Integrated anti-vascular and immune-chemotherapy for colorectal carcinoma using a pH-responsive polymeric delivery system.

Colorectal carcinoma (CRC) has become one of the most prevalent malignant tumors and exploring a potential therapeutic strategy with diminished drug-associated adverse effects to combat CRC is urgent. Herein, we designed a pH-responsive polymer to efficiently encapsulate a stimulator of interferon genes (STING) agonist (5,6- dimethylxanthenone-4-acetic acid, termed ASA404) and a common clinically used chemotherapeutic agent (1-hexylcarbamoyl-5-fluorouracil, termed HCFU). Investigations in vitro demonstrated that polymer encapsulation endowed the system with a pH-dependent disassembly behavior (pHt 6.37), which preferentially selected cancerous cells with a favorable dose reduction (dose reduction index (DRI) of HCFU was 4.09). Moreover, the growth of CRC in tumor-bearing mice was effectively suppressed, with tumor suppression rates up to 94.74%, and a combination index (CI) value of less than one (CI = 0.41 for CT26 cell lines), indicating a significant synergistic therapeutic effect. Histological analysis of the tumor micro-vessel density and enzyme-linked immunosorbent assay (ELISA) tests indicated that the system increased TNF-α and IFN-ß levels in serum. Therefore, this research introduces a pH-responsive polymer-based theranostic platform with great potential for immune-chemotherapeutic and anti-vascular combination therapy of CRC.

Low-cost pyrolysis of biomass-derived nitrogen-doped porous carbon: Chlorella vulgaris replaces melamine as a nitrogen source.

Porous carbon generated from biomass has a rich pore structure, is inexpensive, and has a lot of promise for use as a carbon material for energy storage devices. In this work, nitrogen-doped porous carbon was prepared by co-pyrolysis using bagasse as the precursor and chlorella as the nitrogen source. ZnCl2 acts as both an activator and a nitrogen fixer during activation to generate pores and reduce nitrogen loss. The thermal weight loss experiments showed that the pyrolysis temperatures of bagasse and chlorella overlap, which created the possibility for the synthesis of nitrogen-rich biochar. The optimum sample (ZBC@C-5) possessed a surface area of 1508 m2g-1 with abundant nitrogen-containing functional groups. ZBC@C-5 in the three-electrode system exhibited 244.1F/g at 0.5A/g, which was extremely close to ZBC@M made with melamine as the nitrogen source. This provides new opportunities for the use of low-cost nitrogen sources. Furthermore, the devices exhibit better voltage retention (39%) and capacitance retention (96.3%). The goal of this research is to find a low cost, and effective method for creating nitrogen-doped porous carbon materials with better electrochemical performance for highly valuable applications using bagasse and chlorella.

Hemodynamics and arrhythmia disorder caused by lithium poisoning: A case report. / 锂中毒导致心律失常、血流动力学障碍1例.

Bipolar affective disorder refers to a category of mood disorders characterized clinically by the presence of both manic or hypomanic episodes and depressive episodes. Lithium stands out as the primary pharmacological intervention for managing bipolar affective disorder. However, its therapeutic dosage closely approaches toxic levels. Toxic symptoms appear when the blood lithium concentration surpasses 1.4 mmol/L, typically giving rise to gastrointestinal and central nervous system reactions. Cardiac toxicity is rare but serious in cases of lithium poisoning. The study reports a case of a patient with bipolar affective disorder who reached a blood lithium concentration of 6.08 mmol/L after the patient took lithium carbonate sustained-release tablets beyond the prescribed dosage daily and concurrently using other mood stabilizers. This resulted in symptoms such as arrhythmia, shock, impaired consciousness, and coarse tremors. Following symptomatic supportive treatment, including blood dialysis, the patient's physical symptoms gradually improved. It is necessary for clinicians to strengthen the prevention and recognition of lithium poisoning.

CncC-Keap1-P450s pathway is involved in the detoxification of emamectin benzoate in the spongy moth Lymantria dispar.

