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.

Repurposing of Drugs for Cardiometabolic Disorders: An Out and Out Cumulation.

Cardiometabolic disorders (CMD) is a constellation of metabolic predisposing factors for atherosclerosis such as insulin resistance (IR) or diabetes mellitus (DM), systemic hypertension, central obesity, and dyslipidemia. Cardiometabolic diseases (CMDs) continue to be the leading cause of mortality in both developed and developing nations, accounting for over 32% of all fatalities globally each year. Furthermore, dyslipidemia, angina, arrhythmia, heart failure, myocardial infarction (MI), and diabetes mellitus are the major causes of death, accounting for an estimated 19 million deaths in 2012. CVDs will kill more than 23 million individuals each year by 2030. Nonetheless, new drug development (NDD) in CMDs has been increasingly difficult in recent decades due to increased costs and a lower success rate. Drug repositioning in CMDs looks promising in this scenario for launching current medicines for new therapeutic indications. Repositioning is an ancient method that dates back to the 1960s and is mostly based on coincidental findings during medication trials. One significant advantage of repositioning is that the drug's safety profile is well known, lowering the odds of failure owing to undesirable toxic effects. Furthermore, repositioning takes less time and money than NDD. Given these facts, pharmaceutical corporations are becoming more interested in medication repositioning. In this follow-up, we discussed the notion of repositioning and provided some examples of repositioned medications in cardiometabolic disorders.

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.

Bedaquiline: An Insight Into its Clinical Use in Multidrug-Resistant Pulmonary Tuberculosis.

Every year, the World Health Organization reports 500,000 new cases of drug-resistant tuberculosis (TB), which poses a serious global danger. The increased number of XDR-TB and MDR-TB cases reported worldwide necessitates the use of new therapeutic approaches. The main issues with the antitubercular medications now in use for the treatment of multidrug-resistant tuberculosis are their poor side effect profile, reduced efficacy, and antimicrobial resistance. One possible remedy for these problems is bedaquiline. The need for better treatment strategies is highlighted by the strong minimum inhibitory concentrations that bedaquiline (BDQ), a novel anti-TB medicine, exhibits against both drug-resistant and drug-susceptible TB. Bedaquiline may be able to help with these problems. Bedaquiline is a medication that is first in its class and has a distinct and particular mode of action. Bedaquiline is an ATP synthase inhibitor that is specifically directed against Mycobacterium tuberculosis and some nontuberculous mycobacteria. It is metabolized by CYP3A4. Bedaquiline preclinical investigations revealed intralesional drug biodistribution. The precise intralesional and multi-compartment pharmacokinetics of bedaquiline were obtained using PET bioimaging and high-resolution autoradiography investigations. Reduced CFU counts were observed in another investigation after a 12-week course of therapy. Meta-analyses and systematic reviews of phase II trials on bedaquiline's efficacy in treating drug-resistant tuberculosis in patients reported higher rates of cure, better culture conversion, and lower death rates when taken in conjunction with a background regimen. Here is a thorough medication profile for bedaquiline to aid medical professionals in treating individuals with tuberculosis.

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.

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.

Fabrication of Nanoformulation Containing Carvedilol and Silk Protein Sericin against Doxorubicin Induced Cardiac Damage in Rats.

Nanotechnology has emerged as an inspiring tool for the effective delivery of drugs to help treat Coronary heart disease (CHD) which represents the most prevalent reason for mortality and morbidity globally. The current study focuses on the assessment of the cardioprotective prospective ofanovel combination nanoformulation of sericin and carvedilol. Sericin is a silk protein obtained from Bombyx mori cocoon and carvedilol is a synthetic nonselective ß-blocker. In this present study, preparation of chitosan nanoparticles was performed via ionic gelation method and were evaluated for cardioprotective activity in doxorubicin (Dox)-induced cardiotoxicity. Serum biochemical markers of myocardial damage play a substantial role in the analysis of cardiovascular ailments and their increased levels have been observed to be significantly decreased in treatment groups. Treatment groups showed a decline in the positivity frequency of the Troponin T test as well. The NTG (Nanoparticle Treated Group), CSG (Carvedilol Standard Group), and SSG (Sericin Standard Group) were revealed to have reduced lipid peroxide levels (Plasma and heart tissue) highly significantly at a level of p < 0.01 in comparison with the TCG (Toxic Control Group). Levels of antioxidants in the plasma and the cardiac tissue were also established to be within range of the treated groups in comparison to TCG. Mitochondrial enzymes in cardiac tissue were found to be elevated in treated groups. Lysosomal hydrolases accomplish a significant role in counteracting the inflammatory pathogenesis followed by disease infliction, as perceived in the TCG group. These enzyme levels in the cardiac tissue were significantly improved after treatment with the nanoformulation. Total collagen content in the cardiac tissue of the NTG, SSG, and CSG groups was established to be highly statistically significant at p < 0.001 as well as statistically significant at p < 0.01, respectively. Hence, the outcomes of this study suggest that the developed nanoparticle formulation is effective against doxorubicin-induced cardiotoxicity.

