[Effect on Danggui Shaoyao Powder on mitophagy in rat model of Alzheimer's disease based on PINK1-Parkin pathway].

This study investigated the mechanism of Danggui Shaoyao Powder(DSP) against mitophagy in rat model of Alzheimer's disease(AD) induced by streptozotocin(STZ) based on PTEN induced putative kinase 1(PINK1)-Parkin signaling pathway. The AD rat model was established by injecting STZ into the lateral ventricle, and the rats were divided into normal group, model group, DSP low-dose group(12 g·kg~(-1)·d~(-1)), DSP medium-dose group(24 g·kg~(-1)·d~(-1)), and DSP high-dose group(36 g·kg~(-1)·d~(-1)). Morris water maze test was used to detect the learning and memory function of the rats, and transmission electron microscopy and immunofluorescence were employed to detect mitophagy. The protein expression levels of PINK1, Parkin, LC3BⅠ/LC3BⅡ, and p62 were assayed by Western blot. Compared with the normal group, the model group showed a significant decrease in the learning and memory function(P<0.01), reduced protein expression of PINK1 and Parkin(P<0.05), increased protein expression of LC3BⅠ/LC3BⅡ and p62(P<0.05), and decreased occurrence of mitophagy(P<0.01). Compared with the model group, the DSP medium-and high-dose groups notably improved the learning and memory ability of AD rats, which mainly manifested as shortened escape latency, leng-thened time in target quadrants and elevated number of crossing the platform(P<0.05 or P<0.01), remarkably activated mitophagy(P<0.05), up-regulated the protein expression of PINK1 and Parkin, and down-regulated the protein expression of LC3BⅠ/LC3BⅡ and p62(P<0.05 or P<0.01). These results demonstrated that DSP might promote mitophagy mediated by PINK1-Parkin pathway to remove damaged mitochondria and improve mitochondrial function, thereby exerting a neuroprotective effect.

Mitochondrial quality control in stroke: From the mechanisms to therapeutic potentials.

Mitochondrial damage is a critical contributor to stroke-induced injury, and mitochondrial quality control (MQC) is the cornerstone of restoring mitochondrial homeostasis and plays an indispensable role in alleviating pathological process of stroke. Mitochondria quality control promotes neuronal survival via various adaptive responses for preserving mitochondria structure, morphology, quantity and function. The processes of mitochondrial fission and fusion allow for damaged mitochondria to be segregated and facilitate the equilibration of mitochondrial components such as DNA, proteins and metabolites. The process of mitophagy is responsible for the degradation and recycling of damaged mitochondria. This review aims to offer a synopsis of the molecular mechanisms involved in MQC for recapitulating our current understanding of the complex role that MQC plays in the progression of stroke. Speculating on the prospect that targeted manipulation of MQC mechanisms may be exploited for the rationale design of novel therapeutic interventions in the ischaemic stroke and haemorrhagic stroke. In the review, we highlight the potential of MQC as therapeutic targets for stroke treatment and provide valuable insights for clinical strategies.

[Baicalin inhibits LPS/IFN-γ-induced inflammation via TREM2/TLR4/NF-κB pathway in BV2 cells].