The detoxification of insecticides in insects is dependent on the expression and activity of multiple detoxification enzymes. As an important modulator of detoxification enzymes, the CncC-Keap1 pathway was involved in the detoxification of various pesticides. However, whether the CncC-Keap1 pathway is involved in the detoxification of emamectin benzoate (EMB) is unclear. In this study, we cloned the LdCncC and LdKeap1 from spongy moths (Lymantria dispar). Our results showed that EMB exposure induced oxidative stress, and activated the CncC-Keap1 pathway at mRNA and protein levels. Removing ROS by N-acetylcysteine remarkably decreased H2O2 levels and restored the expression of LdCncC and LdKeap1. The silencing LdCncC, not LdKeap1, by dsRNA significantly decreased the cytochrome P450 activities, and increased the sensitivity of larvae to EMB. Besides, the expression of CYP6B7v1, CYP321A7 and CYP4S4v1 were significantly decreased after silencing LdCncC. Notably, the knockdown of CYP6B7v1, CYP321A7 or CYP4S4v1 significantly increased the mortality induced by EMB exposure. Therefore, we proposed that activation of CncC-Keap1 pathway induced by ROS increased the detoxification of EMB in spongy moths by regulating the expression of CYP6B7v1, CYP321A7 and CYP4S4v1. Our study strengthened the understanding of the detoxification of EMB from the perspective of CncC-Keap1-P450s pathway.

Effect of microwave pretreatment on pyrolysis of chili straw: thermodynamics, activation energy, and solid reaction mechanism.

In this work, chili straw (CS) was pretreated by microwave at 250 W, 406 W, 567 W, and 700 W. The pyrolysis characteristics, kinetics, thermodynamic parameters, and solid reaction mechanism were investigated. The maximum weight loss rate increases from - 24.72%/°C at P0 to - 28.01%/°C at P700 after microwave pretreatment, and the residual mass decreases from 31.81 at P0 to 26.71% at P700. In addition, microwave pretreatment leads to a decrease in activation energy, ∆H, and ∆G at the end of the pyrolysis (α > 0.7). The solid reaction mechanism of CS pyrolysis is revealed by the Z-master plots method, with un-pretreated CS conforming to P2, D4, F3/2, and F3, respectively. Microwave pretreatment changes the solid reaction mechanism mainly in the third stage, when α = 0.8, the mechanism function changes from f(α) = (1 - α)3 at P0 to f(α) = (1 - α) at P700, and the number of reaction order is reduced, which is profitable for CS pyrolysis.

Unraveling the multi-pollutant removal using M-MoWTi (M = Fe, Mn, Cr) catalyst: experiment and mechanistic study of competition for active sites.

Multi-pollutant removal (MPR) of NO and VOCs simultaneously is efficient of flue gas treatment in coal-fired power plants. But reducing the competition for active sites between NH3, NO, C6H6, and C7H8 remains challenging. Herein, Cr, Mn, and Fe were respectively doped to MoWTi catalyst via wet impregnation. The Fe3+ + Mo5+ ↔ Fe2+ + Mo6+ redox cycle led to an increased proportion of low valence ions (Mo5+ and W5+) and facilitated the creation of active oxygen vacancies with several active sites. It also possessed plentiful mild to strong acid sites with ideal ratio. These factors enhanced catalytic activity of Fe-MoWTi. Remarkable MPR efficiencies of NO, C6H6, and C7H8 were achieved under industrial SCR condition, characterized by low oxygen but high SO2 levels at 340 °C, with removal rates reaching 89.85%, 97.57%, and 86.30% respectively. Theory calculations further revealed that Fe-MoWTi favor NH3 and O2 adsorptions. NO elimination was found to follow both Eley-Rideal (E-R) and Langmuir-Hinshelwood (L-H) processes, supported by in situ DRIFTS analysis. The reactions involving NO/NO2/nitrite/nitrate occurred with NH3(ads)/ NH4+(ads)/NH2 (ads). C6H6 and C7H8 underwent gradual oxidation, formatting alcohols, aldehydes, acids, and maleic acids, before eventually being mineralized to gaseous CO2 and H2O. Findings hold significant potential for application, providing guidance for the development of catalysts with improved resistance against SO2 poisoning and enhanced MPR capabilities.

