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.

Cyclic GMP-AMP synthase (cGAS), a pivotal molecule in innate immunity, has emerged as a keypoint in interdisciplinary research at the intersection of basic immunology and tumor biology. As a cytosolic nucleic acid sensor, cGAS is primarily characterized by its capacity to recognize double-stranded DNA (dsDNA) in the cytosol. Upon binding to dsDNA, cGAS undergoes a conformational change that promotes its dimerization and subsequent enzymatic activation. Once activated, it catalyzes the synthesis of the second messenger 2',3'-cGAMP from ATP and GTP. cGAMP then binds to the adaptor protein STING, which resides on the endoplasmic reticulum (ER) membrane. The binding process triggers STING to traffic from the ER to the Golgi apparatus, where it is phosphorylated by the kinase TBK1. Phosphorylated STING serves as a docking site for the transcription factor IRF3, facilitating its phosphorylation by TBK1. Once phosphorylated, IRF3 forms dimers and translocates to the nucleus, where it drives the expression of type I interferons and pro-inflammatory cytokines, initiating a potent antimicrobial state. The DNA-sensing mechanism of cGAS is inherently non-selective regarding the origin of its ligand. It readily detects exogenous DNA from invading pathogens, thereby playing an indispensable role in host defense against microbial infections. However, this same mechanism also enables cGAS to recognize self-DNA that leaks from the nucleus or mitochondria into the cytosol under various cellular stress conditions. While critical for immunity, the recognition of self-dsDNA by cGAS can disrupt cellular homeostasis and trigger aberrant inflammatory responses. The loss of self-tolerance can precipitate or exacerbate the pathogenesis of autoimmune disorders such as systemic lupus erythematosus (SLE) and Aicardi-Goutières syndrome (AGS), highlighting the dual role of cGAS as both a sentinel for infection and a potential driver of autoimmune pathology. Notably, the subcellular localization of cGAS is not still. Increasing recent researches have revealed that cGAS is also abundant within the nucleus, challenging the traditional view of it solely as a cytosolic nucleic acid sensor. Within the nucleus, cGAS exhibits non-canonical functions that are distinct from its canonical immunological role. First, cGAS exists in a state of stringent immunological silence in the nucleus, with mechanisms involving its competitive binding to histones and its post-translational modifications which block the activation of cGAS enzymatic activity, thus, effectively preventing it from mounting an autoimmune attack on genomic DNA. Second, cGAS plays a critical role in maintaining genomic stability. Upon DNA damage, cGAS is rapidly recruited to the lesion site and participates in the DNA damage repair process. Moreover, under conditions of DNA replication stress, cGAS contributes to the stabilization of replication forks, preventing the cell from entering a state of uncontrolled hyper-replication. Consequently, in light of the dual role of cGAS in both immune regulation and tumor development, the development of small-molecule drugs targeting cGAS holds significant therapeutic promise. This review summarizes the structural characteristics of cGAS and its canonical function as a pattern recognition receptor in the cytosol, including the types of pathogens it recognizes and the autoimmune responses resulting from erroneous recognition of self-DNA. It then focuses on its emerging non-canonical functions within the nucleus, detailing its nucleocytoplasmic shuttling, the mechanisms underlying its nuclear immune quiescence, and its role in mediating DNA damage repair and replication fork stabilization. Finally, the review discusses the progress and application prospects of small-molecule drugs targeting cGAS for the treatment of autoimmune diseases and cancer.

