Corrigendum: The central inflammatory regulator IκBζ: induction regulation and physiological functions.

[This corrects the article DOI: 10.3389/fimmu.2023.1188253.].

Tannic acid alleviates 3-nitropropionic acid-induced ovarian damage in Brandt's vole (Lasiopodomys brandtii).

Tannic acid (TA) is a polyphenol with antioxidant properties present in various plants. In this study, we explored the protective effect of TA against ovarian oxidative stress in Brandt's voles and its underlying mechanism. At various doses, 3-nitropropionic acid (3-NPA) was intraperitoneally injected into Brandt's voles to simulate ovarian oxidative stress. Thereafter, various doses of TA were intragastrically administered to examine the protective effect of TA against 3-NPA-induced ovarian damage. Changes in inflammation, autophagy, apoptosis, and oxidative stress-related factors were investigated through various biochemical and histological techniques. Ovarian oxidative stress was successfully induced by the intraperitoneal administration of 12.5 mg/kg 3-NPA for 18 days. As a result, the ovarian coefficient decreased and ovarian tissue fibrosis was induced. TA treatment effectively alleviated the increase in luteinizing hormone and follicle-stimulating hormone levels; the decrease in estradiol, progesterone, and anti-Müllerian hormone levels; and the decline in fertility induced by 3-NPA. Compared to that in the 3-NPA group, TA decreased the expression of autophagy-related proteins beclin-1 and LC3, as well as the level of apoptosis. It also activated the AKT/mTOR signaling pathway, downregulated PTEN and p-NF-κB expression, and upregulated Nrf2 expression. In conclusion, our findings indicate that TA could inhibit autophagy via the regulation of AKT/mTOR signaling, suppressing oxidative damage and inflammatory responses through Nrf2 to alleviate 3-NPA-induced ovarian damage. Collectively, the current findings highlight the protective effects of TA in Brandt's vole, where it promotes the maintenance of normal ovarian function.

RNA-seq transcriptome analysis provides new insights into the negative effects of tannic acid on the intestinal function of Brandt's voles (Lasiopodomys brandtii).

Tannic acid (TA), a significant plant secondary metabolite, is contained in the daily food of Brandt's voles. Its adverse effect on gut function has been shown in earlier research, but the underlying molecular mechanisms remain uncertain. In this study, male Brandt's vole (13 weeks old) were divided into two groups and given 0 (control) or 1,200 (TA-treated) mg•kg-1 TA for 18 days. Then RNA sequencing was used to conduct a thorough transcriptome analysis on the duodenum, jejunum, and ileum of Brandt's voles. Results showed that TA significantly increased serum total cholesterol concentration (P < 0.05) and decreased the nutrient digestibility (P < 0.05) of Brandt's voles. Furthermore, there were 174 differentially expressed genes (DEGs) in the duodenum, 96 DEGs in the jejunum, and 88 DEGs in the ileum between the control and TA-treated groups. Enrichment analysis revealed that many genes associated with bile secretion, fat digestion and absorption, innate immune response, and tight junction such as ABCG2, ABCG8, PEAK1, and IFR2, etc. were altered after TA treatment, which were verified by quantitative real-time PCR. These findings suggested that TA can change the expression of intestinal genes, thereby, altering nutrition metabolism and immunological function, eventually hindering the growth of Brandt's voles. The results of this study provide a theoretical basis for explaining how TA affects the gut function of Brandt's voles at the molecular level.

Cardiac-specific deletion of BRG1 ameliorates ventricular arrhythmia in mice with myocardial infarction.

