Neuroinflammation and neovascularization in diabetic eye diseases (DEDs): identification of potential pharmacotherapeutic targets.

The goal of this review is to increase public knowledge of the etiopathogenesis of diabetic eye diseases (DEDs), such as diabetic retinopathy (DR) and ocular angiosarcoma (ASO), and the likelihood of blindness among elderly widows. A widow's life in North India, in general, is fraught with peril because of the economic and social isolation it brings, as well as the increased risk of death from heart disease, hypertension, diabetes, depression, and dementia. Neovascularization, neuroinflammation, and edema in the ocular tissue are hallmarks of the ASO, a rare form of malignant tumor. When diabetes, hypertension, and aging all contribute to increased oxidative stress, the DR can proceed to ASO. Microglia in the retina of the optic nerve head are responsible for causing inflammation, discomfort, and neurodegeneration. Those that come into contact with them will get blind as a result of this. Advanced glycation end products (AGE), vascular endothelial growth factor (VEGF), protein kinase C (PKC), poly-ADP-ribose polymerase (PARP), metalloproteinase9 (MMP9), nuclear factor kappaB (NFkB), program death ligand1 (PDL-1), factor VIII (FVIII), and von Willebrand factor (VWF) are potent agents for ocular neovascularisation (ONV), neuroinflammation and edema in the ocular tissue. AGE/VEGF, DAG/PKC, PARP/NFkB, RAS/VEGF, PDL-1/PD-1, VWF/FVIII/VEGF, and RAS/VEGF are all linked to the pathophysiology of DEDs. The interaction between ONV and ASO is mostly determined by the VWF/FVIII/VEGF and PDL-1/PD-1 axis. This study focused on retinoprotective medications that can pass the blood-retinal barrier and cure DEDs, as well as the factors that influence the etiology of neovascularization and neuroinflammation in the eye.

Interlinked role of ASN, TDP-43 and Miro1 with parkinopathy: Focus on targeted approach against neuropathy in parkinsonism.

Parkinsonism is a complex neurodegenerative disease that is difficult to differentiate because of its idiopathic and unknown origins. The hereditary parkinsonism known as autosomal recessive-juvenile parkinsonism (AR-JP) is marked by tremors, dyskinesias, dystonic characteristics, and manifestations that improve sleep but do not include dementia. This was caused by deletions and point mutations in PARK2 (chromosome 6q25.2-27). Diminished or unusual sensations (paresthesias), loss of neuron strength both in the CNS and peripheral nerves, and lack of motor coordination are the hallmarks of neuropathy in parkinsonism. The incidence of parkinsonism during oxidative stress and ageing is associated with parkinopathy. Parkinopathy is hypothesized to be triggered by mutation of the parkin (PRKN) gene and loss of normal physiological functions of PRKN proteins, which triggers their pathogenic aggregation due to conformational changes. Two important genes that control mitochondrial health are PRKN and phosphatase and tensin homologue deleted on chromosome 10-induced putative kinase 1 (PINK1). Overexpression of TAR DNA-binding protein-43 (TDP-43) increases the aggregation of insoluble PRKN proteins in OMM. Foreign α-synuclein (ASN) promotes parkinopathy via S-nitrosylation and hence has a neurotoxic effect on dopaminergic nerves. Miro1 (Miro GTPase1), a member of the RAS superfamily, is expressed in nerve cells. Due to PINK1/PRKN and Miro1's functional relationship, an excess of mitochondrial calcium culminates in the destruction of dopaminergic neurons. An interlinked understanding of TDP-43, PINK1/PRKN, ASN, and Miro1 signalling in the communication among astrocytes, microglia, neurons, and immune cells within the brain explored the pathway of neuronal death and shed light on novel strategies for the diagnosis and treatment of parkinsonism.

Lead Finding from Selected Flavonoids with Antiviral (SARS-CoV-2) Potentials Against COVID-19: An In-silico Evaluation.

BACKGROUND: COVID-19 is a pandemic respiratory contagious viral (SARS-CoV-2) disease associated with high morbidity and mortality worldwide. Currently, there are no effective preventive or treatment strategies for COVID-19 and it has been declared as a global health emergency by WHO. In silico molecular docking studies can be useful to predict the binding affinity between the phytocompound and the target protein and play a vital role in finding an inhibitor through structure-based drug design. OBJECTIVE: In this aspect, our objective was to screen essential flavonoids against possible protein targets such as SARS-CoV-2 spike glycoprotein receptor binding domain (RBD-S) and host Angiotensin Converting Enzyme-2 protease domain (PD-ACE-2) using in silico molecular docking studies. METHODS: Approximately 49 flavonoids were identified and were evaluated for their drug-likeness based on Lipinski rule, bioactivity scores, antiviral and toxicity profiles using SwissADME, Molinspiration, PASS and GUSAR online tools. The flavonoids that passed Lipinski rule were subjected to in silico analysis through molecular docking on RBD-S and PD-ACE-2 using Molegro Virtual Docker v6.0. RESULTS: The bioactive flavonoids that showed NIL violations and were found in compliance with Lipinski rule were selected for docking studies. In silico analysis reported that biochanin A and silymarin bind significantly at the active sites of RBD-S and PD-ACE-2 with a MolDock score of -78.41and -121.28 kcal/mol respectively. Bioactivity scores, antiviral potential and toxicity profiles were predicted for the top interacting phytocompounds and substantial relevant data was reported. CONCLUSION: The current outcomes created a new paradigm for understanding biochanin A and silymarin bioflavonoids as potent inhibitors of RBD-S and PD-ACE-2 targets respectively. Further work can be extended to confirm their therapeutic potential for COVID-19.

A trimethoxy flavonoid isolated from stem extract of Tabebuia chrysantha suppresses angiogenesis in angiosarcoma.

OBJECTIVES: This research aimed to evaluate the antiangiogenic activity of isolated flavonoid 4a,5,8,8a-tetrahydro-5-hydroxy-3,7,8-trimethoxy-2-(3,4-dimethoxyphenyl) chromen-4-one (TMF) from Tabebuia chrysantha. STAT3-MMP9 signalling is a signal transduction mechanism that promotes angiogenesis in various cancers. METHODS: The tumour xenografting chicken embryo chorioallantoic membrane (CAM) model-based ex vivo assay was used to evaluate the activity of TMF. The Western blot, densitometric analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to evaluate the activity of the MMP9. Zebrafish embryos were used to evaluate embryotoxicity, and in vitro free radical scavenging activity of flavonoid was also elucidated. KEY FINDINGS: This research assessed the high level of STAT3, p-ERK, VEGF-R and MMP9 in the tissue extract of the control group, and also, the suppression of angiogenesis in the treatment groups was due to scavenged ROS and RNS, dephosphorylation of STAT3 and ERK, and suppression of MMP9 gene expression. CONCLUSION: The isolated flavonoid named TMF from T. chrysantha functions as specific regulators of target proteins of angiosarcoma. The STAT3-MMP9 signalling may be used as an effective prognostic marker of angiosarcoma.