Cyclic GMP-AMP synthase (cGAS), a pivotal molecule in innate immunity, has emerged as a keypoint in interdisciplinary research at the intersection of basic immunology and tumor biology. As a cytosolic nucleic acid sensor, cGAS is primarily characterized by its capacity to recognize double-stranded DNA (dsDNA) in the cytosol. Upon binding to dsDNA, cGAS undergoes a conformational change that promotes its dimerization and subsequent enzymatic activation. Once activated, it catalyzes the synthesis of the second messenger 2',3'-cGAMP from ATP and GTP. cGAMP then binds to the adaptor protein STING, which resides on the endoplasmic reticulum (ER) membrane. The binding process triggers STING to traffic from the ER to the Golgi apparatus, where it is phosphorylated by the kinase TBK1. Phosphorylated STING serves as a docking site for the transcription factor IRF3, facilitating its phosphorylation by TBK1. Once phosphorylated, IRF3 forms dimers and translocates to the nucleus, where it drives the expression of type I interferons and pro-inflammatory cytokines, initiating a potent antimicrobial state. The DNA-sensing mechanism of cGAS is inherently non-selective regarding the origin of its ligand. It readily detects exogenous DNA from invading pathogens, thereby playing an indispensable role in host defense against microbial infections. However, this same mechanism also enables cGAS to recognize self-DNA that leaks from the nucleus or mitochondria into the cytosol under various cellular stress conditions. While critical for immunity, the recognition of self-dsDNA by cGAS can disrupt cellular homeostasis and trigger aberrant inflammatory responses. The loss of self-tolerance can precipitate or exacerbate the pathogenesis of autoimmune disorders such as systemic lupus erythematosus (SLE) and Aicardi-Goutières syndrome (AGS), highlighting the dual role of cGAS as both a sentinel for infection and a potential driver of autoimmune pathology. Notably, the subcellular localization of cGAS is not still. Increasing recent researches have revealed that cGAS is also abundant within the nucleus, challenging the traditional view of it solely as a cytosolic nucleic acid sensor. Within the nucleus, cGAS exhibits non-canonical functions that are distinct from its canonical immunological role. First, cGAS exists in a state of stringent immunological silence in the nucleus, with mechanisms involving its competitive binding to histones and its post-translational modifications which block the activation of cGAS enzymatic activity, thus, effectively preventing it from mounting an autoimmune attack on genomic DNA. Second, cGAS plays a critical role in maintaining genomic stability. Upon DNA damage, cGAS is rapidly recruited to the lesion site and participates in the DNA damage repair process. Moreover, under conditions of DNA replication stress, cGAS contributes to the stabilization of replication forks, preventing the cell from entering a state of uncontrolled hyper-replication. Consequently, in light of the dual role of cGAS in both immune regulation and tumor development, the development of small-molecule drugs targeting cGAS holds significant therapeutic promise. This review summarizes the structural characteristics of cGAS and its canonical function as a pattern recognition receptor in the cytosol, including the types of pathogens it recognizes and the autoimmune responses resulting from erroneous recognition of self-DNA. It then focuses on its emerging non-canonical functions within the nucleus, detailing its nucleocytoplasmic shuttling, the mechanisms underlying its nuclear immune quiescence, and its role in mediating DNA damage repair and replication fork stabilization. Finally, the review discusses the progress and application prospects of small-molecule drugs targeting cGAS for the treatment of autoimmune diseases and cancer.

Objective: To identify early clinical predictors associated with dysphagia and delayed swallowing recovery in patients with traumatic brain injury (TBI). Methods: In this retrospective study, we enrolled adult TBI patients admitted to the rehabilitation unit of a tertiary medical center between June 2019 and June 2023. Data on baseline characteristics, neurological status, imaging findings, and rehabilitation-related variables were collected. Swallowing function was assessed using two indicators: (1) nasogastric (NG) tube retention and (2) the Functional Oral Intake Scale (FOIS) scores at 1, 4, and 12 weeks post-injury. Regression analyses were conducted to identify predictors associated with dysphagia and swallowing recovery. Results: A total of 160 patients were included. At 1 week post-injury, longer intensive care unit (ICU) stay, poor initial sitting balance and use of sedative medication in ICU were associated with NG tube retention. At 4 weeks, lower initial Rancho Los Amigos Scale (RLAS) scores, immobility-related complications, longer hospitalization, and temporal lobe hematomas were associated with persistent NG tube dependence. By 12 weeks, older age, delayed ability to follow commands, and poor initial sitting balance remained associated with NG tube retention. FOIS outcomes were also associated with older age, delayed time to follow commands, impaired initial sitting balance, prolonged ICU stay, temporal lobe hematomas, lower initial RLAS scores, immobility-related complications, prolonged endotracheal tube placement and extended hospital stays. Conclusion Impaired cognitive status, poor physical function, immobility-related complications, and temporal lobe hematomas were key factors associated with dysphagia and delayed oral intake in individuals with TBI.

BACKGROUND:With the development of computer-aided design and computer-aided manufacturing technology,zirconia abutments with a titanium base are widely used in clinic due to its good application advantages,but there are still some problems and a lack of consensus design standards. OBJECTIVE:To review the fabrication methods of Ti-base zirconia abutment,and the effect of abutment connection,emergence design,abutment angle,and bonding on mechanical properties of Ti-base zirconia abutment. METHODS:Relevant literature published from 2010 to 2023 was searched in CNKI and PubMed databases with the search terms"zirconia abutment,titanium base"in Chinese and English,respectively.The search time limit was extended for some classical literature.The relevant literature was obtained through inclusion and exclusion criteria,and 57 eligible documents were included for review. RESULTS AND CONCLUSION:It is recommended that clinicians try to select antirotational titanium bases or rotational titanium bases with a Morse taper connection.Implants should be placed in the correct axial angulation of not more than 15° or with an inclination to the palatal side when using angled zirconia abutments.When a≥30° labial inclination is followed for implant placement,the bite force must be decreased effectively to reduce the risk of mechanical and biological complications of implants,abutments,and prostheses.Ti-base zirconia abutments with a higher gingival height should be selected,and its restorative angle should not exceed 40°.Multilink Hybrid Abutment could be the first choice for extraoral bonding of zirconia abutment to titanium bases.

