ANKRD22 promotes resolution of psoriasiform skin inflammation by antagonizing NIK-mediated IL-23 production.

Inflammation resolution is an essential process for preventing the development of chronic inflammatory diseases. However, the mechanisms that regulate inflammation resolution in psoriasis are not well understood. Here, we report that ANKRD22 is an endogenous negative orchestrator of psoriasiform inflammation because ANKRD22-deficient mice are more susceptible to IMQ-induced psoriasiform inflammation. Mechanistically, ANKRD22 deficiency leads to excessive activation of the TNFRII-NIK-mediated noncanonical NF-κB signaling pathway, resulting in the hyperproduction of IL-23 in DCs. This is due to ANKRD22 being a negative feedback regulator for NIK because it physically binds to and assists in the degradation of accumulated NIK. Clinically, ANKRD22 is negatively associated with IL-23A expression and psoriasis severity. Of greater significance, subcutaneous administration of an AAV carrying ANKRD22-overexpression vector effectively hastens the resolution of psoriasiform skin inflammation. Our findings suggest ANKRD22, an endogenous supervisor of NIK, is responsible for inflammation resolution in psoriasis, and may be explored in the context of psoriasis therapy.

Plant-derived citronellol can significantly disrupt cell wall integrity maintenance of Colletotrichum camelliae.

Anthracnose, a fungal disease, commonly infects tea plants and severely impacts the yield and quality of tea. One method for controlling anthracnose is the application of citronellol, a plant extract that exhibits broad-spectrum antimicrobial activity. Herein, the physiological and biochemical mechanism by which citronellol controls anthracnose caused by Colletotrichum camelliae was investigated. Citronellol exhibited excellent antifungal activity based on direct and indirect mycelial growth inhibition assays, with EC50 values of 76.88 mg/L and 29.79 µL/L air, respectively. Citronellol also exhibited good control effects on C. camelliae in semi-isolated leaf experiments. Optical and scanning electron microscopy revealed that citronellol caused C. camelliae mycelia to thin, fracture, fold and deform. Transmission electron microscopy revealed that the mycelial cell walls collapsed inward and separated, and the organelles became blurred after treatment with citronellol. The sensitivity of C. camelliae to calcofluor white staining was significantly enhanced by citronellol, while PI staining showed minimal fluorescence, and the relative conductivity of mycelia were not significantly different. Under citronellol treatment, the expression levels of ß-1,3-glucanase, chitin synthase, and chitin deacetylase-related genes were significantly decreased, while the expression levels of chitinase genes were increased, leading to lower chitinase activity and increased ß-1,3-glucanase activity. Therefore, citronellol disrupted the cell wall integrity of C. camelliae and inhibited normal mycelial growth.

A vaccine delivery system promotes strong immune responses against SARS-CoV-2 variants.

Global coronavirus disease 2019 (COVID-19) pandemics highlight the need of developing vaccines with universal and durable protection against emerging SARS-CoV-2 variants. Here we developed an extended-release vaccine delivery system (GP-diABZI-RBD), consisting the original SARS-CoV-2 WA1 strain receptor-binding domain (RBD) as the antigen and diABZI stimulator of interferon genes (STING) agonist in conjunction with yeast ß-glucan particles (GP-diABZI) as the platform. GP-diABZI-RBD could activate STING pathway and inhibit SARS-CoV-2 replication. Compared to diABZI-RBD, intraperitoneal injection of GP-diABZI-RBD elicited robust cellular and humoral immune responses in mice. Using SARS-CoV-2 GFP/ΔN transcription and replication-competent virus-like particle system (trVLP), we demonstrated that GP-diABZI-RBD-prototype vaccine exhibited the strongest and durable humoral immune responses and antiviral protection; whereas GP-diABZI-RBD-Omicron displayed minimum neutralization responses against trVLP. By using pseudotype virus (PsVs) neutralization assay, we found that GP-diABZI-RBD-Prototype, GP-diABZI-RBD-Delta, and GP-diABZI-RBD-Gamma immunized mice sera could efficiently neutralize Delta and Gamma PsVs, but had weak protection against Omicron PsVs. In contrast, GP-diABZI-RBD-Omicron immunized mice sera displayed the strongest neutralization response to Omicron PsVs. Taken together, the results suggest that GP-diABZI can serve as a promising vaccine delivery system for enhancing durable humoral and cellular immunity against broad SARS-CoV-2 variants. Our study provides important scientific basis for developing SARS-CoV-2 VOC-specific vaccines.

