Research progress in the detection of trace heavy metal ions in food samples.

Food safety is the basis for ensuring human survival and development. The threat of heavy metal ions to food safety has become a social concern with the rapid growth of the economy and the accompanying environmental pollution. Some heavy metal ions are highly toxic even at trace levels and pose significant health risks to humans. Therefore, ultrasensitive detection of heavy metal ions in food samples is important. In this mini-review, recent advances in the analytical methods based on nanomaterials for detecting trace heavy metal ions in food samples are summarized in three categories: electrochemical, colorimetric, and fluorescent methods. We present the features and sensing mechanisms of these three methods, along with typical examples to illustrate their application in the detection of heavy metal ions in foods. This mini-review ends with a discussion of current challenges and future prospects of these approaches for sensing heavy metal ions. The review will help readers understand the principles of these methods, thereby promoting the development of new analytical methods for the detection of heavy metal ions in food samples.

Mechanism of targeting the mTOR pathway to regulate ferroptosis in NSCLC with different EGFR mutations.

Patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations can be treated with EGFR-tyrosine kinase inhibitors (TKIs). Although EGFR-TKI-targeted drugs bring survival promotion in patients with EGFR mutations, drug resistance is inevitable, so it is urgent to explore new treatments to overcome drug resistance. In addition, wild-type EGFR lacks targeted drugs, and new targeted therapies need to be explored. Ferroptosis is a key research direction for overcoming drug resistance. However, the role and mechanism of regulating ferroptosis in different EGFR-mutant NSCLC types remains unclear. In the present study, H1975 (EGFR T790M/L858R mutant), A549 (EGFR wild-type) and H3255 (EGFR L858R mutant) NSCLC cell lines were used. The expression of ferroptosis markers in these cell lines was detected using western blotting and reverse transcription-quantitative PCR. Cell viability was determined using the MTT assay and reactive oxygen species (ROS) levels were measured using flow cytometry. The results showed that, compared with EGFR wild-type/sensitive mutant cells, EGFR-resistant mutant cells were more sensitive to the ferroptosis inducer, erastin. Furthermore, the mammalian target of rapamycin (mTOR) inhibitor, everolimus (RAD001), induced cell death in all three cell lines in a dose-dependent manner. The ferroptosis inhibitor, ferrostatin-1, could reverse cell death in EGFR-resistant mutant and EGFR wild-type cells induced by RAD001, but could not reverse cell death in EGFR-sensitive mutant cells. Compared with EGFR wild-type/sensitive mutant cells, EGFR-resistant mutant cells were more sensitive to RAD001 combined with erastin. In addition, a high-dose of RAD001 reduced the expression levels of ferritin heavy-chain polypeptide 1 (FTH1), glutathione peroxidase 4 (GPX4) and ferroportin and significantly increased ROS and malondialdehyde (MDA) levels in EGFR-resistant mutant and EGFR wild-type cells. In the present study, GPX4 inhibitor only or combined with RAD001 inhibited the AKT/mTOR pathway in EGFR-resistant mutant cells. Therefore, the results of the present study suggested that inhibition of the mTOR pathway may downregulate the expression of ferroptosis-related proteins in EGFR-resistant and EGFR wild-type NSCLC cells, increase the ROS and MDA levels and ultimately induce ferroptosis.

Synthetic Peptides with Genetic-Codon-Tailored Affinity for Assembling Tetraspanin CD81 at Cell Interfaces and Inhibiting Cancer Metastasis.

Probing biomolecular interactions at cellular interfaces is crucial for understanding and interfering with life processes. Although affinity binders with site specificity for membrane proteins are unparalleled molecular tools, a high demand remains for novel multi-functional ligands. In this study, a synthetic peptide (APQQ) with tight and specific binding to the untargeted extracellular loop of CD81 evolved from a genetically encoded peptide pool. With tailored affinity, APQQ flexibly accesses, site-specifically binds, and forms a complex with CD81, enabling in-situ tracking of the dynamics and activity of this protein in living cells, which has rarely been explored because of the lack of ligands. Furthermore, APQQ triggers the relocalization of CD81 from diffuse to densely clustered at cell junctions and modulates the interplay of membrane proteins at cellular interfaces. Motivated by these, efficient suppression of cancer cell migration, and inhibition of breast cancer metastasis were achieved in vivo.

