USP12 positively regulates M-MDSC function to inhibit antitumour immunity through deubiquitinating and stabilizing p65.

The relative abundance of myeloid-derived suppressor cells (MDSCs) compared to cytotoxic T cells determines the outcomes of diseases and the efficacy of immunotherapy. Ubiquitin-specific peptidase 12 (USP12), a member of the USP family of deubiquitinases, targets multiple signalling pathways and regulates diverse biological processes, including cell proliferation and survival. It is well known that ubiquitylation is an important mechanism for regulating the immune response. However, it is unclear whether USP12 regulates tumour growth by influencing MDSCs. In the present study, we reported that USP12 deficiency decreased infiltration and impaired the suppressor function of monocytic (M)-MDSCs, resulting in increased CD8+ T-cell response and decelerated tumour growth. USP12-knockout M-MDSCs were less potent in inhibiting the proliferation of CD8+ T cells and their ability to secrete IFN-γ. Furthermore, USP12 deficiency inhibited the suppressor function of M-MDSCs by downregulating the negative regulatory molecules inducible nitric oxide synthase and PD-L1, through deubiquitinating and stabilizing p65. Our results suggest that USP12 is a positive regulator of M-MDSCs and may serve as a potential target for antitumor therapy.

Amino-functionalized NH2-MIL-125(Ti)-decorated hierarchical flowerlike Znln2S4 for boosted visible-light photocatalytic degradation.

Developing novel heterojunction photocatalysts with visible-light response and remarkable photocatalytic activity have been verified to applying for the photodegradation of antibiotics in water environment. Herein, NH2-MIL-125(Ti) was integrated with flowerlike ZnIn2S4 to construct NH2-MIL-125(Ti)@ZnIn2S4 heterostructure using a one-pot solvothermal method. The photocatalytic performance was evaluated by the degradation of tetracycline (TC) under visible light illumination. The optimized NM(2%)@ZIS possesses a photodegradation rate (92.8%) and TOC removal efficiency (58.5%) superior to pristine components, which can be principally attributed to the positive cooperative effects of well-matched energy level positions, strong visible-light-harvesting capacity, and abundant coupling interfaces between the two. Moreover, the probable TC degradation mechanism was also clarified using the active species trapping experiments. This study inspires further design and construction of NH2-MIL-125(Ti) and ZnIn2S4 based photocatalysts for effective removal of antibiotics in water environment.

Pam2 lipopeptides enhance the immunosuppressive activity of monocytic myeloid-derived suppressor cells by STAT3 signal in chronic inflammation.

Chronic inflammation develops when the immune system is unable to clear a persistent insult. Unresolved chronic inflammation leads to immunosuppression to maintain the internal homeostatic conditions, which is mediated primarily by myeloid-derived suppressor cells (MDSCs). Toll-like receptors 2 (TLR2) has an important role in chronic inflammation and can be activated by a vast number and diversity of TLR2 ligands, for example Pam2CSK4. However, the regulatory effect of TLR2 signaling on MDSCs in chronic inflammation remains controversial. This study demonstrated that heat-killed Mycobacterium bovis BCG-induced pathology-free chronic inflammation triggered suppressive monocytic MDSCs (M-MDSCs) that expressed TLR2. Activation of TLR2 signaling by Pam2CSK4 treatment enhanced immunosuppression of M-MDSCs by upregulating inducible nitric oxide synthase (iNOS) activity and nitric oxide (NO) production partly through signal transducer and activator of transcription 3 (STAT3) activation. Thus, TLR2 has a fundamental role in promoting the MDSC-mediated immunosuppressive environment during chronic inflammation and might represent a potentially therapeutic target in chronic inflammation disease.

[Hypoxemia induced the changing structure of the lung tissue in SD rat though changing blood clotting and the effects of breviscapine's intervention].

