BACKGROUND:Tumor microenvironment can participate in the occurrence and development of gastric cancer and promote chemotherapy resistance in various ways.Among them,the tumor microenvironment crosstalk mediated by exosomal miRNAs can induce matrix reprogramming,participate in tumor heterogeneity,and form a microenvironment conducive to tumor proliferation,migration,invasion,immune escape,and chemotherapy resistance.OBJECTIVE:To review the mechanism of action of exosomal miRNAs in the microenvironment of gastric cancer and its application in the diagnosis and prognosis assessment of gastric cancer in recent years.METHODS:"Exosomal miRNAs,gastric cancer,angiogenesis,apoptosis,proliferation,migration,autophagy,invasion,immune response,chemotherapy resistance,biomarker"for English search terms and"exosomal miRNAs,gastric cancer"for Chinese search terms were searched in PubMed and CNKI databases.The search period was from 2017 to 2024.After preliminary screening by reading the title and abstract,the articles with poor correlation and repeated content were excluded,and 77 articles were finally included for induction and discussion.RESULTS AND CONCLUSION:(1)Exosomes,as important carriers of intercellular information exchange,can carry a variety of information substances such as miRNA,and realize intercellular signal transmission through three ways:activation of cell surface receptors on target cells,fusion with the plasma membrane of recipient cells,and endocytosis.(2)Exosomal miRNAs play an important role in the progression of gastric cancer by regulating the proliferation,apoptosis,autophagy,angiogenesis,invasion and metastasis,immune response,and the formation of drug resistance of gastric cancer cells.(3)The interaction between miRNAs and target mRNA and its regulatory network are widely found in tumorigenesis and human cancer development.Different types of exosomal miRNAs have different effects on the regulation of apoptosis of gastric cancer cells,and the effects of different exosomal miRNAs on apoptosis related proteins and pathways of gastric cancer cells are screened.Rational use of its inducers or inhibitors can regulate the apoptosis level of gastric cancer cells.(4)Exosomal miRNAs of different cell origin play an important role in the establishment of tumor microenvironment,angiogenesis,immune response,and chemotherapy resistance by inducing M1-polarized macrophages to M2 type.(5)Exosomal miRNAs exist extensively and stably in blood and other body fluids,and their differential expression in patients with gastric cancer can be used as a basis for diagnosis,prognosis,and treatment of patients with gastric cancer.Currently,exosomal miRNAs widely studied as biomarkers include miR-379-5p,miR-590-5p,miR-29s,miR-21,etc.Among them,the sensitivity and specificity of miR-590-5p are 63.7％and 86％,respectively.The expression level of miR-590-5p is closely related to the overall survival rate and the depth of invasion of gastric cancer patients.(6)The design of exosomal miRNAs mimics or inhibitors and their targeted delivery to the tumor site using nano-delivery vectors(such as exosomes and liposomes)to restore the normal level of miRNAs may be a new strategy for the treatment of gastric cancer.(7)Although exosomal miRNAs have great application prospects in the diagnosis and treatment of gastric cancer patients,there are still some problems to be solved.For example,the potential targets and mechanisms of exosomal miRNAs have not been fully explored,and their effectiveness and safety need to be further confirmed.The extraction and purification of exosomes lack standardized large-scale preparation processes.

BACKGROUND:At present,chemotherapeutic drugs are mainly used for the treatment of tumors,but there are problems such as drug resistance and adverse reactions.The exosome drug delivery system not only avoids the toxicity of synthetic nanoparticles,but also increases the bioavailability and biocompatibility of the drugs.It can be modified by biological,physical,and chemical methods to form a new type of nano-drug delivery platform.OBJECTIVE:To review the construction strategy of exosome drug delivery system,the application status of exosome drug delivery system in tumor diseases and the current challenges.METHODS:PubMed and CNKI were searched with"exosomal,tumor,microvesicle,extracellular vesicles,engineered,therapeutics,characterization,isolation,drug delivery,targeting,modification strategies,physics,chemistry,biology"as English search terms and"exosomes,drug delivery,tumor"as Chinese search terms.A total of 132 articles were included for in-depth induction and discussion.RESULTS AND CONCLUSION:(1)The technical methods of exosome extraction,including ultracentrifugation,filtration,and kit extraction,can efficiently isolate exosomes,but the process is complicated and time-consuming,and large-scale extraction of exosomes cannot be achieved.(2)Engineered exosomes can be divided into four categories:gene editing engineering,which improves function through genetic modification;endogenous engineering,using inflammatory factors and other pretreatment to enhance drug delivery;exogenously engineered to encapsulate drugs directly in exosomes;hybrid engineering,combining exosomes with lipid nanoparticles to form new particles.Some have entered clinical trials for cancer treatment,but most are at an early stage.In contrast,genetically engineered exosomes are considered as an important direction for future drug delivery due to their high targeting and customization potential.(3)There are still many limitations to realize the clinical transformation of engineered exosomes.At the technical level,large-scale production,purification,and drug loading efficiency are urgent to be solved.In production,high cost and batch stability affect its popularity.In terms of safety,immunogenicity and potential toxicity need to be comprehensively evaluated.Furthermore,the imperfect regulatory policies and the complexity of the approval process also constitute obstacles to its clinical translation.(4)In the future,it is necessary to promote the clinical translation process through technical innovation,cost control,safety improvement,and policy improvement.

