Maternal folic acid over-supplementation impairs cardiac function in mice offspring by inhibiting SOD1 expression.

BACKGROUND: Folic acid (FA) supplementation during pregnancy aims to protect foetal development. However, maternal over-supplementation of FA has been demonstrated to cause metabolic dysfunction and increase the risk of autism, retinoblastoma, and respiratory illness in the offspring. Moreover, FA supplementation reduces the risk of congenital heart disease. However, little is known about its possible adverse effects on cardiac health resulting from maternal over-supplementation. In this study, we assessed the detrimental effects of maternal FA over-supplementation on the cardiac health of the offspring. METHODS AND RESULTS: Eight-week-old C57BL/6J pregnant mice were randomly divided into control and over-supplemented groups. The offspring cardiac function was assessed using echocardiography. Cardiac fibrosis was assessed in the left ventricular myocardium by histological analysis. Proteomic, protein, RNA, and DNA methylation analyses were performed by liquid chromatography-tandem mass spectrometry, western blotting, real-time quantitative PCR, and bisulfite sequencing, respectively. We found that maternal periconceptional FA over-supplementation impaired cardiac function with the decreased left ventricular ejection fraction in the offspring. Biochemical indices and tissue staining further confirmed impaired cardiac function in offspring caused by maternal FA over-supplementation. The combined proteomic, RNA expression, and DNA methylation analyses suggested that key genes involved in cardiac function were inhibited at the transcriptional level possibly due to increased DNA methylation. Among these, superoxide dismutase 1 was downregulated, and reactive oxygen species (ROS) levels increased in the mouse heart. Inhibition of ROS generation using the antioxidant N-acetylcysteine rescued the impaired cardiac function resulting from maternal FA over-supplementation. CONCLUSIONS: Our study revealed that over-supplementation with FA during mouse pregnancy is detrimental to cardiac function with the decreased left ventricular ejection fraction in the offspring and provides insights into the mechanisms underlying the association between maternal FA status and health outcomes in the offspring.

Negative association of atmospheric pollutants with semen quality: A cross-sectional study in Taiyuan, China.

BACKGROUND: In recent decades, the quality of male semen has decreased worldwide. Air pollution has been linked to lower semen quality in several studies. However, the effects of atmospheric pollutants on different semen characteristics have not always been consistent. The aim of this study was to investigate the association between the Air Quality Index (AQI) and six atmospheric pollutants (PM2.5, PM10, SO2, NO2, CO, and O3), semen quality, and their key exposure window periods. METHODS: This study included 1711 semen samples collected at the reproductive clinics of the First Affiliated Hospital of Shanxi Medical University in Taiyuan, Shanxi, China, from October 10, 2021, to September 30, 2022. We evaluated the association of AQI and six atmospheric pollutants with semen quality parameters throughout sperm development and three key exposure windows in men using single-pollutant models, double-pollutant models, and subgroup analyses of semen quality-eligible groups. RESULTS: Both the single-pollutant model and subgroup analyses showed that PM, CO, and O3 levels were negatively correlated with total and progressive motility. At 70-90 d before semen collection, CO exposure and semen volume (ß =-1.341, 95 % CI: -1.805, -0.877, P <0.001), total motility (ß =-2.593, 95 % CI: -3.425, -1.761, P <0.001), and progressive motility (ß =-4.658, 95 % CI: -5.556, -3.760, P <0.001) were negatively correlated. At 0-9 days before semen collection, CO was negatively correlated with normal morphology (ß =-3.403, 95 % CI: -5.099, -1.708, P <0.001). Additionally, the AQI was adversely associated with total and progressive motility in subgroup analyses of the semen quality-eligible groups. CONCLUSIONS: During the entire sperm development process, multiple air pollutants were determined to have an adverse correlation with semen quality parameters. AQI was significant marker for the combined effects of various atmospheric pollutants on male reproductive health.

B2R-Targeting Radiotracer for PET/MR Imaging of Hepatocellular Carcinoma and Guiding Anti-B2R Therapy.

