystallographic and cryo-electron microscopic (cryo-EM) structures of these receptors were unavailable, and the investigation of their mechanisms of action and putative ligand–receptor interactions was driven by site-directed mutagenesis studies of the receptors and targeted structure–activity relationship (SAR) studies of the endogenous and derivative synthetic ligands. Synthetic derivatives of the endogenous agonist ligand α-MSH have evolved into a suite of powerful ligands such as NDP-MSH (melanotan I), melanotan II (MTII), and SHU9119. This suite of tool compounds now enables the study of the melanocortin receptors and serves as scaffolds for FDA-approved drugs, means of validating stably expressing melanocortin receptor cell lines, core ligands in assessing cryo-EM structures of active and inactive receptor complexes, and essential references for high-throughput discovery and mechanism of action studies. Herein, we review the history and significance of a finite set of these essential tool compounds and discuss how they are being utilized to further the field’s understanding of melanocortin receptor physiology and greater druggability.