Effect of Compressive Modulus of Porous PVA Hydrogel Coating on the Preventing Adhesion of Polypropylene Mesh.

PP mesh is a widely used prosthetic material in hernia repair. However, visceral adhesion is one of the worst complications of this operation. Hence, an anti-adhesive PP mesh is developed by coating porous polyvinyl alcohol (PVA) hydrogel on PP surface via freezing-thawing process method. The compressive modulus of porous PVA hydrogel coating is first regulated by the addition of porogen sodium bicarbonate (NaHCO3) at various quality ratios with PVA. As expected, the porous hydrogel coating displayed modulus more closely resembling that of native abdominal wall tissue. In vitro tests demonstrate the modified PP mesh show superior coating stability, excellent hemocompatibility, and good cytocompatibility. In vivo experiments illustrate that PP mesh coated by the PVA4 hydrogel that mimicked the modulus of native abdominal wall could prevent adhesion effectively. Based on this, the rapamycin (RPM) is loaded into the porous PVA4 hydrogel coating to further improve anti-adhesive property of PP mesh. The Hematoxylin and eosin (H&E) and Masson trichrome (MT) staining results verified that the resulting mesh could alleviate the inflammation response and reduce the deposition of collagen around the implantation zone. The biomimetic mechanical property and anti-adhesive property of modified PP mesh make it a valuable candidate for application in hernioplasty.

pH Homeodynamics and Male Fertility: A Coordinated Regulation of Acid-Based Balance during Sperm Journey to Fertilization.

pH homeostasis is crucial for spermatogenesis, sperm maturation, sperm physiological function, and fertilization in mammals. HCO3- and H+ are the most significant factors involved in regulating pH homeostasis in the male reproductive system. Multiple pH-regulating transporters and ion channels localize in the testis, epididymis, and spermatozoa, such as HCO3- transporters (solute carrier family 4 and solute carrier family 26 transporters), carbonic anhydrases, and H+-transport channels and enzymes (e.g., Na+-H+ exchangers, monocarboxylate transporters, H+-ATPases, and voltage-gated proton channels). Hormone-mediated signals impose an influence on the production of some HCO3- or H+ transporters, such as NBCe1, SLC4A2, MCT4, etc. Additionally, ion channels including sperm-specific cationic channels for Ca2+ (CatSper) and K+ (SLO3) are directly or indirectly regulated by pH, exerting specific actions on spermatozoa. The slightly alkaline testicular pH is conducive to spermatogenesis, whereas the epididymis's low HCO3- concentration and acidic lumen are favorable for sperm maturation and storage. Spermatozoa pH increases substantially after being fused with seminal fluid to enhance motility. In the female reproductive tract, sperm are subjected to increasing concentrations of HCO3- in the uterine and fallopian tube, causing a rise in the intracellular pH (pHi) of spermatozoa, leading to hyperpolarization of sperm plasma membranes, capacitation, hyperactivation, acrosome reaction, and ultimately fertilization. The physiological regulation initiated by SLC26A3, SLC26A8, NHA1, sNHE, and CFTR localized in sperm is proven for certain to be involved in male fertility. This review intends to present the key factors and characteristics of pHi regulation in the testes, efferent duct, epididymis, seminal fluid, and female reproductive tract, as well as the associated mechanisms during the sperm journey to fertilization, proposing insights into outstanding subjects and future research trends.

Ruthenium-Catalyzed Meta-Selective Trifluoroisopropylation of Arenes.

This work reports the mild and efficient Ru-catalyzed trifluoroisopropylation of arenes using 2-bromo-1,1,1-trifluoropropane. Various bioactive molecules, such as purine and nucleoside derivatives, were well-suited for this transformation, affording the corresponding products in moderate-to-good yields. This method provides an efficient strategy for synthesizing trifluoroisopropyl molecules for drug discovery.

Exploring the oncogenic potential of circSOD2 in clear cell renal cell carcinoma: a novel positive feedback loop.

