Syndecan-1 Expression Research Articles

Crotamine/siRNA Nanocomplexes for Functional Downregulation of Syndecan-1 in Renal Proximal Tubular Epithelial Cells.

Proteinuria drives progressive tubulointerstitial fibrosis in native and transplanted kidneys, mainly through the activation of proximal tubular epithelial cells (PTECs). During proteinuria, PTEC syndecan-1 functions as a docking platform for properdin-mediated alternative complement activation. Non-viral gene delivery vectors to target PTEC syndecan-1 could be useful to slow down alternative complement activation. In this work, we characterize a PTEC-specific non-viral delivery vector composed of the cell-penetrating peptide crotamine complexed with a syndecan-1 targeting siRNA. Cell biological characterization was performed in the human PTEC HK2 cell line, using confocal microscopy, qRT-PCR, and flow cytometry. PTEC targeting in vivo was carried out in healthy mice. Crotamine/siRNA nanocomplexes are positively charged, about 100 nm in size, resistant to nuclease degradation, and showed in vitro and in vivo specificity and internalization into PTECs. The efficient suppression of syndecan-1 expression in PTECs mediated by these nanocomplexes significantly reduced properdin binding (p < 0.001), as well as the subsequent complement activation by the alternative complement pathway (p < 0.001), as observed in either normal or activated tubular conditions. To conclude, crotamine/siRNA-mediated downregulation of PTEC syndecan-1 reduced the activation of the alternative complement pathway. Therefore, we suggest that the present strategy opens new venues for targeted proximal tubular gene therapy in renal diseases.

New insights into the molecular basis of spinal neurofibromatosis type 1.

Spinal neurofibromatosis (SNF) is a form of neurofibromatosis type 1 (NF1) characterized by bilateral neurofibromas involving all spinal roots. The pathogenic mechanisms determining the SNF form are currently unknown. To verify the presence of genetic variants possibly related to SNF or classic NF1, we studied 106 sporadic NF1 and 75 SNF patients using an NGS panel of 286 genes encoding RAS pathway effectors and neurofibromin interactors and evaluated the expression of syndecans (SDC1, SDC2, SDC3, SDC4), the NF1 3' tertile interactors, by quantitative real-time PCR. We previously identified 75 and 106 NF1 variants in SNF and NF1 cohorts, respectively. The analysis of the distribution of pathogenic NF1 variants in the three NF1 tertiles showed a significantly higher prevalence of NF1 3' tertile mutations in SNF than in the NF1 cohort. We hypothesized a potential pathogenic significance of the 3' tertile NF1 variants in SNF. The analysis of syndecan expression on PBMCs RNAs from 16 SNF, 16 classic NF1 patients and 16 healthy controls showed that the expression levels of SDC2 and SDC3 were higher in SNF and NF1 patients than in controls; moreover, SDC2, SDC3 and SDC4 were significantly over expressed in patients mutated in the 3' tertile compared to controls. Two different mutational NF1 spectra seem to characterize SNF and classic NF1, suggesting a pathogenic role of NF1 3' tertile and its interactors, syndecans, in SNF. Our study, providing new insights on a possible role of neurofibromin C-terminal in SNF, could address effective personalized patient management and treatments.

Store-operated Ca2+ entry-sensitive glycolysis regulates neutrophil adhesion and phagocytosis in dairy cows with subclinical hypocalcemia

