Small Molecular Compounds Research Articles

Activated aggregation strategies to construct size-increasing nanoparticles for cancer therapy.

The development of novel therapeutic strategies and modalities for tumors is still one of the important areas of current scientific research. Low permeability and short residence time of drugs in solid tumor areas are important reasons for the low efficiency of existing therapeutic strategies. Typically, nanoparticles with large size displayed enhanced residence time but low permeability. Therefore, to prolong the retention time of materials in solid tumors, size-increasing strategies have been developed to directly generate large-scale nanoparticles using small molecular compounds or increase the size of small nanoparticles in solid tumor areas. In this review, we summarize recently reported activatable aggregation systems that could be activated by cancer-related substances for cancer therapy and classify them by the mechanisms that lead to aggregation. In the end, we propose some potential challenges briefly from the view of our opinion. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Enantiomeric Hydrogen-bonded Chains Driving Ferroelectric and Nonlinear Optical Behavior

Organic multiferroic materials have been widely investigated due to their novel physical properties and broad applications. However, the discovery of organic small-molecular multiferroic compounds is still rare. Herein, based on the chemical design strategy of introducing homochirality, we present a pair of enantiomeric organic small-molecular compounds [HDABCO (1,4-diazabicyclo[2.2.2]octonium)][l- and d-MA (malic acid)], which displays high Curie temperatures (Tc) of 409/412 K, superior optoelectronic performance, and unique ferroelectric and ferroelastic nature. In comparison with the reported ferroelectrics with the [HDABCO]+ cation chain structure, the enantiomers show a neutral one-dimensional chain, where hydrogen bonds connect [HDABCO]+ cations and [MA]− anions. Strikingly, [HDABCO][l- and d-MA] exhibit a large second harmonic generation (SHG) intensity of about 2.46 and 2.53 times that of KH2PO4 (KDP), exceeding those of all the organic ferroelectrics (about 0.2–1 × KDP). With excellent SHG signal and ferroic properties, as well as the merit of low acoustic impedance z0 matching that of the body and easy processing, [HDABCO][l- and d-MA] are potential candidates for future biocompatible electronic devices with multi-functionality.

Non-target metabolomics reveals the changes of small molecular substances in duck breast meat under different preservation time

Poultry products are an essential animal source of protein for humans. Many factors could destroy the balance of the poultry production chain and cause an overstock of products, which need to be stored in the frozen storage warehouse for a long time. The long-term frozen storage may affect the quality of meat products. In this study, the changes of small molecular substances were revealed in duck meat during long-term storage using non-targeted metabolomics. The results showed that compared with fresh meat, even if the meat is stored under frozen storage conditions, the number of differential metabolites of frozen storage meat continues to increase with the prolongation of storage time, indicating that the meat composition has changed significantly with the storage time increased. With the increase in storage time, the nitrogen-containing small molecular compounds in duck meat increased (carnosine and anserine, aspartic acid, and tyrosine, 1H-indole-3-acetamide, 2-Hydroxyphenethylamine, 2-Naphylamine, allocystathionine, and O-phosphoethanolamine), the nucleotides decomposition process strengthened (IMP and AMP, GMP and UMP), and the content of organic acid increased (5-hydroxy indole acetic acid, 5-hydroxypentanoic acid and phenylacetate, taurine) and carbohydrate (1-O-sinapoyl-beta-d-glucose, 4-O-beta-d-glucopyranosyl-d-mannose, and alpha-d-glucose). These small molecular substances can be used as biomarkers to detect long-term stored duck meat deterioration. KEGG enrichment analysis showed that protein catabolism, nucleotide catabolism, fat decomposition and oxidation, and carbohydrate decomposition were the main metabolic processes of meat deterioration during the long-term storage of duck meat. In addition, Non-target metabolome technology is a powerful tool to reveal the meat deterioration process during long-term storage systematically. This study provided a reference for optimizing domestic poultry meat storage methods and ensuring food safety.