Malignant ventricular arrhythmia (VA) after myocardial infarction (MI) is mainly caused by myocardial electrophysiological remodeling. Brahma-related gene 1 (BRG1) is an ATPase catalytic subunit that belongs to a family of chromatin remodeling complexes called Switch/Sucrose Non-Fermentable Chromatin (SWI/SNF). BRG1 has been reported as a molecular chaperone, interacting with various transcription factors or proteins to regulate transcription in cardiac diseases. In this study, we investigated the potential role of BRG1 in ion channel remodeling and VA after ischemic infarction. Myocardial infarction (MI) mice were established by ligating the left anterior descending (LAD) coronary artery, and electrocardiogram (ECG) was monitored. Epicardial conduction of MI mouse heart was characterized in Langendorff-perfused hearts using epicardial optical voltage mapping. Patch-clamping analysis was conducted in single ventricular cardiomyocytes isolated from the mice. We showed that BRG1 expression in the border zone was progressively increased in the first week following MI. Cardiac-specific deletion of BRG1 by tail vein injection of AAV9-BRG1-shRNA significantly ameliorated susceptibility to electrical-induced VA and shortened QTc intervals in MI mice. BRG1 knockdown significantly enhanced conduction velocity (CV) and reversed the prolonged action potential duration in MI mouse heart. Moreover, BRG1 knockdown improved the decreased densities of Na+ current (INa) and transient outward potassium current (Ito), as well as the expression of Nav1.5 and Kv4.3 in the border zone of MI mouse hearts and in hypoxia-treated neonatal mouse ventricular cardiomyocytes. We revealed that MI increased the binding among BRG1, T-cell factor 4 (TCF4) and ß-catenin, forming a transcription complex, which suppressed the transcription activity of SCN5A and KCND3, thereby influencing the incidence of VA post-MI.

Effect of Food Restriction on Food Grinding in Brandt's Voles.

Food grinding is supposed to be influenced by multiple factors. However, how those factors affecting this behavior remain unclear. In this study, we investigated the effect of food restriction on food grinding in Brandt's voles (Lasiopodomys brandtii), as well as the potential role of the gut microbiota in this process, through a comparison of the variations between voles with different food supplies. Food restriction reduced the relative amount of ground food to a greater extent than it lowered the relative food consumption, and altered the abundance of Staphylococcus, Aerococcus, Jeotgalicoccus, and Un--s-Clostridiaceae bacterium GM1. Fecal acetate content for the 7.5 g-food supply group was lower than that for the 15 g-food supply group. Our study indicated that food restriction could effectively inhibit food grinding. Further, Un--s-Clostridiaceae bacterium GM1 abundance, Aerococcus abundance, and acetate content were strongly related to food grinding. Variations in gut microbial abundance and short-chain fatty acid content induced by food restriction likely promote the inhibition of food grinding. These results could potentially provide guidance for reducing food waste during laboratory rodent maintenance.

Broad protective RBD heterotrimer vaccines neutralize SARS-CoV-2 including Omicron sub-variants XBB/BQ.1.1/BF.7.

SARS-CoV-2 variants with severe immune evasion are a major challenge for COVID-19 prevention, especially the circulating Omicron XBB/BQ.1.1/BF.7 strains. Thus, the next-generation of broad-spectrum vaccines are urgently needed. Previously, we developed a COVID-19 protein subunit vaccine, ZF2001, based on the RBD-homodimer as the immunogen. To adapt SARS-CoV-2 variants, we developed chimeric RBD-heterodimers to induce broad immune responses. In this study, we further explored the concept of tandem RBD homotrimer and heterotrimer. Prototype SARS-CoV-2 RBD-homotrimer, prototype-Delta-BA.1 (PDO) RBD-heterotrimer and Delta-BA.2-BA.5 (DBA2BA5) RBD-heterotrimer were designed. Biochemical and cryo-EM structural characterization demonstrated total epitope exposure of the RBD-trimers. In mouse experiments, PDO and DBA2BA5 elicited broad SARS-CoV-2 neutralization. Potent protection against SARS-CoV-2 variants was observed in challenge assays and was correlated with neutralizing antibody titer. This study validated the design strategy of tandem RBD-heterotrimers as multivalent immunogens and presented a promising vaccine candidate, DBA2BA5, eliciting broad-spectrum immune responses, including against the circulating XBB/BF.7/BQ.1.1.