Design, Synthesis, and Bioactivity of Novel Quinazolinone Scaffolds Containing Pyrazole Carbamide Derivatives as Antifungal Agents.

In this study, 32 novel quinazolinone-scaffold-containing pyrazole carbamide derivatives were designed and synthesized in a search for a novel fungicide against Rhizoctonia solani. Single-crystal X-ray diffraction of 3-(difluoromethyl)-N-(2-((6,7-difluoro-4-oxoquinazolin-3(4H)-yl)methyl)phenyl)-1-methyl-1H-pyrazole-4-carboxamide (6a11) confirmed the structure of the target compounds. The in vitro antifungal activity of the target compounds against R. solani was evaluated at 100 µg/mL. The structure-activity relationship analysis results revealed that antifungal activity was highest when the substitution activity was at position 6. Moreover, the position and number of chlorine atoms directly affected the antifungal activity. Further in vitro bioassays revealed that 6a16 (EC50 = 9.06 mg/L) had excellent antifungal activity against R. solani that was higher than that of the commercial fungicide fluconazole (EC50 = 12.29 mg/L) but lower than that of bixafen (EC50 = 0.34 mg/L). Scanning electron microscopy), 7.33 (SEM) revealed that N-(2-((6,8-dichloro-4-oxoquinazolin-3(4H)-yl)methyl)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide (6a16) also affected the mycelial morphology. The findings revealed that molecular hybridization was an effective tool for designing antifungal candidates. Meanwhile, pyrazolecarbamide derivatives bearing a quinazolinone fragment exhibited potential antifungal activity against R. solani.

A Review on the Extraction, Bioactivity, and Application of Tea Polysaccharides.

Tea is a non-alcoholic drink containing various active ingredients, including tea polysaccharides (TPSs). TPSs have various biological activities, such as antioxidant, anti-tumor, hypoglycemic, and anti-cancer activities. However, TPSs have a complex composition, which significantly limits the extraction and isolation methods, thus limiting their application. This paper provides insight into the composition, methodological techniques for isolation and extraction of the components, biological activities, and functions of TPSs, as well as their application prospects.

CrowdMed-II: a blockchain-based framework for efficient consent management in health data sharing.

The healthcare industry faces serious problems with health data. Firstly, health data is fragmented and its quality needs to be improved. Data fragmentation means that it is difficult to integrate the patient data stored by multiple health service providers. The quality of these heterogeneous data also needs to be improved for better utilization. Secondly, data sharing among patients, healthcare service providers and medical researchers is inadequate. Thirdly, while sharing health data, patients' right to privacy must be protected, and patients should have authority over who can access their data. In traditional health data sharing system, because of centralized management, data can easily be stolen, manipulated. These systems also ignore patient's authority and privacy. Researchers have proposed some blockchain-based health data sharing solutions where blockchain is used for consensus management. Blockchain enables multiple parties who do not fully trust each other to exchange their data. However, the practice of smart contracts supporting these solutions has not been studied in detail. We propose CrowdMed-II, a health data management framework based on blockchain, which could address the above-mentioned problems of health data. We study the design of major smart contracts in our framework and propose two smart contract structures. We also introduce a novel search contract for searching patients in the framework. We evaluate their efficiency based on the execution costs on Ethereum. Our design improves on those previously proposed, lowering the computational costs of the framework. This allows the framework to operate at scale and is more feasible for widespread adoption.

Antiapoptotic properties of MALT1 protease are associated with redox homeostasis in ABC-DLBCL cells.

Mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) protease presents crucial antiapoptotic properties in activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL); however, the mechanism is unclear. Here, we reported that inhibition of MALT1 protease in ABC-DLBCL cells led to cell apoptosis, along with elevated mitochondrial reactive oxygen species production and a reduced oxygen consumption rate. These alterations induced by MALT1 protease inhibition were associated with reduced expression of glutaminase (GLS1) and glutathione levels. We further show that MALT1 protease was required for the activation and nuclear translocation of c-Jun, which functions as a transcription factor of the GLS1 gene by binding directly to its promoter region. Taken together, MALT1 protease maintained mitochondrial redox homeostasis and mitochondrial bioenergetics through the MALT1-c-Jun-GLS1-coupled metabolic pathway to defend against apoptosis in ABC-DLBCL cells, which raises exciting possibilities regarding targeting of the MALT1-c-Jun-GLS1 axis as a potential therapeutic strategy against ABC-DLBCL.

Structure-aided optimization of 3-O-ß-chacotriosyl ursolic acid as novel H5N1 entry inhibitors with high selective index.

Currently, entry inhibitors contribute immensely in developing a new generation of anti-influenza virus drugs. Our earlier studies have identified that 3-O-ß-chacotriosyl ursolic acid (1) could inhibit H5N1 pseudovirus by targeting hemagglutinin (HA). In the present study, a series of C-28 modified pentacyclic triterpene saponins via conjugation with a series of amide derivatives were synthesized and their antiviral activities against influenza A/Duck/Guangdong/99 virus (H5N1) in MDCK cells were evaluated. The SARs analysis of these compounds revealed that introduction of certain amide structures at the 17-COOH of ursolic acid could significantly enhance both their antiviral activity and selective index. This study indicated that the attachment of the methoxy group or Cl atom to the phenyl ring at the ortho- or para-position was crucial to improve inhibitory activity. Mechanism studies demonstrated that these title triterpenoids could bind tightly to the viral envelope HA to block the attachment of viruses to host cells, which was consistent with docking studies.

Syntheses, antiviral activities and induced resistance mechanisms of novel quinazoline derivatives containing a dithioacetal moiety.

A series of novel quinazoline derivatives containing a dithioacetal moiety were designed and synthesized, and their structures were characterized by 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, and high-resolution mass spectrometry. Bioassay results indicated that compound 4b exhibited remarkable protective activity against cucumber mosaic virus (CMV, EC50 = 248.6 µg/mL) and curative activity against potato virus Y (EC50 = 350.5 µg/mL), which were better than those of ningnanmycin (357.7 µg/mL and 493.7 µg/mL, respectively). Moreover, compound 4b could increase the chlorophyll content in plants, improve photosynthesis, and effectively induce tobacco anti-CMV activity.

Use of D-glucose-fenpiclonil conjugate as a potent and specific inhibitor of sucrose carriers.

Until now, specific inhibitors of sucrose carriers were not available. This led us to study the properties of the recently synthesized D-glucose-fenpiclonil conjugate (D-GFC). This large amphiphilic glucoside exhibited an extremely low phloem systemicity in contrast to L-amino acid-fenpiclonil conjugates. Using Ricinus seedlings, the effect of D-GFC on 0.5 mM [14C]sucrose (Suc), 3-O-[3H]methylglucose, and [3H]glutamine uptake by cotyledon tissues was compared with that of p-chloromercuribenzenesulfonic acid (PCMBS). D-GFC dramatically inhibited H+-Suc symport at the same concentrations as PCMBS (0.5 and 1 mM), but in contrast to the thiol reagent, it did not affect 3-O-methylglucose and glutamine transport, nor the acidification of the incubation medium by cotyledon tissues. Similarly, 0.5 mM D-GFC inhibited active Suc uptake by Vicia faba leaf tissues and by Saccharomyces cerevisiae cells transformed with AtSUC2, a gene involved in Suc phloem loading in Arabidopsis, by approximately 80%. The data indicated that D-GFC was a potent inhibitor of Suc uptake from the endosperm and of Suc phloem loading. It is the first chemical known to exhibit such specificity, at least in Ricinus, and this property permitted the quantification of the two routes involved in phloem loading of endogenous sugars after endosperm removal.

Synthesis and biological evaluation of acylated oligorhamnoside derivatives structurally related to mezzettiaside-6 with cytotoxic activity.

