Secretory Trefoil Factor 1 (TFF1) promotes gemcitabine resistance through chemokine receptor CXCR4 in Pancreatic Ductal Adenocarcinoma.

Gemcitabine is the first-line treatment option for patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). However, the frequent adoption of resistance to gemcitabine by cancer cells poses a significant challenge in treating this aggressive disease. In this study, we focused on analyzing the role of trefoil factor 1 (TFF1) in gemcitabine resistance in PDAC. Analysis of PDAC TCGA and cell line datasets indicated an enrichment of TFF1 in the gemcitabine-resistant classical subtype and suggested an inverse correlation between TFF1 expression and sensitivity to gemcitabine treatment. The genetic ablation of TFF1 in PDAC cells enhanced their sensitivity to gemcitabine treatment in both in vitro and in vivo tumor xenografts. The biochemical studies revealed that TFF1 contributes to gemcitabine resistance through enhanced stemness, increasing migration ability of cancer cells, and induction of anti-apoptotic genes. We further pursued studies to predict possible receptors exerting TFF1-mediated gemcitabine resistance. Protein-protein docking investigations with BioLuminate software revealed that TFF1 binds to the chemokine receptor CXCR4, which was supported by real-time binding analysis of TFF1 and CXCR4 using SPR studies. The exogenous addition of TFF1 increased the proliferation and migration of PDAC cells through the pAkt/pERK axis, which was abrogated by treatment with a CXCR4-specific antagonist AMD3100. Overall, the present study demonstrates the contribution of the TFF1-CXCR4 axis in imparting gemcitabine resistance properties to PDAC cells.

A hybrid cell image segmentation method based on the multilevel improvement of data.

Over the years, several methods have been developed for the segmentation of cell images. Most of the related techniques operate directly on the raw data (noisy cell samples) of the medical image which leads to adverse effects on the structure of leucocytes because the medical images are affected by multiple distortions (varying illumination, deficient background light intensity, and non-uniform staining). To overcome these problems, we came up with an improved solution that performs the qualitative enhancement of cell images for the smooth extraction of cell-nucleus. Although various segmentation methods have adopted an image improvement operation in practice. These methods also amplify the magnitude of image noise which leads to over-sampling and under-sampling of data points. This mis-labelling of data points is minimized by the developed approach which adopts a collaborative fusion strategy (CNN and Nuclear-norm approach) for the qualitative improvement of cell images. The enhanced cell samples were forwarded to the U-net (deep learning model) model for the semantic segmentation of cell images. The performance evaluation of the model was performed on three biomedical cell imaging datasets, which include the ALL-IDB (99.89% accuracy, 99.51% recall, and 99.01% precision), CellaVision (99.68% accuracy, 98.75% precision, and 97.94% specificity) and JTSC (98.45% accuracy, 97.42% precision, and 97.21% specificity) dataset. The results were compared with the state-of-art methods in which the adopted hybrid approach has overpowered the related techniques in the quantitative and qualitative domains.

Prevalence of Thiamine Deficiency in Pregnancy and its impact on fetal outcome in an area endemic for thiamine deficiency.

BACKGROUND: Pregnancy is a metabolically challenging state with increased nutritional demand. Thiamine is an important cofactor in various metabolic pathways and thus its deficiency could have a serious impact on both maternal and fetal outcomes. Kashmir has thiamine deficiency in endemic proportions, with multiple reports of infantile beriberi, postpartum neuropathy, and gastric beriberi. This prompted us to assess the extent of the burden of thiamine deficiency during pregnancy. METHODS: This cross-sectional study was conducted for a period of two years in pregnant women attending the antenatal clinic. A demographic, clinical, biochemical, and dietary assessment was done in all participants. The whole blood thiamine levels were assessed by high-performance liquid chromatography. RESULTS: A total of 492 participants were included in the study with a mean age of 30.30±4.57 years and a mean BMI of 24.25±3.32 Kg/m2. The mean whole blood thiamine level of all participants was 133.29±14.32 nmol/L. Low thiamine status was present in 38.2% (n = 188) of participants. Participants with low thiamine had poor perinatal outcomes, with 3.1% (n = 6) reporting early infant death. CONCLUSION: A high prevalence of thiamine deficiency occurs in pregnant women of Kashmir. Low thiamine is associated with poor nutritional status as well as poor perinatal outcomes. TRIAL REGISTRATION: CTRI/2022/07/044217.

