Copper-Catalyzed Asymmetric [3 + 2] Cycloaddition of N-2,2,2-Trifluoroethylisatin Ketimines to Access Three Classes of Polyfunctionalized Spiro-Pyrrolidine-Oxindole Motifs.

A facile copper-catalyzed [3 + 2] cycloaddition of N-2,2,2-trifluoroethylisatin ketimines with various electron-deficient alkenes to access structurally polyfunctionalized spiro-pyrrolidine-oxindole motifs has been developed. Under the catalytic system, the N-2,2,2-trifluoroethylisatin ketimines could be utilized to react with a series of exocyclic alkenes, including 2-acylamino acrylates, 3-methylene-ß-lactams, and sterically hindered cycloalkenes represented by cyclobutenone, to obtain a variety of densely functionalized spiro-pyrrolidine frameworks bearing an α-amino acid ester, ß-lactam, and cyclobutanone, respectively, in generally good yields with excellent diastereo- and enantioselectivities.

Evaluation of the clinical efficacy of Ru'ai Shuhou recipe for the prevention of lung metastases from breast cancer: a retrospective study based on propensity score matching.

Background: Breast cancer lung metastasis occurs at a high rate and at an early stage, and is the leading cause of death in breast cancer patients. The aim of this study was to investigate the effect of Ru'ai Shuhou Recipe (RSR) intervention on the occurrence of recurrent metastases, especially lung metastases, in postoperative patients with breast cancer. Materials and Methods: A retrospective cohort study was implemented at Shuguang Hospital of Shanghai University of Traditional Chinese Medicine in China between January 2014 to January 2019. Female patients were included according to the propensity score matching (PSM) method and balanced on the basis of general and clinical information such as age, body mass index, neo-adjuvant therapy, and surgical approach. Patients with pathological diagnosis of breast cancer were included in this study. Breast cancer patients were divided into exposed and non-exposed groups according to whether they took RSR-based botanical drugs after surgery. Kaplan-Meier survival analysis and Cox survival analysis to explore the relationship between RSR and 5-year disease-free survival and incidence of lung metastases in breast cancer patients after surgery. Results: 360 female patients were assessed and 190 patients were included in the study after PSM (95 in each of the exposed and non-exposed groups). Of the 190 patients after PSM, 55.79% were over 50 years of age. The mean follow-up time was 60.55 ± 14.82 months in the exposed group and 57.12 ± 16.37 months in the non-exposed group. There was no significant baseline characteristics difference between two groups. Kaplan-Meier analysis showed that the 5-year incidence of lung metastases was significantly lower in the exposed group, and the disease-free survival of patients was significantly longer. Cox univariate and multivariate analysis showed that neoadjuvant chemotherapy and lymph node metastasis were independent risk factors for the development of breast cancer lung metastasis, with risk ratios of 17.188 and 5.812, while RSR treatment was an independent protective factor against the development of breast cancer lung metastasis, with a risk ratio of 0.290. Conclusion: Standard biomedical treatment combined with RSR intervention can better prevent breast cancer recurrence and metastasis, reduce the incidence of lung metastasis in patients, and improve long-term prognosis.

Major depressive disorder elevates the risk of dentofacial deformity: a bidirectional two-sample Mendelian randomization study.

Background: The association between psychiatric disorders and dentofacial deformities has attracted widespread attention. However, their relationship is currently unclear and controversial. Methods: A two-sample bidirectional MR analysis was performed to study the causal relationship between dentofacial deformity and eight psychiatric disorders, including major depressive disorder, panic disorder, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, Alzheimer's disease, autism spectrum disorder, and neuroticism. Inverse variance weighted, weighted median, MR-Egger regression, weighted mode four methods, and further sensitivity analyses were conducted. Results: The major depressive disorder affected dentofacial deformity, with an OR = 1.387 (95% CI = 1.181-1.629, P = 6.77×10-5). No other psychiatric disorders were found to be associated with dentofacial deformity. In turn, dentofacial deformity were associated with neuroticism, with an OR = 1.050 (95% CI = 1.008-1.093, P = 0.018). And there was no evidence that dentofacial deformity would increase the risk of other psychiatric disorders. Conclusions: Major depressive disorder might elevate the risk of dentofacial deformities, and dentofacial deformity conditions would increase the risk of the incidence of neuroticism.

