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Biomedicine & Pharmacotherapy =... Sep 2023Metastasis accounts for the majority of cancer-associated mortalities, representing a huge health and economic burden. One of the mechanisms that enables metastasis is... (Review)
Review
Metastasis accounts for the majority of cancer-associated mortalities, representing a huge health and economic burden. One of the mechanisms that enables metastasis is hypersialylation, characterized by an overabundance of sialylated glycans on the tumor surface, which leads to repulsion and detachment of cells from the original tumor. Once the tumor cells are mobilized, sialylated glycans hijack the natural killer T-cells through self-molecular mimicry and activatea downstream cascade of molecular events that result in inhibition of cytotoxicity and inflammatory responses against cancer cells, ultimately leading to immune evasion. Sialylation is mediated by a family of enzymes known as sialyltransferases (STs), which catalyse the transfer of sialic acid residue from the donor, CMP-sialic acid, onto the terminal end of an acceptor such as N-acetylgalactosamine on the cell-surface. Upregulation of STs increases tumor hypersialylation by up to 60% which is considered a distinctive hallmark of several types of cancers such as pancreatic, breast, and ovarian cancer. Therefore, inhibiting STs has emerged as a potential strategy to prevent metastasis. In this comprehensive review, we discuss the recent advances in designing novel sialyltransferase inhibitors using ligand-based drug design and high-throughput screening of natural and synthetic entities, emphasizing the most successful approaches. We analyse the limitations and challenges of designing selective, potent, and cell-permeable ST inhibitors that hindered further development of ST inhibitors into clinical trials. We conclude by analysing emerging opportunities, including advanced delivery methods which further increase the potential of these inhibitors to enrich the clinics with novel therapeutics to combat metastasis.
Topics: Humans; N-Acetylneuraminic Acid; Neoplasms; Cytidine Monophosphate N-Acetylneuraminic Acid; Polysaccharides; Sialyltransferases
PubMed: 37421784
DOI: 10.1016/j.biopha.2023.115091 -
American Journal of Medical Genetics.... Nov 2022
Topics: Humans; Mucopolysaccharidoses; Mucopolysaccharidosis VI; N-Acetylgalactosamine-4-Sulfatase
PubMed: 35959767
DOI: 10.1002/ajmg.a.62934 -
Frontiers in Physiology 2022Synthetic oligonucleotide technologies are DNA or RNA based molecular compounds that are utilized to disrupt gene transcription or translation in target tissues or... (Review)
Review
Synthetic oligonucleotide technologies are DNA or RNA based molecular compounds that are utilized to disrupt gene transcription or translation in target tissues or cells. Optimally, oligonucleotides are 10-30 base pairs in length, and mediate target gene suppression through directed sequence homology with messenger RNA (mRNA), leading to mRNA degradation. Examples of specific oligonucleotide technologies include antisense oligonucleotides (ASO), short hairpin RNAs (shRNA), and small interfering RNAs (siRNA). and studies that model obesity related disorders have demonstrated that oligonucleotide technologies can be implemented to improve the metabolism of cells and tissues, exemplified by improvements in fat utilization and hepatic insulin signaling, respectively. Oligonucleotide therapy has also been associated with reductions in lipid accumulation in both the liver and adipose tissue in models of diet-induced obesity. Recent advances in oligonucleotide technologies include the addition of chemical modifications such as N-acetylgalactosamine (GalNAc) conjugates that have been successful at achieving affinity for the liver, in turn improving specificity, and thus reducing off target effects. However, some challenges are still yet to be overcome relating to hepatic injury and off-target effects that have been reported with some compounds, including ASOs. In summary, oligonucleotide-based therapies are an effective tool to elucidate mechanistic insights into metabolic pathways and provide an attractive avenue for translational research into the clinic.
PubMed: 35295579
DOI: 10.3389/fphys.2022.839471 -
British Journal of Pharmacology Sep 2023Complement activation may drive hypertension through its effects on immunity and tissue integrity.
BACKGROUND AND PURPOSE
Complement activation may drive hypertension through its effects on immunity and tissue integrity.
EXPERIMENTAL APPROACH
We examined expression of C3, the central protein of the complement cascade, in hypertension.
