Selective N=S Coupling Reactions of N-Methoxy Arylamides and Sulfoxides Catalyzed by Iron Salt.

An iron-catalyzed selective N=S coupling of N-methoxy amides and sulfoxides has been developed and was found to be a highly efficient method for the synthesis of N-acyl sulfoximines. Electron-donating as well as electron-withdrawing groups on the phenyl ring are tolerated, and even sensitive substituents are compatible. The current catalytic transformation was conducted under an air atmosphere and can be easily scaled up to a gram scale with a catalyst loading of only 1 mol %. In this case, both coupling partners are used in their native forms, thus obviating prior functionalization and activation.

TSPAN1 overexpression as an indicator of poor prognosis in estrogen receptor-positive breast cancer.

Background: Tetraspanin 1 (TSPAN1) is a newly discovered protein of the tetrameric protein family encoded by the TSPAN1 gene localized in the 1p34 chromosome region. TSPAN1 has been shown to be associated with various malignancies. In this study, we aimed to investigate the prognostic significance of TSPAN1 in breast cancer. Estrogen receptor-positive (ER+) breast cancer is the largest breast cancer subgroup, and ER-targeted therapies have significantly prolonged survival and improved symptoms in advanced breast cancer. TSPAN1 overexpression was found to be associated with a poor prognosis in ER+ breast cancer. Methods: We analyzed the expression of TSPAN1 in breast cancer tissues and cell lines using western blotting and quantitative reverse transcription polymerase chain reaction (RT-qPCR). Results: TSPAN1 expression was higher in breast cancer cells as compared with normal breast tissue. There was a significant association between a high TSPAN1 level and a low survival rate. Inhibition of TSPAN1 significantly reduced the proliferation and invasion of BT474 cells both in vitro and in vivo. The downregulation of TSPAN1 in breast cancer cells significantly reduced the levels of p-mitogen-activated protein kinase 1 (MEK1) (S298) and p-extracellular signal-regulating kinase (ERK) 1/2. Conclusions: TSPAN1 modulates downstream extracellular matrix (ECM) receptor signaling cascades and promotes cellular proliferation and invasion in breast cancer. TSPAN1 inhibition may be a potential new treatment strategy for breast cancer.

PRRSV NSP1α degrades TRIM25 through proteasome system to inhibit host antiviral immune response.

Porcine reproductive and respiratory syndrome (PRRS) is the most economically significant disease caused by porcine reproductive and respiratory syndrome virus (PRRSV). Type I interferon (IFN) induces a large number of interferon-stimulated genes (ISGs) expression to inhibit PRRSV infection. To survive in the host, PRRSV has evolved multiple strategies to antagonize host innate immune response. Previous studies have reported that PRRSV N protein decreases the expression of TRIM25 and TRIM25-mediated RIG-I ubiquitination to suppress IFN-ß production. However, whether other PRRSV proteins inhibit the antiviral function of TRIM25 is less well understood. In this study, we first found that PRRSV NSP1α decreased ISGylation of TRIM25. Meanwhile, NSP1α significantly suppressed TRIM25-mediated IFN-ß production to promote PRRSV replication. Further studies demonstrated that PRRSV NSP1α reduced the protein level of TRIM25 in proteasome system but did not regulate the transcription level of TRIM25. In addition, the function of NSP1α in TRIM25 degradation did not rely on its papain-like cysteine protease activity. Taken together, PRRSV NSP1α antagonizes the antiviral response of TRIM25 by mediating TRIM25 degradation to promote PRRSV replication. Our data identify TRIM25 as a natural target of PRRSV NSP1α and reveal a novel mechanism that PRRSV induces TRIM25 degradation and inhibits host antiviral immune response.

Developing oxaliplatin and IL-15 Co-carried gels as drug depots to enable triple-interlocked combination therapy for colorectal cancer.