Robust and protective immune responses induced by heterologous prime-boost vaccination with DNA-protein dimeric RBD vaccines for COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic posed great impacts on public health. To fight against the pandemic, robust immune responses induced by vaccination are indispensable. Previously, we developed a subunit vaccine adjuvanted by aluminum hydroxide, ZF2001, based on the dimeric tandem-repeat RBD immunogen, which has been approved for clinical use. This dimeric RBD design was also explored as an mRNA vaccine. Both showed potent immunogenicity. In this study, a DNA vaccine candidate encoding RBD-dimer was designed. The humoral and cellular immune responses induced by homologous and heterologous prime-boost approaches with DNA-RBD-dimer and ZF2001 were assessed in mice. Protection efficacy was studied by the SARS-CoV-2 challenge. We found that the DNA-RBD-dimer vaccine was robustly immunogenic. Priming with DNA-RBD-dimer followed by ZF2001 boosting induced higher levels of neutralizing antibodies than homologous vaccination with either DNA-RBD-dimer or ZF2001, elicited polyfunctional cellular immunity with a TH 1-biased polarization, and efficiently protected mice against SARS-CoV-2 infection in the lung. This study demonstrated the robust and protective immune responses induced by the DNA-RBD-dimer candidate and provided a heterologous prime-boost approach with DNA-RBD-dimer and ZF2001.

Targeting c-Jun Is a Potential Therapy for Luminal Breast Cancer Bone Metastasis.

Luminal breast cancer has the highest bone metastasis frequency among all breast cancer subtypes; however, its metastatic mechanism has not been elucidated because of a lack of appropriate models. We have previously developed useful bone metastatic cell lines of luminal breast cancer using MCF7 cells. In this study, we characterized bone metastatic MCF7-BM cell lines and identified c-Jun as a novel bone metastasis marker of luminal breast cancer. The protein level of c-Jun was upregulated in MCF7-BM cells compared with that in parental cells, and its deficiency resulted in the suppression of tumor cell migration, transformation, and reduced osteolytic ability. In vivo, dominant-negative c-Jun exhibited smaller bone metastatic lesions and a lower metastatic frequency. Histologic analysis revealed that c-Jun expression was heterogeneous in bone metastatic lesions, whereas c-Jun overexpression mediated a vicious cycle between MCF7-BM cells and osteoclasts by enhancing calcium-induced migration and releasing the osteoclast activator BMP5. Pharmacological inhibition of c-Jun by the Jun amino-terminal kinase (JNK) inhibitor JNK-IN-8 effectively suppressed tumorigenesis and bone metastasis in MCF7-BM cells. Furthermore, c-Jun downstream signals were specifically correlated with the clinical prognosis of patients with the luminal subtype of breast cancer. Our results illustrate the potential benefits of a therapy that targets c-Jun to prevent bone metastasis in luminal breast cancer. IMPLICATIONS: c-Jun expression mediates bone metastasis in luminal breast cancer by forming a vicious cycle in the bone microenvironment, which reveals potential strategies for subtype-specific bone metastasis therapy.

The central inflammatory regulator IκBζ: induction, regulation and physiological functions.

IκBζ (encoded by NFKBIZ) is the most recently identified IkappaB family protein. As an atypical member of the IkappaB protein family, NFKBIZ has been the focus of recent studies because of its role in inflammation. Specifically, it is a key gene in the regulation of a variety of inflammatory factors in the NF-KB pathway, thereby affecting the progression of related diseases. In recent years, investigations into NFKBIZ have led to greater understanding of this gene. In this review, we summarize the induction of NFKBIZ and then elucidate its transcription, translation, molecular mechanism and physiological function. Finally, the roles played by NFKBIZ in psoriasis, cancer, kidney injury, autoimmune diseases and other diseases are described. NFKBIZ functions are universal and bidirectional, and therefore, this gene may exert a great influence on the regulation of inflammation and inflammation-related diseases.

Efficient electroreduction of CO to acetate using a metal-azolate framework with dicopper active sites.

Electrochemical reduction of CO to value-added products, especially C2 products, provides a potential approach to achieve carbon neutrality and overcome the energy crisis. Herein, we report a metal-azolate framework (CuBpz) with dicopper active sites as an electrocatalyst for the electrochemical CO reduction reaction (eCORR). As a result, CuBpz achieved an impressive faradaic efficiency (FE) of 47.8% for yielding acetate with a current density of -200 mA cm-2, while no obvious degradation was observed over 60 hours of continuous operation at a current density of -200 mA cm-2. Mechanism studies revealed that the dicopper site can promote C-C coupling between two C1 intermediates, thereby being conducive to the generation of the key *CH2COOH intermediate.