BACKGROUND:Tumor microenvironment can participate in the occurrence and development of gastric cancer and promote chemotherapy resistance in various ways.Among them,the tumor microenvironment crosstalk mediated by exosomal miRNAs can induce matrix reprogramming,participate in tumor heterogeneity,and form a microenvironment conducive to tumor proliferation,migration,invasion,immune escape,and chemotherapy resistance.OBJECTIVE:To review the mechanism of action of exosomal miRNAs in the microenvironment of gastric cancer and its application in the diagnosis and prognosis assessment of gastric cancer in recent years.METHODS:"Exosomal miRNAs,gastric cancer,angiogenesis,apoptosis,proliferation,migration,autophagy,invasion,immune response,chemotherapy resistance,biomarker"for English search terms and"exosomal miRNAs,gastric cancer"for Chinese search terms were searched in PubMed and CNKI databases.The search period was from 2017 to 2024.After preliminary screening by reading the title and abstract,the articles with poor correlation and repeated content were excluded,and 77 articles were finally included for induction and discussion.RESULTS AND CONCLUSION:(1)Exosomes,as important carriers of intercellular information exchange,can carry a variety of information substances such as miRNA,and realize intercellular signal transmission through three ways:activation of cell surface receptors on target cells,fusion with the plasma membrane of recipient cells,and endocytosis.(2)Exosomal miRNAs play an important role in the progression of gastric cancer by regulating the proliferation,apoptosis,autophagy,angiogenesis,invasion and metastasis,immune response,and the formation of drug resistance of gastric cancer cells.(3)The interaction between miRNAs and target mRNA and its regulatory network are widely found in tumorigenesis and human cancer development.Different types of exosomal miRNAs have different effects on the regulation of apoptosis of gastric cancer cells,and the effects of different exosomal miRNAs on apoptosis related proteins and pathways of gastric cancer cells are screened.Rational use of its inducers or inhibitors can regulate the apoptosis level of gastric cancer cells.(4)Exosomal miRNAs of different cell origin play an important role in the establishment of tumor microenvironment,angiogenesis,immune response,and chemotherapy resistance by inducing M1-polarized macrophages to M2 type.(5)Exosomal miRNAs exist extensively and stably in blood and other body fluids,and their differential expression in patients with gastric cancer can be used as a basis for diagnosis,prognosis,and treatment of patients with gastric cancer.Currently,exosomal miRNAs widely studied as biomarkers include miR-379-5p,miR-590-5p,miR-29s,miR-21,etc.Among them,the sensitivity and specificity of miR-590-5p are 63.7％and 86％,respectively.The expression level of miR-590-5p is closely related to the overall survival rate and the depth of invasion of gastric cancer patients.(6)The design of exosomal miRNAs mimics or inhibitors and their targeted delivery to the tumor site using nano-delivery vectors(such as exosomes and liposomes)to restore the normal level of miRNAs may be a new strategy for the treatment of gastric cancer.(7)Although exosomal miRNAs have great application prospects in the diagnosis and treatment of gastric cancer patients,there are still some problems to be solved.For example,the potential targets and mechanisms of exosomal miRNAs have not been fully explored,and their effectiveness and safety need to be further confirmed.The extraction and purification of exosomes lack standardized large-scale preparation processes.