Chemo-immunotherapy, which involves the simultaneous use of chemotherapy drug and immunotherapeutic agent to achieve synergistic effects, plays a crucial role in cancer treatment. However, the immunosuppressive microenvironment, insufficient tumor specificity, and serious systemic side effects hinder their synergistic therapeutic effects and clinical applications. Herein, T cell and natural killer (NK) cell, which are the most important immune effector cells, were both activated to reverse the immunosuppressive microenvironment. To simplify drug carriers, oxaliplatin was selected as the chemotherapy drug which can both induce the ICD effect and activate T cells. IL-15 was selected to activate NK cells. To enhance the productivity of the carrier and reduce side effects, the easy-prepared thermosensitive hydrogel (OXL/IL-15 TG) was developed to co-load oxaliplatin-loaded liposomes (OXL) and IL-15. Colorectal cancer, suitable for in situ administration, was selected as model cancer. The resulting novel triple-interlocked combination therapy could directly kill the tumor cells, induces ICD effect and activate NK cells. After administration, OXL/IL-15 TG was formed serving as a drug depot, slowing releasing OXL and IL-15 non-interferencely. OXL around 165.47±7.04 nm was passively delivered to tumor tissue, killing tumor cells and inducing ICD effect. The results demonstrated that IL-15 stimulated the activation of NK cells. In tumor-bearing mice models, OXL/IL-15 TG exhibited a remarkable and noteworthy anti-tumor efficacy, and expanded survival rate. Notably, OXL/IL-15 TG led to an enhanced infiltration of CD3+CD8+ T cells and CD3-CD49+ NK cells within the tumor tissue. Overall, the triple-interlocked combination therapy provided a new idea for colorectal cancer therapy.

Exploring the immune escape mechanisms in gastric cancer patients based on the deep AI algorithms and single-cell sequencing analysis.

Gastric cancer is a prevalent and deadly malignancy, and the response to immunotherapy varies among patients. This study aimed to develop a prognostic model for gastric cancer patients and investigate immune escape mechanisms using deep machine learning and single-cell sequencing analysis. Data from public databases were analysed, and a prediction model was constructed using 101 algorithms. The high-AIDPS group, characterized by increased AIDPS expression, exhibited worse survival, genomic variations and immune cell infiltration. These patients also showed immunotherapy tolerance. Treatment strategies targeting the high-AIDPS group identified three potential drugs. Additionally, distinct cluster groups and upregulated AIDPS-associated genes were observed in gastric adenocarcinoma cell lines. Inhibition of GHRL expression suppressed cancer cell activity, inhibited M2 polarization in macrophages and reduced invasiveness. Overall, AIDPS plays a critical role in gastric cancer prognosis, genomic variations, immune cell infiltration and immunotherapy response, and targeting GHRL expression holds promise for personalized treatment. These findings contribute to improved clinical management in gastric cancer.

Effects of sitagliptin activation of the stromal cell-derived factor-1/CXC chemokine receptor 4 signaling pathway on the proliferation, apoptosis, inflammation, and osteogenic differentiation of human periodontal ligament stem cells induced by lipopolysaccharide.

OBJECTIVES: This study aimed to investigate the effects of sitagliptin on the proliferation, apoptosis, inflammation, and osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) in lipopolysaccharide (LPS)-induced inflammatory microenvironment and its molecular mechanism. METHODS: hPDLSCs were cultured in vitro and treated with different concentrations of sitagliptin to detect cell viability and subsequently determine the experimental concentration of sitagliptin. An hPDLSCs inflammation model was established after 24 h of stimulation with 1 µg/mL LPS and divided into blank, control, low-concentration sitagliptin (0.5 µmol/L), medium-concentration sitagliptin (1 µmol/L), and high-concentration sitagliptin (2 µmol/L), high-concentrationsitagliptin+stromal cell derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) pathway inhibitor (AMD3100) (2 µmol/L+10 µg/mL) groups. A cell-counting kit-8 was used to detect the proliferation activity of hPDLSCs after 24, 48, and 72 h culture. The apoptosis of hPDLSCs cultured for 72 h was detected by flow cytometry. After inducing osteogenic differentiation for 21 days, alizarin red staining was used to detect the osteogenic differentiation ability of hPDLSCs. The alkaline phosphatase (ALP) activity in hPDLSCs was determined using a kit. The levels of inflammatory factors [tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6] in the supernatant of hPDLSCs culture were detected by enzyme-linked immunosorbent assay. The mRNA expressions of osteogenic differentiation genes [Runt-associated transcription factor 2 (RUNX2), osteocalcin (OCN), osteopontin (OPN)], SDF-1 and CXCR4 in hPDLSCs were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). Western blot analysis was used to determine SDF-1 and CXCR4 protein expression in hPDLSCs. RESULTS: Compared with the blank group, the proliferative activity, number of mineralized nodules, staining intensity, ALP activity, and RUNX2, OCN, OPN mRNA, SDF-1, and CXCR4 mRNA and protein expression levels of hPDLSCs in the control group significantly decreased. The apoptosis rate and levels of TNF-α, IL-1ß, and IL-6 significantly increased (P<0.05). Compared with the control group, the proliferative activity, number of mineralized nodule, staining intensity, ALP activity, and RUNX2, OCN, OPN mRNA, SDF-1, and CXCR4 mRNA and protein expression levels of hPDLSCs in low-, medium-, and high-concentration sitagliptin groups increased. The apoptosis rate and levels of TNF-α, IL-1ß, and IL-6 decreased (P<0.05). AMD3100 partially reversed the effect of high-concentration sitagliptin on LPS-induced hPDLSCs (P<0.05). CONCLUSIONS: Sitagliptin may promote the proliferation and osteogenic differentiation of hPDLSCs in LPS-induced inflammatory microenvironment by activating the SDF-1/CXCR4 signaling pathway. Furthermore, it inhibited the apoptosis and inflammatory response of hPDLSCs.

