Gut microbiota and its metabolites in Alzheimer's disease: from pathogenesis to treatment.

Introduction: An increasing number of studies have demonstrated that altered microbial diversity and function (such as metabolites), or ecological disorders, regulate bowel-brain axis involvement in the pathophysiologic processes in Alzheimer's disease (AD). The dysregulation of microbes and their metabolites can be a double-edged sword in AD, presenting the possibility of microbiome-based treatment options. This review describes the link between ecological imbalances and AD, the interactions between AD treatment modalities and the microbiota, and the potential of interventions such as prebiotics, probiotics, synbiotics, fecal microbiota transplantation, and dietary interventions as complementary therapeutic strategies targeting AD pathogenesis and progression. Survey methodology: Articles from PubMed and china.com on intestinal flora and AD were summarized to analyze the data and conclusions carefully to ensure the comprehensiveness, completeness, and accuracy of this review. Conclusions: Regulating the gut flora ecological balance upregulates neurotrophic factor expression, regulates the microbiota-gut-brain (MGB) axis, and suppresses the inflammatory responses. Based on emerging research, this review explored novel directions for future AD research and clinical interventions, injecting new vitality into microbiota research development.

Cognitive decline as the main manifestation of diabetic striatal disease but without involuntary movements: a case report.

Diabetic striatopathy (DS) is a rare central nervous system complication of diabetes mellitus, characterized mainly by non-ketotic hyperglycemia and lateralized involuntary movements. Patients with diabetic striatopathy manifested solely by subacute cognitive decline were rarely reported. In this paper, we report a patient with DS who presented solely with subacute cognitive decline without involuntary movements, and cranial CT showed bilateral high density in the basal ganglia. In contrast, SWI showed microhemorrhages in the right caudate nucleus head. After one week of treatment, including glycemic control, the patient showed significant improvement in cognitive function, while a repeat cranial CT showed improved hyperdensity in the right basal ganglia region. 1 month later, at telephone follow-up, the patient's symptoms did not recur.

Production of a promising modular proteinaceous self-assembled delivery system for vaccination.

Recently, there have been enormous advances in nano-delivery materials, especially safer and more biocompatible protein-based nanoparticles. Generally, proteinaceous nanoparticles (such as ferritin and virus-like particles) are self-assembled from some natural protein monomers. However, to ensure their capability of assembly, it is difficult to upgrade the protein structure through major modifications. Here, we have developed an efficient orthogonal modular proteinaceous self-assembly delivery system that could load antigens with an attractive coupling strategy. In brief, we constructed a nanocarrier by fusing two orthogonal domains-a pentameric cholera toxin B subunit and a trimer forming peptide-and an engineered streptavidin monomer for binding biotinylated antigens. After successfully preparing the nanoparticles, the receptor-binding domain of SARS-CoV-2 spike protein and influenza virus haemagglutination antigen are used as model antigens for further evaluation. We found that the biotinylated antigen is able to bind to the nanoparticles with high affinity and achieve efficient lymph node drainage when loaded on the nanoparticles. Then, T cells are greatly activated and the formation of germinal centers is observed. Experiments of two mouse models demonstrate the strong antibody responses and prophylactic effects of these nanovaccines. Thus, we establish a proof-of-concept for the delivery system with the potential to load diverse antigen cargos to generate high-performance nanovaccines, thereby offering an attractive platform technology for nanovaccine preparation.

Self-Assembled Proteinaceous Nanoparticles for Co-Delivery of Antigens and Cytosine Phosphoguanine (CpG) Adjuvants: Implications for Nanovaccines.

Nanotechnology has developed rapidly, giving rise to "nanovaccinology". In particular, protein-based nanocarriers have gained widespread attention because of their excellent biocompatibility. As the development of flexible and rapid vaccines is challenging, modular extensible nanoparticles are urgently needed. In this study, a multifunctional nanocarrier capable of delivering various biomolecules (including polysaccharides, proteins, and nucleic acids) was designed by fusing the cholera toxin B subunit with streptavidin. Then, the nanocarrier was used to prepare a bioconjugate nanovaccine against S. flexneri by co-delivery of antigens and CpG adjuvants. Subsequent experimental results indicated that the nanovaccine with multiple components could stimulate both adaptive and innate immunity. Moreover, combining nanocarriers and CpG adjuvants with glycan antigens could improve the survival of vaccinated mice during the interval of two vaccination injections. The multifunctional nanocarrier and the design strategy demonstrated in this study could be utilized in the development of many other nanovaccines against infectious diseases.

Preparation of a Klebsiella pneumoniae conjugate nanovaccine using glycol-engineered Escherichia coli.