Androgen receptor signaling and pyrethroids: Potential male infertility consequences.

Infertility is a global health concern inflicting a considerable burden on the global economy and a severe socio-psychological impact. Approximately 15% of couples suffer from infertility globally, with a male factor contribution of approximately 50%. However, male infertility remains largely unexplored, as the burden of infertility is mostly assigned to female people. Endocrine-disrupting chemicals (EDCs) have been proposed as one of the factors causing male infertility. Pyrethroids represent an important class of EDCs, and numerous studies have associated pyrethroid exposure with impaired male reproductive function and development. Therefore, the present study investigated the potentially toxic effects of two common pyrethroids, cypermethrin and deltamethrin, on androgen receptor (AR) signaling. The structural binding characterization of cypermethrin and deltamethrin against the AR ligand-binding pocket was performed using Schrodinger's induced fit docking (IFD) approach. Various parameters were estimated, such as binding interactions, binding energy, docking score, and IFD score. Furthermore, the AR native ligand, testosterone, was subjected to similar experiments against the AR ligand-binding pocket. The results revealed commonality in the amino acid-binding interactions and overlap in other structural parameters between the AR native ligand, testosterone, and the ligands, cypermethrin and deltamethrin. The estimated binding energy values of cypermethrin and deltamethrin were very high and close to those calculated for AR native ligand, testosterone. Taken together, the results of this study suggested potential disruption of AR signaling by cypermethrin and deltamethrin, which may result in androgen dysfunction and subsequent male infertility.

An Analysis of the Structural Relationship between Thyroid Hormone-Signaling Disruption and Polybrominated Diphenyl Ethers: Potential Implications for Male Infertility.

Polybrominated diphenyl ethers (PBDEs) are a common class of anthropogenic organobromine chemicals with fire-retardant properties and are extensively used in consumer products, such as electrical and electronic equipment, furniture, textiles, and foams. Due to their extensive use, PBDEs have wide eco-chemical dissemination and tend to bioaccumulate in wildlife and humans with many potential adverse health effects in humans, such as neurodevelopmental deficits, cancer, thyroid hormone disruption, dysfunction of reproductive system, and infertility. Many PBDEs have been listed as chemicals of international concern under the Stockholm Convention on Persistent Organic Pollutants. In this study, the aim was to investigate the structural interactions of PBDEs against thyroid hormone receptor (TRα) with potential implications in reproductive function. Structural binding of four PBDEs, i.e., BDE-28, BDE-100, BDE-153 and BDE-154 was investigated against the ligand binding pocket of TRα using Schrodinger's induced fit docking, followed by molecular interaction analysis and the binding energy estimation. The results indicated the stable and tight binding of all four PDBE ligands and similarity in the binding interaction pattern to that of TRα native ligand, triiodothyronine (T3). The estimated binding energy value for BDE-153 was the highest among four PBDEs and was more than that of T3. This was followed by BDE-154, which is approximately the same as that of TRα native ligand, T3. Furthermore, the value estimated for BDE-28 was the lowest; however, the binding energy value for BDE-100 was more than BDE-28 and close to that of TRα native ligand, T3. In conclusion, the results of our study suggested the thyroid signaling disruption potential of indicated ligands according to their binding energy order, which can possibly lead to disruption of reproductive function and infertility.

Potential Disruption of Systemic Hormone Transport by Tobacco Alkaloids Using Computational Approaches.