Hypocalcemia in dairy cows is associated with a decrease of neutrophil adhesion and phagocytosis, an effect driven partly by changes in the expression of store-operated Ca2+ entry (SOCE)-related molecules. It is well-established in non-ruminants that neutrophils obtain the energy required for immune function through glycolysis. Whether glycolysis plays a role in the acquisition of energy by neutrophils during hypocalcemia in dairy cows is unknown. To address this relationship, we performed a cohort study and then a clinical trial. Neutrophils were isolated at 2 d postcalving from lactating Holstein dairy cows (average 2.83 ± 0.42 lactations, n = 6) diagnosed as clinically healthy (CON) or with plasma concentrations of Ca2+ < 2.0 mmol/L as a criterion for diagnosing subclinical hypocalcemia (HYP, average 2.83 ± 0.42 lactations, n = 6). In the first experiment, neutrophils were isolated from blood of CON and HYP cows and used to analyze aspects of adhesion and phagocytosis function through QRT-PCR along with confocal laser scanning microscopy, mRNA expression of the glycolysis-related gene hexokinase 2 (HKII) and components of the SOCE moiety ORAI calcium release-activated calcium modulator 1 [ORAI1, ORAI2, ORAI3, stromal interaction molecule 1 (STIM1) and STIM2]. Results showed that adhesion and phagocytosis function were reduced in HYP cows. The mRNA expression of adhesion-related syndecan-4 (SDC4), integrin β9 (ITGB9) and integrin β3 (ITGB3) and phagocytosis-related molecules complement component 1 R subcomponent (C1R), CD36, tubulinß1 (TUBB1) were significantly decreased in the HYP group. In the second experiment, to address how glycolysis affects neutrophil adhesion and phagocytosis, neutrophils isolated from CON and HYP cows were treated with 2 μM of the HKII inhibitor Benserazide-d3 or 1 μM of the fructose-bisphosphatase 1 (FBP1) inhibitor MB05032 for 1 h. Results revealed that the HKII inhibitor Benserazide-d3 reduced phagocytosis and the mRNA abundance of ITGB9, and CD36 in the HYP group. The FBP1 inhibitor MB05032 increased adhesion and phagocytosis and increased mRNA abundance of HKII, ITGB9, and CD36 in the HYP group. Lastly, to investigate the mechanism whereby SOCE-sensitive glycolysis affects neutrophil adhesion and phagocytosis, isolated neutrophils were treated with 1 μM of the SOCE activator thapsigagin or 50 μM of the inhibitor 2-APB for 1 h. Results showed that thapsigargin increased mRNA abundance of HKII, ITGB9, and CD36, and increased adhesion and phagocytosis in the HYP group. In contrast, 2-APB decreased mRNA abundance of HKII and both adhesion and phagocytosis of neutrophils in the CON group. Overall, the data indicated that SOCE-sensitive intracellular Ca2+ levels affect glycolysis and help regulate adhesion and phagocytosis of neutrophils during hypocalcemia in dairy cows.

Syndecan-4 is a maestro of gastric cancer cell invasion and communication that underscores poor survival

Gastric cancer is a dominating cause of cancer-associated mortality with limited therapeutic options. Here, we show that syndecan-4 (SDC4), a transmembrane proteoglycan, is highly expressed in intestinal subtype gastric tumors and that this signature associates with patient poor survival. Further, we mechanistically demonstrate that SDC4 is a master regulator of gastric cancer cell motility and invasion. We also find that SDC4 decorated with heparan sulfate is efficiently sorted in extracellular vesicles (EVs). Interestingly, SDC4 in EVs regulates gastric cancer cell-derived EV organ distribution, uptake, and functional effects in recipient cells. Specifically, we show that SDC4 knockout disrupts the tropism of EVs for the common gastric cancer metastatic sites. Our findings set the basis for the molecular implications of SDC4 expression in gastric cancer cells and provide broader perspectives on the development of therapeutic strategies targeting the glycan-EV axis to limit tumor progression.

Group-3 innate lymphoid cells protect from intestinal inflammation via syndecan-4

Abstract Group-3 innate lymphoid cells (ILC3s) are a recently described set of tissue resident immune cells which are enriched in the intestine, express RORγt, and secrete a variety of effector cytokines to orchestrate homeostasis, inflammation, and immunity. Crucially, intestinal ILC3 function and frequency is dysregulated during inflammatory bowel disease (IBD). However, it remains unclear how ILC3s sense and respond to the heterogeneity of signals present in the intestinal microenvironment or how this cell type becomes disrupted during intestinal inflammation. Recently, a single-cell RNA-sequencing analysis in our laboratory identified that syndecan-4 is highly expressed within ILC3s. Syndecans are a class of heparan sulfate proteoglycans which can become dysregulated in the intestinal epithelium and the lamina propria of IBD patients. Further, mice lacking global expression of syndecan-4 show a heightened susceptibility to models of intestinal inflammation. However, cell-specific and molecular mechanisms for this protection have yet to be elucidated. Here, we unexpectedly identify that syndecan-4 is significantly enriched among ILC3s relative to other intestinal immune cells. IL-1 selectively upregulates ILC3-specific syndecan-4, but during acute and chronic mouse modeling of intestinal inflammation, ILC3 expression of syndecan-4 is reduced. Mice lacking ILC3-specific syndecan-4 exhibit exacerbated susceptibility to intestinal inflammation resulting in greater loss of intestinal epithelial architecture compared to controls. Collectively, our data indicate that syndecan-4 represents a novel pathway by which ILC3s orchestrate intestinal health and limit tissue damage during inflammation. Research in the Sonnenberg Laboratory is supported by the National Institutes of Health (R01AI143842, R01AI123368, R01AI145989, U01AI095608, R21CA249274, R01AI162936 and R01CA274534), the NIAID Mucosal Immunology Studies Team (MIST), an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund, Linda and Glenn Greenberg, the Dalton Family Foundation, and the Roberts Institute for Research in IBD. B.F. is supported by the NIAID of the National Institutes of Health training grant T32 (5 T32 AI 134632-5). G.F.S. is a CRI Lloyd J. Old STAR.

