Negative logarithm of the acid dissociation constant(pK_(a))significantly influences the absorption,dis-tribution,metabolism,excretion,and toxicity(ADMET)properties of molecules and is a crucial indicator in drug rese...Negative logarithm of the acid dissociation constant(pK_(a))significantly influences the absorption,dis-tribution,metabolism,excretion,and toxicity(ADMET)properties of molecules and is a crucial indicator in drug research.Given the rapid and accurate characteristics of computational methods,their role in predicting drug properties is increasingly important.Although many pK_(a) prediction models currently exist,they often focus on enhancing model precision while neglecting interpretability.In this study,we present GraFpKa,a pK_(a) prediction model using graph neural networks(GNNs)and molecular finger-prints.The results show that our acidic and basic models achieved mean absolute errors(MAEs)of 0.621 and 0.402,respectively,on the test set,demonstrating good predictive performance.Notably,to improve interpretability,GraFpKa also incorporates Integrated Gradients(IGs),providing a clearer visual description of the atoms significantly affecting the pK_(a) values.The high reliability and interpretability of GraFpKa ensure accurate pKa predictions while also facilitating a deeper understanding of the relation-ship between molecular structure and pK_(a) values,making it a valuable tool in the field of pK_(a) prediction.展开更多
Objective Oral squamous cell carcinoma(OSCC)is an aggressive cancer with a high mortality rate.San-Zhong-Kui-Jian-Tang(SZKJT),a Chinese herbal formula,has long been used as an adjuvant therapy in cancer clinical pract...Objective Oral squamous cell carcinoma(OSCC)is an aggressive cancer with a high mortality rate.San-Zhong-Kui-Jian-Tang(SZKJT),a Chinese herbal formula,has long been used as an adjuvant therapy in cancer clinical practice.Although its therapeutic effects and molecular mechanisms in OSCC have been previously elucidated,the potential interactions and mechanisms between the active phytochemicals and their therapeutic targets are still lacking.Methods The present study employed network pharmacology and topology approaches to establish a“herbal ingredients–active phytochemicals–target interaction”network to explore the potential therapeutic targets of SZKJT-active phytochemicals in the treatment of OSCC.The role of the target proteins in oncogenesis was assessed via GO and KEGG enrichment analyses,and their interactions with the active phytochemicals of SZKJT were calculated via molecular docking and dynamic simulations.The pharmacokinetic properties and toxicity of the active phytochemicals were also predicted.Results A total of 171 active phytochemicals of SZKJT fulfilled the bioavailability and drug-likeness screening criteria,with the flavonoids quercetin,kaempferol,and naringenin having the greatest potential.The 4 crucial targets of these active phytochemicals are PTGS2,TNF,BCL2,and CASP3,which encode cyclooxygenase-2,tumor necrosis factor(TNF),BCL-2 apoptosis regulator,and caspase-3,respectively.The interactions between phytochemicals and target proteins were predicted to be thermodynamically feasible and stable via molecular docking and dynamics simulations.Finally,the results revealed that the IL-6/JAK/STAT3 pathway and TNF signaling via NF-κB are the two prominent pathways targeted by SZKJT.Conclusion In summary,this study provides computational data for in-depth exploration of the mechanism by which SZKJT activates phytochemicals to treat OSCC.展开更多
This study investigates the relationships between exposures to ambient air pollution—specifically particulate matter 2.5 (PM_(2.5)) and its metabolites—and the risk of depression.Nonlinear and linear regression,Baye...This study investigates the relationships between exposures to ambient air pollution—specifically particulate matter 2.5 (PM_(2.5)) and its metabolites—and the risk of depression.Nonlinear and linear regression,Bayesian kernel machine regression,and toxicogenomic analysis were key approaches.PM_(2.5)exposure was positively associated with the risk of developing depression,whereas phenylglyoxylic acid exposure was negatively associated with depression risk.We found a significant overall relationship between ambient air pollution and depression,particularly at the 55th and 60th percentiles.Although statistical significance was not reached at the 65th percentile,there was a noticeable upward trend,indicating a potential association.Interestingly,no significant connection was found between a combination of metabolites from ambient air pollution and depression.PM_(2.5)and phenylglyoxylic acid emerged as the most influential compounds in the models,respectively.PM_(2.5)exposure altered the expression of 42 specific targets associated with depression,especially POMC,SCL6A4,IL6,and SOD2.The study identified specific pathways related to insulin secretion,energy metabolism,blood circulation,tube diameter,and maintenance of blood vessel diameter,as well as key molecular mechanisms involving hsa-miR-124-3p,hsa-miR-155-5p,hsa-miR-16-5p,and SP1.These mechanisms were found to underlie the etiology of depression associated with PM_(2.5)exposure.In conclusions,PM_(2.5)and phenylglyoxylic acid were found to be associated with depression.Further work is needed to gain insight into the molecular mechanisms by which these chemicals affect depression,especially pathways related to insulin secretion and blood circulation.展开更多
Thymus serpyllum L.,often known as wild thyme,has been used since ancient times due to its multifaceted culinary and medicinal attributes.It is usually utilized in folk medicine to manage different health issues.This ...Thymus serpyllum L.,often known as wild thyme,has been used since ancient times due to its multifaceted culinary and medicinal attributes.It is usually utilized in folk medicine to manage different health issues.This work aimed to investigate the chemical composition and biological characteristics of T.serpyllum essential oil(EO),including its antimicrobial,antioxidant,and anti-inflammatory capabilities.Moreover,we have prompted an in-silico simulation to reveal the underlying mode of action of these properties.The chemical characterization of T.serpyllum(EO)by Gas Chromatography-Mass Spectrometry(GC-MS)indicated sabinene(17.33%),terpinen-4-ol(11.73%),phellandral(13.18%),and thymol(10.54%)as main components.The antimicrobial screening utilized the disc-diffusion technique,MIC,and MBC assays.The disc-diffusion test’s results revealed significant anti-Candida activity and notable antibacterial efficacy.The MIC and MBC tests showed that T.serpyllum EO effectively stops bacterial growth,including Gram-positive and Gram-negative strains and Candida strains.The tolerance level ratio demonstrated that this EO exhibits bactericidal and fungicidal effects on all tested bacteria and Candida strains.Also,T.serpyllum EO presented effective inhibitory activity against the 5-lipoxygenase(5-LOX)enzyme(IC50=744.19±0.1µg/mL)(p<0.05).It also effectively affected FRAP,β-carotene,DPPH,and ABTS radicals.In light of these findings,T.serpyllum holds promise for diverse applications across pharmaceuticals,nutraceuticals,and the food industry.However,further research and collaboration between traditional knowledge and modern medicine are crucial to fully realizing its potential benefits in these fields.展开更多
Background:Pistacia integerrima,a cornerstone of traditional medicine,is renowned for its therapeutic applications against various health conditions,including cancer and hepatitis.This study investigates the pharmacol...Background:Pistacia integerrima,a cornerstone of traditional medicine,is renowned for its therapeutic applications against various health conditions,including cancer and hepatitis.This study investigates the pharmacological potential of bioactive compounds derived from Pistacia integerrima in inhibiting 5-lipoxygenase(5-LOX),a key enzyme implicated in inflammation and cancer progression.The current study aimed to evaluate the lipoxygenase inhibitory activity of bioactive compounds from Pistacia integerrima and assess their potential for therapeutic development in the context of inflammation and cancer treatment.Methods:Three major compounds-spinacetin(1),patuletin(2),and pistagremic acid(3)-were isolated from Pistacia integerrima and analyzed for their lipoxygenase inhibitory activity.Biochemical assays and molecular docking studies were performed to assess their effectiveness in inhibiting 5-LOX.Results:All three compounds demonstrated significant inhibition of lipoxygenase activity.Spinacetin(1)and patuletin(2)exhibited the most potent inhibitory effects,with IC_(50)values of 40.34μM and 45.04μM,respectively.Molecular docking studies revealed that patuletin(2)had the highest binding affinity(−7.717 kcal/mol)against 5-LOX,followed by spinacetin(1)with a binding affinity of−6.074 kcal/mol.In-depth in silico analysis highlighted the drug-likeness of spinacetin(1)and its favorable toxicological profile,suggesting its suitability for therapeutic development.Conclusion:The study demonstrates that compounds from Pistacia integerrima,particularly spinacetin and patuletin,have significant lipoxygenase inhibitory activity,with spinacetin showing promise as a lead candidate for lipoxygenase-targeted therapies.The findings reinforce the therapeutic relevance of Pistacia integerrima and suggest that its bioactive compounds may serve as safer,plant-based alternatives to conventional anti-inflammatory and anticancer treatments.展开更多
