Ectosomal PKM2 Promotes HCC by Inducing Macrophage Differentiation and Remodeling the Tumor Microenvironment.

Tumor-derived extracellular vesicles are important mediators of cell-to-cell communication during tumorigenesis. Here, we demonstrated that hepatocellular carcinoma (HCC)-derived ectosomes remodel the tumor microenvironment to facilitate HCC progression in an ectosomal PKM2-dependent manner. HCC-derived ectosomal PKM2 induced not only metabolic reprogramming in monocytes but also STAT3 phosphorylation in the nucleus to upregulate differentiation-associated transcription factors, leading to monocyte-to-macrophage differentiation and tumor microenvironment remodeling. In HCC cells, sumoylation of PKM2 induced its plasma membrane targeting and subsequent ectosomal excretion via interactions with ARRDC1. The PKM2-ARRDC1 association in HCC was reinforced by macrophage-secreted cytokines/chemokines in a CCL1-CCR8 axis-dependent manner, further facilitating PKM2 excretion from HCC cells to form a feedforward regulatory loop for tumorigenesis. In the clinic, ectosomal PKM2 was clearly detected in the plasma of HCC patients. This study highlights a mechanism by which ectosomal PKM2 remodels the tumor microenvironment and reveals ectosomal PKM2 as a potential diagnostic marker for HCC.

Prospective evaluation of cardiovascular risk and mortality in patients with psoriasis: An American population-based study.

The association between psoriasis and cardiovascular disease (CVD) has long been discussed and continually refined. However, there is currently a lack of prospective studies on the cardiovascular risk attributed to psoriasis in the United States general population. Representative adult participants were selected from the National Health and Nutrition Examination Survey (NHANES). Risks of cardiovascular symptoms and diseases prevalence were evaluated between participants with and without psoriasis. The hazards for all-cause mortality and CVD mortality were stratified by psoriasis status. Mediation analysis was then conducted to identify potential mediators between psoriasis and cardiac death. Overall, 19 741 participants were included in the current study, 542 (2.7%) had psoriasis and 19 199 (97.3%) did not have psoriasis. After adjusting for known CVD risk factors, odds for hypertension (OR = 1.37, 95% CI: 1.13-1.66, p = 0.001), hypercholesterolemia (OR = 1.37, 95% CI: 1.13-1.64, p < 0.001) and angina pectoris (OR = 1.74, 95% CI: 1.11-2.60, p = 0.011) were higher in psoriasis patients. Compared with participants without psoriasis, moderate/severe but not mild patients showed significantly higher CVD mortality (HR = 2.55, 95% CI: 1.27-5.15, p = 0.009). This result was supported by subgroup analyses. Mediation analysis further suggested that the direct effect of moderate/severe psoriasis on CVD mortality accounted for 81.4% (65.8%-97.1%). Besides, the indirect effect might derive from disturbance of serum albumin, urea nitrogen and uric acid. Moderate-to-severe psoriasis is an independent risk factor for cardiovascular disease, making it necessary to regularly conduct cardiovascular disease-related examinations for patients with higher severity of psoriasis in clinical settings.

Synergistic Coupling of Charge Extraction and Sinking in Cu5FeS4/Ni3S2@NF for Photoassisted Electrocatalytic Oxygen Evolution.

Exploring low-cost and high-performance oxygen evolution reaction (OER) catalysts has attracted great attention due to their crucial role in water splitting. Here, a bifunctional Cu5FeS4/Ni3S2@NF catalyst was in situ formed on a nickel (Ni) foam toward efficient photoassisted electrocatalytic (P-EC) OER, which displays an ultralow overpotential of 260 mV at 30 mA cm-2 in alkaline solution, outperforming most previously reported Ni-based catalysts. It also shows great potential in degradation of antibiotics as an alternative anode reaction to OER owing to the prompt transfer of photogenerated holes. The photocurrent test and transient photovoltage spectroscopy indicate that the synergistic coupling of charge extraction and sinking effects in Cu5FeS4 and Ni3S2 is critical for boosting the OER activity via photoassistance. Electrochemical active surface area and electrochemical impedance spectroscopy tests further prove that the photogenerated electromotive force can effectively compensate the overpotential of OER. This work not only provides a good guidance for integrating photocatalysis and electrocatalysis, but also indicates the key role of synergistic extraction and utilization of photogenerated charge carriers in P-EC.

White Matter Hypoperfusion Associated with Leukoaraiosis Predicts Intracranial Hemorrhage after Intravenous Thrombolysis.