Diffusion kurtosis imaging and diffusion weighted imaging comparison in diagnosis of early hypoxic-ischemic brain edema.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) refers to cerebral hypoxic-ischemic injury caused by asphyxia during perinatal period, which is one of the important causes of neonatal death and sequelae. Early and accurate diagnosis of HIE is of great significance for the prognostic evaluation of patients. The purpose of this study is to explore the efficacy of diffusion-kurtosis imaging (DKI) and diffusion-weighted imaging (DWI) in the diagnosis of early HIE. METHODS: Twenty Yorkshire newborn piglets (3-5 days) were randomly divided into control group and experimental group. DWI and DKI scanning were performed at timepoints of 3, 6, 9, 12, 16, and 24 h after hypoxic-ischemic exposure. At each timepoint, the parameter values obtained by each group scan were measured, and the lesion area of the apparent diffusion coefficient (ADC) map and mean diffusion coefficient (MDC) map were measured. (For better interpretation of this study, we replaced the description of MD with MDC). Then, we completely removed the brain for pathological examination, and observed the state of cells and mitochondria in the ADC/MDC matching area (the actual area of the lesion), and the mismatch area (the area around the lesion). RESULTS: In the experimental group, the ADC and MDC values decreased with time, but the MDC decreased more significantly and the change rate was higher. Both MDC and ADC values changed rapidly from 3 to 12 h and slowly from 12 to 24 h. The MDC and ADC images showed obvious lesions at 3 h for the first time. At this time, the area of ADC lesions was larger than that of MDC. As the lesions developed, the area of ADC maps was always larger than that of the MDC maps within 24 h. By observing the microstructure of the tissues by light microscopy, we found that the ADC and MDC matching area in the experimental group showed swelling of neurons, infiltration of inflammatory cells, and local necrotic lesions. Consistent with the observation under light microscope, pathological changes were observed in the matching ADC and MDC regions under electron microscopy as well, including collapse of mitochondrial membrane, fracture of partial mitochondrial ridge, and emergence of autophagosomes. In the mismatching region, the above pathological changes were not observed in the corresponding region of the ADC map. CONCLUSIONS: DKI's characteristic parameter MDC is better than ADC (parameter of DWI) to reflect the real area of the lesion. Therefore, DKI is superior to DWI in diagnosing early HIE.

Rapid evaluation of heterologous chimeric RBD-dimer mRNA vaccine for currently-epidemic Omicron sub-variants as booster shot after inactivated vaccine.

With continuous mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the severe immune escape of Omicron sub-variants urges the development of next-generation broad-spectrum vaccines, especially as booster jabs after high-level vaccination coverage of inactivated vaccines in China and many other countries. Previously, we developed a coronavirus disease 2019 (COVID-19) protein subunit vaccine ZF2001® based on the tandem homo-prototype receptor-binding domain (RBD)-dimer of the SARS-CoV-2 spike protein. We upgraded the antigen into a hetero-chimeric prototype (PT)-Beta or Delta-BA.1 RBD-dimer to broaden the cross-protection efficacy and prove its efficiency with protein subunit and mRNA vaccine platforms. Herein, we further explored the hetero-chimeric RBD-dimer mRNA vaccines and evaluated their broad-spectrum activities as booster jabs following two doses of inactivated vaccine (IV) in mice. Our data demonstrated that the chimeric vaccines significantly boosted neutralizing antibody levels and specific T-cell responses against the variants, and PT-Beta was superior to Delta-BA.1 RBD as a booster in mice, shedding light on the antigen design for the next-generation COVID-19 vaccines.

Efficacy and safety of direct oral anticoagulants for the treatment of cancer-associated venous thromboembolism: A systematic review and Bayesian network meta-analysis.

