Three-Step Depletion Strategy of Glutathione: Tunable Metal-Organic-Framework-Engineered Nanozymes for Driving Oxidative/Nitrative Stress to Maximize Ferroptosis Therapy.

Ferroptosis is a novel type of nonapoptotic programmed cell death involving the accumulation of lipid peroxidation (LPO) to a lethal threshold. Herein, we propose tunable zeolitic imidazolate framework (ZIFs)-engineered biodegradable nanozymes for ferroptosis mediated by both reactive oxygen species (ROS) and nitrogen species (RNS). l-Arginine is utilized as an exogenous nitric oxide donor and loaded into hollow ZIFs@MnO2 artificial nanozymes, which are formed by etching ZIFs with potassium permanganate and simultaneously generating a MnO2 shell in situ. The constructed nanozymes with multienzyme-like activities including peroxidase, oxidase, and catalase can release satisfactory ROS and RNS through a cascade reaction, consequently promoting the accumulation of LPO. Furthermore, it can improve the efficiency of ferroptosis through a three-step strategy of glutathione (GSH) depletion; that is, the outer MnO2 layer consumes GSH under slightly acidic conditions and RNS downregulates SLC7A11 and glutathione reductase, thus directly inhibiting GSH biosynthesis and indirectly preventing GSH regeneration.

Crossing the River by Feeling the Stones: Experiences with PD-1 Inhibitors in Geriatric Oncology People, a Case Report and Literature Review.

Currently, lung cancer remains one of the deadliest cancers, with a very high mortality rate, accounting for approximately 18% of all cancer-related deaths. Non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancer deaths. In particular, elderly patients generally have poor tolerance to chemotherapy or cannot tolerate chemotherapy. This case analysis focuses on an elderly patient with non-small cell lung cancer stage IV. The patient was an 86-year-old female with poor nutritional status and low body weight (27 kg) and could not tolerate platinum-based dual-drug first-line chemotherapy. This patient had tumour cells in alveolar lavage fluid without conditions examined for pd-l1 expression. However, the efficacy of previous first-line immunotherapy was positive, and the patient and his family members agreed to apply it, so there was no contraindication to apply anlotinib + pembrolizumab. Results were reviewed after two cycles, and CR was used to evaluate the efficacy. After four cycles, the efficacy was evaluated as complete remission (CR), the patient developed immune-related side effects, immunotherapy was suspended, and maintenance therapy with anlotinib was used. The most recent review was in 2023-6-9, and PET/CT indicated that the patient had sustained CR. In general, this case provides support for the successful possibility of a treatment strategy for elderly patients with poor physical fitness who cannot tolerate platinum-based doublet chemotherapy and who have driver gene-negative squamous cell lung cancer (PS>0-1).

Reconciling ASPP-p53 binding mode discrepancies through an ensemble binding framework that bridges crystallography and NMR data.

ASPP2 and iASPP bind to p53 through their conserved ANK-SH3 domains to respectively promote and inhibit p53-dependent cell apoptosis. While crystallography has indicated that these two proteins employ distinct surfaces of their ANK-SH3 domains to bind to p53, solution NMR data has suggested similar surfaces. In this study, we employed multi-scale molecular dynamics (MD) simulations combined with free energy calculations to reconcile the discrepancy in the binding modes. We demonstrated that the binding mode based solely on a single crystal structure does not enable iASPP's RT loop to engage with p53's C-terminal linker-a verified interaction. Instead, an ensemble of simulated iASPP-p53 complexes facilitates this interaction. We showed that the ensemble-average inter-protein contacting residues and NMR-detected interfacial residues qualitatively overlap on ASPP proteins, and the ensemble-average binding free energies better match experimental KD values compared to single crystallgarphy-determined binding mode. For iASPP, the sampled ensemble complexes can be grouped into two classes, resembling the binding modes determined by crystallography and solution NMR. We thus propose that crystal packing shifts the equilibrium of binding modes towards the crystallography-determined one. Lastly, we showed that the ensemble binding complexes are sensitive to p53's intrinsically disordered regions (IDRs), attesting to experimental observations that these IDRs contribute to biological functions. Our results provide a dynamic and ensemble perspective for scrutinizing these important cancer-related protein-protein interactions (PPIs).

