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1.
Neuron ; 112(16): 2783-2798.e9, 2024 Aug 21.
Article in English | MEDLINE | ID: mdl-38959892

ABSTRACT

The lateral septum (LS) is composed of heterogeneous cell types that are important for various motivated behaviors. However, the transcriptional profiles, spatial arrangement, function, and connectivity of these cell types have not been systematically studied. Using single-nucleus RNA sequencing, we delineated diverse genetically defined cell types in the LS that play distinct roles in reward processing. Notably, we found that estrogen receptor 1 (Esr1)-expressing neurons in the ventral LS (LSEsr1) are key drivers of reward seeking via projections to the ventral tegmental area, and these neurons play an essential role in methamphetamine (METH) reward and METH-seeking behavior. Extended exposure to METH increases the excitability of LSEsr1 neurons by upregulating hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, thereby contributing to METH-induced locomotor sensitization. These insights not only elucidate the intricate molecular, circuit, and functional architecture of the septal region in reward processing but also reveal a neural pathway critical for METH reward and behavioral sensitization.


Subject(s)
Methamphetamine , Neurons , Reward , Septal Nuclei , Animals , Mice , Neurons/physiology , Neurons/metabolism , Methamphetamine/pharmacology , Septal Nuclei/physiology , Septal Nuclei/metabolism , Male , Ventral Tegmental Area/physiology , Ventral Tegmental Area/metabolism , Estrogen Receptor alpha/metabolism , Estrogen Receptor alpha/genetics , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics , Neural Pathways/physiology , Mice, Inbred C57BL , Drug-Seeking Behavior/physiology
2.
Nat Chem Biol ; 2024 Jul 04.
Article in English | MEDLINE | ID: mdl-38965384

ABSTRACT

Targeted protein degradation (TPD) is an emerging therapeutic strategy that would benefit from new chemical entities with which to recruit a wider variety of ubiquitin E3 ligases to target proteins for proteasomal degradation. Here we describe a TPD strategy involving the recruitment of FBXO22 to induce degradation of the histone methyltransferase and oncogene NSD2. UNC8732 facilitates FBXO22-mediated degradation of NSD2 in acute lymphoblastic leukemia cells harboring the NSD2 gain-of-function mutation p.E1099K, resulting in growth suppression, apoptosis and reversal of drug resistance. The primary amine of UNC8732 is metabolized to an aldehyde species, which engages C326 of FBXO22 to recruit the SCFFBXO22 Cullin complex. We further demonstrate that a previously reported alkyl amine-containing degrader targeting XIAP is similarly dependent on SCFFBXO22. Overall, we present a potent NSD2 degrader for the exploration of NSD2 disease phenotypes and a new FBXO22-recruitment strategy for TPD.

3.
Aquat Toxicol ; 273: 106999, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38875954

ABSTRACT

The coexistence of multiple emerging contaminants imposes a substantial burden on the ecophysiological functions in organisms. The combined toxicity and underlying mechanism requires in-depth understanding. Here, marine blue mussel (Mytilus galloprovincialis L.) was selected and exposed to 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and perfluorooctanoic acid (PFOA) individually and in combination at environmental related concentrations to elucidate differences in stress responses and potential toxicological mechanisms. Characterization and comparison of accumulation, biomarkers, histopathology, transcriptomics and metabolomics were performed. Co-exposure resulted in differential accumulation patterns, exacerbated histopathological alterations, and different responses in oxidative stress and biomarkers for xenobiotic transportation. Moreover, the identified differentially expressed genes (DEGs) and differential metabolites (DEMs) in mussels were found to be annotated to different metabolic pathways. Correlation analyses further indicated that DEGs and DEMs were significantly correlated with the above biomarkers. BDE-47 and PFOA altered the genes and metabolites related to amino acid metabolism, energy and purine metabolism, ABC transporters, and glutathione metabolism to varying degrees, subsequently inducing accumulation differences and combined toxicity. Furthermore, the present work highlighted the pivotal role of Nrf2-keap1 detoxification pathway in the acclimation of M. galloprovincialis to reactive oxygen species (ROS) stress induced by BDE-47 and PFOA. This study enabled more comprehensive understanding of combined toxic mechanism of multi emerging contaminants pollution.


