Prognostic value of metabolic tumor volume and lesion dissemination from baseline PET/CT in patients with diffuse large B-cell lymphoma: Further risk stratification of the group with low-risk and high-risk NCCN-IPI.

PURPOSE: The purpose of this study was to determine the prognostic value of metabolic tumor volume and lesion dissemination from baseline PET/CT in patients with diffuse large B-cell lymphoma (DLBCL) and the prognostic value of them in the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) subgroups. METHODS: A total of 113 patients who underwent 18F-FDG PET/CT examination in our institution were retrospectively collected. The MTV was measured by iterative adaptive algorithm. The location of the lesion was obtained according to its three-dimensional coordinates, and Dmax was obtained. SDmax is derived from Dmax standardized by body surface area (BSA). The X-tile method was used to determine the optimal cut-off values for MTV, Dmax and SDmax. Cox regression analysis was used to perform univariate and multivariate analyses. Patient survival rates were derived from Kaplan-Meier curves and compared using the log-rank test. RESULTS: The median follow-up time was 24 months. The median of MTV was 196.86 cm3 (range 2.54-2925.37 cm3), and the optimal cut-off value was 489 cm3. The median of SDmax was 0.25 m-1 (range 0.12-0.51 m-1), and the best cut-off value was 0.31 m-1. MTV and SDmax were independent prognostic factors of PFS (all P < 0.001). Combined with MTV and SDmax, the patients were divided into three groups, and the difference of PFS among the groups was statistically significant (P < 0.001), and was able to stratify the risk of NCCN-IPI patients in the low-risk (NCCN-IPI < 4) and high-risk (NCCN-IPI ≥ 4) groups (P = 0.001 and P = 0.031). CONCLUSION: MTV and SDmax are independent prognostic factors for PFS in DCBCL patients, which describe tumor burden and tumor dissemination characteristics, respectively. The combination of the two could facilitate risk stratification between the low-risk and high-risk NCCN-IPI groups.

Self-Assembling Anchorage of Hyaluronic Acid on the Nanoparticle Surface Confers Superiority of Triple Negative Breast Cancer Treatment.

Triple-negative breast cancer (TNBC) has been listed as one of the most fatal diseases, and no effective targeting treatment is clinically available. Although CD44-targeting hyaluronic acid (HA) has been utilized as targeting ligands in many studies, no facile ways have been developed through HA self-assembly at the nanoparticle surface. Herein, we reported N-isopropylacrylamide-grafted chitosan-based nanoparticles self-assembling with HA (HA-NPs) through electrostatic forces and loaded with curcumin (CUR). The HA-NPs displayed pH-responsive properties due to the chemical modification of chitosan, and the preparation process was optimized by central composite design-response surface methodology. HA anchorage confers the vehicle with tumor-targeting capability. HA-NPs displayed more robust effects of inhibiting TNBC primary tumor growth than free CUR and a plain counterpart but without increased systemic cytotoxicity. In addition, in vivo pharmacokinetic studies showed that HA-NPs significantly increased the in vivo residence time of free CUR and improved the bioavailability of CUR. These findings suggested that chitosan-based HA-NPs may provide a feasible and unique strategy to achieve CD44 targeting and enhance its efficacy in vivo for the treatment of advanced TNBC.

Response of soil microbial communities to petroleum hydrocarbons at a multi-contaminated industrial site in Lanzhou, China.

