CD44 Expression Research Articles

Hypoxia-Regulated CD44 and xCT Expression Contributes to Late Postoperative Epilepsy in Glioblastoma

Background/Objectives: Late epilepsy occurring in the late stage after glioblastoma (GBM) resection is suggested to be caused by increased extracellular glutamate (Glu). To elucidate the mechanism underlying postoperative late epilepsy, the present study aimed to investigate the expressions and relations of molecules related to Glu metabolism in tumor tissues from GBM patients and cultured glioma stem-like cells (GSCs). Methods: Expressions of CD44, xCT and excitatory amino acid transporter (EAAT) 2 and extracellular Glu concentration in GBM patients with and without epilepsy were examined and their relationships were analyzed. For the study using GSCs, expressions and relationships of the same molecules were analyzed and the effects of CD44 knock-down on xCT, EAAT2, and Glu were investigated. In addition, the effects of hypoxia on the expressions of these molecules were investigated. Results: Tumor tissues highly expressed CD44 and xCT in the periphery of GBM with epilepsy, whereas no significant difference in EAAT2 expression was seen between groups with and without epilepsy. Extracellular Glu concentration was higher in patients with epilepsy than those without epilepsy. GSCs displayed reciprocal expressions of CD44 and xCT. Concentrations of extracellular Glu coincided with the degree of xCT expression, and CD44 knock-down elevated xCT expression and extracellular Glu concentrations. Hypoxia of 1% O2 elevated expression of CD44, while 5% O2 increased xCT and extracellular Glu concentration. Conclusions: Late epilepsy after GBM resection was related to extracellular Glu concentrations that were regulated by reciprocal expression of CD44 and xCT, which were stimulated by differential hypoxia for each molecule.

Polymorphisms in immunosuppression-related genes are associated with AML

BackgroundAcute myeloid leukemia (AML) is a hematologic malignancy with poor overall survival (OS). The immunosuppressive microenvironment significantly impacts AML development and chemoresistance. Despite new immunotherapeutic strategies entering standard clinical care for various tumors, progress in AML remains poor. Multi-omics analyses, such as single-cell transcriptomics, have revealed many potential new targets to improve AML prognosis from an immunological perspective.MethodsDNA from 307 AML patients and 316 healthy individuals were extracted. We detected nine single nucleotide polymorphisms (SNPs) in five immunosuppression-related genes (CIITA, CD200, CD163, MRC1 and LILRB4) in these samples. SNP genotyping was performed on the MassARRAY platform. We then analyzed the relationship between these SNPs and AML susceptibility, treatment response, and prognosis.ResultsOur findings indicated that rs4883263 in the CD163 gene is a protective factor for AML susceptibility and chromosomal karyotype abnormalities. Additionally, rs4883263 in CD163 was related to low PLT count at diagnosis, while rs2272022 in CD200 was protective against low PLT count. rs4780335 in CIITA was associated with high WBC count at diagnosis and worse OS. Furthermore, rs1048801 in LILRB4 was linked to worse AML treatment response, lower OS, and may be an independent prognostic risk factor for AML. Lastly, expressions of CD163, CIITA, LILRB4, and CD200 were higher in AML patients than that in normal controls.ConclusionsOur findings on SNP associations in AML immunosuppression-related genes provide important reference points for predicting treatment outcomes in AML patients.

CD73 promotes the maturation of murine NK cells and their survival in the tumor microenvironment.

Natural Killer (NK) cells are crucial in recognizing and eliminating tumor cells, making them pivotal in antitumor responses. Adenosine, the product of ATP hydrolysis mediated by CD39 and CD73 ectonucleotidases, has been reported to reduce the proliferation and maturation of NK cells. In this study, we investigate the expression of CD73 in NK cells and its impact on maturation, phenotype, survival, and function. Our findings reveal that while splenic NK cells express minimal levels of CD73, its expression is induced upon activation and in the tumor microenvironment upon adoptive transfer to tumor-bearing mice. Notably, within the tumor microenvironment, CD73 expression in NK cells correlates with elevated levels of PD-L1 and CD226. Accordingly, analysis of human melanoma datasets uncovers a subset of immature tumor-infiltrating NK cells expressing CD73. To further understand the role of CD73 on NK cells, we used a CD73 knockout (KO) murine model and observed that CD73-deficient NK cells display a more immature phenotype and heightened proliferative activity than wild-type (WT) NK cells. Additionally, CD73-deficient NK cells exhibit elevated levels of P2X7R and reduced CD39 expression, suggesting an increased susceptibility to ATP-induced death. Following adoptive transfer to tumor-bearing mice, CD73KO NK cells are present at a lower frequency but demonstrate similar control over tumor growth compared to WT NK cells. In conclusion, our study demonstrates the upregulation of CD73 in NK cells infiltrating tumors and underscores its role as a checkpoint regulating the functional maturation of NK cells.