This study investigated the mechanism of baicalin on lipopolysaccharide(LPS)/interferon γ(IFN-γ)-induced inflammatory microglia based on the triggering receptor expressed on myeloid cells 2(TREM2)/Toll-like receptor 4(TLR4)/nuclear factor kappaB(NF-κB) pathway. Specifically, LPS and IFN-γ were used to induce inflammation in mouse microglia BV2 cells. Then the normal group, model group, low-dose(5 µmol·L~(-1)) baicalin group, medium-dose(10 µmol·L~(-1)) baicalin group, high-dose(20 µmol·L~(-1)) baicalin group, and minocycline(10 µmol·L~(-1)) group were designed. Cell viability was detected by CCK-8 assay and cell morphology was observed under bright field. The expression of interleukin-1ß(IL-1ß), interleukin-4(IL-4), inducible nitric oxide synthase(iNOS), interleukin-6(IL-6), interleukin-10(IL-10), and arginase-1(Arg-1) mRNA was detected by real-time quantitative PCR, the protein expression of tumor necrosis factor-α(TNF-α), IL-1ß, TREM2, TLR4, inhibitor kappaB-alpha(IκBα), p-IκBα, NF-κB p65 and p-NF-κB p65 by Western blot, and transfer of NF-κB p65 from cytoplasm to nucleus by cellular immunofluorescence. Compared with the normal group, most of the BV2 cells in the model group tended to demonstrate the pro-inflammatory M1 amoeba morphology, and the model group showed significant increase in the mRNA levels of IL-1ß, IL-6, and iNOS, decrease in the mRNA levels of IL-4, IL-10, and Arg-1(P<0.01), rise of the protein expression of TNF-α, IL-1ß, TLR4, p-IκBα, and p-NF-κB p65(P<0.01), reduction in TREM2 protein expression, and increase in the expression of NF-κB p65 in nucleus. Compared with the model group, baicalin groups and minocycline group showed the recovery of BV2 cell morphology, significant decrease in the mRNA levels of IL-1ß, IL-6 and iNOS, increase in the mRNA levels of IL-4, IL-10, and Arg-1(P<0.01), reduction in the protein expression of TNF-α, IL-1ß, TLR4, p-IκBα, and p-NF-κB p65(P<0.05), rise of TREM2 protein expression, and decrease in the expression of NF-κB p65 in nucleus. In summary, these results suggest that baicalin can regulate the imbalance between TREM2 and TLR4 of microglia and inhibit the activation of downstream NF-κB, thus promoting the polarization of microglia from pro-inflammatory phenotype to anti-inflammatory phenotype.

Dibenzocyclooctadiene lignans from Kadsura coccinea alleviate APAP-induced hepatotoxicity via oxidative stress inhibition and activating the Nrf2 pathway in vitro.

Phytochemical investigation on the roots of Kadsura coccinea led to the isolation five previously unknown dibenzocyclooctadiene lignans, named heilaohusuins A-E (1-5). Their structures determined by NMR spectroscopy, HR-ESI-MS, and ECD spectra. Hepatoprotection effects of a series of dibenzocyclooctadiene derivatives (1-68) were investigated against acetaminophen (APAP) induced HepG2 cells. Compounds 2, 10, 13, 21, 32, 41, 46, and 49 showed remarkable protective effects, increasing the viabilities to > 52.2% (bicyclol, 52.1 ± 1.3%) at 10 µM. The structure-activity relationships (SAR) for hepatoprotective activity were summarized, according to the activity results of dibenzocyclooctadiene derivatives. Furthermore, we found that one new dibenzocyclooctadiene lignan heilaohusuin B attenuates hepatotoxicity, the mechanism might be closely correlated with oxidative stress inhibition via activating the Nrf2 pathway.

Curcumin Acetylsalicylate Extends the Lifespan of Caenorhabditis elegans.

Aspirin and curcumin have been reported to be beneficial to anti-aging in a variety of biological models. Here, we synthesized a novel compound, curcumin acetylsalicylate (CA), by combining aspirin and curcumin. We characterized how CA affects the lifespan of Caenorhabditis elegans (C. elegans) worms. Our results demonstrated that CA extended the lifespan of worms in a dose-dependent manner and reached its highest anti-aging effect at the concentration of 20 µM. In addition, CA reduced the deposition of lipofuscin or "age pigment" without affecting the reproductivity of worms. CA also caused a rightward shift of C. elegans lifespan curves in the presence of paraquat-induced (5 mM) oxidative stress or 37 °C acute heat shock. Additionally, CA treatment decreased the reactive oxygen species (ROS) level in C. elegans and increased the expression of downstream genes superoxide dismutase (sod)-3, glutathione S-transferase (gst)-4, heat shock protein (hsp)-16.2, and catalase-1 (ctl-1). Notably, CA treatment resulted in nuclear translocation of the DAF-16 transcription factor, which is known to stimulate the expression of SOD-3, GST-4, HSP-16, and CTL-1. CA did not produce a longevity effect in daf-16 mutants. In sum, our data indicate that CA delayed the aging of C. elegans without affecting reproductivity, and this effect may be mediated by its activation of DAF-16 and subsequent expression of antioxidative genes, such as sod-3 and gst-4. Our study suggests that novel anti-aging drugs may be developed by combining two individual drugs.

Resolving neuroinflammation, the therapeutic potential of the anti-malaria drug family of artemisinin.

