Oridonin attenuates carrageenan-induced pleurisy via activation of the KEAP-1/Nrf2 pathway and inhibition of the TXNIP/NLRP3 and NF-κB pathway in mice.

The classic NLRP3 inflammasome and NF-κB molecular pathways are activated in many inflammatory-related diseases, such as pleurisy. Because oridonin (Ori) has been indicated as a covalent NLRP3 inhibitor with strong anti-inflammasome activity, we herein aimed to assess the effects of Ori in a mouse model of carrageenan (CAR)-induced pleurisy. The results showed that CAR caused hemorrhaging and exudation of lung tissues and the release of inflammatory factors (TNF-α, IL-6 and IL-1ß), effects that were significantly reduced by treatment with Ori. In addition, increased neutrophil infiltration, protein concentrations and volumes were found in the exudates of the CAR group, and these phenomena were suppressed by Ori treatment. Regarding cellular pathways, Ori could alleviate the CAR-activated NF-κB and TXNIP/NLRP3 pathways. Additionally, oxidative stress was shown to be involved in the pathogenesis of pleurisy, but possible mechanisms remain to be explored. Herein, Ori reversed the CAR-induced depletion of GSH and SOD and the CAR-induced increases in ROS, MPO and MDA levels. Furthermore, Ori inhibited NOX-4 levels, initiated the dissociation of KEAP-1 from Nrf2, activated the downstream genes HO-1 and exerted antioxidative effects on CAR-induced pleurisy. In conclusion, Ori conferred protection against CAR-induced pleurisy via Nrf2-dependent antioxidative and NLRP3-dependent anti-inflammatory properties.

Coupling PtNi Ultrathin Nanowires with MXenes for Boosting Electrocatalytic Hydrogen Evolution in Both Acidic and Alkaline Solutions.

Developing an efficient electrocatalyst for the hydrogen evolution reaction (HER) working in both acidic and alkaline solutions is highly desirable, but still remains challenging. Here, Ptx Ni ultrathin nanowires (NWs) with tunable compositions (x = 1.42, 3.21, 5.67) are in situ grown on MXenes (Ti3 C2 nanosheets), serving as electrocatalysts toward HER. Such Ptx Ni@Ti3 C2 electrocatalysts exhibit excellent HER performance in both acidic and alkaline solutions, with the Pt3.21 Ni@Ti3 C2 being the best one. Specifically, Pt3.21 Ni@Ti3 C2 achieves record-breaking performance in terms of lowest overpotential (18.55 mV) and smallest Tafel slope (13.37 mV dec-1 ) for HER in acidic media to date. Theory calculations and X-ray photoelectron spectroscopy analyses demonstrate that the coupling of MXenes with the NWs not only approaches the Gibbs free energy for hydrogen adsorption close to zero through the electron transfer between them in acidic media, but also provides additional active sites for water dissociation in alkaline solution, both of them being beneficial to the HER performance.

Pterostilbene Reduces Acetaminophen-Induced Liver Injury by Activating the Nrf2 Antioxidative Defense System via the AMPK/Akt/GSK3ß Pathway.

BACKGROUND/AIMS: Pterostilbene (Pts), a natural dimethylated analog of resveratrol from blueberries, exerts antioxidative and anti-apoptotic effects in various diseases. This study aims to investigate the protective effects and mechanism of Pts against acetaminophen (APAP)-induced hepatotoxicity in vivo. METHODS: C57BL/6 mice were treated with APAP or APAP+Pts. HepG2 cells were used to further explore the underlying mechanisms in vitro. The effects of Pts on hepatotoxicity were measured by commercial kits, Hematoxylin and Eosin (H&E) straining, TUNEL assay, Western blot analysis, and Flow cytometry assay. RESULTS: In vivo, Pts treatment effectively protected against APAP-induced severe liver injury by decreasing the lethality rate, the serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, liver histological injury, liver malondialdehyde (MDA) formation and myeloperoxidase (MPO) levels and by increasing liver glutathione (GSH) and superoxide dismutase (SOD) levels. Moreover, in Pts-treated mice, the nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway was activated; however, APAP-induced c-Jun NH2-terminal kinase (JNK) activation, mitochondrial Bcl-2 Associated X Protein (Bax) translocation, apoptosis-inducing factor (AIF) levels and cytochrome c release were attenuated. In vitro, Pts was found to reverse hydrogen peroxide (H2O2) -induced cytotoxicity, reactive oxygen species (ROS) production and apoptosis that depended on Nrf2 activation. Moreover, Pts induced a dose-dependent increase in the phosphorylation of AMP-activated protein kinase (AMPK), serine/threonine kinase (Akt), and glycogen synthase kinase 3ß (GSK3ß) in HepG2 cells. Moreover, Pts protect against APAP or H2O2-induced toxicity were effectively attenuated or abolished in HepG2 Nrf2-/- cells and Nrf2-/- mice. CONCLUSION: Our data suggest that Pts protects against APAP-induced toxicity by activating Nrf2 via the AMPK/Akt/GSK3ß pathway.