The bradykinin B2 receptor (B2R) is overexpressed in a wide variety of tumors and is a well-defined target for tumor imaging and therapy. The hybrid positron emission tomography/magnetic resonance imaging (PET/MRI) scanner is considered a noninvasive and advanced instrument for precise tumor imaging. In this work, we developed a novel B2R-targeting radiotracer, 68Ga-DOTA-icatibant, for quantifying B2R expression. 68Ga-DOTA-icatibant showed high stability, fast clearance and specific binding to B2R. PET/MR imaging revealed excellent tumor accumulation, and the uptake in tumors could be blocked by DOTA-icatibant. Icatibant-mediated anti-B2R therapy downregulated B2R expression in tumor cells and inhibited the growth of HepG2 tumors, and the decrease in tumor uptake was monitored by timely PET/MR imaging. Hematoxylin and eosin (H&E) and immunohistochemical staining results further demonstrated that the efficacy of anti-B2R could be accurately monitored with the developed PET/MR imaging radiotracer. 68Ga-DOTA-icatibant can be utilized to noninvasively determine B2R expression and dynamically and sensitively monitor the efficacy of anti-B2R therapy.

Branched-Chain Amino Acids Deficiency Promotes Diabetic Neuropathic Pain Through Upregulating LAT1 and Inhibiting Kv1.2 Channel.

Diabetic neuropathic pain (DNP), one of the most common complications of diabetes, is characterized by bilateral symmetrical distal limb pain and substantial morbidity. To compare the differences  is aimed at serum metabolite levels between 81 DNP and 73 T2DM patients without neuropathy and found that the levels of branched-chain amino acids (BCAA) are significantly lower in DNP patients than in T2DM patients. In high-fat diet/low-dose streptozotocin (HFD/STZ)-induced T2DM and leptin receptor-deficient diabetic (db/db) mouse models, it is verified that BCAA deficiency aggravated, whereas BCAA supplementation alleviated DNP symptoms. Mechanistically, using a combination of RNA sequencing of mouse dorsal root ganglion (DRG) tissues and label-free quantitative proteomic analysis of cultured cells, it is found that BCAA deficiency activated the expression of L-type amino acid transporter 1 (LAT1) through ATF4, which is reversed by BCAA supplementation. Abnormally upregulated LAT1 reduced Kv1.2 localization to the cell membrane, and inhibited Kv1.2 channels, thereby increasing neuronal excitability and causing neuropathy. Furthermore, intraperitoneal injection of the LAT1 inhibitor, BCH, alleviated DNP symptoms in mice, confirming that BCAA-deficiency-induced LAT1 activation contributes to the onset of DNP. These findings provide fresh insights into the metabolic differences between DNP and T2DM, and the development of approaches for the management of DNP.

Neopterin mediates sleep deprivation-induced microglial activation resulting in neuronal damage by affecting YY1/HDAC1/TOP1/IL-6 signaling.

INTRODUCTION: Sleep deprivation (SD) is a common disorder in modern society. Hippocampus is an important region of the brain for learning, memory, and emotions. Dysfunction of hippocampus can lead to severe learning and memory disorder, significantly affecting quality of life. SD is accompanied by hippocampal microglia activation and a surge in inflammatory factors, but the precise mechanism remains unclear. Moreover, the ongoing unknown persists regarding how activated microglia in SD lead to neuronal damage. Topoisomerase 1 (TOP1) plays an essential role in the inflammatory process, including the tumor system and viral infection. In this study, we observed a significant elevation in TOP1 levels in the hippocampus of mice subjected to SD. Therefore, we hypothesize that TOP1 may be implicated in SD-induced microglia activation and neuronal damage. OBJECTIVES: To investigate the role of TOP1 in SD-induced microglial activation, neuronal damage, and neurobehavioral impairments, and the molecular basis of SD-induced elevated TOP1 levels. METHODS: TOP1-specific knockout mice in microglia were used to study the effects of TOP1 on microglial activation and neuronal damage. Transcription factor prediction, RNA interference, ChIP-qPCR, ChIP-seq database analysis, and luciferase reporter assays were performed to explore the molecular mechanisms of YY1 transcriptional activation. Untargeted metabolic profiling was employed to investigate the material basis of YY1 transcriptional activation. RESULTS: Knockdown of TOP1 in hippocampal microglia ameliorates SD-induced microglial activation, inflammatory response, and neuronal damage. Mechanistically, TOP1 mediates the release of IL-6 from microglia, which consequently leads to neuronal dysfunction. Moreover, elevated TOP1 due to SD were associated with neopterin, which was attributed to its promotion of elevated levels of H3K27ac in the TOP1 promoter region by disrupting the binding of YY1 and HDAC1. CONCLUSION: The present study reveals that TOP1-mediated microglial activation is critical for SD induced hippocampal neuronal damage and behavioral impairments.