Background The high work intensity and possible subsequently increased susceptibility to occupational hazards of calcium carbide plants may lead to hypertension in workers, but there are few studies on the relationship between occupational hazard exposure and hypertension in workers involving the production process of calcium carbide. Objective To explore the influence of occupational hazards on the incidence of hypertension in calcium carbide plants. Methods Using historical cohort design, the employees of a calcium carbide factory in the western part of Inner Mongolia Autonomous Region were selected as research subjects. According to the pre-determined inclusion and exclusion criteria, the study population comprised an exposure group of 377 employees (including furnace workers, inspection workers, and maintenance workers) exposed to dust, noise & carbon monoxide, and a control group of 388 employees (including central control workers, electricians, and administrative personnel) without above-mentioned exposure. The total sample size was 765 participants. The follow-up period was from April 2011 to October 2022, and the study endpoint was defined as the conclusion of the follow-up period or diagnosed hypertension in annual occupational health examination. Information on general demographic characteristics, living habits, and work status was collected from all study subjects. Cox proportional hazards regression model was used to analyze the association between occupational hazard exposure and the risk of hypertension among the calcium carbide plant employees. Results The average age, mean systolic and diastolic blood pressure, proportion of males, smoking rate, and alcohol consumption rate in the exposure group were higher than those in the control group (P<0.05). Compared to baseline, both systolic and diastolic blood pressure levels increased in the exposure group and the control group at the end of the follow-up (P<0.05). At the end of the follow-up, the average differences between systolic/ diastolic blood pressure and baseline values in the exposure group were higher than those in the control group (P<0.05). During the follow-up period, a total of 223 cases of hypertension occurred, with a total follow-up of 2785 person-years, resulting in an incidence density of 8007.18 per 100000 person-years, an average age of onset of (35.90±8.22) years, and an average working age of onset of (2.69±1.97) years. The incidence density in the exposure group was 128.71% higher than that in the control group, and the risk of hypertension in the exposure group was 2.115 times that of the control group. The risk of hypertension was 2.199 times higher for men than for women, 1.344 times higher for those aged 30 and above than for those under 30, 1.546 times higher for smokers than for non-smokers, and 1.750 times higher for drinking workers than for non-drinking ones. The results of Cox proportional hazards regression modeling indicated that the hazard ratio (95%CI) of hypertension among the employees exposed to dust, noise, and carbon monoxide was 2.254 (1.703, 2.982), 1.594 (1.107, 2.295), and 1.567 (1.079, 2.274), respectively, when different covariates (gender, age, smoking, and alcohol consumption) were included. The results of Log-rank test showed that there were statistically significant differences in the distribution of disease-free survival between the exposure group and the control group (P<0.05). Conclusion Occupational exposures to dust, noise, and carbon monoxide may increase the risk of hypertension among calcium carbide plant workers.

Objective:To investigate the miRNA-mRNA regulatory network in a rat model of Tourette syndrome(TS)using transcriptomic technology and to screen key signaling pathways and potential traditional Chinese medicine(TCM)candidates for intervention.Methods:A TS rat model was established using iminodipropionitrile(IDPN).RNA sequencing was performed to identify differentially expressed miRNAs and mRNAs in the brain tissues of TS rats.Bioinformatics analysis was applied to construct interaction networks,and network pharmacology was further employed to screen potential TCM compounds.Results:After 7 days of IDPN modeling,the model group exhibited motor and stereotypical behavioral changes,with behavioral scores greater than 3 points.Hema toxylin-eosin(HE)staining revealed irregular neuronal nuclear morphology,uneven chromatin distribution,nuclear pyknosis,and increased glial cell density.KEGG enrichment analysis identified key pathways:calcium signaling pathway,neuroactive ligand-receptor interaction,p53 signaling pathway,ECM-receptor interaction,and TGF-β signaling pathway.miR-125a-3p,miR-106-3p,and miR-760-3p were identified as pivotal miRNAs.Potential TCM candidates included Ajuga decumbens,Acanthopanax bark,Codonopsis pilosula,Stephania japonica,Os Draconis,Notopterygium root,Siraitia grosvenorii,Zanthoxylum nitidum root,Morinda officinalis,and Corydalis yanhusuo.Conclusion:The miRNAs miR-106-3p,miR-125a-3p,and miR-760-3p may mediate TS pathogenesis by altering critical signaling networks,including the calcium signaling pathway,neuroactive ligand-receptor interaction,and ECM-receptor interaction pathways,leading to neuroimmune inflammation and dopaminergic system dysregulation.TCM compounds such as Corydalis yanhusuo and Ajuga decumbens may exert therapeutic effects through multi-component synergistic regulation of these miRNAs and downstream pathways.

