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Pharmaceuticals (Basel, Switzerland) Oct 2023Ascidians are marine invertebrates that synthesize sulfated glycosaminoglycans (GAGs) within their viscera. Ascidian GAGs are considered analogues of mammalian GAGs and...
Ascidians are marine invertebrates that synthesize sulfated glycosaminoglycans (GAGs) within their viscera. Ascidian GAGs are considered analogues of mammalian GAGs and possess great potential as bioactive compounds, presenting antitumoral and anticoagulant activity. Due to its worldwide occurrence and, therefore, being a suitable organism for large-scale mariculture in many marine environments, our main objectives are to study GAGs regarding composition, structure, and biological activity. We also aim to develop efficient protocols for sulfated polysaccharides extraction and purification for large-scale production and clinical applications. GAGs derived from viscera were extracted by proteolytic digestion, purified by ion-exchange liquid chromatography, and characterized by agarose gel electrophoresis and enzymatic treatments. Anticoagulant activity was evaluated by APTT assays. Antitumoral activity was assessed in an in vitro model of tumor cell culture using MTT, clonogenic, and wound healing assays, respectively. Our results show that presents three distinct polysaccharides; among them, two were identified: a dermatan sulfate and a fucosylated dermatan sulfate. Antitumoral activity was confirmed for the total polysaccharides (TP). While short-term incubation does not affect tumor cell viability at low concentrations, long-term TP incubation decreases LLC tumor cell growth/proliferation at different concentrations. In addition, TP decreased tumor cell migration at different concentrations. In conclusion, we state that presents great potential as an alternative GAG source, producing compounds with antitumoral properties at low concentrations that do not possess anticoagulant activity and do not enhance other aspects of malignancy, such as tumor cell migration. Our perspectives are to apply these molecules in future preclinical studies for cancer treatment as antitumoral agents to be combined with current treatments to potentiate therapeutic efficacy.
PubMed: 37895872
DOI: 10.3390/ph16101401 -
Updates in Surgery Apr 2024Chronic venous disease (CVD) and hemorrhoidal disease (HD) are among the most common vascular diseases in the world, with CVD affecting 22-41% of the population in... (Review)
Review
Chronic venous disease (CVD) and hemorrhoidal disease (HD) are among the most common vascular diseases in the world, with CVD affecting 22-41% of the population in Europe and HD having a point prevalence of 11-39%. The burden is substantial in terms of the effect of symptoms on patients' health-related quality of life (HRQoL) and direct/indirect medical costs. Treatment begins with lifestyle changes, compression in CVD and topical therapies in HD, and escalates as needed through oral therapies first and eventually to surgery for severe disease. CVD and HD share etiological features and pathological changes affecting the structure and function of the tissue extracellular matrix. Mesoglycan, a natural glycosaminoglycan (GAG) preparation composed primarily of heparan sulfate and dermatan sulfate, has been demonstrated to positively impact the underlying causes of CVD and HD, regenerating the glycocalyx and restoring endothelial function, in addition to having antithrombotic, profibrinolytic, anti-inflammatory, antiedema and wound-healing effects. In clinical trials, oral mesoglycan reduced the severity of CVD signs and symptoms, improved HRQoL, and accelerated ulcer healing. In patients with HD, mesoglycan significantly reduced the severity of signs and symptoms and the risk of rectal bleeding. In patients undergoing excisional hemorrhoidectomy, adding mesoglycan to standard postoperative care reduced pain, improved HRQoL, reduced incidence of thrombosis, and facilitated an earlier return to normal activities/work, compared with standard postoperative care alone. The clinical effects of mesoglycan in patients with CVD or HD are consistent with the agent's known mechanisms of action.
