Emoxypine succinate modulates behavioral and molecular responses in zebrafish model of iron Overload-Induced neuroinflammation via CDK5/GSK3- ß and NLRP3 inflammasome pathway.

Excessive iron accumulation in the brain plays a significant role in neurodegenerative processes, contributing to the pathogenesis of Alzheimer's disease (AD). AD, a prominent neurological disorder affecting the central nervous system, is characterized by the accumulation of beta-amyloid (Aß) and tau phosphorylation. This accumulation leads to the subsequent development of cognitive impairments, particularly in learning and memory functions. This study investigates the neuroprotective effects of emoxypine succinate in a zebrafish model of iron overload-induced neurodegeneration. Iron was administered to the zebrafish for 28 days to induce neurodegeneration. Following induction, Emoxypine succinate was employed as a treatment intervention for 14 days (concentrations of 4 mg/L, 8 mg/L, and 12 mg/L). Following the end of the treatment, behavioral tests (Y maze test, Novel tank test) were conducted on the zebrafish, and the biochemical (MDA, Catalase, SOD, GSH) and molecular parameters (AchE, Iron levels, IL-1ß, TNF-α, CDK-5, GSK-3ß, and NLRP3) of the zebrafish brain were also assessed. In the novel tank test, emoxypine succinate-treated groups exhibited significantly increased time in the upper zone (p < 0.001), higher distance travelled (p < 0.001), and shorter latency to the top (p < 0.001) compared to the negative control. Similarly, the Y-maze test revealed improved time in the novel arm (p < 0.001) and total distance travelled (p < 0.001) in treated groups versus the negative control. Assessment of oxidative stress parameters demonstrated significant reductions in oxidative stress in emoxypine succinate-treated groups. Furthermore, AChE activity decreased significantly (p < 0.001), and brain iron levels decreased substantially (p < 0.001) in treated groups, indicating positive therapeutic outcomes. Molecular analysis showed a significant reduction in pro-inflammatory markers like IL-1ß, TNF-α, CDK-5, GSK-3ß, and NLRP3 (p < 0.001). This comprehensive study highlights the potential efficacy of emoxypine succinate in mitigating neurodegeneration associated with iron dysregulation.

Challenges and Opportunities of Metal Chelation Therapy in Trace Metals Overload-Induced Alzheimer's Disease.

Essential trace metals like zinc (Zn), iron (Fe), and copper (Cu) play an important physiological role in the metabolomics and healthy functioning of body organs, including the brain. However, abnormal accumulation of trace metals in the brain and dyshomeostasis in the different regions of the brain have emerged as contributing factors in neuronal degeneration, Aß aggregation, and Tau formation. The link between these essential trace metal ions and the risk of AD has been widely studied, although the conclusions have been ambiguous. Despite the absence of evidence for any clinical benefit, therapeutic chelation is still hypothesized to be a therapeutic option for AD. Furthermore, the parameters like bioavailability, ability to cross the BBB, and chelation specificity must be taken into consideration while selecting a suitable chelation therapy. The data in this review summarizes that the primary intervention in AD is brain metal homeostasis along with brain metal scavenging. This review evaluates the impact of different trace metals (Cu, Zn, Fe) on normal brain functioning and their association with neurodegeneration in AD. Also, it investigates the therapeutic potential of metal chelators in the management of AD. An extensive literature search was carried out on the "Web of Science, PubMed, Science Direct, and Google Scholar" to investigate the effect of trace elements in neurological impairment and the role of metal chelators in AD. In addition, the current review highlights the advantages and limitations of chelation therapies and the difficulties involved in developing selective metal chelation therapy in AD patients.

Promising effects of emoxypine and its succinate derivative in the management of various diseases-with insights on recent patent applications.