Total petroleum hydrocarbon (TPH) contamination poses threats to ecological systems and human health. Many studies have reported its negative impacts on soil microbes, but limited information is known about microbial change and response to multiple TPH contamination events. In this study, we investigated TPH contamination level, microbial community structure and functional genes at a multi-contaminated industrial site in Lanzhou, where a benzene spill accident caused the drinking water crisis in 2014. TPHs distribution in soils and groundwater indicated multiple TPH contamination events in history, and identified the spill location where high TPH level (6549 mg kg-1) and high ratio of low-molecular-weight TPHs (>80%) were observed. In contrast, TPH level was moderate (349 mg kg-1) and the proportion of low-molecular-weight TPHs was 44% in soils with a long TPH contamination history. After the spill accident, soil bacterial communities became significant diverse (p = 0.047), but the dominant microbes remained the same as Pseudomonadaceae and Comamonadaceae. The abundance of hydrocarbon-degradation related genes increased by 10-1000 folds at the site where the spill accident occurred in multi-contaminated areas and was significantly related to 2-ring PAHs. Such changes of microbial community and hydrocarbon-degradation related genes together indicated the resilience of soil indigenous microbes toward multiple contamination events. Our results proved the significant change of bacterial community and huge shift of hydrocarbon-degradation related genes after the spill accident (multiple contamination events), and provided a deep insight into microbial response at industrial sites with a long period of contamination history.

Discovery of Se-containing flavone in Se-enriched green tea and the potential application value in the immune regulation.

Selenium (Se)-enriched green tea has been recognized as a possible source of supplemental Se, while the structural and physiological activities of Se-containing flavone are still unclear. In this study, a Se-containing flavone was isolated from Se-enriched green tea by high-speed counter-current chromatography (HSCCC) and characterized through UHPLC-Q-Orbitrap, FT-IR and NMR. Results proved that HSeO3- can be combined with the alcohol hydroxyl of 2-phenylchromone in flavone and the content of Se-containing flavone in tea was 15690.4 µg L-1. Additionally, Se-containing flavone can effectively inhibit the production of nitric oxide (NO), and downregulate expression of TNF-α and IL-6. Compared with regular flavone extracted from green tea (43.24 pg mL-1), release of IL-10 was higher in Se-containing flavone group (53.37 pg mL-1), indicating that Se-containing flavone played an important role in the process of severe inflammatory injury. The results indicated that Se-containing flavone was an attractive natural ingredient for developing novel functional foods.

Microbiome-metabolome responses of Fuzhuan brick tea crude polysaccharides with immune-protective benefit in cyclophosphamide-induced immunosuppressive mice.

The present study investigated the immune-protective effect of polysaccharides from Fuzhuan brick tea (FBTPs) in cyclophosphamide (Cy)-induced immunosuppressive mice. The results showed that high-dose of FBTPs administration remarkably alleviated Cy-evoked immune damage through improving the body features, organ indices, immune responses and oxidative stress in the mice. Further microbiota analysis revealed that FBTPs obviously restored Cy-evoked microbial dysbiosis by increasing several beneficial bacteria Lactobacillus, Allobaculum, Unclassified_f_Lachnospiraceae and norank_f_Lachnospiraceae, while reducing Bacteroides, norank_f_Ruminococcaceae, Colidextribacter, Alloprevotella, norank_f_Desulfovibrionaceae and Helicobacter. Meanwhile, metabolomics analysis found that FBTPs significantly altered a range of microbial metabolites, including inosine, deoxyinosine, taurine, sinapic acid, maltotriose, butyric acid, lysophosphatidyl cholines (LysoPCs), lysophosphatidic acids (LysoPAs) and choline. These altered metabolites were involved in purine metabolism, ABC transporters, sulfur metabolism, neuroactive ligand-receptor interaction, biosynthesis of phenylpropanoids, carbohydrate digestion and absorption, protein digestion and absorption, choline metabolism in cancer and glycerophospholipid metabolism pathways, which were mainly related to immune responses, antioxidant capacity and energy supply of the immunosuppressive mice. Additionally, some significant correlations were observed between the specific microbiota and effective metabolites. These results provide a novel insight into the immune-protective effect of FBTPs on regulating the intestinal microbiota and metabolism, which are helpful for thoroughly understanding the nutrition of FBTPs and providing a solid basis for the deeper utilization of Fuzhuan brick tea (FBT).

Impacts of groundwater level fluctuation on soil microbial community, alkane degradation efficiency and alkane-degrading gene diversity in the critical zone: Evidence from an accelerated water table fluctuation simulation.

