Construction of Inverse-Opal ZnIn2S4 with Well-Defined 3D Porous Structure for Enhancing Photocatalytic H2 Production.

The conversion of solar energy into hydrogen using photocatalysts is a pivotal solution to the ongoing energy and environmental challenges. In this study, inverse opal (IO) ZnIn2S4 (ZIS) with varying pore sizes is synthesized for the first time via a template method. The experimental results indicate that the constructed inverse opal ZnIn2S4 has a unique photonic bandgap, and its slow photon effect can enhance the interaction between light and matter, thereby improving the efficiency of light utilization. ZnIn2S4 with voids of 200 nm (ZIS-200) achieved the highest hydrogen production rate of 14.32 µ mol h-1. The normalized rate with a specific surface area is five times higher than that of the broken structures (B-ZIS), as the red edge of ZIS-200 is coupled with the intrinsic absorption edge of the ZIS. This study not only developed an approach for constructing inverse opal multi-metallic sulfides, but also provides a new strategy for enriching efficient ZnIn2S4-based photocatalysts for hydrogen evolution from water.

Exploring the immune-inflammatory mechanism of Maxing Shigan Decoction in treating influenza virus A-induced pneumonia based on an integrated strategy of single-cell transcriptomics and systems biology.

BACKGROUND: Influenza is an acute respiratory infection caused by influenza virus. Maxing Shigan Decoction (MXSGD) is a commonly used traditional Chinese medicine prescription for the prevention and treatment of influenza. However, its mechanism remains unclear. METHOD: The mice model of influenza A virus pneumonia was established by nasal inoculation. After 3 days of intervention, the lung index was calculated, and the pathological changes of lung tissue were detected by HE staining. Firstly, transcriptomics technology was used to analyze the differential genes and important pathways in mouse lung tissue regulated by MXSGD. Then, real-time fluorescent quantitative PCR (RT-PCR) was used to verify the changes in mRNA expression in lung tissues. Finally, intestinal microbiome and intestinal metabolomics were performed to explore the effect of MXSGD on gut microbiota. RESULTS: The lung inflammatory cell infiltration in the MXSGD group was significantly reduced (p < 0.05). The results of bioinformatics analysis for transcriptomics results show that these genes are mainly involved in inflammatory factors and inflammation-related signal pathways mediated inflammation biological modules, etc. Intestinal microbiome showed that the intestinal flora Actinobacteriota level and Desulfobacterota level increased in MXSGD group, while Planctomycetota in MXSGD group decreased. Metabolites were mainly involved in primary bile acid biosynthesis, thiamine metabolism, etc. This suggests that MXSGD has a microbial-gut-lung axis regulation effect on mice with influenza A virus pneumonia. CONCLUSION: MXSGD may play an anti-inflammatory and immunoregulatory role by regulating intestinal microbiome and intestinal metabolic small molecules, and ultimately play a role in the treatment of influenza A virus pneumonia.

Heat stress induces IL-1ß and IL-18 overproduction via ROS-activated NLRP3 inflammasome: implication in neuroinflammation in mice with heat stroke.

Heat stroke induced cerebral damage via neuroinflammation. This study aimed to approach whether heat stress would promote NOD-like receptor protein 3 (NLRP3) inflammasome via reactive oxygen species (ROS). The mice were randomly divided into the sham group, the heat stress group, and the heat stress + TEMPOL (ROS scavenger) group. And the NLRP3 -/- mice were applied and divided into the NLRP3 -/-  + sham group and the NLRP3 -/-  + heat stress group. Furthermore, the BV2 cells were divided into four groups following the intervention measures: the heat stress + TEMPOL group, the heat stress + Z-VAD-FMK (caspase-1 inhibitor) group, the heat stress group, and the control group. ROS levels were examined. The expression levels of NLRP3, caspase-1, IL-1ß, and IL-18 were detected by western blotting and double immunofluorescence. We found that heat stress attack induced excessive ROS in microglia and subsequently activated NLRP3 inflammasome in both mice and BV2 cells. When ROS scavenged, the expression level of NLRP3 was downregulated. Furthermore, with NLRP3 inflammasome activation, the expression levels of caspase-1, IL-1ß, and IL-18 were increased. In NLRP3 -/- mice, however, the caspase-1, IL-1ß, and IL-18 were significantly declined. Further experiments showed that pretreatment of caspase-1 inhibitor decreased the expression levels of IL-1ß and IL-18. These results suggest that heat stress attack caused neuroinflammation via excessive ROS activating the NLRP3 inflammasome in microglia cells.

