Targeting Abnormal Tau Phosphorylation for Alzheimer's Therapeutics.

Alzheimer's disease (AD) is a widespread neurodegenerative disorder characterized by progressive memory and cognitive decline, posing a formidable public health challenge. This review explores the intricate interplay between two pivotal players in AD pathogenesis: ß-amyloid (Aß) and tau protein. While the amyloid cascade theory has long dominated AD research, recent developments have ignited debates about its centrality. Aß plaques and tau NFTs are hallmark pathologies in AD. Aducanumab and lecanemab, monoclonal antibodies targeting Aß, have been approved, albeit amidst controversy, raising questions about the therapeutic efficacy of Aß-focused interventions. On the other hand, tau, specifically its hyperphosphorylation, disrupts microtubule stability and contributes to neuronal dysfunction. Various post-translational modifications of tau drive its aggregation into NFTs. Emerging treatments targeting tau, such as GSK-3ß and CDK5 inhibitors, have shown promise in preclinical and clinical studies. Restoring the equilibrium between protein kinases and phosphatases, notably protein phosphatase-2A (PP2A), is a promising avenue for AD therapy, as tau is primarily regulated by its phosphorylation state. Activation of tau-specific phosphatases offers potential for mitigating tau pathology. The evolving landscape of AD drug development emphasizes tau-centric therapies and reevaluation of the amyloid cascade hypothesis. Additionally, exploring the role of neuroinflammation and its interaction with tau pathology present promising research directions.

Empagliflozin-A Sodium Glucose Co-transporter-2 Inhibitor: Overview of Its Chemistry, Pharmacology, and Toxicology.

BACKGROUND: Empagliflozin is a sodium glucose co-transporter-2 (SGLT2) inhibitor that has gained significant attention in the treatment of type 2 diabetes mellitus. Understanding its chemistry, pharmacology, and toxicology is crucial for the safe and effective use of this medication. OBJECTIVE: This review aims to provide a comprehensive overview of the chemistry, pharmacology, and toxicology of empagliflozin, synthesizing the available literature to present a concise summary of its properties and implications for clinical practice. METHODS: A systematic search of relevant databases was conducted to identify studies and articles related to the chemistry, pharmacology, and toxicology of empagliflozin. Data from preclinical and clinical studies, as well as post-marketing surveillance reports, were reviewed to provide a comprehensive understanding of the topic. RESULTS: Empagliflozin is a selective SGLT2 inhibitor that works by constraining glucose reabsorption in the kidneys, causing increased urinary glucose elimination. Its unique mechanism of action provides glycemic control, weight reduction, and blood pressure reduction. The drug's chemistry is characterized by its chemical structure, solubility, and stability. Pharmacologically, empagliflozin exhibits favorable pharmacokinetic properties with rapid absorption, extensive protein binding, and renal elimination. Clinical studies have demonstrated its efficacy in improving glycemic control, reducing cardiovascular risks, and preserving renal function. However, adverse effects, for instance, urinary tract infections, genital infections, and diabetic ketoacidosis have been reported. Toxicological studies indicate low potential for organ toxicity, mutagenicity, or carcinogenicity. CONCLUSION: Empagliflozin is a promising SGLT2 inhibitor that offers an innovative approach to the treatment of type 2 diabetes mellitus. Its unique action mechanism and favorable pharmacokinetic profile contribute to its efficacy in improving glycemic control and reducing cardiovascular risks. While the drug's safety profile is generally favorable, clinicians should be aware of potential adverse effects and monitor patients closely. More study is required to determine the longterm safety and explore potential benefits in other patient populations. Overall, empagliflozin represents a valuable addition to the armamentarium of antidiabetic medications, offering significant benefits to patients suffering from type 2 diabetes mellitus. This study covers all aspects of empagliflozin, including its history, chemistry, pharmacology, and various clinical studies, case reports, and case series.

Navigating the dementia landscape: Biomarkers and emerging therapies.