C-Myc-induced hypersialylation of small cell lung cancer facilitates pro-tumoral phenotypes of macrophages.

Immunosuppressive myeloid cell populations have been documented in small cell lung cancer (SCLC) subtypes, playing a key role in remolding the tumor microenvironment (TME). However, the cancer-associated transcriptional features of monocytes and tumor-associated macrophages (TAMs) in SCLC remain poorly understood. Herein, we analyzed the molecular features and functions of monocyte/macrophage subsets aiming to inhibit monocyte recruitment and pro-tumor behavior of macrophages. We observe that NEUROD1-high SCLC subtype (SCLC-N) exhibits subtype-specific hypersialylation induced by the unique target c-Myc (MYC) of NEUROD1. The hypersialylation can alter macrophage phenotypes and pro-tumor behavior by regulating the expression of the immune-inhibiting lectin receptors on monocyte-derived macrophages (MDMs) in SCLC-N. Inhibiting the aberrant sialic acid metabolic pathways in SCLC can significantly enhance the phagocytosis of macrophages. This study provides a comprehensive overview of the cancer-specific immune signature of monocytes and macrophages and reveals tumor-associated biomarkers as potential therapeutic targets for SCLC.

Peptide-derived coordination frameworks for biomimetic and selective separation.

Peptide-derived metal-organic frameworks (PMOFs) have emerged as a class of biomimetic materials with attractive performances in analytical and bioanalytical chemistry. The incorporation of biomolecule peptides gives the frameworks conformational flexibility, guest adaptability, built-in chirality, and molecular recognition ability, which greatly accelerate the applications of PMOFs in enantiomeric separation, affinity separation, and the enrichment of bioactive species from complicated samples. This review focuses on the recent advances in the engineering and applications of PMOFs in selective separation. The unique biomimetic size-, enantio-, and affinity-selective performances for separation are discussed along with the chemical structures and functions of MOFs and peptides. Updates of the applications of PMOFs in adaptive separation of small molecules, chiral separation of drug molecules, and affinity isolation of bioactive species are summarized. Finally, the promising future and remaining challenges of PMOFs for selective separation of complex biosamples are discussed.

Giant Enhancement of Raman Scattering by a Hollow-Core Microstructured Optical Fiber Allows Single Exosome Probing.

Microstructured optical fibers (MOFs) provide solutions for breaking through the bottlenecks in areas of high-power transmission and high-efficiency optical waveguides. Other than transporting light waves, MOFs can synergistically combine microfluidics and optics in a single fiber with an unprecedented light path length not readily achievable by planar optofluidic configurations. Here, we demonstrate that hollow-core anti-resonant optical fibers (HcARFs) can significantly enhance Raman scattering by over three orders of magnitude (EF ≈ 5000) compared with a planar setup, due to the joint mechanisms of strong light-matter interaction in the fiber core and the cumulative effect of the fiber. The giant enhancement enables us to develop the first optical fiber sensor to achieve single cancer exosome detection via a sandwich-structured strategy. This enables a multiplexed analysis of surface proteins of exosome samples, potentially allowing an accurate identification of the cellular origin of exosomes for cancer diagnosis. Our findings could expand the applications of HcARF in many exciting areas beyond the waveguide.

Induction of reproductive injury by bisphenol A and the protective effects of cyanidin-3-O-glucoside and protocatechuic acid in rats.