OBJECTIVES: White matter hyperintensity is common in patients receiving intravenous thrombolysis. Some studies have expressed concern about the increased risk of hemorrhagic transformation and poor prognosis for those patients with pre-existing leukoaraiosis. The purpose of this study was to evaluate hypoperfusion associated with leukoaraiosis before thrombolysis using CT perfusion and to explore whether chronic white matter hypoperfusion increases risks of intracranial hemorrhage and poor clinical prognosis. MATERIALS AND METHODS: We collected 175 patients underwent intravenous thrombolysis with complete CT perfusion data and follow-up MRI between June 2017 and January 2020. We measured cerebral blood flow, cerebral blood volume, mean transit time and transit time to the peak at both periventricular and subcortical layers in the cerebral hemisphere contralateral to the stroke. The differences of white matter perfusion were compared between groups with different leukoaraiosis severity. Univariate analysis was used to compare in incidence of hemorrhagic transformation and poor prognosis between the hypoperfusion and normal perfusion groups. Further, we examined association between white matter hypoperfusion and intracranial hemorrhage after thrombolysis using logistic regression. RESULTS: The length of periventricular transit time to the peak was independently associated with a higher risk of intracranial hemorrhage after thrombolysis (OR=4.740, 95%CI=1.624-13.837, P=0.004). The best predictive value was 4.012. But there was no significant difference in poor prognosis at 3 months between hypoperfusion (periventricular transit time to the peak≥4.012 s) and normal perfusion (periventricular transit time to the peak<4.012 s) group. CONCLUSIONS: Image presentations of white matter hypoperfusion reflected the severity of leukoaraiosis. White matter hypoperfusion was independently associated with intracranial hemorrhage after intravenous thrombolysis. However, hypoperfusion would not increase the risk of poor prognosis.

Quasi-type-II Cu-In-Zn-S/Ni-MOF heterostructure with prolonged carrier lifetime for photocatalytic hydrogen production.

Visible-driven photocatalytic hydrogen production using narrow-bandgap semiconductors has great potential for clean energy development. However, the widespread use of these semiconductors is limited due to problems such as severe charge recombination and slow surface reactions. Herein, a quasi-type-II heterostructure was constructed by combining bifunctional Ni-based metal-organic framework (Ni-MOF) nanosheets with BDC (1,4-benzenedicarboxylic acid) linker coupled with Cu-In-Zn-S quantum dots (CIZS QDs). This heterostructure exhibited a prolonged charge carrier lifetime and abundant active sites, leading to significantly improved hydrogen production rate. The optimized rate achieved by the CIZS/Ni-MOF heterostructure was 2642 µmol g-1 h-1, which is 5.28 times higher than that of the CIZS QDs. This improved performance can be attributed to the quasi-type-II band alignment between the CIZS QDs and Ni-MOF, which facilitates effective delocalization of the photogenerated electrons within the system. Additional photoelectrochemical tests confirmed the well-maintained photoluminescence and prolonged charge carrier lifetime of the CIZS/Ni-MOF heterostructure. This study provides valuable insights into the use of multifunctional MOFs in the development of highly efficient composite photocatalysts, extending beyond their role in light harvesting and charge separation.

Full-length GSDME mediates pyroptosis independent from cleavage.

Gasdermin (GSDM) family proteins, known as the executors of pyroptosis, undergo protease-mediated cleavage before inducing pyroptosis. We here discovered a form of pyroptosis mediated by full-length (FL) GSDME without proteolytic cleavage. Intense ultraviolet-C irradiation-triggered DNA damage activates nuclear PARP1, leading to extensive formation of poly(ADP-ribose) (PAR) polymers. These PAR polymers are released to the cytoplasm, where they activate PARP5 to facilitate GSDME PARylation, resulting in a conformational change in GSDME that relieves autoinhibition. Moreover, ultraviolet-C irradiation promotes cytochrome c-catalysed cardiolipin peroxidation to elevate lipid reactive oxygen species, which is then sensed by PARylated GSDME, leading to oxidative oligomerization and plasma membrane targeting of FL-GSDME for perforation, eventually inducing pyroptosis. Reagents that concurrently stimulate PARylation and oxidation of FL-GSDME, synergistically promoting pyroptotic cell death. Overall, the present findings elucidate an unreported mechanism underlying the cleavage-independent function of GSDME in executing cell death, further enriching the paradigms and understanding of FL-GSDME-mediated pyroptosis.

Temporal patterns of organ dysfunction in COVID-19 patients hospitalized in the intensive care unit: A group-based multitrajectory modeling analysis.

