PM2.5 induced neurotoxicity through unbalancing vitamin B12 metabolism by gut microbiota disturbance.

Fine particulate matter (PM2.5) in the atmosphere is easily accompanied by toxic and harmful substances, causing serious harm to human health, including cognitive impairment. Vitamin B12 (VitB12) is an essential micronutrient that is synthesized by bacteria and contributes to neurotransmitter synthesis as a nutrition and signaling molecule. However, the relationship between VitB12 attenuation of cognitive impairment and intestinal microbiota regulation in PM2.5 exposure has not been elucidated. In this study, we demonstrated that PM2.5 caused behavioral defects and neuronal damage in Caenorhabditis elegans (C. elegans), along with significant gene expression changes in neurotransmitter receptors and a decrease in VitB12 content, causing behavioral defects and neuronal damage in C. elegans. Methylcobalamin (MeCbl), a VitB12 analog, alleviated PM2.5-induced neurotoxicity in C. elegans. Moreover, using in vivo and in vitro models, we discovered that long-term exposure to PM2.5 led to changes in the structure of the gut microbiota, resulting in an imbalance of the VitB12-associated metabolic pathway followed by cognitive impairment. MeCbl supplementation could increase the diversity of the bacteria, reduce harmful substance contents, and restore the concentration of short-chain fatty acids (SCFAs) and neurotransmitters to the level of the control group to some degree. Here, a new target to mitigate the harm caused by PM2.5 was discovered, supplying MeCbl for relieving intestinal and intracellular neurotransmitter disorders. Our results also provide a reference for the use of VitB12 to target the adjustment of the human intestinal microbiota to improve metabolic disorders in people exposed to PM2.5.

[Quality analysis of Rosae Radix et Rhizoma].

Rosae Radix et Rhizoma is a herbal medicine in a variety of famous Chinese patent medicines, while the quality standard for this medicine remains to be developed due to the insufficient research on the quality of Rosae Radix et Rhizoma from different sources. Therefore, this study comprehensively analyzed the components in Rosae Radix et Rhizoma of different sources from the aspects of extract, component category content, identification based on thin-lay chromatography, active component content determination, and fingerprint, so as to improve the quality control. The results showed that the content of chemical components varied in the samples of different sources, while there was little difference in the chemical composition among the samples. The content of components in the roots of Rosa laevigata was higher than that in the other two species, and the content of components in the roots was higher than that in the stems. The fingerprints of triterpenoids and non-triterpenoids were established, and the content of five main triterpenoids including multiflorin, rosamultin, myrianthic acid, rosolic acid, and tormentic acid in Rosae Radix et Rhizoma was determined. The results were consistent with those of major component categories. In conclusion, the quality of Rosae Radix et Rhizoma is associated with the plant species, producing area, and medicinal parts. The method established in this study lays a foundation for improving the quality standard of Rosae Radix et Rhizoma and provides data support for the rational use of the stem.

Lead dissociation and redistribution properties of actual contaminated farmland soil after long-term EKAPR treatment.

Electrokinetic-assisted phytoremediation (EKAPR) is a potential technology much affected by the metal species and accessibility to plant roots. In this study, Pb-contaminated red soil was remediated with Sedum plumbizincicola to investigate the changes in soil pH, available nutrients, dissociation and redistribution of Pb under a long-term periodic reversal direct-current electric field. This approach could effectively activate soil P, K, organic matter (OM) and Pb, without significant soil acidification; the effect was positively correlated with applied voltage. Soil Pb can be continuously dissociated, migrated, and tended to accumulate in the middle region. The maximum Pb removal rate in the anodic section of the EKAPR system was 21.4%, and the aggregation rate in middle regions was 14.4%, higher than the available Pb content of the original soil. The Pb desorption in aqueous solution increased significantly with increasing voltage, irrespective of the solution pH. At a voltage of 20 V, the Pb cumulative desorption content reached 91.1 mg kg-1 (pH = 7), which was 2.7 times than that without electric field (33.2 mg kg-1). Compared to original soil (2.80 mg kg-1) and the control (14.54 mg kg-1), the available Pb in the anode section of EKAPR system (20.66 mg kg-1) increased by 637.9% and 42.1%, respectively. These results indicated that except for the indirect influence of soil pH changes, electrodynamics can directly promote the bioavailability and dissociation of Pb at the soil-water interface. This finding provides a new perspective for further studies on the mechanism of Pb speciation evolution and accumulation changes using EKAPR.