Artemisinin (Qinghaosu) and its semi-synthetic derivatives have been demonstrated to alleviate neuroinflammatory response in the central nerve system (CNS). In this review, we summarized that artemisinins are capable to treat neuroinflammtion-related CNS diseases in both direct (via regulating inflammatory process in the CNS, exerting anti-oxidative stress and neuroprotective effect, and preventing Aß accumulation) and indirect (via maintaining BBB integrity, suppressing systemic inflammation and alleviating intestinal inflammtion) manner. However, the precise mechanism of their anti-neuroinflammatory effects and potential neurotoxicity, which hindered further progress in these aspects, remains unclear. We suggest that further understanding of the PK/PD properties and structure-action relationship of atemisinin and its derivatives will facilitate the development of new therapeutics with better curative effects and safety.

[Analysis on medication rules for treatment of dementia by ancient physicians based on data mining methods].

To analyze the medication features and regularity of prescriptions of Chinese medicine in treating patients with dementia based on ancient medical records. In the article, we retrieved the ancient medical records related to the treatment of dementia (from the Han Dynasty to the late Qing period) in Chinese Medical Classics, Chinese Ancient Medical Books and digital library, and then set up a medical records normalized database. The medication features and prescription rules for dementia were analyzed by frequency statistics and association rules (Apriori algorithm, improved mutual information algorithm and complex system entropy clustering). Finally, a total of 156 prescriptions were selected, involving 123 Chinese herbs, with a total frequency of 11 747 for the herbs, and 8 core prescriptions were mined. After the association rules between the frequency and prescriptions for the treatment of dementia were determined, we found that the most commonly used herbs included Fuling (Poria), Yuanzhi (Polygalae Radix), Renshen (Ginseng Radix et Rhizoma), Shichangpu (Acori Tatarinowii Rhizoma), Gancao (Glycyrrhizae Radix et Rhizoma), Danggui (Angelicae Sinensis Radix), Maidong (Ophiopogonis Radix), Baizhu (Bletillae Rhizoma), Dihuang (Rehmanniae Radix) and Ganjiang (Zingiberis Rhizoma); the frequently-used drugs compatibility was mainly for tonifying Qi-blood, regulating Yin and Yang and inducing resuscitation. The drugs were mainly of warm nature and sweet (mild) flavor, and the channel tropism of drugs mainly distributed to the heart, liver, spleen and kidney. The core prescriptions were composed of Renshen (Ginseng Radix et Rhizoma), Fuling (Poria), Yuanzhi (Polygalae Radix), Shichangpu (Acori Tatarinowii Rhizoma), and Baizhu(Bletillae Rhizoma). In conclusion, high frequency herbs and core prescriptions reflect the prescriptions by ancient physicians mainly focus on Qi-replenishing, spleen-invigorating and heart-nourishing, but also reflect the prescription rules of nourishing Yin, enriching blood, eliminating phlegm and warming Yang for the treatment of dementia. The medication features and prescription rules for the treatment of dementia obtained by association rules are useful to guide the clinical practice of Chinese medicine in treatment of dementia.

Haplodeficiency of Cathepsin D does not affect cerebral amyloidosis and autophagy in APP/PS1 transgenic mice.

Autophagy and lysosomal function are important for protein homeostasis and their dysfunction have been associated with Alzheimer's disease (AD). Increased immunoreactivities of an important lysosomal protease, cathepsin D (Cat D), are evident in amyloid plaques and neurons in patients with AD. This study tests the hypothesis that deleting one allele of the cathepsin D gene (Ctsd) impacts cerebral ß-amyloidosis in amyloid-ß precursor protein (APP)sw/PS1dE9 (APP/PS1) double transgenic mice. Despite a significant 38% decrease in Cat D level in APP/PS1/Ctsd+/- compared with APP/PS1/Ctsd+/+ mice, no changes in steady state levels and deposition of Aß were found in the brain. There were also no differences in APP processing, the levels of two other Aß-degrading proteases, the levels of autophagy related protein, such as LAMP2, P62, LC3-I, LC3-II, and Beclin-1, or the markers of neuroinflammation, observed between the APP/PS1/Ctsd+/+ and APP/PS1/Ctsd+/- mice. Our findings demonstrate that in wild-type mice, Cat D protein levels are either in excess or redundant with other factors in the brain, and at least one allele of Ctsd is dispensable for cerebral ß-amyloidosis and autophagy in APP/PS1 transgenic mice.

Polyacetylenic Oleanane-Type Triterpene Saponins from the Roots of Panax japonicus.

