Traditional Chinese medicine improved diabetic kidney disease through targeting gut microbiota.

CONTEXT: Diabetic kidney disease (DKD) affects nearly 40% of diabetic patients, often leading to end-stage renal disease that requires renal replacement therapies, such as dialysis and transplantation. The gut microbiota, an integral aspect of human evolution, plays a crucial role in this condition. Traditional Chinese medicine (TCM) has shown promising outcomes in ameliorating DKD by addressing the gut microbiota. OBJECTIVE: This review elucidates the modifications in gut microbiota observed in DKD and explores the impact of TCM interventions on correcting microbial dysregulation. METHODS: We searched relevant articles from databases including Web of Science, PubMed, ScienceDirect, Wiley, and Springer Nature. The following keywords were used: diabetic kidney disease, diabetic nephropathy, gut microbiota, natural product, TCM, Chinese herbal medicine, and Chinese medicinal herbs. Rigorous criteria were applied to identify high-quality studies on TCM interventions against DKD. RESULTS: Dysregulation of the gut microbiota, including Lactobacillus, Streptococcus, and Clostridium, has been observed in individuals with DKD. Key indicators of microbial dysregulation include increased uremic solutes and decreased short-chain fatty acids. Various TCM therapies, such as formulas, tablets, granules, capsules, and decoctions, exhibit unique advantages in regulating the disordered microbiota to treat DKD. CONCLUSION: This review highlights the importance of targeting the gut-kidney axis to regulate microbial disorders, their metabolites, and associated signaling pathways in DKD. The Qing-Re-Xiao-Zheng formula, the Shenyan Kangfu tablet, the Huangkui capsule, and the Bekhogainsam decoction are potential candidates to address the gut-kidney axis. TCM interventions offer a significant therapeutic approach by targeting microbial dysregulation in patients with DKD.

Poricoic acid A suppresses renal fibroblast activation and interstitial fibrosis in UUO rats via upregulating Sirt3 and promoting ß-catenin K49 deacetylation.

Renal interstitial fibrosis is the common pathological process of various chronic kidney diseases to end-stage renal disease. Inhibition of fibroblast activation attenuates renal interstitial fibrosis. Our previous studies show that poricoic acid A (PAA) isolated from Poria cocos is a potent anti-fibrotic agent. In the present study we investigated the effects of PAA on renal fibroblast activation and interstitial fibrosis and the underlying mechanisms. Renal interstitial fibrosis was induced in rats or mice by unilateral ureteral obstruction (UUO). UUO rats were administered PAA (10 mg·kg-1·d-1, i.g.) for 1 or 2 weeks. An in vitro model of renal fibrosis was established in normal renal kidney fibroblasts (NRK-49F cells) treated with TGF-ß1. We showed that PAA treatment rescued Sirt3 expression, and significantly attenuated renal fibroblast activation and interstitial fibrosis in both the in vivo and in vitro models. In TGF-ß1-treated NRK-49F cells, we demonstrated that Sirt3 deacetylated ß-catenin (a key transcription factor of fibroblast activation) and then accelerated its ubiquitin-dependent degradation, thus suppressing the protein expression and promoter activity of pro-fibrotic downstream target genes (twist, snail1, MMP-7 and PAI-1) to alleviate fibroblast activation; the lysine-49 (K49) of ß-catenin was responsible for Sirt3-mediated ß-catenin deacetylation. In molecular docking analysis, we found the potential interaction of Sirt3 and PAA. In both in vivo and in vitro models, pharmacological activation of Sirt3 by PAA significantly suppressed renal fibroblast activation via facilitating ß-catenin K49 deacetylation. In UUO mice and NRK-49F cells, Sirt3 overexpression enhanced the anti-fibrotic effect of PAA, whereas Sirt3 knockdown weakened the effect. Taken together, PAA attenuates renal fibroblast activation and interstitial fibrosis by upregulating Sirt3 and inducing ß-catenin K49 deacetylation, highlighting Sirt3 functions as a promising therapeutic target of renal fibroblast activation and interstitial fibrosis.

Treatments of heating and ultrasound improve the inhibition of gallocatechin gallate on tyrosinase.