Tobacco/nicotine is one of the most toxic and addictive substances and continues to pose a significant threat to global public health. The harmful effects of smoking/nicotine affect every system in the human body. Nicotine has been associated with effects on endocrine homeostasis in humans such as the imbalance of gonadal steroid hormones, adrenal corticosteroid hormones, and thyroid hormones. The present study was conducted to characterize the structural binding interactions of nicotine and its three important metabolites, cotinine, trans-3'-hydroxycotinine, and 5'-hydroxycotinine, against circulatory hormone carrier proteins, i.e., sex-hormone-binding globulin (SHBG), corticosteroid-binding globulin (CBG), and thyroxine-binding globulin (TBG). Nicotine and its metabolites formed nonbonded contacts and/or hydrogen bonds with amino acid residues of the carrier proteins. For SHBG, Phe-67 and Met-139 were the most important amino acid residues for nicotine ligand binding showing the maximum number of interactions and maximum loss in ASA. For CBG, Trp-371 and Asn-264 were the most important amino acid residues, and for TBG, Ser-23, Leu-269, Lys-270, Asn-273, and Arg-381 were the most important amino acid residues. Most of the amino acid residues of carrier proteins interacting with nicotine ligands showed a commonality with the interacting residues for the native ligands of the proteins. Taken together, the results suggested that nicotine and its three metabolites competed with native ligands for binding to their carrier proteins. Thus, nicotine and its three metabolites may potentially interfere with the binding of testosterone, estradiol, cortisol, progesterone, thyroxine, and triiodothyronine to their carrier proteins and result in the disbalance of their transport and homeostasis in the blood circulation.

Insights into the Endocrine Disrupting Activity of Emerging Non-Phthalate Alternate Plasticizers against Thyroid Hormone Receptor: A Structural Perspective.

Many endocrine-disrupting chemicals (EDCs) have a ubiquitous presence in our environment due to anthropogenic activity. These EDCs can disrupt hormone signaling in the human and animal body systems including the very important hypothalamic-pituitary-thyroid (HPT) axis causing adverse health effects. Thyroxine (T4) and triiodothyronine (T3) are hormones of the HPT axis which are essential for regulation of metabolism, heart rate, body temperature, growth, development, etc. In this study, potential endocrine-disrupting activity of the most common phthalate plasticizer, DEHP, and emerging non-phthalate alternate plasticizers, DINCH, ATBC, and DEHA against thyroid hormone receptor (TRα) were characterized. The structural binding characterization of indicated ligands was performed against the TRα ligand binding site employing Schrodinger's induced fit docking (IFD) approach. The molecular simulations of interactions of the ligands against the residues lining a TRα binding pocket, including bonding interactions, binding energy, docking score, and IFD score were analyzed. In addition, the structural binding characterization of TRα native ligand, T3, was also done for comparative analysis. The results revealed that all ligands were placed stably in the TRα ligand-binding pocket. The binding energy values were highest for DINCH, followed by ATBC, and were higher than the values estimated for TRα native ligand, T3, whereas the values for DEHA and DEHP were similar and comparable to that of T3. This study suggested that all the indicated plasticizers have the potential for thyroid hormone disruption with two alternate plasticizers, DINCH and ATBC, exhibiting higher potential for thyroid dysfunction compared to DEHA and DEHP.

An Investigation on the Behaviour of Geosynthetic Reinforced Quarry Waste Bases (QWB) Under Vertical loading.

The strength and rigidity of base course can significantly affect the performance of pavements. The rigidity of roadways relies on the infill material used in base layers which is interdependent on its thickness and quality. With the increase in the base thickness, the performance of the base course improves but the cost associated with it also increases. Since the natural aggregates are not adequately available, use of waste materials in road construction can prove economical and environmental friendly. In this study, efficacy of geosynthetic (geocells and non-woven geotextile) reinforced quarry waste as an alternative base course materials (BCM) were investigated under static loading conditions (plate load test-PLT). By increasing the geocell height from 100 to 150 mm, the bearing capacity (BC) increased from 450 to 840 kPa. Similarly due to combined use of geocell and geotextile, BC increased from 500 to 890 kPa. The experimental results depict that the geosynthetic reinforcement increases the load bearing capacity of QWB's by 85%. Moreover, the artificial neural network analysis (ANN) was performed to predict the deformation on top of footing while considering different influential parameters. The results obtained from the ANN analysis were in good fit.

