Syndecan-1 Expression Research Articles

Evaluation of Syndecan-1 Expression in Iraqi Patients with Papillary Thyroid Carcinoma

Papillary thyroid carcinoma (PTC) represents the most prevalent kind of thyroid gland cancer, making up around 80% of all occurrences of thyroid cancer. Evidence shows that Syndecan-1 (SDC-1) expression is lost in a number of benign and malignant epithelial neoplasms, although its expression profile in thyroid gland neoplasms is yet unknown. Therefore, the aim of this study was to assess SDC-1 expression in papillary thyroid carcinoma patients, as well as the relationship between age and gender and SDC-1 expression. To undertake a detailed investigation of SDC-1 in normal and malignant tissues, tissue sections were used to examine SDC-1 expression in 70 tissue samples, 50 distinct PTC (6 males and 44 females) and 20 normal tissue types (10 from each gender) as control. Ages in each group ranged from 20 to 60 years. The results showed a statistically different level of SDC-1 expression in patients and control. There was no significant relationship between SDC-1 expression and gender or age, in accordance with recent research findings which suggest that SDC- 1 might be exploited as a prognostic indicator or a target in cancer treatment in the future.

Endothelial eNOS deficiency causes podocyte injury through NFAT2 and heparanase in diabetic mice

The pivotal role of endothelial nitric oxide synthase (eNOS) in diabetic nephropathy (DN) has been demonstrated using global eNOS knockout (eNOSGKO) mice. However, the precise role of endothelially expressed eNOS and how its deficiency advances DN are still unclear. Here, we targeted endothelial eNOS expression (E-eNOSKO) after the onset of diabetes using the floxed eNOS and endSCL-CreERT alleles. Diabetes was induced by low-dose streptozotocin injections. To evaluate the role of nuclear factor of activated T cells-2 (NFAT2) in podocyte injury in this condition, podocyte-specific NFAT2KO mice were also generated on eNOSGKO mice. The mechanisms of podocyte injury were investigated using cultured podocytes. Compared with diabetic wild-type mice, diabetic E-eNOSKO mice showed more advanced DN accompanied by NFAT2 expression in podocytes. NO donor suppressed NFAT2 expression and activation in high-glucose cultured podocytes as well as in diabetic E-eNOSKO mice. Furthermore, podocyte-specific deletion of NFAT2 attenuated DN in diabetic eNOSGKO mice accompanied by decreased heparanase (HPSE) expression in podocytes. Consistent with this finding, HPSE was upregulated by NFAT2 transfection and suppressed by NFAT2 siRNA or NO donor treatment in cultured podocytes. HPSE transfection reduced podocyte attachment to extracellular matrix concurrent with syndecan-4 (SDC4) shedding, and this effect was attenuated by co-transfection of SDC4. Finally, HPSE inhibitor treatment attenuated podocyte injury in diabetic E-eNOSKO mice with increased SDC4 expression in podocytes. Collectively, our data suggest that endothelial eNOS deficiency causes podocyte HPSE expression in diabetic mice through NFAT2, and HPSE promotes podocyte detachment in part through SDC4 shedding, advancing DN.

Decreased expression of Syndecan- 1 (CD138) in the endometrium of adenomyosis patients suggests a potential pathogenetic role.

Adenomyosis is a special subtype of endometriosis, affecting the myometrium, affecting about 20% of women in the reproductive age period. Clinical symptoms and intensity are diverse and can vary from heavy menstrual bleeding and dysmenorrhea to infertility and repeated pregnancy losses. Thus, patients often present with a long history of illness pending presumptive clinical or surgical diagnosis. A definitive diagnosis of adenomyosis is made upon histopathological examination verifying ectopic endometrial tissue (endometrial glands and/or stroma) within the myometrium, surrounded by hyperplastic and hypertrophic smooth muscles. However, nowadays ultrasonographic and/or MRI signs can precisely detect it as well. The precise etiology and pathogenesis remain unclear. One theory assumes that adenomyosis occurs through metaplastic transformation or migration of stem cell-like cells. Our study examined the immunohistochemical expression of the transmembrane proteoglycan Syndecan-1 (CD 138), a multifunctional matrix receptor and signaling co-receptor, in the endometrium of 35 patients (n = 21 with adenomyosis and n = 14 as a control group) in the period 2016-2017. As a pilot study, we concluded that Syndecan-1 is downregulated in adenomyosis patients compared to the control group, supporting its potential role in the development of adenomyosis. Our study did not find a correlation between the immune-expression of Syndecan-1 and the menstrual cycle phase. For clinical significance in relation to our results, the investigated data showed that the downregulation of Syndecan-1 in adenomyotic patients in our study may suggest a role in promoting the invasiveness of endometriotic islands within the myometrium. However, further studies are still needed to understand the mechanistic contribution of Syndecan-1 to the pathogenesis of adenomyosis.

