Extended phase space thermodynamics of regular-AdS black hole.

After obtaining an exact regular-AdS black hole resulting from the coupling of general relativity with nonlinear electrodynamics (NED), we explore the thermodynamics of the extended phase space, treating the cosmological constant ( Λ ) as the pressure (P) of the black holes and its conjugate as thermodynamic volume (V). Considering the NED parameter (g), we investigate the Hawking temperature, entropy, Gibb's free energy and specific heat at the horizon radius. Due to the presence of NED charge, the black hole exhibits van der Waals-like phase transition instead of Hawking-Page phase transition, which could be observed through the G - T plots, which display a swallowtail pattern below the critical pressure, and it gives rise to second-order phase transitions when pressure attains its critical value. The first-order phase transition shares similarities with the liquid-gas phase transition. We determine the exact critical points and explore the influence of NED on P - V criticality, revealing that the isotherms undergo a liquid-gas-like phase transition for temperatures below its critical value T C , especially at lower T C . The identical critical exponent to that of the van der Waals fluid suggests that the NED does not alter the critical exponents, as observed in other arbitrary AdS black holes.

Synergistic inhibition of glioblastoma multiforme through an in-silico analysis of luteolin and ferulic acid derived from Angelica sinensis and Cannabis sativa: Advancements in computational therapeutics.

The primary objective of this study is to uncover novel therapeutic agents for the treatment of Glioblastoma Multiforme (GBM), a highly aggressive form of brain cancer, and Alzheimer's Disease (AD). Given the complexity and resistance associated with both conditions, the study underscores the imperative need for therapeutic alternatives that can traverse the biological intricacies inherent in both neuro-oncological and neurodegenerative disorders. To achieve this, a meticulous, target-based virtual screening was employed on an ensemble of 50 flavonoids and polyphenol derivatives primarily derived from plant sources. The screening focused predominantly on molecular targets pertinent to GBM but also evaluated the potential overlap with neural pathways involved in AD. The study utilized molecular docking and Molecular Dynamic (MD) simulation techniques to analyze the interaction of these compounds with a key biological target, protein tyrosine phosphatase receptor-type Z (PTPRZ). Out of the 50 compounds examined, 10 met our stringent criteria for binding affinity and specificity. Subsequently, the highest value of binding energy was observed for the synergistic binding of luteolin and ferulic acid with the value of -10.5 kcal/mol. Both compounds exhibited inherent neuroprotective properties and demonstrated significant potential as pathway inhibitors in GBM as well as molecular modulators in AD. Drawing upon advanced in-silico cytotoxicity predictions and sophisticated molecular modeling techniques, this study casts a spotlight on the therapeutic capabilities of polyphenols against GBM. Furthermore, our findings suggest that leveraging these compounds could catalyze a much-needed paradigm shift towards more integrative therapeutic approaches that span the breadth of both neuro-oncology and neurodegenerative diseases. The identification of cross-therapeutic potential in flavonoids and polyphenols could drastically broaden the scope of treatment modalities against both fatal diseases.

Analysis of some flavonoids for inhibitory mechanism against cancer target phosphatidylinositol 3-kinase (PI3K) using computational tool.

Cancer has been one of the leading causes of mortality worldwide over the past few years. Some progress has been made in the development of more effective cancer therapeutics, resulting in improved survival rates. However, the desired outcome in the form of successful treatment is yet to be achieved. There is high demand for the development of innovative, inexpensive, and effective anticancer treatments using natural resources. Natural compounds have been increasingly discovered and used for cancer therapy owing to their high molecular diversity, novel biofunctionality, and minimal side effects. These compounds can be utilized as chemopreventive agents because they can efficiently inhibit cell growth, control cell cycle progression, and block several tumor-promoting signaling pathways. PI3K is an important upstream protein of the PI3K-Akt-mTOR pathway and a well-established cancer therapeutic target. This study aimed to explore the small molecules, natural flavonoids, viz. quercetin, luteolin, kaempferol, genistein, wogonin, daidzein, and flavopiridol for PI3Kγ kinase activity inhibition. In this study, the binding pose, interacting residues, molecular interactions, binding energies, and dissociation constants were investigated. Our results showed that these flavonoids bound well with PI3Kγ with adequate binding strength scores and binding energy ranging from (-8.19 to -8.97 Kcal/mol). Among the explored ligands, flavopiridol showed the highest binding energy of -8.97 Kcal/mol, dock score (-44.40), and dissociation constant term, pKd of 6.58 against PI3Kγ. Based on the above results, the stability of the most promising ligand, flavopiridol, against PI3Kγ was evaluated by molecular dynamics simulations for 200 ns, confirming the stable flavopiridol and PI3Kγ complex. Our study suggests that among the selected flavonoids specifically flavopiridol may act as potential inhibitors of PI3Kγ and could be a therapeutic alternative to inhibit the PI3Kγ pathway, providing new insights into rational drug discovery research for cancer therapy.