BACKGROUND: Existing studies have found that circular RNAs (circRNAs) act as sponges for micro RNAs (miRNAs) to control downstream genes. However, the specific functionalities and mechanisms of circRNAs in human clear cell renal cell carcinoma (ccRCC) have yet to be thoroughly investigated. METHODS: Patient cohorts from online databases were used to screen candidate circRNAs, while another cohort from our hospital was obtained for validation. CircSOD2 was identified as a potential oncogenic target, and its relevant characteristics were investigated during ccRCC progression through various assays. A positive feedback loop containing downstream miRNA and its target gene were identified using bioinformatics and validated by luciferase reporter assays, RNA pull-down, and high-throughput sequencing. RESULTS: CircSOD2 expression was elevated in tumor samples and significantly correlated with overall survival (OS) and the tumor stage of ccRCC patients, which appeared in the enhanced proliferation, invasion, and migration of tumor cells. Through competitive binding to circSOD2, miR-532-3p can promote the expression of PAX5 and the progression of ccRCC, and such regulation can be salvaged by miR-532-3p inhibitor. CONCLUSION: A novel positive feedback loop, PAX5/circSOD2/miR-532-3p/PAX5 was identified in the study, indicating that the loop may play an important role in the diagnosis and prognostic prediction in ccRCC patients.

Assessing the efficiency of eligibility criteria for low-dose computed tomography lung screening in China according to current guidelines.

BACKGROUND: Evidence from observational studies indicates that lung cancer screening (LCS) guidelines with high rates of lung cancer (LC) underdiagnosis, and although current screening guidelines have been updated and eligibility criteria for screening have been expanded, there are no studies comparing the efficiency of LCS guidelines in Chinese population. METHODS: Between 2005 and 2022, 31,394 asymptomatic individuals were screened using low-dose computed tomography (LDCT) at our institution. Demographic data and relevant LC risk factors were collected. The efficiency of the LCS for each guideline criteria was expressed as the efficiency ratio (ER). The inclusion rates, eligibility rates, LC detection rates, and ER based on the different eligibility criteria of the four guidelines were comparatively analyzed. The four guidelines were as follows: China guideline for the screening and early detection of lung cancer (CGSL), the National Comprehensive Cancer Network (NCCN), the United States Preventive Services Task Force (USPSTF), and International Early Lung Cancer Action Program (I-ELCAP). RESULTS: Of 31,394 participants, 298 (155 women, 143 men) were diagnosed with LC. For CGSL, NCCN, USPSTF, and I-ELCAP guidelines, the eligibility rates for guidelines were 13.92%, 6.97%, 6.81%, and 53.46%; ERe for eligibility criteria were 1.46%, 1.64%, 1.51%, and 1.13%, respectively; and for the inclusion rates, they were 19.0%, 9.5%, 9.3%, and 73.0%, respectively. LCs which met the screening criteria of CGSL, NCCN, USPSTF, and I-ELCAP guidelines were 29.2%, 16.4%, 14.8%, and 86.6%, respectively. The age and smoking criteria for CGSL were stricter, hence resulting in lower rates of LC meeting the screening criteria. The CGSL, NCCN, and USPSTF guidelines showed the highest underdiagnosis in the 45-49 age group (17.4%), while the I-ELCAP guideline displayed the highest missed diagnosis rate (3.0%) in the 35-39 age group. Males and females significantly differed in eligibility based on the criteria of the four guidelines (P < 0.001). CONCLUSIONS: The I-ELCAP guideline has the highest eligibility rate for both males and females. But its actual efficiency ratio for those deemed eligible by the guideline was the lowest. Whereas the NCCN guideline has the highest ERe value for those deemed eligible by the guideline.

Characterizing the mechanism of action for mRNA therapeutics for the treatment of propionic acidemia, methylmalonic acidemia, and phenylketonuria.

