The neuroprotective ability of alkaloid-rich leaf extract of Dalbergiella welwitschii in streptozotocin-induced type 2 diabetic rats were investigated in this study. Dalbergiella welwitshii leaf alkaloid-rich extract was obtained using standard procedure. Streptozotocin was injected into the experimental animals intraperitoneally at a dose of 45 mg/mg body weight. Prior to this, the animals were given 20% (w/v) fructose for one week. The animals were grouped into five (n = 8), comprising of normal control (NC), diabetic control (DC), diabetic rats treated with low (50 mg/mg body weight) and high (100 mg/kg body weight) doses of Dalbergiella welwitschii alkaloid-rich leaf extracts (i.e., DWL and DWH respectively) and 200 mg/kg body weight of metformin (MET). The animals were sacrificed on the 21st day, blood and brain tissue were harvested and used for the determination of neurotransmitters, cholinesterase, some ATP activities, oxidative stress biomarkers and histological examination. The results show that diabetic rats placed on DWL, DWH and MET significantly (p < 0.05) reduced cholinergic, elevated some ATPase activities and ameliorated oxidative stress biomarkers. These were supported by the histological examination by improving neuroprotective effects in diabetic rats administered DWL, DWH and MET. Hence, it can be presumed that DWL and DWH could be beneficial in treating diabetic neurodegenerative diseases.

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays a pivotal role in various biological processes, through integrating external and internal signals, facilitating gene transcription and protein translation, as well as by regulating mitochondria and autophagy functions. mTOR kinase operates within two distinct protein complexes known as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which engage separate downstream signaling pathways impacting diverse cellular processes. Although mTORC1 has been extensively studied as a pro-proliferative factor and a pro-aging hub if activated aberrantly, mTORC2 received less attention, particularly regarding its implication in aging regulation. However, recent studies brought increasing evidence or clues for us, which implies the associations of mTORC2 with aging, as the genetic elimination of unique subunits of mTORC2, such as RICTOR, has been shown to alleviate aging progression in comparison to mTORC1 inhibition. In this review, we first summarized the basic characteristics of mTORC2, including its protein architecture and signaling network. We then focused on reviewing the molecular signaling regulation of mTORC2 in cellular senescence and organismal aging, and proposed the multifaceted regulatory characteristics under senescent and nonsenescent contexts. Next, we outlined the research progress of mTOR inhibitors in the field of antiaging and discussed future prospects and challenges. It is our pleasure if this review article could provide meaningful information for our readers and call forth more investigations working on this topic.

BACKGROUND: Hypertension is a recognized risk factor for Parkinson\'s disease (PD). The renin-angiotensin system (RAS) inhibitors are widely used to treat hypertension. However, the association of RAS inhibitor use with PD has still been an area of controversy.
METHODS: Thus, we conducted a meta-analysis to investigate the relationship between RAS inhibitor use and PD. PUBMED and EMBASE databases were searched for articles published up to Oct 2023. All studies that examined the relationship between RAS inhibitor use and the incidence of PD were included.
RESULTS: Seven studies with total 3,495,218 individuals met our inclusion criteria for this meta-analysis. Overall, RAS inhibitor use was associated with a reduction in PD risk (OR = 0.88, 95%CI = 0.79-0.98) compared with the controls. When restricted the analysis to individuals with RAS inhibitor use indication, RAS inhibitor exposure was also associated with a decreased risk of PD (OR = 0.76, 95%CI = 0.62-0.92). Pooled results of cohort studies also did support a protective role of angiotensin converting enzyme inhibitors (ACEIs) (OR = 0.97, 95%CI = 0.89-1.07) users and angiotensin II receptor blockers (ARBs) (OR = 0.8, 95%CI = 0.63-1.02) in PD.
CONCLUSIONS: Overall, RAS inhibitor use as a class is associated with a reduction in PD risk. However, the findings of ACEIs and ARBs may be limited by small sample size. Future well-designed studies considering the classification by inhibitor type, duration, dose, or property of BBB penetration of RAS inhibitors are needed to clarify the contribution of these exposure parameters on the risk of PD.

The overexpression, accumulation, and cell-to-cell transmission of α-synuclein leads to the deterioration of Parkinson\'s disease (PD). Previous studies suggest that Baicalein (BAI) can bind to α-synuclein and inhibit α-synuclein aggregation and secretion. However, it is still unclear whether BAI can intervene with the pathogenic molecules in α-synuclein-mediated PD pathways beyond directly targeting α-synuclein per se.
This study aimed to systematically investigate BAI\'s potential targets in PD-related A53T mutant α-synuclein-mediated pathways by integrating data mining, network pharmacological analysis, and molecular docking simulation techniques.
The results suggest that BAI may target genes that are dysregulated in synaptic transmission, vesicle trafficking, gene transcription, protein binding, extracellular matrix formation, and kinase activity in α-synucleinmediated pathways. NFKB1, STAT3, and CDKN1A are BAI\'s potential hub targets in these pathways.
Our findings highlight BAI\'s potentiality to modulate α-synuclein-mediated pathways beyond directly targeting α-synuclein per se.