The field of dementia research has witnessed significant developments in our understanding of neurodegenerative disorders, with a particular focus on Alzheimer's disease (AD) and Frontotemporal Dementia (FTD). Dementia, a collection of symptoms arising from the degeneration of brain cells, presents a significant healthcare challenge, especially as its prevalence escalates with age. This abstract delves into the complexities of these disorders, the role of biomarkers in their diagnosis and monitoring, as well as emerging neurophysiological insights. In the context of AD, anti-amyloid therapy has gained prominence, aiming to reduce the accumulation of amyloid-beta (Aß) plaques in the brain, a hallmark of the disease. Notably, Leqembi recently received full FDA approval, marking a significant breakthrough in AD treatment. Additionally, ongoing phase 3 clinical trials are investigating novel therapies, including Masitinib and NE3107, focusing on cognitive and functional improvements in AD patients. In the realm of FTD, research has unveiled distinct neuropathological features, including the involvement of proteins like TDP-43 and progranulin, providing valuable insights into the diagnosis and management of this heterogeneous condition. Biomarkers, including neurofilaments and various tau fragments, have shown promise in enhancing diagnostic accuracy. Neurophysiological techniques, such as transcranial magnetic stimulation (TMS), have contributed to our understanding of AD and FTD. TMS has uncovered unique neurophysiological signatures, highlighting impaired plasticity, hyperexcitability, and altered connectivity in AD, while FTD displays differences in neurotransmitter systems, particularly GABAergic and glutamatergic circuits. Lastly, ongoing clinical trials in anti-amyloid therapy for AD, such as Simufilam, Solanezumab, Gantenerumab, and Remternetug, offer hope for individuals affected by this devastating disease, with the potential to alter the course of cognitive decline. These advancements collectively illuminate the evolving landscape of dementia research and the pursuit of effective treatments for these challenging conditions.

Emerging Nanotechnology for the Treatment of Alzheimer's Disease.

Nanotechnology is a great choice for medical research, and the green synthesis approach is a novel and better way to synthesize nanoparticles. Biological sources are cost-effective, environmentally friendly, and allow large-scale production of nanoparticles. Naturally obtained 3 ß-hydroxy-urs-12-en-28-oic acids reported for neuroprotective and dendritic structure are reported as solubility enhancers. Plants are free from toxic substances and act as natural capping agents. In this review, the pharmacological properties of ursolic acid (UA) and the structural properties of the dendritic structure are discussed. UA acid appears to have negligible toxicity and immunogenicity, as well as favorable biodistribution, according to the current study, and the dendritic structure improves drug solubility, prevents drug degradation, increases circulation time, and potentially targets by using different pathways with different routes of administration. Nanotechnology is a field in which materials are synthesized at the nanoscale. Nanotechnology could be the next frontier of humankind's technological advancement. Richard Feynman first used the term 'Nanotechnology' in his lecture, "There is Plenty of Room at the Bottom," on 29th December, 1959, and since then, interest has increased in the research on nanoparticles. Nanotechnology is capable of helping humanity by solving major challenges, particularly in neurological disorders like Alzheimer's disease (AD), the most prevalent type, which may account for 60-70% of cases. Other significant forms of dementia include vascular dementia, dementia with Lewy bodies (abnormal protein aggregates that form inside nerve cells), and a number of illnesses that exacerbate frontotemporal dementia. Dementia is an acquired loss of cognition in several cognitive domains that are severe enough to interfere with social or professional functioning. However, dementia frequently co-occurs with other neuropathologies, typically AD with cerebrovascular dysfunction. Clinical presentations show that neurodegenerative diseases are often incurable because patients permanently lose some neurons. A growing body of research suggests that they also advance our knowledge of the processes that are probably crucial for maintaining the health and functionality of the brain. Serious neurological impairment and neuronal death are the main features of neurodegenerative illnesses, which are also extremely crippling ailments. The most prevalent neurodegenerative disorders cause cognitive impairment and dementia, and as average life expectancy rises globally, their effects become more noticeable.

Consequence of Dementia and Cognitive Impairment by Primary Nucleation Pathway.