Salvia miltiorrhiza stem-leaf of total phenolic acid conversion products alleviate myocardial ischemia by regulating metabolic profiles, intestinal microbiota and metabolites.

Myocardial ischemia (MI) is a significant contributor to ischemic heart diseases like angina pectoris and myocardial infarction. Reactive oxygen species produced during MI can trigger lipid peroxidation, damaging cell structure and function. Salvia miltiorrhiza (SM) has been widely used clinically in the treatment of cardiovascular diseases. However, in the process of rooting, the aboveground parts of this plant are usually discarded by tons. To make better use of these plant resources, the phenolic acids extracted and purified from the aerial part of SM were studied and chemically transformed, and the potential protective effect and possible mechanism of salvianolic acids containing a higher content of salvianolic acid A on MI were obtained. The transformed products of SM stem-leaves total phenolic acids with 8.16 % salvianolic acid A showed a better protective effect on the isoproterenol (ISO)-induced acute MI injury rat model. It can improve ST segment changes and has good antioxidant, anti-inflammatory and anticoagulant effects. In addition, the dysbiosis of gut microbiota and the related metabolic levels of short chain fatty acids (SCFAs), phenylalanine and glycerophospholipids were improved. This was achieved by reducing the abundance of Bacteroides, Faecalibaculum, and L-phenylalanine levels. In addition, the abundance of probiotics in Butyricoccus, Roseburia, and norank_f_Eubacterium_coprostanoligenes_group, as well as the contents of propionic acid and isobutyric acid, LPCs and PCs were increased. In conclusion, total phenolic acids of SM stem-leaves showed protective effects against ISO-induced rats, especially the strongest effect after conversion, which is a new option for the prevention and treatment of MI.

Xianlian Jiedu Decoction alleviates colorectal cancer by regulating metabolic profiles, intestinal microbiota and metabolites.

BACKGROUND: Xianlian Jiedu Decoction (XLJDD) has been used for the treatment of colorectal cancer (CRC) for several decades because of the prominent efficacy of the prescription. Despite the clear clinical efficacy of XLJDD, the anti-CRC mechanism of action is still unclear. PURPOSE: The inhibitory effect and mechanism of XLJDD on CRC were investigated in the azoxymethane/dextran sulfate sodium (AOM/DSS)-induced mice. METHODS: The AOM/DSS-induced mice model was adopted to evaluate the efficacy after administering the different doses of XLJDD. The therapeutic effects of XLJDD in treating AOM/DSS-induced CRC were investigated through histopathology, immunofluorescence and ELISA analysis methods. In addition, metabolomics profile and 16S rRNA analysis were used to explore the effective mechanisms of XLJDD on CRC. RESULTS: The results stated that the XLJDD reduced the number of tumor growth on the inner wall of the colon and the colorectal weight/length ratio, and suppressed the disease activity index (DAI) score, meanwhile XLJDD also increased body weight, colorectal length, and overall survival rate. The treatment of XLJDD also exhibited the ability to lower the level of inflammatory cytokines in serum and reduce the expression levels of ß-catenin, COX-2, and iNOS protein in colorectal tissue. The findings suggested that XLJDD has anti-inflammatory properties and may provide relief for those suffering from inflammation-related conditions. Mechanistically, XLJDD improved gut microbiota dysbiosis and associated metabolic levels of short chain fatty acids (SCFAs), sphingolipid, and glycerophospholipid. This was achieved by reducing the abundance of Turicibacter, Clostridium_sensu_stricto_1, and the levels of sphinganine, LPCs, and PCs. Additionally, XLJDD increased the abundance of Enterorhabdus and Alistipes probiotics, as well as the content of butyric acid and isovaleric acid. CONCLUSION: The data presented in this article demonstrated that XLJDD can effectively inhibit the occurrence of colon inner wall tumors by reducing the level of inflammation and alleviating intestinal microbial flora imbalance and metabolic disorders. It provides a scientific basis for clinical prevention and treatment of CRC.

