Boosting antitumor efficacy of nanoparticles by modulating tumor mechanical microenvironment.

Nanoparticles have shown great potential for tumor targeting delivery via enhanced permeability and retention effect. However, the tumor mechanical microenvironment, characterized by dense extracellular matrix (ECM), high tumor stiffness and solid stress, leads to only 0.7% of administered dose accumulating in solid tumors and even fewer (∼0.0014%) reaching tumor cells, limiting the therapeutic efficacy of nanoparticles. Furthermore, the tumor mechanical microenvironment can regulate tumor cell stemness, promote tumor invasion, metastasis and reduce treatment efficacy. In this review, methods detecting the mechanical are introduced. Strategies for modulating the mechanical microenvironment including elimination of dense ECM by physical, chemical and biological methods, disruption of ECM formation, depletion or inhibition of cancer-associated fibroblasts, are then summarized. Finally, prospects and challenges for further clinical applications of mechano-modulating strategies to enhance the therapeutic efficacy of nanomedicines are discussed. This review may provide guidance for the rational design and application of nanoparticles in clinical settings.

Sodium oligomannate alters gut microbiota, reduces cerebral amyloidosis and reactive microglia in a sex-specific manner.

It has recently become well-established that there is a connection between Alzheimer's disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aß deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-dependent manner. In this regard, we were intrigued by the finding that a marine-derived oligosaccharide, GV-971, was reported to alter gut microbiota and reduce Aß amyloidosis in the 5XFAD mouse model that were treated at a point when Aß burden was near plateau levels. Utilizing comparable methodologies, but with distinct technical and temporal features, we now report on the impact of GV-971 on gut microbiota, Aß amyloidosis and microglial phenotypes in the APPPS1-21 model, studies performed at the University of Chicago, and independently in the 5X FAD model, studies performed at Washington University, St. Louis.Methods To comprehensively characterize the effects of GV-971 on the microbiota-microglia-amyloid axis, we conducted two separate investigations at independent institutions. There was no coordination of the experimental design or execution between the two laboratories. Indeed, the two laboratories were not aware of each other's experiments until the studies were completed. Male and female APPPS1-21 mice were treated daily with 40, 80, or 160 mg/kg of GV-971 from 8, when Aß burden was detectable upto 12 weeks of age when Aß burden was near maximal levels. In parallel, and to corroborate existing published studies and further investigate sex-related differences, male and female 5XFAD mice were treated daily with 100 mg/kg of GV-971 from 7 to 9 months of age when Aß burden was near peak levels. Subsequently, the two laboratories independently assessed amyloid-ß deposition, metagenomic, and neuroinflammatory profiles. Finally, studies were initiated at the University of Chicago to evaluate the metabolites in cecal tissue from vehicle and GV-971-treated 5XFAD mice.Results These studies showed that independent of the procedural differences (dosage, timing and duration of treatment) between the two laboratories, cerebral amyloidosis was reduced primarily in male mice, independent of strain. We also observed sex-specific microbiota differences following GV-971 treatment. Interestingly, GV-971 significantly altered multiple overlapping bacterial species at both institutions. Moreover, we discovered that GV-971 significantly impacted microbiome metabolism, particularly by elevating amino acid production and influencing the tryptophan pathway. The metagenomics and metabolomics changes correspond with notable reductions in peripheral pro-inflammatory cytokine and chemokine profiles. Furthermore, GV-971 treatment dampened astrocyte and microglia activation, significantly decreasing plaque-associated reactive microglia while concurrently increasing homeostatic microglia only in male mice. Bulk RNAseq analysis unveiled sex-specific changes in cerebral cortex transcriptome profiles, but most importantly, the transcriptome changes in the GV-971-treated male group revealed the involvement of microglia and inflammatory responses.Conclusions In conclusion, these studies demonstrate the connection between the gut microbiome, neuroinflammation, and Alzheimer's disease pathology while highlighting the potential therapeutic effect of GV-971. GV-971 targets the microbiota-microglia-amyloid axis, leading to the lowering of plaque pathology and neuroinflammatory signatures in a sex-dependent manner when given at the onset of Aß deposition or when given after Aß deposition is already at higher levels.