An enforced block diagonal low-rank representation method for the classification of medical image patterns.

Low-rank representation based methods have been used on a variety of medical imaging databases for the segmentation and classification of biomedical images. The subspace segmentation of the data is performed by generating the block diagonal coefficient matrix. Whereas, the data is classified by performing the partitioning of the low-rank representation matrix. There exist several such methods for analysing medical images. The major difference between them lies in the construction of the data dictionary. Most of the time, the input data pattern is used as the dictionary for learning the representation matrix. The direct use of the input data for learning the representation degrades the performance of the model because medical images are subjected to outliers of multiple types, which include environmental lighting, image appearance and varying illumination. These types of errors induce noise in the data. It has been observed that the representation-based model is robust when the training data is clean. If the training data contains corrupted subsamples, the performance of the model drops down. We have addressed the mentioned problem by adopting a class-wise dictionary learning approach. In which the pattern of each class is learnt as the set of tuples in the dictionary. The model has been evaluated on several medical imaging datasets, which includes the Break-his dataset, ALL-IDB, biomedical images, covid CT and chest X-ray. The classification performance of the model is best for the biomedical database (99.16%) followed by the Covid dataset (94%), ALL-IDB database (93.47%) and Break-his dataset (93%).

Structural binding perspectives of common plasticizers and a flame retardant, BDE-153, against thyroxine-binding globulin: potential for endocrine disruption.

The human exposure to diverse endocrine-disrupting chemicals (EDCs) has increased dramatically over several decades with very adverse health effects. Plasticizers and flame retardants constitute important classes of EDCs interfering in endocrine physiology including the thyroid function. Thyroxine (T4) is an important hormone regulating metabolism and playing key roles in developmental processes. In this study, six phthalate and nonphthalate plasticizers and one flame retardant (BDE-153) were subjected to structural binding against thyroxine-binding globulin (TBG). The aim was to understand their potential role in thyroid dysfunction using structural binding approach. The structural study was performed using Schrodinger's induced fit docking, followed by binding energy estimations of ligands and the molecular interaction analysis between the ligands and the amino acid residues in the TBG ligand-binding pocket. The results indicated that all the compounds packed tightly into the TBG ligand-binding pocket with similar binding pattern to that of TBG native ligand, T4. A high majority of TBG interacting amino acid residues for ligands showed commonality with native ligand, T4. The estimated binding energy values were highest for BDE-153 followed by nonphthalate plasticizer, DINCH, with values comparable with native ligand, T4. The estimated binding energy values of other plasticizers DEHP, DEHT, DEHA, ATBC, and TOTM were less than DINCH. In conclusion, the tight docking conformations, amino acid interactions, and binding energy values of the most of the indicated ligands were comparable with TBG native ligand, T4, suggesting their potential for thyroid dysfunction. The results revealed highest potential thyroid disruptive action for BDE-153 and DINCH.

Organotin Antifouling Compounds and Sex-Steroid Nuclear Receptor Perturbation: Some Structural Insights.