Parkinson\'s disease (PD) is a neurodegenerative disorder that mainly affects the elder population, and its etiology is enigmatic. Both environmental risks and genetics may influence the development of PD. Excess copper causes neurotoxicity and accelerates the progression of neurodegenerative diseases. However, the underlying mechanisms of copper-induced neurotoxicity remain controversial. In this study, A53T transgenic α-synuclein (A53T) mice and their matching wild-type (WT) mice were treated with a low dose of copper (0.13 ppm copper chlorinated drinking water, equivalent to the copper exposure of human daily copper intake dose) for 4 months, and copper poisoning was performed on human A53T mutant SHSY5Y cells overexpressed with α-synuclein (dose of 1/4 IC50), to test the effects of copper exposure on the body. The results of the open field test showed that the moto function of Cu-treated mice was impaired. Proteomics revealed changes in neurodevelopment, transport function, and mitochondrial membrane-related function in Cu-treated WT mice, which were associated with reduced expression of mitochondrial complex (NDUFA10, ATP5A), dopamine neurons (TH), and dopamine transporter (DAT). Mitochondrial function, nervous system development, synaptic function, and immune response were altered in Cu-treated A53T mice. These changes were associated with increased mitochondrial splitting protein (Drp1), decreased mitochondrial fusion protein (OPA1, Mfn1), abnormalities in mitochondrial autophagy protein (LC3BII/I, P62), decreased dopamine neuron (TH) expression, increased α-synuclein expression, inflammatory factors (IL-6, IL-1β, and TNF-α) release and microglia (Iba1) activation. In addition, we found that Cu2+ (30 μM) induced excessive ROS production and reduced mitochondrial ATP production in human A53T mutant α-synuclein overexpressing SHSY5Y cells by in vitro experiments. In conclusion, low-dose copper treatment altered critical proteins involved in mitochondrial, neurodevelopmental, and inflammatory responses and affected mitochondria\'s ROS and ATP production levels.

Alzheimer\'s disease (AD) is a major neurological disease affecting elderly individuals worldwide. Existing drugs only reduce the symptoms of the disease without addressing the underlying causes. Commonly, Aβ25-35 peptide aggregation is the main reason for AD development. Recently, the discovery of multiple protein-targeting molecules has provided a new strategy for treating AD. This study demonstrates the neuroprotective potential of oxymatrine against multiple mechanisms, such as acetylcholinesterase, mitochondrial damage, and β-amyloid-induced cell toxicity. The in vitro cell culture studies showed that oxymatrine possesses significant potential to inhibit acetylcholine esterase and promotes antioxidant, antiapoptotic effects while preventing Aβ25-35 peptide aggregation in PC12 cells. Furthermore, oxymatrine protects PC12 cells against Aβ25-35-induced cytotoxicity and down-regulates the reactive oxygen species generation. The in vivo acute toxicological studies confirm the safety of oxymatrine without causing organ damage or death in animals. Overall, this study provided evidence that oxymatrine is an efficient neuroprotective agent, with a potential to be a multifunctional drug for Alzheimer\'s disease treatment. These findings present a reliable and synergistic approach for treating AD.

Alzheimer\'s disease (AD), the most common cause of dementia, is a chronic neurodegenerative disease induced by multiple factors. The high incidence and the aging of the global population make it a growing global health concern with huge implications for individuals and society. The clinical manifestations are progressive cognitive dysfunction and lack of behavioral ability, which not only seriously affect the health and quality of life of the elderly, but also bring a heavy burden to the family and society. Unfortunately, almost all the drugs targeting the classical pathogenesis have not achieved satisfactory clinical effects in the past two decades. Therefore, the present review provides more novel ideas on the complex pathophysiological mechanisms of AD, including classical pathogenesis and a variety of possible pathogenesis that have been proposed in recent years. It will be helpful to find out the key target and the effect pathway of potential drugs and mechanisms for the prevention and treatment of AD. In addition, the common animal models in AD research are outlined and we examine their prospect for the future. Finally, Phase I, II, III, and IV randomized clinical trials or on the market of drugs for AD treatment were searched in online databases (Drug Bank Online 5.0, the U.S. National Library of Medicine, and Alzforum). Therefore, this review may also provide useful information in the research and development of new AD-based drugs.

