Similar Compounds Research Articles

SALVIANOLIC ACID A ATTENUATES ANGIOTENSIN II-INDUCED CARDIAC FIBROSIS THROUGH REGULATING THE TXNIP SIGNALING PATHWAY.

Cardiac fibrosis, characterized by excessive collagen accumulation in heart tissues, poses a significant clinical challenge in various heart diseases and complications. Although salvianolic acid A (Sal A) from Danshen ( Salvia miltiorrhiza ) has shown promise in the treatment of ischemic heart disease, myocardial infarction, and atherosclerosis, its effects on cardiac fibrosis remain unexplored. Our study investigated the efficacy of Sal A in reducing cardiac fibrosis and elucidated its underlying molecular mechanisms. We observed that Sal A demonstrated significant cardioprotective effects against Angiotensin II (Ang II)-induced cardiac remodeling and fibrosis, showing a dose-dependent reduction in fibrosis in mice and suppression of cardiac fibroblast proliferation and fibrotic protein expression in vitro . RNA sequencing revealed that Sal A counteracted Ang II-induced upregulation of Txnip, and subsequent experiments indicated that it acts through the inflammasome and ROS pathways. These findings establish the antifibrotic effects of Sal A, notably attenuated by Txnip overexpression, and highlight its significant role in modulating inflammation and oxidative stress pathways. This underscores the importance of further research on Sal A and similar compounds, especially regarding their effects on inflammation and oxidative stress, which are key factors in various cardiovascular diseases.

Ubiqutin Proteasomes System (UPS) - an Intriguing Weapon of Plants and It's Modification by Plant Pathogens as Virulence Mechanism

Plants' ubiquitin-26S proteasome degradation system (UPS) is involved in the signal transduction of numerous cellular functions, including pathogen-triggered host immunological responses. Pathogens that attack create effectors that are translocated into host cells and disrupt defensive signals in the host in specific ways. Certain bacterial effectors, which are presently best understood in Pseudomonas syringae, exploit or depend on the host UPS for their activity, which may not come as a surprise given the extensive role of the host proteasome in plant immunology. Interestingly, certain strains of P. syringae express syringolin A, a virulence factor that uses a unique mechanism to irreversibly block the proteasome. This section summarizes the UPS's defense function for plants and how effectors use it. It also covers the biology, taxonomic distribution, and emerging implications for virulence strategies of syringolin A and similar compounds.

N-Heterocyclic germylenes supported by bulky dianionic N,N-chelating ligands

In this contribution, three novel diamine pro-ligands, incorporating sterically bulky aryl and aliphatic N-substituents, have been developed; viz. (NCNTCHP)H2 (NCNTCHP = {(TCHP)NCH2}2CH2, TCHP = 2,4,6-tricyclohexylphenyl), (NONTCHP)H2 (NONTCHP = {(TCHP)NSiMe2}2O), and (NONAd)H2 (NONAd = {(Ad)NSiMe2}2O; Ad = 1-adamantyl). Through salt metathesis or transamination synthetic approaches, the N-heterocyclic germylenes, [:Ge(NCNTCHP)], [:Ge(NONTCHP)], and [:Ge(NONAd)], have been prepared and crystallographically characterized. The electronic structure of each germylene was studied by DFT calculations. The steric profile of the germanium-bound ligands was also assessed using computational models, and the results compared to those for structurally similar compounds. Significant steric crowding of the germanium centre (>70 % ligand coverage) was observed for [:Ge(NCNTCHP)] and [:Ge(NONTCHP)], while [:Ge(NONAd)] exhibited substantially less steric saturation at the metal centre (∼62 % ligand coverage). Through these studies, we have shown the potential suitably of the developed ligands to stabilise other low-valent main-group species.