Three new polyacetylenic oleanane-type triterpenoids, baisanqisaponins A-C (1-3), and one new oleanane-type triterpenoid, chikusetsusaponin-V ethyl ester (4), together with 19 known compounds (5-23), were isolated from the roots of Panax japonicus. The structures were elucidated on the basis of spectroscopic analyses and chemical methods. Compounds 1-3 feature a rare panaxytriol group containing a polyacetylene on the saponin skeleton. Neuroprotective activity was evaluated for compounds 1-17, and angiotensin II-induced vascular smooth muscle cell proliferation inhibition was tested for compounds 5-7 and 10-12.

Farnesyltransferase haplodeficiency reduces neuropathology and rescues cognitive function in a mouse model of Alzheimer disease.

Isoprenoids and prenylated proteins have been implicated in the pathophysiology of Alzheimer disease (AD), including amyloid-ß precursor protein metabolism, Tau phosphorylation, synaptic plasticity, and neuroinflammation. However, little is known about the relative importance of the two protein prenyltransferases, farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT), in the pathogenesis of AD. In this study, we defined the impact of deleting one copy of FT or GGT on the development of amyloid-ß (Aß)-associated neuropathology and learning/memory impairments in APPPS1 double transgenic mice, a well established model of AD. Heterozygous deletion of FT reduced Aß deposition and neuroinflammation and rescued spatial learning and memory function in APPPS1 mice. Heterozygous deletion of GGT reduced the levels of Aß and neuroinflammation but had no impact on learning and memory. These results document that farnesylation and geranylgeranylation play differential roles in AD pathogenesis and suggest that specific inhibition of protein farnesylation could be a potential strategy for effectively treating AD.

HDL and cognition in neurodegenerative disorders.

High-density lipoproteins (HDLs) are a heterogeneous group of lipoproteins composed of various lipids and proteins. HDL is formed both in the systemic circulation and in the brain. In addition to being a crucial player in the reverse cholesterol transport pathway, HDL possesses a wide range of other functions including anti-oxidation, anti-inflammation, pro-endothelial function, anti-thrombosis, and modulation of immune function. It has been firmly established that high plasma levels of HDL protect against cardiovascular disease. Accumulating evidence indicates that the beneficial role of HDL extends to many other systems including the central nervous system. Cognition is a complex brain function that includes all aspects of perception, thought, and memory. Cognitive function often declines during aging and this decline manifests as cognitive impairment/dementia in age-related and progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. A growing concern is that no effective therapy is currently available to prevent or treat these devastating diseases. Emerging evidence suggests that HDL may play a pivotal role in preserving cognitive function under normal and pathological conditions. This review attempts to summarize recent genetic, clinical and experimental evidence for the impact of HDL on cognition in aging and in neurodegenerative disorders as well as the potential of HDL-enhancing approaches to improve cognitive function.

Simvastatin treatment enhances NMDAR-mediated synaptic transmission by upregulating the surface distribution of the GluN2B subunit.

The ramifications of statins on plasma cholesterol and coronary heart disease have been well documented. However, there is increasing evidence that inhibition of the mevalonate pathway may provide independent neuroprotective and procognitive pleiotropic effects, most likely via inhibition of isoprenoids, mainly farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). FPP and GGPP are the major donors of prenyl groups for protein prenylation. Modulation of isoprenoid availability impacts a slew of cellular processes including synaptic plasticity in the hippocampus. Our previous work has demonstrated that simvastatin (SV) administration improves hippocampus-dependent spatial memory, rescuing memory deficits in a mouse model of Alzheimer's disease. Treatment of hippocampal slices with SV enhances long-term potentiation (LTP), and this effect is dependent on the activation of Akt (protein kinase B). Further studies showed that SV-induced enhancement of hippocampal LTP is driven by depletion of FPP and inhibition of farnesylation. In the present study, we report the functional consequences of exposure to SV at cellular/synaptic and molecular levels. While application of SV has no effect on intrinsic membrane properties of CA1 pyramidal neurons, including hyperpolarization-activated cyclic-nucleotide channel-mediated sag potentials, the afterhyperpolarization (AHP), and excitability, SV application potentiates the N-methyl D-aspartate receptor (NMDAR)-mediated contribution to synaptic transmission. In mouse hippocampal slices and human neuronal cells, SV treatment increases the surface distribution of the GluN2B subunit of the NMDAR without affecting cellular cholesterol content. We conclude that SV-induced enhancement of synaptic plasticity in the hippocampus is likely mediated by augmentation of synaptic NMDAR components that are largely responsible for driving synaptic plasticity in the CA1 region.