Early modulation of the gut microbiome by female sex hormones alters amyloid pathology and microglial function.

It is well-established that women are disproportionately affected by Alzheimer's disease. The mechanisms underlying this sex-specific disparity are not fully understood, but several factors that are often associated-including interactions of sex hormones, genetic factors, and the gut microbiome-likely contribute to the disease's etiology. Here, we have examined the role of sex hormones and the gut microbiome in mediating Aß amyloidosis and neuroinflammation in APPPS1-21 mice. We report that postnatal gut microbiome perturbation in female APPPS1-21 mice leads to an elevation in levels of circulating estradiol. Early stage ovariectomy (OVX) leads to a reduction of plasma estradiol that is correlated with a significant alteration of gut microbiome composition and reduction in Aß pathology. On the other hand, supplementation of OVX-treated animals with estradiol restores Aß burden and influences gut microbiome composition. The reduction of Aß pathology with OVX is paralleled by diminished levels of plaque-associated microglia that acquire a neurodegenerative phenotype (MGnD-type) while estradiol supplementation of OVX-treated animals leads to a restoration of activated microglia around plaques. In summary, our investigation elucidates the complex interplay between sex-specific hormonal modulations, gut microbiome dynamics, metabolic perturbations, and microglial functionality in the pathogenesis of Alzheimer's disease.

Engineered Probiotic-Based Personalized Cancer Vaccine Potentiates Antitumor Immunity through Initiating Trained Immunity.

Cancer vaccines hold great potential for clinical cancer treatment by eliciting T cell-mediated immunity. However, the limited numbers of antigen-presenting cells (APCs) at the injection sites, the insufficient tumor antigen phagocytosis by APCs, and the presence of a strong tumor immunosuppressive microenvironment severely compromise the efficacy of cancer vaccines. Trained innate immunity may promote tumor antigen-specific adaptive immunity. Here, a personalized cancer vaccine is developed by engineering the inactivated probiotic Escherichia coli Nissle 1917 to load tumor antigens and ß-glucan, a trained immunity inducer. After subcutaneous injection, the cancer vaccine delivering model antigen OVA (BG/OVA@EcN) is highly accumulated and phagocytosed by macrophages at the injection sites to induce trained immunity. The trained macrophages may recruit dendritic cells (DCs) to facilitate BG/OVA@EcN phagocytosis and the subsequent DC maturation and T cell activation. In addition, BG/OVA@EcN remarkably enhances the circulating trained monocytes/macrophages, promoting differentiation into M1-like macrophages in tumor tissues. BG/OVA@EcN generates strong prophylactic and therapeutic efficacy to inhibit tumor growth by inducing potent adaptive antitumor immunity and long-term immune memory. Importantly, the cancer vaccine delivering autologous tumor antigens efficiently prevents postoperative tumor recurrence. This platform offers a facile translatable strategy to efficiently integrate trained immunity and adaptive immunity for personalized cancer immunotherapy.

Tumor-repopulating cell-derived microparticles elicit cascade amplification of chemotherapy-induced antitumor immunity to boost anti-PD-1 therapy.

Immune checkpoint blockade (ICB) therapy, particularly antibodies targeting the programmed death receptor 1 (PD-1) and its ligand (PD-L1), has revolutionized cancer treatment. However, its efficacy as a standalone therapy remains limited. Although ICB therapy in combination with chemotherapy shows promising therapeutic responses, the challenge lies in amplifying chemotherapy-induced antitumor immunity effectively. This relies on efficient drug delivery to tumor cells and robust antigen presentation by dendritic cells (DCs). Here, we developed tumor-repopulating cell (TRC)-derived microparticles with exceptional tumor targeting to deliver doxorubicin (DOX@3D-MPs) for improve anti-PD-1 therapy. DOX@3D-MPs effectively elicit immunogenic tumor cell death to release sufficient tumor antigens. Heat shock protein 70 (HSP70) overexpressed in DOX@3D-MPs contributes to capturing tumor antigens, promoting their phagocytosis by DCs, and facilitating DCs maturation, leading to the activation of CD8+ T cells. DOX@3D-MPs significantly enhance the curative response of anti-PD-1 treatment in large subcutaneous H22 hepatoma, orthotopic 4T1 breast tumor and Panc02 pancreatic tumor models. These results demonstrate that DOX@3D-MPs hold promise as agents to improve the response rate to ICB therapy and generate long-lasting immune memory to prevent tumor relapse.