Syndecans modulate ghrelin receptor signaling.

Ghrelin is a gut hormone that enhances food intake and growth hormone secretion through its G-protein coupled receptor the growth hormone secretagogue receptor (GHSR). Recently, we showed that ghrelin interacts with syndecans (SDCs), a family of membrane proteins known to modulate hypothalamic appetite signaling. Here, we investigated whether SDCs impact ghrelin signaling at GHSR by assessing ghrelin-induced intracellular Ca2+ mobilization (iCa2+) and inositol phosphate1 (IP1) production in HEK293 cells. Compared with controls, the overexpression of SDCs dose-dependently increased the maximum iCa2+ response 2-4-fold, without affecting EC50. The IP1 response was similarly amplified by SDCs, but also indicated that they reduce constitutive (ghrelin-independent) activity of GHSR. These enhanced responses occurred despite a SDC dose-dependent reduction in plasma membrane GHSR levels. Although ghrelin-stimulated Gαq activation was unaltered by SDC1 expression, it failed to restore iCa2+ responsiveness in GNAQ/11 knockout cells, indicating dependence on Gαq/11, not another Gα subunit. This suggests that SDCs modulate either signaling downstream of Gαq/11 or quenching of β-arrestin2 recruitment to GHSR. Indeed, expression of SDCs at levels that only modestly suppress cell surface receptor, reduced ghrelin-induced β-arrestin2 recruitment by ~80%. SDC co-expression also delayed the peak β-arrestin2 response. However, peak β-arrestin2 recruitment follows the peak iCa2+ response, making it unclear if reduced β-arrestin2 recruitment potentiated Ca2+ signaling. Altogether, SDCs enhanced iCa2+/IP1 and reduced β-arrestin2 recruitment by GHSR in response to ghrelin, likely by modulating signaling downstream of Gαq. This could be a novel mechanism through which SDCs affect metabolism and obesity.

ScRNA-Seq Analysis Revealed CAFs Regulating HCC Cells via PTN Signaling.

Cancer-associated fibroblasts (CAFs) play a pivotal role in shaping the microenvironment of hepatocellular carcinoma (HCC). However, the mechanisms through which CAFs influence the progression of HCC remain incompletely understood. Single-cell RNA sequencing datasets (GSE158723 and GSE112271) were retrieved from the Gene Expression Omnibus (GEO) database at the National Center for Biotechnology Information (NCBI) and analyzed using R software. Our analysis suggested that CAFs may promote liver cancer cell development, possibly through the interaction of pleiotrophin (PTN) and syndecan-2 (SDC2). Clinical samples from HCC patients were collected and processed into frozen sections and single-cell suspensions for Masson staining, immunofluorescence staining, and flow cytometry. Additionally, Huh7 liver cancer cells and LO2 normal liver cells were cultured and subjected to immunofluorescence assays using cell slides. The proportion of CAFs in cancerous tissues was higher than in adjacent non-cancerous tissues, and pleiotrophin (PTN) expression was elevated in cancer tissues compared to adjacent tissues. These findings aligned with the results of the single-cell RNA sequencing (scRNA-seq) analysis. Furthermore, SDC2 expression was significantly upregulated in Huh7 liver cancer cells compared to LO2 normal liver cells. This study suggests that CAFs may contribute to HCC progression via the PTN/SDC2 signaling pathway. Our findings provide deeper insights into the interactions between CAFs and HCC cells within the tumor microenvironment (TME).