CNP Ameliorates Macrophage Inflammatory Response and Atherosclerosis.

BACKGROUND: CNP (C-type natriuretic peptide), an endogenous short peptide in the natriuretic peptide family, has emerged as an important regulator to govern vascular homeostasis. However, its role in the development of atherosclerosis remains unclear. This study aimed to investigate the impact of CNP on the progression of atherosclerotic plaques and elucidate its underlying mechanisms. METHODS: Plasma CNP levels were measured in patients with acute coronary syndrome. The potential atheroprotective role of CNP was evaluated in apolipoprotein E-deficient (ApoE-/-) mice through CNP supplementation via osmotic pumps, genetic overexpression, or LCZ696 administration. Various functional experiments involving CNP treatment were performed on primary macrophages derived from wild-type and CD36 (cluster of differentiation 36) knockout mice. Proteomics and multiple biochemical analyses were conducted to unravel the underlying mechanism. RESULTS: We observed a negative correlation between plasma CNP concentration and the burden of coronary atherosclerosis in patients. In early atherosclerotic plaques, CNP predominantly accumulated in macrophages but significantly decreased in advanced plaques. Supplementing CNP via osmotic pumps or genetic overexpression ameliorated atherosclerotic plaque formation and enhanced plaque stability in ApoE-/- mice. CNP promoted an anti-inflammatory macrophage phenotype and efferocytosis and reduced foam cell formation and necroptosis. Mechanistically, we found that CNP could accelerate HIF-1α (hypoxia-inducible factor 1-alpha) degradation in macrophages by enhancing the interaction between PHD (prolyl hydroxylase domain-containing protein) 2 and HIF-1α. Furthermore, we observed that CD36 bound to CNP and mediated its endocytosis in macrophages. Moreover, we demonstrated that the administration of LCZ696, an orally bioavailable drug recently approved for treating chronic heart failure with reduced ejection fraction, could amplify the bioactivity of CNP and ameliorate atherosclerotic plaque formation. CONCLUSIONS: Our study reveals that CNP enhanced plaque stability and alleviated macrophage inflammatory responses by promoting HIF-1α degradation, suggesting a novel atheroprotective role of CNP. Enhancing CNP bioactivity may offer a novel pharmacological strategy for treating related diseases.

Local delivery of stem cell spheroids with protein/polyphenol self-assembling armor to improve myocardial infarction treatment via immunoprotection and immunoregulation.

Stem cell therapies have shown great potential for treating myocardial infarction (MI) but are limited by low cell survival and compromised functionality due to the harsh microenvironment at the disease site. Here, we presented a Mesenchymal stem cell (MSC) spheroid-based strategy for MI treatment by introducing a protein/polyphenol self-assembling armor coating on the surface of cell spheroids, which showed significantly enhanced therapeutic efficacy by actively manipulating the hostile pathological MI microenvironment and enabling versatile functionality, including protecting the donor cells from host immune clearance, remodeling the ROS microenvironment and stimulating MSC's pro-healing paracrine secretion. The underlying mechanism was elucidated, wherein the armor protected to prolong MSCs residence at MI site, and triggered paracrine stimulation of MSCs towards immunoregulation and angiogenesis through inducing hypoxia to provoke glycolysis in stem cells. Furthermore, local delivery of coated MSC spheroids in MI rat significantly alleviated local inflammation and subsequent fibrosis via mediation macrophage polarization towards pro-healing M2 phenotype and improved cardiac function. In general, this study provided critical insight into the enhanced therapeutic efficacy of stem cell spheroids coated with a multifunctional armor. It potentially opens up a new avenue for designing immunomodulatory treatment for MI via stem cell therapy empowered by functional biomaterials.