BACKGROUND: Engineered strains of Escherichia coli have been used to produce bioconjugate vaccines using Protein Glycan Coupling Technology (PGCT). Nanovaccines have also entered the vaccine development arena with advances in nanotechnology and have been significantly developed, but chassis cells for conjugate nanovaccines have not been reported. RESULTS: To facilitate nanovaccine preparation, a generic recombinant protein (SpyCather4573) was used as the acceptor protein for O-linked glycosyltransferase PglL, and a glycol-engineered Escherichia coli strain with these two key components (SC4573 and PglL) integrated in its genome was developed in this study. The targeted glycoproteins with antigenic polysaccharides produced by our bacterial chassis can be spontaneously bound to proteinous nanocarriers with surface exposed SpyTag in vitro to form conjugate nanovaccines. To improve the yields of the targeted glycoprotein, a series of gene cluster deletion experiments was carried out, and the results showed that the deletion of the yfdGHI gene cluster increased the expression of glycoproteins. Using the updated system, to the best of our knowledge, we report for the first time the successful preparation of an effective Klebsiella pneumoniae O1 conjugate nanovaccine (KPO1-VLP), with antibody titers between 4 and 5 (Log10) after triple immunization and up to 100% protection against virulent strain challenge. CONCLUSIONS: Our results define a convenient and reliable framework for bacterial glycoprotein vaccine preparation that is flexible and versatile, and the genomic stability of the engineered chassis cells promises a wide range of applications for biosynthetic glycobiology research.

A bioconjugate vaccine against Brucella abortus produced by engineered Escherichia coli.

Brucellosis, mainly caused by Brucella, is a widespread zoonotic disease worldwide, with no available effective vaccine for human use. Recently, bioconjugate vaccines against Brucella have been prepared in Yersinia enterocolitica O:9 (YeO9), whose O-antigen structure is similar to that of Brucella abortus. However, the pathogenicity of YeO9 still hinders the large-scale production of these bioconjugate vaccines. Here, an attractive system for the preparation of bioconjugate vaccines against Brucella was established in engineered E. coli. Briefly, the OPS gene cluster of YeO9 was modularized into five individual fragments and reassembled using synthetic biological methods through standardized interfaces, then introduced into E. coli. After confirming the synthesis of targeted antigenic polysaccharides, the exogenous protein glycosylation system (PglL system) was used to prepare the bioconjugate vaccines. A series of experiments were conducted to demonstrate that the bioconjugate vaccine could effectively evoke humoral immune responses and induce the production of specific antibodies against B. abortus A19 lipopolysaccharide. Furthermore, the bioconjugate vaccines provide protective roles in both lethal and non-lethal challenge of B. abortus A19 strain. Using the engineered E. coli as a safer chassis to prepare bioconjugate vaccines against B. abortus paves the way for future industrial applications.

Enhancement of Immune Response of Bioconjugate Nanovaccine by Loading of CpG through Click Chemistry.

CpG is a widely used adjuvant that enhances the cellular immune response by entering antigen-presenting cells and binding with receptors. The traditional physical mixing of the antigen and CpG adjuvant results in a low adjuvant utilization rate. Considering the efficient delivery capacity of nanovaccines, we developed an attractive strategy to covalently load CpG onto the nanovaccine, which realized the co-delivery of both CpG and the antigen. Briefly, the azide-modified CpG was conjugated to a bioconjugate nanovaccine (NP-OPS) against Shigella flexneri through a simple two-step reaction. After characterization of the novel vaccine (NP-OPS-CpG), a series of in vitro and in vivo experiments were performed, including in vivo imaging, lymph node sectioning, and dendritic cell stimulation, and the results showed that more CpG reached the lymph nodes after covalent coupling. Subsequent flow cytometry analysis of lymph nodes from immunized mice showed that the cellular immune response was greatly promoted by the nanovaccine coupled with CpG. Moreover, by analyzing the antibody subtypes of immunized mice, NP-OPS-CpG was found to further promote a Th1-biased immune response. Thus, we developed an attractive method to load CpG on a nanovaccine that is simple, convenient, and is especially suitable for immune enhancement of vaccines against intracellular bacteria.

Traditional Chinese Patent Medicine in the Treatment of Alzheimer's Disease: A Systematic Review and Network Meta-Analysis.

