Target Molecules Research Articles

Papillary thyroid cancer and its gene polymorphism; A molecular mechanistic perspective

Thyroid cancer stands as the predominant malignancy within the endocrine system, comprising about 1% of newly identified cancer instances. Papillary Thyroid Cancer (PTC) is the predominant form of thyroid cancer, representing 80% or more of thyroid malignancies. Thyroid carcinoma harbours assorted genetic alterations which are highly prevalent, several of these characteristics are unique to this form of cancer. The conventional oncogenic genetic modifications frequently observed in thyroid carcinoma encompass RAS mutations RET/PTC rearrangements and PAX8-peroxisome proliferator-activated receptor g (PPARg) fusion oncogene. The lately discovered activating mutation in BRAF (the gene for the B-type RAF kinase, BRAF) the most widespread genetic modification in thyroid cancer (30-83%). RKIP (RAF kinase inhibitory protein) had formerly been delineated as a phospholipid binding protein. Mammalian RKIP/PEBP differs from other identified proteins and its role is still being clarified. RKIP over-expression can inhibit MEK interaction with RAF-1 and B-RAF. It plays a role in thyroid cancer progression and lymph node metastasis. So, elucidating mutational profile and protein expression of above cell signalling molecules will be very useful in determining a proper therapeutic target for anti-cancer molecules. Given that tumors often possess numerous genetic and cell signalling abnormalities, thus inhibiting a single signalling pathway is often therapeutically inefficacious, more success could be foreseen with agents directed against multiple cellular pathways.By determining the genetic profile and protein expression of mentioned MAP Kinase pathway molecules new targets can be identified for chemotherapic drugs and novel strategies will be charted out to make modifications in the map kinase pathway with the aim to stop the occurrence and distant metastasis of thyroid cancer.

Retrosynthesis Zero: Self-Improving Global Synthesis Planning Using Reinforcement Learning.

The field of computer-aided synthesis planning (CASP) has witnessed significant growth in recent years. Still, many CASP programs rely on large data sets to train neural networks, resulting in limitations due to the data quality and prior knowledge from chemists. In response, we propose Retrosynthesis Zero (ReSynZ), a reaction template-based method that combines Monte Carlo Tree Search with reinforcement learning inspired by AlphaGo Zero. Unlike other single-step reaction template-based CASP methods, ReSynZ takes complete synthesis paths for complex molecules, determined by reaction rules, as input for training the neural network. ReSynZ enables neural networks trained with relatively small reaction data sets (tens of thousands of data) to generate multiple synthesis pathways for a target molecule and suggest possible reaction conditions. On multiple data sets of molecular retrosynthesis, ReSynZ demonstrates excellent predictive performance compared to existing algorithms. The advantages, such as self-improving model features, flexible reward settings, the potential to surpass human limitations in chemical synthesis route planning, and others, make ReSynZ a valuable tool in chemical synthesis design.

Indium(III)-Catalyzed Haloalkynylation Reaction of Alkynes.

Green chemistry strives for sustainability at the molecular level and is gaining increasing relevance in the development of chemical reactions. The haloalkynylation reaction is a highly atom-economical C-C coupling reaction that was previously only achieved using transition metal catalysts. It enables the introduction of an alkyne unit and a halogen atom into the target molecule. Herein, we present a haloalkynylation reaction catalyzed by indium(III) halides. The use of indium(III) bromide as a catalyst leads exclusively to the cis addition products with yields up to 86 %. In addition, iodoacetylenes can be applied for the first time for the haloalkynylation reaction of internal alkynes which is an important step forward in the development of industrially relevant and sustainable catalysts. In contrast to gold catalysis, which proceeds via a similar mechanism, the use of alkyl-substituted haloacetylenes as reagents is also possible. Based on 13C labeling experiments and quantum chemical calculations, we postulate two possible mechanisms for the indium(III)-catalyzed haloalkynylation reactions.

A Hybrid Nanotube Stamp System in Intracellular Protein Delivery for Cancer Treatment and NMR Analytical Techniques.

