Targeting the JAK2/STAT3 signaling pathway with natural plants and phytochemical ingredients: A novel therapeutic method for combatting cardiovascular diseases.

The aim of this article is to introduce the roles and mechanisms of the JAK2/STAT3 pathway in various cardiovascular diseases, such as myocardial fibrosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, and myocardial ischemiareperfusion. In addition, the effects of phytochemical ingredients and different natural plants, mainly traditional Chinese medicines, on the regulation of different cardiovascular diseases via the JAK2/STAT3 pathway are discussed. Surprisingly, the JAK2 pathway has dual roles in different cardiovascular diseases. Future research should focus on the dual regulatory effects of different phytochemical ingredients and natural plants on JAK2 to pave the way for their use in clinical trials.

Hybrid Therapeutic Device (CUHK-OA-M2) for Relieving Symptoms Induced by Knee Osteoarthritis.

The symptoms of knee osteoarthritis (KOA) severely affect the life quality of the elderly population. Low-level laser therapy, heat therapy, and massage therapy are widely used as independent treatments for joint disorders. However, there are very limited reports of a combination of these therapies into an integrated device for KOA so far. This study aims to develop a novel hybrid therapeutic device that can meet various requirements for knee therapy. Our hybrid therapeutic device (CUHK-OA-M2) integrated with low-level laser therapy, heat therapy, and local massage therapy can effectively provide patients with KOA with relief from their clinical symptoms. A pilot test of 50 community-dwelling elderly volunteers with KOA was performed. Finally, 43 volunteers completed two treatment periods (30 days each) and two post-treatment periods (30 days each). The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were collected and analyzed after each period. The outputs of the low-level laser, heating, and massage therapies significantly decreased the WOMAC scores in terms of pain, stiffness, function and total WOMAC after two treatment periods (p < 0.05). Although the score increased slightly after the post-treatment period, it was still lower than the baseline, indicating the treatment outcome could last for an extended period. Therefore, our CUHK-OA-M2 device, as an integrated multi-functional hybrid therapeutic device, is therapeutically significant for treating osteoarthritis symptoms on the knee joints of elderly subjects.

Programmed-stimuli responsive carrier-free multidrug delivery system for highly efficient trimodal combination therapy.

Programmed response, carrier-free, and multimodal therapy drug delivery systems (DDS) are promising solutions to multidirectional cytotoxic effects, inefficient antitumor, and severe side effects for cancer therapy. Here, three widely used clinical drugs, interferon α1b (IFNα1b), indocyanine green (ICG), and doxorubicin (DOX), were prepared into carrier-free DDS IFNα1b-ICG-DOX (IID) by a simple one-step method without additional any reagents. IID can achieve smart and programmed DDS by combining low pH and near-infrared (NIR) light stimuli-responsive controlled release. In pH = 7.4 environments, our IID is about 380 nm in size with negative charge rounded particles; while they enter into the acid environment (pH < 7), hydrogen ions (H+) trigger DOX release, their size becomes larger and the surface charge turns positive. These larger particles are rapidly disintegrated after exposure to NIR light and then the remaining DOX, IFNα1b, and ICG are released. In vivo, the IID with larger size and positive charge resulting from low pH is is easy to accumulate in tumor tissue. Tumors can be exposed to NIR light when needed to control the release of these three drugs. Hence, DOX, ICG, and IFNα1b can be enriched in the tumor to the high efficiency of combined chemotherapy, photothermal therapy, and immunotherapy.

Huoxue Qingre decoction used for treatment of coronary heart disease network analysis and metabolomic evaluation.

