IntroductionMany cytokines have been used as candidate biomarkers of acute graft-versus-host disease (aGVHD). Among these, the roles of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, IL-10, IL-17A, and IL-1β in aGVHD remain debatable, whereas IL-2, IL-12P70, IL-4, IL-5, and IFN-α are key elements in the pathological process of aGVHD. This study aimed to verify whether these 12 cytokines could serve as potential biomarkers of aGVHD in patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT).MethodsIn this retrospective study, 155 patients were stratified into control (non-aGVHD) and experimental (aGVHD) groups based on the occurrence of aGVHD. The association between cytokine levels and aGVHD occurrence was evaluated.ResultsThe expression levels of IL-5, IL-8, and IL-10 were significantly elevated in patients with aGVHD compared to those in patients without aGVHD. The results of multivariate analysis revealed that IL-5, IL-8, and IL-10 were independent risk variables for aGVHD. These three cytokines formed a composite biomarker panel with a good predictive ability for aGVHD. The panel remained an independent predictor in multivariable analysis (HR = 3.34, 95% CI: 1.66 - 6.69, P < 0.001). The composite biomarker panel demonstrated robust discriminative performance upon internal validation with 1000 bootstrap resamples.DiscussionThe composite biomarker panel comprising IL-5, IL-8, and IL-10 may serve as an important biomarker for predicting aGVHD occurrence.

BACKGROUND:Emerging evidence highlights the pivotal role of ferroptosis in the pathophysiology of diabetic nephropathy (DN). This study aimed to identify potential ferroptosis-related genes (FRGs) in DN through bioinformatics and experimental validation. METHODS:Datasets for diabetic nephropathy (DN) and ferroptosis-related gene sets were obtained from the Gene Expression Omnibus (GEO) database and the Ferroptosis Database, respectively. Differential expression analysis identified ferroptosis-related genes (DE-FRGs) in DN, and machine learning was applied to screen key genes. The risk model's accuracy was evaluated using receiver operating characteristic (ROC) curve analysis. Potential small chemical compounds associated with DE-FRGs and DN were also explored. Expression of DE-FRGs was measured by Quantitative Reverse Transcription PCR (qRT-PCR) in kidneys of DN mice and by Enzyme-linked immunosorbent assay (ELISA) in serum from DN patients versus non-DN controls. RESULTS:Analysis identified 125 DE-FRGs enriched in ferroptosis and DN-related pathways. Machine learning pinpointed nine diagnostic biomarkers, which were validated by ROC curves, and 13 potential therapeutic compounds. Among the DE-FRGs, qRT-PCR verified dysregulation of interleukin-33 (IL-33), retinoic acid receptor responder protein 2 (RARRES2), enhancer of zeste homolog 2 (EZH2), gap junction protein alpha 1 (GJA1), and hypoxia-inducible lipid droplet associated (HILPDA) in DN kidneys. Importantly, serum levels of EZH2 and IL-33 were significantly elevated in DN patients, underscoring their critical role in pathogenesis and potential as therapeutic targets. CONCLUSIONS:In conclusion, this study identified IL-33 and EZH2 as key DE-FRGs in DN, offering new insights into the molecular mechanisms underlying the disease.

In this study, we significantly improved the PEC performance of glycerol oxidation by introducing an amorphous NiOOH co-catalyst onto BiVO4 photoanodes. The effects of the bias voltage and pH on the selectivity of glycerol conversion products were meticulously investigated. The research demonstrated that increasing the bias voltage promoted glycerol oxidation, with an optimal voltage of 0.7 V leading to a significant increase in both the glycerol conversion rate and DHA selectivity, reaching up to 68 %. Additionally, pH played a critical role in the selectivity of glycerol oxidation products, with neutral to slightly alkaline conditions (pH=8) being the most conducive for DHA production. This study provides a promising strategy for sustainable glycerol valorization and offers a comprehensive understanding of the factors influencing PEC glycerol oxidation on NiOOH/BiVO4 photoanodes.