Petroleum hydrocarbons are hazardous to ecosystems and human health, commonly containing n-alkanes and polycyclic aromatic hydrocarbons. Previous researches have studied alkane degraders and degrading genes under aerobic or anaerobic conditions, but seldom discussed them in the intermittent saturation zone which is a connective area between the vadose zone and the groundwater aquifer with periodic alteration of oxygen and moisture. The present study investigated the difference in alkane degradation efficiency, bacterial community, and alkane degrading gene diversity in aerobic, anaerobic, and aerobic-anaerobic fluctuated treatments. All biotic treatments achieved over 90% of n-alkane removal after 120 days of incubation. The removal efficiencies of n-alkanes with a carbon chain length from 16 to 25 were much higher in anaerobic scenarios than those in aerobic scenarios, explained by different dominant microbes between aerobic and anaerobic conditions. The highest removal efficiency was found in fluctuation treatments, indicating an accelerated n-alkane biodegradation under aerobic-anaerobic alternation. In addition, the copy numbers of the 16S rRNA gene and two alkB genes (alkB-P and alkB-R) declined dramatically when switched from aerobic to anaerobic scenarios and oppositely from anaerobic to aerobic conditions. This suggested that water level fluctuation could notably change the presence of aerobic alkane degrading genes. Our results suggested that alkane degradation efficiency, soil microbial community, and alkane-degrading genes were all driven by water level fluctuation in the intermittent saturation zone, helping better understand the effects of seasonal water table fluctuation on the biodegradation of petroleum hydrocarbons in the subsurface environment.

Comparison of water- and alkali-extracted polysaccharides from Fuzhuan brick tea and their immunomodulatory effects in vitro and in vivo.

In the present study, the purpose is to compare the effect of water extraction and alkali-assisted extraction on the structural characteristics and immunomodulatory activity of polysaccharides from Fuzhuan brick tea (FBTPs). The results indicated that water-extracted FBTPs (W-FBTPs) and alkali-extracted FBTPs (A-FBTPs) had similar molecular weights but different monosaccharide compositions, of which A-FBTPs had a higher yield and uronic acid groups corresponding to galacturonic acid (GalA). Moreover, A-FBTPs had stronger ability to promote phagocytic capacity, acid phosphatase activity and nitric oxide (NO) secretion in macrophages in vitro. In the in vivo study, A-FBTPs exhibited a promising effect to adjust the immune imbalance by enhancing the body features, antioxidant activities, immune response and intestinal mucosal barrier in cytoxan (CTX)-induced immunosuppressive mice. Besides, A-FBTP supplementation effectively improved CTX-induced gut microbiota dysbiosis, including promoting the abundance of beneficial bacteria (e.g., Lactobacillus) and short chain fatty acid (SCFA)-producing bacteria (e.g., Lachnospiraceae, Prevotellaceae and Ruminococcaceae), along with reducing the growth of potentially pathogenic microbes (e.g., Desulfovibrionaceae and Helicobacter). These findings suggested that alkaline extraction might be a promising way to obtain high-quality acidic polysaccharides from Fuzhuan brick tea (FBT), and A-FBTPs could be developed as novel potential prebiotics and immunomodulators for further application in food formulations.

New insights into metabolomics profile generation in fermented tea: the relevance of bacteria and metabolites in Fuzhuan brick tea.

BACKGROUND: The contribution of bacteria to fermented tea is not clear and the associated research is relatively limited. To reveal the role of microorganisms in fermented tea processing, the microbial community and metabolites of Fuzhuan brick tea (FBT), a Chinese traditional fermented tea, were revealed via high-throughput sequencing and liquid chromatography-mass spectrometry (LC-MS). RESULTS: In FBT, bacterial communities had a higher abundance and diversity, Lactococcus and Bacillus were the main bacteria, and Eurotium was the predominant fungus. The predictive metabolic function indicated the pathways of cellular growth, environmental information, genetics and material metabolism of bacterial communities were abundant, whereas the fungal community predictive metabolic function was almost saprotroph. Using LC-MS, 1143 and 536 metabolites were defined in positive and negative ion mode, respectively. There were essential correlations between bacterial populations and metabolites, such that Bacillus was correlated significantly with 44 metabolites (P < 0.05) and Enterococcus was significantly associated with 15 metabolites (P < 0.05). Some of the main active components were significantly correlated with the bacteria, such as Enterococcus, Lactococcus and Carnobacterium. CONCLUSION: Not only Eurotium, but also the bacteria were involved in the changes of metabolomics profile in fermented FBT. The present study assists in providing new insights into metabolomics profile generation in fermented tea. The present research lays a foundation for controlling the FBT fermentation by artificial inoculation to improve quality. © 2021 Society of Chemical Industry.