Objective: Network pharmacology provides new methods and references for the research of traditional Chinese medicine, but some problems remain, such as single evaluation components and index methods, imperfect relevant databases, unscientific prediction results, and lack of verification of results. Herein, we used a modified network pharmacology research method to explore the potential network analysis mechanism of Huoxue Qingre decoction in the treatment of coronary heart disease and utilized clinical trials for assessment. Methods: Based on literature research, the targets corresponding to the drug were obtained with the assistance of the TCMSP database and Swiss Target Prediction, and the target proteins were corrected using the UniProt database. The targets related to coronary heart disease was obtained through the GeneCards database. A protein-protein interaction network diagram was constructed, and a "component-intersection target" network diagram was drawn based on Cytoscape 3.6.2 software. The mapped targets were imported into the DAVID bioinformatics platform, which underwent Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and the network pharmacology prediction results were evaluated through clinical trials. Results: We obtained 151 compounds related to Huoxue Qingre decoction, 286 genes after evaluation and deduplication, and 426 genes related to coronary heart disease. Finally, 81 common target genes were obtained with 32 pathways according to the KEGG pathway enrichment analysis. The validation results of the clinical trials showed that a total of 98 differential metabolites were found in the treatment of coronary heart disease with Huoxue Qingre decoction, involving a total of 16 metabolic pathways. Compared with the network pharmacology prediction results, it was found that only the pathways in cancer (hsa05200) were the common pathways in the top 32 signaling pathways predicted by network pharmacology. The expanded network pharmacology prediction results revealed that the sphingolipid signaling pathway (hsa04071) and prostate cancer pathway (hsa05215) matched the predicted metabolic pathways, with differential metabolites of N-oleoyl-D-sphingomyelin and 1-methyl-6-phenyl-1h-imidazole[4,5-b]pyridine-2-amine. Conclusion: Through the network analysis and metabolomic evaluation, there may be three signaling pathways that involve the Huoxue Qingre decoction in the treatment of coronary heart disease: pathways in cancer (hsa05200), sphingolipid signaling pathway (hsa04071), and prostate cancer pathway (hsa05215).

Low-temperature plasma induced phosphate groups onto coffee residue-derived porous carbon for efficient U(VI) extraction.

For the continuous utilization of nuclear energy and efficient control of radioactive pollution, low-cost materials with high efficient U(VI) removal are of great importance. In this study, low temperature plasma method was applied for the successful modification of O-phosphorylethanolamine (O-PEA) on the porous carbon materials. The produced materials (Cafe/O-PEA) could adsorb U(VI) efficiently with the maximum sorption capacity of 648.54 mg/g at 1 hr, T=298 K, and pH=6.0, much higher than those of most carbon-based composites. U(VI) sorption was mainly controlled by strong surface complexation. From FTIR, SEM-EDS and XPS analyses, the sorption of U(VI) was related to the complexation with -NH2, phosphate and -OH groups on Cafe/O-PEA. The low temperature plasma method was an efficient, environmentally friendly and low-cost method for surface modification of materials for the effective enrichment of U(VI) from aqueous solutions.

Silver Mesoporous Silica Nanoparticles: Fabrication to Combination Therapies for Cancer and Infection.

The integration of silver nanoparticles (Ag NPs) with mesoporous silica nanoparticles (MSNs) protects the former from aggregation and promotes the controlled release of silver ions, resulting in therapeutic significance on cancer and infection. The unique size, shape, pore structure and silver distribution of silver mesoporous silica nanoparticles (Ag-MSNs) embellish them with the potential to perform combined imaging and therapeutic actions via modulating optical and drug release properties. Here, we comprehensively review the recent progress in the fabrication and application of Ag-MSNs for combination therapies for cancer and infection. We first elaborate on the fabrication of star-shaped structure, core-shell structure, and Janus structure Ag-MSNs. We then highlight Ag-MSNs as a multifunctional nanoplatform to surface-enhanced Raman scattering-based detection, non-photo-based cancer theranostics and photo-based cancer theranostics. In addition, we detail Ag-MSNs for combined antibacterial therapy via drug delivery and phototherapy. Overall, we summarize the challenges and future perspectives of Ag-MSNs that make them promising for diagnosis and therapy of cancer and infection.

