Diastereoselective dearomatization of indoles via photocatalytic hydroboration on hydramine-functionalized carbon nitride.

A protocol for trans-hydroboration of indole derivatives using heterogeneous photocatalysis with NHC-borane has been developed, addressing a persistent challenge in organic synthesis. The protocol, leveraging high crystalline vacancy-engineered polymeric carbon nitride as a catalyst, enables diastereoselective synthesis, expanding substrate scope and complementing existing methods. The approach emphasizes eco-friendliness, cost-effectiveness, and scalability, making it suitable for industrial applications, particularly in renewable energy contexts. The catalyst's superior performance, attributed to its rich carbon-vacancies and well-ordered structure, surpasses more expensive homogeneous alternatives, enhancing viability for large-scale use. This innovation holds promise for synthesizing bioactive compounds and materials relevant to medicinal chemistry and beyond.

Explosive Leidenfrost-Droplet-Mediated Synthesis of Monodispersed High-Entropy-Alloy Nanoparticles for Electrocatalysis.

High-entropy-alloy nanoparticles (HEA NPs) exhibit promising potential in various catalytic applications, yet a robust synthesis strategy has been elusive. Here, we introduce a straightforward and universal method, involving the microexplosion of Leidenfrost droplets housing carbon black and metal salt precursors, to fabricate PtRhPdIrRu HEA NPs with a size of ∼2.3 nm. The accumulated pressure within the Leidenfrost droplet triggers an intense explosion within milliseconds, propelling the carbon support and metal salt rapidly into the hot solvent through explosive force. The exceptionally quick temperature rise ensures the coreduction of metal salts, and the dilute local concentration of metal ions limits the final size of the HEA NPs. Additionally, the explosion process can be fine-tuned by selecting different solvents, enabling the harvesting of diverse HEA NPs with superior electrocatalytic activity for alcohol electrooxidation and hydrogen electrocatalysis compared to commercial Pt (Pd) unitary catalysts.

Fatty acids metabolism in ozone-induced pulmonary inflammatory injury: Evidence, mechanism and prevention.

Ozone (O3) is a major air pollutant that directly threatens the respiratory system, lung fatty acid metabolism disorder is an important molecular event in pulmonary inflammatory diseases. Liver kinase B1 (LKB1) and nucleotide-binding domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome not only regulate inflammation, but also have close relationship with fatty acid metabolism. However, the role and mechanism of LKB1 and NLRP3 inflammasome in lung fatty acid metabolism, which may contribute to ozone-induced lung inflammation, remain unclear, and effective strategy for preventing O3-induced pulmonary inflammatory injury is lacking. To explore these, mice were exposed to 1.00 ppm O3 (3 h/d, 5 days), and pulmonary inflammation was determined by airway hyperresponsiveness, histopathological examination, total cells and cytokines in bronchoalveolar lavage fluid (BALF). Targeted fatty acids metabolomics was used to detect medium and long fatty acid in lung tissue. Then, using LKB1-overexpressing adenovirus and NLRP3 knockout (NLRP3-/-) mice to explore the mechanism of O3-induced lung fatty acid metabolism disorder. Results demonstrated that O3 exposure caused pulmonary inflammatory injury and lung medium and long chain fatty acids metabolism disorder, especially decreased dihomo-γ-linolenic acid (DGLA). Meanwhile, LKB1 expression was decreased, and NLRP3 inflammasome was activated in lung of mice after O3 exposure. Additionally, LKB1 overexpression alleviated O3-induced lung inflammation and inhibited the activation of NLRP3 inflammasome. And we found that pulmonary fatty acid metabolism disorder was ameliorated of NLRP3 -/- mice compared with those in wide type mice after O3 exposure. Furthermore, administrating DGLA intratracheally prior to O3 exposure significantly attenuated O3-induced pulmonary inflammatory injury. Taken together, these findings suggest that fatty acids metabolism disorder is involved in O3-induced pulmonary inflammation, which is regulated by LKB1-mediated NLRP3 pathway, DGLA supplement could be a useful preventive strategy to ameliorate ozone-associated lung inflammatory injury.

Plasma-activated water improves the accessibility of chitinase to chitin by decreasing molecular weight and breaking crystal structure.