Organotin compounds (OTCs) are a commercially important group of organometallic compounds of tin used globally as polyvinyl chloride stabilizers and marine antifouling biocides. Worldwide use of OTCs has resulted in their ubiquitous presence in ecosystems across all the continents. OTCs have metabolic and endocrine disrupting effects in marine and terrestrial organisms. Thus, harmful OTCs (tributyltin) have been banned by the International Convention on the Control of Harmful Antifouling Systems since 2008. However, continued manufacturing by non-member countries poses a substantial risk for animal and human health. In this study, structural binding of common commercial OTCs, tributyltin (TBT), dibutyltin (DBT), monobutyltin (MBT), triphenyltin (TPT), diphenyltin (DPT), monophenyltin (MPT), and azocyclotin (ACT) against sex-steroid nuclear receptors, androgen receptor (AR), and estrogen receptors (ERα, ERß) was performed using molecular docking and MD simulation. TBT, DBT, DPT, and MPT bound deep within the binding sites of AR, ERα, and Erß, showing good dock score, binding energy and dissociation constants that were comparable to bound native ligands, testosterone and estradiol. The stability of docking complex was shown by MD simulation of organotin/receptor complex with RMSD, RMSF, Rg, and SASA plots showing stable interaction, low deviation, and compactness of the complex. A high commonality (50-100%) of interacting residues of ERα and ERß for the docked ligands and bound native ligand (estradiol) indicated that the organotin compounds bound in the same binding site of the receptor as the native ligand. The results suggested that organotins may interfere with the natural steroid/receptor binding and perturb steroid signaling.

Structural Aspects of Potential Endocrine-Disrupting Activity of Stereoisomers for a Common Pesticide Permethrin against Androgen Receptor.

Endocrine-disrupting chemicals (EDCs) are a serious global public health and environmental concern. Pyrethroids are insecticide chemicals that are extensively used for crop protection and household purposes but have been identified as EDCs. On account of their ubiquitous environmental presence, human exposure occurs via food, dermal, or inhalation routes and is associated with health problems, including reproductive dysfunction. Permethrin is the most commonly used pyrethroid, and with two chiral centers in its structure, it has four stereoisomeric forms (two enantiomer pairs), i.e., permethrin (1R,3R)-cis, permethrin (1R,3S)-trans, permethrin (1S,3S)-cis, and permethrin (1S,3R)-trans. The current study was performed for predicting the potential endocrine-disrupting activity of the aforementioned four stereoisomers of permethrin against the androgen receptor (AR). The structural binding characterization and binding energy estimations in the AR binding pocket were done using induced fit docking. The structural binding data indicated that all stereoisomers were placed stably in the AR binding pocket and that the estimated binding energy values were comparable to the AR native ligand, except for permethrin (1S,3S)-cis. Furthermore, the commonality in the amino acid interactions to that of the AR native ligand and the binding energy values suggested the potential AR-disrupting activity of all the stereoisomers; however, stereoselective differences were not observed. Taken together, the results suggest that human exposure to permethrin, either as a racemate mixture or in individual stereoisomer form, could potentially interfere with AR function, which may lead to male reproductive dysfunction.

Endocrine Disruption: Structural Interactions of Androgen Receptor against Di(2-ethylhexyl) Phthalate and Its Metabolites.

Diethylhexyl phthalate (DEHP) is a commonly used plasticizer in the manufacture of polyvinyl chloride plastics for household and commercial use. DEHP is a ubiquitous ecocontaminant and causes developmental and reproductive problems in children and adults. After exposure, DEHP is metabolized by endogenous hydrolysis and oxidation into the primary metabolite, mono-(2-ethylhexyl) phthalate (MEHP), and the secondary metabolites, mono-(2-ethyl-5-hydroxhexyl)phthalate (5-OH-MEHP), mono-(2-ethyl-5-oxohexyl) phthalate (5-oxo-MEHP), mono-(2-ethyl-5-carboxypentyl) phthalate (5-cx-MEPP), and mono-[(2-carboxymethyl)hexyl] phthalate (2-cx-MMHP). Very few studies have been reported on the adverse effects of DEHP metabolites, and the available information indicates that the metabolites might also be equally or more active as compared to the parent compound. In the present study, induced fit docking was used for structural binding characterization of the above five DEHP metabolites with androgen receptor (AR) to predict the potential endocrine-disrupting effects of these metabolites in AR signaling. All the DEHP metabolites interacted with the ligand-binding pocket of AR forming amino-acid residue interactions, hydrogen bonding, and pi-pi interactions. The binding energy of DEHP with AR was similar to that of native ligand testosterone. The amino-acid residue interactions of DEHP metabolites had 91-100% similarity compared to that of testosterone. In addition, all the DEHP metabolites and testosterone showed a common hydrogen bonding interaction with amino-acid Arg-752 of AR. Taken together, the structural binding data in the present study suggested the potential for DEHP metabolites to disrupt AR signaling, which may lead to androgen-related reproductive dysfunction.

