ACS Pharmacology and Translational Science最新文献

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing globally. MASLD is characterized by clinically significant liver steatosis, and a subset of patients progress to more severe metabolic-disorder-associated steatohepatitis (MASH) with liver inflammation and fibrosis. Cannabinoid receptor 1 (CB1) antagonism is a proven therapeutic strategy for the treatment of the phenotypes that underlie MASLD, though work on early centrally penetrant compounds largely ceased following adverse psychiatric indications in humans. We present here preclinical testing of a CB1 neutral antagonist, N-[1-[8-(2-Chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidin-4l]methanesulfonamide (RTI-348), with minimal brain exposure when administered to mice. In a diet-induced model of MASLD-induced MASH, administration of RTI-348 decreased the total body and liver weight gain. Animals treated with RTI-348 showed reduced steatosis. Furthermore, they produced lower plasma alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH), biomarkers associated with liver damage. Mice maintained on the MASH diet had elevated expression of genes associated with profibrogenesis, immune response, and extracellular matrix remodeling, and treatment with RTI-348 mitigated these diet-induced changes in gene expression. Using an intracranial electrical self-stimulation model, we also demonstrated that RTI-348 does not produce an anhedonia response, as seen with the first-generation CB1 inverse agonist rimonabant. Altogether, the results herein point to RTI-348 as a promising neutral antagonist for MASH.

The escalating prevalence of new psychoactive substances (NPSs) poses a significant public health challenge, evidenced by the vast chemical diversity, with over 500 substances reported annually to the United Nations Office on Drugs and Crime-Early Warning Advisory (UNODC-EWA) in the past five years. Among NPSs, synthetic cathinones are gaining a lot of popularity among users. Notably, synthetic cathinones accounted for approximately 50% of the total quantity of NPSs reported as seized by EU Member States in 2021. Preliminary data from UNODC indicates that a total of 209 synthetic cathinones have been reported to date. As their popularity grows, studying the structure–activity relationship (SAR) of synthetic cathinones is essential. SAR studies elucidate how structural features impact biological effects, aiding in toxicity prediction, regulatory compliance, and forensic identification. Additionally, SAR studies play a pivotal role in guiding drug policies, aiding authorities in categorizing and regulating newly emerging synthetic cathinones, mitigate public health risks and offer valuable insights into potential therapeutic applications. Thus, our Review consolidates recent findings on the effects of different substitutions in the chemical scaffold of synthetic cathinones on their mechanism of action as well as pharmacological and toxicological effects of synthetic cathinones, thus enhancing understanding of the SAR of synthetic cathinones’ pharmacology and potential implications.

Synthetic DNAzyme-based structures enable dynamic cell regulation. However, engineering an effective and targeted DNAzyme-based structure to perform customizable multistep regulation remains largely unexplored. Herein, we designed a membrane-anchored DNAzyme-based molecular machine to implement dynamic inter- and intracellular cascade regulation, which realizes efficient T-cell/cancer cell interactions and subsequent receptor mediated cancer cell uptake. Using CD8⁺ T-cells and HeLa cancer cells as a proof of concept, we demonstrate that the designed DNAzyme-based molecular machine enables customized cascade regulation including (1) specific recognition between T-cells and cancer cells, (2) specific response and fluorescence sensing upon extracellular stimuli, and (3) cascade regulation including intercellular distance shortening, cell–cell communication, and intracellular delivery of anticancer drugs. Together, this work provides a promising pathway for customized cascade cell regulation based on a DNAzyme-based molecular machine, which enables enhanced cancer therapy by combining T-cell immunotherapy and chemotherapy.

The potential for multiorgan toxicities is a significant barrier to the therapeutic use of doxorubicin (DOX) in cancer treatment. With regard to DOX-induced acute cardiotoxicity in rats, the current investigation sought to assess the cardioprotective function of α-bisabolol (BSB) as well as the underlying pharmacological and molecular processes. Acute cardiotoxicity was induced in the rats by the intraperitoneal injection of DOX (12.5 mg/kg, single dosage). Over the course of 5 days, the rats were administered 25 mg/kg of BSB orally twice a day. The DOX administration induced cardiac damage, as evidenced by altered cardiospecific diagnostic markers and macroscopic enzyme mapping assay. The occurrence of mitochondrial oxidative stress was observed by a significant decline in antioxidant defense along with an increase in lipid peroxidation. DOX also perturbed DNA damage, mitochondrial biogenesis, mitochondrial fission and dysfunction, ER stress, Hippo signaling, and caspase-dependent and independent apoptosis including necroptosis and ferroptosis in the myocardium of rats. Conversely, it has been noted that the administration of BSB preserves the myocardium and reverses all cellular, molecular, and structural disruptions in the cardiac tissues of rats exposed to DOX-induced toxicity. The results that are currently available unequivocally show the cardioprotective role of BSB in DOX-induced cardiotoxicity. This effect is attributed to BSB’s strong antioxidant, antilipid peroxidative, and antiapoptotic properties, which are mediated by advantageous changes in multiple signaling pathways.