Clinical application of repetitive transcranial magnetic stimulation in improving functional impairments post-stroke: review of the current evidence and potential challenges.

In recent years, the stroke incidence has been increasing year by year, and the related sequelae after stroke, such as cognitive impairment, motor dysfunction, and post-stroke depression, seriously affect the patient's rehabilitation and daily activities. Repetitive transcranial magnetic stimulation (rTMS), as a safe, non-invasive, and effective new rehabilitation method, has been widely recognized in clinical practice. This article reviews the application and research progress of rTMS in treating different functional impairments (cognitive impairment, motor dysfunction, unilateral spatial neglect, depression) after stroke in recent years, and preliminary summarized the possible mechanisms. It has been found that the key parameters that determine the effectiveness of rTMS in improving post-stroke functional impairments include pulse number, stimulated brain areas, stimulation intensity and frequency, as well as duration. Generally, high-frequency stimulation is used to excite the ipsilateral cerebral cortex, while low-frequency stimulation is used to inhibit the contralateral cerebral cortex, thus achieving a balance of excitability between the two hemispheres. However, the specific mechanisms and the optimal stimulation mode for different functional impairments have not yet reached a consistent conclusion, and more research is needed to explore and clarify the best way to use rTMS. Furthermore, we will identify the issues and challenges in the current research, explore possible mechanisms to deepen understanding of rTMS, propose future research directions, and offer insightful insights for better clinical applications.

Salvianolic acid B and tanshinone IIA synergistically improve early diabetic nephropathy through regulating PI3K/Akt/NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic nephropathy (DN) is one of the most common and serious complications of diabetes, which lacks effective treatment. Salviae Miltiorrhizae Radix Et Rhizoma is one of the key compatible traditional Chinese medicine in the prescription for the treatment of DN. Salvianolic acid B and tanshinone IIA are two monomer active components with high content and clear structure in Salvia miltiorrhiza, which can effectively improve early (DN), respectively. AIM OF THE STUDY: To evaluate the compatible effect of salvianolic acid B and tanshinone IIA on early DN rats and elucidate the mechanism. METHODS: Early DN rats were induced by streptozotocin combined with high glucose and high fat diet, and intervened by salvianolic acid B, tanshinone IIA and their combinations. The pathological sections of kidney, liver and biochemical indexes were analyzed. Network pharmacology method was used to predict the possible mechanism. The mechanisms were elucidated by metabolomics, Elisa, and Western blot. RESULTS: Given our analysis, salvianolic acid B and tanshinone IIA can synergistically regulate 24 h UTP, Urea and Scr and improve kidney damage in early DN rats. The metabolic abnormalities of early DN rats were improved by regulating the biosynthesis of saturated fatty acids, glycerol phospholipid metabolism, steroid biosynthesis, alanine, and arachidonic acid. Salvianolic acid B combined with tanshinone IIA at a mass ratio of 13.4:1 can significantly reduce kidney inflammation, up-regulate p-PI3K/PI3K and p-Akt/Akt and down-regulate p-NF-κB/NF-κB, which better than the single-used group and can be reversed by PI3K inhibitor LY294002. CONCLUSION: Salvianolic acid B and tanshinone IIA can synergistically improve glucose and lipid disorders, liver and kidney damage, and resist kidney inflammation in early DN rats, and the mechanism may be related to regulating PI3K/Akt/NF-κB signaling pathway.

Upregulation of miR-21-5p rescues the inhibition of cardiomyocyte proliferation induced by high glucose through negative regulation of Rhob.