BACKGROUND: Gallocatechin gallate (GCG), a catechin of tea polyphenols, possesses inhibitory ability against tyrosinase, but few studies have reported how common processing methods affect it. In this research, the influence of heating and ultrasound treatments on the inhibition of GCG against tyrosinase was explored by ultraviolet-visible absorption, fluorescence spectroscopy, high-performance liquid chromatography and liquid chromatography-tandem mass spectrometry. RESULTS: Both heating and ultrasound treatments of GCG alone improved GCG's inhibitory ability against tyrosinase compared with the untreated, and a combination of heating and ultrasound treatment (100 °C, 20 min + 630 W, 20 min) further decreased the relative tyrosinase activity to 26.8%. The treated GCG exhibited a stronger fluorescence quenching effect on tyrosinase, but did not have any influence on the static quenching mechanism. Compared to the untreated GCG, the binding constants of treated GCG by heating, ultrasound and their combination with tyrosinase significantly increased, but the number of binding sites was still approximately one and the main driving force of the treated GCG was still hydrophobic interaction. After treatments of heating, ultrasound and their combination, the composition of GCG solutions was changed. CONCLUSION: The enhanced inhibition of treated GCG on tyrosinase may be due to partial conversion of GCG into epigallocatechin-3-gallate (EGCG) and gallic acid (GA), which may cooperate with GCG to better inhibit the enzyme activity. This study has provided some valuable information for the application of catechins against tyrosinase in food processing and cosmetic industry. © 2022 Society of Chemical Industry.

Intrarenal 1-methoxypyrene, an aryl hydrocarbon receptor agonist, mediates progressive tubulointerstitial fibrosis in mice.

Recent studies have shown that endogenous metabolites act via aryl hydrocarbon receptor (AhR) signalling pathway in tubulointerstitial fibrosis (TIF) pathogenesis. However, the mechanisms underlying endogenous metabolite-mediated AhR activation are poorly characterised. In this study, we conducted untargeted metabolomics analysis to identify the significantly altered intrarenal metabolites in a mouse model of unilateral ureteral obstruction (UUO). We found that the levels of the metabolite 1-methoxypyrene (MP) and the mRNA expression of AhR and its target genes CYP1A1, CYP1A2, CYP1B1 and COX-2 were progressively increased in the obstructed kidney at Weeks 1, 2 and 3. Furthermore, these changes were positively correlated with progressive TIF in UUO mice. In NRK-52E, RAW 264.7 and NRK-49F cells, MP dose-dependently upregulated the mRNA expression of AhR and its four target genes and the protein expression of nuclear AhR, accompanied by the upregulated protein expression of collagen I, α-SMA and fibronectin, as well as downregulated E-cadherin expression. Consistently, oral administration of MP in mice progressively enhanced AhR activity and upregulated profibrotic protein expression in the kidneys; these effects were partially inhibited by AhR knockdown in MP-treated mice and cell lines. In addition, we screened and identified erythro-guaiacylglycerol-ß-ferulic acid ether (GFA), which was isolated from Semen plantaginis, as a new AhR antagonist. GFA significantly attenuated TIF in MP-treated NRK-52E cells and mice by partially antagonising AhR activity. Our results suggest that MP activates AhR signalling, thus mediating TIF through epithelial-mesenchymal transition and macrophage-myofibroblast transition. MP is a crucial metabolite that contributes to TIF via AhR signalling pathway.

Exploring the Inhibition of Quercetin on Acetylcholinesterase by Multispectroscopic and In Silico Approaches and Evaluation of Its Neuroprotective Effects on PC12 Cells.

This study investigated the inhibitory mechanism of quercetin in acetylcholinesterase (AChE) and its neuroprotective effects on ß-amyloid25-35-induced oxidative stress injury in PC12 cells. Quercetin inhibited AChE in a reversible mixed manner with an IC50 of 4.59 ± 0.27 µM. The binding constant of quercetin with AChE at 25 °C was (5.52 ± 0.05) × 104 L mol-1. Hydrogen bonding and van der Waals forces were the main interactions in forming the stable quercetin-AChE complex. Computational docking revealed that quercetin was dominant at the peripheral aromatic site in AChE and induced enzymatic allosterism; meanwhile, it extended deep into the active center of AChE and destabilized the hydrogen bond network, which caused the constriction of the gorge entrance and prevented the substrate from entering the enzyme, thus resulting in the inhibition of AChE. Molecular dynamics (MD) simulation emphasized the stability of the quercetin-AChE complex and corroborated the previous findings. Interestingly, a combination of galantamine hydrobromide and quercetin exhibited the synergistic inhibition effect by binding to different active sites of AChE. In a ß-amyloid25-35-induced oxidative stress injury model in PC12 cells, quercetin exerted neuroprotective effects by increasing the glutathione level and reducing the malondialdehyde content and reactive oxygen species levels. These findings may provide novel insights into the development and application of quercetin in the dietary treatment of Alzheimer's disease.

Deciphering the cellular mechanisms underlying fibrosis-associated diseases and therapeutic avenues.

Fibrosis is the excessive deposition of extracellular matrix components, which results in disruption of tissue architecture and loss of organ function. Fibrosis leads to high morbidity and mortality worldwide, mainly due to the lack of effective therapeutic strategies against fibrosis. It is generally accepted that fibrosis occurs during an aberrant wound healing process and shares a common pathogenesis across different organs such as the heart, liver, kidney, and lung. A better understanding of the fibrosis-related cellular and molecular mechanisms will be helpful for development of targeted drug therapies. Extensive studies revealed that numerous mediators contributed to fibrogenesis, suggesting that targeting these mediators may be an effective therapeutic strategy for antifibrosis. In this review, we describe a number of mediators involved in tissue fibrosis, including aryl hydrocarbon receptor, Yes-associated protein, cannabinoid receptors, angiopoietin-like protein 2, high mobility group box 1, angiotensin-converting enzyme 2, sphingosine 1-phosphate receptor-1, SH2 domain-containing phosphatase-2, and long non-coding RNAs, with the goal that drugs targeting these important mediators might exhibit a beneficial effect on antifibrosis. In addition, these mediators show profibrotic effects on multiple tissues, suggesting that targeting these mediators will exert antifibrotic effects on different organs. Furthermore, we present a variety of compounds that exhibit therapeutic effects against fibrosis. This review suggests therapeutic avenues for targeting organ fibrosis and concurrently identifies challenges and opportunities for designing new therapeutic strategies against fibrosis.

Safety-by-Design of Metal Oxide Nanoparticles Based on the Regulation of their Energy Edges.

The safety of metal oxide (MOx) nanoparticles (NPs) has been highly concerned because of their wide application and potential toxicological injury. The safe-by-design strategy is usually developed to make safer MOx NPs based on regulation of their physicochemical properties. In the present study, manganese oxide (Mn3 O4 ) NPs, as a representative of insoluble toxic MOx NPs, are doped with a series of transition metal to regulate their conduction band energy (Ec ) out of biological redox potential range (BRPR) or Fermi energy (Ef ) far away from valence band energy (Ev ), aiming at completely eliminating the toxicity or significantly reducing the toxicity. It is found that all these M-doping cannot move Ec of Mn3 O4 NPs out of the BRPR but zinc (Zn)-, copper (Cu)-, and chromium (Cr)-doping do move Ef far away from Ev , where Zn-doping results in the largest |Ef - Ev | value. Various abiotic, in vitro and in vivo assessments reveal that Zn-, Cu-, and Cr-doped Mn3 O4 NPs can generate lower amount of •OH and trigger weaker injury than Mn3 O4 NPs, where Zn-doped Mn3 O4 NPs show the lowest toxicity. Regulating Ef far away from Ev becomes a feasible safe-by-design approach to achieve safe MOx NPs.

Nitric Oxide Stimulated Programmable Drug Release of Nanosystem for Multidrug Resistance Cancer Therapy.

Nitric oxide (NO) molecular messenger can reverse the multidrug resistance (MDR) effect of cancer cells through reducing P-glycoprotein (P-gp) expression, beneficial for creating a favorable microenvironment for the treatment of doxorubicin (Dox)-resistant cancer cells. Development of sophisticated nanosystems to programmably release NO and Dox becomes an efficient strategy to overcome the MDR obstacles and achieve promising therapeutic effects in Dox-resistant cancer. Herein, a NO stimulated nanosystem was designed to engineer a significant time gap between NO and Dox release, promoting MDR cancer therapy. A o-phenylenediamine-containing lipid that can hydrolyze in response to NO was embedded in the phospholipid bilayer structure of liposome to form NO-responsive liposome, which could further encapsulate l-arginine (l-Arg)/Dox-loaded gold@copper sulfide yolk-shell nanoparticls (ADAu@CuS YSNPs) to form ADLAu@CuS YSNPs. Under 808 nm laser irradiation, the unique resonant energy transfer (RET) process and reactive oxygen species (ROS) generation in the confined space of ADLAu@CuS YSNPs could effectively convert l-Arg into NO, regionally destabilizing the phospholipid bilayer structure, as a result of NO release. However, at this early stage Dox could not be released from YSNPs due to the molecular scaffold limit. As the NO release progressed, the NO-responsive liposome layer was deteriorated more severely, allowing Dox to escape. This NO and Dox sequential release of ADLAu@CuS YSNPs could significantly inhibit P-gp expression and enhance Dox accumulation in Dox-resistant MCF-7/ADR cells, leading to promising in vitro and in vivo therapeutic effects and presenting their great potential for MDR cancer therapy.

Molecular imprinting: perspectives and applications.

Molecular imprinting technology (MIT), often described as a method of making a molecular lock to match a molecular key, is a technique for the creation of molecularly imprinted polymers (MIPs) with tailor-made binding sites complementary to the template molecules in shape, size and functional groups. Owing to their unique features of structure predictability, recognition specificity and application universality, MIPs have found a wide range of applications in various fields. Herein, we propose to comprehensively review the recent advances in molecular imprinting including versatile perspectives and applications, concerning novel preparation technologies and strategies of MIT, and highlight the applications of MIPs. The fundamentals of MIPs involving essential elements, preparation procedures and characterization methods are briefly outlined. Smart MIT for MIPs is especially highlighted including ingenious MIT (surface imprinting, nanoimprinting, etc.), special strategies of MIT (dummy imprinting, segment imprinting, etc.) and stimuli-responsive MIT (single/dual/multi-responsive technology). By virtue of smart MIT, new formatted MIPs gain popularity for versatile applications, including sample pretreatment/chromatographic separation (solid phase extraction, monolithic column chromatography, etc.) and chemical/biological sensing (electrochemical sensing, fluorescence sensing, etc.). Finally, we propose the remaining challenges and future perspectives to accelerate the development of MIT, and to utilize it for further developing versatile MIPs with a wide range of applications (650 references).

Dispersive liquid-liquid microextraction for four phenolic environmental estrogens in water samples followed by determination using capillary electrophoresis.

Dispersive liquid-liquid microextraction (DLLME) coupled with CE was successfully developed for simultaneous determination of four types of phenolic environmental estrogens (PEEs), namely hexestrol (HS), bisphenol A (BPA), diethylstilbestrol (DES) and dienestrol (DS). Several parameters affecting DLLME and CE conditions were systematically investigated including the type and volume of extraction solvent and dispersive solvent, extraction time, salt, pH value, surfactant, buffer solution and so on. Under the optimal conditions, DLLME-CE exhibited strong enrichment ability, presenting high enrichment factors of 467, 241, 367 and 362 for HS, BPA, DES and DS, respectively, as well as low detection limits of 0.3, 0.6, 0.6 and 0.3 µg/L, respectively. Excellent linearity was achieved in the range of 2.0-150 µg/L for HS and DS, and 4.0-300 µg/L for BPA and DES, with correlation coefficients R>0.9983. Recoveries ranging from 70.4 to 108.1% were obtained with tap water, lake water and seawater samples spiked at three concentration levels and the relative standard deviations (RSDs, for n = 5) were 2.1-9.7%. This DLLME-CE method with high selectivity and sensitivity, high stability, simplicity, cost-effectiveness, eco-friendliness was proved potentially applicable for the rapid and simultaneous determination of PEEs in complicated water samples.

Dual Regulation of Nicotine on NLRP3 Inflammasome in Macrophages with the Involvement of Lysosomal Destabilization, ROS and α7nAChR.

Nicotine, the primary alkaloid in tobacco products, has been shown to have immunoregulatory function in at least 20 diseases. The biological mechanism of action of nicotine immunoregulation is complex, resulting in an improvement of some disease states and exacerbation of others. Given the central role of the NLRP3 inflammasome in macrophages among multiple inflammatory diseases, this study examined how nicotine alters NLRP3 inflammasome activation in macrophages. NLRP3 inflammasome activation was examined mechanistically in the context of different nicotine dosages. We show NLRP3 inflammasome activation, apoptosis-associated speck-like protein (ASC) expression, caspase-1 activity and subsequent IL-1ß secretion were positively correlated with nicotine in a dose-dependent relationship, and destabilization of lysosomes and ROS production were also involved. At high concentrations of nicotine surpassing 0.25 mM, NLRP3 inflammasome activity declined, along with increased expression of the anti-inflammatory Alpha7 nicotinic acetylcholine receptor (α7nAChR) and the inhibition of TLR4/NF-κB signaling. Consequently, high doses of nicotine also reduced ASC expression, caspase-1 activity and IL-1ß secretion in macrophages. Collectively, these results suggest a dual regulatory function of nicotine on NLRP3 inflammasome activation in macrophages, that is involved with the pro-inflammatory effects of lysosomal destabilization and ROS production. We also show nicotine mediates anti-inflammatory effects by activating α7nAChR at high doses.

Property-activity relationship between physicochemical properties of PM2.5 and their activation of NLRP3 inflammasome.

Air pollution is becoming severe environment factor affecting human health. More and more research has indicated that fine particulate matter (PM2.5) plays a critical role in causing pulmonary inflammation or fibrosis, which potentially is ascribed to the activation of nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome. However, the underlying property-activity relationship between the physicochemical properties of PM2.5 and their activation of NLRP3 inflammasome remains unclear. Herein, various ways, such as metal chelation, organic extraction, ROS consumption, charge neutralization and particle dispersion, were applied to interfere with the effects of metal ion, polycyclic aromatic hydrocarbons (PAHs), reactive oxygen species (ROS), charge and size. It was found that aggregated size and PAHs could activate the NLRP3 inflammasome through lysosome rupture and potassium efflux, respectively. Metal ion, PAHs and surface ROS could also activate the NLRP3 inflammasome through mitochondrial ROS production. However, neutralization of PM2.5 with the negative surface charge could not relieve the activation of NLRP3 inflammasome. Furthermore, oropharyngeal aspiration of various modified PM2.5 were adopted to explore their effects on lung fibrosis, which showed the consistent results with those in cellular levels. Removal of metal ion, PAHs and ROS as well as reduction of size of PM2.5 could reduce collagen deposition in the lung tissue of mice, while the charge neutralization of PM2.5 increased this collagen deposition. This study provides great insights to clarify the property-activity relationship of PM2.5.

Tumor microcalcification-mediated relay drug delivery for photodynamic immunotherapy of breast cancer.

Spatiotemporal targeting of tumor-associated macrophages (TAMs) and tumor cells is emerging as a promising strategy for tumor therapy. Tumor microcalcifications that specifically bind to bisphosphonates are potentially used to design efficient relay drug delivery nanosystems to achieve spatiotemporal drug modulation. Here, we developed manganese dioxide (MnO2)-embedded and LyP-1 peptide-labeled liposomal nanoparticles (NPs) for photodynamic immunotherapy of breast cancer; zoledronic acid (Zol) was encapsulated in the hydrophilic cavity of liposomes, and a hydrophobic photosensitizer (IR780) was embedded in the phospholipid bilayer of liposomes. These Lipo Zol/IR NPs generated O2 bubbles through MnO2 in response to H2O2 in the tumor microenvironment, leading to the degradation of the liposomal membrane, which triggered the release of Zol and provided O2 for photodynamic therapy. The released Zol attached to microcalcifications and was selectively phagocytosed by TAMs, leading to the induction of death or repolarization of TAMs from the immunosuppressive M2 phenotype to the immunostimulatory M1 phenotype. The remaining liposomal fragments embedded with IR780 then preferentially targeted tumor cells through LyP-1 peptide and produced abundant reactive oxygen species (ROS) under near infrared (NIR) laser irradiation, resulting in the death of tumor cells and mild immune activation. All in vitro and in vivo studies demonstrated the effective photodynamic and immunoregulatory performance of Lipo Zol/IR NPs. STATEMENT OF SIGNIFICANCE: Spatiotemporal targeting of tumor-associated macrophages (TAMs) and tumor cells remains a challenge in tumor photodynamic immunotherapy for promoting synergy and reducing side effects. Here, we developed tumor microcalcification-mediated relay drug delivery nanoliposomes for breast cancer therapy. H2O2 in the tumor microenvironment (TME) triggers the breakage of nanoliposomes, thereby causing the separation of zoledronic acid (Zol) and the photosensitizer IR780 and allowing them to perform their respective functions. Microcalcifications enable Zol to target TAMs, resulting in immunomodulation. LyP-1 guides IR780 to target tumor cells for PDT with adequate O2 supply. These nanoliposomes enable precise spatiotemporal targeting of different types of cells in the TME and promote the synergy between immunotherapy and PDT while ensuring the effectiveness of both methods.

