Itaconate protects ferroptotic neurons by alkylating GPx4 post stroke.

Neuronal ferroptosis plays a key role in neurologic deficits post intracerebral hemorrhage (ICH). However, the endogenous regulation of rescuing ferroptotic neurons is largely unexplored. Here, we analyzed the integrated alteration of metabolomic landscape after ICH using LC-MS and MALDI-TOF/TOF MS, and demonstrated that aconitate decarboxylase 1 (Irg1) and its product itaconate, a derivative of the tricarboxylic acid cycle, were protectively upregulated. Deficiency of Irg1 or depletion of neuronal Irg1 in striatal neurons was shown to exaggerate neuronal loss and behavioral dysfunction in an ICH mouse model using transgenic mice. Administration of 4-Octyl itaconate (4-OI), a cell-permeable itaconate derivative, and neuronal Irg1 overexpression protected neurons in vivo. In addition, itaconate inhibited ferroptosis in cortical neurons derived from mouse and human induced pluripotent stem cells in vitro. Mechanistically, we demonstrated that itaconate alkylated glutathione peroxidase 4 (GPx4) on its cysteine 66 and the modification allosterically enhanced GPx4's enzymatic activity by using a bioorthogonal probe, itaconate-alkyne (ITalk), and a GPx4 activity assay using phosphatidylcholine hydroperoxide. Altogether, our research suggested that Irg1/itaconate-GPx4 axis may be a future therapeutic strategy for protecting neurons from ferroptosis post ICH.

Targeted macrophage phagocytosis by Irg1/itaconate axis improves the prognosis of intracerebral hemorrhagic stroke and peritonitis.

BACKGROUND: Macrophages are innate immune cells whose phagocytosis function is critical to the prognosis of stroke and peritonitis. cis-aconitic decarboxylase immune-responsive gene 1 (Irg1) and its metabolic product itaconate inhibit bacterial infection, intracellular viral replication, and inflammation in macrophages. Here we explore whether itaconate regulates phagocytosis. METHODS: Phagocytosis of macrophages was investigated by time-lapse video recording, flow cytometry, and immunofluorescence staining in macrophage/microglia cultures isolated from mouse tissue. Unbiased RNA-sequencing and ChIP-sequencing assays were used to explore the underlying mechanisms. The effects of Irg1/itaconate axis on the prognosis of intracerebral hemorrhagic stroke (ICH) and peritonitis was observed in transgenic (Irg1flox/flox; Cx3cr1creERT/+, cKO) mice or control mice in vivo. FINDINGS: In a mouse model of ICH, depletion of Irg1 in macrophage/microglia decreased its phagocytosis of erythrocytes, thereby exacerbating outcomes (n = 10 animals/group, p < 0.05). Administration of sodium itaconate/4-octyl itaconate (4-OI) promoted macrophage phagocytosis (n = 7 animals/group, p < 0.05). In addition, in a mouse model of peritonitis, Irg1 deficiency in macrophages also inhibited phagocytosis of Staphylococcus aureus (n = 5 animals/group, p < 0.05) and aggravated outcomes (n = 9 animals/group, p < 0.05). Mechanistically, 4-OI alkylated cysteine 155 on the Kelch-like ECH-associated protein 1 (Keap1), consequent in nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and transcriptional activation of Cd36 gene. Blocking the function of CD36 completely abolished the phagocytosis-promoting effects of Irg1/itaconate axis in vitro and in vivo. INTERPRETATION: Our findings provide a potential therapeutic target for phagocytosis-deficiency disorders, supporting further development towards clinical application for the benefit of stroke and peritonitis patients. FUNDING: The National Natural Science Foundation of China (32070735, 82371321 to Q. Li, 82271240 to F. Yang) and the Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education (KZ202010025033 to Q. Li).

Liver inflammation activity in patients with autoimmune hepatitis with normal alanine aminotransferase and immunoglobulin G levels.