Urological Procedures in Urolithiasis and Their Association with Chronic Kidney Disease.

BACKGROUND AND OBJECTIVES: Epidemiological evidence suggests that patients with urolithiasis are at increased risk for end-stage renal disease (ESRD). It is unclear if urological intervention impacts the progression of chronic kidney disease (CKD). METHODS: We conducted a retrospective observational cohort study of patients in the Marshfield Epidemiologic Study Area database between January 1991 and May 2007, where 1,340 patients diagnosed with urolithiasis were extracted. Of the 1,340 subjects, 446 had urological procedures for management of urolithiasis. Those that underwent these procedures were compared to those that did not. Cox proportional hazards models adjusted for age, gender, and comorbidities were performed to evaluate the risk for CKD, elevated serum creatinine, and any-cause mortality. RESULTS: Baseline comorbidities in patients with and without procedures were not significantly different except for obesity (P<0.0001). Subjects that underwent procedures were at increased risk for elevated serum creatinine (Hazard Ratio (HR) [95% CI] =1.49 [1.19-1.85]) when compared to those that did not undergo a urologic procedure during the study period. The results did not reveal a significant difference in incidence of CKD or any-cause mortality. CONCLUSIONS: Patients who undergo urologic procedures are at increased risk for elevated creatinine. Urological procedures do not appear to impact incidence of CKD or mortality and, in fact, may prevent long-term renal dysfunction.

ETHYLENE RESPONSE FACTOR 96 positively regulates Arabidopsis resistance to necrotrophic pathogens by direct binding to GCC elements of jasmonate - and ethylene-responsive defence genes.

The ERF (ethylene responsive factor) family is composed of transcription factors (TFs) that are critical for appropriate Arabidopsis thaliana responses to biotic and abiotic stresses. Here we identified and characterized a member of the ERF TF group IX, namely ERF96, that when overexpressed enhances Arabidopsis resistance to necrotrophic pathogens such as the fungus Botrytis cinerea and the bacterium Pectobacterium carotovorum. ERF96 is jasmonate (JA) and ethylene (ET) responsive and ERF96 transcripts accumulation was abolished in JA-insensitive coi1-16 and in ET-insensitive ein2-1 mutants. Protoplast transactivation and electrophoresis mobility shift analyses revealed that ERF96 is an activator of transcription that binds to GCC elements. In addition, ERF96 mainly localized to the nucleus. Microarray analysis coupled to chromatin immunoprecipitation-PCR of Arabidopsis overexpressing ERF96 revealed that ERF96 enhances the expression of the JA/ET defence genes PDF1.2a, PR-3 and PR-4 as well as the TF ORA59 by direct binding to GCC elements present in their promoters. While ERF96-RNAi plants demonstrated wild-type resistance to necrotrophic pathogens, basal PDF1.2 expression levels were reduced in ERF96-silenced plants. This work revealed ERF96 as a key player of the ERF network that positively regulates the Arabidopsis resistance response to necrotrophic pathogens.

Three in one: An effective and universal vaccine expressing heterologous tandem RBD trimer by rabies virus vector protects mice against SARS-CoV-2.