Pancreatic ductal adenocarcinoma (PDAC) is the seventh most common cause of cancer-related mortality. Despite different methods of treatment, nearly more than 90% of patients with PDAC die shortly after diagnosis. Contrary to promising results in other cancers, immune checkpoint inhibitors (ICIs) showed limited success in PDAC. Recent studies have shown that noncoding RNAs (ncRNAs) are extensively involved in PDAC cell–immune cell interaction and mediate immune evasion in this vicious cancer. PDAC cells recruit numerous ncRNAs to widely affect the phenotype and function of immune cells through various mechanisms. For instance, PDAC cells upregulate miR-301a and downregulate miR-340 to induce M2 polarization of macrophages or overexpress miR-203, miR-146a, and miR-212-3p to downregulate toll-like receptor 4 (TLR4), CD80, CD86, CD1a, major histocompatibility complex (MHC) II, and CD83, thereby evading recognition by dendritic cells. By downregulating miR-4299 and miR-153, PDAC cells can decrease the expression of NK group 2D (NKG2D) and MHC class I chain-related molecules A and B (MICA/B) to blunt the natural killer (NK) cell response. PDAC cells also highly express lncRNA AL137789.1, hsa_circ_0046523, lncRNA LINC00460, and miR-155-5p to upregulate immune checkpoint proteins and escape T cell cytotoxicity. On the other hand, ncRNAs derived from suppressive immune cells promote proliferation, invasion, and drug resistance in PDAC cells. ncRNAs can be applied to overcome resistance to ICIs, monitor the immune microenvironment of PDAC, and predict response to ICIs. This Review article comprehensively discusses recent findings regarding the roles of ncRNAs in the immune evasion of PDAC.

Psoriasis is a chronic, inflammatory dermatosis characterized by thickened, reddened, and scaly skin lesions. Norfloxacin is a fluoroquinolone antibiotic with enhanced antioxidant, anti-inflammatory, and immunomodulatory bioactivities. The aim of this study was to figure out the possible impact of topical norfloxacin on an imiquimod-induced model of psoriasis in mice. Thirty albino-type mice were split into five distinct groups of six animals each. The control group included healthy mice that had not received any treatment. The induction group was given the vehicle 2 h after the topical imiquimod, once daily for 8 days. Two hours after receiving topical imiquimod, the treatment groups including calcipotriol, norfloxacin 2.5%, and norfloxacin 5% were given topical ointments containing calcipotriol 0.005%, norfloxacin 2.5%, and norfloxacin 5%, for 8 days. Topical norfloxacin ointment significantly reduced the severity of imiquimod-exacerbated psoriatic lesions including erythema, shiny-white scaling, and acanthosis and fixed histological abnormalities. Furthermore, imiquimod-subjected mice treated with a higher concentration of norfloxacin ointment exhibited dramatically lower skin levels of inflammation-related biomarkers like IFN-γ, TNF-α, IL-6, IL-17A, IL-23, and TGF-β but higher levels of IL-10. They also demonstrated a notable decrease in angiogenesis parameters such as VEGF and IL-8, a substantial reduction in oxidative indicators like MDA and MPO, and a considerable rise in antioxidant enzymes like SOD and CAT. This study offers novel evidence that norfloxacin may assist in controlling inflammatory dermatoses like psoriasis by minimizing the severity of psoriatic plaques, correcting histological alterations, and diminishing the production of inflammatory, oxidative, and angiogenetic parameters.

Establishing target engagement is fundamental to effective target-based drug development. It paves the way for efficient medicinal chemistry design and definitive answers about target validation in the clinic. For irreversible targeted covalent inhibitor (TCI) drugs, there is a unique opportunity to establish and quantify the target engagement or occupancy. This is typically accomplished by using a covalent molecular probe, often a TCI analogue, derivatized to allow unoccupied target sites to be tracked; the difference of total sites minus unoccupied sites yields the occupied sites. When such probes are not available or the target is not readily accessible to covalent probes, another approach is needed. Receptor tyrosine-protein kinase erbB-2 (HER2) occupancy by afatinib presents such a case. Available HER2 covalent probes were unable to consistently modify HER2 after sample preparation, resulting in inadequate data. We demonstrate an alternative quantitative probe-free occupancy (PFO) method. It employs the immunoprecipitation of HER2 and direct mass spectrometer analysis of the cysteine-containing peptide that is targeted and covalently occupied by afatinib. Nontarget HER2 peptides provide normalization to the total protein. We show that HER2 occupancy by afatinib correlates directly to the inhibition of the receptor tyrosine kinase activity in NCI-N87 cells in culture and in vivo using those cells in a mouse tumor xenograft mode.