Objective:To investigate mutations in the Chikungunya(CHIKV)envelope genome region and evaluate their potential impact on B lymphocyte epitopes via in silico analysis.Methods:E1,E2 and 6K protein genes were sequenced ...Objective:To investigate mutations in the Chikungunya(CHIKV)envelope genome region and evaluate their potential impact on B lymphocyte epitopes via in silico analysis.Methods:E1,E2 and 6K protein genes were sequenced from viral RNA isolated from 13 CHIKV-positive serum samples from Alagoas State,Brazil,during the 2016 outbreak.Phylogenetic analysis,experimental epitope identification in the immune epitope database(IEDB)and in silico approaches were employed to predict the potential impact of the detected mutations.Results:The sequences were clustered via phylogenetic analysis.The CHIKV isolates belong to the ECSA genotype,with 13 detected amino acid mutations.Five mutations are located on the surface of the viral particle in regions critical for cellular receptor interaction.Nine mutations are known experimentally validated epitopes for B and T cells.In B-cell epitope predictions,mutations affect sequences within three conformational epitopes in E2 and one in E1,as well as linear epitopes.Notably,the E2-G60D mutation found in the Alagoas strain has been previously reported to influence the vector competence of Aedes aegypti,the primary vector in Brazil.Conclusions:Genomic surveillance and an in-depth understanding of viral mutations are crucial for adapting public health strategies and improving the outbreak response.These findings could have significant public health implications,such as the development of more effective vaccines,diagnostic tests,and antiviral therapies.展开更多
Objective:To explore the effect of a hydrogel of Piper longum(P.longum)root against biofilm-forming multidrug-resistant(MDR)Staphylococcus aureus(S.aureus)through in vitro,in silico,and in vivo studies.Methods:We isol...Objective:To explore the effect of a hydrogel of Piper longum(P.longum)root against biofilm-forming multidrug-resistant(MDR)Staphylococcus aureus(S.aureus)through in vitro,in silico,and in vivo studies.Methods:We isolated the P.longum root ethanolic extract and the compounds using p-HPLC.In vitro antibacterial and antibiofilm activities of P.longum root extract and isolated alkamide compounds against biofilm-forming MDR S.aureus(ATCC 33591)were assessed using agar diffusion and broth microdilution methods,respectively.In silico investigations were conducted to investigate the interaction of alkamide compounds with three target proteins glycogen synthase kinase 3β(GSK3β),matrix metalloproteinases-8(MMP-8),and inducible nitric oxide synthase(iNOS).In addition,the wound healing effect of P.longum root extract 2%and 5%(w/v)-containing hydrogels was determined in mice.Results:The ethanolic root extract of P.longum and its compounds exhibited in vitro antibacterial activity with minimum inhibitory concentrations between 50µg/mL and 700µg/mL,as well as significantly reduced biofilm formation.Piperdardine isolated from P.longum root extract had the best molecular docking score(-9.7,-9.8,and-9.2 kcal/mol)with target proteins GSK3β,MMP-8,and iNOS.In vivo studies showed that P.longum hydrogels significantly lowered the number of colony-forming units(P<0.05).The P.longum 5%(w/v)hydrogel-treated group showed enhanced wound healing activity,achieving a wound contraction rate of 99.34%on day 14.Furthermore,histopathological analysis confirmed increased re-epithelialization and reduced inflammation in mice treated with P.longum 5%(w/v)hydrogel.Conclusions:P.longum root extract has pharmacological potential as an antibacterial and wound-healing agent,and further research is required to confirm its efficacy and clinical application.展开更多
Background:Epidemiological studies have confirmed that longer exposure to insecticides like cypermethrin(CYP)significantly increases the risk of male reproductive toxicity.Crocus sativus L.has been recognized due to i...Background:Epidemiological studies have confirmed that longer exposure to insecticides like cypermethrin(CYP)significantly increases the risk of male reproductive toxicity.Crocus sativus L.has been recognized due to its therapeutic properties,but its exact role and molecular mechanisms in treatment of reproductive dysfunction remain unclear.Methods:During this study,36 rats were randomly divided into six groups(n=6):control,CYP-induced(60 mg/kg),standard(leuprolide 3 mg/kg)and three treatment groups receiving aqueous,ethanolic,and oil extracts(50 mg/kg or 20 mL/kg)for post-toxicity induction.Results:The finding represented that exposure of CYP significantly increased oxidative stress,disrupted testicular architecture,and markedly reduced testosterone levels(P<0.05).Importantly,Crocus sativus L.treatment alleviated these changes by increasing the expression of Nrf2(nuclear factor erythroid 2-related factor 2),restoring the activity of antioxidant enzymes,and enhancing testicular histomorphology.Surprisingly,molecular docking established a high binding affinity of Crocus sativus L.phytoconstituents such as gallic acid,cinnamic acid and quercetin to the Nrf2-Keap1 complex.It is worth noting that,Crocus sativus L.exhibited a high level of protection against reproductive toxicity caused by CYP in male rats,which was mediated by the activation of Nrf2 pathway,reduction of oxidative damage,and favorable ADMET characteristics.Conclusion:Notably,this research provides a more valid,safe,and effective method of developing new drugs for reproductive disorders,however,further investigation is needed to support the research findings and implement it in clinical practice.展开更多
The variation of the O_(2) content in the suction gas,in the range from 7 to 30 vol.%,during the iron ore sintering process,is investigated.Miniaturized laboratory-scale sintering experiments are carried out using an ...The variation of the O_(2) content in the suction gas,in the range from 7 to 30 vol.%,during the iron ore sintering process,is investigated.Miniaturized laboratory-scale sintering experiments are carried out using an industry-like raw mixture to study the effects of O_(2) variation on the sintering process with particular emphasis on the off-gas composition,specific sintering parameters and the sinter strength as well as the chemical composition of the sinter.After the ignition at the bed surface,the gas hood is placed on the sintering column,allowing a synthetic gas mixture to be drawn through the sinter bed until the burn-through point is reached.For additional interpretation of the experimental results,the theoretical coke combustion rate as a function of the oxygen partial pressure was calculated and plotted against the experimentally measured peak temperature in the sinter bed of the respective sinter series.An increasing O_(2) content in the suction gas results in a faster flame front speed combined with a more gradual temperature rise of the heat wave and longer dwell time in the melt phase formation temperature range.Due to the more pronounced flame front,both sinter yield and strength increase,resulting in lower return rates.Below 12 vol.%O_(2),a sharp decrease in sinter yield and strength can be observed,probably due to the low extent of melt phase formation and the associated minor formation of silico ferrite of calcium and aluminum(SFCA).The carbon burnout as well as the calcination increases with increasing the O_(2) content in the suction gas,resulting in higher levels of CO_(2) in the off-gas,with more or less constant amounts of CO above 15 vol.%O_(2).The amounts of NO and SO_(2) show a similar trend with a continuous increase with increasing O_(2) supply,with the SO_(2) breakthrough starting earlier and being released over a shorter period.The chemical analysis of the sinter indicates the highest Fe(II)values in the range of 12–21 vol.%O_(2) in the suction gas.展开更多
