Neuroprotective effects of quercetin produced by an endophytic fungus Nigrospora oryzae isolated from Tinospora cordifolia.

AIMS: Alzheimer's disease is considered one of the most prevalent neurodegenerative disorders and dementia is the core symptom of this disease. This study was aimed to test the bioactive compounds produced by endophytic fungus for the inhibition of acetylcholinesterase (AChE) activity and to identify the compound responsible for this activity. METHODS AND RESULTS: Endophytic fungi were isolated from the medicinal plant Tinospora cordifolia and screened for AChE inhibition and antioxidant activity. The extract of one of the isolates Nigrospora oryzae (GL15) showed maximum AChE inhibition as well as antioxidant activity. The compound responsible for AChE inhibition (fraction 3) was identified as quercetin based on UV, FTIR spectra, HPLC and ESI-MS analyses. Furthermore, the identification of quercetin in the extract of fraction 3 was confirmed by 1 H NMR analysis. This extract showed anti-dementia-like activity in scopolamine (SCO) model. The minimal effective dose of the extract of fraction 3 modulated the SCO-provoked cognitive deficits such as impairments in spatial recognition memory and latency period in Y-maze test and passive avoidance test, respectively. The SCO-induced modulation in cholinergic pathway was ameliorated by the extract of N. oryzae in hippocampus, resulting in decrease in AChE activity and restoration of cytoarchitecture of hippocampus. CONCLUSIONS: The bioactive compound quercetin produced by N. oryzae may cure the learning and memory shortfalls via AChE-mediated mechanism in experimental mice. SIGNIFICANCE AND IMPACT OF THE STUDY: The endophytic fungus N. oryzae serves as a potential source for the bioactive compound quercetin, which plays an important role in the management of Alzheimer's disease.

Design and development of 1,3,4-oxadiazole derivatives as potential inhibitors of acetylcholinesterase to ameliorate scopolamine-induced cognitive dysfunctions.

The novel hybrids bearing 4-aminopyridine (4-AP) tethered with substituted 1,3,4-oxadiazole nucleus were designed, synthesized, and evaluated for their potential AChE inhibitory property along with significant antioxidant potential. The inhibitory potential (IC50) of synthesized analogs was evaluated against human cholinesterases (hAChE and hBChE) using Ellman's method. Among all the compounds, 9 with 4-hydroxyl substituent showed maximum hAChE inhibition with the non-competitive type of enzyme inhibition (IC50 = 1.098 µM; Ki = 0.960 µM). Further, parallel artificial membrane permeation assay (PAMPA-BBB) showed significant BBB permeability in most of the synthesized compounds. Meanwhile, compound 9 also inhibited AChE-induced Aß aggregation (38.2-65.9%) by thioflavin T assay. The in vivo behavioral studies showed dose-dependent improvement in learning and memory by compound 9. The ex vivo studies also affirmed the significant AChE inhibition and antioxidant potential of compound 9 in brain homogenates.

The neurotransmitter puzzle of Alzheimer's: Dissecting mechanisms and exploring therapeutic horizons.

Alzheimer's Disease (AD) represents a complex interplay of neurological pathways and molecular mechanisms, with significant impacts on patients' lives. This review synthesizes the latest developments in AD research, focusing on both the scientific advancements and their clinical implications. We examine the role of microglia in AD, highlighting their contribution to the disease's inflammatory aspects. The cholinergic hypothesis, a cornerstone of AD research, is re-evaluated, including the role of Alpha-7 Nicotinic Acetylcholine Receptors in disease progression. This review places particular emphasis on the neurotransmission systems, exploring the therapeutic potential of GABAergic neurotransmitters and the role of NMDA inhibitors in the context of glutamatergic neurotransmission. By analyzing the interactions and implications of neurotransmitter pathways in AD, we aim to shed light on emerging therapeutic strategies. In addition to molecular insights, the review addresses the clinical and personal aspects of AD, underscoring the need for patient-centered approaches in treatment and care. The final section looks at the future directions of AD research and treatment, discussing the integration of scientific innovation with patient care. This review aims to provide a comprehensive update on AD, merging scientific insights with practical considerations, suitable for both specialists and those new to the field.

Advances in Alzheimer's disease: A multifaceted review of potential therapies and diagnostic techniques for early detection.