Chitooligosaccharides, the hydrolysis products of chitin, have superior biological activities and application value to those of chitin itself; however, the ordered and highly crystalline structure of chitin renders its degradation by chitinase difficult. Herein, the effects of plasma-activated water (PAW) pre-treatment on the physicochemical properties, crystal structure, and enzymatic hydrolysis of chitin were investigated. The hydrolysis of PAW-pre-treated chitin (PAW activation time of 5 min) using chitinase from Vibrio harveyi (VhChit2) yielded 71 % more reducing sugar, compared with that from untreated chitin, with the degree of chitin hydrolysis increasing from 13 % without pre-treatment to 23 % post-treatment. Moreover, the amount of VhChit2 adsorbed by chitin increased from 41.7 to 58.2 mg/g. Fourier transform infrared spectrometry revealed that PAW could break the ß-1,4-glycosidic bonds of chitin (but had no effects on the hydrogen and amido bonds), thereby decreasing the molecular weight and crystallinity of the polysaccharide, which caused its structural damage and enhanced its enzymatic hydrolysis by chitinase. Consequently, PAW pre-treatment can be considered a simple, effective, and environmentally-friendly method for the biotransformation of chitin as its easier hydrolysis yields high-value products.

USP22 as a key regulator of glycolysis pathway in osteosarcoma: insights from bioinformatics and experimental approaches.

Background: Osteosarcoma is the most common primary malignant bone tumor, but its pathogenesis remains unclear. Ubiquitin-specific processing peptidase 22 (USP22) is reported to be highly expressed and associated with tumor malignancy and prognosis in cancers. However, the role and mechanism of USP22 in osteosarcoma is not fully understood. This study aims to investigate the function and potential mechanism of USP22 in osteosarcoma using bioinformatics analysis combined with experimental validation. Methods: We first integrated transcriptomic datasets and clinical information of osteosarcoma from GEO and TCGA databases to assess the expression and prognostic value of USP22 in osteosarcoma. Then, differential expression analysis and weighted gene co-expression network analysis (WGCNA) were conducted to identify USP22-related co-expressed genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore the biological functions and signaling pathways of USP22 co-expressed genes. To validate the accuracy of bioinformatics analyses, we downregulated USP22 expression in osteosarcoma cell line Sao-2 using siRNA and assessed its effect on cell proliferation, migration, invasion, apoptosis, and regulation of key signaling pathways. Results: We found that USP22 was highly expressed in osteosarcoma tissues and correlated with poor prognosis in osteosarcoma patients. USP22 also showed potential as a diagnostic marker for osteosarcoma. In addition, 344 USP22-related co-expressed genes were identified, mainly involved in signaling pathways such as glycolysis, oxidative phosphorylation, spliceosome, thermogenesis, and cell cycle. The in vitro experiments confirmed the accuracy and reliability of bioinformatics analyses. We found that downregulation of USP22 could inhibit Sao-2 cell proliferation, migration, invasion, and induce apoptosis. Furthermore, downregulation of USP22 significantly reduced aerobic glycolysis levels in Sao-2 cells and inhibited the expression of key enzymes and transporters in aerobic glycolysis pathways such as HK2, PKM2, and GLUT1. Conclusions: USP22 plays a critical role in the occurrence, development, and prognosis of osteosarcoma. USP22 could influence Sao-2 cell proliferation, apoptosis, migration, and invasion by regulating the glycolysis pathway, thereby promoting osteosarcoma progression. Therefore, USP22 may be a potential therapeutic target for the treatment of osteosarcoma.

Immune Responses in Discharged COVID-19 Patients With and Without Long COVID Symptoms.

The immune mechanisms of long coronavirus disease 2019 (COVID) are not yet fully understood. We aimed to investigate the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific memory immune responses in discharged COVID-19 patients with and without long COVID symptoms. In this cross-sectional study, we included 1041 hospitalized COVID-19 patients with the original virus strain in Wuhan (China) 12 months after initial infection. We simultaneously conducted a questionnaire survey and collected peripheral blood samples from the participants. Based on the presence or absence of long COVID symptoms during the follow-up period, we divided the patients into 2 groups: a long COVID group comprising 480 individuals and a convalescent group comprising 561 individuals. Both groups underwent virus-specific immunological analyses, including enzyme-linked immunosorbent assay, interferon-γ-enzyme-linked immune absorbent spot, and intracellular cytokine staining. At 12 months after infection, 98.5% (1026/1041) of the patients were found to be seropositive and 93.3% (70/75) had detectable SARS-CoV-2-specific memory T cells. The long COVID group had significantly higher levels of receptor binding domain (RBD)-immunoglobulin G (IgG) levels, presented as OD450 values, than the convalescent controls (0.40 ± 0.22 vs 0.37 ± 0.20; P = .022). The magnitude of SARS-CoV-2-specific T-cell responses did not differ significantly between groups, nor did the secretion function of the memory T cells. We did not observe a significant correlation between SARS-CoV-2-IgG and magnitude of memory T cells. This study revealed that long COVID patients had significantly higher levels of RBD-IgG antibodies when compared with convalescent controls. Nevertheless, we did not observe coordinated SARS-CoV-2-specific cellular immunity. As there may be multiple potential causes of long COVID, it is imperative to avoid adopting a "one-size-fits-all" approach to future treatment modalities.

