Idiopathic pulmonary fibrosis(IPF) is a chronic progressive interstitial lung disease characterized by a complex pathogenesis and limited treatment options. Although studies have indicated that lipid metabolism dysregulation is associated with the progression of IPF, the core regulatory mechanisms remain unclear. By integrating RNA sequencing data from the GEO database, we identified four key genes related to lipid metabolism: peroxisome proliferator-activated receptor gamma(PPARG), secreted phosphoprotein 1(SPP1), caspase 3(CASP3), and platelet endothelial cell adhesion molecule 1(PECAM1). Further validation using single-cell RNA sequencing revealed the cell-specific expression patterns of these genes. The results found that PPARG was significantly downregulated in alveolar macrophages while SPP1 was significantly upregulated. Mechanistic studies indicated that PPARG negatively regulated SPP1 expression, and the interaction between SPP1 and cluster of differentiation 44(CD44) activated intercellular signaling pathways that promoted fibrosis. Through network pharmacology and molecular docking, it was predicted that the bioactive components of the traditional Chinese medicine formula, namely Buyang Huanwu Decoction may target PPARG to modulate lipid metabolism pathways. In a bleomycin-induced rat model with IPF, this paper randomly divided the rats into six groups(control, group, model group, pirfenidone group, and low, middle, and high-dose groups of Buyang Huanwu Decoction). The results demonstrated that Buyang Huanwu Decoction treatment significantly improved tissue pathological damage, reduced collagen deposition, and alleviated lipid metabolism dysregulation. Western blot analysis confirmed that Buyang Huanwu Decoction mediated the upregulation of PPARG and inhibited the activation of the SPP1/CD44 pathway. The multi-omics study elucidated the role of the PPARG/SPP1/CD44 pathway as a key regulatory factor in lipid metabolism in IPF, providing evidence that Buyang Huanwu Decoction exerted its antifibrotic effects through this novel mechanism and thus offering new insights into the therapeutic prospects for IPF.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Signal Transduction/drug effects* ; PPAR gamma/genetics* ; Humans ; Osteopontin/genetics* ; Lipid Metabolism/drug effects* ; Idiopathic Pulmonary Fibrosis/genetics* ; Hyaluronan Receptors/genetics* ; Rats ; Male ; Rats, Sprague-Dawley ; Molecular Docking Simulation

BACKGROUND: Lung cancer currently ranks first globally in both incidence and mortality. Pemetrexed (PMX) serves as a first-line treatment for lung adenocarcinoma (LUAD), but the patients often develop drug resistance during therapy. Milk exosome (mEXO) have the advantages of low immunogenicity, high tissue affinity, and low cost, and mEXO itself has anti-tumor effects. Hyaluronan (HA) naturally bind to CD44, a receptor which is highly expressed in LUAD tissues. This study aims to construct hyaluronan-modified milk exosome (HA-mEXO) and preliminarily investigate their molecular mechanisms for reversing PMX resistance through cellular experiments. METHODS: Exosomes were extracted from milk using high-speed centrifugation, and HA-mEXO was constructed. PMX-resistant A549 and PC-9 cell lines were treated with mEXO and HA-mEXO, respectively. CCK-8 assays, colony formation assays, Transwell assays, and flow cytometry were performed to evaluate proliferation, colony formation, migration, invasion, and apoptosis phenotypes in the treated resistant cell lines. Finally, transcriptomic sequencing, analysis, and cellular functional recovery experiments were conducted to investigate the mechanism by which HA-mEXO reverses PMX resistance in LUAD cells. RESULTS: The expression of CD44 in A549 and PC-9 LUAD drug-resistant cell lines was significantly higher than that in parental cells, and the uptake rate of HA-mEXO by drug-resistant cell lines was significantly higher than that of mEXO. Compared to the mEXO group, HA-mEXO-treated A549 and PC-9 resistant cells exhibited significantly reduced half maximal inhibitory concentration (IC50) values for PMX, markedly diminished clonogenic, migratory, and invasive capabilities, and a significantly increased proportion of apoptotic cells. Western blot analysis revealed that, compared to parental cells, A549 and PC-9 drug-resistant cells exhibited downregulated ZNF516 expression and upregulated ABCC5 expression. Immunofluorescence analysis revealed that HA-mEXO treatment downregulated ABCC5 expression in A549 and PC-9 drug-resistant cells compared to the PBS group, whereas co-treatment with HA-mEXO and ZNF516 knockdown showed no significant change in ABCC5 expression. CONCLUSIONS HA-mEXO carrying ZNF516 suppress ABCC5 expression, thereby enhancing the sensitivity of A549 and PC-9 LAUD drug-resistant cells to PMX.
Humans ; Hyaluronic Acid/chemistry* ; Drug Resistance, Neoplasm/drug effects* ; Exosomes/chemistry* ; Adenocarcinoma of Lung/genetics* ; Pemetrexed/pharmacology* ; Animals ; Lung Neoplasms/pathology* ; Milk/chemistry* ; Cell Proliferation/drug effects* ; Apoptosis/drug effects* ; Cell Line, Tumor ; Hyaluronan Receptors/metabolism*