Self‐assembly imprinting fabrication of shell‐crosslinking fluorescent nanoparticles for the detection of sialic acid

AbstractA new strategy for preparing sialic acid (SA)‐quenching fluorescent nanoparticles by macromolecular self‐assembly and molecular imprinting technique is suggested. An amphiphilic block copolymer polystyrene‐b‐poly(glycidyl methacrylate) (PS‐b‐PGMA) was designed and synthesized. After functionalization, PS‐b‐PGMA was co‐assembled with the template molecule SA to prepare SA‐imprinted fluorescent nanoparticles, named as nano‐FMIPs. In this process, the shell layers of nanoparticles were photo‐crosslinked upon 365 nm UV light to stabilize the recognition site. The size of the crosslinked shell was found to be increased to 420 ± 5 nm by TEM and DLS measurements. After extraction of SA, recognition cavities complementary in shape, size, and chemical function toward the template SA were left on the surface of nano‐FMIPs, which can selectively rebind the target SA in a mixture of structurally similar compounds. It is found that SA can significantly quench the fluorescence intensity of nano‐FMIPs linearly within a concentration range of 1 × 10−2 ~ 2 × 10−6 mol L−1 and a detection limit of 1.55 × 10−6 mol L−1. This strategy provides a new approach for preparing surface‐imprinted nano‐FMIPs for the quantitative detection of SA, and the nano‐FMIPs may have great potential for biomedical application.

Comparison of the Real-World Reporting of Symptoms and Well-Being for the HER2-Directed Trastuzumab Biosimilar Ogivri With Registry Data for Herceptin in the Treatment of Breast Cancer: Prospective Observational Study (OGIPRO) of Electronic Patient-Reported Outcomes.

Trastuzumab has had a major impact on the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). Anti-HER2 biosimilars such as Ogivri have demonstrated safety and clinical equivalence to trastuzumab (using Herceptin as the reference product) in clinical trials. To our knowledge, there has been no real-world report of the side effects and quality of life (QoL) in patients treated with biosimilars using electronic patient-reported outcomes (ePROs). The primary objective of this prospective observational study (OGIPRO study) was to compare the ePRO data related to treatment side effects collected with the medidux app in patients with HER2-positive BC treated with the trastuzumab biosimilar Ogivri (prospective cohort) to those obtained from historical cohorts treated with Herceptin alone or combined with pertuzumab and/or chemotherapy (ClinicalTrials.gov NCT02004496 and NCT03578731). Patients were treated with Ogivri alone or combined with pertuzumab and/or chemotherapy and hormone therapy in (neo)adjuvant and palliative settings. Patients used the medidux app to dynamically record symptoms (according to the Common Terminology Criteria for Adverse Events [CTCAE]), well-being (according to the Eastern Cooperative Oncology Group Performance Status scale), QoL (using the EQ-5D-5L questionnaire), cognitive capabilities, and vital parameters over 6 weeks. The primary endpoint was the mean CTCAE score. Key secondary endpoints included the mean well-being score. Data of this prospective cohort were compared with those of the historical cohorts (n=38 patients; median age 51, range 31-78 years). Overall, 53 female patients with a median age of 54 years (range 31-87 years) were enrolled in the OGIPRO study. The mean CTCAE score was analyzed in 50 patients with available data on symptoms, while the mean well-being score was evaluated in 52 patients with available data. The most common symptoms reported in both cohorts included fatigue, taste disorder, nausea, diarrhea, dry mucosa, joint discomfort, tingling, sleep disorder, headache, and appetite loss. Most patients experienced minimal (grade 0) or mild (grade 1) toxicities in both cohorts. The mean CTCAE score was comparable between the prospective and historical cohorts (29.0 and 30.3, respectively; mean difference -1.27, 95% CI -7.24 to 4.70; P=.68). Similarly, no significant difference was found for the mean well-being score between the groups treated with the trastuzumab biosimilar Ogivri and Herceptin (74.3 and 69.8, respectively; mean difference 4.45, 95% CI -3.53 to 12.44; P=.28). Treatment of patients with HER2-positive BC with the trastuzumab biosimilar Ogivri resulted in equivalent symptoms, adverse events, and well-being as found for patients treated with Herceptin as determined by ePRO data. Hence, integration of an ePRO system into research and clinical practice can provide reliable information when investigating the real-world tolerability and outcomes of similar therapeutic compounds. ClinicalTrials.gov NCT05234021; https://clinicaltrials.gov/study/NCT05234021.