Messenger RNA (mRNA) therapeutics delivered via lipid nanoparticles hold the potential to treat metabolic diseases caused by protein deficiency, including propionic acidemia (PA), methylmalonic acidemia (MMA), and phenylketonuria (PKU). Herein we report results from multiple independent preclinical studies of mRNA-3927 (an investigational treatment for PA), mRNA-3705 (an investigational treatment for MMA), and mRNA-3210 (an investigational treatment for PKU) in murine models of each disease. All 3 mRNA therapeutics exhibited pharmacokinetic/pharmacodynamic (PK/PD) responses in their respective murine model by driving mRNA, protein, and/or protein activity responses, as well as by decreasing levels of the relevant biomarker(s) when compared to control-treated animals. These preclinical data were then used to develop translational PK/PD models, which were scaled allometrically to humans to predict starting doses for first-in-human clinical studies for each disease. The predicted first-in-human doses for mRNA-3927, mRNA-3705, and mRNA-3210 were determined to be 0.3, 0.1, and 0.4 mg/kg, respectively.

Low ankle-brachial index is associated with higher cardiovascular mortality in individuals with nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Ankle brachial index (ABI) is a risk factor for cardiovascular mortality, but it is unclear whether ABI is associated with cardiovascular mortality in patients with nonalcoholic fatty liver disease (NAFLD). The current study aimed to evaluate the association between ABI with cardiovascular and all-cause mortality in patients with NAFLD. METHODS: We performed a cohort study using the data of the1999-2004 National Health and Nutrition Examination Survey data of adults. Mortality data were followed up to December 2015. NAFLD was defined by the hepatic steatosis index or the US fatty liver index. ABI was classified into three groups: ABI ≤ 0.9 (low value); 0.9 < ABI ≤ 1.1 (borderline value); ABI greater than 1.1 (normal value). RESULTS: We found that low ABI was associated with an increased risk of cardiovascular mortality in patients with NAFLD (HR: 2.42, 95% CI 1.10-5.33 for low value ABI vs normal value ABI, P for trend = 0.04), and the relationship was linearly and negatively correlated in the range of ABI < 1.4. However, low ABI was not associated with all-cause mortality in patients with NAFLD. Stratified by cardiovascular disease, ABI remains inversely correlated with cardiovascular mortality in NAFLD patients without cardiovascular disease. Stratified by diabetes, ABI is inversely correlated with cardiovascular mortality in NAFLD patients regardless of diabetes status. CONCLUSIONS: Low ABI is independently associated with higher cardiovascular mortality in NAFLD cases. This correlation remains significant even in the absence of pre-existing cardiovascular disease or diabetes.

Unlocking Genetic Mysteries during the Epic Sperm Journey toward Fertilization: Further Expanding Cre Mouse Lines.

The spatiotemporal expression patterns of genes are crucial for maintaining normal physiological functions in animals. Conditional gene knockout using the cyclization recombination enzyme (Cre)/locus of crossover of P1 (Cre/LoxP) strategy has been extensively employed for functional assays at specific tissue or developmental stages. This approach aids in uncovering the associations between phenotypes and gene regulation while minimizing interference among distinct tissues. Various Cre-engineered mouse models have been utilized in the male reproductive system, including Dppa3-MERCre for primordial germ cells, Ddx4-Cre and Stra8-Cre for spermatogonia, Prm1-Cre and Acrv1-iCre for haploid spermatids, Cyp17a1-iCre for the Leydig cell, Sox9-Cre for the Sertoli cell, and Lcn5/8/9-Cre for differentiated segments of the epididymis. Notably, the specificity and functioning stage of Cre recombinases vary, and the efficiency of recombination driven by Cre depends on endogenous promoters with different sequences as well as the constructed Cre vectors, even when controlled by an identical promoter. Cre mouse models generated via traditional recombination or CRISPR/Cas9 also exhibit distinct knockout properties. This review focuses on Cre-engineered mouse models applied to the male reproductive system, including Cre-targeting strategies, mouse model screening, and practical challenges encountered, particularly with novel mouse strains over the past decade. It aims to provide valuable references for studies conducted on the male reproductive system.

Gibberellic acid targeting ZBTB16 reduces NF-κB dependent inflammatory stress in sepsis-induced neuroinflammation.