Classification of cognitive ability of healthy older individuals using resting-state functional connectivity magnetic resonance imaging and an extreme learning machine.

BACKGROUND: Quantitative determination of the correlation between cognitive ability and functional biomarkers in the older brain is essential. To identify biomarkers associated with cognitive performance in the older, this study combined an index model specific for resting-state functional connectivity (FC) with a supervised machine learning method. METHODS: Performance scores on conventional cognitive test scores and resting-state functional MRI data were obtained for 98 healthy older individuals and 90 healthy youth from two public databases. Based on the test scores, the older cohort was categorized into two groups: excellent and poor. A resting-state FC scores model (rs-FCSM) was constructed for each older individual to determine the relative differences in FC among brain regions compared with that in the youth cohort. Brain areas sensitive to test scores could then be identified using this model. To suggest the effectiveness of constructed model, the scores of these brain areas were used as feature matrix inputs for training an extreme learning machine. classification accuracy (CA) was then tested in separate groups and validated by N-fold cross-validation. RESULTS: This learning study could effectively classify the cognitive status of healthy older individuals according to the model scores of frontal lobe, temporal lobe, and parietal lobe with a mean accuracy of 86.67%, which is higher than that achieved using conventional correlation analysis. CONCLUSION: This classification study of the rs-FCSM may facilitate early detection of age-related cognitive decline as well as help reveal the underlying pathological mechanisms.

Template-Free Synthesis of Boron-Doped Graphitic Carbon Nitride Porous Nanotubes for Enhanced Photocatalytic Hydrogen Evolution.

The photocatalytic activity of g-C3N4 can be enhanced by improving photoinduced carrier separation and exposing sufficient reactive sites. In this study, we synthesized B-doped porous tubular g-C3N4 (BCNT) using a H3BO3-assisted supramolecular self-template method, wherein H3BO3 helped in B-doping, building a porous structure, and maintaining one-dimensional nanotubes. The tubular structure had an ultrathin tube wall and large aspect ratio, which are conducive to the directional transmission and separation of photogenerated carriers; moreover, the abundant pore structure of the tube wall could fully expose the reactive sites. The introduction of B and the cyano group modulated the bandgap of g-C3N4 and elevated the position of the conduction band, thus enhancing the photoreduction ability and effectively improving the hydrogen evolution performance. Consequently, the hydrogen evolution of BCNT-2 (220.8, 53.2 µmol·h-1) was 1.82 and 1.54 times that of ultrathin g-C3N4 nanosheets (CNN, 121.3, 34.6 µmol·h-1) under simulated sunlight and LED lamp irradiation, respectively. Thus, this work provides in-depth insights into the rational design of one-dimensional g-C3N4 nanotubes with high hydrogen evolution activity under visible irradiation.

Efficacy, tolerability, and safety of the oral phosphate binder VS-505 (AP301).

