Metabolic Syndrome and Risk of Amyotrophic Lateral Sclerosis: Insights from a Large-Scale Prospective Study.

OBJECTIVE: Although metabolic abnormalities are implicated in the etiology of neurodegenerative diseases, their role in the development of amyotrophic lateral sclerosis (ALS) remains a subject of controversy. We aimed to identify the association between metabolic syndrome (MetS) and the risk of ALS. METHODS: This study included 395,987 participants from the UK Biobank to investigate the relationship between MetS and ALS. Cox regression model was used to estimate hazard ratios (HR). Stratified analyses were performed based on gender, body mass index (BMI), smoking status, and education level. Mediation analysis was conducted to explore potential mechanisms. RESULTS: In this study, a total of 539 cases of ALS were recorded after a median follow-up of 13.7 years. Patients with MetS (defined harmonized) had a higher risk of developing ALS after adjusting for confounding factors (HR: 1.50, 95% CI: 1.19-1.89). Specifically, hypertension and high triglycerides were linked to a higher risk of ALS (HR: 1.53, 95% CI: 1.19-1.95; HR: 1.31, 95% CI: 1.06-1.61, respectively). Moreover, the quantity of metabolic abnormalities showed significant results. Stratified analysis revealed that these associations are particularly significant in individuals with a BMI <25. These findings remained stable after sensitivity analysis. Notably, mediation analysis identified potential metabolites and metabolomic mediators, including alkaline phosphatase, cystatin C, γ-glutamyl transferase, saturated fatty acids to total fatty acids percentage, and omega-6 fatty acids to omega-3 fatty acids ratio. INTERPRETATION: MetS exhibits a robust association with an increased susceptibility to ALS, particularly in individuals with a lower BMI. Furthermore, metabolites and metabolomics, as potential mediators, provide invaluable insights into the intricate biological mechanisms. ANN NEUROL 2024.

Folding during sheeting improved qualities of dried noodles through gluten network proteins.

The texture properties after cooking for 12 min were selected to optimize the sheeting parameters, and the results were verified using the comprehensive quality of dried noodles. The distribution of water, characteristics of gluten protein, and interaction between gluten network and starch were analyzed to clarify the mechanism of the quality of dried noodles. Results showed that the optimal folding angle was 45°, under this condition, the largest anti-extension displacement perpendicular to the rolling direction and the smallest cooking loss were obtained. The hardness and smoothness of cooked noodles increased by about 14% to 17%. Further, the transverse relaxation time of strongly bound water significantly decreased, while the relative content and binding strength increased. The hydrogen bonds and α-helix contents increased by about 68.8% and 53.1%, respectively. Folding and sheeting enhanced the combination of starch granules and gluten network causing, decreased in the average length and porosity of the gluten network. It is depicted from the results that the method of optimizing the sheeting process based on the texture of dried noodles cooked for 12 min was feasible. And the 45° folding and sheeting could help to improve the quality of dried noodles.

Transition Metal Ru(II) Catalysts Immobilized Nanoreactors for Conditional Bioorthogonal Catalysis in Cells.

Employing transition metal catalysts (TMCs) to perform bioorthogonal activation of prodrugs and pro-fluorophores in biological systems, particularly in a conditional fashion, remains a challenge. Here, we used a mesoporous organosilica nanoscaffold (RuMSN), which localizes Ru(II) conjugates on the pore wall, enabling the biorthogonal photoreduction reactions of azide groups. Due to easily adjustable surface charges and pore diameter, this efficiently engineering RuMSN catalyst, with abundant active sites on the inner pore well, could spontaneously repel or attract substrates with different molecular sizes and charges and thus ensure selective bioorthogonal catalysis. Depending on it, engineering RuMSN nanoreactors showed fascinating application scales from conditional bioorthogonal activation of prodrugs and pro-fluorophores in either intra- or extracellular localization to performing intracellular concurrent and tandem catalysis together with natural enzymes.

A polydopamine-gated biodegradable cascade nanoreactor for pH-triggered and photothermal-enhanced tumor-specific nanocatalytic therapy.