Cell microparticles loaded with tumor antigen and resiquimod reprogram tumor-associated macrophages and promote stem-like CD8+ T cells to boost anti-PD-1 therapy.

The durable response rate to immune checkpoint blockade such as anti-programmed cell death-1 (PD-1) antibody remains relatively low in hepatocellular carcinoma (HCC), mainly depending on an immunosuppressive microenvironment with limited number of CD8+ T cells, especially stem-like CD8+ T cells, in tumor tissues. Here we develop engineered microparticles (MPs) derived from alpha-fetoprotein (AFP)-overexpressing macrophages to load resiquimod (R848@M2pep-MPsAFP) for enhanced anti-PD-1 therapy in HCC. R848@M2pep-MPsAFP target and reprogram immunosuppressive M2-like tumor-associated macrophages (TAMs) into M1-like phenotype. Meanwhile, R848@M2pep-MPsAFP-reprogrammed TAMs act as antigen-presenting cells, not only presenting AFP antigen to activate CD8+ T cell-mediated antitumor immunity, but also providing an intra-tumoral niche to maintain and differentiate stem-like CD8+ T cells. Combination immunotherapy with anti-PD-1 antibody generates strong antitumor immune memory and induces abundant stem-like CD8+ T cell proliferation and differentiation to terminally exhausted CD8+ T cells for long-term immune surveillance in orthotopic and autochthonous HCC preclinical models in male mice. We also show that the R848-loaded engineered MPs derived from macrophages overexpressing a model antigen ovalbumin (OVA) can improve anti-PD-1 therapy in melanoma B16-OVA tumor-bearing mice. Our work presents a facile and generic strategy for personalized cancer immunotherapy to boost anti-PD-1 therapy.

Hydrophobicity-Adaptive Polymers Trigger Fission of Tumor-Cell-Derived Microparticles for Enhanced Anticancer Drug Delivery.

Tumor-cell-derived microparticles (MPs) can function as anticancer drug-delivery carriers. However, short blood circulation time, large-size-induced insufficient tumor accumulation and penetration into tumor parenchyma, as well as limited cellular internalization by tumor cells and cancer stem cells (CSCs), and difficult intracellular drug release restrict the anticancer activity of tumor-cell-derived MP-based drug-delivery systems. In this work, hydrophobicity-adaptive polymers based on poly(N-isopropylacrylamide) are anchored to tumor-cell-derived MPs for enhanced delivery of the anticancer drug doxorubicin (DOX). The polymers are hydrophilic in blood to prolong the circulation time of DOX-loaded MPs (DOX@MPs), while rapidly switching to hydrophobic at the tumor acidic microenvironment. The hydrophobicity of polymers drives the fission of tumor-cell-derived MPs to form small vesicles, facilitating tumor accumulation, deep tumor penetration, and efficient internalization of DOX@MPs into tumor cells and CSCs. Subsequently, the hydrophobicity of polymers in acidic lysosomes further promotes DOX release to nuclei for strong cytotoxicity against tumor cells and CSCs. The work provides a facile and simple strategy for improved anticancer drug delivery of tumor-cell-derived MPs.

The gut microbiome regulates astrocyte reaction to Aß amyloidosis through microglial dependent and independent mechanisms.