The cytotoxicity effect and identification of bioactive compounds of Prismatomeris glabra crude leaf extracts against breast cancer cells

BackgroundDespite the fact that natives of Southeast Asia have been consuming Prismatomeris glabra for decades for a variety of health benefits, research on this species is not as extensive as that on other species due to its limited distribution. The purpose of this study was to determine the cytotoxicity and identify the bioactive compounds of P. glabra crude leaf extracts against the MCF-7 cell line.ResultsWe first examined the potential cytotoxic activity of P. glabra using the MTT assay against the MCF-7 cell line to determine the IC50 of the plant extracts at various concentrations at three time points (24 h, 48 h, and 72 h). Across all time points, the MTT assay revealed that the aqueous extract exhibited the lowest IC50 values (p < 0.05) compared to the ethanol and methanol extracts. All plant extracts exerted the ability to induce cell death in the MCF-7 cell line at all time points, and the optimal time for P. glabra to manifest its antiproliferative activities and promote cell death was 48 h. LC–MS analysis was conducted to reveal the components in plant extracts. Forty compounds were discovered in P. glabra's extracts, with the majority being flavonoids and triterpenoids. Five similar compounds were present in all three extracts. Further research should be conducted on these compounds to unveil a compound that fulfils the criteria as a promising anticancer agent. This research is of the utmost importance, as it provides a fundamental framework for the identification of alternative therapies for breast cancer and contributes implicitly to the development of new drugs.ConclusionsThis study discovered that P. glabra crude leaf extracts have the potential to inhibit the MCF-7 cell line by inducing cell death.

Computer-Assisted Drug Discovery of Potential African Anti-SARS-CoV-2 Natural Products Targeting the Helicase Protein

Objectives: In our continuous efforts to combat COVID-19, our objective was to conduct a comprehensive computer-aided drug design study utilizing 4924 African natural metabolites sourced from diverse databases across various African regions from 1962 to 2019. The primary goal was to target the SARS-CoV-2 helicase, a crucial enzyme in viral replication. Methods: We employed structural fingerprint and molecular similarity studies with VXG, the co-crystallized ligand, as a reference. Subsequently, docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies were conducted. Results: The structural fingerprint analysis identified 200 structurally similar compounds, then the molecular similarity studies selected 40 compounds. Among them, 15 metabolites with low free energies, favorable binding modes, and promising ADMET properties were identified. Four compounds were excluded according to the toxicity studies. Compound 1552, 1-(( S)-2,3-dihydro-2-(( R)-1-hydroxypropan-2-yl)benzofuran-5-yl)ethenone, exhibited the most favorable docking results. Molecular dynamics simulations conclusively demonstrated its stable binding to the SARS-CoV-2 helicase, characterized by low energy and optimal dynamics. Conclusion: The findings suggest promising avenues for potential COVID-19 cures, encouraging further exploration through in vitro and in vivo studies of the identified compounds, particularly compound 1552.

The Impact of Substitution of Diphenyl Dialumene on the Molecular Structure and Energetic Properties

The molecular structure, energetic properties, electronic, and vibrational spectroscopy of meta-substituted phenyl dialumene, DPD (Ar–Al=Al–Ar; Ar of the formula C6H5X2, where X = H, CH3, NH2, OH, F, Cl, Br, NO2, and COOH) are investigated by DFT. The singlet states of unsubstituted and substituted DPD adopt trans-planar geometry, while the triplet states adopt non-planar trans-bent geometry. The Al=Al bond length of unsubstituted DPD-H in a singlet state is calculated to be 2.734 Å, and there is no systematic and significant change upon substitution (2.734–2.744 Å). The substitution affects the absolute energy, ionization potential, electron affinity, and reorganization energy. The wavelength of maximum absorbance of DPD-H is determined to be 443 nm, and the substitute analogues DPD-X (X = OH, F, Cl, Br, NO2, CHO, COOH) show a hypsochromic shift, while DPD-CH3 and DPD-NH2 exhibit a bathochromic effect. The HOMO to LUMO+1 transition is the major transition for the meta-substituted DPD, except for X=NO2, where the transition is to LUMO+2. Considering the reorganization energy values, meta-substituted DPD can be useful as hole transporters. In addition, the theoretical data will aid in predicting the behavior of this class of compounds, facilitating the design and synthesis of similar compounds with desired properties.