Inhibition of beta-catenin shows therapeutic potential in head and neck squamous cell carcinoma in vitro

Beta-catenin is known to be a vital component of the canonical Wnt signaling cascade, involved in the carcinogenesis of different solid tumors. We aimed to evaluate the effects of Beta-catenin inhibition in head and neck squamous cell carcinoma (HNSCC) in vitro. The small molecular compound MSAB was used to inhibit Wnt/Beta-catenin signaling in a human papillomavirus (HPV)-positive and HPV-negative cell line and its effects on cell proliferation, migration, colony formation, apoptosis, as well as radiosensitizing properties were assessed. Significant antineoplastic effects were observed in both cell lines. Interestingly, stronger anti-neoplastic and radiosensitizing effects were observed in the HPV-negative cell line, whereas stronger anti-migratory potential was detected in HPV-positive HNSCC cells. In conclusion, our findings suggest MSAB as a potential therapeutic agent for HNSCC. Further studies are warranted to unravel the mechanistic background of our findings.

Detailed mechanisms of amoxicillin decomposition in supercritical water by ReaxFF reactive molecular dynamics simulation

The abuse of antibiotics in China has aroused widespread concern, and the resistance genes of antibiotics in the natural environment seriously threaten human health. The supercritical water gasification (SCWG) technology is a clean and efficient technology for the treatment of antibiotic wastewater. In this paper, amoxicillin is selected as the representative antibiotic in wastewater, and the detailed mechanisms of amoxicillin decomposition in supercritical water (SCW) are studied by ReaxFF reactive molecular dynamics (MD) simulation. The results show that the decomposition process of amoxicillin in SCW includes carbon ring opening, carbon chain breaking and small molecular compounds conversion. The molecular vibration leads to the breaking of CN and CS bonds. The OH radical is vital to the ring opening of benzene ring and the breaking of carbon chain. However, the yield of NO increases with increasing OH radical concentrations. The ReacNetGenerator tool is used for the first time to analyze the migration path of nitrogen and sulfur in the SCWG system. It shows that H2 has a great effect on the transformation of sulfur, and OH radicals dominate the transformation of nitrogen. Decreasing the reaction time and the concentration of OH radicals result in inhibiting the NO production. This study will provide a theoretical guidance for understanding SCWG process of antibiotic-containing wastewater.

Integrated bioinformatics analysis uncovers characteristic genes and molecular subtyping system for endometriosis.

Objective: Endometriosis is a chronic inflammatory estrogen-dependent disease with the growth of endometrial tissues outside the uterine cavity. Nevertheless, the etiology of endometriosis is still unclear. Integrated bioinformatics analysis was implemented to reveal the molecular mechanisms underlying this disease. Methods: A total of four gene expression datasets (GSE7305, GSE11691, GSE23339, and GSE25628) were retrieved from the GEO, which were merged into a meta-dataset, followed by the removal of batch effects via the sva package. Weighted gene co-expression network analysis (WGCNA) was implemented, and endometriosis-related genes were screened under normal and endometriosis conditions. Thereafter, characteristic genes were determined via Lasso analysis. The diagnostic performance was estimated via receiver operating characteristic curves, and epigenetic and post-transcriptional modifications were analyzed. Small molecular compounds were predicted. Unsupervised clustering analysis was conducted via non-negative matrix factorization algorithm. The enriched pathways were analyzed via gene set enrichment analysis or GSVA. Immune features were evaluated according to immune-checkpoints, HLA, receptors, chemokines, and immune cells. Results: In total, four characteristic genes (BGN, AQP1, ELMO1, and DDR2) were determined for endometriosis, all of which exhibited the favorable efficacy in diagnosing endometriosis. Their aberrant levels were modulated by epigenetic and post-transcriptional modifications. In total, 51 potential drugs were predicted against endometriosis. The characteristic genes exhibited remarkable associations with immunological function. Three subtypes were classified across endometriosis, with different mechanisms and immune features. Conclusion: Our study reveals the characteristic genes and novel molecular subtyping of endometriosis, contributing to the early diagnosis and intervention in endometriosis.

Aging-based molecular classification and score system in ccRCC uncovers distinct prognosis, tumor immunogenicity, and treatment sensitivity.