In contrast to intracellular gene transfer, the direct delivery of expressed proteins is a significantly challenging yet essential technique for elucidating cellular functions, including protein complex structure, liquid-liquid phase separation, therapeutic applications, and reprogramming. In this study, we developed a hybrid nanotube (HyNT) stamp system that physically inserts the HyNTs into adhesive cells, enabling the injection of target molecules through HyNT ducts. This system demonstrates the capability to deliver multiple proteins, such as lactate oxidase (LOx) and ubiquitin (UQ), to approximately 1.8 × 107 adhesive cells with a delivery efficiency of 89.9% and a viability of 97.1%. The delivery of LOx enzyme into HeLa cancer cells induced cell death, while enzyme-delivered healthy cells remained viable. Furthermore, our stamp system can deliver an isotope-labeled UQ into adhesive cells for detection by nuclear magnetic resonance (NMR).

Position-specific carbon stable isotope analysis of glyphosate: isotope fingerprinting of molecules within a mixture.

Glyphosate [N-(phosphonomethyl) glycine] is a widely used herbicide and a molecule of interest in the environmental sciences, due to its global use in agriculture and its potential impact on ecosystems. This study presents the first position-specific carbon isotope (13C/12C) analyses of glyphosates from multiple sources. In contrast to traditional isotope ratio mass spectrometry (IRMS), position-specific analysis provides 13C/12C ratios at individual carbon atom positions within a molecule, rather than an average carbon isotope ratio across a mixture or a specific compound. In this work, glyphosate in commercial herbicides was analyzed with only minimal purification, using a nuclear magnetic resonance (NMR) spectroscopy method that detects 1H nuclei with bonds to either 13C or 12C, and isolates the signals of interest from other signals in the mixture. Results demonstrate that glyphosate from different sources can have significantly different intramolecular 13C/12C distributions, which were found to be spread over a wide range, with δ13C Vienna Peedee Belemnite (VPDB) values of -28.7 to -57.9‰. In each glyphosate, the carbon with a bond to the phosphorus atom was found to be depleted in 13C compared to the carbon at the C2 position, by 4 to 10‰. Aminomethylphosphonic acid (AMPA) was analyzed for method validation; AMPA contains only a single carbon position, so the 13C/12C results provided by the NMR method could be directly compared with traditional isotope ratio mass spectrometry. The glyphosate mixtures were also analyzed by IRMS to obtain their average 13C/12C ratios, for comparison with our position-specific results. This comparison revealed that the IRMS results significantly disguise the intramolecular isotope distribution. Finally, we introduce a 31P NMR method that can provide a position-specific 13C/12C ratio for carbon positions with a C-P chemical bond, and the results obtained by 1H and 31P for C3 carbon agree with one another within their analytical uncertainty. These analytical tools for position-specific carbon isotope analysis permit the isotopic fingerprinting of target molecules within a mixture, with potential applications in a range of fields, including the environmental sciences and chemical forensics.

A comprehensive evaluation of serum circCSPP1 as a novel diagnostic and prognostic biomarker for gastric cancer

PurposeGastric cancer (GC) has high incidence and mortality due to its low early screening efficiency. Circular RNAs (CircRNAs) are a new class of non-coding RNAs which is closely related to GC. Nevertheless, the clinical application value of circRNAs in GC are largely unknown. Therefore, we studied the role of a novel circRNA named circCSPP1 in patients with GC. MethodsCircRNA sequencing was performed to screen out the target molecule. Real-time fluorescent quantitative PCR (RT-qPCR) was utilized to detect the expression level of circCSPP1 in GC tissues, cells, and serum. Gel and Sanger sequencing were utilized to verify the ring structure of circCSPP1. RNase R enzyme digestion experiment and actinomycin D experiment were verifed the advantage of circCSPP1 as a diagnostic biomarker in patients with GC when that compared with linear RNA. The correlation between the expression level of serum circCSPP1 and clinicopathological data of GC patients was further analyzed. Receiver operating characteristic curve (ROC) and the area under ROC curve (AUC) were utilied to evaluate the diagnostic performance. ResultsCircCSPP1 has a circular structure which with resistance to RNA exonuclease digestion and long half-life compared with linear RNA. In our study, circCSPP1 was first found up-regulated in patients with GC. Serum circCSPP1 level was decreased significantly after surgical resection whereas increased after recurrence. High expression of circCSPP1 was associated with poor survival rates. The expression level of circCSPP1 was significantly correlated to tumor size, T stage, lymph node metastasis, and TNM stage. The AUC of serum circCSPP1 was 0.834, with high sensitivity and specificity in discriminating patients with GC from healthy donors. More importantly, the combined diagnosis of circCSPP1, CEA, and CA19–9 achieved the superior AUC of 0.882, with the highest specificity. ConclusionSerum circCSPP1 may prove to be a potential non-invasive auxiliary diagnostic biomarker for patients with GC.