OBJECTIVE: To investigate the expressions of plasminogen activator inhibitor-1 (PAI-1), activated protein C (APC) and the histology structures of the rat lung tissues in the different hypoxia time; and to investigate the effects of breviscapine to the above changes. METHODS: Eighty SD rats were randomly divided into A (control), B (hypoxia), C (hypoxia + low-dose breviscapine) and D (hypoxia + high-dose breviscopine) groups with 20 rats in each group. Each hypoxia group placed daily pressure (101 kpa, 10% O2) environment for 8 h, low-dose and high-dose breviscapine groups were given of 10 mg/kg, 40 mg/kg breviscapine by intraperitoneal injection. On the 3rd, 7th, 14th and 21st d, 5 rats were randomly taken from each group and were killed for examination. The hematoxylin and eosin stain (HE stain) was performed for observation on pathological changes in the rat lung tissues. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was performed for detection of the mRNA levels of transforming growth factor (TGF-beta1) and Plasminogen activator inhibitor-1 (PAI-1). Western blot analysis was applied for detection of the expression of PAI-1. Besides, APC in the bronchoalveolar lavage fluid (BALF) was determined by ELISA. RESULTS: (1) The HE stain demonstrated that compared with A group, the degree of thickening of alveolar septal the mRNA expressions of TGF-beta1 and PA-1, and the protein expressions of PAI-1 in B group were increased (P < 0.05), and the expression of APC in the BALF was decreased (P < 0.05). And with prolonged hypoxia, the more significant of these changes were observed. Positive correlation was found between the mRNA levels of PAI-1 and TGF-beta1 (r = 0.936, P < 0.05). (2) Compared with B group, the increased thicknesses of alveolar septal in C and D groups were lightened, the mRNA expressions of TGF-beta1 and PAI-1, and the protein expression of PAI-1 were decreased (P < 0.05), and the expressions of APC in the BALF was increased (P < 0.05). With increasing dose, the expression levels of each factor gradually reduced or increased. CONCLUSION: Hypoxia may cause coagulant function abnormality to increase clotting activity and reduce fibrinolytic activity and the anticoagulant activity, inducing alveolar septal thickening, and the mechanism of above changes may related to the TGF-beta1 signaling pathways. Breviscapine could improve hypoxia-induced hypercoagulable state that alleviate alveolar septal thickening.

Ternary dual S-scheme In2O3/SnIn4S8/CdS heterojunctions for boosted light-to-hydrogen conversion.

Developing artificial S-scheme systems with highly active catalysts is significant to long-term solar-to-hydrogen conversion. Herein, CdS nanodots-modified hierarchical In2O3/SnIn4S8 hollow nanotubes were synthesized by an oil bath method for water splitting. Benefiting from the synergy among the hollow structure, tiny size effect, matched energy level positions, and abundant coupling heterointerfaces, the optimized nanohybrid attains an impressive photocatalytic hydrogen evolution rate of 110.4 µmol/h, and the corresponding apparent quantum yield reaches 9.7% at 420 nm. On In2O3/SnIn4S8/CdS interfaces, the migration of photoinduced electrons from both CdS and In2O3 to SnIn4S8via intense electronic interactions contributes to the ternary dual S-scheme modes, which are beneficial to promote faster spatial charge separation, deliver better visible light-harvesting ability, and provide more reaction active sites with high potentials. This work reveals protocols for rational design of on-demand S-scheme heterojunctions for sustainably converting solar energy into hydrogen in the absence of precious metals.

Cytotoxic phenyl polyketides from Hypericum curvisepalum N. Robson.

(±)-Hypecurvone A (1) and B (2), two new undescribed phenyl polyketides, along with seven known analogues (3-9) were isolated from the whole plant of Hypericum curvisepalum. Chiral separation of 1 and 2 yielded two pairs of enantiomers 1a/1b and 2a/2b, respectively. The structures of these compounds were elucidated by extensive spectroscopic analyses and ECD spectra simulations. All isolates exhibited moderate cytotoxicity against human hepatocellular carcinoma SMMC-7721 cells, and compound 3 also showed weak cytotoxicity toward MGC-803 cells. The cytotoxicity of these compounds was found to be related to enhanced mitochondria-mediated apoptosis and inhibition of the G2/M phase of the cell cycle.

S-scheme photocatalysis induced by ZnIn2S4 nanoribbons-anchored hierarchical CeO2 hollow spheres for boosted hydrogen evolution.

Developing S-scheme systems with impressive photocatalytic performance is of huge meaning in realizing the long-term conversion of solar energy into hydrogen. Herein, ZnIn2S4 nanoribbons were integrated with hierarchical CeO2 hollow spheres to construct heterostructure using an oil bath approach under mild conditions. The optimized CeO2/ZnIn2S4 presented a superior photocatalytic hydrogen production rate of 69 µmol/h, which is about 4.9 and 11.5 times greater than pristine ZnIn2S4 and CeO2, respectively. In addition, its apparent quantum yield achieved 7.6% at 420 nm. The improved photoactivity of the CeO2/ZnIn2S4 heterojunction can be referable to the cooperative effects of the aligned bandgap structures, strong visible-light-harvesting capacity, and interfacial interactions via the internal electric field. This study provides insights into the protocols for rational design of S-scheme heterojunction catalysts for high-efficiency hydrogen evolution via sustainable photocatalytic water splitting.

Treatment for a B-cell acute lymphoblastic leukemia patient carrying a rare TP53 c.C275T mutation: A case report.