ObjectiveAging is a complex biological process and a major risk factor for cancer development. This study was conducted to develop a novel aging-based molecular classification and score system in clear cell renal cell carcinoma (ccRCC).MethodsIntegrative analysis of aging-associated genes was performed among ccRCC patients in the TCGA and E-MTAB-1980 cohorts. In accordance with the transcriptional expression matrix of 173 prognostic aging-associated genes, aging phenotypes were clustered with the consensus clustering approach. The agingScore was generated to quantify aging phenotypes with principal component analysis. Tumor-infiltrating immune cells and the cancer immunity cycle were quantified with the ssGSEA approach. Immunotherapy response was estimated through the TIDE algorithm, and a series of tumor immunogenicity indicators were computed. Drug sensitivity analysis was separately conducted based on the GDSC, CTRP, and PRISM analyses.ResultsThree aging phenotypes were established for ccRCC, with diverse prognosis, clinical features, immune cell infiltration, tumor immunogenicity, immunotherapeutic response, and sensitivity to targeted drugs. The agingScore was developed, which enabled to reliably and independently predict ccRCC prognosis. Low agingScore patients presented more undesirable survival outcomes. Several small molecular compounds and three therapeutic targets, namely, CYP11A1, SAA1, and GRIK4, were determined for the low agingScore patients. Additionally, the high agingScore patients were more likely to respond to immunotherapy.ConclusionOverall, our findings introduced an aging-based molecular classification and agingScore system into the risk stratification and treatment decision-making in ccRCC.

Comparison of different small molecular weight alcohols for sustaining sulfidogenic bioreactors maintained at moderately low pH.

Sulfate-reducing bacteria (SRB) catalyse the dissimilatory reduction of sulfate to hydrogen sulfide using a wide range of small molecular weight organic compounds, and hydrogen, as electron donors. Here we report the effects of different combinations of small molecular weight alcohols on the performance and bacterial composition of a moderately low pH sulfidogenic bioreactor (pH 4.0–5.5) operated at 35°C in continuous flow mode. Ethanol alone and methanol or ethanol used in combination with glycerol were evaluated based on their equivalent amounts of carbon. Although evidenced that methanol was utilised as electron donor to fuel sulfidogenesis at pH 5.5, rates of sulfate reduction/sulfide production were negatively impacted when this alcohol was first introduced to the system, though these rates increased in subsequent phases as a result of adaptation of the microbial community. Further increased dosage of methanol again caused rates of sulfidogenesis to decrease. Methanol addition resulted in perturbations of the bioreactor microbial community, and species not previously detected were present in relatively large abundance, including the sulfate-reducer Desulfovibrio desulfuricans. Ethanol utilization was evidenced by the increase in rates of sulfidogenesis as the dosage of ethanol increased, with rates being highest when the bioreactor was fed with ethanol alone. Concentrations of acetate in the effluent liquor also increased (up to 8 mM) as a result of incomplete oxidation of ethanol. This alcohol continued to be used as the electron donor for sulfate reduction when the bioreactor pH was decreased incrementally (to pH 4.0), but rates of sulfidogenesis decreased. The relative abundance of Dv. desulfuricans diminished as the bioreactor pH was lowered, while that of the acidophilic Firmicute Desulfosporosinus acididurans increased. This study has shown that all three alcohols can be used to fuel microbial sulfidogenesis in moderately acidic liquors, though the cost-effectiveness, availability and toxicity to the microbial community will dictate the choice of substrate.

Identification of biomarkers, pathways and potential therapeutic agents for salt-sensitive hypertension using RNA-seq.

BackgroundSalt-sensitive hypertension (SSH) is a common type of essential hypertension in China. In recent years, although an increasing number of researches have focused on SSH, few studies have been researched on patients with SSH. The objective of this study was to explore the genes and pathways linked with SSH using RNA-sequencing (RNA-seq).Materials and methodsWe used RNA-seq to analyze the transcriptome of peripheral blood mononuclear cells (PBMCs) of five SSH patients and five SRH patients. Next, we analyzed the differentially expressed genes (DEGs) using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and Gene Set Enrichment (GSEA) enrichment analysis. Then, Cytoscape was used to construct the protein-protein interaction (PPI) network and the hub genes. Finally, CMAP analysis found that several small molecular compounds could reverse the altered DEGs.ResultsA total of 431 DEGs were found in the PBMC samples, including 294 up-regulated and 137 down-regulated genes. Functional enrichment analysis found significant enrichment in immune-related associations such as inflammation, chemokine, and cytokine-cytokine receptor interaction. The hub genes of the two modules were IL-6, IL-1A, CCL2, CCL3L3, and BUB1. In addition, we identified two small molecular compounds (iopromide and iloprost) that potentially interacted with DEGs.ConclusionThis study suggests some potential biomarkers for the diagnosis of SSH. It provides new insights into SSH diagnosis and possible future clinical treatment.

Regulation of Embryonic Stem Cell Self-Renewal.