Despite the great potential of cascade catalytic reactions in tumor treatment, uncontrolled catalytic activities in vivo lead to inevitable off-target toxicity to normal tissues, which greatly hampers their clinical conversion. Herein, an intelligent cascade nanoreactor (hMnO2-Au@PDA, hMAP) was constructed by depositing glucose oxidase (GOx)-mimicking ultrasmall gold nanoparticles (Au NPs) into honeycomb-shaped manganese oxide (hMnO2) nanostructures and then coating them with polydopamine (PDA) to achieve pH-responsive and photothermal-enhanced nanocatalytic therapy. Upon exposure to the mild acidic tumor microenvironment (TME), the PDA gatekeeper would collapse, and the inner hMnO2 could simultaneously deplete glutathione (GSH) and generate Mn2+, while a considerable amount of H2O2 produced from the oxidation of glucose by GOx-mimicking Au NPs could accelerate the Mn2+-mediated Fenton-like reaction, yielding sufficient highly toxic ˙OH. More importantly, the pH-responsive cascade reaction between Au NPs and hMnO2 could be further enhanced by localized hyperthermia induced from PDA under near-infrared (NIR) laser irradiation, thereby inducing significant cell apoptosis in vitro and tumor inhibition in vivo. This work provided a promising paradigm by innovatively designing a TME-responsive and photothermal-enhanced cascade catalytic nanoreactor for safe and efficient cancer therapy.

Small-Molecule-Selective Organosilica Nanoreactors for Copper-Catalyzed Azide-Alkyne Cycloaddition Reactions in Cellular and Living Systems.

We reported the synthesis of a tris(triazolylmethyl)amine (TTA)-bridged organosilane, functioning as Cu(I)-stabilizing ligands, and the installation of this building block into the backbone of mesoporous organosilica nanoparticles (TTASi) by a sol-gel way. Upon coordinating with Cu(I), the mesoporous CuI-TTASi, with a restricted metal active center inside the pore, functions as a molecular-sieve-typed nanoreactor to efficiently perform Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reactions on small-molecule substrates but fails to work on macromolecules larger than the pore diameter. As a proof of concept, we witnessed the advantages of selective nanoreactors in screening protein substrates for small molecules. Also, the robust CuI-TTASi could be implanted into the body of animal models including zebrafish and mice as biorthogonal catalysts without apparent toxicity, extending its utilization in vivo ranging from fluorescent labeling to in situ drug synthesis.

Mesoporous Silica-Coated Silver Nanoframes as Drug-Delivery Vehicles for Chemo/Starvation/Metal Ion Multimodality Therapy.

Cutting off the energy supply by glucose oxidase (GOx) to starve cancer cells has been a feasible and efficient oncotherapy strategy. The employment of GOx can effectively starve tumor cells by aerobic hydrolysis of glucose hopefully strengthening the abnormality (including the decrease in pH, the increase of hypoxia, and toxic hydrogen peroxide) in the tumor microenvironment (TME). On this basis, we designed and fabricated a GOx-conjugated yolk-shell Ag@mSiO2 nanoframe with Ag NPs and GOx-conjugated mesoporous silica as the yolk and the shell, respectively, to make full use of changes the GOx induces in TME. Specifically, lower pH and H2O2 could accelerate the transformation of Ag nanoparticles to poisonous Ag ions. At the same time, the anabatic hypoxia condition in turn activated chemotherapy drug tirapazamine (TPZ) to exert a chemotherapeutic effect, thereby achieving effective chemo/starvation and metal ion multimodality therapy. The drug release experiment in vitro demonstrated that the GOx is the key to the nanocarriers, which can activate the whole system. The excellent cellular uptake performances of nanocarriers were corroborated by a confocal laser scanning microscope (CLSM). In addition, its superb cancer-killing effect has been confirmed by cytotoxicity and apoptosis experiments. These results indicated that the drug-delivery system achieved the cascade cancer-killing process in situ and synergistic chemo/starvation/metal ion therapy, which has a bright prospect for treating cancer.

A CD44-targeted Cu(ii) delivery 2D nanoplatform for sensitized disulfiram chemotherapy to triple-negative breast cancer.

Recent studies have suggested that the anticancer activity of disulfiram (DSF, an FDA-approved alcohol-abuse drug) is Cu-dependent. Low system toxicity and explicit pharmacokinetic characteristics of DSF necessitate safe and effective Cu supplementation in local lesion for further applications. Herein, we presented a new conceptual 'nanosized coordination transport' strategy of Cu(ii) that was realized in porphyrin-based metal-organic frameworks, Sm-TCPP, with strong binding ability to Cu(ii) due to their coordination interactions. Sm-TCPP(Cu) was coated by hyaluronic acid (HA) that termed by Sm-TCPP(Cu)@HA, acting as 'beneficial horse' to target the tumor-localized HA receptor (CD44), thus liberating Cu(ii) ions in cellular overexpressed reductants. The CD44-mediated Cu(ii) accumulation efficiency of Sm-TCPP(Cu)@HA was benchmarked in vitro and vivo against the free TCPP (Cu) via ICP-MS analysis. More importantly, the sensitization effects of Sm-TCPP(Cu)@HA on the anticancer activity of DSF were demonstrated in vivo and in vitro. This study offered a new class of targeted Cu supplements to sensitize DSF for the effective treatment of cancer and established a versatile methodology for constructing a safe and specific delivery of metal ions within living organisms.

