Soy Peptide Supplementation Mitigates Undernutrition through Reprogramming Hepatic Metabolism in a Novel Undernourished Non-Human Primate Model.

In spite of recent advances in the field of undernutrition, current dietary therapy relying on the supply of high protein high calorie formulas is still plagued with transient recovery of impaired organs resulting in significant relapse of cases. This is partly attributed to the inadequacy of current research models in recapitulating clinical undernutrition for mechanistic exploration. Using 1636 Macaca fascicularis monkeys, a human-relevant criterion for determining undernutrition weight-for-age z-score (WAZ), with a cutoff point of ≤ -1.83 is established as the benchmark for identifying undernourished nonhuman primates (U-NHPs). In U-NHPs, pathological anomalies in multi-organs are revealed. In particular, severe dysregulation of hepatic lipid metabolism characterized by impaired fatty acid oxidation due to mitochondria dysfunction, but unlikely peroxisome disorder, is identified as the anchor metabolic aberration in U-NHPs. Mitochondria dysfunction is typified by reduced mito-number, accumulated long-chain fatty acids, and disruption of OXPHOS complexes. Soy peptide-treated U-NHPs increase in WAZ scores, in addition to attenuated mitochondria dysfunction and restored OXPHOS complex levels. Herein, innovative criteria for identifying U-NHPs are developed, and unknown molecular mechanisms of undernutrition are revealed hitherto, and it is further proved that soypeptide supplementation reprogramed mitochondrial function to re-establish lipid metabolism balance and mitigated undernutrition.

Interaction-based screening, Monte Carlo Bayesian inference-based de novo design and in vitro verification of adenine-binding peptide.

One of the main reasons for hyperuricemia is high purine intake. The primary strategy for treating hyperuricemia is blocking the purine metabolism enzyme. However, by binding the purine bases directly, we suggested a unique therapeutic strategy that might interfere with purine metabolism. There have been numerous reports of extensive interactions between proteins and purine bases. Adenine, constituting numerous protein co-factors, can interact with the adenine-binding motif. Using Bayesian Inference and Markov chain Monte Carlo sampling, we created a novel adenine-binding peptide Ile-Tyr-Val-Thr based on the structure of the adenine-binding motifs. Ile-Tyr-Val-Thr generates a semi-pocket that can clip the adenine within, as demonstrated by docking. Then, using thermodynamic techniques, the interaction between Ile-Tyr-Val-Thr and adenine was confirmed. The KD value is 1.50e-5 (ΔH = -20.2 kJ/mol and ΔG = -27.6 kJ/mol), indicating the high affinity. In brief, the adenine-binding peptide Ile-Tyr-Val-Thr may help lower uric acid level by blocking the absorption of food-derived adenine.

Exome-Based Amino Acid Optimization: A Dietary Strategy to Satisfy Human Nutritional Demands and Enhance Muscle Strength in Breast Tumor Mice Undergoing Chemotherapy.

Breast cancer patients undergoing chemotherapy often experience muscle wasting and weakness, which impact their quality of life. A potential solution lies in customizing amino acid compositions based on exome-derived formulations (ExAAs). The study hypothesized that tailoring dietary amino acids using ExAAs could enhance muscle health. Theoretical amino acid requirements were calculated from the genome's exome region, and a breast cancer mouse model undergoing paclitaxel treatment was established. The mice were supplemented with a cancer-specific nutritional formula (QJS), and the effects of QJS and amino acid-adjusted QJS (adjQJS) were compared. Both formulations improved the nutritional status without compromising tumor growth. Notably, adjQJS significantly enhanced muscle strength compared to QJS (1.51 ± 0.25 vs. 1.30 ± 0.08 fold change, p < 0.05). Transcriptome analysis revealed alterations in complement and coagulation cascades, with an observed upregulation of C3 gene expression in adjQJS. Immune regulation also changed, showing a decrease in B cells and an increase in monocytes in skeletal muscle with adjQJS. Importantly, adjQJS resulted in a notable increase in Alistipes abundance compared to QJS (10.19 ± 0.04% vs. 5.03 ± 1.75%). This study highlights the potential of ExAAs as valuable guide for optimizing amino acid composition in diets for breast cancer patients undergoing chemotherapy.