Bovine coronavirus(BCoV)poses a significant threat to the global cattle industry,causing both respiratory and gastrointestinal infections in cattle populations.This necessitates the development of efficacious vaccines...Bovine coronavirus(BCoV)poses a significant threat to the global cattle industry,causing both respiratory and gastrointestinal infections in cattle populations.This necessitates the development of efficacious vaccines.While several inactivated and live BCoV vaccines exist,they are predominantly limited to calves.The immunization of adult cattle is imperative for BCoV infection control,as it curtails viral transmission to calves and ameliorates the impact of enteric and respiratory ailments across all age groups within the herd.This study presents an in silico methodology for devising a multiepitope vaccine targeting BCoV.The spike glycoprotein(S)and nucleocapsid(N)proteins,which are integral elements of the BCoV structure,play pivotal roles in the viral infection cycle and immune response.We constructed a remarkably effective multiepitope vaccine candidate specifically designed to combat the BCoV population.Using immunoinformatics technology,B-cell and T-cell epitopes were predicted and linked together using linkers and adjuvants to efficiently trigger both cellular and humoral immune responses in cattle.The in silico construct was characterized,and assessment of its physicochemical properties revealed the formation of a stable vaccine construct.After 3D modeling of the vaccine construct,molecular docking revealed a stable interaction with the bovine receptor bTLR4.Moreover,the viability of the vaccine’s high expression and simple purification was demonstrated by codon optimization and in silico cloning expression into the pET28a(+)vector.By applying immunoinformatics approaches,researchers aim to better understand the immune response to bovine coronavirus,discover potential targets for intervention,and facilitate the development of diagnostic tools and vaccines to mitigate the impact of this virus on cattle health and the livestock industry.We anticipate that the design will be useful as a preventive treatment for BCoV sickness in cattle,opening the door for further laboratory studies.展开更多
Background:Aldehyde dehydrogenase(ALDH)genes constitute an important family of supergenes that play key roles in synthesizing various biomolecules and maintaining cellular homeostasis by catalyzing the oxidation of al...Background:Aldehyde dehydrogenase(ALDH)genes constitute an important family of supergenes that play key roles in synthesizing various biomolecules and maintaining cellular homeostasis by catalyzing the oxidation of aldehyde products.With climate change increasing the exposure of plants to abiotic stresses such as salt and drought,ALDH genes have been identified as important contributors to stress tolerance.In particular,they help to reduce stress-induced lipid peroxidation.Objectives:This study aims to identify and characterize members of the ALDH supergene family in Phaseolus vulgaris through a genome-wide bioinformatic analysis and investigate their role in response to abiotic stressors such as drought and salt stress.Methods:Genome-wide identification of 26 ALDH genes in P.vulgaris was performed using bioinformatics tools.The identified ALDH proteins were ana-lyzed for molecular weight,amino acid number,and exon number.Phylogenetic analysis was performed to clas-sify P.vulgaris,Arabidopsis thaliana,and Glycine max ALDH proteins into different groups.Strong links between these genes and functions related to growth,development,stress responses,and hormone signaling were identified by cis-element analysis in promoter regions.In silico expression,analysis was performed to assess gene expression levels in different plant tissues.Results:RT-qPCR results showed that the expression of ALDH genes was signif-icantly altered under drought and salt stress in beans.This study provides a comprehensive characterization of the ALDH supergene family in P.vulgaris,highlighting their potential role in abiotic stress tolerance.Conclusion:Thesefindings provide a basis for future research on the functional roles of ALDH genes in enhancing plant resis-tance to environmental stressors.展开更多
Modulated electro-hyperthermia (mEHT) targets tissue’s natural electric and thermal heterogeneities to heat the cancer cells selectively. The applied 13.56 MHz radiofrequency (RF) is a carrier of the low-frequency mo...Modulated electro-hyperthermia (mEHT) targets tissue’s natural electric and thermal heterogeneities to heat the cancer cells selectively. The applied 13.56 MHz radiofrequency (RF) is a carrier of the low-frequency modulation. The high-frequency part was chosen to select the malignant lesion using the specialties of the tumor: the higher conductivity and dielectric constant of the tumor than its host. The electric field selects the tumor, and the low-frequency amplitude modulation polarizes and excites the transmembrane proteins of the malignant cells. The dominant absorption of the energy by the microscopic clusters of the membrane rafts acts like nanoparticle heating. Exciting the membrane produces various apoptotic signals. The processes were modeled using silico and phantom experiments, which proved the concept. The preclinical verification was made in vitro and in vivo, and in the end, clinical proofs validated the method. Our objective is to follow all the development steps from the laboratory to the clinics in a trilogy of articles. This present is the first part, which deals with in silico, phantom, and in vitro research.展开更多
Background: Retinoblastoma, the most common intraocular pediatric cancer, presents complexities in its genetic landscape that necessitate a deeper understanding for improved therapeutic interventions. This study lever...Background: Retinoblastoma, the most common intraocular pediatric cancer, presents complexities in its genetic landscape that necessitate a deeper understanding for improved therapeutic interventions. This study leverages computational tools to dissect the differential gene expression profiles in retinoblastoma. Methods: Employing an in silico approach, we analyzed gene expression data from public repositories by applying rigorous statistical models, including limma and de seq 2, for identifying differentially expressed genes DEGs. Our findings were validated through cross-referencing with independent datasets and existing literature. We further employed functional annotation and pathway analysis to elucidate the biological significance of these DEGs. Results: Our computational analysis confirmed the dysregulation of key retinoblastoma-associated genes. In comparison to normal retinal tissue, RB1 exhibited a 2.5-fold increase in expression (adjusted p Conclusions: Our analysis reinforces the critical genetic alterations known in retinoblastoma and unveils new avenues for research into the disease’s molecular basis. The discovery of chemoresistance markers and immune-related genes opens potential pathways for personalized treatment strategies. The study’s outcomes emphasize the power of in silico analyses in unraveling complex cancer genomics.展开更多
BACKGROUND Colonization with Helicobacter pylori(H.pylori)has a strong correlation with gastric cancer,and the virulence factor CagA is implicated in carcinogenesis.Studies have been conducted using medicinal plants w...BACKGROUND Colonization with Helicobacter pylori(H.pylori)has a strong correlation with gastric cancer,and the virulence factor CagA is implicated in carcinogenesis.Studies have been conducted using medicinal plants with the aim of eliminating the pathogen;however,the possibility of blocking H.pylori-induced cell differentiation to prevent the onset and/or progression of tumors has not been addressed.This type of study is expensive and time-consuming,requiring in vitro and/or in vivo tests,which can be solved using bioinformatics.Therefore,prospective computational analyses were conducted to assess the feasibility of interaction between phenolic compounds from medicinal plants and the CagA oncoprotein.AIM To perform a computational prospecting of the interactions between phenolic compounds from medicinal plants and the CagA oncoprotein of H.pylori.METHODS In this in silico study,the structures of the phenolic compounds(ligands)kaempferol,myricetin,quercetin,ponciretin(flavonoids),and chlorogenic acid(phenolic acid)were selected from the PubChem database.These phenolic compounds were chosen based on previous studies that suggested medicinal plants as non-drug treatments to eliminate H.pylori infection.The three-dimensional structure model of the CagA oncoprotein of H.pylori(receptor)was obtained through