Alzheimer's disease (AD) remains one of the most formidable neurological disorders, affecting millions globally. This review provides a holistic overview of the therapeutic strategies, both conventional and novel, aimed at mitigating the impact of AD. Initially, we delve into the conventional approach, emphasizing the role of Acetylcholinesterase (AChE) inhibition, which has been a cornerstone in AD management. As our understanding of AD evolves, several novel potential approaches emerge. We discuss the promising roles of Butyrylcholinesterase (BChE) inhibition, Tau Protein inhibitors, COX-2 inhibition, PPAR-γ agonism, and FAHH inhibition, among others. The potential of the endocannabinoids (eCB) system, cholesterol-lowering drugs, metal chelators, and MMPs inhibitors are also explored, culminating in the exploration of the pivotal role of microRNA in AD progression. Parallel to these therapeutic insights, we shed light on the novel tools and methodologies revolutionizing AD research. From the quantitative analysis of gene expression by qRTPCR to the evaluation of mitochondrial function using induced pluripotent stem cells (iPSCs), the advances in diagnostic and research tools offer renewed hope. Moreover, we explore the current landscape of clinical trials, highlighting the leading drug interventions and their respective stages of development. This comprehensive review concludes with a look into the future perspectives, capturing the potential breakthroughs and innovations on the horizon. Through a synthesis of current knowledge and emerging research, this article aims to provide a consolidated resource for clinicians, researchers, and academicians in the realm of Alzheimer's disease.

Microglial mediators in autoimmune Uveitis: Bridging neuroprotection and neurotoxicity.

Autoimmune uveitis, a severe inflammatory condition of the eye, poses significant challenges due to its complex pathophysiology and the critical balance between protective and detrimental immune responses. Central to this balance are microglia, the resident immune cells of the central nervous system, whose roles in autoimmune uveitis are multifaceted and dynamic. This review article delves into the dual nature of microglial functions, oscillating between neuroprotective and neurotoxic outcomes in the context of autoimmune uveitis. Initially, we explore the fundamental aspects of microglia, including their activation states and basic functions, setting the stage for a deeper understanding of their involvement in autoimmune uveitis. The review then navigates through the intricate mechanisms by which microglia contribute to disease onset and progression, highlighting both their protective actions in immune regulation and tissue repair, and their shift towards a pro-inflammatory, neurotoxic profile. Special emphasis is placed on the detailed pathways and cellular interactions underpinning these dual roles. Additionally, the review examines the potential of microglial markers as diagnostic and prognostic indicators, offering insights into their clinical relevance. The article culminates in discussing future research directions, and the ongoing challenges in translating these findings into effective clinical applications. By providing a comprehensive overview of microglial mechanisms in autoimmune uveitis, this review underscores the critical balance of microglial activities and its implications for disease management and therapy development.

Microglial-mediated immune mechanisms in autoimmune uveitis: Elucidating pathogenic pathways and targeted therapeutics.

This review offers a comprehensive examination of the role of microglia in the pathogenesis of autoimmune uveitis, an inflammatory eye disease with significant potential for vision impairment. Central to our discussion is the dual nature of microglial cells, which act as both protectors and potential perpetrators in the immune surveillance of the retina. We explore the mechanisms of microglial activation, highlighting the key signaling pathways involved, such as NF-κB, JAK/STAT, MAPK, and PI3K/Akt. The review also delves into the genetic and environmental factors influencing microglial behavior, underscoring their complex interaction in disease manifestation. Advanced imaging techniques and emerging biomarkers for microglial activation, pivotal in diagnosing and monitoring the disease, are critically assessed. Additionally, we discuss current and novel therapeutic strategies targeting microglial activity, emphasizing the shift towards more precise and personalized interventions. This article aims to provide a nuanced understanding of microglial dynamics in autoimmune uveitis, offering insights into potential avenues for effective treatment and management.

Dynamin-1 is a potential mediator in Cancer-Related Cognitive Impairment.