OBJECTIVE: Sepsis is frequently complicated by neuroinflammation. Gibberellic acid (GA3) is recognized for its anti-inflammatory properties. In this study, our objective was to investigate whether GA3 could alleviate Nuclear factor-kappa B (NF-κB) -dependent inflammatory stress in sepsis-induced neuroinflammation. METHODS: C57BL/6 J mice were administered 10 mg/kg lipopolysaccharide (LPS) to induce sepsis. BV2 cells were pre-incubated with GA3 and subjected lipopolysaccharide stimulation to replicate the inflammatory microglia during sepsis. Subsequently, we assessed the release of IL-6, TNF-α, and IL-1ß, along with the expression of Zbtb16, NF-κB, and IκB. To investigate whether any observed anti-inflammatory effects of GA3 were mediated through a Zbtb16-dependent mechanism, Zbtb16 was silenced using siRNA. RESULTS: GA3 improved the survival of sepsis mice and alleviated post-sepsis cognitive impairment. Additionally, GA3 attenuated microglial M1 activation (pro-inflammatory phenotype), inflammation, and neuronal damage in the brain. Moreover, GA3 inhibited the release of TNF-α, IL-6, and IL-1ß in microglia stimulated with LPS. The NF-κB signaling pathway emerged as one of the key molecular pathways associated with the impact of GA3 on LPS-stimulated microglia. Lastly, GA3 upregulated Zbtb16 expression in microglia that had been downregulated by LPS. The inhibitory effects of GA3 on microglial M1 activation were partially reversed through siRNA knockdown of Zbtb16. CONCLUSIONS: Pre-incubation of microglia with GA3 led to the upregulation of the NF-κB regulator, Zbtb16. This process counteracted LPS-induced microglial M1 activation, resulting in an anti-inflammatory effect upon subsequent LPS stimulation.

Iridium-Catalyzed Ortho-Selective C-H Borylation of Aryl Ketones with Transient Imine Ligands.

Ortho-selective C-H borylation of aromatic ketones has not been extensively explored. Herein, we report the iridium-catalyzed ortho-selective C-H borylation of aromatic ketones using in situ-formed imine as the ligand. Good compatibility is observed for various substituted acetophenones and other aromatic ketones, and corresponding products are obtained with medium to excellent yields.

Association of the triglyceride-glucose index and its related parameters with frailty.

BACKGROUND: Frailty is a dynamic geriatric condition. Limited studies have examined the association of the triglyceride-glucose (TyG) index and its related indicators [TyG index, triglyceride glucose-waist to height ratio (TyG-WHtR), triglyceride glucose-waist circumference (TyG-WC), and triglyceride glucose-body mass index (TyG-BMI)] with frailty, and the potential links among them remain unclear. On the basis of data from the National Health and Nutrition Examination Survey (NHANES), this study investigated the potential relationships of the TyG index and its related indices with frailty. METHODS: This research included 7,965 participants from NHANES 2003-2018. The relationship of the TyG index and its related indices with frailty was investigated with binary logistic regression analyses, restricted cubic spline (RCS), and receiver operating characteristic (ROC) curve. Potential influences were further investigated through stratified analyses and interaction tests. RESULTS: The prevalence of frailty in the participants of this study was 25.59%, with a average frailty index of 0.16 (0.00). In the three regression analysis models, the continuous TyG index and its associated indices were positively associated with frailty. In addition, quartiles of TyG, TyG-WC, TyG-WHtR, and TyG-BMI were significantly associated with increased frailty prevalence in the fully adjusted models (TyG Q4 vs. Q1, OR = 1.58, 95% CI: 1.19, 2.09, P = 0.002; TyG-WC Q4 vs. Q1, OR = 2.40, 95% CI: 1.90, 3.04, P < 0.001; TyG-WHtR Q4 vs. Q1, OR = 2.26, 95% CI: 1.82, 2.81, P < 0.001; TyG- BMI Q4 vs. Q1, OR = 2.16, 95% CI: 1.76, 2.64, P < 0.001). According to RCS analysis, TyG, TyG-WC, TyG-WHtR, and TyG-BMI were linearly and positively associated with frailty. ROC curves revealed that TyG-WHtR (AUC: 0.654) had greater diagnostic value for frailty than TyG (AUC: 0.604), TyG-BMI (AUC: 0.621), and TyG-WC (AUC: 0.629). All of the stratified analyses and interaction tests showed similar results. CONCLUSIONS: Elevated TyG and its associaed indices are associated with an increased prevalence of frailty. Reasonable control of blood glucose and blood lipids, and avoidance of obesity, may aid in reducing the occurrence of frailty in middle-aged and older adults.