molecular modeling using computational tools from the I-Tasser platform,employing the threading methodology.The primary sequence of CagA was sourced from GenBank(BAK52797.1).A screening was conducted to identify binding sites in the structure of the CagA oncoprotein that could potentially interact with the ligands,utilizing the GRaSP online platform.Both the ligands and receptor were prepared for molecular docking using AutoDock Tools 4(ADT)software,and the simulations were carried out using a combination of ADT and AutoDock Vina v.1.2.0 software.Two sets of simulations were performed:One involving the central region of CagA with phenolic compounds,and another involving the carboxy-terminus region of CagA with phenolic compounds.The receptor-ligand complexes were then analyzed using PyMol and BIOVIA Discovery Studio software.RESULTS The structure model obtained for the CagA oncoprotein exhibited high quality(C-score=0.09)and was validated using parameters from the MolProbity platform.The GRaSP online platform identified 24 residues(phenylalanine and leucine)as potential binding sites on the CagA oncoprotein.Molecular docking simulations were conducted with the three-dimensional model of the CagA oncoprotein.No complexes were observed in the simulations between the carboxy-terminus region of CagA and the phenolic compounds;however,all phenolic compounds interacted with the central region of the oncoprotein.Phenolic compounds and CagA exhibited significant affinity energy(-7.9 to-9.1 kcal/mol):CagA/kaempferol formed 28 chemical bonds,CagA/myricetin formed 18 chemical bonds,CagA/quercetin formed 16 chemical bonds,CagA/ponciretin formed 13 chemical bonds,and CagA/chlorogenic acid formed 17 chemical bonds.Although none of the phenolic compounds directly bound to the amino acid residues of the K-Xn-R-X-R membrane binding motif,all of them bound to residues,mostly positively or negatively charged,located near this region.CONCLUSION In silico,the tested phenolic compounds formed stable complexes with CagA.Therefore,they could be tested in vitro and/or in vivo to validate the findings,and to assess interference in CagA/cellular target interactions and in the oncogenic differentiation of gastric cells.展开更多
Fusobacterium nucleatum is an anaerobic, commensal, gram-negative oral bacterium that is carcinogenic and causes a wide range of human diseases. The present study focused on the analysis of the hypothetical protein, H...Fusobacterium nucleatum is an anaerobic, commensal, gram-negative oral bacterium that is carcinogenic and causes a wide range of human diseases. The present study focused on the analysis of the hypothetical protein, HMPREF3221_01179, derived from F. nucleatum strain MJR7757B, employing various computational methods to anticipate both its structure and functional characteristics. NCBI conserved domain analysis, NCBI BLASTp and MEGA Phylogenetic tree study characterize the target protein as an outer membrane efflux protein (ToIC family) which facilitate the bacterial transmembrane transport. With a molecular weight of 52120.02 Da, an isoelectric point (pI) of 8.33, and an instability index of 29.47, the protein is anticipated to exhibit good solubility in the extracellular space and crucial stability for pharmaceutical applications. The protein’s structure meets quality standards during the construction and refinement of its 3D model. The efflux inhibitor Arginine beta-naphthylamide exhibits a significant binding affinity (-7.1 kcal/mol) to the binding site of the target protein. The in-silico analysis improves the understanding of the protein and facilitates future investigations into therapeutic medication.展开更多
The synthesis of new 4-imino-4H-chromeno[2,3-d]pyrimidin-3(5H)-amine in four steps including one step under microwave dielectric heating is reported. The structural identity of the synthesized compounds was establishe...The synthesis of new 4-imino-4H-chromeno[2,3-d]pyrimidin-3(5H)-amine in four steps including one step under microwave dielectric heating is reported. The structural identity of the synthesized compounds was established according to their spectroscopic analysis, such as FT-IR, NMR and mass spectroscopy. These new compounds were tested for their antiproliferative activities on seven representative human tumoral cell lines (Huh7 D12, Caco2, MDA-MB231, MDA-MB468, HCT116, PC3 and MCF7) and also on fibroblasts. Among them, only the compounds 6c showed micromolar cytotoxic activity on tumor cell lines (1.8 50 50 > 25 μM). Finally, in silico ADMET studies ware performed to investigate the possibility of using of the identified compound 6c as potential anti-tumor compound.展开更多
Background: Cosmetic formulations, and particularly solar products which contain mineral and chemical UV-filters, are often suspected of causing harmful effects on marine fauna and flora. After the publication of our ...Background: Cosmetic formulations, and particularly solar products which contain mineral and chemical UV-filters, are often suspected of causing harmful effects on marine fauna and flora. After the publication of our work in 2019 concerning the ecotoxicological effects of such formulations on corals (Seriatopora hystrix), we here provide some new information about the biodegradability and the ecotoxicological effects of these products on marine zoo- and phytoplankton. Therefore, we choose to realize in silico and in vitro studies of the biodegradability of several solar products but also to evaluate the ecotoxicological effects of these products on one phytoplankton, i.e. Phaeodactylum tricornutum, and one zooplankton, i.e. Acartia tonsa, of a great importance for sea species survival (notably as sources of food). Materials and methods: Two different approaches were used to study the biodegradability of the tested products: One in silico method and an in vitro one. 2 solar products were involved in the in silico study which consisted in the determination of the degradation factor (DF) of each ingredient of the tested formulas in order to finally obtain their estimated biodegradability percentage. Already available data concerning each ingredient coupled to a computer model developed with one of our partners were used to achieve this study. The in vitro study involved 8 formulas containing UV-filters and was led by following the OECD 301 F guidelines. Ecotoxicological studies of 7 of the formulas containing UV-filters were for their part realized by following the ISO 10253 guidelines for the experiments led with Phaeodactylum tricornutum, and the ISO 14669 guidelines for the experiments led with Acartia tonsa. In these studies, the effect of each tested product on crustaceans’ mortality and algal growth inhibition was assessed. Results: The in silico study predicted that formulas containing chemical UV-filters display a high biodegradability (superior to the threshold value of 60% given by the OECD 301 F guidelines). In the in vitro part of our work, the 8 tested formulas showed a biodegradability slightly inferior to the one predicted in the in silico experiments. Therefore, in order to evaluate if these calculated biodegradability value could have significant harmful effects on zoo- or phytoplankton, we studied the effect of our products regarding the growth inhibition on Phaeodactylum tricornutum and the mortality on Acartia tonsa. In this last part of the study, all the tested products were classified as “non ecotoxic” following an internal classification based on Part 4 entitled “Environmental Hazards” of Globally Harmonized System of Classification and Labelling of Chemicals (GHS), 9<sup>th</sup> edition (2021). Conclusions: These results are notably in line with those published by our teams in 2019 on the effects of solar cosmetic products on corals and seem to confirm that formulas containing mineral and chemical UV-filters can be daily used without displaying significant noxious effects on marine fauna and flora. .展开更多
根据日本晴cab4基因序列(GenBank:AK104499.1)设计引物,用RT-PCR的方法从籼稻9311中克隆了叶绿素a/b结合蛋白基因的全长cDNA,命名为cab-9311(cab gene from 9311)。insilico分析表明:cab-9311与cab4基因同源性为99%,编码的蛋白含有244...根据日本晴cab4基因序列(GenBank:AK104499.1)设计引物,用RT-PCR的方法从籼稻9311中克隆了叶绿素a/b结合蛋白基因的全长cDNA,命名为cab-9311(cab gene from 9311)。insilico分析表明:cab-9311与cab4基因同源性为99%,编码的蛋白含有244个氨基酸,与cab4基因编码的蛋白同源性为98%。蛋白分子质量为26.9kD,理论等电点为6.52。第54位～第216位氨基酸是一个典型的叶绿素a/b结合蛋白功能域(chlorophyll a/bbinding domain)。跨膜分析和蛋白质三级预测显示,该蛋白在C端有一个典型的跨膜区。亚细胞定位分析表明该蛋白定位于叶绿体,是一个叶绿体内囊体膜上的锚定蛋白。展开更多
基金upported by the National Key Research and Development Program of China(Grant No.:2023YFF1204904)the National Natural Science Foundation of China(Grant Nos.:U23A20530 and 82173746)Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism(Shanghai Municipal Education Commission,China).
