Nanoparticles loaded with natural medicines for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that disrupts cognitive function and severely affects the quality of life. Existing drugs only improve cognitive function and provide temporary relief of symptoms but do not stop or delay disease progression. Recently, natural medicines, especially Chinese herbal medicines, have gained attention in the treatment of AD due to their antioxidant, anti-inflammatory, and neuroprotective effects. However, conventional oral dosage forms lack brain specificity and have side effects that lead to poor patient compliance. Utilizing nanomedicine is a promising approach to improve brain specificity, bioavailability, and patient compliance. This review evaluates recent advances in the treatment of AD with nanoparticles containing various natural medicines. This review highlights that nanoparticles containing natural medicines are a promising strategy for the treatment of AD. It is believed that this technology can be translated into the clinic, thereby providing opportunities for AD patients to participate in social activities.

Probiotic supplements are effective in people with cognitive impairment: a meta-analysis of randomized controlled trials.

CONTEXT: Cognitive function is a significant concern among the elderly and has a major negative effect on their quality of life. Probiotics have a positive effect on improving cognition, but the exact nature of the association between probiotic supplements and cognitive function is poorly understood. OBJECTIVE: The purpose of this systematic review was to evaluate how probiotic supplements improve cognitive function. DATA SOURCES: A systematic search was conducted of the PubMed, Web of Science, the Cochrane Library, Embase, and ClinicalTrials.gov databases for all relevant studies published in English, with no date restrictions. DATA EXTRACTION: The estimated, pooled results were analyzed with a standardized mean difference (SMD) and a corresponding 95% confidence interval (95%CI). Publication bias was analyzed by the Egger's and Begg's tests. Funnel plots were also constructed to assess the probability of publication bias. The robustness of the results was tested using the method of sequential removal and cumulation of each trial. DATA ANALYSIS: Overall, the pooled SMD showed significant differences between the probiotic and placebo groups (SMD = 0.64; 95%CI, 0.15-1.12), with significant heterogeneity (I2 = 92%). Subgroup analyses showed a significant effect of probiotics on cognition in the studies involving populations with Alzheimer's disease and cognitive impairment (SMD = 1.34; 95%CI, 0.51-2.16; P < 0.01). In addition, subgroup analysis showed that single probiotic strains, receiving probiotic supplements over 12 weeks, and doses >1 × 109 CFU/g were more beneficial for improving cognitive impairment. CONCLUSIONS: According to this meta-analysis, probiotic supplementation had a highly significant effect on cognitive function in people with cognitive impairment or Alzheimer's disease. For people without cognitive impairment, probiotic supplementation may be ineffective.

Study on molecular biological mechanism of Chinese herbal medicines for the treatment of gastric precancerous lesions based on data mining and network pharmacology.

