Protein of yak milk residue: Structure, functionality, and the effects on the quality of non-fat yogurt.

The purpose of this study was to compare the structural and functional of protein from yak milk residue, which collected from different elevations (MRP1 and MRP2) in Tibet, as well as their potential for enhancing the quality of non-fat yogurt. The results showed that MRP1 exhibited higher levels of ß-sheet, turbidity, particle size, and gel properties. MRP2 had better flexibility, emulsification, foaming, water/oil absorption capacity. The addition of MRP1 (3%) could improve texture and sensory properties of yogurt. Although MRP2 yogurt had higher hardness, gumminess, chewiness and water holding capacity, poor mouthfeel. Rheological test showed that MRPs yogurt exhibited typical gel-like and shear-thinning behavior. Moreover, the fortification of non-fat yogurts with MRP1 brought the formation of larger protein clusters with a more tightly knit network of smaller pores. These results indicate that MRP1 can be used as a fat substitute to improve the quality of non-fat yogurt.

Characterization of lipid composition and nutritional quality of yak ghee at different altitudes: A quantitative lipidomic analysis.

Efficient and comprehensive analysis of lipid profiles in yak ghee samples collected from different elevations is crucial for optimal utilization of these resources. Unfortunately, such research is relatively rare. Yak ghee collected from three locations at different altitudes (S2: 2986 m; S5: 3671 m; S6: 4508 m) were analyzed by quantitative lipidomic. Our analysis identified a total of 176 lipids, and 147 s lipid of them were upregulated and 29 lipids were downregulated. These lipids have the potential to serve as biomarkers for distinguishing yak ghee from different altitudes. Notably, S2 exhibited higher levels of fatty acids (21:1) and branched fatty acid esters of hydroxy fatty acids (14:0/18:0), while S5 showed increased levels of phosphatidylserine (O-20:0/19:1) and glycerophosphoric acid (19:0/22:1). S6 displayed higher levels of triacylglycerol (17:0/20:5/22:3), ceramide alpha-hydroxy fatty acid-sphingosine (d17:3/34:2), and acyl glucosylceramides (16:0-18:0-18:1). Yak ghee exhibited a high content of neutralizing glycerophospholipids and various functional lipids, including sphingolipids and 21 newly discovered functional lipids. Our findings provide insights into quantitative changes in yak ghee lipids during different altitudes, development of yak ghee products, and screening of potential biomarkers.

LATS2 condensates organize signalosomes for Hippo pathway signal transduction.

Biomolecular condensates have been proposed to mediate cellular signaling transduction. However, the mechanism and functional consequences of signal condensates are not well understood. Here we report that LATS2, the core kinase of the Hippo pathway, responds to F-actin cytoskeleton reduction and forms condensates. The proline-rich motif (PRM) of LATS2 mediates its condensation. LATS2 partitions with the main components of the Hippo pathway to assemble a signalosome for LATS2 activation and for its stability by physically compartmentalizing from E3 ligase FBXL16 complex-dependent degradation, which in turn mediates yes-associated protein (YAP)-transcriptional coactivator with PDZ-binding motif (TAZ) recruitment and inactivation. This oncogenic FBXL16 complex blocks LATS2 condensation by binding to the PRM region to promote its degradation. Disruption of LATS2 condensation leads to tumor progression. Thus, our study uncovers that the signalosomes assembled by LATS2 condensation provide a compartmentalized and reversible platform for Hippo signaling transduction and protein stability, which have potential implications in cancer diagnosis and therapeutics.

SRCAP complex promotes lung cancer progression by reprograming the oncogenic transcription of Hippo-YAP/TAZ signaling pathway.