Dynamin-1 (DNM1) consolidates memory through synaptic transmission and modulation and has been explored as a therapeutic target in Alzheimer's disease. Through a two-prong approach, this study examined its role in cancer-related cognitive impairment (CRCI) pathogenesis using human and animal models. The human study recruited newly diagnosed, chemotherapy-naïve adolescent and young adult cancer and non-cancer controls to complete a cognitive instrument (FACT-Cog) and blood draws for up to three time points. Concurrently, a syngeneic young-adult WT (C57BL/6 female) mouse model of breast cancer was developed to study DNM1 expression in the brain. Samples from eighty-six participants with 30 adolescent and young adult (AYA) cancer and 56 non-cancer participants were analyzed. DNM1 levels were significantly lower among cancer participants compared to non-cancer prior to treatment. While receiving cancer treatment, cognitively impaired patients were found with a significant downregulation of DNM1, but not among those without impairment. In murine breast cancer-bearing mice receiving chemotherapy, we consistently found a significant decline in DNM1 immunoreactivity in the hippocampal CA1 and CA3 subregions. Observed in both human and animal studies, the downregulation of DNM1 is linked with the onset of CRCI. Future research should explore the potential of DNM1 in CRCI pathogenesis and therapeutics development.

Regulatory roles of microRNAs in modulating mitochondrial dynamics, amyloid beta fibrillation, microglial activation, and cholinergic signaling: Implications for alzheimer's disease pathogenesis.

Alzheimer's Disease (AD) remains a formidable challenge due to its complex pathology, notably involving mitochondrial dysfunction and dysregulated microRNA (miRNA) signaling. This study delves into the underexplored realm of miRNAs' impact on mitochondrial dynamics and their interplay with amyloid-beta (Aß) aggregation and tau pathology in AD. Addressing identified gaps, our research utilizes advanced molecular techniques and AD models, alongside patient miRNA profiles, to uncover miRNAs pivotal in mitochondrial regulation. We illuminate novel miRNAs influencing mitochondrial dynamics, Aß, and tau, offering insights into their mechanistic roles in AD progression. Our findings not only enhance understanding of AD's molecular underpinnings but also spotlight miRNAs as promising therapeutic targets. By elucidating miRNAs' roles in mitochondrial dysfunction and their interactions with hallmark AD pathologies, our work proposes innovative strategies for AD therapy, aiming to mitigate disease progression through targeted miRNA modulation. This contribution marks a significant step toward novel AD treatments, emphasizing the potential of miRNAs in addressing this complex disease.

Benzimidazole-derived carbohydrazones as dual monoamine oxidases and acetylcholinesterase inhibitors: design, synthesis, and evaluation.

A series of novel benzimidazole-derived carbohydrazones was designed, synthesized and evaluated for their dual inhibition potential against monoamine oxidases (MAOs) and acetylcholinesterase (AChE) using multitarget-directed ligand approach (MTDL). The investigated compounds have exhibited moderate to excellent in vitro MAOs/AChE inhibitory activity at micromolar to nanomolar concentrations. Compound 12, 2-(1H-Benzo[d]imidazol-1-yl)-N'-[1-(4-hydroxyphenyl) ethylidene]acetohydrazide has emerged as a lead dual MAO-AChE inhibitor by exhibiting superior multi-target activity profile against MAO-A (IC50 = 0.067 ± 0.018 µM), MAO-B (IC50 = 0.029 ± 0.005 µM) and AChE (IC50 = 1.37 ± 0.026 µM). SAR studies suggest that the site A (hydrophobic ring) and site C (semicarbazone linker) modifications attempted on the semicarbazone-based MTDL resulted in a significant enhancement in the MAO-A/B inhibitory potential and a drastic decrease in the AChE inhibitory activity. Further, molecular docking and dynamics simulation experiments disclosed the possible molecular interactions of inhibitors inside the active site of respective enzymes. Also, computational prediction of drug-likeness and ADME parameters of test compounds revealed their drug-like characteristics.Communicated by Ramaswamy H. Sarma.

Long-term exposure of 2450 MHz electromagnetic radiation induces stress and anxiety like behavior in rats.

