Current Molecular Medicine - Volume 22, Issue 8, 2022

Covalent conjugation of hyaluronidase with copolymeric glycosaminoglycans (GAG, heparin and dermatan sulfate) considerably inactivates the enzyme, while conjugation with polymeric GAG (chondroitin sulfate and hyaluronan) improves its stability. These effects are associated with structural differences of these GAG caused by С-5 epimerization of glucuronic and iduronic acid residues and different effects of (α[1 – 4] and α[1 – 3] relative to β[1 – 4] and β[1 – 3]) glycosidic bonds. Pronounced effects of galactose C-4 epimers (in comparison with glucose) and disaccharide mixture (lactose, cellobiose, maltose) on endoglycosidase activity of hyaluronidase emphasize the importance of its diversified multi-contact microenvironment. For a better understanding of the mechanisms regulating hyaluronidase activity, molecular docking and molecular dynamics were chosen. Stabilization effect of chondroitin ligands on heat inactivation of hyaluronidase was demonstrated. An increase in denaturation temperature by 10-15oC hampers blocking of the active site entrance and prevents the enzyme inactivation. Enzyme-GAG interactions were examined by molecular docking with molecular dynamic elaboration. Gradual chemical modification of hyaluronidase was based on the calculated sequence of preferential binding of GAG. Theoretically, covalent binding of chondroitin sulfate trimers at cs7 or cs7, cs1 and cs5 on the enzyme surface provides complete protection against heparin inhibition. Computational investigation of hyaluronidase microenvironment and interactions which limit the enzyme activity allows identification of the best GAG regulators of hyaluronidase endoglycosidase activity and their experimental verification.

Cancer is an important health issue worldwide. Cancer therapy is multifaceted, and drug resistance is still the major limiting factor in the treatment of patients with this disease. Although the mechanisms of anticancer drug resistance have been broadly investigated, a massive biological signal pathway of Non-coding RNAs (ncRNAs) involved in this process has not been completely understood. Long noncoding RNAs (lncRNAs) are a kind of transcripts with a minimum length of 200 nucleotides in size, which have a limited potential for coding proteins. The roles of these RNA molecules have been evaluated in relation to several pathological processes, including tumor formation and progression. Increasing evidence has recently reported that non-coding RNAs (ncRNAs), particularly long non-coding RNAs, have significant roles in many cellular and genomic processes, and because of their potential in regulation specific genes, they are also involved in drug resistance. In this review, we review the literature on the features of lncRNA, their regulation roles in the gene expression related to chemo resistance, and the potential of these RNAs as targeted therapies for personalized treatment in cancers.

Immune tolerance is established in the eye to prevent permanent blindness associated with destructive damage to the cornea and retina caused by immune cell infiltration; hence, the immune responses and subsequent inflammations are strongly suppressed. While non-infectious uveitis develops from a disruption of immune tolerance in the eye, its onset is a result of accumulating etiologic factors, including genetic predisposition, environmental factors, and aging. Many non-infectious uveitis cases are genetically predisposed to human leukocyte antigen (HLA) as the most substantial disease susceptibility region. HLA class I molecules are critical for natural killer (NK) cells to distinguish between self and non-self. The killer cell Ig-like receptor (KIR) family is one of the essential components of these receptors. Evidence has accumulated that NK cells are involved in innate and acquired immunity by interacting with other immunocompetent cells to develop several autoimmune diseases. This review summarizes the possible role of KIR in the development of non-infectious uveitis.

Acute retinal necrosis normally occurs at the periphery retina and gradually merges and progresses to the posterior pole. Optic neuropathy and central retinal artery occlusion as initial manifestation is very rare. We report the case of a patient with optic neuropathy and central retinal vessels as the first manifestations of acute retinal necrosis. Antiviral drugs, corticosteroids, and drugs that improve blood circulation were given. The necrotic retina and swollen optic disc disappeared gradually. However, the final vision of this eye declined to no light perception. From the first case report in 2001 to now, a total of 8 sporadic cases have been reported. The average onset age is 60.85±14.05 years. Most of them had no history of virus infection. Cardiovascular disease history maybe a risk factor. Acute retinal necrosis should be considered in patients with retinal vascular occlusion accompanied by granulomatous anterior uveitis. Further research is needed to determine whether treatments in addition to antiviral and corticosteroid therapy are needed.