Mn-Doping-induced hierarchical petal growth of a flower-like 3D MOF assembled with black phosphorous nanosheets as an electrochemical aptasensor of human stress-induced phosphoprotein 1.

Herein, we report the preparation of Mn-doped Ni-based metal-organic frameworks (Mn-MOF) with 3D hierarchical flower-like superstructures through solvothermal synthesis. The Mn-MOF was assembled with 2D black phosphorous nanosheets (BPNSs) to achieve novel 2D/3D BPNSs/Mn-MOF nanocomposites, followed by the direct coupling of methylene blue (MB)-labeled DNA aptamer on the interface of the nanocomposites-modified glassy carbon electrode (GCE). The aptamer/BPNSs/Mn-MOF/GCE platform was utilized for the capture and efficient detection of stress-induced phosphoprotein 1 (STIP1). Experimental results confirmed that Mn-doping-induced the hierarchical petal growth of the flower-like 3D MOF and its assembly with BPNSs. GCE surface modifications with various components were studied by measuring electrochemical curves. The morphologies, microstructures and spectra of products were characterized. The optimal conditions used for electrochemical measurements were assessed. A smart aptasensor was explored by the aptamer/BPNSs/Mn-MOF/GCE that had multiple attractive merits, including synergistic effects of components, porous superstructures of hierarchical flower-like 3D Mn-MOF and specific aptamer-target recognition. The merits endowed this aptasensor with selective and sensitive signal responses to STIP1 over interferences. This aptasensor enabled the efficient detection of STIP1 in a broad range of 2 × 10-3-1 × 104 ng mL-1, accompanied by a low limit of detection of 1 pg mL-1. This aptasensor realized the successful determination of STIP1 in practical samples, exhibiting high reliability and practicability.

Assembly of black phosphorus quantum dots-doped MOF and silver nanoclusters as a versatile enzyme-catalyzed biosensor for solution, flexible substrate and latent fingerprint visual detection of baicalin.

In this work, a versatile enzyme-catalyzed biosensor was developed by using the assembled nanohybrids of black phosphorus quantum dots (BPQDs)-doped metal-organic frameworks (MOF) and silver nanoclusters (AgNCs). The nanohybrids of AgNCs/BPQDs/MOF exhibit dual-emissive fluorescence (FL) centers at 630 nm (red) and 535 nm (blue) under excitation at 440 nm. Baicalin enhances the activity of catalase and catalytic decomposition of H2O2. With increase of baicalin contents in the mixture containing nanohybrids, catalase and H2O2, the catalase-caused decomposition of H2O2 was accelerated and the excessive H2O2 was consumed. Baicalin can restrain the oxidation capability of H2O2. The red-FL (response signal) of AgNCs adhering to MOF increases, while blue-FL (reference signal) of BPQDs doped into MOF has negligible changes. A new ratiometric FL biosensor was designed based on nanohybrids and enzyme-catalyzed reaction. This biosensor enables the detection of baicalin in the range of 0.01-500 µg mL-1, with a limit of detection of 3 ng mL-1. This biosensor has high sensitivity, selectivity and stability for baicalin detection in practical samples. Especially, it performed the solution, flexible substrate and latent fingerprint visual detection of baicalin through direct observation of FL color shades with naked eyes. This work explored a facile and efficient semi-quantitative method for versatile FL visual detection, which can promote the development of advanced chemo/bio-sensors and analysis methods.

