Endothelial cell specific molecule 1 promotes epithelial-mesenchymal transition of cervical cancer via the E-box binding homeobox 1.

OBJECTIVE: To investigate the mechanism of endothelial cell specific molecule 1 (ESM1) promoting cervical cancer cell proliferation and EMT characteristics through zinc finger E-box binding homeobox 1 (ZEB1)/EMT pathway. METHODS: The correlation between ESM1 expression and prognosis of cervical cancer patients was analyzed by bioinformatics. SiHa, HeLa cell lines and corresponding control cell lines with stable ESM1 expression were obtained. Cell proliferation ability was detected by CCK-8 assay. The invasion and migration ability of Hela and SiHa cells were detected by Transwell assay and scratch closure assay. Expressions of EMT-related markers E-cadherin and Vimentin were detected by real-time PCR. The ability of silenced ESM1 to tumor formation in vivo was detected by tumor formation in nude mice. The effects of aloe-emodin on inhibit ESM1 expression and its inhibitory effect on cervical cancer cells in vitro and in vivo were analyzed by the same method. RESULTS: ESM1 was highly expressed in cervical cancer, and the high expression of ESM1 was associated with poor prognosis of cervical cancer patients. CCK-8 results showed that the proliferation, invasion and migration of Hela and SiHa cells were significantly reduced after siRNA interfered with ESM1 expression. Overexpression of ESM1 promoted the proliferation and migration of cervical cancer cells. Mechanism studies have shown that the oncogenic effect of ESM1 is realized through the ZEB1/PI3K/AKT pathway. High throughput drug screening found that aloe-emodin can target ESM1. Inhibitory effect of aloe emodin on ESM1/ZEB1/EMT signaling pathway and cervical cancer cells. CONCLUSION: The silencing of ESM1 expression may inhibit the proliferation, invasion, metastasis and epithelial-mesenchymal transformation of cervical cancer cells by inhibiting ZEB1/PI3K/AKT. Aloe-emodin is a potential treatment for cervical cancer, which can play an anti-tumor role by inhibiting ESM1/ZEB1.

Untargeted lipidomics of bronchopulmonary dysplasia induced by hyperoxia exposure in rats.

Background: Bronchopulmonary dysplasia (BPD), characterized by impaired lung development, remains a leading cause of morbidity and mortality in premature infants. The synthesis and metabolism of lipids play a critical role in normal lung development, such as dipalmitoylphosphatidylcholine, a key component of pulmonary surfactant (PS). Therefore, we conducted a lipidomics study of rat lung tissue to explore the changes of pulmonary lipid composition in the progression of BPD disease. Methods: In this study, we exposed neonatal Sprague-Dawley (SD) rats to hyperoxia for 14 days. After hyperoxia exposure, the lung tissues of rats were analyzed pathologically, and untargeted lipidomics was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Hematoxylin-eosin (H&E) staining showed that the alveoli enlarged, the number of alveoli decreased and the pulmonary surfactant-associated protein D (SFTPD) decreased in hyperoxia-exposed rats. A total of 620 pulmonary lipids were detected by LC-MS/MS, covering 27 lipid categories. The most common lipids were triacylglycerol (TAG), followed by phosphatidylcholine (PC) and phosphatidylethanolamine (PE). Conclusions: Compared with those rats exposed to normoxic conditions, the lipid levels in the lungs of rats exposed to hyperoxia for 14 days generally decreased, with the levels of TAG and PC decreasing most significantly. In short, our results provide a clue for finding therapeutic targets and biomarkers of a BPD rat model lung liposome.

