Cancer remains a leading cause of global mortality, necessitating the development of advanced therapeutic strategies with enhanced efficacy and reduced systemic toxicity. Among promising bioactive agents, lactoferrin (LF)—a multifunctional iron-binding glycoprotein abundantly found in mammalian milk and exocrine secretions—has garnered significant interest for its potent and multifaceted anti-cancer properties. This review provides a comprehensive analysis of the current understanding of LF’s role in oncology, encompassing its structural biology, diverse mechanisms of action, and groundbreaking advancements in its application through nano-engineering. LF exerts anti-tumor effects through multiple pathways, including extracellular action, intracellular action, and immune regulation. It demonstrates a remarkable affinity for cancer cell membranes, binding to overexpressed anionic components such as glycosaminoglycans and sialic acids, as well as to specific receptors including the low-density lipoprotein receptor-related protein-1 (LRP-1). This selective binding facilitates targeted uptake. Upon internalization, LF orchestrates a direct assault by inducing cell-cycle arrest in phases such as G0/G1 or S phase through the modulation of key regulators including cyclins, CDKs, and p53. Furthermore, it promotes programmed cell death via apoptotic pathways, involving caspase activation and downregulation of anti-apoptotic proteins such as survivin. A more recently elucidated mechanism is the induction of ferroptosis, an iron-dependent form of cell death characterized by overwhelming lipid peroxidation. Beyond direct cytotoxicity, LF acts as a potent immunomodulator. It enhances natural killer (NK) cell activity, modulates T-lymphocyte populations, and crucially reprograms tumor-associated macrophages (TAMs) from a pro-tumor M2 state to an anti-tumor M1 state, thereby reversing the immunosuppressive tumor microenvironment (TME). The translation of LF’s potential has been significantly accelerated by nanotechnology. The inherent biocompatibility and natural tumor-targeting capabilities of LF make it an ideal platform for sophisticated drug-delivery systems. This review details various fabrication strategies for LF-based nanoparticles (NPs), including self-assembly, sol-in-oil emulsion, and electrostatic nanocomplexes, among others. Research demonstrates that nano-formulations not only protect LF from degradation but also enhance its bioactivity and anti-cancer potency. More importantly, LF NPs serve as versatile carriers for a wide array of therapeutic agents, including conventional chemotherapeutics, natural compounds, and imaging agents. These engineered systems enable synergistic therapy and facilitate site-specific delivery. Notably, the ability of LF to bind to receptors on the blood-brain barrier (BBB) has been leveraged to develop nano-systems for glioblastoma treatment. Other innovative designs utilize LF to modulate the TME—for instance, by alleviating tumor hypoxia to sensitize cells to radiotherapy and chemotherapy. Despite compelling pre-clinical evidence, the clinical translation of LF and its nano-formulations remains nascent. While early-phase trials have established a favorable safety profile for recombinant human LF, larger Phase III studies have yielded mixed results, underscoring the complexity of its action in humans. Key challenges include enhancing drug targeting, optimizing loading efficiency, ensuring batch-to-batch reproducibility, and achieving deep tumor penetration. Future research must focus on the rational design of next-generation LF-NPs. This entails developing standardized manufacturing protocols, engineering “smart” stimuli-responsive systems for targeted drug release in the TME, and constructing multi-targeting platforms. A concerted interdisciplinary effort is paramount to bridge the gap between bench and bedside. In conclusion, LF, particularly in its nano-engineered forms, represents a highly promising and versatile agent in the oncological arsenal, holding immense potential for precise and effective cancer therapy.