Clarifying the Direct Generation of •OH Radicals in Photocatalytic O2 Reduction: Theoretical Prediction Combined with Experimental Validation.

This work systematically studied thermocatalytic and photocatalytic pathways of formaldehyde degradation and H-assisted O2 reduction over a Pt13/anatase-TiO2(101) composite via DFT calculations together with constrained molecular dynamics (MD) simulations. We show that photocatalytic O2 reduction on Pt/TiO2 can directly generate •OH radicals (*O2 → *OOH → •OH) via two hydrogenation steps with small barriers, and the product selectivity (*H2O2 or •OH) is decided by the relative position between catalyst Fermi level and •OH/*H2O2 redox potential (theoretical determination of 0.07 V referencing to the SHE). Such a novel reaction channel was furthermore validated at the liquid-solid interface via constrained MD simulations and experimental electron paramagnetic resonance detections, and a wide range of H resources, e.g., *HCHO, *HCO, *H (H+ + e-), can always drive the direct •OH generation. The additional portion of e--triggered •OH radicals are prone to diffuse into solution or the TiO2 surface and furthermore cooperate with the conventional h+-driven photooxidations.

Optimized inhaled LNP formulation for enhanced treatment of idiopathic pulmonary fibrosis via mRNA-mediated antibody therapy.

Lipid nanoparticle-assisted mRNA inhalation therapy necessitates addressing challenges such as resistance to shear force damage, mucus penetration, cellular internalization, rapid lysosomal escape, and target protein expression. Here, we introduce the innovative "LOOP" platform with a four-step workflow to develop inhaled lipid nanoparticles specifically for pulmonary mRNA delivery. iLNP-HP08LOOP featuring a high helper lipid ratio, acidic dialysis buffer, and excipient-assisted nebulization buffer, demonstrates exceptional stability and enhanced mRNA expression in the lungs. By incorporating mRNA encoding IL-11 single chain fragment variable (scFv), scFv@iLNP-HP08LOOP effectively delivers and secretes IL-11 scFv to the lungs of male mice, significantly inhibiting fibrosis. This formulation surpasses both inhaled and intravenously injected IL-11 scFv in inhibiting fibroblast activation and extracellular matrix deposition. The HP08LOOP system is also compatible with commercially available ALC0315 LNPs. Thus, the "LOOP" method presents a powerful platform for developing inhaled mRNA nanotherapeutics with potential for treating various respiratory diseases, including idiopathic pulmonary fibrosis.

Ventral posteromedial nucleus of the thalamus gates the spread of trigeminal neuropathic pain.

BACKGROUND: Widespread neuropathic pain usually affects a wide range of body areas and inflicts huge suffering on patients. However, little is known about how it happens and effective therapeutic interventions are lacking. METHODS: Widespread neuropathic pain was induced by partial infraorbital nerve transection (p-IONX) and evaluated by measuring nociceptive thresholds. In vivo/vitro electrophysiology were used to evaluate neuronal activity. Virus tracing strategies, combined with optogenetics and chemogenetics, were used to clarify the role of remodeling circuit in widespread neuropathic pain. RESULTS: We found that in mice receiving p-IONX, along with pain sensitization spreading from the orofacial area to distal body parts, glutamatergic neurons in the ventral posteromedial nucleus of the thalamus (VPMGlu) were hyperactive and more responsive to stimulations applied to the hind paw or tail. Tracing experiments revealed that a remodeling was induced by p-IONX in the afferent circuitry of VPMGlu, notably evidenced by more projections from glutamatergic neurons in the dorsal column nuclei (DCNGlu). Moreover, VPMGlu receiving afferents from the DCN extended projections further to glutamatergic neurons in the posterior insular cortex (pIC). Selective inhibition of the terminals of DCNGlu in the VPM, the soma of VPMGlu or the terminals of VPMGlu in the pIC all alleviated trigeminal and widespread neuropathic pain. CONCLUSION: These results demonstrate that hyperactive VPMGlu recruit new afferents from the DCN and relay the extra-cephalic input to the pIC after p-IONX, thus hold a key position in trigeminal neuropathic pain and its spreading. This study provides novel insights into the circuit mechanism and preclinical evidence for potential therapeutic targets of widespread neuropathic pain.

m6A-mediated HDAC9 upregulation promotes particulate matter-induced airway inflammation via epigenetic control of DUSP9-MAPK axis and acts as an inhaled nanotherapeutic target.

