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Chemical Biology & Drug Design Jan 2024Considering the therapeutic efficacy of Stachydrine on breast cancer (BC), this study aims to decipher the relevant mechanism. The effects of Stachydrine on BC cell...
Considering the therapeutic efficacy of Stachydrine on breast cancer (BC), this study aims to decipher the relevant mechanism. The effects of Stachydrine on BC cell viability, proliferation and apoptosis were firstly investigated. Then, Bioinformatics was applied to sort out the candidate interacting with Stachydrine as well as its expression and downstream target in BC. Relative expressions of genes of interest as well as proliferation- and apoptosis-related factors in BC cells were quantified through quantitative reverse-transcription PCR and western blot as appropriate. As a result, Stachydrine inhibited the proliferation, down-regulated the expressions of proliferating cell nuclear antigen and CyclinD1, enhanced cell cycle arrest and apoptosis, and up-regulated the levels of Cleaved caspase-3 and Cleaved caspase-9 in BC cells. Phospholipase A2 Group IIA (PLA2G2A) was predicted as the candidate interacting with Stachydrine and to be lowly expressed in BC. PLA2G2A silencing reversed while PLA2G2A overexpression reinforced the effects of Stachydrine. Decorin (DCN) was the downstream target of PLA2G2A and also lowly expressed in BC. PLA2G2A silencing counteracted yet overexpressed PLA2G2A strengthened the promoting effects of Stachydrine on DCN level. Collectively, Stachydrine inhibits the growth of BC cells to promote cell cycle arrest and apoptosis via PLA2G2A/DCN axis.
Topics: Humans; Female; Breast Neoplasms; Apoptosis; Cell Cycle Checkpoints; Cell Proliferation; Cell Line, Tumor; MicroRNAs; Group II Phospholipases A2; Decorin; Proline
PubMed: 38230769
DOI: 10.1111/cbdd.14429 -
The importance of biglycan, decorin and TGF-1 levels in the diagnosis of non-small cell lung cancer.Cancer Biomarkers : Section a of... Dec 2023Despite Non-small cell lung cancer (NSCLC) ranks among the most deadly cancers worldwide, and currently, apart from a low percentage, targetable molecules have not been...
BACKGROUND
Despite Non-small cell lung cancer (NSCLC) ranks among the most deadly cancers worldwide, and currently, apart from a low percentage, targetable molecules have not been identified in its etiopathogenesis. The relationship between the proteoglycans decorin and biglycan, which are present in the extracellular matrix of cells, and transforming growth factor Beta-1 (TGF-B1), has been shown in many cancers. We investigated the significance of these molecules in NSCLC.
METHODS
Fasting serum levels of decorin, biglycan, and TGF-B1 were obtained from 48 newly diagnosed NSCLC patients and compared with those of 48 adult control subjects matched for age and demographics. Demographic data, baseline laboratory values, and ELISA results were compared between the groups.
RESULTS
The median age was 65(39-83) similar in both groups. There was no relation between demographic and clinical parameters and the levels of decorin, biglycan, and TGF-B1 in the NSCLC group. However, in comparison to the control group, NSCLC patients had significantly higher levels of biglycan (42.55 ± 27.40 vs. 24.38 ± 12.05 ng/mL, p= 0.026) and TGF-B1 (15.55 ± 9.16 vs. 10.07 ± 7.8 pg/mL, p= 0.001), while decorin levels were significantly lower (6.64 ± 1.92 vs. 10.28 ± 3.13 ng/mL, p= 0.002). In the multivariate regression analysis; Decorin < 8.13 ng/mL (OR, 10.96; 95% CI: 3.440-34.958), current smoking (OR, 3.81; 95% CI: 1.320-10.998), COPD (OR, 43.6; 95% CI: 2.082-913.081), and lower BMI (OR, 1.22; 95% CI: 1.070-1.405, p= 0.003) were identified as independent predictive markers for NSCLC diagnosis.
CONCLUSION
The decreased serum decorin level is an independent marker for NSCLC. Further studies are needed to investigate the prognostic significance of decorin on survival and its potential as a target in treatment.