The development of safe and effective carriers is crucial for improving the in vivo stability of siRNA drugs and facilitating their clinical translation. Chitosan (CS), a natural cationic polymer, shows great potential in nucleic acid drug delivery. To optimize the physicochemical properties of CS/siRNA nanoparticles (NPs) and increase their siRNA delivery efficacy, in this study, hyaluronic acid (HA) was added into CS to form stable complex NPs through electrostatic interactions. The HA component is able to target the CD44 receptors on the surface of tumor cells, facilitating efficient siRNA delivery. First, we systematically investigated the effects of the molecular weights and mass ratio of CS and HA on the physicochemical properties of CS/HA NPs. The results showed that at HA: CS mass ratios of approximately 5:5 and 6:4, the complex NPs exhibited small particle sizes, narrow size distribution, and high storage stability. Under similar conditions, the size of CS/HA NPs increased with the increase in the molecular weights of CS and HA. Based on these findings, suitable conditions were selected to prepare CS/HA NPs for siRNA delivery. Cell experiments demonstrated that the introduction of HA effectively reduced the cytotoxicity of the CS delivery system and enhanced the NP uptake. The CS/HA/siRNA NPs achieved 50% to 60% silencing of the luciferase gene in HeLa-Luc cells. CS/HA NPs formed smaller nanoparticles with siRNA than pure CS and mediated specific interactions with tumor cells via HA, leading to efficient siRNA delivery. These findings provide valuable insights into the construction of natural polymer composite nanoparticles for application in siRNA delivery.
Hyaluronic Acid/chemistry* ; Chitosan/chemistry* ; RNA, Small Interfering/administration & dosage* ; Nanoparticles/chemistry* ; Humans ; Particle Size ; HeLa Cells ; Hyaluronan Receptors

Cancer ranks as the second leading cause of death globally and has surpassed cardiovascular diseases to become the primary cause of mortality in developed countries. Cancer stem cells (CSCs), which play crucial roles in cancer recurrence, metastasis, and drug resistance, have attracted significant attention in targeted therapeutic strategies. Aptamers, with unique three-dimensional structures capable of specifically recognizing the surface markers of CSCs, show promising potential in targeted drug delivery systems. Compared with conventional antibodies, aptamers are praised for small molecular weights, low production costs, and easy chemical modification. This review systematically summarizes recent advances in aptamer research targeting the surface markers of CSCs, with particular emphasis on aptamer-drug conjugate systems targeting the markers including EpCAM, CD133, CD44, and ABCG2. Both in vitro cellular studies and in vivo animal models have demonstrated the definite anti-cancer efficacy of aptamer-based drug delivery systems, which are of great significance to develop novel therapeutic strategies and improving the therapeutic effects of CSC-targeted treatment. Thus, aptamer-based drug delivery system has broad application prospects in the field of precise cancer treatment.
Humans ; Neoplastic Stem Cells/metabolism* ; Aptamers, Nucleotide/therapeutic use* ; Drug Delivery Systems/methods* ; Neoplasms/drug therapy* ; Biomarkers, Tumor/metabolism* ; Animals ; Epithelial Cell Adhesion Molecule ; AC133 Antigen ; Hyaluronan Receptors