Increasing evidence shows that maternal hyperglycemia inhibits cardiomyocyte (CM) proliferation and promotes cell apoptosis during fetal heart development, which leads to cardiac dysplasia. Accumulating evidence suggests that the overexpression of miR-21 in CMs has a protective role in cardiac function. Therefore, we investigated whether miR-21 can rescue CM injury caused by high glucose. First, we performed biological function analysis of miR-21-5p overexpression in H9c2 cells treated with high glucose. We found that the proliferation of H9c2 cells treated with high glucose decreased significantly and was rescued after overexpression of miR-21-5p. CCK-8 and EdU incorporation assays were performed to assess cell proliferation. The cell proliferation of the miR-21-5p mimic transfection group was improved compared with that of the NC mimic group (*p < 0.05, miR-21-5p mimics vs. NC mimics) when the proliferation of H9c2 cells was reduced by high glucose (****p < 0.0001, high glucose (HG) vs. normal glucose (NG)). Then, we verified the targeted and negative regulation of miR-21-5p on Rhob using a dual-luciferase activity assay and RT-qPCR, respectively. We further demonstrated that miR-21-5p regulates Rhob to rescue the inhibition of CM proliferation induced by high glucose. The CCK-8 results showed that the cell proliferation of the siRNA-Rhob group was higher than that of the NC mimic group (***p < 0.001) and that of the cotransfection group with Up-Rhob plasmids and miR-21-5p mimics was lower than that of the miR-21-5p mimic group (*p < 0.05). Conclusion: Overexpression of miR-21-5p rescues the inhibition of high glucose-induced CM proliferation through regulation of Rhob.

miR-136 Regulates the Proliferation and Adipogenic Differentiation of Adipose-Derived Stromal Vascular Fractions by Targeting HSD17B12.

Fat deposition involves the continuous differentiation of adipocytes and lipid accumulation. Studies have shown that microRNA miR-136 and 17ß-hydroxysteroid dehydrogenase type 12 (HSD17B12) play important roles in lipid accumulation. However, the regulatory mechanism through which miR-136 targets HSD17B12 during ovine adipogenesis remains unclear. This study aimed to elucidate the role of miR-136 and HSD17B12 in adipogenesis and their relationship in ovine adipose-derived stromal vascular fractions (SVFs). The target relationship between miR-136 and HSD17B12 was predicted and confirmed using bioinformatics and a dual-luciferase reporter assay. The results showed that miR-136 promoted proliferation and inhibited adipogenic differentiation of ovine SVFs. We also found that HSD17B12 inhibited proliferation and promoted adipogenic differentiation of ovine SVFs. Collectively, our results indicate that miR-136 facilitates proliferation and attenuates adipogenic differentiation of ovine SVFs by targeting HSD17B12. These findings provide a theoretical foundation for further elucidation of the regulatory mechanisms of lipid deposition in sheep.

Proteome profiling of early gestational plasma reveals novel biomarkers of congenital heart disease.

Prenatal diagnosis of congenital heart disease (CHD) relies primarily on fetal echocardiography conducted at mid-gestational age-the sensitivity of which varies among centers and practitioners. An objective method for early diagnosis is needed. Here, we conducted a case-control study recruiting 103 pregnant women with healthy offspring and 104 cases with CHD offspring, including VSD (42/104), ASD (20/104), and other CHD phenotypes. Plasma was collected during the first trimester and proteomic analysis was performed. Principal component analysis revealed considerable differences between the controls and the CHDs. Among the significantly altered proteins, 25 upregulated proteins in CHDs were enriched in amino acid metabolism, extracellular matrix receptor, and actin skeleton regulation, whereas 49 downregulated proteins were enriched in carbohydrate metabolism, cardiac muscle contraction, and cardiomyopathy. The machine learning model reached an area under the curve of 0.964 and was highly accurate in recognizing CHDs. This study provides a highly valuable proteomics resource to better recognize the cause of CHD and has developed a reliable objective method for the early recognition of CHD, facilitating early intervention and better prognosis.

Noninvasive Characterization of Metabolic Changes in Ischemic Stroke Using Z-spectrum-fitted Multiparametric Chemical Exchange Saturation Transfer-weighted Magnetic Resonance Imaging.