A novel versatile yolk-shell nanosystem based on NIR-elevated drug release and GSH depletion-enhanced Fenton-like reaction for synergistic cancer therapy.

In this study, a versatile doxorubicin (DOX)-loaded yolk-shell nano-particles (HMCMD) assembled with manganese dioxide (MnO2) as the core and copper sulfide (HMCuS) as the mesoporous (∼ 6.4 nm) shell, was designed and synthesized. The resulting HMCMD possess excellent photothermal conversion efficiency. The DOX release from the yolk-shell nanoparticles could be promoted by laser irradiation, which increased the chemotherapy of DOX. Meanwhile, Mn2+ could be released from the HMCMD through a redox reaction between MnO2 and abundant glutathione (GSH) in tumor cells. The released Mn2+ could promote the decomposition of the intracellular hydrogen peroxide (H2O2) by Fenton-like reaction to generate the highly toxic hydroxyl radicals (·OH), thus exhibiting the effective chemodynamic therapy (CDT). Additionally, the efficiency of Mn2+-mediated CDT could be effectively enhanced by NIR irradiation. Further modification of polyethylene glycol (PEG) would improve the water solubility of the HMCMD to promote the uptake by MCF-7 cells. Hence, the HMCMD with synergistic effects of chemotherapy and chemodynamic/photothermal therapy would provide an alternative strategy in antitumor research.

Low-Temperature Trigger Nitric Oxide Nanogenerators for Enhanced Mild Photothermal Therapy.

Surmounting the restriction issues of nitric oxide (NO) delivery to realize their precious on-demand release is highly beneficial for the widespread deployment of gas therapy for application in biomedicine. Herein, by employing core-shell structure Au@SiO2 nanomaterials with high photothermal performance, a novel strategy was proposed by integrating photothermal conversion nanomaterials and heat-triggered NO donors (RSNO) into a nanoplatform, which achieved photothermal therapy (PTT)-enhanced NO gas therapy under near-infrared (NIR) radiation. Specifically, 2-phenylethynesulfonamide (PES), an inhibitor of heat shock protein 70 (HSP-70), was loaded into the NO nanogenerators to realize effective low-temperature (∼45 °C) PTT. The obtained results showed that the near-infrared radiation (NIR) mediated mild PTT and gas therapy by releasing NO showed a substantially improved synergistic effect based on in vitro and in vivo results in breast cancer (MCF-7) models. Our study points out a strategy to realize mild photothermal therapy by inhibiting the expression of HSP-70 and simultaneously providing an avenue to achieve controllable release of NO. More important, this research highlights the great potential of multifunctional therapeutic agents in the synergistic treatment of cancer.

Biomimetic Platinum Nanozyme Immobilized on 2D Metal-Organic Frameworks for Mitochondrion-Targeting and Oxygen Self-Supply Photodynamic Therapy.

Photodynamic therapy (PDT) as a noninvasive therapy mode has attracted considerable attention in the field of oncotherapy. However, the PDT efficacy is restricted either by the tumor hypoxia environment or the inherent properties of photosensitizers (PSs) including bad water solution, photobleaching, and easy aggregation. Herein, we designed and synthesized a new two-dimensional (2D) metal-organic framework, Sm-tetrakis(4-carboxyphenyl)porphyrin (TCPP) nanosheets, by assembling transition metal ions (Sm3+) and PSs (TCPP), on which the catalase (CAT)-mimicking platinum nanozymes were then in situ grown for sufficient oxygen supply during PDT. The prepared Sm-TCPP with nanoplate morphology (∼100 nm in diameter) and ultrathin thickness (<10 nm) showed significantly enhanced 1O2 generation capacity due to the improved physicochemical properties and the enhanced intersystem crossing from heavy Sm nodes. More importantly, the CAT-mimicking Pt nanozyme on the Sm-TCPP nanosheets could effectively convert over-expressed H2O2 in the tumor microenvironment into O2 to relieve tumor hypoxia. Further, the triphenylphosphine (TPP) molecule was introduced to Sm-TCPP-Pt to develop a mitochondrion-targeting and O2 self-supply PDT system. The in vitro and in vivo experimental results based on the MCF-7 breast cancer model revealed that Sm-TCPP-Pt/TPP could relieve tumor hypoxia and the generated reactive oxygen species nearby intracellular mitochondria significantly induced cell apoptosis. This study offers an engineering strategy to integrate 2D PS-based metal-organic frameworks and nanozymes into a nanoplatform to surmount the pitfalls of traditional PDT.