Detection of pTDP-43 via routine muscle biopsy: A promising diagnostic biomarker for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, pathologically characterized by TDP-43 aggregates. Recent evidence has been indicated that phosphorylated TDP-43 (pTDP-43) is present not only in motor neurons but also in muscle tissues. However, it is unclear whether testing pTDP-43 aggregation in muscle tissue would assist in the diagnosis of ALS. We propose three key questions: (i) Is aggregation of pTDP-43 detectable in routine biopsied muscles? (ii) Can detection of pTDP-43 aggregation discriminate between ALS and non-ALS patients? (iii) Can pTDP-43 aggregation be observed in the early stages of ALS? We conducted a diagnostic study comprising 2 groups: an ALS group in which 18 cases underwent muscle biopsy screened from a registered ALS cohort consisting of 802 patients and a non-ALS control group, in which we randomly selected 54 muscle samples from a biospecimen bank of 684 patients. Among the 18 ALS patients, 3 patients carried pathological GGGGCC repeats in the C9ORF72 gene, 2 patients carried SOD1 mutations, and 7 patients were at an early stage with only one body region clinically affected. The pTDP-43 accumulation could be detected in routine biopsied muscles, including biceps brachii, deltoid, tibialis anterior, and quadriceps. Abnormal aggregation of pTDP-43 was present in 94.4% of ALS patients (17/18) compared to 29.6% of non-ALS controls (16/54; p < 0.001). The pTDP-43 aggregates were mainly close to the sarcolemma. Using a semi-quantified pTDP-43 aggregates score, we applied a cut-off value of 3 as a diagnostic biomarker, resulting in a sensitivity of 94.4% and a specificity of 83.3%. Moreover, we observed that accumulation of pTDP-43 occurred in muscle tissues prior to clinical symptoms and electromyographic lesions. Our study provides proof-of-concept for the detection of pTDP-43 accumulation via routine muscle biopsy which may serve as a novel biomarker for diagnosis of ALS.

Central administration of AICAR attenuates hypertension via AMPK/Nrf2 pathway in the hypothalamic paraventricular nucleus of hypertensive rats.

BACKGROUND: Oxidative stress and inflammatory cytokines in the hypothalamus paraventricular nucleus (PVN) have been implicated in sympathetic nerve activity and the development of hypertension, but the specific mechanisms underlying their production in the PVN remains to be elucidated. Previous studies have demonstrated that activation of nuclear transcription related factor-2 (Nrf2) in the PVN reduced the production of reactive oxygen species (ROS) and inflammatory mediators. Moreover, AMP-activated protein kinase (AMPK), has been observed to decrease ROS and inflammatory cytokine production when activated in the periphery. 5-amino-1-ß-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) is an AMPK agonist. However, little research has been conducted on the role of AMPK in the PVN during hypertension. Therefore, we hypothesized that AICAR in the PVN is involved in regulating AMPK/Nrf2 pathway, affecting ROS and inflammatory cytokine expression, influencing sympathetic nerve activity. METHODS: Adult male Sprague-Dawley rats were utilized to induce two-kidney, one-clip (2K1C) hypertension via constriction of the right renal artery. Bilateral PVN was microinjected with either artificial cerebrospinal fluid or AICAR once a day for 4 weeks. RESULTS: Compared to the SHAM group, the PVN of 2K1C hypertensive rats decreased p-AMPK and p-Nrf2 expression, increased Fra-Like, NAD(P)H oxidase (NOX)2, NOX4, tumor necrosis factor-α and interleukin (IL)-1ß expression, elevated ROS levels, decreased superoxide dismutase 1 and IL-10 expression, and elevated plasma norepinephrine levels. Bilateral PVN microinjection of AICAR significantly ameliorated these changes. CONCLUSION: These findings suggest that repeated injection of AICAR in the PVN suppresses ROS and inflammatory cytokine production through the AMPK/Nrf2 pathway, reducing sympathetic nerve activity and improving hypertension.

Association between bacterial vaginosis with human papillomavirus in the United States (NHANES 2003-2004).