Acute toxicology on Danio rerio embryo and adult from Chinese traditional medicine preparation Danggui Shaoyao san.

ETHNOPHARMACOLOGICAL RELEVANCE: Although the Traditional Chinese Medicine (TCM) prescription of Danggui Shaoyao San (DSS) presents substantial clinical efficacy and promising clinical prospects, the safety of DSS and its extracts have been inadequately investigated. The larva-adult duality of the zebrafish model offers a more efficient approach for evaluating the safety of herbal preparations in the fields of toxicology and pharmacology. AIM OF THE STUDY: To investigate the acute toxicity of the extract derived from Danggui Shaoyao San, a traditional Chinese medicine preparation, on both Danio rerio embryos and adult organisms. MATERIALS AND METHODS: The components of DSS were identified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The hatching rate of Danio rerio juveniles with different concentrations of DSS was calculated and the morphological changes of juveniles after administration were observed through a microscope. The behavioral trajectory of the adult fish was recorded by the observation tower of the automated Danio rerio analysis system, and DSS's effects on the behavior was analyzed. The pathological changes of Danio rerio gills, livers, kidneys, intestines and spermaries were examined using HE staining. RESULTS: Compared with the control group, 25, 50 and 100 mg/L of DSS did not elicit any significant impacts on the hatching rate and morphology. Both 200 mg/L and the propylene glycol 2% reduced the hatching rate and caused the morphological teratogenic changes of the juvenile fish. The dosage of DSS below 100 mg/L had no discernible effect on the behavior of the adult fish, whereas the application of propylene glycol 2% was found to stimulate the adult fish, resulting in a notable increase in high-speed movement distance. 100 mg/L DSS group was not observed to cause any noticeable damage to the gills, livers, intestines and spermaries of Danio rerio, only mild nephrotoxicity was detected. The propylene glycol 2% group was found to result in pathological changes such as hyperplasia of epithelial cells on secondary lamellae, liver cell outline loss or atypia, tubal disorganization, goblet cell hypertrophy and irregularly arranged spermatozoa. CONCLUSION: A viable approach for conducting toxicological studies on TCM preparations was developed and tested in this research. The findings showed that Danggui Shaoyao San has minimal acute toxicity to embryos and adult organisms at concentrations up to 100 mg/L. These results indicate that Danggui Shaoyao San is a safe TCM preparation.

Bergenin mitigates neuroinflammatory damage induced by high glucose: insights from Zebrafish, murine microbial cell line, and rat models.

Background: The escalating global burden of diabetes and its associated cognitive impairment underscores the urgency for effective interventions. Bergenin shows promise in regulating glucose metabolism, mitigating inflammation, and improving cognitive function. Zebrafish models offer a unique platform for assessing drug efficacy and exploring pharmacological mechanisms, complemented by subsequent investigations in cell and rat models. Methods: The experimental subjects included zebrafish larvae (CZ98:Tg (mpeg1:EGFP) ihb20Tg/+ ), adult zebrafish (immersed in 2% glucose), BV2 cell line (50 mM glucose + 10 µm Aß1-42), and a streptozotocin (STZ) bilateral intracerebroventricular injection rat model. Bergenin's effects on the toxicity, behavior, and cognitive function of zebrafish larvae and adults were evaluated. The Morris water maze assessed cognitive function in rats. Neuronal histopathological changes were evaluated using HE and Nissl staining. qPCR and Western blot detected the expression of glycolysis enzymes, inflammatory factors, and Bergenin's regulation of PPAR/NF-κB pathway in these three models. Results: 1) In zebrafish larvae, Bergenin interventions significantly reduced glucose levels and increased survival rates while decreasing teratogenicity rates. Microglial cell fluorescence in the brain notably decreased, and altered swimming behavior tended to normalize. 2) In adult zebrafish, Bergenin administration reduced BMI and blood glucose levels, altered swimming behavior to slower speeds and more regular trajectories, enhanced recognition ability, decreased brain glucose and lactate levels, weakened glycolytic enzyme activities, improved pathological changes in the telencephalon and gills, reduced expression of pro-inflammatory cytokines, decreased ins expression and increased expression of irs1, irs2a, and irs2b, suggesting a reduction in insulin resistance. It also altered the expression of pparg and rela. 3) In BV2 cell line, Bergenin significantly reduced the protein expression of glycolytic enzymes (GLUT1, HK2, PKFKB3, and PKM2), lowered IL-1ß, IL-6, and TNF-α mRNA expression, elevated PPAR-γ protein expression, and decreased P-NF-κB-p65 protein expression. 4) In the rat model, Bergenin improves learning and memory abilities in STZ-induced rats, mitigates neuronal damage in the hippocampal region, and reduces the expression of inflammatory factors IL-1ß, IL-6, and TNF-α. Bergenin decreases brain glucose and lactate levels, as well as glycolytic enzyme activity. Furthermore, Bergenin increases PPARγ expression and decreases p-NF-κB p65/NF-κB p65 expression in the hippocampus. Conclusion: Bergenin intervenes through the PPAR-γ/NF-κB pathway, redirecting glucose metabolism, alleviating inflammation, and preventing high glucose-induced neuronal damage.