Dual-ligand lanthanide metal-organic framework for ratiometric fluorescence detection of the anthrax biomarker dipicolinic acid.

Dipicolinic acid (DPA) is a unique biomarker of Bacillus anthracis. Development of a simple, fast, sensitive and timely DPA detection method is of great importance and interest for preventing mass disease outbreaks and treatment of anthrax. In this work, a novel lanthanide-doped fluorescence probe was constructed by coordination of Eu3+ with bifunctional UiO-66-(COOH)2-NH2 MOFs materials for efficient monitoring DPA. UiO-66-(COOH)2-NH2 MOFs were prepared using Zr4+ as a metal node, 1,2,4,5-benzenetetracarboxylic acid (H4BTC) and 2-aminoterephthalic acid (NH2-BDC) as bridging ligand through a simple one-pot synthesis method. By virtue their abundant carboxyl groups, UiO-66-(COOH)2-NH2 can readily grasp Eu3+ to form UiO-66-(COOH)2-NH2/Eu with coordinated water molecules at Eu sites. Upon interaction with DPA molecules, the coordinated H2O molecules were replaced by DPA molecules which transfer energy to Eu3+ in UiO-66-(COOH)2-NH2/Eu and sensitize Eu3+ luminescence. Meanwhile, DPA has a characteristic absorption band at 270 nm, which overlapped with the excitation spectrum of NH2-BDC, allowing the fluorescence of UiO-66-(COOH)2-NH2/Eu at 453 nm to be greatly quenched by DPA through inner filter effect (IFE). Therefore, the rationally designed UiO-66-(COOH)2-NH2/Eu complex not only exhibits strong hydrophilicity and high dispersion, but also serves as ratiometric fluorescence sensing platform for monitoring DPA concentration. This sensing platform showed a satisfactory linear relationship from 0.2 µM to 40 µM with a limit of detection of 25.0 nM and a noticeable fluorescence color change from blue to red, holding a great promise in practical applications.

L-histidine functionalized ZiF-8 with aggregation-induced emission for detection of tetracycline.

In this study, we constructed zinc based metal-organic framework functionalized by L-histidine (His@ZiF-8). The His@ZiF-8 had high porosity, large surface area, abundant carboxyl and amino group, which has been found to greatly enhance the aggregation-induced emission (AIE) of tetracycline (TC). After the His@ZiF-8 enrichment with TC, the TC exhibited strong fluorescence emission peak at 565 nm based on AIE. Under the optimal conditions, the fluorescence intensity of TC exhibited a good linear relationship with TC concentration within 0.1-80 µM with a low limit of detection of 28.6 nM. Antibiotic analogs such as neomycin, chloramphenico, ampicillin, kanamycin, and erythromycin have no obvious interference. In addition, the developed method was successfully used to the detection of TC in milk, river water, and honey.

Elastic net-based identification of GAMT as potential diagnostic marker for early-stage gastric cancer.

Early-stage gastric cancer (GC) is asymptomatic. How to diagnose the early-stage GC is challenging. The sensitivity and specificity of diagnosing signatures for early-stage patients are still poor. Elastic-net-based analysis was used to identify potential diagnostic signatures of early-stage GC. The expression level of candidate gene was evaluated by immunohistochemistry staining. The potential function of candidate gene was verified by overexpressing in vitro. Consensus genes (including GAMT) were identified using the different strengths of the penalty. Surprisingly, GAMT was still identified even if some multicollinear variables were deleted directly. IHC staining showed that there are no GAMT-positive signals in the cell nuclei of all tumor tissues, while GAMT does express in nuclei of adjacent normal tissue. There are 16.33% positive cell nuclei in paracancerous tissues. In addition, the number of larger-area colonies of overexpression-GAMT group, empty-vector group, and AGS group is 70±29.21, 151.33±15.95, and 111.67±22.03, respectively. Number of larger colonies in group with overexpression of GAMT is significantly less than control groups. Elastic-net-penalty-based workflow is a effective tool to identify diagnostic biomarker for early-stage solid tumor. GAMT has strong potential to be the diagnostic biomarker for the early-stage GC.