PubMed: 38217588
DOI: 10.3233/CBM-230238 -
The Ocular Surface Apr 2024Corneal fibrosis and neovascularization (CNV) after ocular trauma impairs vision. This study tested therapeutic potential of tissue-targeted adeno-associated virus5...
PURPOSE
Corneal fibrosis and neovascularization (CNV) after ocular trauma impairs vision. This study tested therapeutic potential of tissue-targeted adeno-associated virus5 (AAV5) mediated decorin (DCN) and pigment epithelium-derived factor (PEDF) combination genes in vivo.
METHODS
Corneal fibrosis and CNV were induced in New Zealand White rabbits via chemical trauma. Gene therapy in stroma was delivered 30-min after chemical-trauma via topical AAV5-DCN and AAV5-PEDF application using a cloning cylinder. Clinical eye examinations and multimodal imaging in live rabbits were performed periodically and corneal tissues were collected 9-day and 15-day post euthanasia. Histological, cellular, and molecular and apoptosis assays were used for efficacy, tolerability, and mechanistic studies.
RESULTS
The AAV5-DCN and AAV5-PEDF combination gene therapy significantly reduced corneal fibrosis (p < 0.01 or p < 0.001) and CNV (p < 0.001) in therapy-given (chemical-trauma and AAV5-DCN + AAV5-PEDF) rabbit eyes compared to the no-therapy given eyes (chemical-trauma and AAV5-naked vector). Histopathological analyses demonstrated significantly reduced fibrotic α-smooth muscle actin and endothelial lectin expression in therapy-given corneas compared to no-therapy corneas on day-9 (p < 0.001) and day-15 (p < 0.001). Further, therapy-given corneas showed significantly increased Fas-ligand mRNA levels (p < 0.001) and apoptotic cell death in neovessels (p < 0.001) compared to no-therapy corneas. AAV5 delivered 2.69 × 10 copies of DCN and 2.31 × 10 copies of PEDF genes per μg of DNA. AAV5 vector and delivered DCN and PEDF genes found tolerable to the rabbit eyes and caused no significant toxicity to the cornea.
CONCLUSION
The combination AAV5-DCN and AAV5-PEDF topical gene therapy effectively reduces corneal fibrosis and CNV with high tolerability in vivo in rabbits. Additional studies are warranted.
Topics: Animals; Rabbits; Cornea; Corneal Neovascularization; Decorin; Dependovirus; Disease Models, Animal; Eye Proteins; Fibrosis; Genetic Therapy; Genetic Vectors; Nerve Growth Factors; Serpins
PubMed: 38191093
DOI: 10.1016/j.jtos.2024.01.001 -
Analytical Methods : Advancing Methods... Jan 2024Chondroitin sulphate (CS) and dermatan sulphate are negatively charged linear heteropolysaccharides. These glycosaminoglycans (GAG) are involved in cellular signalling...
Chondroitin sulphate (CS) and dermatan sulphate are negatively charged linear heteropolysaccharides. These glycosaminoglycans (GAG) are involved in cellular signalling binding to growth factors. CS is expressed in a range of tissue and biological fluids and is highly expressed in the placenta. There is evidence that decorin; a CS proteoglycan is significantly decreased in pre-eclampsia and fetal growth restriction. It is considered that GAG chain composition may influence cellular processes that are altered in pre-eclampsia. The goal of the present study was to develop an LC-MS method with precolumn procainamide labelling for the disaccharide compositional analysis of CS. The method was used to investigate whether the disaccharide composition of placenta-extracted CS is altered in pre-eclampsia. The study revealed differential disaccharide compositions of placental chondroitin sulphate between pre-eclampsia and other pregnancy conditions. This suggests that the method may have diagnostic potential for pregnancy disorders. Furthermore, the findings suggest that CS sulphation might play a significant role in maternal labour.
Topics: Female; Pregnancy; Humans; Chondroitin Sulfates; Procainamide; Pre-Eclampsia; Disaccharides; Placenta; Glycosaminoglycans
PubMed: 38189556
DOI: 10.1039/d3ay01578e -
Revista Brasileira de Ginecologia E... Dec 2023The serum ischemia modified albumin (IMA), biglycan, and decorin levels of pregnant women who were hospitalized for threatened preterm labor were measured.