Targeting Ikaros and Aiolos with pomalidomide fails to reactivate or induce apoptosis of the latent HIV reservoir.

HIV persists in people living with HIV (PLHIV) on antiretroviral therapy (ART) in long-lived and proliferating latently infected CD4+ T cells that selectively express pro-survival proteins, including the zinc finger proteins, Ikaros and Aiolos. In this study, we investigated whether pomalidomide, an immunomodulatory agent that induces degradation of Ikaros and Aiolos, could increase the death of HIV-infected cells and/or reverse HIV latency. Using an in vitro model of CD4+ T cells infected with a green fluorescent protein (GFP) reporter virus, pomalidomide increased the expression of the pro-survival protein B cell lymphoma (Bcl)-2 and did not increase apoptosis of GFP+ HIV productively infected CD4+ T cells. Pomalidomide also increased the expression of CD155 and UL16-binding protein (ULBP) stress proteins on GFP+ HIV productively infected CD4+ T cells, but this did not translate to enhanced clearance following co-culture with a natural killer (NK) cell line. Using CD4+ T cells from PLHIV on ART, pomalidomide ex vivo activated memory CD4+ T cells resulting in elevated HLA-DR expression and induced CD4+ T cell proliferation but only in the presence of T cell receptor stimulation with anti-CD3 and anti-CD28. There was no effect on cell-associated HIV RNA or the frequency of intact HIV DNA. In conclusion, despite an increase in stress protein expression, promoting Ikaros and Aiolos degradation in CD4+ T cells using pomalidomide did not directly induce apoptosis of HIV-infected cells or induce HIV latency reversal.IMPORTANCEPeople living with HIV (PLHIV) require lifelong antiretroviral therapy (ART) due to the persistence of latently infected cells. The zinc finger proteins, Ikaros and Aiolos, have recently been implicated in promoting the persistence of latently infected cells. In this study, we investigated the effects of pomalidomide, an immunomodulatory imide drug that induces the degradation of Ikaros and Aiolos, on HIV latency reversal and death of infected cells. Using CD4+ T cells from people living with HIV on suppressive antiretroviral therapy, as well as an in vitro model of productive HIV infection, we found that pomalidomide induced T cell activation and expression of stress proteins but no evidence of latency reversal or selective death of infected cells.

Oxidative Score and Microvesicle Profile Suggest Cardiovascular Risk in Chronic Kidney Disease

Chronic kidney disease (CKD) is associated with a high incidence of cardiovascular disease (CVD) due to the accumulation of uremic toxins, altered redox state, and chronic systemic inflammation. This study aimed to analyze the relationship between the redox status of patients with CKD and the phenotype of microvesicles (MVs) subtypes, and cardiovascular events. The oxidative stress level of each participant was determined using an individualized OXY-SCORE. The relationship between pro-oxidant and antioxidant parameters and the expression of membrane markers in endothelial-derived microvesicles (EMVs) and platelet-derived microvesicles (PMVs) was established. Patients with advanced CKD (ACKD) and hemodialysis (HD) had a higher OXY-SCORE than healthy subjects (HS), whereas peritoneal dialysis (PD) patients had similar scores to HS. PD patients showed elevated PMVs and CD41 expression, whereas HD patients had higher EMVs and CD31 expression. Patients with ACKD had higher tissue factor (TF) expression in the PMVs and EMVs. TF expression was correlated with xanthine oxidase (XO) activity and was negatively correlated with antioxidant parameters. Patients with cardiovascular events show elevated TF. In conclusion, microvesicles and oxidative stress may serve as markers of cardiovascular risk in CKD, with TF expression in PMVs and EMVs being potential predictive and prognostic biomarkers of CVD.

The inhibitory effects of nimotuzumab on CD276 expression and immune escape in head and neck squamous cell carcinoma: Insights into anticancer mechanisms.

