The association between blood pressure variability and renal damage in patients with primary aldosteronism.

This research examines the association between blood pressure variability (BPV) and renal damage in a cohort of 129 primary aldosteronism (PA) patients, employing ambulatory blood pressure monitoring (ABPM) for comparative analysis with individuals diagnosed with essential hypertension (EH). The study reveals that PA patients exhibited significantly elevated levels of cystatin C and urine microalbumin/creatinine ratio (UACR). Additionally, a higher prevalence of non-dipping blood pressure patterns in PA patients suggests an increased risk of circadian blood pressure regulation disturbances. Notably, while most BPV indices were comparable between the two groups, the standard deviation of 24-h weighted diastolic blood pressure was markedly lower in the PA cohort, distinguishing it as a unique variable. Through multiple linear regression analysis, the duration of hypertension, angiotensin II concentrations, and daytime systolic blood pressure standard deviation emerged as significant determinants of estimated glomerular filtration rate (eGFR) in PA patients. Furthermore, UACR was significantly influenced by variables including the 24-h weighted standard deviation (wSD) of systolic BP, glycosylated hemoglobin levels, nocturnal systolic BP peaks, aldosterone-renin ratio (ARR), and total cholesterol, with the most pronounced association observed with the 24-h wSD of systolic BP (ß = 0.383).The study also found significant correlations between the 24-h wSD of systolic BP, ARR, HbA1c, serum potassium levels, and 24-h urinary microalbumin, underscoring the critical role of the 24-h wSD of systolic BP (ß = 0.267). These findings underscore the imperative of an integrated management strategy for PA, addressing the intricate interconnections among metabolic abnormalities, blood pressure variability, and renal health outcomes.

The Diurnal Transcriptome Reveals the Reprogramming of Lung Adenocarcinoma Cells Under a Time-Restricted Feeding-Mimicking Regimen.

BACKGROUND: The processes of tumor growth and circadian rhythm are intimately intertwined; thus, rewiring circadian metabolism by time-restricted feeding (TRF) may contribute to delaying carcinogenesis. However, research on the effect of a TRF cellular regimen on cancer is lacking. OBJECTIVE: Investigate the circadian signatures of TRF in lung cancer in vitro. METHODS: We first developed a cellular paradigm mimicking in vivo TRF and collected cells for transcriptome analysis. We further confirmed the effect on tumor cells upon 6-h TRF-mimicking (6-h TRFM) by real-time PCR, Lumicycle experiments, CCK-8, and flow cytometry assays. RESULTS: We found that A549 lung adenocarcinoma cells treated with 6-h TRFM conditions displayed robust diurnal rhythms of transcriptomes, as well as modulation of the core clock genes relative to other different cellular regimens used in this study, including the fasting-mimicking conditions (ie, short-term starvation) and the serum-free regime. Notably, pathway analysis of oscillating genes exclusively in 6-h TRFM showed that some circadian genes were enriched in tumor-related pathways, such as the oxytocin signaling pathway, HIF-1 signaling pathway, and pentose and glucuronate interconversions. Moreover, in line with the circadian pathway enrichment results, 6-h TRFM robustly inhibited cell proliferation and induced cell apoptosis and cell cycle arrest in lung adenocarcinoma A549 cells, lung adenocarcinoma H460 cells, esophageal carcinoma Eca-109 cells, and breast adenocarcinoma MCF-7 cells. CONCLUSIONS: Our findings provide the first in vitro mimicking medium for TRF intervention and indicate that 6-h TRFM is sufficient to reprogram the circadian signatures of lung adenocarcinoma cells and inhibit the progression of multiple tumors.

Six-hour time-restricted feeding inhibits lung cancer progression and reshapes circadian metabolism.

