Rational design of a 'two-in-one' immunogen DAM drives potent immune response against mpox virus.

The global outbreak of the mpox virus (MPXV) in 2022 highlights the urgent need for safer and more accessible new-generation vaccines. Here, we used a structure-guided multi-antigen fusion strategy to design a 'two-in-one' immunogen based on the single-chain dimeric MPXV extracellular enveloped virus antigen A35 bivalently fused with the intracellular mature virus antigen M1, called DAM. DAM preserved the natural epitope configuration of both components and showed stronger A35-specific and M1-specific antibody responses and in vivo protective efficacy against vaccinia virus (VACV) compared to co-immunization strategies. The MPXV-specific neutralizing antibodies elicited by DAM were 28 times higher than those induced by live VACV vaccine. Aluminum-adjuvanted DAM vaccines protected mice from a lethal VACV challenge with a safety profile, and pilot-scale production confirmed the high yield and purity of DAM. Thus, our study provides innovative insights and an immunogen candidate for the development of alternative vaccines against MPXV and other orthopoxviruses.

The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway.

PI3K and PTEN lipid phosphatase control the level of cellular phosphatidylinositol (3,4,5)-trisphosphate, an activator of AKT kinases that promotes cell growth and survival. Mutations activating AKT are commonly observed in human cancers. We report here that ENTPD5, an endoplasmic reticulum (ER) enzyme, is upregulated in cell lines and primary human tumor samples with active AKT. ENTPD5 hydrolyzes UDP to UMP to promote protein N-glycosylation and folding in ER. Knockdown of ENTPD5 in PTEN null cells causes ER stress and loss of growth factor receptors. ENTPD5, together with cytidine monophosphate kinase-1 and adenylate kinase-1, constitute an ATP hydrolysis cycle that converts ATP to AMP, resulting in a compensatory increase in aerobic glycolysis known as the Warburg effect. The growth of PTEN null cells is inhibited both in vitro and in mouse xenograft tumor models. ENTPD5 is therefore an integral part of the PI3K/PTEN regulatory loop and a potential target for anticancer therapy.

The anti-inflammatory mechanism of SAHA in acute pancreatitis through HDAC5/SLIT2/Akt/ß-catenin axis.

Acute pancreatitis (AP) is widely recognized to be an inflammation-related disease, in which HDAC was upregulated. The anti-inflammatory role of suberoylanilide hydroxamic acid (SAHA), a HDAC inhibitor, has been documented. In this context, this research was implemented to figure out whether SAHA manipulated inflammation in AP. Subsequent to induction of AP mouse model, HDAC5 expression was detected. The binding of HDAC5 and SLIT2 was detected by Co-Immunoprecipitation and Chromatin immunoprecipitation assays. SAHA treatment and gain- and loss-of-function approaches were used in AP mice and lipopolysaccharide (LPS)-induced pancreatic acinar cells. In mice, biochemical methods were implemented to measure activities of pancreatic lipase, trypsin, myeloperoxidase (MPO) and pancreatic edema, TUNEL staining to determine pancreatic cell apoptosis, and flow cytometry to assess the total number of leukocytes and neutrophils in pancreas. In pancreatic acinar cells, CCK-8 was performed to evaluate cell viability. HDAC5 exhibited overexpression in AP mice. Mechanical analysis showed that HDAC5 facilitated SLIT2 deacetylation to downregulate SLIT2, thus activating Akt/ß-catenin pathway in pancreatic acinar cells. SAHA treatment, HDAC5 silencing or SLIT2 overexpression diminished inflammation in AP in vivo and in vitro. SAHA treatment, HDAC5 silencing or SLIT2 overexpression reduced activities of pancreatic lipase, trypsin, MPO, pancreatic edema and cell apoptosis in AP mice as well as elevated viability of LPS-induced pancreatic acinar cells. SAHA might exert anti-inflammatory effects in AP mice via HDAC5/SLIT2/Akt/ß-catenin axis.

Metabolomic and Proteomic Analysis of ApoE4-Carrying H4 Neuroglioma Cells in Alzheimer's Disease Using OrbiSIMS and LC-MS/MS.