CD276 has been identified as a novel immune checkpoint, and its overexpression is associated with immune evasion and poor prognosis in various tumors, including head and neck squamous cell carcinoma (HNSCC). Nimotuzumab, a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody, has been approved for various solid tumors. However, it remains unclear whether its anticancer efficacy involves a reduction in CD276 expression. The purpose of this study was to investigate the regulatory effects and potential mechanisms of nimotuzumab on CD276 expression both in vitro and in vivo. In a coculture system, nimotuzumab showed inhibitory effects on TGF-β-induced upregulation of CD276 at both the transcriptional and protein levels in HNSCC cell lines. Mechanistic studies revealed that nimotuzumab primarily suppressed TGF-β-induced CD276 upregulation by blocking EGFR/MEK/ERK, which was further validated by MEK and ERK inhibitors. In xenograft and mice HNSCC models, nimotuzumab exerted antitumor effects accompanied by significantly reduced CD276 expression during tumor progression. Analysis of tumor-infiltrating lymphocytes (TILs) profiles indicated that nimotuzumab orchestrated the tumor immune microenvironment (TIME) by notably increasing the frequency of T lymphocytes, including cytotoxic T lymphocytes and helper T lymphocytes, as well as macrophage cells. However, no significant changes were observed in the populations of NK cells, DC cells, and neutrophils. These findings offer new insights into the anticancer mechanisms of nimotuzumab and its underlying synergy in combined treatments with immunotherapy for HNSCC.

Immunohistochemical Expression of Differentiated Embryonic Chondrocyte 1 and Cluster of Differentiation 44 in Oral Potentially Malignant Disorders

Background and Objectives: Oral cancer remains a critical global health concern, with oral squamous cell carcinoma (OSCC) being the most prevalent form. Oral potentially malignant disorders (OPMDs), such as oral leukoplakia (OLK), oral lichen planus (OLP), and actinic cheilitis (AC), often precede OSCC. Identifying reliable biomarkers is vital for assessing malignant transformation risk. The present study aimed to evaluate the immunohistochemical expression of differentiated embryonic chondrocyte 1 (DEC1), a marker of dysplasia severity, and cluster of differentiation 44 (CD44), which is associated with cancer progression, in OPMD and OSCC tissues. Materials and Methods: A retrospective analysis was conducted on 145 biopsy specimens from January 2015 to January 2023, comprising normal mucosa (NM), OLK, OLP, AC, and OSCC. DEC1 and CD44 expression levels were assessed using immunohistochemical staining. Positivity scores were determined based on staining intensity and extent, with statistical analyses performed using SPSS software (SPSS Inc., Chicago, IL, USA, version 29.0 for Windows). Results: It was found that CD44 expression significantly increased across OPMD and OSCC compared to NM (p < 0.001). Conversely, DEC1 expression was consistent across lesion types and dysplasia levels. CD44 expression was the highest in AC and OSCC, underscoring its potential role as a progression marker. Conclusions: The results indicate that CD44 is a more sensitive marker for assessing dysplastic severity and malignant transformation, while DEC1 may serve as a complementary marker for early-stage evaluation. Further research involving larger cohorts is needed to confirm these findings.

Effect of CD10-positive cells on osteogenic differentiation of human maxillary/mandibular bone marrow-derived mesenchymal stem cells

This study was aimed at investigating the effect of CD10-positive cells within the maxillary/mandibular bone marrow-derived mesenchymal stem cells (MBMSCs) on osteogenic differentiation of MBMSCs. CD10 expression in iliac bone marrow-derived MSCs (IBMSCs), MBMSCs, and gingival fibroblasts was measured using flow cytometry. The osteogenic potential of 19 MBMSC lines was evaluated, and based on it, they were classified into osteogenic-High and osteogenic-Low groups. The percentage of CD10-positive cells in each group was compared. Effect of coculturing gingival fibroblasts and CD10-positive cells on the osteogenic potential of MBMSCs was also assessed. Expression of tissue inhibitor of metalloprotease-1 (TIMP-1) in osteogenic-High and osteogenic-Low MBMSCs was measured using quantitative real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. The molecular mechanisms underlying the regulation of osteogenic differentiation in MBMSCs were investigated. CD10 was not expressed in IBMSCs, but was highly expressed in fibroblasts. In MBMSCs, the CD10-positivity rate varied considerably between cells. MBMSCs with a high-CD10 positivity rate showed low osteogenic potential. Coculture with fibroblasts or CD10-positive cells reduced the osteogenic potential of MBMSCs. TIMP-1 was highly expressed in CD10-positive cells, and osteogenic-Low MBMSCs showed significantly higher TIMP-1 expression compared with osteogenic-High MBMSCs. β-catenin signaling was suppressed in osteogenic-Low MBMSCs. This study revealed that TIMP-1 secreted from CD10-positive cells may be involved in the suppression of the osteogenic potential of MBMSCs by contamination with CD10-positive cells. This finding provides important insights for developing bone regeneration therapies using MBMSCs.

