MADET: a Manually Curated Knowledge Base for Microbiomic Effects on Efficacy and Toxicity of Anticancer Treatments.

A plethora of studies have reported the associations between microbiota and multiple diseases, leading to the development of at least four databases to demonstrate microbiota-disease associations, i.e., gutMDisorder, mBodyMap, Gmrepo, and Amadis. Moreover, gut microbiota mediates drug efficacy and toxicity, whereas a comprehensive database to elucidate the microbiota-drug associations is lacking. Here, we report an open-access knowledge base, MADET (Microbiomics of Anticancer Drug Efficacy and Toxicity), which harbors 483 manually annotated microbiota-drug associations from 26 studies. MADET provides user-friendly functions allowing users to freely browse, search, and download data conveniently from the database. Users can customize their search filters in MADET using different types of keywords, including bacterial name (e.g., Akkermansia muciniphila), anticancer treatment (e.g., anti-PD-1 therapy), and cancer type (e.g., lung cancer) with different types of experimental evidence of microbiota-drug association and causation. We have also enabled user submission to further enrich the data documented in MADET. The MADET database is freely available at https://www.madet.info. We anticipate that MADET will serve as a useful resource for a better understanding of microbiota-drug associations and facilitate the future development of novel biomarkers and live biotherapeutic products for anticancer therapies. IMPORTANCE Human microbiota plays an important role in mediating drug efficacy and toxicity in anticancer treatment. In this work, we developed a comprehensive online database, which documents over 480 microbiota-drug associations manually curated from 26 research articles. Users can conveniently browse, search, and download the data from the database. Search filters can be customized using different types of keywords, including bacterial name (e.g., Akkermansia muciniphila), anticancer treatment (e.g., anti-PD-1 therapy), and cancer type (e.g., lung cancer), with different types of experimental evidence of microbiota-drug association. We anticipate that this database will serve as a convenient platform for facilitating research on microbiota-drug associations, including the development of novel biomarkers for predicting drug outcomes as well as novel live biotherapeutic products for improving the outcomes of anticancer drugs.

Transformer-Based Deep-Learning Algorithm for Discriminating Demyelinating Diseases of the Central Nervous System With Neuroimaging.

Background: Differential diagnosis of demyelinating diseases of the central nervous system is a challenging task that is prone to errors and inconsistent reading, requiring expertise and additional examination approaches. Advancements in deep-learning-based image interpretations allow for prompt and automated analyses of conventional magnetic resonance imaging (MRI), which can be utilized in classifying multi-sequence MRI, and thus may help in subsequent treatment referral. Methods: Imaging and clinical data from 290 patients diagnosed with demyelinating diseases from August 2013 to October 2021 were included for analysis, including 67 patients with multiple sclerosis (MS), 162 patients with aquaporin 4 antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD), and 61 patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Considering the heterogeneous nature of lesion size and distribution in demyelinating diseases, multi-modal MRI of brain and/or spinal cord were utilized to build the deep-learning model. This novel transformer-based deep-learning model architecture was designed to be versatile in handling with multiple image sequences (coronal T2-weighted and sagittal T2-fluid attenuation inversion recovery) and scanning locations (brain and spinal cord) for differentiating among MS, NMOSD, and MOGAD. Model performances were evaluated using the area under the receiver operating curve (AUC) and the confusion matrices measurements. The classification accuracy between the fusion model and the neuroradiological raters was also compared. Results: The fusion model that was trained with combined brain and spinal cord MRI achieved an overall improved performance, with the AUC of 0.933 (95%CI: 0.848, 0.991), 0.942 (95%CI: 0.879, 0.987) and 0.803 (95%CI: 0.629, 0.949) for MS, AQP4+ NMOSD, and MOGAD, respectively. This exceeded the performance using the brain or spinal cord MRI alone for the identification of the AQP4+ NMOSD (AUC of 0.940, brain only and 0.689, spinal cord only) and MOGAD (0.782, brain only and 0.714, spinal cord only). In the multi-category classification, the fusion model had an accuracy of 81.4%, which was significantly higher compared to rater 1 (64.4%, p=0.04<0.05) and comparable to rater 2 (74.6%, p=0.388). Conclusion: The proposed novel transformer-based model showed desirable performance in the differentiation of MS, AQP4+ NMOSD, and MOGAD on brain and spinal cord MRI, which is comparable to that of neuroradiologists. Our model is thus applicable for interpretating conventional MRI in the differential diagnosis of demyelinating diseases with overlapping lesions.