Layered Double Hydroxide Derivatives for Polyolefin Upcycling.

While Ru-catalyzed hydrogenolysis holds significant promise in converting waste polyolefins into value-added alkane fuels, a major constraint is the high cost of noble metal catalysts. In this work, we propose, for the first time, that Co-based catalysts derived from CoAl-layered double hydroxide (LDH) are alternatives for efficient polyolefin hydrogenolysis. Leveraging the chemical flexibility of the LDH platform, we reveal that metallic Co species serve as highly efficient active sites for polyolefin hydrogenolysis. Furthermore, we introduced Ni into the Co framework to tackle the issue of restricted hydrogenation ability associated with contiguous Co-Co sites. In-situ analysis indicates that the integration of Ni induces electron transfer and facilitates hydrogen spillover. This dual effect synergistically enhances the hydrogenation/desorption of olefin intermediates, resulting in a significant reduction in the yield of low-value CH4 from 27.1 to 12.6%. Through leveraging the unique properties of LDH, we have developed efficient and cost-effective catalysts for the sustainable recycling and valorization of waste polyolefin materials.

Exploring the effective compounds and potential mechanisms of Shengxian Decoction against coronary heart disease by UPLC-Q-TOF/MS and network pharmacology analysis.

As a well-known classical Chinese medicine prescription, Shengxian Decoction (SXD) has been applied for a century to treat cardiovascular diseases, especially coronary heart disease (CHD), but the potentially effective compounds and underlying mechanisms remain unclear. With ultra-performance liquid chromatography-quadrupole-time of flight-mass spectrometry (UPLC-Q-TOF/MS) and network pharmacology analysis, the potential effective compounds of SXD and their pharmacological mechanisms against CHD were identified and revealed. 57 effective compounds with favorable pharmacokinetic characteristics and biological activities were screened through UPLC-Q-TOF/MS analysis, database and literature mining, interacting with 96 CHD-related targets to support potential synergistic therapeutic actions. Systematic analysis of the PPI network and microarray data further revealed six core targets, including TNF, IL-1ß, IL-6, TP53, VEGFA and PTGS2, which were mainly involved in fluid shear stress and atherosclerosis, lipid and atherosclerosis, PI3K-Akt signaling pathway et al. Moreover, the proposed contribution indexes of effective compounds indicated these compounds, including isoferulic acid, quercetin, calycosin, ferulic acid, kaempferol, calycosin 7-O-glycoside, formononetin, astragaloside IV and saikosaponin D, as the core compounds of SXD. The molecular docking results confirmed that those core compound-target pairs exhibited strong binding energy. Furthermore, we validated that SXD significantly alleviated myocardial tissue injury in CHD rats and reversed H/R-induced decreases in H9c2 cell viability by attenuating the production of TNF, IL-6 and IL-1ß, and reducing cardiomyocyte apoptosis via down-regulating the TP53, caspase3 and cytochrome C mRNA expression levels as well as caspase3, caspase9 and cytochrome C protein expression levels according to RT-qPCR and Western blot results. Our findings explained the pharmacological mechanisms underlying the effectiveness of SXD in the treatment of CHD, and laid a foundation for future basic and clinical research of SXD.

Theoretical calculations and experimental verification of carbon dioxide reduction electrocatalyzed by metalloporphyrin.