BACKGROUND: Accumulating evidence has suggested an oncogenic effect of diurnal disruption on cancer progression. To test whether targeting circadian rhythm by dietary strategy suppressed lung cancer progression, we adopted 6-h time-restricted feeding (TRF) paradigm to elucidate whether and how TRF impacts lung cancer progression. METHODS: This study used multiple lung cancer cell lines, two xenograft mouse models, and a chemical-treated mouse lung cancer model. Stable TIM-knockdown and TIM-overexpressing A549 cells were constructed. Cancer behaviors in vitro were determined by colony formation, EdU proliferation, wound healing, transwell migration, flow cytometer, and CCK8 assays. Immunofluorescence, pathology examinations, and targeted metabolomics were also used in tumor cells and tissues. mCherry-GFP-LC3 plasmid was used to detect autophagic flux. RESULTS: We found for the first time that compared to normal ad libitum feeding, 6-h TRF inhibited lung cancer progression and reprogrammed the rhythms of metabolites or genes involved in glycolysis and the circadian rhythm in tumors. After TRF intervention, only timeless (TIM) gene among five lung cancer-associated clock genes was found to consistently align rhythm of tumor cells to that of tumor tissues. Further, we demonstrated that the anti-tumor effect upon TRF was partially mediated by the rhythmic downregulation of the TIM and the subsequent activation of autophagy. Combining TRF with TIM inhibition further enhanced the anti-tumor effect, comparable to treatment efficacy of chemotherapy in xenograft model. CONCLUSIONS: Six-hour TRF inhibits lung cancer progression and reshapes circadian metabolism, which is partially mediated by the rhythmic downregulation of the TIM and the subsequent upregulation of autophagy.

Diagnostic accuracy of using multiple cytokines to predict aldosterone-producing adenoma.

Here, we aimed to study the important cytokines in plasma to identify the aldosterone-producing adenoma (APA). 19 unilateral primary aldosteronism (UPA) patients and 19 healthy people were divided into UPA group and Control group, and the serum of bilateral adrenal veins and inferior vena cava collected by adrenal blood sampling (AVS) in UPA patients and the serum from the healthy subjects were all used to detect multiple cytokines by Luminex immunoassays. Additionally, The UPA patients subjected to laparoscopic adrenalectomy were divided into different groups by pathological results for further study. According our results, IP-10, CXCL9 and RANTES were significantly higher in UPA group compared with control group, and the combination of the three cytokines have significant predictive power for predicting UPA, while the correlational analyses demonstrated that IP-10 and CXCL9 were positively correlated with BP and HR, while EGF was positively correlated with HDL. Additionally, IL-1b was suggested to be the most potential diagnostic biomarker to discriminate the APA and unilateral adrenal hyperplasia (UAH). The present findings might suggest a possibility of IP-10, CXCL9 and RANTES served as a sign to help UPA diagnosis and finally used to assist the diagnosis of APA, while IL-1b was suggested to be the most potential diagnostic biomarker to identify the APA from the UAH patients.

Exploring heterogeneity of tumor immune cells and adrenal cells in aldosterone-producing adenomas using single-cell RNA-seq and investigating differences by sex.

The mechanism behind the higher incidence of aldosterone-producing adenoma (APA) in women compared to men is not yet understood. In this study, we utilized single-cell RNA sequencing (scRNA-seq) to investigate the immune cell infiltration and adrenal cell characteristics in APA. Our findings revealed a high presence of immune cells in the tumor microenvironment, with macrophages and T lymphocytes being the most prevalent. Comparison of infiltrating cells between males and females showed that female CD8+T cells had stronger cytotoxic and inflammation-related functions, while female myeloid cells had more enrichment in inflammatory pathways. Additionally, we found that female adrenal cells had greater upregulation of immune-related and antigen presentation pathways. Furthermore, our analysis revealed that zona glomerulosa (ZG) cells had a higher capability for aldosterone synthesis. These results provide a deeper understanding of the APA microenvironment in patients of different sexes and offer new insights into the onset of APA.

Effects of renal denervation on endogenous ouabain in spontaneously hypertensive rats.