Embryonic stem cells (ESCs) are a type of cells capable of self-renewal and multi-directional differentiation. The self-renewal of ESCs is regulated by factors including signaling pathway proteins, transcription factors, epigenetic regulators, cytokines, and small molecular compounds. Similarly, non-coding RNAs, small RNAs, and microRNAs (miRNAs) also play an important role in the process. Functionally, the core transcription factors interact with helper transcription factors to activate the expression of genes that contribute to maintaining pluripotency, while suppressing the expression of differentiation-related genes. Additionally, cytokines such as leukemia suppressor factor (LIF) stimulate downstream signaling pathways and promote self-renewal of ESCs. Particularly, LIF binds to its receptor (LIFR/gp130) to trigger the downstream Jak-Stat3 signaling pathway. BMP4 activates the downstream pathway and acts in combination with Jak-Stat3 to promote pluripotency of ESCs in the absence of serum. In addition, activation of the Wnt-FDZ signaling pathway has been observed to facilitate the self-renewal of ESCs. Small molecule modulator proteins of the pathway mentioned above are widely used in in vitro culture of stem cells. Multiple epigenetic regulators are involved in the maintenance of ESCs self-renewal, making the epigenetic status of ESCs a crucial factor in this process. Similarly, non-coding RNAs and cellular energetics have been described to promote the maintenance of the ESC’s self-renewal. These factors regulate the self-renewal and differentiation of ESCs by forming signaling networks. This review focused on the role of major transcription factors, signaling pathways, small molecular compounds, epigenetic regulators, non-coding RNAs, and cellular energetics in ESC’s self-renewal.

Fabrication and characterization of Ti/polyaniline-Co/PbO2–Co for efficient electrochemical degradation of cephalexin in secondary effluents

The traditional interlayer of PbO2 electrode possessed many problems, such as short service lifetime and limited specific surface area. Herein, a novel and efficient Ti/polyaniline-Co/PbO2–Co electrode was conctructed employing cyclic voltammetry to introduce a Co-doped polyaniline interlayer and anodic electrodeposition to synthetize a β-PbO2-Co active layer. Compared with pristine PbO2 electrode, Ti/polyaniline-Co/PbO2–Co exhibited more compact crystalline shape and higher active sites amounts. Pratically, the electrochemical degradation of 5 mg L−1 cephalexin in real secondary effluents was effectively achieved by the novel anode with 87.42% cephalexin removal and 71.8% COD mineralization after 120 min of 15 mA cm−2 electrolysis. The hydroxyl radical production and electrochemical stability were increased by 3.16 and 3.27 times respectively. The cephalexin degradation pathway was investigated by combining a density functional theory-based theoretical approach and LC-QTrap-MS/MS. The most likely cleavage point of the β-lactam ring was the O=C–N bond, whose attack would produce small molecular compounds containing the thiazole and 4, 6-thiazine rings. Further oxidation produced inorganic ions; quantitative investigations indicated the amino groups to undergo decomposition to form aqueous NH4+, which was further oxidized to NO3−. The accumulation of NO3− and SO42−, combined with a decrease in toxicity toward Escherichia coli, demonstrated the efficient mineralization of cephalexin on the Ti/polyaniline-Co/PbO2–Co electrode.

Comprehensive Analysis of the Aberrance and Functional Significance of Ferroptosis in Gastric Cancer.

Objective: Ferroptosis is a type of iron-dependent necrosis related to cancer. Nevertheless, the features of ferroptosis in gastric cancer (GC) remain poorly understood. This study conducted a systematic analysis of ferroptosis regulators in GC. Methods: We gathered five GC cohorts, namely, TCGA-STAD, GSE84437, GSE62254, GSE26901, and GSE15459. Unsupervised clustering analysis was adopted to cluster GC patients into different ferroptosis subtypes based on ferroptosis regulators. Immune cell infiltration and hallmark pathway activity were estimated via ssGSEA. The ferroptosis index was developed with the PCA computational method. Response to chemotherapy agents and small molecular compounds was inferred via GDSC, CTRP, and PRISM projects. Two anti-PD-1 therapy cohorts were gathered and the potential of FPI in predicting immune response was assessed. Results: Expression profiles, genetic mutations, DNA methylation, prognostic implications, and drug sensitivity of ferroptosis regulators were characterized in GC. Three ferroptosis subtypes were clustered with distinct prognosis, hallmark pathway activity, and tumor-infiltrating immune cells. Ferroptosis levels were quantified based on the expression of prognostic ferroptosis-related signatures. The significant relationships between FPI and clinicopathological characteristics were observed. Furthermore, high FPI was in relation to poor prognosis, inflamed tumor microenvironment (TME) as well as high sensitivity to chemotherapy agents (docetaxel and cisplatin), and CTRP- and PRISM-derived compounds. Also, FPI acted as a promising predictor of immune response. Conclusion: Collectively, our findings identified a novel ferroptosis-based subtype classification of GC, and revealed the potential of ferroptosis in forming TME diversity and complexity, and guiding individualized treatment.