Facile synthesis of δ-MnO2 biotemplated by waste tobacco stem-silks for enhanced removal of Sb(III).

The elimination of antimony pollution has attracted increasing concerns because of its high toxicity to human health and the natural environment. In this work, biomimetic δ-MnO2 was synthesized by using waste tobacco stem-silks as biotemplate (Bio-δ-MnO2) and used in the capture of Sb(III)from aqueous solution. The tobacco stem-silks not only provided unique wrinkled morphologies but also contained carbon element self-doped into the resulting samples. The maximum Sb(III) adsorption capacity reached 763.4 mg∙g -1, which is 2.06 times higher than δ-MnO2 without template (370.0 mg∙g -1), 4.53 times than tobacco stem-silks carbon (168.5 mg∙g -1), and 10.39 times than commercial MnO2 (73.5 mg∙g -1), respectively. The isotherm and kinetic studies indicated that the adsorption behavior was consistent with the Langmuir isotherm model and the pseudo-second-order kinetic equation. As far as we are aware, the adsorption capacity of Bio-δ-MnO2 is much higher than that of most Sb(III) adsorbents. FT-IR, XPS, SEM, XRD, and Zeta potential analyses showed that the main mechanism for the adsorption of Sb(III) by Bio-δ-MnO2 includes electrostatic attraction, surface complexation, and redox. Overall, this study provides a new sustainable way to convert agricultural wastes to more valuable products such as biomimetic adsorbent for Sb(III) removal in addition to conventional activated carbon and biochar.

Copper/Nickel/Cobalt modified molybdenum-tungsten-titanium dioxide-based catalysts for multi-pollution control of nitrogen oxide, benzene, and toluene: Enhanced redox capacity and mechanism study.

Previous studies have indicated the potential of monometallic-modified TiO2 catalysts in controlling nitrogen oxide (NOx) and volatile organic compounds (VOCs) in coal-fired flue gas. Unfortunately, increasing selective catalytic reduction (SCR) activity under complicated coal-fired flue gas status is tricky. In this study, modified Co-MoWTiO2 catalysts with multiple active sites were synthesized using the wet impregnation method, which exhibited excellent multi-pollution control ability of NO, benzene and toluene under low oxygen and high SO2 concentrations. The modification of Mo and Co achieved high dispersion and electron transfer. The interaction between W5+/W6+ and Co2+/Co3+ promoted gas-phase O2 adsorption on the catalyst surface, forming of reactive oxygen species (Oα). Density functional theory (DFT) calculations informed that the doping of Co effectively enhanced the NH3 and O2 adsorption capacity of the catalyst, and Co possessed the maximum adsorption energy for NH3 and O2. Possible pathways of multi-pollution control of NO, C6H6, and C7H8 were speculated. NH3/NH4+ on the Lewis/Bronsted acid site is reacted with intermediates of NO (e.g., NO2, nitrite, nitrate) via the Langmuir-Hinshelwood and Eley-Rideal mechanism. The introduction of NO and NH3 did not disrupt the oxidation pathways of benzene and toluene. Following the Mars-van Krevelen mechanism, C6H6 and C7H8 were progressively mineralized by Oα into CO2 and H2O.

Transcriptome analysis and identification of the low potassium stress-responsive gene SiSnRK2.6 in foxtail millet (Setaria italica L.).