Unlocking potential inhibitors for Bruton's tyrosine kinase through in-silico drug repurposing strategies.

Bruton's tyrosine kinase (BTK) is a non-receptor protein kinase that plays a crucial role in various biological processes, including immune system function and cancer development. Therefore, inhibition of BTK has been proposed as a therapeutic strategy for various complex diseases. In this study, we aimed to identify potential inhibitors of BTK by using a drug repurposing approach. To identify potential inhibitors, we performed a molecular docking-based virtual screening using a library of repurposed drugs from DrugBank. We then used various filtrations followed by molecular dynamics (MD) simulations, principal component analysis (PCA), and Molecular Mechanics Poisson Boltzmann Surface Area (MM-PBSA) analysis to further evaluate the binding interactions and stability of the top-ranking compounds. Molecular docking-based virtual screening approach identified several repurposed drugs as potential BTK inhibitors, including Eltrombopag and Alectinib, which have already been approved for human use. All-atom MD simulations provided insights into the binding interactions and stability of the identified compounds, which will be helpful for further experimental validation and optimization. Overall, our study demonstrates that drug repurposing is a promising approach to identify potential inhibitors of BTK and highlights the importance of computational methods in drug discovery.

Investigating a Library of Flavonoids as Potential Inhibitors of a Cancer Therapeutic Target MEK2 Using in Silico Methods.

The second leading cause of death in the world is cancer. Mitogen-activated protein kinase (MAPK) and extracellular signal-regulated protein kinase (ERK) 1 and 2 (MEK1/2) stand out among the different anticancer therapeutic targets. Many MEK1/2 inhibitors are approved and widely used as anticancer drugs. The class of natural compounds known as flavonoids is well-known for their therapeutic potential. In this study, we focus on discovering novel inhibitors of MEK2 from flavonoids using virtual screening, molecular docking analyses, pharmacokinetic prediction, and molecular dynamics (MD) simulations. A library of drug-like flavonoids containing 1289 chemical compounds prepared in-house was screened against the MEK2 allosteric site using molecular docking. The ten highest-scoring compounds based on docking binding affinity (highest score: -11.3 kcal/mol) were selected for further analysis. Lipinski's rule of five was used to test their drug-likeness, followed by ADMET predictions to study their pharmacokinetic properties. The stability of the best-docked flavonoid complex with MEK2 was examined for a 150 ns MD simulation. The proposed flavonoids are suggested as potential inhibitors of MEK2 and drug candidates for cancer therapy.

A virtual screening investigation to identify bioactive natural compounds as potential inhibitors of cyclin-dependent kinase 9.

Cyclin-dependent kinase 9 (CDK9) is a transcription-associated protein involved in controlling the cell cycle and is often deregulated in stress conditions. CDK9 is being studied as a well-known druggable target for developing effective therapeutics against a wide range of cancer, cardiac dysfunction and inflammatory diseases. Owing to the significance of CDK9 in the etiology of hematological and solid malignancies, its structure, biological activity, regulation and its pharmacological inhibition are being explored for therapeutic management of cancer. We employed a structure-based virtual high-throughput screening of bioactive compounds from the IMPPAT database to discover potential bioactive inhibitors of CDK9. The preliminary results were obtained from the Lipinski criteria, ADMET parameters and sorting compounds without any PAINS patterns. Subsequently, binding affinity and selectivity analyses were used to find effective CDK9 hits. This screening resulted in the identification of two natural compounds, Glabrene and Guggulsterone with high affinity and specificity for the CDK9 binding site. Both compounds exhibit drug-like characteristics, as projected by ADMET analysis, physicochemical data and PASS evaluation. Both compounds preferentially bind to the ATP-binding pocket of CDK9 and interact with functionally important residues. Further, the dynamics and consistency of CDK9 interaction with Glabrene and Guggulsteron were evaluated through all-atom molecular dynamic (MD) simulations which suggested the stability of both complexes. The results might be deployed to introduce novel CDK9 inhibitors that may treat life-threatening diseases, including cancer.Communicated by Ramaswamy H. Sarma.