Comprehensive Network-Based Analyses Reveal Novel Renal Function-Related Targets in Acute Kidney Injury.

Background: Acute kidney injury (AKI) is a common clinical syndrome with limited methods of treatment and diagnosis. Although several molecules associated with AKI have been discovered, molecular mechanisms underlying AKI still remain unclear. Weighted gene co-expression network analysis (WGCNA) is a novel method to uncover the relationship between co-expression genes and clinical traits at the system level. Methods: First, by employing WGCNA in transcriptional data on 30 patients with well/poor functioning kidney graft, we identified two co-expression modules that were significantly related to serum creatinine (SCr). Second, based on the modules, potential small molecular compound candidates for developing targeted therapeutics were obtained by connectivity map analysis. Furthermore, multiple validations of expression in space/time were carried out with two classical AKI models in vivo and other five databases of over 152 samples. Results: Two of the 14 modules were found to be closely correlated with SCr. Function enrichment analysis illustrated that one module was enriched in the immune system, while the other was in the metabolic process. Six key renal function-related genes (RFRGs) were finally obtained. Such genes performed well in cisplatin-induced or cecal ligation and puncture-induced AKI mouse models. Conclusion: The analysis suggests that WGCNA is a proper method to connect clinical traits with genome data to find novel targets in AKI. The kidney tissue with worse renal function tended to develop a “high immune but low metabolic activity” expression pattern. Also, ACSM2A, GLYAT, CORO1A, DPEP1, ALDH7A1, and EPHX2 are potential targets of molecular diagnosis and treatment in AKI.

Urolithins and intestinal health.

There are trillions of microorganisms in the human intestine. They can react to the intestinal microenvironment by metabolizing food or producing small molecular compounds to affect the host's digestive ability and resist the risk of infection and autoimmune diseases. Many studies have revealed that intestinal flora and its metabolites play an important role in human physiology and the development of diseases. Urolithins are kind of intestinal microbiota metabolites of ellagitannins (ETs) and ellagic acid (EA) with potent biological activity in vivo. However, different individuals have different intestinal flora. According to the different metabolites from ETs and EA, it is divided into three metabo-types including UM-A, UM-B and UM-0. This paper reviews the origin of urolithins, the urolithin producing microorganisms and the effects of urolithins on regulating intestinal diseases. This review will provide a theoretical basis for the regulation of urolithins in the homeostasis of intestinal flora and a reference for the scientific utilization of urolithins and foods rich in ETs and EA.

Chemical Structure and Immune Activation of a Glucan From Rhizoma Acori Tatarinowii

Rhizoma Acori Tatarinowii is a traditional Chinese herb used to treat depression and coronary heart disease. Studies on its active components mainly focus on small molecular compounds such as asarone and other essential oil components, while the large molecular active components such as polysaccharides are ignored. In this study, we aimed to study the chemical structure and immune activation of polysaccharides from Rhizoma Acori Tatarinowii. In this study, a polysaccharide (RATAPW) was isolated and purified by DEAE-52 cellulose and Sephadex G-100 column chromatography from alkali extraction polysaccharide of Rhizoma Acori Tatarinowii. The average molecular weight of RATAPW was 2.51 × 104 Da, and the total carbohydrate contents of RATAPW were 98.23 ± 0.29%. The monosaccharide composition, methylation, and nuclear magnetic resonance (NMR) analysis results displayed that the polysaccharide was α-1,4-glucan with short α-1,6 branches. Immunofluorescence assay and inhibitor neutralization assay indicated that RATAPW could promote the TNF-α production of RAW264.7 macrophage through the nuclear factor kappa B (NF-κB) molecular signaling pathway. Treatment with 200 μg/ml of RATAPW enhanced a 38.77% rise in the proliferation rate of spleen lymphocytes. RATAPW also enhances ConA-induced T cells and lipopolysaccharide (LPS)-induced B cell proliferation in a dose-dependent effect. Our study lays a foundation for the discovery of natural polysaccharide immune modulators or functional food from Rhizoma Acori Tatarinowii.

