Microglia-targeted inhibition of miR-17 via mannose-coated lipid nanoparticles improves pathology and behavior in a mouse model of Alzheimer's disease.

Neuroinflammation and accumulation of Amyloid Beta (Aß) accompanied by deterioration of special memory are hallmarks of Alzheimer's disease (AD). Effective preventative and treatment options for AD are still needed. Microglia in AD brains are characterized by elevated levels of microRNA-17 (miR-17), which is accompanied by defective autophagy, Aß accumulation, and increased inflammatory cytokine production. However, the effect of targeting miR-17 on AD pathology and memory loss is not clear. To specifically inhibit miR-17 in microglia, we generated mannose-coated lipid nanoparticles (MLNPs) enclosing miR-17 antagomir (Anti-17 MLNPs), which are targeted to mannose receptors readily expressed on microglia. We used a 5XFAD mouse model (AD) that recapitulates many AD-related phenotypes observed in humans. Our results show that Anti-17 MLNPs, delivered to 5XFAD mice by intra-cisterna magna injection, specifically deliver Anti-17 to microglia. Anti-17 MLNPs downregulated miR-17 expression in microglia but not in neurons, astrocytes, and oligodendrocytes. Anti-17 MLNPs attenuated inflammation, improved autophagy, and reduced Aß burdens in the brains. Additionally, Anti-17 MLNPs reduced the deterioration in spatial memory and decreased anxiety-like behavior in 5XFAD mice. Therefore, targeting miR-17 using MLNPs is a viable strategy to prevent several AD pathologies. This selective targeting strategy delivers specific agents to microglia without the adverse off-target effects on other cell types. Additionally, this approach can be used to deliver other molecules to microglia and other immune cells in other organs.

Optimization of the Preparation Process of Glucuronomannan Oligosaccharides and Their Effects on the Gut Microbiota in MPTP-Induced PD Model Mice.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder, and accumulating evidence suggests a link between dysbiosis of the gut microbiota and the onset and progression of PD. In our previous investigations, we discovered that intraperitoneal administration of glucuronomannan oligosaccharides (GMn) derived from Saccharina japonica exhibited neuroprotective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. However, the complicated preparation process, difficulties in isolation, and remarkably low yield have constrained further exploration of GMn. In this study, we optimized the degradation conditions in the preparation process of GMn through orthogonal experiments. Subsequently, an MPTP-induced PD model was established, followed by oral administration of GMn. Through a stepwise optimization, we successfully increased the yield of GMn, separated from crude fucoidan, from 1~2/10,000 to 4~8/1000 and indicated the effects on the amelioration of MPTP-induced motor deficits, preservation of dopamine neurons, and elevation in striatal neurotransmitter levels. Importantly, GMn mitigated gut microbiota dysbiosis induced by MPTP in mice. In particular, GM2 significantly reduced the levels of Akkermansia, Verrucomicrobiota, and Lactobacillus, while promoting the abundance of Roseburia and Prevotella compared to the model group. These findings suggest that GM2 can potentially suppress PD by modulating the gut microbiota, providing a foundation for the development of a novel and effective anti-PD marine drug.

D-mannose alleviates intervertebral disc degeneration through glutamine metabolism.

