Preventive effect of aripiprazole once-monthly on relapse into mood episodes in bipolar disorder: A multicenter, one-year, retrospective, mirror image study.

BACKGROUND: We conducted a one-year, retrospective, mirror-image study to investigate the clinical effectiveness and safety of aripiprazole once monthly (AOM) in patients with bipolar disorder (BD). We compared pre-treatment conditions with outcomes after 12 months of AOM treatment. METHODS: Seventy-five bipolar patients were recruited from 12 hospitals in Korea. We included 75 patients with BD who had received at least three AOM treatments from September 2019 to September 2022 and had accessible electronic medical record (EMRs) for the year before and after the baseline visit. RESULTS: The overall number of mood episodes significantly decreased from a mean of 1.5 ± 1.2 episodes pre-AOM to 0.5 ± 1.2 episodes post-AOM. Manic episodes significantly decreased from 0.8 ± 0.8 episodes pre-AOM to 0.2 ± 0.5 episodes post-AOM, and depressive episodes significantly decreased from 0.5 ± 0.8 episodes pre-AOM to 0.2 ± 0.6 episodes post-AOM (p = 0.017). Moreover, the number of psychiatric medications and pills and the proportion of patients treated with complex polypharmacy were significantly decreased post-AOM. LIMITATIONS: The small sample size was insufficient to fully represent the entire population of individuals with BD, and potential selection bias was introduced due to only including subjects who received AOM three or more times. CONCLUSION: The results of this study suggest that AOM can reduce mood episode relapse and may be clinically beneficial in the treatment of BD patients, potentially reducing issues associated with polypharmacy in some individuals.

Nucleophilic covalent ligand discovery for the cysteine redoxome.

With an eye toward expanding chemistries used for covalent ligand discovery, we elaborated an umpolung strategy that exploits the 'polarity reversal' of sulfur when cysteine is oxidized to sulfenic acid, a widespread post-translational modification, for selective bioconjugation with C-nucleophiles. Here we present a global map of a human sulfenome that is susceptible to covalent modification by members of a nucleophilic fragment library. More than 500 liganded sulfenic acids were identified on proteins across diverse functional classes, and, of these, more than 80% were not targeted by electrophilic fragment analogs. We further show that members of our nucleophilic fragment library can impair functional protein-protein interactions involved in nuclear oncoprotein transport and DNA damage repair. Our findings reveal a vast expanse of ligandable sulfenic acids in the human proteome and highlight the utility of nucleophilic small molecules in the fragment-based covalent ligand discovery pipeline, presaging further opportunities using non-traditional chemistries for targeting proteins.

Chaperone-directed ribosome repair after oxidative damage.

Because of the central role ribosomes play for protein translation and ribosome-mediated mRNA and protein quality control (RQC), the ribosome pool is surveyed and dysfunctional ribosomes degraded both during assembly, as well as the functional cycle. Oxidative stress downregulates translation and damages mRNAs and ribosomal proteins (RPs). Although damaged mRNAs are detected and degraded via RQC, how cells mitigate damage to RPs is not known. Here, we show that cysteines in Rps26 and Rpl10 are readily oxidized, rendering the proteins non-functional. Oxidized Rps26 and Rpl10 are released from ribosomes by their chaperones, Tsr2 and Sqt1, and the damaged ribosomes are subsequently repaired with newly made proteins. Ablation of this pathway impairs growth, which is exacerbated under oxidative stress. These findings reveal an unanticipated mechanism for chaperone-mediated ribosome repair, augment our understanding of ribosome quality control, and explain previous observations of protein exchange in ribosomes from dendrites, with broad implications for aging and health.

Aryloxypropanolamine targets amyloid aggregates and reverses Alzheimer-like phenotypes in Alzheimer mouse models.