Trichinellaspiralis C-type lectin mediates larva invasion of gut mucosa via binding to syndecan-1 and damaging epithelial integrity in mice

C-type lectin (CTL) plays a vital role in parasite adhesion, invading host's cells and immune escape. The objective of this research was to explore whether recombinant T. spiralis CTL (rTsCTL) binding with syndecan-1 damages intestine epithelial integrity and mediates T. spiralis intrusion in mice. The results showed that rTsCTL interacted with syndecan-1 and activated STAT3 pathway in gut epithelium, decreased tight junctions (TJs) expressions and damaged gut epithelium integrity, promoted T. spiralis intrusion, and increased expression level of inflammatory cytokine and mucin. The syndecan-1 inhibitor (β-xyloside) and STAT3 phosphorylation inhibitor (Stattic) significantly suppressed syndecan-1 expression and STAT3 pathway activation, reduced the expression levels of TJs, pro-inflammatory cytokines (TNF-α and IL-1β), Muc2 and Muc5ac, and declined intestinal permeability in T. spiralis-infected mice. These results revealed that the inhibitors suppressed T. spiralis invasion and development in gut mucosa, decreased intestinal adult burdens and relieved gut inflammation. These findings further testified that the in vivo binding of TsCTL with syndecan-1 destroyed enteral mucosal epithelial integrity and promoted T. spiralis intrusion of gut mucosa via activating STAT3 pathway and decreasing TJs expression. TsCTL could be deemed as a promising vaccine target to interrupt T. spiralis infection.

Overwork induces vascular endothelial barrier dysfunction in mice

To investigate the impact of overwork on vascular endothelial barrier function in mice. Thirty KM mice were randomized equally into control, overwork for 2 weeks (W2) group and 4 weeks (W4) group. In the latter two groups, the mice were subjected to continuous standing in water for 8 h followed by restraint for 3 h to simulate overwork on a daily basis for 2 and 4 weeks. After modeling, 4 mice from each group were intraperitoneally injected with Evans blue dye to assess vascular permeability. In the other 6 mice, serum IL-1β levels were measured using ELISA, and arterial tissues were collected for histological examination and detection of mRNA expressions of occludin, claudin-5, ZO-1, JAM-A and VE-cadherin; immunofluorescence assay was used to detect the protein expressions of claudin-5, ZO-1, VE-cadherin, and Syndecan-1. The mice in W2 and W4 groups exhibited slower weight gain, hair loss, reduced activity, and significantly increased serum IL-1β levels. Vascular permeability was significantly increased in W4 group. In W2 group, the endothelial cells were swollen and dissociated, and the intima was rough and irregular; arterial intimal rupture was observed in W4 group. The mRNA expressions of occludin, claudin-5, ZO-1 and JAM-A in the arterial tissues were significantly increased in W2 group but decreased in W4 group, while VE-cadherin mRNA expression were reduced in both groups (P < 0.05). The protein expressions of claudin-5, ZO-1, VE-cadherin, and Syndecan-1 were all significantly reduced in W4 group. Prolonged overwork can cause damage of the intercellular junction complexes in arterial endothelial cells and the endothelial glycocalyx to result in impaired barrier function and increased vascular permeability in mice.

Effect of chronic periodontitis on the endothelial glycocalyx of rat penile corpus cavernosum.