Topics: Humans; Hemorrhoids; Quality of Life; Vascular Diseases; Glycosaminoglycans; Chronic Disease
PubMed: 38356039
DOI: 10.1007/s13304-024-01776-9 -
Veterinary Sciences Nov 2023The gastrointestinal (GI) mucosal barrier is often exposed to inflammatory and erosive insults, resulting in gastric lesions. Glycosaminoglycans (GAGs), such as...
The gastrointestinal (GI) mucosal barrier is often exposed to inflammatory and erosive insults, resulting in gastric lesions. Glycosaminoglycans (GAGs), such as hyaluronic acid (HA), chondroitin sulfate (CS), and N-acetylglucosamine (NAG) have shown potential beneficial effects as GI protectants. This study aimed to evaluate the gastroprotective effects of oral GAGs in rats with indomethacin-induced GI lesions. Forty-five Sprague-Dawley rats (8-9 weeks-old, 228 ± 7 g) were included in the study, divided into five study groups, and given, administered orally, either sucralfate (positive control group; PC), NAG (G group), sodium alginate plus HA and CS (AHC group), sodium alginate plus HA, CS, and NAG (AHCG group), or no treatment (negative control group; NC). Animals were administered 12.5 mg/kg indomethacin orally 15 min after receiving the assigned treatment. After 4 h, stomach samples were obtained and used to perform a macroscopic evaluation of gastric lesions and to allow histological assessment of the gastric wall (via H/E staining) and mucous (via PAS staining). The AHCG group showed significant gastroprotective improvements compared to the NC group, and a similar efficacy to the PC group. This combination of sodium alginate with GAGs might, therefore, become a safe and effective alternative to prescription drugs for gastric lesions, such as sucralfate, and have potential usefulness in companion animals.
PubMed: 38133218
DOI: 10.3390/vetsci10120667 -
Orphanet Journal of Rare Diseases May 2024Mucopolysaccharidosis VII (MPS VII) is an ultra-rare, autosomal recessive, debilitating, progressive lysosomal storage disease caused by reduced activity of...
Disease characteristics, effectiveness, and safety of vestronidase alfa for the treatment of patients with mucopolysaccharidosis VII in a novel, longitudinal, multicenter disease monitoring program.
BACKGROUND
Mucopolysaccharidosis VII (MPS VII) is an ultra-rare, autosomal recessive, debilitating, progressive lysosomal storage disease caused by reduced activity of β-glucuronidase (GUS) enzyme. Vestronidase alfa (recombinant human GUS) intravenous enzyme replacement therapy is an approved treatment for patients with MPS VII.
METHODS
This disease monitoring program (DMP) is an ongoing, multicenter observational study collecting standardized real-world data from patients with MPS VII (N ≈ 50 planned) treated with vestronidase alfa or any other management approach. Data are monitored and recorded in compliance with Good Clinical Practice guidelines and planned interim analyses of captured data are performed annually. Here we summarize the safety and efficacy outcomes as of 17 November 2022.
RESULTS
As of the data cutoff date, 35 patients were enrolled: 28 in the Treated Group and seven in the Untreated Group. Mean (SD) age at MPS VII diagnosis was 4.5 (4.0) years (range, 0.0 to 12.4 years), and mean (SD) age at DMP enrollment was 13.9 (11.1) years (range, 1.5 to 50.2 years). Ten patients (29%) had a history of nonimmune hydrops fetalis. In the 23 patients who initiated treatment prior to DMP enrollment, substantial changes in mean excretion from initial baseline to DMP enrollment were observed for the three urinary glycosaminoglycans (uGAGs): dermatan sulfate (DS), -84%; chondroitin sulfate (CS), -55%; heparan sulfate (HS), -42%. Also in this group, mean reduction from initial baseline to months 6, 12, and 24 were maintained for uGAG DS (-84%, -87%, -89%, respectively), CS (-70%, -71%, -76%, respectively), and HS (+ 3%, -32%, and - 41%, respectively). All adverse events (AEs) were consistent with the known vestronidase alfa safety profile. No patients discontinued vestronidase alfa. One patient died.