Enhanced pyrolysis of lignocellulosic biomass by room-temperature dilute sulfuric acid pretreatment

In the present work, the effects of dilute sulfuric acid (0.2 wt%) pretreatment at room temperature (30 °C) on the pyrolytic behaviors of pubescens, rice straw, willow, and cypress were studied. For herbaceous biomass, the degradation temperatures (Ta) of cellulose increased by around 20 °C, and the yields of bio-char in slow pyrolysis decreased by around 4 % after the pretreatment. For the pretreated softwood biomass, a decreased Ta and an increased yield of bio-char were found for willow, while little variation for cypress was detected. Regarding the typical small molecular products in the bio-oil after the pretreatment, levoglucosan (LGA) was only found in those of the pretreated pubescens (14.3 %, 400 °C) and cypress (4.5 %, 400 °C; 9.3 %, 500 °C), whereas levoglucosenone (LGO) was only found in that of the pretreated willow (9.7 %, 400 °C; 10.5 %, 500 °C). Increased yield of the small lignin-derived compounds was found for rice straw (from 7.9 % to 14.5 %), while decreased yields were found for willow and cypress. For the oligomeric part in bio-oil, significantly promoted production of holocellulose-derived oligomers was found with slightly increased proportions of heavy oligomers (>1300 Da). Meanwhile, the production of lignin-derived oligomers was apparently promoted as well, especially for rice straw. In the 500 °C pyrolysis of the two woody biomass samples, in addition to more complete degradation (higher yields of bio-oil and small-molecular compounds, and lower yield of bio-char), it was also found that the proportion of the oligomers in 256–500 Da increased significantly, and more holocellulose-derived oligomers were found. It was, therefore, speculated that a higher pyrolysis temperature would mainly promote the pyrolysis of cellulose and hemicellulose.

Generating and screening de novo compounds against given targets using ultrafast deep learning models as core components.

Deep learning is an artificial intelligence technique in which models express geometric transformations over multiple levels. This method has shown great promise in various fields, including drug development. The availability of public structure databases prompted the researchers to use generative artificial intelligence models to narrow down their search of the chemical space, a novel approach to chemogenomics and de novo drug development. In this study, we developed a strategy that combined an accelerated LSTM_Chem (long short-term memory for de novo compounds generation), dense fully convolutional neural network (DFCNN), and docking to generate a large number of de novo small molecular chemical compounds for given targets. To demonstrate its efficacy and applicability, six important targets that account for various human disorders were used as test examples. Moreover, using the M protease as a proof-of-concept example, we find that iteratively training with previously selected candidates can significantly increase the chance of obtaining novel compounds with higher and higher predicted binding affinities. In addition, we also check the potential benefit of obtaining reliable final de novo compounds with the help of MD simulation and metadynamics simulation. The generation of de novo compounds and the discovery of binders against various targets proposed here would be a practical and effective approach. Assessing the efficacy of these top de novo compounds with biochemical studies is promising to promote related drug development.

Bis-chalcone polyphenols with potential preventive and therapeutic effects on PD: Design, synthesis and in vitro disaggregation activity against α-synuclein oligomers and fibrils

α-Syn fibrils, which are neurotoxic, play a key role in the development of PD. Maintaining α-Syn proteostasis by suitable molecule ligands is an effective approach to prevent aggregation. Disintegrating the existed oligomers and fibrils into individual α-Syn by small molecular compounds is a more efficient way to treat PD. This work designed and synthesized two series of bis-chalcone polyphenol compounds, which possess a sheet-like conjugated skeleton with stronger H-bonding, π-stacking, and hydrophobic interaction with α-Syn protein residues. Some compounds have shown high α-Syn aggregation inhibitory activities in vitro with IC50 down to 0.64 μM. The inhibition goes throughout the aggregation process from the lag to the stationary phase by stabilizing α-Syn proteostasis conformation and preventing β-sheets aggregation, especially in the lag phase. In addition, the inhibitors present good disintegration abilities against the existed α-Syn oligomers and fibrils. The preliminary mechanism studies suggest that the inhibitors could quickly and randomly bind to the specific site closed to the β-sheet domain in the fibril, resulting in unstable and collapse of the protein fibril and yielding a complex system with aggregates of different sizes and monomers. The inhibitors, which could penetrate the blood-brain barrier, are expected to develop into the drug candidates for PD targeting α-Syn aggregation.