Exposure to particulate matter (PM) can cause airway inflammation and worsen various airway diseases. However, the underlying molecular mechanism by which PM triggers airway inflammation has not been completely elucidated, and effective interventions are lacking. Our study revealed that PM exposure increased the expression of histone deacetylase 9 (HDAC9) in human bronchial epithelial cells and mouse airway epithelium through the METTL3/m6A methylation/IGF2BP3 pathway. Functional assays showed that HDAC9 upregulation promoted PM-induced airway inflammation and activation of MAPK signaling pathway in vitro and in vivo. Mechanistically, HDAC9 modulated the deacetylation of histone 4 acetylation at K12 (H4K12) in the promoter region of dual specificity phosphatase 9 (DUSP9) to repress the expression of DUSP9 and resulting in the activation of MAPK signaling pathway, thereby promoting PM-induced airway inflammation. Additionally, HDAC9 bound to MEF2A to weaken its anti-inflammatory effect on PM-induced airway inflammation. Then, we developed a novel inhaled lipid nanoparticle system for delivering HDAC9 siRNA to the airway, offering an effective treatment for PM-induced airway inflammation. Collectively, we elucidated the crucial regulatory mechanism of HDAC9 in PM-induced airway inflammation and introduced an inhaled therapeutic approach targeting HDAC9. These findings contribute to alleviating the burden of various airway diseases caused by PM exposure.

Can Subsurface Oxygen Species in Oxides Participate in Catalytic Reactions? An 17O Solid-State Nuclear Magnetic Resonance Study.

The impacts of subsurface species of catalysts on reaction processes are still under debate, largely due to a lack of characterization methods for distinguishing these species from the surface species and the bulk. By using 17O solid-state nuclear magnetic resonance (NMR) spectroscopy, which can distinguish subsurface oxygen ions in CeO2 (111) nanorods, we explore the effects of subsurface species of oxides in CO oxidation reactions. The intensities of the 17O NMR signals due to surface and subsurface oxygen ions decrease after the introduction of CO into CeO2 nanorods, with a more significant decrease observed for the latter, confirming the participation of subsurface oxygen species. Density functional theory calculations show that the reaction involves subsurface oxygen ions filling the surface oxygen vacancies created by the direct contact of surface oxygen with CO. This new approach can be extended to the study of the role of oxygen species in other catalytic reactions.

Surface Reconstruction-Induced Photocatalytic Methanol Reduction Reaction on a Rutile TiO2(001) Surface.

Photochemistry of methanol on TiO2 surfaces is of great importance both fundamentally and industrially. Methanol was previously reported only to occur photogenerated hole-participating oxidation reactions on TiO2 surfaces. Herein, we report that, upon UV light illumination, the methoxy species formed by methanol dissociation at the 5-fold coordinated Ti4+ sites (CH3O(a)Ti5c) of a reconstructed rutile TiO2(001)-(1 × 1) surface also undergoes the C-O bond cleavage into methyl fragments mediated by photogenerated electrons, in addition to the well-established photogenerated hole-participating oxidation reactions. Upon subsequent heating, the resulting methyl species undergoes hydrogenation and coupling reactions into methane and ethane, respectively. Accompanying theoretical calculations showed that the lowest unoccupied molecular orbital (LUMO) of CH3O(a)Ti5c is localized almost at the conduction band minimum of the CH3O-adsorbed reconstructed rutile TiO2(001)-(1 × 1) surface, indicating the likely TiO2 → CH3O(a)Ti5c interfacial photoexcited-electron transfer. These results greatly broaden the photochemistry of methanol on TiO2 surfaces and demonstrate a photocatalytic methanol-to-hydrocarbon reaction route.