CONCLUSIONS
To date, the DMP has collected invaluable MPS VII disease characteristic data. The benefit-risk profile of vestronidase alfa remains unchanged and favorable for its use in the treatment of pediatric and adult patients with MPS VII. Reductions in DS and CS uGAG demonstrate effectiveness of vestronidase alfa to Month 24. Enrollment is ongoing.
Topics: Humans; Mucopolysaccharidosis VII; Glucuronidase; Male; Child, Preschool; Female; Child; Enzyme Replacement Therapy; Recombinant Proteins; Infant; Longitudinal Studies; Adolescent
PubMed: 38715031
DOI: 10.1186/s13023-024-03176-z -
Cell Death Discovery Oct 2023Dermatan sulfate epimerase (DSE) is a C5 epiminase that plays a key role in converting chondroitin sulfate into dermal sulfate. DSE is often upregulated during...
Dermatan sulfate epimerase (DSE) is a C5 epiminase that plays a key role in converting chondroitin sulfate into dermal sulfate. DSE is often upregulated during carcinogenesis of some types of cancer and can regulate growth factor signaling in cancer cells. However, the expression and function of DSE in human melanoma have not been reported. In this study, we investigated the influence of tumor-derived DSE in melanoma progression and the potential mechanism of their action. First, proteomic analysis of collected melanoma tissues revealed that DSE was significantly down-regulated in melanoma tissues. DSE silenced or overexpressed melanoma cells were constructed to detect the effect of DSE on melanoma cells, and it was found that the up-regulation of DSE significantly inhibited the proliferation, migration and invasion of melanoma cells. Data analysis and flow cytometry were used to evaluate the immune subpopulations in tumors, and it was found that the high expression of DSE was closely related to the invasion of killer immune cells. Mechanistically, DSE promoted the expression of VCAN, which inhibited the biological activity of melanoma cells. Together, these results suggest that DSE is downregulated in melanoma tissues, and that high expression of DSE can promote melanoma progression by inducing immune cell infiltration and VCAN expression.
PubMed: 37833287
DOI: 10.1038/s41420-023-01676-8 -
Cellular Signalling Mar 2024Microtia is one of the most common craniofacial birth defects worldwide, and its primary clinical manifestation is auricle deformity. Epigenetic factors are known to...
Microtia is one of the most common craniofacial birth defects worldwide, and its primary clinical manifestation is auricle deformity. Epigenetic factors are known to contribute to the etiology of microtia, yet the involvement of circular RNAs (circRNAs) in human auricle development and their association with microtia remains poorly understood. In this study, we aimed to analyze differentially expressed circRNAs and explore their functional implications in isolated microtia. By employing circRNA microarray analysis and bioinformatics approaches, we identified 340 differentially expressed circRNAs in auricle cartilage of patients with isolated microtia, comprising 152 upregulated and 188 downregulated circRNAs. A circRNA-mRNA co-expression network was constructed, followed by gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Subsequently, we selected four significantly upregulated circRNAs from the co-expression network based on their association with cartilage development and validated their expressions in 30 isolated microtia and 30 control clinical auricle cartilage samples. Among these circRNAs, circCOL1A2, the most significantly upregulated circRNA, was selected as a representative circRNA for investigating its role in isolated microtia. Overexpression of circCOL1A2 significantly inhibited chondrocyte proliferation and chondrogenic differentiation of human mesenchymal stem cells. Additionally, circCOL1A2 upregulated Dermatan Sulfate Epimerase Like (DSEL) expression by sponging miR-637 through the competing endogenous RNA (ceRNA) mechanism. Notably, the downregulation of DSEL attenuated the inhibitory effect of circCOL1A2 overexpression on cell proliferation and chondrogenic differentiation. Collectively, these findings highlight the involvement of circCOL1A2 in the pathogenesis of isolated microtia and emphasize the potential significance of dysregulated circRNAs in disease development.
