Current Medicinal Chemistry - Volume 29, Issue 40, 2022

Background: Catalytic hydrolysis of cyclic guanosine monophosphate (cGMP) by phosphodiesterase 6 (PDE6) is critical in phototransduction signalling in photoreceptors. Mutations in the genes encoding any of the three PDE6 subunits are associated with retinitis pigmentosa, the most common form of inherited retinal diseases. The RD1 mouse carries a naturally occurring nonsense mutation in the Pde6b gene. The RD1 mouse retina rapidly degenerates and fails to form rod photoreceptor outer segments due to the elevated cGMP level and subsequent excessive Ca²⁺ influx. In this study, we aim to test whether the PDE5 expression, a non-photoreceptor-specific member of the PDE superfamily, rescues photoreceptors in the RD1 retina. Methods: Electroporation used the PDE5 expression plasmid to transfect neonatal RD1 mice. The mouse retina degeneration was assessed by retinal sections’ stains with DAPI. The expression and localization of phototransduction proteins in photoreceptors were analysed by immunostaining. The expression of proteins in cultured cells was analysed by immunoblotting. Results: The exogenous PDE5 expression, a non-photoreceptor-specific member of the PDE superfamily, prevents photoreceptor degeneration in RD1 mice. Unlike endogenous photoreceptor-specific PDE6 localised in the outer segments of photoreceptors, ectopically- expressed PDE5 was distributed in inner segments and synaptic terminals. PDE5 also promoted the development of the outer segments in RD1 mice. PDE5 co-expression with rhodopsin in cultured cells showed enhanced rhodopsin expression. Conclusion: Lowering the cGMP level in photoreceptors by PDE5 is sufficient to rescue photoreceptors in RD1 retinas. cGMP may also play a role in rhodopsin expression regulation in photoreceptors.

Retinal degenerative diseases are the main retinal diseases that threaten vision. Most retinal degenerative diseases are inherited diseases, including autosomal recessive inheritance, autosomal dominant inheritance, X-linked inheritance, and mitochondrial inheritance; therefore, emerging gene therapy strategies may provide an alternative method of treatment. Currently, three viral vectors are usually used in gene therapy studies: adenovirus, lentivirus, and adeno-associated virus. Other gene therapies have their own advantages, such as DNA nanoparticles, antisense oligonucleotides, and gene editing therapies. In addition, retinal degenerative diseases are often accompanied by abnormalities of retinal cells, including photoreceptor and retinal pigment epithelial cells. At present, stem cell transplantation is a promising new treatment for retinal degenerative diseases. Common sources of stem cells include retinal progenitor cells, induced pluripotent stem cells, embryonic stem cells, and mesenchymal stem cells. In addition, retina explant cultures in vitro can be used as an effective platform for screening new therapies for retinal degenerative diseases. Drugs that actually reach the retinal layer are more controlled, more consistent, and less invasive when using retinal explants. Furthermore, studies have shown that the imbalance of the gut microbiota is closely related to the occurrence and development of diabetic retinopathy. Therefore, the progression of diabetic retinopathy may be restrained by adjusting the imbalance of the gut microbiota. The purpose of this review is to discuss and summarize the molecular mechanisms and potential therapeutic strategies of retinal degenerative diseases.

Age-related macular degeneration (AMD) is a complex disease that mainly affects people over 50 years of age. Even though management of the vascularisation associated with the “wet” form of AMD is effective using anti-VEGF drugs, there is currently no treatment for the “dry” form of AMD. Given this, it is imperative to develop methods for disease prevention and treatment. For this review, we searched scientific articles via PubMed and Google Scholar, and considered the impact of nutrients, specific dietary patterns, and probiotics on the incidence and progression of AMD. Many studies revealed that regular consumption of foods that contain ω-3 fatty acids is associated with a lower risk for late AMD. Particular dietary patterns, such as the Mediterranean diet that contains ω-3 FAs-rich foods (nuts, olive oil, and fish), seem to be protective against AMD progression compared to Western diets that are rich in fats and carbohydrates. Furthermore, randomized controlled trials that investigated the role of nutrient supplementation in AMD have shown that treatment with antioxidants, such as lutein/zeaxanthin, zinc, and carotenoids, may be effective against AMD progression. More recent studies have investigated the association of the antioxidant properties of gut bacteria, such as Bacteroides and Eysipelotrichi, with lower AMD risk in individuals whose microbiota is enriched with them. These are promising fields of research that may yield the capacity to improve the quality of life for millions of people, allowing them to live with a clear vision for longer and avoiding the high cost of vision-saving surgery.

Cutaneous melanoma (CM) is an aggressive and highly metastatic solid tumor associated with drug resistance. Before 2011, despite therapies based on cytokines or molecules inhibiting DNA synthesis, metastatic melanoma led to patient death within 18 months from diagnosis. However, recent studies on bidirectional interactions between melanoma cells and tumor microenvironment (TME) have had a significant impact on the development of new therapeutic strategies represented by targeted therapy and immunotherapy. In particular, the heterogeneous stromal fibroblast populations, including fibroblasts, fibroblast aggregates, myofibroblasts, and melanoma associated fibroblasts (MAFs), represent the most abundant cell population of TME and regulate cancer growth differently. Therefore, in this perspective article, we have highlighted the different impacts of fibroblast populations on cancer development and growth. In particular, we focused on the role of MAFs in sustaining melanoma cell survival, proliferation, migration and invasion, drug resistance, and immunoregulation. The important role of constitutively activated MAFs in promoting CM growth and immunoediting makes this cell type a promising target for cancer therapy.

According to the latest epidemiological data, breast cancer has recently been the most frequently diagnosed malignancy. To date, a body of evidence has established the involvement of multiple - and frequently interrelated - genetic and environmental factors in the pathogenesis of the disease. Emerging research on cancer prevention has highlighted the deterrence potential of interventions targeting environmental risk factors, particularly diet. In this aspect, the current review reveals the latest scientific results regarding epigallocatechin-3-gallate (EGCG) - a catechin most commonly found in green tea, as a potential chemopreventive dietary agent against breast cancer. in vitro studies on EGCG have demonstrated its effect on cell cycle progression and its potential to suppress several intracellular signaling pathways involved in breast cancer pathogenesis. In addition, EGCG possesses specific apoptosis-inducing characteristics that seem to enhance its role as a regulator of cell survival. Preclinical data seem to support using EGCG as an effective adjunct to EGFR-targeting treatments. The authors’ appraisal of the literature suggests that although preclinical evidence has documented the anticarcinogenic features of EGCG, limited large-scale epidemiological studies are investigating the consumption of EGCG - containing nutrients in the prevention and management of breast cancer risk. This literature review aims to liaise between preclinical and epidemiological research, surveying the existing evidence and unraveling relevant knowledge gaps.

Ample data pertaining to the use of MDSCs have been documented. However, the potency of natural products in targeting MDSCs in the light of the tumor immune microenvironment (TME) has not been discussed vividly. The current review is an amalgamation of the documented literature pertaining to the effectiveness of various natural products supported by in silico experimental data. The combination of bioinformatics to wet bench experimentation with natural products against cancer specifically targeting MDSCs can be a promising approach to mitigate cancer.