Injectable Gelled Multiple Emulsion for Glucose-Responsive Insulin Delivery.

A glucose-responsive insulin delivery system that sustains blood glucose equilibrium for an extended duration can address the low therapeutic window of insulin in diabetes treatment. Herein, insulin is loaded in a water-in-oil-in-water (W1/O/W2) gelled multiple emulsion using poly (4-vinylphenylboronic acid) (PVPBA) homopolymer as an effective emulsifier. The gelled multiple emulsion exhibits a high encapsulation efficiency (99%), enhanced stability and remarkable shear-thinning behavior, making it easy to inject. Under hyperglycemic conditions, the gelled emulsion system instantly binds to glucose molecules and reduces the hydrogen bonds of the PVPBA homopolymer, resulting in insulin release. In a streptozotocin-induced type 1 diabetic mouse model, a single subcutaneous injection of the gelled emulsion rapidly responds to high blood glucose concentration (BGC) and release insulin in a glucose dependent manner, thus prolonging the antihyperglycemic effect compared with free insulin.

Effects of tanshinone IIA on endothelial cell dysfunction in uremic condition.

An arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis in uremic patients, yet its dysfunction poses a significant clinical challenge. Venous stenosis, primarily caused by venous neointimal hyperplasia, is a key factor in the failure of vascular access. During vascular access dysfunction, endothelial cells (ECs) transform mechanical stimuli into intracellular signals and interact with vascular smooth muscle cells. Tanshinone IIA, an important compound derived from Salvia miltiorrhiza, has been widely used to treat cardiovascular diseases. However, its role in modulating ECs under uremic conditions remains incompletely understood. In this research, ECs were exposed to sodium tanshinone IIA sulfonate (STS) and subjected to shear stress and uremic conditions. The results indicate that STS can reduce the suppressive effects on the expression of NF-κB p65, JNK and Collagen I in uremia-induced ECs. Moreover, the downregulation of NF-κB p65, JNK and Collagen I can be enhanced through the inhibition of ERK1/2 and the upregulation of Caveolin-1. These findings suggest that tanshinone IIA may improve EC function under uremic conditions by targeting the Caveolin-1/ERK1/2 pathway, presenting tanshinone IIA as a potential therapeutic agent against AVF immaturity caused by EC dysfunction.

Photomediated One-Pot Three-Component Approach Enables the Formal Direct N-Acylation/Sulfonylation and α-C-H Functionalization of 1,2,3,4-Tetrahydroisoquinoline.

N-Acyl/sulfonyl-α-functionalized 1,2,3,4-tetrahydroisoquinolines (THIQs) are significant structural motifs in organic synthesis and drug discovery. However, the one-pot approach enabling direct difunctionalization of THIQs remains challenging. Herein we report a photomediated one-pot three-component strategy to access N-acyl/sulfonyl-α-functionalized THIQs. This method features the use of oxygen (from air) as the green oxidant, high atom and step economy, and decent structural diversity. The synthetic applicability of the method was further demonstrated via the facile construction of valuable bioactive molecules. Mechanistic studies indicated that oxidation with singlet oxygen and the acceptor-less dehydrogenation were involved in the photoredox process.

PV and SST neurons in the anterior cingulate cortex regulate social disorders in adulthood induced by sensory abnormalities in childhood.