The rapid emergence of Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2) variants, coupled with severe immune evasion and imprinting, has jeopardized the vaccine efficacy, necessitating urgent development of broad protective vaccines. Here, we propose a strategy employing recombinant rabies viruses (RABV) to create a universal SARS-CoV-2 vaccine expressing heterologous tandem receptor-binding domain (RBD) trimer from the SARS-CoV-2 Prototype, Delta, and Omicron strains (SRV-PDO). The results of mouse immunization indicated that SRV-PDO effectively induced cellular and humoral immune responses, and demonstrated higher immunogenicity and broader SARS-CoV-2 neutralization compared to the recombinant RABVs that only expressed RBD monomers. Moreover, SRV-PDO exhibited full protection against SARS-CoV-2 in the challenge assay. This study demonstrates that recombinant RABV expressing tandem RBD-heterotrimer as a multivalent immunogen could elicit a broad-spectrum immune response and potent protection against SARS-CoV-2, making it a promising candidate for future human or veterinary vaccines and offering a novel perspective in other vaccine design.

Facile synthesis of defect-rich RuCu nanoflowers for efficient hydrogen evolution reaction in alkaline media.

Developing high-performance electrocatalysts toward hydrogen evolution reaction (HER) in alkaline media is highly desirable for industrial applications in the field of water splitting but is still challenging. Herein, we successfully synthesized RuCu nanoflowers (NFs) with tunable atomic ratios using a facile wet chemistry method. The Ru3Cu NFs need only 55 mV to achieve a current density of 10 mA cm-2, which shows ideal durability with only 4 mV decay after 2000 cycles, largely outperforming the catalytic properties of commercial Pt/C. The Ru3Cu NFs comprise many nanosheets that can provide more active sites for HER. In addition, the introduction of Cu can modulate the electronic structure of Ru, facilitate water dissociation, and optimize H adsorption/desorption ability. Thus, the flower-like structure together with the proper incorporation of Cu boosts HER performance.

An inactivated recombinant rabies virus chimerically expressed RBD induces humoral and cellular immunity against SARS-CoV-2 and RABV.

Many studies suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can infect various animals and transmit among animals, and even to humans, posing a threat to humans and animals. There is an urgent need to develop inexpensive and efficient animal vaccines to prevent and control coronavirus disease 2019 (COVID-19) in animals. Rabies virus (RABV) is another important zoonotic pathogen that infects almost all warm-blooded animals and poses a great public health threat. The present study constructed two recombinant chimeric viruses expressing the S1 and RBD proteins of the SARS-CoV-2 Wuhan01 strain based on a reverse genetic system of the RABV SRV9 strain and evaluated their immunogenicity in mice, cats and dogs. The results showed that both inactivated recombinant viruses induced durable neutralizing antibodies against SARS-CoV-2 and RABV and a strong cellular immune response in mice. Notably, inactivated SRV-nCoV-RBD induced earlier antibody production than SRV-nCoV-S1, which was maintained at high levels for longer periods. Inactivated SRV-nCoV-RBD induced neutralizing antibodies against both SARS-CoV-2 and RABV in cats and dogs, with a relatively broad-spectrum cross-neutralization capability against the SARS-CoV-2 pseudoviruses including Alpha, Beta, Gamma, Delta, and Omicron, showing potential to be used as a safe bivalent vaccine candidate against COVID-19 and rabies in animals.

Treat the "Untreatable" by a Photothermal Agent: Triggering Heat and Immunological Responses for Rabies Virus Inactivation.

Rabies is a fatal neurological zoonotic disease caused by the rabies virus (RABV), and the approved post-exposure prophylaxis (PEP) procedure remains unavailable in areas with inadequate medical systems. Although strategies have been proposed for PEP and postinfection treatment (PIT), because of the complexity of the treatment procedures and the limited curative outcome, developing an effective treatment strategy remains a holy grail in rabies research. Herein, a facile approach is proposed involving photothermal therapy (PTT) and photothermally triggered immunological effects to realize effective PEP and PIT simultaneously. The designed photothermal agent (N+ TT-mCB nanoparticles) featured positively charged functional groups and high photo-to-heat efficiency, which are favorable for virus targeting and inactivation. The level of the virus at the site of infection in mice is significantly decreased upon treatment with orthotopic PTT, and the transfer of the virus to the brain is significantly inhibited. Furthermore, the survival ratio of the mice three days postinfection is increased by intracranial injection of N+ TT-mCB and laser irradiation. Overall, this work provides a platform for the effective treatment of RABV and opens a new avenue for future antiviral studies.