Cancer remains a leading cause of global mortality, necessitating the development of advanced therapeutic strategies with enhanced efficacy and reduced systemic toxicity. Among promising bioactive agents, lactoferrin (LF)—a multifunctional iron-binding glycoprotein abundantly found in mammalian milk and exocrine secretions—has garnered significant interest for its potent and multifaceted anti-cancer properties. This review provides a comprehensive analysis of the current understanding of LF’s role in oncology, encompassing its structural biology, diverse mechanisms of action, and groundbreaking advancements in its application through nano-engineering. LF exerts anti-tumor effects through multiple pathways, including extracellular action, intracellular action, and immune regulation. It demonstrates a remarkable affinity for cancer cell membranes, binding to overexpressed anionic components such as glycosaminoglycans and sialic acids, as well as to specific receptors including the low-density lipoprotein receptor-related protein-1 (LRP-1). This selective binding facilitates targeted uptake. Upon internalization, LF orchestrates a direct assault by inducing cell-cycle arrest in phases such as G0/G1 or S phase through the modulation of key regulators including cyclins, CDKs, and p53. Furthermore, it promotes programmed cell death via apoptotic pathways, involving caspase activation and downregulation of anti-apoptotic proteins such as survivin. A more recently elucidated mechanism is the induction of ferroptosis, an iron-dependent form of cell death characterized by overwhelming lipid peroxidation. Beyond direct cytotoxicity, LF acts as a potent immunomodulator. It enhances natural killer (NK) cell activity, modulates T-lymphocyte populations, and crucially reprograms tumor-associated macrophages (TAMs) from a pro-tumor M2 state to an anti-tumor M1 state, thereby reversing the immunosuppressive tumor microenvironment (TME). The translation of LF’s potential has been significantly accelerated by nanotechnology. The inherent biocompatibility and natural tumor-targeting capabilities of LF make it an ideal platform for sophisticated drug-delivery systems. This review details various fabrication strategies for LF-based nanoparticles (NPs), including self-assembly, sol-in-oil emulsion, and electrostatic nanocomplexes, among others. Research demonstrates that nano-formulations not only protect LF from degradation but also enhance its bioactivity and anti-cancer potency. More importantly, LF NPs serve as versatile carriers for a wide array of therapeutic agents, including conventional chemotherapeutics, natural compounds, and imaging agents. These engineered systems enable synergistic therapy and facilitate site-specific delivery. Notably, the ability of LF to bind to receptors on the blood-brain barrier (BBB) has been leveraged to develop nano-systems for glioblastoma treatment. Other innovative designs utilize LF to modulate the TME—for instance, by alleviating tumor hypoxia to sensitize cells to radiotherapy and chemotherapy. Despite compelling pre-clinical evidence, the clinical translation of LF and its nano-formulations remains nascent. While early-phase trials have established a favorable safety profile for recombinant human LF, larger Phase III studies have yielded mixed results, underscoring the complexity of its action in humans. Key challenges include enhancing drug targeting, optimizing loading efficiency, ensuring batch-to-batch reproducibility, and achieving deep tumor penetration. Future research must focus on the rational design of next-generation LF-NPs. This entails developing standardized manufacturing protocols, engineering “smart” stimuli-responsive systems for targeted drug release in the TME, and constructing multi-targeting platforms. A concerted interdisciplinary effort is paramount to bridge the gap between bench and bedside. In conclusion, LF, particularly in its nano-engineered forms, represents a highly promising and versatile agent in the oncological arsenal, holding immense potential for precise and effective cancer therapy.

It is considered that lean metabolic associated fatty liver disease （MAFLD） is characte-rized by a state of "lean body but fatty liver". From the perspective of the pathomechanism evolution of "spleen failing to disperse essence， while kidney failing to transform qi"， the disease is systematically treated under the principle that spleen and kidney deficiency as the root and liver constraint with phlegm stasis as the branch. Spleen deficiency with impaired transformation and transportation leads to failure in the distribution of refined substances， initiating lipid turbidity accumulation and obstruction. Kidney dysfunction in qi transformation results in insufficient essence and blood， forming the root of bodily malnourishment. Over time， this further gives rise to liver constraint and loss of dispersing function， disorder in the movement of essential substances， and congealing of phlegm and stasis within hepatic collaterals. The dysfunction of three organs including spleen， kidney and liver constitutes the pathological basis of metabolic disturbances involving qi， blood， body fluids and essence. Treatment should follow the principle of "nourishing the healthy qi leads to spontaneous resolution of pathogenic accumulation"， with three approaches. First， fortifying the spleen and eliminating dampness， using Sini Powder （四逆散） and Erchen Pingwei Powder （二陈平胃散） to restore the transport and transformation function of the middle jiao （焦）， thereby guiding essential substances back to their proper physiological pathways. Second， tonifying the kidney and resolving turbidity， using Jinkui Shenqi Pill （金匮肾气丸） and Effective Integration Decoction （一贯煎） to replenish the lower jiao， promoting the restoration of essence and the transformation of turbid pathogen. Third， soothing the liver and resolving stasis， using Liujunzi Decoction （六君子汤） and Xiaozhi Qinggan Decoction （消脂清肝汤） to vent qi and blood stagnation， thereby interrupting disease progression. Together， these three methods reinforce healthy qi while eliminating pathogen， facilitating the restoration of proper essence transformation and the resolution of lipid turbidity.