OBJECTIVE: This study aimed to noninvasively characterize the metabolic alterations in ischemic brain tissues using Z-spectrum-fitted multiparametric chemical exchange saturation transfer-weighted magnetic resonance imaging (CEST-MRI). METHODS: Three sets of Z-spectrum data with saturation power (B1) values of 1.5, 2.5, and 3.5 µT, respectively, were acquired from 17 patients with ischemic stroke. Multiple contrasts contributing to the Z-spectrum, including fitted amide proton transfer (APTfitted), +2 ppm peak (CEST@2ppm), concomitantly fitted APTfitted and CEST@2ppm (APT&CEST@2ppm), semisolid magnetization transfer contrast (MT), aliphatic nuclear Overhauser effect (NOE), and direct saturation of water (DSW), were fitted with 4 and 5 Lorentzian functions, respectively. The CEST metrics were compared between ischemic lesions and contralateral normal white matter (CNWM), and the correlation between the CEST metrics and the apparent diffusion coefficient (ADC) was assessed. The differences in the Z-spectrum metrics under varied B1 values were also investigated. RESULTS: Ischemic lesions showed increased APTfitted, CEST@2ppm, APT&CEST@2ppm, NOE, and DSW as well as decreased MT. APT&CEST@2ppm, MT, and DSW showed a significant correlation with ADC [APT&CEST@2ppm at the 3 B1 values: R=0.584/0.467/0.551; MT at the 3 B1 values: R=-0.717/-0.695/-0.762 (4-parameter fitting), R=-0.734/-0.711/-0.785 (5-parameter fitting); DSW of 4-/5-parameter fitting: R=0.794/0.811 (2.5 µT), R=0.800/0.790 (3.5 µT)]. However, the asymmetric analysis of amide proton transfer (APTasym) could not differentiate the lesions from CNWM and showed no correlation with ADC. Furthermore, the Z-spectrum contrasts varied with B1. CONCLUSION: The Z-spectrum-fitted multiparametric CEST-MRI can comprehensively detect metabolic alterations in ischemic brain tissues.

Detection of CYFRA 21-1 in human serum by an electrochemical immunosensor based on UiO-66-NH2@CMWCNTs and CS@AuNPs.

In this study, an electrochemical immunosensor was constructed to detect the cytokeratin 19 fragment antigen 21-1 (CYFRA 21-1) in human serum. CYFRA 21-1 is the most sensitive tumor marker of non-small cell lung cancer (NSCLC), its content in normal human serum should be less than 3.3 ng/mL. When lung cancer cells dissolve or die, a myriad of CYFRA 21-1 is released into a tumor patient's blood circulation, and its serum content elevates strikingly. Consequently, detecting CYFRA 21-1 by an electrochemical biosensor is expected to provide a new method for the early detection and prevention of lung cancer. In this study, a composite of UiO-66-NH2 and carboxylated multi-walled carbon nanotubes (CMWCNTs) was used as the substrate material of a sensor; the resulting sensor had a large specific surface area and strong electrical conductivity. Moreover, gold nanoparticles (AuNPs) were used to bind to antibodies through an Au-S bonds. Also, a supersensitive detection of CYFRA 21-1 was achieved through the specific bindings of antigens and antibodies. Under optimal detection conditions, the change of current signal intensity of the immunosensor was proportional to the logarithm of CYFRA 21-1 concentration and had a linear relation in the range of 0.005-400 ng/mL, while the detection limit was 1.15 pg/mL (S/N = 3). The proposed immunosensor had high precision, stability, and selectivity. More importantly, the sensor was been successfully applied to detect CYFRA 21-1 in human serum with high recovery, providing a new method for early screening and dynamic monitoring of lung cancer.

Insights into the in vitro digestibility of pork myofibrillar protein with different ionic polysaccharides from the perspective of gel characteristics.

In this work, the simulated gastrointestinal digestion of myofibrillar protein gels (MPGs) with anionic xanthan (XMP) and sodium alginate (SMP)/cationic chitosan (CSMP)/neutral curdlan (CMP) and konjac (KMP) was investigated to develop muscle-gelled foods with good qualities before and after eating. The results indicated that the neutral CMP and KMP groups had higher gel strength and protein digestibility than the CSMP group. Xanthan and sodium alginate facilitated myosin degradation in gastrointestinal digestion because of the weak wraps between protein and anionic polysaccharides, gaining plentiful peptides (1790 and 1692 respectively) with molecular weights below 2000 Da. Chitosan and neutral curdlan could improve the strength of MP gel but inhibited proteolysis and resulted in low contents of released amino acids via the strong cross-linked network blocking trypsin contact. This work provides a theoretical basis for developing low-fat meat products with good qualities and digestion behaviors by simply controlling the ionic types of polysaccharides.

A scientometrics and visualization analysis of oxidative stress modulator Nrf2 in cancer profiles its characteristics and reveals its association with immune response.