Drug repurposing against galectin-3 using simulation-based studies.

The protein galectin, which binds to carbohydrates and is involved in a number of therapeutic processes including cell proliferation, inflammatory responses, apoptosis, etc., has been discovered as a potential therapeutic target. Galectin-3 is a stable biomarker that exhibits both increased and decreased expression in a variety of illnesses and infections, regardless of sex, age, or body mass index. The goal of the current study is to apply bioinformatics techniques to examine the possibility of cardiovascular medications to inhibit Galectin-3-related biological activities. Unsupervised clustering techniques, molecular docking, and guided molecular dynamics (MD) simulation were used to create a computational pipeline that was used to screen potential chemical compounds from a library of chemical compounds with related molecular fingerprints. Utilizing input factors such as gene expression, mode of action, and chemical descriptors, clustering enables prioritization of medicinal molecules. Twenty-four compounds were screened and repurposed against Galectin-3 utilizing molecular docking as part of the cluster-facilitated virtual screening technique. The polar interactions that Arg144, Glu184, Arg162, His158, and Asn174 have with Bufalin, Cymarin, and Ouabalin have the highest binding affinities, according to docking studies. Studies using MD simulations confirm the tested compounds' ability to inhibit Galectin-3. Galactin-3 targeted experimental and in vivo animal model-based validation studies using Bufalin, Cymarin, and Ouabalin are also necessary.Communicated by Ramaswamy H. Sarma.

Computational insights into the stereo-selectivity of catechins for the inhibition of the cancer therapeutic target EGFR kinase.

The epidermal growth factor receptor (EGFR) plays a crucial role in regulating cellular growth and survival, and its dysregulation is implicated in various cancers, making it a prime target for cancer therapy. Natural compounds known as catechins have garnered attention as promising anticancer agents. These compounds exert their anticancer effects through diverse mechanisms, primarily by inhibiting receptor tyrosine kinases (RTKs), a protein family that includes the notable member EGFR. Catechins, characterized by two chiral centers and stereoisomerism, demonstrate variations in chemical and physical properties due to differences in the spatial orientation of atoms. Although previous studies have explored the membrane fluidity effects and transport across cellular membranes, the stereo-selectivity of catechins concerning EGFR kinase inhibition remains unexplored. In this study, we investigated the stereo-selectivity of catechins in inhibiting EGFR kinase, both in its wild-type and in the prevalent L858R mutant. Computational analyses indicated that all stereoisomers, including the extensively studied catechin (-)-EGCG, effectively bound within the ATP-binding site, potentially inhibiting EGFR kinase activity. Notably, gallated catechins emerged as superior EGFR inhibitors to their non-gallated counterparts, revealing intriguing binding trends. The top four stereoisomers exhibiting high dock scores and binding energies with wild-type EGFR comprise (-)-CG (-)-GCG (+)-CG, and (-)-EGCG. To assess dynamic behavior and stability, molecular dynamics simulations over 100 ns were conducted for the top-ranked catechin (-)-CG and the widely investigated catechin (-)-EGCG with EGFR kinase. This study enhances our understanding of how the stereoisomeric nature of a drug influences inhibitory potential, providing insights that could guide the selection of specific stereoisomers for improved efficacy inexisting drugs.

In vitro screening of anti-viral and virucidal effects against SARS-CoV-2 by Hypericum perforatum and Echinacea.

Hypericum perforatum and Echinacea are reported to have antiviral activities against several viral infections. In this study, H. perforatum (St. John's Wort) and Echinacea were tested in vitro using Vero E6 cells for their anti-viral effects against the newly identified Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) through its infectious cycle from 0 to 48 h post infection. The hypericin of H. perforatum and the different parts (roots, seeds, aerial) of two types of Echinacea species (Echinacea purpurea and Echinacea angustifolia) were tested for their anti-viral activities to measure the inhibition of viral load using quantitative real-time polymerase chain reaction (qRT-PCR) on cell culture assay. Interestingly, the H. perforatum-Echinacea mixture (1:1 ratio) of H. perforatum and Echinacea was tested as well on SARS-CoV-2 and showed crucial anti-viral activity competing H. perforatum then Echinacea effects as anti-viral treatment. Therefore, the results H. perforatum and Echinacea species, applied in this study showed significant anti-viral and virucidal effects in the following order of potency: H. perforatum, H. perforatum-Echinacea mixture, and Echinacea on SARS-CoV-2 infectious cycle. Additionally, molecular simulation analysis of the compounds with essential proteins (Mpro and RdRp) of the SARS-CoV-2 revealed the most potent bioactive compounds such as Echinacin, Echinacoside, Cyanin, Cyanidin 3-(6''-alonylglucoside, Quercetin-3-O-glucuronide, Proanthocyanidins, Rutin, Kaempferol-3-O-rutinoside, and Quercetin-3-O-xyloside. Thus, based on the outcome of this study, it is demanding the setup of clinical trial with specific therapeutic protocol.