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.

Dendrimers: A Neuroprotective Lead in Alzheimer Disease: A Review on its Synthetic approach and Applications.

Alzheimer disease is a neurodegenerative disease that is signified by cognitive decline, memory loss, and erratic behavior. Dendrimers are a type of polymer that has a well-defined structure, a high degree of molecular uniformity, and a low polydispersity which have shown to be effective intracellular drug carriers for bring down the in numerous cases. The data reported by the clinical trials and chemical bonds of dendrimers loading and biological properties that may be used in the bringing out the treatment of nano formulation for Alzheimer disease. Below-range dendrimers have an unlocked figure, but higher-range dendrimers have a more globular and dense structure so handling is difficult. Dendrimers are similar in size to a variety of biological structures; for example, fifth-generation polyamidoamine (PAMAM) dendrimers are similar in size and shape to haemoglobin (5.5 nm diameter). Each generation of dendrimer is described in terms of size, shape, molecular weight, and the number of surface functional groups, with increasing growth specified in terms of 'generation number.' In contrast, Hawker and Frechet were the first to report the convergent approach. A stepwise repeating reaction strategy is used to synthesize dendrimers radically from a central core. The value of dendrimers as drug carriers is discussed in this paper. The information presented in this article can provide useful references for further studies on making dendrimers and applications.

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.

Pleiotropic Benefits of Statins in Cardiovascular Diseases.

In 1976, Japanese microbiologist Akira Endo discovered the first statin as a product of the fungus Penicillium citrinum that inhibited the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Their primary mode of action is to lower the blood cholesterol by decreasing hepatic cholesterol production, which upregulates hepatic low-density lipoprotein (LDL) receptors and increases LDL-cholesterol clearance. In addition to cholesterol lowering, statins inhibit other downstream products of the mevalonate pathway, causing the so-called pleiotropic effects. As a result of their pleiotropic effects statins modulate virtually all known processes of atherosclerosis and have beneficial effects outside the cardiovascular system Statins inhibit the post-translational prenylation of small GTP-binding proteins such as Rho, Rac, as well as their downstream effectors such as Rho kinase and nicotinamide adenine dinucleotide phosphate oxidases since they suppress the synthesis of isoprenoid intermediates in the cholesterol biosynthetic pathway altering the expression of endothelial nitric oxide synthase, the stability of atherosclerotic plaques, production of proinflammatory cytokines, reactive oxygen species, platelet reactivity, development of cardiac hypertrophy and fibrosis in cell culture and animal experiments. Inhibition of Rho and Rho-associated coiled-coil containing protein kinase (ROCK), has emerged as the principle mechanisms underlying the pleiotropic effects of statins. However, the relative contributions of statin pleiotropy to clinical outcomes are debatable and difficult to measure because the amount of isoprenoid inhibition by statins corresponds to some extent with the amount of LDL-cholesterol decrease. This article examines some of the existing molecular explanations underlying statin pleiotropy and discusses if they have clinical relevance in cardiovascular diseases.

Aftermath of AGE-RAGE Cascade in the pathophysiology of cardiovascular ailments.

Amidst several pathophysiological cascades, Advanced Glycation End products (AGEs) have been identified as a pivotal aetiology behind the pathogenesis and progression of cardiovascular disorders, by inducing oxidative stress and inflammation of myocardial and vascular tissues. Non-enzymatic glycation of reducing sugars with amino acids in proteins, lipids, and nucleic acids produce AGEs, which are a diverse set of compounds. Although AGEs are mostly generated endogenously, current research suggests that nutrition is a major exogenous source of AGEs. Extracellular and intracellular structure and function are affected by the presence and accumulation of AGEs in several cardiac cell types. AGEs give rise to several microvascular and macrovascular problems by establishing cross-links between molecules in the extracellular matrix's basement membrane as well as interacting with receptors for advanced glycation end products (RAGE). The transcription factor nuclear factor kappa B and its RAGE target genes are upregulated when RAGE is activated by AGEs. Engagement increases oxidative stress and triggers inflammatory and fibrotic responses, all of which contribute to the onset and progression of life-threatening cardiovascular diseases. This article discusses the probable targets of glycation in cardiac cells, as well as the underlying mechanisms that lead to heart failure.