OBJECTIVE: To explore the molecular biological mechanisms of Chinese herbal medicines for the treatment of gastric precancerous lesions by data mining and network pharmacology. METHODS: The keywords "gastric precancerous lesions""gastric precancerous disease""gastric mucosal intraepithelial neoplasia""gastric mucosal heterogeneous hyperplasia""gastric precancerous state""chronic gastritis, atrophic""combined Chinese and Western medicine""Chinese medicine therapy""efficacy evaluation" "randomized controlled trial"were searched in China Journal Full-text Database, Wanfang Data, VIP database, PubMed and Embase from 2001 to 2021. The information was extracted from the literature which met the inclusion and exclusion criteria, and the database was constructed to identify the high-frequency herbal medicines. The top six Chinese herbal medicines were analyzed by the network pharmacology methods, including the acquisition of herbs compounds and gastric precancerous lesions targets using Pharmacology Database and Analysis Platform and GeneCards databases, construction of protein-protein interaction network, and screening of core targets, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of core targets through Metascape platform, etc., to elucidate their active components, targets and pathways. RESULTS: A total of 482 compound prescriptions with 603 herbal medicines were included, and the top 6 herbal medicines with higher application frequency were Ume plum (63.35%), Curcuma longa (58.54%), Paeonia lactiflora (54.06%), Salvia miltiorrhiza (49.92%), Rhizoma alba (46.43%), and Astragalus membranaceus (45.44%). The results of the network pharmacological analysis showed that the active ingredients were 4 types from Ume plum, 3 from Curcuma longa, 9 from Paeonia lactiflora, 13 from Salvia miltiorrhiza, 7 from Astragalus alba, and 9 from Astragalus; 77 predicted targets were in Ume plum, 11 in Curcuma longa, 33 in Paeonia lactiflora, 58 in Salvia miltiorrhiza, 65 in Astragalus alba and 89 in Astragalus; and 98 crossover genes were obtained after these targets were compared with the disease genes, among which HSP90AA1, AKT1, TP53, STAT3, MAPK1 and TNF had higher relevance to the treatment of gastric precancerous lesions. The results of the GO enrichment analysis showed that the active ingredients of high frequency Chinese medicine mostly acted through biological processes such as response to inorganic substance, response to hormone, gland development, positive regulation of cell migration, positive regulation of cell motility, etc. The targets include cellular components such as vesicle lumen, secretory granule lumen, cytoplasmic vesicle lumen, transcription regulator complex, and with molecular functions such as kinase binding, protein kinase binding and DNA-binding transcription factor binding. The results of the KEGG pathway enrichment analysis showed that Paeonia lactiflora, Ulmus lucidus, Salvia miltiorrhiza and Astragalus mainly act through the cancer pathway and PI3K-AKT pathway; Curcuma longa and Rhizoma alba mainly act through the cancer pathway and proteoglycans in cancer, and all six herbs were involved in the cancer pathway and five herbs are involved in the PI3K-AKT pathway. CONCLUSION: In this study, we obtained the top 6 high-frequency Chinese herbal medicines in the treatment of gastric precancerous lesions by data mining method, and revealed that their mechanisms are involved in cell proliferation, differentiation, immunity, inflammation and other processes mainly through cancer pathway, PI3K-AKT signaling pathway, proteoglycans in cancer.

Efficacy and Safety of Chinese Medicine Lianhua Qingwen for Treating COVID-19: An Updated meta-Analysis.

The traditional Chinese medicine formula Lianhua Qingwen (LQ) combined with western medicine therapy is beneficial to coronavirus disease-19 (COVID-19), but there is still a lack of strong evidence-based. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of LQ combined with western medicine for patients with COVID-19. Seven databases (Chinese and English) were searched by two independent reviewers. Search for relevant keywords such as "Chinese medicine," "Chinese herbal medicine," and "Lianhua Qingwen" in the titles and abstracts of articles retrieved in the databases. Randomized controlled trials or case-control studies that reported sufficient data of participants before and after the intervention were included. Two researchers independently reviewed the studies and extracted the data. Fixed-or random-effect model was used to calculate the overall pooled risk estimates. Forest plots were generated to show pooled results. Seven studies involving 916 participants were included in the meta-analysis. Overall, compared with the control group, the total efficacy (OR = 2.23, 95% CI 1.56, 3.18), adverse events (OR = 0.42, 95% CI 0.18, 0.97), chest computed tomography manifestations (OR = 1.74, 95% CI 1.12, 2.72), and aggravation rate of conversion to severe cases (OR = 0.47, 95% CI 0.30, 0.75) of the intervention group were better. Moreover, the intervention group has an advantage over the control group in improving clinical symptoms (fever, cough, fatigue, chest tightness, shortness of breath, and expectoration) and shortening the fever duration (p < 0.05). Our findings indicate that LQ combined with western medicine may be more effective in treating COVID-19. However, due to the urgency of SARS-CoV-2 outbreaks leading to low methodological quality and not rigorous designs. This meta-analysis cannot draw clear conclusions. PROSPERO registration number: CRD42020190757.

An Overview of Systematic Reviews of Chinese Herbal Medicine for Alzheimer's Disease.