Subject(s)
Biomarkers , Caprylates , Fluorocarbons , Halogenated Diphenyl Ethers , Water Pollutants, Chemical , Animals , Halogenated Diphenyl Ethers/toxicity , Water Pollutants, Chemical/toxicity , Fluorocarbons/toxicity , Caprylates/toxicity , Biomarkers/metabolism , Oxidative Stress/drug effects , Transcriptome/drug effects , Mytilus edulis/drug effects , Mytilus edulis/genetics
4.
J Chem Inf Model ; 64(13): 5344-5355, 2024 Jul 08.
Article in English | MEDLINE | ID: mdl-38916159

ABSTRACT

We herewith applied a priori a generic hit identification method (POEM) for difficult targets of known three-dimensional structure, relying on the simple knowledge of physicochemical and topological properties of a user-selected cavity. Searching for local similarity to a set of fragment-bound protein microenvironments of known structure, a point cloud registration algorithm is first applied to align known subpockets to the target cavity. The resulting alignment then permits us to directly pose the corresponding seed fragments in a target cavity space not typically amenable to classical docking approaches. Last, linking potentially connectable atoms by a deep generative linker enables full ligand enumeration. When applied to the WD40 repeat (WDR) central cavity of leucine-rich repeat kinase 2 (LRRK2), an unprecedented binding site, POEM was able to quickly propose 94 potential hits, five of which were subsequently confirmed to bind in vitro to LRRK2-WDR.


Subject(s)
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Molecular Docking Simulation , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/chemistry , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors , Binding Sites , Protein Domains , Humans , Ligands , Protein Binding , WD40 Repeats , Algorithms
5.
Mar Pollut Bull ; 203: 116427, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38735169

ABSTRACT

Perfluorooctanoic acid (PFOA), which widely presents in marine environment, may produce some adverse effects to aquatic organism. Mytilus edulis are popular due to their high protein and low fat content in China. However, few studies have investigated the effects of PFOA on the quality of aquatic products. Here, PFOA effects on basic nutritional indices in M. edulis were measured, and possible mechanisms were explored. PFOA caused clear variation in physiological and biochemical indices of M. edulis. The contents of some important proteins, nutrients, and amino acids etc. dropped. Integrating metabolomics data, we speculate PFOA exposure triggered inflammation and oxidative stress in mussels, interfered with the metabolic pathways related to the quality and the transport and absorption pathways of metal ions, and affected the levels of some important elements and metabolites, thus decreasing the nutritional quality of M. edulis. The study provides new insights into PFOA adverse effects to marine organism, and may offer some references for some researchers to assess food quality and ecological risk to pollutants.


Subject(s)
Caprylates , Fluorocarbons , Mytilus edulis , Water Pollutants, Chemical , Caprylates/toxicity , Fluorocarbons/toxicity , Animals , Mytilus edulis/drug effects , Water Pollutants, Chemical/toxicity , Nutritive Value , China , Oxidative Stress/drug effects
6.
Onco Targets Ther ; 17: 339-344, 2024.
Article in English | MEDLINE | ID: mdl-38644954

ABSTRACT

Gastric adenocarcinoma (GAS) is a rare subtype of mucinous adenocarcinoma characterized by gastric differentiation and is unrelated to human papillomavirus (HPV) infection. This report discusses a 40-year-old female who presented with abdominal distension accompanied by increased abdominal circumference. CT of the abdomen and pelvis showed a large 21.0*12.7*26.0 cm mass later diagnosed as GAS combined with squamous cell carcinoma on surgical pathology. Immunohistological staining of GAS was positive for CK7, MUC6, PAX-8 CEA, and P53 (wild type) and negative for CDX2, CK20, ER, PR, P16, and WT1. The proliferative index (Ki-67) was 20%. Immunohistochemical staining of squamous cell carcinoma was positive for P16 and P53 (wild type), and the proliferative index (Ki-67) was 90%. However, the pathogenesis and molecular mechanisms of GAS have not been fully elucidated. As more cases are identified and reported, additional targeted therapies can be developed and tested in these patients.