INTRODUCTION: Direct oral anticoagulants (DOACs) could effectively prevent the occurrence of cancer-associated venous thromboembolism (CAVTE), which incidence rate was estimated to be 4-20%. But the efficacy and safety remain controversial between DOACs and low molecular weight heparin (LMWH). MATERIALS AND METHODS: PubMed, Cochrane Library, Embase, ClinicalTrials.gov databases for randomized controlled trials (RCTs) were systematically searched from inception to March 15, 2022. A random-effects model was used to report the odds ratio (OR) and 95% confidence interval (CI) for both direct and network meta-analyses. RESULTS: Seven studies were included totaling 3242 patients. A lower rate of recurrence VTE was noted in the DOACs compared with LMWH (OR 0.62, 95% CI 0.47-0.82, I2=0.0%). The aspect of major bleeding (MB) was similar (OR 1.30, 95% CI 0.77-2.18, I2=34.9%). When assessing clinically relevant nonmajor bleeding (CRNMB) (OR 1.61, 95% CI 1.17-2.22, I2=20.7%) and clinically relevant bleeding (CRB) (OR 1.39, 95% CI 1.11-1.74, I2=0.0%), a higher risk of events was observed in DOACs. In subgroup analyses, the MB of gastrointestinal and genitourinary malignancies had a higher rate in the DOACs. For ranking, apixaban ranked the first in prevention of VTE and reducing MB events. Edoxaban had the highest risk drug in MB. In terms of CRNMB and CRB, LMWH showed the lowest risk. CONCLUSIONS: Compared with LMWH, DOACs seemed to have a decreased risk of recurrence VTE while increasing CRNMB and CRB. DOACs and LMWH were equivalent to the aspect of MB, but DOACs had a higher MB risk in patients with gastrointestinal and genitourinary malignancies. Apixaban may be the lowest risk compared to the other DOACs in precaution of VTE and reducing bleeding events.

miR-133a-3p/TRPM4 axis improves palmitic acid induced vascular endothelial injury.

Background: Vascular endothelial injury is a contributing factor to the development of atherosclerosis and the resulting cardiovascular diseases. One particular factor involved in endothelial cell apoptosis and atherosclerosis is palmitic acid (PA), which is a long-chain saturated fatty acid. In addition, transient receptor potential melastatin 4 (TRPM4), a non-selective cation channel, plays a significant role in endothelial dysfunction caused by various factors related to cardiovascular diseases. Despite this, the specific role and mechanisms of TRPM4 in atherosclerosis have not been fully understood. Methods: The protein and mRNA expressions of TRPM4, apoptosis - and inflammation-related factors were measured after PA treatment. The effect of TRPM4 knockout on the protein and mRNA expression of apoptosis and inflammation-related factors was detected. The changes of intracellular Ca2+, mitochondrial membrane potential, and reactive oxygen species were detected by Fluo-4 AM, JC-1, and DCFH-DA probes, respectively. To confirm the binding of miR-133a-3p to TRPM4, a dual luciferase reporter gene assay was conducted. Finally, the effects of miR-133a-3p and TRPM4 on intracellular Ca2+, mitochondrial membrane potential, and reactive oxygen species were examined. Results: Following PA treatment, the expression of TRPM4 increases, leading to calcium overload in endothelial cells. This calcium influx causes the assemblage of Bcl-2, resulting in the opening of mitochondrial calcium channels and mitochondrial damage, ultimately triggering apoptosis. Throughout this process, the mRNA and protein levels of IL-1ß, ICAM-1, and VCAM1 significantly increase. Database screenings and luciferase assays have shown that miR-133a-3p preferentially binds to the 3'UTR region of TRPM4 mRNA, suppressing TRPM4 expression. During PA-induced endothelial injury, miR-133a-3p is significantly decreased, but overexpression of miR-133a-3p can attenuate the progression of endothelial injury. On the other hand, overexpression of TRPM4 counteracts the aforementioned changes. Conclusion: TRPM4 participates in vascular endothelial injury caused by PA. Therefore, targeting TRPM4 or miR-133a-3p may offer a novel pharmacological approach to preventing endothelial injury.

A Porous π-π Stacking Framework with Dicopper(I) Sites and Adjacent Proton Relays for Electroreduction of CO2 to C2+ Products.