PULMONARY VASCULAR ENDOTHELIAL GLYCOCALYX DEGRADATION CONTRIBUTES TO ACUTE LUNG INJURY IN EXPERIENCING HEATSTROKE.

Objectives: This study investigated the role and potential involvement of pulmonary vascular glycocalyx degradation in acute lung injury in rats with severe heatstroke (HS). Methods: Rats in an established HS model were exposed to a heated environment for 60 min in an incubator (temperature, 40°C ± 2°C; humidity, 65% ± 5%). Following pretreatment with heparanase III (HPSE III) or heparin, pathological lung injury, arterial blood gas, alveolar barrier disruption, and hemodynamic changes were evaluated. The vascular endothelial structures of the lungs were examined using electron microscopy. The concentration of Evans blue dye in the lungs and arterial blood gas were assessed. An enzyme-linked immunosorbent assay was used to quantify the plasma concentration of heparan sulfate proteoglycan. The expression of glypican-1 and syndecan-1 in pulmonary vessels was measured using immunofluorescence. Western blots were used to detect the expression of TNF-α, IL-6, and vascular endothelial biomarkers in the rat lungs. Pulmonary apoptosis was assessed using a TUNEL (terminal dUTP nick end labeling) assay, and the concentrations of malondialdehyde were measured. Results: Glycocalyx shedding aggravated lung injuries. Severe histopathological damage was observed, and indexes of lung function deviated from abnormal ranges. In addition, pulmonary vascular endothelial cells were disrupted. Compared with the HS group, the plasma concentration of heparan sulfate proteoglycan significantly increased in the HPSE group ( P < 0.05). The expression of glypican-1 and syndecan-1 decreased, and the extravasation of Evans blue dye increased ( P < 0.01). Endothelial biomarker expression increased in the lung tissue, whereas occludin expression decreased. Moreover, TNF-α and IL-6 were overexpressed following heat stress. Furthermore, apoptosis of pulmonary tissues and the concentration of malondialdehyde in rat lungs increased in the HS and HPSE groups. Conclusions : Heatstroke induced pulmonary glycocalyx degradation, which increased vascular permeability and aggravated vascular endothelial dysfunction, contributing to apoptosis, inflammation, and oxidation in the pulmonary tissues.

Unravelling the Effects of Syndecan-4 Knockdown on Skeletal Muscle Functions.

The remodelling of the extracellular matrix plays an important role in skeletal muscle development and regeneration. Syndecan-4 is a cell surface proteoglycan crucial for muscle differentiation. Syndecan-4-/- mice have been reported to be unable to regenerate following muscle damage. To investigate the consequences of the decreased expression of Syndecan-4, we have studied the in vivo and in vitro muscle performance and the excitation-contraction coupling machinery in young and aged Syndecan-4+/- (SDC4) mice. In vivo grip force was decreased significantly as well as the average and maximal speed of voluntary running in SDC4 mice, regardless of their age. The maximal in vitro twitch force was reduced in both EDL and soleus muscles from young and aged SDC4 mice. Ca2+ release from the sarcoplasmic reticulum decreased significantly in the FDB fibres of young SDC4 mice, while its voltage dependence was unchanged regardless of age. These findings were present in muscles from young and aged mice as well. On C2C12 murine skeletal muscle cells, we have also found altered calcium homeostasis upon Syndecan-4 silencing. The decreased expression of Syndecan-4 leads to reduced skeletal muscle performance in mice and altered motility in C2C12 myoblasts via altered calcium homeostasis. The altered muscle force performance develops at an early age and is maintained throughout the life course of the animal until old age.

Comparative immunohistochemical analysis of WT-1, Syndecan and Snail in Ameloblastoma and odontogenic keratocyst: A retrospective study.