PURPOSE: To investigate the role of renal denervation (RDN) on endogenous ouabain (EO) secretion in spontaneously hypertensive rats (SHR). METHODS: Sixteen 12-week-old male SHR were randomly separated into the renal denervation group (RDNX group) and sham operation group (sham group), and eight age-matched Wistar Kyoto rats (WKY) were served as control group. EO concentrations, the Na+- K+-ATPaseactivity, and the expression of Na+-K+-ATPase were assessed. RESULTS: EO levels in serum, kidneys and hypothalamus of sham group were higher than in RDNX group (p < 0.05). Renal Na+-K+-ATPase activity subjected to denervation surgery showed significantly reduction when compared with the sham groups (p < 0.05). A positive correlation existed between norepinephrine (NE) content and Na+-K+-ATPase activity in the kidney (r2 = 0.579). Renal Na+-K+-ATPase α1 subunit mRNA expression was down-regulated in the RDNX group compared with the sham group (P < 0.05), while renal Na+-K+-ATPase α1 subunit mRNA expression was no statistical significance between the groups (P = 0.63). Immunohistochemical analysis showed that there were significant differences in the renal expression of Na+-K+-ATPasebetween the three groups (P < 0.05). CONCLUSIONS: These experiments demonstrate that RDN exerted an anti-hypertensive effect with reduction of EO levels and Na+-K+-ATPase activity and Na+-K+-ATPase α1 subunit expression of kidney in SHR.

A direct interaction between RhoGDIα/Tau alleviates hyperphosphorylation of Tau in Alzheimer's disease and vascular dementia.

RhoGDIα is an inhibitor of RhoGDP dissociation that involves in Aß metabolism and NFTs production in Alzheimer's disease (AD) by regulating of RhoGTP enzyme activity. Our previous research revealed that RhoGDIα, as the target of Polygala saponin (Sen), might alleviate apoptosis of the nerve cells caused by hypoxia/reoxygenation (H/R). To further clarify the role of RhoGDIα in the generation of NFTs, we explored the relationship between RhoGDIα and Tau. We found out that RhoGDIα and Tau can bind with each other and interact by using coimmunoprecipitation (Co-IP) and GST pulldown methods in vitro. This RhoGDIα-Tau partnership was further verified by using immunofluorescence colocalization and fluorescence resonance energy transfer (FRET) approaches in PC12 cells. Using the RNA interference (RNAi) technique, we found that the RhoGDIα may be involved in an upstream signaling pathway for Tau. Subsequently, in Aß25-35- and H/R-induced PC12 cells, forced expression of RhoGDIα via cDNA plasmid transfection was found to reduce the hyperphosphorylation of Tau, augment the expression of bcl-2 protein, and inhibit the expression of Bax protein (reducing the Bax/bcl-2 ratio) and the activity of caspase-3. In mouse AD and VaD models, forced expression of RhoGDIα via injection of a viral vector (pAAV-EGFP-RhoGDIα) into the lateral ventricle of the brain alleviated the pathological symptoms of AD and VaD. Finally, GST pulldown confirmed that the binding sites on RhoGDIα for Tau were located in the range of the ΔC33 fragment (aa 1-33). These results indicate that RhoGDIα is involved in the phosphorylation of Tau and apoptosis in AD and VaD. Overexpression of RhoGDIα can inhibit the generation of NFTs and delay the progress of these two types of dementia.

Combined time-restricted feeding and cisplatin enhance the anti-tumor effects in cisplatin-resistant and -sensitive lung cancer cells.

