Targeting epigenetic modifications as a potential therapeutic option for diabetic retinopathy

Diabetic retinopathy (DR) is the leading cause of visual impairment in adults of working age (20–65 years) in developed countries. The metabolic memory phenomena (persistent effect of a glycemic insult even after retrieved) associated with it has increased the risk of developing the complication even after the termination of the glycemic insult. Hence, the need for finding early diagnosis and treatment options has been of great concern. Epigenetic modifications which generally occur during the beginning stages of the disease are responsible for the metabolic memory effect. Therefore, the therapy based on the reversal of the associated epigenetic mechanism can bring new insight in the area of early diagnosis and treatment mechanism. This review discusses the diabetic retinopathy, its pathogenesis, current treatment options, need of finding novel treatment options, and different epigenetic alterations associated with DR. However, the main focus is emphasized on various epigenetic modifications particularly DNA methylation which are responsible for the initiation and progression of diabetic retinopathy and the use of different epigenetic inhibitors as a novel therapeutic option for DR.     

Photoactivation of DNA thiobases as a potential novel therapeutic option

The thiopurines, 6-thioguanine and 6-mercaptopurine, are antileukemic agents that are incorporated into DNA following retrieval by the purine salvage pathway (see [1] for a review). Their toxicity requires active DNA mismatch repair (MMR), and thiopurine resistance is an acknowledged phenotype of MMR-defective cells [2, 3]. In addition to these direct cytotoxic effects, DNA thiobases have distinctive photochemical properties [4], the therapeutic potential of which has not been extensively evaluated. We report here that the thiopyrimidine nucleoside 4-thiothymidine is incorporated into DNA. It does not induce MMR-related toxicity, but it interacts synergistically with UVA light and dramatically sensitizes cultured human cells to very low, nonlethal UVA doses. 4-thiothymidine induced UVA dose enhancements of around 100-fold in DNA repair-proficient cells. Nucleotide excision repair-defective xeroderma pigmentosum cells were sensitized up to 1000-fold, implicating bulky DNA photoproducts in the lethal effect. The synergistic action of thiothymidine plus UVA required thymidine kinase, indicating a selective toxicity toward rapidly proliferating cells. Cooperative UVA cytotoxicity is a general property of DNA thiobases, and 6-thioguanine and 4-thiodeoxyuridine were also UVA sensitizers. Thiobase/UVA treatment may offer a novel therapeutic approach for the clinical management of nonmalignant conditions like psoriasis or for superficial tumors that are accessible to phototherapy.     

Stochastic gene expression stabilization as a new therapeutic strategy for cancer

Current differentiation therapies for cancer may not be effective because it might not be enough to only use molecules targeting chromatin remodelers. It may also be necessary to stabilize the re-expressed genes to convert malignant cells into benign ones.     

Regulation of autophagy as a therapeutic option in glioblastoma

Apoptosis - Around three out of one hundred thousand people are diagnosed with glioblastoma multiforme, simply called glioblastoma, which is the most common primary brain tumor in adults. With a...     

Silibinin as a potential therapeutic for sulfur mustard injuries

Sulfur mustard (SM) is a vesicating chemical warfare agent causing skin blistering, ulceration, impaired wound healing, prolonged hospitalization and permanent lesions. Silibinin, the lead compound from Silybum marianum, has also been discussed as a potential antidote to SM poisoning. However, its efficacy has been demonstrated only with regard to nitrogen mustards. Moreover, there are no data on the efficacy of the water-soluble prodrug silibinin-bis-succinat (silibinin-BS).     