The purpose of this experimental study was to evaluate and compare the degree of expression of Wilm's Tumor Gene-1 (WT-1), Syndecan (CD 138) and Snail in Ameloblastoma and odontogenic keratocyst (OKC) and to analyse their potential role in pathogenesis. Immunohistochemical analysis was performed to evaluate WT-1, Syndecan and Snail expression in Ameloblastoma (n = 20) and OKC (n = 20). Topographical immunoexpression pattern of Ameloblast-like cells, Stellate Reticulum-like cells in Ameloblastoma and basal layer as well as suprabasal layer of cells of OKC were also compared. The results obtained were subjected to ANOVA test and Tukey HSD test through SPSS software 20.0 for Microsoft Windows. WT-1 and Snail overexpression was seen in both Ameloblastoma and OKCs. Syndecan, responsible for maintaining normal cellular morphology, cell-cell adhesion and differentiation was significantly downregulated in both the lesions. The Ameloblasts-like cells and the basal cells showed significantly higher immunopositivity for WT-1 and Syndecan as compared to that of basal cells. An inverse relation was noted for Snail protein. The ANOVA test predicted a statistically significant difference of expression across the lesions with a P value <0.0001 for Syndecan and Snail. The under-expression of epithelial membrane protein Syndecan-1 and upregulation of EMT transcription factor Snail can promote local invasion and is indicative of poor prognosis of these lesions. The overexpression of WT-1 results in tumorigenesis, proliferation and localized aggressiveness of Ameloblastoma and intrabony growth of OKC. Further investigation on the biologic behaviour of OKC is still recommended to arrive at more specific conclusions regarding its nature.

MiR-19a-3p affected ox-LDL-induced SDC-1/TGF-β1/Smad3 pathway in atherosclerosis.

Syndecan-1 (SDC-1) was a critical membrane proteoglycan and an important component of the glycocalyx in endothelial cells, but its role in atherosclerosis remains unknown. This study attempted to investigate the role of SDC-1 in atherosclerotic-related endothelial cell injury. Bioinformatics analyzed the differential miRNAs between atherosclerosis and healthy. Subjects with coronary atherosclerosis, which were diagnosed with intravascular atherosclerosis (IVUS), were enrolled as non-vulnerable plaque and vulnerable plaque in Changsha Central Hospital. Human aortic endothelial cells (HAECs) were induced by oxidized low-density lipoprotein (ox-LDL) to construct an in vitro model. A dual luciferase reporter assay was applied to analyze the target between miR-19a-3p and SDC-1. The cell proliferation and apoptosis were detected by CCK8 and flow cytometry, respectively. SDC-1 and cholesterol efflux was determined by ELISA. The expression of ATP-binding cassette (ABC) transports A1 (ABCA1), miR-19a-3p, ABCG1 and SDC-1 genes were detected by RT-qPCR. The expressions of SDC-1, ABCA1, ABCG1, TGF-β1, Smad3 and p-Smad3 proteins were detected by western blot. Our results found that miR-19a-3p was down-regulated in atherosclerosis. ox-LDL decreased miR-19a-3p expression, increased cholesterol efflux and the expression of ABCA1, ABCG1 and SDC-1 in HAECs. Vulnerable plaque tissues in patients with coronary atherosclerosis showed palpable fibrous necrosis and calcification with elevated blood SDC-1 levels. miR-19a-3p could bind to SDC-1. Overexpression of miR-19a-3p promoted cell proliferation, inhibited apoptosis and cholesterol efflux, down-regulated the expression of SDC-1, ABCA1, ABCG1, TGF-β1 and p-Smad3 proteins in ox-LDL-induced HAECs. In conclusion, miR-19a-3p targeting SDC-1 inhibited the ox-LDL-induced activation of the TGF-β1/Smad3 pathway in HAECs.

Expression of Syndecan-1 and Cyclin D1 in Salivary Gland Tumors in Relation to Clinicopathological Parameters.

Salivary tumors have various morphological features and might share some histopathological findings. They are considered a problematic area in diagnosis due to complex clinicopathological features and different biological behavior. To identify the pathological behavior of salivary tumors immunohistochemically. This retrospective study involved thirty formalin-fixed paraffin-embedded blocks of salivary gland tumors. These tumors were stained immunohistochemically with syndecan-1 and cyclin D1. Chi-Square test was used to relate immunoscoring, intracellular localization, intensity, and invasion to different salivary tumors. The correlation of these two markers was done by spearman's rho test. P-value <0.05 was considered statistically significant. The mean age of the patients was 48.69 ± 17.7. The parotid gland was the most commonly reported site in benign tumors, and regarding malignant tumors, maxilla was the most prevalent site. Syndecan-1 in benign tumors showed a predominate score 3, most widely detected in pleomorphic adenoma. Malignant salivary tumors showed 89.4% positive expression with a more frequent score 3, most commonly found in adenocystic carcinoma. Cyclin D1 expressed in all benign salivary tumors, with prominent diffuse mixed intracellular localization in pleomorphic adenoma. Malignant tumors revealed an expression of 94.7%. Moderate scoring with mixed intracellular localization was recorded in adenocystic carcinoma, followed by mucoepidermoid carcinoma. There was a significant correlation between the two markers in response to the distribution of immunostaining in different cell compartments. Syndecan-1 and cyclin D1 showed a significant combined role in salivary tumor progression. Interestingly notable ductal-myoepithelial cells affect epithelial morphogenesis, and growth of pleomorphic adenoma was observed. Furthermore, basophilic cells of cribriform adenocystic carcinomas might control the aggressiveness and proliferation rate of these tumors.

