Monu Yadav

: A hallmark of Neurodegenerative Diseases (NDs) is protein misfolding, aggregation, and accumulation in specific brain regions. The accumulation of insoluble, misfolded protein aggregates is usually referred to as amyloid formation. This process leads to cellular dysfunction, destruction of neurons, loss of neuronal connections in specific brain areas, and brain damage. Despite the involvement of distinct pathogenic proteins, the underlying mechanisms of misfolding and aggregate formation are remarkably similar across various NDs. In this review, we present a comprehensive overview of the medicinal chemistry and mechanistic insights into phytochemicals and synthetic small molecules with potential for the treatment of neurodegenerative disorders. Various small molecules have been reported to have therapeutic effects by inhibiting the misfolding, aggregation, and accumulation of pathogenic proteins, such as amyloid-β, tau, and α- synuclein. This review mainly covers natural product-derived small molecules, notably polyphenols (including flavonoids and non-flavonoid polyphenols), as well as other phytochemical classes, such as quinones and alkaloids, along with their possible mechanisms of action. In addition, synthetic small molecules, osmolytes, metal chelators, and repurposed drugs for neurodegenerative disorders are thoroughly discussed.

Alzheimer's disease (AD) is a typical neurodegenerative illness, and it is a main cause of dementia, affecting millions of older populations throughout the world. Although the exact causes of AD are still not clear, the disorder is known to be considered by the accumulation of amyloid plaques and tau tangles in the neuronal cells. Currently, available drugs such as cholinesterase inhibitors and NMDA antagonists can help manage symptoms but don’t address the underlying causes of the disease. New experimental treatments targeting amyloid and tau proteins show promise but are still in clinical trials. Recently, β-Amyloid has gained attention as an emerging target to develop new medications as it is strongly involved in the pathophysiology of AD. β-Amyloidpathies are directly or indirectly linked with multiple pathways, including GSK3β, insulin resistance, NMDA dysfunction, AMP-activated kinase, cholesterol mechanism, mitochondrial dysfunction, neuroinflammation, and SIRT1. However, several β-Amyloid targeting therapies employing various mechanisms have shown partial success in clinical trials, possibly due to a lack of understanding of the molecular link of this peptide with other pathways. Therefore, this paper has discussed the β- Amyloid molecular mechanisms involved in pathophysiological pathways to manage neuronal disorders and intracellular signal transduction effectively.

Background: The current study aimed to investigate the chemical interaction of naringenin with the possible receptors and enzymes involved in the pathogenesis of cognitive deficits and tested their ADME and toxicity. Furthermore, in‐vivo studies have also done to evaluate the effect of naringenin and its nanoparticles on STZ‐induced cognitive decline in mice.Method: Naringenin were evaluated against the active sites of β‐secretase 1 (PDB: 3UQU), human insulin‐degrading enzyme (PDB: 4RE9), insulin receptor tyrosine kinase (PDB: 1IR3), glycogen synthase kinase‐3 β (PDB: 3L1S), phosphoprotein phosphatase 2A (PDB: 3P71), human superoxide dismutase I (PDB: 5YT0), catalase‐3 (PDB:3EJ6), and human acetylcholinesterase (PDB: 4EY7) in comparison of rivastigmine using molecular docking studies. Further, the naringenin and rivastigmine were subjected to test their pharmacokinetic and lead‐likeness properties by employing the Swiss ADME web server. Moreover, a toxicity study has been performed for both naringenin and rivastigmine with the help of a Protox‐II web server.Result: Naringenin has a better binding affinity than rivastigmine with all the potential receptors. In in‐vivo behavioral, biochemical mitochondrial and histopathological studies, naringenin nanoformulation showed more significant cognitive enhancement results as compared to pure naringenin when studied against STZ induced cognitive deficits.Conclusion: The results demonstrated that it would be worthwhile to explore more naringenin nanoformulation to expose the therapeutic effects for the treatment of cognitive deficits and neuroprotecive effects.

This paper aims to study the phytochemical analysis of Buchanania lanzan oil and the anticancer property of its PEG-coated chitosan nanoformulation. The GC-MS analysis of Buchanania lanzan oil showed 24 compounds. In literature, pharmacology active compounds like β –sitosterol, stigmasterol, sitosterol, fucosterol, campesterol, stearic acid, tocopherol, γ-tocopherol, squalene, n-hexadecanoic acid, and palmitic acid reported to have a therapeutic effect on cancerous cells. 32 factorial design is a type of experimental design, was utilized to optimize the nanoformulation to achieve maximum entrapment efficiency and minimum particle size. Independent factors were the chitosan and PEG concentration while dependent factors were entrapment efficiency and particle size. The optimized Buchanania lanzan oil encapsulated nanoformulation (BOCNo) has a particle size of 490.18 nm and entrapment efficiency of 59.08%. Buchanania lanzan oil and optimized BOCNo has shown significant anticancer activity against prostate cancer (PC3), lung cancer (A549), and liver cancer (MIAPACA) cell lines having IC 50 value of 9.03g/ml, 7.50g/ml, and 15.63g/ml and 11.84g/ml, 19.50g/ml, and 17.09g/ml respectively. Anticancer effect of PEG-coated nanoformulations of Buchanania lanzan oil attributed to better penetration by increased permeability and fusion of drug molecules. Buchanania lanzan oil and BOCNo have a promising cytotoxic potential against prostate cancer, lung cancer, and liver cancer by owning the presence of therapeutically active compounds which synergistically act via multiple protective mechanisms.