An acquired loss of cognition in several cognitive domains that is severe enough to interfere with social or professional functioning is called dementia. As well as a moderately in-depth mental status examination by a clinician to identify impairments in memory, language, attention, visuospatial cognition, such as spatial orientation, executive function, and mood, the diagnosis of dementia requires a history evaluating for cognitive decline and impairment in daily activities, with confirmation from a close friend or family member. The start and organization of the cognitive assessment can be helped by short screening tests for cognitive impairment. Clinical presentations show that neurodegenerative diseases are often incurable because patients permanently lose some types of neurons. It has been determined through an assessment that, at best, our understanding of the underlying processes is still rudimentary, which presents exciting new targets for further study as well as the development of diagnostics and drugs. A growing body of research suggests that they also advance our knowledge of the processes that are probably crucial for maintaining the health and functionality of the brain. We concentrate on a number of the animal models of memory problems that have been mentioned in this review article because dementia has numerous etiologies. Serious neurological impairment and neuronal death are the main features of neurodegenerative illnesses, which are also extremely crippling ailments. The most prevalent neurodegenerative disorders are followed by those primary nucleation pathways responsible for cognitive impairment and dementia.

Ferulic Acid: Signaling Pathways in Aging.

The need for clinical remedies to the multiple age-related deficiencies in skin function brought on by extrinsic and intrinsic causes is increased by these demographic changes. Reactive oxygen species (ROS), mitochondrial deoxyribonucleic acid (mtDNA) mutations, telomere shortening, as well as other factors, contribute to the aging of the skin. In this overview, the issue of human skin aging is introduced, along with several pathways and the protective effects of ferulic acid in light of current patents. The complex antioxidant effect of ferulic acid depends on the "sweeping" away of free radicals as well as the suppression of the synthesis of ROS or nitrogen. Furthermore, Cu (II) or Fe protonated metal ions are chelated by this acid (II). Ferulic acid is a free radical scavenger as well as an enzyme inhibitor, increasing the activity of enzymes that scavenge free radicals while decreasing the activity of enzymes that speed up the creation of free radicals. AMPK signalling, which can regulate cellular homeostasis, stress tolerance, cell survival and proliferation, cell death, and autophagy, has recently been linked to aging and lifespan. Therefore, Caenorhabditis elegans (C. elegans) and rodents had longer life-spans due to specific AMPK activation. By inhibiting the TGF-ß/Smad signalling pathway, UV irradiation can reduce the production of procollagen. Glycation changes the skin's physical characteristics, making it less elastic and stiffer. . Excessive free radicals simultaneously trigger the nuclear factor kappa B (NF- κB) signalling pathway, increasing TNF levels and matrix metalloproteinase production (MMPs).

Clinical Manifestation of AGE-RAGE Axis in Neurodegenerative and Cognitive Impairment Disorders.

The receptor of Advanced Glycation Endproducts (RAGE) and Advanced Glycation Endproducts (AGE) have multiple functions in our body and their restraint are being observed in neurodegenerative and memory impairment disorders. The review of different pathways allows an understanding of the probable mechanism of neurodegeneration and memory impairment involving RAGE and AGE. Commonly we observe AGE accumulation in neural cells and tissues but the extent of accumulation increases with the presence of memory impairment disorder. The presence of AGEs can also be seen in morbid accumulation, pathological structures in the form of amyloid clots, and nervous fibrillary tangles in Alzheimer's Disease (AD) and memory impairment disease.Many neuropathological and biochemical aspects of AD are explained by AGEs, including widespread protein crosslinking, glial activation of oxidative stress, and neuronal cell death. Oxidative stress is due to different reasons and glycation end products set in motion and form or define various actions which are normally due to AGE changes in a pathogenic cascade. By regulating the transit of ß-amyloid in and out of the brain or altering inflammatory pathways, AGE and it's ensnare receptor such as soluble RAGE may function as blockage or shield AD development. RAGE activates the transcription-controlling factor Necrosis Factor (NF-κB) and increases the protraction of cytokines, like a higher number of Tumor Necrosis Factor (TNF-α) and Interleukin (IL-I) by inducing several signal transduction cascades. Furthermore, binding to RAGE can pro-activate reactive oxygen species (ROS), which is popularly known to cause neuronal death.

Receptor for Advanced Glycation End Products: Dementia and Cognitive Impairment.