BACKGROUND: Intervertebral disc degeneration (IVDD) is a multifaceted condition characterized by heterogeneity, wherein the balance between catabolism and anabolism in the extracellular matrix of nucleus pulposus (NP) cells plays a central role. Presently, the available treatments primarily focus on relieving symptoms associated with IVDD without offering an effective cure targeting its underlying pathophysiological processes. D-mannose (referred to as mannose) has demonstrated anti-catabolic properties in various diseases. Nevertheless, its therapeutic potential in IVDD has yet to be explored. METHODS: The study began with optimizing the mannose concentration for restoring NP cells. Transcriptomic analyses were employed to identify the mediators influenced by mannose, with the thioredoxin-interacting protein (Txnip) gene showing the most significant differences. Subsequently, small interfering RNA (siRNA) technology was used to demonstrate that Txnip is the key gene through which mannose exerts its effects. Techniques such as colocalization analysis, molecular docking, and overexpression assays further confirmed the direct regulatory relationship between mannose and TXNIP. To elucidate the mechanism of action of mannose, metabolomics techniques were employed to pinpoint glutamine as a core metabolite affected by mannose. Next, various methods, including integrated omics data and the Gene Expression Omnibus (GEO) database, were used to validate the one-way pathway through which TXNIP regulates glutamine. Finally, the therapeutic effect of mannose on IVDD was validated, elucidating the mechanistic role of TXNIP in glutamine metabolism in both intradiscal and orally treated rats. RESULTS: In both in vivo and in vitro experiments, it was discovered that mannose has potent efficacy in alleviating IVDD by inhibiting catabolism. From a mechanistic standpoint, it was shown that mannose exerts its anti-catabolic effects by directly targeting the transcription factor max-like protein X-interacting protein (MondoA), resulting in the upregulation of TXNIP. This upregulation, in turn, inhibits glutamine metabolism, ultimately accomplishing its anti-catabolic effects by suppressing the mitogen-activated protein kinase (MAPK) pathway. More importantly, in vivo experiments have further demonstrated that compared with intradiscal injections, oral administration of mannose at safe concentrations can achieve effective therapeutic outcomes. CONCLUSIONS: In summary, through integrated multiomics analysis, including both in vivo and in vitro experiments, this study demonstrated that mannose primarily exerts its anti-catabolic effects on IVDD through the TXNIP-glutamine axis. These findings provide strong evidence supporting the potential of the use of mannose in clinical applications for alleviating IVDD. Compared to existing clinically invasive or pain-relieving therapies for IVDD, the oral administration of mannose has characteristics that are more advantageous for clinical IVDD treatment.

d-mannose targets PD-1 to lysosomal degradation and enhances T cell-mediated anti-tumor immunity.

High expression of programmed cell death protein 1 (PD-1), a typical immune checkpoint, results in dysfunction of T cells in tumor microenvironment. Antibodies and inhibitors against PD-1 or its ligand (PD-L1) have been widely used in various malignant tumors. However, the mechanisms by which PD-1 is regulated are not fully understood. Here, we report a mechanism of PD-1 degradation triggered by d-mannose and the universality of this mechanism in anti-tumor immunity. We show that d-mannose inactivates GSK3ß via promoting phosphorylation of GSK3ß at Ser9, thereby leading to TFE3 translocation to nucleus and subsequent PD-1 proteolysis induced by enhanced lysosome biogenesis. Notably, combination of d-mannose and PD-1 blockade exhibits remarkable tumor growth suppression attributed to elevated cytotoxicity activity of T cells in vivo. Furthermore, d-mannose treatment dramatically improves the therapeutic efficacy of MEK inhibitor (MEKi) trametinib in vivo. Our findings unveil a universally unrecognized anti-tumor mechanism of d-mannose by destabilizing PD-1 and provide strategies to enhance the efficacy of both immune checkpoint blockade (ICB) and MEKi -based therapies.

Integrating network pharmacology and experimental validation reveals therapeutic effects of D-mannose on NAFLD through mTOR suppression.

Non-alcoholic fatty liver disease (NAFLD), a chronic liver condition and metabolic disorder, has emerged as a significant health issue worldwide. D-mannose, a natural monosaccharide widely existing in plants and animals, has demonstrated metabolic regulatory properties. However, the effect and mechanism by which D-mannose may counteract NAFLD have not been studied. In this study, network pharmacology followed by molecular docking analysis was utilized to identify potential targets of mannose against NAFLD, and the leptin receptor-deficient, genetically obese db/db mice was employed as an animal model of NAFLD to validate the regulation of D-mannose on core targets. As a result, 67 targets of mannose are predicted associated with NAFLD, which are surprisingly centered on the mechanistic target of rapamycin (mTOR). Further analyses suggest that mTOR signaling is functionally enriched in potential targets of mannose treating NAFLD, and that mannose putatively binds to mTOR as a core mechanism. Expectedly, repeated oral gavage of supraphysiological D-mannose ameliorates liver steatosis of db/db mice, which is based on suppression of hepatic mTOR signaling. Moreover, daily D-mannose administration reduced hepatic expression of lipogenic regulatory genes in counteracting NAFLD. Together, these findings reveal D-mannose as an effective and potential NAFLD therapeutic through mTOR suppression, which holds translational promise.