Research progress on carbon materials in tumor photothermal therapy.

At present, cancer remains one of the leading causes of human death worldwide, and surgery, radiotherapy and chemotherapy are still the main methods of cancer treatment. However, these treatments have their drawbacks. Surgical treatment often struggles with the complete removal of tumor tissue, leading to a high risk of cancer recurrence. Additionally, chemotherapy drugs have a significant impact on overall health and can easily result in drug resistance. The high risk and mortality of cancer and other reasons promote scientific researchers to unremittingly develop and find a more accurate and faster diagnosis strategy and effective cancer treatment method. Photothermal therapy, which utilizes near-infrared light, offers deeper tissue penetration and minimal damage to surrounding healthy tissues. Compared to conventional radiotherapy and other treatment methods, photothermal therapy boasts several advantages, including high efficiency, non-invasiveness, simplicity, minimal toxicity, and fewer side effects. Photothermal nanomaterials can be categorized as either organic or inorganic materials. This review primarily focuses on the behavior of carbon materials as inorganic materials and their role in tumor photothermal treatment. Furthermore, the challenges faced by carbon materials in photothermal treatment are discussed.

Synergistic Binding of ATP and Nucleic Acids Necessitates UPF1's ATPase Functional Cycle.

UPF1 is a core protein in the nonsense mRNA degradation (NMD) surveillance pathway that degrades aberrant mRNA. UPF1 has both ATPase and RNA helicase activities, but it exhibits mutually exclusive binding of ATP and RNA. This suggests intricate allosteric coupling between ATP and RNA binding that remains unresolved. In this study, we used molecular dynamics simulations and dynamic network analyses to probe the dynamics and free energy landscapes covering UPF1 crystal structures resolved in the Apo state, the ATP bound state, and the ATP-RNA bound (catalytic transition) state. Free energy calculations show that in the presence of ATP and RNA, the transition from the Apo state to the ATP bound state is an uphill process but becomes a downhill process when transitioning to the catalytic transition state. Allostery potential analyses reveal that the Apo and catalytic transition states are mutually allosterically activated toward each other, reflecting the intrinsic ATPase function of UPF1. The Apo state is also allosterically activated toward the ATP bound state. However, binding ATP alone leads to an allosterically trapped state that is difficult to revert to either the Apo or the catalytic transition state. The high allostery potential of Apo UPF1 toward different states results in a "first come, first served" mechanism that requires the synergistic binding of ATP and RNA to drive the ATPase cycle. Our results reconcile UPF1's ATPase and RNA helicase activities within an allostery framework and may apply to other SF1 helicases, as we demonstrate that UPF1's allostery signaling pathways prefer the RecA1 domain over the equally fold-conserved RecA2 domain, and this preference coincides with higher sequence conservation in the RecA1 domain across typical human SF1 helicases.

Menin-MLL1 Interaction Small Molecule Inhibitors: A Potential Therapeutic Strategy for Leukemia and Cancers.

Encoded by the MEN1 gene, menin protein is a fusion protein that is essential for the oncogenic transformation of mixed-lineage leukemia (MLL) and leads to acute leukemia (AL). Therefore, accumulating evidence has demonstrated that inhibition of the high-affinity relationship between menin and mixed-lineage leukemia 1 (MLL1 and KMT2A) is an effective treatment for MLL-rearranged (MLL-r) leukemia in vitro and in vivo. Meanwhile, recent studies found that menin-MLL1 interaction inhibitors exhibited a firm tumor suppressive ability in specific cancer cells, such as prostate cancer, breast cancer, liver cancer, and lung cancer. Overall, it seems to serve as a novel therapeutic means for cancers. Herein, we review the recent progress in exploring the inhibitors of small molecule menin-MLL1 interactions. The molecular mechanisms of these inhibitors' functions and their application prospects in the treatment of AL and cancers are explored.