Chronic periodontitis may induce erectile dysfunction (ED), however, the specific mechanism involved is unclear. The endothelial glycocalyx (eGlx) is a structure that can regulate endothelial nitric oxide synthase (eNOS) phosphorylation on the cavity surface of vessels. To investigate whether chronic periodontitis leads to ED by affecting the eGlx. Twenty-four 4-week-old male Sprague‒Dawley rats were randomly divided into four groups (n=6): the control group, chronic periodontitis group, chronic periodontitis + heparin group (subcutaneous heparin 200 U/kg/day, 7 days), and control + heparin group. Four weeks after the induction of periodontitis in the rats, the maximum intra-cavernous pressure/mean arterial pressure (ICPmax/MAP), serum C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), nitric oxide (NO), heparin sulfate (HS), syndecan-1 (SDC-1), heparanase (HPSE), eNOS, and phosphor-eNOS (p-eNOS) concentration were measured, and the eGlx of the penile corpus cavernosum was observed by transmission electron microscopy (TEM). Chronic periodontitis can degrade eGlx on the rat penile corpus cavernosum by increasing serum CRP, TNF-α, and IL-6 levels, reducing the p-eNOS/eNOS ratio and the NO concentration in the penile corpus cavernosum, and resulting in the inhibition of the erectile function. Serum CRP, TNF-α, and IL-6 levels and HPSE expression in penile cavernous tissue were significantly greater in the chronic periodontitis group than in the control group and the chronic periodontitis + heparin group (P<0.05). The average thickness of the eGlx muscle in the penile corpus cavernosum in the chronic periodontitis group was significantly lower than those in the control group and chronic periodontitis + heparin group (P<0.05). The HS concentration, SDC-1 expression, p-eNOS/eNOS, NO concentration, and ICPmax/MAP in the chronic periodontitis group were significantly lower than those in the control group and chronic periodontitis+ heparin group (P<0.01). The eGlx on penile cavernosum vessels may be a new therapeutic target for the treatment of ED. This study revealed that chronic periodontitis promotes the decomposition of vascular eGlx in the rat penile corpus cavernosum, however, it is not clear whether chronic periodontitis inhibits the synthesis of eGlx. Chronic periodontitis can degrade eGlx on the rat penile corpus cavernosum by increasing serum CRP, TNF-α, and IL-6 levels, reducing the p-eNOS/eNOS ratio and the NO concentration in penile cavernous tissue, and resulting in the inhibition of the erectile function. Heparin inhibited eGlx decomposition and improved erectile function in rats with chronic periodontitis.

Abstract C019: A novel SDC1-targeted therapeutic antibody inhibits macropinocytosis and induces anti-tumor immunity in pancreatic cancer

Abstract Given that the mutated KRAS oncogene (KRAS*) dominates the genetic landscape of pancreatic ductal adenocarcinoma (PDAC), the development of KRAS* inhibitors represents a significant breakthrough in PDAC therapy. However, emerging evidence suggests that PDAC may eventually overcome its dependency on KRAS* and develop resistance to KRAS* inhibitor treatment. Our laboratory is dedicated to uncovering novel, accessible therapeutic targets that govern the mechanisms essential for KRAS*- driven PDAC cell survival. Our recent work has identified Syndecan1 (SDC1), a major heparan sulfate proteoglycan, as a critical mediator of KRAS* activity, promoting nutrient salvaging and fueling cancer cell growth, even in cases where PDAC cells have evaded KRAS* targeted therapy. Our finding positions SDC1 as a promising new therapeutic target for PDAC therapy. In our pursuit of new therapeutic approaches that can directly and specifically target SDC1 activity, we have successfully developed a monoclonal antibody against SDC1 (22B mAb), which exhibits remarkable sensitivity and specificity for human SDC1. Our results indicate that 22B mAb exerts substantial inhibition of PDAC cell growth in vitro and desirable tumor inhibitory effects in vivo in murine PDAC tumors and human PDAC cell-derived xenograft tumors. Interrogation of mechanism of actions further demonstrates that 22B elicits both direct effect in inhibiting macropinocytosis to block nutrient salvage of PDAC cells and indirect effect in inducing antibody-dependent cellular cytotoxicity (ADCC) to eliminate tumor cells. Notably, our 22B mAb synergizes with KRAS* inhibitors, chemotherapy, or immunotherapy, resulting in significantly enhanced therapeutic effects. In summary, our 22B mAb represents the first in class of anti-SDC1 antibody that not only directly targets the PDAC cells but also elicits immune cell-mediated killing. Additionally, our antibody holds the potential for developing new anti-PDAC therapeutic strategies, including antibody drug conjugates with cytotoxic or radionuclides payloads, for SDC1 targeted therapy/theranostics in PDAC. Thus, our newly developed 22B therapeutic antibody provides an alternate strategy for PDAC treatment and opens up new research horizons in therapeutic targeting of SDC1 in other malignancies characterized by aberrant SDC1 expression. Citation Format: Zecheng Yang, Madelaine S Theardy, Shuaitong Chen, Yongkun Wei, Mitsunobu Takeda, Xiaofei Wang, Jun Yao, Jennifer Li, Jangho Park, Yangxi Zheng, Long T Vien, Laura Bover, Haoqiang Ying, Wantong Yao. A novel SDC1-targeted therapeutic antibody inhibits macropinocytosis and induces anti-tumor immunity in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C019.

Syndecan-1 inhibition promotes antitumor immune response and facilitates the efficacy of anti-PD1 checkpoint immunotherapy.