The regulation of Cytochrome f by mannose treatment in broccoli and its relationship with programmed cell death in tobacco BY-2 cells.

It is well established that programmed cell death (PCD) occurred in broccoli during postharvest senescence, but no studies have been conducted on the regulation of broccoli cytochrome f by mannose treatment and its relationship with PCD. In this study, we treated broccoli buds with mannose to investigate the changes in color, total chlorophyll content, gene expression related to chlorophyll metabolism, chloroplast structure, and cytochrome f determination during postharvest storage. In addition, to investigate the effect of cytochrome f on PCD, we extracted cytochrome f from broccoli and treated Nicotiana tabacum L. cv Bright Yellow 2 (BY-2) cells with extracted cytochrome f from broccoli at various concentrations. The results showed that cytochrome f can induce PCD in tobacco BY-2 cells, as evidenced by altered cell morphology, nuclear chromatin disintegration, DNA degradation, decreased cell viability, and increased caspase-3-like protease production. Taken together, our study indicated that mannose could effectively delay senescence of postharvest broccoli by inhibiting the expression of gene encoding cytochrome f which could induce PCD.

Preparation of glycopeptide-modified pH-sensitive liposomes for promoting antigen cross-presentation and induction of antigen-specific cellular immunity.

Cross-presentation, exogenous antigen presentation onto major histocompatibility complex class I molecules on antigen presenting cells, is crucially important for inducing antigen-specific cellular immune responses for cancer immunotherapy and for the treatment of infectious diseases. One strategy to induce cross-presentation is cytosolic delivery of an exogenous antigen using fusogenic or endosomolytic molecule-introduced nanocarriers. Earlier, we reported liposomes modified with pH-responsive polymers to achieve cytosolic delivery of an antigen. Polyglycidol-based or polysaccharide-based pH-responsive polymers can provide liposomes with delivery performance of antigenic proteins into cytosol via membrane fusion with endosomes responding to acidic pH, leading to induction of cross-presentation. Mannose residue was introduced to pH-responsive polysaccharides to increase uptake selectivity to antigen presenting cells and to improve cross-presentation efficiency. However, direct introduction of mannose residue into pH-responsive polysaccharides suppressed cytoplasmic delivery performance of liposomes. To avoid such interference, for this study, mannose-containing glycans were incorporated separately into pH-responsive polysaccharide-modified liposomes. Soybean agglutinin-derived glycopeptide was used as a ligand for lectins on antigen presenting cells. Incorporation of glycopeptide significantly increased the cellular uptake of liposomes by dendritic cell lines and increased cross-presentation efficiency. Liposomes incorporated both glycopeptide and pH-responsive polysaccharides exhibited strong adjuvant effects in vitro and induced the increase of dendritic cells, M1 macrophages, and effector T cells in the spleen. Subcutaneous administration of these liposomes induced antigen-specific cellular immunity, resulting in strong therapeutic effects in tumor-bearing mice. These results suggest that separate incorporation of glycopeptides and pH-responsive polysaccharides into antigen-loaded liposomes is an effective strategy to produce liposome-based nanovaccines to achieve antigen cross-presentation and induction of cellular immunity towards cancer immunotherapy.

The Interaction between Collagen 1 and High Mannose Type CD133 Up-Regulates Glutamine Transporter SLC1A5 to Promote the Tumorigenesis of Glioblastoma Stem Cells.

Targeting the niche components surrounding glioblastoma stem cells (GSCs) helps to develop more effective glioblastoma treatments. However, the mechanisms underlying the crosstalk between GSCs and microenvironment remain largely unknown. Clarifying the extracellular molecules binding to GSCs marker CD133 helps to elucidate the mechanism of the communication between GSCs and the microenvironment. Here, it is found that the extracellular domain of high mannose type CD133 physically interacts with Collagen 1 (COL1) in GSCs. COL1, mainly secreted by cancer-associated fibroblasts, is a niche component for GSCs. COL1 enhances the interaction between CD133 and p85 and activates Akt phosphorylation. Activation of Akt pathway increases transcription factor ATF4 protein level, subsequently enhances SLC1A5-dependent glutamine uptake and glutathione synthesis. The inhibition of CD133-COL1 interaction or down-regulation of SLC1A5 reduces COL1-accelerated GSCs self-renewal and tumorigenesis. Analysis of glioma samples reveals that the level of COL1 is correlated with histopathological grade of glioma and the expression of SLC1A5. Collectively, COL1, a niche component for GSCs, enhances the tumorigenesis of GSCs partially through CD133-Akt-SLC1A5 signaling axis, providing a new mechanism underlying the cross-talk between GSCs and extracellular matrix (ECM) microenvironment.