Precise engineering of acorn-like Janus nanoparticles for cancer theranostics.

The anisotropic Janus nanoparticles (JNPs) provide synergistic effects by concentrating multiple properties on a single carrier. Herein, we reported a novel and simple approach to fabricate acorn-like poly(acrylic acid)-mesoporous calcium phosphate/polydopamine (PAA-mCaP/PDA) JNPs, which were selectively functionalized with methoxy-poly(ethylene glycol)thiol (PEG-SH) on PDA domains to obtain superior stability, while the other mCaP sides served as a storage space and passage for the anti-cancer drug of doxorubicin (DOX). The unique acorn-like PAA-mCaP/PDA-PEG JNPs were utilized as novel theranostic agents for photoacoustic (PA) imaging-guided synergistic cancer chemo-phototherapy. More importantly, this synthetic strategy can be applied to synthesize various mesoporous Janus nanocarriers, paving the way toward designed synthesis of acorn-like JNPs in nanomedicine, biosensing and catalysis. STATEMENT OF SIGNIFICANCE: The distinct acorn-like poly(acrylic acid)-mesoporous calcium phosphate/polydopamine Janus nanoparticles (PAA-mCaP/PDA JNPs) with a spherical-shaped PAA-mCaP core and PDA half-shell were fabricated for the first time. To achieve superior stability, the acorn-like PAA-mCaP/PDA JNPs were selectively functionalized with methoxy-poly(ethylene glycol)thiol (PEG-SH) on PDA domains to obtain acorn-like PAA-mCaP/PDA-PEG JNPs. The resultant acorn-like PAA-mCaP/PDA-PEG JNPs own an excellent biocompatibility, high drug-loading contents, good photothermal conversion efficiency, photoacoustic (PA) imaging capacity and pH/NIR dual-responsive properties, enabling the acorn-like JNPs to be applied for PA imaging-guided synergistic cancer chemo-phototherapy. More importantly, the synthetic approach could be extended to prepare acorn-like mesoporous inorganic substances/PDA JNPs for specific applications.

Ionic liquid-assisted synthesis of porous boron-doped graphitic carbon nitride for photocatalytic hydrogen production.

This work presents a simple way to prepare boron-doped graphitic carbon nitride (B/g-C3N4), exhibiting an enhanced photocatalytic performance to split water for hydrogen production. B/g-C3N4 was synthesized via the pyrolysis of urea and 1-ethyl-3-methylimidazolium tetrafluoroborate ([Emim]BF4), which was adopted as the boron source. The aggregate of B/g-C3N4 nanosheets shows a porous structure since some bubbles are generated under the heat decomposition of ionic liquids. The porous structure is conducive to the exposure of more active sites. Moreover, B-doping will form some localized electronic energy levels in the band gap of g-C3N4, thereby extending its visible light response. As impacted by the porous structure of B/g-C3N4 aggregate and the narrow the band gap, the photocatalytic hydrogen generation rate (901 µmol h-1 g-1) is increased, almost 3 times faster than g-C3N4 (309 µmol h-1 g-1). This work proposed a simple method to prepare the aggregate of B/g-C3N4 nanosheets exhibiting pores under ionic liquid assistance. It can be a novel method to design porous polymer photocatalysts.

Selective Oxidation of Propylene on Cu2O(111) and Cu2O(110) Surfaces: A Systematically DFT Study.