Bisphenol A (BPA) has attracted growing attention as a well-known environmental pollutant due to its high risk of male reproductive toxicity. In this study, transcriptomics profiling combined with metabolomic techniques was applied to explore the intervention effects of BPA-induced male reproductive toxicity. We demonstrated that cyanidin-3-O-glucoside (C3G) and its main metabolite protocatechuic acid (PCA) significantly increased testosterone and luteinizing hormone (LH) levels in the serum of rats, and improved sperm quality. Furthermore, we identified and screened differentially expressed genes (DEGs) and metabolites (DMs) that functionally enriched in the steroidogenesis-related pathways. Next, the validated results found that C3G and PCA significantly up-regulated the gene expressions of Star, Cyp11a1, Cyp17a1, Cyp19a1, Cyp7a1, Hsd3b1, Hsd3b2, Hsd17b3, Scrab1, and Ass1 in testicular. In Leydig cells, C3G and PCA dramatically alleviated apoptosis, ROS accumulation, and cell cycle arrest caused by BPA. In addition, molecular docking and simulation results implied that C3G and PCA competitively with BPA bind to the estrogen receptors α and ß (ERα and ERß) and shared common key amino acids. The main interaction modes between small molecules and estrogen receptors included π-π stacking, salt bridges, hydrogen bonds, and hydrophobic interactions. Therefore, our study sheds light on C3G and PCA supplementation can protect male reproduction from BPA-induced injury.

Approaching the Dimerization Mechanism of Small Molecule Inhibitors Targeting PD-L1 with Molecular Simulation.

Inhibitors blocking the PD-1/PD-L1 immune checkpoint demonstrate impressive anti-tumor immunity, and small molecule inhibitors disclosed by the Bristol-Myers Squibb (BMS) company have become a hot topic. In this work, by modifying the carbonyl group of BMS-202 into a hydroxyl group to achieve two enantiomers (MS and MR) with a chiral center, we found that this is an effective way to regulate its hydrophobicity and thus to reduce the negative effect of polar solvation free energy, which enhances the stability of PD-L1 dimer/inhibitor complexes. Moreover, we studied the binding modes of BMS-200 and BMS-202-related small molecule inhibitors by molecular dynamics simulation to explore their inhibitory mechanism targeting PD-L1 dimerization. The results showed that the size exclusion effect of the inhibitors triggered the rearrangement of the residue ATyr56, leading to the formation of an axisymmetric tunnel-shaped pocket, which is an important structural basis for improving the binding affinity of symmetric inhibitors with PD-L1. Furthermore, after inhibitor dissociation, the conformation of ATyr123 and BMet115 rearranged, which blocked the entrance of the binding pocket, while the reverse rearrangements of the same residues occurred when the PD-L1 monomer was complexed with the inhibitors, preparing PD-L1 for dimerization. Overall, this study casts a new light on the inhibitory mechanism of BMS inhibitors targeting PD-L1 dimerization and provides an idea for designing novel small molecule inhibitors for future cancer immunotherapy.

Is the Triggering of PD-L1 Dimerization a Potential Mechanism for Food-Derived Small Molecules in Cancer Immunotherapy? A Study by Molecular Dynamics.

Using small molecules to inhibit the PD-1/PD-L1 pathway is an important approach in cancer immunotherapy. Natural compounds such as capsaicin, zucapsaicin, 6-gingerol and curcumin have been proposed to have anticancer immunologic functions by downregulating the PD-L1 expression. PD-L1 dimerization promoted by small molecules was recently reported to be a potential mechanism to inhibit the PD-1/PD-L1 pathway. To clarify the molecular mechanism of such compounds on PD-L1 dimerization, molecular docking and molecular dynamics simulations were performed. The results evidenced that these compounds could inhibit PD-1/PD-L1 interactions by directly targeting PD-L1 dimerization. Binding free energy calculations showed that capsaicin, zucapsaicin, 6-gingerol and curcumin have strong binding ability with the PD-L1 dimer, where the affinities of them follow the trend of zucapsaicin > capsaicin > 6-gingerol ≈ curcumin. Analysis by residue energy decomposition, contact numbers and nonbonded interactions revealed that these compounds have a tight interaction with the C-sheet, F-sheet and G-sheet fragments of the PD-L1 dimer, which were also involved in the interactions with PD-1. Moreover, non-polar interactions between these compounds and the key residues Ile54, Tyr56, Met115 and Ala121 play a key role in stabilizing the protein−ligand complexes in solution, in which the 4'-hydroxy-3'-methoxyphenyl group and the carbonyl group of zucapsaicin, capsaicin, 6-ginger and curcumin were significant for the complexation of small molecules with the PD-L1 dimer. The conformational variations of these complexes were further analyzed by free energy landscape (FEL) and principal component analysis (PCA) and showed that these small molecules could make the structure of dimers more stable. This work provides a mechanism insight for food-derived small molecules blocking the PD-1/PD-L1 pathway via directly targeting the PD-L1 dimerization and offers theoretical guidance to discover more effective small molecular drugs in cancer immunotherapy.