The objective of this study was to evaluate the efficacy and safety of Chinese patent medicine compared with western medicine in the treatment of Alzheimer's disease using the Network Meta-analysis. This study retrieved relevant studies from 7 databases, and the retrieval time was from the establishment of each database to June 2022. After the screening, data extraction, and quality assessment, 47 studies were finally analyzed, involving 11 Chinese patent medicines. The results demonstrated that Chinese patent medicine intervention was superior to oral western medicine treatment in improving the patient's condition as assessed by the Mini-mental State Examination (MMSE), Activities of Daily Living (ADL), effective rate, and Alzheimer's Disease Assessment Scale-Cognitive section (ADAS-Cog). Particularly, the effect of Chinese patent medicine combined with western medicine intervention was prominent. Meanwhile, Chinese patent medicine intervention in AD did not significantly increase the risk of adverse reactions. The results of the Network Meta-analysis demonstrated that Chinese patent medicine combined with western medicine had statistically significant differences in the MMSE score, ADL score, effective rate, and ADAS-Cog score, compared with both western medicine alone and Chinese patent medicine alone. In terms of adverse reactions, the difference between Chinese patent medicine intervention and simple oral western medicine was statistically significant. The results of further ranking probability analysis demonstrated that Chinese patent medicine combined with western medicine intervention ranked first in terms of MMSE, ADL, effective rate, and ADAS-Cog. Additionally, oral Chinese patent medicine intervention alone ranked first in reducing adverse reactions. In the funnel plots of the MMSE, ADL, and effective rate, most studies were symmetrically distributed on both sides of the midline, where small sample effects and publication bias might exist to some extent. However, this conclusion still needs to be combined with clinical syndrome differentiation and treatment, and more large-sample, multi-center, high-quality studies are needed for further verification.

Gunao-Yizhi decoction combined with donepezil for vascular dementia: A systematic review and meta-analysis.

BACKGROUND: Gunao-Yizhi decoction has the effects of supplementing intelligence, strengthening marrow, resolving phlegm, and reducing turbidity. It is clinically used for the treatment of vascular dementia (VaD). However, there is still a lack of systematic evaluation of its efficacy and safety. This review conducted a systematic review of the current evidence on the efficacy and safety of Gunao-Yizhi decoction combined with donepezil for VaD. METHODS: China National Knowledge Infrastructure (CNKI), Wanfang database (Wanfang), Chinese Science and Technology Periodical Database (VIP), China Biology Medicine disc (CBM), MEDLINE, EMBASE, and Cochrane Library were searched for randomized controlled trials on Gunao-Yizhi decoction combined with donepezil for VaD. RevMan 5.3 software was used for data analysis. RESULTS: Twelve studies were obtained, including 1036 patients. Compared with donepezil alone, meta-analysis showed that Gunao-Yizhi decoction combined with donepezil could improve clinical efficacy, mini-mental state examination (MMSE) score, Hasegawa dementia scale (HDS), increase the level of superoxide dismutase (SOD) in serum, and reduce the level of malonaldehyde dismutas (MDA) in serum. The GRADE system was adopted to evaluate the outcome index. Clinical efficiency and the MMSE score were evaluated as very-low-quality evidence. HDS score, serum SOD level, and serum MDA level were evaluated as low-quality evidence. CONCLUSION: Gunao-Yizhi decoction combined with donepezil has a significant prevalence in the treatment of vascular dementia, with no increase in adverse events. Gunao-Yizhi decoction can be recommended for routine use in the treatment of VaD.

Construction of Orthogonal Modular Proteinaceous Nanovaccine Delivery Vectors Based on mSA-Biotin Binding.

Proteinaceous nanovaccine delivery systems have significantly promoted the development of various high-efficiency vaccines. However, the widely used method of coupling the expression of scaffolds and antigens may result in their structural interference with each other. Monovalent streptavidin (mSA) is a short monomer sequence, which has a strong affinity for biotin. Here, we discuss an orthogonal, modular, and highly versatile self-assembled proteinaceous nanoparticle chassis that facilitates combinations with various antigen cargos by using mSA and biotin to produce nanovaccines. We first improved the yield of these nanoparticles by appending a short sugar chain on their surfaces in a constructed host strain. After confirming the strong ability to induce both Th1- and Th2-mediated immune responses based on the plasma cytokine spectrum from immunized mice, we further verified the binding ability of biotinylated nanoparticles to mSA-antigens. These results demonstrate that our biotinylated nanoparticle chassis could load both protein and polysaccharide antigens containing mSA at a high affinity. Our approach thus offers an attractive technology for combining nanoparticles and antigen cargos to generate various high-performance nanovaccines. In particular, the designed mSA connector (mSA containing glycosylation modification sequences) could couple with polysaccharide antigens, providing a new attractive strategy to prepare nanoscale conjugate vaccines.

Expression of Bordetella pertussis Antigens Fused to Different Vectors and Their Effectiveness as Vaccines.