Combination therapy as an important treatment option for lung cancer has been attracting attention due to the primary and acquired resistance of chemotherapeutic drugs in the clinical application. In the present study, as a new therapy strategy, concomitant treatment with time-restricted feeding (TRF) plus cisplatin (DDP) on lung cancer growth was investigated in DDP-resistant and DDP-sensitive lung cancer cells. We first found that TRF significantly enhanced the drug susceptibility of DDP in DDP-resistant A549 (A549/DDP) cell line, illustrated by reversing the inhibitory concentration 50 (IC50) values of A549/DDP cells to normal level of parental A549 cells. We also found that TRF markedly enhanced DDP inhibition on cell proliferation, migration, as well as promoted apoptosis compared to the DDP alone group in A549, H460 and A549/DDP cells lines. We further revealed that the synergistic anti-tumor effect of combined DDP and TRF was greater than that of combined DDP and simulated fasting condition (STS), a known anti-tumor cellular medium. Moreover, mRNA sequence analysis from A549/DDP cell line demonstrated the synergistic anti-tumor effect involved in upregulated pathways in p53 signaling pathway and apoptosis. Notably, compared with the DDP alone group, combination of TRF and DDP robustly upregulated the P53 protein expression without mRNA level change by regulating its stability via promoting protein synthesis and inhibiting degradation, revealed by cycloheximide and MG132 experiments. Collectively, our results suggested that TRF in combination with cisplatin might be an additional novel therapeutic strategy for patients with lung cancer.

Bioinformatics analysis of genes related to ferroptosis in hepatic ischemia-reperfusion injury.

Background: Primary liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer death worldwide in 2020, and it ranks fifth in global incidence. Liver resection or liver transplantation are the two most prominent surgical procedures for treating primary liver cancer. Both inevitably result in HIRI, causing severe complications for patients and affecting their prognosis and quality of survival. Ferroptosis, a newly discovered mode of cell death, is closely related to HIRI. We used bioinformatics analysis to explore the relationship between the two further. Methods: The GEO database dataset GSE112713 and the FerrDB database data were selected to use bioinformatic analysis methods (difference analysis, FRGs identification, GO analysis, KEGG analysis, PPI network construction and analysis, Hub gene screening with GO analysis and KEGG analysis, intergenic interaction prediction, drug-gene interaction prediction, miRNA prediction) for both for correlation analysis. The GEO database dataset GSE15480 was selected for preliminary validation of the screened Hub genes. Results: We analysed the dataset GSE112713 for differential gene expression before and after hepatic ischemia-reperfusion and identified by FRGs, yielding 11 genes. These 11 genes were subjected to GO, and KEGG analyses, and PPI networks were constructed and analysed. We also screened these 11 genes again to obtain 5 Hub genes and performed GO analysis, KEGG analysis, intergenic interaction prediction, drug-gene interaction prediction, and miRNA prediction on these 5 Hub genes. Finally, we obtained preliminary validation of all these 5 Hub genes by dataset GSE15480. Conclusion: There is a close relationship between HIRI and ferroptosis, and inhibition of ferroptosis can potentially be a new approach to mitigate HIRI treatment in the future.

Sufentanil promotes autophagy and improves ischemia-reperfusion-induced acute kidney injury via up-regulating microRNA-145. / 舒芬太尼通过上调microRNA-145促进自噬和改善缺血再灌注诱导的急性肾损伤.

OBJECTIVES: Sufentanil has a good protective effect on myocardial and liver injury caused by ischemia reperfusion (IR), but its protective effect on kidney is still unclear. This study aims to investigate whether sufentanil can prevent IR-induced acute kidney injury (AKI) and to determine whether its efficacy is related to miR-145-mediated autophagy. METHODS: A total of 40 rats were randomly divided into 5 groups (n=8 in each group): A sham group, an IR group, a sufentanil group, a sufentanil+miR-145 inhibitor control group (an anti-NC group) and a sufentanil+miR-145 inhibitor group (an anti-miR-145 group). Except for the sham group, the other groups established a rat AKI model induced by IR. The sufentanil group, the sufentanil+anti-NC group, and the sufentanil+anti-miR-145 were injected with sufentanil (1 µg/kg) through femoral vein 30 min before ischemia. The sufentanil+anti-NC group and the sufentanil+anti-miR-145 group were injected with miR-145 inhibitor control or anti-miR-145 (80 mg/kg) through the tail vein before sufentanil pretreatment. The structure and function of kidneys harvested from the rats were evaluated, and the protein levels of autophagy-related proteins, oxidative stress levels, and apoptosis levels were measured. RESULTS: Compared with the IR group, the renal structure and function were improved in the sufentanil group. The levels of blood urea nitrogen (BUN), creatinine (Cr), urinary kidney injury molecule 1 (KIM-1), neutrophil gelatinase related lipid transporter (NGAL), tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6 and ROS were significantly decreased (all P<0.05). In addition, compared with the IR group, the levels of Beclin-1 and LC3 in renal tissues in the sufentanil group were significantly increased (both P<0.05), and the apoptosis in renal tissues was significantly reduced (P<0.05). Compared with the sufentanil+anti-NC group, the levels of BUN, Cr, KIM-1, NGAL, TNF-α, IL-1ß, IL-6 and ROS in the sufentanil+anti-miR-145 group were significantly increased (all P<0.05), the levels of Beclin-1 and LC3 in renal tissues were significantly decreased (both P<0.05), and the apoptosis in renal tissues was significantly increased (P<0.05). CONCLUSIONS: Sufentanil can prevent the AKI induced by IR, which is related to the up-regulation of miR-145-mediated autophagy.