BACKGROUND: Aggregated amyloid-ß (Aß) is considered a pathogenic initiator of Alzheimer's disease (AD), in strong association with tau hyperphosphorylation, neuroinflammation, synaptic dysfunction, and cognitive decline. As the removal of amyloid burden from AD patient brains by antibodies has shown therapeutic potential, the development of small molecule drugs inducing chemical dissociation and clearance of Aß is compelling as a therapeutic strategy. In this study, we synthesized and screened aryloxypropanolamine derivatives and identified 1-(3-(2,4-di-tert-pentylphenoxy)-2-hydroxypropyl)pyrrolidin-1-ium chloride, YIAD002, as a strong dissociator of Aß aggregates. METHODS: The dissociative activity of aryloxypropanolamine derivatives against Aß aggregates were evaluated through in vitro assays. Immunohistochemical staining, immunoblot assays, and the Morris water maze were used to assess the anti-Alzheimer potential in YIAD002-treated 5XFAD and transgenic APP/PS1 mice. Target-ligand interaction mechanism was characterized via a combination of peptide mapping, fluorescence dissociation assays, and constrained docking simulations. RESULTS: Among 11 aryloxypropanolamine derivatives, YIAD002 exerted strongest dissociative activity against ß-sheet-rich Aß aggregates. Upon oral administration, YIAD002 substantially reduced amyloid burden and accordingly, improved cognitive performance in the Morris water maze and attenuated major pathological hallmarks of AD including tauopathy, neuroinflammation, and synaptic protein loss. Mechanism studies suggest that YIAD002 interferes with intermolecular ß-sheet fibrillation by directly interacting with KLVFFA and IGLMVG domains of Aß. In addition, YIAD002 was found to possess dissociative activity against aggregates of pyroglutamate-modified Aß and tau. CONCLUSIONS: Collectively, our results evince the potential of chemical-driven dissociation of Aß aggregates by aryloxypropanolamines as a therapeutic modality of the amyloid clearance approach.

Reaction-based fluorogenic probes for detecting protein cysteine oxidation in living cells.

'Turn-on' fluorescence probes for detecting H2O2 in cells are established, but equivalent tools to monitor the products of its reaction with protein cysteines have not been reported. Here we describe fluorogenic probes for detecting sulfenic acid, a redox modification inextricably linked to H2O2 signaling and oxidative stress. The reagents exhibit excellent cell permeability, rapid reactivity, and high selectivity with minimal cytotoxicity. We develop a high-throughput assay for measuring S-sulfenation in cells and use it to screen a curated kinase inhibitor library. We reveal a positive association between S-sulfenation and inhibition of TK, AGC, and CMGC kinase group members including GSK3, a promising target for neurological disorders. Proteomic mapping of GSK3 inhibitor-treated cells shows that S-sulfenation sites localize to the regulatory cysteines of antioxidant enzymes. Our studies highlight the ability of kinase inhibitors to modulate the cysteine sulfenome and should find broad application in the rapidly growing field of redox medicine.

Global profiling of distinct cysteine redox forms reveals wide-ranging redox regulation in C. elegans.

Post-translational changes in the redox state of cysteine residues can rapidly and reversibly alter protein functions, thereby modulating biological processes. The nematode C. elegans is an ideal model organism for studying cysteine-mediated redox signaling at a network level. Here we present a comprehensive, quantitative, and site-specific profile of the intrinsic reactivity of the cysteinome in wild-type C. elegans. We also describe a global characterization of the C. elegans redoxome in which we measured changes in three major cysteine redox forms after H2O2 treatment. Our data revealed redox-sensitive events in translation, growth signaling, and stress response pathways, and identified redox-regulated cysteines that are important for signaling through the p38 MAP kinase (MAPK) pathway. Our in-depth proteomic dataset provides a molecular basis for understanding redox signaling in vivo, and will serve as a valuable and rich resource for the field of redox biology.

Endogenous SO2-dependent Smad3 redox modification controls vascular remodeling.

Sulfur dioxide (SO2) has emerged as a physiological relevant signaling molecule that plays a prominent role in regulating vascular functions. However, molecular mechanisms whereby SO2 influences its upper-stream targets have been elusive. Here we show that SO2 may mediate conversion of hydrogen peroxide (H2O2) to a more potent oxidant, peroxymonosulfite, providing a pathway for activation of H2O2 to convert the thiol group of protein cysteine residues to a sulfenic acid group, aka cysteine sulfenylation. By using site-centric chemoproteomics, we quantified >1000 sulfenylation events in vascular smooth muscle cells in response to exogenous SO2. Notably, ~42% of these sulfenylated cysteines are dynamically regulated by SO2, among which is cysteine-64 of Smad3 (Mothers against decapentaplegic homolog 3), a key transcriptional modulator of transforming growth factor ß signaling. Sulfenylation of Smad3 at cysteine-64 inhibits its DNA binding activity, while mutation of this site attenuates the protective effects of SO2 on angiotensin II-induced vascular remodeling and hypertension. Taken together, our findings highlight the important role of SO2 in vascular pathophysiology through a redox-dependent mechanism.