Untargeted Lipidomics Revealed the Protective Effects of Cyanidin-3-O-glucoside on Bisphenol A-Induced Liver Lipid Metabolism Disorder in Rats.

Bisphenol A (BPA) is an estrogenic endocrine disruptor that induces metabolic disorders. Cyanidin-3-O-glucoside (C3G) has multiple functional activities and is the most abundant anthocyanin belonging to the flavonoid subgroup. This study aimed to investigate the protective effect of C3G on BPA-induced liver lipid metabolism disorder and explore its mechanism via lipidomics analysis. The results showed that C3G supplementation significantly ameliorated the serum levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, triacylglycerols (TG), and alanine and aspartate aminotransferase (ALT and AST). Furthermore, liver lipidomics indicated that C3G effectively facilitated the recovery of differential lipid metabolites, including TGs, phosphatidylethanolamines, phosphatidylcholines, lysophosphatidylcholines, phosphatidylinositol, cholesteryl esters, and phosphatidylserine, and reversed the levels of hepatic lipid synthesis-related genes. Our results suggest that C3G has an effective regulatory effect on BPA-induced disorders of lipid metabolism.

(Re-)Directing Oligomerization of a Single Building Block into Two Specific Dynamic Covalent Foldamers through pH.

Dynamic foldamers are synthetic folded molecules which can change their conformation in response to an external stimulus and are currently at the forefront of foldamer chemistry. However, constitutionally dynamic foldamers, which can change not only their conformation but also their molecular constitution in response to their environment, are without precedent. We now report a size- and shape-switching small dynamic covalent foldamer network which responds to changes in pH. Specifically, acidic conditions direct the oligomerization of a dipeptide-based building block into a 16-subunit macrocycle with well-defined conformation and with high selectivity. At higher pH the same building block yields another cyclic foldamer with a smaller ring size (9mer). The two foldamers readily and repeatedly interconvert upon adjustment of the pH of the solution. We have previously shown that addition of a template can direct oligomerization of the same building block to yet other rings sizes (including a 12mer and a 13mer, accompanied by a minor amount of 14mer). This brings the total number of discrete foldamers that can be accessed from a single building block to five. For a single building block system to exhibit such highly diverse structure space is unique and sets this system of foldamers apart from proteins. Furthermore, the emergence of constitutional dynamicity opens up new avenues to foldamers with adaptive behavior.

Metal-Organic Framework Accelerated One-Step Capture and Reduction of Palladium to Catalytically Active Nanoparticles.

Recovery of noble metals and in situ transforming to functional materials hold great promise in the sustainability of natural resources but remain as a challenge. Herein, the variable chemical microenvironments created by the inorganic-organic hybrid composition of metal-organic frameworks (MOFs) were exploited to tune the metal-support interactions, thus establishing an integrated strategy for recovering and reducing palladium (Pd). Assisted by sonic waves and alcoholic solvent, selective capture of Pd(II) from a complicated matrix to directly afford Pd nanoparticles (NPs) in MOFs can be achieved in one step within several minutes. Mechanism investigation reveals that the Pd binding site and the energy barriers between ionic and metallic status are sensitive to chemical environments in different frameworks. Thanks to the clean, dispersive, and uniform nature of Pd NPs, Pd@MOFs synthesized from a complicated environment exhibited high catalytic activity toward 4-nitrophenol reduction and Suzuki coupling reactions.