Structural Study of N-(1,3-Benzothiazol-2-yl)-4-Halobenzenesulfonylhydrazides: Hirshfeld Surface Analysis and PIXEL Calculations

Hydrazonylsulfones such as Bt-NHNHSO2R and their iminotautomers have been studied as optical materials and for their biological potential. In this work, a structural study has been carried out on N-(1,3-benzothiazol-2-yl)-4-(halogenobenzenesulfonyl)-hydrazides (1: X = F, Cl, Br). For (1: X = F), single-crystal X-ray diffraction, Hirshfeld surface analysis, and PIXEL calculations were conducted, while in (1: X = Cl) and (1: X = Br), only single-crystal X-ray diffraction studies were successfully conducted due to the disordering of the solvent. Each compound crystallises with two independent but similar amino tautomers in the asymmetric units: compound (1: X = F) crystallises in the monoclinic P21/c, and the isostructural pair (X: 1 = Cl and Br) crystallises in the tetragonal P-421c space group. In the most stable motif of the supramolecular arrangement, the molecules of the asymmetric unit are connected by classical N–H(hydrazinyl)···N(thiazoyl) hydrogen bonds and several face-to-face, offset π···π interactions. This motif has a very powerful influence on the crystal structure due to its direct links with the other weaker motifs. Other significant intermolecular interactions found in the structure include N–H(hydrazonyl)···O(sulfonate) bonds. Analogous intermolecular interactions were found in similar compounds, leading to the conclusion that those interactions are the most important instabilizing the solid state of hydrazonylsulfones.

Chemical Constituents and Biological Activities of Bruguiera Genus and Its Endophytes: A Review.

The genus Bruguiera, a member of the Rhizophoraceae family, is predominantly found in coastal areas as a mangrove plant, boasting a rich and diverse community of endophytes. This review systematically compiled approximately 496 compounds derived from both the Bruguiera genus and its associated endophytes, including 152 terpenoids, 17 steroids, 16 sulfides, 44 alkaloids and peptides, 66 quinones, 68 polyketides, 19 flavonoids, 38 phenylpropanoids, 54 aromatic compounds, and 22 other compounds. Among these, 201 compounds exhibited a spectrum of activities, including cytotoxicity, antimicrobial, antioxidant, anti-inflammatory, antiviral, antidiabetic, insecticidal and mosquito repellent, and enzyme inhibitory properties, etc. These findings provided promising lead compounds for drug discovery. Certain similar or identical compounds were found to be simultaneously present in both Bruguiera plants and their endophytes, and the phenomenon of their interaction relationship was discussed.

Revealing the role of calcium ion intercalation of hydrated vanadium oxides for aqueous zinc-ion batteries

Exploring suitable high-capacity V2O5-based cathode materials is essential for the rapid advancement of aqueous zinc ion batteries (ZIBs). However, the typical problem of slow Zn2+ diffusion kinetics has severely limited the feasibility of such materials. In this work, unique hydrated vanadates (CaVO, BaVO) were obtained by intercalation of Ca2+ or Ba2+ into hydrated vanadium pentoxide. In the CaVO//Zn and BaVO//Zn batteries systems, the former delivered up to a 489.8 mAh g−1 discharge specific capacity at 0.1 A g−1. Moreover, the remarkable energy density of 370.07 Wh kg−1 and favorable cycling stability yard outperform BaVO, pure V2O5, and many reported cathodes of similar ionic intercalation compounds. In addition, pseudocapacitance analysis, galvanostatic intermittent titration (GITT) tests, and Trasatti analysis revealed the high capacitance contribution and Zn2+ diffusion coefficient of CaVO, while an in-depth investigation based on EIS elucidated the reasons for the better electrochemical performance of CaVO. Notably, ex-situ XRD, XPS, and TEM tests further demonstrated the Zn2+ insertion/extraction and Zn-storage mechanism that occurred during the cycle in the CaVO//Zn battery system. This work provides new insights into the intercalation of similar divalent cations in vanadium oxides and offers new solutions for designing cathodes for high-capacity aqueous ZIBs.