Lysine-specific demethylase 1 in primary sensory neurons participates in chronic compression of dorsal root ganglion-induced neuropathic pain.

Low back and radicular pain syndromes, usually caused by local inflammation and irritation to the nerve root and dorsal root ganglion (DRG), are common throughout medical practice, but sufficient pain relief is scarce. In this study, we employed a chronic compression of DRG (CCD)-induced radicular pain model in rats to explore whether lysine-specific demethylase 1 (LSD1), a histone demethylase and transcriptional co-repressor, is involved in the pathological process of radicular pain. We found that LSD1 was expressed in various-sized DRG neurons by immunohistochemistry. CCD induced the upregulation of LSD1 in compressed L4-L5 DRGs. Moreover, either LSD1 small interfering RNAs or LSD1 inhibitor attenuated CCD-induced pain hypersensitivities. LSD1 was also upregulated in the injured lumbar 4 (L4) DRG in a spinal nerve ligation (SNL)-induced neuropathic pain mouse model. Nevertheless, LSD1 was not altered in L3-L5 DRGs in complete Freund's adjuvant-induced inflammatory pain mouse model, paclitaxel- or streptozotocin-induced neuropathic pain models. Furthermore, knockdown of LSD1 in the injured L4 DRG reversed SNL-induced pain hypersensitivities in mice. Therefore, we speculate that nerve injury induced the upregulation of LSD1 in the injured DRGs, which contributes to neuropathic pain hypersensitivities; thus, LSD1 may serve as a potential target for the treatment of radicular pain and neuropathic pain.

Preparation of alginate-whey protein isolate and alginate-pectin-whey protein isolate composites for protection and delivery of Lactobacillus plantarum.

Probiotics are sensitive to external conditions, resulting in low survival rates after being ingested or during food production, transportation and storage. In order to improve the survival rate of Lactobacillus plantarum (LP) during gastrointestinal digestion, storage, and freeze-drying, alginate-whey protein isolate (ALG-WPI) and alginate-pectin-whey protein isolate (ALG-PEC-WPI) composites were employed to encapsulate LP. The encapsulation efficiency of ALG-WPI-LP and ALG-PEC-WPI-LP beads both reached more than 99 %. Scanning electron microscopy (SEM) indicated that dense and rough aggregates were formed on the surface of both composites, and attached LP cells could be observed inside the beads. The ALG-WPI and ALG-PEC-WPI composites can protect the viability of LP in simulated gastric fluid (SGF) and release the probiotics in simulated intestinal fluid (SIF). The storage stability of LP at 4 °C was improved by about 15 % in comparison with bare LP and the survival rates of LP in ALG-WPI-LP and ALG-PEC-WPI-LP powders after freeze-drying were increased by 65.37 % and 72.06 %, respectively. The formation mechanism of ALG-WPI and ALG-PEC-WPI composites was further explored by fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and thermogravimetric analysis (TGA). The ALG-WPI and ALG-PEC-WPI composites have great potential to protect and deliver probiotics in food systems.

Effects of expressive art therapy on health status of patients with chronic obstructive pulmonary disease: a community-based cluster randomized controlled trial.