Background and aims: Normal serum transaminases and immunoglobulin G (IgG) levels are surrogate markers for hepatic histologic disease activity in autoimmune hepatitis (AIH). This study aimed to evaluate liver inflammation in patients with AIH with normal serum alanine aminotransferase (ALT) and IgG levels. Methods: Two hundred and five AIH patients who underwent liver biopsy in four medical centers were included. Logistic regression analysis was used to identify risk factors associated with advanced inflammation. Results: One hundred and thirty-one (63.9 %) AIH patients had advanced liver inflammation, and 108 (52.7 %) patients had advanced liver fibrosis. 60.0 % of patients with normal ALT and 51.7 % of patients with normal ALT and IgG had advanced inflammation. However, 76.7 % and 35.0 % of patients with or without advanced fibrosis with normal ALT had advanced inflammation, while the corresponding proportions of advanced inflammation were 78.6 % and 26.7 % in patients with normal ALT and IgG, respectively. Moreover, 81.0 % and 44.8 % of patients with and without cirrhosis with normal ALT had advanced inflammation, while the corresponding proportions were 83.3 % and 29.4 % in patients with normal ALT and IgG, respectively. Red cell distribution width (OR = 1.325, 95%CI 1.045-1.681, P = 0.020) and PT (OR = 1.514, 95%CI 1.138-2.014, P = 0.004) were independent factors associated with advanced inflammation. Conclusions: High proportion of advanced inflammation was found in AIH patients with normal ALT and IgG levels despite without advanced fibrosis. Although using non-invasive methods may contribute to rule out liver fibrosis in AIH patients with normal ALT and IgG levels, liver biopsy is encouraged to assess liver inflammation.

Retraction Notice to: miRNA-129/FBW7/NF-κB, a Novel Regulatory Pathway in Inflammatory Bowel Disease.

[This retracts the article DOI: 10.1016/j.omtn.2019.10.048.].

IL-10 protects against OPC ferroptosis by regulating lipid reactive oxygen species levels post stroke.

Accumulation of reactive oxygen species (ROS), especially on lipids, induces massive cell death in neurons and oligodendrocyte progenitor cells (OPCs) and causes severe neurologic deficits post stroke. While small compounds, such as deferoxamine, lipostatin-1, and ferrostatin-1, have been shown to be effective in reducing lipid ROS, the mechanisms by which endogenously protective molecules act against lipid ROS accumulation and subsequent cell death are still unclear, especially in OPCs, which are critical for maintaining white matter integrity and improving long-term outcomes after stroke. Here, using mouse primary OPC cultures, we demonstrate that interleukin-10 (IL-10), a cytokine playing roles in reducing neuroinflammation and promoting hematoma clearance, significantly reduced hemorrhage-induced lipid ROS accumulation and subsequent ferroptosis in OPCs. Mechanistically, IL-10 activated the IL-10R/STAT3 signaling pathway and upregulated the DLK1/AMPK/ACC axis. Subsequently, IL-10 reprogrammed lipid metabolism and reduced lipid ROS accumulation. In addition, in an autologous blood injection intracerebral hemorrhagic stroke (ICH) mouse model, deficiency of the endogenous Il-10, specific knocking out Il10r or Dlk1 in OPCs, or administration of ACC inhibitor was associated with increased OPC cell death, demyelination, axonal sprouting, and the cognitive deficits during the chronic phase of ICH and vice versa. These data suggest that IL-10 protects against OPC loss and white matter injury by reducing lipid ROS, supporting further development of potential clinical applications to benefit patients with stroke and related disorders.

Ultrasound-propelled liposome circumvention and siRNA silencing reverse BRAF mutation-arised cancer resistance to trametinib.