Metal-functionalized porphyrin-like graphene structures are promising electrocatalysts for carbon dioxide reduction reaction (CO2RR) as their metal centers can modulate activity. Yet, the role of metal center of metalloporphyrins (MTPPs) in CO2 reaction activity is still lacking deep understanding. Here, CO2RR mechanism on MTPPs with five different metal centers (M = Fe, Co, Cu, Zn and Ni) are examined by first-principles calculations. The *COOH formation is the rate determined step on the five MTPP structures, and the CoTPP exhibits the best CO2RR activity while ZnTPP and NiTPP are the worst, which is also verified by our experiment. The CO2RR activity is controlled by adsorption states of intermediates (*CO, *COOH), i.e., chemisorption (e.g., on CoTPP) and physisorption (on ZnTPP and NiTPP) of intermediates will lead to good and poor activity, respectively. The deeper the d-band center of the porphyrin ring complexed metal atom, the weaker bonding of MTPP with CO and COOH. Theoretical calculations and experimental results indicate that MTPPs with Co and Fe centers lead to a reduction in the energy barriers for the two uphill reaction steps in the electrocatalytic CO2 reduction process, thereby enhancing CO2 reduction electrocatalytic activity. Faradaic efficiency of CO is correlated with the reaction energy barrier of the first proton-coupled electron reduction process, displaying a strong linear correlation. This work provides a fundamental understanding of MTPPs used as electrocatalysts for CO2RR.

Simultaneous removal of phenanthrene and Pb using novel PPG-CNTs-nZVI beads.

PPG-CNTs-nZVI bead was synthesized by polyvinyl alcohol, pumice, carbon nanotube, and guar gum-nanoscale zero-valent iron to be applied on simultaneously removal of polycyclic aromatic hydrocarbons (PAHs; phenanthrene) and heavy metals (Pb2+) via adsorption. The individual and simultaneous removal efficiency of phenanthrene and Pb2+ using the PPG-CNTs-nZVI beads was evaluated with a range of initial concentrations of these two pollutants. The kinetics and isotherms of phenanthrene and Pb2+ adsorption by the PPG-CNTs-nZVI beads were also determined. The PPG-CNTs-nZVI beads show reasonably high phenanthrene adsorption capacities (up to 0.16 mg/g), and they absorbed 85% of the phenanthrene (initial concentration 0.5 mg/L) in 30 min. High Pb2+ adsorption capabilities were also demonstrated by the PPG-CNTs-nZVI beads (up to 11.6 mg/g). The adsorption fits the Langmuir model better than the Freundlich model. The adsorption still remained stable with various ionic strength circumstances and a wide pH range (2-5). Additionally, the co-adsorption of phenanthrene and Pb2+ by the PPG-CNTs-nZVI beads resulted in synergistic effects. Particularly, phenanthrene-Pb2+ complex formation via π-cation interactions demonstrated a greater affinity than phenanthrene or Pb2+ alone. The present findings suggest that PPG-CNTs-nZVI beads may be effective sorbents for the simultaneous removal of PAHs and heavy metals from contaminated waters.

Hydrogen Bubbles: Harmonizing Local Hydrogen Transfer for Efficient Plastic Hydro-Depolymerization.

Hydro-depolymerization presents a promising avenue for transforming plastic waste into high-value hydrocarbons, offering significant potential for value-added recycling. However, a major challenge in this method arises from kinetic limitations due to insufficient hydrogen concentration near the active sites, requiring optimal catalytic performance only at higher hydrogen pressures. In this study, we address this hurdle by developing "hydrogen bubble catalysts" featuring Ru nanoparticles within mesoporous SBA-15 channels (Ru/SBA). The distinctive feature of Ru/SBA catalysts lies in their capacity for physical hydrogen storage and chemically reversible hydrogen spillover, ensuring a timely and ample hydrogen supply. Under identical reaction conditions, the catalytic activity of Ru/SBA surpassed that of Ru/SiO2 (no hydrogen storage capacity) by over 4-fold. This substantial enhancement in catalytic performance provides significant opportunities for near atmospheric pressure hydro-depolymerization of plastic waste.

Microglial AT1R Conditional Knockout Ameliorates Hypoperfusive Cognitive Impairment by Reducing Microglial Inflammatory Responses.