BACKGROUND AND OBJECTIVE: This study was performed to investigate the effect of expressive art therapy (EAT) on the health status of patients with chronic obstructive pulmonary disease (COPD). METHODS: This community-based cluster randomized controlled trial involved patients with COPD from 16 communities in China. Participants received either EAT plus usual care (UC) or UC only. General practitioners were trained in EAT before the intervention. The primary outcomes were depression and anxiety symptoms, measured with the Hospital Anxiety and Depression Scale (HADS) and expressed as the HADS score for depression or anxiety (HADS-D or HADS-A, respectively). The secondary outcomes were the quality of life and dyspnoea, measured with the COPD assessment test (CAT). Dyspnoea was assessed using the modified Medical Research Council (mMRC) dyspnoea scale. Lung function was expressed as the forced expiratory volume in 1 s as a percentage of the predicted value [FEV1 (% pred)]. Outcome data were collected from all participants at baseline, 2 and 6 months. RESULTS: In total, 360 participants with COPD and comorbid depression were included in the analysis with the control group of 181 receiving UC only and the intervention group of 179 receiving EAT plus UC. The EAT group showed significantly greater improvement in the HADS-D and HADS-A scores than the UC group at 2 months (p < 0.0001 and p < 0.001, respectively) and 6 months (p < 0.001 for both). The CAT and mMRC scores were significantly lower in the EAT group than in the UC group at 2 and 6 months (p < 0.001 for all). The FEV1 (% pred) was significantly higher in the EAT group than in the UC group at 6 months (p < 0.01). CONCLUSION: General practitioners can deliver EAT interventions. EAT can effectively reduce anxiety and depression symptoms and dyspnoea, improve quality of life and improve the pulmonary function of patients with COPD.

Facile and Selective Determination of Total Phthalic Acid Esters Level in Soft Drinks by Molecular Fluorescence Based on Petroleum Ether Microextraction and Selective Derivation by H2SO4.

Determining the level of phthalic acid esters (PAEs) in packaged carbonated beverages is a current need to ensure food safety. High-selectivity and -accuracy identification of individual PAEs can be achieved by chromatographic and mass spectrometric (MS) techniques. However, these methods are slow; involve complicated, expensive instruments in professional laboratories; and consume a large amount of organic solvents. As such, a food analysis method is needed to conveniently and rapidly evaluate multiple contaminants on site. In this study, with the assistance of ultrasound, we quickly determined the total PAEs in soft drinks using 1.5 mL of petroleum ether in one step. Then, we determined the characteristic molecular fluorescence spectrum of all PAEs in samples (excitation (Ex)/emission (Em) at 218/351 nm) using selectively concentrated sulfuric acid derivatization. The relative standard deviations of the fluorescent intensities of mixed solutions with five different PAEs were lower than 7.1% at three concentration levels. The limit of detection of the proposed method is 0.10 µmol L-1, which matches that of some of the chromatographic methods, but the proposed method uses less organic solvent and cheaper instruments. These microextraction devices and the fluorescence spectrometer are portable and provide an instant result, which shows promise for the evaluation of the total level of PAEs in beverages on site. The proposed method successfully detected the total level of PAEs in 38 kinds of soft drink samples from local supermarkets, indicating its potential for applications in the packaged beverage industry.

pH/Thermal-Sensitive Nanoplatform Capable of On-Demand Specific Release to Potentiate Drug Delivery and Combinational Hyperthermia/Chemo/Chemodynamic Therapy.

Therapeutic platforms with spatiotemporal control were recently of considerable interest. However, the site-specific regulation of chemotherapeutics release remains an enormous challenge. Herein, a versatile nanoplatform capable of tumor-specific delivery and controlled drug release, coined as PDDFe, was constructed for elevating cancer theranostics. Iron-oxide nanoparticles (IONPs) and doxorubicin (Dox) were encapsulated in pH/thermal-sensitive micelles composed of poly(ethylene)glycol-poly(ß-amino esters) and dipalmitoyl phosphatidylcholine to obtain tumor-targeted dual-responsive nanoplatforms. With remarkable magnetic targeting effects, PDDFe specifically accumulated at tumor locations. After internalization by cancer cells, the acidic environment and localized heat generated by hyperthermia therapy would spur PDDFe to become loose and collapse to liberate its payload. In addition to boosting the release, the increased temperature also resulted in direct tumor damage. Meanwhile, the released Dox and IONPs, respectively, stimulated chemotherapy and chemodynamic therapy to jointly destroy cancer, thus leading to a pronounced therapeutic effect. In vivo magnetic resonance/fluorescence/photoacoustic imaging experiments validated that the dual-sensitive nanoplatforms were able to accumulate at the tumor sites. Treatment with PDDFe followed by alternating magnetic field and laser irradiation could prime hyperthermia/chemo/chemodynamic therapy to effectively retard tumor growth. This work presents a nanoplatform with a site-specific controlled release characteristic, showing great promises in potentiating drug delivery and advancing combinational cancer therapy.