Anti-biofilm mechanism of a synthetical low molecular weight poly-d-mannose on Salmonella Typhimurium.

In this study, a low molecular weight poly-d-mannose (LMWM) was separated from a mixed polysaccharide synthesized previously. Monosaccharide composition, Fourier-Transform infrared spectroscopy (FT-IR), periodate oxidation and smith degradation were determined. After safety evaluation, the inhibition of LMWM on the different biofilm formation stages of Salmonella enterica serovar Typhimurium (S. Typhimurium) was tested in vitro. Furthermore, the effect of LMWM on the adhesion of S. Typhimurium to Caco-2 cells and cell surface hydrophobicity (CSH) were observed. Results indicated that LMWM was a homopolysaccharide without cytotoxicity and hemolysis, containing both α-mannose and ß-mannose. It showed obvious anti-biofilm activity on S. Typhimurium and mainly activated on the initial adhesion and formation stage, even better than the commercial S. cerevisiae mannan (CM). LMWM inhibited the adhesion of S. Typhimurium on Caco-2 cells with the inhibition rate of 61.04 % at 2 mg/ml. Meanwhile, LMWM decreased the hydrophobicity of S. Typhimurium cell surface. In conclusion, the inhibitory effect on S. Typhimurium biofilm was not caused by bacteriostatic or bactericidal activity of LMWM. The specific anti-adhesion and the decrease of bacterial CSH by LMWM may closely relate to anti-biofilm mechanism. This study provides some supports for the application of LMWM as antibiotics alternative on S. Typhimurium in the future.

Cellular signaling in the hypoxic cancer microenvironment: Implications for drug resistance and therapeutic targeting.

The rewiring of cellular metabolism is a defining characteristic of cancer, as tumor cells adapt to acquire essential nutrients from a nutrient-poor environment to sustain their viability and biomass. While hypoxia has been identified as a major factor depriving cancer cells of nutrients, recent studies have revealed that cancer cells distant from supporting blood vessels also face nutrient limitations. To overcome this challenge, hypoxic cancer cells, which heavily rely on glucose as an energy source, employ alternative pathways such as glycogen metabolism and reductive carboxylation of glutamine to meet their energy requirements for survival. Our preliminary studies, alongside others in the field, have shown that under glucose-deficient conditions, hypoxic cells can utilize mannose and maltose as alternative energy sources. This review aims to comprehensively examine the hypoxic cancer microenvironment, its association with drug resistance, and potential therapeutic strategies for targeting this unique niche. Furthermore, we will critically evaluate the current literature on hypoxic cancer microenvironments and explore state-of-the-art techniques used to analyze alternate carbohydrates, specifically mannose and maltose, in complex biological fluids. We will also propose the most effective analytical methods for quantifying mannose and maltose in such biological samples. By gaining a deeper understanding of the hypoxic cancer cell microenvironment and its role in drug resistance, novel therapeutic approaches can be developed to exploit this knowledge.

Therapeutic potential of Pseudomonas aeruginosa-mannose sensitive hemagglutinin (PA-MSHA) in cancer treatment.

Pseudomonas aeruginosa is a Gram-negative bacteria and it has been demonstrated that immunization with the outer membrane proteins of the microbe produces most of the relevant human antibodies. The peritrichous P. aeruginosa strain with MSHA fimbriae (PA-MSHA strain) has been found to be effective in the inhibition of growth and proliferation of different types of cancer cells. Furthermore, it has been revealed that PA-MSHA exhibits cytotoxicity because of the presence of MSHA and therefore it possesses anti-carcinogenic ability against different types of human cancer cell lines including, gastric, breast, hepatocarcinoma and nasopharyngeal cells. Studies have revealed that PA-MSHA exhibits therapeutic potential against cancer growth by induction of apoptosis, arrest of cell cycle, activating NF-κB/TLR5 pathway, etc. In China, PA-MSHA injections have been approved for the treatment of malignant tumor patients from very long back. The present review article demonstrates the therapeutic potential of PA-MSHA against various types of human cancers and explains the underlying mechanism.