Demethylation of E-cadherin gene in nasopharyngeal carcinoma could serve as a potential therapeutic strategy

E-cadherin has been proven to be widely down-regulated and tightly associated with tumour invasion and metastasis in multiple human cancer types. Recent research demonstrated that aberrant methylation around gene promoter region attributes to E-cadherin silencing. However, the detailed information about this epigenetic inactivation in nasopharyngeal carcinoma (NPC) is rare. The aim of this study was to probe more into the basic mechanism of E-cadherin methylation in NPC and elucidate the application of demethylating agents to restore E-cadherin expression. To address this question, we initially studied E-cadherin methylation status in NPC primary tumours and cell lines by methylation-specific PCR, and compared it with E-cadherin expression. Methylated E-cadherin was detected in 13 of 20 (65%) NPC clinical specimens and 2 of 2 (100%) NPC cell lines (HNE-1 and CNE-2), which was inversely correlated with E-cadherin expression. The detailed methylation profile at individual CpGs within CpG island of E-cadherin promoter region was confirmed by bisulphite sequencing. E-cadherin gene could be demethylated and reactivated in HNE-1 and CNE-2 cells upon treatment with 5-aza-dC, a DNA demethylating agent. Our findings indicate that frequent aberrant methylation of E-cadherin may play an important role in downregulation of E-cadherin, and demethylation therapy could serve as a promising strategy for NPC patients. Furthermore, a high frequency of E-cadherin methylation (9/20, 45%) in peripheral blood of NPC patients suggests its potential clinical application as an early diagnostic or predictive marker.     

GIP as a potential therapeutic agent?

Glucose-dependent insulinotropic polypeptide (GIP) is released from K-cells in the gut after meal ingestion, and acts in concert with glucagon-like peptide 1 (GLP-1) to augment glucose-stimulated insulin secretion. While derivatives of GLP-1 are under active investigation for the treatment of type 2 diabetes, the case is different for GIP. Indeed, the insulinotropic effect of GIP is almost absent in patients with type 2 diabetes. In addition, the unfavourable pharmacokinetic profile of native GIP obviates its clinical application. Different analogues of GIP exhibiting prolonged stability and enhanced biological potency have been generated in order improve the anti-diabetic properties of GIP. However, glucose-normalisation, as is typically observed during the intravenous administration of GLP-1 in patients with type 2 diabetes, has not yet been achieved with GIP or its derivatives. Since GIP appears to play a role in lipid physiology and elevated levels of GIP have been associated with obesity, antagonising GIP action has been proposed as a therapeutic strategy for obesity. This concept has recently been reinforced by the observation that GIP receptor knock-out mice are protected from high-fat diet-induced obesity. However, eliminating the effect of endogenous GIP may at the same time impair postprandial insulin secretion, thereby severely disturbing glucose homeostasis. Therefore, therapeutic strategies based on either augmenting or antagonising GIP action are far from being established alternatives for the future therapy of type 2 diabetes or obesity.     

Wnt signaling as a potential therapeutic target for frontotemporal dementia

Progranulin mutations result in frontotemporal dementia, but the underlying pathophysiology has remained largely unexplained. New data by Geschwind and colleagues in this issue of Neuron uncovered that the Wnt/FZD2 signaling pathway is an early and critical contributor to disease pathology.     

Interleukin-23 as a potential therapeutic target for rheumatoid arthritis

Cytokine-mediated immunity plays a crucial role in the pathogenesis of various autoimmune diseases, including rheumatoid arthritis (RA). Increasing evidence has revealed the importance of IL-23, which closely resembles IL-12 structurally and immunologically, in linking innate and adaptive immunity. IL-23, a newly identified heterodimeric pro-inflammatory cytokine, is composed of a p40 subunit in common with IL-12 and a unique p19 subunit. Recent evidence suggests that IL-23, rather than IL-12, is the crucial factor in the pathogenesis of various immune-mediated disorders. In addition, recent studies have explored the role of IL-23 in patients with RA. An elevated expression of IL-23 has been demonstrated in the synovial fibroblasts and plasma of patients with RA. Moreover, an association between IL-23 and IL-23R polymorphisms with susceptibility to RA has been reported. Therefore, the targeting of IL-23 or the IL-23 receptor has been proposed as a potential therapeutic approach for RA. In this review we will discuss the biological features of IL-23, and summarize recent advances in our understanding of the role of IL-23 in the pathogenesis and treatment of RA.     