BACKGROUND: Previous studies show that antibiotic-mediated (abx) alteration of the gut microbiome (GMB) results in a reduction of amyloid beta (Aß) plaques and proinflammatory microglial phenotype in male APPPS1-21 mice. However, the effect of GMB perturbation on astrocyte phenotypes and microglial-astrocyte communication in the context of amyloidosis has not been examined. METHODS: To study whether the GMB modulates astrocyte phenotype in the context of amyloidosis, APPPS1-21 male and female mice were treated with broad-spectrum abx leading to GMB perturbation. GFAP + astrocytes, plaque-associated astrocytes (PAA), PAA morphological parameters, and astrocyte complement component C3 levels were quantified using a combination of immunohistochemistry, immunoblotting, widefield microscopy, and confocal microscopy. Furthermore, these same astrocyte phenotypes were assessed in abx-treated APPPS1-21 male mice that received either fecal matter transplant (FMT) from untreated APPPS1-21 male donors to restore their microbiome or vehicle control. To assess complete absence of the GMB on astrocyte phenotypes, the same astrocyte phenotypes were quantified in APPPS1-21 male mice raised in germ-free (GF) or specific-pathogen free conditions (SPF). Lastly, we assessed whether microglia are necessary for abx-induced astrocyte phenotypes by depleting microglia in APPPS1-21 male mice via treatment with a colony-stimulating factor 1 receptor (CSF1R) inhibitor (PLX5622) and vehicle control or PLX5622 and abx. RESULTS: Herein, we demonstrate that postnatal treatment of male APPPS1-21 mice with broad-spectrum abx leading to GMB perturbation reduces GFAP + reactive astrocytes and PAAs, suggesting that the GMB plays a role in regulating reactive astrocyte induction and recruitment to Aß plaques. Additionally, we show that compared to controls, PAAs in abx-treated male APPPS1-21 mice exhibit an altered morphology with increased number and length of processes and reduced astrocytic complement C3, consistent with a homeostatic phenotype. GFAP + astrocyte reduction, PAA reduction, astrocyte morphological changes, and C3 levels are restored when abx-treated mice are subject to FMT from untreated APPPS1-21 male donor mice. Next, we found that APPPS1-21 male mice raised in GF conditions have similar astrocyte phenotypes as abx-treated male APPPS1-21 male mice. Correlational analysis revealed that pathogenic bacteria depleted by abx correlate with GFAP + astrocytosis, PAAs, and astrocyte morphological changes. Finally, we determined that abx-mediated reduction in GFAP + astrocytosis, PAAs, and astrocytic C3 expression is independent of microglia. However, abx-induced astrocyte morphological alterations are dependent on the presence of microglia, suggesting that there is both microglial independent and dependent GMB control of reactive astrocyte phenotypes. CONCLUSIONS: We show for the first time, in the context of amyloidosis, that the GMB plays an important role in controlling reactive astrocyte induction, morphology, and astrocyte recruitment to Aß plaques. GMB regulation of these astrocytic phenotypes is both independent and dependent on microglia.

Identifying Early-Stage Changes in Volatile Organic Compounds of Ceratocystis fimbriata Ellis & Halsted-Infected Sweet Potatoes (Ipomoea batatas L. Lam) Using Headspace Gas Chromatography-Ion Mobility Spectrometry.

Ceratocystis fimbriata Ellis & Halsted is the pathogen causing black rot in sweet potatoes that can lead to flavor change and toxin release. This study detected the volatile organic compounds (VOCs) of C. fimbriata-infected sweet potatoes in the early stages using headspace gas chromatography-ion mobility spectrometry (HS-GC-IMS). A total of 55 VOCs were identified, including aldehydes, alcohols, esters, ketones, and others. The content of aldehydes and ketones showed a decreasing trend, while alcohols and esters showed an increasing trend. An increase in infection time elevated the content of malondialdehyde (MDA) and pyruvate, while the starch content decreased, the content of soluble protein initially increased, then decreased, and the activities of lipoxygenase (LOX), pyruvate decarboxylase (PDC), alcohol dehydrogenase (ADH), and phenylalanine ammonia-lyase (PAL) increased. The changes in VOCs were closely related to the content of MDA, starch, pyruvate, and the activities of LOX, PDC, ADH, and PAL. Sweet potatoes showed a good discrimination effect by principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) from 0 to 72 h. Twenty-five differential VOCs could be used as early-stage characteristic compounds of C. fimbriata-infected sweet potatoes for early disease monitoring.

Relative comparison of chronic kidney disease-mineral and bone disorder rat models.