The pathophysiological processes of dementia and cognitive impairment are linked to advanced glycation end products (AGEs) and their receptor (RAGE).The neurofibrillary tangles (NFTs) of abnormally hyperphosphorylated tau protein and senile plaques (SPs), which are brought on by amyloid beta (Aß) deposition, are the hallmarks of Alzheimer's disease (AD), a progressive neurodegenerative condition. Advanced glycation end products that are produced as a result of vascular dysfunction are bound by the receptor for advanced glycation end products (RAGE). Dementia and cognitive impairment could develop when RAGE binds to Aß and produces reactive oxygen species, aggravating Aß buildup and ultimately resulting in SPs and NFTs. RAGE could be a more powerful biomarker than Aß because it is implicated in early AD. The resident immune cells in the brain known as microglia are essential for healthy brain function. Microglia is prominent in the amyloid plaques' outside border as well as their central region in Alzheimer's disease. Microglial cells, in the opinion of some authors, actively contribute to the formation of amyloid plaques. In this review, we first discuss the early diagnosis of dementia and cognitive impairment, and then detail the interaction between RAGE and Aß and Tau that is necessary to cause dementia and cognitive impairment pathology, and it is anticipated that the creation of RAGE probes will help in the diagnosis and treatment of dementia and cognitive impairment.

Neurodegeneration: Microglia: Nf-Kappab Signaling Pathways.

Microglia is cells of mesodermal/mesenchymal origin that migrate into the central nervous system (CNS) to form resident macrophages inside the special brain microenvironment. Intact with both neuronal and non-neuronal cells, microglia is highly active cells. Continuous process extension and retraction allows microglia to scan the brain parenchyma for threats. They are also able to change their morphology from ramified to amoeboid, which is a sign of cell activity. In response to pleiotropic stimuli such as neurotransmitters, cytokines, and plasma proteins, microglia express a diverse range of receptors. As controllers of synaptic activities and phagocytosis of developing neurons, they serve a critical role in the healthy brain and have significant effects on synaptic plasticity and adult neurogenesis. A frequent cause of hypoparathyroidism is a mutation in the gene glial cells missing-2 (GCM2). Neonatal hypoparathyroidism has an amorphic recessive GCM2 mutation, while autosomal dominant hypoparathyroidism has a dominant-negative GCM2 mutation. Curiously, familial isolated hyperparathyroidism has been associated with activating GCM2 mutation. In addition to seizures, neurocognitive impairment, carpopedal spasm, tingling and numbness are common clinical manifestations of hypoparathyroidism. Biogenic amines are a group of four neurotransmitters that belong to that category and these include serotonin, dopamine, norepinephrine, and epinephrine. Numerous antidepressants prevent the reuptake from occurring the brain-gut axis is hardwired through the CNS, enteric nervous system (ENS), neuroendocrine linkages and highly innervated nerve plexuses.

An in-Depth Analysis of Ovarian Cancer: Pathogenesis and Clinical Manifestation.

Ovarian cancer is characterized by the establishment of tolerance, the recurrence of disease, as well as a poor prognosis. Gene signatures in ovarian cancer cells enable cancer medicine research, therapy, prevention, & management problematic. Notwithstanding advances in tumor puncture surgery, novel combinations regimens, and abdominal radiation, which can provide outstanding reaction times, the bulk of gynecological tumor patients suffer from side effects & relapse. As a consequence, more therapy alternatives for individuals with ovarian cancer must always be studied to minimize side effects and improve progression-free and total response rates. The development of cancer medications is presently undergoing a renaissance in the quest for descriptive and prognostic ovarian cancer biomarkers. Nevertheless, abnormalities in the BRCA2 or BRCA1 genes, a variety of hereditary predispositions, unexplained onset and progression, molecular tumor diversity, and illness staging can all compromise the responsiveness and accuracy of such indicators. As a result, current ovarian cancer treatments must be supplemented with broad-spectrum & customized targeted therapeutic approaches. The objective of this review is to highlight recent contributions to the knowledge of the interrelations between selected ovarian tumor markers, various perception signs, and biochemical and molecular signaling processes, as well as one's interpretation of much more targeted and effective treatment interventions.

Nanoemulsion: An Advanced Vehicle For Efficient Drug Delivery.

Advanced drug delivery system has now gained preference over the conventional drug delivery system. One such research is nanoemulsion which is famous among the researchers because of ease of formation, stability, clarity, increased absorption rate leading to increasing in bioavailability and potential to form a formulation with both lipophilic as well as the hydrophilic drug. Long lasting stability (up to years) and ability to encapsulate both lipophilic and hydrophilic drug has given this colloidal system a valuable position in drug delivery. This article contains information on components required for its fabrication, preparation methods and evaluation parameters along with its application in drug delivery and future aspects of this advanced drug delivery system.