Background: Nrf2, an essential and fascinating transcription factor, enjoys a dual property in the occurrence and development of inflammation and cancer. For over two decades, numerous studies regarding Nrf2 in cancer have been reported, whereas there is still a lack of a scientometrics and visualization analysis of Nrf2 in cancer. Hence, a scientometric study regarding the oxidative stress modulator Nrf2 was implemented. Methods: After the quality screening, we defined 7168 relevant studies from 2000 to 2021. CiteSpace, VOSviewer, R software, and GraphPad Prism were used for the following scientometric study and visualization analysis, including field profiles, research hotspots, and future predictions. Results: The total number of publications and citations are 1058 and 54,690, respectively. After polynomial fitting curve analysis, two prediction functions of the annual publication number (y = 3.3909x2 - 13585x + 1 E+07) and citation number (185.45x2 - 743669x + 7 E+08) were generated. After scientometric analysis, we found that Biochemistry Molecular Biology correlates with Nrf2 in cancer highly, and Free Radical Biology and Medicine is a good choice for submitting Nrf2-related manuscripts. The current research hotspots of Nrf2 in cancer mainly focus on cancer therapy and its cellular and molecular mechanisms. "antioxidant response element (87.5)", "gene expression (43.98)", "antioxidant responsive element (21.14)", "chemoprevention (20.05)", "carcinogenesis (19.2)", "cancer chemoprevention (18.45)", "free radical (17.15)", "response element (14.17)", and "chemopreventive agent (14.04)" are important for cancer therapy study. In addition, "glutathione-S-transferase (47)", "keap1 (15.39)", and "heme oxygenase 1 gene (24.35)" are important for inflammation and cell fate study. More interestingly, by performing an "InfoMap" algorithm, the thematic map showed that the "immune response" is essential to oxidative stress modulator Nrf2 but not well developed, indicating it deserves further exploration. Conclusion: This study revealed field profiles, research hotspots, and future directions of oxidative stress modulator Nrf2 in inflammation and cancer research, and our findings will offer a vigorous roadmap for further studies in this field.

Nuclear ATR lysine-tyrosylation protects against heart failure by activating DNA damage response.

Dysregulated amino acid increases the risk for heart failure (HF) via unclear mechanisms. Here, we find that increased plasma tyrosine and phenylalanine levels are associated with HF. Increasing tyrosine or phenylalanine by high-tyrosine or high-phenylalanine chow feeding exacerbates HF phenotypes in transverse aortic constriction and isoproterenol infusion mice models. Knocking down phenylalanine dehydrogenase abolishes the effect of phenylalanine, indicating that phenylalanine functions by converting to tyrosine. Mechanistically, tyrosyl-tRNA synthetase (YARS) binds to ataxia telangiectasia and Rad3-related gene (ATR), catalyzes lysine tyrosylation (K-Tyr) of ATR, and activates the DNA damage response (DDR) in the nucleus. Increased tyrosine inhibits the nuclear localization of YARS, inhibits the ATR-mediated DDR, accumulates DNA damage, and elevates cardiomyocyte apoptosis. Enhancing ATR K-Tyr by overexpressing YARS, restricting tyrosine, or supplementing tyrosinol, a structural analog of tyrosine, promotes YARS nuclear localization and alleviates HF in mice. Our findings implicate facilitating YARS nuclear translocation as a potential preventive and/or interfering measure against HF.

[Mechanism of Sijunzi Decoction in treatment of Alzheimer's disease based on UPLC-Q-TOF-MS, network pharmacology, and experimental verification].