7.
J Med Chem ; 67(7): 5837-5853, 2024 Apr 11.
Article in English | MEDLINE | ID: mdl-38533580

ABSTRACT

The methyl-lysine reader protein SPIN1 plays important roles in various human diseases. However, targeting methyl-lysine reader proteins has been challenging. Very few cellularly active SPIN1 inhibitors have been developed. We previously reported that our G9a/GLP inhibitor UNC0638 weakly inhibited SPIN1. Here, we present our comprehensive structure-activity relationship study that led to the discovery of compound 11, a dual SPIN1 and G9a/GLP inhibitor, and compound 18 (MS8535), a SPIN1 selective inhibitor. We solved the cocrystal structure of SPIN1 in complex with 11, confirming that 11 occupied one of the three Tudor domains. Importantly, 18 displayed high selectivity for SPIN1 over 38 epigenetic targets, including G9a/GLP, and concentration dependently disrupted the interactions of SPIN1 and H3 in cells. Furthermore, 18 was bioavailable in mice. We also developed 19 (MS8535N), which was inactive against SPIN1, as a negative control of 18. Collectively, these compounds are useful chemical tools to study biological functions of SPIN1.


Subject(s)
Lysine , Tudor Domain , Humans , Animals , Mice , Structure-Activity Relationship
8.
Sci Total Environ ; 923: 171358, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38438024

ABSTRACT

Tetrabromobisphenol A (TBBPA) and Perfluorooctane sulfonate (PFOS) are emerging contaminants which coexist in marine environments, posing significant risks to ecosystems and human health. The behavior of these contaminants in the presence of dissolved organic matter (DOM), specifically the co-contamination of TBBPA and PFOS, is not well understood. The bioaccumulation, distribution, elimination, and toxic effects of TBBPA and PFOS on thick-shell mussels (Mytilus unguiculatus V.), with the absence and presence of humic acid (HA), a typical DOM, were studied. The results showed that the uptake of TBBPA decreased and the uptake of PFOS increased when exposed to 1 mg/L HA. However, at higher concentrations of HA (5 and 25 mg/L), the opposite effect was observed. Combined exposure to HA, TBBPA, and PFOS resulted in oxidative stress in the digestive gland, with the severity of stress dependent on exposure time and HA dose. Histological analysis revealed a positive correlation between HA concentration and tissue damage caused by TBBPA and PFOS. This study provides insights into the influence of HA on the bioaccumulation-elimination patterns and toxicity of TBBPA and PFOS in marine bivalves, offering valuable data for ecological and health risk assessments of combined pollutants in aquatic environments rich in DOM.


Subject(s)
Alkanesulfonic Acids , Fluorocarbons , Mytilus , Polybrominated Biphenyls , Water Pollutants, Chemical , Animals , Humans , Humic Substances , Ecosystem , Bioaccumulation , Polybrominated Biphenyls/toxicity , Water Pollutants, Chemical/toxicity
9.
J Appl Toxicol ; 44(7): 978-989, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38448046