Structural studies on the endocrine-disrupting role of polybrominated diphenyl ethers (PBDEs) in thyroid diseases.

Polybrominated diphenyl ethers (PBDEs) are synthetic brominated flame retardants with extensive applications in daily-life consumer products. However, PBDEs have become ubiquitous environmental contaminants due to their leach-out capability. The hazardous human health effects and endocrine-disrupting activity of PBDEs have led many governmental organizations to impose ban on their manufacture, causing their gradual phase out from commercial products. However, PBDEs and their metabolites are still being detected from biological and environmental samples owing to their persistence and bioaccumulation. The PDBE metabolites in these samples are present in concentrations often higher and even with higher toxic potential than parent PBDEs. The two commonly detected environmental PBDE congeners, 2,2',4,4'-tetra-bromodiphenyl ether (BDE-47) and 2,2',4,4',5-penta-bromodiphenyl ether (BDE-99), and their HO- and MeO- metabolites were considered in this study for their potential disrupting activity on thyroid hormone transport. Specifically, the study involved structural binding characterization of BDE-47 and BDE-99 including their two HO- and two MeO- metabolites with thyroxine-binding globulin (TBG), which is the main thyroid hormone transport protein in blood. The results showed that the binding pattern and molecular interactions of above two PBDEs and their metabolites exhibited overall similarity to native ligand, thyroxine in dock score, binding energy, and amino acid interactions with TBG. The BDE-99 and its metabolites were predicted to have stronger binding to TBG than BDE-47 with the metabolite 5-MeO-BDE-99 showing equal binding affinity to that of thyroxine. It is concluded that BDE-47 and BDE-99 and their metabolites have the potential to disrupt thyroid hormone transport and interfere in thyroid function.

Endocrine disruption: Molecular interactions of environmental bisphenol contaminants with thyroid hormone receptor and thyroxine-binding globulin.

Many bisphenol A (BPA) analogs have been commercially used recently, such as 2,2-bis(4-hydroxyphenyl)butane (BPB), 4,4'-ethylidenebisphenol, 4,4'-methylenediphenol (BPF), 4,4'-(1,4-phenylenediisopropylidene)bisphenol (BPP), 4,4'-dihydroxydiphenyl sulfone (BPS), 4,4'-cyclohexylidenebisphenol (BPZ), 4,4'-(hexafluoroisopropylidene)diphenol (BPAF), 4,4'-(1-phenylethylidene)bisphenol (BPAP), and 2,2-bis(4-hydroxy-3,5-dimethylphenyl)propane (TMBPA), to circumvent adverse effects of BPA. However, their increasing use is also contaminating the environment, which is a potential cause of concern for human health. Thyroid hormone transport and signaling are potential targets for endocrine-disrupting activity of BPA analogs. Thyroxine-binding globulin (TBG) is the major carrier protein for thyroxine (T4) and triiodothyronine (T3) in blood. Thyroid hormones exert their action through thyroid hormone receptors (TRα and TRß). This report presents the thyroid-disrupting potential of indicated nine BPA analogs from structure-based studies with TBG and TRα. Each BPA analog formed important polar and hydrophobic interactions with a number of residues of TBG and TRα. Majority of TBG residues (77-100%) and TRα residues (70-91%) interacting with BPA analogs were common with those of native ligands T4 and T3, respectively. Majority of BPA analogs interacted with TBG forming a salt bridge interaction at Lys-270. The hydrogen-bonding interaction of T3 with TRα at His-381 was also shared by majority of analogs. The binding energy for BPP, BPB, BPZ, BPAP, and TMBPA with both proteins was closer to binding energy of respective native ligands. The similarity in structural binding characteristics suggested potential disrupting activity of thyroid hormone signaling and transport.