BACKGROUND:At present,chemotherapeutic drugs are mainly used for the treatment of tumors,but there are problems such as drug resistance and adverse reactions.The exosome drug delivery system not only avoids the toxicity of synthetic nanoparticles,but also increases the bioavailability and biocompatibility of the drugs.It can be modified by biological,physical,and chemical methods to form a new type of nano-drug delivery platform.OBJECTIVE:To review the construction strategy of exosome drug delivery system,the application status of exosome drug delivery system in tumor diseases and the current challenges.METHODS:PubMed and CNKI were searched with"exosomal,tumor,microvesicle,extracellular vesicles,engineered,therapeutics,characterization,isolation,drug delivery,targeting,modification strategies,physics,chemistry,biology"as English search terms and"exosomes,drug delivery,tumor"as Chinese search terms.A total of 132 articles were included for in-depth induction and discussion.RESULTS AND CONCLUSION:(1)The technical methods of exosome extraction,including ultracentrifugation,filtration,and kit extraction,can efficiently isolate exosomes,but the process is complicated and time-consuming,and large-scale extraction of exosomes cannot be achieved.(2)Engineered exosomes can be divided into four categories:gene editing engineering,which improves function through genetic modification;endogenous engineering,using inflammatory factors and other pretreatment to enhance drug delivery;exogenously engineered to encapsulate drugs directly in exosomes;hybrid engineering,combining exosomes with lipid nanoparticles to form new particles.Some have entered clinical trials for cancer treatment,but most are at an early stage.In contrast,genetically engineered exosomes are considered as an important direction for future drug delivery due to their high targeting and customization potential.(3)There are still many limitations to realize the clinical transformation of engineered exosomes.At the technical level,large-scale production,purification,and drug loading efficiency are urgent to be solved.In production,high cost and batch stability affect its popularity.In terms of safety,immunogenicity and potential toxicity need to be comprehensively evaluated.Furthermore,the imperfect regulatory policies and the complexity of the approval process also constitute obstacles to its clinical translation.(4)In the future,it is necessary to promote the clinical translation process through technical innovation,cost control,safety improvement,and policy improvement.

Objective·To investigate an optimal severe periodontitis mouse model by comparing two induction methods:simple ligature and ligature combined with injection of Porphyromonas gingivalis lipopolysaccharide(P.g.LPS).Methods·Fifteen C57BL/6 mice were divided into three groups:a healthy control group,a simple ligature-induced periodontitis group,and a ligature combined with P.g.LPS injection-induced periodontitis group.After 14 d,the following evaluations were conducted:tooth mobility and probing depth under a stereomicroscope;alveolar bone resorption[bone volume fraction,bone mineral density,the distance from the cemento-enamel junction(CEJ)to the alveolar bone crest(ABC),and the area between CEJ and ABC]analyzed via micro computed tomography(Micro-CT)and stereomicroscopic examination.The serum levels of inflammatory cytokines interleukin-1β(IL-1β)and tumor necrosis factor-α(TNF-α)were assessed by enzyme-linked immunosorbent assay(ELISA).Results·Compared with the simple ligature group,mice in the ligature with P.g.LPS injection group exhibited significantly increased tooth mobility[(2.20±0.45)vs(1.40±0.55)]and probing depth[(1.05±0.21)mm vs(0.58±0.39)mm],with statistically significant differences(P＜0.05).The ligature with P.g.LPS injection group also demonstrated significantly reduced bone volume fraction[(16.44%±3.35%)vs(28.97%±7.90%)]and bone mineral density[(0.42±0.04)g/cm3 vs(0.55±0.08)g/cm3],as well as increased distance from CEJ to ABC[(0.88±0.03)mm vs(0.74±0.12)mm]and area between CEJ and ABC[(0.34±0.01)mm2 vs(0.30±0.02)mm2],all with statistically significant differences(all P＜0.05).Additionally,serum levels of TNF-α and IL-1β were significantly elevated in the ligature with P.g.LPS injection group compared to the simple ligature group(both P＜0.05).Conclusion·The method of ligature combined with continuous P.g.LPS injection is more effective for constructing a severe periodontitis mouse model,making it suitable for studying the progression and treatment of severe periodontitis.