Background: Multiple systematic reviews (SRs) have been conducted to evaluate the efficacy and safety of Chinese herbal medicine (CHM) in patients with Alzheimer's disease (AD). Here, we aim to perform an overview to assess the methodological quality and quality of evidence of the SRs to provide convincing data on the treatment of AD with CHM. Method: Six electronic databases including Chinese and English were searched, until April 31, 2021. Two researchers independently screen documents and extract data according to the predesigned rules. A Measure Tool to Assessment System Reviews 2 (AMSTAR-2) was used to investigate the methodological quality, and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) was used to determine the quality of evidence for outcomes. Results: Twelve qualified SRs including 163 randomized controlled trials were reviewed. The methodological quality of the included SRs was considered extremely low assessed through AMSTAR-2. Compared with western medicines (WM) alone, CHM as an adjuvant treatment has shown significant effects in improving Mini-mental State Examination, Alzheimer's Disease Assessment Scale-Cognitive, and Clinical Dementia Rating scores. The same is true for CHM alone. Regarding the effect on Activities Daily Living, neither the single CHM nor the combination with WM has an obvious effect. For the total effective rate, both single CHM and the combination with WM shown significant effects. Nine SRs suggested that CHM as adjuvant therapy or single-use had fewer adverse events than WM. Additionally, the quality of evidence for the main outcome was reviewed as low or extremely low according to GRADE profiler data. Conclusion: Current evidence suggests that CHM may be beneficial in improving the cognitive function of AD patients. However, we should be cautious about the evidence due to methodological flaws and low quality. High-quality RCTs are further needed to confirm the efficacy and safety of CHM for AD.

Low vitamin D status is associated with coronavirus disease 2019 outcomes: a systematic review and meta-analysis.

BACKGROUND: Observational studies suggest that the risk and clinical prognosis of coronavirus disease 2019 (COVID-19) are related to low vitamin D status; however, the data are inconsistent. OBJECTIVES: We conducted a systematic review and meta-analysis to assess the association between low vitamin D status and COVID-19. METHODS: A systematic search was conducted with PubMed, Embase, and the Cochrane Library from database inception to September 25, 2020. The standardized mean difference (SMD) or odds ratio (OR) and corresponding 95% confidence interval (CI) was applied to estimate pooled results. Random - or fixed-effect models based on heterogeneity were used for the meta-analysis. Funnel plots and Egger regression tests were used to assess publication bias. RESULTS: A total of ten articles with 361,934 participants were selected for meta-analysis. Overall, the pooled OR in the fixed-effect model showed that vitamin D deficiency or insufficiency was associated with an increased risk of COVID-19 (OR = 1.43, 95% CI 1.00-2.05). In addition, COVID-19-positive individuals had lower vitamin D levels than COVID-19-negative individuals (SMD = -0.37, 95% CI = -0.52 to -0.21). Significant heterogeneity existed in both endpoints. Funnel plots and Egger regression tests revealed significant publication bias. CONCLUSIONS: This systematic review and meta-analysis indicated that low vitamin D status might be associated with an increased risk of COVID-19 infection. Further studies are needed to evaluate the impact of vitamin D supplementation on the clinical severity and prognosis in patients with COVID-19. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no: CRD42020216740.

Identifying the Mechanisms and Molecular Targets of Yizhiqingxin Formula on Alzheimer's Disease: Coupling Network Pharmacology with GEO Database.