Zirconium-rich magnetic polyoxometalate-based metal-organic framework: Tailored for phosphopeptide analysis from lung cancer A549 cells.

Polyoxometalate-based metal-organic frameworks (POMOFs) have become a promising affinity material for separation and enrichment. The analysis of protein phosphorylation represents a challenge for the development of efficient enrichment materials. Here, a novel zirconium-rich magnetic POMOF was successfully designed and prepared for the enrichment of phosphopeptides. The binding affinity of the nanomaterial partly came from Fe-O clusters in the MOF. The Lewis acid-base interactions between V-O clusters and zirconium ions in V10O28-Zr4+ and phosphate groups in phosphopeptides further strengthened the enrichment ability. The zirconium-rich magnetic POMOF was employed to capture phosphopeptides from non-fat milk, human saliva, and serum. Additionally, 748 unique phosphopeptide peaks were detected from the tryptic digests of lung cancer A549 cell proteins with a high specificity (86.9 %). POMOFs will become an active competitor for the design of protein affinity materials and will provide a new approach for phosphopeptide analysis.

Itaconic Acid-Based Organic-Polymer Monolithic Column for Hydrophilic Capillary Electrochromatography and Its Application in Pharmaceutical Analysis.

Itaconic acid is an excellent hydrophilic monomer owing to the dicarboxylic group possessing strong polarity. This study reports on the preparation of a new organic-polymer monolithic column poly(itaconic acid-co-3-(acryloyloxy)-2-hydroxypropyl methacrylate) (poly(IA-co-AHM)) featuring excellent hydrophilic chromatography ability and its application in pharmaceutical analysis. The monolithic column was successfully synthesized by using the monomer itaconic acid and the cross-linker AHM through an in situ copolymerization method. Optical microscopy, scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FTIR) were employed for the characterization of the poly(IA-co-AHM) monolithic column, and all of these demonstrated that the prepared itaconic acid-based monolithic column exhibited satisfactory permeability and a homogeneous porous structure. Owing to the carboxylic groups of itaconic acid, a cathodic electroosmotic flow (EOF) was generated on the itaconic acid-based monolithic column among the pH ranges of the mobile phase from 4.0 to 9.0. Depending on the powerful hydrophilic interactions, different kinds of polar substances, including thioureas, nucleoside drugs, sulfonamides, and polypeptides, were separated efficiently by the itaconic acid-based monoliths poly(IA-co-AHM). The separations of polar compounds were successfully realized, even at a lower level of 50% acetonitrile content on this monolithic column. The highest column efficiencies corresponding to N,N'-dimethylthiourea and idoxuridine were 102 720 and 124 267 N/m, respectively. The poly(IA-co-AHM) monolithic column displayed excellent repeatability, whose relative standard deviations (RSDs) of the retention time and peak area were both lower than 5.0%. All experimental results demonstrated that the new itaconic acid-functionalized monolithic column was greatly appropriate to separate the polar compounds under the HILIC mode.

Nano-Regulator Inhibits Tumor Immune Escape via the "Two-Way Regulation" Epigenetic Therapy Strategy.