As an important part of tumor microenvironment, neutrophils are poorly understood due to their spatiotemporal heterogeneity in tumorigenesis. Here we defined, at single-cell resolution, CD44-CXCR2- neutrophils as tumor-specific neutrophils (tsNeus) in both mouse and human gastric cancer (GC). We uncovered a Hippo regulon in neutrophils with unique YAP signature genes (e.g., ICAM1, CD14, EGR1) distinct from those identified in epithelial and/or cancer cells. Importantly, knockout of YAP/TAZ in neutrophils impaired their differentiation into CD54+ tsNeus and reduced their antitumor activity, leading to accelerated GC progression. Moreover, the relative amounts of CD54+ tsNeus were found to be negatively associated with GC progression and positively associated with patient survival. Interestingly, GC patients receiving neoadjuvant chemotherapy had increased numbers of CD54+ tsNeus. Furthermore, pharmacologically enhancing YAP activity selectively activated neutrophils to suppress refractory GC, with no significant inflammation-related side effects. Thus, our work characterized tumor-specific neutrophils in GC and revealed an essential role of YAP/TAZ-CD54 axis in tsNeus, opening a new possibility to develop neutrophil-based antitumor therapeutics.
Humans ; Animals ; Mice ; Adaptor Proteins, Signal Transducing/metabolism* ; Transcription Factors/metabolism* ; Stomach Neoplasms/pathology* ; Neutrophils/pathology* ; Signal Transduction/genetics* ; YAP-Signaling Proteins ; Tumor Microenvironment ; Hyaluronan Receptors/genetics*

OBJECTIVE: To investigate the value of CD44 METHODS: Flow cytometry was used to detected the proportion of CD44 RESULTS: The percentage of CD44 CONCLUSION HCD44
Flow Cytometry ; Humans ; Hyaluronan Receptors ; Induction Chemotherapy ; Leukemia, Myeloid, Acute/drug therapy* ; Neoplasm, Residual ; Prognosis ; Spleen

OBJECTIVE: To investigate the effects of low-dose decitabine on levels of soluble CD44 and GDF11, and hematopoietic function in elderly patients with myelodysplastic syndrome (MDS). METHODS: Ninety-nine patients with senile myelodysplastic syndrome (MDS) admitted to our hospital from October 2015 to October 2017 were divided into group A, B and C according to their treatment, each with 33 cases.The patients in group A were treated with low-dose decitabine, the patients in group B were treated with usual dose of decitabine, and the patients in group C were treated with low-dose decitabine plus G-GSF, cytarabine, and aclarithromycin. The changes of soluble CD44, GDF11 levels and hematopoietic function (sTfR/E) were compared before and after treatment. The clinical remission rate and adverse reaction rate in 3 groups were analyzed. RESULTS: Before treatment, the levels of CD44, GDF11 and sTfR/E were not significantly different between the 3 groups (P＞0.05). After treatment, the levels of CD44 and GDF11 were significantly decreased in these groups, while the serum levels of sTfR/E were significantly increased, and there was no significant difference between the 3 groups (P＞0.05). After treatment, the total effective rates of A, B, and C 3 group were 82.3%, 81.8%, and 78.8%, respectively, without statistically significant difference (P＞0.05). During the treatment, the incidence of non-hemotoxic adverse reactions in group A was 8.8%, significantly lower than that in group B and C (30.3%, 27.3%) (P＜0.05, P＜0.05), the incidence of hemotoxic adverse reactions in group A was 39.4%, significantly lower than that 63.6% and 66.7% in group B and C (P＜0.05, P＜0.05). CONCLUSION Low-dose decitabine alone is effective in treating elderly patients with MDS as compared with conventional dose and combination therapy, moreover can significantly reduce the levels of CD44 and GDF11, improve hematopoietic function and low the adverse reactions. Thereby the low dose of decitabine may be a new choice for clinical treatment of MDS.
Aged ; Antineoplastic Combined Chemotherapy Protocols ; Azacitidine ; Bone Morphogenetic Proteins ; Decitabine ; administration & dosage ; therapeutic use ; Growth Differentiation Factors ; Hematopoietic Stem Cell Transplantation ; Humans ; Hyaluronan Receptors ; Myelodysplastic Syndromes ; drug therapy ; Treatment Outcome