Methylcobalamin Alleviates Neuronal Apoptosis and Cognitive Decline Induced by PM2.5 Exposure in Mice.

BACKGROUND: Fine particulate matter (particulate matter 2.5, PM2.5) is considered one of the harmful factors to neuronal functions. Apoptosis is one of the mechanisms of neuronal injury induced by PM2.5. Methylcobalamine (MeCbl) has been shown to have anti-apoptotic and neuroprotective effects. OBJECTIVE: The current work tried to explore the neuroprotective effects and mechanisms that MeCbl protects mice against cognitive impairment and neuronal apoptosis induced by chronic real-time PM2.5 exposure. METHODS: Twenty-four 6-week-old male C57BL/6 mice were exposed to ambient PM2.5 and fed with MeCbl for 6 months. Morris water maze was used to evaluate the changes of spatial learning and memory ability in mice. PC12 cells and primary hippocampal neurons were applied as the in vitro model. Cell viability, cellular reactive oxygen species (ROS) and the expressions of apoptosis-related proteins were examined. And cells were stained with JC-1 and mitochondrial membrane potential was evaluated. RESULTS: In C57BL/6 mice, MeCbl supplementation alleviated cognitive impairment and apoptosis-related protein expression induced by PM2.5 exposure. In in vitro cell model, MeCbl supplementation could effectively rescue the downregulation of cell viability induced by PM2.5, and inhibited the increased levels of ROS, cellular apoptosis, and the expressions of apoptosis related proteins related to PM2.5 treatment, which may be associated with modulation of mitochondrial function. CONCLUSION: MeCbl treatment alleviated cognitive impairment and neuronal apoptosis induced by PM2.5 both in vivo and in vitro. The mechanism for the neuroprotective effects of MeCbl may at least be partially dependent on the regulation of mitochondrial apoptosis.

Mn(II)-directed dual-photosensitizers co-assemblies for multimodal imaging-guided self-enhanced phototherapy.

Phototherapy has attracted increasing attention in cancer therapy owing to its non-invasive nature, high spatiotemporal selectivity, and negligible side effects. However, a single photosensitizer often exhibits poor photothermal conversion efficiency or insufficient reactive oxygen species (ROS) productivity. Even worse, the ROS can be consumed by tumor overexpressed reductive glutathione, resulting in severely compromised phototherapy. In this paper, we prepared a MnII-coordination driven dual-photosensitizers co-assemblies (IMCP) for imaging-guided self-enhanced PDT/PTT. Specifically, a photothermal agent indocyanine green (ICG), a photodynamic agent chlorin e6 (Ce6), and a transition metal ion (MnII/III) were chosen to synthesize the nanodrug via coordination-driven co-assembly. The as-prepared IMCP exhibited extremely high photosensitizer payload (96 wt%), excellent physiological stability, and outstanding tumor accumulation. Moreover, the existence of MnII not only assists the nanostructure formation but also could competitively coordinate with GSH to minimize the unnecessary ROS consumption, thus improving PDT efficiency. Meanwhile, benefiting from the intrinsic fluorescence, photoacoustic imaging ability of photosensitizers, and the MRI contrast potential of MnII/III, IMCP exhibited superior imaging potential for guiding tumor phototherapy. By changing the excitation wavelength suitably, IMCP could realize the switch between PTT and PDT. In short, the dual-PSs co-assembled nanotheranostic has great potential for multi-modal imaging guided phototherapy.

A carrier-free metal-coordinated dual-photosensitizers nanotheranostic with glutathione-depletion for fluorescence/photoacoustic imaging-guided tumor phototherapy.