MIF/CD74 axis in hepatic stellate cells mediates HBV-related liver fibrosis.

Chronic hepatitis B virus (HBV) infection is a major risk factor for liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Despite advances in understanding HBV-related liver diseases, effective therapeutic strategies remain limited. Macrophage migration inhibitory factor (MIF) has been implicated in various inflammatory and fibrotic conditions, but its role in HBV-induced liver fibrosis has not been fully explored. This study investigates the involvement of MIF in liver fibrosis and evaluates its potential as a therapeutic target. We found that MIF expression was significantly elevated in hepatic stellate cells (HSCs) following stimulation with HBVcc (HBV cell culture) or HBV surface antigen (HBsAg). Through its receptor CD74, MIF enhanced the TGF-β/SMAD signaling pathway, promoting HSC activation and liver fibrosis progression. Histological analysis revealed higher MIF and CD74 expression in HBsAg-positive individuals compared to HBsAg-negative controls. Moreover, MIF expression correlated with the activation of fibrosis markers, including α-SMA and TGF-β-related proteins. Inhibition of MIF with the specific inhibitor ISO-1 attenuated fibrosis progression, suggesting that targeting MIF could offer a promising approach for treating HBV-related liver fibrosis. Our findings underscore the critical role of the MIF/CD74 axis in liver fibrosis and provide a basis for future therapeutic strategies targeting MIF in chronic liver diseases.

Histopathological growth patterns of gastric cancer liver metastasis and their association with patient prognosis.

484 Background: The histopathological growth patterns (HGPs) of liver metastasis reflect the complicated and varied interactions between tumor cells and the host microenvironment. We studied HGPs of gastric cancer liver metastasis (GCLM) and sought to predict them using radiomic and clinical variables. Methods: Hepatectomy was performed in 62 patients with GCLM at our university hospital between 2011 and 2021. HGPs were evaluated according to international consensus guidelines, and were classified as either desmoplastic HGP (dHGP) or non-dHGP. CD4, CD8, VEGF and CD31 were analyzed by immunohistochemistry. Eight hundred and fifty-one radiomics features were extracted from CT portal venous phase images and the optimal radiomics signature was determined by univariate analysis and LASSO regression. Multivariable regression analyses and ROC curves were used to assess the predictive performance of HGPs with a radiomic and clinical combined model. Results: Among 62 patients, 14 were categorized as dHGP, and 48 as non-dHGP. Non-dHGP vs. d-HGP was associated with higher tumor N stage and CEA level, and with decreased CD8 + T cells, and lower VEGF and CD31 expression. HGP status was independently associated with patient cancer-specific survival (CSS) (P＜0.05) multivariately.Analysis of percent relative contribution revealed that HGP ranked first for CSS (35.9%), ahead of T (28.9%) and N (28.9%) stage. A model with combined radiomic and clinical features demonstrated robust performance with area under the curve (AUC) values of 0.993 and 0.933 in the training and validation sets, respectively. Conclusions: Non-invasive determination of radiomic and clinical features was shown to predict HGPs types. Compared to dHGP, GCLM with non-dHGP exhibited significantly lower immune cell infiltration and decreased angiogenesis. Among features examined in GCLM, HGP was the most robust for prognostication. Univariate and multivariate analysis of prognostic factors for cancer-specific survival. Characteristics Univariate analysis Multivariate rergression analysis HR (95%CI) P HR (95%CI) P Gender ( Women vs Men ) 1.13(0.61-2.09) 0.71 Age ( >60years vs ≤60years) 1.08(0.60-1.70) 0.98 HGP ( non-desmoplastic HGP vs desmoplastic HGP ) 3.63(1.78-7.41) 0.00 3.48(1.37-8.88) 0.01 T stage ( T3-T4 vs T1-T2 ) 2.03(1.08-3.80) 0.03 2.29(1.15-4.58) 0.02 N stage ( N1-N3 vs N0 ) 3.46(1.66-7.23) 0.00 2.54(1.17-5.56) 0.02 CEA ( >5ng/ml vs ≤5ng/ml ) 2.37(1.25-4.48) 0.01 1.56(0.70-3.48) 0.27

AFP shields hepatocellular carcinoma from macrophage phagocytosis by regulating HuR-mediated CD47 translocation in cellular membrane.