Abstract 1404: Novel STAT3 inhibitors targeting the STAT3 dimerization

Abstract Background The STAT3 pathway may drive prostate cancer (PCa) progression to metastatic castration-resistant prostate cancer (mCRPC). STAT3 may serve as a good target for the treatment of prostate cancer. The function of STAT3 relies significantly on its SH2 domain, which promotes STAT3 homo- or hetero-dimerization, protein-protein interaction and nuclear translocation of the STAT3 dimers needed for transcription. Due to this important role, the STAT3 SH2 domain becomes an attractive therapeutic target. In a drug discovery and development program we have found two small molecular compounds named 323-1 and 323-2 that were identified as novel STAT3 SH2 domain inhibitors in a series of experiments. Material and methods In silico computational modeling, Drug Affinity Responsive Target Stability (DARTS) and Fluorescence Polarization (FP) assays were performed to examine whether compounds 323-1 and 323-2 could bind to the STAT3 protein. The antitumor activity of compounds 323-1 and 323-2 was firstly determined by clonogenic assays in different prostate tumor cells, then validated in the humanised NOD/SCID mouse CRPC model. Effects of compound 323-1 and 323-2 on STAT3 transcriptional activity were determined by the luciferase assay and protein levels by western blotting. Results In silico computational modeling, DARTS and FP assays altogether determined 323-1 and 323-2 as direct STAT3 inhibitors targeting the STAT3 SH2 domain and inhibiting both phosphorylated and non-phosphorylated STAT3 dimerization. Computational docking predicted that both 323 compounds bind to three subpockets of the STAT3 SH2 domain with full inhibition of STAT3. FP assay further confirmed that 323s target the STAT3 SH2 domain by competitively abrogating the interaction between STAT3 and the SH2-binding peptide GpYLPQTV. Compared with S3I-201, the 323 compounds exhibited stronger inhibition of STAT3 and reduced the level of IL-6-stimulated phosphorylation of STAT3 (Tyr705) in LNCaP cells over the phosphorylation of STAT1 (Tyr701) induced by IFN-ɣ in PC3 cells or the phosphorylation of STAT1 (Ser727) in DU145 cells. Both compounds down-regulated STAT3 target genes MCL1 and cyclin D1. The in-vivo data supported that 323s significantly inhibited LNCaP cell generated CRPC tumor growth. Thus, the two compounds are promising leading compounds for the treatment of cancers with hyper-activated STAT3. Conclusions Here we report that these compounds modulate the IL-6/STAT3 pathway by 1) inhibition of STAT3 phosphorylation on Tyr705 and 2) disruption of STAT3 dimerization by directly targeting its SH2 domain; 3) inhibition of STAT3 transcriptional activity. Thus, the compounds 323-1 and 323-2 are promising new leading compounds for therapeutic STAT3 inhibition. Citation Format: Yaping Hua, Waqas Azeem, Anne Margrete Øyan, Karl-Henning Kalland. Novel STAT3 inhibitors targeting the STAT3 dimerization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1404.

A green pretreatment approach of corn stalk wastes for obtaining micro/nano-cellulose fibers, monosaccharides and lignin fractions

Efficient separation of carbohydrates and lignin from lignocellulosic biomass, and further high-value conversion are still the main challenge of biorefinery. Oxygen-enhanced alkali treatment as a green method for separating polysaccharides and lignin from gramineous materials with environmental, economic and low energy consumption. Herein, oxygen-enhanced alkali technology was used to pretreatment corn stalk pith, and then realize high-value transformation. The results showed that oxygen-enhanced alkali treatment combined with acid precipitation, ethanol precipitation, enzymatic hydrolysis or ultrasonic can achieve clean, efficient separation and subsequent high-value transformation of various components of corn pith. The enzymatic efficiencies of solid and liquid polysaccharides were 75.42% and 50.52% respectively, and the structure of micro/nano-cellulose fiber is mostly flaky and granular. In addition, the separated lignin contains many small molecular compounds, which has the potential value of further utilization. In this study, oxygen-enhanced alkali treatment can achieve clean, efficient separation and subsequent high-value transformation of various components in corn stalk or lignocellulosic biomass, which has important practical significance.