Ferroptosis therapy, which uses ferroptosis inducers to produce lethal lipid peroxides and induce tumor cell death, is considered a promising cancer treatment strategy. However, challenges remain regarding how to increase the accumulation of reactive oxygen species (ROS) in the tumor microenvironment (TME) to enhance antitumor efficacy. In this study, a hyaluronic acid (HA) encapsulated hollow mesoporous manganese dioxide (H-MnO2) with double-shell nanostructure is designed to contain iron coordinated cyanine near-infrared dye IR783 (IR783-Fe) for synergistic ferroptosis photodynamic therapy against tumors. The nano photosensitizer IR783-Fe@MnO2-HA, in which HA actively targets the CD44 receptor, subsequently dissociates and releases Fe3+ and IR783 in acidic TME. First, Fe3+ consumes glutathione to produce Fe2+, which promotes the Fenton reaction in cells to produce hydroxyl free radicals (·OH) and induce ferroptosis of tumor cells. In addition, MnO2 catalyzes the production of O2 from H2O2 and enhances the production of singlet oxygen (1O2) by IR783 under laser irradiation, thus increasing the production and accumulation of ROS to provide photodynamic therapy. The highly biocompatible IR783-Fe@MnO2-HA nano-photosensitizers have exhibited tumor-targeting ability and efficient tumor inhibition in vivo due to the synergistic effect of photodynamic and ferroptosis antitumor therapies.

Targeted elimination of damaged or overexpressed proteins within the tumor serves a pivotal role in regulating cellular function and restraining tumor cell growth. Researchers have been striving to identify safer and more effective methods for protein removal. Here, we propose the synergistic employment of a small molecule degrading agent (PROTAC) and siRNA to attain enhanced protein clearance efficiency and tumor therapeutic effects. Co-delivery liposomes were prepared to facilitate the efficient encapsulation of PROTAC and siRNA. Specifically, the cationic liposome significantly improved the solubility of the insoluble PROTAC (DT2216). The cationic polymer(F-PEI) achieved efficient encapsulation of the nucleic acid drug, thereby promoting endocytosis and enhancing the therapeutic impact of the drug. Both in vivo and in vitro experiments demonstrated remarkable degradation of target proteins and inhibition of tumor cells by the co-delivery system. In conclusion, the co-delivery liposomes furnished a nano-delivery system proficient in effectively encapsulating both hydrophilic and hydrophobic drugs, thereby presenting a novel strategy for targeted combination therapy in treating tumors.

Twelve new hybrid compounds of Esculetin with nitricoxide (NO)donors and/or mitochondrial targeting groups were designed, synthesized,and evaluated for their anti-tumor activity and mechanism in vitro and in vivo. Notably, the mostpotent compound A11 exhibited nanomolar antiproliferativeactivity on triple-negative breast cancer (TNBC) MDA-MB-231 cells(IC50 = 8 nM) with a strikingly selective inhibitory effect.The mechanism of A11 involves targeting MDA-MB-231 cells'mitochondria, releasing a high NO concentration, and increasing theexpression of cyclophilin D (CypD), leading to increased reactiveoxygen species (ROS) and triggering cancer cell apoptosis. Additionally, A11 could arrest the cell cycle at the G2/M phase to achieveanti-tumor effects. Moreover, A11 demonstrated a superiorTNBC inhibition rate and diminished toxicity relative to doxorubicin(DOX) in vivo. In summary, A11 serves as a noteworthycontender for TNBC treatment with high potency and minimal toxicity.

Lung cancer is one of the most common malignant tumors in China. Most patients are already in the mid to advanced stages during the consultation and the survival rate is less than 23 % with a poor prognosis. Therefore, effective dialectical diagnosis of advanced cancer can guide individualized treatment to improve survival. Phospholipids are the building blocks of cell membranes and abnormal phospholipid metabolism is associated with plentiful diseases. Most studies of disease markers use blood as a sample. However, urine covers extensive metabolites that are produced during the body's metabolic processes. Therefore, the study of markers in urine can be used as a complement to improve the diagnosis rate of marker diseases. Moreover, urine is characterized by high water content, high polarity, and high inorganic salt, therefore the detection of phospholipids in urine is challenging. In this study, an original Polydimethylsiloxane (PDMS)-titanium dioxide (TiO2) composite film for sample pre-treatment coupled with the LC-MS/MS method for the determination of phospholipids in the urine with high selectivity and low matrix effects was prepared and developed. The extraction process was scientifically optimized by the single-factor test. After systematic validation, the established method was successfully applied to the accurate determination of phospholipid substances in the urine of lung cancer patients and healthy subjects. In conclusion, the developed method has great potential for the development of lipid enrichment analysis in urine and can be used as a beneficial tool for cancer diagnosis and Chinese medicine syndrome typing.