Assembly of Black Phosphorus Nanosheets and MOF to Form Functional Hybrid Thin-Film for Precise Protein Capture, Dual-Signal and Intrinsic Self-Calibration Sensing of Specific Cancer-Derived Exosomes.

As the emerging and noninvasive biomarkers, exosomes play an important role in cancer screening, cancer-related immune response, and the physiological process. The sensitive, specific, and efficient detection of cancer cell-derived exosomes is of significance for early cancer diagnosis of patients. This work developed a novel dual-signal and intrinsic self-calibration aptasensor of exosomes based on a functional hybrid thin-film platform. This platform was constructed via facile assembly of black phosphorus nanosheets (BPNSs) and ferrocene (Fc)-doped metal-organic frameworks (ZIF-67) on indium tin oxide (ITO) slice, followed by combining methylene blue (MB)-labeled single- strand DNA aptamer on ITO slice. The resultant aptamer-BPNSs/Fc/ZIF-67/ITO platform had dual redox-signal responses of MB (labeled on aptamer) and Fc (doped into ZIF-67). In the presence of specific cancer cell-derived exosomes, the redox current of MB regularly reduced and that of Fc (as reference) hardly changed. An intrinsic self-calibration aptasensor was achieved and enabled sensitive detection of exosomes, showing a limit of detection down to 100 particles mL-1. The aptasensor with a capability of precise protein capture can efficiently determine specific cancer cell-derived exosomes in practical human serum and plasma samples from healthy individuals and breast cancer patients. In light of excellent performances, this aptasensor can be expanded to multiple biomarkers from cell line exosomes and is beneficial for exploring advanced techniques for high-performance detection of exosomes derived from different types of cancer cells. This work promotes the development of current techniques for early cancer screening and clinical diagnosis.

The combined effect of oleonuezhenide and wedelolactone on proliferation and osteoblastogenesis of bone marrow mesenchymal stem cells.

BACKGROUND: Regulation of the survival and differentiation of bone marrow mesenchymal stem cells is an essential consideration in the development of targeted drugs for treatment of osteoporosis. PURPOSE: The present study aimed to evaluate the combined effect of wedelolactone and oleonuezhenide, two compounds from Chinese formula Er-Zhi-Wan, on osteoblastogenesis and the underlying molecular mechanisms. METHODS: MTT assay was taken to evaluate cell proliferation. The alkaline phosphatase (ALP) activity assay was used to determine the activity of ALP. Alizarin red S (ARS) staining was taken to indicate the intensity of the calcium deposits. Quantitative real-time PCR and Western blot were performed to the levels of Runx2, Osteocalcin, and Osterix expression in mouse bone marrow mesenchymal stem cells (BMSCs). Ovariectomized mouse model and bone histomorphometric analysis were also used to research the effects of wedelolactone and oleonuezhenide on bone loss caused by ovariectomy. RESULTS: Wedelolactone combined with oleonuezhenide enhanced osteoblast differentiation and bone mineralization. Osteoblastogenesis-related marker genes including osteocalcin, Runx2, and osteorix were upregulated in the presence of wedelolactone and oleonuezhenide. At the molecular level, oleonuezhenide did not affect GSK-3ß phosphorylation induced by wedelolactone, but elevated casein kinase 2-alpha (CK2α) expression, resulting in ß-catenin and Runx2 nuclear translocation. In addition, 30 µM wedelolactone-induced cytotoxicity in bone marrow mesenchymal stem cells was relieved by 9 µM oleonuezhenide. These cells were protected by oleonuezhenide and maintained osteoblastic activity. Oleonuezhenide increased Wnt5a and CK2α expression. Wedelolactone-reduced extracellular signal-regulated kinase (ERK) phosphorylation was reversed by oleonuezhenide. In ovariectomized mice, administration of wedelolactone and oleonuezhenide prevented ovariectomy-induced bone loss by enhancing osteoblastic activity. CONCLUSION: These results suggested that oleonuezhenide enhanced the effects of wedelolactone on osteoblastogenesis. These two compounds could be developed as a combined therapeutic agent for osteoporosis.

Caulerpa lentillifera polysaccharides enhance the immunostimulatory activity in immunosuppressed mice in correlation with modulating gut microbiota.

