A Review on Tau Targeting Biomimetics Nano Formulations: Novel Approach for Targeting Alzheimer's Diseases.

Central nervous system disorders are prevalent, profoundly debilitating, and poorly managed. Developing innovative treatments for these conditions, including Alzheimer's disease, could significantly improve patients' quality of life and reduce the future economic burden on healthcare systems. However, groundbreaking drugs for central nervous system disorders have been scarce in recent years, highlighting the pressing need for advancements in this field. One significant challenge in the realm of nanotherapeutics is ensuring the precise delivery of drugs to their intended targets due to the complex nature of Alzheimer's disease. Although numerous therapeutic approaches for Alzheimer's have been explored, most drug candidates targeting amyloid-ß have failed in clinical trials. Recent research has revealed that tau pathology can occur independently of amyloid-ß and is closely correlated with the clinical progression of Alzheimer's symptoms. This discovery suggests that tau could be a promising therapeutic target. One viable approach to managing central nervous system disorders is the administration of nanoparticles to neurons, intending to inhibit tau aggregation by directly targeting p-tau. In Alzheimer's disease, beta-amyloid plaques and neurofibrillary tau tangles hinder neuron transmission and function. The disease also triggers persistent inflammation, compromises the blood-brain barrier, leads to brain shrinkage, and causes neuronal loss. While current medications primarily manage symptoms and slow cognitive decline, there is no cure for Alzheimer's.

Recent Advances in Molecular Pathways and Therapeutic Implications for Peptic Ulcer Management: A Comprehensive Review.

Peptic ulcers, recognized for their erosive impact on the gastrointestinal mucosa, present a considerable challenge in gastroenterology. Epidemiological insights underscore the global prevalence of peptic ulcers, affecting 5-10+% of individuals, with a yearly incidence of 0.3 to 1.9 cases per thousand. Recent decades have witnessed a decline in complications, attributed to improved diagnostics and therapeutic advancements. The review deepens into H. pylori-associated and NSAID-induced ulcers, emphasizing their distinct prevalence in developing and industrialized nations, respectively. Despite advancements, managing peptic ulcers remains challenging, notably in H. pylori-infected individuals facing recurrence and the rise of antibiotic resistance. The pathophysiology unravels the delicate balance between protective and destructive factors, including the intricate molecular mechanisms involving inflammatory mediators such as TNF-α, ILs, and prostaglandins. Genetic and ethnic factors, rare contributors, and recent molecular insights further enhance our understanding of peptic ulcer development. Diagnostic approaches are pivotal, with upper gastrointestinal endoscopy standing as the gold standard. Current treatment strategies focus on H. pylori eradication, NSAID discontinuation, and proton pump inhibitors. Surgical options become imperative for refractory cases, emphasizing a comprehensive approach. Advances include tailored H. pylori regimens, the emergence of vonoprazan, and ongoing vaccine development. Challenges persist, primarily in antibiotic resistance, side effects of acid suppressants, and translating natural compounds into standardized therapies. Promising avenues include the potential H. pylori vaccine and the exploration of natural compounds, with monoterpenes showing therapeutic promise. This review serves as a compass, guiding healthcare professionals, researchers, and policymakers through the intricate landscape of peptic ulcer management.

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.

Ferroptosis: A Frontier in Osteoporosis.

Reduced bone mass and degeneration of the microarchitecture of bone tissue are the hallmarks of osteoporosis, a bone metabolic disease that increases skeletal fragility and fracture susceptibility. Osteoporosis is primarily caused by unbalanced bone remodeling, in which bone synthesis is outpaced by bone resorption caused by osteoclasts. Along with the bone-building vitamins calcium and vitamin D, typical medications for treating osteoporosis include bisphosphonates and calcitonin. The present therapies effectively stop osteoclast activation that is too high, however they come with varying degrees of negative effects. Numerous factors can contribute to osteoporosis, which is characterized by a loss of bone mass and density due to the deterioration of the bone's microstructure, which makes the bone more fragile. As a result, it is a systemic bone condition that makes patients more likely to fracture. Interest in the function of ferroptosis in the pathophysiology of osteoporosis is developing. In this review, we go through the shape of the cell, the fundamental mechanisms of ferroptosis, the relationship between osteoclasts and osteoblasts, the association between ferroptosis and diabetic osteoporosis, steroid-induced osteoporosis, and the relationship between ferroptosis and postmenopausal osteoporosis. The functions of ferroptosis and osteoporosis in cellular function, signaling cascades, pharmacological inhibition, and gene silencing have been better understood thanks to recent advances in biomedical research.

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.

Dendrimers: Patents for Alzheimer's Disease.