Tuning Proapoptotic Activity of a Phosphoric-Acid-Tethered Tetraphenylethene by Visible-Light-Triggered Isomerization and Switchable Protein Interactions for Cancer Therapy.

We herein report a phosphoric-acid-substituted tetraphenylethene (T-P) capable of adapting its geometric configuration and biological activity to the microenvironment upon light irradiation for apoptosis modulation. Different from most ultraviolet-responsive isomerization, T-P undergoes cis-trans isomerization under visible light irradiation, which is biocompatible and thus photo-modulation is possible in living biosystems. By using alkaline phosphatase (ALP) and albumin as dual targets, T-P isomers display different protein binding selectivity, cancer-cell internalization efficiency and apoptosis-inducing ability. The proapoptotic activity was found to be kinetically controlled by the enzymatic reaction with ALP and regulated by co-existing albumin. Motivated by these findings, two-way modulation of proapoptotic effect and on-demand boosting anticancer efficacy were realized in vitro and in vivo using light and endogenous proteins as multiple non-invasive switching stimuli.

Exposure to Bisphenol A Caused Hepatoxicity and Intestinal Flora Disorder in Rats.

Bisphenol A (BPA) is a globally utilized industrial chemical and is commonly used as a monomer of polycarbonate plastics and epoxy resins. Recent research reveals that BPA could cause potential adverse biological effects and liver dysfunction. However, the underlying mechanisms of BPA-induced hepatoxicity and gut dysbiosis remain unclear and deserve further study. In this study, male Sprague Dawley rats were exposed to different doses (0, 30, 90, and 270 mg/kg bw) of BPA by gavage for 30 days. The results showed that the high dose of BPA decreased superoxide dismutase (SOD), glutathione (GSH), and increased malondialdehyde (MDA) levels. Moreover, a high dose of BPA caused a significant increase in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C), while high-density lipoprotein cholesterol (HDL-C) was significantly decreased in BPA-treated rats. The gene expression of PGC-1α and Nrf1 were decreased in the liver of high doses of BPA-administrated rats, as well as the protein levels of SIRT1, PGC-1α, Nrf2, and TFAM. However, the protein expression of IL-1ß was significantly increased in BPA-treated rats. In addition, BPA weakened the mitochondrial function of hepatocytes and promoted cell apoptosis in the liver by up-regulating the protein levels of Bax, cleaved-Caspase3, and cleaved-PARP1 while down-regulating the Bcl-2 in the liver. More importantly, a high dose of BPA caused a dramatic change in microbiota structure, as characterized at the genus level by increasing the ratio of Firmicutes to Bacteroidetes (F/B), and the relative abundance of Proteobacteria in feces, while decreasing the relative abundance of Prevotella_9 and Ruminococcaceae_UCG-014, which is positively correlated with the content of short-chain fatty acids (SCFAs). In summary, our data indicated that BPA exposure caused hepatoxicity through apoptosis and the SIRT1/PGC-1α pathway. BPA-induced intestinal flora and SCFA changes may be associated with hepatic damage. The results of this study provide a new sight for the understanding of BPA-induced hepatoxicity.

One-step synthesis of well-defined molecularly imprinted nanospheres for the class-selective recognition and separation of ß-blockers in human serum.