Density functional theory calculations with a Hubbard U correction were used to investigate the selective oxidation of propylene on Cu2O(111) and Cu2O(110) surfaces, and the mechanism for the selective oxidation of propylene was discussed. On both surfaces, acrolein can be generated by two H-stripping reactions in the allylic hydrogen stripping path, while propylene oxide (PO), propanal, and acetone can be created through the propylene oxametallacycle intermediates in the epoxidation path. Our calculation results indicated that Cu2O has a high crystal plane-controlled phenomenon for the selective oxidation of propylene. It was found that the formations of propanal and acetone are unfavorable kinetically and acrolein is the main product on the (111) surface. On the (110) surface, the activation barrier of acrolein formation is too high to produce and PO becomes the favored product, which is different from the case of the (111) surface. Moreover, energetic span model analysis was carried out to discuss the selective oxidation of propylene on these two surfaces and confirm the above calculations. The present study can help people to design the proper crystal plane catalyst to get the target product of PO with high selectivity and activity in the selective oxidation of propylene.

Facile Approach to Synthesize Gold Nanorod@Polyacrylic Acid/Calcium Phosphate Yolk-Shell Nanoparticles for Dual-Mode Imaging and pH/NIR-Responsive Drug Delivery.

A facile strategy to fabricate gold nanorod@polyacrylic acid/calcium phosphate (AuNR@PAA/CaP) yolk-shell nanoparticles (NPs) composed with a PAA/CaP shell and an AuNR yolk is reported. The as-obtained AuNR@PAA/CaP yolk-shell NPs possess ultrahigh doxorubicin (DOX) loading capability (1 mg DOX/mg NPs), superior photothermal conversion property (26%) and pH/near-infrared (NIR) dual-responsive drug delivery performance. The released DOX continuously increased due to the damage of the CaP shell at low pH values. When the DOX-loaded AuNR@PAA/CaP yolk-shell NPs were exposed to NIR irradiation, a burst-like drug release occurs owing to the heat produced by the AuNRs. Furthermore, AuNR@PAA/CaP yolk-shell NPs are successfully employed for synergic dual-mode X-ray computed tomography/photoacoustic imaging and chemo-photothermal cancer therapy. Therefore, this work brings new insights for the synthesis of multifunctional nanomaterials and extends theranostic applications.

Dual drug delivery and sequential release by amphiphilic Janus nanoparticles for liver cancer theranostics.

Co-delivery of two drugs with diverse physicochemical properties and specific administration order for cancer theranostics are vitally important for drug resistance conquering and side effects reducing. Consequently, we explored a unique amphiphilic PCL-AuNC/Fe(OH)3-PAA Janus nanoparticle (JNP) to simultaneously preserve the hydrophilic drug (doxorubicin) and hydrophobic drug (docetaxel) in their distinct domains. Owing to their extraordinary heterostructure and independent pH and NIR sensitive properties, the optional sequential drug release by a single inorganic JNP was realized for the first time, and the results presented the synchronous release of two drugs had 5% better therapeutic effect. In addition, the excellent computed X-ray tomography/magnetic resonance (CT/MR) imaging capabilities from AuNC and Fe(OH)3 suggested our JNPs could effectively guide the cancer therapy. Furthermore, the mice treated with dual drug loaded PCL-AuNC/Fe(OH)3-PAA JNPs under near infrared (NIR) laser irradiation showed better tumor inhibition than solo drug, cocktail and dual drug treated groups, indicating the effectivity and significance of combined cancer therapy.

Near-infrared light and pH-responsive Au@carbon/calcium phosphate nanoparticles for imaging and chemo-photothermal cancer therapy of cancer cells.

A simple, mild and reproducible synthetic route was developed to fabricate the multifunctional Au@carbon/calcium phosphate core-shell nanoparticles (Au@C/CaP NPs), which act as an efficient nanoplatform for pH/near-infrared (NIR) dual-responsive drug delivery, X-ray computed tomography (CT) imaging and synergistic chemo-photothermal cancer therapy in vitro.

Tunable fabrication of folic acid-Au@poly(acrylic acid)/mesoporous calcium phosphate Janus nanoparticles for CT imaging and active-targeted chemotherapy of cancer cells.

