Specific Target Research Articles

MicroLOCK: Highly stable microgel biosensor using locked nucleic acids as bioreceptors for sensitive and selective detection of let-7a

Chemically modified oligonucleotides can solve biosensing issues for the development of capture probes, antisense, CRISPR/Cas, and siRNA, by enhancing their duplex-forming ability, their stability against enzymatic degradation, and their specificity for targets with high sequence similarity as microRNA families. However, the use of modified oligonucleotides such as locked nucleic acids (LNA) for biosensors is still limited by hurdles in design and from performances on the material interface. Here we developed a fluorogenic biosensor for non-coding RNAs, represented by polymeric PEG microgels conjugated with molecular beacons (MB) modified with locked nucleic acids (MicroLOCK). By 3D modeling and computational analysis, we designed molecular beacons (MB) inserting spot-on LNAs for high specificity among targets with high sequence similarity (95%). MicroLOCK can reversibly detect microRNA targets in a tiny amount of biological sample (2μL) at 25°C with a higher sensitivity (LOD 1.3fM) without any reverse transcription or amplification. MicroLOCK can hybridize the target with fast kinetic (about 30min), high duplex stability without interferences from the polymer interface, showing high signal-to-noise ratio (up to S/N=7.3). MicroLOCK also demonstrated excellent resistance to highly nuclease-rich environments, in real samples. These findings represent a great breakthrough for using the LNA in developing low-cost biosensing approaches and can be applied not only for nucleic acids and protein detection but also for real-time imaging and quantitative assessment of gene targeting both in vitro and in vivo.

Ellagic acid improves the symptoms of early-onset Alzheimer's disease: Behavioral and physiological correlates

Oryza sativa is a globally recognized staple food, rich in essential phyto-phenolic compounds such as γ-Oryzanol (OZ), Ferulic acid (FA), and Ellagic acid (EA). These phytochemicals are known for their potential to beneficially modulate molecular biochemistry. The present investigation aimed to evaluate the neuroprotective and cognitive enhancement effects of Oryza sativa phyto-phenolics in a model of early-onset Alzheimer's disease (EOAD) induced by Aβ (1-42) in animals. In-silico studies suggested that FA, OZ, and EA have target specificity for Aβ, with EA being further selected based on its potent in-vitro Aβ anti-aggregatory effects for exploring neurodegenerative conditions. The in-vivo experiments demonstrated that EA exerts therapeutic effects in Aβ-induced EOAD, modulating both biochemical and behavioral outcomes. EA treatment at two dose levels, EA70 and EA140 (70 μM and 140 μM, respectively, administered i.c.v.), significantly counteracted Aβ aggregation and modulated the Ca2⁺/Calpain/GSK-3β/CDK5 signaling pathways, exhibiting anti-tauopathy effects. Additionally, EA was shown to exert anti-inflammatory effects by preventing astroglial activation, modulating FAIM-L expression, and protecting against TNF-α-induced apoptotic signals. Moreover, the neuromodulatory effects of EA were attributed to the regulation of CREB levels, Dnm-1 expression, and synaptophysin levels, thereby enhancing LTP and synaptic plasticity. EA also induced beneficial cytological and behavioral changes, improving both long-term and short-term spatial memory as well as associative learning behavior in the animal model, which underscores its cognitive enhancement properties.

Biomimetic copper-containing nanogels for imaging-guided tumor chemo-chemodynamic-immunotherapy