KEY MESSAGE: The transcriptome is beneficial for dissecting the mechanism of millet in response to low potassium stress and SiSnRK2.6 was identified as a potential target for improving low potassium stress tolerance. Foxtail millet (Setaria italica L.), which originated in China, has high nutrient utilization character. Nevertheless, the molecular mechanism of its tolerance to low potassium stress is largely unclear. In this research, the low potassium tolerant variety "Yugu28" was screened out by low potassium stress treatment, and the transcriptome of "Yugu28" under low potassium stress was comprehensively analyzed. A total of 4254 differentially expressed genes (DEGs) were identified, including 1618 up-regulated and 2636 down-regulated genes, respectively. In addition, there were 302 transcription factor (TF) genes in the DEGs and MYB TFs accounted for the highest proportion, which was 14.9%. After functional analysis of all DEGs, a total of 7 genes involved in potassium transport and potassium ion channels and 50 genes corresponding to hormones were screened. The expression levels of randomly selected 17 DEGs were verified by qRT-PCR and the results coincided well with the RNA-seq analysis, indicating the reliability of our transcriptome data. Moreover, one of the ABA signaling pathway genes, SiSnRK2.6, was identified and selected for further functional verification. Compared with the wild type, transgenic rice with ecotopic expression of SiSnRK2.6 showed remarkably increased root length and root number, indicating that overexpression of SiSnRK2.6 can enhance the resistance of transgenic plants to low potassium stress.

Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis.

Importance: The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals. Objective: To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. Design, Setting, and Participants: This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022. Main Outcomes and Measures: For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z < -1.96) or supranormal (z > 1.96) scores. Results: Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [<11.42%]) and similar to that of healthy individuals (<115 individuals [<9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (ß = -0.08; 95% CI, -0.13 to -0.02; P = .02 for false discovery rate) and IQ (ß = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate). Conclusions and Relevance: In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.

Impact of waste separation on the biological nitrogen removal in a MSW incineration leachate treatment plant: Performance and microbial community shift.

After waste separation program was launched in China in 2019, incineration leachate treatment plants are facing a challenge of effective removal of nitrogen from leachate due to lack of sufficient carbon source. In this study, the performance of a biological incineration leachate treatment process (anaerobic digestion (AD) - two-stage anoxic/aerobic (A/O) process) was evaluated after adopting the waste separation program, and the changes in the microbial community and function was analyzed using 16S rRNA amplicon sequencing technology. Results showed that after the waste separation, the influent chemical oxygen demand (COD) concentration reduced by 90% (from 19,300 to 1780 mg L-1) with the COD/N ratio decreased from 12.3 to 1.4, which led to a decreased nitrogen removal efficiency (NRE) of <65% and a high effluent NO3- accumulation (445.8-986.5 mg N·L-1). By bypassing approximately 60% of the influent to the two-stage A/O process and adding external carbon source (glucose), the mean NRE increased to 86.3 ± 7.4%. Spearman's analysis revealed that refractory compounds in the bypassed leachate were closely related to the variations in bacterial community composition and nitrogen removal function in the two-stage A/O, leading to a weakened correlation of microbial network. KEGG functional pathway predictions based on Tax4Fun also confirmed that the bypassed leachate induced xenobiotic compounds to the two-stage A/O process, the relative abundance of nitrogen metabolism was reduced by 32%, and more external carbon source was required to ensure the satisfactory nitrogen removal of >80%. The findings provide a good guide for regulation of incineration leachate treatment processes after the waste separation.

Comprehensive Scrna-Seq Analysis and Identification of CD8_+T Cell related Gene Markers for Predicting Prognosis and Drug Resistance of Hepatocellular Carcinoma.