BACKGROUND: Yizhiqingxin formula (YZQX) is a promising formula for the treatment of Alzheimer's disease (AD) with significant clinical effects. Here, we coupled a network pharmacology approach with the Gene Expression Omnibus (GEO) database to illustrate comprehensive mechanisms and screen for molecular targets of YZQX for AD treatment. METHODS: First, active ingredients of YZQX were screened for the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database with the absorption, distribution, metabolism, and excretion (ADME) parameters. Subsequently, putative targets of active ingredients were predicted using the DrugBank database. AD-related targets were retrieved by analyzing published microarray data (accession number GSE5281). Protein-protein interaction (PPI) networks of YZQX putative targets and AD-related targets were constructed visually and merged to identify candidate targets for YZQX against AD using Cytoscape 3.7.2 software. We performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to further clarify the biological functions of the candidate targets. The gene-pathway network was established to filter for key target genes. RESULTS: Forty-three active ingredients were identified, and 193 putative target genes were predicted. Seven hundred and ten targets related to AD were screened with |log2 FC| > 1 and P < 0.05. Based on the PPI network, 110 target genes of YZQX against AD were identified. Moreover, 32 related pathways including the PI3K-Akt signaling pathway, MAPK signaling pathway, ubiquitin-mediated proteolysis, apoptosis and the NF-kappa B signaling pathway were significantly enriched. In the gene-pathway network, MAPK1, AKT1, TP53, MDM2, EGFR, RELA, SRC, GRB2, CUL1, and MYC targets are putative core genes for YZQX in AD treatment. CONCLUSION: YZQX against AD may exert its neuroprotective effect via the PI3K-Akt signaling pathway, MAPK signaling pathway, and ubiquitin-mediated proteolysis. YZQX may be a promising drug that can be used in the treatment of AD.

Efficacy and safety of Lianhua Qingwen in the treatment of patients with moderate COVID-19 infection: A protocol for systematic review and meta analysis.

BACKGROUND: As of June 2020, more than 7 million cases of coronavirus disease (COVID-2019) have been reported worldwide. At present, there is no vaccine or antiviral for the novel coronavirus pneumonia. Lianhua Qingwen (LQ), a Chinese medicine formula, has been authorized by the Chinese government for treating COVID-2019. This systematic review and meta-analysis will evaluate the efficacy and safety of LQ on patients with COVID-19. METHODS: Two independent reviewers will search the following databases of the China Biology Medicine disc, China National Knowledge Infrastructure, China Science and Technology Periodical Database, Wanfang database, Embase, PubMed, and Cochrane Library from the date of conception to June 1, 2020. We will use the MeSH/Emtree terms, combining free-text words that were properly adjusted for the different databases in all of the search strategies. We will take primary clinical symptoms, total efficacy, and adverse event into consideration for our primary outcomes. As secondary outcomes, we will estimate the chest computed tomography manifestations, the rate of conversion to severe cases, and secondary clinical symptoms. We will evaluate the quality of including studies through the risk of bias assessment tool provided by the Cochrane Collaboration. Fixed-or random-effect model will be utilized to calculate the overall pooled risk estimates. Forest plots will be generated to prove the pooled results. Sensitivity analysis will be carried out to identify sources of heterogeneity. The Begg rank correlation test and Egger linear regression test will be used to explore publication bias. RESULTS: This systematic review and meta-analysis will compare the primary and secondary outcomes at baseline and endpoint in the treatment and control groups to investigate the efficacy and safety of LQ for treatment COVID-2019. DISCUSSION: Data from this study will provide strong evidence for clinical decision if the findings are positive.PROSPERO registration number: CRD42020190757.

Shenmayizhi Formula Combined with Ginkgo Extract Tablets for the Treatment of Vascular Dementia: A Randomized, Double-Blind, Controlled Trial.

Shenmayizhi formula (SMYZF) has been shown to have an effect on vascular dementia (VaD) in previous studies. The aim of this study was to evaluate whether a combination of SMYZF with Ginkgo extract tablets improves mild-to-moderate VaD. In this 12-week, randomized, double-blind, controlled study, we randomly assigned 196 patients with VaD (aged 50-85 years) to either the SMYZF group (n = 98) or the Ginkgo group (n = 98). All patients received Ginkgo extract tablets as a basic treatment, while the SMYZF group also received SMYZF treatment. We evaluated the participants at baseline and after 12 weeks of the intervention for the following: the Mini-Mental State Examination (MMSE), National Institutes of Health Stroke Scale (NIHSS), activities of daily living (ADL), Chinese Medicine Symptom Scale (CM-SS) scores, serum endothelin-1 (ET-1), nitric oxide (NO), vascular endothelial growth factor (VEGF), von Willebrand factor (vWF), neuron-specific enolase (NSE), brain-derived neurotrophic factor (BDNF), and homocysteine (Hcy) serum levels. Both interventions significantly increased MMSE scores and decreased NIHSS, ADL, and CM-SS scores. The SMYZF group showed greater improvement in MMSE, NIHSS, and CM-SS scores. Both groups showed a significant decrease in serum ET-1 and an increase in serum VEGF. Furthermore, serum NO increased, and vWF decreased significantly in the SMYZF group. Changes in serum ET-1 and NO were greater in the SMYZF group. Both groups showed a significant increase in serum BDNF and a decrease in serum NSE and Hcy. Improvement in serum NSE and BDNF was greater in the SMYZF group. SMYZF combined with Ginkgo extract tablets improved vascular endothelial and cognitive functions, as well as the syndromes diagnosed based on the traditional Chinese medicine in patients with VaD.