AQP2 Promotes Astrocyte Activation by Modulating the TLR4/NFκB-p65 Pathway Following Intracerebral Hemorrhage.

Microglial and astrocyte activation and related cytokine secretion play key roles in secondary brain injury following intracerebral hemorrhage (ICH). We assessed the role of aquaporin (AQP)2 in immune response after ICH. We prospectively collected data from 33 patients with ICH and analyzed the serum AQP2 levels in these patients and age-matched healthy controls. A correlation analysis was also performed between patient serum AQP2 levels and clinical factors. In the rat ICH model, double-fluorescence staining for glial fibrillary acidic protein (GFAP) and AQP2 was performed to investigate the relationship between astrocytes and AQP2. Relative mRNA expression levels of GFAP and AQP2 were also measured. In the rat astrocyte cell line CTX-TNA2, toll-like receptor (TLR)4/nuclear factor kappa B (NFκB)-p65 pathway activation and GFAP levels were measured. The indirect influence of AQP2 on microglial polarization was assessed following exposure to the medium of astrocytes treated with AQP2-overexpression plasmid or silencing RNA. We found that the serum AQP2 expression was lower in patients with ICH. Sex and blood neutrophil count influenced serum AQP2 concentrations in patients with ICH on admission. Lower serum AQP2 levels were inversely correlated with 90-day Modified Rankin Scale scores after ICH, but were not correlated with National Institute of Health stroke scale (NIHSS) scores on admission. AQP2 overexpression and localization in GFAP-labeled astrocytes were observed in rats. AQP2 overexpression induced astrocyte activation with GFAP upregulation via TLR/NFκB-p65 signaling pathway activation in the rat astrocyte cell line CTX-TNA2. Astrocyte activation promoted interleukin-1ß secretion. The medium of AQP2-overexpression astrocytes promoted the pro-inflammatory M1 phenotype in the immortal rat (HAPI) microglial cell line. Therefore, serum AQP2 is negatively correlated with post-ICH prognosis and may be a marker of inflammation in early-stage ICH. AQP2 overexpression promotes astrocyte activation and pro-inflammatory secretion, affects astrocyte-microglia crosstalk, and indirectly induces microglial polarization, which may augment inflammation after ICH.

Role of Butylphthalide in Immunity and Inflammation: Butylphthalide May Be a Potential Therapy for Anti-Inflammation and Immunoregulation.

Inflammation and immunity play an essential role in disease pathogenesis. 3-N-Butylphthalide (NBP), a group of compounds extracted from seeds of Apium graveolens (Chinese celery), has been demonstrated as an efficient and effective therapy for ischemic stroke. The amount of research on NBP protective effect is increasing at pace, such as microcircular reconstruction, alleviating inflammation, ameliorating brain edema and blood-brain barrier (BBB) damage, mitochondrial function protection, antiplatelet aggregation, antithrombosis, decreasing oxidative damage, and reducing neural cell apoptosis. There has been increasing research emphasizing the association between NBP and immunity and inflammation in the past few years. Hence, it is aimed at reviewing the related literature and summarizing the underlying anti-inflammatory and immunoregulatory function of NBP in various disorders.

GM130 protects against blood-brain barrier disruption and brain injury after intracerebral hemorrhage by regulating autophagy formation.

Blood-brain barrier (BBB) disruption following intracerebral hemorrhage (ICH) significantly contributes to neurological deficits. Tight junction (TJ) protein loss in brain endothelial cells leads to BBB disruption. We previously revealed the importance of the Golgi apparatus (GA) in maintaining TJ integrity in mouse brain endothelial (bEnd.3) cells, but the specific mechanisms remain unknown. Herein, we investigated the potential role of the GA in BBB damage and neurological dysfunction after ICH using bEnd.3 cells and hemin to mimic hemorrhage in vitro. We used a rat hemorrhage stroke model to evaluate the role of the GA in BBB disruption during ICH. GM130 levels decreased with ICH length in vivo and in vitro. TJ protein destruction further increased following GM130 silencing. GM130 overexpression alleviated TJ protein impairment and improved BBB integrity. bEnd.3 cells treated with an autophagy inhibitor showed reduced TJ protein damage following GM130 silencing. The intracerebroventricular injection of an autophagy inhibitor rescued GM130 silencing-induced BBB leakage. Thus, TJ proteins were destroyed by excessive autophagic pathway activation following ICH, whereas GM130 protected against TJ damage by maintaining proper autophagy. We suggest that GM130-regulated selective autophagy modulates BBB integrity and GM130 upregulation suppresses the autophagy-lysosome pathway, which might maintain BBB function. Therefore, GA protection is beneficial for ICH, and GM130 is a potential therapeutic target for its treatment.