Molecular interactions of thyroxine binding globulin and thyroid hormone receptor with estrogenic compounds 4-nonylphenol, 4-tert-octylphenol and bisphenol A metabolite (MBP).

AIM: Endocrine disruption due to environmental chemical contaminants is a global human health issue. The aim of present study was to investigate the structural binding aspects of possible interference of commonly detected environmental contaminants on thyroid function. MATERIAL AND METHODS: Three compounds, 4-tert-octylphenol (4-tert-OP), 4-nonylphenol (4-NP), and 4-methyl-2,4-bis(4-hydroxypentyl)pent-1-ene (MBP) were subjected to induced fit docking (IFD) against thyroxine binding globulin (TBG) and thyroid hormone receptor (THR). Structural analysis included molecular interactions of the amino acid residues and binding energy estimation between the ligands and the target proteins. KEY RESULTS: All the ligands were successfully placed in the ligand binding pocket of TBG and THR using induced fit docking (IFD). The IFD results revealed high percentage of commonality in interacting amino acid residues between the aforementioned compounds and the native ligand for both TBG and THR. The results of our study further revealed that all the compounds have the potential to interfere with thyroid transport and signaling. However, MBP showed higher binding affinity for both TBG and THR, suggesting higher thyroid disruptive potential as compared to 4-t-OP and 4-NP. Furthermore, our results also suggest that the reported disruptive effects of BPA could actually be exerted through its metabolite; MBP. SIGNIFICANCE: This work implies that all the three compounds 4-NP, 4-t-OP and especially MBP have the potential to interfere with thyroid hormone transport and signaling. This potentially leads to disruption of thyroid hormone function.

A novel terpenoid class for prevention and treatment of KRAS-driven cancers: Comprehensive analysis using in situ, in vitro, and in vivo model systems.

Inhibiting the disease progression in KRAS-driven cancers after diagnosis has been a difficult task for clinicians to manage due to the lack of effective intervention/preventive therapies. KRAS-driven cancers depend on sustained KRAS signaling. Although developing inhibitors of KRAS signaling has proven difficult in the past, the quest for identifying newer agents has not stopped. Based on studies showing terpenoids as modulators of KRAS-regulated downstream molecular pathways, we asked if this chemical family has an affinity of inhibiting KRAS protein activity. Using crystal structure as a bait in silico, we identified 20 terpenoids for their KRAS protein-binding affinity. We next carried out biological validation of in silico data by employing in situ, in vitro, patient-derived explant ex vivo, and KPC transgenic mouse models. In this report, we provide a comprehensive analysis of a lup-20(29)-en-3b-ol (lupeol) as a KRAS inhibitor. Using nucleotide exchange, isothermal titration calorimetry, differential scanning fluorimetry, and immunoprecipitation assays, we show that lupeol has the potential to reduce the guanosine diphosphate/guanosine triphosphate exchange of KRAS protein including mutant KRASG12V . Lupeol treatment inhibited the KRAS activation in KRAS-activated cell models (NIH-panel, colorectal, lung, and pancreatic intraepithelial neoplasia) and patient tumor explants ex vivo. Lupeol reduced the three-dimensional growth of KRAS-activated cells. The pharmacokinetic analysis showed the bioavailability of lupeol after consumption via oral and intraperitoneal routes in animals. Tested under prevention settings, the lupeol consumption inhibited the development of pancreatic intraepithelial neoplasia in LSL-KRASG12D/Pdx-cre mice (pancreatic ductal adenocarcinoma progression model). These data suggest that the selected members of the triterpene family (such as lupeol) could be exploited as clinical agents for preventing the disease progression in KRAS-driven cancers which however warrants further investigation.

Structural binding interactions of tetrabromobisphenol A with sex steroid nuclear receptors and sex hormone-binding globulin.