Two partially acylated oligorhamnoside derivatives 1 and 2 structurally related to the natural product mezzettiaside-6 were synthesized via a '2 + 1 + 1' convergent strategy. The bioassay results showed that the introduction of the acetyl groups to the 2-position of the terminal l-rhamnose was helpful to improve in vitro cytotoxicity. Compound 1 showed both extensive in vitro cytotoxicity in tumor cell lines and potential antimultidrug resistance capability. Preliminary mechanistic studies demonstrated that compound 1 could inhibit cell growth by inducing apoptosis, arresting cell cycle progression at the S phase in K562 cells.

Anti-Toxoplasma gondii antibodies as a risk factor for the prevalence and severity of systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease characterized by the presence of numerous autoantibodies. The interaction of infectious agents (viruses, bacteria and parasites) and a genetically susceptible host may be a key mechanism for SLE. Toxoplasma gondii is a widespread intracellular parasite that has been implicated in the pathogenesis of autoimmune diseases. However, the relationship between T. gondii infection and the increased risk of SLE in Chinese populations remains unclear. METHODS: The seroprevalence of T. gondii infection was assessed in 1771 serum samples collected from Chinese individuals (908 healthy controls and 863 SLE patients) from different regions of China using an enzyme-linked immunosorbent assay. Serum autoantibodies and clinical information were obtained and analysed. RESULTS: Our observations revealed a higher prevalence of anti-T. gondii antibodies (ATxA) immunoglobulin G (IgG) in serum samples from SLE patients (144/863, 16.7%) than in those from the healthy controls (53/917, 5.8%; P < 0.0001), indicating a 2.48-fold increased risk of SLE in the ATxA-IgG+ population, after adjustment for age and sex (95% confidence interval [CI] 1.70-3.62, P < 0.0001). ATxA-IgG+ SLE patients also showed a 1.75-fold higher risk of developing moderate and severe lupus symptoms (95% CI 1.14-2.70, P = 0.011) compared to ATxA-IgG- patients. Relative to ATxA-IgG- patients, ATxA-IgG+ patients were more likely to develop specific clinical symptoms, including discoid rash, oral ulcer, myalgia and alopecia. Seven antibodies, namely anti-ribosomal RNA protein (rRNP), anti-double stranded DNA (dsDNA), anti-cell membrane DNA (cmDNA), anti-scleroderma-70 (Scl-70), anti-cardiolipin (CL), anti-beta2-glycoprotein-I (B2GPI) and rheumatoid factor (RF), occurred more frequently in ATxA-IgG+ patients. When combined with anti-dsDNA and RF/anti-rRNP/anti-cmDNA/ESR, ATxA-IgG significantly increased the risk for severe lupus. CONCLUSIONS: Our results suggest that ATxA-IgG may be a significant risk factor for SLE prevalence and severity in Chinese populations.

SARS-CoV-2 N protein enhances the anti-apoptotic activity of MCL-1 to promote viral replication.

Viral infection in respiratory tract usually leads to cell death, impairing respiratory function to cause severe disease. However, the diversity of clinical manifestations of SARS-CoV-2 infection increases the complexity and difficulty of viral infection prevention, and especially the high-frequency asymptomatic infection increases the risk of virus transmission. Studying how SARS-CoV-2 affects apoptotic pathway may help to understand the pathological process of its infection. Here, we uncovered SARS-CoV-2 imployed a distinct anti-apoptotic mechanism via its N protein. We found SARS-CoV-2 virus-like particles (trVLP) suppressed cell apoptosis, but the trVLP lacking N protein didn't. Further study verified that N protein repressed cell apoptosis in cultured cells, human lung organoids and mice. Mechanistically, N protein specifically interacted with anti-apoptotic protein MCL-1, and recruited a deubiquitinating enzyme USP15 to remove the K63-linked ubiquitination of MCL-1, which stabilized this protein and promoted it to hijack Bak in mitochondria. Importantly, N protein promoted the replications of IAV, DENV and ZIKV, and exacerbated death of IAV-infected mice, all of which could be blocked by a MCL-1 specific inhibitor, S63845. Altogether, we identifed a distinct anti-apoptotic function of the N protein, through which it promoted viral replication. These may explain how SARS-CoV-2 effectively replicates in asymptomatic individuals without cuasing respiratory dysfunction, and indicate a risk of enhanced coinfection with other viruses. We anticipate that abrogating the N/MCL-1-dominated apoptosis repression is conducive to the treatments of SARS-CoV-2 infection as well as coinfections with other viruses.