BACKGROUND: The balance of vaginal microecology is closely related to human papillomavirus (HPV) infection and cervical lesions. This study aims to investigate the relationship between bacterial vaginosis (BV) and HPV infection. METHODS: In total, 1,310 individuals from the National Health and Nutrition Examination Survey (NHANES, 2003-2004) were included in this study. Logistic regression and subgroup analyses were used to examine the association between BV and HPV infection. RESULTS: A significant positive association was observed between BV and HPV infection in women after adjustment for other confounders (OR = 1.47, 95% confidence interval [CI]: 1.15-1.88). In subgroup analyses, we have found this positive correlation was most prominent among Mexican Americans (OR = 1.83, 95% CI: 1.08-3.08) and non-Hispanic blacks (OR = 1.81, 95% CI: 1.08-3.04). CONCLUSIONS: This cross-sectional study demonstrated a positive association between BV and HPV infection in women.

Alkane-Strengthened Viscoelasticity in Micellar Solutions of Surface-Active Ionic Liquids and Their Potential Application in Enhanced Oil Recovery.

Wormlike micelles (WLMs) are highly sensitive to alkanes, resulting in structural destruction and loss of viscosity. Therefore, the study of WLMs against alkanes holds great significant importance. Surface-active ionic liquids have shown increasing promise for different situations for customizing molecular structures with the specialty of flexible functional assembly. In this paper, we found that WLMs constructed from the long-chain fatty acid surface-active ionic liquid (N,N-dimethylbenzylamine-oleic acid, abbreviated as BD-OA) exhibit strengthened viscoelasticity with the introduction of alkanes, expanding the resistance range to alkane damage. Here, the rheological behavior, microstructure, and dissipative particle dynamics (DPD) simulations of BD-OA WLMs were investigated at macro-, micro-, and mesoscopic scales, before (and after) the introduction of alkane. Our findings confirm the structural transformation of the micellar system from WLMs to lamellar micelles with higher viscoelasticity after alkane induction. The rearrangement of the micelle configuration may be attributed to the infiltration of alkane molecules into the fence layer formed by the BD-OA WLMs, leading to an increase in the boundary accumulation parameter and ultimately resulting in the formation of lower curvature lamellar micelles. More importantly, the against alkanes BD-OA WLMs have exhibited excellent in enhanced oil recovery, which has a promise for substituting common oil-displacing agents in tertiary oil recovery processes.

Resveratrol-derived inhibitors of the E3 ubiquitin ligase PELI1 inhibit the metastasis of triple-negative breast cancer.

Triple-negative breast cancer (TNBC), as the most challenging subtype of breast cancer, exerts highly invasive ability and metastatic nature to the lymph nodes, which is correlated with poor survival rates among patients. Pellino-1 (PELI1) is an E3 ubiquitin ligase involved in tumor invasion and metastasis, and has the potential to be developed as a novel therapeutic target for TNBC. In this study, we identified a potent inhibitor of PELI1, namely compound 3d, on the basis of natural stilbene framework through medicinal chemistry approaches. This novel PELI1 inhibitor 3d showed potent binding affinity to PELI1 (Kd 8.2 µM) in fluorescence quenching assay, and markedly interrupted the interaction of PELI1 and SNAIL/SLUG confirmed by co-immunoprecipitation. Moreover, 3d exhibited potent antitumor activity in inhibiting tumor cell migration in scratch wound healing assay without affecting cell proliferation in vitro, and down-regulated the downstream EMT-effectors of PELI1 as assessed by western blotting. In the experimental lung metastasis model, 3d showed anti-TNBC metastasis efficacy without observable toxicity in vivo.

Diagnostic value of CA125, HE4, and systemic immune-inflammation index in the preoperative investigation of ovarian masses.