D-mannose induces TFE3-dependent lysosomal degradation of EGFR and inhibits the progression of NSCLC.

In non-small cell lung cancer (NSCLC), the overexpression or abnormal activation of epidermal growth factor receptor (EGFR) is associated with tumor progression and drug resistance. EGFR tyrosine kinase inhibitors (TKIs) are currently the first-line treatment of NSCLC. However, patients inevitably acquired EGFR TKIs resistance mutations, which led to disease progression, so it is urgent to find new treatment. Here, we report that D-mannose up-regulates lysosomal activity by enhancing TFE3-mediated lysosomal biogenesis, thereby increasing the degradation of EGFR and significantly down-regulating its protein level. Therefore, D-mannose significantly inhibited the proliferation, migration and invasion of wild-type EGFR (WT-EGFR) and EGFR mutant cells (E746-A750 deletion, L858R and T790M mutations) in vitro. Oral administration of D-mannose strongly inhibited tumor growth in mice, showing similar effects with osimertinib. Taken together, these data suggest that D-mannose may represent a new strategy for clinical treatment of NSCLC.

D-mannose acts as a V-ATPase inhibitor to suppress inflammatory cytokines generation and bacterial killing in macrophage.

Vacuolar-type H+-ATPase (V-ATPase) critically controls phagosome acidification to promote pathogen digestion and clearance in macrophage. However, the specific subunits of V-ATPase have been evidenced to play contradictory functions in inflammatory cytokines generation and secretion exposure to external bacterial or LPS stimulation. Therefore, identifying the unique function of the separate subunit of V-ATPase is extremely important to regulate macrophage function. Here, we found that D-mannose, a C-2 epimer of glucose, suppressed ATP6V1B2 lysosomal translocation to inhibit V-ATPase activity in macrophages, thereby causing the scaffold protein axis inhibitor protein (AXIN) recruitment to lysosomal membrane and AMPK activation. Correspondingly, LPS-stimulated macrophage M1 polarization was significantly suppressed by D-mannose via down-regulating NF-κB signaling pathway in response to AMPK activation, while IL-4 induced macrophage M2 polarization were not affected. Furthermore, the failure of lysosomal localization of ATP6V1B2 caused by D-mannose also led to the acidification defects of lysosome. Therefore, D-mannose displayed a remarkable function in inhibiting macrophage phagocytosis and bacterial killing. Taken together, D-mannose acts a novel V-ATPase suppressor to attenuate macrophage inflammatory production but simultaneously prevent macrophage phagocytosis and bacterial killing.

Biological function, regulatory mechanism, and clinical application of mannose in cancer.

Studies examining the regulatory roles and clinical applications of monosaccharides other than glucose in cancer have been neglected. Mannose, a common type of monosaccharide found in human body fluids and tissues, primarily functions in protein glycosylation rather than carbohydrate metabolism. Recent research has demonstrated direct anticancer effects of mannose in vitro and in vivo. Simply supplementing cell culture medium or drinking water with mannose achieved these effects. Moreover, mannose enhances the effectiveness of current cancer treatments including chemotherapy, radiotherapy, targeted therapy, and immune therapy. Besides the advancements in basic research on the anticancer effects of mannose, recent studies have reported its application as a biomarker for cancer or in the delivery of anticancer drugs using mannose-modified drug delivery systems. This review discusses the progress made in understanding the regulatory roles of mannose in cancer progression, the mechanisms underlying its anticancer effects, and its current application in cancer diagnosis and treatment.

Mannose antagonizes GSDME-mediated pyroptosis through AMPK activated by metabolite GlcNAc-6P.