Alpha fetoprotein(AFP) overexpression connecting with macrophage dysfunction remain poorly defined. In this study, explore AFP regulates macrophage immunomodulation in hepatocellular carcinoma(HCC) through comprehensive in vitro and in vivo studies. Immunohistochemical and immunofluorescence staining was used to analyze the relativity of AFP and cellular membrane CD47 expression in clinical 30 HCC tissues, and the expression of AFP and CD47 in HCC cells. The intelligent living-cell high-throughput imaging analyzer was applied to dynamically track and image of macrophages to phagocytize HCC cells. The effect of AFP on regulating the level of CD47 in cellular membrane and growth of tumor in vivo was performed by animal experiment. The association of AFP and CD47 in HCC cells was detected by single cell analysis. The present results indicated that AFP upregulated the localization of CD47 on the HCC cell surface. CD47 overexpression stimulates HCC to escape immune surveillance by transmitting "don't eat me" signals to macrophages, lead to inhibit macrophage to phagocytize HCC cells. Mechanistically, the results demonstrated that AFP enhanced CD47 membrane translocation by interacting with Hu-Antigen R(HuR), an RNA-binding protein that regulates mRNA stability and translation. AFP alters the subcellular distribution of HuR, increasing its cytoplasmic accumulation and binding to CD47 transcript. AFP enhanced CD47 membrane translocation by interacting with HuR. These findings proved that AFP could inhibit macrophage to phagocytize HCC cells by upregulating the localization of CD47 on the HCC cell surface. Combination of AFP with CD47 blockade may be a potential therapeutic strategy for HCC treatment.

CD155 promotes the progression of colorectal cancer by restraining CD8+ T cells via the PI3K/AKT/NF-κB pathway.

CD155 is a crucial factor in the regulation of T cell function and contributes to immune escape. CD155 upregulation has been found in several types of cancer. However, the mechanism by which CD155 regulates CD8+ T cell function in colorectal cancer remains unclear. Here we investigated the role and mechanism of CD155 in the regulation of CD8+ T cell function. We studied the expression of CD155 in colorectal cancer tissues through western blot, immunohistochemistry, and the TCGA database. We verified the effects of CD155 on the functions of colorectal cancer cells and CD8+ T cells through in vitro experiments. We demonstrated that CD155 affects CD8+ T cell migration and thus promotes tumor growth in a mouse subcutaneous tumor model. We then tested the changes in the PI3K/AKT/NF-κB pathway in CD8+ T cells by flow cytometry. We demonstrated that stable CD155 expression was negatively correlated with prognosis in colorectal cancer patients. In vitro experiments confirmed that CD155 does not affect tumor cell proliferation, migration, or invasion. We also revealed that CD155 downregulated the function and migration of CD8+ T cells in vivo and in vitro. Furthermore, CD155 might regulate CD8+ T cells function via the PI3K/AKT/NF-κB pathway. This study revealed that CD155 can promote the progression of colorectal cancer by regulating the PI3K / AKT-NF-κB pathway to promote the depletion of CD8+ T cells and reduce their migration to the tumor microenvironment. CD155 may become an important prognostic biomarker and an effective target for colorectal cancer immunotherapy.

UBE2T/CDC42/CD276 signaling axis mediates brain metastasis of triple-negative breast cancer via lysosomal autophagy

BackgroundAdvanced triple-negative breast cancer (TNBC) is prone to brain metastasis (BrM). The precise molecular mechanism responsible for this phenomenon has not yet been completely established, so it is vital to comprehend the molecular mechanism behind it.MethodsThe protein chip analysis was conducted to identify any abnormal UBE2T protein expression in TNBC, especially BrM. Here, we used public databases and bioinformatics analysis as well as clinical samples from different cohorts to investigate the interrelationship between UBE2T/CDC42/CD276. This predicted relationship was then repeatedly validated using different in vivo and in vitro experimental methods. Additionally, multiple experimental approaches were implemented, encompassing western blotting, Co-IP, GST pull-down, flow cytometry, mass spectrometry, immunofluorescence, immunohistochemistry, and qRT-PCR to reveal the molecular mechanism of UBE2T-mediated immune escape and BrM.ResultsOur results indicate that expressed at elevated levels in breast cancer, UBE2T is negatively linked to patient prognosis, especially in BrM of TNBC. Data from clinical samples from our different cohorts and TCGA indicate a significant correlation between UBE2T and immunosuppression. Mechanistically, UBE2T directly interacts with CDC42, promoting its K48-linked polyubiquitination and proteasomal degradation, thereby inhibiting CDC42 from degrading CD276 via the autophagy-lysosomal pathway, indirectly upregulating CD276 and thereby impairing the CD8+T cells function, ultimately mediating tumor immune escape and BrM. Finally, animal experimental results also showed that inhibition of UBE2T elevated the TNBC sensitivity to immune checkpoint CD276 blockade and inhibited BrM of TNBC.ConclusionsIn conclusion, our results indicate a new mechanism whereby UBE2T-mediated ubiquitination positively controls the UBE2T/CDC42/CD276 axis to upregulate tumor cell expression of CD276 and thereby impair CD8+T cells function, ultimately leading to tumor cell immune escape and BrM.