Pt-Sn alloy shells with tunable composition and structure on Au nanoparticles for boosting ethanol oxidation.

Combining the core-shell structure with the optimization of surface composition and structure in the shell is a fantastic strategy to enhance the electrocatalytic performances. Here, we synthesized trimetallic Au@PtxSny core-shell nanoparticles (NPs) with tunable composition and structure of Pt-Sn alloyed shells. Impressively, the Au@PtSn core-shell NPs with hexagonal PtSn alloyed shells exhibited the highest mass activity and specific activity toward ethanol oxidation reaction (EOR) in alkaline electrolyte, which are 13.0 and 12.7 times higher than those of the commercial Pt/C. In addition, the Au@PtSn core-shell NPs displayed the best stability compared to commercial Pt/C, with only 44.8% loss vs. 86.8% loss in mass activity after 1,000 s due to the stronger anti-poisoning ability for reaction intermediates. The theory calculations reveal that the introduction of Au core and alloying Pt with Sn both endow Pt with an appropriate d-band center, and thus effectively boosting the EOR activity.

Enhanced electrocatalytic reduction of CO2 to formate via doping Ce in Bi2O3 nanosheets.

Formate is considered as the most economically viable product of the prevalent electrochemical CO2 reduction (ECR) products. However, most of the catalysts for ECR to formate in aqueous solution often suffer from low activity and limited selectivity. Herein, we report a novel Ce-doped Bi2O3 nanosheet (NS) electrocatalyst by a facile solvothermal method for highly efficient ECR to formate. The 5.04% Ce-doped Bi2O3 NSs exhibited a current density of 37.4 mA cm-2 for the production of formate with a high formate faradaic efficiency (FE) of 95.8% at -1.12 V. The formate FE was stably maintained at about 90% in a wide potential range from -0.82 to -1.22 V. More importantly, density functional theory (DFT) calculations revealed that Ce doping can lead to a significant synergistic effect, which promotes the formation and the adsorption of the OCHO* intermediate for ECR, while significantly inhibiting the hydrogen evolution reaction via depressing the formation of *H, thus helping achieve high current density and FE. This work provides an effective and promising strategy to develop efficient electrocatalysts with heteroatom doping and new insights for boosting ECR into formate.

Real-Life Experience of Regorafenib in Patients With Advanced Hepatocellular Carcinoma.

Background: The RESORCE trial reported that regorafenib was effective as the second-line treatment for patients with hepatocellular carcinoma (HCC) after progression on sorafenib. Real-world data are needed to assess clinical outcomes and adverse events in the setting of daily practice. Objective: We aimed to evaluate the efficacy and safety of regorafenib after disease progression with sorafenib in Chinese patients with advanced HCC. Patients and Methods: A total of 41 patients with advanced HCC who did not respond to sorafenib and followed a regorafenib regimen were enrolled in this retrospective study. Overall survival (OS), progression-free survival (PFS), radiological responses, and adverse events (AEs) were evaluated. Survival curves were compared by using the log-rank test and constructed with the Kaplan-Meier method. Results: The median PFS with regorafenib was 6.6 months (range: 5.0-8.2 months), and the median OS with regorafenib was not reached. The 1-year OS rate of regorafenib was 66.4%. The median OS of sequential sorafenib to regorafenib treatment was 35.3 months [95% confidence interval (CI), 24.3-46.3], and the 2-year OS rate of sequential sorafenib to regorafenib treatment was 74.4%. The most common AEs of regorafenib treatment were elevated aspartate aminotransferase [17/41 patients (41.5%)], elevated alanine aminotransferase [16/41 patients (39%)] and hand-foot syndrome [14/41 patients (34.1%)]. Conclusion: Regorafenib appears to be safe and clinically effective in patients with advanced HCC who progressed on first-line sorafenib.

Regulation of innate immune responses by rabies virus.