Tumor immune escape caused by low levels of tumor immunogenicity and immune checkpoint-dependent suppression limits the immunotherapeutic effect. Herein, a "two-way regulation" epigenetic therapeutic strategy is proposed using a novel nano-regulator that inhibits tumor immune escape by upregulating expression of tumor-associated antigens (TAAs) to improve immunogenicity and downregulating programmed cell death 1 ligand 1 (PD-L1) expression to block programmed death-1 (PD-1)/PD-L1. To engineer the nano-regulator, the DNA methyltransferase (DNMT) inhibitor zebularine (Zeb) and the bromodomain-containing protein 4 (BRD4) inhibitor JQ1 are co-loaded into the cationic liposomes with condensing the toll-like receptor 9 (TLR9) agonist cytosine-phosphate-guanine (CpG) via electrostatic interactions to obtain G-J/ZL. Then, asparagine-glycine-arginine (NGR) modified material carboxymethyl-chitosan (CMCS) is coated on the surface of G-J/ZL to construct CG-J/ZL. CG-J/ZL is shown to target tumor tissue and disassemble under the acidic tumor microenvironment (TME). Zeb upregulated TAAs expression to improve the immunogenicity; JQ1 inhibited PD-L1 expression to block immune checkpoint; CpG promote dendritic cell (DC) maturation and reactivated the ability of tumour-associated macrophages (TAM) to kill tumor cells. Taken together, these results demonstrate that the nano-regulator CG-J/ZL can upregulate TAAs expression to enhance T-cell infiltration and downregulate PD-L1 expression to improve the recognition of tumor cells by T-cells, representing a promising strategy to improve antitumor immune response.

Preparation of high-efficiency titanium ion immobilized magnetic graphite nitride nanocomposite for phosphopeptide enrichment.

BACKGROUND: Protein phosphorylation has been implicated in life processes including molecular interaction, protein structure transformation, and malignant disease. An in-depth study of protein phosphorylation may provide vital information for the discovery of early biomarkers. Mass spectrometry (MS)-based techniques have become an important method for phosphopeptide identification. Nevertheless, direct detection remains challenging because of the low ionization efficiency of phosphopeptides and serious interference from non-phosphopeptides. There is a great need for an efficient enrichment strategy to analyze protein phosphorylation prior to MS analysis. RESULTS: In this study, a novel nanocomposite was prepared by introducing titanium ions into two-dimensional magnetic graphite nitride. The nanocomposite was combined with immobilized metal ion affinity chromatography (IMAC) and anion-exchange chromatography mechanisms for phosphoproteome research. The nanocomposite had the advantages of a large specific surface (412.9 m2 g-1), positive electricity (175.44 mV), and excellent magnetic property (35.7 emu g-1). Moreover, it presented satisfactory selectivity (α-casein:ß-casein:bovine serum albumin = 1:1:5000), a low detection limit (0.02 fmol), great recyclability (10 cycles), and high recovery (92.8%). The nanocomposite demonstrated great practicability for phosphopeptides from non-fat milk, human serum, and saliva. Further, the nanocomposite was applied to enrich phosphopeptides from a more complicated specimen, A549 cell lysate. A total of 890 phosphopeptides mapping to 564 phosphoproteins were successfully detected with nano LC-MS. SIGNIFICANCE: We successfully designed and developed an efficient analysis platform for phosphopeptides, which includes protein digestion, phosphopeptide enrichment, and MS detection. The MS-based enrichment platform was further used to analyze phosphopeptides from complicated bio-samples. This work paves the way for the design and preparation of graphite nitride-based IMAC materials for phosphoproteome analysis.

Rapid Detection of Volatile Organic Metabolites in Urine by High-Pressure Photoionization Mass Spectrometry for Breast Cancer Screening: A Pilot Study.

