ObjectiveTo observe the clinical efficacy and safety of Zhinao capsules in the treatment of mild and moderate sleep disorders in Alzheimer's disease patients with the syndrome of spleen-kidney deficiency and combined phlegm and stasis. MethodsA randomized， double-blind， placebo， controlled clinical trial design was adopted， and 60 Alzheimer's disease patients aged 50-85 years with mild and moderate sleep disorders due to spleen-kidney deficiency and combined phlegm and stasis were included. According to the randomized numble table method， the patients were assigned into a treatment group and a control group （30 in each group， with 29 patients in the treatment group and 28 patients in the control group finally completing the trial）. The treatment group was treated with donepezil hydrochloride tablets combined with Zhinao capsules， and the control group was treated with donepezil hydrochloride tablets combined with the simulant of Zhinao capsules for 12 weeks. The Pittsburgh sleep quality index （PSQI）， smart bracelet sleep monitoring， epworth sleeping scale （ESS）， Mini-Mental State Examination （MMSE）， Activities of Daily Living （ADL）， and traditional Chinese medicine symptoms were scored. Furthermore， the brain-derived neurotrophic factor （BDNF） and gamma-aminobutyric acid （GABA） levels were measured. ResultsAfter 12 weeks of treatment， the total response rate of clinical efficacy assessment in the treatment group reached 89.7%， which was significantly higher than that （21.4%） in the control group （Z=-5.14， P<0.01）. After treatment， the TCM symptom scores declined in both groups （P<0.01）， and the scores in the treatment group were lower than those in the control group （P<0.01）. After treatment， the treatment group showed decreased total score and seven component scores of the PSQI scale （P<0.05， P<0.01）， and the scores in the treatment group were lower than those in the control group （P<0.05， P<0.01）. After treatment， the treatment group showed increases in the duration of deep sleep， light sleep， rapid eye movement sleep， and total sleep at night and decreases in the time to fall asleep， the number of awakenings from sleep at night， and the time for sporadic daytime naps （P<0.01）. The control group did not show significant changes in the duration of light sleep， time to fall asleep， and number of awakenings from sleep at night. Moreover， the treatment group outperformed the control group in terms of the indicators above （P<0.05， P<0.01）. After treatment， the treatment group showed decreased scores of ESS， ADL and its subscales physical self-maintenance scale （PSMS）， and Instrumental Activities of daily living scale （IADLs） and increased score of MMSE and levels of BDNF and GABA （P<0.05， P<0.01）. There was no significant difference in PSMS between the two groups， and the treatment group was significantly better than the control group in terms of the rest of the above indicators （P<0.05， P<0.01）. Patients in neither groups complained of uncomfortable symptoms. ConclusionZhinao capsules have significant clinical efficacy in treating patients with mild and moderate sleep disorders in Alzheimer's disease patients with the syndrome of spleen-kidney deficiency and combined phlegm and stasis. Zhinao capsules can significantly reduce PSQI， ESS， and ADL scores， increase the MMSE score and the expression of BDNF and GABA， effectively optimize the structure of sleep， improve the intelligence， and enhance the ability of daily life， without causing uncomfortable symptoms. The mechanism may be related to the increase in the expression of sleep/wake-related neurotransmitters.