Teachers' Dispositions Toward Mindfulness in EFL/ESL Classrooms in Teacher-Student Interpersonal Relationships.

The psychological factors of English as a foreign language (EFL) and English as a second language (ESL) teachers have significant roles in any language learning context. Previous studies in the related literature have shown that L2 learners' learning, psychological factors, and emotional factors are closely related to teachers' psychological factors. Mindfulness as one of the psychological attributes of L2 teachers and as a complex and multi-faceted construct influences l2 teachers' professional development. Hence, this study aims to review the notion of mindfulness and its role in L2 teaching as a profession and pave a way for further research, highlighting its indispensable role in teacher-student relationships. To achieve this goal, this study has reviewed the theoretical perspectives of mindfulness, the construct of mindful L2 teaching education, and mindfulness as a closely related concept to teacher wellbeing. Based on the findings, some pedagogical implications for the policymakers, teacher trainers, materials developers, L2 teachers, and learners are provided. Finally, directions for future research are suggested to the interested L2 researchers.

Combined Transcriptome and Proteome Analysis of Maize (Zea mays L.) Reveals A Complementary Profile in Response to Phosphate Deficiency.

A deficiency in the macronutrient phosphate (Pi) brings about various changes in plants at the morphological, physiological and molecular levels. However, the molecular mechanism for regulating Pi homeostasis in response to low-Pi remains poorly understood, particularly in maize (Zea mays L.), which is a staple crop and requires massive amounts of Pi. Therefore, in this study, we performed expression profiling of the shoots and roots of maize seedlings with Pi-tolerant genotype at both the transcriptomic and proteomic levels using RNA sequencing and isobaric tags for relative and absolute quantitation (iTRAQ). We identified 1944 differentially expressed transcripts and 340 differentially expressed proteins under low-Pi conditions. Most of the differentially expressed genes were clustered as regulators, such as transcription factors involved in the Pi signaling pathway at the transcript level. However, the more functional and metabolism-related genes showed expression changes at the protein level. Moreover, under low-Pi conditions, Pi transporters and phosphatases were specifically induced in the roots at both the transcript and protein levels, and increased amounts of mRNA and protein of two purple acid phosphatases (PAPs) and one UDP-sulfoquinovose synthase (SQD) were specifically detected in the roots. The new insights provided by this study will help to improve the P-utilization efficiency of maize.

Analysis of the Efficacy and Mechanism of Action of Xuebijing Injection on ARDS Using Meta-Analysis and Network Pharmacology.