In-silico Drug Repurposing of Abiraterone-based Compounds as 17α-Hydroxylase Inhibitors for Breast Cancer Treatment Using Drug-Drug Transcriptomic Similarity Analysis and Molecular Docking

This research explores abiraterone-based compounds’ in-silico drug repurposing potential as inhibitors of 17α-hydroxylase for breast cancer treatment, employing a multifaceted approach integrating molecular docking and drug-drug transcriptomic similarity analysis. Drug-drug transcriptomic similarity analysis revealed abiraterone to be the most transcriptomically similar compound, suggesting shared biological effects and repurposing opportunities. Molecular docking results identified abiraterone as a lead compound with a robust binding affinity and interacting amino acids within the active site of 17α-hydroxylase. Other compounds, including marbofloxacin, ataluren, zafirlukast, and montelukast, exhibited promising binding scores and diverse interactions, reinforcing their potential as potent inhibitors. Cell line-specific responses and connectivity patterns provided nuanced insights, guiding the selection of compounds. Overall, our findings underscore abiraterone-based compounds, especially abiraterone itself, as promising candidates for experimental validation, offering a significant stride in the pursuit of targeted and repurposed therapeutics for breast cancer treatment

Adsorption Behaviors and Mechanism of Phenol and Catechol in Wastewater by Magnetic Graphene Oxides: A Comprehensive Study Based on Adsorption Experiments, Mathematical Models, and Molecular Simulations.

This study provides a comprehensive analysis of the adsorption behaviors and mechanisms of phenol and catechol on magnetic graphene oxide (MGO) nanocomposites based on adsorption experiments, mathematical models, and molecular simulations. Through systematic experiments, the influence of various parameters, including contact time, pH conditions, and ionic strength, on the adsorption efficacy was comprehensively evaluated. The optimal contact time for adsorption was identified as 60 min, with the observation that an increase in inorganic salt concentration adversely affected the MGOs' adsorption capacity for both phenol and catechol. Specifically, MGOs exhibited a superior adsorption performance under mildly acidic conditions. The adsorption isotherm was well represented by the Langmuir model, suggesting monolayer coverage and finite adsorption sites for both pollutants. In terms of adsorption kinetics, a pseudo-first-order kinetic model was the most suitable for describing phenol adsorption, while catechol adsorption conformed more closely to a pseudo-second-order model, indicating distinct adsorption processes for these two similar compounds. Furthermore, this research utilized quantum chemical calculations to decipher the interaction mechanisms at the molecular level. Such calculations provided both a visual representation and a quantitative analysis of the interactions, elucidating the underlying physical and chemical forces governing the adsorption phenomena. The findings could not only offer crucial insights for the treatment of coal industrial wastewater containing phenolic compounds with bridging macroscopic observations with microscopic theoretical explanations but also advance the understanding of material-pollutant interactions in aqueous environments.

Abstract 3527: Application of a deep learning based drug sensitivity prediction model on a novel anticancer drug

Abstract Discovery of a candidate drug molecule through the preclinical stages is an iterative multiparametric process until a candidate is selected for investigational new drug submission enabling studies. This iterative approach takes up significant time and effort to design, synthesize, and test new compounds. A specific testing step is evaluation of half maximal inhibitory concentration (IC50) of compounds on cell line (CL) models. To augment CL testing, computational approaches predicting the IC50 of a drug can be used to guide choice of optimization as the molecule goes through hit to lead optimization onto candidate selection. DeepDSC [1] is a deep learning (DL) model developed to predict the IC50 in a specific CL of a given drug by integrating public data from large-scale drug screens and high-throughput RNAseq profiling. The Cancer Cell Line Encyclopedia (CCLE) [2] and Genomics of Drug Sensitivity (GDSC) [3] projects compiled pharmacological profiles of 23 and 139 drugs across 491 and 655 cancer CLs, respectively. A 10-fold cross validation (CV) approach was employed to train DeepDSC on the datasets independently and reported the average root mean squared error (RMSE) and the coefficient of determination (R2) on the held-out sets across the folds. However, the model’s generalizability to novel compounds not in the dataset, specifically compounds that are structurally dissimilar, is yet to be tested. In this regard, the DeepDSC model was retrained, with modifications, on a subset of the GDSC dataset - GDSC2 - to access the generalizability of DL models on BRG399, a proprietary microtubule targeting agent (MTA) developed by BPGbio Inc. GDSC2 was used since data generated for BRG399 and GDSC2 share the same potency assay (CellTiter-Glo [6]), The GDSC2 set was split into training and held-out sets using a 80-20 random split. Further, we chose to optimize the learning rate for both the autoencoder and feed forward networks (FFN), and the L2 regularization factor for the FFN only. Hyperparameters were optimized using 5-fold CV on the training set. Finally, we evaluated the predictive performance of the model on BRG399, which was not present in the training set. We encoded each compound in GDSC2 (n=234) using Circular Fingerprints [4] and observed an average Jaccard (or Tanimoto) distance (JD) [5] of 0.892 across 27261 drug pairs. BRG399 showed an average JD of 0.873 across 234 drug pairs, with the most similar compound JD of 0.785. Our retrained DeepDSC model had RMSE 1.15 and R2 0.82 on the training set and RMSE 1.19 and R2 0.86 on the held-out set. However, on BRG399 tested CLs (n=101) model had RMSE 1.84 and R2 &amp;lt; 0, which indicated that predictions were on average worse compared to a mean-predictor model for BRG399. These results suggest that DL models that can generalize predictions to a held-out set for compounds that were present in the training set may not accurately predict IC50 of novel compounds not in the training set. Citation Format: Nischal M. Chand, Vivek Vishnudas, Michael A. Kiebish, Anjan Thakurta, Niven R. Narain, Stephane Gesta, Gregory M. Miller. Application of a deep learning based drug sensitivity prediction model on a novel anticancer drug [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3527.