A novel, facile and reproducible method was explored to construct uniform folic acid-Au@poly(acrylic acid)/mesoporous calcium phosphate Janus nanoparticles (FA-Au@PAA/mCaP JNPs), which act as an efficient nanoplatform for X-ray computed tomography (CT) imaging and active-targeted chemotherapy in vitro.

Designed Synthesis of Au/Fe3 O4 @C Janus Nanoparticles for Dual-Modal Imaging and Actively Targeted Chemo-Photothermal Synergistic Therapy of Cancer Cells.

Elaborately designed novel multifunctional Janus nanoparticles (JNPs) have attracted considerable attention owing to their anisotropic surface properties and various functionalities that allow them to house several components for the detection and targeting of cancer cells. In this work, we report a novel and facile approach to synthesize Au/Fe3 O4 @C JNPs, which were further selectively functionalized with amino-poly(ethylene glycol)thiol (NH2 -PEG-SH) and folic acid (FA) on the exposed Au domains to achieve high contrast for X-ray computed tomography (CT) imaging, excellent stability, good biocompatibility, as well as cancer cell-specific targeting. Meanwhile, the other Fe3 O4 @C sides with mesoporous structure served as a drug delivery vehicle for doxorubicin (DOX), an efficient photothermal therapy (PTT) agent, and a magnetic resonance (MR) imaging contrast agent. Taking these features together, these unique multifunctional JNPs provide an intriguing nanoplatform for dual-modal CT and MR imaging-guided actively targeted chemo-photothermal synergistic cancer therapy.

Designed Synthesis of Lipid-Coated Polyacrylic Acid/Calcium Phosphate Nanoparticles as Dual pH-Responsive Drug-Delivery Vehicles for Cancer Chemotherapy.

Herein, we report a facile strategy to prepare supported lipid-bilayer-coated polyacrylic acid/calcium phosphate nanoparticles (designated as PAA/CaP@SLB NPs) as a new dual pH-responsive drug-delivery platform for cancer chemotherapy. The synthesized PAA/CaP NPs exhibited both a high payload of doxorubicin (DOX) and dual pH-responsive drug-release properties. Additionally, the coated lipid bilayer had the ability to enhance the cellular uptake of PAA/CaP NPs without affecting the pH-responsive drug release. Moreover, the blank PAA/CaP@SLB NPs exhibited excellent biocompatibility and the DOX-loaded PAA/CaP@SLB NPs markedly increased the cellular accumulation of DOX and its cytotoxic effects on HepG-2 cells. Furthermore, when used to evaluate the in vivo therapeutic efficacy in mice with the hepatocarcinoma cell line (H-22), the DOX-loaded PAA/CaP@SLB NPs exhibited superior inhibition of tumor growth compared with the free DOX group. Thus, PAA/CaP@SLB NPs are a promising drug-delivery vehicle to increase the therapeutic efficacy of anticancer drugs.

Precise synthesis of unique polydopamine/mesoporous calcium phosphate hollow Janus nanoparticles for imaging-guided chemo-photothermal synergistic therapy.

Multifunctional polymer-inorganic Janus nanoparticles (JNPs) that simultaneously have therapeutic and imaging functions are highly desired in biomedical applications. Here, we fabricated spherical polydopamine/mesoporous calcium phosphate hollow JNPs (PDA/mCaP H-JNPs) via a novel and facile approach. The obtained PDA/mCaP H-JNPs were further selectively functionalized with indocyanine green (ICG) and methoxy-poly(ethylene glycol)thiol (PEG-SH) on PDA domains to achieve a superior photoacoustic (PA) imaging capability and stability, while the other mCaP sides with hollow cavities served as storage spaces and passages for the anti-cancer drug, doxorubicin (DOX). The resultant PEG-ICG-PDA/mCaP H-JNPs possess excellent biocompatibility, a competent drug loading capability, high photothermal conversion efficiency, strong near-infrared (NIR) absorbance, and pH/NIR dual-responsive properties, enabling the H-JNPs to be applied for PA imaging-guided synergistic cancer chemo-phototherapy in vitro and in vivo. Furthermore, the synthetic approach could be extended to prepare PDA/various mesoporous inorganic H-JNPs with spherical shapes for specific applications.