The silver nanoparticle is a good antibacterial material being used as a broad-spectrum fungicide, including against some multidrug-resistant strains. Compared with the normal chemical and physical preparation methods, green synthesis has attracted wide attention, because of the pharmaceutical activities of the natural product, mild reaction conditions, and environmentally friendly, etc. In this study, the synthesis of silver nanoparticles (Ag NPs) was prepared from Bletilla striata polysaccharide (BSP) and characterized by UV-vis spectroscopy and Dynamic Light Scattering (DLS). Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) indicated the morphology of Ag NPs was subspherical with an average size of 20–35 nm. Bletilla striata polysaccharide not only can be used as a natural reducing agent, but also has good repairing ability. Moreover, the antibacterial experimental results showed its great antimicrobial activity against Gram-positive bacteria (Staphylococcus aureus), Gram-negative bacteria (Escherichia coli) and Candida albicans.

The transient receptor potential canonical (TRPC) channels, encoded in seven non-allelic genes, are important contributors to calcium fluxes, are strongly associated with various diseases. Here we explored the consequences of ablating all seven TRPCs in mice focusing on colitis. We discovered that absence of all seven TRPC proteins in mice (TRPC HeptaKO mice) promotes the development of dextran sulfate sodium (DSS)-induced colitis. RNA-sequence analysis highlighted an extremely pro-inflammatory profile in colons of DSS-treated TRPC HeptaKO mice, with an amount of increased pro-inflammatory cytokines and chemokines. Flow cytometry analysis showed that the infiltration of Ly6Chi monocytes and neutrophils in colonic lamina propria was significantly increased in DSS-treated TRPC HeptaKO mice. Results also revealed that macrophages from TRPC HeptaKO mice exhibited M1 polarization and enhanced secretion of pro-inflammatory factors. In addition, the composition of gut microbiota was markedly disturbed in DSS-treated TRPC HeptaKO mice. However, upon antibiotic cocktail (Abx)-treatment, TRPC HeptaKO mice showed no significant differences with WT mice in disease severity. Collectively, these data suggest that ablation of all TRPCs promotes the development of DSS-induced colitis by inducing pro-inflammatory macrophages and gut microbiota disorder.

In recent years, fms-like tyrosine kinase 3 (FLT3) was confirmed as an exciting target for treatment of AML. However, resistance to FLT3 inhibitors caused by ac-quired point mutations in tyrosine kinase domain (TKD) have limited their sustained efficacious. Thus, there remains an unmet need to develop high-efficacy FLT3 inhibitors against both FLT3 internal tandem duplication (ITD) and FLT3 (TKD) mutations. Herein, we describe the discovery of compound LT-540-717 (32), a potent FLT3 inhibitor (IC50: 0.62 nM), starting from FN-1501. Compound 32 exhibited highly inhibitory activity against several acquired FLT3 mutations including FLT3 (ITD, D835V), FLT3 (ITD, F691L), FLT3 (D835Y) and FLT3 (D835V). Additionally, 32 displayed potent antiproliferative activity against FLT3-mutation driven BaF3 and AML cells. Oral administration of 32 (25 mg/kg, QD) significantly prohibited tumor growth (tumor-inhibition rate is 94.18%), and no obvious side effect was observed even when increasing dose to 50 mg/kg (tumor-inhibition rate is 93.98%). Furthermore, 32 showed an acceptable bioavailability (F = 33.3% in rat and 72.7% in beagles), a suitable half-life time (T-1/2 = 3.5 h in rat and T-1/2 = 11.1 h in beagles), and a satisfactory metabolic stability. In summary, these results show the therapeutic potential of 32 to become a new anti-AML drug, especially for AML harboring dual FLT3 (ITD, TKD) mutations.