Tumor cell-originated events prevent efficient antitumor immune response and limit the application of anti-PD1 checkpoint immunotherapy. We show that syndecan-1 (SDC1) has a critical role in the regulation of T cell-mediated control of tumor growth. SDC1 inhibition increases the permeation of CD8+ T cells into tumors and triggers CD8+ T cell-mediated control of tumor growth, accompanied by increased proportions of progenitor-exhausted and effector-like CD8+ T cells. SDC1 deficiency alters multiple signaling events in tumor cells, including enhanced IFN-γ-STAT1 signaling, and augments antigen presentation and sensitivity to T cell-mediated cytotoxicity. Combinatory inhibition of SDC1 markedly potentiates the therapeutic effects of anti-PD1 in inhibiting tumor growth. Consistently, the findings are supported by the data from human tumors showing that SDC1 expression negatively correlates with T cell presence in tumor tissues and the response to immune checkpoint blockade therapy. Our findings suggest that SDC1 inhibits antitumor immunity, and that targeting SDC1 may promote anti-PD1 response for cancer treatment.

Effect of long-term MgSO4 treatment on placental Syndecan1 expression in preeclampsia

Effect of long-term MgSO4 treatment on placental Syndecan1 expression in preeclampsia

Therapeutic targeting of Syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers.

The therapeutic benefit of recently developed mutant KRAS (mKRAS) inhibitors has been limited by the rapid onset of resistance. Here, we aimed to delineate the mechanisms underlying acquired resistance to mKRAS inhibition and identify actionable targets for overcoming this clinical challenge. Previously, we identified Syndecan-1 (SDC1) as a key effector for pancreatic cancer progression whose surface expression is driven by mKRAS. By leveraging both pancreatic and colorectal cancer models, we found that surface SDC1 expression was initially diminished upon mKRAS inhibition, but recovered in tumor cells that bypass mKRAS dependency. Functional studies showed that these tumors depended on SDC1 for survival, further establishing SDC1 as a driver for the acquired resistance to mKRAS inhibition. Mechanistically, we revealed that the YAP1-SDC1 axis was the major driving force for bypassing mKRAS dependency to sustain nutrient salvage machinery and tumor maintenance. Specifically, YAP1 activation mediated the recovery of SDC1 localization on cell surface that sustained macropinocytosis and enhanced the activation of multiple RTKs, promoting resistance to KRAS-targeted therapy. Overall, our study has provided the rationale for targeting the YAP-SDC1 axis to overcome resistance to mKRAS inhibition, thereby revealing new therapeutic opportunities for improving the clinical outcome of patients with KRAS-mutated cancers.

Syndecan-4 inhibition attenuates cartilage degeneration in temporomandibular joint osteoarthritis.

Syndecan 4 (SDC4), a type I transmembrane proteoglycan, serves as a critical link between chondrocytes and the extracellular matrix. This study aimed to explore the role of SDC4 in cartilage degeneration of temporomandibular joint osteoathritis (TMJOA). Condylar chondrocytes were stimulated with varying concentrations of recombinant rat interleukin-1β (rrIL-1β) and SDC4 small interfering RNA (si-SDC4). Anti-SDC4 ectodomain-specific antibodies or IgG were intra-articularly administrated in a TMJOA model rats. SDC4 conditional knockout (SDC4-cKO) and Sdc4flox/flox mice were induced TMJOA. Cartilage degeneration was assessed using haematoxylin & eosin (H&E) and safranin O (SO) staining. Protein levels of SDC4, matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase with a thrombospondin motifs 5 (ADAMTS5), tumour necrosis factor α (TNFα), type II collagen (Col-II), aggrecan (ACAN), cleaved caspase 3 (CASP3), Ki67 and related pathways in condylar cartilage were evaluated by immunohistochemical (IHC) staining or western blot assays. SDC4 expression was evidently increased in MIA-model animals compared to control groups. rrIL-1β stimulation increased the expression of SDC4, MMP3 and ADAMTS5 expression in chondrocytes, while decreasing the expression of Col-II. These effects were reversed by si-SDC4 invitro. Invivo, SDC4 blockade reduced the death of chondrocytes and the loss of cartilage matrix, which was evidenced by increased expression of Col-II and ACAN, and a decrease in SDC4, MMP13 and cleaved-CASP3-positive cells. Furthermore, the protein levels of ACAN and Ki67 were elevated, and the ERK1/2 and P38 signalling pathways were activated following SDC4 inhibition. SDC4 inhibition significantly ameliorates condylar cartilage degeneration, which was mediated, at least partly, through P38 and ERK1/2 signalling. Inhibition of SDC4 may be of great value for the treatment of TMJOA.