Tetrabromobisphenol A (TBBPA) is a widely used brominated flame retardant owing to its efficient fire-breaking property. However, leaching of TBBPA into the environment has been a global health concern due to the endocrine-disrupting activity (EDA) associated with TBBPA exposure. Limited studies are available on the hazardous effects of TBBPA on reproductive function. The aim of the present study was the structural characterization of potential EDA of TBBPA in reproductive hormone signaling and transport including steroid nuclear receptors, such as estrogen receptor alpha (ERα), estrogen receptor beta (ERß), androgen receptor (AR), progesterone receptor (PR), and the steroid transport protein, sex hormone-binding globulin (SHBG). The structural binding characterization of TBBPA with the sex steroid nuclear receptors and transport protein was performed by induced-fit docking using the Schrödinger 2017 suite. The results revealed that the TBBPA binding pattern and molecular interactions with the indicated receptors and transport protein displayed overall similarity with their respective native ligands. The estimated binding energy value of TBBPA for ERα was similar to the native ligand, estradiol, indicating tight binding and greater potential for TBBPA to disrupt ERα signaling. For ERß, AR, PR and SHBG, the estimated binding energy values were also close to their respective native ligands, indicating potential for interference in native hormone signaling and transport. In conclusion, TBBPA exposure in humans may potentially cause disruption of sex steroid signaling and transport, and thus lead to reproductive dysfunction.

Naringenin prevents doxorubicin-induced toxicity in kidney tissues by regulating the oxidative and inflammatory insult in Wistar rats.

This study is undertaken to investigate the effects of naringenin on doxorubicin- (Dox) induced nephrotoxicity in Wistar rats. Dox 10 mg/kg body weight was administered intraperitoneally once and naringenin 50 and 100 mg/kg body weight was administered orally daily for 21 d. Dox-induced oxidative stress lead to steep elevation in blood urea nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), and kidney injury molecule-1 (KIM-1), compared to control, treatment with naringenin preserved kidney functions. With Dox treatment significant decrease in antioxidant enzymes with increase in malondialdehyde (MDA) compared to control was observed. Naringenin treatment reversed these values compared to Dox in kidney tissue. Dox treatment showed increased tissue nitric oxide levels naringenin treatment decreased nitric oxide (NO) in kidney tissue. Furthermore, Dox-induced inflammatory burst as indicated by up-regulation of nuclear factor-κB (NF-κB), tumour necrosis factor-α (TNF-α) tissue levels and prostaglandin-E2 (PGE-2). All such events were normalised back to normal by naringenin treatment.

ß-Sitosterol derived compound from onion husks non-polar fraction reduces quorum sensing controlled virulence and biofilm production.

Quorum sensing is an important regulatory factor of P. aeruginosa virulence induction such as BF, motility, formations of proteases, pyocyanin, and some toxins. The aim of the current study is to detect the effect of the pet.ether extract from onion husk and compound drive from it on quorum sensing and virulence formations of P. aeruginosa. Quorum sensing inhibiting effect of the pet.ether extract of onion husk and a compound drive from it, was evaluated by C. violaceum reporter using dilution method as well as an antioxidant by using DPPH. The efficacious of: Quorum sensing inhibiting on pet.ether fraction and compound derived from it, were investigated for their activities toward biofilm and pyocyanin synthesis as well as motility from P. aeruginosa. The pet.ether fraction and compound derived from it of onion husk exhibited potent antimicrobial, antioxidant and Quorum sensing inhibiting effects. The pet.ether fraction and compound derived from it possesses significant reduction on pyocyanin and biofilm induction of P. aeruginosa. Moreover, they significantly inhibited swimming motilities of P. aeruginosa. For the first time, our study showed the medical importance of Allium cepa L. as antimicrobial, antioxidant as well as Quorum sensing inhibiting and virulence suppressors of P. aeruginosa. Thus, these might emphasized on Allium cepa L as a natural source for attenuating toxins of the Pseudomonas.