The term ferroptosis coined in 2012 causes acute kidney injury (AKI). However, its pathway mechanism in AKI is poorly understood. In this study, we conducted an RNA-sequence analysis of kidneys in AKI and normal mice to explore the pathway mechanism of ferroptosis. Consequently, differentially expressed genes highlighted Acyl-CoA synthetase long-chain family (ACSL4), a known promotor for ferroptosis. Besides, RT-PCR, Western blot, and immunohistochemical analyses confirmed its upregulation. HIF-1α was downregulated in I/R-AKI mice, and in vitro studies confirmed a negative regulation of HIF-1α on ACSL4. To explore the role of ACSL4 in AKI, we constructed ACSL4 knockout in kidney tubules of mice-as Cdh16Cre-ACSL4F/F mice. Results revealed that ACSL4 knockout significantly reduced ferroptosis and inhibited the functional and pathological injury of AKI mice. Meanwhile, the kidneys of Cdh16Cre-ACSL4F/F mice demonstrated a significantly decreased inflammation and macrophage infiltration. Further, additional explorations were explored to decipher a more thorough understanding of ferroptotic immunogenicity. As a result, neutrophils were not directly recruited by ferroptotic cells, but by ferroptotic cell-induced macrophages. Further, ACSL4 inhibitor rosiglitazone significantly inhibited AKI. Collectively, these data provide novel insights into the AKI pathogenesis, and defined ACSL4 as an effective target in AKI.

目的 从药师角度总结支气管哮喘(以下简称"哮喘")患者用药技能、依从性和有效性的评价方法,为药师开展临床干预研究和管理哮喘患者提供参考.方法 参考诊疗指南、循证医学证据文献和临床实践经验,从用药技能(吸入技术)、依从性和有效性3个方面阐述具有临床价值的哮喘患者药物治疗的评价方法.结果 吸入技术评分表是哮喘患者用药技能的重要评价方法.依从性主要借助Morisky用药依从性问卷或哮喘药物依从性报告量表进行评价.有效性评价方法包括直接评价指标(临床表现、急性发作和缓解药物治疗情况、检查指标如肺功能指标和呼出气一氧化氮等)和间接评价工具(即各种量表,包括哮喘控制测试问卷、儿童哮喘控制测试问卷、儿童呼吸和哮喘控制测试问卷、哮喘相关生命质量量表等).结论 将用药技能、依从性和有效性方面的评价方法结合起来,可以更好地评价哮喘患者的药物治疗效果.药师应在实践中应用并完善这些评价方法,以对哮喘患者实施更好的药学干预.

As potential mimics of natural enzymes, nanozymes can overcome many disadvantages associated with the use of natural enzymes, such as the need for complex preparation and purification processes, high cost, poor stability, and low recycling efficiency. Utilizing the unique advantages of nanomaterials, nanozymes have been widely used in biosensing, environmental protection, disease diagnosis and treatment, etc. Among these applications, biological detection is a hot research area that researchers are interested in. Although a lot of studies have been carried out on the topic of nanozyme-based biological detection, there are few reviews on the application of nanozymes in food quality and safety detection. This paper systematically introduces the latest research progress relating to nanozymes in the field of food quality and safety detection in recent years, including the detection of ions, common functional factors, toxins, antibiotics, and bacteria. Finally, we analyze the challenges associated with nanozyme use in the field of food analysis. We hope that this review will be of great significance for understanding the properties of nanozymes and for developing novel nanomaterials with enzyme-mimicking activities for food analysis.

Metal-containing nanomaterials have attracted substantial research efforts due to their rich compositional and structural diversity as well as the broad possible applications. However, the most metal-containing nanomaterials are normally only used as new delivery vehicles in the field of biomedicine but do not possess biological activity by itself. Herein, we modified dendritic polyethylene glycol on one folate–nickel nanotube to fabricate a new-type of metal-containing nanotube PEG-FA-Ni NTs. We found PEG-FA-Ni NTs have exhibited excellent in vitro and in vivo antitumor activity comparable to the positive drugs doxorubicin and cisplatin. Meanwhile, this study indicates that the PEG-FA-Ni NTs may achieve more optimal antitumor effects by damaging DNA, blocking cell cycle, and ultimately inducing apoptosis. All the results showed that PEG-FA-Ni NTs could be a potent nanomedicine for the further development and application on cancer therapy.

