MiR-335-3p, a neuron-enriched microRNA, has been reported to be involved in aging and age-related neurological diseases. However, the role of miR-335-3p in cholesterol metabolism of astrocytes, and whether it affects neuronal functions, particularly during aging process, largely remains unknown. In this study, we uncover that miR-335-3p is significantly increased in aged cultured astrocytes and aged hippocampal brains, accompanied by decreased cellular cholesterol and diminished expression of HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase) and 3-hydroxy-3-methylglutaryl-CoA synthase-1 (HMGCS1), both step-limiting enzymes in cholesterol synthesis pathway. We also demonstrate that miR-335-3p suppresses HMGCS1 post-transcriptionally by directly binding to its 3'UTR, and HMGCR through binding mediated by SFRS2. More importantly, aged mice with miR-335-3p deficiency in hippocampal brains exhibit improved learning and memory, accompanied by enhanced levels of postsynaptic density protein 95 (PSD95). We further reveal that the level change of PSD95 is resulted from altered cholesterol metabolism. Our findings provide a novel insight into the regulatory role of miR-335-3p in cholesterol metabolism in astrocytes, and consequently cognitive functions during aging.

Medicinal plants are becoming more popular in the treatment of various diseases because of the adverse effects of the current therapy, especially antioxidant plant components such as phenols and flavonoids have a protective role against oxidative stress-induced degenerative diseases like diabetes. Thus, the purpose of this study was to investigate β-cell protection and antidiabetic activities of Crassocephalum crepidioides (Asteraceae) Benth. S. Moore. The in-vitro study was conducted by the pancreatic β-cell culture and α-amylase inhibition technique which includes two methods, namely starch-iodine method and 3,5-dinitrosalicylic acid (DNSA) method. On the other hand, the in-vivo study was performed by oral glucose tolerance test (OGTT) method and alloxan-induced diabetes method by using Wistar albino rat. At the end pancreatic specimens were removed and processed for histopathological study. The plant extract showed significant (*p < 0.05, **p < 0.01) effect on hyperglycemia as compared to standard (Gliclazide) in OGTT. The plant extract showed efficient protection activity of pancreatic β-cell from cell death in INS-1 cell line by significantly reduced (*p < 0.05, **p < 0.01) the levels alloxan-induced apoptosis and intracellular reactive oxygen species (ROS) accumulation. In addition, the plant extract showed a significant (*p < 0.05, **p < 0.01) effect on hyperglycemia by increases in percent of β-cells present in each islet (45% – 60%) compared to the diabetic group. The result showed that C. crepidioides had β-cell protection and antidiabetic activities in pancreatic β-cell culture and Wistar albino rat.

The sedative and anxiolytic potential of Leea indica (Burm. f.) Merr., a Bangladeshi tribal medicinal plant was studied for the first time. The crude methanol extract of L. indica leaves was evaluated for its central nervous system (CNS) depressant effect using rodent behavioral models, such as hole cross, open field and thiopental sodium induced sleeping time tests for its sedative properties and an elevated plus-maze (EPM) test for its anxiolytic potential, respectively. The methanol extract of L. indica at doses of 200 mg/kg, p.o. and 400 mg/kg, p.o., displayed a dose dependent suppression of motor activity, exploratory behavior (in hole cross and open field tests) and prolongation of thiopental induced sleeping time in mice; the highest CNS depressant effect was shown at a dose of 400 mg/kg, p.o. In the EPM test, both doses of methanol extract significantly (p < 0.01) increased exploration to and time spent by the treated mice in EPM open arms in a dose dependent manner. These results provide in vivo evidence that leaves of L. indica in general have significant sedative and anxiolytic effects. However, these results may rationalize the scientific basis for use of this plant in traditional medicine for treatment of anxiety and related disorders.

Acetylcholinesterase (AChE) holds significance in Alzheimer's disease (AD), where cognitive impairment correlates with insufficient acetylcholine levels. AChE's role involves the breakdown of acetylcholine, moderating cholinergic neuron activity to prevent overstimulation and signal termination. Hence, inhibiting AChE emerges as a potential treatment avenue for AD. A library of 2500 compounds, derived from 25 traditionally used medicinal plants, was constructed using the IMPAAT database of traditional medicinal plants. The canonical SMILES of these compounds were collected and underwent virtual screening based on physicochemical properties, with subsequent determination of IC₅₀ values for the screened compounds followed by analysis using machine learning (ML). Subsequently, a molecular docking study elucidated both binding affinity and interactions between these compounds and AChE. The top three compounds, exhibiting robust binding affinities, underwent MM-GBSA analysis for molecular docking validation, succeeded by pharmacokinetics and toxicity evaluations to gauge safety and efficacy. These three compounds underwent MD simulation studies to assess protein–ligand complex conformational stability. Additionally, Density Functional Theory (DFT) was employed to ascertain HOMO, LUMO, energy gap, and molecular electrostatic potential. Among 2500 compounds, physicochemical properties-based virtual screening identified 80 with good properties, of which 32 showed promising IC₅₀ values. Molecular docking studies of these 32 compounds revealed various binding energies with AChE, with the best three compounds (CID 102267534, CID 15161648, CID 12441) selected for further analysis. MM-GBSA studies confirmed the promising binding energies of these three compounds, validating the molecular docking study. Further, the MD simulation studies have confirmed the structural and conformational stability of these three protein–ligand complexes. Finally, DFT calculations revealed favorable chemical features of these compounds. Thus, we can conclude that these three compounds (CID 102267534, CID 15161648, CID 12441) may inhibit the activity of AChE and can be useful as a treatment for Alzheimer's disease.

RNA binding proteins, the key regulators in gene expression at the posttranscriptional level, remain largely uncharacterized with respect to aging and relevant cognitive deterioration. Here, we report that the levels of SFRS11 are substantially decreased in the prefrontal cortex (PFC) of aged brains. Notably, mice with SFRS11 deficiency in the PFC show impaired learning and memory. We demonstrate that SFRS11 directly binds to the 3' UTR of LRP8 mRNA, as well as to the third exon of apoE mRNA, resulting in stabilization of these mRNAs, eventually deactivating JNK signaling. Importantly, restoration of LRP8 and apoE reduces JNK signaling that is significantly enhanced in SFRS11-deficient cells. In addition, LRP8 and apoE rescue aging-like phenotypes induced by SFRS11 loss. Our findings demonstrate that age-dependent loss of SFRS11 in the PFC reduces levels of apoE and LRP8, leading to activation of the JNK pathway, ultimately influencing cognitive deficits.

Microglia, the unique and motile immune cells of the central nervous system (CNS), function as a security guard in maintaining CNS homeostasis, primarily through calcium signaling. The calcium dynamics in microglia control important functions such as phagocytosis, cytokine release, and migration. Calcium dysregulation in microglia has been linked to several CNS disorders, like Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and ischemic stroke (IS). Calcium entering through channels such as voltage-gated calcium channels (VGCCs), store-operated calcium entry (SOCE), and transient receptor potential (TRP) channels is essential for microglial activation and pro-inflammatory responses. Under pathological conditions, like the formation of amyloid-β plaques in AD, aggregation of α-synuclein in PD, and oxidative stress in MS, calcium dysregulation exacerbates neuroinflammation, mitochondrial dysfunction, and neurodegeneration. Therapeutic strategies targeting calcium signaling pathways, using calcium channel blockers and antioxidant interventions, show promise for alleviating microglial activation and slowing down disease progression. This review summarizes the underlying mechanisms of microglial calcium dysregulation and potential therapeutic benefits for restoring microglial calcium balance in CNS disorders.