Effect of oral and intraperitoneal administration of walnut-derived pentapeptide PW5 on cognitive impairments in APPSWE/PS1ΔE9 mice.

Food-derived bioactive peptides, encrypted in native protein sequence, have attracted enormous research attention due to its potential in the prevention and/or treatment of a broad range of diseases. However, administration route poses a great challenge to their development and commercial applications. Patient-friendly delivery of bioactive peptides which also enhances its efficacy urgently remain to be addressed. Here we compared the effects of oral administration (PO) to intraperitoneal injection (IP) of a walnut-derived bioactive pentapeptide PW5 (Pro-Pro-Lys-Asn-Trp) in cognitive improvement capacity in APPSWE/PS1ΔE9 transgenic mice. Strikingly, we found that only PO administration of PW5 could effectively ameliorate cognitive impairments and reduce the ß-amyloid deposits in the brain compared to the IP administration. This may be attributable to alterations in the gut microbiota communities, including alterations in microbial α- and ß-diversities after PO treatment, leading to the reversal of the relative abundances of ten differential genera (e.g. Acinetobacter, Lactobacillus, Akkermansia, Allobaculum, Adlercreutzia, Coriobacteriaceae, unclassified_p_ Firmicutes, Desulfovibrionaceae, Oscillospira and Anaeroplasma) which are highly correlated with disease progression. Thus, this study has leveraged on PW5 to proof the superior efficacy of oral delivery to injection delivery in improving cognitive impairments in vivo, suggesting that oral delivery might be highly recommended as a prioritized delivery route in the development of food-derived peptides.

A sensitive fluorescence "turn on" nanosensor for glutathione detection based on Ce-MOF and gold nanoparticles.

Glutathione (GSH) as an essential biothiol maintains redox homeostasis in human body, the aberrant level of it has been related to various diseases. In this work, we constructed a facile and environment-friendly strategy by using Ce based metal-organic frameworks and gold nanoparticles (AuNPs) for detection of GSH. The fluorescence intensity of the Ce-MOF was quenched by AuNPs, which is ascribed to the existence of fluorescence resonance energy transfer (FRET) and electrostatic interaction between Ce-MOFs and AuNPS. Because of the formation of Au-SH between AuNPs and GSH, the addition GSH induced the Ce-MOF/AuNPs and prevented the occurrence of FRET and electrostatic interaction between Ce-MOFs and AuNPS, which futher recovered the fluorescence of Ce-MOF. Under the optimized conditions, this "turn-on" sensing process revealed a high selectivity toward GSH and displayed good linearity in range of 0.2-32.5 µM with low detection limit of 58 nM. In addition, the practicability of the strategy was testified through analyzing GSH in real human serum samples.

Silver nanoparticles combined with amino-functionalized UiO-66 for sensitive detection of glutathione.

Herein, a fluorescent nanosensor has been constructed for detection of glutathione (GSH) based on NH2-UiO-66 and AgNPs. The NH2-UiO-66 was synthesized where 2-amino-terephthalic acid as the organic ligand and Zr4+ as the center metal ions. The AgNPs can enhance the fluorescence of NH2-UiO-66 based on metal enhanced fluorescence (MEF) effect. Moreover, in the present of GSH, the fluorescence of NH2-UiO-66@AgNPs was quenched via electrostatic interaction and Ag-S reaction. The present sensing strategy shows good linear relation with the concentration of GSH in the range of 0.2-1.0 µM and 1.0-30 µM, and the limit of detection is 79 nM. Furthermore, our fluorescent nanosensor was utilized to detect GSH in human serum with a recovery of 96.8-102.5%. The results indicated that NH2-UiO-66@AgNPs is successfully applied for high sensitive and selective detection of GSH in human serum.

Exploring the microbiota-Alzheimer's disease linkage using short-term antibiotic treatment followed by fecal microbiota transplantation.