This study aimed to ascertain the diagnostic accuracy of CA125, HE4, systemic immune-inflammation index (SII), fibrinogen-to-albumin ratio (FAR), prognostic nutritional index (PNI), and their combination for ovarian cancer (OC) to discover an optimal combined diagnostic index for early diagnosis of OC. A thorough investigation was conducted to ascertain the correlation between these markers and the pathological characteristics of OC, thereby providing a foundation for early identification and treatment of this disorder. One hundred seventy patients with documented OC and benign ovarian tumors (BOTs) treated at Hebei General Hospital between January 2019 and December 2022 were included in this retrospective study. Data analysis was conducted using IBM SPSS Statistics version V26.0, MedCalc Statistical Software version 19.4.0, and the R Environment for Statistical Computing software (R Foundation for Statistical Computing). Isolated CA125 showed the best application value for differentiating benign ovarian tumors from OC when the defined variables were compared separately. The combination of CA125, HE4, FAR, SII, and PNI displayed a greater area under the operating characteristic curve curve than any one of them or other combinations of the 5 variables. Compared to CA125 alone, the combination of CA125, HE4, FAR, SII, and PNI showed a slight gain in sensitivity (83.91%), negative predictive value (83.91%), accuracy (85.88%), and a decrease in negative likelihood ratio (0.180%). Higher preoperative CA125, HE4, SII, and FAR levels, and lower PNI levels predicted a higher probability of advanced OC progression and lymph node metastasis. FAR has better application value than other inflammation-related markers (PNI and SII). This study suggests that preoperative serum SII, PNI, and FAR may be clinically valuable markers in patients with OC. FAR has better application value than other inflammation-related markers (PNI and SII). As we delve deeper into the inflammatory mechanisms associated with tumors, we may discover more effective combinations of tumor and inflammatory biomarkers.

MRI-based machine learning models predict the malignant biological behavior of meningioma.

BACKGROUND: The WHO grade and Ki-67 index are independent indices used to evaluate the malignant biological behavior of meningioma. This study aims to develop MRI-based machine learning models to predict the malignant biological behavior of meningioma from the perspective of the WHO grade, Ki-67 index, and their combination. METHODS: This multicenter, retrospective study included 313 meningioma patients, of which 70 were classified as high-grade (WHO II/III) and 243 as low-grade (WHO I). The Ki-67 expression was classified into low-expression (n = 216) and high-expression (n = 97) groups with a threshold of 5%. Among them, there were 128 patients with malignant biological behavior whose WHO grade or Ki-67 index increased either or both. Data from Center A and B are were utilized for model development, while data from Center C and D were used for external validation. Radiomic features were extracted from the maximum cross-sectional area (2D) region of Interest (ROI) and the whole tumor volume (3D) ROI using different paraments from the T1, T2-weighted, and T1 contrast-enhanced sequences (T1CE), followed by five independent feature selections and eight classifiers. 240 prediction models were constructed to predict the WHO grade, Ki-67 index and their combination respectively. Models were evaluated by cross-validation in training set (n = 224). Suitable models were chosen by comparing the cross-validation (CV) area under the curves (AUC) and their relative standard deviations (RSD). Clinical and radiological features were collected and analyzed; meaningful features were combined with radiomic features to establish the clinical-radiological-radiomic (CRR) models. The receiver operating characteristic (ROC) analysis was used to evaluate those models in validation set. Radiomic models and CRR models were compared by Delong test. RESULTS: 1218 and 1781 radiomic features were extracted from 2D ROI and 3D ROI of each sequence. The selected grade, Ki-67 index and their combination radiomic models were T1CE-2D-LASSO-LR, T1CE-3D-LASSO-NB, and T1CE-2D-LASSO-LR, with cross-validated AUCs on the training set were 0.857, 0.798, and 0.888, the RSDs were 0.06, 0.09, and 0.05, the validation set AUCs were 0.829, 0.752, and 0.904, respectively. Heterogeneous enhancement was found to be associated with high grade and Ki-67 status, while surrounding invasion was associated with the high grade status, peritumoral edema and cerebrospinal fluid space surrounding tumor were correlated with the high Ki-67 status. The Delong test showed that these significant radiological features did not significantly improve the predictive performance. The AUCs for CRR models predicting grade, Ki-67 index, and their combination in the validation set were 0.821, 0.753, and 0.906, respectively. CONCLUSIONS: This study demonstrated that MRI-based machine learning models could effectively predict the grade, Ki-67 index of meningioma. Models considering these two indices might be valuable for improving the predictive sensitivity and comprehensiveness of prediction of malignant biological behavior of meningioma.