Deuterated Alkyl Sulfonium Salt Reagents; Importance of H/D Exchange Methods in Drug Discovery.

Deuterated drugs (heavy drugs) have recently been spotlighted as a new modality for small-molecule drugs because the pharmacokinetics of pharmaceutical drugs can be enhanced by replacing C-H bonds with more stable C-D bonds at metabolic positions. Therefore, deuteration methods for drug candidates are a hot topic in medicinal chemistry. Among them, the H/D exchange reaction (direct transformation of C-H bonds to C-D bonds) is a useful and straightforward method for creating novel deuterated target molecules, and over 20 reviews on the synthetic methods related to H/D exchange reactions have been published in recent years. Although various deuterated drug candidates undergo clinical trials, approved deuterated drugs possess CD3 groups in the same molecule. However, less diversification, except for the CD3 group, is a problem for future medicinal chemistry. Recently, we developed various deuterated alkyl (dn-alkyl) sulfonium salts based on the H/D exchange reaction of the corresponding hydrogen form using D2O as an inexpensive deuterium source to introduce CD3, CH3CD2, and ArCH2CD2 groups into drug candidates. This concept summarises recent reviews related to H/D exchange reactions and novel reagents that introduce the CD3 group, and our newly developed electrophilic dn-alkyl reagents are discussed.

Engineering the Signal Resolution of a Paper-Based Cell-Free Glutamine Biosensor with Genetic Engineering, Metabolic Engineering, and Process Optimization

Specialized cancer treatments have the potential to exploit glutamine dependence to increase patient survival rates. Glutamine diagnostics capable of tracking a patient’s response to treatment would enable a personalized treatment dosage to optimize the tradeoff between treatment success and dangerous side effects. Current clinical glutamine testing requires sophisticated and expensive lab-based tests, which are not broadly available on a frequent, individualized basis. To address the need for a low-cost, portable glutamine diagnostic, this work engineers a cell-free glutamine biosensor to overcome assay background and signal-to-noise limitations evident in previously reported studies. The findings from this work culminate in the development of a shelf-stable, paper-based, colorimetric glutamine test with a high signal strength and a high signal-to-background ratio for dramatically improved signal resolution. While the engineered glutamine test is important progress towards improving the management of cancer and other health conditions, this work also expands the assay development field of the promising cell-free biosensing platform, which can facilitate the low-cost detection of a broad variety of target molecules with high clinical value.

Remote-Carbonyl-Directed Consecutive Arylation of Terminal Alkenes for the Synthesis of Tetrasubstituted Olefins

The highly efficient synthesis of all-carbon tetrasubstituted olefins has been concerned for decades, especially for multi-aryl substituted olefins which widely used in functional organic materials and pharmaceuticals. This work presents a carbonyl-directed palladium-catalyzed consecutive arylation of terminal alkenes with aryl iodides under mild conditions, a series of triarylated tetrasubstituted olefins were obtained in moderate yields. Because a weak chelation effect is generally difficult to support such a thorough tri-fold Heck arylation, and the β-trans-selective alkenyl C–H activation cannot be achieved via a twisted endo-metallacyclic intermediate, thus, the key to success is the compatibility between several mechanisms, including Heck, C–H activation and E,Z-isomerization. Here, the judicious selection of a flexible-alkyl-chain-tethered carbonyl group seems to be critical, it provides a proper chelation effect that not only assists a distal alkenyl functionalization or isomerization, but also avoids byproducts caused by other possible β-H elimination or migration. The strategy developed herein greatly streamlines the preparation of the target molecules, and the protocol covers a range of readily available terminal alkenes bearing native directing groups (e.g., aldehyde, ketone and ester), and aryl iodides.