Objective: The aim of this study is to establish a suitable animal model of chronic kidney disease-mineral and bone disorder (CKD-MBD) by comparing CKD-MBD rat models induced by 5/6 Nx, AN, and UUO, accompanied by a low-calcium and high-phosphorus diet. Methods: Sprague‒Dawley rats were randomly divided into four groups: control group, 5/6 nephrectomy (5/6 Nx) group, Adriamycin nephropathy (AN) group, and unilateral ureteral obstruction (UUO) group. Serum biochemical indices were measured to evaluate renal function, mineral and bone metabolism, the severity of CKD-MBD, and the status of bone transformation. Hematoxylin-eosin staining (HE) and Masson's trichrome (Masson) staining were used for histopathological analysis of the kidney. Goldner's trichrome (Goldner) and tartrate-resistant acid phosphatase (TRAP) staining were utilized to observe bone mineralization and osteoclasts in the femur, respectively. Micro-CT images were applied to study the structure of the femur. The expression levels of osterix and cathepsin K in the femur were measured by immunohistochemistry (IHC) to confirm the status of bone transformation. Results: The levels of serum creatinine (Scr) and blood urea nitrogen (BUN) in the 5/6 Nx and AN group rats were significantly higher than those in the control rats, and this change was accompanied by marked changes in the levels of calcium (Ca), phosphate (Pi), intact parathyroid hormone (i-PTH), fibroblast growth factor 23 (FGF23), osteocalcin (OC), and cross-linked C-telopeptide of type 1 collagen (CTX-1); UUO group rats exhibited slight and inconsistent variations in the levels of Scr, BUN, Ca, Pi, i-PTH, FGF23, OC, and CTX-1 in serum. Histopathological analysis of the kidney showed that the UUO group rats suffered serious fibrosis and 5/6 Nx group rats exhibited severe focal calcification. Histopathological analysis of the femur showed that the AN group rats had minimal bone mineralization and that the 5/6 Nx group rats had overactive osteoclasts. Micro-CT revealed that the AN model had the most severe bone destruction and that the 5/6 Nx model had the least severe bone loss among the three models. The expression of cathepsin K in the femur was significantly increased in all models, while the expression of osterix in the femur was only significantly increased in the 5/6 Nx model. Conclusion: 5/6 Nx, AN, and UUO accompanied by a low-calcium and high-phosphorus diet successfully induced CKD-MBD in rats. The 5/6 NX model presented the progression of high-turnover bone disease, with consistency between biochemical indices in serum and histomorphometric analysis of the femur, and the AN and UUO models developed a severe deterioration in bone quantity and severe bone resorption; however, the changes in biochemical indices were subtle in the UUO model, and liver injury was obvious in the AN model.

The impact of COVID-19-related chronic disease is gradually emerging: discovery and trends from a bibliometric analysis.

OBJECTIVE: To conduct a literature survey of COVID-19-related chronic diseases to inform future research. METHODS: Publications on COVID-19 and chronic disease were retrieved from PubMed using MeSH Major Topic, including the terms COVID-19, SARS-CoV-2, Chronic Disease and Noncommunicable Diseases. Bibliometric features, journals, research areas, countries, funding agencies and citation reports, were extracted from Web of Science and highly cited papers identified and summarized. Fisher's exact probability test was used to associate highly cited papers with countries. RESULTS: A total of 1034 English-language publications were included. Urology/nephrology was the most active research area (n=230), PLOS ONE the most frequently involved journal (n=29) and the United States of America (USA) had the greatest research output (n=223). A medium number of publications were in the areas of hematology and immunology and these papers had a high citation rate. No statistically significant difference was found in the ratio of highly cited papers: total papers across high-output countries (P=0.668). The USA, Europe and China were the sources of the most highly cited articles and productive funding agencies. CONCLUSIONS: The influence of COVID-19 on chronic disease has received considerable attention. Hematology and immunology may continue to be productive research fields. Much research remains to be done to characterize the emerging chronic effects of COVID-19 on human health.

Early Discrimination and Prediction of C. fimbriata-Infected Sweetpotatoes during the Asymptomatic Period Using Electronic Nose.