文摘Negative logarithm of the acid dissociation constant(pK_(a))significantly influences the absorption,dis-tribution,metabolism,excretion,and toxicity(ADMET)properties of molecules and is a crucial indicator in drug research.Given the rapid and accurate characteristics of computational methods,their role in predicting drug properties is increasingly important.Although many pK_(a) prediction models currently exist,they often focus on enhancing model precision while neglecting interpretability.In this study,we present GraFpKa,a pK_(a) prediction model using graph neural networks(GNNs)and molecular finger-prints.The results show that our acidic and basic models achieved mean absolute errors(MAEs)of 0.621 and 0.402,respectively,on the test set,demonstrating good predictive performance.Notably,to improve interpretability,GraFpKa also incorporates Integrated Gradients(IGs),providing a clearer visual description of the atoms significantly affecting the pK_(a) values.The high reliability and interpretability of GraFpKa ensure accurate pKa predictions while also facilitating a deeper understanding of the relation-ship between molecular structure and pK_(a) values,making it a valuable tool in the field of pK_(a) prediction.
文摘Objective Oral squamous cell carcinoma(OSCC)is an aggressive cancer with a high mortality rate.San-Zhong-Kui-Jian-Tang(SZKJT),a Chinese herbal formula,has long been used as an adjuvant therapy in cancer clinical practice.Although its therapeutic effects and molecular mechanisms in OSCC have been previously elucidated,the potential interactions and mechanisms between the active phytochemicals and their therapeutic targets are still lacking.Methods The present study employed network pharmacology and topology approaches to establish a“herbal ingredients–active phytochemicals–target interaction”network to explore the potential therapeutic targets of SZKJT-active phytochemicals in the treatment of OSCC.The role of the target proteins in oncogenesis was assessed via GO and KEGG enrichment analyses,and their interactions with the active phytochemicals of SZKJT were calculated via molecular docking and dynamic simulations.The pharmacokinetic properties and toxicity of the active phytochemicals were also predicted.Results A total of 171 active phytochemicals of SZKJT fulfilled the bioavailability and drug-likeness screening criteria,with the flavonoids quercetin,kaempferol,and naringenin having the greatest potential.The 4 crucial targets of these active phytochemicals are PTGS2,TNF,BCL2,and CASP3,which encode cyclooxygenase-2,tumor necrosis factor(TNF),BCL-2 apoptosis regulator,and caspase-3,respectively.The interactions between phytochemicals and target proteins were predicted to be thermodynamically feasible and stable via molecular docking and dynamics simulations.Finally,the results revealed that the IL-6/JAK/STAT3 pathway and TNF signaling via NF-κB are the two prominent pathways targeted by SZKJT.Conclusion In summary,this study provides computational data for in-depth exploration of the mechanism by which SZKJT activates phytochemicals to treat OSCC.
文摘This study investigates the relationships between exposures to ambient air pollution—specifically particulate matter 2.5 (PM_(2.5)) and its metabolites—and the risk of depression.Nonlinear and linear regression,Bayesian kernel machine regression,and toxicogenomic analysis were key approaches.PM_(2.5)exposure was positively associated with the risk of developing depression,whereas phenylglyoxylic acid exposure was negatively associated with depression risk.We found a significant overall relationship between ambient air pollution and depression,particularly at the 55th and 60th percentiles.Although statistical significance was not reached at the 65th percentile,there was a noticeable upward trend,indicating a potential association.Interestingly,no significant connection was found between a combination of metabolites from ambient air pollution and depression.PM_(2.5)and phenylglyoxylic acid emerged as the most influential compounds in the models,respectively.PM_(2.5)exposure altered the expression of 42 specific targets associated with depression,especially POMC,SCL6A4,IL6,and SOD2.The study identified specific pathways related to insulin secretion,energy metabolism,blood circulation,tube diameter,and maintenance of blood vessel diameter,as well as key molecular mechanisms involving hsa-miR-124-3p,hsa-miR-155-5p,hsa-miR-16-5p,and SP1.These mechanisms were found to underlie the etiology of depression associated with PM_(2.5)exposure.In conclusions,PM_(2.5)and phenylglyoxylic acid were found to be associated with depression.Further work is needed to gain insight into the molecular mechanisms by which these chemicals affect depression,especially pathways related to insulin secretion and blood circulation.
文摘Thymus serpyllum L.,often known as wild thyme,has been used since ancient times due to its multifaceted culinary and medicinal attributes.It is usually utilized in folk medicine to manage different health issues.This work aimed to investigate the chemical composition and biological characteristics of T.serpyllum essential oil(EO),including its antimicrobial,antioxidant,and anti-inflammatory capabilities.Moreover,we have prompted an in-silico simulation to reveal the underlying mode of action of these properties.The chemical characterization of T.serpyllum(EO)by Gas Chromatography-Mass Spectrometry(GC-MS)indicated sabinene(17.33%),terpinen-4-ol(11.73%),phellandral(13.18%),and thymol(10.54%)as main components.The antimicrobial screening utilized the disc-diffusion technique,MIC,and MBC assays.The disc-diffusion test’s results revealed significant anti-Candida activity and notable antibacterial efficacy.The MIC and MBC tests showed that T.serpyllum EO effectively stops bacterial growth,including Gram-positive and Gram-negative strains and Candida strains.The tolerance level ratio demonstrated that this EO exhibits bactericidal and fungicidal effects on all tested bacteria and Candida strains.Also,T.serpyllum EO presented effective inhibitory activity against the 5-lipoxygenase(5-LOX)enzyme(IC50=744.19±0.1µg/mL)(p<0.05).It also effectively affected FRAP,β-carotene,DPPH,and ABTS radicals.In light of these findings,T.serpyllum holds promise for diverse applications across pharmaceuticals,nutraceuticals,and the food industry.However,further research and collaboration between traditional knowledge and modern medicine are crucial to fully realizing its potential benefits in these fields.