SLC38A5 aggravates DC-mediated psoriasiform skin inflammation via potentiating lysosomal acidification.

Amino acid (aa) metabolism is closely correlated with the pathogenesis of psoriasis; however, details on aa transportation during this process are barely known. Here, we find that SLC38A5, a sodium-dependent neutral aa transporter that counter-transports protons, is markedly upregulated in the psoriatic skin of both human patients and mouse models. SLC38A5 deficiency significantly ameliorates the pathogenesis of psoriasis, indicating a pathogenic role of SLC38A5. Surprisingly, SLC38A5 is almost exclusively expressed in dendritic cells (DCs) when analyzing the psoriatic lesion and mainly locates on the lysosome. Mechanistically, SLC38A5 potentiates lysosomal acidification, which dictates the cleavage and activation of TLR7 with ensuing production of pro-inflammatory cytokines such as interleukin-23 (IL-23) and IL-1ß from DCs and eventually aggravates psoriatic inflammation. In summary, this work uncovers an auxiliary mechanism in driving lysosomal acidification, provides inspiring insights for DC biology and psoriasis etiology, and reveals SLC38A5 as a promising therapeutic target for treating psoriasis.

Synthesis and Bioactivity of Novel Sulfonate Scaffold-Containing Pyrazolecarbamide Derivatives as Antifungal and Antiviral Agents.

Novel pyrazolecarbamide derivatives bearing a sulfonate fragment were synthesized to identify potential antifungal and antiviral agents. All the structures of the key intermediates and target compounds were confirmed by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). The single-crystal X-ray diffraction of the compound T22 showed that pyrazole carbamide is a sulfonate. The in vitro antifungal activities of the target compounds against Colletotrichum camelliae, Pestalotiopsis theae, Gibberella zeae, and Rhizoctonia solani were evaluated at 50 µg/ml. Among the four pathogens, the target compounds exhibited the highest antifungal activity against Rhizoctonia solani. The compound T24 (EC50 = 0.45 mg/L) had higher antifungal activity than the commercial fungicide hymexazol (EC50 = 10.49 mg/L) against R. solani, almost similar to bixafen (EC50 = 0.25 mg/L). Additionally, the target compounds exhibited protective effects in vivo against TMV. Thus, this study reveals that pyrazolecarbamide derivatives bearing a sulfonate fragment exhibit potential antifungal and antiviral activities.

The Study of Amidoxime-Functionalized Cellulose Separate Th(IV) from Aqueous Solution.

Selective extraction of low-concentration thorium (Th(IV)) from wastewater is a very important research topic. In this paper, amidoxime cellulose was synthesized, and its composition and structure were characterized by FT-IR, SEM, XPS, and elemental analysis. The adsorption experiment results showed that the adsorption reaction was a spontaneous exothermic process. When the solid-liquid ratio was 0.12 g/L and the pH value was 3.5, the adsorption percentage of the Th(IV) in water onto amidoxime-functionalized cellulose (AO-CELL) could reach over 80%. The maximum adsorption capacity can reach to 450 mg/g. At the same time, the adsorption selectivity, desorption process and reusability of the material were also studied. The results showed that the AO-CELL had a good selectivity for Th(IV) in the system with Sr2+, Cu2+, Mg2+, Zn2+, Pb2+, Ni2+, and Co2+ as co-ions. In the nitric acid concentration of 0.06 mol/L system, the AO-CELL desorption rate of Th(IV) can reach 95%, and the adsorption rate of Th(IV) in aqueous solution of AO-CELL is still above 60% when the AO-CELL is reused four times. The above results show that the amidoxime cellulose adsorption material synthesized by our research group has good selective adsorption performance for Th(IV) of a low concentration in an aqueous solution and has a good practical application value.

Glycosyl-Radical-Based Synthesis of C-Alkyl Glycosides via Photomediated Defluorinative gem-Difluoroallylation.