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.

Diagnostic Accuracy of Various Radiological Measurements in the Evaluation and Differentiation of Flatfoot: A Cross-Sectional Study.

Arch angle is used to indicate flatfoot, but in some cases, it is not easily defined. The presence of flatfoot deformity remains difficult to diagnose due to a lack of reliable radiographic assessment tools. Although various assessment methods for flatfoot have been proposed, there is insufficient evidence to prove the diagnostic accuracy of the various tools. The main purpose of the study was to determine the best radiographic measures for flatfoot concerning the arch angle. Fifty-two feet radiographs from thirty-two healthy young females were obtained. Five angles and one index were measured using weight-bearing lateral radiographs; including arch angle, calcaneal pitch (CP), talar-first metatarsal angle (TFM), lateral talar angle (LTA), talar inclination angle (TIA) and navicular index (NI). Receiver-operating characteristics were generated to evaluate the flatfoot diagnostic accuracy for all radiographic indicators and Matthews correlation coefficient was calculated to determine the cutoff value for each measure. The strongest correlation was between arch angle and CP angle [r = -0.91, p ≤ 0.0001, 95% confidence interval (CI) (from -0.94 to -0.84)]. Also, significant correlations were found between arch angle and NI [r = 0.62, p ≤ 0.0001, 95% CI (0.42 to 0.76)], and TFM [r = 0.50, p ≤ 0.0001, 95% CI (from 0.266 to 0.68)]. Furthermore, CP (cutoff, 12.40) had the highest accuracy level with value of 100% sensitivity and specificity followed by NI, having 82% sensitivity and 89% specificity for the cutoff value of 9.90. In conclusion, CP angle is inversely correlated with arch angle and considered a significant indicator of flatfoot. Also, the NI is easy to define radiographically and could be used to differentiate flat from normal arched foot among young adults.

NAT10: An RNA cytidine transferase regulates fatty acid metabolism in cancer cells.

BACKGROUND: N-4 cytidine acetylation (ac4C) is an epitranscriptomics modification catalyzed by N-acetyltransferase 10 (NAT10); important for cellular mRNA stability, rRNA biogenesis, cell proliferation and epithelial to mesenchymal transition (EMT). However, whether other crucial pathways are regulated by NAT10-dependent ac4C modification in cancer cells remains unclear. Therefore, in this study, we explored the impact of NAT10 depletion in cancer cells using unbiased RNA-seq. METHODS: High-throughput sequencing of knockdown NAT10 in cancer cells was conducted to identify enriched pathways. Acetylated RNA immunoprecipitation-seq (acRIP-seq) and RIP-PCR were used to map and determine ac4C levels of RNA. Exogenous palmitate uptake assay was conducted to assess NAT10 knockdown cancer cells using Oil Red O staining and lipid content analysis. Gas-chromatography-tandem mass spectroscopy (GC/MS) was used to perform untargeted lipidomics. RESULTS: High-throughput sequencing of NAT10 knockdown in cancer cells revealed fatty acid (FA) metabolism as the top enriched pathway through the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis in differentially downregulated genes. FA metabolic genes such as ELOLV6, ACSL1, ACSL3, ACSL4, ACADSB and ACAT1 were shown to be stabilised via NAT10-dependent ac4C RNA acetylation. Additionally, NAT10 depletion was shown to significantly reduce the levels of overall lipid content, triglycerides and total cholesterol. Further, NAT10 depletion in palmitate-loaded cancer cells showed decrease in ac4C levels across the RNA transcripts of FA metabolic genes. In untargeted lipidomics, 496 out of 2 279 lipids were statistically significant in NAT10 depleted cancer cells, of which pathways associated with FA metabolism are the most enriched. CONCLUSIONS: Conclusively, our results provide novel insights into the impact of NAT10-mediated ac4C modification as a crucial regulatory factor during FA metabolism and showed the benefit of targeting NAT10 for cancer treatment.

A novel injectable platelet-rich fibrin reinforced papilla reconstruction technique.