文摘Background:Pistacia integerrima,a cornerstone of traditional medicine,is renowned for its therapeutic applications against various health conditions,including cancer and hepatitis.This study investigates the pharmacological potential of bioactive compounds derived from Pistacia integerrima in inhibiting 5-lipoxygenase(5-LOX),a key enzyme implicated in inflammation and cancer progression.The current study aimed to evaluate the lipoxygenase inhibitory activity of bioactive compounds from Pistacia integerrima and assess their potential for therapeutic development in the context of inflammation and cancer treatment.Methods:Three major compounds-spinacetin(1),patuletin(2),and pistagremic acid(3)-were isolated from Pistacia integerrima and analyzed for their lipoxygenase inhibitory activity.Biochemical assays and molecular docking studies were performed to assess their effectiveness in inhibiting 5-LOX.Results:All three compounds demonstrated significant inhibition of lipoxygenase activity.Spinacetin(1)and patuletin(2)exhibited the most potent inhibitory effects,with IC_(50)values of 40.34μM and 45.04μM,respectively.Molecular docking studies revealed that patuletin(2)had the highest binding affinity(−7.717 kcal/mol)against 5-LOX,followed by spinacetin(1)with a binding affinity of−6.074 kcal/mol.In-depth in silico analysis highlighted the drug-likeness of spinacetin(1)and its favorable toxicological profile,suggesting its suitability for therapeutic development.Conclusion:The study demonstrates that compounds from Pistacia integerrima,particularly spinacetin and patuletin,have significant lipoxygenase inhibitory activity,with spinacetin showing promise as a lead candidate for lipoxygenase-targeted therapies.The findings reinforce the therapeutic relevance of Pistacia integerrima and suggest that its bioactive compounds may serve as safer,plant-based alternatives to conventional anti-inflammatory and anticancer treatments.
基金supported by Decit/SCTIE-Ministério da Saúde,Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq),Fundação de AmparoàPesquisa do Estado de Alagoas(FAPEAL)and Secretaria de Estado da Saúde de Alagoas(SESAU-AL)[PPSUS 60030000841/2016].
文摘Objective:To investigate mutations in the Chikungunya(CHIKV)envelope genome region and evaluate their potential impact on B lymphocyte epitopes via in silico analysis.Methods:E1,E2 and 6K protein genes were sequenced from viral RNA isolated from 13 CHIKV-positive serum samples from Alagoas State,Brazil,during the 2016 outbreak.Phylogenetic analysis,experimental epitope identification in the immune epitope database(IEDB)and in silico approaches were employed to predict the potential impact of the detected mutations.Results:The sequences were clustered via phylogenetic analysis.The CHIKV isolates belong to the ECSA genotype,with 13 detected amino acid mutations.Five mutations are located on the surface of the viral particle in regions critical for cellular receptor interaction.Nine mutations are known experimentally validated epitopes for B and T cells.In B-cell epitope predictions,mutations affect sequences within three conformational epitopes in E2 and one in E1,as well as linear epitopes.Notably,the E2-G60D mutation found in the Alagoas strain has been previously reported to influence the vector competence of Aedes aegypti,the primary vector in Brazil.Conclusions:Genomic surveillance and an in-depth understanding of viral mutations are crucial for adapting public health strategies and improving the outbreak response.These findings could have significant public health implications,such as the development of more effective vaccines,diagnostic tests,and antiviral therapies.
基金supported by NPDF fellowship grants from the Central Council for Research in Ayurvedic Sciences,Ministry of AYUSH,Govt.of India(HQ-ESTT012/60/2022-ESTT/6783).
文摘Objective:To explore the effect of a hydrogel of Piper longum(P.longum)root against biofilm-forming multidrug-resistant(MDR)Staphylococcus aureus(S.aureus)through in vitro,in silico,and in vivo studies.Methods:We isolated the P.longum root ethanolic extract and the compounds using p-HPLC.In vitro antibacterial and antibiofilm activities of P.longum root extract and isolated alkamide compounds against biofilm-forming MDR S.aureus(ATCC 33591)were assessed using agar diffusion and broth microdilution methods,respectively.In silico investigations were conducted to investigate the interaction of alkamide compounds with three target proteins glycogen synthase kinase 3β(GSK3β),matrix metalloproteinases-8(MMP-8),and inducible nitric oxide synthase(iNOS).In addition,the wound healing effect of P.longum root extract 2%and 5%(w/v)-containing hydrogels was determined in mice.Results:The ethanolic root extract of P.longum and its compounds exhibited in vitro antibacterial activity with minimum inhibitory concentrations between 50µg/mL and 700µg/mL,as well as significantly reduced biofilm formation.Piperdardine isolated from P.longum root extract had the best molecular docking score(-9.7,-9.8,and-9.2 kcal/mol)with target proteins GSK3β,MMP-8,and iNOS.In vivo studies showed that P.longum hydrogels significantly lowered the number of colony-forming units(P<0.05).The P.longum 5%(w/v)hydrogel-treated group showed enhanced wound healing activity,achieving a wound contraction rate of 99.34%on day 14.Furthermore,histopathological analysis confirmed increased re-epithelialization and reduced inflammation in mice treated with P.longum 5%(w/v)hydrogel.Conclusions:P.longum root extract has pharmacological potential as an antibacterial and wound-healing agent,and further research is required to confirm its efficacy and clinical application.
文摘Background:Epidemiological studies have confirmed that longer exposure to insecticides like cypermethrin(CYP)significantly increases the risk of male reproductive toxicity.Crocus sativus L.has been recognized due to its therapeutic properties,but its exact role and molecular mechanisms in treatment of reproductive dysfunction remain unclear.Methods:During this study,36 rats were randomly divided into six groups(n=6):control,CYP-induced(60 mg/kg),standard(leuprolide 3 mg/kg)and three treatment groups receiving aqueous,ethanolic,and oil extracts(50 mg/kg or 20 mL/kg)for post-toxicity induction.Results:The finding represented that exposure of CYP significantly increased oxidative stress,disrupted testicular architecture,and markedly reduced testosterone levels(P<0.05).Importantly,Crocus sativus L.treatment alleviated these changes by increasing the expression of Nrf2(nuclear factor erythroid 2-related factor 2),restoring the activity of antioxidant enzymes,and enhancing testicular histomorphology.Surprisingly,molecular docking established a high binding affinity of Crocus sativus L.phytoconstituents such as gallic acid,cinnamic acid and quercetin to the Nrf2-Keap1 complex.It is worth noting that,Crocus sativus L.exhibited a high level of protection against reproductive toxicity caused by CYP in male rats,which was mediated by the activation of Nrf2 pathway,reduction of oxidative damage,and favorable ADMET characteristics.Conclusion:Notably,this research provides a more valid,safe,and effective method of developing new drugs for reproductive disorders,however,further investigation is needed to support the research findings and implement it in clinical practice.