ABSTRACT

Fuzi, an effective common herb, is often combined with Gancao to treat disease in clinical practice with enhancing its efficacy and alleviating its toxicity. The major toxic and bioactive compounds in Fuzi and Gancao are aconitine (AC) and glycyrrhizic acid (GL), respectively. This study aims to elucidate detoxification mechanism between AC and GL from pharmacokinetic perspective using physiologically based pharmacokinetic (PBPK) model. In vitro experiments exhibited that AC was mainly metabolized by CYP3A1/2 in rat liver microsomes and transported by P-glycoprotein (P-gp) in Caco-2 cells. Kinetics assays showed that the Km and Vmax of AC towards CYP3A1/2 were 2.38 µM and 57.3 pmol/min/mg, respectively, whereas that of AC towards P-gp was 11.26 µM and 147.1 pmol/min/mg, respectively. GL markedly induced the mRNA expressions of CYP3A1/2 and MDR1a/b in rat primary hepatocytes. In vivo studies suggested that the intragastric and intravenous administration of GL significantly reduced systemic exposure of AC by 27% and 33%, respectively. Drug-drug interaction (DDI) model of PBPK predicted that co-administration of GL would decrease the exposure of AC by 39% and 45% in intragastric and intravenous dosing group, respectively. The consistency between predicted data and observed data confirmed that the upregulation of CYP3A1/2 and P-gp was the crucial detoxification mechanism between AC and GL. Thus, this study provides a demonstration for elucidating the compatibility mechanisms of herbal formula using PBPK modeling and gives support for the clinical co-medication of Fuzi and Gancao.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1 , Aconitine , Cytochrome P-450 CYP3A , Glycyrrhizic Acid , Microsomes, Liver , Animals , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A/genetics , Aconitine/pharmacokinetics , Aconitine/analogs & derivatives , Aconitine/toxicity , Glycyrrhizic Acid/pharmacokinetics , Glycyrrhizic Acid/pharmacology , Humans , Caco-2 Cells , Male , Microsomes, Liver/metabolism , Microsomes, Liver/drug effects , Rats , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Rats, Sprague-Dawley , Models, Biological , Inactivation, Metabolic
10.
Article in English | MEDLINE | ID: mdl-38547701

ABSTRACT

Interindividual exposure differences have been identified in oral targeted antineoplastic drugs (OADs) owing to the pharmacogenetic background of the patients and their susceptibility to multiple factors, resulting in insufficient efficacy or adverse effects. Therapeutic drug monitoring (TDM) can prevent sub-optimal concentrations of OADs and improve their clinical treatment. This study aimed to develop and validate an LC-MS/MS method for the simultaneous quantification of 11 OADs (gefitinib, imatinib, lenvatinib, regorafenib, everolimus, osimertinib, sunitinib, tamoxifen, lapatinib, fruquintinib and sorafenib) and 2 active metabolites (N-desethyl sunitinib and Z-endoxifen) in human plasma. Protein precipitation was used to extract OADs from the plasma samples. Chromatographic separation was performed using an Eclipse XDB-C18 (4.6 × 150 mm, 5 µm) column with a gradient elution of the mobile phase composed of 2 mM ammonium acetate with 0.1 % formic acid in water (solvent A) and methanol (solvent B) at a flow rate of 0.8 mL/min. Mass analysis was performed using positive ion mode electrospray ionization in multiple-reaction monitoring mode. The developed method was validated following FDA bioanalytical guidelines. The calibration curves were linear over the range of 2-400 ng/mL for gefitinib, imatinib, lenvatinib, regorafenib, and everolimus; 1-200 ng/mL for osimertinib, sunitinib, N-desethyl sunitinib, tamoxifen, and Z-endoxifen; and 5-1000 ng/mL for lapatinib, fruquintinib, and sorafenib, with all coefficients of correlation above 0.99. The intra- and inter-day imprecision was below 12.81 %. This method was successfully applied to the routine TDM of gefitinib, lenvatinib, regorafenib, osimertinib, fruquintinib, and sorafenib to optimize the dosage regimens.


Subject(s)
Acrylamides , Aniline Compounds , Antineoplastic Agents , Indoles , Neoplasms , Phenylurea Compounds , Pyridines , Pyrimidines , Quinolines , Tamoxifen/analogs & derivatives , Humans , Sunitinib , Imatinib Mesylate , Sorafenib , Lapatinib , Chromatography, Liquid/methods , Drug Monitoring/methods , Liquid Chromatography-Mass Spectrometry , Gefitinib , Everolimus , Tandem Mass Spectrometry/methods , Antineoplastic Agents/therapeutic use , Tamoxifen/therapeutic use , Neoplasms/drug therapy , Solvents , Reproducibility of Results , Chromatography, High Pressure Liquid/methods
11.
J Ethnopharmacol ; 326: 117909, 2024 May 23.
Article in English | MEDLINE | ID: mdl-38350503