Formation of black triangles due to the loss of interdental papilla is one of the utmost perplexing esthetic problems of the periodontium. Many surgical and nonsurgical treatment options have been researched upon to obtain complete papillary fill, but minimally invasive procedures have always been the choice of treatment both for the operator as well as the patient. This article describes the use of injectable platelet-rich fibrin (i-PRF) as a novel nonsurgical technique for the reconstruction of deficient interdental papilla. This is probably the first article that describes the use of i-PRF for the nonsurgical treatment of black triangles. Six sites with the presence of deficient interdental papilla in four patients were selected for this case series. After completion and reevaluation of scaling and root planing, autologous i-PRF was injected at the base of the interdental papilla using the insulin syringe. Photographs obtained before the treatment and at 1, 3, and 6 months after the intervention were assessed by Image J software along with clinical measurements. The use of novel nonsurgical injectable PRF technique allows clinician to successfully treat deficient interdental papilla.

Structural-Guided Identification of Small Molecule Inhibitor of UHRF1 Methyltransferase Activity.

Ubiquitin-like containing plant homeodomain Ring Finger 1 (UHRF1) protein is recognized as a cell-cycle-regulated multidomain protein. UHRF1 importantly manifests the maintenance of DNA methylation mediated by the interaction between its SRA (SET and RING associated) domain and DNA methyltransferase-1 (DNMT1)-like epigenetic modulators. However, overexpression of UHRF1 epigenetically responds to the aberrant global methylation and promotes tumorigenesis. To date, no potential molecular inhibitor has been studied against the SRA domain. Therefore, this study focused on identifying the active natural drug-like candidates against the SRA domain. A comprehensive set of in silico approaches including molecular docking, molecular dynamics (MD) simulation, and toxicity analysis was performed to identify potential candidates. A dataset of 709 natural compounds was screened through molecular docking where chicoric acid and nystose have been found showing higher binding affinities to the SRA domain. The MD simulations also showed the protein ligand interaction stability of and in silico toxicity analysis has also showed chicoric acid as a safe and nontoxic drug. In addition, chicoric acid possessed a longer interaction time and higher LD50 of 5000 mg/kg. Moreover, the global methylation level (%5 mC) has been assessed after chicoric acid treatment was in the colorectal cancer cell line (HCT116) at different doses. The result showed that 7.5 µM chicoric acid treatment reduced methylation levels significantly. Thus, the study found chicoric acid can become a possible epidrug-like inhibitor against the SRA domain of UHRF1 protein.

Venetoclax-Resistant MV4-11 Leukemic Cells Activate PI3K/AKT Pathway for Metabolic Reprogramming and Redox Adaptation for Survival.

Venetoclax (ABT199) is a selective B-cell lymphoma 2 (BCL-2) inhibitor. The US FDA recently approved it to be used in combination with low-dose cytarabine or hypomethylating agents in acute myeloid leukemia (AML) or elderly patients non-eligible for chemotherapy. However, acquiring resistance to venetoclax in AML patients is the primary cause of treatment failure. To understand the molecular mechanisms inherent in the resistance to BCL-2 inhibitors, we generated a venetoclax-resistant cell line model and assessed the consequences of this resistance on its metabolic pathways. Untargeted metabolomics data displayed a notable impact of resistance on the PI3K/AKT pathway, the Warburg effect, glycolysis, the TCA cycle, and redox metabolism. The resistant cells showed increased NADPH and reduced glutathione levels, switching their energy metabolism towards glycolysis. PI3K/AKT pathway inhibition shifted resistant cells towards oxidative phosphorylation (OXPHOS). Our results provide a metabolic map of resistant cells that can be used to design novel metabolic targets to challenge venetoclax resistance in AML.

Exploring the Natural Compounds in Flavonoids for Their Potential Inhibition of Cancer Therapeutic Target MEK1 Using Computational Methods.

The Mitogen-Activated Protein Kinase (MAPK) signaling pathway plays an important role in cancer cell proliferation and survival. MAPKs' protein kinases MEK1/2 serve as important targets in drug designing against cancer. The natural compounds' flavonoids are known for their anticancer activity. This study aims to explore flavonoids for their inhibition ability, targeting MEK1 using virtual screening, molecular docking, ADMET prediction, and molecular dynamics (MD) simulations. Flavonoids (n = 1289) were virtually screened using molecular docking and have revealed possible inhibitors of MEK1. The top five scoring flavonoids based on binding affinity (highest score for MEK1 is -10.8 kcal/mol) have been selected for further protein-ligand interaction analysis. Lipinski's rule (drug-likeness) and absorption, distribution, metabolism, excretion, and toxicity predictions were followed to find a good balance of potency. The selected flavonoids of MEK1 have been refined with 30 (ns) molecular dynamics (MD) simulation. The five selected flavonoids are strongly suggested to be promising potent inhibitors for drug development as anticancer therapeutics of the therapeutic target MEK1.