2D MXene, Ti3 C2 (TC), has displayed enormous potential in applications in photothermal therapy (PTT), attributing to its biocompatibility and outstanding photothermal conversion capability. However, some tumor ablations are difficult to be realized completely by monotherapy due to the essential defects of monotherapy and intricate tumor microenvironment (TME). In this work, the appropriate doped Fe2+ ions are anchored into the layers of 2D ultrathin TC nanosheets (TC NSs) to synthesize a novel multifunctional nanoshell of Fe(II)-Ti3 C2 (FTC) through interlayer electrostatic adsorption. FTC possesses superior photothermal conversion efficiency (PTCE) than TC NSs, attributing to the enhanced conductivity promoted by interlaminar ferrous ion-channels. Moreover, Fenton reaction based on ferrous ions endows FTC the abilities of reactive oxide species (ROS) releasing and glutathione (GSH) suppression triggered by near-infrared (NIR) laser, featuring splendid biocompatibility and curative effect in hypoxic TME. Meanwhile, magnetic resonance imaging (MRI) responding in FTC reveals the potential as an integrated diagnosis and treatment nanoplatform. FTC could provide new insights into the development of multimoded synergistic nanoplatform for biological applications, especially breaking the shackles of MXenes merely used as a photo-thermal agent (PTA), adopting it to bioimaging sensor and drug loading.

Tumor microenvironment (TME) responsive polymeric micelles are promising carriers for drug delivery. In order to meet the needs of various applications, multifarious TME-responsive switches are used to construct smart polymeric micelles, which causes the complexity and corpulence of the polymeric micelle system and increases the difficulty of preparation. In this study, we designed and synthesized an ingenious TME-responsive switch through grafting disulfide bond-modified piperidinepropionic acid (CPA) on copolymer poly(ethylene glycol)-b-poly(aspartate)(PEG-b-PAsp) and built a novel pH/reduction-responsive PEG-b-PAsp-g-CPA polymeric micelle delivery system. The CPA-pendants can reverse the surface charge of the polymeric micelle from negative to positive at pH 6.5 because of the protonation of piperidine groups, thereby enhancing the internalization of cell. Subsequently, more piperidine groups are protonated at pH 5.0 which will increase the hydrophilicity of polymeric micelles and cause the hydrophobic core to swell, thus making the disulfide bonds packed in the core to be more easily broken by GSH. With the synergistic effect of the pH-triggered protonation of piperidine groups and reduction triggered break of disulfide bonds, the polymeric micelles will disintegrate and achieve efficient intracellular drug release. The TME-responsive polymeric micelles exhibited good biological safety, enhanced internalization, and rapid intracellular doxorubicin (DOX) release in vitro. Moreover, the PEG-b-PAsp-g-CPA/DOX polymeric micelles showed excellent antitumor efficacy and low systemic toxicity in lung tumor-bearing BALB/C mice. These results indicated that the novel integrated TME-responsive switch CPA helps the PEG-b-PAsp-g-CPA polymeric micelles to obtain excellent TME-responsiveness and antitumor drug delivery capabilities, while it also makes the preparation of TME-responsive polymeric micelles simpler and more convenient. This work provides a new idea for the architecture of TME-responsive polymeric micelles.

Alzheimer's disease (AD) is a neurodegenerative disease, the main pathological features include deposition of neurofibrillary tangles composed of the abnormally hyperphosphorylated tau protein and plaques deposition composed of beta-amyloid (A beta) peptide. MicroRNAs and aberrant glycosylation both play key roles in a variety of diseases, especially AD. Our previous study showed that N-acetylglucosaminyltransferase III (GnT-III) was expressed strongly in AD model mice. GnT-III is a glycosyltransferase responsible for synthesizing a bisecting N-acetylglucosamine residue. Here, we report the potential therapeutic effects of microRNA-23b (miR-23b) against AD by targeting GnT-III. In this study, the role of miR-23b in GnT-III-mediated amelioration of AD-related symptoms and pathologies, and mechanisms were investigated. We used A beta(1-)(42)-induced mouse and PC12 cell models to evaluate the effects of miR-23b on cognitive impairment, neurotoxicity, tau, and amyloid pathology. Bioinformatics analysis showed that GnT-III may be targeted by miR-23b, and it was verified by dual-luciferase reporter gene assays. Furthermore, a mechanistic study showed that activation of the Akt/GSK-3 beta signaling pathway can contribute to tau-lesion inhibition by miR-23b, and miR-23b can also restrain oxidative stress by altering A beta-precursor protein processing. Taken together, we conclude that overexpression of miR-23b can interrupt the pathogenesis of AD.