Rabies virus (RABV) is an infectious and neurotropic pathogen that causes rabies and infects humans and almost all warm-blooded animals, posing a great threat to people and public safety. It is well known that innate immunity is the critical first line of host defense against viral infection. It monitors the invading pathogens by recognizing the pathogen-associated molecular patterns and danger-associated molecular patterns through pattern-recognition receptors, leading to the production of type I interferons (IFNα/ß), inflammatory cytokines, and chemokines, or the activation of autophagy or apoptosis to inhibit virus replication. In the case of RABV, the innate immune response is usually triggered when the skin or muscle is bitten or scratched. However, RABV has evolved many ways to escape or even hijack innate immune response to complete its own replication and eventually invades the central nervous system (CNS). Once RABV reaches the CNS, it cannot be wiped out by the immune system or any drugs. Therefore, a better understanding of the interplay between RABV and innate immunity is necessary to develop effective strategies to combat its infection. Here, we review the innate immune responses induced by RABV and illustrate the antagonism mechanisms of RABV to provide new insights for the control of rabies.

COVID-19 prevention and control strategies: learning from the Macau model.

Background: Macau is a densely populated international tourist city. Compared to most tensely populated countries/territories, the prevalence and mortality of COVID-19 in Macau are lower. The experiences in Macau could be helpful for other areas to combat the COVID-19 pandemic. This article introduced the endeavours and achievements of Macau in combatting the COVID-19 pandemic. Method: Both qualitative and quantitative analysis methods were used to explore the work, measures, and achievements of Macau in dealing with the COVID-19 pandemic. Results: The results revealed that Macau has provided undifferentiated mask purchase reservation services, COVID-19 vaccination services to all residents and non-residents in Macau along with delivering multilingual services, in Chinese, English and Portuguese, to different groups of the population. To facilitate the travels of people, business and trades between Macau and mainland China, the Macau government launched the Macau Health Code System, which uses the health status declaration, residence history declaration, contact history declaration of the declarant to match various relevant backend databases within the health authority and provide a risk-related colour code operations. The Macau Health Code System connects to the Chinese mainland's own propriety health code system seamlessly, whilst effectively protecting the privacy of the residents. Macau has also developed the COVID-19 Vaccination Appointment system, the Nucleic Acid Test Appointment system, the Port and Entry/Exit Quarantine system, the medical and other supporting systems. Conclusion: The efforts in Macau have achieved remarkable results in COVID-19 prevention and control, effectively safeguarding the lives and health of the people and manifesting the core principle of "serving the public". The measures used are sustainable and can serve as an important reference for other countries/regions.

Strain effect in Pd@PdAg twinned nanocrystals towards ethanol oxidation electrocatalysis.

The strain effect is a critical knob to tune the catalytic performance and has received unprecedented research interest recently. However, it is difficult to distinguish the strain effect from the synergistic effect, especially in alloyed catalysts. Here we have synthesized Pd@PdAg icosahedra and {111} truncated bi-pyramids with only different surface strains between them as electrocatalysts for the ethanol oxidation reaction (EOR). Due to the same exposed facets and compositions of the two electrocatalysts, their EOR performances are mainly determined by the surface strains of PdAg alloys. These two electrocatalysts provide a perfect model to investigate the role of the strain effect in tuning the EOR performance. It is indicated that Pd@PdAg {111} truncated bi-pyramids with a surface strain of 0.3% show better catalytic activity and durability than Pd@PdAg icosahedra with a surface strain of 2.1% including commercial Pd/C. Density functional theory (DFT) calculations reveal that the lowered d-band center of 0.3% strained PdAg alloys relative to 2.1% strained ones reduced the adsorption energy of the acetate-evolution key intermediate *CH3CO, thereby promoting the enhancement in the catalytic performance of Pd@PdAg nanocrystals for the EOR. Electrochemical analysis further verifies this demonstration on the key role of the strain effect in PdAg alloys for tuning catalytic performance.

Sn-Doped Bi2O3 nanosheets for highly efficient electrochemical CO2 reduction toward formate production.