BACKGROUND: Sleep is the restorative mechanism involved in the maintenance of physiological and psychological balance. Anxiety is recognized as a typical outcome of sleep deprivation (SLD) that interferes with the normal daily life of the person. The present study was designed to assess the antianxiety effects of cardamom oil in mice subjected to sleep deprivation (SLD)-induced anxiety and to explore possible underlying mechanisms for this activity. METHODS: Cardamom oil (140, 280, and 560 µL/kg intraperitoneal [i.p.]) and midazolam (8 mg/kg i.p.) were administered daily to different groups of mice for 15 consecutive days to sleep-deprived mice. anxiety-like behavior was induced by 48 h of SLD, and the antianxiety activity was evaluated using the elevated plus maze (EPM) test, light–dark, hole board, and marble-burying models. RESULTS: Cardamom oil significantly diminished the SLD-induced anxiety-like behaviors in mice as indicated by increased time spent in open arms (EPM), average time spent in lit box (light–dark model), number of head dips (hole board) and decreased number of marbles buried (marble-burying model) as compared to SLD animals. In biochemical studies, chronic administration of cardamom oil significantly increased γ-amino butyric acid (GABA), serotonin (5-HT), reduced glutathione (GSH), and catalase levels, while decreasing lipid peroxidation. CONCLUSION: Both behavioral and biochemical results revealed the protective effect of cardamom oil against SLD-induced anxiety. The underlying mechanism of action appears to involve the enhancement of GABAergic and serotoninergic neurotransmission, as well as the antioxidant properties of cardamom oil.

The present study was designed to evaluate the antipsychotic-like activity of dark chocolate against Ketamine-induced psychosis in animals and to explore the possible underlying mechanisms for this activity. Dark chocolate (200, 400 mg/kg, along with diet), haloperidol (1mg/kg, i.p.), and olanzapine (5mg/kg, i.p) were administered daily to different groups of mice and rats; after 30 min Ketamine was injected for 21 successive days. The antipsychotic- like activity was assessed using an actophotometer, stereotypic behaviors, forced swim test (FST), and passive avoidance test. Dark Chocolate (DC) and olanzapine remarkably decreased the immobility period of Ketamine-treated mice in FST, indicating the beneficial effect of DC against depressive or negative symptoms of psychosis. There was no significant effect on the locomotor activity of the mice with the administration of DC, while it showed a reducing impact against stereotypic behaviors. Furthermore, DC significantly reduced the time taken by the rats to climb the pole, showing the effect of DC on cognition. In addition, acetylcholinesterase (AChE) activity, malondialdehyde (MDA), and tissue necrosis factor (TNF-α) levels were markedly decreased and increased GABA and enhanced reduced glutathione (GSH) levels with the treatment of DC. Furthermore, DC was also effective in reducing the ketamine induced hyperchromatic nuclei, perinuclear vacuolization, and dilated vascular channels in the cortex part of the brain. Behavioral, biochemical, and histopathological studies suggest the protective effect of DC against Ketamine induced psychosis.

Objective: Boldine is a plant-derived bioactive compound that has a beneficial impact on human health. Boldine is an aporphine alkaloid mainly obtained from the leaves and bark of the Chilean Boldo tree ( Peumus boldus , Family: Monimiaceae). There are plenty of preclinical evidence supports that boldine exerts its beneficial effects against various diseases. Lumiskin™, a patented and marketed formulation by Revitol Skincare for skin brightening, contains Dicetyl boldine, a boldine derivative. Content: All the available information on the Chilean boldo tree ( P. boldus Molina) species was actualized by systematically searching the scientific databases (PubMed, SciFinder, Web of Science, Google Scholar, Scopus and others) and scientific literature. This article covers the recent advances in pharmacokinetic, toxicological, pharmacological/biological activities, and molecular mechanisms of the bioactive compound to understand health benefits of boldine better. Summary: Boldine exerts antioxidant, hepatoprotective, anti-atherosclerotic, anti-diabetic, analgesic, antipyretic, anti-inflammatory, anti-epileptic, neuroprotective, nephroprotective, anti-arthritis, anticancer and nootropic effects. Moreover, boldine exhibits its various pharmacological activities by altering antioxidant parameters (MDA, superoxide dismutase, glutathione), peroxynitrite, inflammatory markers apoptotic index, caspase-3, acetyl-cholinesterase, myeloperoxidase, TNF-α (Tumor necrosis factor-α), iNOS, Bcl-2-associated X protein (BAX), ACE-1(Angiotensin-converting enzyme-1), dopamine D2 receptors and nicotinic acetylcholine receptor. Boldine has the potential to modulate a variety of biological networks. Outlook: Due to its versatile pharmacological effects reported in various experimental animals as well as in randomized clinical trials for the treatment of facial melasma and for treatment of urinary stone lithotripsy in children as a complementary phytotherapy; in the future, this compound might be developed as a novel drug for a different indication

Mitochondria are important organelles for high energy synthesis, reactive oxygen species balancing, antiapoptotic molecule production, membrane stability, intracellular calcium buffering, neuroplasticity and neurotransmission. Dysfunction in mitochondria is considered to be involved in the pathophysiology of mental problems. It has been observed that several drug types used to treat brain illnesses can harm mitochondria by altering the oxidative phosphorylation system and the gene expression of mitochondria-related proteins. In some studies, it has been observed that mitochondrial biogenesis shows a therapeutic effect in the management of mitochondrial disorders. Many therapeutic compounds are effective in the activation of mitochondrial biogenesis. The comorbidity of mental problems observed in those with mitochondrial dysfunction and the change in the efficacy of the cellular respiratory system have attracted researchers to understand the pathways and possible therapeutic strategies in neurological disorders. This article has attempted to understand the impact of mitochondrial function and mitochondrial dysfunction in the pathogenesis of brain disorders to develop potential therapeutic drugs.