As a promising noninvasive tumor treatment modality, dual phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), has drawn extensive research interest in imaging-guided synergistic antitumor treatment. However, developing a high-efficient phototherapeutic agent is still a huge challenge, since single photosensitizer often suffers from the insufficient photothermal conversion efficiency (PCE) or low reactive oxygen species (ROS) productivity. Moreover, the overexpression of reductive glutathione (GSH) in tumor cells also severely compromises PDT efficiency. Here, inspired by the glutathione oxidase activity of high-valent transition metal ions, we designed a copper-coordinated nanotheranostic (PhA@NanoICG) by the coordination-driven co-assembly of photothermal-agent indocyanine green (ICG) and photodynamic-agent pheophorbide A (PhA), in which Cu2+ acted as a bridge to tightly associate ICG with PhA. Such carrier-free metal-coordinated nanotheranostics exhibited ultra-high dual-photosensitizers co-loading (~96.74 wt%) and excellent structural stability. Notably, NanoICG significantly increase the PCE of ICG via J-aggregation induced UV-vis absorption red-shift. Once PhA@NanoICG accumulated in tumor sites, they could be disassembled triggered by the weakly acidic and highly reducible tumor microenvironment. Moreover, the Cu2+ can deplete intracellular GSH and impair cellular antioxidant defense system, reducing the unnecessary ROS consumption caused by glutathione. Under fluorescence/photoacoustic imaging-guided laser irradiation, local hyperthermia and ROS were generated to induce tumor cells apoptosis. The in vitro and in vivo experiments consistently confirm that PhA@NanoICG could induce remarkable tumor inhibition through self-enhanced PTT and PDT, which may pave a new way for cancer therapy.

Erythrocyte membrane bioengineered nanoprobes via indocyanine green-directed assembly for single NIR laser-induced efficient photodynamic/photothermal theranostics.

Traditional combinational photodynamic therapy (PDT) and photothermal therapy (PTT) were limited in clinical therapy of cancer due to exceptionally low drug payload and activation by light with separate wavelengths. We have accidentally discovered that zinc phthalocyanine (ZNPC, a typical hydrophobic photosensitizer) and indocyanine green (ICG, a clinically approved fluorescence probe) could be co-assembled into carrier-free nanodrugs (almost 100 wt%) for single NIR laser-induced efficient PDT/PTT. Interestingly, ICG could act as "transformers" for modulating the geometric shape of ZNPC/ICG co-assembling structures from needle-like/spindle-like structure via cubic structure finally to spherical structure. Unfortunately, the nanodrugs suffered from rapid immune clearance. The ZNPC-ICG nanoprobes were further embedded into the erythrocyte membrane (RBC)-camouflaged framework. The designed ZNPC-ICG@RBC could be efficiently accumulated within the tumor sites (continue for ~60 h) and rapidly internalized into cancer cells upon laser irradiation rather than macrophage RAW264.7 cells. Compared with the free ZnPC or ICG, the biomimetic ZNPC-ICG@RBC nanoprobes exhibited amplified therapeutic effects by simultaneously producing ROS and hyperthermia, thereby synergistically improving antitumor efficiency and eliminating the tumors without any regrowth under the guidance of fluorescence imaging. The co-delivery of ZnPC and ICG via a biomimetic carrier-free system might be a promising strategy for bimodal phototherapy of cancer.

Vitamin B12 Enriched in Spinach and its Effects on Gut Microbiota.