Microglia are immune cells found in the central nervous system (CNS) involved in infection combat and cellular debris clean. These glial cells are involved in synaptogenesis during brain development by their interactions with neurons and other glial cells. These relations are associated with the secretion of signaling molecules, such as chemokines and neurotrophic factors. Microglia cells influence synapsis and neuron morphology during different phases of development. Also, other systems, for example, gut microbiota, indirectly affect microglial functions and morphology. Several factors that can occur in different development periods, including intrauterine through adult life, could impact microglia. Impairment in these cells could be associated with the development of some psychiatric conditions, such as schizophrenia, autistic spectrum disorder (ASD), and depression. This review focuses on describing microglia functions in the maintenance of CNS and how they are associated with other systems, as the gutmicrobiota brain axis and environmental stressors, such as stress, maternal deprivation, sleep deprivation, immune activation, and ethanol exposure, that can influence the function of the microglia during neurodevelopment.

Backgound and objective: Early chemoprevention in Oral Potentially Malignant Disorders (OPMDs) and Oral Cancer (OC) has been extensively researched in order to mitigate the malignant transformation and progression of the lesion. Many agents have been attempted, but their cost inefficacy and inadequate outcomes posed a major hindrance in their successful adoption. Retinoid Based Therapy (RBT) though a cheap and effective treatment option, could not achieve much clinical usage because of variable responsiveness in clinical outcomes. Such clinical response variability may be attributed to the repression of retinoid receptors by Preferentially Expressed Antigen of Melanoma (PRAME) protein molecule. Therefore, in order to make RBT successful, targeting PRAME by various immunotherapies is an exciting area of research investigation. This review provides an insight into the various immunotherapeutic strategies targeting PRAME and their usefulness in retinoid-resistant OPMD and OC. Method of data collection: An exhaustive internet-based literature search following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines was carried out in PUBMED and Google SCHOLAR database using terms ‘Anti-PRAME’ OR ‘PRAME Immunotherapy’ OR ‘PRAME Vaccines’ AND ‘Cancer’ AND ‘Retinoid resistance’. Only articles in the English language with at least 1 citation, published in a journal with impact factor ≥ 1, having relevance to the context and availability of full text were considered. Results: After an initial search, 342 articles were yielded on the basis of inclusion criteria and, by reading the abstract and availability of full text, a total of 124 articles were selected. Further reading the full texts and considering articles from the references of the selected articles, a total of 65 articles were finally included in the review. Conclusion: Our analysis of the literature suggests that PRAME screening in OC and OPMDs prior to RBT should be done. In PRAME positive cases, approaches like PRAME based immunotherapy in the form of Cancer vaccine therapy [Acellular PRAME vaccine, PRAME pulsed Dendritic Cells (DC)]; Adoptive T Cell therapy/T Cell Receptor-T Cell therapy, Antibody therapy/Chimeric Antigen Receptor-T Cell therapy along with Presented antigen modulation Therapies employing histone deacetylase inhibitors and demethylation agents seem plausible. In the future, a combination therapy employing either PRAME vaccines or antibodies or Adoptive T cell Therapy and ATRA could be used in retinoid resistant OC and OPMDs.

Objective: The relative balance of osteoblasts in bone formation and osteoclasts in bone resorption is crucial for maintaining bone health. With age, this balance between osteoblasts and osteoclasts is broken, resulting in bone loss. Anabolic drugs are continuously being developed to counteract this low bone mass. Recombinant proteins are used as biotherapeutics due to being relatively easy to produce on a large scale and are cost-effective through various expression systems. This study aimed to develop a recombinant protein that would positively impact osteoblast differentiation and mineralized nodule formation using unique cartilage matrix-associated protein (UCMA). Methods: A recombinant glutathione-S-transferase (GST)-UCMA fusion protein was generated in an E.coli system, and purified by affinity chromatography. MC3T3-E1 osteoblast cells and Osterix (Osx)-knockdown stable cells were cultured for 14 days to investigate osteoblast differentiation and nodule formation in the presence of the recombinant GST-UCMA protein. The differentiated cells were assessed by alizarin red S staining and quantitative PCR of the osteoblast differentiation marker osteocalcin. In addition, cell viability in the presence of the recombinant GST-UCMA protein was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell adhesion assay. Results: The isolation of both purified recombinant GST-only and GST-UCMA proteins were confirmed at 26 kDa and 34 kDa, respectively, by Coomassie staining and western blot analysis. Neither dose-dependent nor time-dependent presence of recombinant GST-UCMA affected MC3T3-E1 cell viability. However, MC3T3-E1 cell adhesion to the recombinant GST-UCMA protein increased dose-dependently. Osteoblast differentiation and nodule formation were promoted in both MC3T3-E1 osteoblast cells and Osxknockdown stable cells when cultured in the presence of recombinant GST-UCMA protein. Conclusion: A recombinant GST-UCMA protein induces osteogenic differentiation and mineralization, suggesting its potential use as an anabolic drug to increase low bone mass in osteoporotic patients.