The Role of New 3D Pathology and Lymphocyte Expression of Interstitial Inflammation in Pediatric-Onset Lupus Nephritis.

Lupus nephritis (LN) is a common and severe manifestation of pediatric-onset systemic lupus erythematosus (pSLE). It is one of the major causes of long-term glucocorticoid/immune suppressants use in pSLE. It causes long-term glucocorticoid/immune suppressants use and even end-stage renal disease (ESRD) in pSLE. It is now well known that high chronicity, especially the tubulointerstitial components in the renal biopsy, predicts a poor renal outcome. Interstitial inflammation (II), a component of activity in LN pathology, can be an early predictor for the renal outcome. With the advent of 3D pathology and CD19-targeted CAR-T cell therapy in the 2020s, the present study focuses on detailed pathology and B cell expression in II. We recruited 48 pSLE patients with class III/IV LN to analyze the risk of ESRD based on different II scores. We also studied 3D renal pathology and immunofluorescence (IF) staining of CD3, 19, 20, and 138 in patients with a high II score but low chronicity. Those pSLE LN patients with II scores of 2 or 3 showed a higher risk for ESRD (p = 0.003) than those with II scores of 0 or 1. Excluding patients with chronicity >3, high II scores still carried a higher risk for ESRD (p = 0.005). Checking the average scores from the renal specimens from different depths, the II, and chronicity showed good consistency between 3D and 2D pathology (interclass correlation coefficient [ICC], II = 0.91, p = 0.0015; chronicity = 0.86, p = 0.024). However, the sum of tubular atrophy plus interstitial fibrosis showed no good consistency (ICC = 0.79, p = 0.071). The selected LN patients with negative CD19/20 IF stains showed scattered CD3 infiltration and a different IF pattern of Syndecan-1 expression. Our study provides unique data in LN, including 3D pathology and different in situ Syndecan-1 patterns in LN patients.

Differential effects of temperature and mTOR and Wnt-planar cell polarity pathways on syndecan-4 and CD44 expression in growth-selected turkey satellite cell populations.

Satellite cells (SCs) comprise a heterogeneous population of muscle stem cells. Thermal stress during the first week after hatch alters proliferation, myogenesis, and adipogenesis of SCs of turkey pectoralis major (p. major) muscle via mechanistic target of rapamycin (mTOR) and wingless-type mouse mammary tumor virus integration site family/planar cell polarity (Wnt/PCP) pathways. Pivotal genes in mTOR and Wnt/PCP pathways are mTOR and frizzled-7 (Fzd7), respectively. The objective of this study was to determine the differential effects of thermal stress on SDC4 and CD44 expression in turkey p. major muscle SCs and how the expression of SDC4 and CD44 is modulated by the mTOR and Wnt/PCP pathways. Satellite cells were isolated from the p. major muscle of 1-week-old faster-growing modern-commercial (NC) turkeys and slower-growing historic Randombred Control Line 2 (RBC2) turkeys, and were challenged with hot (43°C) and cold (33°C) thermal stress for 72 h of proliferation followed by 48 h of differentiation. The NC line SCs were found to contain a lower proportion of SDC4 positive and CD44 negative (SDC4+CD44-) cells and a greater proportion of SDC4 negative and CD44 positive (SDC4-CD44+) cells compared to the RBC2 line at the control temperature (38°C) at both 72 h of proliferation and 48 h of differentiation. In general, at 72 h of proliferation, the proportion of SDC4+CD44- cells decreased with heat stress (43°C) and increased with cold stress (33°C) relative to the control temperature (38°C) in both lines, whereas the proportion of SDC4-CD44+ cells increased with heat stress and decreased with cold stress. In general, the expression of SDC4 and CD44 in the NC SCs showed greater response to both hot and cold thermal stress compared to the RBC2 cells. Knockdown of mTOR or Fzd7 expression increased the proportion of SDC4+CD44- cells while the proportion of SDC4-CD44+ cells decreased during differentiation with line differences being specific to treatment temperatures. Thus, differential composition of p. major muscle SCs in growth-selected commercial turkey may be resulted, in part, from the alteration in SDC4 and CD44 expression. Results indicate differential temperature sensitivity and mTOR and Wnt/PCP pathway responses of growth-selected SC populations and this may have long-lasting effect on muscle development and growth.