Deficiency of Calpain-1 attenuates atherosclerotic plaque and calcification and improves vasomotor dysfunction in Apolipoprotein E knockout mice through inhibiting inflammation.

Atherosclerosis (AS) and atherosclerotic calcification (AC) are closely related to the cardiovascular diseases, largely due to its induction of vasomotor dysfunction. We previously reported that Calpain-1 inhibitor attenuated AS and AC. The present study was designed to investigate the effects and potential mechanisms of Calpain-1 knockout (Calpain-1 KO) in Apolipoprotein E KO (ApoE KO) mice on AS, AC, aortic vasomotor function as well as the liver dysfunction. We hybridized ApoE KO mice with Calpain-1 KO mice to obtain ApoE/Calpain-1 double KO (A×C DKO) mice. The formation of AS and AC was evaluated and liver function was determined. Aortic vasomotor function was assessed. Contents of TNF-α, IL-6, IL-18, IL-1β and NO and the activity of AST, ALT, ALP and eNOS in serum were quantified. The mRNA expression of CD68, SR-A, CD36, PPAR-γ, LXR-α, ABCA1, BMP-2, OPN, ALP and Runx2 in aorta and/or liver were measured. The results showed that in comparison to C57 mice, ApoE KO mice demonstrated the significant increases in the areas of AS and AC, the increases in the mRNA expression of CD68 in the aorta, the increases in the AST, ALT and ALP activity in serum. ApoE KO mice also showed the dysfunction of the aortic contraction induced by phenylephrine and of the relaxation induced by acetylcholine. However, compared with ApoE KO mice, A×C DKO mice exhibited the significant attenuation of AS and AC and the downregulation of mRNA expression of CD68 in aorta. A×C DKO mice revealed the reduction of AST, ALT and ALP activity in serum, the improvements in aortic contraction and relaxation as well as the increases in eNOS activity and NO content in serum. A×C DKO mice also showed the decreases in the contents of TNF-α, IL-6, IL-18 and IL-1β in serum. The mRNA expression of CD68 in aorta, SR-A and CD36 in both aorta and liver of A×C DKO mice was downregulated, while that of PPAR-γ, LXR-α, and ABCA1 was upregulated in comparison of ApoE KO mice. In addition, the mRNA expression of BMP-2, OPN, ALP and Runx2 in aorta of A×C DKO mice was downregulated in comparison of ApoE KO mice. The results suggested that deficiency of Calpain-1 attenuated the formation of AS and AC and improved vasomotor and liver dysfunction in ApoE KO mice through anti-inflammation, and modulation of the mRNA expression of genes related to AS and AC.

Sinensetin attenuates LPS-induced acute pulmonary inflammation in mice and RAW264.7 cells by modulating NF-κB p65-mediated immune resistance and STAT3-mediated tissue resilience.