ß-blockers are a class of medications that are used to treat abnormal heart rhythms and hypertension. Molecularly imprinted polymers (MIPs) capable of selective recognizing and extracting ß-blockers from complex biological samples hold great promise in bioanalytical and biomedical applications, but developing such artificial receptor materials is still challenging. Herein, we introduce a simple one-step method for the synthesis of well-defined molecularly imprinted nanospheres in high yield (83.6-94.4%) via reversible addition-fragmentation chain transfer (RAFT) precipitation polymerization for the selective recognition and extraction of the ß-blockers from human serum. The prepared MIPs are characterized in terms of morphology, pore properties, binding kinetics, capacity, selectivity, and recognition mechanisms. The uniform nanoscale-imprinted layer favored the rapid mass transfer of ß-blockers. The binding studies showed the high adsorption capacity (126.8 µmol/g) and selectivity of the developed nanomaterial. The investigation on the recognition mechanism reveals that multiple driving forces participate in the binding between MIP and ß-blockers, where hydrogen bonding plays as the dominating role for the specific recognition. The MIP was successfully applied for the direct enrichment of five ß-blockers from human serum with HPLC recoveries ranging from 82.9 to 100.3% and RSD of 0.5-6.9% (n = 3).

Hydrazone bond-oriented molecularly imprinted nanocomposites for the selective separation of protein via the well-defined recognition sites.

The development of hydrazone bond-oriented epitope imprinting strategy is reported to synthesize the polymeric binders for the selective recognition of a protein-ß2-microglobulin through either its N- or C-terminal epitope. The dynamic reversibility of hydrazone bond facilitated not only the oriented assembly of the template peptide hydrazides onto the substrate but also the efficient removal of them from the imprinted cavities. The well-defined surface imprinted layer was successfully constructed through the precise control over the polymerization of silicate esters. Binding performance of the C-terminal peptide imprinted nanocomposite was significantly improved after tuning the non-covalent interactions using the sequence-matching aromatic co-monomers. The dissociation constant (Kd) between the optimized nanocomposite and epitope peptide was 0.5 µmol L-1. The nanomaterial was utilized for the selective extraction and determination of ß2-microglobulin from human urine by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and HPLC-UV with satisfied recoveries of 93.1-112.3% in a concentration range 1.0-50.0 µg⋅mL-1.

Effects of Bisphenol A on reproductive toxicity and gut microbiota dysbiosis in male rats.

Bisphenol A (BPA) is an environmental endocrine disruptor. Recent studies have shown an association between decreased spermatogenesis and gut microbiota alteration. However, the potential associations and mechanisms of BPA exposure on spermatogenesis, hormone production, and gut microbiota remain unknown. This study aims to investigate BPA-induced male reproductive toxicity and the potential link with gut microbiota dysbiosis. Male Sprague Dawley rats were exposed to BPA at different doses by oral gavage for thirty consecutive days. The extent of testicular damage was evaluated by basic parameters of body weight and hematoxylin-eosin (H&E) staining. Next, we determined the mRNA levels and protein levels of apoptosis, histone-related factors, and mammalian target of rapamycin (mTOR) pathway in testes. Finally, 16 S rDNA sequencing was used to analyze gut microbiota composition after BPA exposure. BPA exposure damaged testicular histology, significantly decreased sperm count, and increased sperm abnormalities. In addition, BPA exposure caused oxidative stress and cell apoptosis in testes. The levels of histone (H2A, H3) were significantly increased, while ubiquitin histone H2A (ub-H2A) and ubiquitin histone H2B (ub-H2B) were markedly reduced. Furthermore, BPA activated the PI3K and AKT expression, but the protein expressions of mTOR and 4EBP1 in testes were inhibited significantly. Additionally, the relative abundance of class Gammaproteobacteria, and order Betaproteobacteriales was significantly higher when treated with a high dose of BPA compared to the control group, which was negatively correlated with testosterone level. This study highlights the relationship between BPA-induced reproductive toxicity and gut microbiota disorder and provides new insights into the prevention and treatment of BPA-induced reproductive damage.

Recent Progress of Exosome Isolation and Peptide Recognition-Guided Strategies for Exosome Research.