BACKGROUND: The course of organ dysfunction (OD) in Corona Virus Disease 2019 (COVID-19) patients is unknown. Herein, we analyze the temporal patterns of OD in intensive care unit-admitted COVID-19 patients. METHODS: Sequential organ failure assessment scores were evaluated daily within 2 weeks of admission to determine the temporal trajectory of OD using group-based multitrajectory modeling (GBMTM). RESULTS: A total of 392 patients were enrolled with a 28-day mortality rate of 53.6%. GBMTM identified four distinct trajectories. Group 1 (mild OD, n = 64), with a median APACHE II score of 13 (IQR 9-21), had an early resolution of OD and a low mortality rate. Group 2 (moderate OD, n = 140), with a median APACHE II score of 18 (IQR 13-22), had a 28-day mortality rate of 30.0%. Group 3 (severe OD, n = 117), with a median APACHR II score of 20 (IQR 13-27), had a deterioration trend of respiratory dysfunction and a 28-day mortality rate of 69.2%. Group 4 (extremely severe OD, n = 71), with a median APACHE II score of 20 (IQR 17-27), had a significant and sustained OD affecting all organ systems and a 28-day mortality rate of 97.2%. CONCLUSIONS: Four distinct trajectories of OD were identified, and respiratory dysfunction trajectory could predict nonpulmonary OD trajectories and patient prognosis.

Association Between Trichoscopic Features and Serum Hormone Levels and Vitamin D Concentration in Patients with Androgenetic Alopecia in Eastern China: A Cross-Sectional Study.

Purpose: Androgenetic alopecia (AGA) is a common dermatological condition, with reported associations between serum vitamin D and sex hormone levels. However, the relationship between these factors and the severity of hair loss remains unclear. Patients and Methods: Our cross-sectional study included 310 AGA patients who visited the dermatology clinic and underwent trichoscopy examinations throughout 2021. We collected data on serum sex hormones and 25(OH)D levels during their consultations. TrichoScan analysis was used to characterize and quantify AGA severity based on hair density and vellus hair proportions in the central scalp area, which were then correlated with the collected indicators. Results: The study findings reflect the basic demographic characteristics of AGA patients in the Chinese population. We discovered a significant negative correlation between serum SHBG levels and AGA severity in women, but no association was found in men. Serum testosterone, estradiol, dehydroepiandrosterone sulfate, and 25(OH)D levels showed no significant correlation with the severity of androgenetic alopecia, regardless of gender. Conclusion: To our knowledge, this is the first study to investigate the relationship between serum sex hormones, vitamin D, and AGA severity using trichoscopic scalp hair features.

Crystalline Ni-Fe phosphide/amorphous P doped Fe-(oxy)hydroxide heterostructure as a multifunctional electrocatalyst for solar cell-driven hydrogen production.

Hydrogen production by electrocatalytic water splitting is considered to be an effective and environmental method, and the design of an electrocatalyst with high efficiency, low cost, and multifunction is of great importance. Herein, we developed a crystalline NiFe phosphide (NiFeP)/amorphous P-doped FeOOH (P-FeOOH) heterostructure (defined as P-NiFeOxHy) as a high-efficiency multifunctional electrocatalyst for water electrolysis. The NiFeP nanocrystals provide remarkable electronic conductivity and plenty of active sites, the amorphous P-FeOOH improves the adsorption energy of oxygen-containing species, and the crystalline/amorphous heterostructure with superhydrophilic and superaerophobic surface generates synergistic effects, providing plentiful active sites and efficient charge/mass transfer. Benefiting from this, the designed P-NiFeOxHy displays ultralow overpotentials of 159.2 and 20.8 mV to achieve 10 mA cm-2 for oxygen evolution reaction and hydrogen evolution reaction, and also shows the superior performance of urea oxidation reaction with a low voltage of 1.37 V at 10 mA cm-2 in 1 M KOH with 0.33 M urea. In-situ Raman spectra and ex-situ XPS analysis were also used to investigate the catalytic process and reveal the surface structure evolution of P-NiFeOxHy under electrochemical oxidation. Accordingly, the designed P-NiFeOxHy is employed as both cathode and anode to assemble into the urea-assisted water electrolysis device, which can reach 10 mA cm-2 with a low 1.36 V and could be further driven by a solar cell. The work reveals a design of superior activity, cost-effective and multifunctional electrocatalysts for water splitting.

Mannose antagonizes GSDME-mediated pyroptosis through AMPK activated by metabolite GlcNAc-6P.