BRAF-V600E mutation is regarded as the source of lung cancer resistance to trametinib (Tr), and no solution available for completely addressing this intractable resistance has emerged yet. Herein, the combination of ultrasonic (US) propelled folic acid (FA)-modified liposomes strategy and BRAF-driven gene silencing program is proposed to effectively reverse Tr's resistance to lung cancer. Meanwhile, the prepared cationic nanoliposomes can assist Tr drug and BRAF siRNA to escape lysosome disposal, thereby avoiding Tr drug pumping out or siRNA degradation. More significantly, loaded BRAF siRNA is designed to silence BRAF-V600E mutation genes via modulating BRAF-ERK-pathway and remarkably reverse the PC9R resistance to Tr. Systematic experiments validate that these cooperatively sensitize PC9R cells to Tr and shrink resistant NSCLC in vivo, especially after combining with FA-mediated targeting and US-enhanced permeability that permits more intratumoral accumulations of Tr. Such a biocompatible targeting drug-resistance liberation agent and its underlying design strategy lay a foundation avenue to completely reverse tumor resistance, which is preferable to treat BRAF mutation-arised resistance of various tumors, holding high clinical translation potentials.

Algorithm Design and Convergence Analysis for Coexistence of Cognitive Radio Networks in Unlicensed Spectrum.

This paper focuses on achieving the low-cost coexistence of the networks in an unlicensed spectrum by making them operate on non-overlapping channels. For achieving this goal, we first give a universal convergence analysis framework for the unlicensed spectrum allocation algorithm. Then, a one-timescale iteration-adjustable unlicensed spectrum allocation algorithm is developed, where the step size and timescale parameter can be jointly adjusted based on the system performance requirement and signal overhead concern. After that, we derive the sufficient condition for the one-timescale algorithm. Furthermore, the upper bound of convergence error of the one-timescale spectrum allocation algorithm is obtained. Due to the multi-timescale evolution of the network states in the wireless network, we further propose a two-timescale iteration-adjustable joint frequency selection and frequency allocation algorithm, where the frequency selection iteration timescale is set according to the slow-changing statistical channel state information (CSI), whereas the frequency allocation iteration timescale is set according to the fast-changing local CSI. Then, we derive the convergence condition of two-timescale algorithms and the upper bound of the corresponding convergence error. The experimentalresults show that the small timescale adjustment parameter and large step size can help decrease the convergence error. Moreover, compared with traditional algorithms, the two-timescale policy can achieve throughput similar to traditional algorithms with very low iteration overhead.

Relationship between bilirubin and systemic lupus erythematosus: A systematic review and meta-analysis.

AIMS: Systemic lupus erythematosus (SLE) is an autoimmune disease with a high prevalence worldwide. This study aimed to examine the correlation between serum bilirubin levels and SLE. METHODS: The Cochrane library, Embase, PubMed, and China National Knowledge Infrastructure (CNKI) databases were examined and assessed until March 2023. RevMan 5.3 software was utilized for the analysis of clinical trails. RESULTS: Five case-control studies were chosen and incorporated, examining the levels of serum bilirubin in patients with SLE compared to healthy individuals, as well as in active SLE patients versus inactive ones, in different sexes and in SLE patients with or without lupus nephritis (LN). The results of this meta-analysis demonstrated that serum bilirubin in healthy individuals were obviously increased compared to SLE patients (MD = 4.76; 95% CI, 3.15-6.38, p < .00001). Additionally, inactive SLE patients had higher levels of bilirubin than active SLE patients (MD = 3.15; 95% CI, 0.46-5.84, p = .02), and SLE patients without lupus nephritis had higher levels of serum bilirubin than those with lupus nephritis (MD = 4.91;95% CI, 2.87-6.95, p < .00001). Nevertheless, there were no disparities observed among SLE patients of varying sexes (MD = 0.34; 95% CI, -0.01 to 0.69, p = .06). CONCLUSION: The concentration of serum bilirubin may potentially be used as an indicator for estimating the advancement of SLE and reflecting the presence of kidney complications in individuals with SLE. Furthermore, more high quality studies were needed to identify these findings.