Multi-Targeted Peptide-Modified Gold Nanoclusters for Treating Solid Tumors in the Liver.

Apoptosis and autophagy determine the fate of cancer cells. However, simply promoting apoptosis of tumor cells is limited in the treatment of unresectable solid liver tumors. Generally, autophagy is considered the anti-apoptotic "guardian". But the pro-apoptotic effects of autophagy can be activated by excessive endoplasmic reticulum (ER) stress. Here, amphiphilic peptide-modified glutathione (GSH)-gold nanocluster aggregates (AP1 P2 -PEG NCs) were designed with the enrichment of solid liver tumors and the prolonged stress in the ER, which can achieve the mutual promotion of autophagy and apoptosis in liver tumor cells. In this study, orthotopic and subcutaneous liver tumor models show the anti-tumor effectiveness of AP1 P2 -PEG NCs, with a better antitumor effect than sorafenib, biosafety (Lethal Dose, 50% (LD50 ) of 827.3 mg kg-1 ), wide therapeutic window (non-toxic in 20 times of therapeutic concentration) and high stability (blood half-life of 4 h). These findings identify an effective strategy to develop peptide-modified gold nanocluster aggregates with low toxicity, high potency, and selectivity for solid liver tumors treatment.

Elucidating the Multimodal Anticancer Mechanism of an Organometallic Terpyridine Platinum(II) N-Heterocyclic Carbene Complex against Triple-Negative Breast Cancer In Vitro and In Vivo.

Treatment of triple-negative breast cancer (TNBC) has long been a medical challenge because of the lack of effective therapeutic targets. Targeting lipid, carbohydrate, and nucleotide metabolism pathways has recently been proven as a promising option in view of three heterogeneous metabolic-pathway-based TNBC subtypes. Here, we present a multimodal anticancer platinum(II) complex, named Pt(II)caffeine, with a novel mode of action involving simultaneous mitochondrial damage, inhibition of lipid, carbohydrate, and nucleotide metabolic pathways, and promotion of autophagy. All these biological processes eventually result in a strong suppression of TNBC MDA-MB-231 cell proliferation both in vitro and in vivo. The results indicate that Pt(II)caffeine, influencing cellular metabolism at multiple levels, is a metallodrug with increased potential to overcome the metabolic heterogeneity of TNBC.

Luteolin Attenuates Hypertension via Inhibiting NF-κB-Mediated Inflammation and PI3K/Akt Signaling Pathway in the Hypothalamic Paraventricular Nucleus.

BACKGROUND: Luteolin is widely distributed among a number of vegetal species worldwide. The pharmacological effects of luteolin are diverse and amongst antioxidant, free radical scavenging, and anti-inflammatory activities. Preliminary study showed that luteolin can ameliorate hypertension. However, the precise mechanism needs further investigation. There is no evidence that luteolin affects the paraventricular nucleus of the hypothalamus (PVN), a brain nucleus associated with a critical neural regulator of blood pressure. Our main aim was to explore the effect of luteolin on the PI3K/Akt/NF-κB signaling pathway within the PVN of hypertensive rats. METHODS: spontaneously hypertensive rats (SHRs) and corresponding normotensive control rats, the Wistar Kyoto (WKY) rats were divided into four groups and subsequently treated for 4 weeks with bilateral PVN injections of either luteolin (20 µg/0.11 µL, volume: 0.11 µL/h) or vehicle (artificial cerebrospinal fluid). RESULTS: luteolin infusion to the PVN significantly decreased some hemodynamic parameters including the mean arterial pressure (MAP), heart rate (HR), circulating plasma norepinephrine (NE) and epinephrine (EPI). Additionally, there was a decrease in the expressions of the phosphatidylinositol 3-kinase (p-PI3K) and phosphorylated protein kinase-B (p-AKT), levels of reactive oxygen species (ROS), NAD(P)H oxidase subunit (NOX2, NOX4) in the PVN of SHRs. Meanwhile, the expression of inflammatory cytokines and the activity of nuclear factor κB (NF-κB) p65 in the PVN of SHRs were lowered. Furthermore, immunofluorescence results showed that injection of luteolin in the PVN reduced the expression of tyrosine hydroxylase (TH), and increased that of superoxide dismutase (SOD1) and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN of SHRs. CONCLUSION: Our novel findings revealed that luteolin lowered hypertension via inhibiting NF-κB-mediated inflammation and PI3K/Akt signaling pathway in the PVN.