Chronic cerebral hypoperfusion (CCH) can cause vascular cognitive impairment and dementia. AT1R, angiotensin II type I receptor, plays a vital role in central nervous system pathologies, but its concrete function in vascular dementia is still unclear. Herein, we investigated the effects of AT1R during CCH by conditional knockout of the microglial AT1R and candesartan treatment. Using the bilateral carotid artery stenosis (BCAS) model, we found that the AT1R is crucial in exacerbating CCH-induced cognitive impairment via regulating microglial activation. The levels of AT1R were increased in the hippocampus and the hippocampal microglia after CCH induction. Microglial AT1R conditional knockout ameliorated cognitive impairment by reducing inflammatory responses and microglial activation, and so did candesartan treatment. However, we observed restoration of cerebral blood flow (CBF) but no significant neuronal loss in the hippocampus at 28 days after BCAS. Finally, we screened three hub genes (Ctss, Fcer1g, Tyrobp) associated with CCH. Our findings indicated that microglial expression of AT1R is critical for regulating neuroinflammation in CCH, and AT1R antagonism may be a feasible and promising method for ameliorating CCH-caused cognitive impairment.

Association of spouse's vision impairment with depressive symptoms and cognitive decline in partner: A nationally representative study in China.

BACKGROUND: Although several previous studies have reported on the relationship between vision impairment and caregiver mental health, mixed results were obtained, and only one study reported the association between spousal vision impairment and partner depression. Therefore, our study aimed to examine the association between spousal vision impairment and the partner's depressive symptoms and cognitive decline. METHODS: This cross-sectional study gathered baseline data from the China Health and Retirement Longitudinal Study (CHARLS) in 2011. A total of 10,956 couples were included in the study. Vision impairment was assessed by respondents' self-reported distance or near vision. Multivariate logistic and linear regression were conducted to evaluate the association between the spouse's vision impairment and the partner's depressive symptoms and cognitive function. RESULTS: The prevalence of partners with depressive symptoms was significantly higher among spouses with vision impairment than among those without (43.3 % vs. 32.5 %; P < 0.001), and cognitive function was significantly lower (spousal vision impairment 14.4 ± 4.5 vs. no spousal vision impairment 15.5 ± 4.6; P < 0.001). After fully adjusting for potential confounders, the partner had greater odds of depressive symptoms for spouses with vision impairment than for those without (odds ratio: 1.525; 95 % confidence interval [CI]: 1.387 to 1.677). Furthermore, spousal vision impairment was negatively associated with the partner's cognitive function (ß = -0.640; 95 % CI: -0.840 to -0.440). Sensitivity analysis was performed, and consistent results were obtained (all P < 0.05). LIMITATIONS: Visual function was assessed by self-reporting. CONCLUSIONS: A spouse's vision impairment is associated with depressive symptoms and cognitive decline in the partner. The findings imply the importance of considering the partner's mental health when managing their spouse's vision impairment.

Sulforaphane inhibits the migration and invasion of BPDE-induced lung adenocarcinoma cells by regulating NLRP12.

This study aims to explore the impact and underlying mechanism of sulforaphane (SFN) intervention on the migration and invasion of lung adenocarcinoma induced by 7, 8-dihydroxy-9, 10-epoxy-benzo (a) pyrene (BPDE). Human lung adenocarcinoma A549 cells were exposed to varying concentrations of BPDE (0.25, 0.50, and 1.00 µM) and subsequently treated with 5 µM SFN. Cell viability was determined using CCK8 assay, while migration and invasion were assessed using Transwell assays. Lentivirus transfection was employed to establish NLRP12 overexpressing A549 cells. ELISA was utilized to quantify IL-33, CXCL12, and CXCL13 levels in the supernatant, while quantitative real-time PCR (qRT-PCR) and Western Blot were used to analyze the expression of NLRP12 and key factors associated with canonical and non-canonical NF-κB pathways. Results indicated an increase in migratory and invasive capabilities, concurrent with heightened expression of IL-33, CXCL12, CXCL13, and factors associated with both canonical and non-canonical NF-κB pathways. Moreover, mRNA and protein levels of NLRP12 were decreased in BPDE-stimulated A549 cells. Subsequent SFN intervention attenuated BPDE-induced migration and invasion of A549 cells. Lentivirus-mediated NLRP12 overexpression not only reversed the observed phenotype in BPDE-induced cells but also led to a reduction in the expression of critical factors associated with both canonical and non-canonical NF-κB pathways. Collectively, we found that SFN could inhibit BPDE-induced migration and invasion of A549 cells by upregulating NLRP12, thereby influencing both canonical and non-canonical NF-κB pathways.

Zinc hybrid polyester barrier membrane accelerates guided tissue regeneration.