Cells and nervous system connections that are crucial for movement, coordination, strength, sensation, and thought are gradually damaged in neurodegenerative illnesses. Amyloid beta (Aß)- accumulating macromolecules in the brain are the primary cause of the disease's chronic symptoms, according to analysis carried out during the last 20 years. Plaques and clumps of amyloid- build up in the brain, obstructing neuronal signals and destroying neural connections. Tau, a protein that results in the formation of "neurofibrillary tangles" in the brain, another hallmark of neuronal death, has been the focus of a lot of research. Dendrimers Delivery (DDs) is one of the most promising advancements in nanotechnology for biomedical applications, particularly drug delivery. Some of the main categories of dendrimers employed in the successful management of neurodegenerative illnesses are polyamidoamine dendrimers (PAMAM) dendrimers, polypropylenimine dendrimers (PPI), Poly-l-lysine dendrimers (PLL), and carbosilane dendrimers. The tight blood-brain barrier (BBB), which limits the entry of medications or therapeutic agents, makes it difficult to treat central nervous system disorders. Dendrimers have attracted the attention of scientists more than other non-invasive methods of drug delivery across the BBB and improve the uptake of medicines in the brain's target tissues. The major benefits of dendrimers include their adaptability, biocompatibility, ability to load pharmaceuticals into the core and surface, and nanosize. This review has updated the status of the patent and clinical trials literature pertaining to dendrimer use in AD.

AGE RAGE Pathways: Cardiovascular Disease and Oxidative Stress.

It is well established that Advanced Glycation End Products (AGEs) and their receptor (RAGE) are primarily responsible for the development of cardiovascular disease. As a result, diabetic therapy is very interested in therapeutic strategies that can target the AGE-RAGE axis. The majority of the AGE-RAGE inhibitors showed encouraging outcomes in animal experiments, but more information is needed to completely understand their clinical effects. The main mechanism implicated in the aetiology of cardiovascular disease in people with diabetes is oxidative stress and inflammation mediated by AGE-RAGE interaction. Numerous PPAR-agonists have demonstrated favourable outcomes in the treatment of cardio-metabolic illness situations by inhibiting the AGE-RAGE axis. The body's ubiquitous phenomena of inflammation occur in reaction to environmental stressors such tissue damage, infection by pathogens, or exposure to toxic substances. Rubor (redness), calor (heat), tumour (swelling), colour (pain), and in severe cases, loss of function, are its cardinal symptoms. When exposed, the lungs develop silicotic granulomas with the synthesis of collagen and reticulin fibres. A natural flavonoid called chyrsin has been found to have PPAR-agonist activity as well as antioxidant and anti-inflammatory properties. The RPE insod2+/animals underwent mononuclear phagocyte-induced apoptosis, which was accompanied with decreased superoxide dismutase 2 (SOD2) and increased superoxide generation. Injections of the serine proteinase inhibitor SERPINA3K decreased proinflammatory factor expression in mice with oxygen-induced retinopathy, decreased ROS production, and increased levels of SOD and GSH.

Ferroptosis Signaling Pathways: Alzheimer's Disease.

The involvements of iron metabolism, lipid peroxidation, and oxidative stress in Alzheimer's disease (AD) development have recently received a lot of attention. We also observe that these pathogenic occurrences play a key role in regulating ferroptosis, a unique regulatory cell death that is iron-dependent, oxidative, and non-apoptotic. Iron is a crucial component that makes up a subunit of the oxidase responsible for lipid peroxidation. A family of non-heme iron enzymes known as lipoxygenases (LOXs) can cause ferroptosis by oxidising polyunsaturated fatty acids in cellular membranes (PUFAs). Toxic lipid hydroperoxides are produced in large part by the iron in LOX active sites. Deferoxamine and deferiprone, two iron chelators, could also treat ferroptosis by eliminating the crucial catalytic iron from LOXs. Phospholipids containing polyunsaturated fatty acids are the main substrates of lipid peroxidation in ferroptosis, which is favourably controlled by enzymes like ACSL4, LPCAT3, ALOXs, or POR. Selective stimulation of autophagic degradation pathways leads to an increase in iron accumulation and lipid peroxidation, which promotes ferroptosis. We highlighted recent advancements in our understanding of ferroptosis signaling routes in this study. One form of regulated necrotic cell death known as ferroptosis has been linked to a number of diseases, including cancer, neurological disorders, and ischemia/reperfusion injury. Cerebrospinal fluid (CSF) ferritin may be a good indicator of the amount of iron in the brain because it is the main protein that stores iron.

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.

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.

AGEs RAGE Pathways: Alzheimer's Disease.

Neurofibrillary tangles and plaques containing tau serve as the biological markers for Alzheimer disease (AD) and pathogenesis is widely believed to be driven by the production and deposition of the ß-amyloid peptide (Aß). The ß-amyloid peptide (Aß) that results from the modification of the amyloid precursor protein (APP) by builds up as amyloid deposits in neuronal cells. Thus, a protein misfolding process is involved in the production of amyloid. In a native, aqueous buffer, amyloid fibrils are usually exceedingly stable and nearly insoluble. Although amyloid is essentially a foreign substance made of self-proteins, the immune system has difficulty identifying and eliminating it as such for unknown reasons. While the amyloidal deposit may have a direct role in the disease mechanism in some disease states involving amyloidal deposition, this is not always the case. Current research has shown that PS1 (presenilin 1) and BACE (beta-site APP-cleaving enzyme) have - and -secretase activity that increases ß-amyloid peptide (Aß). Wealth of data has shown that oxidative stress and AD are closely connected that causes the death of neuronal cells by producing reactive oxygen species (ROS). Additionally, it has been demonstrated that advanced glycation end products (AGEs) and ß-amyloidal peptide (Aß) together increase neurotoxicity. The objective of this review is to compile the most recent and intriguing data of AGEs and receptor for advanced glycation end products (RAGE) pathways which are responsible for AD.