Emoxypine and its succinate derivative share a common hydroxypridine structure, which is similar to pyridoxine. These compounds have been utilized therapeutically and industrially, owing to the wide range of properties offered. This includes antihypoxic, neuroprotective and cardioprotective effects, along with pharmacokinetic benefits such as the ability to cross the blood brain barrier (BBB), owing to its relatively small size and low molecular weight. It was observed that emoxypine exhibited iron chelating property in vitro, indicating its usage as a promising therapeutic strategy in the management of neurodegenerative conditions such as Alzheimer's disease (AD), as well as hematologic disorders like thalassemia and hemochromatosis. In addition to this, it has been observed to exert a potent antioxidant effect, therefore, it may be considered for the amelioration of disorders resulting from free radical injury. Studies on its mechanism of action and implications on cellular and molecular levels would help to further the understanding of its benefits, as well as prospects for filing patents for novel applications. The primary focus of this review is to shed light on the broad spectrum of pharmacological properties offered by emoxypine and its succinate derivative, and to highlight the scope for an increased number of pre-clinical and clinical trials to assess its safety and efficacy. In addition to this, the highlights of this article include the recent patents filed and scope for novel applications of these agents.

The Brilliance of the Zebrafish Model: Perception on Behavior and Alzheimer's Disease.

Alzheimer's disease (AD) has become increasingly prevalent in the elderly population across the world. It's pathophysiological markers such as overproduction along with the accumulation of amyloid beta (Aß) plaques and neurofibrillary tangles (NFT) are posing a serious challenge to novel drug development processes. A model which simulates the human neurodegenerative mechanism will be beneficial for rapid screening of potential drug candidates. Due to the comparable neurological network with humans, zebrafish has emerged as a promising AD model. This model has been thoroughly validated through research in aspects of neuronal pathways analogous to the human brain. The cholinergic, glutamatergic, and GABAergic pathways, which play a role in the manifested behavior of the zebrafish, are well defined. There are several behavioral models in both adult zebrafish and larvae to establish various aspects of cognitive impairment including spatial memory, associative memory, anxiety, and other such features that are manifested in AD. The zebrafish model eliminates the shortcomings of previously recognized mammalian models, in terms of expense, extensive assessment durations, and the complexity of imaging the brain to test the efficacy of therapeutic interventions. This review highlights the various models that analyze the changes in the normal behavioral patterns of the zebrafish when exposed to AD inducing agents. The mechanistic pathway adopted by drugs and novel therapeutic strategies can be explored via these behavioral models and their efficacy to slow the progression of AD can be evaluated.

Therapeutic and Industrial Applications of Curdlan With Overview on Its Recent Patents.

Curdlan is an exopolysaccharide, which is composed of glucose linked with ß-(1,3)-glycosidic bond and is produced by bacteria, such as Alcaligenes spp., Agrobacterium spp., Paenibacillus spp., Rhizobium spp., Saccharomyces cerevisiae, Candida spp., and fungal sources like Aureobasidium pullulan, Poria cocos, etc. Curdlan has been utilized in the food and pharmaceutical industries for its prebiotic, viscosifying, and water-holding properties for decades. Recently, the usefulness of curdlan has been further explored by the pharmaceutical industry for its potential therapeutic applications. Curdlan has exhibited immunoregulatory and antitumor activity in preclinical settings. It was observed that curdlan can prevent the proliferation of malarial merozoites in vivo; therefore, it may be considered as a promising therapy for the treatment of end-stage malaria. In addition, curdlan has demonstrated potent antiviral effects against human immunodeficiency virus (HIV) and Aedes aegypti virus. It has been suggested that the virucidal properties of curdlans should be extended further for other deadly viruses, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the current severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2/COVID-19). The prebiotic property of curdlan would confer beneficial effects on the host by promoting the growth of healthy microbiota in the gut and consequently help to reduce gastrointestinal disorders. Therefore, curdlan can be employed in the manufacture of prebiotics for the management of various gastrointestinal dysbiosis problems. Studies on the mechanism of action of curdlan-induced suppression in microbial and tumor cells at the cellular and molecular levels would not only enhance our understanding regarding the therapeutic effectiveness of curdlan but also help in the discovery of new drugs and dietary supplements. The primary focus of this review is to highlight the therapeutic interventions of curdlan as an anticancer, anti-malaria, antiviral, and antibacterial agent in humans. In addition, our review provides the latest information about the chemistry and biosynthesis of curdlan and its applications for making novel dairy products, functional foods, and nutraceuticals and also details about the recent patents of curdlan and its derivatives.

