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Oxidation of dopamine can cause various side effects, which ultimately leads to cell death and contributes to Parkinson's disease (PD). To counteract dopamine oxidation, newly synthesized dopamine is quickly transported into vesicles via vesicular monoamine transporter 2 (VMAT2) for storage. VMAT2 expression is reduced in patients with PD, and studies have shown increased accumulation of dopamine oxidation byproducts and α-synuclein in animals with low VMAT2 expression. Conversely, animals that overexpress VMAT2 show better protection for dopamine neurons. Based on these findings, this study used histone deacetylase inhibitors (HDACi) to increase VMAT2 expression, reduce dopamine-induced oxidative stress, and evaluate the resulting behavioral improvements in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD animal model. LMK-235 not only increased VMAT2 expression at various concentrations in the SH-SY5Y cell line differentiated into dopaminergic cells but also demonstrated effective cytoprotective properties in several toxicity assays. It significantly raised VMAT2 expression in both the striatum and the ventral tegmental area of an MPTP-induced PD model, supporting its role in reversing behavioral abnormalities linked to PD. In addition to these results, coadministration of LMK-235 with L-DOPA, a standard therapy for PD, restored typical behavioral patterns, highlighting the potential of HDACi in alleviating PD symptoms. The expression of VMAT2 induced by LMK-235, an inhibitor of Class IIa histone deacetylases primarily found in the nervous system, aids in sequestering dopamine into vesicles, potentially enhancing cell survival by inhibiting dopamine oxidation. Additionally, upregulation of VMAT2 has been shown to offer effective protection against MPTP-induced toxicity and significantly improve behavioral abnormalities associated with PD. Coadministration with L-DOPA produced the most notable improvement in behavioral outcomes. Altogether, these findings suggest that the overexpression of VMAT2 may offer a promising strategy for developing treatments for PD by mitigating dopaminergic neuron death resulting from dopamine oxidation., (© 2025 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Hepatocellular carcinoma (HCC) is by far the predominant malignant liver cancer, with both high morbidity and mortality. Early diagnosis and surgical resections are imperative for improving the survival of HCC patients. However, limited by clinical diagnosis methods, it is difficult to accurately distinguish tumor tissue and its boundaries in the early stages of cancer. Herein, we report two fluorescent probes, cLG and hLR , for the detection of cancer and healthy cells, respectively, enabling the precise diagnosis of liver cancer by providing complementary imaging. These two fluorescent probes could selectively stain the target cells in the liver tissue imaging, which is confirmed by H&E and antibody staining. Moreover, for the first time, the cancerous area and healthy area are clearly identified by the cocktail of these two probes, suggesting its potential to be used in fluorescence-guided surgery. Finally, we identify transporter SLC27A2 as the gating target of cLG through a systematic transporter screen using a CRISPR activation library. SMPD1 was identified as the target of hLR through a thermal proteome profiling. Therefore, the development of these two highly specific probes offers complementary imaging and provides a unique diagnostic tool for cancer disease, even for fluorescence-guided surgery., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Diabetic retinopathy is a disease that can cause vision loss leading to blindness in people with diabetes. Improved methods to treat and prevent vision loss in diabetic patients are in high demand owing to limited current treatment procedures. Herein, we report a new class of transglutaminase 2 (TGase2) inhibitors for the treatment of diabetic retinopathy based on 7-aminoquinoline-5,8-dione derivatives. 7-Amino-2-phenylquinoline-5,8-dione 11 and 7-amino-2-{4-[(1-methylpiperidin-4-yl)oxy]phenyl}quinoline-5,8-dione 23 exhibited potent inhibitory activities against TGase2 in a fibrinogen array-based on-chip TGase2 activity assay and in an in situ assay in human retinal microvascular endothelial cells, with IC 50 values of 5.88 and 1.12 μM in vitro, and 0.09 and 0.07 μM in situ, respectively. Pharmacokinetically favorable 7-amino-2-{4-[(1-isopropylpiperidin-4-yl)oxy] phenyl}quinoline-5,8-dione 22 inhibited vascular leakage in the retinas of streptozotocin-induced diabetic mice via oral administration. Results from the AL5 kinetic assay and a molecular docking study suggest that the inhibitors may bind to TGase2 remote from the active site.