Acute pulmonary inflammation is a severe lower respiratory tract infection. Sinensetin (SIN), a polymethoxyflavone with strong anti-inflammatory properties, is known to ameliorate LPS-induced acute inflammatory lung injury, but its molecular mechanisms are not fully understood. This study aimed to provide insight into the pharmacological mechanisms of SIN in attenuating acute pulmonary inflammation. In LPS-induced inflammation assays in vivo and in vitro, SIN significantly reduced the mRNA levels of inflammatory genes including MCP-1, ICAM1, Ccl3, Ccl4, Ccl5, Ccl7, Cxcl9, Cxcl10, IL1α, IL1β, IL6, IL11, IL18, IL27, TNF-α, IFN-γ, TLR4, MyD88, F4/80, COX2, iNOS, NLRP3, ASC, JAK2, STAT3, STAT4, and Bcl2l1, as well as increased the mRNA levels of anti-inflammatory genes such as IL4, IL10, and IL12α. Besides, SIN markedly decreased the expression of CD68, TLR4, MyD88, phospho-IκBα (S32/S36), phospho-NF-κB p65 (S536), MCP-1, ICAM1, phospho-JAK2 (Tyr1008), phospho-STAT1 (S727), phospho-STAT3 (Y705), and phospho-STAT4 (Y693), inhibited NF-κB p65 translocation into the nucleus, thereby blocking in combination with STAT transcription factors to induce target gene expression. Further GC-MS/MS and LC-MS/MS metabolomic analysis revealed that SIN significantly increased the abundance of anti-inflammatory metabolites, such as L-alanine, L-carnitine, L-glutamic acid, Glycine, and L-cysteine. In conclusion, the results indicated that SIN attenuated LPS-induced acute pulmonary inflammation by modulating NF-κB p65-mediated immune resistance and STAT3-mediated tissue resilience. All these favorable findings presented critical insights into the remarkable abilities and health benefits of SIN in ameliorating inflammatory lung disease.

Enhanced Biodegradation and Biocompatibility of Vascular Grafts Through Oriented Core-Shell Fibrous Structure and Incorporation of Sodium Tanshinone IIA Sulfonate.

Microstructure and biological activity have been pivotal factors in the modification of vascular grafts. Equally crucial, however, are degradation behavior and mechanical stability, both of which are key to long-term success of grafts. To optimize these properties, we prepared oriented fiber membranes with core-shell structures through coaxial electrospinning, incorporating varying concentrations of sodium tanshinone IIA sulfonate (STS). In this design, poly-ethylene oxide (PEO)/STS served as the core layer, while poly-L-lactide-co-caprolactone (PLCL) formed the shell. Our findings revealed that both random and oriented fiber membranes exhibited excellent mechanical properties. Notably, compared to random fiber membranes, the oriented counterparts showed enhanced hydrophilicity and a tunable degradation rate. Furthermore, the sustained release of STS from the membranes inhibited platelet adhesion and significantly promote cell diffusion, growth, and proliferation. Importantly, the oriented fiber membranes loaded with STS were able to induce a highly organized cell arrangement and upregulate the expression of CD144 and vWF in endothelial cells. These promising findings suggest that oriented core-shell fiber membranes loaded with PEO/STS could offer valuable insights into vascular graft design and hold potential for further exploration in animal studies.

PAX2 induces endometrial cancer by inhibiting mitochondrial function via the CD133-AKT1 pathway.

Endometrial cancer (EC) is a malignancy of the endometrial epithelium. The prevalence and mortality rates associated with the disease are on the rise globally. A total of 20 cases of type I EC tissues were collected for transcriptomic sequencing, our findings indicate that PAX2 is highly expressed in EC tissues and is closely related to the pathogenesis of EC. PAX2 is a member of the paired homeobox domain family and has been linked to the development of a number of different tumours. In normal endometrial tissue, PAX2 is methylated; however, in EC, it is demethylated. Nevertheless, few studies have focused on its role in EC. A protein-protein interaction (PPI) analysis revealed a regulatory relationship between PAX2 and CD133, which in turn affects the activity of AKT1. CD133 is a well-known marker of tumor stem cells and is involved in tumor initiation, metastasis, recurrence, and drug resistance; AKT1 promotes cell survival by inhibiting apoptosis and is considered a major promoter of many types of cancer. Nevertheless, further investigation is required to ascertain whether PAX2 affects the progression of EC by regulating the CD133-AKT1 pathway. The present study demonstrated that PAX2 promoted cell proliferation, migration, invasion and adhesion, and inhibited apoptosis. Its mechanism of action was found to be the inhibition of mitochondrial oxidative phosphorylation, promotion of glycolysis, increase in mitochondrial copy number, and increase in the levels of reactive oxygen species (ROS) and hexokinase, as well as the concentration of mitochondrial calcium ions. This was achieved through the promotion of CD133 expression and the phosphorylation of AKT1. In conjunction with the aforementioned regulatory pathways, the progression of EC is facilitated.