Senegenin Rescues PC12 Cells with Oxidative Damage Through Inhibition of Ferroptosis.

Oxidative stress is one of the pathological mechanisms of Alzheimer's disease (AD), and ferroptosis has been determined to be involved in neurodegenerative diseases such as AD. Senegenin (Sen) prevents oxidative damage in nerve cells via a mechanism that may be highly related to ferroptosis. However, the mechanism of ferroptosis pathway involvement in AD is unclear. In this study, we established a model of PC12 cytotoxic injury induced by Aß25-35, and we detected the level of oxidative damage, MMP, and ferroptosis-related protein expression. The results showed that, compared with control group, the level of ROS increased, GPX activities decreased, and MDA levels increased in Aß25-35 group. Aß25-35 could induce mitochondrial depolarization in PC12 cells and Fer-1 could not reverse this damage. WB revealed that Aß25-35 group had increased ACSL4 and PEBP1 proteins, and decreased GPX4 protein. After adding Sen in the model, the level of oxidative damage was reduced, and mitochondrial depolarization was reversed compared with Aß25-35 group. WB suggested that the expression of ACSL4 and PEBP1 proteins decreased, and the expression of GPX4 protein increased by Sen treatment. In conclusion, we found that Sen exhibits strong neuroprotective activity against Aß25-35 induced oxidative damage and lipid metabolic associated with ferroptosis. Inhibiting nerve cell ferroptosis might facilitate the future development of strategies to AD.

Renal denervation inhibits the renin-angiotensin-aldosterone system in spontaneously hypertensive rats.

This study was conducted to explore the effect of renal denervation (RDN) on the renin-angiotensin-aldosterone system (RAAS) in spontaneously hypertensive rats (SHRs). Our experimental rats were randomly divided into the RDN group conducted by painting 10% phenol on the bilateral renal nerves (RDNX), the shamoperation group simply painting with saline (Sham), and the normotension control group (WKY) following all the animal blood and tissues of kidney, hypothalamus, and adrenal gland collected and examined 2 weeks after RDN operation. We found that the aldosterone (ALD) levels in serum and tissues all decreased in the RDNX group compared with the Sham group (p < .05). Meantime, the expression of angiotensin II type1 receptor (AT1R) mRNA also exhibited significantly reduced by 2.22-fold in the RDNX group compared to the Sham group identical to the expression of AT1R protein in the renal cortex and outer stripe of the outer medulla (OSOM) subjected to denervation surgery, which manifested the lower ATIR protein expression than the Sham group (p < .05). Besides, the expression of angiotensin II (Ang II) protein in the cortex , OSOM, and inner stripe of the outer medulla were all attenuated by RDN in comparison with the Sham group (p < .05). RDN reduced intrarenal RAAS and circulating RAAS to lower blood pressure and repair renal function.

Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials.