In this study, the immunostimulatory activity of Caulerpa lentillifera polysaccharides (CLP) was elucidated in cytoxan (CTX)-induced immunosuppressed BALB/c mice. The results showed that CLP ameliorated the CTX-evoked damage to body weight, colon length and thymus/spleen indexes and enhanced the secretions of interleukin (IL)-1ß, tumor necrosis factor (TNF)-α and superoxidase dismutase (SOD) in serum and thymic, splenic and colonic tissues of the immunosuppressed mice. Besides, CLP promoted the production of secretory immunoglobulin A (SIgA) and mucin2 in the colonic tissue of the immunosuppressed mice. Associated with the above immunostimulatory effects, CLP positively affected the production of short chain fatty acids (SCFAs) and microbiota diversity and composition, such as improvement in the growth of Lactobacillus, Coriobacteriaceae, Ruminococcaceae, Clostridium_XVIII and Helicobacter, whereas it suppressed the microbial populations of Bacteroides, Barnesiella and Lachnospiraceae. These findings suggested that CLP modulated SCFA production and gut microbiota in the immunosuppressed mice, evoking the colonic mucosal immunity, which might activate the systemic immunity in blood, thymus and spleen. The results could be helpful for understanding the functions of CLP, supporting their potential as novel prebiotics and immunostimulators.

Selective Strengthening of Intracortical Excitatory Input Leads to Receptive Field Refinement during Auditory Cortical Development.

In the primary auditory cortex (A1) of rats, refinement of excitatory input to layer (L)4 neurons contributes to the sharpening of their frequency selectivity during postnatal development. L4 neurons receive both feedforward thalamocortical and recurrent intracortical inputs, but how potential developmental changes of each component can account for the sharpening of excitatory input tuning remains unclear. By combining in vivo whole-cell recording and pharmacological silencing of cortical spiking in young rats of both sexes, we examined developmental changes at three hierarchical stages: output of auditory thalamic neurons, thalamocortical input and recurrent excitatory input to an A1 L4 neuron. In the thalamus, the tonotopic map matured with an expanded range of frequency representations, while the frequency tuning of output responses was unchanged. On the other hand, the tuning shape of both thalamocortical and intracortical excitatory inputs to a L4 neuron became sharpened. In particular, the intracortical input became better tuned than thalamocortical excitation. Moreover, the weight of intracortical excitation around the optimal frequency was selectively strengthened, resulting in a dominant role of intracortical excitation in defining the total excitatory input tuning. Our modeling work further demonstrates that the frequency-selective strengthening of local recurrent excitatory connections plays a major role in the refinement of excitatory input tuning of L4 neurons.SIGNIFICANCE STATEMENT During postnatal development, sensory cortex undergoes functional refinement, through which the size of sensory receptive field is reduced. In the rat primary auditory cortex, such refinement in layer (L)4 is mainly attributed to improved selectivity of excitatory input a L4 neuron receives. In this study, we further examined three stages along the hierarchical neural pathway where excitatory input refinement might occur. We found that developmental refinement takes place at both thalamocortical and intracortical circuit levels, but not at the thalamic output level. Together with modeling results, we revealed that the optimal-frequency-selective strengthening of intracortical excitation plays a dominant role in the refinement of excitatory input tuning.

Aphthous ulcer drug inhibits prostate tumor metastasis by targeting IKKɛ/TBK1/NF-κB signaling.