Topics: Humans; RNA, Circular; MicroRNAs; Congenital Microtia; Gene Expression Profiling; Cartilage
PubMed: 38123043
DOI: 10.1016/j.cellsig.2023.111017 -
Cureus Dec 2023Mucopolysaccharidoses are rare lysosomal storage disorders in which glycosaminoglycans accumulate in tissues, causing multiorgan dysfunction. Mucopolysaccharidosis type...
Mucopolysaccharidoses are rare lysosomal storage disorders in which glycosaminoglycans accumulate in tissues, causing multiorgan dysfunction. Mucopolysaccharidosis type I is an autosomal recessive disease caused by a deficiency of the enzyme alpha-L-iduronidase, resulting in the accumulation of dermatan and heparan sulfate. Early diagnosis is crucial for early treatment and improved outcomes. We report the case of a female child with classic clinical features who was diagnosed early which allowed hematopoietic stem cell transplantation and slowed disease progression. She presented at birth with linea alba and umbilical and inguinal hernias. Since the first months of life, she had recurrent respiratory infections. At nine months, a motor delay was noticed, and at 20 months, craniosynostosis was corrected with surgery. Coarse facial features, thoracolumbar kyphosis, and hepatomegaly prompted a urinary glycosaminoglycan study at 22 months, which showed elevated levels. Alfa-L-iduronidase activity in dried blood spot testing was low, compatible with mucopolysaccharidosis type I. Molecular testing of gene performed for genetic counseling, revealed the pathogenic variants c.1205G>A (p.Trp402Ter) and c.1598C>G (p.Pro533Arg) in compound heterozygosity. At 26 months, her development quotient was average for her age. She started enzyme replacement therapy at 29 months and underwent hematopoietic stem cell transplantation at 33 months, which softened the coarse features, reduced respiratory infections, and improved hepatomegaly. However, at age five, her development quotient was 76 (mean = 100, standard deviation = 15). This intellectual impairment might have been prevented with an earlier diagnosis and treatment.
PubMed: 38222174
DOI: 10.7759/cureus.50595 -
JCI Insight Nov 2023Mucopolysaccharidosis VI (MPS VI) is a rare lysosomal disease arising from impaired function of the enzyme arylsulfatase B (ARSB). This impairment causes aberrant...
Mucopolysaccharidosis VI (MPS VI) is a rare lysosomal disease arising from impaired function of the enzyme arylsulfatase B (ARSB). This impairment causes aberrant accumulation of dermatan sulfate, a glycosaminoglycan (GAG) abundant in cartilage. While clinical severity varies along with age at first symptom manifestation, MPS VI usually presents early and strongly affects the skeleton. Current enzyme replacement therapy (ERT) does not provide effective treatment for the skeletal manifestations of MPS VI. This lack of efficacy may be due to an inability of ERT to reach affected cells or to the irreversibility of the disease. To address the question of reversibility of skeletal phenotypes, we generated a conditional by inversion (COIN) mouse model of MPS VI, ArsbCOIN/COIN, wherein Arsb is initially null and can be restored to WT using Cre. We restored Arsb at different times during postnatal development, using a tamoxifen-dependent global Cre driver. By restoring Arsb at P7, P21, and P56-P70, we determined that skeletal phenotypes can be fully rescued if Arsb restoration occurs at P7, while only achieving partial rescue at P21 and no significant rescue at P56-P70. This work has highlighted the importance of early intervention in patients with MPS VI to maximize therapeutic impact.
Topics: Mice; Animals; Humans; Mucopolysaccharidosis VI; N-Acetylgalactosamine-4-Sulfatase; Phenotype; Glycosaminoglycans; Skeleton
PubMed: 37751300
DOI: 10.1172/jci.insight.171312 -
Molecular Genetics and Metabolism... Dec 2023Mucopolysaccharidosis type II (MPS II, OMIM 309900) is an X-linked disorder caused by a deficiency of lysosomal enzyme iduronate-2-sulfatase (IDS). The clinical...