Pyroptosis is a type of regulated cell death executed by gasdermin family members. However, how gasdermin-mediated pyroptosis is negatively regulated remains unclear. Here, we demonstrate that mannose, a hexose, inhibits GSDME-mediated pyroptosis by activating AMP-activated protein kinase (AMPK). Mechanistically, mannose metabolism in the hexosamine biosynthetic pathway increases levels of the metabolite N-acetylglucosamine-6-phosphate (GlcNAc-6P), which binds AMPK to facilitate AMPK phosphorylation by LKB1. Activated AMPK then phosphorylates GSDME at Thr6, which leads to blockade of caspase-3-induced GSDME cleavage, thereby repressing pyroptosis. The regulatory role of AMPK-mediated GSDME phosphorylation was further confirmed in AMPK knockout and GSDMET6E or GSDMET6A knock-in mice. In mouse primary cancer models, mannose administration suppressed pyroptosis in small intestine and kidney to alleviate cisplatin- or oxaliplatin-induced tissue toxicity without impairing antitumor effects. The protective effect of mannose was also verified in a small group of patients with gastrointestinal cancer who received normal chemotherapy. Our study reveals a novel mechanism whereby mannose antagonizes GSDME-mediated pyroptosis through GlcNAc-6P-mediated activation of AMPK, and suggests the utility of mannose supplementation in alleviating chemotherapy-induced side effects in clinic applications.

D-mannose reduces adipogenesis by inhibiting the PI3K/AKT signaling pathway.

PURPOSE: To explore the effects and potential mechanisms of D-mannose on adipogenic differentiation of two kinds of representative mesenchymal stem cells (MSCs). METHODS: We cultured two kinds of representative MSCs, human adipose tissue-derived stromal cells (hADSCs) as well as human bone marrow mesenchymal stem cells (hBMSCs), with adipogenic-induced medium containing D-mannose or D-fructose as the control. Oil red O staining, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot (WB) were used to detect whether D-mannose had effects on adipogenic differentiation of MSCs. RNA sequencing (RNA-seq) transcriptomic analysis was further used to explore the potential mechanisms of D-mannose on adipogenic differentiation of MSCs. After that, qRT-PCR and WB were used to verify the results of RNA-seq. Last, we removed bilateral ovaries of female rats to establish an estrogen deficiency obesity model, and gave D-mannose intragastric administration. One month later, the femurs of rats were sliced for oil red O staining, and the inhibitory effect of D-mannose on lipid formation in vivo was studied. RESULTS: Oil red O staining, qRT-PCR and WB in vitro demonstrated that D-mannose inhibited the adipogenic differentiation of both hADSCs and hBMSCs. Oil red O staining of femur sections proved that D-mannose was able to reduce in vivo adipogenesis. The results of RNA-seq transcriptomic analysis revealed that the adipogenesis-inhibition effects of D-mannose were performed by antagonizing the PI3K/AKT signaling pathway. Besides, qRT-PCR and WB further verified the results of RNA-seq. CONCLUSION: Our study indicated that D-mannose was able to reduce adipogenic differentiation of both hADSCs and hBMSCs by antagonizing the PI3K/AKT signaling pathway. D-mannose is expected to be a safe and effective treatment strategy for obesity.

Multivalent calix[4]arene-based mannosylated dendrons as new FimH ligands and inhibitors.

We report the synthesis and biological characterization of a novel class of multivalent glycoconjugates as hit compounds for the design of new antiadhesive therapies against urogenital tract infections (UTIs) caused by uropathogenic E. coli strains (UPEC). The first step of UTIs is the molecular recognition of high mannose N-glycan expressed on the surface of urothelial cells by the bacterial lectin FimH, allowing the pathogen adhesion required for mammalian cell invasion. The inhibition of FimH-mediated interactions is thus a validated strategy for the treatment of UTIs. To this purpose, we designed and synthesized d-mannose multivalent dendrons supported on a calixarene core introducing a significant structural change from a previously described family of dendrimers bearing the same dendrons units on a flexible pentaerythritol scaffold core. The new molecular architecture increased the inhibitory potency against FimH-mediated adhesion processes by about 16 times, as assessed by yeast agglutination assay. Moreover, the direct molecular interaction of the new compounds with FimH protein was assessed by on-cell NMR experiments acquired in the presence of UPEC cells.

Mannose facilitates Trichinella spiralis expulsion from the gut and alleviates inflammation of intestines and muscles in mice.