Developing multifunctional nanoplatforms to comprehensively modulate the tumor microenvironment and enhance diagnostic and therapeutic outcomes still remains a great challenge. Here, we report the facile construction of a multivariate nanoplatform based on cancer cell membrane (CM)-encapsulated redox-responsive poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) co-loaded with Cu(II) and chemotherapeutic drug toyocamycin (Toy) for magnetic resonance (MR) imaging-guided combination tumor chemodynamic therapy/chemoimmunotherapy. We show that redox-responsive PVCL NGs formed through precipitation polymerization can be aminated, conjugated with 3,4-dihydroxyhydrocinnamic acid for Cu(II) complexation, physically loaded with Toy, and finally camouflaged with CMs. The created ADCT@CM NGs with an average size of 113.0 nm are stable under physiological conditions and can efficiently release Cu(II) and Toy under tumor microenvironment with a high level of glutathione. Meanwhile, the developed NGs are able to enhance cancer cell oxidative stress and endoplasmic reticulum stress by synergizing the effects of chemodynamic therapy mediated by Cu-based Fenton-like reaction and Toy-mediated chemotherapy, thereby triggering significant immunogenic cell death (ICD). In a melanoma mouse model, the NGs show potent immune activation effects to reinforce tumor therapeutic efficacy through ICD induction and immune modulation including high levels of immune cytokine secretion, increased tumor infiltration of CD8+ cytotoxic T cells, and reduced tumor infiltration of regulatory T cells. With the CM coating and Cu(II) loading, the developed NG platform demonstrates homologous tumor targeting and T1-weighted MR imaging, hence providing a general biomimetic NG platform for ICD-facilitated tumor theranostic nanoplatform. Statement of significanceDeveloping multifunctional nanoplatforms to comprehensively modulate the tumor microenvironment (TME) and enhance theranostic outcomes remains a challenge. Here, a cancer cell membrane (CM)-camouflaged nanoplatform based on aminated poly(N-vinylcaprolactam) nanogels (NGs) co-loaded with Cu(II) and toyocamycin (Toy) was prepared for magnetic resonance (MR) imaging-guided combination tumor chemodynamic therapy/chemoimmunotherapy. The tumor targeting specificity and efficient TME-triggered release of Cu(II) and Toy could enhance tumor cell oxidative stress and endoplasmic reticulum stress by synergizing the effects of chemodynamic therapy mediated by Cu-based Fenton-like reaction and Toy-mediated chemotherapy, respectively, thereby leading to significant immunogenic cell death (ICD) and immune response. With the CM coating and Cu(II) loading, the developed NG platform also demonstrates good T1-weighted tumor MR imaging performance. Hence, this study provides a general biomimetic NG platform for ICD-facilitated tumor theranostics.

Single-cell RNA sequencing of nc886, a non-coding RNA transcribed by RNA polymerase III, with a primer spike-in strategy.

Single-cell RNA sequencing (scRNA-seq) has emerged as a versatile tool in biology, enabling comprehensive genomic-level characterization of individual cells. Currently, most scRNA-seq methods generate barcoded cDNAs by capturing the polyA tails of mRNAs, which exclude many non-coding RNAs (ncRNAs), especially those transcribed by RNA polymerase III (Pol III). Although previously thought to be expressed constitutively, Pol III-transcribed ncRNAs are expressed variably in healthy and disease states and play important roles therein, necessitating their profiling at the single-cell level. In this study, we developed a measurement protocol for nc886 as a model case and initial step for scRNA-seq for Pol III-transcribed ncRNAs. Specifically, we spiked in an oligo-tagged nc886-specific primer during the polyA tail capture process for the 5'scRNA-seq. We then produced sequencing libraries for standard 5' gene expression and oligo-tagged nc886 separately, to accommodate different cDNA sizes and ensure undisturbed transcriptome analysis. We applied this protocol in three cell lines that express high, low, and zero levels of nc886. Our results show that the identification of oligo tags exhibited limited target specificity, and sequencing reads of nc886 enabled the correction of non-specific priming. These findings suggest that gene-specific primers (GSPs) can be employed to capture RNAs lacking a polyA tail, with subsequent sequence verification ensuring accurate gene expression counting. Moreover, we embarked on an analysis of differentially expressed genes in cell line sub-clusters with differential nc886 expression, demonstrating variations in gene expression phenotypes. Collectively, the primer spike-in strategy allows combined analysis of ncRNAs and gene expression phenotype.