The activation of YAP/TAZ, a pair of paralogs of transcriptional coactivators, initiates a dysregulated transcription program, which is a key feature of human cancer cells. However, it is not fully understood how YAP/TAZ promote dysregulated transcription for tumor progression. In this study, we employed the BioID method to identify the interactome of YAP/TAZ and discovered that YAP/TAZ interact with multiple components of SRCAP complex, a finding that was further validated through endogenous and exogenous co-immunoprecipitation, as well as immunofluorescence experiments. CUT&Tag analysis revealed that SRCAP complex facilitates the deposition of histone variant H2A.Z at target promoters. The depletion of SRCAP complex resulted in a decrease in H2A.Z occupancy and the oncogenic transcription of YAP/TAZ target genes. Additionally, the blockade of SRCAP complex suppressed YAP-driven tumor growth. In a genetically engineered lung adenocarcinoma mouse model and non-small cell lung cancer patients, SRCAP complex and H2A.Z deposition were found to be upregulated. This upregulation was statistically correlated with YAP expression, pathological stages, and poor survival in lung cancer patients. Together, our study uncovers that SRCAP complex plays a critical role in YAP/TAZ oncogenic transcription by coordinating H2A.Z deposition during cancer progression, providing potential targets for cancer diagnosis and prevention.

Exploration on anti-hypoxia properties of peptides: a review.

Peptides are important components of human nutrition and health, and considered as safe, nontoxic, and easily absorbed potential drugs. Anti-hypoxia peptides are a kind of peptides that can prevent hypoxia or hypoxia damage. In this paper, the sources, preparations, and molecular mechanisms of anti-hypoxia peptides were systemically reviewed. The combination of bioinformatics, chemical synthesis, enzymatic hydrolysis, and microbial fermentation are recommended for efficient productions of anti-hypoxic peptides. The mechanisms of anti-hypoxic peptides include interference with glycolytic process and HIF-1α pathway, mitochondrial apoptosis, and inflammatory response. In addition, bioinformatics analysis, including virtual screening and molecular docking, provides an alternative or auxiliary method for exploring the potential anti-hypoxic activities and mechanisms of peptides. The potential challenges and prospects of anti-hypoxic peptides are also discussed. This paper can provide references for researchers in this field and promote further research and clinical applications of anti-hypoxic peptides in the future.

Simultaneous Delivery of Dual Inhibitors of DNA Damage Repair Sensitizes Pancreatic Cancer Response to Irreversible Electroporation.

Pancreatic ductal adenocarcinoma (PDAC) is an abysmal disease refractory to most standard therapies. Irreversible electroporation (IRE) is a local ablative technique for the clinical treatment of solid tumors, including locally advanced and unresectable PDAC, by intratumorally delivering high-intensity electric pulses to permanently disrupt cell membranes and induce cell death. But the distribution of electric field is uneven within the tumor, and in some regions, tumor cells only experience temporary perturbation to their cell membrane, a phenomenon denoted as reversible electroporation (RE). These tumor cells may survive and therefore are the main culprit of tumor relapse after IRE. We herein showed that RE, although not killing tumor cells, induced DNA double-strand breaks and activated DNA damage repair (DDR) responses. Using reactive oxygen species-sensitive polymeric micelles coloaded with Olaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), and AZD0156, an inhibitor of ataxia telangiectasia mutated (ATM), the resultant nanoformulation (M-TK-OA) disrupted both homologous recombination and nonhomologous end joining signaling of the DDR response and impaired colony formation in pancreatic cancer cells after RE. The combination of IRE and M-TK-OA significantly prolonged animal survival in both subcutaneous and orthotopic murine PDAC models and elicited CD8+ T cell-mediated antitumor immunity with a sustained antitumor memory. The efficacy of combined IRE and M-TK-OA treatments was partially attributed to the activation of cyclic GMP-AMP synthase-stimulator of interferon genes innate immune responses. Our study suggests that dual inhibition of PARP and ATM with nanomedicine is a promising strategy to enhance the pancreatic cancer response to IRE.

Biological functions of active ingredients in quinoa bran: Advance and prospective.

Quinoa is known to be a rich source of nutrients and bioactive components. Quinoa bran, used mainly as animal feed in processing by-products, is also a potential source of bioactive ingredients being conducive to human health. The importance of nutrition and function of quinoa seed has been discussed in many studies, but the bioactive properties of quinoa bran often are overlooked. This review systemically summarized the progress in bioactive components, extraction, and functional investigations of quinoa bran. It suggests that chemically assisted electronic fractionation could be used to extract albumin from quinoa bran. Ultrasound-assisted extraction method is a very useful method for extracting phenolic acids, triterpene saponins, and flavonoids from quinoa bran. Based on in vitro and in vivo studies for biological activities, quinoa bran extract exhibits a wide range of beneficial properties, including anti-oxidant, anti-diabetes, anti-inflammation, anti-bacterial and anti-cancer functions. However, human experiments and action mechanisms need to investigate. Further exploring quinoa bran will promote its applications in functional foods, pharmaceuticals, and poultry feed in the future.