Sweetpotato is prone to disease caused by C. fimbriata without obvious lesions on the surface in the early period of infection. Therefore, it is necessary to explore the possibility of developing an efficient early disease detection method for sweetpotatoes that can be used before symptoms are observed. In this study, sweetpotatoes were inoculated with C. fimbriata and stored for different lengths of time. The total colony count was detected every 8 h; HS-SPME/GC-MS and E-nose were used simultaneously to detect volatile compounds. The results indicated that the growth of C. fimbriata entered the exponential phase at 48 h, resulting in significant differences in concentrations of volatile compounds in infected sweetpotatoes at different times, especially toxic ipomeamarone in ketones. The contents of volatile compounds were related to the responses of the sensors. E-nose was combined with multiple chemometrics methods to discriminate and predict infected sweetpotatoes at 0 h, 48 h, 64 h, and 72 h. Among the methods used, linear discriminant analysis (LDA) had the best discriminant effect, with sensitivity, specificity, precision, and accuracy scores of 100%. E-nose combined with K-nearest neighbours (KNN) achieved the best predictions for ipomeamarone contents and total colony counts. This study illustrates that E-nose is a feasible and promising technology for the early detection of C. fimbriata infection in sweetpotatoes during the asymptomatic period.

Reversing insufficient photothermal therapy-induced tumor relapse and metastasis by regulating cancer-associated fibroblasts.

Insufficient tumor accumulation and distribution of photosensitizers as well as low antitumor immunity severely restrict the therapeutic efficacy of photothermal therapy (PTT). Cancer-associated fibroblasts (CAFs) play a key role in tumor extracellular matrix (ECM) remodeling and immune evasion. Reshaping tumor microenvironment via CAF regulation might provide a potential approach for complete tumor elimination in combination with PTT. Here, tumor cell-derived microparticles co-delivering calcipotriol and Indocyanine green (Cal/ICG@MPs) are developed to modulate CAFs for improved PTT efficacy. Cal/ICG@MPs efficiently target tumor tissues and regulate CAFs to reduce tumor ECM, resulting in enhanced tumor accumulation and penetration of ICG to generate strong PTT efficacy and activate CD8+ T cell-mediated antitumor immunity. In addition, Cal/ICG@MPs-triggered CAF regulation enhances tumor infiltration of CD8+ T cells and ameliorates CAF-induced antigen-mediated activation-induced cell death of tumor-specific CD8+ T cells in response to PTT, eliciting long-term antitumor immune memory to inhibit tumor recurrence and metastasis. Our results support Cal/ICG@MPs as a promising drug to improve PTT efficacy in cancer treatment.

[Toxicity mechanism of Rhododendri Mollis Flos: based on serum metabolomics and network toxicology].

This study aims to explore the toxicity mechanism of Rhododendri Mollis Flos(RMF) based on serum metabolomics and network toxicology. The toxic effect of RMF on normal rats was evaluated according to the symptoms, serum biochemical indexes, and histopathology. Serum metabolomics was combined with multivariate statistical analysis to search endogenous differential metabolites and related metabolic pathways. The toxic components, targets, and signaling pathways of RMF were screened by network toxicology technique, and the component-target-metabolite-metabolic pathway network was established with the help of serum metabolomics. The result suggested the neurotoxicity, hepatotoxicity, and cardiotoxicity of RMF. A total of 31 differential metabolites and 10 main metabolic pathways were identified by serum metabolomics, and 11 toxic components, 332 related target genes and 141 main signaling pathways were screened out by network toxicology. Further analysis yielded 7 key toxic components: grayanotoxin Ⅲ,grayanotoxinⅠ, rhodojaponin Ⅱ, rhodojaponin Ⅴ, rhodojaponin Ⅵ, rhodojaponin Ⅶ, and kalmanol, which acted on the following 12 key targets: androgen receptor(AR), albumin(ALB), estrogen receptor ß(ESR2), sex-hormone binding globulin(SHBG), type 11 hydroxysteroid(17-beta) dehydrogenase(HSD17 B11), estrogen receptor α(ESR1), retinoic X receptor-gamma(RXRG), lactate dehydrogenase type C(LDHC), Aldo-keto reductase(AKR) 1 C family member 3(AKR1 C3), ATP binding cassette subfamily B member 1(ABCB1), UDP-glucuronosyltransferase 2 B7(UGT2 B7), and glutamate-ammonia ligase(GLUL). These targets interfered with the metabolism of gamma-aminobutyric acid, estriol, testosterone, retinoic acid, 2-oxobutyric acid, and affected 4 key metabolic pathways of alanine, aspartate and glutamate metabolism, cysteine and methionine metabolism, steroid hormone biosynthesis, and retinol metabolism. RMF exerts toxic effect on multiple systems through multiple components, targets, and pathways. Through the analysis of key toxic components, target genes, metabolites, and metabolic pathways, this study unveiled the mechanism of potential neurotoxicity, cardiotoxicity, and hepatotoxicity of RMF, which is expected to provide a clue for the basic research on toxic Chinese medicinals.