Icariin targets p53 to protect against ceramide-induced neuronal senescence: Implication in Alzheimer's disease

BackgroundAlzheimer's disease (AD) is a leading cause of dementia. The aging brain is particularly vulnerable to various stressors, including increased levels of ceramide. However, the role of ceramide in neuronal cell senescence and AD progression and whether icariin, a natural flavonoid glucoside, could reverse neuronal senescence remain inadequately understood. AimIn this study, we explore the role of ceramide in neuronal senescence and AD, and whether icariin can counteract these effects. MethodsWe pretreated HT-22 cells with icariin and then induced senescence with ceramide. Various assays were employed to assess cell senescence, such as reactive oxygen species (ROS) production, cell cycle progression, β-galactosidase staining, and expression of senescence-associated proteins. In vivo studies utilized APP/PS1 mice and C57BL/6J mice injected with ceramide to evaluate behavioral changes, histopathological alterations, and senescence-associated protein expression. Transcriptomics, molecular docking, molecular dynamics simulations, and cellular thermal shift assays were employed to verify the interaction between icariin and P53. The specificity of icariin targeting of P53 was further confirmed through rescue experiments utilizing the P53 activator Navtemadlin. ResultsOur data demonstrated that ceramide could induce neuronal senescence and AD-related pathologies, which were reversed by icariin. Moreover, molecular studies revealed that icariin directly targeted P53, and its neuroprotective effects were attenuated by P53 activation, providing evidence for the role of P53 in icariin-mediated neuroprotection. ConclusionIcariin demonstrates a protective effect against ceramide-induced neuronal senescence by inhibiting the P53 pathway. This identifies a novel mechanism of action for icariin, offering a novel therapeutic approach for AD and other age-related neurodegenerative diseases.

Accurate design, simulation and implementation of AC/DC inductors for power electronic converters

AbstractThis article proposes a holistic and improved methodology for the inductors' design in power electronic circuits operating at high frequencies. This methodology includes an analytical design, a finite element modeling of the electromagnetic behavior with JMAG software, a simulation analysis in a Simulink environment, and experimental verification of the effectiveness of inductor design in a laboratory‐scale step‐up boost power converter prototype. The holistic approach allowed us to achieve all target specifications such as maximum power (300 W), minimum voltage (60 V), inductance (1.77 mH), and maximum current ripple (1 A). It guarantees the losses' minimization in core and copper (21.47 W), and marginal errors below 4% between the analytical, simulated, and experimental values.

A plug-and-play monofunctional platform for targeted degradation of extracellular proteins and vesicles

Existing strategies use bifunctional chimaeras to mediate extracellular protein degradation. However, these strategies rely on specific lysosome-trafficking receptors to facilitate lysosomal delivery, which may raise resistance concerns due to intrinsic cell-to-cell variation in receptor expression and mutations or downregulation of the receptors. Another challenge is establishing a universal platform applicable in multiple scenarios. Here, we develop MONOTAB (MOdified NanOparticle with TArgeting Binders), a plug-and-play monofunctional degradation platform that can drag extracellular targets into lysosomes for degradation. MONOTAB harnesses the inherent lysosome-targeting ability of certain nanoparticles to obviate specific receptor dependency and the hook effect. To achieve high modularity and programmable target specificity, we utilize the streptavidin-biotin interaction to immobilize antibodies or other targeting molecules on nanoparticles, through an antibody mounting approach or by direct binding. Our study reveals that MONOTAB can induce efficient degradation of diverse therapeutic targets, including membrane proteins, secreted proteins, and even extracellular vesicles.

Performance comparison of three commercial multiplex molecular panels for respiratory viruses at a South African academic hospital.