The Discovery of the Potential Attractive Compounds of Bactrocera dorsalis (Hendel)

Bactrocera dorsalis (Hendel) (B. dorsalis) is an important agricultural invasive pest that causes significant economic losses in tropical and subtropical fruit and vegetable crops. In this study, the proteins related to the sense of smell and taste of B. dorsalis, such as OBP, PBP, OR, IR, SNMP and CSP, were screened based on B. dorsalis transcriptome data. By integrating the compounds that were reported to be attractive to B. dorsalis, similar compounds of hydrocarbon compounds were obtained. Molecular docking was used to predict the binding between the similar compounds and the OBP, PBP, OR, IR, SNMP and CSP proteins. Network pharmacology was used to screen the potentially attractive compounds, and ecological experiments with B. dorsalis were finally conducted to verify the effect of these potentially attractive compounds on B. dorsalis. The results showed that the G protein-coupled receptor [BR: KO04030] and ion channel [BR: KO04040] pathways were closely related to the odor tropism of B. dorsalis. A total of 84 compounds, such as mitemcinal, exemestane and midecamycin, have potential binding effects on the B. dorsalis odor receptor proteins. The results of the ecological experiments showed that 1 mg/mL and 0.1 mg/mL 19-norandrostenedione, 1 mg/mL progesterone compounds was significantly attractive to B. dorsalis males, while 0.1 mg/mL exemestane was significantly attractive to B. dorsalis females. In this study, network pharmacology technology was used to discover the potential attractive compounds for B. dorsalis, which is important for the development and subsequent prevention and control of B. dorsalis. It can provide a reference in improving the success rates of clinical trials of new pest control products and in reducing the time and cost of drug development.

MICROSTRUCTURE OF CB/SIO2 HYBRID REINFORCED SOLID TYRE TREAD COMPOUND CONTAINING GROUND TYRE RUBBER AND THEIR EFFECT ON FATIGUE RESISTANCE

The possibility of improving the properties of rubber compounds containing ground tyre rubber (GTR) is an active research area. This study investigates the microstructure of carbon black filled tyre tread compound containing 20 phr GTR and compares the microstructure with those of similar compounds reinforced with hybrid carbon black/precipitated silica (CB/SiO2). In the compounds reinforced with hybrid filler, amount of the GTR was maintained at 20 phr, while the amount of the hybrid filler (CB/SiO2 ) were in the ratios 55/5, 50/10 and 45/15 respectively. The compounds were mixed by two-step mixing method using internal mixer and two-roll mill. The vulcanisation of each rubber compound was carried out on a compression moulding machine at 150. Results obtained from scanning electron microscopy of the fractured surfaces showed that the ingredients in the control sample that was not filled with GTR were well dispersed and distributed. The micrograph of the sample containing GTR and mixed at 60 showed that GTR was not very compatible with the matrix. Improved mixing was achieved with increased mixing temperature. The addition of precipitated silica at 5 phr resulted in poor dispersion. The dispersion improved as the amount of silica increased to 10 phr and 15 phr respectively. Results obtained from flex fatigue test show that the compounds filled with hybrid CB/SiO2 in the ratios 50/10 and 45/15 phr exhibited no crack after 1000 cycles due to good dispersion. It is recommended that hybrid CB/SiO2 reinforcement at optimal amount of silica should be utilised to fill rubber compounds containing GTR in order to improve the properties of the vulcanisates.