Electrocatalytic CO2 reduction to formate is considered as a perfect route for efficient conversion of the greenhouse gas CO2 to value-added chemicals. However, it still remains a huge challenge to design a catalyst with both high catalytic activity and selectivity for target products. Here we report a unique Sn-doped Bi2O3 nanosheet (NS) electrocatalyst with different atomic percentages of Sn (1.2, 2.5, and 3.8%) prepared by a simple solvothermal method for highly efficient electrochemical reduction of CO2 to formate. Of them, the 2.5% Sn-doped Bi2O3 NSs exhibited the highest faradaic efficiency (FE) of 93.4% with a current density of 24.3 mA cm-2 for formate at -0.97 V in the H-cell and a maximum current density of nearly 50 mA cm-2 was achieved at -1.27 V. The formate FE is stable maintained at over 90% in a wide potential range from -0.87 V to -1.17 V. Electrochemical and density functional theory (DFT) analyses of undoped and Sn doped Bi2O3 NSs indicated that the strong synergistic effect between Sn and Bi is responsible for the enhancement in the adsorption capacity of the OCHO* intermediate, and thus the activity for formate production. In addition, we coupled 2.5% Sn-doped Bi2O3 NSs with a dimensionally stable anode (DSA) to realize battery-driven highly active CO2RR and OER with decent activity and efficiency.

Facile Synthesis of Pd@PtM (M = Rh, Ni, Pd, Cu) Multimetallic Nanorings as Efficient Catalysts for Ethanol Oxidation Reaction.

Pt-based multimetallic nanorings with a hollow structure are attractive as advanced catalysts due to their fantastic structure feature. However, the general method for the synthesis of such unique nanostructures is still lack. Here we report the synthesis of Pd@PtM (M = Rh, Ni, Pd, Cu) multimetallic nanorings by selective epitaxial growth of Pt alloyed shells on the periphery of Pd nanoplates in combination with oxidative etching of partial Pd in the interior. In situ generation of CO and benzoic acid arising from interfacial catalytic reactions between Pd nanoplates and benzaldehyde are critical to achieve high-quality Pt-based multimetallic nanorings. Specifically, the in-situ generated CO promotes the formation of Pt alloyed shells and their epitaxial growth on Pd nanoplates. In addition, the as-formed benzoic acid and residual oxygen are responsible for selective oxidative etching of partial Pd in the interior. When evaluated as electrocatalysts, the Pd@PtRh nanorings exhibit remarkably enhanced activity and stability for ethanol oxidation reaction (EOR) compared to the Pd@PtRh nanoplates and commercial Pt/C due to their hollow nanostructures.

Predicting mortality in acute ischaemic stroke treated with mechanical thrombectomy: analysis of a multicentre prospective registry.

OBJECTIVES: We aimed to determine predictors of mortality within 90 days and develop a simple score for patients with mechanical thrombectomy (MT). DESIGN: Analysis of a multicentre prospective registry. SETTING: In six participating centres, patients who had an acute ischaemic stroke (AIS) treated by MT between March 2017 and May 2018 were documented prospectively. PARTICIPANTS: 224 patients with AIS were treated by MT. RESULTS: Of 224 patients, 49 (21.9%) patients died, and 87 (38.8%) were independent. Variables associated with 90-day mortality were age, previous stroke, admission National Institutes of Health Stroke Scale (NIHSS), fasting blood glucose and occlusion site. Logistic regression identified four variables independently associated with 90-day mortality: age ≥80 years (OR 3.26, 95% CI 1.45 to 7.33), previous stroke (OR 2.33, 95% CI 1.04 to 5.21), admission NIHSS ≥18 (OR 2.37, 95% CI 1.13 to 4.99) and internal carotid artery or basilar artery occlusion (OR 2.92, 95% CI 1.34 to 6.40). Using these data, we developed predicting 90-day mortality of AIS with MT (PRACTICE) score ranging from 0 to 6 points. The receiver operator curve analysis found that PRACTICE score (area under the curve (AUC)=0.744, 95% CI 0.669 to 0.820) was numerically better than iScore (AUC=0.661, 95% CI 0.577 to 0.745) and Predicting Early Mortality of Ischemic Stroke score (AUC=0.638, 95% CI 0.551 to 0.725) for predicting 90-day mortality. CONCLUSIONS: We developed a simple score to estimate the 90-day mortality of patients who had an AIS treated with MT. But the score needs to be prospectively validated. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR-OOC-17013052).