OBJECTIVE: Childhood sensory abnormalities experience has a crucial influence on the structure and function of the adult brain. The underlying mechanism of neurological function induced by childhood sensory abnormalities experience is still unclear. Our study was to investigate whether the GABAergic neurons in the anterior cingulate cortex (ACC) regulate social disorders caused by childhood sensory abnormalities experience. METHODS: We used two mouse models, complete Freund's adjuvant (CFA) injection mice and bilateral whisker trimming (BWT) mice in childhood. We applied immunofluorescence, chemogenetic and optogenetic to study the mechanism of parvalbumin (PV) neurons and somatostatin (SST) neurons in ACC in regulating social disorders induced by sensory abnormalities in childhood. RESULTS: Inflammatory pain in childhood leads to social preference disorders, while BWT in childhood leads to social novelty disorders in adult mice. Inflammatory pain and BWT in childhood caused an increase in the number of PV and SST neurons, respectively, in adult mice ACC. Inhibiting PV neurons in ACC improved social preference disorders in adult mice that experienced inflammatory pain during childhood. Inhibiting SST neurons in ACC improved social novelty disorders in adult mice that experienced BWT in childhood. CONCLUSIONS: Our study reveals that PV and SST neurons of the ACC may play a critical role in regulating social disorders induced by sensory abnormalities in childhood.

Regulation of the p53/SLC7A11/GPX4 Pathway by Gentamicin Induces Ferroptosis in HEI-OC1 Cells.

BACKGROUND: Gentamicin is a commonly used aminoglycoside antibiotic, with ototoxicity as a significant side effect. Ferroptosis, an iron-dependent form of cell death, has been implicated in a variety of disorders. Whether ferroptosis impacts gentamicin ototoxicity is not yet known. The current work used an in-vitro model to examine the influence of gentamicin-induced ferroptosis on cochlear hair cell damage and probable molecular biological pathways. METHODS: House Ear Institute-Organ of Corti 1 (HEI-OC1) cells were treated with different concentrations of gentamicin for 24 hours, with or without ferrostatin-1 pretreatment, to observe gentamicin-induced ferroptosis. The role of p53/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling in gentamicin-induced ferroptosis was explored by pretreating cells with the p53 inhibitor pifithrin-α (PFT-α). We investigated the effect of gentamicin on cells by assessing cell viability. Cellular proteins were isolated and Western blots were performed to detect changes in the expression of p53, SLC7A11, and GPX4. Fluorescence staining was used to assess levels of reactive oxygen species. An enzymatic detection kit was used to detect glutathione, Fe, and malondialdehyde markers. RESULTS: Gentamicin reduced cell viability, glutathione content, and SLC7A11 and GPX4 protein levels, and increased levels of p53 protein, reactive oxygen species, malondialdehyde, and Fe. These effects were largely blocked by pretreatment with ferrostatin-1. Pretreatment with the p53 inhibitor PFT-α prevented the gentamicin-induced reduction in SLC7A11 and GPX4, which alleviated several features of ferroptosis including glutathione depletion, iron overload, and lipid peroxidation build-up. CONCLUSION: Gentamicin induces ferroptosis in the HEI-OC1 cell line, and the mechanism may be related to the p53/SLC7A11/GPX4 signaling pathway.

Phagocytic Plasma Cells in Teleost Fish Provide Insights into the Origin and Evolution of B Cells in Vertebrates.

Teleost IgM+ B cells can phagocytose, like mammalian B1 cells, and secrete Ag-specific IgM, like mammalian B2 cells. Therefore, teleost IgM+ B cells may have the functions of both mammalian B1 and B2 cells. To support this view, we initially found that grass carp (Ctenopharyngodon idella) IgM+ plasma cells (PCs) exhibit robust phagocytic ability, akin to IgM+ naive B cells. Subsequently, we sorted grass carp IgM+ PCs into two subpopulations: nonphagocytic (Pha-IgM+ PCs) and phagocytic IgM+ PCs (Pha+IgM+ PCs), both of which demonstrated the capacity to secrete natural IgM with LPS and peptidoglycan binding capacity. Remarkably, following immunization of grass carp with an Ag, we observed that both Pha-IgM+ PCs and Pha+IgM+ PCs could secrete Ag-specific IgM. Furthermore, in vitro concatenated phagocytosis experiments in which Pha-IgM+ PCs from an initial phagocytosis experiment were sorted and exposed again to beads confirmed that these cells also have phagocytic capabilities, thereby suggesting that all teleost IgM+ B cells have phagocytic potential. Additionally, we found that grass carp IgM+ PCs display classical phenotypic features of macrophages, providing support for the hypothesis that vertebrate B cells evolved from ancient phagocytes. These findings together reveal that teleost B cells are a primitive B cell type with functions reminiscent of both mammalian B1 and B2 cells, providing insights into the origin and evolution of B cells in vertebrates.