A small-sized and stable 2D metal-organic framework: a functional nanoplatform for effective photodynamic therapy.

The efficiency of photosensitizers in tumor photodynamic therapy (PDT) often compromises their poor water solubility, low extinction coefficients, photobleaching, and dissatisfactory reactive oxygen species (ROS) generation efficiency. Herein, a nanoscale 2D metal-organic framework, Sm-H2TCPP nanosheets, was first synthesized by Sm3+-driven coordination with a porphyrin derivative (tetrakis(4-carboxyphenyl)porphyrin (H2TCPP)) for highly effective PDT of breast cancer. The prepared Sm-H2TCPP possessed nanoplate morphology with ultrathin thickness at the sub-10 nm level and an ultrasmall plane size at the sub-100 nm level. Compared with free H2TCPP, the prominent ROS generation capacity of the well-defined Sm-H2TCPP nanosheets is mainly attributed to their improved physicochemical properties and the enhanced intersystem crossing caused by heavy Sm nodes. The significantly improved PDT efficacy of the Sm-H2TCPP nanosheets was further investigated in vitro and in vivo based on the MCF-7 breast cancer model. It is envisaged that the Sm-H2TCPP nanosheets will offer a new avenue for the development of a new class of potential PDT agents.

Photothermal-Enhanced Inactivation of Glutathione Peroxidase for Ferroptosis Sensitized by an Autophagy Promotor.

Until now, ferroptotic therapeutic strategies remain simple, although ferroptosis has aroused extensive interest owing to its escape from the biocarriers of conventional therapeutic modalities. Herein, we construct a photothermal (PT)- and autophagy-enhanced ferroptotic therapeutic modality based on MnO2@HMCu2-xS nanocomposites (HMCMs) for efficient tumor ablation. The HMCMs possess PT-enhanced glutathione (GSH) depletion capability, thereby inducing PT-enhanced ferroptosis via the reinforced inactivation of glutathione peroxidase 4 (GPX4). Thereafter, the GSH-responsed Mn2+ release could generate reactive oxygen species (ROS) by a Fenton-like reaction to reinforce the intracellular oxidative stress for the lipid hydroperoxide (LPO) accumulation in ferroptosis. Additionally, an autophagy promotor rapamycin (Rapa) was loaded into HMCM for sensitizing cells to ferroptosis due to the indispensable role of autophagy in the ferroptosis process. The in vitro and in vivo data demonstrated that the HMCM exhibited superior anticancer effect in human breast cancer models and that the combined therapeutic system afforded the next generation of ferroptotic therapy for combatting malignant tumors.

Three peroxidovanadium(v) compounds mediated by transition metal cations for enhanced anticancer activity.

Three peroxidovanadium(v) compounds with different ligands (L1-L3) {L1 = N-tris(hydroxymethyl)methylglycine; L2 = ethylenediamine-N,N'-diacetic acid; L3 = 2,2-[(2-amino-2-oxoethyl)imino]diacetic acid} were first synthesized, characterized and further investigated for their anticancer activities under the mediation of transition metal cations. Encouragingly, all compounds showed preferentially enhanced cytotoxicity toward cancer cells (MCF-7 and A549) compared to normal cells (BEAS-2B) under the mediation of transition metal cations (Mn2+ or Fe2+), especially for Mn2+. It was noted that cell death was triggered by the transition metal cation-mediated peroxidovanadium(v) compounds through the induction of early apoptosis, inhibition of cell cycles, and boosting the generation of intracellular reactive oxygen species (ROS). Mechanistic studies further elucidated the vital roles of an acidic environment and transition metal cations for the anticancer activity of peroxidovanadium(v) compounds. Therefore, this study will offer precious insight into the development of the transition metal cation-mediated peroxidovanadium(v) compounds for further clinical translation.