TP53 aberrations [del(17p) or TP53 mutation] predict poor survival with chemoimmunotherapy in patients with chronic lymphocytic leukaemia (CLL). We evaluated long-term efficacy and safety of first-line ibrutinib-based therapy in patients with CLL bearing TP53 aberrations in a pooled analysis across four studies: PCYC-1122e, RESONATE-2 (PCYC-1115/16), iLLUMINATE (PCYC-1130) and ECOG-ACRIN E1912. The pooled analysis included 89 patients with TP53 aberrations receiving first-line treatment with single-agent ibrutinib (n = 45) or ibrutinib in combination with an anti-CD20 antibody (n = 44). All 89 patients had del(17p) (53% of 89 patients) and/or TP53 mutation (91% of 58 patients with TP53 sequencing results available). With a median follow-up of 49·8 months (range, 0·1-95·9), median progression-free survival was not reached. Progression-free survival rate and overall survival rate estimates at four years were 79% and 88%, respectively. Overall response rate was 93%, including complete response in 39% of patients. No new safety signals were identified in this analysis. Forty-six percent of patients remained on ibrutinib treatment at last follow-up. With median follow-up of four years (up to eight years), results from this large, pooled, multi-study data set suggest promising long-term outcomes of first-line ibrutinib-based therapy in patients with TP53 aberrations. Registered at ClinicalTrials.gov (NCT01500733, NCT01722487, NCT02264574 and NCT02048813).

In Situ Preparation of MXenes in Ambient-Temperature Organic Ionic Liquid Aluminum Batteries with Ultrastable Cycle Performance.

A fluorine-free and water-free electrochemical preparation of MXenes is achieved in Lewis acidic molten salts at ambient temperature. In addition, the anode reaction of the MAX phase V2AlC is studied in the organic ionic liquid aluminum battery and the extraction voltages of the metal atoms Al and V in the MAX phase V2AlC are determined. This points out the direction for the constant-voltage electrochemical preparation of MXenes. Furthermore, the electrochemical performance of the etched V2AlC (E-V2AlC) in an aluminum battery is studied. The one-stop preparation-application process prevents the MXenes from contacting water and air, and the MXenes etched in the aluminum battery are more conducive to the intercalation/deintercalation of Al3+. Therefore, E-V2AlC exhibits excellent electrochemical performance in an aluminum battery. Under the conditions of a voltage window of 0.01-2.3 V (V vs Al/Al3+) and a current density of 500 mA g-1, the specific discharge capacity is about 100 mAh g-1 after 6500 cycles. In addition, the energy storage mechanism and Faraday energy storage method of E-V2AlC in an aluminum battery are studied. The diffusion coefficient D of Al3+ is determined by a galvanostatic intermittent titration technique. The reasons for its excellent electrochemical performance are clarified from the perspective of kinetics.

In Silico Analysis of the Gene Expression Patterns between Aldosterone-Producing Adenoma and Nonfunctional Adrenocortical Adenoma.

Primary aldosteronism is the most common form of secondary hypertension, and aldosteronoma makes up a significant proportion of primary aldosteronism cases. Aldosteronoma is also called aldosterone-producing adenoma (APA). Although there have been many studies about APA, the pathogenesis of this disease is not yet fully understood. In this study, we aimed to find out the difference of gene expression patterns between APA and nonfunctional adrenocortical adenoma (NFAA) using a weighted gene coexpression network (WGCNA) and differentially expressed gene (DEG) analysis; only the genes that meet the corresponding standards of both methods were defined as real hub genes and then used for further analysis. Twenty-nine real hub genes were found out, most of which were enriched in the phospholipid metabolic process. WISP2, S100A10, SSTR5-AS1, SLC29A1, APOC1, and SLITRK4 are six real hub genes with the same gene expression pattern between the combined and validation datasets, three of which indirectly or directly participate in lipid metabolism including WISP2, S100A10, and APOC1. According to the gene expression pattern of DEGs, we speculated five candidate drugs with potential therapeutic value for APA, one of which is cycloheximide, an inhibitor for phospholipid biosynthesis. All the evidence suggests that phospholipid metabolism may be an important pathophysiological mechanism for APA. Our study provides a new perspective regarding the pathophysiological mechanism of APA and offers some small molecules that may possibly be effective drugs against APA.