BACKGROUND: Tumor heterogeneity of immune infiltration of cells plays a decisive role in hepatocellular carcinoma (HCC) therapy response and prognosis. This study investigated the effect of different subtypes of CD8+T cells on the HCC tumor microenvironment about its prognosis. METHODS: Single-cell RNA sequencing, transcriptome, and single-nucleotide variant data from LUAD patients were obtained based on the GEO, TCGA, and HCCD18 databases. CD8+ T cells-associated subtypes were identified by consensus clustering analysis, and genes with the highest correlation with prognostic CD8+ T cell subtypes were identified using WGCNA. The ssGSEA and ESTIMATE algorithms were used to calculate pathway enrichment scores and immune cell infiltration levels between different subtypes. Finally, the TIDE algorithm, CYT score, and tumor responsiveness score were utilized to predict patient response to immunotherapy. RESULTS: We defined 3 CD8+T cell clusters (CD8_0, CD8_1, CD8_2) based on the scRNA- seq dataset (GSE149614). Among, CD8_2 was prognosis-related risk factor with HCC. We screened 30 prognosis genes from CD8_2, and identified 3 molecular subtypes (clust1, clust2, clust3). Clust1 had better survival outcomes, higher gene mutation, and enhanced immune infiltration. Furthermore, we identified a 12 genes signature (including CYP7A1, SPP1, MSC, CXCL8, CXCL1, GCNT3, TMEM45A, SPP2, ME1, TSPAN13, S100A9, and NQO1) with excellent prediction performance for HCC prognosis. In addition, High-score patients with higher immune infiltration benefited less from immunotherapy. The sensitivity of low-score patients to multiple drugs including Parthenolide and Shikonin was significantly higher than that of high-score patients. Moreover, high-score patients had increased oxidative stress pathways scores, and the RiskScore was closely associated with oxidative stress pathways scores. And the nomogram had good clinical utility. CONCLUSION: To predict the survival outcome and immunotherapy response for HCC, we developed a 12-gene signature based on the heterogeneity of the CD8+ T cells.

Human HLA-DR+CD27+ regulatory T cells show enhanced antigen-specific suppressive function.

Regulatory T cells (Tregs) have potential for the treatment of autoimmune diseases and graft rejection. Antigen specificity and functional stability are considered critical for their therapeutic efficacy. In this study, expansion of human Tregs in the presence of porcine PBMCs (xenoantigen-expanded Tregs, Xn-Treg) allowed the selection of a distinct Treg subset, coexpressing the activation/memory surface markers HLA-DR and CD27 with enhanced proportion of FOXP3+Helios+ Tregs. Compared with their unsorted and HLA-DR+CD27+ double-positive (DP) cell-depleted Xn-Treg counterparts, HLA-DR+CD27+ DP-enriched Xn-Tregs expressed upregulated Treg function markers CD95 and ICOS with enhanced suppression of xenogeneic but not polyclonal mixed lymphocyte reaction. They also had less Treg-specific demethylation in the region of FOXP3 and were more resistant to conversion to effector cells under inflammatory conditions. Adoptive transfer of porcine islet recipient NOD/SCID IL2 receptor γ-/- mice with HLA-DR+CD27+ DP-enriched Xn-Tregs in a humanized mouse model inhibited porcine islet graft rejection mediated by 25-fold more human effector cells. The prolonged graft survival was associated with enhanced accumulation of FOXP3+ Tregs and upregulated expression of Treg functional genes, IL10 and cytotoxic T lymphocyte antigen 4, but downregulated expression of effector Th1, Th2, and Th17 cytokine genes, within surviving grafts. Collectively, human HLA-DR+CD27+ DP-enriched Xn-Tregs expressed a specific regulatory signature that enabled identification and isolation of antigen-specific and functionally stable Tregs with potential as a Treg-based therapy.

Glutamatergic basis of antipsychotic response in first-episode psychosis: a dual voxel study of the anterior cingulate cortex.