LncRNA TUG1 mediates microglial inflammatory activation by regulating glucose metabolic reprogramming.

Microglia are natural immune cells in the central nervous system, and the activation of microglia is accompanied by a reprogramming of glucose metabolism. In our study, we investigated the role of long non-coding RNA taurine-upregulated gene 1 (TUG1) in regulating microglial glucose metabolism reprogramming and activation. BV2 cells were treated with Lipopolysaccharides (LPS)/Interferon-γ (IFN-γ) to establish a microglial activation model. The glycolysis inhibitor 2-Deoxy-D-glucose (2-DG) was used as a control. The expression levels of TUG1 mRNA and proinflammatory cytokines such as Interleukin-1ß (IL-1ß), Interleukin -6, and Tumor Necrosis Factor-α mRNA and anti-inflammatory cytokines such as IL-4, Arginase 1(Arg1), CD206, and Ym1 were detected by RT-qPCR. TUG1 was silenced using TUG1 siRNA and knocked out using CRISPR/Cas9. The mRNA and protein expression levels of key enzymes involved in glucose metabolism, such as Hexokinase2, Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), Lactate dehydrogenase, Glucose 6 phosphate dehydrogenase, and Pyruvate dehydrogenase (PDH), were determined by RT-qPCR and Western blotting. The glycolytic rate of microglial cells was measured using Seahorse. Differential metabolites were determined by metabolomics, and pathway enrichment was performed using these differential metabolites. Our findings revealed that the expression of TUG1 was elevated in proinflammatory-activated microglia and positively correlated with the levels of inflammatory factors. The expression of anti-inflammatory cytokines such as IL-4, Arg1, CD206, and Ym1 were decreased when induced with LPS/IFN-γ. However, this decrease was reversed by the treatment with 2-DG. Silencing of GAPDH led to an increase in the expression of TUG1 and inflammatory factors. TUG1 knockout (TUG1KO) inhibited the expression of glycolytic key enzymes and promoted the expression of oxidative phosphorylation key enzymes, shifting the metabolic profile of activated microglia from glycolysis to oxidative phosphorylation. Additionally, TUG1KO reduced the accumulation of metabolites, facilitating the restoration of the tricarboxylic acid cycle and enhancing oxidative phosphorylation in microglia. Furthermore, the downregulation of TUG1 was found to reduce the expression of both proinflammatory and anti-inflammatory cytokines under normal conditions. Interestingly, when induced with LPS/IFN-γ, TUG1 downregulation showed a potentially beneficial effect on microglia in terms of inflammation. Downregulation of TUG1 expression inhibits glycolysis and facilitates the shift of microglial glucose metabolism from glycolysis to oxidative phosphorylation, promoting their transformation towards an anti-inflammatory phenotype and exerting anti-inflammatory effects in BV2.

Exploring the multifaceted therapeutic mechanism of Schisanlactone E (XTS) in APP/PS1 mouse model of Alzheimer's disease through multi-omics analysis.

Background: Schisanlactone E, also known as XueTongSu (XTS), is an active compound extracted from the traditional Tujia medicine Kadsura heteroclita ("XueTong"). Recent studies highlight its anti-inflammatory and antioxidant properties, yet the mechanisms of XTS's therapeutic effects on Alzheimer's disease (AD) are unclear. This study aims to elucidate the therapeutic efficacy and mechanisms of XTS in AD. Methods: Ten C57BL/6 mice were assigned to the control group (NC), and twenty APP/PS1 transgenic mice were randomly divided into the model group (M) (10 mice) and the XTS treatment group (Tre) (10 mice). After an acclimatization period of 7 days, intraperitoneal injections were administered over a 60-day treatment period. The NC and M groups received saline, while the Tre group received XTS at 2 mg/kg. Learning and memory abilities were assessed using the Morris Water Maze (MWM) test. Histopathological changes were evaluated using hematoxylin and eosin (HE) and Nissl staining, and immunofluorescence was used to assess pathological products and glial cell activation. Cytokine levels (IL-1ß, IL-6, TNF-α) in the hippocampus were quantified by qPCR. 16S rDNA sequencing analyzed gut microbiota metabolic alterations, and metabolomic analysis was performed on cortical samples. The KEGG database was used to analyze the regulatory mechanisms of XTS in AD treatment. Results: XTS significantly improved learning and spatial memory in APP/PS1 mice and ameliorated histopathological changes, reducing Aß plaque aggregation and glial cell activation. XTS decreased the expression of inflammatory cytokines IL-1ß, IL-6, and TNF-α. It also enhanced gut microbiota diversity, notably increasing Akkermansia species, and modulated levels of metabolites such as isosakuranetin, 5-KETE, 4-methylcatechol, and sphinganine. Pathway analysis indicated that XTS regulated carbohydrate metabolism, neuroactive ligand-receptor interactions, and alanine, aspartate, and glutamate metabolism, mitigating gut microbiota dysbiosis and metabolic disturbances. Conclusion: XTS ameliorates cognitive deficits, pathological changes, and inflammatory responses in APP/PS1 mice. It significantly modulates the gut microbiota, particularly increasing Akkermansia abundance, and influences levels of key metabolites in both the gut and brain. These findings suggest that XTS exerts anti-AD effects through the microbial-gut-brain axis (MGBA).

Research on the anti-oxidant and anti-aging effects of Polygonatum kingianum saponins in Caenorhabditis elegans.

Oxidative stress and its impact on aging are critical areas of research. Natural anti-oxidants, such as saponins found in Polygonatum sibiricum, hold promise as potential clinical interventions against aging. In this study, we utilized the nematode model organism, Caenorhabditis elegans, to investigate the pharmacological effects of Polygonatum sibiricum saponins (PKS) on antioxidation and anti-aging. The results demonstrated a significant anti-aging biological activity associated with PKS. Through experiments involving lifespan and stress, lipofuscin, q-PCR, and ROS measurement, we found that PKS effectively mitigated aging-related processes. Furthermore, the mechanism underlying these anti-aging effects was linked to the SKN-1 signaling pathway. PKS increased the nuclear localization of the SKN-1 transcription factor, leading to the up-regulation of downstream anti-oxidant genes, such as gst-4 and sod-3, and a substantial reduction in intracellular ROS levels within the nematode. In conclusion, our study sheds light on the anti-oxidant and anti-aging properties of PKS in C. elegans. This research not only contributes to understanding the biological mechanisms involved but also highlights the potential therapeutic applications of these natural compounds in combating aging-related processes.

Taking precautions in advance: a lower level of activities of daily living may be associated with a higher likelihood of memory-related diseases.