Syndecan-4 levels in bronchoalveolar lavage fluid and serum in non-small cell lung cancer

BACKGROUND Lung cancer has the highest cancer-related mortality rate worldwide. Research has been conducted to improve early detection and markers of predictive value but only focused on the expression of syndecan-4 (SDC4) in serum. Studies in bronchoalveolar lavage (BAL) fluids of non-small cell lung cancer (NSCLC) patients are still limited. This study aimed to evaluate the clinical value of SDC4 in serum and BAL in NSCLC patients. METHODS Blood serum and BAL fluids were obtained from 44 patients with NSCLC and 41 non-cancer patients as the control. The level of SDC4 was measured. The relationships between SDC4 and clinicopathologic factors were also analyzed. RESULTS Serum SDC4 levels in NSCLC patients were significantly lower than the control group (p = 0.002). Furthermore, the disease stages and serum SDC4 levels had a negative correlation, which was lower in the advanced stage (IIIb/IV) than in the initial stage (I/II/IIIa) (p = 0.517). The same results were obtained from BAL fluids SDC4 levels, which were significantly lower in the advanced stage (IIIb/IV) than in the early stage (I/II/IIIa) (p = 0.007). CONCLUSIONS Serum SDC4 levels in NSCLC patients were lower than those of non-cancer patients. They also performed different results in disease stages. SDC4 could be a helpful biomarker in NSCLC.

Neuroprotective Effect of Ganoderic Acid against Focal Ischemic Stroke Induced by Middle Cerebral Artery Occlusion in the Rats via Suppression of Oxidative Stress and Inflammation.

Swiss Wistar rats were used for the current study. The rats were subjected to middle cerebral artery occlusion (MCAO) to simulate transient focal ischemia, followed by reperfusion. Various neurological parameters, including infarct size, neurological deficit score, brain water content, Evans blue leakage, nitric oxide (NO), inducible nitric oxide synthase (iNOS), lactate dehydrogenase (LDH), antioxidant levels, inflammatory cytokines, apoptosis markers, inflammatory parameters, and matrix metalloproteinases (MMP) levels, were estimated. Additionally, mRNA expressions were evaluated in the brain tissue. Dose dependently treatment of GA significantly (P < 0.001) suppressed the infarct size, neurological deflects score, brain water, evans blue leakage, NO, iNOS, LDH, C-X-C chemokine receptor type 4 (CXCR-4), monocyte chemoattractant protein-1 (MCP-1), S100 calcium-binding protein B (S-100β) and K+-Cl- cotransporter 1 (KCC1) positive cells. GA altered the level of oxidative stress parameters like Total antioxidant capacity (T-AOC), 8-hydroxy-2'-deoxyguanosine (8-OhdG), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH), malonaldehyde (MDA); cytokines viz., tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-1β, IL-6, IL-9, IL-10; inflammatory parameters such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), prostaglandin (PGE2), Nuclear factor kappa B (NF-κB); apoptosis parameters like B-cell leukemia/lymphoma 2 protein (Bcl-2), Bcl-2-associated protein x (Bax), Caspase-3; matrix metallopeptidase (MMP) parameters like MMP-2, MMP-3, and MMP-9, respectively. GA remarkably suppressed the mRNA expression of TRL-4, Syndecan-1, CSF, Aquaporin-1, OCT3, and RFX1. Ganoderic acid exhibited the protection against the cerebral ischemia reperfusion via multiple mechanism.

Dyslipidemia and hyperglycemia induce overexpression of Syndecan-3 in erythrocytes and modulate erythrocyte adhesion.