Nasal administration of mesenchymal stem cells prevents accelerated age-related tauopathy after chemotherapy in mice

BackgroundThere is increasing concern that cancer and cancer treatment accelerate aging and the associated cognitive decline. We showed recently that treatment of 9-month-old male mice with cisplatin causes cognitive deficits that are associated with formation of tau deposits in the hippocampus.Here we explored the capacity of mesenchymal stem cells (MSC) given via the nose to prevent age-related brain tau deposits. Moreover, we more closely examined the cellular distribution of this hallmark of accelerated brain aging in response to treatment of 9-month-old female and male mice with cisplatin.ResultsWe show that cisplatin induces tau deposits in the entorhinal cortex and hippocampus in both sexes. The tau deposits colocalize with syndecan-2. Astrocytes surrounding tau deposits have increased glial fibrillary acidic protein glial fibrillary acidic protein (GFAP) expression. Most of the cisplatin-induced tau deposits were located in microtubule associated protein-2 (MAP-2)+ neurons that were surrounded by aquaporin 4+ (AQP4)+ neuron-facing membrane domains of astrocytes. In addition, some tau deposits were detected in the perinuclear region of GFAP+ astrocytes and in CD31+ endothelial cells. There were no morphological signs of activation of ionized calcium binding adaptor molecule-1+ (Iba-1)+ microglia and no increases in brain cytokine production.Nasal administration of MSC at 48 and 96 hours after cisplatin prevented formation of tau deposits and normalized syndecan-2 and GFAP expression. Behaviorally, cisplatin-induced tau cluster formation was associated with reduced executive functioning and working/spatial memory and nasal administration of MSC at 48 and 96 hours after cisplatin prevented these cognitive deficits. Notably, delayed MSC administration (1 month after cisplatin) also prevented tau cluster formation and cognitive deficits, in both sexes.ConclusionIn summary, nasal administration of MSC to older mice at 2 days or 1 month after completion of cisplatin treatment prevents the accelerated development of tau deposits in entorhinal cortex and hippocampus and the associated cognitive deficits. Since MSC are already in clinical use for many other clinical indications, developing nasal MSC administration for treatment of accelerated brain aging and cognitive deficits in cancer survivors should be feasible and would greatly improve their quality of life.

LHPP Inhibits the Viability, Migration, and Proliferation of PDAC Cells and Significantly Affects the Expression of SDC1 and S100p.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor response to chemotherapy and an extremely poor prognosis. Recent studies have revealed that phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) can inhibit the growth of various cancers. Therefore, the current study was conducted to investigate the antitumor effects of LHPP in PDAC and to explore its mechanism using proteomics analysis. Immunohistochemical analysis of clinical samples demonstrated that LHPP expression levels were lower in tumor tissues compared to adjacent nontumor tissues. Moreover, multivariate COX regression analysis showed that LHPP expression level was an independent prognostic factor for the patients with PDAC. Patients with high LHPP expression had a better prognosis. The lentiviral vectors for normal control (NC), LHPP knockdown (KD), and LHPP overexpression (OE) were infected with BxPC-3 and PANC-1 cell lines. Cell counting kit-8 assay, Transwell assay, and flow cytometry analyses showed that LHPP overexpression significantly inhibited the cell viability, migration, and proliferation of BxPC-3 and PANC-1 cells. Moreover, xenograft tumor model demonstrated that LHPP overexpression inhibited xenograft tumor growth in vivo. Subsequently, proteins with significantly altered expression in BxPC-3 cells after lentivirus infection were detected using proteomics analyses. Interestingly, compared to the NC group, the expression of Syndecan 1 (SDC1) was significantly upregulated in the KD group, while that of S100P was significantly downregulated in the OE group. LHPP might emerge as an important target for delaying the advancement of PDAC, thereby providing a novel therapeutic approach for the treatment of PDAC.

A positive feedback loop of heparanase/syndecan1/nerve growth factor regulates cancer pain progression.