OBJECTIVE: Acute respiratory distress syndrome (ARDS) is defined as the acute onset of noncardiogenic edema and subsequent gas-exchange impairment due to a severe inflammatory process known as cytokine storm. Xuebijing injection (hereinafter referred to as Xuebijing) is a patent drug that was used to treat ARDS or severe pneumonia (SP) in China. However, its efficacy and mechanism of actions remain unclear. In this study, we used meta-analysis and network pharmacology to assess these traits of Xuebijing. METHODS: We searched PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang databases for randomized controlled trials (RCTs) that evaluated Xuebijing therapy for ARDS or SP. The outcomes were total mortality, intensive care unit (ICU) stay time, and TNF-α and IL-6 levels. We performed a meta-analysis using RevMan 5.3 software. The putative targets, top 10 proteins, and possible pathway of Xuebinjing on ARDS were analyzed by network pharmacology. TNF-α and IL-6 were further docked with the six main active components of Xuebinjing using AutoDock 4.2.6 and PyMol 1.5.0.3 software. RESULTS: Fifteen RCTs involving 2778 patients (13 ARDS and 2 SP) were included. Compared with the control, Xuebijing treatment significantly reduced the mortality rate (risk ratio, 0.64 (95% credible interval (CrI), 0.54-0.77)), reduced the ICU stay time (mean difference (MD), -4.51 (95% CrI, -4.97--4.06)), reduced the TNF-α ((MD), -1.23 (95% CrI, -1.38--1.08)) and IL-6 ((MD), -1.15 (95% CrI, -1.52--0.78)) levels. The 56 putative targets, top 10 proteins (MAPK1 (mitogen-activated protein kinase 1), MAPK8 (mitogen-activated protein kinase 8), RELA (transcription factor p65), NFKB1 (nuclear factor NF-kappa-B p105 subunit), JUN (transcription factor AP-1), SRC (proto-oncogene tyrosine-protein kinase), TNF (tumor necrosis factor), HRAS (GTPase HRas), IL6 (interleukin-6), and APP (amyloid-beta A4 protein)), and possible pathways (Ret tyrosine kinase, IL2-mediated signaling events, CD4+/CD8+ T cell-related TCR signaling, p75(NTR)-mediated signaling, CXCR4-mediated signaling events, LPA receptor-mediated events, IL12-mediated signaling events, FAS (CD95) signaling pathway, and immune system) of Xuebinjing's action on ARDS were obtained. The molecular docking results showed that all the six components of Xuebinjing docked with TNF-α, and two components docked with IL-6 got the binding energies lower than -5. CONCLUSION: Our results recommended Xuebijing treatment for patients with ARDS. Xuebijing has therapeutic effects on ARDS patients partly by regulating the immune cell/cytokine pathways and thus inhibiting the cytokine storm. TNF-α is the cytokine both directly and indirectly inhibited by Xuebijing, and IL-6 is the cytokine mainly indirectly inhibited by Xuebijing.

Flexible DNA Hydrogel SERS Active Biofilms for Conformal Ultrasensitive Detection of Uranyl Ions from Aquatic Products.

It is of great significance to sensitively and conveniently detect trace UO22+ ions in biological and environmental samples due to severe health risks. However, such suitable sensors are still scarce. In this work, DNAzyme-based hydrogels modified on Ag NP-grafted PAN nanorods array as flexible SERS biosensor have been developed for ultrasensitive UO22+ ion detection. They were first formed by the substrate strand and enzyme strand comprising the main cleavage-reaction stem-loop complex. Then, a UO22+ ions responsive smart hydrogel capsule was achieved by DNAzyme complex hybridized with DNA polyacrylamide chains. Raman reporter RhB was introduced and intentionally trapped inside the hydrogel. In the absence of UO22+ ions, a tiny Raman signal was presented because RhB was trapped inside the hydrogel and far away from SERS substrates. Conversely, the responsive hydrogel could be specifically attacked by UO22+ ions to release RhB, leading to a strong Raman signal. With the amplified signal procedure, this flexible SERS biofilm accomplished sensitive and selective detection of UO22+ ions with a wide linear range from 1 pM to 0.1 µM and a low detection limit of 0.838 pM. This result is nearly five orders below the EPA-defined maximum contaminant level (180 nM). Furthermore, this biofilm gives full play to the advantages of a flexible biosensor. It can directly detect the aquatic products (such as fish and kelp) polluted by UO22+ ions, demonstrating that this flexible SERS biofilm has promising potential for applications in a rapid environmental safety inspection.

Advances in Research on the circRNA-miRNA-mRNA Network in Coronary Heart Disease Treated with Traditional Chinese Medicine.

There has been an increase in morbidity and mortality related to coronary heart disease (CHD) in China in recent years. Numerous clinical experiences and studies have shown that traditional Chinese medicine (TCM) plays an important role in the prevention, treatment, and prognosis of CHD. However, the mechanism of TCM in the treatment of CHD has not yet been elucidated. The circRNA-miRNA-mRNA network consists of miRNA that is competitively bound by circRNA, and miRNA regulates the transcription level of mRNA. Through literature review, we found that the circRNA-miRNA-mRNA network acts to contribute to certain effects to CHD such as myocardial hypertrophy, myocardial fibrosis, and heart failure. TCM contains constituents that act against CHD by antiatherosclerosis and apoptosis inhibition action, cardiac and cardiomyocyte protection, and these components also promote cell growth and protection of the vascular system by regulating miRNAs. Therefore, we consider that the circRNA-miRNA-mRNA network may be a new regulatory mechanism for the effective treatment of CHD by TCM.