Respiratory infections are a major contributor to hospital admissions. Identification of respiratory pathogens by means of conventional culture and serology methods remains challenging. Multiplex molecular assays are an appealing alternative that endeavours to be rapid, more accurate and less arduous. The study aimed to compare the clinical performance of three commercial multiplex molecular assays for respiratory viruses. Forty-eight respiratory specimens obtained from patients at Tygerberg Hospital in the Western Cape province of South Africa were studied. These specimens were collected between May 2020 and August 2020. The results of the Seegene Anyplex™ II RV16, FilmArray® Respiratory 2.1 plus Panel (FARP), and QIAstat-Dx® Respiratory SARS-CoV-2 Panel (QRP) were analysed based on the overlapping targets. A composite reference standard was applied to provide a standard reference for comparison. The overall sensitivity of the Seegene Anyplex™ II RV16 was 96.6% (57/59), the FARP 98.2% (56/57) and the QRP 80.7% (46/57). The overall specificities were 99.8% (660/661), 99.0% (704/711) and 99.7% (709/711), respectively. The QRP failed to detect coronaviruses and parainfluenza viruses in 41.7% (5/12) and 28.6% (4/14) of positive specimens, respectively, while the FARP produced the lowest target specificity of 88.4% (38/43) for rhinovirus/enterovirus. The overall specificity of all three platforms was comparable; however, the sensitivity of the QRP was inferior to that of the ARV and FARP. This study adds to the body of performance characteristics described for respiratory multiplex panels, especially in the African context where molecular diagnostics for infectious diseases are gaining momentum.

Synthesis and Properties of RNA Modified with Thioamide Internucleoside Linkage.

Recent success of RNA therapeutics has reinvigorated interest in chemical modifications of RNA. As exemplified by the phosphorothioates, modifications of sugar-phosphate backbone have been remarkably impactful but relatively underexplored in therapeutic RNAs. The present study reports synthesis, thermal stability, and RNA interference activity of RNAs modified with thioamide linkages. Compared to the previously studied amide-modified RNA, thioamide linkages strongly destabilized a short self-complementary RNA model duplex. However, in short interfering RNAs amides and thioamides had a similar effect on duplex stability and target RNA cleavage activity and specificity. Hence, the thioamide may be added to the toolbox of chemical biologist as a useful backbone modification well tolerated by the RNA interference machinery.

Unusual Guide-binding Pockets in RNA-targeting pAgo Nucleases

Argonaute nucleases use small nucleic acid guides to recognize and degrade complementary nucleic acid targets. Most prokaryotic Argonautes (pAgos) recognize DNA targets and may play a role in cell immunity against invader genetic elements. We have recently described two related groups of pAgo nucleases that have distinct specificity for DNA guides and RNA targets (DNA > RNA pAgos). Here, we describe additional pAgos from the same clades of the pAgo tree and demonstrate that they have the same unusual nucleic acid specificity. The two groups of DNA > RNA pAgos have non-standard guide-binding pockets in the MID domain and differ in the register of guide DNA binding and target cleavage. In contrast to other pAgos, which coordinate the 5′-end of the guide molecule by their C-terminal carboxyl, DNA > RNA pAgos have an extended C-terminus located away from the MID pocket. We show that modifications of the C-terminus do not affect guide DNA binding, but inhibit cleavage of complementary and mismatched RNA targets by some DNA > RNA pAgos. Our data suggest that the unique C-terminus found in DNA > RNA pAgos can modulate their catalytic properties and can be used as a target for pAgo modifications.

The Block Copolymer Phase Behavior Database.

The Block Copolymer Database (BCDB) is a platform that allows users to search, submit, visualize, benchmark, and download experimental phase measurements and their associated characterization information for di- and multiblock copolymers. To the best of our knowledge, there is no widely accepted data model for publishing experimental and simulation data on block copolymer self-assembly. This proposed data schema with traceable information can accommodate any number of blocks and at the time of publication contains over 5400 block copolymer total melt phase measurements mined from the literature and manually curated and simulation data points of the phase diagram generated from self-consistent field theory that can rapidly be augmented. This database can be accessed via the Community Resource for Innovation in Polymer Technology (CRIPT) web application and the Materials Data Facility. The chemical structure of the polymer is encoded in BigSMILES, an extension of the Simplified Molecular-Input Line-Entry System (SMILES) into the macromolecular domain, and the user can search repeat units and functional groups using the SMARTS search syntax (SMILES Arbitrary Target Specification). The user can also query characterization and phase information using Structured Query Language (SQL) and download custom sets of block copolymer data to train machine learning models. Finally, a protocol is presented in which GPT-4, an AI-powered large language model, can be used to rapidly screen and identify block copolymer papers from the literature using only the abstract text and determine whether they have BCDB data, allowing the database to grow as the number of published papers on the World Wide Web increases. The F1 score for this model is 0.74. This platform is an important step in making polymer data more accessible to the broader community.