Expression analysis and mapping of Viral—Host Protein interactions of Poxviridae suggests a lead candidate molecule targeting Mpox

BackgroundMonkeypox (Mpox) is an important human pathogen without etiological treatment. A viral-host interactome study may advance our understanding of molecular pathogenesis and lead to the discovery of suitable therapeutic targets.MethodsGEO Expression datasets characterizing mRNA profile changes in different host responses to poxviruses were analyzed for shared pathway identification, and then, the Protein–protein interaction (PPI) maps were built. The viral gene expression datasets of Monkeypox virus (MPXV) and Vaccinia virus (VACV) were used to identify the significant viral genes and further investigated for their binding to the library of targeting molecules.ResultsInfection with MPXV interferes with various cellular pathways, including interleukin and MAPK signaling. While most host differentially expressed genes (DEGs) are predominantly downregulated upon infection, marked enrichments in histone modifiers and immune-related genes were observed. PPI analysis revealed a set of novel virus-specific protein interactions for the genes in the above functional clusters. The viral DEGs exhibited variable expression patterns in three studied cell types: primary human monocytes, primary human fibroblast, and HeLa, resulting in 118 commonly deregulated proteins. Poxvirus proteins C6R derived protein K7 and K7R of MPXV and VACV were prioritized as targets for potential therapeutic interventions based on their histone-regulating and immunosuppressive properties. In the computational docking and Molecular Dynamics (MD) experiments, these proteins were shown to bind the candidate small molecule S3I-201, which was further prioritized for lead development.ResultsMPXV circumvents cellular antiviral defenses by engaging histone modification and immune evasion strategies. C6R-derived protein K7 binding candidate molecule S3I-201 is a priority promising candidate for treating Mpox.

Theoretical spectroscopic electronic elucidation with polar and non-polar solvents (IEFPCM model), molecular docking and molecular dynamic studies on bendiocarb -antiallergic drug agent

The potential antiallergic compound bendiocarb was studied theoretically by polar and non-polar (six) solvents (IEFPCM model) by quantum chemical DFT calculations. Rotational potential barriers were estimated for water, acetone, THF, chloroform, benzene, and toluene are 12.62, 12.45, 12.55, 12.69, 12.74 and 12.57 kJ/mol. Analysis was done on the variations in geometries brought about by the electronegative atom’s replacement as well as the intramolecular interactions caused by the benzodioxol ring. NBO analysis as well as geometrical equilibrium have been performed using DFT employing the B3LYP technique with the 6-311G++(d, p) basis set. In vibrational analysis, CH stretching of bendiocarb was theoretically estimated within 3207–3181 cm−1 (gas), 3207–3184 cm−1 (acetone and water), 3207–3182 cm−1 (benzene and toluene), and 3207–3183 cm−1 (chloroform and THF) due to CN vibrations is challenging because of the overlapping and appearance of multiple bands in similar regions. Energy gaps for Bendiocarb in different solvents for water (5.719 eV), acetone (5.716 eV), THF (5.722 eV), chloroform (5.724 eV), benzene (5.731 eV), toluene (5.730 eV), and gas phase (5.746 eV). Lipinski’s rule of five was exploited to guide research on drug similarity and oral action. Using docking simulation against the antiallergic protein, a binding energy of −5.22 kcal/mol, 4P5M has been examined. The protein 4P5M exhibits variations between 0.12 and 0.155 nm for RMSD in molecular dynamic simulation. One can infer information about the pharmacokinetic features of the target molecule from its drug similarity, absorption, distribution, metabolism, excretion, and toxicity properties.

Ag nanopines over Al nanoneedle arrays enable high SERS sensitivity and reproducibility for molecular sensing

In this study, highly uniform 3D Al nanoneedle arrays (AlNNAs) decorated with Ag nanopines are synthesized by anodization of Al foil with prior nanoimprinting and subsequent electrodeposition method, demonstrating remarkable surface-enhanced Raman scattering (SERS) property. The AlNNAs possess a highly ordered periodicity of 1 μm and nanoneedle height of 800 nm, making it an optimal supporting matrix to host Ag-NPs as SERS substrate. Such well-ordered Ag@AlNNAs SERS substrate with precisely electrodeposited Ag nanopines generate high density SERS host spots and abundant sites to adsorb target molecules. As a result, Ag@AlNNAs exhibit high sensitivity for rhodamine 6 G down to 10–13 M and good signal reproducibility with a relative standard deviation of 7.2 %, as well as an average enhancement factor of 4.23 × 109. For practical detection of pollutants, 10–8 M adenine, 10–12 M bisphenol in water, and melamine (10–7 M) in opaque milk are clearly identified by using the Ag@AlNNAs sensor. This study opens a bright way to fabricate SERS substrate with a good balance of sensitivity, reproducibility and cost, indicating promising potential for environmental monitoring and food safety.

