Parkinson's disease (PD) is a neurodegenerative disorder with no absolute cure. The evidence of the involvement of gut microbiota in PD pathogenesis suggests the need to identify certain molecule(s) ...derived from the gut microbiota, which has the potential to manage PD. Osteocalcin (OCN), an osteoblast-secreted protein, has been shown to modulate brain function. Thus, it is of interest to investigate whether OCN could exert protective effect on PD and, if yes, whether the underlying mechanism lies in the subsequent changes in gut microbiota.
The intraperitoneal injection of OCN can effectively ameliorate the motor deficits and dopaminergic neuronal loss in a 6-hydroxydopamine-induced PD mouse model. The further antibiotics treatment and fecal microbiota transplantation experiments confirmed that the gut microbiota was required for OCN-induced protection in PD mice. OCN elevated Bacteroidetes and depleted Firmicutes phyla in the gut microbiota of PD mice with elevated potential of microbial propionate production and was confirmed by fecal propionate levels. Two months of orally administered propionate successfully rescued motor deficits and dopaminergic neuronal loss in PD mice. Furthermore, AR420626, the agonist of FFAR3, which is the receptor of propionate, mimicked the neuroprotective effects of propionate and the ablation of enteric neurons blocked the prevention of dopaminergic neuronal loss by propionate in PD mice.
Together, our results demonstrate that OCN ameliorates motor deficits and dopaminergic neuronal loss in PD mice, modulating gut microbiome and increasing propionate level might be an underlying mechanism responsible for the neuroprotective effects of OCN on PD, and the FFAR3, expressed in enteric nervous system, might be the main action site of propionate. Video abstract.
MicroRNAs (miRNAs) constitute a class of noncoding RNAs that post‐transcriptionally regulate gene expression. Recent evidence indicates that many miRNAs function as oncogenes or tumor suppressors by ...negatively regulating their target genes. In our previous study, using miRNA microarray analysis, we found that miRNA‐182 (miR‐182) was significantly downregulated in human gastric adenocarcinoma tissue samples. Here, we confirmed the downregulation of miR‐182 in a larger sample of gastric tissue samples. Overexpression of miR‐182 suppressed the proliferation and colony formation of gastric cancer cells. An oncogene, encoding cAMP‐responsive element binding protein 1 (CREB1), serves as a direct target gene of miR‐182. A fluorescent reporter assay confirmed that miR‐182 binds specifically to the predicted site of the CREB1 mRNA 3′‐UTR. When miR‐182 was overexpressed in gastric cancer cell lines, both the mRNA and protein levels of CREB1 were depressed. Furthermore, CREB1 was present at a high level in human gastric adenocarcinoma tissues, and this was inversely correlated with miR‐182 expression. Ectopic expression of CREB1 overcame the suppressive phenotypes of gastric cancer cells caused by miR‐182. These results indicate that miR‐182 targets the CREB1 gene and suppresses gastric adenocarcinoma cell growth, suggesting that miR‐182 shows tumor‐suppressive activity in human gastric cancer.
As gene regulators, microRNAs (miRNAs) may function as oncogenes or tumor suppressors. Here, miR‐182 was confirmed to be down‐regulated in gastric cancer tissues, and over‐expression of miR‐182 suppresses proliferation of gastric cancer cells. CREB1 was confirmed to be a direct and functional target gene of miR‐182. Our study suggests that miR‐182 shows a tumor suppressive activity in human gastric cancer
Spatial transcriptomic (ST) clustering employs spatial and transcription information to group spots spatially coherent and transcriptionally similar together into the same spatial domain. Graph ...convolution network (GCN) and graph attention network (GAT), fed with spatial coordinates derived adjacency and transcription profile derived feature matrix are often used to solve the problem. Our proposed method STGIC (spatial transcriptomic clustering with graph and image convolution) is designed for techniques with regular lattices on chips. It utilizes an adaptive graph convolution (AGC) to get high quality pseudo-labels and then resorts to dilated convolution framework (DCF) for virtual image converted from gene expression information and spatial coordinates of spots. The dilation rates and kernel sizes are set appropriately and updating of weight values in the kernels is made to be subject to the spatial distance from the position of corresponding elements to kernel centers so that feature extraction of each spot is better guided by spatial distance to neighbor spots. Self-supervision realized by Kullback-Leibler (KL) divergence, spatial continuity loss and cross entropy calculated among spots with high confidence pseudo-labels make up the training objective of DCF. STGIC attains state-of-the-art (SOTA) clustering performance on the benchmark dataset of 10x Visium human dorsolateral prefrontal cortex (DLPFC). Besides, it's capable of depicting fine structures of other tissues from other species as well as guiding the identification of marker genes. Also, STGIC is expandable to Stereo-seq data with high spatial resolution.