BACKGROUND: VS-505 (AP301), an acacia and ferric oxyhydroxide polymer, is a novel fiber-iron-based phosphate binder. This two-part phase 2 study evaluated the tolerability, safety, and efficacy of oral VS-505 administered three times daily with meals in treating hyperphosphatemia in chronic kidney disease (CKD) patients receiving maintenance hemodialysis (MHD). METHODS: In Part 1, patients received dose-escalated treatment with VS-505 2.25, 4.50, and 9.00 g/day for 2 weeks each, guided by serum phosphorus levels. In Part 2, patients received randomized, open-label, fixed-dosage treatment with VS-505 (1.50, 2.25, 4.50, or 6.75 g/day) or sevelamer carbonate 4.80 g/day for 6 weeks. The primary efficacy endpoint was the change in serum phosphorus. RESULTS: The study enrolled 158 patients (Part 1: 25; Part 2: 133), with 130 exposed to VS-505 in total. VS-505 was well tolerated. The most common adverse events were gastrointestinal disorders, mainly feces discolored (56%) and diarrhea (15%; generally during weeks 1‒2 of treatment). Most gastrointestinal disorders resolved without intervention, and none were serious. In Part 1, serum phosphorus significantly improved (mean change -2.0 mg/dL; 95% confidence interval -2.7, -1.4) after VS-505 dose escalation. In Part 2, serum phosphorus significantly and dose-dependently improved in all VS-505 arms, with clinically meaningful reductions with VS-505 4.50 and 6.75 g/day, and sevelamer carbonate 4.80 g/day (mean change -1.6 (-2.2, -1.0), -1.8 (-2.4, -1.2), and -1.4 (-2.2, -0.5) mg/dL, respectively). In both Parts, serum phosphorus reductions occurred within 1 week of VS-505 initiation, returning to baseline within 2 weeks of VS-505 discontinuation. CONCLUSION: VS-505, a novel phosphate binder, was well tolerated with a manageable safety profile, and effectively and dose-dependently reduced serum phosphorus in CKD patients with hyperphosphatemia receiving MHD. Clinical Trial registration number: NCT04551300.

Investigating the Cytosolic Delivery of Proteins by Lipid Nanoparticles Using the Chloroalkane Penetration Assay.

Protein therapeutics are an expanding area for research and drug development, and lipid nanoparticles (LNPs) are the most prominent nonviral vehicles for protein delivery. The most common methods for assessing protein delivery by LNPs include assays that measure the total amount of protein taken up by cells and assays that measure the phenotypic changes associated with protein delivery. However, assays for total cellular uptake include large amounts of protein that are trapped in endosomes or are otherwise nonfunctional. Assays for functional delivery are important, but the readouts are indirect and amplified, limiting the quantitative interpretation. Here, we apply an assay for cytosolic delivery, the chloroalkane penetration assay (CAPA), to measure the cytosolic delivery of a (-30) green fluorescent protein (GFP) fused to Cre recombinase (Cre(-30)GFP) fusion protein by LNPs. We compare these data to the data from total cellular uptake and functional delivery assays to provide a richer analysis of uptake and endosomal escape for LNP-mediated protein delivery. We also use CAPA for a screen of a small library of lipidoids, identifying those with a promising ability to deliver Cre(-30)GFP to the cytosol of mammalian cells. With careful controls and optimized conditions, we expect that CAPA will be a useful tool for investigating the rate, efficiency, and mechanisms of LNP-mediated delivery of therapeutic proteins.

Construction and Validation of a Nomogram Model to Predict the Severity of Mycoplasma pneumoniae Pneumonia in Children.

Background: This study aimed to develop a nomogram model for early prediction of the severe Mycoplasma pneumoniae pneumonia (MPP) in children. Methods: A retrospective analysis was conducted on children with MPP, classifying them into severe and general MPP groups. The risk factors for severe MPP were identified using Logistic Stepwise Regression Analysis, followed by Multivariate Regression Analysis to construct the nomogram model. The model's discrimination was evaluated using a receiver operating characteristic curve, its calibration with a calibration curve, and the results were visualized using the Hosmer-Lemeshow goodness-of-fit test. Results: Univariate analysis revealed that age, duration of fever, length of hospital-stay, decreased sounds of breathing, respiratory rate, hypokalemia, and incidence of co-infection were significantly different between severe and general MPP. Significant differences (p < 0.05) were also observed in C-reactive protein, procalcitonin, peripheral blood lymphocyte count, neutrophil-to-lymphocyte ratio, ferritin, lactate dehydrogenase, alanine aminotransferase, interleukin-6, immunoglobulin A, and CD4+ T cells between the two groups. Logistic Stepwise Regression Analysis showed that age, decreased sounds of breathing, respiratory rate, duration of fever (OR = 1.131; 95% CI: 1.060-1.207), length of hospital-stay (OR = 1.415; 95% CI: 1.287-1.555), incidence of co-infection (OR = 1.480; 95% CI: 1.001-2.189), ferritin level (OR = 1.003; 95% CI: 1.001-1.006), and LDH level (OR = 1.003; 95% CI: 1.001-1.005) were identified as risk factors for the development of severe MPP (p < 0.05 in all). The above factors were applied in constructing a nomogram model that was subsequently tested with 0.862 of the area under the ROC curve. Conclusion: Age, decreased sound of breathing, respiratory rate, duration of fever, length of hospital-stay, co-infection with other pathogen(s), ferritin level, and LDH level were the significant contributors for the establishment of a nomogram model to predict the severity of MPP in children.