The purpose of this research was to assess the role of heparanase (HPSE)/syndecan1 (SDC1)/nerve growth factor (NGF) on cancer pain from melanoma. The influence of HPSE on the biological function of melanoma cells and cancer pain in a mouse model was evaluated. Immunohistochemical staining was used to analyze HPSE and SDC1. HPSE, NGF, and SDC1 were detected using western blot. Inflammatory factors were detected using ELISA assay. HPSE promoted melanoma cell viability, proliferation, migration, invasion, and tumor growth, as well as cancer pain, while SST0001 treatment reversed the promoting effect of HPSE. HPSE up-regulated NGF, and NGF feedback promoted HPSE. High expression of NGF reversed the inhibitory effect of HPSE down-regulation on melanoma cell phenotype deterioration, including cell viability, proliferation, migration, and invasion. SST0001 down-regulated SDC1 expression. SDC1 reversed the inhibitory effect of SST0001 on cancer pain. The results showed that HPSE promoted melanoma development and cancer pain by interacting with NGF/SDC1. It provides new insights to better understand the role of HPSE in melanoma and also provides a new direction for cancer pain treatment.

Mild hypothermia combined with dexmedetomidine reduced brain, lung, and kidney damage in experimental acute focal ischemic stroke

BackgroundSedatives and mild hypothermia alone may yield neuroprotective effects in acute ischemic stroke (AIS). However, the impact of this combination is still under investigation. We compared the effects of the combination of mild hypothermia or normothermia with propofol or dexmedetomidine on brain, lung, and kidney in experimental AIS. AIS-induced Wistar rats (n = 30) were randomly assigned, after 24 h, to normothermia or mild hypothermia (32–35 °C) with propofol or dexmedetomidine. Histologic injury score and molecular biomarkers were evaluated not only in brain, but also in lung and kidney. Hemodynamics, ventilatory parameters, and carotid Doppler ultrasonography were analyzed for 60 min.ResultsIn brain: (1) hypothermia compared to normothermia, regardless of sedative, decreased tumor necrosis factor (TNF)-α expression and histologic injury score; (2) normothermia + dexmedetomidine reduced TNF-α and histologic injury score compared to normothermia + propofol; (3) hypothermia + dexmedetomidine increased zonula occludens-1 expression compared to normothermia + dexmedetomidine. In lungs: (1) hypothermia + propofol compared to normothermia + propofol reduced TNF-α and histologic injury score; (2) hypothermia + dexmedetomidine compared to normothermia + dexmedetomidine reduced histologic injury score. In kidneys: (1) hypothermia + dexmedetomidine compared to normothermia + dexmedetomidine decreased syndecan expression and histologic injury score; (2) hypothermia + dexmedetomidine compared to hypothermia + propofol decreased histologic injury score.ConclusionsIn experimental AIS, the combination of mild hypothermia with dexmedetomidine reduced brain, lung, and kidney damage.

Expression of syndecan-1 in different grades of oral squamous cell carcinoma: An immunohistochemical study.

Syndecans are a family of transmembrane proteins, belonging to heparin sulphate proteoglycan family and are localized entirely to the epithelial cells with the stratified squamous epithelia. They are involved in cell-cell adhesion and interaction with the extracellular matrix and play a critical role in cell growth, differentiation, cell morphology, and migration. The down regulation of syndecan-1 indicates loss of cellular adhesion and possibility of invasion. The present study is aimed to evaluate the difference in immunohistochemical expression of syndecan-1 in different grades of oral squamous cell carcinoma (OSCC) patients and control group. The present study consists of 42 cases of paraffin-embedded tissue sections of OSCC; 14 well differentiated, 14 moderately differentiated, and 14 poorly differentiated. As a control, 10 paraffin-embedded tissue sections of unaffected oral mucosa were used. The sections were stained for immunohistochemical expression of syndecan -1. The intensity of staining was scored. The immunohistochemistry scores for each sample were obtained by Tissue Quant software. Statistical analysis revealed that there was a significant decrease in intensity of staining between normal and different grades of OSCC. This study shows that as cellular differentiation was lost, syndecan-1 expression was less. This provides an insight and understanding of the pathophysiology of the invasive process of OSCC and helps in establishing the prognostic link.

Sympathetic nerve infiltration promotes stomach adenocarcinoma progression via norepinephrine/β2-adrenoceptor/YKL-40 signaling pathway