A subgroup of patients with schizophrenia is believed to have aberrant excess of glutamate in the frontal cortex; this subgroup is thought to show poor response to first-line antipsychotic treatments that focus on dopamine blockade. If we can identify this subgroup early in the course of illness, we can reduce the repeated use of first-line antipsychotics and potentially stratify first-episode patients to intervene early with second-line treatments such as clozapine. The use of proton magnetic resonance spectroscopy (1H-MRS) to measure glutamate and Glx (glutamate plus glutamine) may provide a means for such a stratification. We must first establish if there is robust evidence linking elevations in anterior cingulate cortex (ACC) glutamate metabolites to poor response, and determine if the use of antipsychotics worsens the glutamatergic excess in eventual nonresponders. In this study, we estimated glutamate levels at baseline in 42 drug-naive patients with schizophrenia. We then treated them all with risperidone at a standard dose range of 2-6 mg/day and followed them up for 3 months to categorize their response status. We expected to see baseline "hyperglutamatergia" in nonresponders, and expected this to worsen over time at the follow-up. In line with our predictions, nonresponders had higher glutamate than responders, but patients as a group did not differ in glutamate and Glx from the healthy control (HC) group before treatment-onset (F1,79 = 3.20, p = 0.046, partial η2 = 0.075). Glutamatergic metabolites did not change significantly over time in both nonresponders and responders over the 3 months of antipsychotic exposure (F1,31 = 1.26, p = 0.270, partial η2 = 0.039). We conclude that the use of antipsychotics without prior knowledge of later response delays symptom relief in a subgroup of first-episode patients, but does not worsen the glutamatergic excess seen at the baseline. Given the current practice of nonstratified use of antipsychotics, longer-time follow-up MRS studies are required to see if improvement in symptoms accompanies a dynamic shift in glutamate profile.

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) alleviate excessive autophagy of ovarian granular cells through VEGFA/PI3K/AKT/mTOR pathway in premature ovarian failure rat model.

BACKGROUND: Premature ovarian failure (POF) is one of the leading causes of female infertility and is accompanied by abnormal endocrine, seriously affecting female quality of life. Previous studies have demonstrated that mesenchymal stem cells (MSCs) transplantation is a promising therapeutic strategy for POF. However, the mechanism remains obscure. This study aims to investigate the therapeutic effect of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on ovarian function in the POF rat model and explore the underlying mechanisms. METHODS: The ovarian function was evaluated by ovarian morphology, histology, estrous cycle, hormone levels (AMH, E2, FSH, and LH), and fertility ability to investigate the effect of hUC-MSCs on the POF rats model. The cytokines levels were assayed in serum using protein array to explore the mechanisms of hUC-MSCs therapy for POF. The excessive autophagy levels were evaluated using a co-culture system of 3D MSCs spheroids with human ovarian granulosa cell line (KGN) or primary ovarian granulosa cells (GCs) to understand the paracrine effect of hUC-MSCs on GCs. The related proteins expression of autophagy and PI3K/AKT/mTOR pathway was detected using Western Blotting and/or in various inhibitors supplement to further demonstrate that vascular endothelial growth factor A (VEGFA) secreted by hUC-MSCs can alleviate excessive autophagy of ovarian GCs via PI3K/AKT/mTOR signaling pathway. The ovarian culture model in vitro was applied to confirm the mechanism. RESULTS: The ovarian function of POF and the excessive autophagy of ovarian GCs were restored after hUC-MSCs transplantation. The protein array result demonstrated that VEGF and PI3K/AKT might improve ovarian function. in vitro experiments demonstrated that VEGFA secreted by hUC-MSCs could decrease oxidative stress and inhibit excessive autophagy of ovarian GCs via PI3K/AKT/mTOR pathway. The ovarian culture model results confirmed this mechanism in vitro. CONCLUSION: The hUC-MSCs can alleviate excessive autophagy of ovarian GCs via paracrine VEGFA and regulate the PI3K/AKT/mTOR signaling pathway, thereby improving the ovarian function of POF.

Cu2+ -Anchored Carbon Nano-Photocatalysts for Visible Water Splitting to Boost Hydrogen Cuproptosis.

Both hydrogen (H2 ) and copper ions (Cu+ ) can be used as anti-cancer treatments. However, the continuous generation of H2 molecules and Cu+ in specific sites of tumors is challenging. Here we anchored Cu2+ on carbon photocatalyst (Cu@CDCN) to allow the continuous generation of H2 and hydrogen peroxide (H2 O2 ) in tumors using the two-electron process of visible water splitting. The photocatalytic process also generated redox-active Cu-carbon centers. Meanwhile, the Cu2+ residues reacted with H2 O2 (the obstacle to the photocatalytic process) to accelerate the two-electron process of water splitting and cuprous ion (Cu+ ) generation, in which the Cu2+ residue promoted a pro-oxidant effect with glutathione through metal-reducing actions. Both H2 and Cu+ induced mitochondrial dysfunction and intracellular redox homeostasis destruction, which enabled hydrogen therapy and cuproptosis to inhibit cancer cell growth and suppress tumor growth. Our research is the first attempt to integrate hydrogen therapy and cuproptosis using metal-enhanced visible solar water splitting in nanomedicine, which may provide a safe and effective cancer treatment.