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Gancao Decoction (GCD) is widely used to treat cholestatic liver injury. However, it is unclear whether is related to prevent hepatocellular necroptosis. AIM OF THE STUDY: The purpose of this study is to clarify the therapeutic effects of GCD against hepatocellular necroptosis induced by cholestasis and its active components. MATERIALS AND METHODS: We induced cholestasis model in wild type mice by ligating the bile ducts or in Nlrp3-/- mice by intragastrical administering Alpha-naphthylisothiocyanate (ANIT). Serum biochemical indices, liver pathological changes and hepatic bile acids (BAs) were measured to evaluate GCD's hepatoprotective effects. Necroptosis was assessed by expression of hallmarkers in mice liver. Moreover, the potential anti-necroptotic effect of components from GCD were investigated and confirmed in ANIT-induced cholestasis mice and in primary hepatocytes from WT mouse stimulated with Tumor Necrosis Factor alpha (TNF-α) and cycloheximide (CHX). RESULTS: GCD dose-dependently alleviated hepatic necrosis, reduced serum aminotranferase activity in both BDL and ANIT-induced cholestasis models. More importantly, the expression of hallmarkers of necroptosis, including MLKL, RIPK1 and RIPK3 phosphorylation (p- MLKL, p-RIPK1, p-RIPK3) were reduced upon GCD treatment. Glycyrrhetinic acid (GA), the main bioactive metabolite of GCD, effectively protected against ANIT-induced cholestasis, with decreased expression of p-MLKL, p-RIPK1 and p-RIPK3. Meanwhile, the expression of Fas-associated death domain protein (FADD), long isoform of cellular FLICE-like inhibitory protein (cFLIPL) and cleaved caspase 8 were upregulated upon GA treatment. Moreover, GA significantly increased the expression of active caspase 8, and reduced that of p-MLKL in TNF-α/CHX induced hepatocytes necroptosis. CONCLUSIONS: GCD substantially inhibits necroptosis in cholestatic liver injury. GA is the main bioactive component responsible for the anti-necroptotic effects, which correlates with upregulation of c-FLIPL and active caspase 8.


Subject(s)
Cholestasis , Drugs, Chinese Herbal , Glycyrrhetinic Acid , Glycyrrhiza , Mice , Animals , Tumor Necrosis Factor-alpha/pharmacology , Caspase 8 , Necroptosis , Liver , Cholestasis/chemically induced , Cholestasis/drug therapy , Cholestasis/pathology , Glycyrrhetinic Acid/pharmacology , 1-Naphthylisothiocyanate/toxicity
12.
J Imaging Inform Med ; 37(3): 1023-1037, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38351222

ABSTRACT

Autism spectrum disorder (ASD) is a pervasive brain development disease. Recently, the incidence rate of ASD has increased year by year and posed a great threat to the lives and families of individuals with ASD. Therefore, the study of ASD has become very important. A suitable feature representation that preserves the data intrinsic information and also reduces data complexity is very vital to the performance of established models. Topological data analysis (TDA) is an emerging and powerful mathematical tool for characterizing shapes and describing intrinsic information in complex data. In TDA, persistence barcodes or diagrams are usually regarded as visual representations of topological features of data. In this paper, the Regional Homogeneity (ReHo) data of subjects obtained from Autism Brain Imaging Data Exchange (ABIDE) database were used to extract features by using TDA. The average accuracy of cross validation on ABIDE I database was 95.6% that was higher than any other existing methods (the highest accuracy among existing methods was 93.59%). The average accuracy for sampling with the same resolutions with the ABIDE I on the ABIDE II database was 96.5% that was also higher than any other existing methods (the highest accuracy among existing methods was 75.17%).