Trichinellosis is a major zoonotic parasitosis which is a vital risk to meat food safety. It is requisite to exploit new strategy to interdict food animal Trichinella infection and to obliterate Trichinella from food animals to ensure meat safety. Mannose is an oligosaccharide that specifically binds to the carbohydrate-recognition domain of C-type lectin; it has many physiological functions including reliving inflammation and regulating immune reaction. The purpose of this study was to investigate the suppressive role of mannose on T. spiralis larval invasion and infection, its effect on intestinal and muscle inflammation, and immune responses after challenge. The results showed that compared to the saline-treated infected mice, the mannose-treated infected mice had less intestinal adult and muscle worm burdens, mild inflammation of intestine and muscle of infected mice. The levels of specific anti-Trichinella IgG (IgG1/IgG2a), IgA and sIgA in mannose-treated infected mice were obviously inferior to saline-treated infected mice (P < 0.01). Furthermore, the levels of two cytokines (IFN-γ and IL-4) in mannose-treated infected mice were also significantly lower than the saline-treated infected mice (P < 0.01). The protective effect of the mannose against Trichinella infection might be not related to specific antibody and cellular immune responses. The above results demonstrated that mannose could be considered as a novel adjuvant therapeutic agent for anti-Trichinella drugs to block larval invasion at early stage of Trichinella infection.

Mannose-mediated nanodelivery of methotrexate to macrophages augments rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that gravely jeopardizes the quality of life of numerous people. Methotrexate (MTX) is a disease-modifying anti-rheumatic drug commonly used in clinics; however, it suffers from slow onset, moderate efficacy, and adverse reactions such as renal dysfunction, myelosuppression, and bone erosion after long-term treatment. Here, we explored macrophage targeted delivery of MTX using mannose-installed chimaeric polymersomes (Man-PMTX) as an advanced treatment for RA. Man-PMTX exhibited high (∼18 wt%) and robust loading of MTX, uniform size of 51-55 nm, minimal hemolytic activity, and glutathione-actuated drug release property. Man-PMTX showed better uptake by activated macrophages than PMTX, and more repolarization of bone marrow-derived macrophages (BMDMs) to anti-inflammatory M2 type macrophages and less secretion of TNF-α and IL-1ß compared with free MTX and PMTX. In vivo studies revealed that Man-PMTX showed significantly higher accumulation in inflammatory joints than in healthy joints and effectively treated RA by relieving inflammation, repolarizing macrophages from M1 type to M2 type, and mitigating proinflammatory cytokines. Accordingly, Man-PMTX effectively protected the synovium and bone from damage. Mannose-mediated nanodelivery of methotrexate to macrophages appears to be an attractive strategy to augment rheumatoid arthritis therapy.

D-Mannose prevents bone loss under weightlessness.

BACKGROUND: Astronauts undergo significant microgravity-induced bone loss during space missions, which has become one of the three major medical problems hindering human's long-term space flight. A risk-free and antiresorptive drug is urgently needed to prevent bone loss during space missions. D-mannose is a natural C-2 epimer of D-glucose and is abundant in cranberries. This study aimed to investigate the protective effects and potential mechanisms of D-mannose against bone loss under weightlessness. METHODS: The hind legs of tail-suspended (TS) rats were used to mimic weightlessness on Earth. Rats were administered D-mannose intragastrically. The osteoclastogenic and osteogenic capacity of D-mannose in vitro and in vivo was analyzed by micro-computed tomography, biomechanical assessment, bone histology, serum markers of bone metabolism, cell proliferation assay, quantitative polymerase chain reaction, and western blotting. RNA-seq transcriptomic analysis was performed to detect the underlying mechanisms of D-mannose in bone protection. RESULTS: The TS rats showed lower bone mineral density (BMD) and poorer bone morphological indices. D-mannose could improve BMD in TS rats. D-mannose inhibited osteoclast proliferation and fusion in vitro, without apparent effects on osteoblasts. RNA-seq transcriptomic analysis showed that D-mannose administration significantly inhibited the cell fusion molecule dendritic cell-specific transmembrane protein (DC-STAMP) and two indispensable transcription factors for osteoclast fusion (c-Fos and nuclear factor of activated T cells 1 [NFATc1]). Finally, TS rats tended to experience dysuria-related urinary tract infections (UTIs), which were suppressed by treatment with D-mannose. CONCLUSION: D-mannose protected against bone loss and UTIs in rats under weightlessness. The bone protective effects of D-mannose were mediated by inhibiting osteoclast cell fusion. Our findings provide a potential strategy to protect against bone loss and UTIs during space missions.