Mechanical stretch promotes apoptosis and impedes ciliogenesis of primary human airway basal stem cells.

BACKGROUND: Airway basal stem cells (ABSCs) have self-renewal and differentiation abilities. Although an abnormal mechanical environment related to chronic airway disease (CAD) can cause ABSC dysfunction, it remains unclear how mechanical stretch regulates the behavior and structure of ABSCs. Here, we explored the effect of mechanical stretch on primary human ABSCs. METHODS: Primary human ABSCs were isolated from healthy volunteers. A Flexcell FX-5000 Tension system was used to mimic the pathological airway mechanical stretch conditions of patients with CAD. ABSCs were stretched for 12, 24, or 48 h with 20% elongation. We first performed bulk RNA sequencing to identify the most predominantly changed genes and pathways. Next, apoptosis of stretched ABSCs was detected with Annexin V-FITC/PI staining and a caspase 3 activity assay. Proliferation of stretched ABSCs was assessed by measuring MKI67 mRNA expression and cell cycle dynamics. Immunofluorescence and hematoxylin-eosin staining were used to demonstrate the differentiation state of ABSCs at the air-liquid interface. RESULTS: Compared with unstretched control cells, apoptosis and caspase 3 activation of ABSCs stretched for 48 h were significantly increased (p < 0.0001; p < 0.0001, respectively), and MKI67 mRNA levels were decreased (p < 0.0001). In addition, a significant increase in the G0/G1 population (20.2%, p < 0.001) and a significant decrease in S-phase cells (21.1%, p < 0.0001) were observed. The ratio of Krt5+ ABSCs was significantly higher (32.38% vs. 48.71%, p = 0.0037) following stretching, while the ratio of Ac-tub+ cells was significantly lower (37.64% vs. 21.29%, p < 0.001). Moreover, compared with the control, the expression of NKX2-1 was upregulated significantly after stretching (14.06% vs. 39.51%, p < 0.0001). RNA sequencing showed 285 differentially expressed genes, among which 140 were upregulated and 145 were downregulated, revealing that DDIAS, BIRC5, TGFBI, and NKX2-1 may be involved in the function of primary human ABSCs during mechanical stretch. There was no apparent difference between stretching ABSCs for 24 and 48 h compared with the control. CONCLUSIONS: Pathological stretching induces apoptosis of ABSCs, inhibits their proliferation, and disrupts cilia cell differentiation. These features may be related to abnormal regeneration and repair observed after airway epithelium injury in patients with CAD.

Activation of the p62-Keap1-Nrf2 pathway protects against oxidative stress and excessive autophagy in ovarian granulosa cells to attenuate DEHP-induced ovarian impairment in mice.

Di-(2-ethylhexyl) phthalate (DEHP) is widely used in various plastics but has been demonstrated to cause female reproductive toxicity. However, the exact mechanism underlying the ovarian damage induced by DEHP remains unclear. In this study, DEHP was administered orally to 5-week-old female mice for 30 days at doses of 0, 250, 500, and 1000 mg/kg/day. The findings demonstrated that DEHP exposure disrupted ovarian function and follicular development as well as induced oxidative stress and autophagy in ovarian granulosa cells (GCs). Further, 200 µM mono-(2-ethylhexyl) phthalate (MEHP), the primary metabolite of DEHP in vivo, induced autophagy in both human ovarian granulosa cells line (KGN) and mouse primary GCs within 24 h in vitro. However, it did not affect the p62-dependent autophagy flux. Furthermore, MEHP-induced autophagy was inhibited by the autophagy inhibitor 3-MA and exacerbated by the autophagy activator rapamycin, indicating that MEHP induces excessive autophagy in GCs. Subsequently, we found that MEHP-induced autophagic cell death was primarily attributed to oxidative damage from elevated intracellular ROS levels. Meanwhile, MEHP exposure induced nuclear translocation of erythroid-derived factor 2-related factor (Nrf2), a key regulator of antioxidant activity resulting in activating antioxidant effects. Interestingly, we also found that MEHP-induced increase in p62 competitively binds Keap1, thereby facilitating nuclear translocation of Nrf2 and establishing a positive feedback loop in antioxidant regulation. Therefore, this study demonstrated that inhibition of Nrf2 could aggravate oxidative damage and enhance excessive autophagy caused by MEHP, while activation of Nrf2 could reverse the trend. These findings have also been reinforced in studies of cultured ovaries in vitro. Our study suggests that the p62-Keap1-Nrf2 pathway may serve as a potential protective mechanism against DEHP-induced oxidative stress and excessive autophagy in mouse GCs.