Erythrocytes are important vascular components that play vital roles in maintaining vascular homeostasis, in addition to carrying oxygen. Previously, we reported that the changes in the internal milieu (e.g. hyperglycemia or hypercholesterolemia) increase erythrocyte adhesion to various extracellular matrix components, potentially through altering glycosaminoglycans (GAGs). In this study, we have investigated the expression of syndecan (Sdc) family members that could be involved in mediating cytoadherence under conditions of dyslipidemia and hyperglycemia. Among the Sdc family members analysed, we found significant overexpression of Sdc-3 in erythrocyte membranes harvested from high-fat-fed control and diabetic animals. Animal studies revealed a positive correlation between Sdc-3 expression, blood sugar levels and erythrocyte adhesion. In the human study, diabetic cohorts with body mass index >24.9 showed significantly increased expression of Sdc-3. Interestingly, blocking the Sdc-3 moiety with an anti-Sdc-3 antibody revealed that the core protein might not be directly involved in erythrocyte adhesion to fibronectin despite the GAGs bringing about adhesion. Lastly, Nano liquid chromatography-mass spectrometry/MS verified the presence of Sdc-3 in erythrocyte membranes. In conclusion, the high-fat diet and diabetes modulated Sdc-3 expression in the erythrocyte membrane, which may alter its adhesive properties and promote vascular complications.

Correlation of syndecan gene amplification with metastatic potential and clinical outcomes in carcinomas.

Cell surface receptors play crucial roles in cellular responses to extracellular ligands, helping to modulate the functions of a cell based on information coming from outside the cell. Syndecan refers to a family of cell adhesion receptors that regulate both extracellular and cytosolic events. Alteration of syndecan expression disrupts regulatory mechanisms in a cell type-specific fashion, often leading to serious diseases, notably cancer. Given the multifaceted functions and distinct tissue distributions of syndecan, it will be important to unravel the gene-level intricacies of syndecan expression and thereby further understand its involvement in various carcinogenic processes. Although accumulating evidence indicates that the protein expression patterns of syndecan family members are significantly altered in cancer cells, the underlying gene-level mechanisms remain largely unknown. This review endeavors to explore syndecan gene expression levels across different cancer types by scrutinizing extensive cancer genome datasets using tools such as cBioPortal. Our analysis unveils that somatic mutations in SDC genes are rare occurrences, whereas copy number alterations are frequently observed across diverse cancers, particularly in SDC2 and SDC4. Notably, amplifications of SDC2 and SDC4 correlate with heightened metastatic potential and dismal prognosis. This underscores the recurrent nature of SDC2 and SDC4 amplifications during carcinogenesis and sheds light on their role in promoting cancer activity through augmented protein expression. The identification of these amplifications not only enriches our understanding of carcinogenic mechanisms but also hints at the potential therapeutic avenue of targeting SDC2 and SDC4 to curb cancer cell proliferation and metastasis.

IL-34 and its receptors as predictors of brain metastasis and prognosis in lung adenocarcinoma: Unveiling insights through bioinformatic and immunohistochemical investigations

BackgroundBrain metastasis (BM) is a prevalent form of metastasis in lung adenocarcinoma (LUAD), necessitating investigations into the underlying mechanisms. Interleukin 34 (IL-34) and its receptors, macrophage colony-stimulating factor-1 receptor (CSF-IR), Syndecan-1 (SDC-1), and protein-tyrosine phosphatase zeta receptor (PTPRZ1), are known to play pivotal roles in the metastasis of malignant tumors, thereby holding promise as potential biomarkers for studying BM in LUAD. MethodsWe performed immunohistochemistry to analyze the expression of IL-34, CSF-1R, SDC-1, and PTPRZ1 in 10 pairs of LUAD primary tissues and BMs, along with 96 unpaired primary tissues and 68 unpaired BMs. Subsequently, we evaluated the association between protein expression and the occurrence of BM. Furthermore, Kaplan-Meier survival curve analysis was conducted on both network and clinical data to explore the association between protein expression and patient prognosis and survival. ResultsAt the protein level, the expression of IL-34 and its receptors showed significant variation between paired primary tumors and BMs in 10 LUAD patients. The levels of IL-34, CSF-1R, and SDC-1 expression are typically elevated in brain metastatic lesions of LUAD compared to primary LUAD tumors. Furthermore, patients with high CSF-1R expression in primary LUAD are at a greater risk of developing brain metastases. High expression of IL-34 and CSF-1R in primary LUAD lesions indicated poor disease-free survival (DFS) and overall survival (OS), while high expression of SDC-1 indicated poor OS. Cox multivariate analysis further revealed that CSF-1R and IL-34+CSF-1R positivity independently affected LUAD OS. These findings were further substantiated in unpaired samples. ConclusionsOur results indicate significant alterations in the expression of IL-34 and its receptors, CSF-1R and SDC-1, between LUAD primary lesions and BMs, with increased expression observed in BMs. LUAD patients with positive CSF-1R expression in primary lesions exhibited a higher likelihood of developing BM, and high expression of IL-34, CSF-1R, and SDC-1 correlated with poor prognosis. These findings contribute novel insights towards identifying potential treatment or diagnostic targets for metastatic LUAD.