Meat and fermented foods are the main source of vitamin B12 (cobalamin) for human beings. Therefore, daily cobalamin intake is a big problem for vegans. In this study, cyanocobalamin (CNCBL) was added to the culture broth for cobalamin enrichment in spinach. After 36 h of cultivation, the accumulated CNCBL in the spinach leaves (wet weight) was as high as 0.48% (concentration), and the leaves still contained 0.94 ± 0.11 µg/g CNCBL after boiling, which could provide consumer daily requirement of CNCBL. Because CNCBL supplementation had adverse effects on gut microbiota, this study focused on the effect of the combination of spinach and CNCBL on gut microbiota as well. After the boiled leaves were passed through an in vitro gastrointestinal tract simulation system, it was found that the spinach protected CNCBL against the low-pH gastric acid. Moreover, compared with the CNCBL supplement group, the relative abundances of Bacteroides and Firmicutes increased, and the relative abundance of Proteobacteria, especially Escherichia spp., reduced. Analysis of short-chain fatty acids (SCFAs) showed that cobalamin-rich spinach was positively correlated with Bacteroides, propionate, and butyrate. The results showed that the method of enriching spinach with CNCBL was effective and had beneficial effects on gut microbiota and SCFAs.

Electrochemically Controlled Synthesis of Ultrathin Nickel Hydroxide Nanosheets for Electrocatalytic Oxygen Evolution.

The development of oxygen evolution reaction (OER) catalysts with high activity and high stability through convenient and economical methods is greatly important for the promotion of hydrogen energy based on electrolysis technology. Herein, by using an unconventional high electrodeposition potential, novel petal-like clusters constructed by cross-linking ultrathin nickel hydroxide nanosheets were controllably synthesized on nickel foam (or copper foam or carbon cloth) and the effect of electrodeposition conditions on their OER performance was carefully explored. Due to the abundant catalytically active sites, promoting electron conduction/mass transmission from the specific micro-nano structure, as well as the ultrasmall thickness of ∼3.0 nm, the optimized α-Ni(OH)2/NF self-supporting electrode exhibits excellent electrocatalytic performance for OER, merely requiring low overpotentials of 192 and 240 mV to yield current densities of 10 and 100 mA cm-2 in 1.0 M KOH, respectively, which surpassed those of all of the reported nickel hydroxide/oxides and the benchmark RuO2. Moreover, α-Ni(OH)2/NF can drive the high-current density (500-1000 mA cm-2) OER at low overpotentials, meeting the requirements of potential industrial applications.

Gut microbiota affect the formation of calcium oxalate renal calculi caused by high daily tea consumption.

Kidney stones are a common and frequently occurring disease worldwide. Stones can cause urinary tract obstruction, pain, haematuria, and other symptoms. In this study, the relationship between calcium oxalate renal calculi and gut microbiota was considered. The dietary habits of 30 patients with calcium oxalate kidney stones and 30 healthy people were investigated. The 16S rDNA sequences and short-chain fatty acids (SCFAs) in their stool samples were analysed. We identified 5 genera of the gut microbiota as biomarkers for calcium oxalate renal calculi, namely, Bacteroides, Phascolarctobacterium, Faecalibacterium, Akkermansia, and Lactobacillus, with a receiver operating characteristic (ROC) curve value of 0.871 (95% confidence interval (CI) 0.785-0.957). Phascolarctobacterium and Faecalibacterium showed a positive relationship with SCFA synthesis to reduce the risk of kidney stones. Meanwhile, according to the analysis, Lactobacillus spp. made the largest contribution (79%) to prevent kidney stones caused by tea consumption, since tea offers the great parts of oxalate in kidney stone formation. Three strains of Lactobacillus spp. were isolated from stools of a healthy person with a high level of tea consumption who did not suffer from kidney stones. All these strains survived in the colon with supplementation of high concentrations of tea and efficiently degraded oxalic acid (Ca. 50%) in an in vitro colonic simulation. Therefore, a suitable adjustment of the gut microbiota or SCFA concentration enhanced the degradation of oxalate from food, which can be applied to prevent the formation of calcium oxalate renal calculi caused by tea. KEY POINTS: • Five genera, including Lactobacillus, were identified as biomarkers for calcium oxalate renal calculi. • Lactobacillus is a potential gut bacterium associated with preventing kidney stone formation. • Isolated Lactobacillus strains have the ability to degrade oxalic acid in vitro.

[Research progress of tannins in traditional Chinese medicines in recent ten years].