Preparation of fluorescent nanoparticles based on broken-rice starch for live-cell imaging.

Native broken-rice starch was used to create starch nanoparticles (StNPs) with particle sizes ranging from 100 nm to 800 nm. The fluorescent isothiocyanate poly-l-lysine StNPs (FITC-PLL-StNPs) were created in two steps. First, the StNPs were electrostatically modified by poly-l-lysine (PLL) molecules rich in amino acids. Second, fluorescein isothiocyanate reacted with some amino groups on PLL molecules (FITC). Fluorescence spectrophotometry was used to determine the degree of substitution (DS) and fluorescent properties of fluorescent starches. The study found that FITC-PLL-StNP-200 has higher fluorescence stability, more phagocytic cells, and a better and clearer fluorescence detecting effect than FITC-PLL-St, FITC-PLL-StNP-100, FITC-PLL-StNP-400, and FITC-PLL-StNP-800. The biological evaluation results showed that FITC-PLL-StNP-200 did not affect the viability of HeLa cells at the lysosome labeling concentration. These findings suggest that FITC-PLL-StNP-200 has strong and stable fluorescence, indicating that FITC-PLL-StNP-200 can be used as a fluorescent probe and lysosome marker in a variety of applications, particularly in biomedicine.

Local Release of TGF-ß Inhibitor Modulates Tumor-Associated Neutrophils and Enhances Pancreatic Cancer Response to Combined Irreversible Electroporation and Immunotherapy.

Pancreatic cancer is a deadly disease with little response to standard therapies. Irreversible electroporation (IRE) has emerged as a novel ablative technique for the clinical treatment of pancreatic cancer. Combinations of IRE and immunotherapies, including anti-programmed death 1 (αPD1) immune checkpoint blockade, have shown promising efficacy in both preclinical and clinical studies. However, tumor recurrence remains an obstacle that needs to be overcome. It herein is shown that IRE induces a substantial infiltration of neutrophils into pancreatic tumors. These neutrophils are then polarized into a protumor phenotype by immunosuppressive cues, in particular transforming growth factor ß (TGF-ß). Using glutathione-responsive degradable mesoporous silica nanoparticles loaded with SB525334, an inhibitor of TGF-ß1 receptor, it is demonstrated that local inhibition of TGF-ß within the tumor microenvironment promotes neutrophil polarization into an antitumor phenotype, enhances pancreatic cancer response to combined IRE and αPD1 therapy, and induces long-term antitumor memory. The therapeutic efficacy is also attributed to tumor infiltration by CD8+ cytotoxic T cells, depletion of regulatory T cells, and maturation of antigen-presenting dendritic cells. Thus, modulating neutrophil polarization with nanomedicine is a promising strategy for treating pancreatic cancer.

[Resistance to thyroid hormone syndrome due to p.Cys446Ser variant of THRbeta gene in a pedigree].

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with resistance to thyroid hormone syndrome (RTH). METHODS: Exons 7 to 10 of the THRbeta gene were sequenced for the proband and members of his pedigree. RESULTS: Three patients from the pedigree were identified. All have presented with palpitation, fatigue, goiter, elevated free thyroid hormone and free triiodothyronine, and normal or elevated thyrotropin. Genetic testing revealed that the proband, his mother, second sister and one of her daughters had carried a heterozygous c.1336T>A variant of the THRbeta gene, which resulted in substitution of Cysteine by Serine at position 446. The variant was unreported previously. Based on the American College of Medical Genetics and Genomics standards and guidelines, the c.1336T>A(p.Cys446Ser) variant of THRbeta gene was predicted to be lilely pathogenic(PM1+PM2+PM5+PP3). CONCLUSION: The c.1336T>A variant, identified in the exon 10 of the THRbeta gene, probably underlay the RTH in this pedigree. Genetic testing has validated the clinical diagnosis for this pedigree.

Protocol to establish a lung adenocarcinoma immunotherapy allograft mouse model with FACS and immunofluorescence-based analysis of tumor response.

Anti-PD-1/PD-L1 therapy shows long-term effects in many cancer types, but resistance and relapse remain the main limitations of this therapy. Here, we describe a protocol to evaluate the tumor response to immunotherapy in a mouse lung cancer model. The protocol includes the establishment of the lung cancer mouse model, anti-PD-1 treatment, tumor-infiltrating lymphocyte isolation, immunofluorescence, and flow cytometry analysis. This protocol can also be applied to other cancer types and immunotherapies. For complete details on the use and execution of this protocol, please refer to Yu et al. (2021).

Interferon-γ induces tumor resistance to anti-PD-1 immunotherapy by promoting YAP phase separation.

Interferon-γ (IFN-γ)-mediated adaptive resistance is one major barrier to improving immunotherapy in solid tumors. However, the mechanisms are not completely understood. Here, we report that IFN-γ promotes nuclear translocation and phase separation of YAP after anti-PD-1 therapy in tumor cells. Hydrophobic interactions of the YAP coiled-coil domain mediate droplet initiation, and weak interactions of the intrinsically disordered region in the C terminus promote droplet formation. YAP partitions with the transcription factor TEAD4, the histone acetyltransferase EP300, and Mediator1 and forms transcriptional hubs for maximizing target gene transcriptions, independent of the canonical STAT1-IRF1 transcription program. Disruption of YAP phase separation reduced tumor growth, enhanced immune response, and sensitized tumor cells to anti-PD-1 therapy. YAP activity is negatively correlated with patient outcome. Our study indicates that YAP mediates the IFN-γ pro-tumor effect through its nuclear phase separation and suggests that YAP can be used as a predictive biomarker and target of anti-PD-1 combination therapy.

Peptides Isolated from Yak Milk Residue Exert Antioxidant Effects through Nrf2 Signal Pathway.

Food-derived bioactive peptides are considered as the important sources of natural bioactive ingredients. Approximately 3094 peptides were identified by nESI-LC-MS/MS in the hydrolyzed yak milk residue. Peptide KALNEINQF (T10) is the strongest antioxidant peptide. The damage model of H2O2-induced human umbilical vein endothelial cells (HUVECs) was used to evaluate the antioxidant effect. After treatment with 25, 50, or 100 µg/mL T10 peptide, T10 obviously decreased H2O2-induced damage and increased the cell survival. Comparing with the H2O2-induced damage group, superoxide dismutase (SOD) activities were significantly increased 1.03, 1.1, and 1.33 times, and glutathione reductase (GR) activities were significantly increased 1.11, 1.30, and 1.43 times, respectively. Malondialdehyde (MDA) also reduced 1.41, 1.54, and 1.72 times, respectively. T10 inhibited H2O2-induced apoptosis in HUVECs, and protein expressions of the apoptosis-related genes bcl-2 and bax were increased and decreased by 1.95 and 1.44 times, respectively, suggesting T10 decreases apoptosis of the mitochondria-dependent pathway. Comparing with the H2O2-induced damage group, the RNA expressions of Nrf2, HO-1, and NQO1 were significantly increased by 2.00, 2.11, and 1.94 times; the protein expressions of p-Nrf2, HO-1, and NQO1 were significantly increased by 2.67, 1.73, and 1.04 times; and Keap1 was downregulated by 3.9 and 1.32 times, respectively. T10 also regulated the Nrf2 pathway and expressions of related genes (Keap1, HO-1, and NQO1), and blocking the Nrf2 pathway in the model decreased the protective effect of T10. Taken together, T10 peptide isolated from yak milk residue has a protective effect against H2O2-induced damage in HUVECs and the molecular mechanisms are involved in the regulation of Nrf2 signaling pathway and cell apoptosis.

Preparation and characterization of broken-rice starch nanoparticles with different sizes.

Broken-rice starch nanoparticles with different mean particle diameters for 100, 200, 400 and 800 nm were prepared by nanoprecipitation, alkali freezing, cross-linking and H2SO4 hydrolysis methods respectively, and their structural, morphological and physicochemical properties were systematically characterized. The results showed that broken-rice starch nanoparticles had higher water absorption rate, and the maximum water absorption rate was obtained from the 100 nm starch granules being 91.53%, which means an increase about 2.07-fold in water absorption rate as compared with native rice starch. The stability of native rice starch is the worst, but the viscosity characteristic value is always higher than that of starch nanoparticles in the whole gelatinization process. The FT-IR spectrum showed that only starch nanoparticles prepared by cross-linking method showed the characteristic peak of secondary amide structure at 1714 cm-1, but the structure of was basically the same as native starch. The X-ray diffraction pattern revealed that there were obvious characteristic diffraction peaks near 2θ for 15°, 17°, 19° and 23° for the 800 nm starch nanoparticles and native rice starch, while the characteristic diffraction peaks of other starch nanoparticles disappeared in varying degrees due to the changed crystal structure.

Systematic evaluation of the physicochemical properties and the volatile flavors of yak meat during chilled and controlled freezing-point storage.

In this study, the physicochemical properties (total volatile basic nitrogen (TVB-N), pH, and peroxide value) and the volatile flavors of yak meat were systematically evaluated during chilled (0 °C) and controlled freezing-point (- 2 °C) storage. The TVB-N reached 15.21 mg/100 g after 18 days of storage at 0 °C, which exceeded the secondary freshness value according to the Chinese national standard. For storage at - 2 °C, the TVB-N did not exceed 15 mg/100 g until 24 days. Compared with storage at 0 °C, the samples stored at - 2 °C had a slower rate of increase in TVB-N, pH, and peroxide values. The changes in volatile compounds in yak meat during storage at - 2 °C and 0 °C for 24 days were investigated using headspace solid-phase microextraction (HS-SPME) followed by gas chromatography-mass spectrometry (GC-MS). The correlations between the changes in the volatile compound contents and meat quality deterioration revealed significant negative correlations (r min = 0.902, p < 0.05) between some aldehyde flavor components (nonanal, heptanal, benzaldehyde, decanal, and myristal) and TVB-N in the samples stored at controlled freezing-point and chilled temperatures. The decreases in nonanal, benzaldehyde, and myristal contents in yak meat followed zero order reaction kinetics. This result indicated, because of the highly selective and sensitive colorimetric detection method, that volatile compounds can effectively predict the decay in quality of yak meat stored at low temperature in advance. Thus, based on physicochemical and volatile flavor analyses, a new method is proposed to investigate the storage and preservation of yak meat.

An efficient TP-FRET-based lysosome-targetable fluorescent probe for imaging peroxynitrite with two well-resolved emission channels in living cells, tissues and zebrafish.

Peroxynitrite (ONOO-), an important role of reactive oxygen species (ROS) in vivo, and studies showed abnormal of ROS can induce lysosomal membrane permeabilization (LMP) and lead to the death of cells. Thus, it is of great significance for designing an effective method for investigating relationship between physiology and pathology between ONOO- and lysosome. Herein, for the first time, we adopted a Förster resonance energy transfer (FRET) strategy to construct a lysosome-targetable small molecular ratiometric two-photon (TP) fluorescent probe (NpRh-ONOO) for detecting ONOO- in living cells, tissues and zebrafish. Specifically, a TP fluorophore and a rhodamine B fluorophore are directly connected by a flexible piperidine linker to form the TP-FRET-scaffold, a hydrazide as ONOO- reactive set, and a dimethylamino as lysosome targeting-group, which shows a target-modulated ratiometric TP fluorescence response, two well-resolved emission peaks separated by 73 nm, rapid response (<10 s), high selectivity and sensitivity with the detection limit is as low as 3.3 nM for ONOO-. These prominent features of probe were then applied for ratiometric bioimaging both exogenous and endogenous peroxynitrite in living cells, tissues and zebrafish, demonstrating it can be used as a powerful tool for biological research of lysosomal peroxynitrite in biological systems.

Effect of Saccharomyces uvarum on lipid oxidation and carbonyl compounds in silver carp mince during cold storage.