Despite surpassing lung cancer as the most frequently diagnosed cancer, female breast cancer (BC) still lacks rapid detection methods for screening that can be implemented on a large scale in practical clinical settings. However, urine is a readily available biofluid obtained non-invasively and contains numerous volatile organic metabolites (VOMs) that offer valuable metabolic information concerning the onset and progression of diseases. In this work, a rapid method for analysis of VOMs in urine by using high-pressure photon ionization time-of-flight mass spectrometry (HPPI-TOFMS) coupled with dynamic purge injection. A simple pretreatment process of urine samples by adding acid and salt was employed for efficient VOM sampling, and the numbers of metabolites increased and the detection sensitivity was improved after the acid (HCl) and salt (NaCl) addition. The established mass spectrometry detection method was applied to analyze a set of training samples collected from a local hospital, including 24 breast cancer patients and 27 healthy controls. Statistical analysis techniques such as principal component analysis, partial least squares discriminant analysis, and the Mann-Whitney U test were used, and nine VOMs were identified as differential metabolites. Finally, acrolein, 2-pentanone, and methyl allyl sulfide were selected to build a metabolite combination model for distinguishing breast cancer patients from the healthy group, and the achieved sensitivity and specificity were 92.6% and 91.7%, respectively, according to the receiver operating characteristic curve analysis. The results demonstrate that this technology has potential to become a rapid screening tool for breast cancer, with significant room for further development.

GPD1 inhibits the carcinogenesis of breast cancer through increasing PI3K/AKT-mediated lipid metabolism signaling pathway.

Glycerol 3-phosphate dehydrogenase 1 (GPD1) acts as a tumor suppressor in various types of cancer. However, the mechanisms of GPD1 anti-tumor remain unclear in breast cancer. This study aims to explore the function and clinical relevance of GPD1 in breast cancer. We confirmed that GPD1 inhibited the ability of proliferation, migration, and invasion in GPD1 overexpression breast cancer cells by CCK-8, wound healing, and Transwell assays, respectively. We found that GPD1 overexpression activated the lipid synthesis pathway and PI3K/AKT signaling pathway. The inhibitory effect of GPD1 on breast cancer cells was also weakened after treatment with LY294002, a PI3K/AKT pathway inhibitor. These results indicated that GPD1 suppressed the carcinogenesis of breast cancer through increasing PI3K/AKT-mediated lipid signaling pathways. Meanwhile, we detected that the relationship between GPD1 level and survival rate presents a positive correlation in breast cancer patients from the Cancer Genome Atlas (TCGA) database. Therefore, GPD1 can be a prognostic biomarker and target in developing therapeutic strategies for breast cancer patients.

Driving natural killer cell-based cancer immunotherapy for cancer treatment: An arduous journey to promising ground.

Immunotherapy represents one of the most effective strategies for cancer treatment. Recently, progress has been made in using natural killer (NK) cells for cancer therapy. NK cells can directly kill tumor cells without pre-sensitization and thus show promise in clinical applications, distinct from the use of T cells. Whereas, research and development on NK cell-based immunotherapy is still in its infancy, and enhancing the therapeutic effects of NK cells remains a key problem to be solved. An incompletely understanding of the mechanisms of action of NK cells, immune resistance in the tumor microenvironment, and obstacles associated with the delivery of therapeutic agents in vivo, represent three mountains that need to be scaled. Here, we firstly describe the mechanisms underlying the development, activity, and maturation of NK cells, and the formation of NK­cell immunological synapses. Secondly, we discuss strategies for NK cell-based immunotherapy strategies, including adoptive transfer of NK cell therapy and treatment with cytokines, monoclonal antibodies, and immune checkpoint inhibitors targeting NK cells. Finally, we review the use of nanotechnology to overcome immune resistance, including enhancing the anti-tumor efficiency of chimeric antigen receptor-NK, cytokines and immunosuppressive-pathways inhibitors, promoting NK cell homing and developing NK cell-based nano-engagers.

Liver-derived FGF21 is required for the effect of time-restricted feeding on high-fat diet-induced fatty liver in mice.

Nonalcoholic fatty liver disease (NAFLD), which leads to insulin resistance, steatosis, and even hepatocellular carcinoma, is the most common chronic liver disease worldwide, however, effective treatment is still lacking. This study determined the role of liver FGF21 and the mechanisms underlying the protective effects of time-restricted feeding (TRF) in NAFLD. FGF21 liver knockout (FGF21 LKO) mice and C57BL/6 wild-type (WT) mice were fed either a normal or a high-fat diet (HFD) for 16 weeks. Mice with diet-induced obesity (DIO) were also used. The mice were fed either ad libitum or in a time-restricted manner. Serum FGF21 levels were significantly increased after 16 weeks of TRF. TRF prevented body weight gain, improved glucose homeostasis, and protected against high-fat diet-induced hepatosteatosis and liver damage. The expression of genes related to liver lipogenesis and inflammation was reduced in TRF mice, but the expression of genes involved in fatty acid ß-oxidation was increased. However, those beneficial effects of TRF were blunted in the FGF21 LKO mice. Moreover, TRF promoted improvements in insulin sensitivity and liver damage in DIO mice. Our data show that liver FGF21 signaling was involved in the effect of TRF on high-fat diet-induced fatty liver.