Iron Overload Induces Hepatic Ferroptosis and Insulin Resistance by Inhibiting the Jak2/stat3/slc7a11 Signaling Pathway.

Recent studies showed that patients with iron overload had increased risk of insulin resistance or diabetes. Ferroptosis is a new type of cell death mainly caused by iron-dependent oxidative damage. In the present study, we investigated potential mechanisms of iron overload induced hepatic ferroptosis and insulin resistance through in vivo and in vitro experiments. In vivo, the mice models of iron overload were established by intraperitoneal injection of iron dextran. The changes of body weight, serum ferritin and blood glucose were measured. Hematoxylin-eosin (HE) and Perl's stainings were used to observe the pathological changes and iron deposition in the liver of mice. In vitro, HepG2 cells were treated with ferric ammonium citrate (FAC, 9 mmol/L, 24 h) to establish the cell models of iron overload. The labile iron pool, cell viability, glucose consumption and glycogen contents were measured. The ultrastructure of mitochondria was observed by transmission electron microscope (TEM). The malondialdehyde (MDA) and glutathione (GSH) kits were used to detect lipid peroxidation in liver tissues of mice and HepG2 cells. RT-PCR and Western blot were used to detect the mRNA and protein expression levels of ferroptosis factors and JAK2/STAT3 signaling pathway. In this study, we used the iron chelator deferasirox in mice and HepG2 cells. Iron overload caused weight loss, elevated serum ferritin, fasting blood glucose, fasting insulin, HOMA-IR, impaired glucose tolerance, and decreased insulin sensitivity in mice. HE staining and Perls staining showed clumps of iron deposition in the liver of iron overload mice. Iron overload could reduce the glucose consumption, increase MDA contents of HepG2 cells, while reduce glycogen and GSH contents in liver tissues of mice and HepG2 cells. TEM showed deletion of mitochondrial ridge and rupture of outer membrane in HepG2 cells with iron overload. Iron chelator deferasirox could significantly improve the above indicators, which might be related to the activation of JAK2/STAT3/SLC7A11 signaling pathway and hepatic ferroptosis. Iron overload could induce hepatic ferroptosis and insulin resistance by inhibiting the JAK2/STAT3/SLC7A11 signaling pathway, and the iron chelator deferasirox might improve hepatic insulin resistance induced by iron overload.

Multifunctional Drug- and AuNRs-Loaded ROS-Responsive Selenium-Containing Polyurethane Nanofibers for Smart Wound Healing.

Elevated levels of ROS, bacterial infection, inflammation, and improper regeneration are the factors that need to be addressed simultaneously for achieving effective wound healing without scar formation. This study focuses on the fabrication of electrospun ROS-responsive selenium-containing polyurethane nanofibers incorporating deferoxamine mesylate (Def), indomethacin (Indo), and gold nanorods (AuNRs) as proangiogenesis, anti-inflammatory, and antibacterial agents for synchronized delivery to a full-thickness wound in vivo. The structure of the fabricated nanofibers was analyzed by various techniques. Toxicity was checked by CCK-8 and hemolytic assays. The efficiency of wound healing in vitro was verified by a transwell assay and cell scratch assay. The wound healing efficiency of the nanofibers was assayed in full-thickness wounds in a rat model. The multifunctional nanofibers had a porous structure, enhanced antioxidation, antibacterial activity, and promoted wound healing. They eradicated TNF-α and IL-6, increased IL-10 expression, and revealed the angiogenic potential by increased expression of HIF-1α, VEGF, and CD31.

Polypropylene mesh coated with hyaluronic acid/polyvinyl alcohol composite hydrogel for preventing bowel adhesion.