Crystalline porous materials sustained by supramolecular interactions (e.g., π-π stacking interactions) are a type of molecular crystals showing considerable stability, but their applications are rarely reported due to the high difficulty of their construction. Herein, a stable π-π stacking framework formed by a trinuclear copper(I) compound [Cu3(HBtz)3(Btz)Cl2] (CuBtz, HBtz = benzotriazole) with pyrazolate-bridged dicopper(I) sites is reported and employed for electrochemical CO2 reduction, showing an impressive performance of 73.7 ± 2.8% Faradaic efficiency for C2+ products [i.e., ethylene (44%), ethanol (21%), acetate (4.7%), and propanol (4%)] with a current density of 7.9 mA cm-2 at the potential of -1.3 V versus RHE in an H-type cell and a Faradic efficiency (61.6%) of C2+ products with a current density of ≈1 A cm-2 and a reaction rate of 5639 µmol m-2 s-1 at the potential of -1.6 V versus RHE in a flow cell device, representing an impressive performance reported to date. In-situ infrared spectroscopy, density functional theory calculations, and control experiments revealed that the uncoordinated nitrogen atoms of benzotriazolates in the immediate vicinity can act as proton relays and cooperate with the dicopper(I) site to promote the hydrogenation process of the *CO intermediate and the C-C coupling, resulting in the highly selective electroreduction of CO2 to C2+ products.

Immunogenicity, efficacy and safety of COVID-19 vaccines: an update of data published by 31 December 2021.

The unprecedented coronavirus disease 2019 (COVID-19) pandemic has caused a disaster for public health in the last 2 years, without any sign of an ending. Various vaccines were developed rapidly as soon as the outbreak occurred. Clinical trials demonstrated the reactogenicity, immunogenicity and protection efficacy in humans, and some of the vaccines have been approved for clinical use. However, waves of infections such as the recently circulating Omicron variant still occur. Newly emerging variants, especially the variants of concern, and waning humoral responses pose serious challenges to the control of the COVID-19 pandemic. Previously, we summarized the humoral and cellular immunity, safety profiles and protection efficacy of COVID-19 vaccines with clinical data published by 21 May 2021. In this review, we summarize and update the published clinical data of COVID-19 vaccines and candidates up to 31 December 2021.

Genome-Wide Analysis of the Peptidase M24 Superfamily in Triticum aestivum Demonstrates That TaM24-9 Is Involved in Abiotic Stress Response.

The peptidase M24 (Metallopeptidase 24, M24) superfamily is essential for plant growth, stress response, and pathogen defense. At present, there are few systematic reports on the identification and classification of members of the peptidase M24 proteins superfamily in wheat. In this work, we identified 53 putative candidate TaM24 genes. According to the protein sequences characteristics, these members can be roughly divided into three subfamilies: I, II, III. Most TaM24 genes are complex with multiple exons, and the motifs are relatively conserved in each sub-group. Through chromosome mapping analysis, we found that the 53 genes were unevenly distributed on 19 wheat chromosomes (except 3A and 3D), of which 68% were in triads. Analysis of gene duplication events showed that 62% of TaM24 genes in wheat came from fragment duplication events, and there were no tandem duplication events to amplify genes. Analysis of the promoter sequences of TaM24 genes revealed that cis-acting elements were rich in response elements to drought, osmotic stress, ABA, and MeJA. We also studied the expression of TaM24 in wheat tissues at developmental stages and abiotic stress. Then we selected TaM24-9 as the target for further analysis. The results showed that TaM24-9 genes strengthened the drought and salt tolerance of plants. Overall, our analysis showed that members of the peptidase M24 genes may participate in the abiotic stress response and provided potential gene resources for improving wheat resistance.

Protective prototype-Beta and Delta-Omicron chimeric RBD-dimer vaccines against SARS-CoV-2.

Breakthrough infections by SARS-CoV-2 variants become the global challenge for pandemic control. Previously, we developed the protein subunit vaccine ZF2001 based on the dimeric receptor-binding domain (RBD) of prototype SARS-CoV-2. Here, we developed a chimeric RBD-dimer vaccine approach to adapt SARS-CoV-2 variants. A prototype-Beta chimeric RBD-dimer was first designed to adapt the resistant Beta variant. Compared with its homotypic forms, the chimeric vaccine elicited broader sera neutralization of variants and conferred better protection in mice. The protection of the chimeric vaccine was further verified in macaques. This approach was generalized to develop Delta-Omicron chimeric RBD-dimer to adapt the currently prevalent variants. Again, the chimeric vaccine elicited broader sera neutralization of SARS-CoV-2 variants and conferred better protection against challenge by either Delta or Omicron SARS-CoV-2 in mice. The chimeric approach is applicable for rapid updating of immunogens, and our data supported the use of variant-adapted multivalent vaccine against circulating and emerging variants.