Upregulation of MHC-I and downregulation of PD-L1 expression by doxorubicin and deferasirox codelivered liposomal nanoparticles for chemoimmunotherapy of melanoma.

Tumor immunotherapy is a promising strategy to activate the immune system and eliminate tumors. Major histocompatibility complex I (MHC-I) is usually applied to potentiate antigen presentation, but it is associated with upregulation of programmed death ligand 1 (PD-L1) expression, which is unfavorable for activation of immune responses. Moreover, poor permeability of various therapeutic antibodies results in the limited immune response rates of most patients. It is necessary to develop combined small molecule drug delivery systems for simultaneous upregulation of MHC-I expression and downregulation of PD-L1 expression, promoting effective tumor treatment. A moderate dose of doxorubicin hydrochloride (DOX) can induce upregulation of MHC-I expression, while deferasirox (DFX) can inhibit the PI3K-Akt pathway, which potentially downregulates PD-L1 expression. In the present study, we designed a pH-sensitive liposome to incorporate DOX in the hydrophilic cavity and embed DFX in the hydrophobic shell, forming a dual delivery system (DOX-DFXL). In a B16F10 melanoma-bearing mouse model, DOX and DFX were released in acidic tumor microenvironment, which further lead to enhanced antigen presentation and infiltration of T cells into tumor tissues as a result of tumor remission. This codelivery system holds great potential for clinical applications of tumor immunotherapy.

1-Hydroxypyrene mediates renal fibrosis through aryl hydrocarbon receptor signalling pathway.

BACKGROUND AND PURPOSE: In chronic kidney disease (CKD), patients inevitably reach end-stage renal disease and require renal transplant. Evidence suggests that CKD is associated with metabolite disorders. However, the molecular pathways targeted by metabolites remain enigmatic. Here, we describe roles of 1-hydroxypyrene in mediating renal fibrosis. EXPERIMENTAL APPROACH: We analysed 5406 urine and serum samples from patients with Stage 1-5 CKD using metabolomics, and 1-hydroxypyrene was identified and validated using longitudinal and drug intervention cohorts as well as 5/6 nephrectomised and adenine-induced rats. KEY RESULTS: We identified correlations between the urine and serum levels of 1-hydroxypyrene and the estimated GFR in patients with CKD onset and progression. Moreover, increased 1-hydroxypyrene levels in serum and kidney tissues correlated with decreased renal function in two rat models. Up-regulated mRNA expression of aryl hydrocarbon receptor and its target genes, including CYP1A1, CYP1A2 and CYP1B1, were observed in patients and rats with progressive CKD. Further we showed up-regulated mRNA expression of aryl hydrocarbon receptor and its three target genes, plus up-regulated nuclear aryl hydrocarbon receptor protein levels in mice and HK-2 cells treated with 1-hydroxypyrene, which caused accumulation of extracellular matrix components. Treatment with aryl hydrocarbon receptor short hairpin RNA or flavonoids inhibited mRNA expression of aryl hydrocarbon receptor and its target genes in 1-hydroxypyrene-induced HK-2 cells and mice. CONCLUSION AND IMPLICATIONS: Metabolite 1-hydroxypyrene was demonstrated to mediate renal fibrosis through activation of the aryl hydrocarbon receptor signalling pathway. Targeting aryl hydrocarbon receptor may be an alternative therapeutic strategy for CKD progression.

Therapeutic strategies of iron-based nanomaterials for cancer therapy.

Iron-based nanomaterials have appeared in various cancer treatments owing to their promising functions and safety. Various sophisticated iron-based nanomaterials have been designed to exhibit great therapeutic effects through different strategies. Given the rapid progression, there is a great need to integrate the recent advances to learn about the latest innovation in this field. In this review, we classified the strategies of iron-based nanomaterials for cancer treatment into the following categories: immunotherapy, ferroptosis, magnetic hyperthermia and magneto-mechanical destruction. On the one hand, we discussed the underlining mechanism of iron-based nanomaterials in these therapies and applications; on the other hand, we analyzed the feasible combination of these applications and other therapies. Finally, the current challenges and expectation of iron-based nanomaterials in this field were highlighted.

Biotransformation of soluble-insoluble lanthanum species and its induced NLRP3 inflammasome activation and chronic fibrosis.