Comparative study of AQP4 antibody-related diseases and MOG antibody-related diseases among the population in Hunan, China.

To compare the clinical, imaging, and prognostic characteristics of AQP4 antibody-related diseases and MOG antibody-related diseases. The clinical data of 56 AQP4 antibody-positive patients and 14 MOG antibody-positive patients in the Second Xiangya Hospital of Central South University from June 2016 to June 2019 were collected. 92.9% of the patients with positive AQP4 antibody were females and 64.3% of patients with positive MOG antibody were females (P = 0.004). Patients with positive AQP4 antibody were more likely to have limb movement (P < 0.001) or limb sensory dysfunction (P < 0.001), and were more likely to have limb twitching (P = 0.036). In addition, AQP4 antibody-positive patients were more likely to have positive ANA (P = 0.013) and SSA antibody (P = 0.029), Ro-52 antibody (P = 0.047), immunoglobulin (P = 0.007), thyroid antibody (P = 0.007), abnormal C3 (P = 0.011), abnormal C4 (P = 0.014) than MOG antibody-positive patients. The involvement rate of head in MOG antibody-positive patients was higher than AQP4 antibody-positive patients (P = 0.029). The severity of clinical symptoms in AQP4-positive patients was usually more serious than that in MOG-positive patients (P < 0.001). The residual neurological deficit after treatment in AQP4-positive group was usually more serious than that in MOG-positive group (P < 0.001). AQP4 antibody-positive patients had a higher prevalence in women than MOG antibody-positive patients, and AQP4 antibody-positive patients were more likely to have spinal cord involvement symptoms and connective tissue antibody abnormalities. The EDSS score of them were higher than that of MOG antibody-positive patients after treatment, and the prognosis was worse.

The Golgi Apparatus May Be a Potential Therapeutic Target for Apoptosis-Related Neurological Diseases.

Increasing evidence shows that, in addition to the classical function of protein processing and transport, the Golgi apparatus (GA) is also involved in apoptosis, one of the most common forms of cell death. The structure and the function of the GA is damaged during apoptosis. However, the specific effect of the GA on the apoptosis process is unclear; it may be involved in initiating or promoting apoptosis, or it may inhibit apoptosis. Golgi-related apoptosis is associated with a variety of neurological diseases including glioma, Alzheimer's disease (AD), Parkinson's disease (PD), and ischemic stroke. This review summarizes the changes and the possible mechanisms of Golgi structure and function during apoptosis. In addition, we also explore the possible mechanisms by which the GA regulates apoptosis and summarize the potential relationship between the Golgi and certain neurological diseases from the perspective of apoptosis. Elucidation of the interaction between the GA and apoptosis broadens our understanding of the pathological mechanisms of neurological diseases and provides new research directions for the treatment of these diseases. Therefore, we propose that the GA may be a potential therapeutic target for apoptosis-related neurological diseases.

miR-7-5p Affects Brain Edema After Intracerebral Hemorrhage and Its Possible Mechanism.

Objective: To explore the relationship between miR-7-5p and brain edema after intracerebral hemorrhage and the role of butylphthalide (NBP) in brain edema after intracerebral hemorrhage. Method: Routine blood testing, C-reactive protein results, and computed tomography data were collected 1, 7, and 14 days after intracerebral hemorrhage in six patients. Levels of MMP-9, ZO-1, occludin, IL-6, TNF-α, and miR-7-5p were detected in each patient's serum. Sixty male Sprague-Dawley rats were randomly divided into sham operation, intracerebral hemorrhage, and NBP treatment groups. Dry-wet weight was used to assess brain edema, and Evans blue staining was used to assess the permeability of the blood-brain barrier. Expression levels of IL-6, TNF-α, ZO-1 and occludin, PI3K, AKT, p-AKT, AQP4, and miR-7-5p were analyzed in the rat brains. Result: The blood neutrophil-lymphocyte ratio (NLR) on day 1 was associated with the area of brain edema on day 7. The expression of miR-7-5p decreased after intracerebral hemorrhage, and as a result, the inhibition of the PI3K/AKT pathway was weakened. The decreased inhibition of the PI3K/AKT pathway resulted in an increase in AQP4 expression, which further aggravated brain edema. NBP can upregulate the expression of miR-7-5p, affecting these pathways to reduce brain edema. Conclusion: After intracerebral hemorrhage, miR-7-5p expression in brain tissue is reduced, which may increase the expression of AQP4 by activating the PI3K/AKT pathway. NBP can inhibit this process and reduce brain edema.