Gut microbiota is proven to be involved in the development of beta amyloid (Aß) pathology in Alzheimer's disease (AD). Since there are difficulties in translating microbiota findings based on germ-free mice into clinical practice, here, we used short-term antibiotic cocktail treatment to develop a novel model with a near-germ-free status and without impacting Aß pathology. Three months old APPSWE/PS1ΔE9 mice were fed with antibiotic cocktails for two weeks by gavage to obtain a near "germ-free" status, and then received the donor fecal matter from the 16 months old APPSWE/PS1ΔE9 mice for 7 consecutive days. Fecal pellets were collected prior to antibiotics treatment, following antibiotic exposure, prior to and following fecal microbiota transplantation for gut microbiota analysis. Also, Aß pathology, astrocyte and microglia morphology were further explored. Pre-antibiotic-treated mice successfully allowed engraftment of gut microbiota following 7 consecutive days gavage with aged APPSWE/PS1ΔE9 mice microbiota. Microbiota reconstitution by transplantation was largely attributable to the donor source (e.g. g_Coriobacteriaceae and g_Clostridium) and led to a significant increase in Aß plaques. Surprisingly, astrocyte activation around Aß plaques was suppressed rather than microglia, the well-recognized plaque phagocytic cell type in Aß clearance, following microbiota engraftment. Our findings provide a novel framework for understanding the mechanisms of AD through the gut-brain axis and the translation of gut microbiota manipulation from bench to clinical practice.

Ratiometric fluorescent sensing for phosphate based on Eu/Ce/UiO-66-(COOH)2 nanoprobe.

The sensing of phosphate anion (PO43-) is an important subject for human health and environmental monitoring. Herein, a unique ratiometric fluorescent nanoprobe based on postsynthetic modification of metal-organic frameworks (MOF) UiO-66-(COOH)2 with Eu3+ and Ce3+ ions toward PO43- was proposed (designated as Eu/Ce/Uio-66-(COOH)2). The Eu/Ce/Uio-66-(COOH)2 nanoprobe exhibits three emission peaks at 377 nm, 509 nm, and 621 nm with the single excitation wavelength at 250 nm, respectively. The strong coordinating interaction between Ce3+ and O atoms in the PO43- group can result in the fluorescence quenching at 377 nm, while the fluorescence of 621 nm almost remains unchanged. Such a useful phenomenon is exploited for the construction of a ratiometric fluorescence platform for the detection of PO43-. The assay exhibited a good linear response in the 0.3-20 µM concentration range with the detection limit of 0.247 µM. In addition, this ratiometric fluorescent sensing method not only can be applied to read out PO43- concentration in real water samples, but also shows higher sensitivity, easier preparation and sensing procedures than other detection strategies.

Characterization and analysis of antioxidant activity of walnut-derived pentapeptide PW5 via nuclear magnetic resonance spectroscopy.

The antioxidative activity of natural products has commonly been studied by free radical scavenging methods. However, the mechanisms by which antioxidation is explored by free radical scavenging methods remain largely unknown. This study analyzed the composition of walnut-derived pentapeptides PW5 with potential biological activity and its oxidation reaction products in 2,2'-Azinobis-(3-ethylbenzthiazoline-6-sulphonate) (ABTS) test by nuclear magnetic resonance (NMR) spectroscopy. The amino acid sequence of PW5 peptide successfully characterized as Proline-Proline-Lysine-Asparagine-Tryptophan exhibited significant antioxidant activity with lower IC50 value (0.2210 ± 0.0032 mM) compared to glutathione (GSH, 0.2567 ± 0.0023 mM, p < 0.001). Furthermore, we found that the tryptophan residue was the only residue in PW5 with obvious alteration after treatment with ABTS free radicals, which was linked to its potential antioxidant properties. These findings revealed how NMR-characterized structures and oxidation reaction products may be used to explore the antioxidative mechanisms of food-derived peptides as well as other natural products.

Identification of Microbiota within Aß Plaque in APP/PS1 Transgenic Mouse.