Influence of samarium modification on the phase-change performance and phase structure of tin antimonide.

This work presents the optimization of the crystallization behavior and reliability of Sn15Sb85thin films by doping Sm element. The phase transition behaviors induced by thermal were investigated byin situresistance measurement. With the addition of Sm element, Sn15Sb85film exhibits the superior crystallization temperature (232 °C) and data conservation (172.32 °C for 10 years), larger activation energy of crystallization (4.91 eV) and crystalline resistance (∼103Ω), which contributes to the increased thermal stability of the amorphous state and decrease in the programming energy. The Sm-doping can broaden the energy band gap from 0.55 to 1.07 eV. The amorphous Sm and Sn compositions could retard grain growth and refine grain size from 21.13 to 11.13 nm, combining with x-ray diffraction and x-ray photoelectron spectroscopy. The surface morphology of Sn15Sb85film becomes smoother after Sm doping as determined by atomic force microscopy images, resulting in the improved interfacial reliability. Phase change memory devices based on Sm0.095(Sn15Sb85)0.905films can successfully achieve the complete SET and RESET reversible operation process with high operating speed (200 ns) and low power consumption (1.6 × 10-10J). The results suggest that doping the proper concentration of Sm element will be an effectual solution to adapt and optimize the crystallization properties of Sn15Sb85phase change material.

Influenza H7N9 virus disrupts the monolayer human brain microvascular endothelial cells barrier in vitro.

Influenza H7N9 virus causes human infections with about 40% case fatality rate. The severe cases usually present with pneumonia; however, some present with central nervous system complications. Pneumonia syndrome is attributed to the cytokine storm after infection with H7N9, but the pathogenic mechanism of central nervous system complications has not been clarified. This study used immortalized human brain microvascular endothelial cells hCMEC/D3 to simulate the blood-brain barrier. It demonstrated that H7N9 virus could infect brain microvascular endothelial cells and compromise the blood-brain barrier integrity and permeability by down-regulating the expression of cell junction-related proteins, including claudin-5, occludin, and vascular endothelial (VE)-cadherin. These results suggested that H7N9 could infect the blood-brain barrier in vitro and affect its functions, which could be a potential mechanism for the pathogenesis of H7N9 viral encephalopathy.

[Establishment of a prognostic nomogram model for predicting acute renal injury in patients with moderate and severe burns].

OBJECTIVE: To establish a prediction model of acute kidney injury (AKI) in moderate and severe burn patients, so as to provide basic research evidence for early identification of burn-related AKI. METHODS: Patients who were admitted to the department of plastic burn surgery of the Affiliated Hospital of Southwest Medical University from November 2018 to January 2021 were selected, and their clinical characteristics, laboratory examinations and other indicators were recorded. Multivariate Logistic regression analysis was used to screen out the risk factors of AKI related to moderate and severe burns, and R software was used to establish the nomogram of moderate and severe burn patients complicated with AKI. The Bootstrap method model was used for internal verification by repeating sample for 1 000 times. Consistency index and calibration curve were used to evaluate the accuracy of the model, and the receiver operator characteristic curve (ROC curve) and the area under the curve (AUC) were used to evaluate the prediction efficiency, decision curve analysis (DCA) was used to evaluate the clinical utility of the model. RESULTS: A total of 186 patients with moderate and severe burn were included, among which 54 patients suffered from AKI, and the incidence rate was 29.03%. Multivariate Logistic regression analysis showed that the total burn surface area [TBSA; odds ratio (OR) = 1.072, 95% confidence interval (95%CI) was 1.031-1.115, P = 0.001], estimated glomerular filtration rate (eGFR; OR = 0.960, 95%CI was 0.931-0.990, P = 0.010), neutrophil (NEU; OR = 1.190, 95%CI was 1.021-1.386, P = 0.026), neutrophil/lymphocyte ratio (NLR; OR = 0.867, 95%CI was 0.770-0.977, P = 0.019), D-dimer (OR = 4.603, 95%CI was 1.792-11.822, P = 0.002) were the risk factors for patients with moderate and severe burn complicated with AKI. Taking the above indexes as predictive factors, a nomogram prediction model was established, the ROC curve was plotted with AUC of 0.998 (95%CI was 0.988-1.000). Optimum threshold of ROC curve was -0.862, the sensitivity was 98.0% and the specificity was 98.2%, and the consistency index was 0.998 (95%CI was 0.988-1.000). The calibration curve showed that the prognostic nomogram model was accurate, DCA showed that most patients can benefit from this model. CONCLUSIONS: The burned patients with higher TBSA, NEU, NLR, D-dimer and lower eGFR tend to suffer from AKI. The nomogram based on the above five risk factors has high accuracy and clinical value, which can be used as a predictive tool to evaluate the risk of AKI in moderate and severe burn patients.