OBJECTIVE: To investigate the expression of CD44, CD87 and CD123 in acute leukemia and its correlation with cellular immune markers. METHODS: A total of 166 patients with acute leukemia (AL) admitted from May 2014 to February 2017 were enrolled in AL groups. Among these patients, 100 patients suffered from acute myeloid leukemia, 50 patients suffered from acute lymphoid leukemia, and 16 patients showed B/medullary phenotype. At the same time 50 patients with non-acute leukemia were enrolled in the control group. 5 ml of fasting venous blood collected from the patients in each group, and the percentage of CD44, CD87 and CD123 cells was determined by three-color flow cytometry. Symptomatic chemotherapy was given to the patients with confirmed acute leukemia, and the remission was evaluated after 2 treatmen courses. The Complete remission (CR) was recorded and the percentage of CD44, CD87 and CD123 cells under different curative efficacy were recorded. The correlation of the prognosis patients with CD44, CD87 and CD123 was analyzed by SPSS Pearson correlation analysis software. RESULTS: The positive rates of CD44, CD87 and CD123 in AL group were all higher than those in the control group (P＜0. 05). The positive rates of CD44 and CD123 in acute myeloid leukemia group were higher than those in acute lymphoblastic leukemia group and B/myeloid phenotype group (P＜0. 05). The positive rate of CD44 in acute lymphoid leukemia group was higher than that in B/medullary double phenotype group (P＜0.05). The treatment in the patients of AL group was successfully completed. 132 patients reachel to CR and 34 patients to PR+NR after 2 courses. The positive rates of CD44, CD87 and CD123 in CR patients were lower than those in PR+NR patients (P＜0.05). The results of SPSS Pearson correlation analysis showed that the prognosis of patients with acute leukemia negatively correlated with CD44 and CD87 (P＜0.05). CONCLUSION The expression of CD44, CD87 and CD123 in different phenotype of acute leukemia are different, which correlateds with prognosis. The determination of CD44, CD87 and CD123 can be used to evaluate the prognosis of patients for the reference of clinical treatment.
Humans ; Hyaluronan Receptors ; immunology ; Immunity, Cellular ; Interleukin-3 Receptor alpha Subunit ; immunology ; Leukemia, Myeloid, Acute ; Prognosis ; Receptors, Urokinase Plasminogen Activator ; immunology

OBJECTIVEThis study aims to investigate the expression and relationship of CD44 and CD133 in normal oral mucosa, oral potentially malignant disorder (OPMD), and oral squamous cell carcinoma (OSCC). This work also analyzes the relationship between such expression and clinical factors. This study intends to evaluate the clinical value of using CD44 and CD133 as indices to evaluate the carcinogenic potential of OPMD.

METHODSClinical data from 60 patients with OPMD, 60 patients with OSCC, and 10 cases of normal oral mucosa were analyzed. Double immunohistochemical analysis was applied to investigate the expression of CD44 and CD133 in paraffin sections of normal oral mucosa, OPMD, and OSCC tissues. Subsequently, the relationships between such expression and clinical factors were analyzed.

RESULTSThe positive rates of CD44 expression in the normal oral mucosa, OPMD, and OSCC tissues were 100.00%, 96.67%, and 71.67% (P<0.05), respectively. Meanwhile, the positive rates of CD133 expression in the normal oral mucosa, OPMD, and OSCC tissues were 0.00%, 35.00%, and 63.33% (P<0.05), respectively. The expression of CD44 and CD133 was found to be correlated (P<0.05). Such expression was related to the clinical stages and lymphatic metastasis of OSCC (P<0.05).