Barrier membranes play a pivotal role in the success of guided periodontal tissue regeneration. The biodegradable barriers predominantly used in clinical practice often lack sufficient barrier strength, antibacterial properties, and bioactivity, frequently leading to suboptimal regeneration outcomes. Although with advantages in mechanical strength, biodegradability and plasticity, bioinert aliphatic polyesters as barrier materials are usually polymerized via toxic catalysts, hard to be functionalized and lack of antibacterial properties. To address these challenges, we propose a new concept that controlled release of bioactive substance on the whole degradation course can give a bioinert aliphatic polyester bioactivity. Thus, a Zn-based catalytic system for polycondensation of dicarboxylic acids and diols is created to prepare zinc covalent hybrid polyester (PBS/ZnO). The atomically-dispersed Zn2+ ions entering main chain of polyester molecules endow PBS/ZnO barrier with antibacterial properties, barrier strength, excellent biocompatibility and histocompatibility. Further studies reveal that relying on long-term controlled release of Zn2+ ions, the PBS/ZnO membrane greatly expedites osteogenetic effect in guided tissue regeneration (GTR) by enhancing the mitochondrial function of macrophages to induce M2 polarization. These findings show a novel preparation strategy of bioactive polyester biomaterials based on long term controlled release of bioactive substance that integrates catalysis, material structures and function customization.

The impact of the P2X7 receptor on the tumor immune microenvironment and its effects on tumor progression.

Cancer is a significant global health concern, and finding effective methods to treat it has been a focus of scientific research. It has been discovered that the growth, invasion, and metastasis of tumors are closely related to the environment in which they exist, known as the tumor microenvironment (TME). The immune response interacting with the tumor occurring within the TME constitutes the tumor immune microenvironment, and the immune response can lead to anti-tumor and pro-tumor outcomes and has shown tremendous potential in immunotherapy. A channel called the P2X7 receptor (P2X7R) has been identified within the TME. It is an ion channel present in various immune cells and tumor cells, and its activation can lead to inflammation, immune responses, angiogenesis, immunogenic cell death, and promotion of tumor development. This article provides an overview of the structure, function, and pharmacological characteristics of P2X7R. We described the concept and components of tumor immune microenvironment and the influence immune components has on tumors. We also outlined the impact of P2X7R regulation and how it affects the development of tumors and summarized the effects of drugs targeting P2X7R on tumor progression, both past and current, assisting researchers in treating tumors using P2X7R as a target.

Strictosamide alleviates acute lung injury via regulating T helper 17 cells, regulatory T cells, and gut microbiota.

BACKGROUND: Nauclea officinalis (Pierre ex Pit.) Merr. & Chun (Rubiaceae) is widely used to treat respiratory diseases in China. Strictosamide is its main active component and has significant anti-inflammatory activity. However, the effects and molecular mechanisms of strictosamide in the treatment of acute lung injury (ALI) remain largely unknown. PURPOSE: This study aimed to examine the regulatory effects of strictosamide on T helper 17 cells (Th17 cells)/Regulatory T cells (Treg cells) and gut microbiota in ALI-affected mice. MATERIALS AND METHODS: The ALI model was induced using lipopolysaccharide (LPS) intraperitoneal injection. Hematoxylin-eosin (H&E) staining, the number of inflammatory cells in broncho-alveolar lavage fluid (BALF), the Wet/Dry (W/D) ratio, and myeloperoxidase (MPO) activity were utilized as evaluation indices for the therapeutic efficacy of strictosamide on ALI. Flow cytometry (FCM), enzyme-linked immune sorbent assay (ELISA), quantitative reverse transcription polymerase chain reaction (qRT-PCR), and western blotting were used to determine the regulation of strictosamide on the Th17/Treg cells and the STAT3/STAT5 signaling pathway. The analysis of gut microbiota was conducted using 16S rDNA sequencing. The verification of the relationship between the gut microbiome and immune function was conducted using Spearman analysis. RESULTS: Strictosamide attenuated inflammation on ALI induced by LPS, which reduced the levels of Th17-related factors interleukin (IL)-6 and IL-17 and increased Treg-related factors IL-10 and transforming growth factor (TGF)-ß. In the spleens and whole blood, strictosamide reduced the proportion of Th17 cells and increased the proportion of Treg cells. Furthermore, strictosamide increased Forkhead/winged helix transcription factor 3 (Foxp3) and p-STAT5 protein expression while inhibiting Retinoid-related orphan nuclear receptors-γt (RORγt) and p-STAT3 expression. Moreover, strictosamide reshaped the diversity and structure of the gut microbiota, and influence the associations between immune parameters and gut microbiota in ALI mice. CONCLUSIONS: In summary, the results of the current investigation showed that strictosamide has a therapeutic impact on LPS-induced ALI. The mechanism of action of this effect may be associated with the modulation of Th17 and Treg cells differentiation via the SATA signaling pathway, as well as the impact of the gut microbiota.