BACKGROUND:Troxerutin has been found to have a significant ameliorative effect on brain disorders,but there are fewer studies on the effects of troxerutin on the treatment of cerebral infarction and on neuronal cells. OBJECTIVE:To investigate the mechanism by which troxerutin regulates nuclear factor-κB signaling pathway to reduce brain injury and neuronal apoptosis in cerebral infarction rats. METHODS:Fifty clean grade rats were randomized into healthy group,model group,and troxerutin+nuclear factor-κB agonist group,troxerutin group,and nuclear factor-κB inhibitor group.Except for the healthy group,all other groups were used to establish a rat model of cerebral infarction by arterial ligation.The healthy and model groups were treated once a day with an equal amount of physiological saline by gavage.The troxerutin+nuclear factor-κB agonist group was intervened with 72 mg/kg troxerutin by gavage+20 mg/kg RANK intraperitoneally.The troxerutin group was treated with 72 mg/kg troxerutin by gavage.The nuclear factor κB inhibitor group was intervened intraperitoneally with 120 mg/kg nuclear factor κB inhibitor pyrrolidine disulfiram.Administration in each group was given once a day for 30 continuous days.Zea-longa was used to detect neurological damage in rats,hematoxylin-eosin staining was used to observe pathological changes,TUNEL was used to detect neuronal apoptosis,and immunoblotting and PCR were used to detect the expression of nuclear factor-κB p65 and nuclear factor-κB p50 at protein and mRNA levels,respectively. RESULTS AND CONCLUSION:Compared with the healthy group,the neurological function score,neuronal apoptosis rate,nuclear factor-κB p65,nuclear factor-κB p50 mRNA and protein expression levels were elevated in the model group(P＜0.05).Compared with the model group,the neurological function score,neuronal apoptosis rate,nuclear factor-κB p65 and nuclear factor-κB p50 mRNA and protein expression levels were decreased in the troxerutin+nuclear factor-κB agonist group(P＜0.05).Compared with the troxerutin+nuclear factor-κB agonist group,the neurological function score,neuronal apoptosis rate,nuclear factor-κB p65 and nuclear factor-κB p50 mRNA and protein expression levels were reduced in the troxerutin group and nuclear factor-κB inhibitor group(P＜0.05).In addition,there was no difference between the troxerutin group and the nuclear factor-κB inhibitor group(P＞0.05).In the model group,there was a large number of cytoplasmic vacuolation,obvious edema and necrosis,and a large number of inflammatory cell infiltrations.In the troxerutin+nuclear factor-κB agonist,the swelling of brain tissue was reduced,and reticulate structures and condensed cells were reduced,still with some edema.In the troxerutin group and nuclear factor-κB inhibitor group,brain tissue swelling,neuronal edema degeneration,cytoplasmic vacuolation and neuronal nucleus consolidation were reduced,and the inflammatory cell infiltration was significantly decreased.To conclude,troxrutin can reduce the expression of neurological impairment,inhibit neuronal apoptosis and improve the pathological injury of brain tissue in rats with cerebral infarction,and its mechanism of action may be related to the modulation of nuclear factor-κB expression and related signaling pathways.

Objective:To investigate the efficacy and safety of venetoclax and azacitidine combined with GHA (human granulocyte colony stimulating factor, homoharringtonine and low-dose cytarabine) priming regimen in treatment of patients with relapsed/refractory acute myeloid leukemia.Methods:A retrospective case series study was conducted. Twenty-three patients with relapsed/refractory acute myeloid leukemia (non-acute promyelocytic leukemia) who received treatment with the combination of venetoclax and azacitidine with GHA priming regimen at the Second Affiliated Hospital of Xi'an Jiaotong University from October 2020 to July 2024 were selected, and the treatment efficacy, minimal residual disease (MRD)-negative rate in patients with comprehensive complete remission (cCR) (including complete remission, complete remission with partial hematologic recovery and complete remission with incomplete hematologic recovery) and the adverse reactions were analyzed; patients were followed-up, and their overall survival (OS) was analyzed by using Kaplan-Meier method.Results:The median age of the 23 patients was 60 years (range: 21-79 years), including 10 males and 13 females. The cCR rate for 1 course of treatment was 52.2% (12/23), with 4 cases of MRD negative among cCR patients; 5 cases received 2 courses of treatment, with 3 cases achieving cCR, of which 2 cases were MRD negative; 2 cases received 3 courses of treatment, with 1 case achieving complete remission with incomplete hematologic recovery. Six patients underwent allogeneic hematopoietic stem cell transplantation. The patients were followed up until July 31, 2024, and the median follow-up period was 5.3 months (range: 1.1-41.7 months). Ten cases survived, 12 cases died, 1 case was lost to follow-up, and the median OS time of 23 patients was 7.9 months. The 6-month OS rate was 60.2% (95% CI: 42.7%-84.8%), and the 12-month OS rate was 44.6% (95% CI: 26.8%-74.3%). Common adverse reactions during treatment included infection [69.6% (16/23)], nausea [56.5% (13/23)], febrile neutropenia [52.2% (12/23)], bleeding [52.2% (12/23)], vomiting [34.8% (8/23)], and pneumonia [34.8% (8/23)]. Conclusions:The combination of vinaclotide and azacitidine with GHA priming regimen has certain efficacy and good safety in the treatment of relapsed/refractory acute myeloid leukemia.