Subject(s)
Autism Spectrum Disorder , Humans , Autism Spectrum Disorder/diagnosis , Autism Spectrum Disorder/epidemiology , Magnetic Resonance Imaging , Databases, Factual , Brain/pathology , Brain/diagnostic imaging , Child , Algorithms
13.
Sci Rep ; 14(1): 4509, 2024 02 24.
Article in English | MEDLINE | ID: mdl-38402266

ABSTRACT

The 5'-mRNA-cap formation is a conserved process in protection of mRNA in eukaryotic cells, resulting in mRNA stability and efficient translation. In humans, two methyltransferases, RNA cap guanine-N7 methyltransferase (hRNMT) and cap-specific nucleoside-2'-O-methyltransferase 1 (hCMTr1) methylate the mRNA resulting in cap0 (N7mGpppN-RNA) and cap1 (N7mGpppN2'-Om-RNA) formation, respectively. Coronaviruses mimic this process by capping their RNA to evade human immune systems. The coronaviral nonstructural proteins, nsp14 and nsp10-nsp16, catalyze the same reactions as hRNMT and hCMTr1, respectively. These two viral enzymes are important targets for development of inhibitor-based antiviral therapeutics. However, assessing the selectivity of such inhibitors against human corresponding proteins is crucial. Human RNMTs have been implicated in proliferation of cancer cells and are also potential targets for development of anticancer therapeutics. Here, we report the development and optimization of a radiometric assay for hRNMT, full kinetic characterization of its activity, and optimization of the assay for high-throughput screening with a Z-factor of 0.79. This enables selectivity determination for a large number of hits from various screening of coronaviral methyltransferases, and also screening hRNMT for discovery of inhibitors and chemical probes that potentially could be used to further investigate the roles RNMTs play in cancers.


Subject(s)
Coronavirus Infections , Coronavirus , Humans , Coronavirus/genetics , Guanine/metabolism , Methyltransferases/metabolism , RNA Caps/metabolism , RNA, Messenger/genetics , RNA, Viral/genetics , Viral Nonstructural Proteins/genetics
14.
Sci Total Environ ; 916: 170341, 2024 Mar 15.
Article in English | MEDLINE | ID: mdl-38272093

ABSTRACT

Perfluorooctanoic acid (PFOA) is a toxic pollutant that bioaccumulates and is a significant public health concern due to its ubiquitous and persistent occurrence in global environments. Few studies have evaluated the adverse effects of PFOA on immune system, and this is particularly true for mollusks. Here, the PFOA-associated effects on immune system were evaluated in Ruditapes philippinarum using integrated analysis of metabolomes, microbiomes, and transcriptomes, providing evidence for possible mechanisms related to immunotoxicity. PFOA exposure caused clear variation in several important metabolites related to immune regulatory function within the haemolyph from R. philippinarum, while also altering key metabolic pathways, including those of lipids, unsaturated fatty acids (UFAs), and bile acids (BAs). After exposure to PFOAs, intestinal bacterial communities also clearly changed, with the predominant microflora becoming Mycoplasma and Bacteroidetes that are related to intestinal inflammation. Molecular analyses provided consistent results, wherein the expression of immune-related genes was significantly altered. Integration of the multi-'omics' analyses suggested that the TLR/MyD88/NF-kB pathway, along with PI3K-Akt-mTOR pathway, PPAR-mediated lipid metabolism and the autophagy signaling pathway, likely play important roles in initiating immunotoxic effects in R. philippinarum after PFOA exposure. These results provide further evidence that PFOA exposure can lead to immunologic dysfunction and also provide new insights into the mechanisms of PFAS alteration of bivalve immune function.


Subject(s)
Bivalvia , Fluorocarbons , Gastrointestinal Microbiome , Animals , Phosphatidylinositol 3-Kinases , Fluorocarbons/toxicity , Caprylates/toxicity
15.
Matern Child Nutr ; 20(1): e13557, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37583118