Growing clinical evidence reveals that systematic molecular alterations in the brain occur 20 years before the onset of AD pathological features. Apolipoprotein E4 (ApoE4) is one of the most significant genetic risk factors for Alzheimer's disease (AD), which is not only associated with the AD pathological features such as amyloid-ß deposition, phosphorylation of tau proteins, and neuroinflammation but is also involved in metabolism, neuron growth, and synaptic plasticity. Multiomics, such as metabolomics and proteomics, are applied widely in identifying key disease-related molecular alterations and disease-progression-related changes. Despite recent advances in the development of analytical technologies, screening the entire profile of metabolites remains challenging due to the numerous classes of compounds with diverse chemical properties that require different extraction processes for mass spectrometry. In this study, we utilized Orbitrap Secondary Ion Mass Spectrometry (OrbiSIMS) as a chemical filtering screening tool to examine molecular alterations in ApoE4-carried neuroglioma cells compared to wild-type H4 cells. The findings were compared using liquid chromatography (LC)-MS/MS targeted metabolomics analysis for the confirmation of specific metabolite classes. Detected alterations in peptide fragments by OrbiSIMS provided preliminary indications of protein changes. These were extensively analyzed through proteomics to explore ApoE4's impact on proteins. Our metabolomics approach, combining OrbiSIMS and LC-MS/MS, revealed disruptions in lipid metabolism, including glycerophospholipids and sphingolipids, as well as amino acid metabolism, encompassing alanine, aspartate, and glutamate metabolism; aminoacyl-tRNA biosynthesis; glutamine metabolism; and taurine and hypotaurine metabolism. Further LC-MS/MS proteomics studies confirmed the dysfunction in amino acid and tRNA aminoacylation metabolic processes, and highlighted RNA splicing alterations influenced by ApoE4.

Characteristics of tandem repeat inheritance and sympathetic nerve involvement in GAA-FGF14 ataxia.

BACKGROUND: Intronic GAA repeat expansion ([GAA] ≥250) in FGF14 is associated with the late-onset neurodegenerative disorder, spinocerebellar ataxia 27B (SCA27B, GAA-FGF14 ataxia). We aim to determine the prevalence of the GAA repeat expansion in FGF14 in Chinese populations presenting late-onset cerebellar ataxia (LOCA) and evaluate the characteristics of tandem repeat inheritance, radiological features and sympathetic nerve involvement. METHODS: GAA-FGF14 repeat expansion was screened in an undiagnosed LOCA cohort (n = 664) and variations in repeat-length were analyzed in families of confirmed GAA-FGF14 ataxia patients. Brain magnetic resonance imaging (MRI) was used to evaluate the radiological feature in GAA-FGF14 ataxia patients. Clinical examinations and sympathetic skin response (SSR) recordings in GAA-FGF14 patients (n = 16) were used to quantify sympathetic nerve involvement. RESULTS: Two unrelated probands (2/664) were identified. Genetic screening for GAA-FGF14 repeat expansion was performed in 39 family members, 16 of whom were genetically diagnosed with GAA-FGF14 ataxia. Familial screening revealed expansion of GAA repeats in maternal transmissions, but contraction upon paternal transmission. Brain MRI showed slight to moderate cerebellar atrophy. SSR amplitude was lower in GAA-FGF14 patients in pre-symptomatic stage compared to healthy controls, and further decreased in the symptomatic stage. CONCLUSIONS: GAA-FGF14 ataxia was rare among Chinese LOCA cases. Parental gender appears to affect variability in GAA repeat number between generations. Reduced SSR amplitude is a prominent feature in GAA-FGF14 patients, even in the pre-symptomatic stage.

Ultra-deep mutational landscape in chronic lymphocytic leukemia uncovers dynamics of resistance to targeted therapies.