Adaptive Segmentation Algorithm for Subtle Defect Images on the Surface of Magnetic Ring Using 2D-Gabor Filter Bank.

In order to realize the unsupervised segmentation of subtle defect images on the surface of small magnetic rings and improve the segmentation accuracy and computational efficiency, here, an adaptive threshold segmentation method is proposed based on the improved multi-scale and multi-directional 2D-Gabor filter bank. Firstly, the improved multi-scale and multi-directional 2D-Gabor filter bank was used to filter and reduce the noise on the defect image, suppress the noise pollution inside the target area and the background area, and enhance the difference between the magnetic ring defect and the background. Secondly, this study analyzed the grayscale statistical characteristics of the processed image; the segmentation threshold was constructed according to the gray statistical law of the image; and the adaptive segmentation of subtle defect images on the surface of small magnetic rings was realized. Finally, a classifier based on a BP neural network is designed to classify the scar images and crack images determined by different threshold segmentation methods. The classification accuracies of the iterative method, the OTSU method, the maximum entropy method, and the adaptive threshold segmentation method are, respectively, 85%, 87.5%, 95%, and 97.5%. The adaptive threshold segmentation method proposed in this paper has the highest classification accuracy. Through verification and comparison, the proposed algorithm can segment defects quickly and accurately and suppress noise interference effectively. It is better than other traditional image threshold segmentation methods, validated by both segmentation accuracy and computational efficiency. At the same time, the real-time performance of our algorithm was performed on the advanced SEED-DVS8168 platform.

Adaptive Laboratory Evolution of Probiotics toward Oxidative Stress Using a Microfluidic-Based Platform.

Adaptive laboratory evolution (ALE) can be used to make bacteria less susceptible to oxidative stress. An alternative to large batch scale ALE cultures is to use microfluidic platforms, which are often more economical and more efficient. Microfluidic ALE platforms have shown promise, but many have suffered from subpar cell passaging mechanisms and poor spatial definition. A new approach is presented using a microfluidic Evolution on a Chip (EVoc) design which progressively drives microbial cells from areas of lower H2 O2 concentration to areas of higher concentration. Prolonged exposure, up to 72 h, revealed the survival of adaptive strains of Lacticaseibacillus rhamnosus GG, a beneficial probiotic often included in food products. After performing ALE on this microfluidic platform, the bacteria persisted under high H2 O2 concentrations in repeated trials. After two progressive exposures, the ability of L. rhamnosus to grow in the presence of H2 O2 increased from 1 mm H2 O2 after a lag time of 31 h to 1 mm after 21 h, 2 mm after 28 h, and 3 mm after 42 h. The adaptive strains have different morphology, and gene expression compared to wild type, and genome sequencing revealed a potentially meaningful single nucleotide mutation in the protein omega-amidase.

The microparticulate inks for bioprinting applications.