Divergent evolution of the alcohol-forming pathway of wax biosynthesis among bryophytes.

The plant cuticle is a hydrophobic barrier, which seals the epidermal surface of most aboveground organs. While the cuticle biosynthesis of angiosperms has been intensively studied, knowledge about its existence and composition in nonvascular plants is scarce. Here, we identified and characterized homologs of Arabidopsis thaliana fatty acyl-CoA reductase (FAR) ECERIFERUM 4 (AtCER4) and bifunctional wax ester synthase/acyl-CoA:diacylglycerol acyltransferase 1 (AtWSD1) in the liverwort Marchantia polymorpha (MpFAR2 and MpWSD1) and the moss Physcomitrium patens (PpFAR2A, PpFAR2B, and PpWSD1). Although bryophyte harbor similar compound classes as described for angiosperm cuticles, their biosynthesis may not be fully conserved between the bryophytes M. polymorpha and P.patens or between these bryophytes and angiosperms. While PpFAR2A and PpFAR2B contribute to the production of primary alcohols in P. patens, loss of MpFAR2 function does not affect the wax profile of M. polymorpha. By contrast, MpWSD1 acts as the major wax ester-producing enzyme in M. polymorpha, whereas mutations of PpWSD1 do not affect the wax ester levels of P. patens. Our results suggest that the biosynthetic enzymes involved in primary alcohol and wax ester formation in land plants have either evolved multiple times independently or undergone pronounced radiation followed by the formation of lineage-specific toolkits.

Periplcymarin targets glycolysis and mitochondrial oxidative phosphorylation of esophageal squamous cell carcinoma: Implication in anti-cancer therapy

BackgroundEsophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal cancer (EC) in China, and demonstrates varying levels of resistance to multiple chemotherapeutic agents. Our previous studies have proved that periplocin (CPP), derived from the extract of cortex periplocae, exhibiting the capacity to hinder proliferation and induce apoptosis in ESCC cells. Several studies have identified additional anti-cancer constituents in the extract of cortex periplocae, named periplcymarin (PPM), sharing similar compound structure with CPP. Nevertheless, the inhibitory effects of PPM on ESCC and their underlying mechanisms remain to be further elucidated. PurposeThe aim of this study was to investigate function of PPM inhibiting the growth of ESCC in vivo and in vitro and to explore its underlying mechanism, providing the potential anti-tumor drug for ESCC. MethodsInitially, a comparative analysis was conducted on the inhibitory activity of three naturally compounds obtained from the extract of cortex periplocae on ESCC cells. Among these compounds, PPM was chosen for subsequent investigation owing to its comparatively structure and anti-tumor activity simultaneously. Subsequently, a series of biological functional experiments were carried out to assess the impact of PPM on the proliferation, apoptosis and cell cycle arrest of ESCC cells in vitro. In order to elucidate the molecular mechanism of PPM, various methodologies were employed, including bioinformatics analyses and mechanistic experiments such as high-performance liquid chromatography combined with mass spectrometry (HPLC-MS), cell glycolysis pressure and mitochondrial pressure test. Additionally, the anti-tumor effects of PPM on ESCC cells and potential toxic side effects were evaluated in vivo using the nude mice xenograft assay. ResultsOur study revealed that PPM possesses the ability to impede the proliferation of ESCC cells, induce apoptosis, and arrest the cell cycle of ESCC cells in the G2/M phase in vitro. Mechanistically, PPM exerted its effects by modulating glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), as confirmed by glycolysis pressure and mitochondrial pressure tests. Moreover, rescue assays demonstrated that PPM inhibits glycolysis and OXPHOS in ESCC cells through the PI3K/AKT and MAPK/ERK signaling pathways. Additionally, we substantiated that PPM effectively suppresses the growth of ESCC cells in vivo, with only modest potential toxic side effects. ConclusionOur study provides novel evidence that PPM has the potential to simultaneously target glycolysis and mitochondrial OXPHOS in ESCC cells. This finding highlights the need for further investigation into PPM as a promising therapeutic agent that targets the tumor glucose metabolism pathway in ESCC.