Selective Persulfide Detection Reveals Evolutionarily Conserved Antiaging Effects of S-Sulfhydration.

Life on Earth emerged in a hydrogen sulfide (H2S)-rich environment eons ago and with it protein persulfidation mediated by H2S evolved as a signaling mechanism. Protein persulfidation (S-sulfhydration) is a post-translational modification of reactive cysteine residues, which modulate protein structure and/or function. Persulfides are difficult to label and study due to their reactivity and similarity with cysteine. Here, we report a facile strategy for chemoselective persulfide bioconjugation using dimedone-based probes, to achieve highly selective, rapid, and robust persulfide labeling in biological samples with broad utility. Using this method, we show persulfidation is an evolutionarily conserved modification and waves of persulfidation are employed by cells to resolve sulfenylation and prevent irreversible cysteine overoxidation preserving protein function. We report an age-associated decline in persulfidation that is conserved across evolutionary boundaries. Accordingly, dietary or pharmacological interventions to increase persulfidation associate with increased longevity and improved capacity to cope with stress stimuli.

Elevated hs-CRP level is associated with depression in younger adults: Results from the Korean National Health and Nutrition Examination Survey (KNHANES 2016).

INTRODUCTION: Reports on the association between the level of circulating high-sensitivity C-reactive protein (hs-CRP) and depression have been inconsistent. The aim of this study was to examine the association between hs-CRP and depression in a large sample. METHODS: This study used data obtained from a representative Korean sample of 5447 people who participated in the first (2016) year of the seventh Korean National Health and Nutrition Examination Survey (KNHNES VII-1). Depression was identified using a cutoff of 5 on the Patient Health Questionnaire-9 (PHQ-9), and high hs-CPR level was defined as ≥ 3.0 mg/L. FINDINGS: Participants with a high CRP levels had a significantly higher rate of depression than did those with a low hs-CRP levels (25.1% vs. 19.8%, p = 0.007). Serum hs-CRP was independently associated with the PHQ-9 total score after adjusting for potentially confounding factors (B = 0.014; 95% CI = 0.008-0.020). After controlling for body mass index (BMI), smoking, alcohol use problems, hypertension, diabetes, dyslipidemia, chronic illness related hs-CRP, and metabolic syndrome. Furthermore, elevated hs-CRP level was significantly associated with an increased risk of depression (adjusted OR = 1.44; 95% CI = 1.01-2.07) in younger adults, but no significant association was observed among older adults. CONCLUSION: These findings suggest a significant correlation between high hs-CRP levels and depression in younger adults. Further studies are necessary to investigate the age-specific association and the biological mechanism involved.

Fluorescent 1,4-Naphthoquinones To Visualize Diffuse and Dense-Core Amyloid Plaques in APP/PS1 Transgenic Mouse Brains.

Recent clinical approvals of brain imaging radiotracers targeting amyloid-ß provided clinicians the tools to detect and confirm Alzheimer's disease pathology without autopsy or biopsy. While current imaging agents are effective in postsymptomatic Alzheimer's patients, there is much room for improvement in earlier diagnosis, hence prompting a need for new and improved amyloid imaging agents. Here we synthesized 41 novel 1,4-naphthoquinone derivatives and initially discovered 14 antiamyloidogenic compounds via in vitro amyloid-ß aggregation assay; however, qualitative analyses of these compounds produced conflicting results and required further investigation. Follow-up docking and biophysical studies revealed that four of these compounds penetrate the blood-brain barrier, directly bind to amyloid-ß aggregates, and enhance fluorescence properties upon interaction. These compounds specifically stain both diffuse and dense-core amyloid-ß plaques in brain sections of APP/PS1 double transgenic Alzheimer's mouse models. Our findings suggest 1,4-naphthoquinones as a new scaffold for amyloid-ß imaging agents for early stage Alzheimer's.

Chemical proteomics reveals new targets of cysteine sulfinic acid reductase.