Objective:Analyse the factors affecting whether the first two batches of centralized volume-based purchase of Proprietary Chinese Medicine were selected,the price difference and the rate of reduction,so as to provide a basis for improving the policy of centralized volume-based purchase of Proprietary Chinese Medicine.Methods:The first two batches of centralized volume-based purchase of Proprietary Chinese Medicine were selected for the study.Logistic regression was used to analyse the influencing factors of whether the selection was won or not.Multiple linear regression was used to analyse the influencing factors of price difference/reduction after being selected.Results:Proprietary Chinese Medicine with a high degree of acceptance by medical institutions and belonging to the category of essential medicines have a higher probability of being selected.The probability of selected products in the first batch of centralised purchase is greater for enterprises with a market share of more than 50%.In the first batch of centralized volume-based purchase of Proprietary Chinese Medicine,the price difference of injections and medicines belonging to the catalogue of essential medicines is greater.Price reductions were greater for those with low market share,low recognition by medical institutions,and a large number of enterprises in the A-competition unit and the same competition unit.In the second batch of centralised volume-based purchase of Proprietary Chinese Medicine,the price difference is greater for injections,and those with qualifications for the production of Chinese herbal medicines.the price reduction is greater in the B competitive unit.Conclusion:The centralized volume-based purchase of Proprietary Chinese Medicine has been both'quality-assured'and'price-reduced'.The centralized volume-based purchase of Proprietary Chinese Medicine has been gradually improved,and the tilt towards large enterprises has been reduced,so that the centralized volume-based purchase of Proprietary Chinese Medicine can achieve a'bottom price'.However,it is still necessary to start from the quality of identification,fair competition,and so on,and the centralized volume-based purchase of Proprietary Chinese Medicine fully linked to promote the centralized purchase of Traditional Chinese Medicine Decoction Pieces to a stable and far-reaching.

AIM To compare total sugar,total protein,total phenol,total flavonoid,calycosin-7-O-β-D-glucoside,liquiritin,lobetyolin,quercetin,isoferulic acid,hesperidin,glycyrrhizic acid contents and their antioxidant activities,hypoglycemic activities of big honey pill,small honey pill,water pill,concentrated pill,granule,mixture and decoction of Buzhong Yiqi Recipe.METHODS Anthraquinone-sulfuric acid method,Coomassie brilliant blue method,Folin-phenol colorimetry method,sodium nitrite-aluminum nitrate method and HPLC were adopted in the content determination of total sugar,total protein,total phenol,total flavonoid and seven constituents,respectively,after which the scavenging capacities,reducing powers on DPPH·free radical,ABTS+free radical,hydroxyl free radical,and inhibition capacity on α-glucosidase activity were detected.Subsequently,correlation analysis was performed.RESULTS Total sugar,total protein,total phenol and total flavonoid contents demonstrated significant differences among different dosage forms(P＜0.05,P＜0.01).Calycosin-7-O-β-D-glucoside,glycyrrhizin,codonoside and quercetin displayed the highest contents in the decoction,while those of isoferulic acid,hesperidin and glycyrrhizin were observable in the mixture.The water pill exhibited the strongest antioxidant activity,while those of the concentrated pill and mixture were weak;the big honey pill exhibited the strongest hypoglycemic activity,while that of the decoction was the weakest.Total protein,total phenol,total flavonoid and liquiritin contents displayed significant positive correlations between antioxidant activity(P＜0.05,P＜0.01),while hesperidin content displayed significant negative correlation between the latter(P＜0.05);total protein,calycosin-7-O-β-D-glucoside,codonoside and quercetin contents displayed significant negative correlations between hypoglycemic activity(P＜0.05,P＜0.01).CONCLUSION Active constituent contents and their biological activities of Buzhong Yiqi Recipe with different dosage forms exist differences,total sugar,total protein,total flavonoids,calycosin-7-O-β-D-glucoside,licorice glycoside,hesperidin,codonoside and quercetin can be taken as quality control indices for this prescription.