Neutrophil extracellular traps (NETs), intricate reticular structures released by activated neutrophils, play a pivotal regulatory role in the pathogenesis of malignant tumors. Lung cancer is one of the most prevalent malignancies globally, with persistently high incidence and mortality rates. Recent studies have revealed that NETs dynamically modulate the tumor microenvironment through unique pathological mechanisms, exhibiting complex immunoregulatory characteristics during the progression of lung cancer, and this discovery has increasingly become a focal point in tumor immunology research. This paper provides a comprehensive review of the latest advancements in NETs research related to lung cancer, offering an in-depth analysis of their impact on lung cancer progression, their potential diagnostic value, and the current state of research on targeting NETs for lung cancer prevention and treatment. The aim is to propose novel strategies to enhance therapeutic outcomes and improve the prognosis for lung cancer patients.
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Extracellular Traps/immunology* ; Humans ; Lung Neoplasms/metabolism* ; Neutrophils/metabolism* ; Animals ; Tumor Microenvironment

Objective·To investigate an optimal severe periodontitis mouse model by comparing two induction methods:simple ligature and ligature combined with injection of Porphyromonas gingivalis lipopolysaccharide(P.g.LPS).Methods·Fifteen C57BL/6 mice were divided into three groups:a healthy control group,a simple ligature-induced periodontitis group,and a ligature combined with P.g.LPS injection-induced periodontitis group.After 14 d,the following evaluations were conducted:tooth mobility and probing depth under a stereomicroscope;alveolar bone resorption[bone volume fraction,bone mineral density,the distance from the cemento-enamel junction(CEJ)to the alveolar bone crest(ABC),and the area between CEJ and ABC]analyzed via micro computed tomography(Micro-CT)and stereomicroscopic examination.The serum levels of inflammatory cytokines interleukin-1β(IL-1β)and tumor necrosis factor-α(TNF-α)were assessed by enzyme-linked immunosorbent assay(ELISA).Results·Compared with the simple ligature group,mice in the ligature with P.g.LPS injection group exhibited significantly increased tooth mobility[(2.20±0.45)vs(1.40±0.55)]and probing depth[(1.05±0.21)mm vs(0.58±0.39)mm],with statistically significant differences(P＜0.05).The ligature with P.g.LPS injection group also demonstrated significantly reduced bone volume fraction[(16.44%±3.35%)vs(28.97%±7.90%)]and bone mineral density[(0.42±0.04)g/cm3 vs(0.55±0.08)g/cm3],as well as increased distance from CEJ to ABC[(0.88±0.03)mm vs(0.74±0.12)mm]and area between CEJ and ABC[(0.34±0.01)mm2 vs(0.30±0.02)mm2],all with statistically significant differences(all P＜0.05).Additionally,serum levels of TNF-α and IL-1β were significantly elevated in the ligature with P.g.LPS injection group compared to the simple ligature group(both P＜0.05).Conclusion·The method of ligature combined with continuous P.g.LPS injection is more effective for constructing a severe periodontitis mouse model,making it suitable for studying the progression and treatment of severe periodontitis.

Colorectal cancer(CRC)is the third leading cause of cancer death in the world,and the incidence of colorectal cancer is also increasing year by year,and the treatment options such as radiotherapy,chemotherapy and surgical removal of cancerous sites are not ideal,so there is an urgent need to find a new treatment strategy and solution.The adjuvant treatment of colorectal cancer with traditional Chinese medicine has the characteristics of multi-target,multi-level,multi-link and overall regulation,which plays an increasingly important role in tumor treatment and has become a hot field for anti-tumor drug screening.Skullcap has been widely studied as one of the main drugs adjuvant to treat colorectal cancer by traditional Chinese medicine.This paper reviews the anti-colorectal cancer effect of skullcap and its active ingredients and the current research progress,aiming to provide the background information and the reference for the treatment of colorectal cancer.