The relationship between coronary artery calcification and bone metabolic markers in maintenance hemodialysis patients.

BACKGROUND: To study the influencing factors for coronary artery calcification (CAC) in maintenance hemodialysis (MHD) patients and the relationship between CAC and bone metabolism markers and to attempt to find a reliable marker linking vascular calcification and bone metabolism in MHD patients. METHODS: A total of 123 patients were enrolled. CAC was assessed by multislice spiral computed tomography (MSCT), and the CAC score (CACS) was evaluated using the Agaston method. Routine laboratory parameters, including triglycerides (TG), total cholesterol (TC), glucose (Glu), calcium (Ca), phosphorus (P), magnesium (Mg), etc., were measured. Serum markers of bone metabolism, such as alkaline phosphatase(ALP), calcitonin (CT), 25-hydroxy vitamin D [25-(OH)D], intact parathyroid hormone (iPTH), total type I procollagen amino-terminal peptide (tPINP), N-terminal mid-fragment of osteocalcin (N-MID OC), and ß-type I collagen crosslinked carboxyl-terminal peptide (ß-CTX), were also measured. RESULTS: Among 123 MHD patients, 37 patients (30.08%) did not have CAC, and 86 patients (69.92%) had CAC, including 41 patients (47.67%) with mild calcification and 45 patients (52.33%) with moderate to severe calcification. Age, Body Mass Index(BMI), the prevalence of hypertension and diabetes mellitus, TC, Glu, P, and Ca×P in the calcification group were higher than those in the noncalcification group, whereas Mg, iPTH, tPINP, N-MID OC, and ß-CTX were lower than those in the noncalcified group (P < 0.05). Compared with the mild calcification group (0 0.05). A logistic regression model was used to evaluate the influencing factors for CAC. The results showed that age, BMI, TC, Glu, P, and Ca×P were risk factors for CAC and its severity in MHD patients, whereas diabetes mellitus, Mg, and N-MID OC were protective factors for CAC in MHD patients. In addition, N-MID OC was a protective factor for the severity of CAC. After adjusting for the corresponding confounding factors, the results of the risk factors were consistent, and N-MID OC was still an independent protective factor for CAC and its severity. CONCLUSIONS: Elevated serum P and Ca×P were independent risk factors for CAC in MHD patients, and serum Mg may be an independent protective factor for CAC. CAC was closely related to abnormal bone metabolism and bone metabolic markers in MHD patients. Relatively low bone turnover can promote the occurrence and development of CAC. N-MID OC may be a reliable bone metabolic marker linking vascular calcification and bone metabolism in MHD patients.

Screening and identification of specific cluster miRNAs in N2a cells infected by H7N9 virus.