基金Open access funding provided by Montanuniversität Leoben.
文摘The variation of the O_(2) content in the suction gas,in the range from 7 to 30 vol.%,during the iron ore sintering process,is investigated.Miniaturized laboratory-scale sintering experiments are carried out using an industry-like raw mixture to study the effects of O_(2) variation on the sintering process with particular emphasis on the off-gas composition,specific sintering parameters and the sinter strength as well as the chemical composition of the sinter.After the ignition at the bed surface,the gas hood is placed on the sintering column,allowing a synthetic gas mixture to be drawn through the sinter bed until the burn-through point is reached.For additional interpretation of the experimental results,the theoretical coke combustion rate as a function of the oxygen partial pressure was calculated and plotted against the experimentally measured peak temperature in the sinter bed of the respective sinter series.An increasing O_(2) content in the suction gas results in a faster flame front speed combined with a more gradual temperature rise of the heat wave and longer dwell time in the melt phase formation temperature range.Due to the more pronounced flame front,both sinter yield and strength increase,resulting in lower return rates.Below 12 vol.%O_(2),a sharp decrease in sinter yield and strength can be observed,probably due to the low extent of melt phase formation and the associated minor formation of silico ferrite of calcium and aluminum(SFCA).The carbon burnout as well as the calcination increases with increasing the O_(2) content in the suction gas,resulting in higher levels of CO_(2) in the off-gas,with more or less constant amounts of CO above 15 vol.%O_(2).The amounts of NO and SO_(2) show a similar trend with a continuous increase with increasing O_(2) supply,with the SO_(2) breakthrough starting earlier and being released over a shorter period.The chemical analysis of the sinter indicates the highest Fe(II)values in the range of 12–21 vol.%O_(2) in the suction gas.
文摘Bovine coronavirus(BCoV)poses a significant threat to the global cattle industry,causing both respiratory and gastrointestinal infections in cattle populations.This necessitates the development of efficacious vaccines.While several inactivated and live BCoV vaccines exist,they are predominantly limited to calves.The immunization of adult cattle is imperative for BCoV infection control,as it curtails viral transmission to calves and ameliorates the impact of enteric and respiratory ailments across all age groups within the herd.This study presents an in silico methodology for devising a multiepitope vaccine targeting BCoV.The spike glycoprotein(S)and nucleocapsid(N)proteins,which are integral elements of the BCoV structure,play pivotal roles in the viral infection cycle and immune response.We constructed a remarkably effective multiepitope vaccine candidate specifically designed to combat the BCoV population.Using immunoinformatics technology,B-cell and T-cell epitopes were predicted and linked together using linkers and adjuvants to efficiently trigger both cellular and humoral immune responses in cattle.The in silico construct was characterized,and assessment of its physicochemical properties revealed the formation of a stable vaccine construct.After 3D modeling of the vaccine construct,molecular docking revealed a stable interaction with the bovine receptor bTLR4.Moreover,the viability of the vaccine’s high expression and simple purification was demonstrated by codon optimization and in silico cloning expression into the pET28a(+)vector.By applying immunoinformatics approaches,researchers aim to better understand the immune response to bovine coronavirus,discover potential targets for intervention,and facilitate the development of diagnostic tools and vaccines to mitigate the impact of this virus on cattle health and the livestock industry.We anticipate that the design will be useful as a preventive treatment for BCoV sickness in cattle,opening the door for further laboratory studies.
文摘Background:Aldehyde dehydrogenase(ALDH)genes constitute an important family of supergenes that play key roles in synthesizing various biomolecules and maintaining cellular homeostasis by catalyzing the oxidation of aldehyde products.With climate change increasing the exposure of plants to abiotic stresses such as salt and drought,ALDH genes have been identified as important contributors to stress tolerance.In particular,they help to reduce stress-induced lipid peroxidation.Objectives:This study aims to identify and characterize members of the ALDH supergene family in Phaseolus vulgaris through a genome-wide bioinformatic analysis and investigate their role in response to abiotic stressors such as drought and salt stress.Methods:Genome-wide identification of 26 ALDH genes in P.vulgaris was performed using bioinformatics tools.The identified ALDH proteins were ana-lyzed for molecular weight,amino acid number,and exon number.Phylogenetic analysis was performed to clas-sify P.vulgaris,Arabidopsis thaliana,and Glycine max ALDH proteins into different groups.Strong links between these genes and functions related to growth,development,stress responses,and hormone signaling were identified by cis-element analysis in promoter regions.In silico expression,analysis was performed to assess gene expression levels in different plant tissues.Results:RT-qPCR results showed that the expression of ALDH genes was signif-icantly altered under drought and salt stress in beans.This study provides a comprehensive characterization of the ALDH supergene family in P.vulgaris,highlighting their potential role in abiotic stress tolerance.Conclusion:Thesefindings provide a basis for future research on the functional roles of ALDH genes in enhancing plant resis-tance to environmental stressors.
文摘Modulated electro-hyperthermia (mEHT) targets tissue’s natural electric and thermal heterogeneities to heat the cancer cells selectively. The applied 13.56 MHz radiofrequency (RF) is a carrier of the low-frequency modulation. The high-frequency part was chosen to select the malignant lesion using the specialties of the tumor: the higher conductivity and dielectric constant of the tumor than its host. The electric field selects the tumor, and the low-frequency amplitude modulation polarizes and excites the transmembrane proteins of the malignant cells. The dominant absorption of the energy by the microscopic clusters of the membrane rafts acts like nanoparticle heating. Exciting the membrane produces various apoptotic signals. The processes were modeled using silico and phantom experiments, which proved the concept. The preclinical verification was made in vitro and in vivo, and in the end, clinical proofs validated the method. Our objective is to follow all the development steps from the laboratory to the clinics in a trilogy of articles. This present is the first part, which deals with in silico, phantom, and in vitro research.
文摘Background: Retinoblastoma, the most common intraocular pediatric cancer, presents complexities in its genetic landscape that necessitate a deeper understanding for improved therapeutic interventions. This study leverages computational tools to dissect the differential gene expression profiles in retinoblastoma. Methods: Employing an in silico approach, we analyzed gene expression data from public repositories by applying rigorous statistical models, including limma and de seq 2, for identifying differentially expressed genes DEGs. Our findings were validated through cross-referencing with independent datasets and existing literature. We further employed functional annotation and pathway analysis to elucidate the biological significance of these DEGs. Results: Our computational analysis confirmed the dysregulation of key retinoblastoma-associated genes. In comparison to normal retinal tissue, RB1 exhibited a 2.5-fold increase in expression (adjusted p Conclusions: Our analysis reinforces the critical genetic alterations known in retinoblastoma and unveils new avenues for research into the disease’s molecular basis. The discovery of chemoresistance markers and immune-related genes opens potential pathways for personalized treatment strategies. The study’s outcomes emphasize the power of in silico analyses in unraveling complex cancer genomics.