In this paper, the newly isolated tannins were sorted after a review of the literature concerning tannins in recent 10 years, and their research progress was summarized in terms of extraction, isolation, pharmacological activity and metabolism. Hydrolysable tannins and condensed tannins are the main structural types. Modern research shows that tannins have many pharmacological effects, such as bacteriostasis, antioxidation, antitumor, antivirus and blood glucose reduction, and have broad development prospects. They are usually extracted by water, ethanol and acetone and isolated and purified by macroporous resin and gel column chromatography. The packings commonly adopted for the column chromatography mainly included Sephadex LH-20, Diaion HP-20, MCI-gel CHP-20 and Toyopearl HW-40. Modern analytical techniques such as nuclear magnetic resonance spectroscopy(NMR), fast atom bombardment mass spectrometry(FAB-MS) and circular dichroism(CD) are generally used for the structural identification of tannins. Howe-ver, their isolation, purification and structural identification are still challenging. It is necessary to use a variety of high-throughput screening methods to explore their pharmacological activities and to explore the material basis responsible for their functions through experiments in vivo.

Milk phospholipid supplementation mediates colonization resistance of mice against Salmonella infection in association with modification of gut microbiota.

Gut microbiota-mediated colonization resistance against enteropathogens is known to be greatly influenced by bioactive food compounds. This work aims to investigate the effects of milk phospholipid (MP) supplementation on the colonization resistance of mice to Salmonella enterica serovar Typhimurium (S. Typhimurium) infection, with the focus mainly on the change of gut microbiota. Comparative microbiota analysis based on 16S rRNA gene sequence data of mice under different MP supplementation situations allowed us to identify specific microbiota characteristics associated with the varying degree of susceptibility to S. Typhimurium infection. We found that a moderate dietary intake of MPs (0.05 wt%) significantly increased the relative abundance of Bacteroides spp. (p < 0.05) and the propionate level (p < 0.05) in the mouse colon and enhanced colonization resistance against S. Typhimurium infection, when compared with the un-supplemented S. Typhimurium-infected mice, whereas excessive MP supplementation (0.25 wt%) did not significantly change the level of Bacteroides spp. (p > 0.05) and propionate (p > 0.05) and even enhanced the susceptibility and severity of S. Typhimurium infection. Furthermore, the inhibitory effects of Bacteroides spp. and propionate on S. Typhimurium intestinal colonization were verified in an ex vivo S. Typhimurium-infected 3D colonoid culture system. Our results showed that the supplementation of nutraceuticals may not always be the more the better, particularly under specific pathological conditions, and identification of specific gut microbiota characteristics may have the potential to become an indicator of appropriate supplementation in specific cases.

Ursolic acid reverses liver fibrosis by inhibiting interactive NOX4/ROS and RhoA/ROCK1 signalling pathways.

Liver fibrosis is the reversible deposition of extracellular matrix (ECM) and scar formation after liver damage by various stimuli. The interaction between NOX4/ROS and RhoA/ROCK1 in liver fibrosis is not yet clear. Ursolic acid (UA) is a traditional Chinese medicine with anti-fibrotic effects, but the molecular mechanism underlying these effects is still unclear. We investigated the interaction between NOX4/ROS and RhoA/ROCK1 during liver fibrosis and whether these molecules are targets for the anti-fibrotic effects of UA. First, we confirmed that UA reversed CCl4-induced liver fibrosis. In the NOX4 intervention and RhoA intervention groups, related experimental analyses confirmed the decrease in CCl4-induced liver fibrosis. Next, we determined that the expression of NOX4 and RhoA/ROCK1 was decreased in UA-treated liver fibrotic mice. Furthermore, RhoA/ROCK1 expression was decreased in the NOX4 intervention group, but there was no significant change in the expression of NOX4 in the RhoA intervention group. Finally, we found that liver fibrotic mice showed a decline in their microbiota diversity and abundance, a change in their microbiota composition, and a reduction in the number of potential beneficial bacteria. However, in UA-treated liver fibrotic mice, the microbiota dysbiosis was ameliorated. In conclusion, the NOX4/ROS and RhoA/ROCK1 signalling pathways are closely linked to the development of liver fibrosis. UA can reverse liver fibrosis by inhibiting the NOX4/ROS and RhoA/ROCK1 signalling pathways, which may interact with each other.