Co-occurrence of Anti-N-Methyl-D-Aspartate Receptor Encephalitis and Anti-myelin Oligodendrocyte Glycoprotein Inflammatory Demyelinating Diseases: A Clinical Phenomenon to Be Taken Seriously.

Background: Anti-N-methyl-D-aspartate receptor (NMDAR) immunoglobulin G antibodies which exist on myelin sheaths, composed of oligodendrocytes, especially target GluN1 subunits and are highly characteristic of anti-NMDAR encephalitis which is a newly recognized autoimmune encephalitis (AE) characterized by psychiatric symptoms, behavioral abnormalities, seizures, cognitive impairment and other clinical symptoms. Myelin oligodendrocyte glycoprotein (MOG) is a type of protein which is expressed on the surface of oligodendrocytes and myelin in the central nervous system. Anti-MOG antibodies cause demyelination. In some rare reported cases, these two types of antibodies have been found to co-exist, but the underlying mechanisms remain unknown. Case presentation: Here we report cases of 4 inpatients (median age 31.5 years, age range 27-43 years) from The Second Xiangya Hospital of Central South University between March 2018 and April 2019. Two of the cases were first diagnosed as anti-NMDAR encephalitis and had developed visual impairments in the course of the dosage reduction during corticosteroid therapy. They were found at the time, to have anti-MOG antibody-positive CSF and/or serum. Another patient was diagnosed with anti-MOG inflammatory demyelinating diseases (IDDs) when he tested double positive for both anti-NMDAR and anti-MOG antibodies early in the course of his illness. Over the course of the dosage reduction during corticosteroid therapy, his symptoms deteriorated; however, anti-MOG antibody levels elevated while anti-NDMAR antibody levels remained low. The other patient had initially developed psychiatric symptoms and limb weakness. She was also double positive for anti-NMDAR and anti-MOG antibodies early in the course of her illness. However, over the course of the dosage reduction during corticosteroid therapy, her symptoms worsened and levels of both antibodies elevated. Conclusion: Anti-NMDAR and anti-MOG antibodies may coexist in rare cases. In addition, anti-NMDAR encephalitis and anti-MOG inflammatory demyelinating diseases may occur either simultaneously or in succession. Thus, when a patient is diagnosed with either of these two diseases, but exhibits symptoms of the other disease, the possibility of co-occurrence with both these diseases should be considered and the appropriate antibodies should be accurately detected to enable prompt selection of appropriate treatments by the physicians.

Pregnancy-Related Immune Changes and Demyelinating Diseases of the Central Nervous System.

Demyelinating diseases of the central nervous system comprise a heterogeneous group of autoimmune disorders characterized by myelin loss with relative sparing of axons occurring on a background of inflammation. Some of the most common demyelinating diseases are multiple sclerosis, acute disseminated encephalomyelitis, and neuromyelitis optica spectrum disorders. Besides showing clinical, radiological, and histopathological features that complicate their diagnosis, demyelinating diseases often involve different immunological processes that produce distinct inflammatory patterns. Evidence of demyelination diseases derives mostly from animal studies of experimental autoimmune encephalomyelitis (EAE), a model that relies on direct antibody-antigen interactions induced by encephalitogenic T cells. Pregnancy is characterized by non-self-recognition, immunomodulatory changes and an altered Th1/Th2 balance, generally considered a Th2-type immunological state that protects the mother from infections. During pregnancy, the immune response of patients with autoimmune disease complicated with pregnancy is different. Immune tolerance in pregnancy may affect the course of some diseases, which may reach remission or be exacerbated. In this review, we summarize current knowledge on the immune status during pregnancy and discuss the relationship between pregnancy-related immune changes and demyelinating diseases of the central nervous system.

Application and prospects of butylphthalide for the treatment of neurologic diseases.