Microbes like viruses, bacteria, and fungi have all been reported in the brain of Alzheimer's postmortem patients and/or AD mouse model; however, the relationship between brain microbes and Aß plaque deposition remains to be elucidated. In the present study, we first analyzed bacteria populations in the brain of 4-, 5-, and 6-month-old APP/PS1 mice and then examined the Aß-positive loads of APP/PS1 mouse at 9 months old to identify bacteria in the brain by 16S rDNA sequencing. Finally, blood-brain barrier permeability was measured by injecting dextrans through the tail vein. Surprisingly, the diversity of microbial community gradually decreased in APP/PS1 mouse while wild-type mouse showed no obvious regularity. Moreover, Aß-positive deposits in the brain showed a significantly higher relative abundance of microbiota than Aß-negative tissues and age-matched wild-type mouse brain tissues. In addition, an increase in blood-brain barrier permeability was also observed in APP/PS1 mouse. The present study revealed the exact location of microbes within the Aß plaques in the brain and suggested the potential antimicrobial effect of the Aß peptide. We strongly recommend that future research on microbiota-related AD pathology should focus on the migration route of microbiota into the brain and how the microbiota enhance AD progression.

Boric-acid-modified Fe3O4@PDA@UiO-66 for enrichment and detection of glucose by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Herein, boric-acid-modified multifunctional Zr-based metal-organic frameworks (denoted as Fe3O4@PDA@B-UiO-66) were synthesized by hydrothermal reaction and surface modification. Compared to traditional matrix, Fe3O4@PDA@B-UiO-66 has the advantages of high ionization efficiency, high surface area, low matrix background, porous structure, and numerous boric-acid-active sites. By combining matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), Fe3O4@PDA@B-UiO-66 was used as an adsorbent and matrix for enrichment and detection of glucose, based on a specific reaction between boric acid and glucose. The limit of detection was 58.5 nM. The proposed method provides a simple and efficient approach for the sensitive and quantitative detection of glucose in complex samples based on MALDI-TOF MS. Design and synthesis of boric-acid-modified multifunctional magnetic metal-organic frameworks (designated as Fe3O4@PDA@B-UiO-66) applied as adsorbent and matrix for the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis of glucose in complex biosamples.

Astrocytic trans-Differentiation Completes a Multicellular Paracrine Feedback Loop Required for Medulloblastoma Tumor Growth.

The tumor microenvironment (TME) is critical for tumor progression. However, the establishment and function of the TME remain obscure because of its complex cellular composition. Using a mouse genetic system called mosaic analysis with double markers (MADMs), we delineated TME evolution at single-cell resolution in sonic hedgehog (SHH)-activated medulloblastomas that originate from unipotent granule neuron progenitors in the brain. First, we found that astrocytes within the TME (TuAstrocytes) were trans-differentiated from tumor granule neuron precursors (GNPs), which normally never differentiate into astrocytes. Second, we identified that TME-derived IGF1 promotes tumor progression. Third, we uncovered that insulin-like growth factor 1 (IGF1) is produced by tumor-associated microglia in response to interleukin-4 (IL-4) stimulation. Finally, we found that IL-4 is secreted by TuAstrocytes. Collectively, our studies reveal an evolutionary process that produces a multi-lateral network within the TME of medulloblastoma: a fraction of tumor cells trans-differentiate into TuAstrocytes, which, in turn, produce IL-4 that stimulates microglia to produce IGF1 to promote tumor progression.

Synthesis of magnetic core-shell Fe3O4@PDA@Cu-MOFs composites for enrichment of microcystin-LR by MALDI-TOF MS analysis.

Microcystin-LR (MC-LR) is a toxin released from cyanobacteria in eutrophicated water. MC-LR is the most abundant and the most toxic among microcystins. In this work, core-shell structured copper-based magnetic metal-organic framework (Fe3O4@PDA@Cu-MOFs) composites were synthesized via a solvothermal reaction and a sol-gel method. The Fe3O4@PDA@Cu-MOFs composites showed ultra-high surface area, strong magnetic response and outstanding hydrophilicity. The Fe3O4@PDA@Cu-MOFs composites combined with matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF-MS) were used to analyse the content of MC-LR in real water samples. Under the optimised conditions, our proposed method exhibited good linearity within a concentration range of 0.05-4 µg L-1 and good detection even at low limits (0.015 µg L-1). The method was also successfully applied to analyse traces of MC-LR with quantitative recoveries for the real water samples in the range from 98.67% to 106.15%. Furthermore, it was characterized by high sensitivity, short operation time, being environmental friendly and having the ability to analyse other pollutants in the environment.

Mid infrared light treatment attenuates cognitive decline and alters the gut microbiota community in APP/PS1 mouse model.