PELI1 and EGFR cooperate to promote breast cancer metastasis.

Pellino-1 (PELI1) is an E3 ubiquitin ligase acting as a key regulator for the inflammation and autoimmunity via the ubiquitination of the substrate proteins. There is increasing evidence to support that PELI1 functions as an oncoprotein in tumorigenesis and metastasis. However, the molecular mechanism underlying the high expression and oncogenic roles of PELI1 in cancers remains limited. Herein, we revealed a novel regulation mechanism by which PELI1 and EGFR cooperate to promote breast cancer metastasis. EGFR is positively correlated with PELI1 expression in breast cancers, and its activation led to the phosphorylation of PELI1 at Tyr154 and Thr264, which subsequently activated its E3 ubiquitin ligase. Simultaneously, PELI1 physically interacted with and enhanced the stability of EGFR via the K63-linked polyubiquitination in reverse. The co-inhibition of the PELI1-EGFR showed synergetic effect to repress breast cancer metastasis. Furthermore, we identified a compound S62 as a small molecule disruptor of PELI1/EGFR that effectively repressed breast cancer metastasis. Our study not only uncovered the emerging roles of PELI1/EGFR interaction in the progression of breast cancer, but also provided an effective strategy for the inhibition of metastasis in breast cancer.

Multi-omics analysis identifies potential mechanisms by which high glucose accelerates macrophage foaming.

Atherosclerotic morbidity is significantly higher in the diabetic population. Hyperglycemia, a typical feature of diabetes, has been proven to accelerate foam cell formation. However, the molecular mechanisms behind this process remain unclear. In this study, LPS and IFN-γ were used to convert THP-1-derived macrophages into M1 macrophages, which were then activated with ox-LDL in either high glucose or normal condition. We identified lipids within macrophages by Oil red O staining and total cholesterol detection. The genes involved in lipid absorption, efflux, inflammation, and metabolism were analyzed using qRT-PCR. The mechanisms of high glucose-induced foam cell formation were further investigated through metabolomics and transcriptomics analysis. We discovered that high glucose speed up lipid accumulation in macrophages (both lipid droplets and total cholesterol increased), diminished lipid efflux (ABCG1 down-regulation), and aggravated inflammation (IL1B and TNF up-regulation). Following multi-omics analysis, it was determined that glucose altered the metabolic and transcriptional profiles of macrophages, identifying 392 differently expressed metabolites and 293 differentially expressed genes, respectively. Joint pathway analysis suggested that glucose predominantly disrupted the glycerolipid, glycerophospholipid, and arachidonic acid metabolic pathways in macrophages. High glucose in the glyceride metabolic pathway, for instance, suppressed the transcription of triglyceride hydrolase (LIPG and LPL), causing cells to deposit excess triglycerides into lipid droplets and encouraging foam cell formation. More importantly, high glucose triggered the accumulation of pro-atherosclerotic lipids (7-ketocholesterol, lysophosphatidylcholine, and glycerophosphatidylcholine). In conclusion, this work elucidated mechanisms of glucose-induced foam cell formation via a multi-omics approach.

Enhancement of fatty acid degradation pathway promoted glucoamylase synthesis in Aspergillus niger.