Exosomes are membrane extracellular vesicles secreted by almost all kinds of cells, which are rich in proteins, lipids, and nucleic acids. As a medium of intercellular communication, exosomes play important roles in biological processes and are closely related to the occurrence, and development of many diseases. The isolation of exosomes and downstream analyses can provide important information to the accurate diagnosis and treatment of diseases. However, exosomes are various in a size range from 30 to 200 nm and exist in complex bio-systems, which provide significant challenges for the isolation and enrichment of exosomes. Different methods have been developed to isolate exosomes, such as the "gold-standard" ultracentrifugation, size-exclusion chromatography, and polymer precipitation. In order to improve the selectivity of isolation, affinity capture strategies based on molecular recognition are becoming attractive. In this review, we introduced the main strategies for exosome isolation and enrichment, and compared their strengths and limitations. Furthermore, combined with the excellent performance of targeted peptides, we summarized the application of peptide recognition in exosome isolation and engineering modification.

Metal-Organic Framework-Based Nanoheater with Photo-Triggered Cascade Effects for On-Demand Suppression of Cellular Thermoresistance and Synergistic Cancer Therapy.

Nanomedicine with stable light-heat conversion and spatiotemporally controllable drug activation is crucial for the success of photothermal therapy (PTT). Herein, a metal-organic framework (MOF)-based nanoheater with light-triggered multi-responsiveness is engineered to in-situ and on-demand sensitize cancer cells to local hyperthermia. Well-dispersed platinum nanoparticles synthesized inside nanospaces of the MOF are employed as the near-infrared (NIR)-harvesting unit with stable and high light-heat conversion performance. A conformation switchable polymer shell is constructed as a secondary light-responding unit to gate the targeted activation of a molecular inhibitor against thermoresistance. By cascade transformation of light stimuli to downstream signals, the nanoheater enables inhibitor release to go with local heating at the same time restricted in lesion sites to maximize efficacy and minimize systemic toxicity. The efficient photothermal conversion and the blockage of cellular heat-protective pathways provide a dual-mode of action which selectively sensitizes cancer cells to hyperthermia in a spatiotemporally controlled manner. With NIR as the remote switch, the MOF-based nanosystem demonstrates localized and boosted PTT efficacy against cancer both in vitro and in vivo. These results present nanosized MOFs as tailorable and versatile platforms for synergistic and precise cancer therapy.

Molecular Mechanism of Food-Derived Polyphenols on PD-L1 Dimerization: A Molecular Dynamics Simulation Study.

In cancer immunotherapy, an emerging approach is to block the interactions of programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) using small-molecule inhibitors. The food-derived polyphenols curcumin (CC), resveratrol (RSV) and epigallocatechin gallate (EGCG) have anticancer immunologic functions, which, recently, have been proposed to act via the downregulation of PD-L1 expression. However, it remains unclear whether they can directly target PD-L1 dimerization and, thus, interrupt the PD-1/PD-L1 pathway. To elucidate the molecular mechanism of such compounds on PD-L1 dimerization, molecular docking and nanosecond molecular dynamics simulations were performed. Binding free energy calculations show that the affinities of CC, RSV and EGCG to the PD-L1 dimer follow a trend of CC > RSV > EGCG. Hence, CC is the most effective inhibitor of the PD-1/PD-L1 pathway. Analysis on contact numbers, nonbonded interactions and residue energy decomposition indicate that such compounds mainly interact with the C-, F- and G-sheet fragments of the PD-L1 dimer, which are involved in interactions with PD-1. More importantly, nonpolar interactions between these compounds and the key residues Ile54, Tyr56, Met115, Ala121 and Tyr123 play a dominant role in binding. Free energy landscape and secondary structure analyses further demonstrate that such compounds can stably interact with the binding domain of the PD-L1 dimer. The results provide evidence that CC, RSV and EGCG can inhibit PD-1/PD-L1 interactions by directly targeting PD-L1 dimerization. This provides a novel approach to discovering food-derived small-molecule inhibitors of the PD-1/PD-L1 pathway with potential applications in cancer immunotherapy.