TP53 mutations are associated with poor prognosis in the vast majority of cancers. In this study, we present a pediatric B-cell acute lymphoblastic leukemia (B-ALL) patient carrying a rare TP53 c.C275T mutation. This extremely rare mutation affects an amino acid residue located between the TAD domain and the DNA-binding domain of p53. The patient was resistant to most conventional chemotherapy regimens and remained minimal residual disease (MRD)-positive after five rounds of such regimens. We tested the sensitivity of the patient's leukemic cells to 21 anti-cancer drugs by performing in vitro drug sensitivity assays. The results showed that bortezomib had a very strong killing effect on the patient's leukemic cells. Therefore, we subsequently treated the patient with bortezomib combined with vindesine, cytarabine, and fludarabine. After one course of treatment, the patient became MRD-negative, and there was no recurrence during a 9-month follow-up. In conclusion, our report suggests that the TP53 c.C275T mutation is associated with poor prognosis in B-ALL. Fortunately, bortezomib combined with chemotherapy could achieve a better therapeutic effect than conventional regimens in this type of ALL.

The role of cyclic GMP-AMP synthase and Interferon-I-inducible protein 16 as candidatebiomarkers of systemic lupus erythematosus.

BACKGROUND: Diverse clinical and serological manifestations of systemic lupus erythematosus (SLE) compromise its diagnosis and treatment. A more reliable biomarker for SLE, which can play a critical role in either diagnosis, monitoring the disease progress or evaluating the response to treatment for individualized therapeutic, is necessary. DNA sensor is an important mediator of inflammation in systemic autoimmune diseases. However, the potential role for DNA sensor as disease activity biomarkers for SLE remained obscure. We detected the aberrant activation of DNA sensors and the corresponding IFN-ß response in SLE patients, and to evaluate their potential role as disease biomarkers for SLE. METHODS: We quantified the expressions of IFN-I and DNA sensor, such as cGAS, IFI16, DDX41, DAI and their down-stream adaptor STING in PBMC derived from patients with SLE (n = 100), healthy controls (HCs) (n = 62) by real-time PCR. The relationships between the expression of cGAS or IFI16 and clinical features in SLE patients were investigated. ROC curve analysis was performed to examine the predictive value of cGAS and IFI16 in SLE diagnosis, disease activity monitoring, specific organ manifestation and therapeutic response. RNA interference-mediated depletion of IFI16 or cGAS was conducted to evaluate their impact on IFN-I response. RESULTS: The expressions of cGAS and IFI16 were significantly higher in PBMC from SLE patients, closely correlated with the SLEDAI scores and high anti-dsDNA antibody titers. While the AUC for cGAS (0.767) was less than that of IFI16 and IFN-ß, the AUC for IFI16 (0.856) and IFN-ß (0.856) were similar. Expression of cGAS and IFI16 combine with IFN-ß in PBMC showed high sensitivity (89.2%) and specificity (89.1%) for discrimination between mild and moderate/severe disease activity in SLE. Higher expression of IFI16 was association with ocular disorder in SLE patients. Neither IFI16 nor cGAS was a reliable indicator of therapeutic response. RNA interference-mediated depletion of IFI16 or cGAS prevented active SLE serum-induced upregulating in both IFN-α and IFN-ß. CONCLUSIONS: High expression levels of cGAS and IFI16 in PBMC from SLE patients correlated strongly with disease activity. Both cGAS and IFI16 mediated signaling pathway were account for the robust production of IFN-ß. Expression of cGAS and IFI16 combined with IFN-ß in PBMC might serve as potential biomarkers for early diagnosis and monitoring disease activity in SLE.

Berberine Suppresses EMT in Liver and Gastric Carcinoma Cells through Combination with TGFßR Regulating TGF-ß/Smad Pathway.