It is proposed that the core pathogenesis of porto-sinusoidal vascular disease （PSVD） is characterized by deficiency of healthy qi with collateral stagnation and the binding of stasis and toxin. According to the characteristics of its microvascular lesions， PSVD can be treated through syndrome differentiation in three stages， including the occult stage， progressive stage， and decompensated stage. Considering the properties of insect-derived medicinals， such as rapid movement， penetrating action， and ability to search out pathogen and unblock collaterals， three therapeutic principles are established， which are unblocking collaterals， softening the liver， and dispelling pathogen. Clinically， the New-Modified Chaihu Biejia Decoction （柴胡鳖甲汤） is used as the basic prescription with staged modifications. During the occult stage， medicinals such as Quanxie （Scorpio） and Wugong （Scolopendra） are added to search out pathogen， unblock collaterals， and protect the channels from progression. During the progressive stage， Tubiechong （Eupolyphaga seu Steleophaga） and Qianglang （Catharsius molossus） are added to dispel stasis and soften hard masses， thereby removing concretions and dissipating masses. During the decompensated stage， Shuizhi （Hirudo） and Dilong （Pheretima） are added to eliminate stasis and promote urination， treating blood and fluid retention simultaneously.

Objective To investigate the regulatory effect and molecular mechanism of circ_0044556 on the malignant biological behavior of triple negative breast cancer(TNBC)cells by targeting the miR-338-3p/bromodomain-containing protein 4(BRD4)axis.Methods The TargetScan online website was used to predict the binding sites of circ_0044556 with miR-338-3p and miR-338-3p with BRD4.Dual-luciferase reporter gene assays were performed to determine the relationship among circ_0044556,miR-338-3p,and BRD4 in MDA-MB-231 cells.Quantitative real-time PCR(qRT-PCR)and Western blotting were employed to detect the expression of circ_0044556,miR-338-3p,and BRD4 protein in human TNBC cell line MDA-MB-231 and human normal breast epithelial cells MCF-10A.MDA-MB-231 cells were divided into NC group,si-NC group(transfected with si-NC),si-circ_0044556 group(transfected with si-circ_0044556),si-circ_0044556+inhibitor NC group(transfected with si-circ_0044556 and inhibitor NC),and si-circ_0044556+miR-338-3p inhibitor group(transfected with si-circ_0044556 andmiR-338-3p inhibitor).qRT-PCR was applied to detect the expression of circ_0044556 and miR-338-3p;Western blotting was used to detect the expression of BRD4,E-cadherin,N-cadherin and Vimentin;the CCK-8 assay was applied to detect cell proliferation;flow cytometry was applied to detect cell apoptosis;and Transwell assays were used to detect cell invasion and migration.Thirty nude mice were randomly divided into NC group(tail vein injection of normal saline),si-NC group(tail vein injection of LV-NC),si-circ_0044556 group(tail vein injection of LV-circ_0044556),si-circ_0044556+inhibitor NC group(tail vein injection of LV-circ_0044556 and antiagomir NC),and si-circ_0044556+miR-338-3p inhibitor group(tail vein injection of LV-circ_0044556 and antiagomir miR-338-3p),with 6 mice per group.A xenograft tumor model was constructed by subcutaneous injection of MDA-MB-231 cells into nude mice,and tumor volume and weight were measured.Results TargetScan prediction results showed that the downstream miRNA of circ_0044556 was miR-338-3p,and the downstream target gene of miR-338-3p might be BRD4.Compared with transfecting mimic NC,transfection with miR-338-3p mimic significantly reduced the luciferase activities of WT-circ_0044556(0.34±0.03 vs.1.00±0.15,P<0.05)and WT-BRD4(0.41±0.05 