Fish lipid is highly susceptible to oxidation, resulting in accumulation of toxic substances reactive carbonyl compounds (RCCs), the reduction of nutritional value, and the production of odorous substances. In this study, the effect of yeast (Saccharomyces uvarum) on RCCs, fat acid composition, volatiles, and sensory traits in silver carp mince stored at 4°C was evaluated. Yeast eliminated malondialdehyde, 4-hydroxyl-2-hexenal, and 4-hydroxyl-2-nonenal by about 80%, 68%, and 60%, which increased by about 170%, 340%, and 300% in the control, respectively. Yeast helped retain about 80% of the polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), respectively; only about 53% and 46% of EPA and DHA, respectively, were maintained in the control. Yeast removed off-odors hexanal, nonanal, and decenal, resulting in enhanced sensory traits. These findings were economically important for improving the quality of fish products. It might present an approach to improve the flavor of fish products.

The discovery and expansion of Hippo signaling pathway in Drosophila model.

The discovery of Hippo signaling pathway is another breakthrough of fly genetics. Similar to the other signaling pathways, Hippo pathway also functions crucially in tremendous physiological and pathological conditions, like organ size control and cancer. There are three main stages of Hippo pathway study: Firstly, identifications of core components by fly genetic screens; secondly, regulations by versatile upstream cues, like cytoskeleton, mechanical tension, and nutrition; thirdly, functions in different biological processes, like cell proliferation regulation, stem cell biology, and immunology. In this review, we summarize the current understanding of Hippo pathway and highlight its regulations and transcriptional complex assembly. We also discuss the potential future directions in Drosophila model system.

Alliin, a garlic organosulfur compound, ameliorates gut inflammation through MAPK-NF-κB/AP-1/STAT-1 inactivation and PPAR-γ activation.

SCOPE: In this study, the anti-inflammatory effects and the molecular mechanism of alliin were analyzed in dextran sulfate sodium (DSS)-induced colitis mice and lipopolysaccharide-stimulated RAW264.7 cell model. METHODS: The phenotype of mice was recorded in the DSS-induced and/or alliin (500 mg/kg) groups. Histopathological alterations were analyzed by H&E staining. MPO and MDA of colon tissues were measured. The mRNA expression levels of inflammatory factors were determined by qRT-PCR, and protein expressions of inflammatory factors or activation of kinases were determined by Western blotting. RESULTS: Oral administration of alliin significantly inhibited the decrease of body weight, improved the DAI and decreased the infiltration of inflammatory cells in colonic tissues. The content of NO, MDA, and MPO, the expression of iNOS and inflammatory factors as well as MAPK and the phosphorylation of PPAR-γ were inhibited in alliin-treated group. Treatment with alliin significantly repressed the expression of inflammatory factors in LPS-stimulated RAW264.7 cells. Further research demonstrated that alliin repressed LPS-induced AP-1/NF-κB/STAT-1 activation by inhibiting the phosphorylations of p38, JNK, and ERK1/2-regulated PPAR-γ activation. CONCLUSION: Our results show that alliin ameliorates DSS-induced ulcerative colitis and inhibits the inflammatory responses in LPS-stimulated RAW264.7 cells partly through inhibiting ERK1/2-, JNK-/PPAR-γ-stimulated NF-κB/AP-1/STAT-1 activations.

Role and regulation of Yap in KrasG12D-induced lung cancer.

The Hippo pathway and its downstream transcriptional co-activator Yap influence lung cancer, but the nature of the Yap contribution has been unclear. Using a genetically engineered mouse lung cancer model, we show that Yap deletion completely blocks KrasG12D and p53 loss-driven adenocarcinoma initiation and progression, whereas heterozygosity for Yap partially suppresses lung cancer growth and progression. We also characterize Yap expression during tumor progression and find that nuclear Yap can be detected from the earliest stages of lung carcinogenesis, but at levels comparable to that in aveolar type II cells, which are a cell of origin for lung adenocarcinoma. At later stages of tumorigenesis, variations in Yap levels are detected, which correlate with differences in cell proliferation within tumors. Our observations imply that Yap is not directly activated by oncogenic Kras during lung tumorigenesis, but is nonetheless absolutely required for this tumorigenesis, and support Yap as a therapeutic target in lung adenocarcinoma.