Delta opioid receptors engage multiple signaling cascades to differentially modulate prefrontal GABA release with input and target specificity.

Opioids regulate circuits associated with motivation and reward across the brain. Of the opioid receptor types, delta opioid receptors (DORs) appear to have a unique role in regulating the activity of circuits related to reward without a liability for abuse. In neocortex, DORs are expressed primarily in interneurons, including parvalbumin- and somatostatin-expressing interneurons that inhibit somatic and dendritic compartments of excitatory pyramidal cells, respectively. But how DORs regulate transmission from these key interneuron classes is unclear. We found that DORs regulate inhibition from these interneuron classes using different G-protein signaling pathways that both converge on presynaptic calcium channels, but regulate distinct aspects of calcium channel function. This imposes different temporal filtering effects, via short-term plasticity, that depend on how calcium channels are regulated. Thus, DORs engage differential signaling cascades to regulate inhibition depending on the postsynaptic target compartment, with different effects on synaptic information transfer in somatic and dendritic domains.

Dual-Action Kinase Inhibitors Influence p38α MAP Kinase Dephosphorylation.

Reversible protein phosphorylation directs essential cellular processes including cell division, cell growth, cell death, inflammation, and differentiation. Because protein phosphorylation drives diverse diseases, kinases and phosphatases have been targets for drug discovery, with some achieving remarkable clinical success. Most protein kinases are activated by phosphorylation of their activation loops, which shifts the conformational equilibrium of the kinase towards the active state. To turn off the kinase, protein phosphatases dephosphorylate these sites, but how the conformation of the dynamic activation loop contributes to dephosphorylation was not known. To answer this, we modulated the activation loop conformational equilibrium of human p38α ΜΑP kinase with existing kinase inhibitors that bind and stabilize specific inactive activation loop conformations. From this, we discovered three inhibitors that increase the rate of dephosphorylation of the activation loop phospho-threonine by the PPM serine/threonine phosphatase WIP1. Hence, these compounds are "dual-action" inhibitors that simultaneously block the active site and stimulate p38α dephosphorylation. Our X-ray crystal structures of phosphorylated p38α bound to the dual-action inhibitors reveal a shared flipped conformation of the activation loop with a fully accessible phospho-threonine. In contrast, our X-ray crystal structure of phosphorylated apo human p38α reveals a different activation loop conformation with an inaccessible phospho-threonine, thereby explaining the increased rate of dephosphorylation upon inhibitor binding. These findings reveal a conformational preference of phosphatases for their targets and suggest a new approach to achieving improved potency and specificity for therapeutic kinase inhibitors.

Specifying behavioural and strategy components of de-implementation efforts targeting low-value prescribing practices in secondary health care