Pertussis is an acute respiratory tract infection caused by Bordetella pertussis. Even though its current vaccine coverage is relatively broad, they still have some shortcomings such as short protection time and might be incapable of blocking the spread of the disease. In this study, we developed new pertussis vaccine candidates by separately fusing three pertussis antigens (B. pertussis fimbriae 2 "Fim2", pertussis toxin S1 subunit "PtxS1", and filamentous hemagglutinin "FHA1877-2250") to each of two immune-boosting carrier proteins (B subunits of AB5 toxin family: cholera toxin B subunit "CTB" and shiga toxin B subunit "StxB"). We then immunized mice with these fusion antigens and found that they significantly increased the serum antibody titers and elicited high bactericidal activity against B. pertussis. After CTB-or StxB-fused antigen-immunized mice were challenged with a non-lethal dose of B. pertussis, the bacterial loads in different tissues of these mice were significantly reduced, and their lung damage was nearly invisible. Furthermore, we also demonstrated that these candidate vaccines could provide strong prophylactic effects against a lethal challenge with B. pertussis. Overall, our candidate vaccines conferred better immune protection to mice compared with pertussis antigen alone. This B5 subunit-based vaccine strategy provides a promising option for vaccine design.

Production of a Promising Biosynthetic Self-Assembled Nanoconjugate Vaccine against Klebsiella Pneumoniae Serotype O2 in a General Escherichia Coli Host.

Klebsiella pneumoniae has emerged as a severe opportunistic pathogen with multiple drug resistances. Finding effective vaccines against this pathogen is urgent. Although O-polysaccharides (OPS) of K. pneumoniae are suitable antigens for the preparation of vaccines given their low levels of diversity, the low immunogenicity (especially serotype O2) limit their application. In this study, a general Escherichia coli host system is developed to produce a nanoscale conjugate vaccine against K. pneumoniae using the Nano-B5 self-assembly platform. The experimental data illustrate that this nanoconjugate vaccine can induce an efficient humoral immune response in draining lymph nodes (dLNs) and elicit high titers of the IgG antibody against bacterial lipopolysaccharide (LPS). The ideal prophylactic effects of these nanoconjugate vaccines are further demonstrated in mouse models of both systemic and pulmonary infection. These results demonstrate that OPS with low immunogenicity can be changed into an effective antigen, indicating that other haptens may be applicable to this strategy in the future. To the knowledge, this is the first study to produce biosynthetic nanoconjugate vaccines against K. pneumoniae in E. coli, and this strategy can be applied to the development of other vaccines against pathogenic bacteria.

Effectiveness comparisons of acupuncture treatments for vascular dementia: A protocol for systematic review and network meta-analysis.

BACKGROUND: Vascular dementia (VD) is the second most common form of dementia in the world. Acupuncture therapy has been widely used in clinical treatment. Based on the available evidence, we will rank different acupuncture therapy to determine the most effective acupuncture therapy. METHODS: We will search the following database, including PubMed, Embase, Cochrane, Web of Science, China National Knowledge Infrastructure, Wanfang Database, Chinese Biomedical Literature Database and Chinese Scientific Journals Database database, in order to collect randomized controlled trials on acupuncture in the treatment of VD. We will use Stata 14.2 and WinBUGS 1.4.3 software for Bayesian network meta-analysis and finally evaluated the level of evidence of the results. RESULTS: This study will compare and rank the effectiveness of acupuncture in the treatment of vascular dementia. Outcome indicators included Alzheimer Disease Assessment Scale-Cognitive section and Mini-mental State Examination, Activity of Daily Living, Blessed dementia scale, Hastgawa Dementia Scale, and adverse events. CONCLUSION: Our study will provide support for clinical practice. INPLASY REGISTRATION NUMBER: INPLASY2020110088.

Can Ashi points stimulation have specific effects on shoulder pain? A systematic review of randomized controlled trials.

OBJECTIVE: To provide an evidence-based overview regarding the efficacy of Ashi points stimulation for the treatment of shoulder pain. METHODS: A comprehensive search [PubMed, Chinese Biomedical Literature Database, China National Knowledge Infrastructure (CNKI), Chongqing Weipu Database for Chinese Technical Periodicals (VIP) and Wanfang Database] was conducted to identify randomized or quasi-randomized controlled trials that evaluated the effectiveness of Ashi points stimulation for shoulder pain compared with conventional treatment. The methodological quality of the included studies was assessed using the Cochrane risk of bias tool. RevMan 5.0 was used for data synthesis. RESULTS: Nine trials were included. Seven studies assessed the effectiveness of Ashi points stimulation on response rate compared with conventional acupuncture. Their results suggested significant effect in favour of Ashi points stimulation [odds ratio (OR): 5.89, 95% confidence interval (CI): 2.97 to 11.67, P<0.01, heterogeneity: χ(2) =3.81, P=0.70, I (2) =0% ]. One trial compared Ashi points stimulation with drug therapy. The result showed there was a significantly greater recovery rate in group of Ashi points stimulation (OR: 9.58, 95% CI: 2.69 to 34.12). One trial compared comprehensive treatment on the myofascial trigger points (MTrPs) with no treatment and the result was in favor of MTrPs. CONCLUSIONS: Ashi points stimulation might be superior to conventional acupuncture, drug therapy and no treatment for shoulder pain. However, due to the low methodological quality of included studies, a firm conclusion could not be reached until further studies of high quality are available.