Cysteine sulfinic acid or S-sulfinylation is an oxidative post-translational modification (OxiPTM) that is known to be involved in redox-dependent regulation of protein function but has been historically difficult to analyze biochemically. To facilitate the detection of S-sulfinylated proteins, we demonstrate that a clickable, electrophilic diazene probe (DiaAlk) enables capture and site-centric proteomic analysis of this OxiPTM. Using this workflow, we revealed a striking difference between sulfenic acid modification (S-sulfenylation) and the S-sulfinylation dynamic response to oxidative stress, which is indicative of different roles for these OxiPTMs in redox regulation. We also identified >55 heretofore-unknown protein substrates of the cysteine sulfinic acid reductase sulfiredoxin, extending its function well beyond those of 2-cysteine peroxiredoxins (2-Cys PRDX1-4) and offering new insights into the role of this unique oxidoreductase as a central mediator of reactive oxygen species-associated diseases, particularly cancer. DiaAlk therefore provides a novel tool to profile S-sulfinylated proteins and study their regulatory mechanisms in cells.

Mitochondria-targeting indolizino[3,2-c]quinolines as novel class of photosensitizers for photodynamic anticancer activity.

To achieve efficient photodynamic activity, substantial effort has been dedicated to precise control of the intracellular localization of current photosensitizers (PSs). Given the extremely small radius of action of singlet oxygen, the direct targeting of PSs to the mitochondria is expected to greatly enhance the photodynamic therapy (PDT) activity. Here, we report mitochondria-targeting 6-(furan-2-yl)- and 6-(thiophen-2-yl) indolizino[3,2-c]quinolines (IQs) as novel PSs. IQ derivatives containing 5-membered heterocyclic aromatic rings were synthesized, and their photophysical properties as PSs were characterized. The anticancer potentials of 2a-2f were investigated using various cancer cell lines, and they exhibited dose-dependent and light exposure time-dependent cytotoxicity. Among the synthesized compounds, 2b, which contains a furan ring, showed dual functions as an imaging probe as well as a PS. Real-time confocal fluorescence images revealed the mitochondrial localization of 2b as a primary site of photodamage in live cells. Targeted reactive oxygen species (ROS)-generation capabilities and the photoinduced DNA cleavage of IQs led to mitochondrial dysfunction and photoinduced apoptosis via the intrinsic pathway. 3D RI tomograms of individual live HeLa cells treated with 2b showed that the progress of photoinduced apoptosis was affected by the PS concentration and light irradiation time. The studied IQs (2b, 2d, and 2e) are expected to serve as a new class of heavy-atom-free PSs with low molecular weights less than 350.

Three-Dimensional Computed Tomographic Assessment of Temporomandibular Joint Stability After Orthognathic Surgery.

PURPOSE: Ensuring that the condyle is appropriately positioned and that positional changes are minimal is considered crucial for the temporomandibular joint (TMJ) to function without symptoms after orthognathic surgery. The purposes of this study were to evaluate condylar changes after surgery and to examine the association between these changes and TMJ symptoms. PATIENTS AND METHODS: A retrospective cohort study was conducted in patients with mandibular prognathism who underwent orthognathic surgery. Linear and angular changes in the positioning of the condyle were measured by superimposing 3-dimensional computed tomograms taken before surgery and 3 months after surgery. Clinical symptoms of TMJ pain and sound were recorded at 3, 6, 9, and 12 months after surgery. Possible associations between TMJ symptoms and clinical variables, such as postoperative condylar changes, were investigated using multiple logistic regression analysis. RESULTS: Linear condylar displacement after orthognathic surgery occurred predominantly in the anterior, medial, and inferior directions, with minimal changes (<1 mm) observed. Most angular condylar changes were smaller than 4° and occurred in the inward direction in the axial plane and the posterior direction in the sagittal plane. The best predictor of postoperative TMJ signs and symptoms was the preoperative status of TMJ signs and symptoms. Neither linear nor angular condylar displacement showed a relevant influence on postoperative pain and sound. CONCLUSIONS: Within the ranges of linear (<1 mm) and angular (<4°) condylar displacement noted in this study, displacement was not associated with postoperative TMJ pain and sound.

Synthesis, characterization and biological evaluation of anti-cancer indolizine derivatives via inhibiting ß-catenin activity and activating p53.