Background/AimsDe-implementation, including the removal or reduction of unnecessary or inappropriate prescribing, is crucial to ensure patients receive appropriate evidence-based health care. The utilization of de-implementation efforts is contingent on the quality of strategy reporting. To further understand effective ways to de-implement medical practices, specification of behavioural targets and components of de-implementation strategies are required. This paper aims to critically analyse how well the behavioural targets and strategy components, in studies that focused on de-implementing unnecessary or inappropriate prescribing in secondary healthcare settings, were reported.MethodsA supplementary analysis of studies included in a recently published review of de-implementation studies was conducted. Article text was coded verbatim to two established specification frameworks. Behavioural components were coded deductively to the five elements of the Action, Actor, Context, Target, Time (AACTT) framework. Strategy components were mapped to the nine elements of the Proctor’s ‘measuring implementation strategies’ framework.ResultsThe behavioural components of low-value prescribing, as coded to the AACTT framework, were generally specified well. However, the Actor and Time components were often vague or not well reported. Specification of strategy components, as coded to the Proctor framework, were less well reported. Proctor’s Actor, Action target: specifying targets, Dose and Justification elements were not well reported or varied in the amount of detail offered. We also offer suggestions of additional specifications to make, such as the ‘interactions’ participants have with a strategy.ConclusionSpecification of behavioural targets and components of de-implementation strategies for prescribing practices can be accommodated by the AACTT and Proctor frameworks when used in conjunction. These essential details are required to understand, replicate and successfully de-implement unnecessary or inappropriate prescribing. In general, standardisation in the reporting quality of these components is required to replicate any de-implementation efforts.Trial registrationNot registered.

Extreme resistance to S-methoprene in field-collected Culex pipiens (Diptera: Culicidae) across the Chicago, IL region

Insect growth regulators, like S-methoprene, are heavily relied upon worldwide for larval mosquito chemical control due to their target specificity and long-lasting effects. In this study, susceptibility to S-methoprene was evaluated in Culex pipiens, a globally important vector species. Populations from 14 sites throughout the Chicago area with a long history of S-methoprene use and two sites with minimal use in Wisconsin were examined. Using a bioassay methodology and probit analyses, LC50 and LC90 values were calculated and compared to a susceptible laboratory strain to develop resistance ratios, then categorized for resistance intensity. The resistance ratios observed required the addition of another category, termed ‘extreme’ resistance, indicating resistance ratios greater than 100. ‘Low’ to ‘extreme’ levels of resistance to S-methoprene were detected throughout Illinois populations, with resistance ratios ranging from 2.33 to 1010.52. Resistance was not detected in populations where S-methoprene pressure has been very limited. These 'extreme’ resistance ratios observed have never been documented in a wild vector species mosquito population. The relationships between historical S-methoprene use, resistance detected with laboratory bioassays, and the potential for field product failure remain unclear. However, the profound resistance detected here demonstrates a potential critical threat to protecting public health from mosquito-borne diseases.

Rapid detection of SARS-CoV-2 with a mobile device based on pulse controlled amplification

In the past, vast research has been conducted on biosensors and point-of-care (PoC) diagnostics. Despite rapid advances especially during the SARS-CoV-2 pandemic in this research field a low-cost molecular biosensor exhibiting the user-friendliness of a rapid antigen test, and also the sensitivity and specificity of a PCR test, has not been developed yet. To this end we developed a novel microfluidics based and handheld PoC device, that facilitates viral detection at PCR sensitivity and specificity in less than 40 min, including 15 min sample preparation. This was attained by incorporation of pulse controlled amplification (PCA), a method which uses short electrical pulses to rapidly increase the temperature of a small fraction of the sample volume. In this work, we present a low-cost PCA device with a microfluidic consumable intended for the use in a decentralized or home-setting. We used finite element analysis (FEA) simulations to display the fundamental principle and highlight the critical parameter dependency of PCA, such as pulse length and resistor shape. Furthermore, we integrated a simple and fast workflow for sample preparation and evaluated the limit of detection (LoD) for SARS-CoV-2 viral RNA, which is 0.88 copies/μL (=44 copies/reaction), and thus, comparable to conventional RT-qPCR. Additionally, target specificity of the device was validated. Our device and PCA approach enables cost-effective, rapid and mobile molecular diagnostics while remaining highly sensitive and specific.

How Natural Enzymes and Synthetic Ribozymes Generate Methylated Nucleotides in RNA.