vs.1.05±0.13,P<0.05)in MDA-MB-231 cells.Compared with MCF-10A cells,the expression levels of circ_0044556 and BRD4 protein in MDA-MB-231 cells were significantly increased,while the expression level of miR-338-3p was significantly decreased(P<0.05).Compared with NC group and si-NC group,the expression levels of circ_0044556,the protein expression levels of BRD4,N-cadherin,and Vimentin,and the OD450 value in MDA-MB-231 cells of si-circ_0044556 group and si-circ_0044556+inhibitor NC group were significantly decreased(P<0.05),the number of migrated and invaded cells was significantly reduced(P<0.05),and the expression level of miR-338-3p,the protein expression level of E-cadherin,and the cell apoptosis rate in MDA-MB-231 cells were significantly increased(P<0.05);downregulation of miR-338-3p rescued the inhibitory effect of circ_0044556 knockdown on invasion,migration,and proliferation of MDA-MB-231 cells.Compared with NC group and si-NC group,the tumor volume and weight in si-circ_0044556 group and si-circ_0044556+inhibitor NC group were significantly decreased(P<0.05);compared with si-circ_0044556 group and si-circ_0044556+inhibitor NC group,the tumor volume and weight in si-circ_0044556+miR-338-3p inhibitor group were significantly increased(P<0.05).Conclusion circ_0044556 may promote the malignant biological behaviors of TNBC cells through the miR-338-3p/BRD4 axis.

Diabetic kidney disease(DKD)is a microvascular complication of diabetes mellitus with a complex pathogenesis.Recent studies have revealed that autophagy and ferroptosis,as two forms of programmed cell death,exhibit dynamic interactions in DKD:autophagy maintains homeostasis by eliminating damaged organelles,while ferroptosis is driven by iron-dependent lipid peroxidation.Imbalance between the two exacerbates renal injury.This review systematically summarizes the signaling pathways and key regulatory factors related to autophagy and ferroptosis,as well as their interaction mechanisms[such as nuclear receptor coactivator 4(NCOA4)-mediated ferritinophagy,clock autophagy,and lipid autophagy].It further elaborates the molecular network by which these processes synergistically regulate DKD progression.Additionally,the potential of modern pharmaceuticals and active components of traditional Chinese medicine to improve kidney injury by targeting autophagy and ferroptosis is discussed,proposing that targeting their cross-talk pathways may provide novel therapeutic strategies for DKD,aiming to lay a theoretical foundation for the development of targeted intervention strategies and precision therapeutic regimens.

Decidual natural killer(dNK)cells are the most abundant immune cells in the decidua.The functional acquisition during dNK cell development depends on NK cell education,a process in which the highly polymorphic killer cell immunoglobulin-like receptors(KIRs)and CD94/NKG2s expressed on dNK cells bind to major histocompatibility complex(MHC)class Ⅰmolecules expressed by extravillous trophoblast(EVT)cells.This interaction regulates the effector functions of NK cells.dNK cells participate in the establishment and maintenance of pregnancy by modulating immune tolerance at the maternal-fetal interface.Defects in dNK cell education leading to dNK dysfunction are potential pathological mechanisms underlying adverse pregnancy outcomes such as recurrent pregnancy loss(RPL).This review summarizes the characteristics of dNK cells,dNK cell education and its key associated molecules,and the pathological mechanisms by which poorly educated dNK cells contribute to RPL,aiming to offer insights for predicting and improving pregnancy outcomes in RPL patients associated with dNK cell abnormalities.