New insights into the non-enzymatic function of HDAC6.

Histone deacetylase 6 (HDAC6) is a class IIb histone deacetylase that contains two catalytic domains and a zinc-finger ubiquitin binding domain (ZnF-UBP) domain. The deacetylation function of HDAC6 has been extensively studied with common substrates such as α-tubulin, cortactin, and Hsp90. Apart from its deacetylase activity, HDAC6 ZnF-UBP binds to unanchored ubiquitin of specific sequences and serves as a carrier for transporting aggregated proteins. As a result, aggresomes are formed and protein degradation is facilitated by the autophagy-lysosome pathway. This HDAC6-dependent microtubule transport can be used by cells to assemble and activate inflammasomes, which play a critical role in immune regulation. Even viruses can benefit from the carrier of HDAC6 to assist in uncoating their surfaces during their infection cycle. However, HDAC6 is also capable of blocking virus invasion and replication in a non-enzymatic manner. Given these non-enzymatic functions, HDAC6 is closely associated with various diseases, including neurodegeneration, inflammasome-associated diseases, cancer, and viral infections. Small molecule inhibitors targeting the ubiquitin binding pocket of HDAC6 have been investigated. In this review, we focus on mechanisms in non-enzymatic functions of HDAC6 and discuss the rationality and prospects of therapeutic strategies by intervening the activation of HDAC6 ZnF-UBP in concrete diseases.

Carbenoxolone disodium suppresses the migration of gastric cancer by targeting HDAC6.

Aim: Because of the severe morbidity and mortality of gastric cancer, discovering new candidate drugs has been an urgent issue. The close association between histone deacetylase 6 (HDAC6) and gastric cancer makes the development of HDAC6-targeted anti-gastric cancer drugs a viable idea. Methods & results: Carbenoxolone disodium was identified as a novel HDAC6 inhibitor. Cellular thermal shift assay, surface plasmon resonance assay and molecular docking confirmed its binding ability to HDAC6. Cell viability, wound healing and transwell assays as well as animal studies have demonstrated that carbenoxolone disodium could block the proliferation and migration of gastric cancer cells MGC-803 in vitro and in vivo. Conclusion: This is the first report to indicate that carbenoxolone disodium could be an HDAC6 inhibitor with potential for treatment of gastric cancer.

PRRSV nonstructural protein 11 degrades swine ISG15 by its endoribonuclease activity to antagonize antiviral immune response.

Porcine reproductive and respiratory syndrome virus (PRRSV) is an enveloped positive-stranded RNA virus which causes serious economic losses to pig industry worldwide. Type I IFN induces expression of interferon-stimulated genes 15 (ISG15) to inhibit virus replication. To survive in the host, PRRSV has evolved to antagonize the antiviral response of ISGylation. Previous studies have reported that nonstructural protein 2 of PRRSV inhibits the ISGylation and antiviral function of ISG15 depending on its ovarian tumor (OTU) domain/papain-like protease domain (PLP2). However, whether there are other PRRSV proteins inhibiting ISGylation of cellular proteins is less well understood. In this study, we first found that PRRSV Nsp11 decreased ISGylation of cellular proteins. Meanwhile, the expression level of ISG15 was significantly inhibited by Nsp11. Further mechanistic studies demonstrated that the transcription of ISG15 was reduced by endoribonuclease activity of Nsp11. Finally, we found that the Nsp11-induced degradation of ISG15 was partially relied on autophagy-lysosome system. Taken together, PRRSV Nsp11 antagonizes the antiviral response of ISG15 by its endoribonuclease activity to promote PRRSV replication. Our results reveal a novel mechanism that PRRSV inhibits ISGylation of cellular proteins and impairs host innate immune response.

Duck cGAS inhibits DNA and RNA virus replication by activating IFNs and antiviral ISGs.