ObjectiveTo observe the clinical efficacy and safety of Zhinao capsules in the treatment of mild and moderate sleep disorders in Alzheimer's disease patients with the syndrome of spleen-kidney deficiency and combined phlegm and stasis. MethodsA randomized， double-blind， placebo， controlled clinical trial design was adopted， and 60 Alzheimer's disease patients aged 50-85 years with mild and moderate sleep disorders due to spleen-kidney deficiency and combined phlegm and stasis were included. According to the randomized numble table method， the patients were assigned into a treatment group and a control group （30 in each group， with 29 patients in the treatment group and 28 patients in the control group finally completing the trial）. The treatment group was treated with donepezil hydrochloride tablets combined with Zhinao capsules， and the control group was treated with donepezil hydrochloride tablets combined with the simulant of Zhinao capsules for 12 weeks. The Pittsburgh sleep quality index （PSQI）， smart bracelet sleep monitoring， epworth sleeping scale （ESS）， Mini-Mental State Examination （MMSE）， Activities of Daily Living （ADL）， and traditional Chinese medicine symptoms were scored. Furthermore， the brain-derived neurotrophic factor （BDNF） and gamma-aminobutyric acid （GABA） levels were measured. ResultsAfter 12 weeks of treatment， the total response rate of clinical efficacy assessment in the treatment group reached 89.7%， which was significantly higher than that （21.4%） in the control group （Z=-5.14， P<0.01）. After treatment， the TCM symptom scores declined in both groups （P<0.01）， and the scores in the treatment group were lower than those in the control group （P<0.01）. After treatment， the treatment group showed decreased total score and seven component scores of the PSQI scale （P<0.05， P<0.01）， and the scores in the treatment group were lower than those in the control group （P<0.05， P<0.01）. After treatment， the treatment group showed increases in the duration of deep sleep， light sleep， rapid eye movement sleep， and total sleep at night and decreases in the time to fall asleep， the number of awakenings from sleep at night， and the time for sporadic daytime naps （P<0.01）. The control group did not show significant changes in the duration of light sleep， time to fall asleep， and number of awakenings from sleep at night. Moreover， the treatment group outperformed the control group in terms of the indicators above （P<0.05， P<0.01）. After treatment， the treatment group showed decreased scores of ESS， ADL and its subscales physical self-maintenance scale （PSMS）， and Instrumental Activities of daily living scale （IADLs） and increased score of MMSE and levels of BDNF and GABA （P<0.05， P<0.01）. There was no significant difference in PSMS between the two groups， and the treatment group was significantly better than the control group in terms of the rest of the above indicators （P<0.05， P<0.01）. Patients in neither groups complained of uncomfortable symptoms. ConclusionZhinao capsules have significant clinical efficacy in treating patients with mild and moderate sleep disorders in Alzheimer's disease patients with the syndrome of spleen-kidney deficiency and combined phlegm and stasis. Zhinao capsules can significantly reduce PSQI， ESS， and ADL scores， increase the MMSE score and the expression of BDNF and GABA， effectively optimize the structure of sleep， improve the intelligence， and enhance the ability of daily life， without causing uncomfortable symptoms. The mechanism may be related to the increase in the expression of sleep/wake-related neurotransmitters.

Mild cognitive impairment due to Alzheimer′s disease is an inevitable pathological stage in the early development of Alzheimer′s disease, which can be classified as "microlumps in the brain collaterals" in traditional Chinese medicine. Based on the theory of latent toxin blocking collaterals, this article discusses the etiology and pathogenesis, clinical sequelae, and traditional Chinese medicine intervention strategies for mild cognitive impairment due to Alzheimer′s disease. The onset of mild cognitive impairment due to Alzheimer′s disease is very similar to the latent pathogen theory, which states that "the latent pathogen is latent and then develops, the poison is deep and difficult to cure, and the development can be recognized but the latent pathogen cannot be detected." Combining clinical experience, our team believes that the basic nature of the disease is a slight deficiency and a slight excess of symptoms. A slight deficiency of the five zang viscera and six fu viscera as root and a latent toxin colling collaterals of qi, fire, phlegm, and blood stasis as manifestaion. These usually start from the qi depression and develop into phlegm coagulation and blood stasis, then end up in latent toxin and gradually become the healthy qi deficiency. Therefore, the deficiency of vital qi and incubation of evil, latent toxin blocking collaterals the pathogenesis of early intervention of this disease should be carried out, upholding the idea that "the upper workman treats the disease before it is diagnosed." The principle of strengthening vital qi to eliminate pathogenic factors, slowing down and promoting pathogenic factors elimination, establishing the method of supporting correctness and wisdom, simultaneously detoxifying and clearing the blood stasis, pattern differentiation as the main and the disease differentiation as the first, combining the disease and pattern, and adjusting the macroscopic and microscopic, focusing simultaneously on eliminating and replenishing, dispel phlegm and remove blood stasis, achieve a strong vital qi and the elimination of evil, and enhance intelligence, delay or even block the progression of mild cognitive impairment due to Alzheimer′s disease, improve patients′ quality of life, and provide a theoretical basis for the early clinical prevention and treatment of Alzheimer′s disease.