Alzheimer's disease (AD) as the first most neurodegenerative disease in the elderly still has no effective therapy, suggesting that the intervention toolbox for AD should be expanded. One newly developed strategy involves the use of photobiomodulation, such as near infrared or far infrared light, which has proven to attenuate AD-associated pathology. However, the efficacy of mid infrared light (MIR) in treating AD is under investigated. With this in mind, we assessed the benefits of MIR light of peak wavelength 7.7-10 µm treatment on APP/PS1 transgenic mice. We found that APP/PS1 mice treated with MIR light had improved learning and memory abilities and reduced amyloid-ß (Aß) plaque load in the brain. We also surprisingly found that the gut microbiota composition in APP/PS1 mice treated with MIR light returned to normal (wild type mice) levels. Together, these findings suggested a novel non-invasive and promising avenue for AD treatment via photobiomodulation, and also proposed that future target for AD might be the gut microbiota via the brain-gut-skin axis.

New Discoveries in Hybrid Orbitals to Characterize Molecules and Predict Biomolecular Interactions.

Taking hydrogen bonds as a basis to explore biomolecular properties and interactions, we constructed the lone-pair electron (LPE) index and a molecular orbital fingerprint based on molecular hybrid orbitals to represent the ability of molecules to form hydrogen bonds. Then, a computational model was constructed to predict molecular interactions. The LPE and orbital fingerprint could effectively predict the biological properties and bioactivities of molecules. This study revealed the significance of hybrid orbitals for understanding cell biochemistry.

Walnut-Derived Peptide PW5 Ameliorates Cognitive Impairments and Alters Gut Microbiota in APP/PS1 Transgenic Mice.

SCOPE: Decreasing ß-amyloid (Aß) accumulation is of significance in finding therapeutic candidates for cognitive impairments in Alzheimer's disease (AD). The aim of this study is to investigate the potency of the active components of walnut protein in decreasing Aß aggregation and ameliorating cognitive impairments. METHODS AND RESULTS: Cell model of intracellular Aß42 aggregation is used to explore the active ingredients in walnut protein hydrolysate (WPH). A bioactive peptide (Pro-Pro-Lys-Asn-Trp, PW5) with great anti-Aß42 aggregation activity identified from the WPH is synthesized for in vitro and in vivo experiments. Using classic APP/PS1 mouse model, it is validated that PW5 exerts its effects on cognitive improvement through reducing Aß plaques accumulation. Moreover, metabolomic analysis reveals that serum norepinephrine (NE) and isovalerate levels are significantly increased in response to PW5 intervention, with decreased serum levels of acetylcholine (AChe) and valerate, compared with the vehicle-treated APP/PS1 mice. PW5 feeding also improves gut dysbiosis in APP/PS1 transgenic mice by increasing the relative abundance of Firmicutes and decreasing Proteobacteria and Verrucomicrobia as displayed by 16s rRNA analyses. CONCLUSIONS: These promising results support the utilization of peptide PW5 as an active ingredient in functional foods or potential drug candidate for the prevention and/or treatment of AD.

Novel xanthine oxidase-based cell model using HK-2 cell for screening antihyperuricemic functional compounds.

Hyperuricemia is a metabolic disease caused by disorders of purine metabolism, the prevalence of which has increased worldwide. Here, a cell model for high uric acid production was established in vitro employing cultured human kidney cells (HK-2 cells), and its molecular basis was analyzed using gene expression profile. High performance liquid chromatography (HPLC) was used to monitor the content of metabolites in cell culture media. Adenosine addition was found to induce HK-2 cells to produce uric acid precursors (inosine and hypoxanthine). Furthermore, the cell model was verified by confirming the antihyperuricemic effect of the widely used antihyperuricemic drugs allopurinol, probenecid, and febuxostat, as well as reported bioactive peptides and amino acids, encompassing glutathione, tryptophan and carnosine, which significantly reduced uric acid production in the HK-2 cells (p < 0.05). RNA-Seq technology was used to perform a wide transcriptome analysis of the hyperuricemic cell model, and the results demonstrated that it has the potential to be used as a rapid and valid in vitro model to screen antihyperuricemic compounds that mimics in vivo cell growth patterns.