ObjectiveThis study aimed to address the status, role, and mechanism of sympathetic nerve infiltration in the progression of stomach adenocarcinoma (STAD). MethodsSympathetic nerve and its neurotransmitter NE, β-ARs, and associated signaling molecules in the STAD tissues and the adjacent tissues from 46 STAD patients were examined using immunostaining, HPLC, and western blotting. The effects and mechanisms of β2-AR activation on the proliferation, migration and invasion of AGS and SGC-7901 gastric cancer (GC) cell lines were examined using CCK-8, transwell, and western blotting assays. Correlations between genes and STAD survival were analyzed using bioinformatics. ResultsStriking sympathetic nerve infiltration, elevations of NGF, TrkA, GAP43, TH, S100, NE, β2-AR, YKL-40, syndecan-1, MMP9, CD206, and CD31 were observed in the STAD tissues compared to the adjacent tissues. Activation of β2-AR in the two GC cell lines significantly amplified the expressions of NGF, YKL-40, MMP9, syndecan-1, p-STAT3 and p-ERK, and increased GC cell proliferation, migration and invasion. Bioinformatic analyses revealed positive correlations of NGF, β2-AR, syndecan-1, and macrophage infiltration, respectively, with low survival of STAD, of β2-AR respectively with STAT3, ERK1/2 (MAPK1/3), YKL-40, MMP9, and syndecan-1, and of YKL-40 with MMP9. ConclusionSympathetic nerves significantly infiltrated into human STAD tissues as a result of high NGF and TrkA expressions; elevated NE led to overactivation of β2-AR-STAT3/ERK-YKL-40 signaling pathway, and finally caused cancer cell growth and invasion, M2 macrophage infiltration, angiogenesis, matrix degradation and STAD metastasis and progression.

Effect of miR-21-3p on lung injury in rats with traumatic hemorrhagic shock resuscitated with sodium bicarbonate Ringer's solution.

Restricted fluid resuscitation is the most important early method for treating traumatic hemorrhagic shock (THS). This study sought to explore whether micro ribonucleic acid (miR)-21-3p affected resuscitated THS rats by regulating the glycocalyx and inflammation. MiRNAs extracted from the lung tissues were analyzed by miRNA microarray assays. A rat model of THS was induced by hemorrhage from a left femur fracture. The pathological change in the lung tissues and glycocalyx structure was observed by hematoxylin and eosin staining and a transmission electron microscope examination. The miR-21-3p expression in the lung tissues and serum was detected by real-time quantitative polymerase chain reaction (RT-qPCR). The levels of glycocalyx-related factors and inflammation-related factors were determined by enzyme linked immunosorbent assays. The expression of glycocalyx-related proteins, cell junction-related proteins, and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/nuclear factor kappa B (NF-κB) signaling pathway-related proteins was analyzed by Western blot. After RT-qPCR verification, the variation trend of miR-21-3p was in line with expected trends. The mean arterial pressure (MAP) and heart rate (HR) were decreased, and the lung injury and damage to the glycocalyx were all aggravated in the THS rats resuscitated with sodium bicarbonate Ringer's solution (BRS) or sodium lactate Ringer's solution (LRS). The expression of miR-21-3p was decreased in the THS rats resuscitated with BRS and increased in the THS rats resuscitated with LRS, and the upregulation of miR-21-3p further decreased the MAP and HR, and increased the levels of syndecan-1 (SDC-1), heparanase-1 (HPA1), interleukin (IL)-6, IL-1β, and tumor necrosis factor alpha (TNF-α) in the serum of the THS rats resuscitated with BRS. The upregulation of miR-21-3p also increased the expression of SDC-1, HPA1, β-catenin, matrix metallopeptidase (MMP)2, and MMP9, but decreased the expression of E-cadherin (E-cad) and activated the PI3K/Akt/NF-κB signaling pathway in the THS rats resuscitated with BRS and transfected with miR-21-3p compared to that of the THS rats resuscitated with BRS and transfected with miR-negative control (NC). miR-21-3p promoted inflammation and glycocalyx damage by activating the PI3K/Akt/NF-κB signaling pathway, thereby aggravating the lung injury in the THS rats resuscitated with BRS.

High expression of SDC1 in stromal cells is associated with good prognosis in colorectal cancer.

We have previously reported that patients with high Syndecan 1 (SDC1) expression in colorectal cancer (CRC) cells have a favorable prognosis, and we also found that stromal cells showed upregulation of SDC1, but the clinical significance is unclear. The expression of SDC1 in the stroma cells was assessed by immunohistochemistry using a tissue microarray comprising representative cores from 513 CRC patients. The correlation between the expression of SDC1 in the stroma cells and the clinicopathological features of patients was analyzed. The data showed that the expression of SDC1 in the stroma cells was correlated with the degree of differentiation ( P = 0.012) and tumor location (up or down) ( P = 0.005). Also, CRCs patients with high expression of SDC1 in the stromal cells have a good prognosis ( P = 0.0369). Accumulating evidence indicates that SDC1, whether in tumor cells or stromal cells, plays a tumor-suppressor role in CRCs.