Long term exposure of electromagnetic radiations (EMR) from cell phones and Wi-Fi hold greater propensity to cause anxiety disorders. However, the studies investigating the effects of repeated exposure of EMR are limited. Therefore, we investigated the effects of repeated exposure of discrete frequencies of EMR in experimental animals. Male rats were exposed to EMR (900, 1800 and 2450 MHz) for 28 (1 h/day) days. Long term exposure of EMR (2450 MHz) induced anxiety like behavior. It deregulated the hypothalamic pituitary adrenal (HPA) axis in rats as observed by increase in plasma corticosterone levels apart from decreased corticotrophin releasing hormone-2 (CRH-2) and Glucocorticoid receptor (GR) expression in amygdala. Further, it impaired mitochondrial function and integrity. The expression of Bcl2 showed significant decrease while Bax and ratio of Bax: Bcl2 were increased in the mitochondria and vice versa in cytoplasm indicating altered regulation of apoptosis. EMR exposure caused release of cytochrome-c and expression of caspase-9 ensuing activation of apoptotic cell death. Additional set of experiments performed to estimate the pattern of cell death showed necrotic and apoptotic amygdalar cell death after EMR exposure. Histopathological studies also revealed a significant decrease in neuronal cells in amygdala. The above findings indicate that long-term exposure of EMR radiation (2450 MHz) acts as a stressor and induces anxiety-like behaviors with concomitant pathophysiological changes in EMR subjected rats.

4,6-Diphenylpyrimidine Derivatives as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder with multifactorial pathogenesis. Monoamine oxidase (MAO) and acetylcholinesterase enzymes (AChE) are potential targets for the treatment of AD. A total of 15 new propargyl containing 4,6-diphenylpyrimidine derivatives were synthesized and screened for the MAO and AChE inhibition activities along with ROS production inhibition and metal-chelation potential. All the synthesized compounds were found to be selective and potent inhibitors of MAO-A and AChE enzymes at nanomolar concentrations. VB1 was found to be the most potent MAO-A and BuChE inhibitor with IC50 values of 18.34 ± 0.38 nM and 0.666 ± 0.03 µM, respectively. It also showed potent AChE inhibition with an IC50 value of 30.46 ± 0.23 nM. Compound VB8 was found to be the most potent AChE inhibitor with an IC50 value of 9.54 ± 0.07 nM and displayed an IC50 value of 1010 ± 70.42 nM against the MAO-A isoform. In the cytotoxic studies, these compounds were found to be nontoxic to the human neuroblastoma SH-SY5Y cells even at 25 µM concentration. All the compounds were found to be reversible inhibitors of MAO-A and AChE enzymes. In addition, these compounds also showed good neuroprotective properties against 6-OHDA- and H2O2-induced neurotoxicity in SH-SY5Y cells. All the compounds accommodate nicely to the hydrophobic cavity of MAO-A and AChE enzymes. In the molecular dynamics simulation studies, both VB1 and VB8 were found to be stable in the respective cavities for 30 ns. Thus, 4,6-diphenylpyrimidine derivatives can act as promising leads in the development of dual-acting inhibitors targeting MAO-A and AChE enzymes for the treatment of Alzheimer's disease.

Electromagnetic radiation 2450 MHz exposure causes cognition deficit with mitochondrial dysfunction and activation of intrinsic pathway of apoptosis in rats.

Electromagnetic radiation (EMR) can induce or modulate several neurobehavioral disorders. Duration and frequency of exposure of EMR is critical to develop cognitive disorders. Even though EMR-2450 is widely used, its effects on cognition in relation to mitochondrial function and apoptosis would provide better understanding of its pathophysiological effects. Therefore, a comparative study of different frequencies of EMR exposure would give valuable information on effects of discrete frequencies of EMR on cognition. Male rats were exposed to EMR (900, 1800 and 2450 MHz) every day for 1 h for 28 consecutive days. The cognitive behavior in terms of novel arm entries in Y-maze paradigm was evaluated every week after 1 h to last EMR exposure. Animals exposed to EMR-2450 MHz exhibited significant cognitive deficits. EMR- 2450 MHz caused loss of mitochondrial function and integrity, an increase in amyloid beta expression. There was release of cytochrome-c and activation of apoptotic factors such as caspase-9 and -3 in the hippocampus. Further, there was decrease in levels of acetylcholine, and increase in activity of acetyl cholinesterase, indicating impairment of cholinergic system. Therefore, exposure of EMR-2450 in rats caused cognitive deficit with related pathophysiological changes in mitochondrial and cholinergic function, and amyloidogenesis.