A Novel (−)‑(2S)‑7,4′‑Dihydroxyfavanone Compound for Treating Age-Related Diabetes Mellitus through Immunoinformatics-Guided Activation of CISD3

Age-related diabetes mellitus is increasingly linked to mitochondrial dysfunction. This research identifies CID3, a key regulator of mitochondrial stability, whose activation can mitigate oxidative stress and telomere shortening major contributors to diabetes and ageing.
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A novel (−)-(2S)-7,4′-dihydroxyflavanone compound for treating age-related diabetes mellitus through immunoinformatics-guided activation of CISD3 - Biogerontology

The iron-sulfur domain (CISD) proteins of CDGSH are classified into three classes: CISD1, CISD2, and CISD3. During premature ageing, mutations that affect these proteins, namely their binding sites, could result in reduced protein production and an inability to preserve cellular integrity. Consequently, this leads to the development of conditions such as diabetes. Notably, CISD3 plays a crucial role in the management of age-related disorders such as Wolfram syndrome, which is often referred to as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). Computational analyses have predicted that CISD3 regulates the redox state, safeguards the endoplasmic reticulum and mitochondria, and maintains intracellular calcium levels. CISD3, a member of a recently discovered gene family associated with the CDGSH iron protein apoptotic compensatory response, fulfils a crucial function in mitigating the effects of accelerated ageing. The compound “(−)-(2S)-7,4′-Dihydroxyflavanone” has been discovered by computational drug design as a possible activator of CISD3. It shows potential therapeutic benefits in ameliorating metabolic dysfunction and enhancing glucose regulation. The ligand binds to the binding pocket of the CISD3 protein, increasing the stability of the protein and enhancing its functionality. The current research investigates the binding processes of the molecule in various structures and its anticipated effects on these tissues, therefore providing valuable insights into the mitigation of age-related diabetes and metabolic dysfunction. The projected tripling of the worldwide population of individuals aged 50 and above by 2050 necessitates the urgent development of immunoinformatics-based approaches, including pharmaceutical therapies that target CISD3, to prevent age-related pathologies. The stimulation of CISD3, namely by compounds such as “(−)-(2S)-7,4′-Dihydroxyflavanone”, has the potential to counteract telomere shortening and improve metabolic pathways.

Wolfram syndrome is a rare inherited disorder characterized by a cluster of symptoms including deafness, optic atrophy, diabetes mellitus, and diabetes insipidus. The CDGSH iron-sulfur domain (CISD) protein family consists of three genes: CISD1, CISD2, and CISD3. Each of these genes has a crucial role in the cellular functioning. CISD3 predominantly localizes to the outer mitochondrial membrane. The 2Fe-2S domain is a crucial constituent of these proteins. Extensive bioinformatics studies have demonstrated that the CDGSH protein family, including CISD3, plays a crucial role in maintaining redox balance, calcium homeostasis, and the integrity of the endoplasmic reticulum and mitochondria.(Grifagni et al., 2024) Researchers are examining CISD3 as a potential gene for extending lifespan due to its association with the decline of CDGSH proteins that happens with age, a contributing factor to premature aging.(Chen et al., 2010) Age-related events encompass several physiological changes such as mitochondrial failure, impaired autophagy, disturbed proteostasis, altered nutrition sensing, and degraded intercellular communication.(Kim et al., 2018) These events result in elevated oxidative stress and cellular demise. Computational drug design studies have emphasized the potential involvement of CISD3 in these events.(King et al., 2021) The CISD3 deficit is believed to be caused by the impairment of electron transport and the induction of endoplasmic reticulum stress, resulting in the formation of reactive oxygen species (ROS). Using in silico drug design strategies, the compound (-)-(2S)-7,4'-Dihydroxyflavanon has been discovered as a potential activator of CISD3.(Marjault et al., 2023) These results have been validated in other tissues. From this research, the medical world is great news on how to deal with diabetes and reduce insulin resistance.(Marjault et al., 2022) The biological effects of CDGSH modulators, such as (-)-(2S)-7,4'-Dihydroxyflavanone is well demonstrated concerning its anti-diabetic activity to preserve pancreatic β-cell function and improve the morphological alterations in diabetic pancreas through activation of AMPK pathway. Therefore, the induction of this pathway results in activation of Akt signaling and then attenuates oxidative stress and improves glucose uptake. Human studies have described success for oral formulations of CDGSH modulators as well as trans-resveratrol in the treatment metabolic deficiencies associated with aging.(Nechushtai et al., 2024) One projection expects the number of age-related illnesses to skyrocket between 2030 and 2050. Already one of the most promising areas to look for treatments, this provides an very hopeful path within which new/groundbreaking therapies can be found for this common issue.(Sengupta et al., 2018) The worldwide number of people over 50 years old will triple to smash through the two billion barrier by next few decades. This necessitates the implementation of interventions to delay age-related conditions like diabetes and heart problems, thereby extending both the period of good health and overall lifespan.(Tsai et al., 2015) The compound "(-)-(2S)-7,4'-Dihydroxyflavanone" has been identified as a CISD3 activator, a role that has been largely unexplored until now. This invention utilizes immunoinformatics-based medication design. This revolutionary finding elucidates the mechanism via which these ligands bind to CISD3, hence enhancing its efficacy in the treatment of diabetes, reducing the likelihood of metabolic dysfunction, and improving age-related heart disease.(Ganie et al., 2011) The pancreas and heart are the organs most frequently impacted by age-related co-morbidities, which result from the gradual buildup of cellular and molecular damage during one's lifespan. This innovation enhances the functionality of many metabolic pathways and methods that eliminate impaired cells and hinder the shortening of telomerase, a crucial element in the progression of age-related ailments. This is achieved by using computer-aided instruments.(Homa et al., 2014) There remains a deficiency in comprehension of the role of CISD3 in age-related diseases. Furthermore, extensive study has been conducted on other members of the CDGSH protein family. By activating these proteins with hesperetin, it has been proven that neurodegenerative diseases can be relieved. Hesperetin exhibits limited bioavailability as a result of its poor solubility and constrained absorption in the gastrointestinal tract. However, its potential for usage in therapeutic applications remains unchanged. As a result of this groundbreaking advancement, the bioavailability of hesperetin is enhanced, and its solubility is also increased.(Shen et al., 2021) Hesperetin is ingested orally and subsequently undergoes hydrolysis before being immediately absorbed in the colon. During systemic circulation, it is absorbed through passive diffusion and proton cellular transport, which facilitates its absorption.(Yeh et al., 2020) This process allows it to demonstrate antioxidant, anti-inflammatory, and cell-protective actions. As a consequence, there is an augmentation in the production of the CISD3 protein.

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