Identification of bioactive compounds that contribute to the α-glucosidase inhibitory activity of rosemary.

To investigate the bioactive compounds that contribute to the α-glucosidase inhibitory activity of rosemary, phenolics and triterpene acids were characterized and quantified using quadrupole-Orbitrap mass spectrometry and enzyme assay. Two phenolic diterpenes (carnosol and hydroxy p-quinone carnosic acid) and two triterpene acids (betulinic acid and ursolic acid) were identified as potent α-glucosidase inhibitors. Carnosol, a major diterpene in rosemary, showed significant α-glucosidase inhibitory activity with IC50 value of 12 µg mL-1, and its inhibition mode was competitive. The inhibition mechanism of carnosol on α-glucosidase was further investigated by a combination of surface plasmon resonance (SPR) spectroscopy, fluorescence quenching studies and molecular-modeling techniques. The SPR assay suggested that carnosol had a high affinity to α-glucosidase with equilibrium dissociation constant (KD) value of 72.6 M. Fluorescence quenching studies indicated that the binding between carnosol and α-glucosidase was spontaneous and mainly driven by hydrophobic forces. Molecular docking studies revealed that carnosol bound to the active site of α-glucosidase. Furthermore, the oral administration of carnosol at 30 mg kg-1 significantly reduced the postprandial blood glucose levels of normal mice. This is the first report on the α-glucosidase inhibition and hypoglycemic activity of phenolic diterpenes, and these results could facilitate the utilization of rosemary as a dietary supplement for the treatment of diabetes.

Magnesium and vitamin C supplementation attenuates steroid-associated osteonecrosis in a rat model.

Magnesium (Mg)-based biometal attracts clinical applications due to its biodegradability and beneficial biological effects on tissue regeneration, especially in orthopaedics, yet the underlying anabolic mechanisms in relevant clinical disorders are lacking. The present study investigated the effect of magnesium (Mg) and vitamin C (VC) supplementation for preventing steroid-associated osteonecrosis (SAON) in a rat experimental model. In SAON rats, 50 mg/kg Mg, or 100 mg/kg VC, or combination, or water control was orally supplemented daily for 2 or 6 weeks respectively. Osteonecrosis was evaluated by histology. Serum Mg, VC, and bone turnover markers were measured. Microfil-perfused samples prepared for angiography and trabecular architecture were evaluated by micro-CT. Primary bone marrow cells were isolated from each group to evaluate their potentials in osteoblastogenesis and osteoclastogenesis. The mechanisms were tested in vitro. Histological evaluation showed SAON lesions in steroid treated groups. Mg and VC supplementation synergistically reduced the apoptosis of osteocytes and osteoclast number, and increased osteoblast surface. VC supplementation significantly increased the bone formation marker PINP, and the combination significantly decreased the bone resorption marker CTX. TNFα expression and oxidative injury were decreased in bone marrow in Mg/VC/combination group. Mg significantly increased the blood perfusion in proximal tibia and decreased the leakage particles in distal tibia 2 weeks after SAON induction. VC significantly elevated the osteoblast differentiation potential of marrow cells and improved the trabecular architecture. The combination supplementation significantly inhibited osteoclast differentiation potential of marrow cells. In vitro study showed promoting osteoblast differentiation effect of VC, and anti-inflammation and promoting angiogenesis effect of Mg with underlying mechanisms. Mg and VC supplementation could synergistically alleviate SAON in rats, indicating great translational potentials of metallic minerals for preventing SAON.