BTK inhibitors, Bcl-2 inhibitors, and other targeted therapies have significantly improved the outcomes of patients with chronic lymphocytic leukemia (CLL). With increased survivorship, monitoring disease and deciphering potential mechanisms of resistance to these agents are critical for devising effective treatment strategies. We used duplex sequencing, a technology that enables detection of mutations at ultra-low allelic frequencies, to identify mutations in five genes associated with drug resistance in CLL and followed their evolution in two patients who received multiple targeted therapies and ultimately developed disease progression on pirtobrutinib. In both patients we detected variants that expanded and reached significant cancer cell fractions (CCF). In patient R001, multiple known resistance mutations in both BTK and PLCG2 appeared following progression on zanubrutinib (BTK p.L528W, p.C481S; PLCG2 S707F, L845F, R665W, and D993H). In contrast, patient R002 developed multiple BTK mutations following acalabrutinib treatment, including known resistance mutations p.C481R, p.T474I and p.C481S. We found that pirtobrutinib was able to suppress, but not completely eradicate, BTK p.C481S mutations in both patients, but other resistance mutations such as mutations in PLCG2 and new BTK mutations increased while the patients were receiving pirtobrutinib. For example, BTK p.L528W in patient R001 increased in frequency more than 1,000-fold (from a CCF of 0.02% to 35%), and the CCF in p.T474I in patient R002 increased from 0.03% to 4.2% (more than 100-fold). Our data illuminate the evolutionary dynamics of resistant clones over the patients' disease course and under selective pressure from different targeted treatments.

Development and Validation of a Nomogram for Predicting Survival Based on Ferritin and Transferrin Ratio in Breast Cancer Patients.

BACKGROUND: Our objective is to develop a predictive model utilizing the ferritin and transferrin ratio (FTR) and clinical factors to forecast overall survival (OS) in breast cancer (BC) patients. METHODS: We conducted a retrospective analysis of clinical data from 2858 BC patients diagnosed between 2013 and 2021. Subsequently, the cohort of 2858 BC patients underwent random assignment into distinct subsets: a training cohort comprising 2002 patients and a validation cohort comprising 856 patients, maintaining a proportional ratio of 7:3. Employing multivariable Cox regression analysis within the training cohort, we derived a prognostic nomogram. The predictive performance was assessed using calibration curves, C-index, and decision curve analysis. RESULTS: The final prognostic model included the TNM stage, subtype, hemoglobin levels, and the ferritin-transferrin ratio. The nomogram achieved a C-index of .794 (95% CI: .777-.810). The nomogram demonstrated superior predictive accuracy for OS at 3, 5, and 7 years for BC, with area under the time-dependent curves of .812, .782, and .773, respectively. These values notably outperformed those of the conventional TNM stage. Decision curve analysis reaffirmed the greater net benefit of our nomogram compared to the TNM stage. These findings were subsequently validated in the independent validation cohort. CONCLUSION: The FTR-based prognostic model may predict a patient's OS better than the TNM stage in a clinical setting. The nomogram can provide an early, affordable, and reliable tool for survival prediction, as well as aid clinicians in treatment option-making and prognosis evaluation. However, further multi-center prospective trials are required to confirm the reliability of the existing nomogram.

BackgroundOur objective is to develop a predictive model utilizing the ferritin and transferrin ratio (FTR) and clinical factors to forecast overall survival (OS) in breast cancer (BC) patients.MethodsWe conducted a retrospective analysis of clinical data from 2858 BC patients diagnosed between 2013 and 2021. Subsequently, the cohort of 2858 BC patients underwent random assignment into distinct subsets: a training cohort comprising 2002 patients and a validation cohort comprising 856 patients, maintaining a proportional ratio of 7:3. Employing multivariable Cox regression analysis within the training cohort, we derived a prognostic nomogram. The predictive performance was assessed using calibration curves, C-index, and decision curve analysis.ResultsThe final prognostic model included the TNM stage, subtype, hemoglobin levels, and the ferritin-transferrin ratio. The nomogram achieved a C-index of .794 (95% CI: .777-.810). The nomogram demonstrated superior predictive accuracy for OS at 3, 5, and 7 years for BC, with area under the time-dependent curves of .812, .782, and .773, respectively. These values notably outperformed those of the conventional TNM stage. Decision curve analysis reaffirmed the greater net benefit of our nomogram compared to the TNM stage. These findings were subsequently validated in the independent validation cohort.ConclusionThe FTR-based prognostic model may predict a patient's OS better than the TNM stage in a clinical setting. The nomogram can provide an early, affordable, and reliable tool for survival prediction, as well as aid clinicians in treatment option-making and prognosis evaluation. However, further multi-center prospective trials are required to confirm the reliability of the existing nomogram.

Model-based dosing optimization and therapeutic drug monitoring practices of teicoplanin in patients with complicated or non-complicated methicillin-resistant staphylococcus aureus infection.