Augmented Fluorescence Signaling on a Single BaTiO3 Microbead Optical Booster toward High-Sensitive Biosensing.

In this work, we report a new generation of single microbead bioassay that employs a single BaTiO3 microbead as an optical booster for target biomarker enrichment and optical enhancement toward protein and nucleic acid analysis. The single BaTiO3 microbead can not only concentrate the target molecules by nearly 104-fold but also act as an optical booster to prominently enhance the target-induced fluorescence signal by the whispering gallery mode for improving the excitation efficiency and the microlens effect for promoting the signal collecting efficiency, respectively. Compared with using a conventional single microbead, this optical booster exhibits nearly 2 orders of magnitude higher sensitivity without the assistance of any signal amplification techniques or costly instruments. Moreover, this single microbead optical booster is capable of detecting different kinds of protein and nucleic acid biomarkers in a simple mix-and-read manner, holding great potential for early clinical diagnosis.

Molecularly Imprinted Polymer Biosensor Based on Nitrogen-Doped Electrochemically Exfoliated Graphene/Ti3 CNTX MXene Nanocomposite for Metabolites Detection.

Rapid and accurate quantification of metabolites in different bodily fluids is crucial for a precise health evaluation. However, conventional metabolite sensing methods, confined to centralized laboratory settings, suffer from time-consuming processes, complex procedures, and costly instrumentation. Introducing the MXene/nitrogen-doped electrochemically exfoliated graphene (MXene@N-EEG) nanocomposite as a novel biosensing platform in this work addresses the challenges associated with conventional methods, leveraging the concept of molecularly imprinted polymers (MIP) enables the highly sensitive, specific, and reliable detection of metabolites. To validate our biosensing technology, we utilize agmatine as a significant biologically active metabolite. The MIP biosensor incorporates electrodeposited Prussian blue nanoparticles as a redox probe, facilitating the direct electrical signaling of agmatine binding in the polymeric matrix. The MXene@N-EEG nanocomposite, with excellent metal conductivity and a large electroactive specific surface area, effectively stabilizes the electrodeposited Prussian blue nanoparticles. Furthermore, increasing the content of agmatine-imprinted cavities on the electrode enhances the sensitivity of the MIP biosensor. Evaluation of the designed MIP biosensor in buffer solution and plasma samples reveals a wide linear concentration range of 1.0 nM-100.0 μM (R2 = 0.9934) and a detection limit of 0.1 nM. Notably, the developed microfluidic biosensor offers low cost, rapid response time to the target molecule (10 min of sample incubation), good recovery results for detecting agmatine in plasma samples, and acceptable autonomous performance for on-chip detection. Moreover, its high reliability and sensitivity position this MIP-based biosensor as a promising candidate for miniaturized microfluidic devices with the potential for scalable production for point-of-care applications.

From Protein Structures to Functional Biomimetics

AbstractThe development of complex molecular scaffolds with defined folding properties represents a central challenge in chemical research. Proteins are natural scaffolds defined by a hierarchy of structural complexity and have evolved to manifest unique functional characteristics; for example, molecular recognition capabilities that facilitate the binding of target molecules with high affinity and selectivity. Utilizing these features, proteins have been used as a starting point for the design of synthetic foldamers and enhanced biocatalysts, as well as bioactive reagents in drug discovery. In this account, we describe the strategies used in our group to stabilize protein folds, ranging from the constraint of bioactive peptide conformations to chemical protein engineering. We discuss the evolution of peptides into peptidomimetics to inhibit protein–protein and protein–nucleic acid interactions, and the selective chemical modification of proteins to enhance their properties for biotechnological applications. The reported peptide- and proteomimetic structures cover a broad range of molecular sizes and they highlight the importance of structure stabilization for the design of functional biomimetics.1 Introduction2 Constraining the Conformation of Peptides3 Peptide-Based Covalent Protein Modifiers4 Chemical Protein Engineering5 Conclusions

Strong-field photoelectron holography in the subcycle limit

Strong-field photoelectron holography is promising for the study of electron dynamics and structure in atoms and molecules, with superior spatiotemporal resolution compared to conventional electron and X-ray diffractometry. However, the application of strong-field photoelectron holography has been hindered by inter-cycle interference from multicycle fields. Here, we address this challenge by employing a near-single-cycle field to suppress the inter-cycle interference. We observed and separated two distinct holographic patterns for the first time. Our measurements allow us not only to identify the Gouy phase effect on electron wavepackets and holographic patterns but also to correctly extract the internuclear separation of the target molecule from the holographic pattern. Our work leads to a leap jump from theory to application in the field of strong-field photoelectron holography-based ultrafast imaging of molecular structures.