MR-Forest: A Deep Decision Framework for False Positive Reduction in Pulmonary Nodule Detection.

With the development of deep learning methods such as convolutional neural network (CNN), the accuracy of automated pulmonary nodule detection has been greatly improved. However, the high computational and storage costs of the large-scale network have been a potential concern for the future widespread clinical application. In this paper, an alternative Multi-ringed (MR)-Forest framework, against the resource-consuming neural networks (NN)-based architectures, has been proposed for false positive reduction in pulmonary nodule detection, which consists of three steps. First, a novel multi-ringed scanning method is used to extract the order ring facets (ORFs) from the surface voxels of the volumetric nodule models; Second, Mesh-LBP and mapping deformation are employed to estimate the texture and shape features. By sliding and resampling the multi-ringed ORFs, feature volumes with different lengths are generated. Finally, the outputs of multi-level are cascaded to predict the candidate class. On 1034 scans merging the dataset from the Affiliated Hospital of Liaoning University of Traditional Chinese Medicine (AH-LUTCM) and the LUNA16 Challenge dataset, our framework performs enough competitiveness than state-of-the-art in false positive reduction task (CPM score of 0.865). Experimental results demonstrate that MR-Forest is a successful solution to satisfy both resource-consuming and effectiveness for automated pulmonary nodule detection. The proposed MR-forest is a general architecture for 3D target detection, it can be easily extended in many other medical imaging analysis tasks, where the growth trend of the targeting object is approximated as a spheroidal expansion.

Uncovering the protective mechanism of Huoxue Anxin Recipe against coronary heart disease by network analysis and experimental validation.

Coronary heart disease (CHD) is a leading cause of death and disability worldwide. Huoxue Anxin Recipe (HAR) is a novel Chinese Herbal Medicine formula of that has been used to treat CHD for several decades. Our previous study found that HAR had anti-oxidative effects, and could promote myocardial angiogenesis and improve cardiac function following myocardial infarction (MI) in rats. However, the active compounds, potential targets, and biological processes related to HAR have not been systematically investigated. Here, network pharmacology and experimental validation were used to study the protective mechanisms of HAR against CHD. We identified 124 active components, 124 verified targets, and 111 predictive targets. A total of 1192 genes related to CHD were identified by cDNA microarray and database analysis. A total of 47 putative targets of HAR against CHD were identified, including 32 verified targets and 15 predictive targets. ClueGo enrichment analysis identified 49 biological processes involved in the anti-CHD effects of HAR. Among them, the negative regulation of blood coagulation and regulation of collagen biosynthetic process were experimentally validated. After constructing a protein-protein interaction network and clustering with MECODE and ClusterONE, 162 key proteins (from ClueGo and clustering) were used to construct an internal interaction network. Complement C3 (C3), Fibrinogen alpha (FGA), Fibrinogen gamma (FGG), interleukin-6 (IL6), and Apolipoprotein A1 (APOA1) were the top 5 hub proteins identified by cytoHubber analysis. HAR limited the concentrations of C3, FGA, FGG, and IL6 and increased APOA1 levels. The results indicated that HAR could down-regulate blood coagulation, regulate collagen biosynthesis, inhibit peroxidation and inflammation injury, and promote cholesterol efflux. HAR could be a potential source of novel and effective drugs for CHD.

Fecal microbiome and metabolome of infants fed bovine MFGM supplemented formula or standard formula with breast-fed infants as reference: a randomized controlled trial.