Interleukin 6 (IL-6) is a pleiotropic cytokine that is elevated in inflammatory bowel disease. However, the role of IL-6 deficiency in colitis is not well-defined. Some IL-6 and IL-6 receptor antagonists are associated with severe gastrointestinal immune adverse effects, but the mechanisms of the effects are not clear. This study aimed to investigate the effect of IL-6 in ulcerative colitis in Il6-/- mice. Results indicated that physiological deficiency of IL-6 promoted the development of colitis. Moreover, IL-6 deficiency significantly increased the mRNA levels of monocytes chemokine Ccl2 and its receptor Ccr2 in colon tissues. Similarly, the percentage of Ly6Chigh monocytes and neutrophils were increased in the colon of Il6-/- mice. Intestinal crypts more strongly increased the migration of Il6-/- macrophages than wild-type ones. Moreover, Il6-/- macrophages promoted the migration of neutrophils. Most importantly, RS102895, an antagonist of CCR2, diminished chemotaxis of macrophages and inhibited colitis in Il6-/- mice. Collectively, these results indicate that Il6-/- macrophages migrate to inflamed colon tissues and recruit neutrophils, thereby promoting the effect of Il6-/- on colitis. This study expands our understanding on the effect of IL-6 deficiency in colitis and the development of gastrointestinal immune adverse effects.

Four series of molecular hybrids (37 final products) of neo-tanshinlactone, a natural product extracted from Salvia miltiorrhiza Bunge, and known PD-1/PD-L1 interaction inhibitors were prepared as possible chemotherapeutic agents against triple negative breast cancer. Screening using a homogenous time-resolved fluorescence method resulted in three lead compounds (MZ52 IC50 74 +/- 4 nM; MZ58 IC50 134 +/- 17 nM; MZ61 IC50 225 +/- 19 nM). With less T cell cytotoxicity and effects in activating CD8(+) T cells in a T cell proliferation assay and a functionality experiment, MZ58 was selected as the best candidate for animal experiments. MZ58 exhibited antitumor effects in a subcutaneous transplantation tumor model as well as effects in reducing T cell exhaustion. In conclusion, after in vivo and in vitro experiments, we successfully acquired an effective candidate (MZ58) showing antitumor effects with low cytotoxicity toward T cells as well as the ability to activate CD8(+) T cells and reduce T cell exhaustion.

USP7 as a deubiquitinase plays important roles in regulating the stability of some oncoproteins including MDM2 and DNMT1, and thus represents a potential anticancer target. Through comparative analysis of USP7 co-crystal structures in complex with the reported piperidinol inhibitors, we noticed that the USP7 Phe409 sub-site might have good adaptability to the ligands. Based on this observation, 55 N-aromatic and N-benzyl piperidinol derivatives were designed, synthesized and biologically evaluated, among which compound L55 was identified as a highly selective and potent USP7 inhibitor (IC50 = 40.8 nM, KD = 78.3 nM). X-ray crystallographic studies revealed that L55 bound to USP7 with a new pose that was very different from the previously reported inhibitors. The results of cellular assays showed that L55 had strong antitumor activity against LNCaP (IC50 = 29.6 nM) and RS4; 11 (IC50 = 41.6 nM) cells, probably through inducing cell death and restricting G0/G1 and S phases. Moreover, L55 dose-dependently reduced the protein levels of MDM2 and DNMT1 and increased the protein levels of p53 and p21. These findings could have valuable implications for designing novel structural classes of USP7 inhibitors.