Methylation of RNA nucleotides represents an important layer of gene expression regulation, and perturbation of the RNA methylome is associated with pathophysiology. In cells, RNA methylations are installed by RNA methyltransferases (RNMTs) that are specialized to catalyze particular types of methylation (ribose or different base positions). Furthermore, RNMTs must specifically recognize their appropriate target RNAs within the RNA-dense cellular environment. Some RNMTs are catalytically active alone and achieve target specificity via recognition of sequence motifs and/or RNA structures. Others function together with protein cofactors that can influence stability, S-adenosyl-L-methionine binding, and RNA affinity as well as aiding specific recruitment and catalytic activity. Association of RNMTs with guide RNAs represents an alternative mechanism to direct site-specific methylation by an RNMT that lacks intrinsic specificity. Recently, ribozyme-catalyzed methylation of RNA has been achieved in vitro, and here, we compare these different strategies for RNA methylation from structural and mechanistic perspectives.

Synthesis and in-silico Studies of 4-phenyl thiazol-2-amine Derivatives as Putative Anti-breast Cancer Agents.

Breast cancer (BC) is the second-leading cause of cancer-related fatalities in women after lung cancer worldwide. The development of BC is significantly influenced by estrogen receptors (ERs). The problem with current cancer treatments is selectivity, target specificity, cytotoxicity, and developing resistance. Thiazole scaffolds are gaining popularity in drug discovery due to their broad range of biological activity. It has the extraordinary capacity to control a variety of cellular pathways, and its potential for selective anticancer activity can be explored. Synthesis and in-silico</i> studies of 4-Phenyl thiazol-2-amine derivatives as anti-breast cancer agents and molecular docking was used to assess the compounds' capacity to bind ER-α protein target. In this study, 4-Phenylthiazol-2-amine derivatives (3a-j) have been synthesized, and using Schrodinger software, molecular docking and ADME studies of the compounds were conducted. Most of the synthesized compounds have shown dock scores ranging from -6.658 to - 8.911 kcal/mol, which is better than the standard drug tamoxifen (-6.821 kcal/mol). According to molecular docking, all compounds fit in the protein's active site and have the same hydrophobic pocket as the standard drug tamoxifen. Further, all of the compounds' ADME properties are below acceptable limits. Compound 3e showed the best docking score of -8.911. All compounds' ADME properties are within acceptable limits, and their p/o coefficients fall within a range, suggesting they will all have sufficient absorption at the site of action. These compounds can be evaluated invitro</i> and in-vivo</i> in the future.

Risk of early hepatocellular carcinoma recurrence following liver resection: arbitrary specification or possible target to improve outcome?

Risk of early hepatocellular carcinoma recurrence following liver resection: arbitrary specification or possible target to improve outcome?

In silico analysis of Naringenin and its O-alkyl derivatives for its potential binding with Estrogen Receptor- α

Breast cancer remains the second-most significant cause of female mortality worldwide. The emergence of naturally occurring plant-derived compounds called phytoestrogens has aroused substantial interest in their potential to mitigate breast cancer. Phytoestrogens demonstrate structural similarities to human estrogen and can therefore interact with the estrogen receptors. Naringenin, an important flavonoid and phytoestrogen, has gathered significant attention in the field of cancer due to its potential anti-inflammatory and antioxidant properties while its O-alkyl derivatives can enhance its bioavailability and target specificity. In this study, we have screened Naringenin and four of its O-alkyl derivatives, namely Isosakuranetin, 5-O-Methylnaringenin, Sakuranetin and 4',7-Di-O-methylnaringenin for their binding affinity with estrogen receptor-α (PDB ID: 6VJD). Molecular docking studies targeting estrogen receptor-α (PDB ID: 6VJD) revealed favorable binding energies and interaction patterns for naringenin and its derivatives, suggesting potential as therapeutic agents against breast cancer. Additionally, analysis with SwissADME highlighted the compounds' permeability across the blood-brain barrier (BBB), high absorption rates and water solubility, emphasizing their potential for therapeutic applications beyond breast cancer. Furthermore, the compounds exhibited promising pharmacokinetic profiles, synthetic accessibility and adherence to Lipinski's rule of five, supporting their candidacy for further development as therapeutic agents.