Human milk delivers an array of bioactive components that safeguard infant growth and development and maintain healthy gut microbiota. Milk fat globule membrane (MFGM) is a biologically functional fraction of milk increasingly linked to beneficial outcomes in infants through protection from pathogens, modulation of the immune system and improved neurodevelopment. In the present study, we characterized the fecal microbiome and metabolome of infants fed a bovine MFGM supplemented experimental formula (EF) and compared to infants fed standard formula (SF) and a breast-fed reference group. The impact of MFGM on the fecal microbiome was moderate; however, the fecal metabolome of EF-fed infants showed a significant reduction of several metabolites including lactate, succinate, amino acids and their derivatives from that of infants fed SF. Introduction of weaning food with either human milk or infant formula reduces the distinct characteristics of breast-fed- or formula-fed- like infant fecal microbiome and metabolome profiles. Our findings support the hypothesis that higher levels of protein in infant formula and the lack of human milk oligosaccharides promote a shift toward amino acid fermentation in the gut. MFGM may play a role in shaping gut microbial activity and function.

Smilagenin Protects Dopaminergic Neurons in Chronic MPTP/Probenecid-Lesioned Parkinson's Disease Models.

Current therapies for Parkinson's disease (PD) only offer limited symptomatic alleviation but fail to hamper the progress of the disease. Thus, it is imperative to establish new approaches aiming at protecting or reversing neurodegeneration in PD. Recent work elucidates whether smilagenin (abbreviated SMI), a steroidal sapogenin from traditional Chinese medicinal herbs, can take neuroprotective effect on dopaminergic neurons in a chronic model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) conjuncted with probenecid mice. We reported for the first time that SMI significantly improved the locomotor ability of chronic MPTP/probenecid-lesioned mice. SMI increased the tyrosine hydroxylase (TH) positive and Nissl positive neuron number in the substantia nigra pars compacta (SNpc), augmented striatal DA and its metabolites concentration and elevated striatal dopamine transporter density (DAT). In addition, dopamine receptor D2R not D1R was down-regulated by MPTP/probenecid and slightly raised by SMI prevention. What's more, we discovered that SMI markedly elevated striatal glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) protein levels in SMI prevented mice. And we found that SMI increased GDNF and BDNF mRNA level by promoting CREB phosphorylation in 1-methyl-4-phenylpyridimium (MPP+) treated SH-SY5Y cells. The results illustrated that SMI could prevent the impairment of dopaminergic neurons in chronic MPTP/probenecid-induced mouse model.

The Role of Protein and Free Amino Acids on Intake, Metabolism, and Gut Microbiome: A Comparison Between Breast-Fed and Formula-Fed Rhesus Monkey Infants.

Background: Compared to breast-fed (BF), formula-fed (FF) infants exhibit more rapid weight gain, a different fecal microbial profile, as well as elevated serum insulin, insulin growth factor 1 (IGF-1), and branched chain amino acids (BCAAs). Since infant formula contains more protein and lower free amino acids than breast milk, it is thought that protein and/or free amino acids may be key factors that explain phenotypic differences between BF and FF infants. Methods: Newborn rhesus monkeys (Macaca mulatta) were either exclusively BF or fed regular formula or reduced protein formula either supplemented or not with a mixture of amino acids. Longitudinal sampling and clinical evaluation were performed from birth to 16 weeks including anthropometric measurements, intake records, collection of blood for hematology, serum biochemistry, hormones, and metabolic profiling, collection of urine for metabolic profiling, and collection of feces for 16s rRNA fecal microbial community profiling. Results: Reducing protein in infant formula profoundly suppressed intake, lowered weight gain and improved the FF-specific metabolic phenotype in the first month of age. This time-dependent change paralleled an improvement in serum insulin. All lower protein FF groups showed reduced protein catabolism with lower levels of blood urea nitrogen (BUN), urea, ammonia, albumin, creatinine, as well as lower excretion of creatinine in urine compared to infants fed regular formula. Levels of fecal microbes (Bifidobacterium and Ruminococcus from the Ruminococcaceae family), that are known to have varying ability to utilize complex carbohydrates, also increased with protein reduction. Adding free amino acids to infant formula did not alter milk intake or fecal microbial composition, but did significantly increase urinary excretion of amino acids and nitrogen-containing metabolites. However, despite the lower protein intake, these infants still exhibited a distinct FF-specific metabolic phenotype characterized by accelerated weight gain, higher levels of insulin and C-peptide as well as elevated amino acids including BCAA, lysine, methionine, threonine and asparagine. Conclusions: Reducing protein and adding free amino acids to infant formula resulted in growth and metabolic performance of infants that were more similar to BF infants, but was insufficient to reverse the FF-specific accelerated growth and insulin-inducing high BCAA phenotype.