Polypropylene (PP) mesh is the most widely used prosthetic material in hernia repair. However, the efficacy of implanted PP mesh is often compromised by adhesion between viscera and PP mesh. Thus, there is a recognized need for developing an anti-adhesive PP mesh. Here, a composite hydrogel coated PP mesh with the prevention of adhesion after hernia repair was designed. The composite hydrogel coating was prepared from polyvinyl alcohol (PVA) and hyaluronic acid (HA) by using the freezing-thawing (FT) method. To overcome the shortcoming of the long time of the traditional freezing-thawing method, a small molecule 3,4-dihydroxyphenylacetic acid (DHPA) was introduced to promote the formation of composite hydrogel. The as-prepared composite hydrogel coating displayed modulus more closely resembling that of native abdominal wall tissue. In vitro studies illustrated that the resulting meshes showed excellent coating stability, hemocompatibility, and non-cytotoxicity. In vivo experiments using a rat abdominal wall defect model demonstrated that the composite hydrogel coated PP mesh could prevent the formation of adhesion, alleviate the inflammatory response, and reduce the deposition of collagen around the damaged tissue. These disclosed results manifested that the PP mesh coated with HA/PVA composite hydrogel might be a promising application in preventing adhesion for hernia repair.

Total Syntheses of the Structures Assigned to Denigrins A, B, C, F, and G, 3,4-Diaryl-Pyrrole and -Pyrrolidinone Alkaloids, and the Conversion of Congener B into the Co-metabolite Spirodactylone.

The title marine natural products have been prepared by total synthesis and in the case of congeners 3, 6, and 7 for the first time. Each of these was obtained by manipulation of readily prepared denigrin B (2). The structure, 3, assigned to denigrin C is shown to be incorrect. Reaction of compound 2 with DDQ has led, in high yield, to the related natural product spirodactylone (16), while treating the corresponding permethyl ether 15 with PIFA/BF3·Et2O provides compound 20, embodying an isomeric framework.

Relationship of serum total cholesterol and triglyceride with risk of mortality in maintenance hemodialysis patients: a multicenter prospective cohort study.

OBJECTIVE: The relationship between serum total cholesterol (TC) and triglyceride (TG) levels and mortality in maintenance hemodialysis (MHD) patients remains inconsistent. We aimed to explore the individual and combined association of TC and TG levels with the risk of mortality in Chinese MHD patients. METHODS: 1036 MHD patients were enrolled in this multicenter, prospective cohort study. The serum levels of total cholesterol and triglycerides were measured at baseline. The primary outcome was all-cause mortality and secondary outcome was cardiovascular disease (CVD) mortality. RESULTS: During a median follow-up duration of 4.4 years (IQR= 2.0-7.9 years), 549 (53.0%) patients died, and 297 (28.7%) deaths were attributed to CVD. Compared with patients with TC levels in the first three quartiles (<182.5 mg/dL), a significantly higher risk of all-cause mortality was found in participants with TC in the fourth quartile (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.17-1.76). However, a significantly lower risk of all-cause mortality was observed in participants with TG in the fourth quartile (≥193.9 mg/dL) (HR, 0.78; 95%CI: 0.63-0.98), compared with participants with TG in the first three quartiles. Similar trends were observed in CVD mortality. When analyzed jointly, patients with lower TC (<182.5 mg/dL) and higher TG (≥193.9 mg/dL) levels had the lowest risk of all-cause mortality and CVD mortality.Conclusions: In MHD patients in southern China, higher TC levels were associated with higher risk of mortality, while higher TG levels were related to lower risk of mortality. Patients with lower TC and higher TG levels had the best survival prognosis.

Causality of genetically determined blood metabolites on irritable bowel syndrome: A Mendelian randomization study.