Gut microbiota-driven brain Aß amyloidosis in mice requires microglia.

We previously demonstrated that lifelong antibiotic (ABX) perturbations of the gut microbiome in male APPPS1-21 mice lead to reductions in amyloid ß (Aß) plaque pathology and altered phenotypes of plaque-associated microglia. Here, we show that a short, 7-d treatment of preweaned male mice with high-dose ABX is associated with reductions of Aß amyloidosis, plaque-localized microglia morphologies, and Aß-associated degenerative changes at 9 wk of age in male mice only. More importantly, fecal microbiota transplantation (FMT) from transgenic (Tg) or WT male donors into ABX-treated male mice completely restored Aß amyloidosis, plaque-localized microglia morphologies, and Aß-associated degenerative changes. Transcriptomic studies revealed significant differences between vehicle versus ABX-treated male mice and FMT from Tg mice into ABX-treated mice largely restored the transcriptome profiles to that of the Tg donor animals. Finally, colony-stimulating factor 1 receptor (CSF1R) inhibitor-mediated depletion of microglia in ABX-treated male mice failed to reduce cerebral Aß amyloidosis. Thus, microglia play a critical role in driving gut microbiome-mediated alterations of cerebral Aß deposition.

The value of procalcitonin for predicting urosepsis after mini-percutaneous nephrolithotomy or flexible ureteroscopy based on different organisms.

PURPOSE: To assess the value of procalcitonin (PCT) as an early biomarker for predicting urosepsis caused by Gram-negative (GN) bacteria, Gram-positive (GP) bacteria and fungi following mini-percutaneous nephrolithotomy (mPCNL) and flexible ureteroscopy (FURS). METHODS: A total number of 356 patients with positive preoperative UC (urine cultures) who underwent mPCNL and FURS between June 2017 and January 2021 were retrospectively analyzed. Univariable analysis and multivariable logistic regression analysis were conducted to compare the predictors for urosepsis caused by different organisms. Furthermore, the nomogram was established as a predicted model for urosepsis. RESULTS: Among 356 positive UC, 265 (74.4%) were positive for GN bacteria, 77 (21.4%) for GP bacteria and 14 (3.9%) for fungal pathogens. Escherichia coli (48.9%) were the predominant pathogens and Enterococcus (54/77) were the most common GP bacteria. Multivariate logistic regression analysis showed that positive nitrite (OR 3.31, 95% CI 1.20-9.14; P = 0.021), operative time > 90 min (OR 3.10, 95% CI 1.10-8.75, P = 0.033) and postoperative PCT > 0.1 ng/mL (OR 56.18, 95% CI 15.20-207.64, P < 0.001) were associated with postoperative urosepsis originated in GN infections, while urosepsis caused by GP bacteria and fungi was not associated with PCT > 0.1 ng/mL (P = 0.198), only stone burden > 800 mm2 (OR 3.69, 95% CI 1.01-13.53, P = 0.049) was an independent risk factor. CONCLUSIONS: For patients with positive preoperative UC, postoperative PCT > 0.1 ng/mL was an independent risk factor of post-PCNL and post-FURS urosepsis caused by GN bacteria rather than GP bacteria and fungi.

Xuesaitong injection treating acute myocardial infarction: A systematic review and meta-analysis.