Psychostimulants and alcohol are widely abused substances with the adverse effects on global public health. Substance abuse seriously harms people\'s health and causes various diseases, especially neurodegenerative diseases. Neurodegenerative diseases include Alzheimer\'s disease (AD), Parkinson\'s disease (PD), and amyotrophic lateral sclerosis (ALS). The pathogenesis of neurodegenerative diseases is complex and diverse, usually involving oxidative stress, mitochondrial dysfunction, metal homeostasis disorder, and neuro-inflammation. The precise molecular mechanisms underlying neurodegeneration remain unclear, which is a major obstacle to therapeutic approaches. Therefore, it is urgent to improve the understanding of the molecular mechanisms of neurodegenerative processes and to identify the therapeutic targets for treatment and prevention. Ferroptosis is a regulatory cell necrosis caused by iron ion catalysis and lipid peroxidation induced by reactive oxygen species (ROS), which is thought to be associated with nervous system diseases, particularly neurodegenerative diseases. This review overviewed the ferroptosis process and explored the relationship of ferroptosis with substance abuse and neurodegenerative diseases, which provides a new way to study the molecular mechanisms of neurodegenerative diseases induced by alcohol, cocaine, and methamphetamine (MA), and also provides the potential therapeutic targets for substance abuse-induced neurodegenerative diseases.

BACKGROUND: Globoid cell leukodystrophy (GLD) is a devastating neurodegenerative disease characterized by widespread demyelination caused by galactocerebrosidase defects. Changes in GLD pathogenesis occurring at the molecular level have been poorly studied in human-derived neural cells. Patient-derived induced pluripotent stem cells (iPSCs) are a novel disease model for studying disease mechanisms and allow the generation of patient-derived neuronal cells in a dish.
RESULTS: In this study, we identified gene-expression changes in iPSCs and iPSC-derived neural stem cells (NSCs) from a patient with GLD (K-iPSCs/NSCs) and normal control (AF-iPSCs/NSCs), in order to investigate the potential mechanism underlying GLD pathogenesis. We identified 194 (K-iPSCs vs. AF-iPSCs) and 702 (K-NSCs vs. AF-NSCs) significantly dysregulated mRNAs when comparing the indicated groups. We also identified dozens of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway terms that were enriched for the differentially expressed genes. Among them, 25 differentially expressed genes identified by RNA-sequencing analysis were validated using real-time quantitative polymerase chain reaction analysis. Dozens of pathways involved in neuroactive ligand-receptor interactions, synaptic vesicle cycle signaling, serotonergic synapse signaling, phosphatidylinositol-protein kinase B signaling, and cyclic AMP signaling were identified as potential contributors to GLD pathogenesis.
CONCLUSIONS: Our results correspond to the fact that mutations in the galactosylceramidase gene may disrupt the identified signaling pathways during neural development, suggesting that alterations in signaling pathways contribute to GLD pathogenesis. At the same time, our results demonstrates that the model based on K-iPSCs is a novel tool that can be used to study the underlying molecular basis of GLD.

Exogenous nucleotides (NTs) are considered conditionally essential nutrients, and the brain cannot synthesize NTs de novo. Therefore, the external supplementation of exogenous NTs is of great significance for maintaining normal neuronal metabolism and function under certain conditions, such as brain aging. This study, therefore, sets out to assess the neuroprotective effect of four kinds of single exogenous NTs and a mixture of the NTs, and to elucidate the potential mechanism. A rat pheochromocytoma cell line PC-12 was treated with different concentrations of exogenous NTs after 4 h of exposure to 200 µM H2O2. We found that the exogenous NTs exerted significant neuroprotection through decreasing neuron apoptosis and DNA damage, ameliorating inflammation and mitochondrial dysfunction, promoting cell viability, and augmenting antioxidant activity, and that they tended to up-regulate the NAD+/SIRTI/PGC-1α pathway involved in mitochondrial biogenesis. Among the different NTs, the neuroprotective effect of AMP seemed to be more prominent, followed by the NT mixture, NMN, and CMP. AMP also exhibited the strongest antioxidant activity in H2O2-treated PC-12 cells. UMP was excellent at inhibiting neuronal inflammation and improving mitochondrial function, while GMP offered major advantages in stabilizing mitochondrial membrane potential. The mixture of NTs had a slightly better performance than NMN, especially in up-modulating the NAD+/SIRTI/PGC-1α pathway, which regulates mitochondrial biogenesis. These results suggest that antioxidant activity, anti-inflammatory activity, and protection of mitochondrial function are possible mechanisms of the neuroprotective actions of exogenous NTs, and that the optimization of the mixture ratio and the concentration of NTs may achieve a better outcome.