BACKGROUND: Our recent multi-omics analyses of glucoamylase biosynthesis in Aspergillus niger (A. niger) suggested that lipid catabolism was significantly up-regulated during high-yield period under oxygen limitation. Since the catabolism of fatty acids can provide energy compounds such as ATP and important precursors such as acetyl-CoA, we speculated that enhancement of this pathway might be beneficial to glucoamylase overproduction. RESULTS: Based on previous transcriptome data, we selected and individually overexpressed five candidate genes involved in fatty acid degradation under the control of the Tet-on gene switch in A. niger. Overexpression of the fadE, fadA and cyp genes increased the final specific enzyme activity and total secreted protein on shake flask by 21.3 ~ 31.3% and 16.0 ~ 24.2%, respectively. And a better inducible effect by doxycycline was obtained from early logarithmic growth phase (18 h) than stationary phase (42 h). Similar with flask-level results, the glucoamylase content and total extracellular protein in engineered strains OE-fadE (overexpressing fadE) and OE-fadA (overexpressing fadA) on maltose-limited chemostat cultivation were improved by 31.2 ~ 34.1% and 35.1 ~ 38.8% compared to parental strain B36. Meanwhile, intracellular free fatty acids were correspondingly decreased by 41.6 ~ 44.6%. The metabolomic analysis demonstrated intracellular amino acids pools increased 24.86% and 18.49% in two engineered strains OE-fadE and OE-fadA compared to B36. Flux simulation revealed that increased ATP, acetyl-CoA and NADH was supplied into TCA cycle to improve amino acids synthesis for glucoamylase overproduction. CONCLUSION: This study suggested for the first time that glucoamylase production was significantly improved in A. niger by overexpression of genes fadE and fadA involved in fatty acids degradation pathway. Harnessing the intracellular fatty acids could be a strategy to improve enzyme production in Aspergillus niger cell factory.

Resveratrol in the Hypothalamic Paraventricular Nucleus Attenuates Hypertension by Regulation of ROS and Neurotransmitters.

BACKGROUND: The hypothalamic paraventricular nucleus (PVN) is an important nucleus in the brain that plays a key role in regulating sympathetic nerve activity (SNA) and blood pressure. Silent mating-type information regulation 2 homolog-1 (sirtuin1, SIRT1) not only protects cardiovascular function but also reduces inflammation and oxidative stress in the periphery. However, its role in the central regulation of hypertension remains unknown. It is hypothesized that SIRT1 activation by resveratrol may reduce SNA and lower blood pressure through the regulation of intracellular reactive oxygen species (ROS) and neurotransmitters in the PVN. METHODS: The two-kidney one-clip (2K1C) method was used to induce renovascular hypertension in male Sprague-Dawley rats. Then, bilaterally injections of vehicle (artificial cerebrospinal fluid, aCSF, 0.4 µL) or resveratrol (a SIRT1 agonist, 160 µmol/L, 0.4 µL) into rat PVN were performed for four weeks. RESULTS: PVN SIRT1 expression was lower in the hypertension group than the sham surgery (SHAM) group. Activated SIRT1 within the PVN lowered systolic blood pressure and plasma norepinephrine (NE) levels. It was found that PVN of 2K1C animals injected with resveratrol exhibited increased expression of SIRT1, copper-zinc superoxide dismutase (SOD1), and glutamic acid decarboxylase (GAD67), as well as decreased activity of nuclear factor-kappa B (NF-κB) p65 and NAD(P)H oxidase (NOX), particularly NOX4. Treatment with resveratrol also decreased expression of ROS and tyrosine hydroxylase (TH). CONCLUSION: Resveratrol within the PVN attenuates hypertension via the SIRT1/NF-κB pathway to decrease ROS and restore the balance of excitatory and inhibitory neurotransmitters.

Paenibacillus sabuli sp. nov., isolated from the South China Sea.