This study aims to screen and identify specific cluster miRNAs of H7N9 virus-infected N2a cells and explore the possible pathogenesis of these miRNAs. The N2a cells are infected with H7N9 and H1N1 influenza viruses, and the cells are collected at 12, 24 and 48 h to extract total RNA. To sequence miRNAs and identify different virus-specific miRNAs, high-throughput sequencing technology is used. Fifteen H7N9 virus-specific cluster miRNAs are screened, and eight of them are included in the miRBase database. These cluster-specific miRNAs regulate many signaling pathways, such as the PI3K-Akt signaling pathway, the RAS signaling pathway, the cAMP signaling pathway, actin cytoskeleton regulation and cancer-related genes. The study provides a scientific basis for the pathogenesis of H7N9 avian influenza, which is regulated by miRNAs.

Noninvasive Assessment of Renal Fibrosis of Chronic Kidney Disease in Rats by [68Ga]Ga-FAPI-04 Small Animal PET/CT and Biomarkers.

Renal fibrosis is the most common pathological feature and common pathway of progression in chronic kidney disease (CKD). We evaluated [68Ga]Ga-FAPI-04 small animal positron emission tomography/computed tomography (PET/CT) and biomarkers as noninvasive assessments of renal fibrosis (RF) in CKD rats to generate new ideas for clinical diagnosis. A rat model of renal fibrosis was administered adenine by gavage (n = 28), and the control group was given 0.9% NaCl by gavage (n = 20). At different time points (weeks 1, 2, 4, and 6), five rats were randomly selected from the two groups for [68Ga]Ga-FAPI-04 small animal PET/CT imaging. At the same time, the expression of Fibroblast activation protein (FAP) in renal tissue and the expression levels of type III procollagen N-terminal peptide (PIIINP), transforming growth factor (TGF-ß1), Klotho, and sex-determining region Y-box protein 9 (SOX9) in blood and urine were determined. FAP was highly expressed in the renal tissue of rats in the CKD group and expression increased with the progression of renal fibrosis. [68Ga]Ga-FAPI-04 small animal PET/CT examination showed that the uptake of radioactive tracers in the CKD group was higher than that in the control group, and SUVmax (r = 0.9405) and target-to-background ratio (TBR) (r = 0.9392) were positively correlated with renal fibrosis. The serum levels of PIIINP, TGF-ß1, and SOX9 in CKD rats were significantly higher than those in the control group and were positively correlated with RF (r = 0.8234, r = 0.7733, and r = 0.7135, respectively) and SUVmax (r = 0.8412, r = 0.7763, and r = 0.6814, respectively). Compared with the control group, the level of serum Klotho decreased and was negatively correlated with RF (r = -0.6925) and SUVmax (r = -0.6322). Compared with the control group, the levels of PIIINP and TGF-ß1 in urine were positively correlated with RF (r = 0.8127 and r = 0.8077, respectively) and SUVmax (r = 0.8400 and r = 0.8177, respectively). Urine Klotho decreased compared with the control group and was negatively correlated with RF (r = -0.5919) and SUVmax (r = -0.5995). The change in urine SOX9 was not statistically significant. In conclusion, compared with renal biopsy, [68Ga]Ga-FAPI-04 small animal PET/CT shows renal fibrosis quickly and noninvasively. PIIINP, TGF-ß1, and Klotho in serum and urine may be used as biomarkers of RF, and serum SOX9 is expected to become a new diagnostic biomarker of RF.

The role of urinary Dickkopf-3 in the prediction of acute kidney injury: a systematic review meta-analysis.