Pyroptosis is a type of regulated cell death executed by gasdermin family members. However, how gasdermin-mediated pyroptosis is negatively regulated remains unclear. Here, we demonstrate that mannose, a hexose, inhibits GSDME-mediated pyroptosis by activating AMP-activated protein kinase (AMPK). Mechanistically, mannose metabolism in the hexosamine biosynthetic pathway increases levels of the metabolite N-acetylglucosamine-6-phosphate (GlcNAc-6P), which binds AMPK to facilitate AMPK phosphorylation by LKB1. Activated AMPK then phosphorylates GSDME at Thr6, which leads to blockade of caspase-3-induced GSDME cleavage, thereby repressing pyroptosis. The regulatory role of AMPK-mediated GSDME phosphorylation was further confirmed in AMPK knockout and GSDMET6E or GSDMET6A knock-in mice. In mouse primary cancer models, mannose administration suppressed pyroptosis in small intestine and kidney to alleviate cisplatin- or oxaliplatin-induced tissue toxicity without impairing antitumor effects. The protective effect of mannose was also verified in a small group of patients with gastrointestinal cancer who received normal chemotherapy. Our study reveals a novel mechanism whereby mannose antagonizes GSDME-mediated pyroptosis through GlcNAc-6P-mediated activation of AMPK, and suggests the utility of mannose supplementation in alleviating chemotherapy-induced side effects in clinic applications.

HK1 from hepatic stellate cell-derived extracellular vesicles promotes progression of hepatocellular carcinoma.

Extracellular vesicles play crucial roles in intercellular communication in the tumor microenvironment. Here we demonstrate that in hepatic fibrosis, TGF-ß stimulates the palmitoylation of hexokinase 1 (HK1) in hepatic stellate cells (HSCs), which facilitates the secretion of HK1 via large extracellular vesicles in a TSG101-dependent manner. The large extracellular vesicle HK1 is hijacked by hepatocellular carcinoma (HCC) cells, leading to accelerated glycolysis and HCC progression. In HSCs, the nuclear receptor Nur77 transcriptionally activates the expression of depalmitoylase ABHD17B to inhibit HK1 palmitoylation, consequently attenuating HK1 release. However, TGF-ß-activated Akt functionally represses Nur77 by inducing Nur77 phosphorylation and degradation. We identify the small molecule PDNPA that binds Nur77 to generate steric hindrance to block Akt targeting, thereby disrupting Akt-mediated Nur77 degradation and preserving Nur77 inhibition of HK1 release. Together, this study demonstrates an overlooked function of HK1 in HCC upon its release from HSCs and highlights PDNPA as a candidate compound for inhibiting HCC progression.

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio as Potential Predictors of Prognosis in Acute Ischemic Stroke.

Objective: Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been emerging as the novel inflammatory biomarkers for determining the prognosis of various diseases. This study aimed to investigate the individual and joint effects of NLR and PLR on functional outcomes of acute ischemic stroke (AIS). Methods: Our study involved 448 eligible patients with first-ever AIS. Clinical and laboratory data were collected on admission within 72 h from stroke onset. Unfavorable functional outcome was defined as a modified Rankin Scale score of 3-6 at 3 months after AIS. Cox proportional hazard model and spline regression models was used to estimate the effect of NLR and PLR on risk of adverse outcomes after the last patient who completed a 3-months follow-up was enrolled. Results: After adjusting confounders, NLR were significantly associated with the unfavorable functional outcomes (P-trend < 0.001). So were PLR (P-trend < 0.001). NLR was discovered to have higher predictive value than PLR (AUC = 0.776, 95%CI = 0.727-0.825, P < 0.001; AUC = 0.697, 95%CI = 0.641-0.753, P < 0.001). The optimal cutoff values for NLR and PLR was 3.51 and 141.52, respectively. Stratified analysis performed by cox proportional hazard model showed that high level of NLR and PLR (NLR ≥ 3.51, PLR ≥ 141.52) presented the highest risk of unfavorable functional outcomes (adjusted HR, 3.77; 95% CI: 2.38-5.95; P < 0.001). Followed by single high level of NLR (adjusted HR, 2.32; 95% CI: 1.10-4.87; P = 0.027). Single high level of PLR (NLR < 3.51, PLR ≥ 141.52) also showed higher risk than low level of the combination, but it did not reach statistical significance (adjusted HR, 1.42; 95% CI: 0.75-2.70; P = 0.285). No obvious additive [relative excess risk due to interaction (RERI) not significant] or multiplicative (adjusted HR, 0.71; 95%CI: 0.46-1.09; P = 0.114) interaction was found between the effects of NLR and PLR on the risk of unfavorable functional outcomes. Conclusion: This study demonstrated that both NLR and PLR were independent predictors of 3-months functional outcomes of AIS. They may help to identify high-risk patients more forcefully when combined together.