Diversity-oriented construction of new indolizine scaffolds was accomplished by utilizing domino Knoevenagel condensation/intramolecular aldol cyclization. Biological evaluation revealed anticancer activity of these compounds through inhibition of ß-catenin and activation of p53.

Symmetry-based approach to oligostilbenoids: Rapid entry to viniferifuran, shoreaphenol, malibatol A, and diptoindonesin G.

The recognition of the local symmetric image within benzofuran-based natural oligostilbenoids guided us to design a modular synthetic approach to these molecules by utilizing a three-step sequence consisting of Sonogashira coupling, iodocyclization, and Suzuki coupling. During our synthesis, the relative reactivities of ester, aldehyde, and alkoxy groups on the same aryl ring toward the neighboring alkyne in the iodine-mediated cyclization reactions were explored. Starting from the symmetrical 3,5-dimethoxybenzyl alcohol, this route allowed rapid access to 2,3-diarylbenzofuran, a key intermediate to several oligostilbenoid natural products, in good overall yields.

Reciprocal Regulation of ERα and ERß Stability and Activity by Diptoindonesin G.

ERß is regarded as a "tumor suppressor" in breast cancer due to its anti-proliferative effects. However, unlike ERα, ERß has not been developed as a therapeutic target in breast cancer due to loss of ERß in aggressive cancers. In a small-molecule library screen for ERß stabilizers, we identified Diptoindonesin G (Dip G), which significantly increases ERß protein stability while decreasing ERα protein levels. Dip G enhances the transcription and anti-proliferative activities of ERß, while attenuating the transcription and proliferative effects of ERα. Further investigation revealed that instead of targeting ER, Dip G targets the CHIP E3 ubiquitin ligase shared by ERα and ERß. Thus, Dip G is a dual-functional moiety that reciprocally controls ERα and ERß protein stability and activities via an indirect mechanism. The ERß stabilization effects of Dip G may enable the development of ERß-targeted therapies for human breast cancers.

Mollugin from Rubea cordifolia suppresses receptor activator of nuclear factor-κB ligand-induced osteoclastogenesis and bone resorbing activity in vitro and prevents lipopolysaccharide-induced bone loss in vivo.

Osteopenic diseases, such as osteoporosis, are characterized by progressive and excessive bone resorption mediated by enhanced receptor activator of nuclear factor-κB ligand (RANKL) signaling. Therefore, downregulation of RANKL downstream signals may be a valuable approach for the treatment of bone loss-associated disorders. In this study, we investigated the effects of the naphthohydroquinone mollugin on osteoclastogenesis and its function in vitro and in vivo. Mollugin efficiently suppressed RANKL-induced osteoclast differentiation of bone marrow macrophages (BMMs) and bone resorbing activity of mature osteoclasts by inhibiting RANKL-induced c-Fos and NFATc1 expression. Mollugin reduced the phosphorylation of signaling pathways activated in the early stages of osteoclast differentiation, including the MAP kinase, Akt, and GSK3ß and inhibited the expression of different genes associated with osteoclastogenesis, such as OSCAR, TRAP, DC-STAMP, OC-STAMP, integrin αν, integrin ß3, cathepsin K, and ICAM-1. Furthermore, mice treated with mollugin showed significant restoration of lipopolysaccharide (LPS)-induced bone loss as indicated by micro-CT and histological analysis of femurs. Consequently, these results suggested that mollugin could be a novel therapeutic candidate for bone loss-associated disorders including osteoporosis, rheumatoid arthritis, and periodontitis.

Ovarian metastasis from pulmonary adenocarcinoma.

Metastatic ovarian cancer is not an uncommon finding. Such tumors almost always originate from female genital tract, colon, stomach, or breast. Lung cancer is not a common origin of ovarian metastases. Of all metastatic ovarian tumors, approximately 0.3% arise from lung cancer. Ovarian torsion is not an uncommon finding, but ovarian torsion with cancer is rare. Here, we report a 44-year-old woman who was previously diagnosed with advanced stage lung cancer and who emergently visited our hospital for abdominal pain. An imaging work-up revealed, ovarian torsion and exploratory laparotomy was performed. Pathological examination led to the diagnosis ovarian metastasis from lung cancer. This is the first case of ovarian metastasis from lung cancer, ovarian torsion.