Facile synthesis of polypyrrole@metal-organic framework core-shell nanocomposites for dual-mode imaging and synergistic chemo-photothermal therapy of cancer cells.

In our work, we report a facile approach to fabricate well-dispersed polypyrrole@metal-organic framework (PPy@MOF) core-shell nanocomposites (NCs) with a polypyrrole (PPy) core and an MIL-100(Fe) shell. The adsorbed Fe(iii) ions on the as-fabricated PPy surface were utilized as reactive sites for further growth of the MIL-100(Fe) in the presence of trimesic acid (H3btc). The resulting NCs exhibited strong absorption in the near infrared (NIR) region and possessed an excellent photothermal efficiency of ∼40% resulting from the PPy core. The MOF structure based on Fe(iii) carboxylate materials held great ability for storage/delivery of the hydrophilic anti-cancer drug, doxorubicin (DOX). The released DOX continuously increased due to the damage of the shell at low pH values. When the DOX-loaded PPy@MIL-100(Fe) NCs were exposed to NIR irradiation, owing to the heat produced by the NCs, the local temperature increased, resulting in a faster release of DOX from the MIL-100(Fe) shell. Furthermore, PPy@MIL-100(Fe) NCs were successfully employed for dual-mode magnetic resonance imaging (MRI)/photoacoustic imaging (PAI) and synergistic chemo-photothermal therapy of cancer cells. Therefore, our work could encourage further study in the construction of a multifunctional platform using different MOF nanomaterials for cancer theranostics.

A designed synthesis of multifunctional Fe3O4@carbon/zinc phosphate nanoparticles for simultaneous imaging and synergic chemo-photothermal cancer therapy.

A simple, novel, and reproducible synthetic strategy was developed to fabricate multifunctional Fe3O4@carbon/zinc phosphate core-shell nanoparticles (Fe3O4@C/ZnP NPs), which were employed as pH/near infrared (NIR)-responsive drug carriers for simultaneous magnetic resonance imaging (MRI) and synergistic chemo-photothermal cancer therapy in vitro.

Near-Infrared Light and pH-Responsive Polypyrrole@Polyacrylic acid/Fluorescent Mesoporous Silica Nanoparticles for Imaging and Chemo-Photothermal Cancer Therapy.

We have rationally designed a new theranostic agent by coating near-infrared (NIR) light-absorbing polypyrrole (PPY) with poly(acrylic acid) (PAA), in which PAA acts as a nanoreactor and template, followed by growing small fluorescent silica nanoparticles (fSiO2 NPs) inside the PAA networks, resulting in the formation of polypyrrole@polyacrylic acid/fluorescent mesoporous silica (PPY@PAA/fmSiO2 ) core-shell NPs. Meanwhile, DOX-loaded PPY@PAA/fmSiO2 NPs as pH and NIR dual-sensitive drug delivery vehicles were employed for fluorescence imaging and chemo-photothermal synergetic therapy in vitro and in vivo. The results demonstrate that the PPY@PAA/fmSiO2 NPs show high in vivo tumor uptake by the enhanced permeability and retention (EPR) effect after intravenous injection as revealed by in vivo fluorescence imaging, which is very helpful for visualizing the location of the tumor. Moreover, the obtained NPs inhibit tumor growth (95.6 % of tumors were eliminated) because of the combination of chemo-photothermal therapy, which offers a synergistically improved therapeutic outcome compared with the use of either therapy alone. Therefore, the present study provides new insights into developing NIR and pH-stimuli responsive PPY-based multifunctional platform for cancer theranostics.