BACKGROUND: To systematically evaluate the diagnostic efficacy of urinary Dickkopf-Related Protein 3 (DKK-3) in acute kidney injury and to explore the clinical application value of urinary DKK-3. METHOD: English databases (PubMed, Embase, Cochrane, and WOS) and Chinese databases (VIP, WanFang data, and China National Knowledge Internet) were screened for relevant papers published before March 12, 2023. After literature screening and data extraction, quality assessment was performed according to the QUADAS-2 scoring system. Then, the combined diagnostic and predictive parameters were calculated using a bivariate mixed effect meta-analysis model. Deek's funnel plot asymmetry test assessed publication bias, and Fagan's nomogram plot was used to verify its clinical utility. RESULT: A total of 5 studies involving 2787 patients were included in this meta-analysis, of which 4 focused on contrast-induced acute kidney injury (CI-AKI) and 1 focused on AKI associated with cardiac surgery. The analysis showed that urine Dickkopf-3 has high diagnostic accuracy for AKI, with a sensitivity of 0.55 (95% CI [0.41, 0.68]), specificity of 0.80 (95% CI [0.70, 0.87]), positive likelihood ratio (PLR) of 2.7 [1.8, 4.1], negative likelihood ratio (NLR) of 0.56 [0.42, 0.75], diagnostic odds ratio (DOR) of 5 [3, 9], and AUC of 0.74 [0.70-0.77]. We did not perform subgroup analyses for predictive value due to the small number of included studies. CONCLUSION: Urinary DKK3 may have limited predictive ability for acute kidney injury, especially for AKI associated with cardiac surgery. Therefore, urinary DKK3 may serve as a potential predictor for AKI. However, clinical studies with larger samples are still needed for validation.

Altered serum metabolome associated with vascular calcification developed from CKD and the critical pathways.

Introduction: Vascular calcification (VC) is more likely to be detected in the chronic kidney disease (CKD) population. The mechanism of VC development from CKD is different from that for simple VC and has always been a major research area. The aim of this study was to detect alterations in the metabolome during development of VC in CKD and to identify the critical metabolic pathways and metabolites involved in its pathogenesis. Methods: Rats in the model group were given an adenine gavage combined with a high-phosphorus diet to imitate VC in CKD. The aorta calcium content was measured and used to divide the model group into a VC group and non-vascular calcification group (non-VC group). The control group was fed a normal rat diet and given a saline gavage. Ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) was used to determine the altered serum metabolome in the control, VC, and non-VC groups. The identified metabolites were mapped into the Kyoto Encyclopedia of Genes and Genomes (KEGG) database (https://www.genome.jp/kegg/) for pathway and network analyses. Result: There were 14 metabolites that changed significantly in the VC group, with three metabolic pathways playing critical roles in the pathogenesis of VC in CKD: steroid hormone biosynthesis; valine, leucine and isoleucine biosynthesis; and pantothenate and CoA biosynthesis. Conclusion: Our results indicated changes in the expression of steroid sulfatase and estrogen sulfotransferase, and down-regulation of the in situ synthesis of estrogens in the VC group. In conclusion, the serum metabolome alters significantly during the pathogenesis of VC in CKD. The key pathways, metabolites, and enzymes we identified are worth further study and may become a promising therapeutic target for the treatment of VC in CKD.

Standardization of organoid culture in cancer research.

Establishing a valid in vitro model to represent tumor heterogeneity and biology is critical but challenging. Tumor organoids are self-assembled three-dimensional cell clusters which are of great significance for recapitulating the histopathological, genetic, and phenotypic characteristics of primary tissues. The organoid has emerged as an attractive in vitro platform for tumor biology research and high-throughput drug screening in cancer medicine. Organoids offer unique advantages over cell lines and patient-derived xenograft models, but there are no standardized methods to guide the culture of organoids, leading to confusion in organoid studies that may affect accurate judgments of tumor biology. This review summarizes the shortcomings of current organoid culture methods, presents the latest research findings on organoid standardization, and proposes an outlook for organoid modeling.

Characterization of the volatile profile and its estrogenic activity in Kadsura coccinea fruit.