Tumor metastasis is the major cause of death for prostate cancer (PCa) patients. However, the treatment options for metastatic PCa are very limited. Epithelial-mesenchymal transition (EMT) has been reported to be an indispensable step for tumor metastasis and is suggested to associate with acquisition of cancer stem cell (CSC) attributes. We propose that small-molecule compounds that can reverse EMT or induce mesenchymal-epithelial transition (MET) of PCa cells may serve as drug candidates for anti-metastasis therapy. Methods: The promoters of CDH1 and VIM genes were sub-cloned to drive the expression of firefly and renilla luciferase reporter in a lentiviral vector. Mesenchymal-like PCa cells were infected with the luciferase reporter lentivirus and subjected to drug screening from a 1274 approved small-molecule drug library for the identification of agents to reverse EMT. The dosage-dependent effect of candidate compounds was confirmed by luciferase reporter assay and immunoblotting. Wound-healing assay, sphere formation, transwell migration assay, and in vivo intracardiac and orthotopic tumor xenograft experiments were used to evaluate the mobility, metastasis and tumor initiating capacity of PCa cells upon treatment. Possible downstream signaling pathways affected by the candidate compound treatment were analyzed by RNA sequencing and immunoblotting. Results: Drug screening identified Amlexanox, a drug used for recurrent aphthous ulcers, as a strong agent to reverse EMT. Amlexanox induced significant suppression of cell mobility, invasion, serial sphere formation and in vivo metastasis and tumor initiating capacity of PCa cells. Amlexanox treatment led to downregulation of the IKK-ɛ/ TBK1/ NF-κB signaling pathway. The effect of Amlexanox on EMT reversion and cell mobility inhibition can be mimicked by other IKK-ɛ/TBK1 inhibitors and rescued by reconstitution of dominant active NF-κB. Conclusions: Amlexanox can sufficiently suppress PCa metastasis by reversing EMT through downregulating the IKK-ɛ/TBK1/NF-κB signaling axis.

Sulfated polysaccharide from sea cucumber modulates the gut microbiota and its metabolites in normal mice.

Sulfated polysaccharide from sea cucumber (SCSP) has been demonstrated with various health effects, the mechanism of which, however, remains poorly understood. This study aimed to investigate the possible mechanism exhibited by gut microbiota in response to SCSP. BALB/c mice were fed diets supplemented with SCSP and depolymerized SCSP (d-SCSP) for 42 days. The microbiota composition, short chain fatty acids (SCFAs), lipopolysaccharide-binding protein (LBP), body weight and gut tissue index were analyzed. Results revealed that both SCSP and d-SCSP positively regulated the gut microbiota as indicated by the enriched microbiota diversity, SCFA-producing bacteria and sulfide-degrading bacteria, and decreased harmful bacteria. Moreover, SCSP and d-SCSP not only significantly improved the levels of microbial metabolites including SCFAs and LBP, but also effectively adjusted body weight and gut tissue index. The microbial metabolites were identified to strongly correlate with the growth performance using Pearson's correlation coefficient. We further showed that the modulating effect of SCSP on the gut microbiota was altered by free-radical depolymerization, while the microbial metabolites and related growth performance were not. These findings suggest that SCSP can be used as a gut microbiota manipulator for health promotion and alter the gut microbiota in a molecular weight (Mw) dependent manner.

Enhanced blood-brain barrier transport of vinpocetine by oral delivery of mixed micelles in combination with a message guider.

The blood-brain barrier represents an insurmountable obstacle for the therapy of central nervous system related diseases. Polymeric micelles have many desirable properties for brain targeting by oral delivery, but the stability and targeting efficiency needs to be improved. In this study, it was demonstrated that binary micelle system can compensate the drawbacks of mono system by preparing mixed micelles in combination with PEG-based copolymers. Here, we explored a brain targeting drug delivery system via facile approaches using P123 based mixed micelles in combination with a message guider from traditional Chinese medicine, borneol, for oral delivery. With higher drug-loading, improved stability, prolonged in vitro release profile, increased bioavailability and enhanced brain targeting effect was achieved after peroral delivery of the mixed micelles. More importantly, without extra structure modification for active targeting, it was demonstrated for the first time that oral delivery of vinpocetine loaded mixed micelles together with borneol is an effective way to increase drug concentration in the brain and the targeting efficiency is borneol dose dependent. Such a "simple but effective" modality may shed light on the potential use of polymeric micelles in combination with a message drug to achieve drug brain targeting or other targeting sites via oral delivery.

Synthesis, characterization and liver targeting evaluation of self-assembled hyaluronic acid nanoparticles functionalized with glycyrrhetinic acid.