The prevalence of chronic kidney disease (CKD) in dogs increases with age, and renal fibrosis is an important pathophysiological mechanism in this process. However, only a few drugs that can effectively inhibit fibrosis in the kidneys of dogs are currently available. In this study, we aimed to determine whether pirfenidone, a drug that has shown antifibrotic effects in various clinical studies, also exerts antifibrotic effects on canine renal tubular epithelial cells, Madin-Darby canine kidney cells (MDCK). To this end, we treated MDCK cells with various concentrations of pirfenidone, followed by transforming growth factor-beta1 (TGF-β1) to stimulate fibrotic conditions. A cell viability assay was performed to determine the effect of pirfenidone on cell survival. Fibrosis-related markers and TGF-β1 fibrotic pathway-related markers were assessed using qPCR, Western blot analysis and immunocytochemistry. A one-way analysis of variance (ANOVA) was performed, followed by Tukey's post-hoc test for multiple comparisons. Pirfenidone treatment significantly reduced the expression of profibrotic markers such as α-smooth muscle actin, fibronectin, and collagen. Additionally, it upregulated the expression of E-cadherin, an epithelial marker. Furthermore, pirfenidone effectively inhibited the phosphorylation of key factors involved in the TGF-β1 signaling pathway, including Smad2/3 and ERK1/2. These results demonstrate that pirfenidone suppresses TGF-β1-induced fibrosis in MDCK cells by attenuating epithelial-mesenchymal transition and the relevant signaling pathways., (© 2024. The Author(s).)

The importance of vesicular monoamine transporter 2 (VMAT2) in dopamine regulation, which is considered crucial for neuropsychiatric disorders, is currently being studied. Moreover, the development of disease treatments using histone deacetylase (HDAC) inhibitors (HDACi) is actively progressing in various fields. Recently, research on the possibility of regulating neuropsychiatric disorders has been conducted. In this study, we evaluated whether VMAT2 expression increased by an HDACi can fine-tune neuropsychotic behavior, such as attention deficit hyperactivity disorder (ADHD) and protect against the cell toxicity through oxidized dopamine. First, approximately 300 candidate HDACi compounds were added to the SH-SY5Y dopaminergic cell line to identify the possible changes in the VMAT2 expression levels, which were measured using quantitative polymerase chain reaction. The results demonstrated, that treatment with pimelic diphenylamide 106 (TC-H 106), a class I HDACi, increased VMAT2 expression in both the SH-SY5Y cells and mouse brain. The increased VMAT2 expression induced by TC-H 106 alleviated the cytotoxicity attributed to 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenylpyridinium (MPP + ) and free dopamine treatment. Moreover, dopamine concentrations, both intracellularly and in the synaptosomes, were significantly elevated by increased VMAT2 expression. These results suggest that dopamine concentration regulation by VMAT2 expression induced by TC-H 106 could alter several related behavioral aspects that was confirmed by attenuation of hyperactivity and impulsivity, which were major characteristics of animal model showing ADHD-like behaviors. These results indicate that HDACi-increased VMAT2 expression offers sufficient protections against dopaminergic cell death induced by oxidative stress. Thus, the epigenetic approach could be considered as therapeutic candidate for neuropsychiatric disease regulation., (© 2023 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Coating Zr-based metallic glass, Zr 53 Cu 31 Ni 11 Al 5 (Zr-MG), on a Cu current collector (CC) and Li metal anode (LMA) significantly improves the cycle performance of both types of Li-ion batteries, namely, anode-free Li-ion batteries (AFLBs) and Li metal batteries (LMB). The inherent isotropy and homogeneity of the Zr-MG significantly improve the surface uniformity of the CC and LMA. A 12 nm-thick Zr-MG thin film coating on the CC reduces the overpotential in the AFLB, leading to a more uniform Li plating morphology. The Li film covers almost the entire surface of the Zr-CC, whereas it only covers ≈75% of the bare CC during charging. An LFP||Zr-CC full-cell exhibits a capacity retention of 63.6% after the 100th cycle, with an average CE of 99.55% at a 0.2 C rate. In the case of the LMB, a 12 nm-thick Zr-MG thin film-coated LMA (Zr-LMA) exhibits a stable capacity of up to 1500 cycles. An LFP||Zr-LMA full-cell exhibits capacity retention and CE after 1500 cycles of 66.6% and 99.97%, respectively, at a 1 C rate. Zirconium-MG thin films with atomic-level uniformity, outstanding corrosion resistance, lithiophilic characteristics, and high diffusivity result in superior AFLB and LMB performances., (© 2023 Wiley-VCH GmbH.)

Direct identification of the proteins targeted by small molecules can provide clues for disease diagnosis, prevention, and drug development. Despite concentrated attempts, there are still technical limitations associated with the elucidation of direct interactors. Herein, we report a target-ID system called proximity-based compound-binding protein identification (PROCID), which combines our direct analysis workflow of proximity-labeled proteins (Spot-ID) with the HaloTag system to efficiently identify the dynamic proteomic landscape of drug-binding proteins. We successfully identified well-known dasatinib-binding proteins (ABL1, ABL2) and confirmed the unapproved dasatinib-binding kinases (e.g., BTK and CSK) in a live chronic myeloid leukemia cell line. PROCID also identified the DNA helicase protein SMARCA2 as a dasatinib-binding protein, and the ATPase domain was confirmed to be the binding site of dasatinib using a proximity ligation assay (PLA) and in cellulo biotinylation assay. PROCID thus provides a robust method to identify unknown drug-interacting proteins in live cells that expedites the mode of action of the drug., Competing Interests: Declaration of interests The authors have no competing interests. A patent application has been filed by Seoul National University relating to this work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)