A Gram-positive, rod-shaped, motile, spore-forming bacterium, designated strain IB182496T, was isolated from coastal sand of the South China Sea. The strain grew optimally at pH 7.0-9.0, 20-30 °C, and with NaCl 3.0-5.0 %. The predominant menaquinone was MK-7 and the major cellular fatty acids were anteiso-C15 : 0, iso-C16 : 0 and C16 : 0. The polar lipids in the cell wall included diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, three unidentified phospholipids and one unidentified lipid. The comparison of 16S rRNA gene sequences indicated that strain IB182496T was most closely related to 'Paenibacillus sambharensis' SMB1 and Paenibacillus tarimensis SA-7-6T with similarities of 95.7 and 95.5 %, respectively. The whole-genome average nucleotide identity values between strain IB182496T and the two reference strains were 70.8 and 70.5%, and the digital DNA-DNA hybridization values were 18.7 and 18.0 %, respectively. Genomic analyses showed that strain IB182496T presented a genome of 6.22 Mbp with chromosomal G+C content of 60.3 %, and a total of 5261 genes were predicted. The combined phylogenetic relatedness, phenotypic and genotypic features supported the conclusion that strain IB182496T should be considered as representing a novel species of the genus Paenibacillus, for which we propose the name Paenibacillus sabuli sp. nov. with the type strain IB182496T (=MCCC 1K04627T=JCM 34216T).

Design, synthesis and biological evaluation of novel 4-aminopiperidine derivatives as SMO/ERK dual inhibitors.

The hedgehog (Hh) pathway is tightly related with the formation, metastasis and recurrence of various cancers, which makes it a perfect anticancer target. Smoothened (SMO) is one of its key members. Three drugs targeting the Hh pathway have been successfully used in clinic, and they are all known as SMO inhibitors. However, serious drug resistant problem has limited their clinical application. The interaction of oncogenic ERK pathway with the Hh pathway in multiple ways has been proved as one of the main factors that result in drug resistance. Dual inhibition of the Hh and ERK pathways has displayed synergistic suppression to cancer cells overexpressing both pathways. Herein, we designed and synthesized a series of novel 4-aminopiperidine derivatives as SMO/ERK dual inhibitors, and evaluated their biological activities. The results showed that compounds I-13 displayed strong inhibitory activities towards both SMO and ERK, and it also exhibited significant cytotoxicity against human cholangiocarcinoma RBE cells which overexpress both the Hh and ERK pathways. All the results indicate that compound I-13 is a promising anticancer candidate as a SMO/ERK dual inhibitor.

Regional gain and global loss of 5-hydroxymethylcytosine coexist in genitourinary cancers and regulate different oncogenic pathways.

BACKGROUND: DNA 5-hydroxymethylcytosine (5hmC) is produced by dynamic 5mC oxidation process contributing to tissue specification, and loss of 5hmC has been reported in multiple cancers including genitourinary cancers. However, 5hmC is also cell-type specific, and its variability may exist between differentiated tumor cells and cancer stem cells. Thus, cancer-associated changes in 5hmC may be contributed by distinct sets of tumor cells within the tumor tissues. RESULTS: Here, we applied a sensitive immunoprecipitation-based method (hMeDIP-seq) to analyze 5hmC changes during genitourinary carcinogenesis (including prostate, urothelial and kidney). We confirmed the tissue-specific distribution of 5hmC in genitourinary tissues and identified regional gain and global loss of 5hmC coexisting in genitourinary cancers. The genes with gain of 5hmC during tumorigenesis were functionally enriched in regulating stemness and hypoxia, whereas were associated with poor clinical prognosis irrespective of their differences in tumor type. We identified that gain of 5hmC occurred in soft fibrin gel-induced 3D tumor spheres with a tumor-repopulating phenotype in two prostate cancer cell lines, 22RV1 and PC3, compared with conventional two-dimensional (2D) rigid dishes. Then, we defined a malignant signature derived from the differentially hydroxymethylated regions affected genes of cancer stem-like cells, which could predict a worse clinical outcome and identified phenotypically malignant populations of cells from prostate cancer tumors. Notably, an oxidation-resistant vitamin C derivative, ascorbyl phosphate magnesium, restored 5hmC and killed the cancer stem cell-like cells leading to apoptosis in prostate cancer cell lines. CONCLUSIONS: Collectively, our study dissects the regional gain of 5hmC in maintaining cancer stem-like cells and related to poor prognosis, which provides proof of concept for an epigenetic differentiation therapy with vitamin C by 5hmC reprogramming.