Moringa oleifera, widely utilized in Ayurvedic medicine, is recognized for its leaves, seeds, and velamen possessing traditional effects such as vātahara(wind alleviation), sirovirecaka(brain clearing), and hridya(mental nourishment). This study aims to identify the medicinal part of ■ in the Sārasvata ghee formulation as described in the Bower Manuscript, while investigating the ameliorative effects of different medicinal parts of M. oleifera on learning and memory deficits in mice and elucidating the underlying molecular mechanisms. A total of 144 male ICR mice were randomly assigned to the following groups: control, model(scopolamine hydrobromide, Sco, 2 mg·kg~(-1)), donepezil(donepezil hydrochloride, Don, 3 mg·kg~(-1)), M. oleifera leaf low-, medium-, and high-dose groups(0.5, 1, 2 g·kg~(-1)), M. oleifera seeds low-, medium-, and high-dose groups(0.25, 0.5, 1 g·kg~(-1)), and M. oleifera velamen low-, medium-, and high-dose groups(0.31, 0.62, 1.24 g·kg~(-1)). Learning and memory abilities were assessed using the passive avoidance test and Morris water maze. Nissl and HE staining were employed to examine histopathological changes in the hippocampus. Transcriptomics and targeted metabolomics were used to screen differential genes and metabolites, with MetaboAnalyst 6.0 and O2PLS methods applied to identify key disease-related targets and pathways. RESULTS:: demonstrated that M. oleifera leaf(1 g·kg~(-1)) significantly ameliorated Sco-induced learning and memory deficits, outperforming M. oleifera seeds(0.25 g·kg~(-1)) and M. oleifera velamen(1.24 g·kg~(-1)). This was evidenced by improved behavioral performance, reversal of neuronal damage, and reduced acetylcholinesterase(AChE) activity. Multi-omics analysis revealed that M. oleifera leaf upregulated Tuba1c gene expression through the synaptic vesicle cycle, enhancing glutamate(Glu), dopamine(DA), and acetylcholine(ACh) release via Tuba1c-Glu associations for neuroprotection. M. oleifera seeds targeted the dopaminergic synapse pathway, promoting memory consolidation through Drd2-ACh associations. M. oleifera velamen was associated with the cocaine addiction pathway, modulating dopamine metabolism via Adora2a-DOPAC, with limited relevance to learning and memory. In conclusion, M. oleifera leaf exhibits superior efficacy and mechanistic advantages over M. oleifera seeds and velamen, suggesting that the ■ in the Sārasvata ghee formulation is likely M. oleifera leaf, providing scientific evidence for its identification in ancient texts.