Cyclic GMP-AMP Synthase (cGAS) is a pivotal adaptor of the signaling pathways involving the pattern recognition receptors and plays an important role in apoptosis and immune regulation. The cGAS function in mammals has been investigated extensively; however, the function of duck cGAS (du-cGAS) in response to viral infections is still unclear. This study aimed to clone the mallard (Anas platyrhynchos) cGAS homolog to investigate the function of duck cGAS (du-cGAS) in host antiviral innate immunity. The results showed that the open reading frame (ORF) region of the du-cGAS gene was 1296 bp, encoding 432 amino acids (aa) and exhibiting similar functional domains with its chicken counterpart. Knockdown of the endogenous du-cGAS by specific sgRNA strongly increased the replication of DNA viruses, including duck adenovirus B2 (DAdV B2) and duck short beak and dwarfism syndrome virus (SBDSV). However, the knockout did not impair the replication of novel duck reovirus (NDRV), an RNA virus. Furthermore, the mRNA expressions of type I interferon (IFNs) and vital interferon-stimulated genes (ISGs) were remarkably reduced in the du-cGAS knockout DEF cell line. Inversely, du-cGAS overexpression greatly activated the transcription of IFN-α, IFN-ß, and vital ISGs, and impaired the replication of DAdV B2, SBDSV, and NDRV in the DEF cell line. Importantly, we found that a deletion of 68 aa in the N terminus didn't impair the antiviral function of du-cGAS. Overexpressing NTase Core, C-Domain (Mab21), or Zinc-Ribbon domain independently had no antiviral effects. Generally, these results reveal that du-cGAS is a vital component of the innate immune system of ducks, with a universal antiviral activity, and provides a useful strategy for the control of waterfowl viral diseases.

Curriculum vitae of HDAC6 in solid tumors.

Histone deacetylase 6 (HDAC6) is the only member of the HDAC family that resides primarily in the cytoplasm with two catalytic domains and a ubiquitin-binding domain. HDAC6 is highly expressed in various solid tumors and participates in a wide range of biological activities, including hormone receptors, the p53 signaling pathway, and the kinase cascade signaling pathway due to its unique structural foundation and abundant substrate types. Additionally, HDAC6 can function as an oncogenic factor in solid tumors, boosting tumor cell proliferation, invasion and metastasis, drug resistance, stemness, and lowering tumor cell immunogenicity, so assisting in carcinogenesis. Pan-HDAC inhibitors for cancer prevention are associated with potential cardiotoxicity in clinical investigations. It's interesting that HDAC6 silencing didn't cause any significant harm to normal cells. Currently, the use of HDAC6 specific inhibitors, individually or in combination, is among the most promising therapies in solid tumors. This review's objective is to give a general overview of the structure, biological functions, and mechanism of HDAC6 in solid tumor cells and in the immunological milieu and discuss the preclinical and clinical trials of selective HDAC6 inhibitors. These endeavors highlight that targeting HDAC6 could effectively kill tumor cells and enhance patients' immunity during solid tumor therapy.

Insights into peptide profiling of sturgeon myofibrillar proteins with low temperature vacuum heating.

BACKGROUND: Protein oxidation during food processing causes changes in the balance of protein-molecular interactions and protein-water interactions, ultimately leading to protein denaturation, which results in the loss of a range of functional properties. Therefore, how to control the oxidative modification of proteins during processing has been the focus of research. RESULTS: In the present study, the intrinsic fluorescence value of the myofibrillar proteins (MP) decreased and the surface hydrophobicity value increased, indicating that the heat treatment caused a significant change in the conformation of the MP. With an increase in heating temperature, protein carbonyl content increased, total sulfhydryl content decreased, and protein secondary structure changed from α-helix to ß-sheet, indicating that protein oxidation and aggregation occurred. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that heat treatment can lead to the degradation of proteins, especially myosin heavy chain, although actin had a certain thermal stability. In total, 733 proteins were identified by proteomics, and the protein oxidation caused by low temperature vacuum heating (LTVH) was determined to be mild oxidation dominated by malondialdehyde and 4-hydroxynonenal by oxidation site division. CONCLUSION: The present study has revealed the effect of LTVH treatment on the protein oxidation modification behavior of sturgeon meat, and explored the effect mechanism of LTVH treatment on the processing quality of sturgeon meat from the perspective of protein oxidation. The results may provide a theoretical basis for the precise processing of aquatic products. © 2023 Society of Chemical Industry.