We have developed a stereoselective, glycosyl radical-based method for the synthesis of C-alkyl glycosides via a photomediated defluorinative gem-difluoroallylation reaction. We demonstrate for the first time that glycosyl radicals, generated from glycosyl bromides, can readily participate in a photomediated radical polar crossover process, affording a diverse array of gem-difluoroalkene containing C-glycosides. Notable features of this method include scalability, mild conditions, broad substrate scope, and suitability for the late-stage modification of complex molecules.

Yeast Shells Encapsulating Adjuvant AS04 as an Antigen Delivery System for a Novel Vaccine against Toxoplasma Gondii.

Toxoplasma gondii (T. gondii) infection causes severe zoonotic toxoplasmosis, which threatens the safety of almost one-third of the human population globally. However, there is no effective protective vaccine against human toxoplasmosis. This necessitates anti-T. gondii vaccine development, which is a main priority of public health. In this study, we optimized the adjuvant system 04 (AS04), a vaccine adjuvant constituted by 3-O-desacyl-4'-monophosphoryl lipid A (a TLR4 agonist) and aluminum salts, by packing it within natural extracts of ß-glucan particles (GPs) from Saccharomyces cerevisiae to form a GP-AS04 hybrid adjuvant system. Through a simple mixing procedure, we loaded GP-AS04 particles with the total extract (TE) of T. gondii lysate, forming a novel anti-T. gondii vaccine GP-AS04-TE. Results indicated that the hybrid adjuvant can efficiently and stably load antigens, mediate antigen delivery, facilitate the dendritic uptake of antigens, boost dendritic cell maturation and stimulation, and increase the secretion of pro-inflammatory cytokines. In the mouse inoculation model, GP-AS04-TE significantly stimulated the function of dendritic cells, induced a very strong TE-specific humoral and cellular immune response, and finally showed a strong and effective protection against toxoplasma chronic and acute infections. This work proves the potential of GP-AS04 for exploitation as a vaccine against a range of pathogens.

CFTR is a negative regulator of γδ T cell IFN-γ production and antitumor immunity.

CFTR, a chloride channel and ion channel regulator studied mostly in epithelial cells, has been reported to participate in immune regulation and likely affect the risk of cancer development. However, little is known about the effects of CFTR on the differentiation and function of γδ T cells. In this study, we observed that CFTR was functionally expressed on the cell surface of γδ T cells. Genetic deletion and pharmacological inhibition of CFTR both increased IFN-γ release by peripheral γδ T cells and potentiated the cytolytic activity of these cells against tumor cells both in vitro and in vivo. Interestingly, the molecular mechanisms underlying the regulation of γδ T cell IFN-γ production by CFTR were either TCR dependent or related to Ca2+ influx. CFTR was recruited to TCR immunological synapses and attenuated Lck-P38 MAPK-c-Jun signaling. In addition, CFTR was found to modulate TCR-induced Ca2+ influx and membrane potential (Vm)-induced Ca2+ influx and subsequently regulate the calcineurin-NFATc1 signaling pathway in γδ T cells. Thus, CFTR serves as a negative regulator of IFN-γ production in γδ T cells and the function of these cells in antitumor immunity. Our investigation suggests that modification of the CFTR activity of γδ T cells may be a potential immunotherapeutic strategy for cancer.

SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation.

Excessive inflammatory responses induced upon SARS-CoV-2 infection are associated with severe symptoms of COVID-19. Inflammasomes activated in response to SARS-CoV-2 infection are also associated with COVID-19 severity. Here, we show a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. N protein facilitates maturation of proinflammatory cytokines and induces proinflammatory responses in cultured cells and mice. Mechanistically, N protein interacts directly with NLRP3 protein, promotes the binding of NLRP3 with ASC, and facilitates NLRP3 inflammasome assembly. More importantly, N protein aggravates lung injury, accelerates death in sepsis and acute inflammation mouse models, and promotes IL-1ß and IL-6 activation in mice. Notably, N-induced lung injury and cytokine production are blocked by MCC950 (a specific inhibitor of NLRP3) and Ac-YVAD-cmk (an inhibitor of caspase-1). Therefore, this study reveals a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses.