Exploring Neuron-Specific Steroid Synthesis and DHEAS Therapy in Alzheimer's Disease.

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. Recent studies have suggested a potential role for steroid synthesis in AD pathology. This study investigated the co-localization of steroidogenic enzymes in neuronal cells, changes in enzyme expression in an AD mouse model, and steroid expressions in human AD samples. Additionally, we conducted a steroidomic metabolomics analysis and evaluated the effects of dehydroepiandrosterone sulfate (DHEAS) treatment in an AD mouse model. Immunofluorescence analysis revealed significant co-localization of cytochrome P450 family 17 subfamily A member 1 (CYP17A1) and steroidogenic acute regulatory protein (StAR) proteins with α-synuclein in presynaptic neurons, suggesting active steroid synthesis in these cells. Conversely, such co-localization was absent in astrocytes. In the AD mouse model, a marked decrease in the expression of steroidogenic enzymes (Cyp11a1, Cyp17a1, Star) was observed, especially in areas with amyloid beta plaque accumulation. Human AD and MS brain tissues showed similar reductions in StAR and CYP17A1 expressions. Steroidomic analysis indicated a downregulation of key steroids in the serum of AD patients. DHEAS treatment in AD mice resulted in improved cognitive function and reduced Aß accumulation. Our findings indicate a neuron-specific pathway for steroid synthesis, potentially playing a crucial role in AD pathology. The reduction in steroidogenic enzymes and key steroids in AD models and human samples suggests that impaired steroid synthesis is a feature of neurodegenerative diseases. The therapeutic potential of targeting steroid synthesis pathways, as indicated by the positive effects of DHEAS treatment, warrants further investigation.

TRANSPARENT TESTA GLABRA1 Regulates High-Intensity Blue Light-Induced Phototropism by Reducing CRYPTOCHROME1 Levels.

The asymmetrical distribution of auxin supports high intensity blue light (HBL)-mediated phototropism. Flavonoids, secondary metabolites induced by blue light and TRANSPARENT TESTA GLABRA1 (TTG1), alter auxin transport. However, the role of TTG1 in HBL-induced phototropism in Arabidopsis (Arabidopsis thaliana) remains unclear. We found that TTG1 regulates HBL-mediated phototropism. HBL-induced degradation of CRYPTOCHROME 1 (CRY1) was repressed in ttg1-1, and depletion of CRY1 rescued the phototropic defects of the ttg1-1 mutant. Moreover, overexpression of CRY1 in a cry1 mutant background led to phototropic defects in response to HBL. These results indicated that CRY1 is involved in the regulation of TTG1-mediated phototropism in response to HBL. Further investigation showed that TTG1 physically interacts with CRY1 via its N-terminus and that the added TTG1 promotes the dimerization of CRY1. The interaction between TTG1 and CRY1 may promote HBL-mediated degradation of CRY1. TTG1 also physically interacted with blue light inhibitor of cryptochrome 1 (BIC1) and Light-Response Bric-a-Brack/Tramtrack/Broad 2 (LRB2), and these interactions either inhibited or promoted their interaction with CRY1. Exogenous gibberellins (GA) and auxins, two key plant hormones that crosstalk with CRY1, may confer the recovery of phototropic defects in the ttg1-1 mutant and CRY1-overexpressing plants. Our results revealed that TTG1 participates in the regulation of HBL-induced phototropism by modulating CRY1 levels, which are coordinated with GA or IAA signaling.

Bone transport induces the release of factors with multi-tissue regenerative potential for diabetic wound healing in rats and patients.

Tibial cortex transverse distraction is a surgical method for treating severe diabetic foot ulcers (DFUs), but the underlying mechanism is unclear. We show that antioxidant proteins and small extracellular vesicles (sEVs) with multiple-tissue regenerative potential are released during bone transport (BT) in humans and rats. These vesicles accumulate in diabetic wounds and are enriched with microRNAs (miRNAs) (e.g., miR-494-3p) that have high regenerative activities that improve the circulation of ischemic lower limbs while also promoting neovascularization, fibroblast migration, and nerve fiber regeneration. Deletion of miR-494-3p in rats reduces the beneficial effects of BT on diabetic wounds, while hydrogels containing miR-494-3p and reduced glutathione (GSH) effectively repair them. Importantly, the ginsenoside Rg1 can upregulate miR-494-3p, and a randomized controlled trial verifies that the regimen of oral Rg1 and GSH accelerates wound healing in refractory DFU patients. These findings identify potential functional factors for tissue regeneration and suggest a potential therapy for DFUs.

Rapid Screening of New Psychoactive Substances Using pDART-QqQ-MS.

Drug abuse is a severe social problem worldwide. Particularly, the issue of new psychoactive substances (NPSs) have increasingly emerged. NPSs are structural or functional analogs of traditional illicit drugs, such as cocaine, cannabis, and amphetamine; these molecules provide the same or more severe neurological effects. Usually, immunoassays are utilized in the preliminary screening method. However, NPSs have poor detectability in commercially available immunoassay kits. Meanwhile, various chromatography combined with the mass spectrometry platform have been developed to quantify NPSs. Still, a significant amount of time and resources are required during these procedures. Therefore, we established a rapid analytical platform for NPSs employing paper-loaded direct analysis in real time triple quadrupole mass spectrometry (pDART-QqQ-MS). We implemented this platform for the semiquantitative analysis of forensic drug tests in urine. This platform significantly shrinks the analytical time of a single sample within 30 s and requires a low volume of the specimen. The platform can detect 21 NPSs in urine mixtures at a lower limit of qualification of concentration ranging from 20 to 75 nanograms per milliliter (ng mL-1) and is lower than the cutoff value of currently available immune-based devices for detecting multiple drugs (1000 ng mL-1). Urine samples from drug addicts have been collected to verify the platform's effectiveness. By combining efficiency and accuracy, our platform offers a promising solution for addressing the challenges posed by NPSs in drug abuse detection.

The mechanism and experimental verification of Ixeris sonchifolia promoting apoptosis of hepatocellular carcinoma based on network pharmacology: Ixeris sonchifolia Induces Hepatocellular Carcinoma Apoptosis via the PI3K/AKT Pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Ixeris sonchifolia alias Kudiezi, it was named Ixeris sonchifolia (Bunge) Hance, a synonym for Crepidiastrum sonchifolium (Bunge) Pak & Kawano in the https://www.iplant.cn/. And it was first published in J. Linn. Soc., Bot. 13: 108 (1873), which was named Ixeris sonchifolia (Maxim.) Hance in the MPNS (http://mpns.kew.org). As a widely distributed medicinal and edible wild plant, it possesses unique bitter-cold characteristics and constituents with various pharmacological activities. Its main antitumor substances, same as artemisinin and paclitaxel, are classified as terpenoids and have become research foci in recent years. However, its specific biological activity and role in antitumor treatment remain largely unclear. AIM OF THE STUDY: This study aimed to elucidate the molecular targets and potential mechanisms of hepatocellular carcinoma apoptosis induced by Ixeris sonchifolia. MATERIALS AND METHODS: We used network pharmacology methods to analyze and screen the active ingredients and possible underlying mechanisms of Ixeris sonchifolia in treating liver cancer and employed integrative time- and dose-dependent toxicity, transcriptomics, and molecular biology approaches to comprehensively verify the function of Ixeris sonchifolia extract (IsE) in human hepatoblastoma cell (HepG2) apoptosis and its potential mechanism. RESULTS: A total of 169 common targets were screened by network pharmacology, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that IsE inhibited HepG2 cell activity in a time- and dose-dependent manner. Western blot analysis confirmed that IsE promoted HepG2 cell apoptosis by inhibiting the PI3K/AKT signaling pathway and that the PI3K/AKT inhibitor LY294002 also substantially enhanced IsE-induced apoptosis. The PI3K/AKT signaling pathway exhibited significant differences compared to that in the control group. CONCLUSION: Combining network pharmacology with experimental verification, IsE inhibited mitochondrial function and the PI3K/AKT pathway while inducing hepatoma cell apoptosis. IsE may have promising potential for liver cancer treatment and chemoprevention.

Hepatic organoids move from adolescence to maturity.

Since organoids were developed 15 years ago, they are now in their adolescence as a research tool. The ability to generate 'tissue in a dish' has created enormous opportunities for biomedical research. We examine the contributions that hepatic organoids have made to three areas of liver research: as a source of cells and tissue for basic research, for drug discovery and drug safety testing, and for understanding disease pathobiology. We discuss the features that enable hepatic organoids to provide useful models for human liver diseases and identify four types of advances that will enable them to become a mature (i.e., adult) research tool over the next 5 years. During this period, advances in single-cell RNA sequencing and CRISPR technologies coupled with improved hepatic organoid methodology, which enables them to have a wider range of cell types that are present in liver and to be grown in microwells, will generate discoveries that will dramatically advance our understanding of liver development and the pathogenesis of liver diseases. It will generate also new approaches for treating liver fibrosis, which remains a major public health problem with few treatment options.

Impurities in over-the-counter pseudoephedrine leading to methcathinone detection in urine.

Methcathinone, a psychoactive substance with stimulant properties, has raised concerns in recent years due to its presence in urine screenings, even among individuals with no history of drug abuse. To prevent misjudgment, this work aims to explore the source of methcathinone in urine. A total of 58 urine samples tested positive for methcathinone in the National Taiwan University Hospital cohort, with 27 linked to illicit drug use and 31 from individuals with no drug use history. Co-occurrence analysis revealed a strong association between methcathinone and over-the-counter cold medications containing pseudoephedrine or ephedrine. In an in vivo experiment, participants who consumed pseudoephedrine-containing drugs showed the presence of methcathinone in their urine, suggesting a connection between these substances. Additionally, tests on pharmaceutical products containing pseudoephedrine detected small amounts of methcathinone as impurities. The findings suggest that the presence of methcathinone in nonillicit drug users may be attributed to impurities in over-the-counter pseudoephedrine-containing medications. This raises concerns about potential misinterpretations of drug screening results and underscores the need for more comprehensive criteria for assessing drug use. This study contributes to our understanding of the origin of methcathinone in urine, which has implications for legal justice and drug screening practices.

Perioperative toripalimab and chemotherapy in locally advanced gastric or gastro-esophageal junction cancer: a randomized phase 2 trial.

Perioperative chemotherapy is the standard treatment for locally advanced gastric or gastro-esophageal junction cancer, and the addition of programmed cell death 1 (PD-1) inhibitor is under investigation. In this randomized, open-label, phase 2 study (NEOSUMMIT-01), patients with resectable gastric or gastro-esophageal junction cancer clinically staged as cT3-4aN + M0 were randomized (1:1) to receive either three preoperative and five postoperative 3-week cycles of SOX/XELOX (chemotherapy group, n = 54) or PD-1 inhibitor toripalimab plus SOX/XELOX, followed by toripalimab monotherapy for up to 6 months (toripalimab plus chemotherapy group, n = 54). The primary endpoint was pathological complete response or near-complete response rate (tumor regression grade (TRG) 0/1). The results showed that patients in the toripalimab plus chemotherapy group achieved a higher proportion of TRG 0/1 than those in the chemotherapy group (44.4% (24 of 54, 95% confidence interval (CI): 30.9%-58.6%) versus 20.4% (11 of 54, 95% CI: 10.6%-33.5%)), and the risk difference of TRG 0/1 between toripalimab plus chemotherapy group and chemotherapy group was 22.7% (95% CI: 5.8%-39.6%; P = 0.009), meeting a prespecified endpoint. In addition, a higher pathological complete response rate (ypT0N0) was observed in the toripalimab plus chemotherapy group (22.2% (12 of 54, 95% CI: 12.0%-35.6%) versus 7.4% (4 of 54, 95% CI: 2.1%-17.9%); P = 0.030), and surgical morbidity (11.8% in the toripalimab plus chemotherapy group versus 13.5% in the chemotherapy group) and mortality (1.9% versus 0%), and treatment-related grade 3-4 adverse events (35.2% versus 29.6%) were comparable between the treatment groups. In conclusion, the addition of toripalimab to chemotherapy significantly increased the proportion of patients achieving TRG 0/1 compared to chemotherapy alone and showed a manageable safety profile. ClinicalTrials.gov registration: NCT04250948 .

Adherence to the Singapore Integrated 24-Hour Activity Guidelines by Infants and Toddlers and Its Association With Well-Being.

BACKGROUND: This study estimated the prevalence of Singapore infants and toddlers who met the new Singapore Integrated 24-Hour Activity Guidelines for Early Childhood and examined its association with well-being. METHODS: A total of 267 parents of children aged between 0 and 2 years completed an online questionnaire that consists of the Singaporean Children Lifestyle Questionnaire and either the Pediatric Quality of Life (PedsQL) Inventory Infant Scale or the Strength and Difficulties Questionnaire. Well-being of infants was measured through parent responses to PedsQL and that of toddlers was measured through Strength and Difficulties Questionnaire. Data were benchmarked against age-specific guidelines for physical activity, screen time, and sleep in the Singapore Integrated 24-Hour Activity Guidelines for Early Childhood. RESULTS: A higher percentage of infants (37.3%) than toddlers (20.6%) had met 3 guidelines. In contrast, a lower percentage of infants than toddlers met at least one or did not meet any guidelines (3.8% and 0% for infants vs 22.4% and 1.8% for toddlers, respectively). Infants who met more guidelines had significantly higher parent-reported PedsQL total scale score than infants who met fewer guidelines (P < .05). However, the present study found that the number of guidelines met was not associated to infants' PedsQL scale score and toddlers' total difficulty score (P > .05). CONCLUSION: Adherence to this set of local guidelines should be widely publicized, so parents will have greater awareness and knowledge on cultivating good physical activity, screen time, and sleep habits for their child from a young age.

Chondroitin sulfate and chitosan-coated liposomes as a novel delivery system for betanin: Preparation, characterization and in vitro digestion behavior.

Betanin, a water-soluble pigment known for its high bioactivity, is hindered by pH and temperature sensitivity, weak ionic strength, and low bioavailability. In this study, nanoliposome (NPS), chitosan-coated NPS (CNPS), and chondroitin sulfate-chitosan bilayer-modified nanoliposomes (SCNPS) were prepared based on a layer-by-layer electrostatic interaction method for betanin encapsulation. The increase of polymer layers from NPS to SCNPS led to a monotonic increment from 223.57 to 522.33 nm in size, from -27.73 to 16.70 mV in negative charge and from 0.22 to 0.35 in polydispersity index. The chemical stability against pH (ranging from 2 to 10), ionic type (KCl, CaCl2, ALCl3) and ionic strength (100, 500 mM) significantly impacted the appearance and particle size of the double-layered nanoliposome. In vitro digestion experiment showed that SCNPS displayed higher stability and slower betanin release compared to NPS and CNPS. This study demonstrates that betanin can be efficiently encapsulated by SCNPS with improved stability and bioavailability.

Carbonized Polymer Dots/Bi/ß-Bi2O3 for Efficient Photosynthesis of H2O2 via Redox Dual Pathways.

A novel heterojunction photocatalyst of carbonized polymer dots (CPDs)/Bi/ß-Bi2O3 is successfully synthesized via a one-pot solvothermal method by adjusting the reaction temperature and time. As a solvent and carbon source, ethylene glycol not only supports the conversion of Bi3+ to ß-Bi2O3 but also undergoes its polymerization, cross-linking, and carbonization to produce CPDs. In addition, partial Bi3+ is reduced to Bi by ethylene glycol. As a result, the CPDs and Bi are deposited in situ on the surface of ß-Bi2O3 microspheres. There are four built-in electric fields in the CPDs/Bi/ß-Bi2O3 system, namely, the n-type semiconductor ß-Bi2O3/H2O interface, the p-type CPDs/H2O interface, the ohmic contact between Bi and ß-Bi2O3, and the Schottky junction between Bi and CPDs. Under the action of four built-in electric fields, the Z-type charge separation mechanism is formed. It promotes the effective separation of the photogenerated electron-hole and greatly improves the yield of H2O2. Under irradiation for 2 h, the H2O2 production is 1590 µmol g-1 h-1. The solar energy to H2O2 conversion efficiency is 0.11%.

Amylase-assisted extraction alters nutritional and physicochemical properties of polysaccharides and saponins isolated from Ganoderma spp.

This study aimed to evaluate the efficacy of amylase in hydrolyzing complex carbohydrates of different parts of Ganoderma spp. The aqueous extracts of the Ganoderma samples were analyzed for their selected nutritional composition and physicochemical properties. The purified extracts were also structurally characterized. The aqueous canopy extracts of red-purple Ganoderma had a notably higher total sugar and saponin content than their stalks, but not for the black-type Ganoderma. The enzymatic extraction effectively improved the extraction yields, whereas the amounts of sugars and saponins in some extracts were increased after the enzymatic treatment. The results also showed that only those enzyme-treated cultivated black Ganoderma canopy had increased total sugar and total saponin content. The antioxidant activities of all stalk extracts were higher than the canopy extracts. Their emulsifying properties were comparable with lecithin due to their high saponin content. Therefore, these extracts are new natural emulsifiers.