Identification of COQ2 as a regulator of proliferation and lipid peroxidation through genome-scale CRISPR-Cas9 screening in myeloma cells.

Multiple myeloma (MM) is the second most common malignant haematological disease with a poor prognosis. The limit therapeutic progress has been made in MM patients with cancer relapse, necessitating deeper research into the molecular mechanisms underlying its occurrence and development. A genome-wide CRISPR-Cas9 loss-of-function screening was utilized to identify potential therapeutic targets in our research. We revealed that COQ2 plays a crucial role in regulating MM cell proliferation and lipid peroxidation (LPO). Knockout of COQ2 inhibited cell proliferation, induced cell cycle arrest and reduced tumour growth in vivo. Mechanistically, COQ2 promoted the activation of the MEK/ERK cascade, which in turn stabilized and activated MYC protein. Moreover, we found that COQ2-deficient MM cells increased sensitivity to the LPO activator, RSL3. Using an inhibitor targeting COQ2 by 4-CBA enhanced the sensitivity to RSL3 in primary CD138+ myeloma cells and in a xenograft mouse model. Nevertheless, co-treatment of 4-CBA and RSL3 induced cell death in bortezomib-resistant MM cells. Together, our findings suggest that COQ2 promotes cell proliferation and tumour growth through the activation of the MEK/ERK/MYC axis and targeting COQ2 could enhance the sensitivity to ferroptosis in MM cells, which may be a promising therapeutic strategy for the treatment of MM patients.

Effect of Corticosteroids on Long-term Humoral and Memory T-Cell Responses in Follow-up Visit of Hospitalized Patients With COVID-19.

BACKGROUND: Corticosteroids have beneficial effects in improving outcomes in hospitalized patients with severe COVID-19 by suppressing excessive immune responses. However, the effect of corticosteroids on the humoral and T-cell responses of survivors of COVID-19 1 year after infection remains uncertain because it relates to the extent of immediate, antigen-specific defense provided by protective memory. RESEARCH QUESTION: What is the effect of corticosteroids on long-term humoral and T-cell immune responses? STUDY DESIGN AND METHODS: In this retrospective cohort study conducted at a single center, we analyzed data from a cohort who had survived COVID-19 to compare the 1-year seropositivity and titer changes in neutralizing antibodies (NAbs) and SARS-CoV-2-specific antibodies. Additionally, we evaluated the magnitude and rate of SARS-CoV-2-specific T-cell response in individuals who received corticosteroids during hospitalization and those who did not. RESULTS: Our findings indicated that corticosteroids do not statistically influence the kinetics or seropositive rate of NAbs against the Wuhan strain of SARS-CoV-2 from 6 months to 1 year. However, subgroup analysis revealed a numerical increase of absolute NAbs titers, from 20.0 to 28.2, in categories where long-term (> 15 days) and high-dose (> 560 mg) corticosteroids are administered. Similarly, corticosteroids showed no significant effect on nucleoprotein and receptor-binding domain IgG at 1 year, except for spike protein IgG (ß, 0.08; 95% CI, 0.04-0.12), which demonstrated a delayed decline of titers. Regarding T-cell immunity, corticosteroids did not affect the rate or magnitude of T-cell responses significantly. However, functional assessment of memory T cells revealed higher interferon-γ responses in CD4 (ß, 0.61; 95% CI, 0.10-1.12) and CD8 (ß, 0.63; 95% CI, 0.11-1.15) memory T cells in the corticosteroids group at 1 year. INTERPRETATION: Based on our findings, short-term and low-dose corticosteroid therapy during hospitalization does not have a significant effect on long-term humoral kinetics or the magnitude and rate of memory T-cell responses to SARS-CoV-2 antigens. However, the potential harmful effects of long-term and high-dose corticosteroid use on memory immune responses require further investigation.