BACKGROUND: Irritable bowel syndrome (IBS) is one of the most common functional bowel disorders and dysmetabolism plays an important role in the pathogenesis of disease. Nevertheless, there remains a lack of information regarding the causal relationship between circulating metabolites and IBS. A two-sample Mendelian randomization (MR) analysis was conducted in order to evaluate the causal relationship between genetically proxied 486 blood metabolites and IBS. METHODS: A two-sample MR analysis was implemented to assess the causality of blood metabolites on IBS. The study utilized a genome-wide association study (GWAS) to examine 486 metabolites as the exposure variable while employing a GWAS study with 486,601 individuals of European descent as the outcome variable. The inverse-variance weighted (IVW) method was used to estimate the causal relationship of metabolites on IBS, while several methods were performed to eliminate the pleiotropy and heterogeneity. Another GWAS data was used for replication and meta-analysis. In addition, reverse MR and linkage disequilibrium score regression (LDSC) were employed for additional assessment. Multivariable MR analysis was conducted in order to evaluate the direct impact of metabolites on IBS. RESULTS: Three known and two unknown metabolites were identified as being associated with the development of IBS. Higher levels of butyryl carnitine (OR(95%CI):1.10(1.02-1.18),p = 0.009) and tetradecanedioate (OR(95%CI):1.13(1.04-1.23),p = 0.003)increased susceptibility of IBS and higher levels of stearate(18:0)(OR(95%CI):0.72(0.58-0.89),p = 0.003) decreased susceptibility of IBS. CONCLUSION: The metabolites implicated in the pathogenesis of IBS possess potential as biomarkers and hold promise for elucidating the underlying biological mechanisms of this condition.

Psoralen and Isopsoralen, Two Estrogen-Like Natural Products from Psoraleae Fructus, Induced Cholestasis via Activation of ERK1/2.

With the increasing use of oral contraceptives and estrogen replacement therapy, the incidence of estrogen-induced cholestasis (EC) has tended to rise. Psoralen (P) and isopsoralen (IP) are the major bioactive components in Psoraleae Fructus, and their estrogen-like activities have already been recognized. Recent studies have also reported that ERK1/2 plays a critical role in EC in mice. This study aimed to investigate whether P and IP induce EC and reveal specific mechanisms. It was found that P and IP increased the expression of esr1, cyp19a1b and the levels of E2 and VTG at 80 µM in zebrafish larvae. Exemestane (Exe), an aromatase antagonist, blocked estrogen-like activities of P and IP. At the same time, P and IP induced cholestatic hepatotoxicity in zebrafish larvae with increasing liver fluorescence areas and bile flow inhibition rates. Further mechanistic analysis revealed that P and IP significantly decreased the expression of bile acids (BAs) synthesis genes cyp7a1 and cyp8b1, BAs transport genes abcb11b and slc10a1, and BAs receptor genes nr1h4 and nr0b2a. In addition, P and IP caused EC by increasing the level of phosphorylation of ERK1/2. The ERK1/2 antagonists GDC0994 and Exe both showed significant rescue effects in terms of cholestatic liver injury. In conclusion, we comprehensively studied the specific mechanisms of P- and IP-induced EC and speculated that ERK1/2 may represent an important therapeutic target for EC induced by phytoestrogens.

Topological Defect-Regulated Porous Carbon Anodes with Fast Interfacial and Bulk Kinetics for High-Rate and High-Energy-Density Potassium-Ion Batteries.

Carbonaceous materials are regarded as one of the most promising anodes for potassium-ion batteries (PIBs), but their rate capabilities are largely limited by the slow solid-state potassium diffusion kinetics inside anode and sluggish interfacial potassium ion transfer process. Herein, high-rate and high-capacity PIBs are demonstrated by facile topological defect-regulation of the microstructure of carbon anodes. The carbon lattice of the as-obtained porous carbon nanosheets (CNSs) with abundant topological defects (TDPCNSs) holds relatively high potassium adsorption energy yet low potassium migration barrier, thereby enabling efficient storage and diffusion of potassium inside graphitic layers. Moreover, the topological defects can induce preferential decomposition of anions, leading to the formation of high potassium ion conductive solid electrolyte interphase (SEI) film with decreased potassium ion de-solvation and transfer barrier. Additionally, the dominant sp2-hybridized carbon conjugated skeleton of TDPCNSs enables high electrical conductivity (39.4 S cm-1) and relatively low potassium storage potential. As a result, the as-constructed TDPCNSs anode demonstrates high potassium storage capacity (504 mA h g-1 at 0.1 A g-1), remarkable rate capability (118 mA h g-1 at 40 A g-1), as well as long-term cycling stability.