OBJECTIVE
The serum ischemia modified albumin (IMA), biglycan, and decorin levels of pregnant women who were hospitalized for threatened preterm labor were measured.
METHODS
Fifty-one consecutive pregnant women with a single pregnancy between the 24 and 36 weeks with a diagnosis of threatened preterm labor were included in the present prospective cohort study.
RESULTS
As a result of multivariate logistic regression analysis for predicting preterm delivery within 24 hours, 48 hours, 7 days, 14 days, ≤ 35 gestational weeks, and ≤ 37 gestational weeks after admission, area under the curve (AUC) (95% confidence interval [CI[) values were 0.95 (0.89-1.00), 0.93 (0.86-0.99), 0.91 (0.83-0.98), 0.92 (0.85-0.99), 0.82 (0.69-0.96), and 0.89 (0.80-0.98), respectively. In the present study, IMA and biglycan levels were found to be higher and decorin levels lower in women admitted to the hospital with threatened preterm labor and who gave preterm birth within 48 hours compared with those who gave birth after 48 hours.
CONCLUSION
In pregnant women admitted to the hospital with threatened preterm labor, the prediction preterm delivery of the combined model created by adding IMA, decorin, and biglycan in addition to the TVS CL measurement was higher than the TVS CL measurement alone.
CLINICAL TRIAL REGISTRATION
The present trial was registered at ClinicalTrials.gov, number NCT04451928.
Topics: Infant, Newborn; Female; Pregnancy; Humans; Premature Birth; Decorin; Prospective Studies; Biomarkers; Biglycan; Serum Albumin; Obstetric Labor, Premature; Ischemia
PubMed: 38141595
DOI: 10.1055/s-0043-1772593 -
Antioxidants (Basel, Switzerland) Nov 2023Obesity is a characteristic disease of the twenty-first century that is affecting an increasing percentage of society. Obesity expresses itself in different phenotypes:... (Review)
Review
Obesity is a characteristic disease of the twenty-first century that is affecting an increasing percentage of society. Obesity expresses itself in different phenotypes: normal-weight obesity (NWO), metabolically obese normal-weight (MONW), metabolically healthy obesity (MHO), and metabolically unhealthy obesity (MUO). A range of pathophysiological mechanisms underlie the occurrence of obesity, including inflammation, oxidative stress, adipokine secretion, and other processes related to the pathophysiology of adipose tissue (AT). Body mass index (BMI) is the key indicator in the diagnosis of obesity; however, in the case of the NWO and MONW phenotypes, the metabolic disturbances are present despite BMI being within the normal range. On the other hand, MHO subjects with elevated BMI values do not present metabolic abnormalities. The MUO phenotype involves both a high BMI value and an abnormal metabolic profile. In this regard, attention has been focused on the variety of molecules produced by AT and their role in the development of obesity. Nesfatin-1, neuregulin 4, myonectin, irisin, and brain-derived neurotrophic factor (BDNF) all seem to have protective effects against obesity. The primary mechanism underlying the action of nesfatin-1 involves an increase in insulin sensitivity and reduced food intake. Neuregulin 4 sup-presses lipogenesis, decreases lipid accumulation, and reduces chronic low-grade inflammation. Myonectin lowers the amount of fatty acids in the bloodstream by increasing their absorption in the liver and AT. Irisin stimulates the browning of white adipose tissue (WAT) and consequently in-creases energy expenditure, additionally regulating glucose metabolism. Another molecule, BDNF, has anorexigenic effects. Decorin protects against the development of hyperglycemia, but may also contribute to proinflammatory processes. Similar effects are shown in the case of visfatin and chemerin, which may predispose to obesity. Visfatin increases adipogenesis, causes cholesterol accumulation in macrophages, and contributes to the development of glucose intolerance. Chemerin induces angiogenesis, which promotes the expansion of AT. This review aims to discuss the role of adipokines and myokines in the pathogenesis of the different obesity phenotypes.