BACKGROUND: Although the incidence of acute myocardial infarction (AMI) is decreasing, the mortality in AMI patients remains substantial. Traditional Chinese medicine has shown its role in the prevention and management of AMI. The purpose of this study is to evaluate the clinical efficacy of Xuesaitong injection (XST) for the treatment of AMI by a meta-analysis. METHODS: A literature search was performed in 5 medical databases up to June 1, 2020. Randomized controlled trials involving XST combined with conventional treatment versus conventional treatment were included. A meta-analysis of clinical efficacy, left ventricular function and other objective parameters was performed to evaluate the effects of XST on AMI. RESULTS: Five randomized controlled trials involving 539 participants were eventually included. Meta-analysis showed that the combination of XST and conventional treatment could achieve significantly better effect on improving clinical efficacy (risk ratio: 1.09 [1.01, 1.17]; P = .04), left ventricular ejection fraction (mean difference [MD]: 3.18 [1.69, 4.67]; P < .0001), hypersensitive C-reactive protein (MD: -2.58 [-5.04, -0.12]; P = .04), interleukin 6 (MD: -26.00 [-38.85, -13.16]; P < .0001), cardiac troponin T (MD: -15.85 [-18.09, -13.61]; P < .00001) and creatine kinase myocardial isoenzyme (MD: -73.06 [-79.74, -66.37]; P < .00001). CONCLUSION: XST combined with conventional treatment can achieve better efficacy on clinical performance and some of the AMI related parameters. However the interpretation of the results should be cautious, due to the relatively low quality of included trials. More rigorously designed, large-scaled, randomized controlled trials are warranted to support its clinical use in the future.

Traditional Chinese medicine for acute coronary syndrome: A meta-analysis of clinical manifestations and objective indicators.

BACKGROUND: Modern clinical trials and experimental researches of traditional Chinese medicine (TCM) have been conducted for decades and provided support for the prevention and treatment of acute coronary syndrome (ACS). However the level of evidence and the proper application of TCM were still barely satisfactory. METHODS: In this study, we divided ACS into 3 different stages, including unstable angina, acute myocardial infarction, and post myocardial infarction. Then we systematically reviewed and meta-analyzed the existing randomized controlled trials on both clinical manifestations and objective indicators, in these 3 aspects. RESULTS: The results indicate that TCM can both improve the clinical manifestations and ameliorate the objective parameters in different courses of ACS, including C-reactive protein in unstable angina, left ventricular ejection fraction in acute myocardial infarction and post myocardial infarction. And the incidence of short-term cardiovascular events are lower in TCM intervention group. Some of the improvements lead to potential long-term benefits. CONCLUSION: TCM treatment is beneficial to different courses of ACS. To acquire more solid and comprehensive evidence of TCM in treating ACS, more rigorously designed randomized controlled trials with longer follow-up duration are warranted.

NEAT1 functions as a key mediator of BMP2 to promote osteogenic differentiation of renal interstitial fibroblasts.

Aim: To clarify the mechanism of NEAT1, an aberrantly upregulated lncRNA in Randall's plaques (RP) similar to biomineralization, in mediating osteogenic differentiation of human renal interstitial fibroblasts. Materials & methods: A comprehensive strategy of bioinformatic analysis and experimental verification was performed. Results:BMP2 silence abolished the osteogenic differentiation of human renal interstitial fibroblasts promoted by NEAT1. Mechanically, NEAT1 not only induced the nucleolar translocation of EGR1 binding to BMP2 promotor, but also functioned as a sponge of miR-129-5p in the cytoplasm to promote BMP2 expression. Moreover, there was a positive correlation between NEAT1 and BMP2 expression in RP instead of normal renal papilla. Conclusion:NEAT1 acted as a key mediator of BMP2 to promote human renal interstitial fibroblast osteogenic differentiation, through which NEAT1 might be involved in RP formation.

Lay abstract Kidney stones affect one in ten people in the world, and calcium oxalate (CaOx) stones account for 80% of kidney stones. Calcium and oxalate originate from Randall's plaques (RP) which was identified as an anchor for CaOx in renal papilla (parts of the kidney where collecting ducts open to allow urine to flow to the ureter). RP formation shares similarities with bone formation and blood vessel calcification (hardening caused by calcium salt accumulation). Our findings revealed that long non-coding RNA (long nucleotide sequence not made into protein) NEAT1 controlled genes relating to bone formation in kidney cells known as human renal interstitial fibroblasts which are involved in kidney repair processes. This finding implies human renal interstitial fibroblasts might contribute to kidney calcium phosphate deposits prior to RP formation. Collectively, our study provided a new understanding of how NEAT1 might be involved in RP formation by changing the function of osteogenic-like cells in the kidney.