ABSTRACT

Limited studies have been conducted on Chinese women's willingness to donate milk following perinatal loss. In this study, we explore the relationship among childbirth trauma, willingness to donate milk, and resilience in women following perinatal loss, and the mediating effect of resilience between childbirth trauma and willingness to donate milk. A cross-sectional study was carried out throughout 4 months. We used convenience sampling methods and recruited 241 women following a perinatal loss from eight tertiary hospitals in Sichuan Province, China. Participants completed four questionnaires during a face-to-face individual interview: the general information questionnaire, the Willingness to Donate Milk Scale (WMDS), the City Birth Trauma Scale, and the Brief Resilience Scale. SPSS 20.0 was used to analyze the collected data. In our study, childbirth trauma was negatively correlated with the total and each dimension score of WMDS (p < 0.001). Resilience was positively correlated with the total and each dimension score of WMDS (p < 0.001). Resilience partially mediated the relationship between childbirth-related symptoms and willingness to donate milk (ß = -0.38, 95% confidence interval [CI]: -0.50 to -0.26), which accounted for 69.03% of the total effect. Resilience partially mediated the relationship between general symptoms and willingness to donate milk (ß = -0.31, 95% CI: -0.40 to -0.21), which accounted for 66.89% of the total effect. Resilience partially mediated the relationship between childbirth trauma and willingness to donate milk in women following perinatal loss. Our findings suggest that resilience can play a significant role in mediating the relationship between childbirth trauma and willingness to donate milk in women following perinatal loss. These results could help healthcare professionals design interventions for physical and mental recovery after perinatal loss.


Subject(s)
Milk, Human , Resilience, Psychological , Female , Humans , Pregnancy , Cross-Sectional Studies , Delivery, Obstetric , Surveys and Questionnaires , East Asian People , Fetal Death
16.
Nat Methods ; 21(4): 680-691, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38036855

ABSTRACT

Dopamine (DA) plays multiple roles in a wide range of physiological and pathological processes via a large network of dopaminergic projections. To dissect the spatiotemporal dynamics of DA release in both dense and sparsely innervated brain regions, we developed a series of green and red fluorescent G-protein-coupled receptor activation-based DA (GRABDA) sensors using a variety of DA receptor subtypes. These sensors have high sensitivity, selectivity and signal-to-noise ratio with subsecond response kinetics and the ability to detect a wide range of DA concentrations. We then used these sensors in mice to measure both optogenetically evoked and behaviorally relevant DA release while measuring neurochemical signaling in the nucleus accumbens, amygdala and cortex. Using these sensors, we also detected spatially resolved heterogeneous cortical DA release in mice performing various behaviors. These next-generation GRABDA sensors provide a robust set of tools for imaging dopaminergic activity under a variety of physiological and pathological conditions.


Subject(s)
Dopamine , Nucleus Accumbens , Mice , Animals , Nucleus Accumbens/physiology , Receptors, Dopamine , Brain , Receptors, G-Protein-Coupled
17.
bioRxiv ; 2024 Jan 13.
Article in English | MEDLINE | ID: mdl-37873443

ABSTRACT

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has led to significant global morbidity and mortality. A crucial viral protein, the non-structural protein 14 (nsp14), catalyzes the methylation of viral RNA and plays a critical role in viral genome replication and transcription. Due to the low mutation rate in the nsp region among various SARS-CoV-2 variants, nsp14 has emerged as a promising therapeutic target. However, discovering potential inhibitors remains a challenge. In this work, we introduce a computational pipeline for the rapid and efficient identification of potential nsp14 inhibitors by leveraging virtual screening and the NCI open compound collection, which contains 250,000 freely available molecules for researchers worldwide. The introduced pipeline provides a cost-effective and efficient approach for early-stage drug discovery by allowing researchers to evaluate promising molecules without incurring synthesis expenses. Our pipeline successfully identified seven promising candidates after experimentally validating only 40 compounds. Notably, we discovered NSC620333, a compound that exhibits a strong binding affinity to nsp14 with a dissociation constant of 427 ± 84 nM. In addition, we gained new insights into the structure and function of this protein through molecular dynamics simulations. We identified new conformational states of the protein and determined that residues Phe367, Tyr368, and Gln354 within the binding pocket serve as stabilizing residues for novel ligand interactions. We also found that metal coordination complexes are crucial for the overall function of the binding pocket. Lastly, we present the solved crystal structure of the nsp14-MTase complexed with SS148 (PDB:8BWU), a potent inhibitor of methyltransferase activity at the nanomolar level (IC50 value of 70 ± 6 nM). Our computational pipeline accurately predicted the binding pose of SS148, demonstrating its effectiveness and potential in accelerating drug discovery efforts against SARS-CoV-2 and other emerging viruses.

