Protective Role of Kallistatin in Vascular Injury, Senescence and Aging

Kallistatin, a plasma protein, consists of two essential structural elements, an active site and a heparin-binding domain. Kallistatin exerts pleiotropic effects on angiogenesis, inflammation, fibrosis and tumor growth. This study aims to decipher the role and mechanism of kallistatin in vascular injury, senescence and aging. First, we determined the effect of kallistatin on endothelial-mesenchymal transition (EndMT), a process mediating vascular injury, organ fibrosis and cancer progression. Recombinant human kallistatin via its heparin-binding site blocked TGF-β-induced EndMT, associated with downregulated microRNA (miR)-21-Akt signaling and oxidative stress in human endothelial cells. Kallistatin’s active site is essential for stimulating antioxidant genes, endothelial nitric oxide synthase (eNOS) and sirtuin 1 (SIRT1) by interacting with a tyrosine kinase. These findings indicate that kallistatin suppresses EndMT by inhibiting miR-21-Akt signaling and oxidative stress. Secondly, we determined the role and mechanism of kallistatin in vascular senescence and aging. Kallistatin antagonized TNF- α-induced senescence and oxidative stress, and inhibited miR-34a, a senescence inducer, leading to elevated SIRT1/eNOS synthesis in human endothelial progenitor cells. Kallistatin administration in streptozotocin (STZ)-induced diabetic mice attenuated aortic senescence associated with reduced miR-34a and elevated SIRT1/eNOS levels. Consistently, kallistatin delayed stress-induced organismal aging in Caenorhabditis elegans by inhibiting miR-34 and elevating the longevity gene, sir-2.1 (SIRT1 homolog) synthesis. Therefore, kallistatin reduces vascular senescence and aging by inhibiting miR-34a-SIRT1/eNOS pathway. Thirdly, we determined the role of endogenous kallistatin in endothelial senescence, oxidative stress and inflammation by generating two strains of kallistatin knockout mice, endothelial cell-specific and general kallistatin knockout mice. Kallistatin via inducing an endo-protective miRNA Let-7g antagonized miR-34a-SIRT1-eNOS pathway and inhibited senescence, oxidative stress and inflammation in human endothelial cells. Conversely, kallistatin deficiency in mouse lung endothelial cells aggravated H2O2-induced senescence, oxidative stress and inflammation associated with downregulated Let-7g and antioxidant genes and upregulated miR-34a synthesis, indicating that kallistatin protects against endothelial senescence by modulating Let-7g mediated miR-34a-SIRT1-eNOS pathway. Moreover, systemic depletion of kallistatin exacerbated aortic oxidative stress and renal fibrosis in STZ-induced diabetic mice. These studies indicate that kallistatin plays a novel role in protection against vascular injury, senescence and aging by regulating Let-7g, miR-34a and miR-21 synthesis, and antioxidant gene expression

Opposing Effects of Oxygen Regulation on Kallistatin Expression: Kallistatin as a Novel Mediator of Oxygen-Induced HIF-1-eNOS-NO Pathway

Oxidative stress has both detrimental and beneficial effects. Kallistatin, a key component of circulation, protects against vascular and organ injury. Serum kallistatin levels are reduced in patients and animal models with hypertension, diabetes, obesity, and cancer. Reduction of kallistatin levels is inversely associated with elevated thiobarbituric acid-reactive substance. Kallistatin therapy attenuates oxidative stress and increases endothelial nitric oxide synthase (eNOS) and NO levels in animal models. However, kallistatin administration increases reactive oxygen species formation in immune cells and bacterial killing activity in septic mice. High oxygen inhibits kallistatin expression via activating the JNK-FOXO1 pathway in endothelial cells. Conversely, mild oxygen/hyperoxia stimulates kallistatin, eNOS, and hypoxia-inducible factor-1 (HIF-1) expression in endothelial cells and in the kidney of normal mice. Likewise, kallistatin stimulates eNOS and HIF-1, and kallistatin antisense RNA abolishes oxygen-induced eNOS and HIF-1 expression, indicating a role of kallistatin in mediating mild oxygen’s stimulation on antioxidant genes. Protein kinase C (PKC) activation mediates HIF-1-induced eNOS synthesis in response to hyperoxia/exercise; thus, mild oxygen through PKC activation stimulates kallistatin-mediated HIF-1 and eNOS synthesis. In summary, oxidative stress induces down- or upregulation of kallistatin expression, depending on oxygen concentration, and kallistatin plays a novel role in mediating oxygen/exercise-induced HIF-1-eNOS-NO pathway

Role of Kallistatin Treatment in Aging and Cancer by Modulating miR-34a and miR-21 Expression

Kallistatin is an endogenous protein that regulates differential signaling pathways and a wide spectrum of biological activities via its two structural elements: an active site and a heparin-binding domain. Kallistatin via its heparin-binding site inhibits vascular inflammation and oxidative stress by antagonizing TNF-α-induced NADPH oxidase activity, NF-κB activation, and inflammatory gene expression in endothelial cells. Moreover, kallistatin via its active site inhibits microRNA-34a (miR-34a) synthesis and stimulates eNOS and SIRT1 expression in endothelial progenitor cells, whereas its heparin-binding site is crucial for blocking TNF-α-induced miR-21 expression and oxidative stress, thus reducing cellular senescence. By downregulating miR-34a and miR-21 expression, kallistatin treatment attenuates oxidative damage and aortic senescence in streptozotocin-induced diabetic mice and extends Caenorhabditis elegans lifespan under stress conditions. Likewise, kallistatin through the heparin-binding site inhibits TGF-β-induced miR-21 synthesis and oxidative stress in endothelial cells, resulting in inhibition of endothelial-mesenchymal transition, a process contributing to fibrosis and cancer. Furthermore, kallistatin’s active site is essential for stimulating miR-34a and p53 expression and inhibiting the miR-21-Akt-Bcl-2 signaling pathway, thus inducing apoptosis in breast cancer cells. These findings reveal novel mechanisms of kallistatin in protection against senescence, aging, and cancer development by modulating miR-34a and miR-21 levels and inhibiting oxidative stress