Mesoporous silica-coated gold nanoframes as drug delivery system for remotely controllable chemo-photothermal combination therapy.

Tumor cells experience higher chemotherapy stress under condition of elevated temperature. As a result, developing novel nanoagents that integrates chemotherapy and thermotherapy holds great promise in biomedicine. Herein, utilizing spatially confined galvanic replacement method, we fabricated a yolk-shell Au@mSiO2 nanoframes with Au NPs and mesoporous silica as yolk and shell, respectively, to sever as an excellent drug nanocarrier with effective photothermal conversion efficiency. Taking full advantage of the high temperature response of the Au@mSiO2 nanoframes, the phase change material 1-tetradecanol (TD) was creatively employed as gatekeepers, intelligently controlling the release of loaded agents. Then, the actively targeted Alanine-Alanine-Asparagine, legumain-recognizable oligopeptides was decorated on the surface of the prepared nanoframes. Upon exposure to near-infrared light, the GC-PtAu@mSiO2-TD nanoframes not only exhibited a high localized temperature response, but also triggered the quick release of loaded cargos, and thus improved the chemotherapeutic efficacy. The in vitro cytotoxicity studies indicated the remarkable synergistic effects. Meanwhile, the laser confocal studies and flow cytometry showed the oligopeptides facilitated the intracellular uptake of GC-PtAu@mSiO2-TD nanoframes in MGC-803 cells. Our study highlighted the great potential of the GC-PtAu@mSiO2-TD nanoframes in drug delivery and the combination of chemotherapy and photothermal therapy.

Decoration of Cisplatin on 2D Metal-Organic Frameworks for Enhanced Anticancer Effects through Highly Increased Reactive Oxygen Species Generation.

Herein, a biocompatible 2D metal-organic frameworks (Cu-TCPP(Fe)) based on TCPP(M) (TCPP = tetrakis (4-carboxyphenyl) porphyrin, M = Fe) and copper ion were synthesized as a novel drug carrier. Sequentially, the cisplatin was loaded on the merge of carboxyl-rich Cu-TCPP(Fe) through forming favorable carboxyl-drug interactions. The prepared Pt/Cu-TCPP(Fe) showed highly enhanced cytotoxicity than that of free cisplatin in human pulmonary carcinoma A549 cells, whereas inverse inhibitory effects were observed in human normal BEAS-2B cells. Further, the mechanism of action about the desirable results was also elaborated. Our study highlighted the potential synergies between the nanocarrier and the anticancer drugs.

Iron Oxide Nanocarrier-Mediated Combination Therapy of Cisplatin and Artemisinin for Combating Drug Resistance through Highly Increased Toxic Reactive Oxygen Species Generation.

Combination therapy with multiple drugs through a multi-pronged assault as a strategy to combat cisplatin resistance shows great potential in biochemical therapy for cancer. However, inherent issues such as low drug loading and the poor synergistic effects of multiple drugs partially limit the further application of combination therapy. Here, we synthesized a new compound, ART-Chol, by coupling artemisinin and cholesterol as a base material combined with cyclic (Arg-Gly-Asp-d-Phe-Lys)]-poly(ethylene glycol) distearoylphosphatidylcholine (cRGD-PEG-DSPE) and phospholipids to form a magnetic liposome cRGD-AFePt@NPs encapsulating superparamagnetic ferric oxide nanoparticles and cisplatin for achieving high drug loading and a better synergistic effect. The cRGD-AFePt@NPs could be effectively internalized and responsively release loading cargos under alternating magnetic field irradiation due to local hyperthermia generated from magnetic nanoparticles by hysteresis loss and Néel relaxation. The generated Fe2+/Fe3+ from Fe3O4 NPs in the acid lysosomes motivated cisplatin and catalyzed the Fe-dependent anticancer drug artemisinin (ART) to generate highly toxic ROS through the Fenton reaction, which greatly enhances the anticancer effect of cisplatin with minimized side effects. In vitro cytotoxicity tests demonstrated that the cRGD-AFePt@NPs exhibited a 15.17-fold lower IC50 value of free cisplatin (IC50 = 32.47 µM) against A549/R cells. Further flow-cytometry tests also showed obviously increased intracellular ROS generation and cell apoptosis rates. We highlight the potential for Fe2+/Fe3+-mediated combination therapy of cisplatin and ART for circumventing cisplatin drug resistance.