Mucopolysaccharidosis type II (MPS II, OMIM 309900) is an X-linked disorder caused by a deficiency of lysosomal enzyme iduronate-2-sulfatase (IDS). The clinical manifestations of MPS II involve cognitive decline, bone deformity, and visceral disorders. These manifestations are closely associated with IDS enzyme activity, which catalyzes the stepwise degradation of heparan sulfate and dermatan sulfate. In this study, we established a novel -deficient mice and further assessed the enzyme's physiological role. Using DNA sequencing, we found a genomic modification of the Ids genome, which involved the deletion of a 138-bp fragment spanning from intron 2 to exon 3, along with the insertion of an adenine at the 5' end of exon 3 in the mutated allele. Consistent with previous data, our -deficient mice showed an attenuated enzyme activity and an enhanced accumulation of glycosaminoglycans. Interestingly, we noticed a distinct enlargement of the calvarial bone in both neonatal and young adult mice. Our examination revealed that deficiency led to an enhanced osteoblastogenesis in the parietal bone, a posterior part of the calvarial bone originating from the paraxial mesoderm and associated with an enhanced expression of osteoblastic makers, such as and . In sharp contrast, cell proliferation of the parietal bone in these mice appeared similar to that of wild-type controls. These results suggest that the deficiency of could be involved in an augmented differentiation of calvarial bone, which is often noticed as an enlarged head circumference in MPS II-affected individuals.
PubMed: 38053930
DOI: 10.1016/j.ymgmr.2023.101021 -
Human Gene Therapy Apr 2024Mucopolysaccharidosis type II (MPSII) is a rare pediatric X-linked lysosomal storage disease, caused by heterogeneous mutations in the iduronate-2-sulfatase () gene,...
Mucopolysaccharidosis type II (MPSII) is a rare pediatric X-linked lysosomal storage disease, caused by heterogeneous mutations in the iduronate-2-sulfatase () gene, which result in accumulation of heparan sulfate (HS) and dermatan sulfate within cells. This leads to severe skeletal abnormalities, hepatosplenomegaly, and cognitive deterioration. The progressive nature of the disease is a huge obstacle to achieve full neurological correction. Although current therapies can only treat somatic symptoms, a lentivirus-based hematopoietic stem cell gene therapy (HSCGT) approach has recently achieved improved central nervous system (CNS) neuropathology in the MPSII mouse model following transplant at 2 months of age. In this study, we evaluate neuropathology progression in 2-, 4- and 9-month-old MPSII mice, and using the same HSCGT strategy, we investigated somatic and neurological disease attenuation following treatment at 4 months of age. Our results showed gradual accumulation of HS between 2 and 4 months of age, but full manifestation of microgliosis/astrogliosis as early as 2 months. Late HSCGT fully reversed the somatic symptoms, thus achieving the same degree of peripheral correction as early therapy. However, late treatment resulted in slightly decreased efficacy in the CNS, with poorer brain enzymatic activity, together with reduced normalization of HS oversulfation. Overall, our findings confirm significant lysosomal burden and neuropathology in 2-month-old MPSII mice. Peripheral disease is readily reversible by LV.IDS-HSCGT regardless of age of transplant, suggesting a viable treatment for somatic disease. However, in the brain, higher IDS enzyme levels are achievable with early HSCGT treatment, and later transplant seems to be less effective, supporting the view that the earlier patients are diagnosed and treated, the better the therapy outcome.
Topics: Humans; Child; Mice; Animals; Infant; Mucopolysaccharidosis II; Medically Unexplained Symptoms; Iduronate Sulfatase; Heparitin Sulfate; Genetic Therapy; Nervous System Diseases; Stem Cells
PubMed: 37427450
DOI: 10.1089/hum.2023.002