Divergent Synthesis of Scabrolide A and Havellockate via an exo-exo-endo Radical Cascade.

Here we report a concise and divergent synthesis of scabrolide A and havellockate, representative members of polycyclic marine natural product furano(nor)cembranoids. The synthesis features a highly efficient exo-exo-endo radical cascade. Through the generation of two rings, three C-C bonds, and three contiguous stereocenters in one step, this remarkable transformation not only assembles the bowl-shaped, common 6-5-5 fused ring system from simple building blocks but also precisely installs the functionalities at desired positions and sets the stage for further divergent preparation of both target molecules. Further studies reveal that the robust and unusual 6-endo radical addition in the cascade is likely facilitated by the rigidity of the substrate.

Optical Tweezing Terahertz Probing for a Single Metal Nanoparticle.

Recently, extensive research has been reported on the detection of metal nanoparticles using terahertz waves, due to their potential for efficient and nondestructive detection of chemical and biological samples without labeling. Resonant terahertz nanoantennas can be used to detect a small amount of molecules whose vibrational modes are in the terahertz frequency range with high sensitivity. However, the positioning of target molecules is critical to obtaining a reasonable signal because the field distribution is inhomogeneous over the antenna structure. Here, we combine an optical tweezing technique and terahertz spectroscopy based on nanoplasmonics, resulting in extensive controllable tweezing and sensitive detection at the same time. We observed optical tweezing of a gold nanoparticle and detected it with terahertz waves by using a single bowtie nanoantenna. Furthermore, the calculations confirm that molecular fingerprinting is possible by using our technique. This study will be a prestep of biomolecular detection using gold nanoparticles in terahertz spectroscopy.

Theoretical study of the electron-induced vibrational excitation of H2O

This study presents calculations for cross sections of the vibrational excitation of $ H O X A_1 via electron impact. The theoretical approach employed here is based on first principles only, combining electron-scattering calculations performed using the UK R-matrix codes for several geometries of the target molecule, three-dimensional (3D) vibrational states of H$_2$O, and 3D vibrational frame transformation. The aim is to represent the scattering matrix for the electron incident of the molecule. The vibrational wave functions were obtained numerically, without the normal-mode approximation, so that the interactions and transitions between vibrational states assigned to different normal modes could be accounted for. The thermally averaged rate coefficients were derived from the calculated cross sections for temperatures in the 10-10000 K interval and analytical fits for rate coefficients were also provided. We assessed the uncertainty estimations of the obtained data for subsequent applications of the rate coefficients in modelling the non-local thermal equilibrium (non-LTE) spectra of water in various astrophysical environments.

Paraoxonase-2 shRNA-mediated gene silencing suppresses proliferation and migration, while promotes chemosensitivity in clear cell renal cell carcinoma cell lines.

Clear cell renal cell carcinoma (ccRCC) represents the most common subtype of renal tumor. Despite recent advances in identifying novel target molecules, the prognosis of patients with ccRCC continues to be poor, mainly due to the lack of sensitivity to chemo- and radiotherapy and because of one-third of renal cell carcinoma patients displays metastatic disease at diagnosis. Thus, identifying new molecules for early detection and for developing effective targeted therapies is mandatory. In this work, we focused on paraoxonase-2 (PON2), an intracellular membrane-bound enzyme ubiquitously expressed in human tissues, whose upregulation has been reported in a variety of malignancies, thus suggesting its possible role in cancer cell survival and proliferation. To investigate PON2 involvement in tumor cell metabolism, human ccRCC cell lines were transfected with plasmid vectors coding short harpin RNAs targeting PON2 transcript and the impact of PON2 silencing on cell viability, migration, and response to chemotherapeutic treatment was then explored. Our results showed that PON2 downregulation was able to trigger a decrease in proliferation and migration of ccRCC cells, as well as an enhancement of cell sensitivity to chemotherapy. Thus, taken together, data reported in this study suggest that the enzyme may represent an interesting therapeutic target for ccRCC.