PubMed: 38136166
DOI: 10.3390/antiox12122046 -
Matrix Biology : Journal of the... Jan 2024Traumatic brain injury (TBI) is the leading cause of death and disability due to injury worldwide. Extracellular matrix (ECM) remodeling is known to significantly...
Traumatic brain injury (TBI) is the leading cause of death and disability due to injury worldwide. Extracellular matrix (ECM) remodeling is known to significantly contribute to TBI pathophysiology. Glycosaminoglycans, which are long-chain, variably sulfated polysaccharides abundant within the ECM, have previously been shown to be substantially altered after TBI. In this study, we sought to delineate the dynamics of glycosaminoglycan alterations after TBI and discover the precise biologic processes responsible for observed glycosaminoglycan changes after injury. We performed state-of-the art mass spectrometry on brain tissues isolated from mice after TBI or craniotomy-alone. We observed dynamic changes in glycosaminoglycans at Day 1 and 7 post-TBI, with heparan sulfate, chondroitin sulfate, and hyaluronan remaining significantly increased after a week vis-à-vis craniotomy-alone tissues. We did not observe appreciable changes in circulating glycosaminoglycans in mice after experimental TBI compared to craniotomy-alone nor in patients with TBI and severe polytrauma compared to control patients with mild injuries, suggesting increases in injury site glycosaminoglycans are driven by local synthesis. We subsequently performed an unbiased whole genome transcriptomics analysis on mouse brain tissues 7 days post-TBI and discovered a significant induction of hyaluronan synthase 2, glypican-3, and decorin. The functional role of decorin after injury was further examined through multimodal behavioral testing comparing wild-type and Dcn mice. We discovered that genetic ablation of Dcn led to an overall negative effect of TBI on function, exacerbating motor impairments after TBI. Collectively, our results provide a spatiotemporal characterization of post-TBI glycosaminoglycan alterations in the brain ECM and support an important adaptive role for decorin upregulation after TBI.
Topics: Animals; Humans; Mice; Brain Injuries, Traumatic; Chondroitin Sulfates; Decorin; Extracellular Matrix Proteins; Glycosaminoglycans
PubMed: 38135163
DOI: 10.1016/j.matbio.2023.12.005 -
Biomedical Reports Jan 2024Chemotherapy with temozolomide (TMZ) is an essential part of anticancer therapy used for malignant tumors (mainly melanoma and glioblastoma); however, the long-term...
Chemotherapy with temozolomide (TMZ) is an essential part of anticancer therapy used for malignant tumors (mainly melanoma and glioblastoma); however, the long-term effects on patient health and life quality are not fully investigated. Considering that tumors often occur in elderly patients, the present study was conducted on long-term (4 months) treatment of adult Wistar rats (9 months old, n=40) with TMZ and/or dexamethasone (DXM) to investigate potential behavioral impairments or morphological and molecular changes in their brain tissues. According to the elevated plus maze test, long-term use of TMZ affected the anxiety of the adult Wistar rats, although no significant deterioration of brain morphology or cellular composition of the brain tissue was revealed. The expression levels of all studied heparan sulfate (HS) proteoglycans (HSPGs) (syndecan-1, syndecan-3, glypican-1 and HSPG2) and the majority of the studied chondroitin sulfate (CS) proteoglycans (CSPGs) (decorin, biglycan, lumican, brevican, neurocan aggrecan, versican, Cspg4/Ng2, Cspg5 and phosphacan) were not affected by TMZ/DXM, except for neurocan and aggrecan. Aggrecan was the most sensitive proteoglycan to TMZ/DXM treatment demonstrating downregulation of its mRNA and protein levels following TMZ (-10-fold), DXM (-45-fold) and TMZ-DXM (-80-fold) treatment. HS content was not affected by TMZ/DXM treatment, whereas CS content was decreased 1.5-2.5-fold in the TMZ- and DXM-treated brain tissues. Taken together, the results demonstrated that treatment of adult Wistar rats with TMZ had long-term effects on the brain tissues, such as decreased aggrecan core protein levels and CS chain content and increased anxiety of the experimental animals.