Hepatoviruses promote very-long-chain fatty acid and sphingolipid synthesis for viral RNA replication and quasi-enveloped virus release.

Virus-induced changes in host lipid metabolism are an important but poorly understood aspect of viral pathogenesis. By combining nontargeted lipidomics analyses of infected cells and purified extracellular quasi-enveloped virions with high-throughput RNA sequencing and genetic depletion studies, we show that hepatitis A virus, an hepatotropic picornavirus, broadly manipulates the host cell lipid environment, enhancing synthesis of ceramides and other sphingolipids and transcriptionally activating acyl-coenzyme A synthetases and fatty acid elongases to import and activate long-chain fatty acids for entry into the fatty acid elongation cycle. Phospholipids with very-long-chain acyl tails (>C22) are essential for genome replication, whereas increases in sphingolipids support assembly and release of quasi-enveloped virions wrapped in membranes highly enriched for sphingomyelin and very-long-chain ceramides. Our data provide insight into how a pathogenic virus alters lipid flux in infected hepatocytes and demonstrate a distinction between lipid species required for viral RNA synthesis versus nonlytic quasi-enveloped virus release.

Neuron Navigator 1 (Nav1) regulates the response to cocaine in mice.

Genetic variation accounts for much of the risk for developing a substance use disorder, but the underlying genetic factors and their genetic effector mechanisms are mostly unknown. Inbred mouse strains exhibit substantial and heritable differences in the extent of voluntary cocaine self-administration. Computational genetic analysis of cocaine self-administration data obtained from twenty-one inbred strains identified Nav1, a member of the neuron navigator family that regulates dendrite formation and axonal guidance, as a candidate gene. To test this genetic hypothesis, we generated and characterized Nav1 knockout mice. Consistent with the genetic prediction, Nav1 knockout mice exhibited increased voluntary cocaine intake and had increased motivation for cocaine consumption. Immunohistochemistry, electrophysiology, and transcriptomic studies were performed as a starting point for investigating the mechanism for the Nav1 knockout effect. Nav1 knockout mice had a reduced inhibitory synapse density in their cortex, increased excitatory synaptic transmission in their cortex and hippocampus, and increased excitatory neurons in a deep cortical layer. Collectively, our results indicate that Nav1 regulates the response to cocaine, and we identified Nav1 knockout induced changes in the excitatory and inhibitory synaptic balance in the cortex and hippocampus that could contribute to this effect.

Synergy Effect of the Enhanced Local Electric Field and Built-In Electric Field of CoS/Mo-Doped BiVO4 for Photoelectrochemical Water Oxidation.

Bismuth vanadate is a promising material for photoelectrochemical water oxidation. However, it suffers from a low quantum efficiency, poor stability, and slow water oxidation kinetics. Here, we developed a novel photoanode of CoS/Mo-BiVO4 with excellent photoelectrochemical water oxidation performance. It achieved a photocurrent density of 4.5 mA cm-2 at 1.23 V versus the reversible hydrogen electrode, ∼4 times that of BiVO4. The CoS/Mo-BiVO4 photoanode also exhibited good stability, and the photocurrent density generated by the CoS/Mo-BiVO4 photoanode did not significantly decrease after light irradiation for 2 h. Upon replacement of part of the V with Mo doping in BiVO4, the local electric field around the Mo-O bond was enhanced, thus promoting carrier separation in BiVO4. The CoS was deposited on the surface of Mo-BiVO4, forming a built-in electric field at the interface. Under the action of the bias electric field and the built-in electric field, the carriers of CoS/Mo-BiVO4 were efficiently separated in the direction of the inverse type II heterojunction. In addition, CoS improved the light absorption and charge injection efficiency of the CoS/Mo-BiVO4 photoanode.

Benefit of Nasal Douche in COVID-19 Patients with Recurrence of Positive SARS-CoV-2 Viral RNA.