Efficacy and Safety of Guilingji Capsules () for Treating Mild-to-Moderate Cognitive Impairment: Study Protocol for A Randomized, Double-Blind, Positive-Controlled, Multicenter and Noninferiority Trial.

BACKGROUND: The incidence of cognitive impairment (CI) is gradually increasing, which has attracted more attention from medical researchers worldwide. Definitive mechanisms of pathogenesis remain elusive, and there are few medications that have been proven effective for CI. The utilization of Chinese herbal medicine has shown positive therapeutic effects for a broad spectrum of diseases, including CI. OBJECTIVE: The purpose of this study is to evaluate the safety and efficacy of Guilingji Capsules (GLJC, ) in treating mild-to-moderate CI with Shen (Kidney) and marrow deficiency syndrome. METHODS: This is a randomized, double-blind, positive-controlled, multicenter clinical trial with a noninferiority design that included 348 participants randomly divided into an experimental arm and an active comparator arm. Individuals in the experimental arm (174 cases) took 0.6 g of GLJC once a day and 19.2 mg of Gingko biloba extract mimetic 3 times a day. Individuals in the active comparator arm (174 cases) took 0.6 g of GLJC mimetic once a day and 19.2 mg of Gingko biloba extract in tablet form 3 times a day. The intervention period included two sessions over 24 weeks. The primary outcome be the effectiveness of GLJC on cognitive improvement after 24 weeks of treatment, which was defined as an increase in the Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) Scale. The secondary outcomes were improvement in independence, daily living ability, and Chinese medicine (CM) syndrome, which were measured with the Alzheimer's disease Rating Scale-Cognitive Project (ADAS-Cog), Clinical Dementia Rating (CDR) Total Score, Activities of Daily Living (ADL) Total Score and the Chinese Medicine Symptom Scale (CM-SS), respectively. Serum acetylcholine, acetylcholinesterase, bax and bcl-2 were monitored to explore the mechanism of GLJC on CI. In addition, safety measures, including vital signs, electrocardiography, laboratory indicators (full blood count, kidney and liver function tests, routine urine test and routine stool test) and adverse events, were also recorded. DISCUSSION: The purpose of this trial is to evaluate the efficacy and safety of GLJC in patients with mild-to-moderate CI with kidney and marrow deficiency syndrome. If successful, the results would provide a viable treatment for patients with mild-to-moderate CI. (Clinical Trials.gov. ID: NCT03647384. Registered on 23 August 2018).

Traditional Chinese Medicine for Alzheimer's Disease and Other Cognitive Impairment: A Review.