Nur77-activated lncRNA WFDC21P attenuates hepatocarcinogenesis via modulating glycolysis.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Orphan nuclear receptor Nur77, which is low expressed in HCC, functions as a tumor suppressor to suppress HCC. However, the detailed mechanism is still not well understood. Here, we demonstrate that Nur77 could inhibit HCC development via transcriptional activation of the lncRNA WAP four-disulfide core domain 21 pseudogene (WFDC21P). Nur77 binds to its response elements on the WFDC21P promoter to directly induce WFDC21P transcription, which inhibits HCC cell proliferation, tumor growth, and tumor metastasis both in vitro and in vivo. In clinical HCC samples, WFDC21P expression positively correlated with that of Nur77, and the loss of WFDC21P is associated with worse prognosis. Mechanistically, WFDC21P could inhibit glycolysis by simultaneously interacting with PFKP and PKM2, two key enzymes in glycolysis. These interactions not only abrogate the tetramer formation of PFKP to impede its catalytic activity but also prevent the nuclear translocation of PKM2 to suppress its function as a transcriptional coactivator. Cytosporone-B (Csn-B), an agonist for Nur77, could stimulate WFDC21P expression and suppress HCC in a WFDC21P-dependent manner. Therefore, our study reveals a new HCC suppressor and connects the glycolytic remodeling of HCC with the Nur77-WFDC21P-PFKP/PKM2 axis.

Flightless-I Blocks p62-Mediated Recognition of LC3 to Impede Selective Autophagy and Promote Breast Cancer Progression.

p62 is a receptor that facilitates selective autophagy by interacting simultaneously with cargoes and LC3 protein on the autophagosome to maintain cellular homeostasis. However, the regulatory mechanism(s) behind this process and its association with breast cancer remain to be elucidated. Here, we report that Flightless-I (FliI), a novel p62-interacting protein, promotes breast cancer progression by impeding selective autophagy. FliI was highly expressed in clinical breast cancer samples, and heterozygous deletion of FliI retarded the development of mammary tumors in PyVT mice. FliI induced p62-recruited cargoes into Triton X-100 insoluble fractions (TI) to form aggregates, thereby blocking p62 recognition of LC3 and hindering p62-dependent selective autophagy. This function of Flil was reinforced by Akt-mediated phosphorylation at Ser436 and inhibited by phosphorylation of Ulk1 at Ser64. Obstruction of autophagic clearance of p62-recruited cargoes by FliI was associated with the accumulation of oxidative damage on proteins and DNA, which could contribute to the development of cancer. Heterozygous knockout of FliI facilitated selectively autophagic clearance of aggregates, abatement of ROS levels, and protein oxidative damage, ultimately retarding mammary cancer progression. In clinical breast cancer samples, Akt-mediated phosphorylation of FliI at Ser436 negatively correlated with long-term prognosis, while Ulk1-induced FliI phosphorylation at Ser64 positively correlated with clinical outcome. Together, this work demonstrates that FliI functions as a checkpoint protein for selective autophagy in the crosstalk between FliI and p62-recruited cargoes, and its phosphorylation may serve as a prognostic marker for breast cancer.Significance: Flightless-I functions as a checkpoint protein for selective autophagy by interacting with p62 to block its recognition of LC3, leading to tumorigenesis in breast cancer.Cancer Res; 78(17); 4853-64. ©2018 AACR.

Nur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogenesis through attenuating phosphoenolpyruvate carboxykinase sumoylation.

Gluconeogenesis, an essential metabolic process for hepatocytes, is downregulated in hepatocellular carcinoma (HCC). Here we show that the nuclear receptor Nur77 is a tumour suppressor for HCC that regulates gluconeogenesis. Low Nur77 expression in clinical HCC samples correlates with poor prognosis, and a Nur77 deficiency in mice promotes HCC development. Nur77 interacts with phosphoenolpyruvate carboxykinase (PEPCK1), the rate-limiting enzyme in gluconeogenesis, to increase gluconeogenesis and suppress glycolysis, resulting in ATP depletion and cell growth arrest. However, PEPCK1 becomes labile after sumoylation and is degraded via ubiquitination, which is augmented by the p300 acetylation of ubiquitin-conjugating enzyme 9 (Ubc9). Although Nur77 attenuates sumoylation and stabilizes PEPCK1 via impairing p300 activity and preventing the Ubc9-PEPCK1 interaction, Nur77 is silenced in HCC samples due to Snail-mediated DNA methylation of the Nur77 promoter. Our study reveals a unique mechanism to suppress HCC by switching from glycolysis to gluconeogenesis through Nur77 antagonism of PEPCK1 degradation.