The loss of peroxisome proliferator-activated receptor gamma (PPARγ) exacerbates pulmonary arterial hypertension (PAH), while its upregulation reduces cell proliferation and vascular remodeling, thereby decreasing PAH severity. SGLT2 inhibitors, developed for type 2 diabetes, might also affect signal transduction in addition to modulating sodium-glucose cotransporters. Pulmonary arterial smooth muscle cells (PASMCs) isolated from patients with idiopathic pulmonary arterial hypertension (IPAH) were treated with three SGLT2 inhibitors, canagliflozin (Cana), dapagliflozin (Dapa), and empagliflozin (Empa), to investigate their antiproliferative effects. To assess the impact of Empa on PPARγ, luciferase reporter assays and siRNA-mediated PPARγ knockdown were employed to examine regulation of the γ-secretase complex and its downstream target Notch3. Therapy involving daily administration of Empa was initiated 21 days after inducing hypoxia-induced PAH in mice. Empa exhibited significant antiproliferative effects on fast-growing IPAH PASMCs. Empa activated PPARγ to prevent formation of the γ-secretase complex, with specific impacts on presenilin enhancer 2 (PEN2), which plays a crucial role in maintaining γ-secretase complex stability, thereby inhibiting Notch3. Similar results were obtained in lung tissue of chronically hypoxic mice. Empa attenuated pulmonary arterial remodeling and right ventricle hypertrophy in a hypoxic PAH mouse model. Moreover, PPARγ expression was significantly decreased and PEN2, and Notch3 levels were increased in lung tissue from PAH patients compared with non-PAH lung tissue. Empa reverses vascular remodeling by activating PPARγ to suppress the γ-secretase-Notch3 axis. We propose Empa as a PPARγ activator and potential therapeutic for PAH.

The escalating prevalence of obesity and its related disorders represents a daunting global health challenge. Unfortunately, current pharmacological interventions for obesity remain limited and are often associated with debilitating side effects. Against this backdrop, the psychoactive aminoindane derivative 5-methoxy-2-aminoindane (MEAI) has gained considerable attention for its ability to induce a pleasurable, alcohol-like sensation while curbing alcohol consumption. Given the potential impact of MEAI on food addiction and energy homeostasis, we examined its metabolic efficacy on appetite regulation, obesity, and related comorbidities under acute and chronic settings, utilizing a mouse model of diet-induced obesity (DIO). Our results demonstrated that MEAI treatment significantly reduced DIO-induced overweight and adiposity by preserving lean mass and decreasing fat mass. Additionally, MEAI treatment exhibited positive effects on glycemic control by attenuating DIO-induced hyperglycemia, glucose intolerance, and hyperinsulinemia. Furthermore, MEAI reduced DIO-induced hepatic steatosis by decreasing hepatic lipid accumulation and lowering liver triglyceride and cholesterol levels, primarily by inhibiting de novo lipid synthesis. Metabolic phenotyping revealed that MEAI increased energy expenditure and fat utilization while maintaining food consumption similar to that of the vehicle-treated group. Lastly, MEAI normalized voluntary locomotion actions without any overstimulatory effects. These findings provide compelling evidence for the antiobesity effects of MEAI treatment and call for further preclinical testing. In conclusion, our study highlights the potential of MEAI as a novel therapeutic approach for treating obesity and its associated metabolic disorders, offering hope for the development of new treatment options for this global health challenge.

The deregulation of cell surface heparan sulfate proteoglycans (HSPGs) is a main issue of cancer cells for increasing their malignancy. In these terms, the sulfation pattern of HS, created by an orchestrated activity of enzymes balancing a site-specific sulfation, is of key importance. These enzymes are often deregulated by epigenetic processes in cancer, e.g., being silenced by DNA hypermethylation. Here, we address this issue in human breast cancer cell lines aiming to target epigenetic processes to reactivate HS sulfation, shifting HS into an antithrombotic phenotype for which 3-O-sulfation is particularly important. Treatment of MCF-7 and MDA-MB-231 cells with nontoxic concentrations of 5-azacytidine (azacytidine) and 5-fluoro-2′-deoxycytidine (FdCyd) as DNMT inhibitors or vorinostat for targeting HDAC increased HS3-O-sulfation remarkably, as confirmed by fluorescence microscopy, by upregulating HS3-O-sulfotransferases, detected by quantitative real-time polymerase chain reaction and Western blot. Flow cytometry and microscopic approaches confirm that upon inhibitor treatment, increased HS3-O-sulfation improves cell binding to antithrombin, leading to an antithrombotic activity. Nevertheless, only azacytidine- and vorinostat-treated cells display anticoagulative properties, represented by attenuated thrombin formation, a lower activation of human platelet aggregation, or ATP release. In contrast, FdCyd additionally upregulated tissue factor expression in both cell lines, overshadowing the anticoagulant effects of HS, leading to an overall prothrombotic phenotype. Our data provide evidence for the first time that targeting epigenetic processes in HS sulfation is a valuable means to foster anticoagulative cell properties for decreasing malignancy and metastatic potency. These data warrant further investigations to fine-tune epigenetic targeting and to search for potential biomarkers attributed to these activities.