Three-dimensional (3D) bioprinting has emerged as a groundbreaking technology for fabricating intricate and functional tissue constructs. Central to this technology are the bioinks, which provide structural support and mimic the extracellular environment, which is crucial for cellular executive function. This review summarizes the latest developments in microparticulate inks for 3D bioprinting and presents their inherent challenges. We categorize micro-particulate materials, including polymeric microparticles, tissue-derived microparticles, and bioactive inorganic microparticles, and introduce the microparticle ink formulations, including granular microparticles inks consisting of densely packed microparticles and composite microparticle inks comprising microparticles and interstitial matrix. The formulations of these microparticle inks are also delved into highlighting their capabilities as modular entities in 3D bioprinting. Finally, existing challenges and prospective research trajectories for advancing the design of microparticle inks for bioprinting are discussed.

Rare loss-of-function variants in FLNB cause non-syndromic orofacial clefts.

Orofacial clefts (OFCs) are the most common congenital craniofacial disorders, of which the etiology is closely related to rare coding variants. Filamin B (FLNB) is an actin-binding protein implicated in bone formation. FLNB mutations have been identified in several types of syndromic OFCs and previous studies suggest a role of FLNB in the onset of non-syndromic OFCs (NSOFCs). Here, we report two rare heterozygous variants (p.P441T and p.G565R) in FLNB in two unrelated hereditary families with NSOFCs. Bioinformatics analysis suggests that both variants may disrupt the function of FLNB. In mammalian cells, p.P441T and p.G565R variants are less potent to induce cell stretches than wild type FLNB, suggesting that they are loss-of-function mutations. Immunohistochemistry analysis demonstrates that FLNB is abundantly expressed during palatal development. Importantly, Flnb-/- embryos display cleft palates and previously defined skeletal defects. Taken together, our findings reveal that FLNB is required for development of palates in mice and FLNB is a bona fide causal gene for NSOFCs in humans.

Hollow Filaments from Coaxial Dry-Jet Wet Spinning of a Cellulose Solution in an Ionic Liquid: Wet-Strength and Water Interactions.

Hollow tubing and tubular filaments are highly relevant to membrane technologies, vascular tissue engineering, and others. In this context, we introduce hollow filaments (HF) produced through coaxial dry-jet wet spinning of cellulose dissolved in an ionic liquid ([emim][OAc]). The HF, developed upon regeneration in water (23 °C), displays superior mechanical performance (168 MPa stiffness and 60% stretchability) compared to biobased counterparts, such as those based on collagen. The results are rationalized by the effects of crystallinity, polymer orientation, and other factors associated with rheology, thermal stability, and dynamic vapor sorption. The tensile strength and strain of the HF (dry and wet) are enhanced by drying and wetting cycles (water vapor sorption and desorption experiments). Overall, we unveil the role of water molecules in the wet performance of HF produced by cellulose regeneration from [emim][OAc], which offers a basis for selecting suitable applications.

The role of mitochondrial dynamics in disease.

Mitochondria are multifaceted and dynamic organelles regulating various important cellular processes from signal transduction to determining cell fate. As dynamic properties of mitochondria, fusion and fission accompanied with mitophagy, undergo constant changes in number and morphology to sustain mitochondrial homeostasis in response to cell context changes. Thus, the dysregulation of mitochondrial dynamics and mitophagy is unsurprisingly related with various diseases, but the unclear underlying mechanism hinders their clinical application. In this review, we summarize the recent developments in the molecular mechanism of mitochondrial dynamics and mitophagy, particularly the different roles of key components in mitochondrial dynamics in different context. We also summarize the roles of mitochondrial dynamics and target treatment in diseases related to the cardiovascular system, nervous system, respiratory system, and tumor cell metabolism demanding high-energy. In these diseases, it is common that excessive mitochondrial fission is dominant and accompanied by impaired fusion and mitophagy. But there have been many conflicting findings about them recently, which are specifically highlighted in this view. We look forward that these findings will help broaden our understanding of the roles of the mitochondrial dynamics in diseases and will be beneficial to the discovery of novel selective therapeutic targets.

Pegmolesatide for the treatment of anemia in patients undergoing dialysis: a randomized clinical trial.