The effects of metabolites from three vaginal bacteria on the Syndecan-1 of cervical epithelial cells

This study aims to explore the impact of metabolites from three vaginal bacteria on the expression of Syndecan 1 (SDC-1). Human cervical epithelial cells (HcerEpic) were separately incubated with the cell-free supernatants of Lactobacillus crispatus (LCS group), Gardnerella vaginalis (GVS group), and Atopobium vaginalis (AVS group). LCS showed a proliferative effect on HcerEpic, with the most significant effect observed at a concentration of 30 % (P < 0.001). GVS and AVS exhibited some cytotoxicity, with significant growth inhibitory effects observed at concentrations of 30 % and 40 % (P < 0.01). Therefore, subsequent experiments were conducted using 30 % LCS, 40 % GVS, and 40 % AVS. In terms of cellular morphology, compared to the Control group, the LCS group showed more frequent fusion of cell sheets, with no obvious changes in the morphology of individual cells. In the GVS and AVS groups, some individual cells became round and smaller, with reduced protrusions and even a small amount of floating cells. The metabolic products of the three vaginal bacteria significantly upregulated the expression of IL-1β, IL-6, and TNF-α in HcerEpic (P < 0.05). In the GVS and AVS groups, the level of SDC-1 on the surface of HcerEpic was significantly decreased (P < 0.01), while the concentration of SDC-1 in the cell culture supernatant was significantly increased (P < 0.0001). Additionally, the level of SDC-1 mRNA was significantly downregulated (P < 0.01). In the LCS group, no significant changes were observed in SDC-1 protein and mRNA expression (P > 0.05). LCS promotes HcerEpic proliferation, without significant impact on SDC-1 expression and shedding. This provides molecular evidence for LCS as a protective factor against human papillomavirus infection in the cervix. Metabolites of GV and AV inhibit HcerEpic proliferation, induce cytokine secretion, suppress SDC-1 transcription and expression, and promote SDC-1 shedding.

Gene expression profiling of venous malformations identifies the role of SDC1 in venous endothelial cells

ObjectiveTo obtain insight into the molecular process implicated in venous malformations (VMs) and identify potential targets for treatment of VMs, this study profiled the gene expression pattern in VMs, investigated alterations of syndecan-1 (SDC1) expression in VMs, and tested the hypothesis that aberrant SDC1 expression triggers abnormal angiogenesis and VM development. MethodsMicroarray analysis was performed to identify differentially expressed genes (DEGs) on a transcriptome-wide level in VMs and conjunctive normal. Gene Ontology molecular functional analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were carried out to establish enhancement of biological signaling pathways involved in VMs. Among the DEGs, we focused on SDC1, which is involved in matrix remodeling, cell proliferation and invasion, and angiogenesis. SDC1 expression in VMs was verified by qRT-PCR, western blotting, and immunohistochemistry. Loss-of-function of SDC1 was achieved in human umbilical vein endothelial cells (HUVECs) by siRNA to investigate the roles of SDC1 in cell migration, invasion, and angiogenesis. ResultsCompared with control tissue, the transcriptome study identified 274 upregulated DEGs and 3 downregulated DEGs. The transcript and protein levels of SDC1 were significantly decreased in VMs compared with normal tissue. Inhibition of SDC1 enhanced HUVEC migration, invasion, and angiogenesis. ConclusionOur genome-wide microarray analysis suggests the involvement of numerous genes in VMs. Among them, SDC1 plays a substantial role in the process of angiogenesis and development of VMs. SDC1 may represent a potential target for a molecular therapy for VMs.