KEY RESULTS
Increased C3 expression was found in kidney biopsies and micro-dissected glomeruli of patients with hypertensive nephropathy. Renal single cell RNA sequence data from normotensive and hypertensive patients confirmed expression of C3 in different cellular compartments of the kidney. In angiotensin II (Ang II) induced hypertension renal C3 expression was up-regulated. C3 mice revealed a significant lower albuminuria in the early phase of hypertension. However, no difference was found for blood pressure, renal injury (histology, glomerular filtration rate, inflammation) and cardiac injury (fibrosis, weight, gene expression) between C3 and wildtype mice after Ang II infusion. Also, in deoxycorticosterone acetate (DOCA) salt hypertension, a significantly lower albuminuria was found in the first weeks of hypertension in C3 deficient mice but no significant difference in renal and cardiac injury. Down-regulation of C3 by C3 targeting GalNAc (n-acetylgalactosamine) small interfering RNA (siRNA) conjugate decreased C3 in the liver by 96% and lowered albuminuria in the early phase but showed no effect on blood pressure and end-organ damage. Inhibition of complement C5 by siRNA showed no effect on albuminuria.
CONCLUSION AND IMPLICATIONS
Increased C3 expression is found in the kidneys of hypertensive mice and men. Genetic and therapeutic knockdown of C3 improved albuminuria in the early phase of hypertension but did not ameliorate arterial blood pressure nor renal and cardiac injury.
Topics: Animals; Mice; Albuminuria; Hypertension, Renal; Kidney; Hypertension; Blood Pressure; Angiotensin II; RNA, Small Interfering
PubMed: 37076314
DOI: 10.1111/bph.16097 -
International Journal of Biological... 2022O-glycosylation is a widespread post-translational modification of proteins. Aberrant O-glycosylation is a hallmark of cancer. Here, we show that the polypeptide...
O-glycosylation is a widespread post-translational modification of proteins. Aberrant O-glycosylation is a hallmark of cancer. Here, we show that the polypeptide N-acetylgalactosamine-transferase 1 () is frequently upregulated in gastric cancer and is correlated with poor survival. Overexpression of promoted, whereas knockdown suppressed proliferation, migration, and invasion of gastric cancer cells and . Mechanistically, enhances aberrant initiation of O-glycosylation and results in CD44 glycoproteins modified with abundant Tn antigens, thereby activating the Wnt/β-catenin signaling pathway. Collectively, this study demonstrates that overexpression in gastric cancer promotes the Wnt/β-catenin signaling pathway via abnormal O-glycosylation of CD44 to enhance malignancy, providing a novel strategy for the development of therapeutic reagents against gastric cancer.
Topics: Humans; Wnt Signaling Pathway; Stomach Neoplasms; Glycosylation; Phenotype; Hyaluronan Receptors
PubMed: 36439876
DOI: 10.7150/ijbs.73431 -
Journal of Hepatology Aug 2019Porphyrias are rare inherited disorders caused by specific enzyme dysfunctions in the haem synthesis pathway, which result in abnormal accumulation of specific pathway... (Review)
Review
Porphyrias are rare inherited disorders caused by specific enzyme dysfunctions in the haem synthesis pathway, which result in abnormal accumulation of specific pathway intermediates. The symptoms depend upon the chemical characteristics of these substances. Porphyrins are photoreactive and cause photocutaneous lesions on sunlight-exposed areas, whereas accumulation of porphyrin precursors is related to acute neurovisceral attacks. Current therapies are suboptimal and mostly address symptoms rather than underlying disease mechanisms. Advances in the understanding of the molecular bases and pathogenesis of porphyrias have paved the way for the development of new therapeutic strategies. In this Clinical Trial Watch we summarise the basic principles of these emerging approaches and what is currently known about their application to porphyrias of hepatic origin or with hepatic involvement.
Topics: 5-Aminolevulinate Synthetase; Acetylgalactosamine; Bone Marrow Transplantation; Cholestyramine Resin; Genetic Therapy; Heme; Humans; Liver; Liver Transplantation; Porphyrias, Hepatic; Porphyrins; Pyrrolidines; Receptor, Melanocortin, Type 1; alpha-MSH
PubMed: 31102718
DOI: 10.1016/j.jhep.2019.05.003 -
BioRxiv : the Preprint Server For... Apr 2023Chondroitin sulfate and chondroitin sulfate proteoglycans have been associated with Alzheimer's Disease (AD), and the impact of modified chondroitin sulfates is being...