Objective:To investigate the predictive value of pre-infarction angina(PIA)combined with serum lipo-protein-associated phospholipase A2(Lp-PLA2)for no-reflow during primary percutaneous coronary interven-tion(PCI)in elderly patients with new-onset acute ST-segment elevation myocardial infarction(STEMI).Meth-ods:A total of 189 patients who hospitalized because of acute STEMI and underwent primary PCI within 12h in De-partment of Cardiology,Cangzhou People's Hospital between January 2018 and December 2022 were enrolled.Ac-cording to their TIMI blood flow during PCI,the patients were divided into no reflow group(n=42)and normal re-flow group(n=147).The baseline data were compared between two groups.Multivariate Logistic regression analy-sis was used to analyze the risk factors of no-reflow during PCI.The receiver operating characteristic(ROC)curve was plotted to evaluate the predictive value of PIA and Lp-PLA2 for no-reflow.Results:PI A occurred in 73 cases(38.6％),and no reflow occurred in 42 cases(22.2％)during primary PCI.Compared with patients in normal re-flow group,those in no reflow group had significant higher Lp-PLA2[(341.33±98.32)ng/ml vs.(261.95±75.21)ng/ml]and onset to reperfusion time[(7.02±1.28)h vs.(5.14±1.48)h],and significant lower incidence of PIA(23.8％ vs.42.9％)(P＜0.05 or＜0.01).Multivariate Logistic regression analysis showed that Lp-PLA2(OR=1.528,95％CI 1.028～2.030,P＜0.001),onset to reperfusion time(OR=2.602,95％CI 1.848～3.665,P＜0.001)were independent risk factors for no reflow during PCI in elderly STEMI patients,while PIA was an inde-pendent protective factor(OR=0.261,95％CI 0.101～0.671,P=0.005).The area under ROC curve of Lp-PLA2 combined PIA was 0.863(95％CI 0.806～0.909),which was significantly higher than those of Lp-PLA2[0.733(95％CI 0.664～0.794),Z=2.690,P=0.007]and PIA alone[0.609(95％CI 0.535～0.679),Z=5.657,P＜0.001].Conclusion:Pre-infarction angina has an important protective effect on no-reflow in STEMI patients.High Lp-PLA2 and absence of pre-infarction angina at admission may be good predictors of no-reflow during primary PCI in elderly patients with newly-onset acute STEMI,and it contributes to risk stratification of high risk patients.

OBJECTIVE: This study examines utilizes the advantages of machine learning algorithms to discern key determinants in prognosticate postoperative circulatory complications (PCCs) for older patients. METHODS: This secondary analysis of data from a randomized controlled trial involved 1,720 elderly participants in five tertiary hospitals in Beijing, China. Participants aged 60-90 years undergoing major non-cardiac surgery under general anesthesia. The primary outcome metric of the study was the occurrence of PCCs, according to the European Society of Cardiology and the European Society of Anaesthesiology diagnostic criteria. The analysis metrics contained 67 candidate variables, including baseline characteristics, laboratory tests, and scale assessments. RESULTS: Our feature selection process identified key variables that significantly impact patient outcomes, including the duration of ICU stay, surgery, and anesthesia; APACHE-II score; intraoperative average heart rate and blood loss; cumulative opioid use during surgery; patient age; VAS-Move-Median score on the 1st to 3rd day; Charlson comorbidity score; volumes of intraoperative plasma, crystalloid, and colloid fluids; cumulative red blood cell transfusion during surgery; and endotracheal intubation duration. Notably, our Random Forest model demonstrated exceptional performance with an accuracy of 0.9872. CONCLUSION We have developed and validated an algorithm for predicting PCCs in elderly patients by identifying key risk factors.
Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Cardiovascular Diseases/etiology* ; Machine Learning ; Postoperative Complications/etiology* ; Risk Factors ; Randomized Controlled Trials as Topic ; Secondary Data Analysis