Introduction: Memory-related diseases (MDs) pose a significant healthcare challenge globally, and early detection is essential for effective intervention. This study investigates the potential of Activities of Daily Living (ADL) as a clinical diagnostic indicator for MDs. Utilizing data from the 2018 national baseline survey of the China Health and Retirement Longitudinal Study (CHARLS), encompassing 10,062 Chinese individuals aged 45 or older, we assessed ADL using the Barthel Index (BI) and correlated it with the presence of MDs. Statistical analysis, supplemented by machine learning algorithms (Support Vector Machine, Decision Tree, and Logistic Regression), was employed to elucidate the relationship between ADL and MDs. Background: MDs represent a significant public health concern, necessitating early detection and intervention to mitigate their impact on individuals and society. Identifying reliable clinical diagnostic signs for MDs is imperative. ADL have garnered attention as a potential marker. This study aims to rigorously analyze clinical data and validate machine learning algorithms to ascertain if ADL can serve as an indicator of MDs. Methods: Data from the 2018 national baseline survey of the China Health and Retirement Longitudinal Study (CHARLS) were employed, encompassing responses from 10,062 Chinese individuals aged 45 or older. ADL was assessed using the BI, while the presence of MDs was determined through health report questions. Statistical analysis was executed using SPSS 25.0, and machine learning algorithms, including Support Vector Machine (SVM), Decision Tree Learning (DT), and Logistic Regression (LR), were implemented using Python 3.10.2. Results: Population characteristics analysis revealed that the average BI score for individuals with MDs was 70.88, significantly lower than the average score of 87.77 in the control group. Pearson's correlation analysis demonstrated a robust negative association (r = -0.188, p < 0.001) between ADL and MDs. After adjusting for covariates such as gender, age, smoking status, drinking status, hypertension, diabetes, and dyslipidemia, the negative relationship between ADL and MDs remained statistically significant (B = -0.002, ß = -0.142, t = -14.393, 95% CI = -0.002, -0.001, p = 0.000). The application of machine learning models further confirmed the predictive accuracy of ADL for MDs, with area under the curve (AUC) values as follows: SVM-AUC = 0.69, DT-AUC = 0.715, LR-AUC = 0.7. Comparative analysis of machine learning outcomes with and without the BI underscored the BI's role in enhancing predictive abilities, with the DT model demonstrating superior performance. Conclusion: This study establishes a robust negative correlation between ADL and MDs through comprehensive statistical analysis and machine learning algorithms. The results validate ADL as a promising diagnostic indicator for MDs, with enhanced predictive accuracy when coupled with the Barthel Index. Lower levels of ADL are associated with an increased likelihood of developing memory-related diseases, underscoring the clinical relevance of ADL assessment in early disease detection.

LAMP1 as a novel molecular biomarker to predict the prognosis of the children with autism spectrum disorder using bioinformatics approaches.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that usually manifests in childhood and is thought to be caused by a complex interaction of genetic, environmental, and immune factors. The majority of current ASD diagnostic methods rely on subjective behavioral observation and scale assessment, making early detection difficult. In this study, we confirmed that lysosomal-associated membrane protein 1 (LAMP1), a functional marker of immune cell activation and cytotoxic degranulation, was upregulated in ASD blood, brain cortex, and various genetic animal models or cells using bioinformatics approaches. The prognostic value of LAMP1 was investigated by correlating its expression with clinical ASD rating scales, and the receiver operating characteristic (ROC) curve analysis in ASD also revealed that it has a favorable diagnostic ability in distinguishing ASD from control cohort. According to gene set enrichment analysis (GSEA) results, LAMP1 correlated with genes that were enriched in natural kill and T cell immune function. Taking all of the evidence into account, we discovered that abnormal elevations of LAMP1 mRNA and protein in the blood of ASD children, may influence the development of ASD through its involvement in immune cell activity regulation. This report highlights a novel marker for ASD early detection as well as potential therapeutic targets.

A novel Alzheimer's disease prognostic signature: identification and analysis of glutamine metabolism genes in immunogenicity and immunotherapy efficacy.

Alzheimer's disease (AD) is characterized as a distinct onset and progression of cognitive and functional decline associated with age, as well as a specific neuropathology. It has been discovered that glutamine (Gln) metabolism plays a crucial role in cancer. However, a full investigation of its role in Alzheimer's disease is still missing. This study intended to find and confirm potential Gln-related genes associated with AD using bioinformatics analysis. The discovery of GlnMgs was made possible by the intersection of the WGCNA test and 26 Gln-metabolism genes (GlnMgs). GlnMgs' putative biological functions and pathways were identified using GSVA. The LASSO method was then used to identify the hub genes as well as the diagnostic efficiency of the four GlnMgs in identifying AD. The association between hub GlnMgs and clinical characteristics was also studied. Finally, the GSE63060 was utilized to confirm the levels of expression of the four GlnMgs. Four GlnMgs were discovered (ATP5H, NDUFAB1, PFN2, and SPHKAP). For biological function analysis, cell fate specification, atrioventricular canal development, and neuron fate specification were emphasized. The diagnostic ability of the four GlnMgs in differentiating AD exhibited a good value. This study discovered four GlnMgs that are linked to AD. They shed light on potential new biomarkers for AD and tracking its progression.