Therapeutic Applications of Human and Bovine Colostrum in the Treatment of Gastrointestinal Diseases and Distinctive Cancer Types: The Current Evidence.

The incidence of gastrointestinal disorders (GID) and cancers is escalating all over the world. Limited consumption of colostrum by newborns not only weakens the immune system but also predisposes infants to microbial infections. Colostrum is nature's perfect food, sometimes referred to as the 'elixir of life'. Breast-fed infants have a lower incidence of GI tract infections than infants fed formula or cow's milk. As per WHO statistics, cancer is the most prevalent disease globally and causes 9.6 million deaths worldwide. The current strategies for treating cancer include chemotherapy, radiation, and surgery. However, chemotherapy and radiation exposure are usually associated with serious long-term side effects and deterioration in the quality of life (QOL) of patients. Furthermore, the hospitalization and medication costs for treating cancers are exorbitant and impose high economic burden on healthcare systems. People are desperately looking for cost-effective and affordable alternative therapies for treating GID and cancers. Therefore, there is an urgent need for clinically evaluating the anticancer compounds isolated from plants and animals. Such therapies would not only be economical and have fewer side effects, but also help to improve the QOL of cancer patients. Recently, bovine colostrum (BC) has caught the attention of many investigators to explore its anticancer potential in humans. BC impregnated dressings are highly effective in treating chronic wounds and diabetic foot ulcer. BC is rich in lactoferrin, a glycoprotein with strong antioxidant, anti-inflammatory, anti-cancer, and anti-microbial properties. Intravaginal application of BC tablets is effective in causing the regression of low-grade cervical intraepithelial neoplasia. The underlying mechanisms of BC at cellular, genetic, and molecular levels remain to be ascertained. Oral BC supplement is well-tolerated, but some people may experience problems such as flatulence and nausea. Well-designed, randomized, placebo-controlled, clinical trials are needed to access the therapeutic potential, long-term safety, and optimal doses of BC products. This review is aimed to highlight the anticancer potential of BC and its components, and the therapeutic applications of BC supplements in treating gastrointestinal diseases in children and adults. We also discuss the health promotion benefits and therapeutic potential of BC nutraceuticals in reducing the incidence of non-communicable diseases.

Molecular targets and therapeutic interventions for iron induced neurodegeneration.

Iron overload due to repeated blood transfusions in ß-thalassemia patients or in predisposed diseases like hemochromatosis may prove lethal. Regulation and deposition of iron is a significant process, which is been explored extensively in the past decade. Iron deposition in the body can cause cellular dysregulation, including neuronal damage. Significant research has been conducted in understanding how iron accumulation in the brain leads to neurodegeneration. Iron chelators have been tested pre-clinically and are in clinical trials for determining their potential role in the treatment of neurodegenerative diseases like Alzheimerös (AD) and Parkinsonös (PD). It has been reported that iron chelators show promising effects pre-clinically in the amelioration of neurodegenerative disorders. In the clinical setup, the main challenge for any drug is to penetrate the blood brain barrier (BBB) and to show therapeutic action. Smaller anti-oxidant molecules that cross BBB, can be expended for the treatment of neurodegenerative disorders. This review exclusively presents an assessment of original research articles published from year 2017-2019. It also addresses the mechanism of brain iron accumulation focusing more on AD and PD, their genetic predispositions, the detrimental effects of iron overload leading to neurodegeneration, iron-induced neuronal apoptosis and treatment strategies for the same.