Metabolite profiling and genome-wide association studies reveal response mechanisms of phosphorus deficiency in maize seedling.

Inorganic phosphorus (Pi) is an essential element in numerous metabolic reactions and signaling pathways, but the molecular details of these pathways remain largely unknown. In this study, metabolite profiles of maize (Zea mays L.) leaves and roots were compared between six low-Pi-sensitive lines and six low-Pi-tolerant lines under Pi-sufficient and Pi-deficient conditions to identify pathways and genes associated with the low-Pi stress response. Results showed that under Pi deprivation the concentrations of nucleic acids, organic acids and sugars were increased, but that the concentrations of phosphorylated metabolites, certain amino acids, lipid metabolites and nitrogenous compounds were decreased. The levels of secondary metabolites involved in plant immune reactions, including benzoxazinoids and flavonoids, were significantly different in plants grown under Pi-deficient conditions. Among them, the 11 most stable metabolites showed significant differences under low- and normal-Pi conditions based on the coefficient of variation (CV). Isoleucine and alanine were the most stable metabolites for the identification of Pi-sensitive and Pi-resistant maize inbred lines. With the significant correlation between morphological traits and metabolites, five low-Pi-responding consensus genes associated with morphological traits and simultaneously involved in metabolic pathways were mined by combining metabolites profiles and genome-wide association study (GWAS). The consensus genes induced by Pi deficiency in maize seedlings were also validated by reverse-transcription quantitative polymerase chain reaction (RT-qPCR). Moreover, these genes were further validated in a recombinant inbred line (RIL) population, in which the glucose-6-phosphate-1-epimerase encoding gene mediated yield and correlated traits to phosphorus availability. Together, our results provide a framework for understanding the metabolic processes underlying Pi-deficient responses and give multiple insights into improving the efficiency of Pi use in maize.

Paeonia lactiflora Pall. regulates the NF-κB-NLRP3 inflammasome pathway to alleviate cholestasis in rats.

OBJECTIVES: Cholestasis is a critical risk factor for severe hepatic disease or cirrhosis. The anti-inflammatory effect of Paeonia lactiflora Pall. (PLP), named Chishao in traditional Chinese medicine (TCM), on alpha-naphthylisothiocyanate (ANIT)-induced cholestasis model was tried to be elucidated in this research. METHODS: Therapeutic effect indices on hepatic function, including ALT, AST, TBIL, DBIL, ALP, TBA and γ-GT, were measured. To further investigate the protective mechanism of PLP, the mRNA and protein expression levels of NF-κB-NLRP3 inflammasome pathway were detected. RESULTS: Our results showed that compared with the model group, PLP could significantly reduce the increased serum indices such as ALT, AST, TBIL, DBIL, ALP, TBA and γ-GT induced by ANIT in a dose-dependent way. Moreover, we found that PLP downregulated the mRNA expression levels including IKK, p65, NLRP3, caspase-1 and IL-1ß, especially at the large dose. Furthermore, PLP also significantly inhibited NF-κB-NLRP3 inflammasome pathway by decreasing the protein levels of p65, p-p65, p-IKK, NLRP3, caspase-1 and IL-1ß. CONCLUSIONS: The results indicated that PLP could ameliorate ANIT-induced cholestasis in rats and the anti-inflammatory effect of PLP might be related to regulating NF-κB-NLRP3 inflammasome pathway. This study will provide scientific evidence for PLP as a potential drug candidate for cholestasis.