The Fetal Electrocardiogram (FECG) signal plays a crucial role in monitoring the health of the fetus, but there are numerous challenges in eliminating the maternal thorax signal and reducing noise ...interference. This paper proposes a novel objective function that combines a Least Mean Squares (LMS) adaptive filter with a heuristic algorithms to enhance the quality of the extracted FECG signal. To achieve better results, we introduce the Discrete Artificial Bee Colony (DABC) algorithm with a new initialization strategy, a random wavelet basic function strategy, and Gaussian distribution. These improvements enhance global search capabilities and ensure a faster convergence rate. The application of heuristic algorithms can reduce noise signals and provides clearer and more accurate results compared to the traditional LMS filter. Furthermore, the effectiveness of this innovative algorithm is compared with other widely used heuristic algorithms. The experiment results demonstrate that the novel algorithm significantly enhances performance by up to 8% compared to other conventional extraction methods in some indicators.
•A new objective function is designed to combine heuristic algorithms and LMS filter to extract the FECG signal from AECG signal.•This paper propose a novel Discrete Artificial Bee Colony, which introduce a tailored initialization strategy to improve the algorithm’s convergence speed, based on the specific characteristics of the FECG signal extraction problem. The novel algorithm can obtain clearer extracted signal than other existed heuristic algorithms.•We incorporate the strategies of random wavelet basic functions and Gaussian distribution in the DABC algorithm to enhance the global search ability and prevent the population from prematurely becoming trapped in a local optimum.
Emerging research has revealed regulation of colorectal cancer metabolism by bacteria.
(
) plays a crucial role in the development of colorectal cancer, however, whether
infection modifies metabolism ...in patients with colorectal cancer remains unknown. Here, LC-MS/MS-based lipidomics identified the upregulation of cytochrome P450 monooxygenases, primarily CYP2J2, and their mediated product 12,13-EpOME in patients with colorectal cancer tumors and mouse models, which increased the invasive and migratory ability of colorectal cancer cells
and
by regulating the epithelial-mesenchymal transition (EMT). Metagenomic sequencing indicated a positive correlation between increased levels of fecal
and serum 12,13-EpOME in patients with colorectal cancer. High levels of CYP2J2 in tumor tissues also correlated with high
levels and worse overall survival in patients with stage III/IV colorectal cancer. Moreover,
was found to activate TLR4/AKT signaling, downregulating Keap1 and increasing NRF2 to promote transcription of CYP2J2. Collectively, these data identify that
promotes EMT and metastasis in colorectal cancer by activating a TLR4/Keap1/NRF2 axis to increase CYP2J2 and 12,13-EpOME, which could serve as clinical biomarkers and therapeutic targets for
-infected patients with colorectal cancer. SIGNIFICANCE: This study uncovers a mechanism by which
regulates colorectal cancer metabolism to drive metastasis, suggesting the potential biomarker and therapeutic utility of the CYP2J2/12,13-EpOME axis in
-infected patients.
Glycosylation inactivation is one of the important macrolide resistance mechanisms. The accumulated evidences attributed glycosylation inactivation to a glucosylation modification at the inactivation ...sites of macrolides. Whether other glycosylation modifications lead to macrolides inactivation is unclear. Herein, we demonstrated that varied glycosylation modifications could cause inactivation of midecamycin, a 16-membered macrolide antibiotic used clinically and agriculturally. Specifically, an actinomycetic glycosyltransferase (GT) OleD was selected for its glycodiversification capacity towards midecamycin. OleD was demonstrated to recognize UDP-D-glucose, UDP-D-xylose, UDP-galactose, UDP-rhamnose and UDP-
-acetylglucosamine to yield corresponding midecamycin 2'-
-glycosides, most of which displayed low yields. Protein engineering of OleD was thus performed to improve its conversions towards sugar donors. Q327F was the most favorable variant with seven times the conversion enhancement towards UDP-
-acetylglucosamine. Likewise, Q327A exhibited 30% conversion enhancement towards UDP-D-xylose. Potent biocatalysts for midecamycin glycosylation were thus obtained through protein engineering. Wild OleD, Q327F and Q327A were used as biocatalysts for scale-up preparation of midecamycin 2'-
-glucopyranoside, midecamycin 2'-
-GlcNAc and midecamycin 2'-
-xylopyranoside. In contrast to midecamycin, these midecamycin 2'-
-glycosides displayed no antimicrobial activities. These evidences suggested that besides glucosylation, other glycosylation patterns also could inactivate midecamycin, providing a new inactivation mechanism for midecamycin resistance. Cumulatively, glycosylation inactivation of midecamycin was independent of the type of attached sugar moieties at its inactivation site.