Cognitive impairment (CI) refers to the dysfunction of memory, language, visual space, execution, calculation, understanding, and judgment in one or more aspects. With global aging, CI will become prevalent worldwide. At present, there is no effective cure for CI. However, Nobel laureate Tu Youyou's research on artemisinin has inspired Chinese researchers to focus on traditional Chinese herbs (TCHs) for the treatment of CI. Traditional Chinese Medicine (TCM) has led to a theory for an independent CI system. The pathogenesis of such impairment involves deficiency, phlegm, and stagnation and involves a range of organs, including the brain, kidneys, heart, liver, and spleen. Our current understanding of the etiology and pathogenesis of this condition has led to the realization that TCHs can improve cognitive dysfunction. Clinical research has shown that TCHs can improve the neuropsychological scale score of patients, the TCM symptom score, and the patient's quality of life. Research has also suggested that TCHs can retard Aß deposits and tauopathy, regulate the metabolism of cholinergic neurotransmitters, and so on. However, due to their complexity, little is known of the safety and efficacy of TCHs in patients with CI. It is likely that we will be able to identify the precise mechanisms associated with the action of TCHs in such patients due to the integration of multiple technologies. This paper summarizes the pharmacokinetics, curative effect, and mechanisms of action of traditional Chinese herbs in order to provide a scientific basis for the improvement of cognitive dysfunction by TCHs.

Clinical Experience in Treatment of Alzheimer's Disease with Jiannao Yizhi Formula () and Routine Western Medicine.

OBJECTIVE: To investigate the long-term therapeutic effects of the Chinese medicine Jiannao Yizhi Formula (, JYF) in the treatment of Alzheimer's disease (AD). METHODS: Sixty mild-to-moderate AD participants were recruited and randomly allocated to the treatment (30 with JYF) and the control groups (30 with donepezil) for 6 months with the random numbers. The primary outcomes were scores of Alzheimer's Disease Rating Scale-Cognitive (ADAS-Cog) and Chinese Medicine Symptom Scale (CM-SS). The secondary outcomes were scores of Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Activities of Daily Living (ADL). Safety assessments were conducted at baseline and the 6th month of treatment. Serum levels of acetylcholine (Ach), amyloid-ß protein 42 (Aß42), and the microtubule-associated protein tau (Tau) were also determined by enzyme-liked immunosorbent assay. RESULTS: Fifty-one participants were included in the final analyses (JYF n=27; donepezil n=24). Compared with baseline, both JYF and donepezil increased the MoCA and MMSE scores and decreased the ADAS-Cog and CM-SS scores (P<0.05 or P<0.01). Both drugs increased the serum levels of Ach and decreased the serum levels of Aß42 and Tau (all P<0.05). There was no significant difference in these variables between the two groups, which showed that JYF was not inferior to donepezil. No obviously significant changes were observed in the ADL. No severe adverse events were observed in both groups. CONCLUSION: The effect and safety of JYF for the treatment of AD were not inferior to those of donepezil.

Efficacy and safety of Shenmayizhi decoction as an adjuvant treatment for vascular dementia: Study protocol for a randomized controlled trial.

BACKGROUND: Vascular dementia (VaD) is the second most common cause of dementia. The treatment of VaD still remains a challenge so far. Traditional Chinese Herbal medicine is a promising therapy due to their multiple components and targets. Shenmayizhi decoction (SMYZD), a Chinese Herbal prescription, has been reported its effective in alleviating cognitive dysfunction in clinical practice. However, strong clinical research of SMYZD in the treatment of VaD was lack. Therefore, we design this study to evaluate the adjuvant role of SMYZD in the treatment of VaD. METHODS: This is a multicenter, randomized, blind, controlled trial. A total of 196 eligible patients will be assigned to receive Ginkgo biloba extracts (GBEs) plus SMYZD granule or GBEs plus SMYZD mimetic granule in a 1:1 ratio. The duration of the trial will be 12 weeks, and a follow-up will be performed at the 24th week. The primary outcomes are the National Institute of Health stroke scale (NIHSS) and the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog). The secondary outcomes include the Mini-Mental State Examination (MMSE), the traditional Chinese Medicine (TCM) syndrome scale, Activities of Daily Living (ADL), concentrations of hypersensitive C-reactive protein (Hs-CRP), neuron-specific enolase (NSE) and homocysteine (HCY) in serum. Researchers will record any adverse events throughout the trial. DISCUSSION: This study will provide evidences to evaluate the efficacy and safety of SMYZD in combination with GBEs in treatment of VaD, as well as the adjuvant role of SMYZD in combination. TRIAL IS REGISTERED AT CHINESE CLINICAL TRIAL REGISTRY: ChiCTR1800017359.