Soluble lanthanum (La)(Ⅲ) species that have been extensively used as fertilizers in agriculture can potentially get into the human body through foods and environment. Most soluble La(Ⅲ) species can rapidly transform into insoluble La(Ⅲ) species under physiological conditions, however, their potential biological behavior and chronic toxicity are rarely investigated. In the present study, insoluble La(Ⅲ) species formed under physiological condition were identified as nanoscale or microscale particles, and their major components were found to experience biotransformation process upon contact with cells. Insoluble La(Ⅲ) species could adhere to extracellular membrane or be internalized into cells, capable of activating a nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome. The underlying mechanism could be ascribed to K+ efflux and lysosomal rupture because these insoluble La(Ⅲ) species locating at extracellular membrane could reduce the unsaturated fatty acids of cell membrane, leading to potassium (K+) efflux, and those internalized into cells could consume the phospholipids of lysosomal membrane, leading to lysosomal rupture. Mice daily drinking soluble La(Ⅲ) species to mimic drinking tea process for 90 days were found to present NLRP3 inflammasome activation in liver and kidney, as a result of chronic fibrosis, which is potentially correlated to insoluble La(Ⅲ) species formation.

Thylakoid Membranes with Unique Photosystems Used to Simultaneously Produce Self-Supplying Oxygen and Singlet Oxygen for Hypoxic Tumor Therapy.

Photodynamic therapy (PDT) efficacy has been dramatically limited by the insufficient oxygen (O2 ) level in hypoxic tumors. Although various PDT nanosystems have been designed to deliver or produce O2 in support of reactive oxygen species (ROS) formation, the feature of asynchronous O2 generation and ROS formation still results in the low PDT efficacy. Herein, thylakoid membranes (TM) of chloroplasts is decorated on upconversion nanoparticles (UCNPs) to form UCTM NPs, aiming at realizing spatiotemporally synchronous O2 self-supply and ROS production. Upon 980 nm laser irradiation, UC NPs can emit the red light to activate both photosystem-I and photosystem-II of TM, the Z-scheme electronic structure of which facilitates water to produce O2 and further to singlet oxygen (1 O2 ). UCTM NPs showed excellent biocompatibility, and can effectively remove the hypoxic tumor of mice upon 980 nm laser irradiation. This study develops a new PDT strategy for hypoxic tumor therapy based on photosynthesis.

Neutrophil mediated postoperative photoimmunotherapy against melanoma skin cancer.

Surgery is the primary treatment option for most melanoma; however, high tumor recurrence rate after surgical resection becomes the main cause of death in cancer patients. The development of efficient drug delivery nanosystems to inhibit postoperative tumor recurrence becomes very necessary. In the present study, IR780 molecules and TRP-2 peptide were encapsulated in the hydrophobic shell and hydrophilic interior of TAT peptide functionalized liposomes to form TLipIT NPs, which were further internalized into neutrophils (NEs) to achieve TLipIT/NEs. After being intravenously injected into postoperative B16F10-bearing mice, TLipIT/NEs could actively migrate toward the inflamed residual tumor and release TLipIT through neutrophil extracellular traps (NETs). Under NIR laser irradiation, the TLipIT exhibited both photothermal and photodynamic effects to induce immunogenic cell death for maturation of DCs, and simultaneously, to release TRP-2 peptide as a melanoma associated antigen to further strengthen the maturation of DCs, both of which prompts the activation of T cells and induces potent immune responses. TLipIT/NEs hold great potential for the inhibition of postoperative tumor recurrence.

Copper Phosphide Nanoparticles Used for Combined Photothermal and Photodynamic Tumor Therapy.

Copper-based nanomaterials are widely used in near-infrared (NIR) light-mediated deep tumor treatment because of their abundant photothermal and photodynamic properties. However, copper phosphide (Cu3P) nanoparticles (NPs) are rarely investigated. Herein, Cu3P NPs were prepared to strengthen their local surface plasmon resonance absorption in the NIR region, exhibiting promising photothermal and photodynamic properties. After surface modification by polyethylene glycol, the formed pCu3P NPs showed negligible influence on the viability of 4T1 cells, presenting remarkable biocompatibility. However, with 808 nm irradiation, pCu3P NPs could induce HSP70 and HO-1 protein expression and enhance intracellular reactive oxygen species levels, leading to dramatic cell death. In 4T1 tumor-bearing mice, an intravenous injection of biocompatible pCu3P NP could lead to remarkable aggregation in the tumor region and significantly inhibit tumor growth under 808 nm laser irradiation, presenting great potential for tumor therapy.