Plant Photocatalysts: Photoinduced Oxidation and Reduction Abilities of Plant Leaf Ashes under Solar Light.

Plant leaf ashes were obtained via the high temperature calcination of the leaves of various plants, such as sugarcane, couchgrass, bracteata, garlic sprout, and the yellowish leek. Although the photosynthesis systems in plant leaves cannot exist after calcination, minerals in these ashes were found to exhibit photochemical activities. The samples showed solar light photocatalytic oxidation activities sufficient to degrade methylene blue dye. They were also shown to possess intrinsic dehydrogenase-like activities in reducing the colorless electron acceptor 2,3,5-triphenyltetrazolium chloride to a red formazan precipitate under solar light irradiation. The possible reasons behind these two unreported phenomena were also investigated. These ashes were characterized using a combination of physicochemical techniques. Moreover, our findings exemplify how the soluble and insoluble minerals in plant leaf ashes can be synergistically designed to yield next-generation photocatalysts. It may also lead to advances in artificial photosynthesis and photocatalytic dehydrogenase.

Characterizing the lavage and serum cytokine profiles of interstitial pneumonia with autoimmune features and their implications for progressive fibrosis.

OBJECTIVE: To explore whether cytokines could be potential biomarkers to predict the occurrence of progressive fibrosis (PF) phenotype among interstitial pneumonia with autoimmune features (IPAF) patients. METHODS: This study prospectively collected 51 IPAF and 15 Idiopathic Pulmonary Fibrosis (IPF) patients who were diagnosed at First Affiliated Hospital of Guangzhou Medical University from July 2020 to June 2021. All IPAF patients were followed up for one year to assess the development of PF phenotype. Paired Broncho Alveolar Lavage Fluid (BALF) and serum samples were collected at enrolment and analyzed for differences in 39 cytokines expression. Principal component analysis (PCA) and cluster analysis were conducted to identify a high-risk subgroup of IPAF patients for developing the PF phenotype. Finally, cytokine differences were compared between subgroups to identify potential biomarkers for PF-IPAF occurrence. RESULTS: According to the PCA analysis, 81.25% of PF-IPAF patients share overlapped BALF cytokine profiles with IPF. Cluster analysis indicated IPAF patients in subtype 2 had a higher risk to develop PF phenotype within one year (P = 0.048), characterized by higher levels of CCL2, CXCL12 and lower lymphocyte proportion (LYM%) in BALF. Elevated levels of BALF CCL2 (>299.16 pg./ml) or CXCL12 (>600.115 pg./ml) were associated with a significantly higher risk of developing PF phenotype within one year follow-up period (P = 0.009, 0.001). CONCLUSION: PF-IPAF phenotype exhibits similar inflammatory cytokine profiles to IPF. Cytokine CCL2, CXCL12, and LYM% in BALF serving as potential biomarkers for predicting the PF phenotype in IPAF patients. CLINICAL TRIAL REGISTRATION: Register: Qian Han, Website: http://www.chictr.org.cn/showproj.aspx?proj=61619, Registration number: ChiCTR2000040998.