Background: Pegmolesatide, a synthetic peptide-based erythropoietin (EPO) receptor agonist, is being evaluated as an alternative to epoetin alfa for treating anemia of chronic kidney disease (CKD) in Chinese dialysis patients. There is a critical need for a long-acting, cost-effective erythropoiesis-stimulating agent that does not produce EPO antibodies. Methods: A randomized, open-label, active-comparator, non-inferiority phase three trial was conducted at 43 dialysis centers in China between May 17th, 2019, and March 28th, 2022. Eligible patients aged 18-70 years were randomly assigned (2:1) to receive pegmolesatide once every four weeks or epoetin alfa one to three times per week, with doses adjusted to maintain a hemoglobin level between 10.0 and 12.0 g/dL. The primary efficacy endpoint was the mean change in hemoglobin level from baseline to the efficacy evaluation period in the per-protocol set (PPS) population. Non-inferiority of pegmolesatide to epoetin alfa was established if the lower limit of the two-sided 95% confidence interval for the between-group difference was ≥ -1.0 g/dL. Safety assessment included adverse events and potential anaphylaxis reactions. This trial is registered at ClinicalTrials.gov, NCT03902691. Findings: Three hundreds and seventy-two patients were randomly assigned to the pegmolesatide group (248 patients) or the epoetin alfa group (124 patients). A total of 347 patients (233 in the pegmolesatide group and 114 in the epoetin alfa group) were included in the PPS population. In the PPS, the mean change (standard deviation, SD) in hemoglobin level from baseline to the efficacy evaluation period was 0.07 (0.92) g/dL in the pegmolesatide group and -0.22 (0.97) g/dL in the epoetin alfa group. The between-group difference was 0.29 g/dL (95% confidence interval: 0.11-0.47), verifying non-inferiority of pegmolesatide to epoetin alfa. Adverse events occurred in 231 (94%) participants in the pegmolesatide group and in 110 (89%) in the epoetin alfa group. Hypertension was the most common treatment-related adverse event. No fatal cases of anaphylaxis or hypotension were reported. Interpretation: Monthly subcutaneously injection of pegmolesatide was as effective and safe as conventional epoetin alfa administrated one to three times a week in treating anemia in Chinese dialysis patients. Funding: The study was supported by Hansoh Medical Development Group.

Site-specific nanoswitch circumventing immune resistance via activating TLR and inhibiting PD-L1/PD-1 axis.

Immunotherapy has fundamentally altered cancer treatment; however, its effectiveness is clinically hampered by insufficient intratumoral T lymphocyte infiltration and failed T lymphocyte priming. Additionally, inducing cancer-specific immune responses while sparing normal cells remains challenging. Herein, we developed a redox-activatable polymeric nanoswitch (c-N@IM/JQ) that remained 'off' status in circulation but rapidly switched 'on' after entering the tumor. Toll-like receptor (TLR) 7/8 agonist (imidazoquinoline, IMQ) and bromodomain and extraterminal inhibitor (JQ1) are locked in c-N@IM/JQ with a redox-cleavable linker (switch off). Upon systemic administration, c-N@IM/JQ with c-RGD peptide modification preferentially accumulated at tumor sites and responded to the high glutathione levels to release native IMQ for fully mobilizing T lymphocyte army, and JQ1 for removing the programmed death ligand (PD-L)-1 protection on tumor cells (switch on). These strengthened T lymphocyte armies are easily accessible to these de-protected tumor cells, revitalizing the immune response against tumors.

Combination therapy with budesonide and acetylcysteine alleviates LPS-induced acute lung injury via the miR-381/NLRP3 molecular axis.