AIMS: This study aims to establish a population pharmacokinetic (PK) model of teicoplanin in Chinese adult patients to evaluate the dosing regimen in the label sheet and optimize it. METHODS: Nonlinear mixed-effects modelling was used to estimate PK parameters. Monte Carlo simulations were used to evaluate the attainment of various dosing regimens in achieving the target trough concentrations in patients with normal or decreased renal function. RESULTS: A total of 115 patients were enrolled in this retrospective study. Creatinine clearance (CrCL) and albumin (ALB) were identified as covariates on the clearance of teicoplanin. For the treatment of non-complicated methicillin-resistant Staphylococcus aureus (MRSA) infections in patients with normal renal function and serum ALB concentration, the recommended dosing regimen was 600 mg q12h with five administrations as the loading dose followed by 600 mg qd as the maintenance dose; for the treatment of serious and/or complicated MRSA infections, the recommended dosing regimen was 800 mg q12h with five administrations as the loading dose followed by 800 mg qd as the maintenance dose. It is worth noting that both the loading and maintenance doses ought to be modified based on the patient's renal function and serum ALB concentration. In addition, trough concentrations of teicoplanin were significantly increased every other week. CONCLUSIONS: Both loading dosing and maintenance dosing regimens were recommended to be adjusted according to patient's renal function and serum ALB concentration. In addition, it is necessary to perform follow-up therapeutic drug monitoring of teicoplanin at least once every week.

A Carbazole-based Fluorescent Probe with AIE Performance and a Large Stokes Shift for Peroxynitrite Detection and Imaging in Live Cells.

A carbazole-based fluorescent probe YCN with AIE performance and a large Stokes shift (242 nm) shift was synthesized by attaching 4-acetonitrile pyridine to the 3-phenylaldehyde butylcarbazole. Its structure was characterized by 1H NMR, 13C NMR and MS. Probe YCN has high selectivity and sensitivity toward ONOO-. The addition of ONOO- to the probe YCN solution results in a noticeable color change from pale yellow to colorless under natural light, and a fluorescent color change from bright orange-yellow to bright yellow-green under a 365 nm UV lamp, which can be distinguished by the naked eye. The research results on the reaction mechanism showed that when YCN reacted with ONOO-, -C = C- was oxidized and broken into -CHO, and the ICT effect was significantly inhibited, resulting in changes in UV absorption and fluorescence emission phenomenon. The recognition mechanism was verified by 1H NMR, mass spectrometry (MS) and density function theory (DFT) calculations. The experiments of live cells imaging suggested that compound YCN can be used as a fluorescent probe for the detection of ONOO- in HeLa cells. This result indicates that YCN has potential application prospects in the biological aspects.

Continuous Detection of Cobalt Ions and Pyrophosphates by NAC-CdTe Quantum Dots Fluorescence Probes.

In this work, a simple and sensitive N-acetyl-L-cysteine (NAC)-covered CdTe quantum dots (NAC-CdTe QDs) fluorescence probe for continuous detection of Co2+ and pyrophosphate ions (PPi, P2O74-) was synthesized. The fluorescence of the quantum dots was significantly quenched by Co2+ through the coordination of Co2+ and the carboxyl groups on the NAC-CdTe quantum dots. Interestingly, the combination of NAC-CdTe quantum dots with Co2+ yields a new fluorescence probe of Co2+-modified NAC-CdTe QDs (Co2+@NAC-CdTe). The addition of PPi restored the fluorescence due to the competition between PPi and carboxyl groups with Co2+ causing Co2+ to detach from the surface of Co2+@NAC-CdTe quantum dots. Thus, a sensitive and reversible detection of Co2+ and PPi had been successfully established. The Co2+@NAC-CdTe quantum dots fluorescence probe exhibits excellent selectivity and high sensitivity toward PPi detection with low detection limit of 0.28 µM. In addition, the novel fluorescence probe was successfully applied to detect the concentration of PPi in environmental water samples and in-vitro cells imaging.

A Novel DNBS-based Fluorescent Probe for the Detection of H2S in Cells and on Test Strips.