18.
Exp Hematol ; 130: 104135, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38072134

ABSTRACT

Epigenetic regulators, such as the polycomb repressive complex 2 (PRC2), play a critical role in both normal development and carcinogenesis. Mutations and functional dysregulation of PRC2 complex components, such as EZH2, are implicated in various forms of cancer and associated with poor prognosis. This study investigated the epigenetic vulnerabilities of acute myeloid leukemia (AML) and myelodysplastic/myeloproliferative disorders (MDS/MPN) by performing a chemical probe screen in patient cells. Paradoxically, we observed increased sensitivity to EZH2 and embryonic ectoderm development (EED) inhibitors in AML and MDS/MPN patient cells harboring EZH2 mutations. Expression analysis indicated that EZH2 inhibition elicited upregulation of pathways responsible for cell death and growth arrest, specifically in patient cells with mutant EZH2. The identified EZH2 mutations had drastically reduced catalytic activity, resulting in lower cellular H3K27me3 levels, and were associated with decreased EZH2 and PRC2 component EED protein levels. Overall, this study provides an important understanding of the role of EZH2 dysregulation in blood cancers and may indicate disease etiology for these poor prognosis AML and MDS/MPN cases.


Subject(s)
Enhancer of Zeste Homolog 2 Protein , Leukemia, Myeloid, Acute , Humans , Enhancer of Zeste Homolog 2 Protein/genetics , Enhancer of Zeste Homolog 2 Protein/metabolism , Polycomb Repressive Complex 2/genetics , Polycomb Repressive Complex 2/metabolism , Leukemia, Myeloid, Acute/genetics , Epigenesis, Genetic , Mutation
19.
ACS Med Chem Lett ; 14(12): 1746-1753, 2023 Dec 14.
Article in English | MEDLINE | ID: mdl-38116405

ABSTRACT

The transcription factor YAP-TEAD is the downstream effector of the Hippo pathway which controls cell proliferation, apoptosis, tissue repair, and organ growth. Dysregulation of the Hippo pathway has been correlated with carcinogenic processes. A co-crystal structure of TEAD with its endogenous ligand palmitic acid (PA) as well as with flufenamic acid (FA) has been disclosed. Here we report the development of HC-258, which derives from FA and possesses an oxopentyl chain that mimics a molecule of PA as well as an acrylamide that reacts covalently with TEAD's cysteine. HC-258 reduces the CTGF, CYR61, AXL, and NF2 transcript levels and inhibits the migration of MDA-MB-231 breast cancer cells. Co-crystallization with hTEAD2 confirmed that HC-258 binds within TEAD's PA pocket, where it forms a covalent bond with its cysteine.

20.
Commun Biol ; 6(1): 1272, 2023 12 16.
Article in English | MEDLINE | ID: mdl-38104184

ABSTRACT

Cbl-b is a RING-type E3 ubiquitin ligase that is expressed in several immune cell lineages, where it negatively regulates the activity of immune cells. Cbl-b has specifically been identified as an attractive target for cancer immunotherapy due to its role in promoting an immunosuppressive tumor environment. A Cbl-b inhibitor, Nx-1607, is currently in phase I clinical trials for advanced solid tumor malignancies. Using a suite of biophysical and cellular assays, we confirm potent binding of C7683 (an analogue of Nx-1607) to the full-length Cbl-b and its N-terminal fragment containing the TKBD-LHR-RING domains. To further elucidate its mechanism of inhibition, we determined the co-crystal structure of Cbl-b with C7683, revealing the compound's interaction with both the TKBD and LHR, but not the RING domain. Here, we provide structural insights into a novel mechanism of Cbl-b inhibition by a small-molecule inhibitor that locks the protein in an inactive conformation by acting as an intramolecular glue.


Subject(s)
Neoplasms , Ubiquitin-Protein Ligases , Humans , Ubiquitin-Protein Ligases/chemistry , Protein Binding , Molecular Conformation , Phosphorylation
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