Comparative Study on Histochemical Expression of CD34 in Different Variants of Ameloblastoma

Ameloblastoma is a benign, locally aggressive, tumor of the oral cavity having a high propensity for recurrence. The growth potential of the tumor is linked to the proliferation of preexisting vasculature and is reflected in CD34 expression. has been rephrased as “Mean Vascular Density (MVD) which measures CD34 expression, aids in predicting this proliferation. Objectives: To evaluate the biological behavior of different variants of Ameloblastoma according to expression of CD34 and to correlate it with age and gender. Methods: The present study was analytical, cross-sectional study composed of total 40, already diagnosed cases of ameloblastoma. Immuno-histochemical expression of CD34 was analyzed. Results: Follicular variant has more growth potential in females 21 (62%) and males reveal more vascular growth in plexiform 19 (80%) acanthomatous (50%) and unicystic variant (50%). More endothelial proliferation in age group of > 40 years was seen in follicular variant, whereas, in age group of < 40 years, plexiform type was more dominant. However, relationship between the age groups and MVD scores were found to be insignificant (p > 0.05). Relationship between CD34 expression in ameloblastoma and its histological variants were also found to be statistically non-significant (p=0.9). Conclusions: All variants display highest Mean Vascular Density (MVD) score in posterior mandible. Follicular variant has more growth potential in females while in males it is found more in plexiform, acanthomatous and unicystic variants. More epithelial proliferation in the follicular variety is observed in the age group over 40, whereas more plexiform type was shown in the age group below 40.

Multiplex single-cell profiling of putative cancer stem cell markers ALDH1, SOX9, SOX2, CD44, CD133 and CD15 in endometrial cancer.

The presence of cancer stem cells is linked to aggressive disease and higher risk of recurrence, and multiple markers have been proposed to detect cancer stem cells. However, a detailed evaluation of the expression patterns and the prognostic value of markers relevant for endometrial cancer is lacking. As organoid models are suggested to be enriched in cancer stem cells, such models may prove valuable to define tissue-specific cancer stem cells. To address this, imaging mass cytometry and multiplex single-cell analyses were performed on an endometrial cancer patient series including both tumor biopsies and corresponding patient-derived organoids. An antibody panel focused on cancer stem cell markers was used to identify cancer stem cell phenotypes. Over 70% of epithelial cells in the tumor biopsies expressed at least one putative cancer stem cell marker. We identified distinct cancer cell phenotypes with heterogeneous expression within individual patients and between patient samples. Few differences in the distribution of cancer cell phenotypes were observed between tumor biopsies and corresponding organoids. Cells expressing aldehyde dehydrogenase 1 (ALDH1) were more prevalent in high-grade tumors, while expression of CD44 was more prevalent in grade 1 tumors. Spatial analysis revealed significantly less interaction between ALDH1- and CD44-expressing cells. Gene expression data was used to further investigate selected markers. CD44 gene expression was associated with a favorable prognosis and was further validated using immunohistochemistry. High expression of CD44 was significantly associated with better survival. The general high expression of proposed stem cell markers may indicate alternative roles for these in endometrial cancer.

Immunohistochemical expression of CD34 in hepatocellular carcinoma and non-malignant hepatic nodules: experience at a tertiary care hospital in Bangladesh

Background: Capillarization of sinusoids occur in hepatocellular carcinoma (HCC) and several studies showed these altered sinusoids become immunoreactive for CD34. HCC and some non-malignant hepatic nodules mimic microscopically. The aims of this study were to find out the location and pattern of CD34 expression in HCC and non-malignant hepatic nodules and to see whether CD34 expression can differentiate them. Methods: This cross-sectional study was conducted in the Department of Pathology, BIRDEM General Hospital, Dhaka from March 2020 to February 2022. Thirty-one cases of HCC and 31 cases of non-malignant hepatic nodules were included in this study. Detail microscopic examinations were done regarding HCC, its morphological type, grade, cirrhosis, dysplasia and of other type of non-malignant hepatic nodules. Immunohistochemical staining of CD34 was performed in all cases. Results: No sinusoidal expression of CD34 was found in normal hepatic tissue. In benign hepatic nodules, sinusoids showed none to up to 20% areas of sinusoidal expression with +/++ intensity. HCC showed expression of CD34 in more than 50% areas with an intensity of +++ irrespective of grade and morphological type. Extent of CD34 expression increased significantly with the increasing grade of tumor. In cirrhosis, CD34 expression significantly increased in dysplastic than non-dysplastic cirrhotic nodules. Conclusion: The extent of expression became significantly increased from low grade dysplasia and more significantly increased in HCC than non-malignant hepatic nodules. BIRDEM Med J 2025; 15(1): 22-27