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.

Targeting a transcription factor NF-κB by green tea catechins using in silico and in vitro studies in pancreatic cancer.

Pancreatic cancer remains a lethal disease and a major public health problem globally. Nuclear factor-kappa B (NF-κB) has been identified as a therapeutic target in several cancers and plays an important role in inflammatory responses. Many phytochemicals, including catechins, have been reported in the scientific literature with efficient anticancer potential and minimal side effects. This study aims to gain insights into the inhibitory mechanism of catechin derivatives epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG), and epigallocatechin gallate (EGCG) using in silico and in vitro studies especially considering NF-κB targeting. We explored the binding pose, interacting residues and molecular interactions for catechin derivatives with NF-κB. Docking analysis showed that the catechin derivatives acted as covalent inhibitors with the p65 subunit of NF-κB and interacted with other residues through non-bonding interactions and hydrogen bonds. Further, we validated the effect of EGCG on NF-κB activity in pancreatic cancer cell lines MIAPaCa-2 and SU 86.86. Our in vitro data showed EGCG effectively reduced cell growth and proliferation, induced apoptosis, and inhibited NF-κB activity in the studied cell lines. In addition, EGCG repressed the expression of NF-κB target genes including MMP9, MMP2, cMyc, and BCL-2. Thus, targeting NF-κB with EGCG could be a potential therapeutic alternative for pancreatic cancer treatment.

Evaluation of the correlation between interleukin 1ß levels in peri-implant crevicular fluid as an adjunctive diagnostic marker with clinical and radiographic parameters for assessing the peri-implant health status.

Background: Interleukin-1ß (IL-1ß) is one of the most important cytokines that seems to have an important role in the inflammatory process in gingival and peri-implant tissues. As peri-implant crevicular fluid (PICF) provides with a more swift and objective measure of the disease activity, the present study was conducted to evaluate IL-1ß level in PICF as a biochemical marker and to investigate its correlation with clinical parameters and radiological parameters. Materials and Methods: After evaluating all the patients following inclusion and exclusion criteria, 60 patients were selected for the study. After 3-4 months of implants placement, the implants were exposed following standard surgical procedure. PICF sample from implant site was taken 3 days after suture removal with gingival former still in place followed by measurement of clinical and radiological parameters. Results: There was significant increase in IL-1ß levels in both the follow-ups from baseline with variable and minimal change in the clinical parameters and radiological parameters as well, which shows that IL-1ß levels change significantly even when there is a minimal gingival inflammation. Conclusion: Therefore, IL-1ß level in PICF can be used as an adjunctive diagnostic marker to clinical and radiographic parameters for assessing the peri-implant health status.

A Novel Homozygous Missense Mutation in the Zinc Finger DNA Binding Domain of GLI1 Causes Recessive Post-Axial Polydactyly.

Background: Polydactyly is a prevalent digit abnormality characterized by having extra digits/toes. Mutations in eleven known genes have been associated to cause nonsyndromic polydactyly: GLI3, GLI1, ZRS regulating LMBR1, IQCE, ZNF141, PITX1, MIPOL1, FAM92A, STKLD1, KIAA0825, and DACH1. Method: A single affected family member (IV-4) was subjected to whole-exome sequencing (WES) to identify the causal gene. Bi-directional Sanger sequencing was performed to segregate the identified variant within the family. In silico analysis was performed to investigate the effect of the variant on DNA binding properties. Results: whole-exome sequencing identified a bi-allelic missense variant (c.1010C > T; p. Ser337Leu) in exon nine of GLI1 gene located on chromosome 12q13.3. With the use of Sanger sequencing, the identified variant segregated perfectly with the disease phenotype. Furthermore, in silico analysis of this DNA binding protein revealed that the variant weakened the DNA binding interaction, resulting in indecorous GLI1 function. Conclusion: Herein, we report a novel variant in GLI1 gene, causing autosomal recessive post-axial polydactyly type A (PAPA) type 8. This confirms the critical role of GLI1 in digit development and might help in genotype-phenotype correlation in the future.