A Randomized Trial of the Efficacy of Three Weight Loss Diet Interventions in Overweight/Obese with Polycystic Ovary Syndrome.

BACKGROUND: Polycystic Ovary Syndrome (PCOS) is a highly prevalent, complex, heterogeneous, polygenic endocrine disorder characterized by metabolic and reproductive dysfunction that affects 8-13% of women of reproductive age worldwide. The pathogenesis of PCOS has not been fully clarified and includes genetics, obesity, and insulin resistance (IR). Oxidative stress (OS) of PCOS is independent of obesity. It can induce IR through post-insulin receptor defects, impair glucose uptake in muscle and adipose tissue, and exacerbate IR by reducing insulin secretion from pancreatic ß-cells. OBJECTIVE: To investigate the effects of Calorie Restricted Diet (CRD), High Protein Diet (HPD), and High Protein and High Dietary Fiber Diet (HPD+HDF) on body composition, insulin resistance, and oxidative stress in overweight/obese PCOS patients. METHODS: A total of 90 overweight/obese patients with PCOS were selected to receive an 8- week medical nutrition weight loss intervention at our First Hospital of Peking University, and we randomly divided them into the CRD group (group A), the HPD group (group B), and the HPD+HDF group (group C), with 30 patients in each group. We measured their body composition, HOMA-IR index, and oxidative stress indicators. The t-test, Mann-Whitney U test, analysis of variance (ANOVA), and Kruskal-Wallis H test were used to compare the efficacy of the three methods. RESULTS: After eight weeks, the body weights of the three groups decreased by 6.32%, 5.70% and 7.24%, respectively, and the Visceral Fat Area (VFA) values decreased by 6.8 cm2, 13.4 cm2 and 23.45 cm2, respectively, especially in group C (p >0.05). The lean body mass (LBM), also known as the Fat-Free Mass (FFM) values of group B and group C after weight loss, were higher than that of group A (p >0.05). After weight loss, the homeostatic model assessment of insulin resistance (HOMA-IR) index and malondialdehyde (MDA) were decreased. Superoxide dismutase (SOD) was increased in all three groups (p >0.05), and the changes in SOD and MDA in group B and group C were more significant (p >0.05). HOMA-IR index positively correlated with body mass index (BMI) (r=0.195; p >0.05); MDA positively correlated with percent of body fat (PBF) (r=0.186; p >0.05) and HOMA-IR index (r=0.422; p >0.01); SOD positively correlated with LMI/FFMI (r=0.195; p >0.05), negatively correlated with HOMA-IR index (r=-0.433; p >0.01). CONCLUSION: All three diets were effective in reducing the body weight of overweight/obese patients with PCOS by more than 5% within 8 weeks and could improve both insulin resistance and oxidative stress damage. Compared with CRD, HPD and HPD+HDF diets could better retain lean body mass and significantly improve oxidative stress damage. CLINICAL TRIAL NUMBER: ChiCTR2100054961.

Urine multi-index intelligent detection based on polymer/paper hybrid microfluidic biochip for hyperuricemia monitoring.

Hyperuricemia (HUA) has gradually become a public health burden as an independent risk factor for a variety of chronic diseases. Herein, a user-friendly point-of-care (POC) detection system (namely "Smart-HUA-Monitor") based on smartphone-assisted paper-based microfluidic is proposed for colorimetric quantification of HUA urinary markers, including uric acid (UA), creatinine (CR) and pH. The detection limits of UA and CR were 0.0178 and 0.5983 mM, respectively, and the sensitivity of pH were 0.1. The method was successfully validated in artificial urine samples and 100 clinical samples. Bland-Altman plots showed a high consistency between µPAD and the testing instruments (HITACHI 7600 Automatic Analyzer, URIT-500B Urine Analyzer and AU5800B automatic biochemical analyzer) in hospital. Smart-HUA-Monitor provides an accurate quantitative, rapid, low-cost and reliable tool for the monitoring and early diagnosis of HUA urine indicators.