OBJECTIVE: The 3-N-butylphthalide (NBP) comprises one of the chemical constituents of celery oil. It has a series of pharmacologic mechanisms including reconstructing microcirculation, protecting mitochondrial function, inhibiting oxidative stress, inhibiting neuronal apoptosis, etc. Based on the complex multi-targets of pharmacologic mechanisms of NBP, the clinical application of NBP is increasing and more clinical researches and animal experiments are also focused on NBP. The aim of this review was to comprehensively and systematically summarize the application of NBP on neurologic diseases and briefly summarize its application to non-neurologic diseases. Moreover, recent progress in experimental models of NBP on animals was summarized. DATA SOURCES: Literature was collected from PubMed and Wangfang database until November 2018, using the search terms including "3-N-butylphthalide," "microcirculation," "mitochondria," "ischemic stroke," "Alzheimer disease," "vascular dementia," "Parkinson disease," "brain edema," "CO poisoning," "traumatic central nervous system injury," "autoimmune disease," "amyotrophic lateral sclerosis," "seizures," "diabetes," "diabetic cataract," and "atherosclerosis." STUDY SELECTION: Literature was mainly derived from English articles or articles that could be obtained with English abstracts and partly derived from Chinese articles. Article type was not limited. References were also identified from the bibliographies of identified articles and the authors' files. RESULTS: NBP has become an important adjunct for ischemic stroke. In vascular dementia, the clinical application of NBP to treat severe cognitive dysfunction syndrome caused by the hypoperfusion of brain tissue during cerebrovascular disease is also increasing. Evidence also suggests that NBP has a therapeutic effect for neurodegenerative diseases. Many animal experiments have found that it can also improve symptoms in other neurologic diseases such as epilepsy, cerebral edema, and decreased cognitive function caused by severe acute carbon monoxide poisoning. Moreover, NBP has therapeutic effects for diabetes, diabetes-induced cataracts, and non-neurologic diseases such as atherosclerosis. Mechanistically, NBP mainly improves microcirculation and protects mitochondria. Its broad pharmacologic effects also include inhibiting oxidative stress, nerve cell apoptosis, inflammatory responses, and anti-platelet and anti-thrombotic effects. CONCLUSIONS: The varied pharmacologic mechanisms of NBP involve many complex molecular mechanisms; however, there many unknown pharmacologic effects await further study.

[Optimizing expression of the capsid protein VP2 from human Bocavirus and establish it's seroepidemiology assying methord].

OBJECTIVE: To obtain sufficient recombinant VP2 protein of human Bocavirus and establish it's seroepidemiology assying metbord. METHORD: Tbe capsid protein VP2 DNA genes of HBoV1 and 2 were optimized in accordance with tbe usage of the favorite codons in K coil so as to enhance its protein expression in prokaryotic expressing system. The protein was purified by Ni-NTA column, and its antigenicity was determined by Western Blot. Then establish ELISA to detect the specific anti-VP2 IgG antibodies against HBoV1 and 2 in healthy children aged 3-6 years in Nanjing, China. RESULTS: The recombinant protein 6 x His-VP2 was produced in a larger quantity at 25 degrees C induced by IPTG (1 mmol/L) over night and purified by Ni-NTA column. Seropositive rates of HBoV1 and 2 were 62.2% and 55.5% and their mixed seropositivity was 37%. CONCLUSION: The optimizing expression of the capsid protein VP2 from human Bocavirus constructed successfully and get a high yield under certain conditions. The established ELISA could be used to further analyze seroepidemiology of HBoV in China.

The therapeutic potential of SA-sCD40L in the orthotopic model of superficial bladder cancer.

BACKGROUND: Intravesical administration is an important treatment against superficial bladder cancer and CD40L is essential for the protective anti-tumor immunity. In situ gene therapy with CD40L was demonstrated to successfully inhibit tumor cell growth in the orthotopic mouse model of bladder cancer. In the present study, we prepared streptavidin (SA)-tagged sCD40L and developed a novel immunotherapy for superficial bladder cancer based on the strong interaction between streptavidin and biotin. MATERIAL AND METHODS: The SA-sCD40L fusion protein was expressed in E. coli and purified on the Ni-NTA column. After refolding with dialysis, the bi-function of the fusion protein was determined by flow cytometric analysis for streptaidin-mediated surface modification of MB49 bladder cancer cells and a mouse B cell CD40L-dependent proliferation assay. The mouse orthotopic model of MB49 superficial bladder cancer was used to evaluate the efficacy of SA-sCD40L immunotherapy. RESULTS: The SA-sCD40L fusion protein exhibited both full biotin-binding property and CD40L bioactivity. After intravesical instillation, the SA-sCD40L bi-functional fusion protein was durably immobilized on the biotinylated mucosal surface of bladder wall for up to four days. The SA-sCD40L treatment significantly prolonged the survival of MB49 tumor-bearing mice and cured 50% of mice with MB49 superficial bladder cancer without significant adverse effects. In addition, more tumor-infiltrating CD4(+)or CD8(+) T cells were observed in SA-sCD40L-treated group. CONCLUSION: Intravesical immobilization of SA-sCD40L elicited a strong and long-lasting immunity against the MB49 bladder cancer.