Mudanpioside C Discovered from Paeonia suffruticosa Andr. Acts as a Protein Disulfide Isomerase Inhibitor with Antithrombotic Activities.

Paeonia suffruticosa Andr. is a well-known landscape plant worldwide and also holds significant importance in China due to its medicinal and dietary properties. Previous studies have found that Cortex Moutan (CM), the dried root bark of P. suffruticosa, showed antiplatelet and cardioprotective effects, although the underlying mechanism and active compounds remain to be revealed. In this study, protein disulfide isomerase (PDI) inhibitors in CM were identified using a ligand-fishing method combined with the UHPLC-Q-TOF-MS assay. Further, their binding sites and inhibitory activities toward PDI were validated. The antiplatelet aggregation and antithrombotic activity were investigated. The results showed that two structurally similar compounds in CM were identified as the inhibitor for PDI with IC50 at 3.22 μM and 16.73 μM; among them Mudanpioside C (MC) is the most effective PDI inhibitor. Molecular docking, site-directed mutagenesis, and MST assay unequivocally demonstrated the specific binding of MC to the b'-x domain of PDI (Kd = 3.9 μM), acting as a potent PDI inhibitor by interacting with key amino acids K263, D292, and N298 within the b'-x domain. Meanwhile, MC could dose-dependently suppress collagen-induced platelet aggregation and interfere with platelet activation, adhesion, and spreading. Administration of MC can significantly inhibit thrombosis formation without disturbing hemostasis in mice. These findings present a promising perspective on the antithrombotic properties of CM and highlight the potential application of MC as lead compounds for targeting PDI in thrombosis therapy.

Analysing N-nitrosamine occurrence and sources in karst reservoirs, Southwest China.

N-nitrosamines in reservoir water have drawn significant attention because of their carcinogenic properties. Karst reservoirs containingdissolved organic matter(DOM) are important drinking water sources and are susceptible to contamination because of the fast flow of various contaminants. However, it remains unclear whether N-nitrosamines and their precursor, DOM, spread in karst reservoirs. Therefore, this study quantitatively investigated the occurrence and sources of N-nitrosamines based on DOM properties in three typical karst reservoirs and their corresponding tap water. The results showed that N-nitrosamines were widely spread, with detection frequencies > 85%. Similar dominant compounds, including N-nitrosodimethylamine, N-nitrosomethylethylamine, N-nitrosopyrrolidine, and N-nitrosodibutylamine, were observed in reservoirs and tap water, with average concentrations of 4.7-8.9 and 2.8-6.7ng/L, respectively. The average carcinogenic risks caused by these N-nitrosamines were higher than the risk level of 10-6. Three-dimensional fluorescence excitation-emission matrix modeling revealed that DOM was composed of humus-like component 1 (C1) and protein-like component 2 (C2). Fluorescence indicators showed that DOM in reservoir water was mainly affected by exogenous pollution and algal growth, whereas in tap water, DOM was mainly affected by microbial growth with strong autopoietic properties. In the reservoir water, N-nitrosodiethylamine and N-nitrosopiperidine were significantly correlated with C2 and biological indicators, indicating their endogenously generated sources. Based on the principal component analysis and multiple linear regression methods, five sources of N-nitrosamines were identified: agricultural pollution, microbial sources, humus sources, degradation processes, and other factors, accounting for 46.8%, 36.1%, 7.82%, 8.26%, and 0.96%, respectively. For tap water, two sources, biological reaction processes, and water distribution systems, were identified, accounting for 75.7% and 24.3%, respectively. Overall, this study presents quantitative information on N-nitrosamines' sources based on DOM properties in typical karst reservoirs and tap water, providing a basis for the safety of drinking water for consumers.