CONCLUSIONSCD44 and CD133 can be used individually as clinical indices to evaluate the carcinogenic potential of OPMD.
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AC133 Antigen ; Carcinogenesis ; Carcinoma, Squamous Cell ; Humans ; Hyaluronan Receptors ; Lymphatic Metastasis ; Mouth Mucosa ; Mouth Neoplasms

OBJECTIVETo explore the predictive value of combination detection of Pgp1 expression in cancer tissue and serum CEA level for the prognosis of colorectal cancer (CRC) patients.

METHODSClinicopathological data, complete 5-year follow-up data and CRC tissue samples of 153 CRC patients with stage I( to II( tumor undergoing radical operation in our department from January 2004 to August 2006 were retrospectively collected. Immunohistochemical staining was used to detect the expression level of Pgp1. The combined evaluation of staining intensity and positive cell percentage was performed to determine the expression level of Pgp1. Pgp1 staining (-) and (+) was defined as low expression; and staining (++) and (+++) as high expression. Electrochemiluminescence immunoassay was used to detect the level of serum CEA. CEA > 5 μg/L was defined as positive. χand Fisher's exact test were performed to analyze the association of Pgp1 expression with CEA level and clinicopathological variables. Moreover, Kaplan-Meier method was used to analyze the survival. Univariate and multivariate Cox proportional hazard regression models were used to evaluate the roles of Pgp1 expression combined with serum CEA level in prognosis prediction.

RESULTSOf 153 patients, 105 were males and 48 females with mean age of 59 (27 to 90) years; 41 cases were rectal cancer, and 112 cases colon cancer; 23 patients were TNM stage I( tumor, and 130 patients stage II( tumor; median follow-up time was 64 months; 30 cases were dead. Positive rate of Pgp1 expression in colorectal cancer tissues was 66.0%(101/153). The expression of Pgp1 was associated with gender, tumor location, and survival during the follow-up (all P<0.05). The preoperative positive rate of serum CEA was 28.1% (43/153). The preoperative serum CEA level was associated with tumor recurrence and survival (all P<0.05). Kaplan-Meier analysis showed the overall 5-year survival rate was 81.7%. The 5-year survival rate of patients with high expression of Pgp1 was 88.1%, which was significantly higher than 69.2% of those with low expression of Pgp1(P=0.003). The 5-year survival rate of patients with preoperative positive serum CEA was 72.1%, which was significantly lower than 86.1% of those with preoperative negative serum CEA(P=0.023). Furthermore, the 5-year survival rate of patients with negative Pgp1 plus positive CEA was 66.7%, which was significantly lower than 91.0% of those with positive Pgp1 plus negative CEA(P=0.002). Univariate analysis showed that gender, Pgp1 expression level, preoperative serum CEA level, and Pgp1 combined with CEA were significantly associated with the prognosis of patients(all P<0.05). Multivariate analysis showed that Pgp1 expression was an independent prognostic factor of CRC [HR(95%CI:1.261 to 64.224), P=0.028].

CONCLUSIONSLow expression of Pgp1 in cancer tissue indicates poor prognosis in patients with stage I( and II( tumor. Combination detection of Pgp1 expression and serum CEA can be applied to predict the prognosis of patients with stage I( and II( colorectal cancer.

Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor ; blood ; physiology ; Carcinoembryonic Antigen ; blood ; physiology ; Colonic Neoplasms ; physiopathology ; secretion ; Colorectal Neoplasms ; physiopathology ; secretion ; Female ; Fluorescent Antibody Technique ; Humans ; Hyaluronan Receptors ; metabolism ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Multivariate Analysis ; Neoplasm Proteins ; blood ; physiology ; Neoplasm Recurrence, Local ; physiopathology ; Neoplasm Staging ; Predictive Value of Tests ; Prognosis ; Proportional Hazards Models ; Rectal Neoplasms ; physiopathology ; secretion ; Retrospective Studies ; Sex Factors ; Survival Rate