Animals ; Moringa oleifera/chemistry* ; Male ; Mice ; Seeds/chemistry* ; Plant Leaves/chemistry* ; Mice, Inbred ICR ; Memory Disorders/psychology* ; Transcriptome/drug effects* ; Memory/drug effects* ; Learning/drug effects* ; Metabolomics ; Humans ; Drugs, Chinese Herbal/administration & dosage* ; Maze Learning/drug effects*

OBJECTIVES: To investigate the therapeutic effects and mechanisms of 2,6-dimethoxy-1,4-benzoquinone (2,6-DMBQ) in a mouse model of asthma. METHODS: SPF-grade BALB/c mice were randomly divided into 7 groups (n=8 each group): normal control group, ovalbumin (OVA) group, dimethyl sulfoxide+corn oil group, budesonide (BUD) group, and low, medium, and high dose 2,6-DMBQ groups. An asthma mouse model was established by OVA induction, followed by corresponding drug interventions. Non-invasive lung function tests were performed to measure airway hyperresponsiveness, and enzyme-linked immunosorbent assay was used to determine levels of interleukin (IL)-17, IL-10, and serum immunoglobulin E in bronchoalveolar lavage fluid. A cell counter was employed to detect eosinophil counts in bronchoalveolar lavage fluid, while hematoxylin-eosin staining and periodic acid-Schiff staining were used to assess lung tissue pathological changes. Western blot was conducted to examine the expression of proteins related to the mammalian target of rapamycin pathway (p-AKT/AKT and p-p70S6K/p70S6K), and a fully automated biochemical analyzer was used to evaluate liver and kidney functions. RESULTS: Compared with the normal control group, the OVA group showed increased enhanced pause values, inflammation scores from hematoxylin-eosin staining, positive area from periodic acid-Schiff staining, percentage of eosinophils, IL-17/IL-10 ratio, serum immunoglobulin E levels, and relative expression levels of p-AKT/AKT and p-p70S6K/p70S6K (P<0.05). The BUD group and the medium and high dose 2,6-DMBQ groups exhibited decreased values for these indicators compared to the OVA group (P<0.05). CONCLUSIONS 2,6-DMBQ can inhibit the mTOR pathway to alleviate airway inflammation in asthmatic mice, possibly by mitigating the imbalance between Th17 and regulatory T cells.
Animals ; Asthma/pathology* ; Mice, Inbred BALB C ; Signal Transduction/drug effects* ; Mice ; TOR Serine-Threonine Kinases/physiology* ; Female ; Benzoquinones/pharmacology* ; Immunoglobulin E/blood* ; Interleukin-10/analysis* ; Interleukin-17/analysis* ; Bronchoalveolar Lavage Fluid ; Lung/pathology*

Objective To investigate the effects of cinnamic aldehyde(CA)on Bcl-2-associated X protein(Bax)and Bcl-2 homologous antagonist/killer(Bak)in vascular endothelial cells of diabetic ulcer wound tissues,as well as on cell apoptosis.Methods ① Forty-eight healthy SPF-grade male SD rats(5 weeks old,weighing 180～220 g)were randomly assigned to a control group(12 rats)and a diabetes group(36 rats).The diabetic model was established with an intraperitoneal injection of 50 mg/kg STZ-citrate sodium solution and high-fat diet feeding.The diabetes group was further randomly divided into Model group,CA group,and the rb-bFGF group,with 12 animals in each group.Wounds in the Con and Model groups were disinfected and topically treated with normal saline,CA group received topical application of 4 μmol/L CA in PEG 400 gel,and those of the rb-bFGF group were treated with bevacizumab gel.The wound healing rate of each group was calculated at 3,7 and 14 d after intervention.At 14 d after intervention,pathological changes in the wounds were observed with HE staining,and the expression levels of Bax and Bak were detected by Western blotting.② Human umbilical vein endothelial cell line EA.hy926 was treated with 175 mmol/L glucose for 48 h to establish a cell model of high glucose injury.The experimental cells were divided into control group,model group and CA treatment group.Cell scratch test and tube formation test were performed respectively to determine the migration ability and angiogenesis of the cells.The expression levels of Bax and Bak was detected with immunofluorescence assay,and cell apoptosis was detected by TUNEL staining.Results ①The diabetic rats in the Model group exhibited significantly higher blood glucose level(P<0.05),declined wound healing rate at 7 and 14 d after intervention(P<0.05),and enhanced expression levels of Bax and Bak(P<0.05)when compared with the control group.Pathological observation revealed that,at 14 d after intervention,accompanied with inflammatory reactions,dense infiltration of inflammatory cells,fewer new blood vessels,and continuous fluid exudation in the wound were observed in the Model group,but the control group presented complete epithelialization in full-thickness skin.Compared with the conditions in the Model group,both CA and rb-bFGF treatment improved the epithelialization process,with mature granulation tissues,showing good healing condition,promoted wound healing rate(P<0.05),and decreased the expression levels of Bax and Bak(P<0.05).② The results of cell experiments showed that the cells of the model group showed significantly reduced migration ability and tube formation ability(P<0.05),reduced protein levels of Bax and Bak(P<0.05),and lower apoptotic rate(P<0.05)when compared with the cells in the model group.Conclusion CA can inhibit the expression of apoptosis-related proteins Bax and Bak,promote the migration and tube formation of vascular endothelial cells,and inhibit the cell apoptosis under high glucose condition,which may be an important reason for its promoting wound healing in diabetic ulcer rats.