The ketogenic diet (KD) is a high-fat, adequate-protein, and very-low-carbohydrate diet regimen that mimics the metabolism of the fasting state to induce the production of ketone bodies. The KD has ...long been established as a remarkably successful dietary approach for the treatment of intractable epilepsy and has increasingly garnered research attention rapidly in the past decade, subject to emerging evidence of the promising therapeutic potential of the KD for various diseases, besides epilepsy, from obesity to malignancies. In this review, we summarize the experimental and/or clinical evidence of the efficacy and safety of the KD in different diseases, and discuss the possible mechanisms of action based on recent advances in understanding the influence of the KD at the cellular and molecular levels. We emphasize that the KD may function through multiple mechanisms, which remain to be further elucidated. The challenges and future directions for the clinical implementation of the KD in the treatment of a spectrum of diseases have been discussed. We suggest that, with encouraging evidence of therapeutic effects and increasing insights into the mechanisms of action, randomized controlled trials should be conducted to elucidate a foundation for the clinical use of the KD.
With the global ban on plastics intensifying, the substitution of plastic with paper has garnered increasing attention. However, the inadequate water and oil repellency of pulp molding hinders its ...practical applications. Currently, the common method to enhance the oil and water repellency of pulp molding is by adding fluorinated water and oil repellents. Nevertheless, fluorinated compounds are environmentally and physiologically harmful. Therefore, the development of fluorine-free, water and oil repellent alternatives is crucial. In this study, chitosan and stearic acid were utilized as the first and second layers of the oil and water repellent coatings, respectively. The coated samples exhibited favorable water repellency, with a water contact angle of 116.4°, and excellent oil repellency, achieving a 12/12 rating on the kit scale. Importantly, the samples did not exhibit any leakage after being soaked in hot water and hot oil at 95±5 °C for 30 min, demonstrating remarkable performance as a barrier against hot water and oil. Moreover, the coated samples displayed outstanding mechanical properties, thermal stability, biodegradability, and recyclability. The approach presented in this study is simple, cost-effective, environmentally friendly, and represents a promising technique for producing fluoride-free, oil- and water-resistant pulp molding products.
The sluggish kinetics of the oxygen evolution reaction (OER) always results in a high overpotential at the anode of water electrolysis and an excessive electric energy consumption, which has been a ...major obstacle for hydrogen production through water electrolysis. In this study, we present a CoNi-LDH/Fe MOF/NF heterostructure catalyst with nanoneedle array morphology for the OER. In 1.0 M KOH solution, the heterostructure catalyst only required overpotentials of 275 and 305 mV to achieve high current densities of 500 and 1000 mA/cm2 for OER, respectively. The catalytic activities are much higher than those of the reference single-component CoNi-LDH/NF and Fe MOF/NF catalysts. The improved catalytic performance of the heterostructure catalyst can be ascribed to the synergistic effect of CoNi-LDH and Fe MOF. In particular, when the anodic OER is replaced with the urea oxidation reaction (UOR), which has a relatively lower thermodynamic equilibrium potential and is expected to reduce the cell voltage, the overpotentials required to achieve the same current densities can be reduced by 80 and 40 mV, respectively. The cell voltage required to drive overall urea splitting (OUS) is only 1.55 V at 100 mA/cm2 in the Pt/C/NF||CoNi-LDH/Fe MOF/NF two-electrode electrolytic cell. This value is 60 mV lower compared with that required for overall water splitting (OWS). Our results indicate that a reasonable construction of a heterostructure catalyst can significantly give rise to higher electrocatalytic performance, and using UOR to replace the anodic OER of the OWS can greatly reduce the electrolytic energy consumption.
Among the natural macromolecules potentially used as the scaffold material in hydrogels, xylan has aroused great interest in many fields because of its biocompatibility, low toxicity, and ...biodegradability. In this work, new pH and thermoresponsive hydrogels were prepared by the cross-linking polymerization of maleic anhydride-modified xylan (MAHX) with
-isopropylacrylamide (NIPAm) and acrylic acid (AA) under UV irradiation to form MAHX-
-P(NIPAm-co-AA) hydrogels. The pore volume, the mechanical properties, and the release rate for drugs of hydrogels could be controlled by the degree of substitution of MAHX. These hydrogels were characterized by swelling ability, lower critical solution temperature (LCST), Fourier-transform infrared (FTIR), and SEM. Furthermore, the cumulative release rate was investigated for acetylsalicylic acid and theophylline, as well as the cytocompatibility MAHX-based hydrogels. Results showed that MAHX-based hydrogels exhibited excellent swelling-deswelling properties, uniform porous structure, and the temperature/pH dual sensitivity. In vitro, the cumulative release rate of acetylsalicylic acid for MAHX-based hydrogels was higher than that for theophylline, and in the gastrointestinal sustained drug release study, the acetylsalicylic acid release rate was extremely slow during the initial 3 h in the gastric fluid (24.26%), and then the cumulative release rate reached to 90.5% after sustained release for 5 h in simulated intestinal fluid. The cytotoxicity experiment demonstrated that MAHX-based hydrogels could promote cell proliferation and had satisfactory biocompatibility with NIH3T3 cells. These results indicated that MAHX-based hydrogels, as new drug carriers, had favorable behavior for intestinal-targeted drug delivery.
PDF