The study identified the blood-entering components of Sijunzi Decoction after gavage administration in rats by UPLC-Q-TOF-MS/MS, and investigated the mechanism of Sijunzi Decoction in treating Alzheimer's disease by virtue of network pharmacology, molecular docking, and experimental verification. The blood-entering components of Sijunzi Decoction were identified based on the mass spectra and data from literature and databases. The potential targets of the above-mentioned blood-entering components in the treatment of Alzheimer's disease were searched against PharmMapper, OMIM, DisGeNET, GeneCards, and TTD. Next, STRING was employed to establish a protein-protein interaction(PPI) network. DAVID was used to perform the Gene Ontology(GO) annotation and the Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment. Cytoscape 3.9.0 was used to carry out visual analysis. AutoDock Vina and PyMOL were used for molecular docking of the blood-entering components with the potential targets. Finally, the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt) signaling pathway enriched by the KEGG analysis was selected for validation by animal experiments. The results showed that 17 blood-entering components were detected in the serum samples after administration. Among them, poricoic acid B, liquiritigenin, atractylenolide Ⅱ, atractylenolide Ⅲ, ginsenoside Rb_1, and glycyrrhizic acid were the key components of Sijunzi Decoction in treating Alzheimer's disease. HSP90AA1, PPARA, SRC, AR, and ESR1 were the main targets for Sijunzi Decoction to treat Alzheimer's disease. Molecular docking showed that the components bound well with the targets. Therefore, we hypothesized that the mechanism of Sijunzi Decoction in treating Alzheimer's disease may be associated with the PI3K/Akt, cancer treatment, and mitogen-activated protein kinase(MAPK) signaling pathways. The results of animal experiments showed that Sijunzi Decoction significantly attenuated the neuronal damage in the hippocampal dentate gyrus area, increased the neurons, and raised the ratios of p-Akt/Akt and p-PI3K/PI3K in the hippocampus of mice. In conclusion, Sijunzi Decoction may treat Alzheimer's disease by activating the PI3K/Akt signaling pathway. The findings of this study provide a reference for further studies about the mechanism of action and clinical application of Sijunzi Decoction.

Folic acid protects against age-associated apoptosis and telomere attrition of neural stem cells in senescence-accelerated mouse prone 8.

Folic acid (FA) could improve cognitive performance and attenuate brain cell injury in the aging brain; FA supplementation is also associated with inhibiting neural stem cell (NSC) apoptosis. However, its role in age-associated telomere attrition remains unclear. We hypothesized that FA supplementation attenuates age-associated apoptosis of NSCs in mice via alleviating telomere attrition in senescence-accelerated mouse prone 8 (SAMP8). In this study, 4-month-old male SAMP8 mice were assigned equal numbers to four different diet groups (n = 15). Fifteen age-matched senescence-accelerated mouse resistant 1 mice, fed with the FA-normal diet, were used as the standard aging control group. After FA treatment for 6 months, all mice were sacrificed. NSC apoptosis, proliferation, oxidative damage, and telomere length were evaluated by immunofluorescence and Q-fluorescent in situ hybridization. The results showed that FA supplementation inhibited age-associated NSC apoptosis and prevented telomere attrition in the cerebral cortex of SAMP8 mice. Importantly, this effect might be explained by the decreased levels of oxidative damage. In conclusion, we demonstrate it may be one of the mechanisms by which FA inhibits age-associated NSC apoptosis by alleviating telomere length shortening.

Proteogenomic characterization of cholangiocarcinoma.

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is a highly heterogeneous cancer with limited understanding and few effective therapeutic approaches. We aimed at providing a proteogenomic CCA characterization to inform biological processes and treatment vulnerabilities. APPROACH AND RESULTS: Integrative genomic analysis with functional validation uncovered biological perturbations downstream of driver events including DPCR1 , RBM47 mutations, SH3BGRL2 copy number alterations, and FGFR2 fusions in CCA. Proteomic clustering identified three subtypes with distinct clinical outcomes, molecular features, and potential therapeutics. Phosphoproteomics characterized targetable kinases in CCA, suggesting strategies for effective treatment with CDK and MAPK inhibitors. Patients with CCA with HBV infection showed increased antigen processing and presentation (APC) and T cell infiltration, conferring a favorable prognosis compared with those without HBV infection. The characterization of extrahepatic CCA recommended the feasible application of vascular endothelial-derived growth factor inhibitors. Multiomics profiling presented distinctive molecular characteristics of the large bile duct and the small bile duct of intrahepatic CCA. The immune landscape further revealed diverse tumor immune microenvironments, suggesting immune subtypes C1 and C5 might benefit from immune checkpoint therapy. TCN1 was identified as a potential CCA prognostic biomarker, promoting cell growth by enhancing vitamin B12 metabolism. CONCLUSIONS: We characterized the proteogenomic landscape of 217 CCAs with 197 paired normal adjacent tissues and identified their subtypes and potential therapeutic targets. The multiomics analyses with other databases and some functional validations have indicated strategies regarding the clinical, biological, and therapeutic approaches to the management of CCA.