INTRODUCTION
Chondroitin sulfate and chondroitin sulfate proteoglycans have been associated with Alzheimer's Disease (AD), and the impact of modified chondroitin sulfates is being investigated in several animal and cell-based models of AD. Published reports have shown the role of accumulation of chondroitin 4-sulfate and decline in Arylsulfatase B (ARSB; B-acetylgalactosamine-4-sulfatase) in other pathology, including nerve injury, traumatic brain injury, and spinal cord injury. However, the impact of ARSB deficiency on AD pathobiology has not been reported, although changes in ARSB were associated with AD in two prior reports. The enzyme ARSB removes 4-sulfate groups from the non-reducing end of chondroitin 4-sulfate and dermatan sulfate and is required for their degradation. When ARSB activity declines, these sulfated glycosaminoglycans accumulate, as in the inherited disorder Mucopolysaccharidosis VI.
METHODS
Reports about chondroitin sulfate, chondroitin sulfate proteoglycans and chondroitin sulfatases in Alzheimer's Disease were reviewed. Measurements of SAA2, iNOS, lipid peroxidation, chondroitin sulfate proteoglycan 4, and other parameters were performed in cortex and hippocampus from ARSB-null mice and controls by QRT-PCR, ELISA, and other standard assays.
RESULTS
SAA2 mRNA expression and protein, CSPG4 mRNA, chondroitin 4-sulfate and i-NOS were increased significantly in ARSB-null mice. Measures of lipid peroxidation and redox state were significantly modified.
DISCUSSION
Findings indicate that decline in ARSB leads to changes in expression of parameters associated with AD in the hippocampus and cortex of the ARSB-deficient mouse.
CONCLUSIONS
Further investigation of the impact of decline in ARSB on the development of AD may provide a new approach to prevent and treat AD.
PubMed: 37066366
DOI: 10.1101/2023.04.03.535377 -
Frontiers in Microbiology 2020-linked glycosylation is a post-translational modification found mainly in eukaryotic cells, which covalently attaches oligosaccharides to secreted proteins in certain... (Review)
Review
-linked glycosylation is a post-translational modification found mainly in eukaryotic cells, which covalently attaches oligosaccharides to secreted proteins in certain threonine or serine residues. Most of -glycans have -acetylgalactosamine (GalNAc) as a common core. Several glycoproteins, such as mucins (MUCs), immunoglobulins, and caseins are examples of -glycosylated structures. These glycans are further elongated with other monosaccharides and sulfate groups. Some of them could be found in dairy foods, while others are produced endogenously, in both cases interacting with the gut microbiota. Interestingly, certain gut microbes can access, release, and consume -linked glycans as a carbon source. Among these, , , and are prominent -linked glycan utilizers. Their consumption strategies include specialized -fucosidases and α-sialidases, in addition to endo---acetylgalactosaminidases that release galacto--biose (GNB) from peptides backbones. -linked glycan utilization by certain gut microbes represents an important niche that allows them to predominate and modulate host responses such as inflammation. Here, we focus on the distinct molecular mechanisms of consumption of -linked GalNAc glycans by prominent gut microbes, especially from mucin and casein glycomacropeptide (GMP), highlighting the potential of these structures as emerging prebiotics.
PubMed: 33224127
DOI: 10.3389/fmicb.2020.591568 -
International Journal of Molecular... Jan 2023The use of small interfering RNA (siRNA) in the clinic gives a wide range of possibilities for the treatment of previously incurable diseases. However, the main... (Review)
Review
The use of small interfering RNA (siRNA) in the clinic gives a wide range of possibilities for the treatment of previously incurable diseases. However, the main limitation for biomedical applications is their delivery to target cells and organs. Currently, delivery of siRNA to liver cells is a solved problem due to the bioconjugation of siRNA with N-acetylgalactosamine; other organs remain challenging for siRNA delivery to them. Despite the important role of the ligand in the composition of the bioconjugate, the structure and molecular weight of siRNA also play an important role in the delivery of siRNA. The basic principle is that siRNAs with smaller molecular weights are more efficient at entering cells, whereas siRNAs with larger molecular weights have advantages at the organism level. Here we review the relationships between siRNA structure and its biodistribution and activity to find new strategies for improving siRNA performance.
Topics: RNA, Small Interfering; Tissue Distribution; RNA, Double-Stranded; Hepatocytes; RNA Interference
PubMed: 36674473
DOI: 10.3390/ijms24020956 -
Journal of Inherited Metabolic Disease Jul 2021
Topics: Acetylgalactosamine; Homocysteine; Humans; Porphyria, Acute Intermittent; Pyrrolidines
PubMed: 34145602
DOI: 10.1002/jimd.12411