通过miRNA基因表达谱的基因共表达网络构建对星形细胞瘤的基因靶标进行预测

星形细胞瘤为浸润性生长肿瘤,生长缓慢,多为隐形症状,难以早期发现。多数肿瘤切除后有复发可能,且复发后肿瘤可演变成间变性星形细胞瘤或多形性胶质母细胞瘤。因此寻找其生物标志物早期诊断,并研究新的治疗方法就十分重要。方法:通过选用GEO数据库的星形细胞瘤miRNA表达谱数据,进行差异分析以及靶基因预测,通过2者共表达网络的构建对筛选出的miRNA的研究价值进行探讨。结果:得出hsa-miR-29b-2-5p;hsa-miR-339-5p与hsa-miR-362-3p3个较为关键的miRNA及与3者关系密切的8个mRNA。结论:通过对8个mRNA在癌症中的作用的讨论,肯定了这3个关键miRNA作为潜在靶点的研究价值。     

Cloning and expression analysis of p26 gene in Artemia sinica

The protein p26 is a small heat shock protein that functions as a molecular chaperone to protect embryos by preventing irreversible protein damage during embryonic development. A 542 bp fragment of the p26 gene was cloned and sequenced. The fragment encoded 174 amino acid residues and the amino acid sequence contained the α-crystallin domain. Phylogenetic analysis showed that eight Artemia populations were divided into four major groups. Artemia sinica (YC) belonged to the East Asia bisexual group. Expression of the p26 gene at different developmental stages ofA. sinica was quantified using real-time quantitative polymerase chain reaction followed by cloning and sequencing. The relationship between the quantity of p26 gene expression and embryonic development was analyzed. The results indicated that massive amounts of p26 were expressed during the development of A. sinica. At the developmental stage of 0 h, A. sinica expressed the highest level of p26. As development proceeded, expression levels of the p26 gene reduced significantly. There was a small quantity of p26 gene expression at the developmental stages of 16 h and 24 h. We concluded that p26 might be involved in protecting the embryo from physiological stress during embryonic development.     

d-Alanine as a biomarker and a therapeutic option for severe influenza virus infection and COVID-19

Since the outbreak of coronavirus disease 2019 (COVID-19), biomarkers for evaluating severity, as well as supportive care to improve clinical course, remain insufficient. We explored the potential of d-amino acids, rare enantiomers of amino acids, as biomarkers for assessing disease severity and as protective nutrients against severe viral infections. In mice infected with influenza A virus (IAV) and in patients with severe COVID-19 requiring artificial ventilation or extracorporeal membrane oxygenation, blood levels of d-amino acids, including d-alanine, were reduced significantly compared with those of uninfected mice or healthy controls. In mice models of IAV infection or COVID-19, supplementation with d-alanine alleviated severity of clinical course, and mice with sustained blood levels of d-alanine showed favorable prognoses. In severe viral infections, blood levels of d-amino acids, including d-alanine, decrease, and supplementation with d-alanine improves prognosis. d-Alanine has great potentials as a biomarker and a therapeutic option for severe viral infections.     

Intravascular insulin gene delivery as potential therapeutic intervention in diabetes mellitus

We assessed therapeutic potential of intravascular insulin gene delivery in a diabetic murine model. The rat proinsulin-1 gene cDNA engineered to harbor furin consensus cleavage sequences was inserted into EBV-based plasmid vectors that contained CAG promoter or multimerized rat insulin promoter (RIP). Normal or streptozotocin (STZ)-induced diabetic mice were given an injection of the plasmids via the tail vein under high pressure. Transfection of the CAG-proinsulin construct markedly improved hyperglycemia of diabetic mice, accompanied by a considerable increase in serum insulin concentrations. Although the RIP-plasmid failed to reduce fasting blood glucose, the glucose tolerance test and RT-PCR analysis revealed that insulin production was regulated in the liver in a blood glucose level-dependent manner. The present results suggest a potential therapeutic means of controlling DM.