Design of light/ROS cascade-responsive tumor-recognizing nanotheranostics for spatiotemporally controlled drug release in locoregional photo-chemotherapy.

Carrier-free nanotheranostics with high drug loading and no carrier-related toxicity are highly promising cancer therapy agents. However, the limited tumor accumulation and poorly controlled drug release of these nanotheranostics continue to be major challenges that restrict clinical applications. In this study, we develop a tumor-recognizing carrier-free nanotheranostic with light/reactive oxygen species (ROS) cascade-responsiveness for spatiotemporally selective photo-chemotherapy. The nanotheranostic is constructed by co-assembly of the indocyanine green (ICG) photosensitizer and the mannose-thioketal-doxorubicin conjugate (MAN-TK-DOX) (abbreviated as IMTD), efficiently preventing premature DOX leakage during blood circulation while reducing nonspecific damage to normal tissues/cells. Once accumulated in tumor tissues, IMTD rapidly diffuses into cancer cells via lectin receptors-mediated endocytosis. Photoacoustic/fluorescence-imaging-guided laser irradiation induces local hyperthermia and ROS generation in tumor cells, thereby promoting apoptosis. Together, the ICG-generated ROS and the endogenous ROS in cancer cells synergistically enhance DOX release, resulting in more efficient chemotherapeutic effects. The in vitro and in vivo results consistently demonstrate that IMTD achieves superior tumor accumulation, highly controllable drug release, and synergetic photo-chemotherapy. Therefore, the co-assembly of an ROS-sensitive targeting ligand-chemodrug conjugate and a photosensitizer could be used to develop spatiotemporally light-activatable nanotheranostics for precision cancer therapy. STATEMENT OF SIGNIFICANCE: Synergistic phototherapy and chemotherapy have been considered as a promising cancer treatment modality to maximize the therapeutic efficacy. Unfortunately, most nanodrugs consisting of chemotherapeutic drug and photosensitizer suffer from suboptimal tumor accumulation and poorly controlled drug release, which results in reduced therapeutic outcome. In this study, Mannose (MAN) was conjugated to the anticancer drug doxorubicin (DOX) by a ROS-sensitive thioketal linker (TK), the obtained amphiphilic MAN-TK-DOX could serve as an ideal self-carrier material to deliver photosensitizer, thus to achieve high-efficient tumor-targeting, spatiotemporal controlled drug release, and superior antitumor effect. We believe that the ROS-sensitive amphiphilic targeting ligand-chemodrug conjugate could be developed as a universal approach for designing tumor-targeted nanodrugs with precisely controlled drug release.

Ursolic acid improves the bacterial community mapping of the intestinal tract in liver fibrosis mice.

Liver fibrosis often appears in chronic liver disease, with extracellular matrix (ECM) deposition as the main feature. Due to the presence of the liver-gut axis, the destruction of intestinal homeostasis is often accompanied by the development of liver fibrosis. The inconsistent ecological environment of different intestinal sites may lead to differences in the microbiota. The traditional Chinese medicine ursolic acid (UA) has been proven to protect the liver from fibrosis. We investigated the changes in the microbiota of different parts of the intestine during liver fibrosis and the effect of UA on these changes based on high-throughput sequencing technology. Sequencing results suggest that the diversity and abundance of intestinal microbiota decline and the composition of the microbiota is disordered, the potentially beneficial Firmicutes bacteria are reduced, and the pathways for functional prediction are changed in the ilea and anal faeces of liver fibrosis mice compared with normal mice. However, in UA-treated liver fibrosis mice, these disorders improved. It is worth noting that the bacterial changes in the ilea and anal faeces are not consistent. In conclusion, in liver fibrosis, the microbiota of different parts of the intestines have different degrees of disorder, and UA can improve this disorder. This may be a potential mechanism for UA to achieve anti-fibrosis. This study provides theoretical guidance for the UA targeting of intestinal microbiota for the treatment of liver fibrosis.