Objective:To summarize the medication law and academic experience of Professor Yuan Jinsheng in the treatment of angina pectoris (AP) of coronary heart disease (CHD) through R language data mining technique.Methods:The effective outpatient medical records of Professor Yuan Jinsheng in the treatment of AP of CHD from January 1, 2016 to September 30, 2023 were selected, and the R 4.2.3 was used for frequency statistics, association rule analysis, systematic clustering analysis and correlation analysis of prescription drugs.Results:A total of 292 prescriptions were included, including 268 patients, involving 204 kinds of Chinese materia medica, and the total frequency of Chinese materia medica was 4 253 times. The main properties were warm and neutral, the main tastes were bitter, pungent and sweet, and the main meridians were spleen, lung and liver meridians. The analysis of association rules obtained 125 core TCM combinations, and the commonly used drug pair was Trichosanthis Fructus-Aurantii Fructus Immaturus. The core prescription composed of Aurantii Fructus Immaturus, Chuanxiong Rhizoma, Trichosanthis Fructus, Citri Reticulatae Pericarpium and Salviea Miltiorrhizae Radix et Rhizoma. Seven TCM groups of were obtained by systematic clustering analysis. Correlation analysis showed that the drug pairs with phi coefficient greater than 0.6 were in 8 groups.Conclusions:Studies suggest that AP of CHD is located in the heart, which is related to lung, spleen, liver and kidney, deficiency in root and excess in superficiality, phlegm, blood stasis and qi stagnation are important pathological factors. The treatment is based on the basic principles of tonifying qi, promoting yang, relieving rheumatism, resolving phlegm, activating blood circulation, and promoting qi circulation. It embodies Professor Yuan's academic thoughts and principles of differentiation and treatments of "taking fluency as the main point, regulating the five internal organs and weighing the root and superficiality".

[This corrects the article DOI: 10.1016/j.apsb.2022.05.019.].

The ventral anterior (VA) nucleus of the thalamus is a major target of the basal ganglia and is closely associated with the pathogenesis of Parkinson's disease (PD). Notably, the VA receives direct innervation from the hypothalamic histaminergic system. However, its role in PD remains unknown. Here, we assessed the contribution of histamine to VA neuronal activity and PD motor deficits. Functional magnetic resonance imaging showed reduced VA activity in PD patients. Optogenetic activation of VA neurons or histaminergic afferents significantly alleviated motor deficits in 6-OHDA-induced PD rats. Furthermore, histamine excited VA neurons via H1 and H2 receptors and their coupled hyperpolarization-activated cyclic nucleotide-gated channels, inward-rectifier K⁺ channels, or Ca²⁺-activated K⁺ channels. These results demonstrate that histaminergic afferents actively compensate for Parkinsonian motor deficits by biasing VA activity. These findings suggest that targeting VA histamine receptors and downstream ion channels may be a potential therapeutic strategy for PD motor dysfunction.
Animals ; Histamine/metabolism* ; Male ; Oxidopamine/toxicity* ; Rats ; Ventral Thalamic Nuclei/physiopathology* ; Rats, Sprague-Dawley ; Disease Models, Animal ; Parkinson Disease/metabolism* ; Neurons/physiology* ; Humans ; Optogenetics