BACKGROUND: Acute lung injury (ALI) usually has a high morbidity and mortality rate, but the current treatment is relatively scarce. Both budesonide (Bud) and N-acetylcysteine (NAC) exhibit protective effects in ALI, so we further investigated whether they have a synergistic effect on ALI when used together. METHODS: Establishment of a rat model of ALI with Lipopolysaccharide (LPS). Bud and NAC were administered by nebulized inhalation alone or in combination. Subsequently, HE staining was performed to observe the pathological changes in lungs of rat. Evans blue staining was implemented to assess alveolar permeability, and the pulmonary edema was assessed by measuring the ratio of wet to dry weight of the lung. Moreover, a TUNEL kit was served to test apoptosis in lung tissues. Western blot and immunohistochemistry were analyzed for expression of scorch-related proteins and NLRP3 in lung tissue, respectively. ELISA was implemented to detect inflammatory factor levels in BALF. and RT-qPCR was utilized to assess the expression level of miR-381. After stable transfection of miR-381 inhibitor or OE-NLRP3 in BEAS-2B treated with LPS, Bud and NAC, miR-381 expression was assessed by RT-qPCR, scorch death-related protein expression was measured by western blot, cell proliferation/viability was assayed by CCK-8, apoptosis was measured by flow cytometry, and ELISA was implemented to assess inflammatory factor levels. Furthermore, the Dual-luciferase assay was used to verify the targeting relationship. RESULTS: Bud and NAC treatment alone or in combination with nebulized inhalation attenuated the increased alveolar permeability, pulmonary edema, inflammatory response and scorching in LPS-induced ALI rats, and combined treatment with Bud and NAC was the most effective. In addition, combined treatment with Bud and NAC upregulated miR-381 expression and inhibited NLRP3 expression in cellular models and LPS-induced ALI rats. Transfection of the miR-381 inhibitor and OE-NLRP3 partially reversed the protective effects of Bud and NAC combination treatment on BEAS-2B cell proliferation inhibition, apoptosis, focal death and the inflammatory response. CONCLUSION: Combined Bud and NAC nebulization therapy alleviates LPS-induced ALI by modulating the miR-381/NLRP3 molecular axis.

Outcome benefits of bevacizumab biosimilar (SIBP04) combined with carboplatin and paclitaxel in advanced non-squamous non-small-cell lung cancer patients with EGFR mutation: subgroup analysis of a prospective, randomized phase III clinical trial.

PURPOSE: SIBP04 is a bevacizumab biosimilar, and bevacizumab combined with carboplatin and paclitaxel in advanced non-squamous non-small-cell lung cancer (nsqNSCLC) has been recommended as the first-line treatment choice. However, the efforts of bevacizumab combined with carboplatin and paclitaxel for nsqNSCLC patients with EGFR mutation remained unclear. Here we report an EGFR mutation subgroup analysis of a prospective, randomized phase III clinical trial (NCT05318443). METHODS: In this randomized, double-blind, multi-center, parallel controlled, phase III clinical trial, locally advanced, metastatic NSCLC patients were enrolled, and EGFR expression was examined and considered as a stratification factor. All patients received 4 to 6 cycles of paclitaxel and carboplatin plus SIBP04 or bevacizumab 15 mg/kg intravenously followed by SIBP04 15 mg/kg maintenance until intolerable toxicity, disease progression or death. Patients with EGFR mutation and wild-type were assessed for progression-free survival (PFS) and overall survival (OS). RESULTS: EGFR expression was examined in 398 NSCLC patients (142 with EGFR mutation, 256 with EGFR wild type). PFS in EGFR mutation patients was significantly longer than EGFR wild-type patients (10.91 vs. 7.82 months; HR = 0.692, 95% CI 0.519-0.921, P = 0.011). The median OS in patients with EGFR mutation was not reached while that of EGFR wild-type group was 17.54 months (HR = 0.398, 95% CI 0.275-0.575, P < 0.001). However, there were no significant differences in objective response rate (61.97% vs. 55.86%, P = 0.237) or disease control rate (90.14% vs. 89.84%, P = 0.925). CONCLUSION: Bevacizumab combined with chemotherapy significantly prolonged the PFS and OS of advanced nsqNSCLC patients with EGFR mutation.