Hydrogen sulfide (H2S) plays a key role in the physiology and pathology of organisms, and H2S in the environment is easily absorbed and harmful to health. It is of great significance to develop a probe with good selectivity, high sensitivity and good stability that can detect hydrogen sulfide inside and outside organisms. In this work, we designed a novel "turn-on" fluorescent probe CIM-SDB for the detection of H2S. The probe CIM-SDB used indene-carbazole as the fluorophore and 2,4-dinitrobenzenesulfonyl as the recognition site. The probe CIM-SDB exhibited high selectivity and sensitivity to H2S (detection limit as low as 123 nM). Moreover, the probe CIM-SDB was successfully applied to the detection of intracellular exogenous and endogenous H2S, and the test strips prepared by the probe CIM-SDB could realize the convenient and rapid detection of H2S.

Smoking and idiopathic pulmonary fibrosis: A meta-analysis.

INTRODUCTION: In this study, we aimed to systematically explore the relationship between smoking and idiopathic pulmonary fibrosis (IPF). METHODS: The PubMed, Web of Science and Embase databases were searched to systematically identify eligible studies. The Newcastle‒Ottawa Quality Assessment Scale (NOS) was used to evaluate the quality of the selected studies. The pooled odds ratio (OR) and survival hazard ratio (HR) were calculated with a random effects model using Stata 16.0 software. RESULTS: Thirty studies were enrolled. All of the included studies were considered to have intermediate or high quality. Nine studies were suitable for meta-analysis of ORs, and twenty-one studies were suitable for meta-analysis of survival HR. The pooled analysis revealed a significant difference in the risk of IPF between the smoking group and the never smoking group (OR 1.71, 95% CI 1.27-2.30, P < 0.001), indicating that smoking is a risk factor for IPF. When analyzing pooled survival HRs, never smoking was compared to former smoking or current smoking. Former smoking was shown to be a poor prognostic factor for IPF (HR 1.43, 95% CI 1.18-1.74, P < 0.001), but current smoking was not a significant factor. CONCLUSIONS: Our results indicated that smoking is a risk factor for IPF patients. IMPLICATIONS: In this study, we mainly concluded that smoking is a risk factor for IPF and that former smoking is a poor prognostic factor for IPF. To our knowledge, this is the first meta-analysis report focusing on the association between smoking per se and IPF. Through our current study, we hope to further raise awareness of the relationship between smoking and IPF.

Inhibitory effect of rosmarinic acid on IgE-trigged mast cell degranulation in vitro and in vivo.

BACKGROUND: Rosmarinic acid (RA), a polyphenol from edible-medical Lamiaceae herbs, is known to possess a variety of pharmacological activity, like anti-inflammatory, hepatoprotective and immunoregulation activities. METHODS AND RESULTS: Hereon, we investigated the anti-allergic activity of RA on immunoglobulin E (IgE)-mediated anaphylaxis responses in rat basophilic leukemia (RBL)-2H3 mast cell. RA hindered the morphological changes of IgE-induced degranulated RBL-2H3 cells. The release of two key biomarkers (ß-hexosaminidase (ß-HEX) and histamine) of IgE-induced degranulated mast cells was also remarkably down-regulated by RA intervention in a dose dependent manner. Moreover, RA inhibited IgE-induced ROS overproduction and flux of intracellular Ca2+ in IgE-mediated degranulated mast cells. The q-PCR analysis showed that the expressions of genes (COX 2, PGD 2, LTC 4, HDC, Nrf2, HO-1 and NQO1) involved in MAPK and oxidative stress signaling pathways were significantly regulated by RA intervention. Moreover, the degranulation inhibitory effect of rosmarinic acid was investigated on the anti-DNP IgE/DNP-HSA induced passive cutaneous anaphylaxis (PCA) mice model in vivo. It showed that RA significantly inhibited the PCA reaction and allergic edema of ears in anti-DNP IgE/DNP-HSA stimulated mice. CONCLUSION: These findings suggest that RA has the potential to be used as a therapeutic candidate for allergic diseases by inhibiting mast cell degranulation. This indicates a possible role for RA in managing allergic reactions and related conditions.

A derivative of tanshinone IIA and salviadione, 15a, inhibits inflammation and alleviates DSS-induced colitis in mice by direct binding and inhibition of RIPK2.

Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions primarily affecting the gastrointestinal tract. Previous studies established the role of the NF-κB signaling pathway in the development of IBDs, suggesting that anti-inflammatory therapies might offer a viable treatment strategy. Tanshinone IIA and salviadione, both derived from Salviae Miltiorrhizae Radix et Rhizoma, possess anti-inflammatory and anti-oxidative activities. A series of new compounds were synthesized by hybridizing salviadione with tanshinone. Among these compounds, 15a showed beneficial effects in LPS-induced acute lung injury and diabetes-induced renal injury mouse models. The current study explored the therapeutic efficacy of 15a using both acute and chronic colitis models and elucidated the underlying mechanisms. DSS-induced colitis models were established in mice, where acute colitis was treated with compound 15a (5 or 10 mg·kg-1·d-1) for 8 days, while chronic colitis mice received compound 15a (5 or 10 mg·kg-1·d-1, i.g.) during 2.5% DSS administration. The 15a treatment significantly alleviated DSS-induced pathological and inflammatory damages in both acute and chronic colitis mouse models. In mouse intestinal epithelial cell line MODE-K, pretreatment with compound 15a (5 or 10 µM) significantly suppressed LPS + L18-MDP-induced inflammatory responses. The receptor-interacting serine/threonine kinase 2 (RIPK2) was identified as a direct binding target of compound 15a using microarrays and recombinant human proteins. Moreover, 15a could directly bind to and inhibit the phosphorylation of RIPK2, leading to the suppression of the NF-κB and MAPK signaling pathways. Furthermore, LEU153 and VAL32 were identified within the KD domain of RIPK2 as critical amino residues for the binding of 15a. Briefly, the current findings demonstrate that compound 15a holds promise as a therapeutic agent for managing acute and chronic colitis.

Proteomic analysis of exosomal proteins associated with bone healing speed in a rat tibial fracture model.

This study investigates the impact of exosomes on bone fracture healing in a rat tibial model, distinguishing between fast and slow healing processes. Bone healing and protein expression were assessed through X-ray examinations, hematoxylin and eosin staining, and immunohistochemical staining. Exosomes were isolated, characterized and subjected to liquid chromatography-mass spectrometry for protein analysis. Molecular differences were explored using differentially expressed protein analysis, Kyoto Encyclopedia of Genes and Genomes pathway enrichment and protein-protein interaction networks. Differential bone healing patterns and protein expressions were observed between the control and model groups. Exosomes were successfully isolated and characterized, revealing 2004 identified proteins, including distinct expression profiles. Notably, ribosomal proteins, ferritin and beta-actin emerged as pivotal players in bone fracture healing. This study unveils dynamic changes in bone healing and underscores the role of exosomes in the process. Identified proteins and pathways offer valuable insights for developing innovative therapeutic strategies for bone healing.

PIAS1 upregulation confers protection against Cerulein-induced acute pancreatitis via FTO downregulation by enhancing sumoylation of Foxa2.

OBJECTIVE: This research discussed the specific mechanism by which PIAS1 affects acute pancreatitis (AP). METHODS: PIAS1, Foxa2, and FTO expression was assessed in Cerulein-induced AR42J cells and mice. Loss- and gain-of-function assays and Cerulein induction were conducted in AR42J cells and mice for analysis. The relationship among PIAS1, Foxa2, and FTO was tested. Cell experiments run in triplicate, and eight mice for each animal group. RESULTS: Cerulein-induced AP cells and mice had low PIAS1 and Foxa2 and high FTO. Cerulein induced pancreatic injury in mice and inflammation and oxidative stress in pancreatic tissues, which could be reversed by PIAS1 or Foxa2 upregulation or FTO downregulation. PIAS1 elevated SUMO modification of Foxa2 to repress FTO transcription. FTO upregulation neutralized the ameliorative effects of PIAS1 or Foxa2 upregulation on Cerulein-induced AR42J cell injury, inflammation, and oxidative stress. CONCLUSION: PIAS1 upregulation diminished FTO transcription by increasing Foxa2 SUMO modification, thereby ameliorating Cerulein-induced AP.

Glycyrrhizin attenuates renal inflammation in a mouse Con A-hepatitis model via the IL-25/M2 axis.