PubMed: 38124768
DOI: 10.3892/br.2023.1695 -
Frontiers in Medicine 2023Exposure to solar radiation can cause a range of skin damage, including sunburn, erythema, skin carcinogenesis, the release of reactive oxygen species (ROS),...
INTRODUCTION
Exposure to solar radiation can cause a range of skin damage, including sunburn, erythema, skin carcinogenesis, the release of reactive oxygen species (ROS), inflammation, DNA damage, and photoaging. Other wavelengths beyond UVB, such as UVA, blue light, and infrared radiation, can also contribute to the harmful effects of solar radiation. Reconstructed full-thickness human skin has the potential to serve as effective predictive in vitro tools for evaluating the effects of solar radiation on the skin. The aim of this work was to evaluate the damaging effects of UVA, blue light, and infrared radiation in a full-thickness skin model in terms of viability, inflammation, photoaging, tissue damage, photocarcinogenesis.
METHODS
Full thickness skin models were purchased from Henkel (Phenion FT; Düsseldorf, Germany), and irradiated with increasing doses of UVA, blue light, or infrared radiation. Different endpoints were analyzed on the tissues: Hematoxylin-eosin staining, inflammation mediators, photoaging-related dermal markers and oxidative stress marker GPX1, evaluated by real-time quantitative PCR, as well as photocarcinogenesis markers by Western Blot.
RESULTS AND DISCUSSION
The results showed differential responses in cytokine release for each light source. In terms of photoaging biomarkers, collagen, metalloproteinases 1 and 9, elastin, and decorin were modulated by UVA and blue light exposure, while not all these markers were affected by infrared radiation. Furthermore, exposure to UVA and blue light induced loss of fibroblasts and modulation of the photocarcinogenesis markers p53 and p21. In conclusion, the presented results suggest that the various wavelengths of solar light have distinct and differential damaging effects on the skin. Understanding the differential effects of UVA, blue light, and infrared radiation can serve as a valuable tool to investigate the efficacy of photoprotective agents in full thickness skin models.
PubMed: 38105899
DOI: 10.3389/fmed.2023.1267409 -
Burns : Journal of the International... Mar 2024StrataGraft® (allogeneic cultured keratinocytes and dermal fibroblasts in murine collagen-dsat) is an FDA-approved viable bioengineered allogeneic cellularized...
The viable bioengineered allogeneic cellularized construct StrataGraft® synthesizes, deposits, and organizes human extracellular matrix proteins into tissue type-specific structures and secretes soluble factors associated with wound healing.
BACKGROUND
StrataGraft® (allogeneic cultured keratinocytes and dermal fibroblasts in murine collagen-dsat) is an FDA-approved viable bioengineered allogeneic cellularized construct for adult patients with deep partial-thickness burns requiring surgery. We characterized the structural and functional properties of StrataGraft to improve product understanding by evaluating extracellular matrix (ECM) molecule distribution and secreted protein factor expression in vitro.
METHODS
ECM protein expression was determined using indirect immunofluorescence on construct cross sections using commercial antibodies against collagen III, IV, VI, laminin-332, and decorin. Human collagen I expression was verified by enzyme-linked immunosorbent assay (ELISA) for collagen I C-terminal propeptide. Soluble protein factor secretion was quantified by multiplex biomarker assays and singleplex ELISA in conditioned media from meshed constructs.
RESULTS
StrataGraft cellular components produced collagen I, collagen III, collagen VI, and decorin in patterns indicating an organized ECM. Distributions of collagen IV and laminin-332 indicated formation of basement membranes and dermal-epidermal junctions. Soluble protein factors were observed in the pg/cm/h range from 1 h to the experiment end at 168 h.
CONCLUSIONS
The organization of the ECM proteins was like human skin and the viable cellular components provided sustained secretion of soluble wound healing factors, making StrataGraft an attractive option for treating severe burns.
Topics: Adult; Humans; Animals; Mice; Extracellular Matrix Proteins; Decorin; Burns; Wound Healing; Extracellular Matrix; Collagen Type I; Kalinin; Hematopoietic Stem Cell Transplantation; Fibroblasts
PubMed: 38087659
DOI: 10.1016/j.burns.2023.06.001