Clinical Observation of Infarct Volume ≥150 mL in Endovascular Thrombectomy Treatment.

OBJECTIVES: Whether patients with infarct volume ≥150 mL could benefit from endovascular thrombectomy (EVT) remains unclear. METHODS: Patients (n=104) with anterior circulation Alberta Stroke Program Early Computed Tomography Score <6 were screened for infarct volume ≥150 mL using the Pullicino formula × (1-22%). The following were compared with the baseline at 90 days: the modified Rankin scale score (mRS) ≤3, mortality rate, symptomatic intracranial hemorrhage and any intracranial hemorrhage within 48 hours, and modified Thrombolysis in Cerebral Infarction (mTICI) ≥2b between the EVT and drug therapy (DT) groups. RESULTS: In patients with infarct volumes ≥150 mL, mRS≤3 at 90 days was higher in the EVT group than in the DT group [adjusted odds risk (aOR), 5.52; 95% CI: 1.10-28.24, P=0.04), and mTICI ≥2b at 82.8%. Intracranial hemorrhage within 48 hours occurred in 7 (24.1%) patients in the EVT group and 5 (14.7%) in the DT group (aOR, 0.75; 95% CI: 0.16-3.46; P=0.71). Older age (aOR, 0.94; 95% CI: 0.90-0.99, P=0.01), EVT treatment (aOR, 4.51; 95% CI: 1.60-12.78, P=0.01), and infarct volume ≥150 mL (aOR, 0.11; 95% CI: 0.04-0.31, P<0.01) were significantly associated with patient prognosis. CONCLUSIONS: Patients with infarct volume ≥150 mL who received EVT had a higher proportion of mRS≤3 compared with those who received DT. However, there was no statistically significant difference in intracranial hemorrhage and death between the groups. EVT, smaller infarct volume, and younger age were associated with a good prognosis. The findings require large sample data verification.

Disrupting Smad3 potentiates immunostimulatory function of NK cells against lung carcinoma by promoting GM-CSF production.

Through Smad3-dependent signalings, transforming growth factor-ß (TGF-ß) suppresses the development, maturation, cytokine productions and cytolytic functions of NK cells in cancer. Silencing Smad3 remarkably restores the cytotoxicity of NK-92 against cancer in TGF-ß-rich microenvironment, but its effects on the immunoregulatory functions of NK cells remain obscure. In this study, we identified Smad3 functioned as a transcriptional repressor for CSF2 (GM-CSF) in NK cells. Therefore, disrupting Smad3 largely mitigated TGF-ß-mediated suppression on GM-CSF production by NK cells. Furthermore, silencing GM-CSF in Smad3 knockout NK cells substantially impaired their anti-lung carcinoma effects. In-depth study demonstrated that NK-derived GM-CSF strengthened T cell immune responses by stimulating dendritic cell differentiation and M1 macrophage polarization. Meanwhile, NK-derived GM-CSF promoted the survival of neutrophils, which in turn facilitated the terminal maturation of NK cells, and subsequently boosted NK-cell mediated cytotoxicity against lung carcinoma. Thus, Smad3-silenced NK-92 (NK-92-S3KD) may serve as a promising immunoadjuvant therapy with clinical translational value given its robust cytotoxicity against malignant cells and immunostimulatory functions to reinforce the therapeutic effects of other immunotherapies.

Two Undescribed Coumarins from Notopterygium Incisum with Anti-Inflammatory Activity.

Two previously undescribed coumarins (1-2) were isolated from the root of Notopterygium incisum. The structures of new findings were elucidated by analyses of spectral evidences in HRESIMS, NMR, as well as ICD. The absolute configurations were further confirmed by chemical calculations. 1-2 exhibits obviously anti-inflammatory activity by inhibiting the expression of inflammatory mediators (COX-2, iNOS), as well as reducing the release of NO and the accumulation of ROS in cells. Western blotting analysis revealed that 2 could inhibit the PI3K/AKT pathway by reducing the expression of p-PI3K and p-AKT.