Glycyrrhizin (GL) has immunoregulatory effects on various inflammatory diseases including hepatitis and nephritis. However, the mechanisms underlying the anti-inflammatory effect of GL on renal inflammation are not fully understood. Hepatorenal syndrome (HRS) is a functional acute renal impairment that occurs in severe liver disease, and we found that kidney injury also occurs in Con A-induced experimental hepatitis in mice. We previously found that GL can alleviate Con A-induced hepatitis by regulating the expression of IL-25 in the liver. We wanted to investigate whether GL can alleviate Con A-induced nephritis by regulating IL-25. IL-25 regulates inflammation by modulating type 2 immune responses, but the mechanism by which IL-25 affects kidney disease remains unclear. In this study, we found that the administration of GL enhanced the expression of IL-25 in renal tissues; the latter promoted the generation of type 2 macrophages (M2), which inhibited inflammation in the kidney caused by Con A challenge. IL-25 promoted the secretion of the inhibitory cytokine IL-10 by macrophages but inhibited the expression of the inflammatory cytokine IL-1ß by macrophages. Moreover, IL-25 downregulated the Con A-mediated expression of Toll-like receptor (TLR) 4 on macrophages. By comparing the roles of TLR2 and TLR4, we found that TLR4 is required for the immunoregulatory effect of IL-25 on macrophages. Our data revealed that GL has anti-inflammatory effects on Con A-induced kidney injury and that the GL/IL-25/M2 axis participates in the anti-inflammatory process. This study suggested that GL is a potential therapeutic for protecting against acute kidney injury.

Understanding the Role of Titanium Metal-Organic Framework Nanosheets in Modulating Anode Chemistry for Aqueous Zinc-Ion Batteries.

Aqueous zinc-ion batteries have attracted a continually increasing level of interest for large-scale energy storage because they are highly safe and have high energy density and abundant reserves. However, Zn anodes face significant challenges such as severe dendrite growth and hydrogen evolution reaction (HER). We here propose an efficient Zn2+ sieve strategy for modulating the anode chemistry using two-dimensional NH2-MIL-125 (Ti) metal-organic framework (MOF) nanosheets. Theoretical investigations reveal the crucial role of the Ti MOF in regulating Zn2+ solvation structures for fast diffusion and uniform deposition and decreasing HER reactivity. The structure of the nanosheets enables abundant accessible desolvation sites and shortened ionic pathways. As a result, the MOF nanosheet-protected Zn anode exhibited greatly improved cycling stability in both symmetric cells and full cells. Operando optical monitoring and postmortem analysis revealed effective suppression of dendrite growth and HER by Ti MOF nanosheets. This anti-HER MOF-enabled Zn2+ sieve strategy provides a viable Zn anode and provides new insights for optimizing aqueous batteries.

Effects of rosmarinic acid on immune response and intestinal microbiota in ovalbumin-induced intestinal allergy mice.

BACKGROUND: Rosmarinic acid (RA) is an active polyphenol that is widely found in various edible herbs. This study explored the potential anti-allergic activities and the underlying mechanisms of RA in ovalbumin (OVA)-induced intestinal allergic mice. RESULTS: Forty female BALB/c mice were randomly divided into five groups: control group, model group (OVA sensitized/challenged), RA-Low group (OVA sensitized/challenged, 30 mg kg-1 RA intervention), RA-Middle group (OVA sensitized/challenged, 90 mg kg-1 RA intervention) and RA-High group (OVA sensitized/challenged, 270 mg kg-1 RA intervention). RA effectively attenuated allergic reactions, including alleviating allergic symptoms and regulating the hypothermia of mice in the model group. Moreover, the anaphylactic mediator (OVA-specific IgE, histamine and mMCP-1) levels of OVA allergic mice were markedly decreased after RA intervention. Quantitative polymerase chain reaction analysis showed that RA significantly inhibited Th2 cytokine expression, while Th1 and Treg cytokines were markedly increased. 16S rRNA gene sequence analysis indicated that RA effectively regulated the richness and diversity of the intestinal microbiota in OVA allergic mice. At the phylum level, the relative abundance of Bacteroidetes and Firmicutes and the Firmicutes/Bacteroidetes ratio were altered by RA intervention. At the genus level, RA was found to regulate the disturbances in the relative abundance of Muribaculaceae, Lactobacillus and Prevotella. CONCLUSION: RA exhibited potential anti-allergic activity in OVA allergic mice by regulating hypersensitive immune responses and the intestinal microbiota structure. These results provide important evidence that RA can be developed into a novel functional food-derived ingredient against food allergy. © 2023 Society of Chemical Industry.