Recently, polymeric materials with multiple functions have drawn great attention as the carrier for drug delivery system design. In this study, a series of multifunctional drug delivery carriers, hyaluronic acid (HA)-glycyrrhetinic acid (GA) succinate (HSG) copolymers were synthesized via hydroxyl group modification of hyaluronic acid. It was shown that the HSG nanoparticles had sub-spherical shape, and the particle size was in the range of 152.6-260.7nm depending on GA graft ratio. HSG nanoparticles presented good short term and dilution stability. MTT assay demonstrated all the copolymers presented no significant cytotoxicity. In vivo imaging analysis suggested HSG nanoparticles had superior liver targeting efficiency and the liver targeting capacity was GA graft ratio dependent. The accumulation of DiR (a lipophilic, NIR fluorescent cyanine dye)-loaded HSG-6, HSG-12, and HSG-20 nanoparticles in liver was 1.8-, 2.1-, and 2.9-fold higher than that of free DiR. The binding site of GA on HA may influence liver targeting efficiency. These results indicated that HSG copolymers based nanoparticles are potential drug carrier for improved liver targeting.

Exploring the effect of hydrophilic and hydrophobic structure of grafted polymeric micelles on drug loading.

The objective of this paper is to explore the effect of hydrophilic and hydrophobic structure of grafted polymeric micelles on drug loading, and elucidate whether drug-polymer compatibility, as predicted by Hansen solubility parameters (HSPs), can be used as a tool for drug-polymer pairs screening and guide the design of grafted polymeric micelles. HSPs of 27 drugs and three grafted copolymers were calculated according to group contribution method. The drug-polymer compatibilities were evaluated using the approaches of Flory-Huggins interaction parameters (χFH) and polarity difference (△Xp). Two models, model A and B, were put forward for drug-polymer compatibility prediction. In model A, hydrophilic/hydrophobic part as a whole was regarded as one segment. And, in model B, hydrophilic and hydrophobic segments were evaluated individually. First of all, using chitosan (CS)-grafted-glyceryl monooeate (GMO) based micelle as an example, the suitability of model A and model B for predicating drug-polymer compatibility was evaluated theoretically. Thereafter, corresponding experiments were carried out to check the validity of the theoretical prediction. It was demonstrated that Model B, which evaluates drug compatibility with both hydrophilic and hydrophobic segments of the copolymer, is more reliable for drug-polymer compatibility prediction. Moreover, the approach of model B allows for the selection of a defined grafted polymer with for a specific drug and vice versa. Thus, drug compatibility evaluation via HSPs with both hydrophilic and hydrophobic segments is a suitable tool for the rational design of grafted polymeric micelles. The molecular dynamics (MD) simulation study provided further support to the established model and experimental results.

Separating and characterizing functional alkane degraders from crude-oil-contaminated sites via magnetic nanoparticle-mediated isolation.

Uncultivable microorganisms account for over 99% of all species on the planet, but their functions are yet not well characterized. Though many cultivable degraders for n-alkanes have been intensively investigated, the roles of functional n-alkane degraders remain hidden in the natural environment. This study introduces the novel magnetic nanoparticle-mediated isolation (MMI) technology in Nigerian soils and successfully separates functional microbes belonging to the families Oxalobacteraceae and Moraxellaceae, which are dominant and responsible for alkane metabolism in situ. The alkR-type n-alkane monooxygenase genes, instead of alkA- or alkP-type, were the key functional genes involved in the n-alkane degradation process. Further physiological investigation via a BIOLOG PM plate revealed some carbon (Tween 20, Tween 40 and Tween 80) and nitrogen (tyramine, l-glutamine and d-aspartic acid) sources promoting microbial respiration and n-alkane degradation. With further addition of promoter carbon or nitrogen sources, the separated functional alkane degraders significantly improved n-alkane biodegradation rates. This suggests that MMI is a promising technology for separating functional microbes from complex microbiota, with deeper insight into their ecological functions and influencing factors. The technique also broadens the application of the BIOLOG PM plate for physiological research on functional yet uncultivable microorganisms.