文摘BACKGROUND Colonization with Helicobacter pylori(H.pylori)has a strong correlation with gastric cancer,and the virulence factor CagA is implicated in carcinogenesis.Studies have been conducted using medicinal plants with the aim of eliminating the pathogen;however,the possibility of blocking H.pylori-induced cell differentiation to prevent the onset and/or progression of tumors has not been addressed.This type of study is expensive and time-consuming,requiring in vitro and/or in vivo tests,which can be solved using bioinformatics.Therefore,prospective computational analyses were conducted to assess the feasibility of interaction between phenolic compounds from medicinal plants and the CagA oncoprotein.AIM To perform a computational prospecting of the interactions between phenolic compounds from medicinal plants and the CagA oncoprotein of H.pylori.METHODS In this in silico study,the structures of the phenolic compounds(ligands)kaempferol,myricetin,quercetin,ponciretin(flavonoids),and chlorogenic acid(phenolic acid)were selected from the PubChem database.These phenolic compounds were chosen based on previous studies that suggested medicinal plants as non-drug treatments to eliminate H.pylori infection.The three-dimensional structure model of the CagA oncoprotein of H.pylori(receptor)was obtained through molecular modeling using computational tools from the I-Tasser platform,employing the threading methodology.The primary sequence of CagA was sourced from GenBank(BAK52797.1).A screening was conducted to identify binding sites in the structure of the CagA oncoprotein that could potentially interact with the ligands,utilizing the GRaSP online platform.Both the ligands and receptor were prepared for molecular docking using AutoDock Tools 4(ADT)software,and the simulations were carried out using a combination of ADT and AutoDock Vina v.1.2.0 software.Two sets of simulations were performed:One involving the central region of CagA with phenolic compounds,and another involving the carboxy-terminus region of CagA with phenolic compounds.The receptor-ligand complexes were then analyzed using PyMol and BIOVIA Discovery Studio software.RESULTS The structure model obtained for the CagA oncoprotein exhibited high quality(C-score=0.09)and was validated using parameters from the MolProbity platform.The GRaSP online platform identified 24 residues(phenylalanine and leucine)as potential binding sites on the CagA oncoprotein.Molecular docking simulations were conducted with the three-dimensional model of the CagA oncoprotein.No complexes were observed in the simulations between the carboxy-terminus region of CagA and the phenolic compounds;however,all phenolic compounds interacted with the central region of the oncoprotein.Phenolic compounds and CagA exhibited significant affinity energy(-7.9 to-9.1 kcal/mol):CagA/kaempferol formed 28 chemical bonds,CagA/myricetin formed 18 chemical bonds,CagA/quercetin formed 16 chemical bonds,CagA/ponciretin formed 13 chemical bonds,and CagA/chlorogenic acid formed 17 chemical bonds.Although none of the phenolic compounds directly bound to the amino acid residues of the K-Xn-R-X-R membrane binding motif,all of them bound to residues,mostly positively or negatively charged,located near this region.CONCLUSION In silico,the tested phenolic compounds formed stable complexes with CagA.Therefore,they could be tested in vitro and/or in vivo to validate the findings,and to assess interference in CagA/cellular target interactions and in the oncogenic differentiation of gastric cells.
文摘Fusobacterium nucleatum is an anaerobic, commensal, gram-negative oral bacterium that is carcinogenic and causes a wide range of human diseases. The present study focused on the analysis of the hypothetical protein, HMPREF3221_01179, derived from F. nucleatum strain MJR7757B, employing various computational methods to anticipate both its structure and functional characteristics. NCBI conserved domain analysis, NCBI BLASTp and MEGA Phylogenetic tree study characterize the target protein as an outer membrane efflux protein (ToIC family) which facilitate the bacterial transmembrane transport. With a molecular weight of 52120.02 Da, an isoelectric point (pI) of 8.33, and an instability index of 29.47, the protein is anticipated to exhibit good solubility in the extracellular space and crucial stability for pharmaceutical applications. The protein’s structure meets quality standards during the construction and refinement of its 3D model. The efflux inhibitor Arginine beta-naphthylamide exhibits a significant binding affinity (-7.1 kcal/mol) to the binding site of the target protein. The in-silico analysis improves the understanding of the protein and facilitates future investigations into therapeutic medication.
文摘The synthesis of new 4-imino-4H-chromeno[2,3-d]pyrimidin-3(5H)-amine in four steps including one step under microwave dielectric heating is reported. The structural identity of the synthesized compounds was established according to their spectroscopic analysis, such as FT-IR, NMR and mass spectroscopy. These new compounds were tested for their antiproliferative activities on seven representative human tumoral cell lines (Huh7 D12, Caco2, MDA-MB231, MDA-MB468, HCT116, PC3 and MCF7) and also on fibroblasts. Among them, only the compounds 6c showed micromolar cytotoxic activity on tumor cell lines (1.8 50 50 > 25 μM). Finally, in silico ADMET studies ware performed to investigate the possibility of using of the identified compound 6c as potential anti-tumor compound.
文摘Background: Cosmetic formulations, and particularly solar products which contain mineral and chemical UV-filters, are often suspected of causing harmful effects on marine fauna and flora. After the publication of our work in 2019 concerning the ecotoxicological effects of such formulations on corals (Seriatopora hystrix), we here provide some new information about the biodegradability and the ecotoxicological effects of these products on marine zoo- and phytoplankton. Therefore, we choose to realize in silico and in vitro studies of the biodegradability of several solar products but also to evaluate the ecotoxicological effects of these products on one phytoplankton, i.e. Phaeodactylum tricornutum, and one zooplankton, i.e. Acartia tonsa, of a great importance for sea species survival (notably as sources of food). Materials and methods: Two different approaches were used to study the biodegradability of the tested products: One in silico method and an in vitro one. 2 solar products were involved in the in silico study which consisted in the determination of the degradation factor (DF) of each ingredient of the tested formulas in order to finally obtain their estimated biodegradability percentage. Already available data concerning each ingredient coupled to a computer model developed with one of our partners were used to achieve this study. The in vitro study involved 8 formulas containing UV-filters and was led by following the OECD 301 F guidelines. Ecotoxicological studies of 7 of the formulas containing UV-filters were for their part realized by following the ISO 10253 guidelines for the experiments led with Phaeodactylum tricornutum, and the ISO 14669 guidelines for the experiments led with Acartia tonsa. In these studies, the effect of each tested product on crustaceans’ mortality and algal growth inhibition was assessed. Results: The in silico study predicted that formulas containing chemical UV-filters display a high biodegradability (superior to the threshold value of 60% given by the OECD 301 F guidelines). In the in vitro part of our work, the 8 tested formulas showed a biodegradability slightly inferior to the one predicted in the in silico experiments. Therefore, in order to evaluate if these calculated biodegradability value could have significant harmful effects on zoo- or phytoplankton, we studied the effect of our products regarding the growth inhibition on Phaeodactylum tricornutum and the mortality on Acartia tonsa. In this last part of the study, all the tested products were classified as “non ecotoxic” following an internal classification based on Part 4 entitled “Environmental Hazards” of Globally Harmonized System of Classification and Labelling of Chemicals (GHS), 9<sup>th</sup> edition (2021). Conclusions: These results are notably in line with those published by our teams in 2019 on the effects of solar cosmetic products on corals and seem to confirm that formulas containing mineral and chemical UV-filters can be daily used without displaying significant noxious effects on marine fauna and flora. .