Purpose: The purpose was to review relevant clinical data and formulate recommendations supporting the use of saline as a simple rinse for an early reassuring intervention to reduce the occurrence of re-positive COVID-19 patients. Methods: We conducted a single-centre retrospective cohort study, which enrolled patients with confirmed re-testing positive COVID-19 during 7-60 days after discharge from Third People's Hospital of Shenzhen. By one-to-two propensity score matching for age and sex, the control group of those not re-testing positive during the same period served as matched control. Results: A total of 223 patients were included in our study, 94 in re-positive group and 129 in non-re-positive group. The result shows that the rates of nasal douche treatment in the non-re-positive group were considerably higher than that of the re-positive group. And the Ct value of nasal douche group increased faster than that of non-nasal douche group after the Ct value reaching ≥35. Further analysis revealed that the higher the Ct value at the time of readmission, the shorter the time of average Ct values to reach ≥35. Conclusion: These findings suggest that nasal douche is beneficial to shorten the time of virus nucleic acid turning negative, thereby reducing the incidence of re-positive. The prevention and control of epidemics focuses on re-positive patients with Ct values <35.

Integrative transcriptome and metabolome analysis reveals the mechanisms of light-induced pigmentation in purple waxy maize.

Introduction: Waxy maize, mainly consumed at the immature stage, is a staple and vegetable food in Asia. The pigmentation in the kernel of purple waxy maize enhances its nutritional and market values. Light, a critical environmental factor, affects anthocyanin biosynthesis and results in pigmentation in different parts of plants, including in the kernel. SWL502 is a light-sensitive waxy maize inbred line with purple kernel color, but the regulatory mechanism of pigmentation in the kernel resulting in purple color is still unknown. Methods: In this study, cyanidin, peonidin, and pelargonidin were identified as the main anthocyanin components in SWL502, evaluated by the ultra-performance liquid chromatography (UPLC) method. Investigation of pigment accumulation in the kernel of SWL502 was performed at 12, 17, and 22 days after pollination (DAP) under both dark and light treatment conditions via transcriptome and metabolome analyses. Results: Dark treatment affected genes and metabolites associated with metabolic pathways of amino acid, carbohydrate, lipid, and galactose, biosynthesis of phenylpropanoid and terpenoid backbone, and ABC transporters. The expression of anthocyanin biosynthesis genes, such as 4CL2, CHS, F3H, and UGT, was reduced under dark treatment. Dynamic changes were identified in genes and metabolites by time-series analysis. The genes and metabolites involved in photosynthesis and purine metabolism were altered in light treatment, and the expression of genes and metabolites associated with carotenoid biosynthesis, sphingolipid metabolism, MAPK signaling pathway, and plant hormone signal transduction pathway were induced by dark treatment. Light treatment increased the expression level of major transcription factors such as LRL1, myc7, bHLH125, PIF1, BH093, PIL5, MYBS1, and BH074 in purple waxy maize kernels, while dark treatment greatly promoted the expression level of transcription factors RVE6, MYB4, MY1R1, and MYB145. Discussion: This study is the first report to investigate the effects of light on waxy maize kernel pigmentation and the underlying mechanism at both transcriptome and metabolome levels, and the results from this study are valuable for future research to better understand the effects of light on the regulation of plant growth.

Neural control of cerebral blood flow: scientific basis of scalp acupuncture in treating brain diseases.

Scalp acupuncture (SA), as a modern acupuncture therapy in the treatment of brain diseases, especially for acute ischemic strokes, has accumulated a wealth of experience and tons of success cases, but the current hypothesized mechanisms of SA therapy still seem to lack significant scientific validity, which may not be conducive to its ultimate integration into mainstream medicine. This review explores a novel perspective about the mechanisms of SA in treating brain diseases based on its effects on cerebral blood flow (CBF). To date, abundant evidence has shown that CBF is significantly increased by stimulating specific SA points, areas or nerves innervating the scalp, which parallels the instant or long-term improvement of symptoms of brain diseases. Over time, the neural pathways that improve CBF by stimulating the trigeminal, the facial, and the cervical nerves have also been gradually revealed. In addition, the presence of the core SA points or areas frequently used for brain diseases can be rationally explained by the characteristics of nerve distribution, including nerve overlap or convergence in certain parts of the scalp. But such characteristics also suggest that the role of these SA points or areas is relatively specific and not due to a direct correspondence between the current hypothesized SA points, areas and the functional zones of the cerebral cortex. The above evidence chain indicates that the efficacy of SA in treating brain diseases, especially ischemic strokes, is mostly achieved by stimulating the scalp nerves, especially the trigeminal nerve to improve CBF. Of course, the mechanisms of SA in treating various brain diseases might be multifaceted. However, the authors believe that understanding the neural regulation of SA on CBF not only captures the main aspects of the mechanisms of SA therapy, but also facilitates the elucidation of other mechanisms, which may be of greater significance to further its clinical applications.