Thermal Hall effect in insulating quantum materials

The emerging field of quantum materials involves an exciting new class of materials in which charge, spin, orbital, and lattice degrees of freedom are inter- twined, exhibiting a plethora of exotic physical properties. Quantum materials include, but are not limited to, superconductors, topological quantum matter, and systems with frustrated spins, which enable a wide range of potential applications in biomedicine, energy transport and conversion, quantum sensing, and quantum information processing.S.G. and X.C. acknowledge the support from National Science Foundation under grant No. 2144328. J.Z. acknowledges the support from National Science Foundation through the Center for Dynamics and Control of Materials: an NSF MRSEC unnder Cooperative Agreement No. DMR-1720595.Center for Dynamics and Control of Material

Endoscopic thyroidectomy via areola approach for stage T1 papillary thyroid carcinoma: feasibility, safety, and oncologic outcomes

PurposeTo evaluate the feasibility, safety, and oncologic outcomes associated with endoscopic thyroidectomy via the areolar approach (ETAA), compared with conventional open thyroidectomy (COT) for the treatment of stage T1 papillary thyroid carcinoma (PTC).MethodsBetween January 2021 and June 2022, a total of 1204 patients diagnosed with PTC underwent screening, out of which 138 patients were selected for inclusion in the study population after propensity score matching (92 patients in the ETAA group and 46 patients in the COT group). The study included the collection and analysis of clinicopathologic characteristics, intraoperative outcomes, postoperative outcomes, complications, and follow-up data using R software.ResultsThe operative time for the ETAA group was longer than that for the COT group (160.42 ± 32.21 min vs. 121.93 ± 29.78 min, p < 0.0001). However, there were no significant differences between the two groups in terms of intraoperative blood loss, the extent of surgical resection, the number of dissected lymph nodes, the number of metastatic lymph nodes, and the rate of parathyroid autotransplantation. Postoperative drainage and C-reactive protein levels were higher in the ETAA group than in the COT group, but there were no significant differences in 24-hour visual analogue scale scores, white blood cell counts, drainage duration, or postoperative hospital stay. Complication rates were similar between the two groups, and no permanent recurrent laryngeal nerve palsy or hypoparathyroidism was observed. Patients who underwent ETAA reported greater cosmetic satisfaction and quality of life than those who underwent COT. During the follow-up phase, only one patient in the COT group developed lateral cervical lymph node involvement requiring reoperation.ConclusionETAA is a safe and feasible surgical method for patients with stage T1 PTC, providing results similar to COT in terms of oncologic completeness, while avoiding neck scars, with excellent cosmetic effects.Clinical trial registrationChinese Clinical Trial Registry center, identifier ChiCTR230007710

Rapamycin Ameliorates Kidney Fibrosis by Inhibiting the Activation of mTOR Signaling in Interstitial Macrophages and Myofibroblasts

Interstitial fibrosis is an inevitable outcome of all kinds of progressive chronic kidney disease (CKD). Emerging data indicate that rapamycin can ameliorate kidney fibrosis by reducing the interstitial infiltrates and accumulation of extra cellular matrix (ECM). However, the cellular mechanism that regulates those changes has not been well understood yet. In this study, we revealed the persistent activation of mammalian target of rapamycin (mTOR) signaling in the interstitial macrophages and myofibroblasts, but rarely in injured proximal epithelial cells, CD4+ T cells, neutrophils, or endothelial cells, during the development of kidney fibrosis. Administration of rapamycin to unilateral ureteral obstruction (UUO) mice significantly suppressed the immunoreactivity of mTOR signaling, which decreased the inflammatory responses and ECM accumulation in the obstructed kidneys. Isolated macrophages from rapamycin-treated obstructed kidneys presented less inflammatory activity than vehicle groups. In vitro study confirmed that rapamycin significantly inhibited the fibrogenic activation of cultured fibroblasts (NIH3T3 cells), which was induced by the stimulation of TGF-β1. Further experiment revealed that rapamycin did not directly inhibit the fibrogenesis of HK2 cells with aristolochic acid treatment. Our findings clarified that rapamycin can ameliorate kidney fibrosis by blocking the mTOR signaling in interstitial macrophages and myofibroblasts

On Covariance Matrix Based Spectrum Sensing Over Frequency-Selective Channels

This paper concerns covariance matrix based spectrum sensing over frequency selective channels. The impact of frequency selective channels on the covariance matrix of received signals is analyzed in frequency domain and it is shown that the phases of channel spectra degrade the performance of covariance matrix based detectors. To overcome this problem, we propose a new detector which employs only the magnitude spectra of received signals and thereby achieves considerable performance gain. Theoretical performance, in terms of the false-alarm and detection probabilities of the proposed detector, is analyzed. Simulation results verify our theoretical analyses and demonstrate the superior performance of the proposed detector