Berberine (BBR), a natural alkaloid derived from Coptis, has anticancer activity. Some researchers have found that it could restrain epithelial-mesenchymal transition (EMT) of melanoma, neuroblastoma, and other tumor cells. However, it is unclear whether BBR can reverse EMT in hepatocellular carcinoma (HCC) and gastric carcinoma (GC). In our study, BBR inhibited the migration and invasion of HepG2, MGC803, and SGC7901 cells in a dose-dependent manner. Transcription sequencing assays showed that Vimentin, MMP, and Smad3 were downregulated, but Smad2, Smad6, TAB2, ZO-1, and claudin 7 were upregulated when treated with BBR. GO Enrichment analysis of KEGG pathway showed that BBR significantly inhibited TGF-ß/Smad at 12 h, then, PI3K/Akt and Wnt/ß-catenin signaling pathways at 24 h, which were closely related to the proliferation, migration, and EMT. The results of the transcriptome sequencing analysis were verified by Western Blot. It showed that the expression of epithelial marker E-cadherin and ZO-1 remarkably augmented with BBR treatment, as well as declined mesenchymal markers, including N-cadherin and Vimentin, decreased transcription factor Snail and Slug. The effects of BBR were similar to those of the PI3K inhibitor LY294002 and TGF-ß receptor inhibitor SB431542. Furthermore, ß-catenin and phosphorylation of AKT, Smad2, and Smad3 were changed dose-dependently by BBR treatment, which upregulated p-Smad2 and downregulated the others. Combined with LY or SB, respectively, BBR could enhance the effects of the two inhibitors. Simultaneously, IGF-1 and TGF-ß, which is the activator of PI3K/AKT and TGF-ß/Smad, respectively, could reverse the anti-EMT effect of BBR. The Molecular Docking results showed BBR had a high affinity with the TGF-ß receptor I (TGFßR1), and the binding energy was -7.5 kcal/mol, which is better than the original ligand of TGFßR1. Although the affinity of BBR with TGF-ß receptor II (TGFßR2) was lower than the original ligand of TGFßR2, the more considerable negative binding energy (-8.54 kcal/mol) was obtained. BBR upregulated p-Smad2, which was different from other reports, indicating that the function of Smad2 was relatively complex. Combination BBR with SB could enhance the effect of the inhibitor on EMT, and the results indicated that BBR binding to TGFßR was not competitive with SB to TGFßR since different binding amino acid sites. Our experiments demonstrated BBR increased p-Smad2 and decreased p-Smad3 by binding to TGFßR1 and TGßFR2 inhibiting TGF-ß/Smad, then, PI3K/AKT and other signaling pathways to restrain EMT, metastasis, and invasion in tumor cells. The effect of BBR was similar on the three tumor cells.

Edge-Rich Bicrystalline 1T/2H-MoS2 Cocatalyst-Decorated {110} Terminated CeO2 Nanorods for Photocatalytic Hydrogen Evolution.

Developing all-solid-state Z-scheme systems with highly active photocatalysts are of huge interest in realizing long-term solar-to-fuel conversion. Here we reported an innovative hybrid of {110}-oriented CeO2 nanorods with edge-enriched bicrystalline 1T/2H-MoS2 coupling as efficient photocatalysts for water splitting. In the composites, the metallic 1T phase acts as an excellent solid state electron mediator in the Z-scheme, while the 2H phase and CeO2 are the adsorption sites of the photosensitizer and reactant (H2O), respectively. Through optimal structure and phase engineering, 1T/2H-MoS2@CeO2 heterojunctions simultaneously achieve high charge separation efficiency, proliferated density of exposed active sites, and excellent affinity to reactant molecules, reaching a superior hydrogen evolution rate of 73.1 µmol/h with an apparent quantum yield of 8.2% at 420 nm. Furthermore, density functional theory calculations show that 1T/2H-MoS2@CeO2 possesses the advantages of intensive electronic interaction from the built-in electric field (negative MoS2 and positive charged CeO2) and reduced H2O adsorption/dissociation energies. This work sheds light on the design of on-demand noble-metal-free Z-scheme heterostructures for solar energy conversion.

Bioconversion of yellow wine wastes into microbial protein via mixed yeast-fungus cultures.

The potential for microbial protein production in the mixture of yellow wine lees and rice soaking wastewater was examined. Strong symbiotic effect was observed in fermentation with yeast-fungus mixed culture of Candida utilis and Geochichum candidum at a ratio of 1:1 (v/v). The maximum specific biomass yield of 4.91 ± 0.48 g final biomass/g initial biomass with a protein content of 68.5 ± 1.0% was achieved at inoculum-to-substrate ratio of 10% (v/v) and aeration rate of 1.0 volumeair/volumeliquid/min. The essential amino acids contents of the derived protein were comparable to commercial protein sources with high amounts of methionine (2.87%, based on total protein). The reduction in soluble chemical oxygen demand of 79.4 ± 0.4% was mainly due to uptake of carbohydrate, soluble protein, volatile fatty acids, amino acids, etc. The application of mixed yeast-fungus technology provides a new opportunity for microbial protein production from these low-value organic residue streams.

[Research Progress of Necroptosis in Hematological Malignancies -Review].

Necroptosis is a novel programmed cell death mechanism which is characterized by a necrotic morphology, but the necroptosis is precisely regulated by cellular signaling pathway just like apoptosis. Recently, many reports have revealed that necroptosis contributes to the pathogenesis of inflammation, ischemic reperfusion injury and tumour. Hematological malignancies are a set of hemotopathy diseases with poor prognosis. In this review, the research progress of signaling pathway of necroptosis and its role in hematological malignancies are summarized.