ETHNOPHARMACOLOGICAL RELEVANCE: The fruit of Kadsura coccinea (Lem.) A. C. Smith is an ethnomedicine used to treat abnormal menstruation, menopausal syndrome, and female infertility among the Dong Nationality in China. AIM OF THE STUDY: Our study aimed to identify the volatile oil profiles of the K. coccinea fruit and elucidate their estrogenic activity. MATERIALS AND METHODS: The peel volatile oil (PeO), pulp volatile oil (PuO), and seed volatile oil (SeO) of K. coccinea were extracted using hydrodistillation and qualitatively analyzed using gas chromatography-mass spectrometry (GC-MS). Estrogenic activity was evaluated in vitro using cell assay and in vivo using immature female rats. Serum 17ß-Estradiol (E2) and follicle-stimulating hormone (FSH) levels were detected using ELISA. RESULTS: In total, 46 PeO, 27 PuO, and 42 SeO components representing 89.96%, 90.19%, and 97% of the total composition, respectively, were identified. The compounds with the highest content in PeO, PuO, and SeO were ß-caryophyllene, γ-amorphene, and n-hexadecanoic acid, respectively. PeO induced proliferation of MCF-7 cells with an EC50 of 7.40 µg/mL. Subcutaneous administration of 10 mg/kg PeO significantly increased the weight of the uteri in immature female rats, with no effect on serum E2 and FSH levels. PeO acted as an agonist of ERα and ERß. PuO and SeO showed no estrogenic activity. CONCLUSION: The chemical compositions of PeO, PuO, and SeO of K. coccinea are different. PeO is the main effective fraction for estrogenic activities, providing a new source of phytoestrogen for the treatment of menopausal symptoms.

Hydrochemistry, chemical weathering and their significance on carbon cycle in the Heilong (Amur) River Basin, Northeast China.

Chemical weathering is regarded as a "geological thermostat", affecting the global carbon cycle and long-term climate stability, and hydrochemistry of river is the important way to study weathering. The Heilong River (Amur River), as one of the largest rivers in the temperate/cool temperate zone, has received few studies on the chemical weathering rate and its contribution to the global carbon cycle in the entire Chinese section. This paper presents the hydrochemistry of river water, lake water, and groundwater from the arid upper reaches, the Greater Hinggan Mountains in the middle reaches, and the fluvial plain in the lower reaches of the Heilong River. TDS values range from 26.8 mg/l to 1141 mg/l with an average of 189 mg/l. The arid upper reaches are affected by strong evaporation and/or evaporite minerals dissolution, and the ion contents of some surface water and underground water exceed the quality standard for drinking water. Although the downstream flood plain area is highly industrial and agricultural, water chemistry shows that anthropogenic activities have not significantly deteriorated water quality. The chemical weathering rate of the small granitic and basaltic watersheds in the Heilong River Basin is within the lowest range in the world, which further demonstrates the control of climate factors on chemical weathering. The calculated CO2 consumption flux from silicate weathering in the Heilong River Basin is from 82.3 × 109 to 196 × 109 mol/y, accounting for 0.95%-2.25% of the global consumption values with a proportion of area of ∼1.2%. Compared with other temperate/cool temperate rivers worldwide, it is comparable to the Yenisei River in Siberia, but much higher than the Ob River and Lena River in Siberia, Mackenzie River and Yukon River in North America.

Simultaneously achieving high performance of thermal stability and power consumption via doping yttrium in Sn15Sb85thin film.

The effects of yttrium dopants on the phase change behavior and microstructure of Sn15Sb85films have been systematically investigated. The yttrium-doped Sn15Sb85film has the higher phase transition temperature, ten year data retention ability and crystallization activation energy, which represent a great improvement in thermal stability and data retention. X-ray diffraction, transmission electron microscopy and x-ray photoelectron spectroscopy reveal that the amorphous Sn and Y components restrict the grain growth and decrease the grain size. Raman mode typically associated with Sb is altered when the substance crystallized. Atomic force microscopy results show that the surface morphology of the doped films becomes smoother. T-shaped phase change storage cells based on yttrium-doped Sn15Sb85films exhibit the lower power consumption. The results demonstrate that the crystallization characteristics of Sn15Sb85film can be tuned and optimized through the yttrium dopant for the excellent performances of phase change memory.